Haddad and Winchester's Clinical Management of Poisoning and Drug Overdose, 4th Edition

1600 John F. Kennedy Boulevard Suite 1800 Philadelphia, PA 19103-2899 HADDAD AND WINCHESTER’S CLINICAL MANAGEMENT OF P...

Author: Michael W. Shannon MD MPH FAAP FACEP FAACT FACMT | Stephen W. Borron MD MS FACEP FACMT | Michael Burns MD

281 downloads 2500 Views 44MB Size Report

This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!
Report copyright / DMCA form

DOWNLOAD PDF

1600 John F. Kennedy Boulevard Suite 1800 Philadelphia, PA 19103-2899

HADDAD AND WINCHESTER’S CLINICAL MANAGEMENT OF POISONING AND DRUG OVERDOSE, FOURTH EDITION Copyright © 2007 by Saunders, an imprint of Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Health Sciences Rights Department in Philadelphia, PA, USA: phone: (+1) 215 239 3804, fax: (+1) 215 239 3805, e-mail: [email protected]. You may also complete your request on-line via the Elsevier homepage (http://www.elsevier.com), by selecting “Customer Support” and then “Obtaining Permissions.”

Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment, and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on their own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Editors assume any liability for any injury and/or damage to persons or property arising out or related to any use of the material contained in this book. Previous editions copyrighted 1998, 1990, 1983.

Library of Congress Cataloging-in-Publication Data Haddad and Winchester’s clinical management of poisoning and drug overdose / [edited by] Michael Shannon, Stephen W. Borron, Michael Burns. — 4th ed. p. ; cm. Rev. ed. of: Clinical management of poisoning and drug overdose / [edited by] Lester M. Haddad, Michael W. Shannon, James F. Winchester. 3rd ed. c1998 Included bibliographical references and index. ISBN 978-0-7216-0693-4 1. Poisoning. 2. Medication abuse. 3. Drugs — Overdose. I. Haddad, Lester M. II. Shannon, Michael W. III. Borron, Stephen W. IV. Burns, Michael, MD. V. Clinical management of poisoning and drug overdose. VI. Title: Clinical management of poisoning and drug overdose. [DNLM: 1. Poisoning—therapy. QV 601 H126 2007] RA1211.C584 2007 615.9’08—dc22 2006037454 Acquisitions Editor: Todd Hummel Developmental Editor: Melissa Dudlick Publishing Services Manager: Joan Sinclair Design Direction: Steven Stave Text Designer: Melissa Olson Printed in China Last digit is the print number: 9 8 7 6 5 4 3 2 1

ISBN: 978-0-7218-0693-4

To Elaine, Evan, and Lila, whose patience made this book possible; to Drs. Fred Lovejoy and Gary Fleisher for their mentorship; and to all the toxicology fellows with whom I’ve had the pleasure of working. Thank you. Michael W. Shannon

To Dr. Edward (Mel) Otten, who first encouraged me to study the management of chemical and radiological emergencies; to Drs. James Lockey, James R. Roberts and Suman Wason, who mentored me in my unconventional approach to occupational medicine and toxicology training; to Professors Chantal Bismuth and Frédéric Baud, who afforded me the opportunity to expand my knowledge of toxicology in an international environment; to my family and colleagues, without whose constant support my participation would not have been possible. Stephen W. Borron

I am forever grateful to my wife, Maureen, and children, Ryan, Liam, and Riley, whose unwavering love, support, and understanding during the editing process greatly contributed to the success of this work. Michael J. Burns

C O N T R I B U T O R S

Cynthia K. Aaron, MD, FACMT, FACEP

Linda G. Allison, MD, MPH

Associate Professor of Medicine and Pediatrics Wayne State University School of Medicine Director, Clinical and Medical Toxicology Education Children’s Hospital of Michigan Regional Poison Center Detroit Medical Center Detroit, Michigan

Professor, Physician Assistant Studies Le Moyne College Syracuse, New York

Jawaid Akhtar, MD

Assistant Professor Department of Emergency Medicine University of Pittsburgh Medical Center Medical Toxicologist Pittsburgh Poison Center Children’s Hospital of Pittsburgh Pittsburgh, Pennsylvania Steven E. Aks, DO

Associate Professor of Emergency Medicine Rush University Director, The Toxikon Consortium Chief, Section of Toxicology Department of Emergency Medicine Cook County Hospital Chicago, Illinois Timothy E. Albertson, MD, MPH, PhD

Professor of Medicine, Pharmacology/Toxicology, Emergency Medicine, and Anesthesiology University of California–Davis VA Northern California Hospitals and Clinics Chief, Division of Pulmonary/Critical Care Medicine Medical Director, Sacramento Division California Poison Control System University of California–Davis Medical Center Sacramento, California

Angela C. Anderson, MD, FAAP

Associate Professor Departments of Emergency Medicine and Pediatrics Brown University Medical School Attending Physician Department of Pediatric Emergency Medicine Rhode Island and Hasbro Children’s Hospitals Providence, Rhode Island Juan C. Arias, MD

Postdoctoral Fellow Department of Surgery Division of Emergency Medicine The University of Texas Health Science Center at San Antonio San Antonio, Texas Alexander B. Baer, MD

Clinical Instructor Department of Emergency Medicine University of Virginia Charlottesville, Virginia Attending Physician Rockingham Memorial Hospital Harrisonburg, Virginia Frédéric J. Baud, MD

Professor of Critical Care Medicine Hôpital Lariboisière Université Paris VII Paris, France Carl R. Baum, MD, FAAP, FACMT

Alfred Aleguas, Jr., RPH, BSPharm, PharmD

Adjunct Faculty University of Rhode Island College of Pharmacy Kingston, RI Clinical Manager MA/RI Regional Center for Poison Control and Prevention Boston, Massachusetts Staff Pharmacist The Westerly Hospital Westerly, Rhode Island

Associate Professor of Pediatrics Yale University School of Medicine Attending Physician, Pediatric Medicine Director, Toxicology Service Director, Center for Children’s Environmental Toxicology (toxikid.org) Yale–New Haven Children’s Hospital New Haven, Connecticut

viii

CONTRIBUTORS

Martin Belson, MD

Steven B. Bird, MD

Medical Toxicologist National Center for Environmental Health Pediatric Emergency Medicine Children’s Healthcare of Atlanta Atlanta, Georgia

Assistant Professor of Emergency Medicine Division of Medical Toxicology University of Massachusetts Medical School Worcester, Massachusetts

John G. Benitez, MD, MPH, FACMT, FACPM

RN, Certified Specialist in Poison Information Missouri Regional Poison Control Center St. Louis, Missouri

Associate Professor of Emergency Medicine, Environmental Medicine, and Pediatrics University of Rochester Managing Director and Associate Medical Director Ruth A. Lawrence Poison and Drug Information Center University of Rochester Medical Center Rochester, New York Neal L. Benowitz, MD

Professor of Medicine, Psychiatry, and Biopharmaceutical Sciences University of California-San Francisco Chief of Clinical Pharmacology San Francisco General Hospital San Francisco, California

Carolyn M. Blume-Odom, RN, BSN

Stephen W. Borron, MD, MS

Clinical Professor of Emergency Medicine (Surgery) University of Texas Health Science Center at San Antonio Consultant in Toxicology South Texas Poison Center San Antonio, Texas Associate Clinical Professor of Emergency Medicine, Medicine, and Occupational and Environmental Health The George Washington University Washington, DC Edward W. Boyer, MD, PhD

David P. Betten, MD

Assistant Clinical Professor Department of Emergency Medicine Michigan State University College of Human Medicine East Lansing, Michigan Attending Physician Sparrow Health System Lansing, Michigan Brian Christopher Betts, MD

Chief Resident Internal Medicine Department University of Minnesota Minneapolis, Minnesota Lawrence Stilwell Betts, MD, PhD, CIH, FACOEM

Professor Family and Community Medicine Associate Clinical Professor of Physiological Sciences Eastern Virginia Medical School Norfolk, Virginia President, Lawrence Stilwell Betts, MD, PhD, P.C. Poquoson, Virginia Consultant SafetyCall and International Poison Center Bloomington, Minnesota Michael Beuhler, MD

Clinical Instructor of Emergency Medicine University of North Carolina at Chapel Hill Chapel Hill, North Carolina Medical Director, Carolinas Poison Center Carolinas Medical Center Charlotte, North Carolina

Associate Professor of Emergency Medicine University of Massachusetts Medical School Worcester, Massachusetts Lecturer in Pediatrics Harvard Medical School Assistant in Medicine Children’s Hospital Boston Boston, Massachusetts Chief, Division of Medical Toxicology UMass Memorial Medical Center Worcester, Massachusetts Sally M. Bradberry, BSc, MB, ChB, MRCP

Assistant Director National Poison Information Service (Birmingham Unit) City Hospital Birmingham, United Kingdom Jeffrey Brent, MD, PhD

Clinical Professor of Medicine and Pediatrics University of Colorado Health Sciences Center Denver, Colorado D. Eric Brush, MD

Assistant Professor Department of Emergency Medicine Division of Medical Toxicology University of Massachusetts Medical Center Worcester, Massachusetts Michael J. Burns, MD

Assistant Professor of Medicine Harvard Medical School Co-Director, Division of Medical Toxicology Department of Emergency Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts

CONTRIBUTORS

Javier R. Caldera, MD

Kirk L. Cumpston, DO, FACEP

Clinical Instructor University of Texas Southwestern Medical Center Toxicology Fellow Parkland Memorial Hospital Dallas, Texas

Assistant Professor Department of Emergency Medicine Assistant Medical Director, Virginia Poison Center Medical College of Virginia Hospital Virginia Commonwealth University Health Science Center Richmond, Virginia

Thomas R. Caraccio, PharmD, RPH, DABAT

Associate Professor Department of Emergency Medicine State University of New York at Stony Brook Stony Brook, New York Managing Director Long Island Regional Poison Control Center Winthrop University Hospital Mineola, New York Edward W. Cetaruk, MD

Assistant Clinical Professor of Medicine Department of Medicine Section of Clinical Pharmacology and Toxicology University of Colorado Health Sciences Center Toxicology Associates, PLLC Denver, Colorado Andrew Chan, MB ChB, FRCP (Ldn), FCCP

Associate Professor University of California–Davis Sacramento, California VA Northern California Health Care System Mather, California Peter B. Chase, MD, PhD

Assistant Professor Clinical Emergency Medicine University of Arizona College of Medicine Director, Medical Toxicology Residency Program University Medical Center Consultant Arizona Poison and Drug Information Center Tucson, Arizona James Cisek, MD, MPH

Virginia Commonwealth University University of Richmond Medical Director Community Commitment Bon Secours Health System VCU Medical Center Richmond, Virginia Richard F. Clark, MD

Professor of Medicine University of California–San Diego Director, Division of Medical Toxicology UCSD Medical Center San Diego, California

Steven C. Curry, MD

Department of Medical Toxicology Banner Good Samaritan Regional Medical Center Department of Medicine University of Arizona College of Medicine Phoenix, Arizona Paul I. Dargan, MBBS, MD, MRCP

Consultant Physician and Clinical Toxicologist Guy’s & St. Thomas Poisons Unit Guy’s & St. Thomas NHS Foundation Trust London, UK G. Patrick Daubert, MD

Assistant Professor Director, Clinical and Medical Toxicology Education Assistant Director, California Poison Control System, Sacramento Division University of California–Davis Sacramento, California João Delgado, MD

Assistant Professor of Emergency Medicine University of Connecticut School of Medicine Divisions of Emergency Medicine and Medical Toxicology Hartford Hospital Hartford, Connecticut Valerie A. Dobiesz, MD, FACEP

Associate Professor of Emergency Medicine Associate Residency Director Education Director University of Illinois College of Medicine Chicago, Illinois J. Ward Donovan, MD, FACMT, FACEP

Professor Emeritus Emergency Medicine Pennsylvania State University College of Medicine Hershey, Pennsylvania Medical Director, PinnacleHealth Toxicology Center Chief, Section of Medical Toxicology PinnacleHealth System Hospitals Harrisburg, Pennsylvania Robert P. Dowsett, BM, BS, FACEM

Department of Emergency Medicine Westmead Hospital Westmead, New South Wales, Australia

ix

x

CONTRIBUTORS

Antonio Dueñas-Laita, MD, PhD

Chris Foley, MD

Professor of Clinical Toxicology University of Valladolid School of Medicine Head of Regional Toxicology Unit Río Hortega Hospital Valladolid, Spain

Internist Minnesota Natural Medicine Vadnais Heights, Minnesota

Judith M. Eisenberg, MD, MS

Medical Officer Hazard Evaluations and Technical Assistance Branch Division of Surveillance, Hazard Evaluations and Field Studies Centers for Disease Control and Prevention Cincinnati, Ohio Timothy B. Erickson, MD, FACEP, FACMT, FAACT

Professor of Emergency Medicine Director, Division of Clinical Toxicology Residency Program Director Department of Emergency Medicine University of Illinois College of Medicine Chicago, Illinois Michele Burns Ewald, MD

R. Brent Furbee, MD

Associate Clinical Professor Division of Medical Toxicology Department of Emergency Medicine Indiana University School of Medicine Medical Director Indiana Poison Center Indianapolis, Indiana Ann-Jeannette Geib, MD

Medical Toxicologist PinnacleHealth Toxicology Center Harrisburg Hospital Emergency Physician PinnacleHealth Hospitals Harrisburg, Pennsylvania Robert J. Geller, MD

Department of Pediatrics Harvard University Medical School Attending Physician Children’s Hospital Boston Director, Harvard Medical Toxicology Fellowship Medical Director MA/RI Regional Center for Poison Control and Prevention Boston, Massachusetts

Associate Professor of Pediatrics Emory University School of Medicine Medical Director, Georgia Poison Center Grady Health System Director, Emory Southeast Pediatric Environmental Health Specialty Unit Chief of Pediatrics Emory Service at Grady Health System Atlanta, Georgia

Susan Farrell, MD

Carl A. Germann, MD

Assistant Professor of Medicine Harvard Medical School Director of Student Programs Department of Emergency Medicine Brigham and Women’s Hospital Boston, Massachusetts Tania M. Fatovich, MD, MS-HES

Department of Emergency Medicine Brigham and Women’s Hospital The Gilbert Program in Medical Simulation Harvard Medical School Boston, Massachusetts Miguel C. Fernández, MD

Associate Professor/Clinical Division of Emergency Medicine Department of Surgery Medical and Managing Director The South Texas Poison Center University of Texas Health Science Center at San Antonio San Antonio, Texas J.W. Fijen, MD, PhD

Senior Lecturer in Intensive Care University Medical Center Utrecht Utrecht, Netherlands Senior Medical Consultant National Institute for Public Health and the Environment Bilthoven, Netherlands

Emergency Physician Maine Medical Center Portland, Maine Melissa L. Givens, MD, MPH

Clinical Assistant Professor University of Washington School of Medicine Seattle, Washington Attending Physician Madigan Army Medical Center Tacoma, Washington Ronald E. Goans, PhD, MD, MPH

Clinical Associate Professor Tulane School of Public Health and Tropical Medicine New Orleans, Louisiana Senior Medical Consultant MJW Corporation Amherst, New York Nora Goldschlager, MD

Professor of Clinical Medicine University of California–San Francisco Associate Director, Cardiology Division Director, SFGH Coronary Care Unit, ECG Laboratory, and Pacemaker Clinic San Francisco General Hospital San Francisco, California

CONTRIBUTORS

xi

Andis Graudins, MBBS (Hons), PhD

Matthew W. Hedge, MD

Conjoint Senior Lecturer Faculty of Medicine University of New South Wales Kensington, New South Wales, Australia Senior Staff Specialist Clinical Toxicology and Emergency Medicine Prince of Wales Hospital Randwick, New South Wales, Australia

Assistant Professor Department of Emergency Medicine Wayne State University School of Medicine Associate Medical Director Children’s Hospital of Michigan Regional Poison Center Detroit Receiving Hospital Detroit, Michigan

Michael I. Greenberg, MD, MPH

Professor of Pediatrics and Emergency Medicine University of Pennsylvania School of Medicine Director, Section of Clinical Toxicology Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Professor of Emergency Medicine Drexel University College of Medicine Wayne, Pennsylvania Tee L. Guidotti, MD, MPH, DABT

Professor and Chair Department of Environmental and Occupational Health School of Public Health and Health Services Professor and Director, Division of Occupational Medicine and Toxicology Department of Medicine School of Medicine and Health Sciences The George Washington University Medical Center The George Washington University Hospital Washington, DC Alan H. Hall, MD

Clinical Assistant Professor of Preventive Medicine and Biometrics University of Colorado Health Sciences Center Denver, Colorado President and Chief Medical Toxicologist Toxicology Consulting and Medical Translating Services, Inc. Elk Mountain, Wyoming

Fred M. Henretig, MD

Michael G. Holland, MD, FACMT, FACOEM, FACEP

Clinical Assistant Professor of Emergency Medicine SUNY Upstate Medical University Syracuse, New York Attending Physician Department of Occupational Medicine Glen Falls Hospital Glen Falls, New York Knut Erik Hovda, MD, PhD

Department of Acute Medicine Ulleval University Hospital Oslo, Norway Dag Jacobsen, MD, PhD, FAACT

Professor of Medicine and Clinical Toxicology University of Oslo Director, Department of Acute Medicine Division of Medicine Ulleval University Hospital Oslo, Norway

Christine A. Haller, MD

Alison L. Jones, BSc, MD, FRCP, FRCPE, FiBIOL

Assistant Professor of Medicine and Clinical Pharmacology Division of Clinical Pharmacology Department of Medicine and Laboratory Medicine San Francisco General Hospital University of California, San Francisco San Francisco, California

Professor of Medicine and Clinical Toxicology Faculty of Health University of Newcastle Callaghan, New South Wales, Australia

Daniel A. Handel, MD, MPH

Resident in Emergency Medicine University of Cincinnati Medical Center Cincinnati, Ohio Philippe Hantson, MD, PhD

Professor of Toxicology Catholic University of Louvain Head, Center for Clinical Toxicology Cliniques St.-Luc Brussels, Belgium

David N. Juurlink, BPhm, MD, PhD, FRCPC

Assistant Professor Departments of Medicine, Pediatrics, and Health Policy, Management, and Evaluation University of Toronto Division Head Division of Clinical Pharmacology and Toxicology Staff Physician Division of General Internal Medicine Sunnybrook Health Sciences Centre Consultant Toxicologist Ontario Regional Poison Information Centre The Hospital for Sick Children Toronto, Ontario, Canada

xii

CONTRIBUTORS

Ziad N. Kazzi, MD, FAAEM

Kurt C. Kleinschmidt, MD

Assistant Professor Co-Director, Center for Emerging Infections and Emergency Preparedness Department of Emergency Medicine University of Alabama at Birmingham Birmingham, Alabama

Division of Emergency Medicine Department of Surgery Chief, Section of Toxicology Director, Toxicology Fellowship Program University of Texas Southwestern Medical Center Associate Medical Director Emergency Services Department Parkland Memorial Hospital Dallas, Texas

Nicholas J. Kenyon, MD

Assistant Professor of Medicine University of California–Davis Davis, California Fergus Kerr, MBBS, MPH, FACEM

Clinical Toxicologist Statewide Toxicology Service Deputy Director Emergency Department Austin Health Melbourne, Victoria, Australia Daniel C. Keyes, MD, MPH, FACMT

Physician Advisor Concentra Health Services Carrollton, Texas Clinical Associate Professor Division of Toxicology, Emergency Medicine Department of Surgery University of Texas Southwestern Medical Center Dallas, Texas Edwin M. Kilbourne, MD

Chief Medical Officer National Center for Environmental Health and the Agency for Toxic Substances and Disease Registry Centers for Disease Control and Prevention Atlanta, Georgia Richard Kingston, PharmD

Professor Department of Experimental and Clinical Pharmacology College of Pharmacy University of Minnesota Minneapolis, Minnesota President and Senior Toxicologist Regulatory and Scientific Affairs SafetyCall International Poison Center Bloomington, Minnesota Mark A. Kirk, MD

Assistant Professor Division of Medical Toxicology Department of Emergency Medicine University of Virginia Charlottesville, Virginia Laura J. Klein, MD

Volunteer Clinical Faculty Department of Psychiatry University of Colorado Health Sciences Center Denver, Colorado

Wendy Klein-Schwartz, PharmD, MPH

Associate Professor University of Maryland School of Pharmacy Coordinator of Research and Education Maryland Poison Center Baltimore, Maryland Edward P. Krenzelok, PharmD

Professor of Pharmacy and Pediatrics University of Pittsburgh Director, Pittsburgh Poison Center University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Melisa W. Lai, MD

Department of Pediatrics Harvard Medical School Boston, Massachusetts Frédéric Lapostolle, MD, DMC

Emergency Medicine SAMU 93, EA3409 Hôpital Avicenne Université Paris XIII Bobigny, France Eric J. Lavonas, MD

Division of Medical Toxicology Department of Emergency Medicine Director, Medical Toxicology Hospital Services Medical Director, Hyperbaric Medicine Carolinas Medical Center Charlotte, North Carolina Michael Levine, MD

Resident, Emergency Medicine Harvard Affiliated Emergency Medicine Residency Harvard Medical School Resident, Emergency Medicine Massachusetts General Hospital/Brigham & Women’s Hospital Residency in Emergency Medicine Boston, Massachusetts William J. Lewander, MD

Professor of Pediatrics Brown University School of Medicine Director, Pediatric Emergency Medicine Hasbro Children’s Hospital Rhode Island Children’s Hospital Providence, Rhode Island

CONTRIBUTORS

xiii

Ivan E. Liang, MD

R.B. McFee, DO, MPH

Assistant Professor of Emergency Medicine Tufts University Medical School Attending Physician St. Elizabeth’s Hospital Boston, Massachusetts

Assistant Professor Department of Preventive Medicine State University of New York at Stony Brook Stony Brook, New York Consultant Long Island Regional Poison and Drug Information Center Winthrop University Hospital Mineola, New York

Erica L. Liebelt, MD, FACMT

Associate Professor of Pediatrics and Emergency Medicine University of Alabama at Birmingham School of Medicine Director, Medical Toxicology Services UAB Hospital and Children’s Hospital Birmingham, Alabama James G. Linakis, PhD, MD

Associate Professor of Emergency Medicine and Pediatrics Brown University School of Medicine Associate Director, Pediatric Emergency Medicine Hasbro Children’s Hospital Rhode Island Hospital Providence, Rhode Island Christopher H. Linden, MD

Professor Division of Medical Toxicology Department of Emergency Medicine University of Massachusetts Medical School Worcester, Massachusetts Richard Lynton, MD

Assistant Clinical Professor Department of Internal Medicine University of California School of Medicine Davis, California Attending Physician VA Northern California Health Care System VA Medical Center Sacramento Mather, California Rebekah C. Mannix, MD

Instructor in Pediatrics Staff Physician, Division of Emergency Medicine Children’s Hospital Boston Boston, Massachusetts Jack Maypole, MD

Assistant Professor of Pediatrics Boston University School of Medicine Department of Pediatrics Boston Medical Center Director of Pediatrics South End Community Health Center Boston, Massachusetts

Charles McKay, MD, FACMT, FACEP, ABIM

Associate Professor of Emergency Medicine University of Connecticut School of Medicine Farmington, Connecticut Section Chief Division of Medical Toxicology Department of Traumatology and Emergency Medicine Hartford Hospital Hartford, Connecticut Jude McNally, BSPharm, RPH, DABAT

College of Pharmacy University of Arizona Tucson, Arizona Bruno Mégarbane, MD, PhD

Assistant Professor Université Paris VII Physician in Critical Care Medicine Medical and Toxicological Critical Care Department Hôpital Lariboisière Paris, France J. Meulenbelt, MD, PhD

Senior Lecturer in Intensive Care and Clinical Toxicology University Medical Center Utrecht Utrecht, Netherlands Director, National Poisons Information Center National Institute for Public Health and the Environment Bilthoven, Netherlands Dana B. Mirkin, MD

Occupational Health Physician St. David’s Occupational Health Services Austin, Texas Brent W. Morgan, MD

Associate Professor Emory University Georgia Poison Center Atlanta, Georgia Brian Morrissey, MD

Assistant Professor of Medicine University of California—Davis School of Medicine Davis, California University of California—Davis Medical Center Sacramento, California

xiv

CONTRIBUTORS

Allison A. Muller, BS, PharmD

Wesley Palatnick, MD, FRCPC, DABEM, DABMT

Adjunct Faculty University of Pennsylvania School of Veterinary Medicine Adjunct Assistant Professor Temple University School of Pharmacy Adjunct Assistant Professor University of the Sciences Philadelphia College of Pharmacy Clinical Managing Director The Children’s Hospital of Philadelphia Poison Control Center Philadelphia, Pennsylvania

Professor and Head Section of Emergency Medicine University of Manitoba Medical Director Department of Emergency Medicine Health Sciences Centre Winnipeg, Manitoba, Canada

Nancy G. Murphy, MD

Lecturer Department of Emergency Medicine Dalhousie University Medical Director IWK Regional Poison Centre Halifax, Nova Scotia, Canada Kristine A. Nañagas, MD

Assistant Professor Division of Medical Toxicology Department of Emergency Medicine Indiana University School of Medicine Indiana Poison Center Indianapolis, Indiana Jeffrey B. Nemhauser, MD

Medical Officer Radiation Studies Branch Centers for Disease Control and Prevention Atlanta, Georgia Heikki Erik Nikkanen, MD

Instructor in Medicine Harvard Medical School Attending Physician Department of Emergency Medicine Brigham & Women’s Hospital Attending Physician Division of Medical Toxicology Children’s Hospital Boston, Massachusetts Kent R. Olson, MD, FACEP, FAACT, FACMT

Clinical Professor of Medicine, Pediatrics, and Pharmacy Division of Clinical Pharmacology University of California, San Francisco Medical Director, San Francisco Division California Poison Control System San Francisco, California John D. Osterloh, MD, MS

Chief Medical Officer and Toxicologist Centers for Disease Control and Prevention Atlanta, Georgia

Robert B. Palmer, PhD, DABAT

Toxicologist Toxicology Associates, Prof LLC Assistant Clinical Professor University of Colorado School of Medicine Denver, Colorado Adjunct Associate Professor University of Wyoming Laramie, Wyoming Alberto Perez, MD, FACEP, ABMT

Assistant Clinical Professor University of Connecticut School of Medicine Farmington, Connecticut Emergency Physicion/Medical Toxicologist Windham Community Memorial Hospital Willimantic, Connecticut Holly E. Perry, MD

Assistant Professor of Pediatrics University of Connecticut School of Medicine Consultant Connecticut Regional Poison Control Center Farmington, Connecticut Staff Physician Connecticut Children’s Medical Center Hartford, Connecticut Scott D. Phillips, MD, FACP, FACMT

Associate Clinical Professor Department of Medicine University of Colorado Health Sciences Center Attending Faculty Rocky Mountain Poison and Drug Center Denver, Colorado David C. Pigott, MD

Residency Program Director Associate Professor and Vice Chair for Education Department of Emergency Medicine University of Alabama at Birmingham Birmingham, Alabama Heidi Pinkert, MD

Clinical Assistant Professor of Emergency Medicine Weill Medical College of Cornell University New York, New York Attending Physician Lincoln Medical and Mental Health Center Bronx, New York

CONTRIBUTORS

Alex T. Proudfoot, BSc, MB, FRCPE, FRCP

Michael D. Schwartz, MD

Consultant Clinical Toxicologist National Poison Information Service (Birmingham Unit) Birmingham, United Kingdom

Medical Toxicologist Division of Toxicology Agency for Toxic Substances and Disease Registry Centers for Disease Control and Prevention Georgia Poison Center Atlanta, Georgia

Rouhollah Prueitt, MD

Clinical Instructor University of Texas Southwestern Medical Center Toxicology Fellow Parkland Memorial Hospital Dallas, Texas Lawrence S. Quang, MD

Assistant Professor of Pediatrics Case Western Reserve University School of Medicine Medical Director Greater Cleveland Poison Control Center Attending Physician Division of Pediatric Emergency Medicine and the Mary Ann Swetland Center for Environmental Health Rainbow Babies and Children’s Hospital University Hospitals Case Medical Center Cleveland, Ohio

Donna Seger, MD, FAACT, FACEP, ABMT

Associate Professor of Medicine and Emergency Medicine Department of Medicine and Emergency Medicine Medical Director Tennessee Poison Center Vanderbilt University Medical Center Nashville, Tennessee Michael W. Shannon, MD, MPH, FAAP, FACEP, FAACT, FACMT

Assistant Professor Section of Emergency Medicine The University of Chicago Chicago, Illinois

Chief and CHB Chair Division of Emergency Medicine Children’s Hospital Boston Professor of Pediatrics Harvard Medical School Senior Toxicologist MA/RI Regional Center for Poison Control and Prevention Associate Director The Pediatric Environmental Health Center Boston, Massachusetts

William H. Richardson, MD

Mahesh Shrestha, MD

Medical Director Palmetto Poison Center Palmetto Health Richland Medical Center Clinical Assistant Professor University of South Carolina South Carolina College of Pharmacy Columbia, South Carolina

Adjunct Professor of Medicine and Surgery University of Texas Southwestern Medical School Dallas, Texas Emergency Department Physician Crozer-Chester Medical Center Upland, Pennsylvania

James W. Rhee, MD

xv

Leo J. Sioris, PharmD Jon C. Rittenberger, MD

Instructor Department of Emergency Medicine University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania Steven D. Salhanick, MD

Staff Toxicologist Children’s Hospital Boston Boston, Massachusetts Anthony J. Scalzo, MD, FAAP, FACMT, FAACT

Professor and Director Division of Toxicology St. Louis University School of Medicine Medical Director Missouri Regional Poison Control Center St. Louis, Missouri Heather K. Schuller, PharmD

Clinical Toxicologist SafetyCall International Poison Center Bloomington, Minnesota

Professor Department of Experimental and Clinical Pharmacology College of Pharmacy University of Minnesota Minneapolis, Minnesota Senior Clinical Toxicologist SafetyCall International Poison Center Bloomington, Minnesota Marco L. Sivilotti, MD, MSc, FRCPC, FACEP, FACMT

Associate Professor Departments of Emergency Medicine and Pharmacology and Toxicology Queen’s University Kingston, Ontario, Canada Consultant Ontario Regional Poison Information Center Hospital for Sick Children Toronto, Ontario, Canada

xvi

CONTRIBUTORS

Sara Skarbek-Borowska, MD

Sharon Ternullo, BS, PharmD, CSPI

Assistant Professor Department of Emergency Medicine University of New Mexico School of Medicine Assistant Professor Department of Emergency Medicine The University of New Mexico Health Sciences Center Albuquerque, New Mexico

Adjunct Faculty Albany College of Pharmacy Albany, New York Coordinator of Drug Information Certified Poison Information Specialist Ruth A. Lawrence Regional Poison and Drug Information Center University of Rochester Medical Center Rochester, New York

Susan C. Smolinske, PharmD, DABAT

Associate Professor Department of Pediatrics Wayne State University Managing Director Children’s Hospital of Michigan Regional Poison Control Center Detroit, Michigan Curtis P. Snook, MD, FACEP, FACMT

Consultant Cincinnati Drug and Poison Information Center Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio David G. Spoerke, MS, RPH

Freelance Pharmacognosy Writer Lakewood, Colorado Jeffrey R. Suchard, MD, FAECP, FACMT

Associate Professor of Clinical Emergency Medicine Director of Medical Toxicology Department of Emergency Medicine University of California–Irvine Medical Center Orange, California Young-Jin Sue, MD

Department of Pediatrics Division of Pediatric Emergency Medicine Clinical Associate Professor of Pediatrics Albert Einstein College of Medicine Attending Physician Pediatric Emergency Services Children’s Hospital at Montefiore Bronx, New York Matthew D. Sztajnkrycer, MD, PhD

Assistant Professor of Emergency Medicine Mayo Medical School Consultant Department of Emergency Medicine Mayo Clinic Rochester, Minnesota Staff Toxicologist Hennepin Regional Poison Center Minneapolis, Minnesota

Dung Thai, MD, PhD

Medical Director Medical Sciences Amgen, Inc. South San Francisco, California R. Steven Tharratt, MD, MPVM

Professor of Clinical Internal Medicine School of Medicine University of California–Davis Sacramento Division California Poison Control System Kaiser Permanente North Sacramento, California Jerry D. Thomas, MD

Assistant Professor of Emergency Medicine Emory University School of Medicine Toxicologist Georgia Poison Center Atlanta, Georgia Karen E. Thomas, MPH

Consulting Epidemiologist Georgia Poison Center Atlanta, Georgia Josef G. Thundiyil, MD, MPH

Assistant Clinical Professor of Emergency Medicine Orlando Regional Medical Center Orlando, Florida Anthony J. Tomassoni, MD, MS, FACEP, FACMT

Associate Professor University of Vermont College of Medicine Burlington, Vermont Medical Director Northern New England Poison Center Maine Medical Center Portland, Maine Stephen J. Traub, MD

Assistant Professor of Medicine Harvard Medical School Co-Director Division of Toxicology Beth Israel Deaconess Medical Center Boston, Massachusetts

CONTRIBUTORS

John Harris Trestrail III, BSPharm, RPh, FAACT, DABAT

James F. Wiley II, MD, MPH

Managing Director DeVos Children’s Hospital Regional Poison Center Grand Rapids, Michigan

Professor of Pediatrics and Emergency Medicine/ Traumatology University of Connecticut School of Medicine Consultant Connecticut Regional Poison Control Center Farmingham, Connecticut

J. Allister Vale, MD, FRCP, FRCPS, FFOMFAACT, FCBTS

National Poison Information Service (Birmingham Unit) and West Midlands Poison Unit City Hospital Birmingham, United Kingdom Jason Vena, MD

Fellow in Medical Toxicology University of Connecticut Hartford Hospital Hartford, Connecticut Frank G. Walter, MD, FACEP, FACMT, FAACT

Associate Professor of Emergency Medicine Chief, Division of Medical Toxicology University of Arizona College of Medicine Director of Clinical Toxicology University Medical Center Tucson, Arizona Richard Y. Wang, DO

Senior Medical Officer Organic Analytical Toxicology Branch Division of Laboratory Sciences National Center for Environmental Health Centers for Disease Control and Prevention Atlanta, Georgia Sharita E. Warfield, MD, MS

Associate Clinical Professor Department of Emergency Medicine/Toxicology Wayne State University Detroit, Michigan Attending Physician/Medical Toxicologist Department of Emergency Medicine/Toxicology Detroit Medical Center Detroit, Michigan Paul M. Wax, MD

Clinical Professor of Surgery (Emergency Medicine) University of Texas Southwestern Dallas, Texas Suzanne R. White, MD

Dayanandan Professor and Chair Department of Emergency Medicine Wayne State University School of Medicine Medical Director Children’s Hospital of Michigan Regional Poison Control Center Detroit Medical Center Detroit, Michigan

Saralyn R. Williams, MD

Associate Professor of Clinical Medicine Department of Medicine Department of Emergency Medicine Vanderbilt University Nashville, Tennessee Alan David Woolf, MD, MPH

Associate Professor of Pediatrics Harvard Medical School Program Director Environmental Health Children’s Hospital Boston Boston, Massachusetts Mark Yarema, MD, FRCPC

Division Chief, Research Department of Emergency Medicine Calgary Health Region Calgary, Alberta, Canada Luke Yip, MD, FACMT

Clinical Assistant Professor School of Pharmacy Department of Pharmaceutical Sciences University of Colorado Health Sciences Center Attending Staff Physician Consultant Clinical Toxicologist Department of Medicine Division of Medical Toxicology Denver Health Medical Center Attending Faculty Consultant Clinical Toxicologist Rocky Mountain Poison and Drug Center Denver, Colorado

xvii

P R E F A C E

This fourth edition of Clinical Management of Poisoning and Drug Overdose, is re-titled to include the name of its creators, Lester Haddad and Jim Winchester. While neither of them was formally trained in medical toxicology, Lester and Jim were visionary in recognizing the need for a comprehensive toxicology textbook. From the first edition in 1983 to the 3rd edition in 1998, Haddad and Winchester compiled the key information that clinicians who manage poisoned patients would need; they were successful in their goal of providing a resource that was clear, succinct, and evidence-based, without expansive discussions of underlying molecular biology or exhaustive literature reviews. Equally important, with each edition, Haddad and Winchester recruited medical toxicologists as authors, in order to present recommendations from those who were recognized experts in the field. With plans to write a fourth edition, Drs. Haddad and Winchester entrusted us to continue their vision for this textbook. We are honored to assume this responsibility and hope that we have been successful in maintaining its value. As with previous editions, we write Haddad and Winchester’s Clinical Management of Poisoning and Drug Overdose for emergency physicians, pediatricians, internists, occupational/environmental medicine physicians, and public health officials, as well as medical toxicology fellows, house officers, and medical students. The subspecialty of medical toxicology continues to evolve rapidly. For example, since the last edition of the textbook, no less than 4 new antidotes have entered clinical practice. The number of board certified medical toxicologists now exceeds 300 with these experts providing consultation to poison centers, academic medical centers, emergency departments, laboratories, and government agencies. With the growth of medical toxicology as a subspecialty has also come the same maturation that all new clinical fields undergo. Included in the process of maturation is greater rigor in medical toxicology research, the development of basic science research niches by medical toxicologists, and success with receiving extramural funding from NIH and other agencies that support the principles of high-quality research that advances human health. The establishment of medical toxicology as a distinct clinical subspecialty has greatly benefited poisoned patients. Gone is the era in which there was debate about

whether there was a well-defined body of knowledge about poisonings that called for the creation of a distinct subspecialty; medical toxicologists are now recognized as possessing expertise that truly makes a difference in patient outcome after a poisoning. The U.S. Department of Health and Human Services, in acknowledgement of the importance of poison centers and the medical toxicologists who direct them, has begun to fund poison centers as a vital part of public health. In order to meet the needs of clinicians, this 4th edition of Haddad and Winchester’s Clinical Management of Poisoning and Drug Overdose has added several new features. First, to make this edition as authoritative as possible, we recruited practicing toxicologists to write each chapter. Parenthetically, this is also the first edition in which all the editors are medical toxicologists, who have primary practices in pediatrics, emergency medicine, and occupational/environmental medicine. Second, along with Elsevier, we have attempted to create a textbook with international appeal and value. Contributors to this edition include medical toxicologists in England, Australia, and elsewhere. Our hope is that clinicians from all countries will find each chapter useful and relevant to their practice. Finally, in an era of frequent acts of terrorism and other disasters, we have created a new section, Disasters and Terrorism. New chapters, including Principles of Children’s Environmental Health, IllDefined Toxic Syndromes and Performance Enhancers, reflect new medical issues that clinicians regularly face. The three of us thank our superb group of contributors who provided their thorough and conscientious expertise in each chapter. We thank the supportive staff of Elsevier, particularly Todd Hummel, who helped us navigate the project from beginning to end. We thank our families and loved ones, who permitted us to devote the many hours needed to create a work such as this. Finally, we extend to our readers the hope that this text will benefit them in their pursuit of knowledge about principles of poison management and in the care of their patients. MICHAEL W. SHANNON, MD, MPH STEPHEN W. BORRON, MD, MS MICHAEL J. BURNS, MD

S E C T I O N

A

CONCEPTS IN MEDICAL TOXICOLOGY

1

The History of Toxicology MICHAEL W. SHANNON, MD, MPH

Although it is difficult to provide a strict definition of poison, in its broadest definition the term denotes any substance that has the ability to harm a living organism from either the plant or animal kingdom. However, in the discipline of clinical toxicology, poison generally refers to any agent that can kill, injure, or impair normal physiologic function in humans.1,2 The history of toxicology, including its writers, poisons, and poisoners, is extensive and colorful; the field can clearly claim a lineage that traces back more than 10,000 years. Over these millennia, the science (and art) of poisons and poisoning has been punctuated by events that provide a useful perspective. This chapter provides an overview of select events that have shaped the practice of medical toxicology.

classification scheme for poisons, distinguishing between those of plant, animal, and mineral origin. Another important figure of this era was Mithradates VI, King of Turkey during the period 114–63 BC (Fig. 1-2). Mithradates lived in constant fear of being poisoned.4 He therefore studied antidotes extensively and can be considered a pioneer in the development of antidotal therapy. Mithradatum was the name given to one of his famous antidotes.

The Medieval Era

HISTORICAL TIMELINE

This period of clinical toxicology also contains unique chapters. During this time, apothecaries, corresponding to modern-day pharmacists, provided both “potions and poisons.” Commonly used poisons of this era included arsenic and other heavy metals, amygdalin, strychnine, belladonna, and aconite.

Ancient Times

The Renaissance

Throughout these early years of recorded history, the use of poisons was well described. The Sumerians of Mesopotamia are given credit for chronicling (circa 1400 BC) the world of poisons in their descriptions of the spirit Gula, who was “the mistress of charms and spells.” The ancient Greeks were familiar with the toxicities of metals, particularly arsenic, and the poisonous plant hemlock (Conium maculatum). Developed as a tool for capital punishment, hemlock was used to execute Socrates in 402 BC. The ancient Romans also developed and utilized poisons; homicide with agents including amygdalin (cyanide) and belladonna were favored. Papyri from the period around 300 BC provide evidence that ancient Egyptians understood and exploited the toxic properties of arsenic, copper, lead, and antimony. Dioscorides (AD 40–90), a physician and pharmacologist, is credited with creating the first treatise of toxicology, the Materia Medica (Fig. 1-1).3 In his text, which remained an authoritative reference for the next 15 centuries, he created a

By the Middle Ages, toxicology had reached great prominence. Italian alchemists often devoted their careers to

FIGURE 1-1 Dioscorides. (From Wikipedia: Pedanius Dioscorides.)

3

4


FIGURE 1-2 King Mithradates. (From Anonymous: C. Julius Caesar.)

developing lethal agents. Famous names during this period were the Borgias, a family of reputed poisoners, and Paracelsus. Born Theophrast von Hohenheim, Paracelsus (1493–1541) was an alchemist, physician, and astrologer (Fig. 1-3).5 He is considered one of the “fathers of toxicology.” A committed student of toxicology, Paracelsus is credited with making the famous statement, “All things are poison and nothing is without poison; only the dose makes that a thing which [sic] is no poison.” One of the most important publications of the era was Neopoliani Magioe Naturalis, written in 1589 by Giovanni Battista Porta. This book described different methods of poisoning the unsuspecting.

The 16th through 18th Centuries Throughout the 16th century, the development of poisoning techniques spread rampantly across Europe as Italian alchemists migrated to France. Catherine de

FIGURE 1-3 Paracelsus, painted by a student of Rubens. (From The Alchemy Web Site: Paracelsus.)

FIGURE 1-4 Catherine De Medici. (From Anonymous: Who’s Who in Tudor history.)

Médici is credited with bringing many of the Italian techniques of poisoning to France (Fig. 1-4).6 During this era, the French School of Poisoners became hugely popular. In an effort to contain the growing epidemic of poisoning, King Louis XIV began to limit the availability of toxic agents; for example, he forbade apothecaries from selling arsenic and required purchasers to sign a register. The king ultimately created the Chambre Ardente, a council that was responsible for investigating poisonings. Many members of nobility (e.g., Queen Elizabeth) appointed food tasters to ensure that no poison had been surreptitiously placed in their food. By the 17th century, poisoning had become a scientific discipline; schools of toxicology were established in both Venice and Rome.7

The 19th through 21st Centuries During these centuries, toxicology took several new paths. First, during the Victorian period (19th century), forensic toxicology was developed in an effort to apprehend poisoners. Important techniques of investigation, including postmortem analysis, began to appear. This was also a period of remarkable drug discovery and development, with many pharmaceutical agents proving, as Paracelsus said, to be both beneficial and harmful. Many infamous drugs were developed during this era, including ipecac, cocaine, opium (laudanum), and barbiturates. While all had great therapeutic value, their toxicity was at the same time discovered and eventually feared. Another important aspect of this period was, in parallel with the industrial revolution, the birth of occupational toxicology. As many valuable but toxic consumer products were developed, the need to protect workers from toxicologic threats ushered in a new scientific and public health field. One of the most important figures of this period was Dr. Alice Hamilton (Fig. 1-5).8,9 Dr. Hamilton (1869–1970) was the first U.S. physician to

CHAPTER 1

The History of Toxicology

5

FIGURE 1-5 Alice Hamilton, MD.

name and residence. Authorities eventually discovered her and accused her of being an accomplice to more than 600 homicides. She was arrested and ultimately tortured and strangled in prison. Mary Ann Cotton (1832–1873) is considered one of the most prolific serial killers in English history (Fig. 1-6).10 She is suspected of murdering more than 21 unsuspecting victims before she was caught, convicted, and hanged. Victims of Mary Cotton usually succumbed to a severe gastrointestinal disorder (“gastric fever”), ultimately traced to her penchant for using arsenic to poison her victims. Harold Shipman (1946–2004) was one of the most prolific serial killers in modern history (Fig. 1-7). A British physician, he is estimated to have killed 250 patients between 1970 and 1988. Dr. Shipman’s modus operandi was to prey on the elderly, particularly elderly

devote herself to research in industrial medicine. Writing her first article on the topic in 1908, she went on to become the first woman on the faculty of Harvard University. The 20th and 21st centuries have been filled with many more events and accomplishments in medical toxicology. Perhaps the most important of these has been the development of a mammoth pharmaceutical industry, which can be credited with creating new drugs at a remarkable pace. With the development and use of many drugs has come, often tragically, the discovery of unanticipated toxicities. The study of drug toxicity has also led to important new principles of pharmacology (e.g., drug interactions). Finally, in the current “era of the gene,” pharmacology has added the disciplines of pharmacogenomics, which explores the ways in which an individual’s genetic makeup predetermines how he or she will respond to a medication or even a toxin (e.g., both lead and mercury toxicity are now known to be modulated by several key genes). Another important aspect of 20th and 21st century toxicology has been the focus on poisoning management. Over the past 50 years, poison centers have been created around the world, assisting clinicians and the public in poisoning management; prevention has become an equally important part of the poison control mission.

FIGURE 1-6 Mary Ann Cotton. (From Anonymous: The poisoners—Mary Ann Cotton.)

FAMOUS POISONERS, POISONS, AND POISONINGS Poisoners A 17th century Neapolitan woman known simply as Toffana (1653–1723) invented an arsenic-based face paint called Acqua Toffana. This potion was primarily marketed as a cosmetic; female customers would consult with Toffana to learn the proper uses of the makeup. Reportedly, many women became rich widows after wearing the cosmetic on their cheeks when in the presence of their spouses. Because of her dread of being revealed as a poisoner, Toffana continually changed her

FIGURE 1-7 Dr. Harold Shipman. (From British Broadcasting Corporation: Shipman Draws 7.3M viewers.)

6


women. During home visits he would inject his victims with morphine, giving the appearance that they died from the complications of their advanced years; he was also usually the signatory on the victims’ death certificates. Dr. Shipman was ultimately arrested and convicted of killing 15 men and women. In 2004, while imprisoned, he committed suicide. Shoko Asahara (born Chizuo Matsumoto [1955–]) was the founder of the religious group Aum Shinrikyo (Fig. 1-8).11 In March 1995, on a Monday morning (intentionally timed to produce the greatest number of casualties), he and his followers orchestrated the release of the nerve agent sarin in multiple subway cars carrying Tokyo commuters. In the process, he became the architect of one of the most important events of domestic terrorism in history. Asahara’s apocalyptic efforts actually began in 1994, when his cult first released sarin in a small residential area within the city of Matsumoto; this resulted in injury to more than 600 residents; 7 died in that incident.12,13 In the sarin release in 1995, however, multiple cult members effectively coordinated the widespread release of the poison. Victims developed cholinergic toxicity that was sometimes severe, consisting of miosis, vomiting, abdominal pain, respiratory distress, seizures, and respiratory failure. Ultimately 5500 casualties were produced, of which 984 were moderately affected; at least a dozen victims died.12

Poisons ARSENIC As a poison, arsenic has a long and infamous history. Ancient documents suggest this heavy metal was recognized as early as 500 BC; its first use as a poison is thought to date back to the 8th century. While arsenic was used medicinally (e.g., Fowler’s solution was a widely used 18th and 19th century medication prescribed for dermatitis and for asthma), its primary use was as a poison. Stories of homicidal arsenic poisoning are found

FIGURE 1-8 Shoko Asahara. (From Wikipedia: Profile: Shoko Asahara.)

throughout history. The metal’s toxicity was exploited during World War II with development of the arsenicbased chemical weapon lewisite. The Allies, working diligently, were able to develop an antidote against lewisite, British anti-lewisite (BAL).14 BAL, also known as dimercaprol, proved to be a very valuable chelator; it is still used to treat poisoning by arsenic, lead, and other metals. Other details of arsenic’s history are found in Chapter 74. COCAINE The alkaloid derived from erythroxylon coca is a toxic medicinal that has also enjoyed a long and illustrious history. Coca chewing dates back to 3000 BC; cocaine was isolated and used as a medication in the 19th century. A popular substance, it was added to wine and other beverages, well into the 20th century.15 As a therapeutic agent, cocaine was unique because (1) it had great therapeutic value; (2) it had a very narrow therapeutic window, with toxicity, sometimes life-threatening, appearing even in those who were taking it in appropriate doses; and (3) it was highly addictive. A long list of individuals, including Sigmund Freud, Robert Louis Stevenson, and the legendary American surgeon William Halstead, became addicted to cocaine during their careers. In the 1980s, cocaine alkaloid (first known as “free-base” and then “crack”) appeared, creating an even more addictive drug. Through the 1990s, crack use in the United States became epidemic, producing an extraordinarily large population of cocaine abusers. Cocaine remains one of the most widely abused drugs in the world. Chapter 42 describes cocaine and its history in greater detail. OPIUM (LAUDANUM) The discovery of opium dates back to ancient civilization; Hippocrates wrote of the virtues of poppy wine for medicinal purposes. In the 15th century, Paracelsus mixed it with alcohol, producing “tincture of laudanum.” Through the 17th and 18th centuries, use of opium by people of all socioeconomic strata spread quickly. Like cocaine, the drug was found to have remarkable therapeutic value, which often came at the cost of hopeless addiction. In much of the 19th and early 20th centuries, the opium derivative known as laudanum was widely used to treat a range of illnesses. Heroin succeeded laudanum and equally addicted historical figures such as Elizabeth Barrett Browning, Lenny Bruce, Charlie Parker, William Borroughs, and Janis Joplin. CYANIDE The toxicity of bitter almonds, ground peach pits, and cassava were known well before cyanide was specifically identified in 1782. Once isolated and synthesized, the toxin, being a potent pesticide, was a boon to the agriculture industry. However, its lethal effects on those who were inadvertently exposed after improper handling were also quickly discovered. Cyanide’s greatest infamy, however, is associated with its use during the Hitler regime when, as part of his ethnic cleansing campaign (“The Final Solution”), millions were executed with Zyklon-B, a cyanide-based substance used in the gas

CHAPTER 1

FIGURE 1-9 Zyklon B, a cyanide-containing substance used during the Holocaust. (From Anonymous: Judaism.)

chambers of occupation camps (Fig. 1-9). Cyanide continues to be used as a homicidal agent, in gas chamber executions that are part of capital punishment. The agent is discussed further in Chapter 88.

Poisonings History records many poisoning events made infamous by the large number of individuals affected. Large scale poisonings have included: War-related events (e.g., the use of chemical weapons during both World Wars) Industrial catastrophes (e.g., Minamata Bay, Japan, and Bhopal, India) Climactic/geological events (e.g., the London smog and Lake Nyos “eruption”) Pharmaceutical disasters (e.g., eosinophilia-myalgia syndrome, gasping baby syndrome, and thalidomide disasters) Food-borne poisonings (e.g., “St. Anthony’s fire” and aflatoxin epidemics) Domestic terrorism (e.g., sarin release in Tokyo subways) A brief description of several of these events is described below. EOSINOPHILIA-MYALGIA SYNDROME In 1989, an illness appeared in the United States, characterized by the onset of myalgia, arthralgia, weakness, rash, and scleroderma-like skin changes. Associated laboratory findings included evidence of rhabdomyolysis and a striking eosinophilia.16,17 Known as eosinophiliamyalgia syndrome (EMS), the disease rapidly spread throughout the United States. Epidemiologic investigation quickly traced the disease to use of the dietary supplement L-tryptophan, which had become a popular remedy for insomnia, premenstrual syndrome, depression, and other maladies. Further investigation linked the development of EMS to use of L-tryptophan from specific


7

manufacturing lots.18,19 By March 1990, the Centers for Disease Control and Prevention (CDC) had identified almost 1500 cases of EMS with at least 38 deaths. Ultimately, the L-tryptophan produced by a single manufacturer was incriminated.20,21 Careful inspection of the manufacturing site revealed that a significant production change had recently occurred; the former technique, in which tryptophan was produced by a fermentation process involving the bacterium Bacillus amyloliquefaciens, was altered by the introduction of a new strain of B. amyloliquefaciens. As a result, there appeared to be increased synthesis of several tryptophan intermediates. A specific chemical contaminant, di-tryptophan aminal of acetaldehyde (DTAA) was specifically incriminated (Fig. 1-10) in the development of EMS.22,23 Closure and immediate changes in the manufacturing process led to the disappearance of this disorder as quickly as it began. However, many victims were left with enduring health problems.24 GASPING BABY SYNDROME In spring 1981, an unusual illness appeared in neonatal intensive care units (NICUs). NICU staff noted that newborns who had been clinically stable would suddenly develop multisystem disease, severe metabolic acidosis, and a haunting gasp, which signaled their death. Known as gasping baby syndrome, the illness spread across NICUs nationally. In June 1981, a New Orleans neonatologist, Dr. Juan Gershanik, noted in a postmortem urine analysis for organic acids that large amounts of hippuric acid, a known metabolite of benzyl alcohol, were found. Noticing that vials of bacteriostatic water containing 0.9% benzyl alcohol were present throughout the NICU, Dr. Gershanik reported his suspicion that gasping baby syndrome was the result of excessive benzyl alcohol administration secondary to the liberal use of bacteriostatic saline.25 Other pediatricians began to report similar suspicions.26,27 The Food and Drug

CO2H

CO2H

CH3

CH2JCH2JNHJCHJNHJCHJCH2 N H

N H

A CO2H CH2JCHJNH2 N HJCJCH2 N CO2H CH2JCHJNH2

B FIGURE 1-10 Di-tryptophan aminal of acetaldehyde (DTAA), incriminated in the etiology of the eosinophilia-myalgia syndrome. Original (A) and revised (B) structures are shown.

8


Administration and American Academy of Pediatrics soon recommended that bacteriostatic saline no longer be used in NICUs. When this occurred, neonatal mortality rates around the country fell dramatically; reports of mortality rates falling from 50% to 2% appeared.28,29 There was also a noticeable fall in the incidence of kernicterus and intraventricular hemorrhage among ill neonates.28,30 Ultimately, conservative estimates were that benzyl alcohol was responsible for more than 300 neonatal deaths and thousands of permanent neurologic disabilities. THE THALIDOMIDE DISASTER Thalidomide was developed as a sedative-hypnotic; it became popular soon after it was first marketed in 1957. Known as Contergan in Germany, Distaval in England, and Kevadon in Canada, thalidomide quickly became the third-largest selling drug in Europe; by 1960, it was being sold around the world. Its reported efficacy in the treatment of hyperemesis gravidarum led to even greater use of the drug by pregnant women. However, when the Merrell Company of Cincinnati submitted a New Drug Application to market Kevadon in the United States on September 12, 1960, a young, new FDA scientist, Dr. Frances O. Kelsey, was assigned to perform the review (Fig. 1-11). Dr. Kelsey was dissatisfied with the safety data submitted for thalidomide and denied approval of the drug.31 In the midst of FDA battles with Merrell, in November 1961, McBride and Lenz, working independently of each other, both published reports suggesting a link between the use of thalidomide and development of phocomelia and other limb abnormalities (Fig. 1-12).32 As little as one dose of thalidomide, taken during a critical period of gestation, was found to produce a range of devastating birth defects. The drug was withdrawn in 1962, but not before it had produced more than 10,000

FIGURE 1-11 Food and Drug Administration scientist Frances O. Kelsey, credited with preventing the sale of thalidomide in the United States.

FIGURE 1-12 Thalidomide-associated phocomelia.

children with limb abnormalities. Dr. Kelsey, credited with preventing the thalidomide disaster from occurring in the United States, was awarded the Gold Medal Award for Distinguished Federal Civilian Service by President John F. Kennedy. MINAMATA BAY From 1932 to 1968, the Chisso Corporation near Minamata Bay, Japan, dumped an estimated 27 tons of mercury compounds into Minamata Bay. In 1956, four inhabitants of Minamata Bay were noted to have an unusual neurologic disease, thought initially to be infectious.12 Investigation quickly led to the discovery that many people of the region had similar symptoms of diffuse numbness, slurred speech, and tunnel vision. Ultimately more than 50,000 were affected, with more than 2000 unequivocally having what became known as Minamata disease. The range of symptoms in adults included tingling sensations, muscle weakness, ataxia, tunnel vision, slurred speech, hearing loss, and abnormal behavior. Approximately 30 offspring of the inhabitants were born with severe, devastating neurologic disease, which included spasticity, mental retardation, seizures, and visual disturbances (Fig. 1-13).33

FIGURE 1-13 Childhood victim of Minamata disease. (Photo by W. Eugene Smith. From McCann HG: Mercury found in midwest rain.)

CHAPTER 1


9

LONDON SMOG On December 4, 1952, an unusual temperature inversion struck London. This climatic event trapped the polluted air that was being regularly discharged from the millions of coal fires that burned daily.34 For the subsequent week, concentrations of smog became so thick, visibility fell to a few yards; concentrations of ambient particulate matter were as high as 400 μg/m3.34 Thousands of Londoners developed respiratory ailments, including pneumonia, bronchitis, and asthma. An estimated 12,000 citizens died from respiratory problems produced by “The Great London Smog” (Fig. 1-14). LAKE NYOS On August 21, 1986, Lake Nyos, a large volcanic lake located in Cameroon, released a massive cloud of carbon dioxide. Being heavier than air, the carbon dioxide descended on the villages located in a valley 250 m below. Witnesses described loud rumbling sounds made by the lake followed by the appearance of an enormous white cloud; an estimated 109 m3 of volcanic gas was released.12 Victims succumbed quickly to the anesthetic effects of high-concentration carbon dioxide. Upon arrival of the medical teams, 1700 humans and all animal and insect life in the region were dead.12 BHOPAL One of the most significant industrial disasters in history occurred on the morning of December 3, 1984, at a large chemical plant in Bhopal, India. The plant, owned by Union Carbide, contained large storage tanks of methyl isocyanate gas (the compound was used as a precursor to the pesticide carbaryl). Without warning, during the dark hours of early morning, a methyl isocyanate tank ruptured, spreading the toxic gas across the streets of Bhopal. Wakened by suffocation, large numbers of victims arrived to local hospitals with sudden blindness and respiratory distress. More than 200,000 were affected by the gas; the death toll was estimated to be approximately 2500.12 Many Bhopal survivors were left with chronic, disabling lung disease.35,36

FIGURE 1-15 Reverend Jim Jones.

Jones’s disciples lived in apparent happiness. However, when several residents sent reports of cruel treatment, coercion, and bondage to relatives in the United States, Congressman Leo Ryan went to Jonestown to investigate abuse allegations, bringing with him an 18-member party of officials, reporters, and members of “Concerned Relatives of Peoples Temple Members.” Arriving in Jonestown in November 1978, Congressman Ryan was prevented from interviewing inhabitants and carrying out his planned investigation. When he attempted to leave Jonestown, he was gunned down at an airstrip by Jones disciples. On November 18, 1978, fearing that additional authorities would soon come and possibly close Jonestown, Reverend Jones called for the mass suicide of his disciples. All drank or were forced to drink a grape flavored beverage that contained Valium and cyanide. The 276 children were killed first; a total of 914 died, including Reverend Jones, who died of a selfinflicted gunshot wound (Fig. 1-16).37

JONESTOWN, GUYANA The Reverend Jim Jones was a religious zealot who in 1977, after creating the People’s Temple in San Francisco, created the township of Jonestown in Guyana, South America, bringing with him more than 1000 followers (Fig. 1-15). Initial reports from Jonestown indicated that

FIGURE 1-14 London smog, 1952. (From National Public Radio: London during the killer smog.)

FIGURE 1-16 The mass suicide at Jonestown, Guyana, 1978.

10


ST. ANTHONY’S FIRE Described by a 9th century writer, St. Anthony’s fire, which has appeared several times in history, was the popular name for epidemic ergotism that resulted from the ingestion of rye that had been contaminated with the fungus Claviceps purpurea. Also referred to as “dancing mania,” outbreaks of St. Anthony’s fire appeared repeatedly between the 13th and 16th centuries. It was not until the 17th century that its cause was identified. The last reported outbreak occurred in France in 1951.38 There are also beliefs that women accused of witchcraft in the Salem trials of 1692 had ergot-induced psychosis and seizures.39 Victims of St. Anthony’s fire would typically develop burning pain and gangrene of the extremities, convulsions, hallucinations, and psychosis; death would often ensue. Ergot’s powerful vasocontrictive properties were responsible for the severe extremity vasospasm that produced pain and gangrene. Central nervous system effects were the apparent result of the alkaloid’s effects on serotonin receptors. Interestingly, the study of ergot alkaloids led to the development of the hallucinogen lysergic acid diethylamide (LSD), as well as therapeutic agents including ergotamine, dihydroergotamine, methysergide, and others.

THE DEVELOPMENT OF MEDICAL TOXICOLOGY Since the early 20th century, organized efforts in poisoning management and prevention have led to the development of medical toxicology as a clinical discipline that is distinct from other medical subspecialties. Key events in this process were the establishment of poison control centers, followed by the creation of important supporting organizations.

Poison Control Centers By the 1930s, childhood poisoning had become a common cause of unintentional injury to children, accounting for almost 50% of significant childhood accidents. Household products (e.g., lye) were a particularly common source of severe and often fatal poisoning. However, there was little information on the toxicity of household products that could be used in prompt and effective management of childhood poisoning. In the 1930s, Dr. Jay Arena, a pediatrician at Duke University, began to compile data on the household products, providing advice to local clinicians. Dr. Arena is credited with writing one of the first modern textbooks on poisoning management. Prior to the 1950s, there was no formal system for poisoning treatment in the United States.40 By this time, there were well over 250,000 different brand name products on the market. Health care professionals presented with cases of acute poisoning usually had little knowledge of what ingredients were contained in these new products, making it difficult to treat these patients. A Chicago pharmacist, Louis Gdalman, began recording information on the toxicity of various products on small cards; he also developed a data collection form that he

would use when he provided consultations. In November 1953, he helped to establish the first poison center in the United States at Presbyterian-St Luke’s Hospital. In 1958, the American Association of Poison Control Centers (AAPCC) was formed. From here, poison centers proliferated: By 1970, there were almost 600 centers nationally. At the same time, poisoning fatalities in children dropped dramatically. The AAPCC was instrumental in creating multiple preventive efforts, including the establishment of National Poison Prevention Week and enactment of the Poison Prevention Packaging Act. As poison centers increasingly served the function of a public health agency, the AAPCC developed a means for monitoring and reporting epidemiologic data, known as the Toxic Exposure Surveillance System (TESS). Annual data from TESS are now published by the AAPCC for use by those who are interested in tracking the epidemiology of poisoning (www.aapcc.org). In 2002, a universal telephone number for access to poison control centers (800-2221222) was established, simplifying access to poison centers.

The Subspecialty of Medical Toxicology As principles of poisoning management and prevention established themselves, several organizations were created to support the clinicians who provided this care. In 1968, the American Academy of Clinical Toxicology (AACT) was formed. Consisting of physicians, pharmacists, scientists, and veterinarians, the AACT began to expand the focus of poisoning beyond childhood exposures to adult poisonings, including intentional exposures (attempted suicides), workplace exposures, drug interactions, envenomations, and environmental toxicology. Around the world, similar organizations were established, including the European Association of Poison Centres and Clinical Toxicologists (EAPCCT), the Canadian Association of Poison Control Centers (CAPCC), and the Australian Society of Clinical and Experimental Pharmacologist and Toxicologist (ASCEPT). As these efforts evolved, it became clear that toxicology had evolved into a well-defined medical specialty. As such, standards for training and certification were needed. In 1974 the AACT created the American Board of Medical Toxicology (ABMT), a physician-only organization responsible for establishing fellowship training guidelines and creating a certifying examination. Medical toxicology fellowships began to appear; the first board examination in medical toxicology was given in 1974. However, the field of medical toxicology suffered from ABMT’s position as an independent certifying organization, rather than a member of the American Board of Medical Specialties (ABMS) which, by this time, had established itself as an umbrella organization that housed the specialties and subspecialties recognized by the American Medical Association. The ABMT and medical toxicology therefore struggled to gain the same stature as ABMS specialties and subspecialties. This led to efforts by ABMT leaders to find parent organizations within the ABMS who would sponsor medical toxicology as a new, defined clinical subspecialty. These efforts culminated in

CHAPTER 1

1992 with three ABMS boards—the American Board of Pediatrics, the American Board of Emergency Medicine, and the American Board of Preventive Medicine— agreeing to make medical toxicology a jointly supported subspecialty. The Subboard in Medical Toxicology was formed, providing the first ABMS certifying examination in 1994. Simultaneously, the ABMT was reestablished as the American College of Medical Toxicology (ACMT), with the goal of being a scientific organization that provides support to the medical toxicology community. Currently, there are approximately 300 practicing, board-certified medical toxicologists, indicating the relative youth of the field. These individuals have vital roles in medicine and public health, being in federal agencies (e.g., the Food and Drug Administration, and Centers for Disease Control), medical directors of poison control centers (a requirement for poison center certification), directors of occupational health programs, and physician-scientists.

CONCLUSION Throughout recorded time, toxicology has been part of the fabric of society. While its history has been dark at times, the evolving clinical specialty of poisoning management/prevention and the establishment of medical toxicology as a subspecialty have provided important public health advances. The science of toxicology will undoubtedly continue to provide both important discoveries and other memorable events in future years. REFERENCES 1. Gallo MA: History and scope of toxicology. In Klaassen CD (ed): Toxicology—The Basic Science of Poisons, 5th ed. New York, McGraw-Hill, 1996. 2. Shannon M, Haddad L: Emergency management of poisoning. In Shannon M, Haddad L, Winchester J (eds): Clinical Management of Poisoning and Drug Overdose. Philadelphia, Saunders, 1998, pp 2–31. 3. Anonymous: Pedanius Dioscorides. Wikipedia, http://en. wikipedia.org/wiki/Pedanius_Dioscorides. Accessed May 22, 2006. 4. Lendering J: C. Julius Caesar. http://www.livius.org/caa-can/ caesar/caesar02.html, accessed May 21, 2006. 5. McLean A: Portraits of Paracelsus. The Alchemy Web Site, http:// www.levity.com/alchemy/paracelsus_portraits.html, accessed May 21, 2006. 6. Eakins LE: Who’s Who in Tudor History. http://tudorhistory.org/ people/medici. Accessed May 21, 2006. 7. Holdworth T, Tasker K, Thompson A, et al: The history of poisoning—timeline. In Poisining Through the Ages. http:// www.portfolio.mvm.ed.ac.uk/studentwebs/session2/group12/ contents.html, accessed May 21, 2006. 8. Anonymous: Dr. Alice Hamilton. Chemical Achievers—The Human Face of the Chemical Sciences. The Chemical Heritage Foundation, http://www.chemheritage.org/classroom/chemach/ environment/hamilton.html, accessed May 22, 2006. 9. Centers for Disease Control and Prevention: Alice Hamilton, MD. MMWR 1999; 48:462. http://www.cdc.gov/mmwr/preview/ mmwrhtml/MM4822bx.htm, accessed May 22, 2006. 10. Anonymous: The poisoners—Mary Ann Cotton. The Crime Library—Criminal Minds and Methods. http://www. crimelibrary.com/criminal_mind/forensics/toxicology/5.html, accessed May 22, 2006.


11

11. Anonymous: Profile: Shoko Asahara. Wikipedia, http:// en.wikipedia.org/wiki/Shoko_Asahara, accessed May 22, 2006. 12. Langford N, Ferner R: Episodes of environmental poisoning worldwide. Occup Environ Med 2002;59:855–860. 13. Morita H, Yanagisawa N, Nakajima T, et al: Sarin poisoning in Matsumoto, Japan. Lancet 1995;356:290–293. 14. Vilensky JA, Redman K: British anti-lewisite (dimercaprol): an amazing history. Ann Emerg Med 2003;41:378–383. 15. Anonymous: Written Testimonials in the History of Advertising. Wikipedia, http://en.wikipedia.org/wiki/Testimonial, accessed May 22, 2006. 16. Shapiro S, Kilbourne EM, Eidson M, et al: L-tryptophan and eosinophilia-myalgia syndrome. Lancet 1994;344:817–819. 17. Hertzman PA, Clauw DJ, Kaufman LD, et al: The eosinophiliamyalgia syndrome: status of 205 patients and results of treatment 2 years after onset. Ann Intern Med 1995;122:851–855. 18. Hertzman PA, Blevins WL, Mayer J, et al: Association of the eosinophilia-myalgia syndrome with the ingestion of tryptophan. N Engl J Med 1990;322:869–873. 19. Kamb ML, Murphy JJ, Jones JL, et al: Eosinophilia-myalgia syndrome in L-tryptophan-exposed patients. JAMA 1992;267: 77–82. 20. Slutsker L, Hoesly FC, Miller L, et al: Eosinophilia-myalgia syndrome associated with exposure to tryptophan from a single manufacturer. JAMA 1990;264:213–217. 21. Belognia EA, Hedberg CW, Gleich GJ, et al: An investigation of the cause of the eosinophilia-myalgia syndrome associated with tryptophan use. N Engl J Med 1990;323:357–365. 22. Larkin M: Contaminant found in over-the-counter 5-hydroxy-Ltryptophan. Lancet 1998;352:791. 23. Centers for Disease Control and Prevention: Analysis of Ltryptophan for the etiology of eosinophilia-myalgia syndrome. MMWR 1990;39:589–591. 24. Sullivan EA, Kamb ML, Jones JL, et al: The natural history of eosinophilia-myalgia syndrome in a tryptophan-exposed cohort in South Carolina. Arch Intern Med 1996;156:973–975. 25. Gershanik J, Boecler G, Ensley H, et al: The gasping syndrome and benzyl alcohol poisoning? N Engl J Med 1982;307:1385–1388. 26. Lovejoy FH: Fatal benzyl alcohol poisoning in neonatal intensive care units—a new concern for pediatricians. Am J Dis Child 1982;136:974–975. 27. Brown WJ, Buist NRM, Gipson H, et al: Fatal benzyl alcohol poisoning in a neonatal intensive care unit. Lancet 1982;1:1250. 28. Hiller JL, Benda GI, Rahatzad M, et al: Benzyl alcohol toxicity: impact on mortality and intraventricular hemorrhage among very low birth weight infants. Pediatrics 1986;77:500–506. 29. Committee on Fetus and Newborn and Committee on Drugs: Benzyl alcohol: toxic agent in neonatal units. Pediatrics 1983; 72:356–358. 30. Jardine DS, Rogers K: Relationship of benzyl alcohol to kernicterus, intraventricular hemorrhage, and mortality in preterm infants. Pediatrics 1989;83:153–160. 31. McFadyen RE: Thalidomide in America: a brush with tragedy. Clio Med 1976;2:79–93. 32. Lenz W: Thalidomide and congenital abnormalities. Lancet 1962;1:45–46. 33. Tsubaki T, Irukayama K: Minamata Disease. Amsterdam, Elsevier Scientific, 1977. 34. Donaldson K: The biological effects of coarse and fine particulate matter. Occup Environ Med 2003;60:313–314. 35. Cullinan P, Acquilla S, Dhara VR: Respiratory morbidity 10 years after the Union Carbide gas leak at Bhopal: a cross sectional survey. BMJ 1997;314:338. 36. Desikan P: Bhopal: the lingering tragedy. BMJ 2004;329:1410. 37. Anonymous: Jonestown. Wikipedia, http://en.wikipedia.org/ wiki/Jonestown, accessed May 21, 2006. 38. Fuller JG: The Day of St. Anthony’s Fire. New York, McMillan, 1968. 39. Caporael L: Ergotism: the Satan loosed in Salem? Science 1976;192:21–26. 40. Burda A, Burda N: The nation’s first poison control center: taking a stand against accidental childhood poisoning in Chicago. Vet Hum Toxicol 1997;39:115–119.

2

Emergency Management of Poisoning

A

A General Approach to Poisoning MICHAEL W. SHANNON, MD, MPH

Medical toxicology is one of the most important and dynamic fields in medicine today, since the practicing physician is continually faced with the management of poisoning, drug overdose, and adverse drug effects. The abuse of both prescription and illicit drugs in the United States continues unabated. Because the process of drug approval is more rapid, it is often not until the agent has been in use for some time, during the postmarketing period, before its toxicity is fully appreciated. Defining the incidence of human poisoning is not easy. There are multiple sources of data on drug overdose and substance abuse. The Toxic Exposure Surveillance System (TESS) of the American Association of Poison Control Centers tabulates referrals for human poisoning called into the nation’s poison centers. In 2004, it recorded 2,395,582 exposures, with 1106 deaths; analgesics were the most common cause of a fatal outcome.1 The National Institute of Drug Abuse surveys emergency department visits through its Drug Abuse Warning Network (DAWN), and in 2002 reported that a total of 4427 deaths resulted from drug abuse, with cocaine being the most commonly implicated agent.1,2 However, these sources vastly underestimate the number of toxic events in humans. For example, reports of intoxicated patients who die from trauma, drowning, and fires are not consistently included in any national data set, nor are those of patients with medical complications from therapy, such as chemotherapy or anesthetics. Morbidity that results from chronic abuse (e.g., heart disease from cocaine or nicotine abuse and cirrhosis from alcohol abuse) or industrial exposures, and the long-term effects of environmental hazards, is not rigorously compiled and is probably impossible to quantify. The most common causes of poisoning-related death in the United States have been carbon monoxide poisoning, cocaine use, and tricyclic antidepressant overdose.1 Poisoning with analgesics, aspirin, and acetaminophen also remains a leading cause of death. Calcium channel blocker overdose has surpassed digitalis overdose as the most common cause of cardiovascular drug-related death.

DEFINITION To poison means to injure or kill with a substance that is known or discovered to be harmful. Thus, the term poisoning connotes clinical symptomatology. It also

implies that the toxic exposure is unintentional (e.g., in the case of an elderly patient who misreads a drug label). In contrast, the term overdose implies intentional toxic exposure, either in the form of a suicide attempt or as inadvertent harm secondary to purposeful drug abuse. The terms poisoning and drug overdose often are used interchangeably, especially when prescription drugs are the agents, even though by definition a drug overdose does not produce poisoning unless it causes clinical symptoms. Poisoning has a bimodal incidence, occurring most commonly in children who are 1 to 5 years of age and in the elderly. Overdose, whether motivated by suicidal intent or the result of abuse, occurs through adulthood. Toxic exposure in those between the ages of 6 and 12 years is uncommon; when it occurs, the patient must be assessed carefully to ensure that psychiatric follow-up is provided when indicated.1

THE GENERAL APPROACH TO POISONING The general approach to the poisoned patient can be divided into six phases: (1) stabilization; (2) laboratory assessment; (3) decontamination of the gastrointestinal tract, skin, or eyes; (4) administration of an antidote; (5) elimination enhancement of the toxin; and (6) observation and disposition.

Emergency Management Because overdose patients are often clinically unstable when discovered, resuscitation with establishment of the airway, adequate support of ventilation and perfusion, and maintenance of all vital signs (including temperature) must be accomplished first. Continuous cardiac and pulse oximetry monitoring is essential. Rapid-sequence intubation (RSI) may be indicated in patients with an airway in jeopardy. Naloxone, 2 mg intravenously (IV); thiamine, 100 mg intravenously (IV); and 50% dextrose, 50 mL IV (if patients are shown on Dextrostix testing to be hypoglycemic) are generally given to all adults in coma, once an IV line has been established and appropriate blood studies have been performed.3,4 Maintenance of blood pressure and tissue perfusion may require the provision of volume, correction of acid-base disturbance, administration of pressor agents, and antidotal therapy. Table 2A-1 lists the common emergency antidotes. 13

14


TABLE 2A-1 Common Emergency Antidotes POISON

ANTIDOTE

DOSE*

Acetaminophen

N-acetylcysteine

140 mg/kg initial oral dose, followed Most effective within 16–24 hr; may by 70 mg/kg every 4 hr × 17 doses be useful after chronic intoxication or intravenously as 150 mg/kg × 15 minutes then 50 mg/kg × 4 hr then 100 mg/kg × 16 hr Initial dose 0.5–2 mg (IV); children, Can produce convulsions, bradycardia 0.02 mg/kg 0.2 mg (2 mL) (IV) over 15 sec; Limited indications; recommended repeat 0.2 mg (IV) as necessary; only for reversal of pure initial dose not to exceed 1 mg benzodiazepine sedation Adult: 5–10 mg (IV) initially Stimulates cAMP synthesis, increasing Child: 50–150 ug/kg (IV) initially myocardial contractility Continuous infusion as needed 1 g (10 mL) (IV) over 5 min as initial Avoid extravasation; tissue destructive dose; repeat as necessary in critical patients; doses up to 10 g may be necessary to restore blood pressure 0.5–1.0 U/kg initially then Monitor serum potassium and glucose 0.5–1.0 U/kg/hr as needed to maintain systolic blood pressure 1–3 atmospheres Hyperbaric oxygen may be indicated Administer pearls every 2 min Adult: 10 mL of 3% solution over 3 min (IV) Child: 0.33 mL (10 mg of 3% solution)/kg over 10 minutes Adult: 25% solution, 50 mL (IV) over 10 minutes Child: 25% solution, 1.65 mL/kg Varies by patient weight, serum digoxin concentration, and/or dose ingested Topical exposure: Apply calcium Monitor for hypocalcemia; treat gluconate gel; if pain is not electrolyte disturbances relieved, administer 10% calcium aggressively gluconate 10 mL in 40 mL D5W via IV (Bier block) infusion; if pain is not relieved, administer calcium gluconate by intra-arterial infusion over 4 hr Ingestion: 10% calcium gluconate (IV) Initial dose: 40–90 mg/kg (IV or IM), not to exceed 1 g; Infusion: 15 mg/kg hr (IV) Higher infusion doses may be needed in severe overdose to achieve chelant excess; monitor and treat hypotension 4-6 mg/kg IM, every 4–8 hr Contraindicated if patient has a peanut allergy or G6PD deficiency 10 mg/kg/dose, bid × 28 days Monitor liver function tests, add BAL 35–50 mg/kg/day (maximum if lead level > 70 μg/dL in children, 1.0–1.5g), bid or as a continuous > 100 μg/dL in adults infusion 500 mg/kg of 10% ethanol, then Watch for hypoglycemia, continuous infusion of hypothermia, and lethargy in 100 mg/kg/hr children; solution is hyperosmolar, requiring central venous catheter in children; maintain serum ethanol concentration at 100 mg/dL 15 mg/kg loading dose, 10 mg/kg Significantly safer than ethanol every 12 hr IV 1–2 mg/kg of 1% solution Can produce hemolysis in high dose; (IV) over 5 min give no more than 7 mg/kg/day in adults, 4 mg/kg/day in children; severe or resistant cases may require exchange transfusion

Atropine, anticholinergics Physostigmine Benzodiazepines

Flumazenil

β blockers

Glucagon

Calcium channel blockers

Calcium chloride 10%

Insulin/glucose Carbon monoxide Cyanide

Oxygen Amyl nitrite, then sodium nitrite, then sodium thiosulfate

Digitalis

Digoxin antibody fragments

Hydrofluoric acid

Calcium

Iron

Deferoxamine mesylate

Metals Mercury Arsenic Gold Lead

Methanol

British antilewisite (BAL), also known as dimercaprol DMSA (succimer), CaNa2 EDTA Ethyl alcohol

Fomepizole Nitrites (and other methemoglobin formers)

Methylene blue

COMMENTS

Continued

CHAPTER 2


15

TABLE 2A-1 Common Emergency Antidotes (Cont’d) POISON

ANTIDOTE

DOSE*

COMMENTS

Opiates and opioids

Naloxone

Adults: 0.4–2.0 mg (IV or IM) Child: 0.01–0.1 mg/kg (IV or IM) Adult: 1 mg (IV) Child: 0.25 ug/kg (IV) Adult: 0.5–2 mg IV Child: 0.05 mg/kg Child: 0.05 mg/kg

Larger doses may be necessary after severe overdose or overdose of synthetic agent, e.g., propoxyphene

Nalmafene Organophosphates, nerve agents Carbamates (severe exposure)

Atropine

Pralidoxime (2-PAM)

Tricyclic antidepressants

Sodium bicarbonate

Adult: 1 g (IV) then 500–1000 mg/hr as needed Child 15–40 mg/kg then 15–40 mg/kg/hr Sodium bicarbonate 1–2 ampules (IV), bolus or infusion

Enormous doses of atropine may be needed in severe cases Must be added to atropine if nicotinic or central symptoms are present Administer if QRS interval is ≥ 100 msec; maintain serum pH at 7.45–7.55; avoid severe alkalosis

cAMP, cyclic adenosine monophosphate; DMSA, dimercaptosuccinic acid; EDTA, ethylenediaminetetraacetic acid; G6PD, glucose-6-phosphate deficiency; IM, intramuscularly; IV, intravenously. *Dosage listed may require modification or adjunctive therapy according to specific clinical conditions; see each specific chapter for details.

BOX 2A-1

CLINICAL CONDITIONS AND EXAMPLE AGENTS IN THE POISONED PATIENT THAT MAY NECESSITATE ENDOTRACHEAL INTUBATION

Corrosive ingestion (sodium hydroxide, sulfuric acid) Corrosive inhalation (ammonia, chlorine) Envenomation (hymenoptera, crotalid) Anaphylaxis (hymenoptera) Pulmonary edema (opioids, chemical weapons [e.g., choking agents]) Bronchorrhea (organophosphates or nerve agents) Severe central nervous system (CNS) depression (ethanol, opioids, barbiturates) Cerebrovascular accident (cocaine) Seizures (isoniazid, theophylline) Aspiration (hydrocarbons) Hypercarbia (CNS depressants, nerve agents, botulism)

ADVANCED AIRWAY MANAGEMENT In addition to basic airway management, many victims of poisoning require advanced management that includes endotracheal intubation. Clinical situations in which endotracheal intubation may be necessary in poisoned patients are numerous (Box 2A-1). Intubation offers the advantages of complete airway control, protection from aspiration of gastric contents, provision of a route for suctioning of secretions, and a means of optimizing both oxygenation and ventilation. However, the process of intubating an awake patient is difficult and is associated with potential adverse effects, including coughing, gagging, vomiting, tachycardia or bradycardia, hypertension, hypoxia, and increased intracranial pressure. Moreover, emergency intubation can be challenged by vocal cords that are obscured by secretions, unusual airway anatomy, a full stomach, or active vomiting.

Therefore, this task requires a thorough understanding of advanced airway management principles and of their application in a manner that prevents worsening of the clinical situation. RSI is a method of rapidly obtaining airway control with minimal physiologic disturbance. The process of RSI involves a patterned sequence of preparation, drug administration, intubation, and postintubation management.5-7 In the emergency department, RSI has historically had its greatest role in the patient with severe head trauma in whom intubation could exacerbate already increased intracranial pressure. However, because it is designed to blunt or prevent all adverse responses associated with endotracheal intubation, RSI is the ideal method of intubation in the poisoned patient. With the use of drugs having a short duration of action, RSI also is advantageous because it is a measure that permits temporary airway control for the patient with mildly compromised airway reflexes who requires gastrointestinal decontamination (lavage followed by activated charcoal administration) but who does not require prolonged intubation. RSI requires several essential steps that include the use of pharmacologic agents (Table 2A-2). To be performed safely, RSI must occur in the following sequence. Evaluation The clinician must first evaluate the patient’s airway to determine the necessary equipment and the best technique for safe intubation. Particular attention should be directed to abnormalities in the cervical spine and temporomandibular joint because these will significantly impede rapid and uncomplicated intubation. If there is any question about the stability of the cervical spine, immobilization must be maintained. The oral cavity should be closely examined for the presence of foreign bodies.

16


TABLE 2A-2 Pharmacotherapy Used in Rapid Sequence Intubation AGENT Pretreatment Agents Atropine Lidocaine

0.01–0.02 mg/kg (minimum, 0.1 mg; maximum, 1.0 mg) 1–2 mg/kg

BARBITURATES

3–5 mg/kg 1 mg/kg

BENZODIAZEPINES

Midazolam ETOMIDATE

0.1 mg/kg 0.1–0.3 mg/kg

KETAMINE

1–2 mg/kg

OPIOIDS

Fentanyl PROPOFOL

EQUIPMENT NEEDED FOR ENDOTRACHEAL INTUBATION

DOSE*

Sedatives and Anesthetics Sodium thiopental Methohexital

BOX 2A-2

Syringe for endotracheal cuff inflation 100% oxygen Face mask Bag-valve apparatus Suction equipment Catheter Yankauer suction tube Stylet Magill forceps Oral airway Nasopharyngeal airway (“trumpet”) Laryngoscope handle and blades Endotracheal tubes Tongue depressors Syringe for endotracheal cuff inflation Tape Tincture of benzoin

2–5 μg/kg 2–4 mg/kg

Skeletal Muscle Relaxants

TABLE 2A-3 Age-Specific Endotracheal Tube Sizes

DEPOLARIZING AGENTS

Succinylcholine

1–2 mg/kg

AGE

INTERNAL DIAMETER (mm)

NONDEPOLARIZING AGENTS

DEFASCICULATING DOSE FULL DOSE Pancuronium Vecuronium Atracurium Rocuronium

0.01–0.05 mg/kg 0.01–0.05 mg/kg

0.1 mg/kg 0.1–0.2 mg/kg 0.5 mg/kg 0.5–1.0 mg/kg

*Doses listed are for intravenous administration.

Preparation Before intubation, all necessary equipment must be present so that serious delays or unforeseen complications can be prevented. An IV line should be established and the patient connected to a cardiac monitor and pulse oximeter. The equipment necessary for endotracheal intubation is outlined in Box 2A-2. The proper functioning of all equipment should be ensured before it is used. Appropriate endotracheal tube size also should be determined (Table 2A-3). Unanticipated difficulties with intubation are common; “difficult airway” equipment (e.g., illuminated or fiberoptic-directed endotracheal tubes) should be kept close at hand. Preoxygenation Oxygen should be administered for 2 to 3 minutes before intubation; this produces a washout of nitrogen from the lungs, replacing this gas with an oxygen reservoir. The oxygen reservoir allows several minutes of apnea during which intubation can be performed without the risk of producing hypoxia. Assisted ventilation with bag-valve-mask apparatus should only be

Infant Premature Full term 1–6 mo 6–12 mo

2.5 3.0 3.5 4.0

Child 2 yr 4 yr 6 yr 8 yr 10 yr

4.5 5.0 5.5 6.5 7.0

Adolescent and Adult 12 yr ≥14 yr

7.5 8.0–9.0

Accompanying principles: 1. Small sizes are necessary for nasotracheal intubation. 2. Endotracheal tubes two sizes smaller than age appropriate should be immediately available.

provided if the patient’s own respiratory efforts are inadequate because it risks inflation of the stomach, which increases the likelihood of vomiting. Patients who are breathing spontaneously should be given 100% oxygen by face mask for several minutes before intubation. Pretreatment Pretreatment involves the administration of pharmacologic agents that prevent adverse physiologic changes that may occur during intubation. Agents included in this category are lidocaine and atropine. IV administration of the anesthetic lidocaine appears to blunt the increase in intracranial pressure that

CHAPTER 2

accompanies intubation. Although scientific proof of lidocaine’s efficacy is sparse, it is appropriate— particularly in the patient with suspected intracranial hypertension—to administer lidocaine, 1.0 to 2.0 mg/kg IV, 3 to 4 minutes before intubation.8-10 Bradycardia can accompany RSI in two circumstances. In young children, both posterior pharyngeal stimulation and administration of succinylcholine can result in severe bradycardia. Therefore, in children younger than 5 years, atropine should be administered before induction. The dose of atropine is 0.01 to 0.02 mg/kg (maximum, 1.0 mg). No less than 0.1 mg of atropine should be administered because smaller doses can produce paradoxical bradycardia. Severe bradycardia can also occur in patients of any age who have been exposed to medications or toxins with negative chronotropic actions. For example, in patients who have ingested β antagonists (e.g., propranolol), calcium channel blockers, and digoxin, RSI can produce an abrupt decrease in heart rate or frank cardiac arrest. Therefore, in patients who are undergoing RSI after exposure to these agents, atropine should either be administered prophylactically or kept immediately available should emergency administration become necessary. Induction Induction consists of two components: administration of a sedative/anesthetic agent to produce unconsciousness, and the subsequent administration of an agent that produces complete skeletal muscle relaxation (paralysis); both actions facilitate intubation. Because administration of these drugs leads to apnea and paralysis, it is essential that induction proceed quickly and efficiently; this underscores the importance of having all intubation equipment immediately available and in working order. A number of medications of different pharmacologic classes are used to produce sedation before skeletal muscle relaxation (see Table 2A-2). These drugs include benzodiazepines, opioids, barbiturates, propofol, etomidate, and ketamine. Among the benzodiazepines, midazolam, when given in a dose of 0.1 mg/kg IV (up to a range of 5 to 6 mg in an adult), is ideal because its effects are rapid in onset and short in duration. The drug also offers the advantage of producing muscle relaxation and amnesia. Opioids are another class of drugs that can be used; however, many opioids, such as morphine, may prompt histamine release, with resultant hemodynamic changes. Fentanyl in a dose of 2 to 5 μg/kg is highly effective at producing rapid sedation and relaxation with minimal cardiovascular change. Several barbiturates can produce rapid sedation and relaxation. The most popular of these is sodium thiopental (dose 3 to 5 mg/kg). Equally effective but with a shorter duration of action are methohexital, propofol, and etomidate. Finally, ketamine is a dissociative anesthetic that can produce rapid onset of a state in which the patient is insensitive to pain but maintains an awake appearance and continues to have protective airway reflexes. The typical IV induction dose of ketamine is 1 to 2 mg/kg. Unlike other sedatives/


17

anesthetics, ketamine can produce significant elevations in pulse, blood pressure, intracranial pressure, and myocardial oxygen consumption, and such an increase in any of these could worsen the patient’s clinical condition. Because ketamine has a potent bronchodilating effect, it retains its important role as an induction agent in the patient with severe bronchospasm.11-13 After administration of a sedative/anesthetic, skeletal muscle relaxation is performed. Skeletal muscle relaxants, all of which interrupt acetylcholine function at the myoneural junction, are typically divided into depolarizing and nondepolarizing categories. Depolarizing agents, of which succinylcholine is the model drug, produce muscle depolarization before paralysis; this results in initial generalized muscle fasciculation. Nondepolarizing relaxants produce paralysis without initial depolarization. The nondepolarizing skeletal muscle relaxants include pancuronium, vecuronium, atracurium, and rocuronium. Succinylcholine is the most popular muscle relaxant because it has several desirable properties, including a rapid onset of action (less than 1 minute) and an extremely short duration of action. Customary paralyzing doses of succinylcholine are 1 to 2 mg/kg IV. Despite its efficacy and popularity, succinylcholine can produce several adverse effects. These include hyperkalemia, prolonged paralysis, malignant hyperthermia, and hemodynamic changes. Hyperkalemia, which can be severe, has been most commonly associated with administration of succinylcholine to those with burns, crush injuries, select neuropathies (e.g., Guillain-Barré syndrome), and myopathies (e.g., childhood muscular dystrophies). Prolonged paralysis can occur in those who have a genetic deficiency in serum cholinesterase, the enzyme that inactivates the drug. Prolonged paralysis may also occur in patients with liver disease, the elderly, and those who have ingested anticholinesterase insecticides (carbamates or organophosphates). Malignant hyperthermia is a syndrome characterized by muscle rigidity, hyperthermia, autonomic disturbances, acidosis, rhabdomyolysis, myoglobinuria, renal failure, and coagulopathy. Occurring in genetically predisposed individuals, malignant hyperthermia may appear without warning in those who are given inhalation anesthetics or succinylcholine. The mortality rate associated with this syndrome is approximately 5% to 10%. A malignant hyperthermia-like picture can also occur in children with skeletal muscular disorders (e.g., muscular dystrophy) who are given succinylcholine. Finally, succinylcholineinduced muscle depolarization can lead to transient increases in intracranial and intra-abdominal pressure, with accompanying changes in cardiac output.14 Because of these potential adverse effects, nondepolarizing muscle relaxants are often recommended as adjuncts to or substitutes for succinylcholine use. As adjuncts, nondepolarizing agents, when given before succinylcholine, can prevent muscle fasciculation and its attendant physiologic effects. The so-called “defasciculating dose” of a nondepolarizing agent is approximately one tenth the full dose of that agent. For example, pancuronium can be given in a dose of 0.01 mg/kg IV before the

18


administration of succinylcholine to prevent fasciculation. Nondepolarizing agents can also be used solely for skeletal muscle relaxation. However, they generally have a much slower onset of action (as long as 3 to 5 minutes) and produce a longer duration of paralysis. Also, many nondepolarizing agents stimulate histamine release, producing significant hemodynamic changes. Therefore, they are not ideal agents for RSI. Rocuronium appears to have the most rapid onset of all nondepolarizing agents, approaching that of succinylcholine with regard to time to complete muscle relaxation in the less than ideal conditions generally found during emergency intubation.15 Significant warnings to succinylcholine use in the pediatric population have been recently added, based on the possibility of life-threatening cardiac arrhythmias. According to these new warnings, children with undiagnosed myopathies (e.g., a muscular dystrophy) could develop hyperkalemia sufficient to produce a cardiac disturbance.16 Intubation Suction must be immediately available when intubation is performed. The patient undergoing emergency intubation often has a full stomach; the risk for vomiting and aspiration is therefore significant. This risk is minimized both by the RSI technique and by the direct application of pressure on the cricoid cartilage (Sellick’s maneuver), which occludes the esophagus. Adequate preoxygenation and limiting the duration of the intubation attempt to less than 20 to 30 seconds should prevent significant hypoxia. The differences between the airway of the child and that of the adult have important implications for endotracheal intubation. 1. The child has a relatively large tongue; this makes direct visualization of the larynx difficult. 2. The child has larger tonsils, which also obscure visualization. 3. The infant’s larynx is located more cephalad than that of the adult. As a result, the angle between the tongue and the glottis is more acute, and visualization of the larynx is impaired. 4. The subglottic area of the infant is the narrowest part of the larynx and may impede the passage of an endotracheal tube passed through the vocal cords. Postintubation Management Immediately after successful endotracheal intubation, placement of the endotracheal tube must be confirmed by detection of bilateral equal breath sounds on chest auscultation, end-tidal carbon dioxide monitoring, or chest radiography; of these, chest auscultation is the least sensitive method and should never be used in isolation to confirm endotracheal tube placement. After confirmation, the tube should be secured either with a strap or with benzoin and adhesive tape. Inflation of the endotracheal tube cuff should be performed to minimize aspiration of gastric contents (although aspiration of activated charcoal around cuffed endotracheal tubes is a

frequent occurrence). Until recently, because the airway of the young child has an area of narrowing (“physiologic cuffing”), cuffed endotracheal tubes were not used in the pediatric patient. Pediatric cuffed tubes are now available; their use is encouraged in most circumstances. If long-term intubation is necessary, sedatives/anesthetics and nondepolarizing muscle relaxants should continue to be administered. In unskilled or unprepared hands, emergency endotracheal intubation can have disastrous consequences. Even when performed by the most experienced hands, this complex procedure can have complications that should be anticipated so that they can be quickly recognized and treated. These complications include: Dental or oral cavity trauma Gagging and vomiting Hypoxia Hypercarbia Bradycardia Tachycardia Hypertension Hypotension Increased intracranial pressure Pneumomediastinum Pneumothorax Cardiac arrhythmias Myocardial ischemia or infarction Aspiration Laryngospasm Esophageal intubation Tracheal injury

Circulatory Support Poisoned patients often present to the emergency department with hypotension or frank shock. Provision of circulatory support through interventions that may include volume expansion, vasopressor therapy, antidote administration, and correction of electrolyte and acidbase disturbances is essential in initial management. Many medications and toxins produce hypotension (Box 2A-3). Depending on the ingested substance, the low blood pressure may have a number of causes. For example, blood pressure depressions may occur from direct depression of myocardial contractility (e.g., quinidine), disturbances of central nervous system cardiorespiratory centers (e.g., clonidine), severe gastrointestinal fluid losses (e.g., acetaminophen, iron, arsenic, ricin, mushrooms), peripheral vasodilation (e.g., angiotensin-converting enzyme inhibitors), or a combination of these effects (e.g., theophylline, calcium channel blockers, tricyclic antidepressants). Hypotension also can result from the secondary effects of toxins (e.g., cocaineinduced myocardial infarction). Finally, blood pressure disturbances in the poisoned patient may represent accompanying trauma (e.g., severe spinal cord injury or internal hemorrhage). With the multitude of possible causes, the clinician, on the basis of the known pathophysiology of a particular drug and after having performed a thorough physical assessment, should determine, if at

CHAPTER 2

BOX 2A-3

INTOXICATIONS COMMONLY ASSOCIATED WITH HYPOTENSION

Pharmaceuticals

α Antagonists Angiotensin-converting enzyme (ACE) inhibitors Barbiturates β Blockers Calcium-channel blockers Clonidine Digoxin Monoamine oxidase inhibitors Opioids Phenothiazines Quinidine Theophylline Tricyclic antidepressants Metals and Minerals

Arsenic Iron Envenomations

Marine (scombroid, ciguatera, coelenterates) Reptile (crotalid) Hymenoptera Chemical Weapons

Ricin

all possible, the probable cause of hypotension if he or she is to provide a specific intervention. VOLUME EXPANSION Appropriate cardiac output relies on the adequacy of intravascular volume. After poisoning, intravascular volume may decrease abruptly. This decrease can be absolute, occurring as a result of a direct loss of intravascular volume (e.g., pulmonary edema, gastrointestinal pooling), or relative, resulting from severe peripheral vasodilation (e.g., angiotensin-converting enzyme inhibitor or α-antagonist overdose). In either case, hypotension should first be treated with the administration of volumeexpanding agents.17 Many fluids are acceptable for emergency volume expansion. Normal saline and lactated Ringer’s solution are generally the most readily available isotonic agents. Adults should receive up to 500- to 1000-mL boluses of isotonic fluid while blood pressure is monitored; children should be given 10 to 40 mL/kg. After the administration of each bolus, the patient should be reassessed for improvements in cardiac output. Alternative fluids that can be used for volume expansion in the poisoned patient include albumin and whole blood. Each of these fluids has a role that is best determined by the pathophysiologic mechanism responsible for the hypotension. Being colloid rather than crystalloid in nature, these fluids in theory maintain intravascular volume better than saline solutions do. In clinical situations in which a “leaky capillary syndrome”


19

is mechanistically the source of intravascular volume loss, the use of colloid solutions may be preferred. Whole blood is most valuable in situations in which there is frank blood loss. With severe hemolysis (e.g., after arsine or stibine exposure), exchange transfusion with whole blood may be necessary. Usually, the adequacy of volume expansion is determined clinically by an increase in blood pressure. Other clinical signs of improved cardiac output include resolution of cyanosis and normalization of capillary refill time. Central venous pressure and Swan-Ganz catheter monitoring, although invasive, provide the best evidence of appropriate intravascular volume. Fluid overload is a potential complication of volume expansion. This is most likely to occur in patients who receive excess fluids over a short period of time. Also, after an overdose of a myocardial depressant such as tricyclic antidepressants or quinidine, a fluid bolus that could be tolerated by a healthy individual can produce pulmonary edema in the overdose patient. Therefore, administration of modest boluses of fluid is generally recommended; if cardiac output remains inadequate after fluids have been given, vasopressor therapy should be initiated. VASOPRESSOR THERAPY In the patient with severe hypotension, vasopressor therapy is necessary if blood pressure is not satisfactorily improved after volume expansion. Vasopressors are drugs that can be administered to maintain cardiac output. These agents have specific effects on the heart or blood vessels, augmenting myocardial function or increasing vasomotor tone, or both. With rare exception, vasopressors used in the acute management of hypotension are short-acting drugs that must be given by continuous IV infusion.17 Vasopressors generally act at adrenergic (α and β), D (dopamine), or glucagon receptors (Table 2A-4). The adrenergic system has been further defined with the recognition of two major α-adrenergic receptor subtypes (α1 and α2) and three β-adrenergic receptor subtypes (β1, β2, and β3). Coupled with intracellular G proteins, these membrane-bound receptors effect an intracellular chain of events that includes changes in the activity of adenylate cyclase. This action goes on to modulate the level of intracellular cyclic adenosine monophosphate (cAMP), which in turn alters phospholipase activity or opens gated calcium channels. Although the cellular mechanisms of this system have become much better defined, the general principles of vasopressor action remain unchanged. For example, α-adrenergic receptor agonists produce vascular smooth muscle contraction. β1-Adrenergic receptor agonists produce increased heart rate and contractility, whereas β2-adrenergic receptor agonists promote generalized smooth muscle relaxation (including bronchial and vascular). Vasopressor therapy is designed to improve cardiac output through manipulation of the specific receptor most appropriate for the clinical situation. A number of vasopressors can be used to provide blood pressure support (see Table 2A-4). The

20


TABLE 2A-4 Common Vasopressors by Dose Range and Mechanism of Action RECEPTOR TYPE AGENT Epinephrine (0.1–0.5 μg/kg/min) Low-dose Moderate-dose High-dose Norepinephrine (0.1–0.5 μg/kg/min) Dopamine (2–20 μg/kg/min) Low-dose Moderate-dose High-dose Dobutamine (2–20 μg/kg/min) Phenylephrine (0.1–0.5 μg/kg/min) Nonadrenergic agents Amrinone (5–15 μg/kg/min) Glucagon (50–150 μg/kg/hr) Calcium chloride

a-ADRENERGIC

b1-ADRENERGIC

b2-ADRENERGIC

+++ +++ ++ ++

+++ +++

+ +++ +++

DOPAMINERGIC

+++ +++ +++ + +++

+++

+

+, Mild effect; ++, moderate effect; +++, major effect.

indications for the use of these drugs vary slightly, depending on the clinical circumstance. Epinephrine Epinephrine elevates blood pressure primarily through its α-adrenergic-stimulating properties. This effect also is valuable in improving myocardial and cerebral blood flow. Because it also has prominent β-adrenergic agonist effects, epinephrine is variably effective at producing marked increases in blood pressure. Epinephrine therapy is initiated at a dose of 0.1 to 0.5 μg/kg/min. Epinephrine is particularly effective in intoxications associated with hypotension and bronchospasm (e.g., Hymenoptera envenomation and anaphylactic reactions). Norepinephrine Norepinephrine stimulates both α- and β-adrenergic receptors, with slightly greater stimulation of α-adrenergic receptors. The effect is improved vasomotor tone in conjunction with increased myocardial chronotropy and inotropy. Norepinephrine infusions are typically initiated in a dose of 0.1 to 0.5 μg/kg/min. Dopamine Dopamine is a precursor of norepinephrine. The most popular of vasopressors, dopamine appears to have at least three mechanisms of action: (1) promotion of norepinephrine synthesis, (2) a tyramine-like effect that stimulates release of preformed norepinephrine, and (3) direct stimulation of vascular dopamine receptors. The cardiovascular effects of dopamine are variable, depending on the infusion rate. At relatively low doses (1 to 2 μg/kg/min), the drug dilates renal and mesenteric vessels without marked increases in heart rate or blood pressure. At doses of 2 to 10 μg/kg/min, β-adrenergic receptor stimulation predominates, producing significant increases in cardiac output. Finally, at doses greater than 10 μg/kg/min, α-adrenergic receptor stimulation is the primary action, resulting in marked

peripheral vasoconstriction. The general dose range for dopamine infusion is 2 to 20 μg/kg/min. Dopamine is safe and effective for any type of druginduced hypotension. In the past, there have been theoretic concerns that dopamine’s β-adrenergic effect in the face of phenothiazine or tricyclic antidepressant intoxication would increase the peripheral vasodilatation associated with overdose, exacerbating hypotension. However, experimental data and clinical experience have failed to confirm this adverse effect from dopamine use. Also, with hypotension after monoamine oxidase inhibitor overdose, dopamine’s effects are somewhat unpredictable; it may be relatively ineffective (owing to the lack of preformed norepinephrine), or it can produce an exaggerated response (because of its tyramine-like action). Dobutamine Dobutamine is a synthetic catecholamine with almost exclusive β-adrenergic receptor-stimulating effects. Its primary mechanism of blood pressure improvement is direct myocardial inotropy; thus, reflex peripheral vasodilation may occur with its use. Unlike dopamine, dobutamine does not release preformed norepinephrine. The usual dosage range for dobutamine is 2 to 20 μg/kg/min, although doses as high as 40 μg/kg/min have been used. High-dose infusions often increase myocardial oxygen demands, which, if unmet, can result in myocardial ischemia. Nonetheless, dobutamine is extremely effective in syndromes of heart failure. Phenylephrine Phenylephrine has both α- and β-adrenergic receptorstimulating properties, although its α-adrenergic receptor actions predominate. Phenylephrine is a potent stimulator of vasomotor tone; it is therefore very effective in patients in hypotensive states resulting from severe peripheral vasodilation (e.g., following overdose with an α-adrenergic antagonist, such as prazocin or a phenothiazine neuroleptic, e.g., chlorpromazine). Phenylephrine

CHAPTER 2

infusions are given in a typical dose range of 0.1 to 0.5 μg/kg/min. Amrinone Amrinone is a novel, nonadrenergic cardiac stimulant that improves myocardial contractility while inducing vasodilation. Its mechanism of action appears to be direct inhibition of phosphodiesterase; the result of this is increased intracellular cAMP activity, an action that increases transmembrane calcium flux, potentiating cardiac chronotropy and inotropy. Amrinone’s effects have been compared with those of dobutamine and nitroprusside combination therapy. Amrinone may be particularly valuable in the treatment of calcium channel blocker intoxication; its inhibition of cAMP breakdown results in greater phosphorylation of L-type calcium channels, potentially increasing their permeability. Experimental data support its role in this specific poisoning.18 Amrinone can be used to treat syndromes of left ventricular failure but should not be administered in the presence of myocardial ischemia; like dobutamine, it may increase myocardial demands, resulting in infarction. Because of its potent vasodilating action, amrinone may cause a hypotensive response in those with low intravascular volume. The usual dosage range for this agent is 5 to 15 μg/kg/min; the total daily dose should not exceed 10 mg/kg per day. Glucagon Glucagon is a single-chain pancreatic polypeptide that is an effective inotropic and chronotropic agent. Its mechanism of action is direct stimulation of myocardial glucagon receptors; these receptors, when stimulated, increase the formation of myocardial cAMP. The resultant effect is positive inotropy and, to a lesser degree, positive chronotropy. Glucagon is theoretically most effective after β blocker overdose, in which decreased β-adrenergic receptor activation leads to diminished cAMP production. The hormone may also provide therapeutic benefit in hypotension after calcium channel blocker overdose.18 Glucagon is given in an initial dose of 1 to 10 mg (50 to 150 μg/kg in children). If effective in augmenting blood pressure, it can be given as a continuous infusion of 5 to 10 mg/hr (100 μg/kg/hr in children). Some preparations of glucagon are marketed as a lyophilized compound with a 0.2% phenol-based diluent for reconstitution. While single doses of such a product can be given after standard reconstitution, glucagon for continuous infusion should be reconstituted with saline to prevent phenol toxicity. Adverse effects from glucagon include hyperglycemia, nausea, vomiting, and ileus. Calcium Calcium plays a key role in regulating cardiac inotropy through its binding to troponin C, an action that permits interaction between actin and myosin. Although most of the calcium that produces this change resides in an intracellular calcium pool, extracellular calcium does diffuse into cells and contributes to increased contractility. Although diffusion of calcium into the myocardium is “gated”—that is, it is tightly controlled—high con-


21

centrations of extracellular calcium, particularly in the face of channel blockade (e.g., after overdose of calciumchannel blockers), sometimes improve contractility. Administration of IV calcium chloride is indicated in the management of hypotension resulting from calcium channel blocker overdose (see Table 2A-1), hyperkalemia, and hypocalcemia.

Clinical Evaluation A thorough history taking and physical examination are essential to the diagnosis of the toxic patient. Poisoning should be suspected in any patient who presents with multisystem disturbance until proven otherwise. Although the initial manifestations of poisoning are myriad, a patient with acute poisoning often presents with coma, cardiac arrhythmia, seizures, metabolic acidosis, or gastrointestinal disturbance, either together as symptom complexes or as isolated events. Symptom complexes, or toxidromes (Table 2A-5), may give clues to an unknown poisoning. For example, a patient with a history of depression who presents with coma, seizures, a widened QRS complex or evidence of dysrhythmia on electrocardiography, and dilated pupils has likely taken a tricyclic antidepressant. Hepatic, renal, respiratory, and hematologic disturbances are generally delayed manifestations of poisoning. The clinical evaluation, in addition to the history taking and physical examination, includes an assessment of major signs of toxicity presented by the patient and evaluation of the laboratory data. HISTORY When one suspects poisoning or drug overdose, the primary goal of history taking is identification of the toxic agent. Sometimes diagnosis is easy, as in the case of the toddler who ingests iron tablets in the mother’s presence. Sometimes it is difficult, as in the case of the patient who is hiding a history of drug abuse and passes out at work or who has an unexpected seizure. Prior medical or psychiatric history, current medications, and allergies should be obtained from family or friends if the patient is unable to relate the information. The following questions may be revealing: What other medicines are in the house? What was the patient doing that day? Does the patient live alone, did he or she just lose a job, or have there been recent emotionally traumatic events? Is the patient eating a special diet or taking a new health food, alternative medication, or performance enhancer? Could the patient inadvertently have taken too much of a prescribed medication? If it can be identified, is the substance nontoxic? (See Box 2A-4.) PHYSICAL EXAMINATION The physical examination can help in determining the extent of poisoning and may reveal the presence of a

22


TABLE 2A-5 Examples of Symptom Complexes, or Toxidromes TOXIDROME OR COMPLEX

CONSCIOUSNESS

Cholinergic

Coma

Anticholinergic

POSSIBLE TOXIC AGENT/MECHANISM

PUPILS

OTHER

↑↓

Pinpoint

Agitation, hallucinations, or coma

↑

Dilated

Opioid

Coma

↓

Pinpoint

Extrapyramidal

Wakefulness

↑

—

Fasciculations Incontinence Salivation Wheezing Lacrimation Bradycardia Fever, flushing Dry skin and mucous membranes Urinary retention Track marks Hypothermia Hypotension Torsion of head/neck

Tricyclic antidepressant Coma (initially, agitation)

↓

Dilated

Sedative/hypnotic

Coma

↓

Salicylates

Agitation or lethargy

↑

Sympathomimetic

Agitation, hallucinations

↑

BOX 2A-4

RESPIRATIONS

Cardiac arrhythmia Convulsions Hypotension Prolonged QRS interval Midsize or Hypothermia small Decreased reflexes Hypotension Midsize or Diaphoresis small Tinnitus Alkalosis (early) Acidosis (late) Dilated Seizures Tachycardia Hypertension Diaphoresis Metabolic acidosis Tremor Hyperreflexia

Organophosphate insecticides, carbamates, nicotine

Anticholinergics (atropine, Jimson weed, antihistamines) Opiates, opioids Phenothiazines, haloperidol risperidol Tricyclic antidepressants

Sedatives, barbiturates Aspirin, oil of wintergreen

Cocaine Theophylline Amphetamines Caffeine

NONTOXIC INGESTIONS

Abrasives Adhesives Antacids Antibiotics Baby product cosmetics Ballpoint pen inks Bath oil (castor oil and perfume) Bathtub floating toys Birth control pills Bleach (> isoproterenol. β-Adrenergic receptors have the following order of potency for agonists: isoproterenol > epinephrine ≥ norepinephrine.3 The α-adrenergic receptors are responsible for the excitatory actions of norepinephrine and mediate the contraction of most smooth muscles, particularly vascular smooth muscles, resulting in vasoconstriction. An exception is the gut, where αadrenergic receptor activation relaxes smooth muscle cells. β-Adrenergic receptor activation increases the rate and contractility of the heart, relaxes smooth muscles in the bronchioles and the uterus, and causes vasodilation. α-Adrenoceptors are divided into two types, α1 and α2 receptors. In peripheral tissues, α1 adrenoceptors are located on the postsynaptic membrane, whereas α2 adrenoceptors are located on both presynaptic and postsynaptic membranes. Stimulation of postsynaptic α receptors (α1 and α2) results in vasoconstriction. Stimulation of presynaptic α2 autoreceptors, however, decreases norepinephrine release. Stimulation of postsynaptic α2 adrenoceptors in the brainstem inhibits sympathetic nervous system output and results in sedation. β Adrenoceptors are divided into three types, β1, β2, and β3 receptors. Peripheral β1 receptors are found predominantly in the myocardium. Epinephrine and norepinephrine are equivalent in potency as agonists at this receptor. Peripheral β2 receptors are found on smooth muscle, the myocardium, and numerous other tissues. Epinephrine is 10- to 50-fold more potent at β2 receptors than norepinephrine.2,3 When present, presynaptic β2-adrenergic receptors facilitate the release of norepinephrine from sympathetic nerves. β3Adrenergic receptors are found in fat, skeletal muscle, and other peripheral tissues. Norepinephrine is 10-fold more potent at the β3 receptor compared with epinephrine.2 The physiologic role of this receptor is not fully known. Five subtypes of the dopamine receptor have been identified. The D1 and D5 receptors are coupled to stimulation of adenylate cyclase. D2, D3, and D4 receptors have an opposing effect on adenylate cyclase.14 In the brain, the principal functions mediated by dopamine are the control of movements of behavior, including motivation, cognitive function, and emotion. Newer antipsychotic agents target D2 receptors, and the evidence suggests that patients experience fewer extrapyramidal side effects (see Chapter 38).15 In the pituitary gland, dopamine controls the release of prolactin and α-melanocyte–stimulating hormone. In the cardiovascular system, it is important in the regulation of blood pressure. Dopamine receptors have therefore been identified functionally in tissues related to these effects (e.g., pituitary gland and certain blood vessels). The antihypertensive effects of fenoldopam are mediated by D1 receptor activation in the kidney.16 The largest concentrations of dopamine receptors, however, are in the basal ganglia and the limbic system.

Clinical Neurotoxicology

195

Numerous drugs affect catecholamine neurotransmission. Tyrosine analogues such as metyrosine (α-methyl-p-tyrosine) impair the synthesis of dopamine and norepinephrine by blocking the enzyme tyrosine hydroxylase. Disulfiram and diethyldithiocarbamate inhibit dopamine β-hydroxylase and can produce sympatholytic effects by interfering with the production of norepinephrine from dopamine. Reserpine and tetrabenazine inhibit the uptake of dopamine and other catecholamines into vesicles, causing depletion of endogenous neuronal catecholamines. α-Methyldopa causes dopamine depletion by replacement of dopamine with a relatively inactive false transmitter, α-methyldopamine; this causes hypotension and sedation. Other false neurotransmitters include metaraminol and octopamine. Peripheral presynaptic antiadrenergic drugs such as guanethidine and bretylium inhibit norepinephrine release from the presynaptic terminal by depleting the nerve endings of noradrenaline. The neurotoxin 6hydroxydopamine is taken up by an active uptake mechanism and accumulates in catecholaminecontaining neurons, destroying them through the autooxidative liberation of hydrogen peroxide or from formation of a quinone. Indirect-acting agents are agonists or sympathomimetics that cause release of cytoplasmic norepinephrine in the absence of adrenergic receptor binding and presynaptic vesicle exocytosis. These drugs enter the presynaptic terminals and displace stores of norepinephrine from storage vesicles (e.g., amphetamine and tyramine) or inhibit reuptake of catecholamine already released (e.g., cocaine and tricyclic antidepressants) (Box 10-3).3 Indirect agents typically bind to the amine transport proteins (uptake-1 system) and interfere with uptake of endogenous catecholamines while facilitating reverse transport of cytoplasmic catecholamines into the synaptic cleft.2 Indirect agents exhibit tachyphylaxis—that is, their effects diminish on repeated administration as the catecholamine pools become depleted. Tricyclic antidepressants principally interfere with norepinephrine and serotonin reuptake; dopamine reuptake is affected to a lesser degree (see Chapter 27). Amphetamine also can inhibit reuptake, whereas lithium facilitates reuptake. The MAO inhibitors block metabolism of biogenic amines (norepinephrine, serotonin, dopamine), increasing the synaptic concentration of these neurotransmitters (see Chapter 29). MAO inhibitors also act as indirect agents. Direct-acting agents are agonists that produce their sympathomimetic effects by direct binding to and activation of α- or β-adrenergic receptors (e.g., norepinephrine, epinephrine, and isoproterenol) (see Box 10-3).3 Mixedacting agents (e.g., phenylpropanolamine, dopamine, and pseudoephedrine) produce sympathomimetic effects both directly and indirectly. For instance, phenylpropanolamine (PPA) is a direct agonist on αadrenergic receptors but also acts indirectly to promote release of norepinephrine from sympathetic nerve terminals. The toxicity of PPA is characterized by hypertension and a reflex bradycardia. Ingestion of α2adrenergic agonists such as clonidine or other imidazolines (e.g., oxymetazoline and tetrahydrozoline) may

196

BOX 10-3

EFFECTS OF POISONING BY ORGAN SYSTEM

SYMPATHOMIMETICS

Direct Acting

Indirect Acting

a-Adrenergic Agonists

Amphetamine MAO inhibitors Methylphenidate Pemoline Tricyclic antidepressants Tramadol Phencyclidine Phenmetrazine Tyramine Propylhexedrine

Norepinephrine Metaraminol Phenylephrine Epinephrine Midodrine Dobutamine Methoxamine Ergot alkaloids b-Adrenergic Agonists

Dobutamine Epinephrine Isoproterenol Albuterol/levalbuterol/ salbutamol Metaproterenol Pirbuterol Bitolterol Fenoterol Formoterol Salmeterol Ritodrine Ethylnorepinephrine Prenalterol Isoetharine Terbutaline Clenbuterol

Mixed Acting

Dopamine Ephedrine Phenylpropanolamine Pseudoephedrine Cocaine Mephentermine

MAO, monoamine oxidase. Data from Kandel ER, Schwartz JH, Jessel TM (eds): Principles of Neural Science, 3rd ed. New York, Elsevier Science, 1991; and Hoffman TT, Taylor P: Neurotransmission: the autonomic and somatic motor nervous systems. In Hardman JG, Limbird LE, Gilman AG (eds); Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 115-153.

produce a mixed clinical picture; stimulation of central α2-adrenergic receptors in the brain decreases central sympathetic outflow, whereas stimulation of peripheral α1-adrenergic receptors results in vasoconstriction and transient hypertension (see Chapter 62). Peripheral postsynaptic α-adrenergic antagonists (e.g., phenoxybenzamine, phentolamine, prazosin, hydralazine, and minoxidil) compete with endogenous catecholamines for binding to α1- and α2-adrenergic receptors. The α-adrenergic receptors (primarily α1) also are blocked by tricyclic antidepressants (e.g., amitriptyline and imipramine), certain antipsychotic agents (e.g., phenothiazines, clozapine, and risperidone), antiarrhythmic agents (e.g., quinidine), and certain β blockers (e.g., labetalol and carvedilol). β Blockers primarily antagonize the effects of catecholamines at β-adrenergic receptors (see Chapter 60). β-Blocking drugs occupy β-adrenergic receptors and competitively block receptor occupancy by catecholamines and other β-adrenergic agonists. Most β-blocking drugs are pure antagonists; however, a few are partial agonists (e.g., pindolol and acebutolol) and may produce intrinsic sympathomimetic activity.

Similar to sympathomimetics, dopamine agonists can be direct, indirect, or mixed. Direct agonists bind to and activate various dopamine receptors directly, whereas indirect agents block dopamine uptake and/or stimulate presynaptic dopamine release. Direct dopamine receptor agonists include apomorphine, bromocriptine, fenoldopam, and pergolide. Indirect agonists include agents that cause dopamine release (e.g., benztropine, diphenhydramine, orphenadrine) and those that block dopamine reuptake (e.g., cocaine, amphetamines, methylphenidate, amantadine, benztropine, bupropion, diphenhydramine, and pemoline). Dopamine antagonists include specific receptor antagonists (e.g., antipsychotics, buspirone, metoclopramide, and amoxapine), agents that block synthesis (e.g., metyrosine), agents that prevent vesicle storage (e.g., reserpine and tetrabenazine) or cause dopamine depletion (e.g., α-methyldopa), or agents that destroy dopaminergic neurons (e.g., 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP).2 Sympathomimetic toxicity often leads to CNS and cardiovascular complications. Cocaine (see Chapter 42) and amphetamines (see Chapter 44) produce their clinical effects predominantly from reuptake blockade and enhanced presynaptic release of catecholamines (e.g., norepinephrine and dopamine), serotonin, acetylcholine, and excitatory amino acids (e.g., aspartate and glutamate) from central and peripheral nerve terminals. Amphetamine and cocaine toxicity often includes psychostimulatory (e.g., euphoria, restlessness, excessive speech and motor activity, tremor, and insomnia) and sympathomimetic (e.g., tachycardia, hypertension, hyperthermia, and diaphoresis) effects. Intracerebral and subarachnoid hemorrhage may occur as a result of malignant hypertension and cerebral vasculitis. The actions of pemoline and methylphenidate are similar to those of amphetamine. Many of the phenylamphetamines and amphetamines may produce hallucinations. 5-Methoxy-3,4-methylenedioxyamphetamine (MMDA) can be formed in vivo from myristicin, present in the dried seeds of the nutmeg tree (Myristica fragrans) and can produce psychomimetic effects when consumed in large amounts. Mescaline is an alkaloid component of the peyote cactus and produces psychotomimetic activity by its amphetamine-like actions (see Chapter 45). Cathinone, cathine, and methcathinone, related natural alkaloids found in the leaves and stems of Catha edulis, or khat, produces effects indistinguishable from those of amphetamines. Ephedrine is both an α- and β-adrenergic agonist; in addition, it enhances release of norepinephrine from sympathetic neurons. It is a naturally occurring drug found in various species of the plant Ephedra (ma huang), indigenous to China. Blockade of the nigrostriatal dopamine receptors (primarily D2 receptors) produces extrapyramidal symptoms such as parkinsonism, akathisia, and dystonia (see Chapter 38). Cholinergic input to the caudate and putamen appears to be unaffected, with resultant cholinergic excess. Neuroleptics and drugs such as metoclopramide cause parkinsonism through such a mechanism. Chronic manganese poisoning damages the

CHAPTER 10

globus pallidus, leading to permanent neurologic damage.17 “Manganese madness” is characterized by emotional lability, hallucinations, irritability, and aggressiveness (see Chapter 75). Carbon disulfide, a volatile, lipid-soluble industrial solvent, and carbon monoxide inhalation produce parkinsonian features owing to damage to the globus pallidus. Although acute carbon monoxide poisoning has a high mortality, a delayed extrapyramidal syndrome can develop in those who recover from the acute effects. Carbon monoxide produces symmetric necrosis of the globus pallidus with demyelination of the subcortical white matter.18 Methanol poisoning produces optic atrophy and lowdensity lesions on computed tomography in the region of the putamen, and putaminal necrosis has been confirmed histologically.19 A plant and fungal neurotoxin, 3-nitropropionic acid, found in mildewed sugar cane, is a succinate dehydrogenase inhibitor that produces basal ganglion injury.20 In 1983, some intravenous drug abusers injected MPTP, a compound produced during illicit synthesis of a narcotic related to meperidine.21 MPTP selectively destroys dopaminergic neurons in the substantia nigra, producing a condition indistinguishable from idiopathic Parkinson’s disease. Treatment of these side effects attempts to re-establish the dopamine/acetylcholine balance required for smooth motor movements. A central hyperexcitation syndrome with fever, delirium, and hypertension occurs when MAO inhibitors such as phenelzine, isocarboxazid, or tranylcypromine are coadministered with phenothiazines, tricyclic antidepressants, serotonergic reuptake inhibitors, and sympathomimetic amines (amphetamine, methamphetamine, ephedrine, phenylpropanolamine) (see Chapters 10A and 29). Sympathomimetic amines commonly are found in some nasal sprays, nose drops, and over-thecounter cold preparations. MAO in the gastrointestinal tract and liver prevents access to the general circulation of ingested, indirectly acting agents such as tyramine and phenylethylamine, contained in foods such as aged cheese, yeast, chicken liver, and pickled herring. However, individuals taking MAO inhibitors do not have this protection and can suffer severe hypertensive crises after eating a large amount of tyramine-containing food. An exaggerated response to the usual dose of meperidine also has been observed. Neuroleptic malignant syndrome (NMS) is an uncommon but life-threatening disorder that occurs in those who are sensitive to the extrapyramidal effects of antipsychotics (see Chapters 10A and 38). However, it is important to consider the diagnosis of NMS in any patient who has recently received medications that affect CNS dopaminergic pathways. Lithium, carbamazepine, and cocaine may predispose patients to the development of NMS. The syndrome may begin from a few days to a few weeks after initiation or alteration of neuroleptic drug therapy. NMS is thought to be mediated by a reduction in D2 dopaminergic activity in certain areas of the CNS (e.g., basal ganglia and hypothalamus).22 Rigidity, catatonia, and fluctuating consciousness associated with autonomic hyperactivity, including


197

hyperpyrexia, and elevated serum creatinine kinase concentrations are typical features of NMS.

The Serotonergic System Serotonin (5-HT or 5-hydroxytryptamine) is an indolealkylamine that functions as a neurotransmitter in the CNS. 5-HT also is present in many cells outside the CNS. Peripherally, 5-HT has a major role in gastrointestinal motility and is involved in platelet aggregation. 5-HT does not cross the blood-brain barrier; thus, neurons must synthesize their own transmitters. L-Tryptophan readily crosses the bloodbrain barrier and is taken up into serotonergic nerve terminals via an active transport process. Hydroxylation to 5-hydroxytryptophan (5-HTP) occurs by the enzyme tryptophan hydroxylase and the cofactor tetrahydrobiopterin. This is the rate-limiting step, because the enzyme tryptophan hydroxylase is not saturated under normal conditions. Diets high in L-tryptophan can result in increased synthesis of 5-HT in the CNS. The 5-HTP is decarboxylated by the nonspecific aromatic L-amino acid 5-HTP decarboxylase to 5-HT. The mechanism of sequestration of 5-HT in storage granules is similar to that of catecholamines. 5-HT is then packaged into storage vesicles that protect it from cytosolic degradation by MAO. It is released by an exocytotic mechanism and acts on both presynaptic and postsynaptic receptors. Serotonergic transmission is terminated primarily by reuptake of the amine by a specific 5-HT transporter. After reuptake, the free indolamine is either repackaged or metabolized by MAO and aldehyde dehydrogenase to 5-hydroxyindoleacetic acid. Several serotonin receptors have been cloned and are identified as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7. All 5-HT receptors interact with G proteins except 5-HT3 receptors; the latter are transmitter-gated ion channels. Within the 5-HT1 group there are subtypes 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F. There are three 5-HT2 subtypes, 5-HT2A, 5-HT2B, and 5-HT2C, and two 5-HT5 subtypes, 5-HT5A and 5-HT5B. Some serotonin receptors are presynaptic and others are postsynaptic. Serotonin is involved in feeding, control of sleep and wakefulness, sexual behavior, mood and emotion, thermoregulation, circadian rhythmicity, drug-induced hallucinatory states, and neuroendocrine function in the CNS. It also serves as a precursor for the pineal hormone melatonin. Drugs that alter serotonin neurotransmission may have a wide array of clinical effects; the effects largely depend on the specific body area and serotonin receptor subtype affected. Inhibition of 5-HT uptake has both an antidepressant and anxiolytic effect. Serotonin reuptake is blocked by some of the tricyclic antidepressants; however, the selective serotonin reuptake inhibitors (SSRIs), such as sertraline, fluoxetine, and venlafaxine, are more potent inhibitors of serotonin uptake than of norepinephrine and increase serotonin concentrations in the presynaptic cleft. Trazodone and nefazodone are weak cyclic antidepressants that weakly block 5-HT reuptake and antagonize 5-HT2 receptors. The antidepressant effects

198


of MAO inhibitors are partly mediated by their prevention of 5-HT catabolism. Buspirone represents a new class of antianxiety agent whose anxiolytic action is related to agonism at the 5-HT1A receptor in the brain. 3,4-Methylenedioxyamphetamine (MDMA [“Ecstasy”]), an amphetamine derivative, produces clinical effects primarily by causing the release of serotonin and blocking its reuptake. Other amphetamines and cocaine also promote 5-HT neuronal release and block reuptake. Certain opioids (e.g., dextromethorphan, meperidine) and psychotropics (e.g., amoxapine, tramadol) also inhibit 5-HT reuptake to produce effects. Partial agonist activity at 5-HT2A receptors mediates the psychedelic effects of central hallucinogens of the indoleamine (e.g., lysergic acid diethylamide [LSD] and psilocybin) and phenylethylamine (e.g., mescaline) class (see Chapter 45). LSD also has agonistic activity at 5HT1A and 5-HT1C receptors. Lysergic acid, which is an agonist at many 5-HT receptors, is found in the seeds of several species of the morning glory family (Rivea corymbosa, Ipomoea violacea) and is produced by the fungus Claviceps purpurea, which grows on grain. The hallucinogenic mushrooms of the Psilocybe genus contain the thermostabile indole-alkylamine psilocybin and its dephosphorylated congener, psilocin. These substances are structurally related to serotonin and are about 100 times less potent than LSD. Bufotenin is the hallucinogenic indole derivative similar to serotonin found in cohoba snuff and in the skin and parotid glands of the toad Bufo marinus. Recently, new drugs of abuse have surfaced. 5-MeO-DIPT or “Foxy Methoxy” and alphamethyltryptamine or AMT have similar hallucinogenic effects as psilocybin and are being seen at clubs in large metropolitan areas.23 Metoclopramide and cisapride are 5-HT4 receptor agonists that stimulate gut motility.24 Tryptophan hydroxylase can be blocked by pchlorophenylalanine, thus decreasing the concentration of 5-HT. Drugs such as reserpine that disrupt the storage of catecholamines also impair the storage of 5-HT. Atypical neuroleptics (e.g., risperidone, clozapine), in contrast with conventional agents, strongly block serotonin 5-HT2 receptors in the frontal cortex and striatal system in addition to their antagonism of adrenergic and dopamine receptors; antagonism at 5-HT2A receptors produces independent antipsychotic effects and decreases the risk for developing extrapyramidal movement disorders (see Chapter 38). A new antipsychotic, aripiprazole, has partial agonist activity at both 5-HT1A and 5-HT2A receptors. Mirtazapine is an antidepressant that has numerous receptor effects; part of its activity is mediated by antagonism at 5-HT2 and 5HT3 receptors. The antiemetic effects of ondansetron, granisetron, and metoclopramide are mediated through 5-HT3 receptor antagonism, and agonists at 5-HT1D and 5-HT1B receptors such as sumatriptan are effective in treating migraine headaches.24 Ergot alkaloids are nonspecific, partial 5-HT receptor agonists/antagonists. For instance, dihydroergotamine is thought to produce its antimigraine effects via agonist activity at 5-HT1B and 5-HT1D activity.24 Methysergide produces its effects from 5-HT1 and 5-HT2 receptor antagonism. Like methysergide,

cyproheptadine also is an antagonist at 5-HT1 and 5-HT2 receptors. Concurrent use of two or more serotonergic drugs may result in a marked increase of serotonin in the synapses and may produce the “serotonin syndrome” (see Chapters 10A and 29).25 This important pharmacodynamic interaction has been commonly reported when fluoxetine or one of the SSRIs is used in the presence of an MAO inhibitor. Moreover, other combinations seem just as capable of producing this syndrome. The SSRIs have been implicated in combination with tryptophan, dextromethorphan, and lithium.

Opioids The term opiate was used originally to designate narcotic drugs derived from opium—that is, morphine and codeine and their many semisynthetic derivatives prepared from the seed capsules of the poppy Papaver somniferum (see Chapter 33). Later, the term opioid was coined to refer in a generic sense to all drugs, natural and synthetic, that have morphine-related actions, as well as to the endogenous peptides (e.g., dynorphin A, endorphin, enkephalin) later discovered to have such actions. Opioid receptors differ in their regional distribution in the CNS.26 The opioids induce their biologic effects by interacting with three major classes of receptors, the δ, κ, and μ receptors. More recently an “orphan” receptor has been identified and named ORL (opioid receptor-like) because of a high degree of homology to the “classical” opioid receptors. The σ receptor, however, is no longer regarded as an opioid receptor. Morphine and β-endorphin are potent μ receptor agonists, whereas the enkephalins are less potent. μ Receptors mediate supraspinal analgesia, respiratory depression, miosis, euphoria, and physical dependence. Most of the clinically used opiates such as morphine, methadone, and codeine selectively interact with the μ opioid receptor. Naloxone and naltrexone are more potent antagonists at μ receptors than at δ or κ receptors. The κ receptor mediates spinal analgesia and sedation but not respiratory depression. Agonists at the κ receptor are less addictive and do not produce respiratory depression as severely as do μ agonists. Tramadol is a centrally-acting, partial μ-opioid receptor agonist that is structurally similar to morphine. It also inhibits the uptake of norepinephrine and 5-HT, which suggests that its antinociceptive property is mediated by both opioid and nonopioid mechanisms. The opioid receptors work by activation of G proteins, subsequent inhibition of adenyl cyclase, and activation of receptor-operated potassium channels or suppression of receptor-operated calcium channels.27 Binding to the μ and δ receptors leads to opening of the potassium channel, whereas binding to κ sites results in closing of calcium channels. As a result, membrane hyperpolarization and neuronal suppression occurs. Opioid receptors function primarily by exerting inhibitory modulation of synaptic transmission in both the CNS

CHAPTER 10

and the myenteric plexus. Often they are found on presynaptic nerve terminals, where their action results in decreased release of excitatory neurotransmitters. All three major receptor sites are involved in pain modulation. δ Receptors have been implicated in cardiovascular effects, whereas κ receptors seem to have a role in salt and water balance. Both μ and δ receptors mediate the decreased gastrointestinal motility effects observed with opioids. A given opioid drug may interact to a variable extent with all three types of receptors and can act as an agonist, a partial agonist, or an antagonist at each. Opiates and opioids in overdose cause sedation and respiratory depression. Death usually is due to respiratory failure, generally as a result of apnea or pulmonary aspiration. The respiratory depression is complicated by bradycardia and hypotension. Pinpoint pupils usually are considered to be the classic sign of narcotic poisoning. Miosis is the result of μ and κ receptor activation, which results in an excitatory action on the parasympathetic nerve innervating the pupil. Normeperidine, the metabolite of meperidine, a synthetic opioid structurally different from morphine, is known to produce seizures on multiple dosing.28 The neurotoxicity of normeperidine is manifested by signs of CNS stimulation that include tremors, twitching, myoclonus, and seizures. Treatment consists of administering benzodiazepines to reduce CNS excitation. Naloxone is contraindicated because it may increase the incidence of seizures. Propoxyphene causes delusions, hallucinations, and seizures, often with naloxone-resistant cardiodepression. Opioid-associated depression of respiration and mental status can be reversed by administration of opioid antagonists. Most opioid antagonists compete for binding with agonists at the μ receptor and reverse the effects of endogenous or exogenous ligands by eliciting no postreceptor activity. Opioid receptor antagonists have variable potency and clinical half-lives; the dose administered also determines the duration of antagonist effects.27 The half-life of naloxone is shorter than that of most opioids, and patients may again manifest signs of toxicity after the effect of naloxone wears off. Nalmefene is a new injectable methylene analogue of naltrexone with a half-life of about 11 hours, which is much longer than naloxone’s half-life of 1 to 2 hours. Naltrexone is an opioid receptor antagonist with effects that last up to 48 hours after oral dosing.27 Numerous synthetic agents have been developed that are partial agonist/antagonists (e.g., buprenorphine, pentazocine, butorphanol, meptazinol, and nalbuphine). Opioid reversal in opioid-dependent patients poses a risk of precipitating withdrawal symptoms. Reversal and withdrawal symptoms can be produced following the administration of either a pure antagonist or partial agonist/antagonist to the opiateaddicted or intoxicated patient.

The Cholinergic System Acetylcholine is a neurotransmitter distributed throughout the CNS and peripheral nervous system (PNS). In the PNS, acetylcholine is found in somatic motor nerves,


199

autonomic ganglia, all parasympathetic postganglionic nerves, and a small number of sympathetic postganglionic nerves. In the PNS, the action of acetylcholine is responsible for mediating parasympathetic nerve stimulation. The enzyme choline acetyltransferase catalyzes the acetylation of choline by acetyl coenzyme A to form acetylcholine in the motor nerve terminals. Acetylcholine is sequestered in synaptic vesicles and is released when extracellular calcium enters the neuron after depolarization. The released acetylcholine diffuses through the synaptic cleft to interact with the cholinergic receptor. The action of acetylcholine is terminated by hydrolysis by acetylcholinesterase, which is present in high concentrations in the synapse. Metabolism produces acetate and choline, and the breakdown products are used for resynthesis of acetylcholine. The enzyme acetylcholinesterase is widely distributed throughout the body in both neuronal and non-neuronal tissues. It is known as true or specific cholinesterase, unlike pseudocholinesterase, which is made primarily in the liver and appears in plasma. It has a lower affinity for acetylcholine and metabolizes some drugs, including cocaine and succinylcholine. Nicotinic and muscarinic receptors are the two major cholinergic receptors that mediate the effects of acetylcholine. Both nicotinic and muscarinic receptors are present in the brain, and their properties are similar to those of peripheral receptors. Five muscarinic receptors, glycoproteins designated M1 through M5, have been molecularly cloned and described. Many drugs with actions at peripheral cholinergic receptors are without central effects because they do not cross the blood-brain barrier. Peripheral nicotinic receptors are found in autonomic ganglia (postsynaptic neurons of both sympathetic and parasympathetic neurons) and the neuromuscular junction of skeletal muscles.29 Peripheral muscarinic receptors are responsible for postganglionic parasympathetic neurotransmission; however, some sympathetic responses such as piloerection and sweating also are mediated through muscarinic receptors. Muscarinic receptors also are found in visceral smooth muscle, cardiac muscle, secretory glands, and the endothelial cells of the vasculature. The muscarinic receptors belong to the family of the G protein–coupled receptor. The postsynaptic response initiated by acetylcholine binding to muscarinic receptors is varied and depends on receptor subtype. For instance, stimulation of M1 and M3 receptors results in hydrolysis of polyphosphoinositides and release of intracellular calcium.30 In contrast, stimulation of M2 and M4 receptors is linked to adenyl cyclase inhibition and subsequent increased potassium efflux and membrane hyperpolarization. The decreased heart rate observed from vagus nerve stimulation is mediated by M2 receptors.30 Nicotinic receptors are part of a ligand-gated channel composed of five polypeptide subunits. Nicotinic neuronal receptors show ligand specificity distinct from receptors in the neuromuscular junction (NMJ). Stimulation of these nicotinic channels at the NMJ by acetylcholine results in sodium influx, membrane depolarization, and a triggered action potential. At some

200


nicotinic receptors in the PNS and CNS, calcium influx may accompany sodium influx to generate postsynaptic excitatory potentials. The cholinergic receptor agonists and the cholinesterase inhibitors comprise a large group of drugs that mimic the effects of acetylcholine. Direct cholinergic agonists are divided into esters of choline (e.g., acetylcholine and methacholine) and alkaloids (e.g., muscarine, nicotine, pilocarpine, bethanechol, and carbachol). Most cholinergic agonists bind to both muscarinic and nicotinic receptors, but a few are highly selective. Their spectrum of action depends on the receptor type stimulated—that is, muscarinic or nicotinic. The immediate peripheral clinical effects of excessive muscarinic stimulation include salivation, vomiting, diarrhea, sweating, cutaneous vasodilation, miosis, and bronchial vasoconstriction, whereas excessive nicotinic stimulation leads to muscle fasciculation, weakness, paralysis, hypertension, tachycardia, vomiting, and diarrhea (see Chapter 76). Central muscarinic agonist effects include sedation, coma, extrapyramidal movement disorders, and seizures. Central nicotinic agonist effects include seizures. Muscarinic antagonists block the actions of acetylcholine at muscarinic sites and block responses evoked by stimulation of parasympathetic nerves (see Chapter 39). At therapeutic doses, muscarinic antagonists do not bind to nicotinic receptors and neuromuscular blockers do not bind to muscarinic receptors. Ganglion blockers such as hexamethonium, mecamylamine, and trimethaphan block the action of acetylcholine and similar agonists at the nicotinic receptors of both parasympathetic and sympathetic ganglia. They are seldom used clinically. Jimson weed (Datura stramonium) and deadly nightshade (Atropa belladonna) contain the alkaloids atropine, hyoscyamine, and hyoscine. These alkaloids also are found in other plants belonging to the Solanaceae family. These alkaloids are competitive muscarinic receptor antagonists and in toxic amounts produce the anticholinergic (antimuscarinic) syndrome characterized by hot dry skin, hyperthermia, hyperactivity, confusion, delirium and hallucinations, and eventually coma, respiratory depression, and cardiovascular collapse (see Chapter 39). Neuroleptics, tricyclic antidepressants, antiparkinson drugs, and certain antihistamines, skeletal muscle relaxants, and glaucoma medications also have antimuscarinic activity, and overdoses may mimic atropine poisoning. Physostigmine is used as an antidote in anticholinergic poisoning. It is a tertiary amine compound that crosses the blood-brain barrier and acts as a reversible inhibitor of acetylcholinesterase. Direct-acting muscarinic receptor agonists such as pilocarpine and choline esters produce predictable signs of muscarinic excess when given in overdose. Amanita muscaria contains clinically insignificant amounts of muscarine, a cholinergic agonist, but mushrooms of the genera Inocybe, Clitocybe, and Omphalotus contain muscarine and usually are responsible if cholinergic symptoms dominate. Peripheral effects are recognized clinically as the “SLUDGE” phenomenon of salivation, lacrimation, urination, defecation, gastrointestinal

cramping, and emesis. All the effects are blocked by atropine and its congeners. Cholinesterase inhibitors are used as insecticides and nerve gas poisons (see Chapters 76 and 105A). Nerve agents are organophosphorus compounds that are similar to but much more potent than organophosphorus insecticides. They lead to accumulation of acetylcholine, with hyperactivity at both muscarinic and nicotinic receptors and stimulation of the CNS. Atropine blocks the action of excess acetylcholine primarily at muscarinic sites, decreasing secretions, bronchoconstriction, and intestinal motility. Oximes such as pralidoxime work by reactivating phosphorylated cholinesterase enzyme and protecting the enzyme from further inhibition. They act primarily at nicotinic sites with reversal of skeletal muscle weakness and should be used in conjunction with atropine. Pralidoxime’s action on muscarinic symptoms is less pronounced than that of atropine. However, early administration of the oximes after poisoning is essential because nerve agents binding to the active site of acetylcholinesterase undergo a rapid process of “aging” (i.e., the chemical bond between the nerve agent and acetylcholinesterase becomes progressively resistant to deactivators, starting minutes after nerve agent poisoning). An “intermediate syndrome” has been described 1 to 4 days after the acute phase of organophosphate toxicity, presenting with sudden respiratory paralysis, cranial nerve palsy, and weakness of neck flexors and proximal limb muscles, but this may be related to inadequate pralidoxime therapy.31,32 In addition, some organophosphates such as tri-ortho-cresyl phosphate cause a peripheral neuropathy associated with axonal demyelination that usually appears 2 to 3 weeks after exposure. Preceding cholinergic symptoms may be mild or even absent. These axonal effects are independent of cholinesterase inhibition and are due to inhibition of a second enzyme known as neuropathy target esterase. Acetylcholine is also the neurotransmitter found at the NMJ. A number of biologic toxins produce effects at the NMJ. Cessation of toxic exposure usually results in complete recovery. A number of toxins disrupt neuromuscular transmission by altering the release of acetylcholine or by producing receptor blockade. The heat-labile neurotoxin botulinum produced by the anaerobic bacterium Clostridium botulinum produces muscle paralysis by preventing the release of acetylcholine from nerve terminals (see Chapter 26). Venoms of snakes, such as the Mojave rattlesnake, impair neuromuscular transmission by postsynaptic receptor blockade, which may be irreversible or partially reversible, in addition to inhibiting acetylcholine release (see Chapter 21B).33 The black widow spider (Latrodectus mactans) and some species of tarantula produce a venom (α-latrotoxin) that causes presynaptic release and depletion of acetylcholine from presynaptic vesicles through both calcium dependent and calcium independent mechanisms (see Chapter 22A).34,35 Other arachnids that produce neurotoxins include ticks, funnel-web spiders, and scorpions. The funnel-web spider toxin (atraxotoxin) contains calcium channel inhibitors that can produce neuromuscular blockade. A

CHAPTER 10

toxin found in the salivary glands of pregnant North American ticks (Dermacentor andersoni and D. variabilis) causes presynaptic block of acetylcholine release but can also affect conduction in small-diameter motor and sensory axons.36 Removal of the tick often is curative, leading to complete clinical recovery. Drugs called hemicholiniums can block transmission at the neuromuscular junction by blocking the uptake of choline. Cholinesterase inhibitors such as the organophosphate compounds and carbamates inactivate acetylcholinesterase by phosphorylation, preventing acetylcholine degradation to produce a syndrome of cholinergic excess. Direct nicotinic receptor antagonists competitively block activity at the NMJ and result in weakness or muscle paralysis. NMJ blocking agents may block nicotinic receptors without activity (e.g., nondepolarizing) or may initially stimulate activity and subsequently block activity due to persistent binding (e.g., depolarizing blockade). Nondepolarizing agents include d-tubocurarine, atracurium, pancuronium, vecuronium, and rocuronium. Depolarizing blockers include succinylcholine and decamethonium. Many therapeutic drugs produce NMJ blockade by multiple presynaptic and postsynaptic actions. These agents include inhalational anesthetics (e.g., halothane, isoflurane), antibiotics (e.g., aminoglycosides, tetracyclines), magnesium salts, local anesthetics (e.g., lidocaine), corticosteroids, and calcium channel blockers.37 The sodium channel of cholinergic neurons is the target of several potent poisons. Venoms of the Centruroides genus of scorpions of Arizona and Mexico and Leiurus quinquestriatus are neurotoxic (see Chapter 22B). They affect sodium channels with resultant prolongation of action potentials as well a spontaneous depolarization of nerves of both the adrenergic and parasympathetic nervous systems. Tetrodotoxin found in the puffer fish species, suborder Tetraodontoidea, selectively blocks fast sodium channels in nerves and muscle membranes (see Chapter 25). It is found in fish (Echinodermata), the California newt (Taricha), blueringed octopus (Hapalochlaena maculosa), frogs (Atelopus), and marine bacteria. Tetrodotoxin relaxes vascular smooth muscle and blocks preganglionic cholinergic motor, sensory, and sympathetic neurotransmission. Saxitoxin, produced by the dinoflagellate Protogonyaulax catenella and by some bacteria, is found in planktoneating shellfish (clams, oysters, mussels, scallops) and has an action similar to that of tetrodotoxin. Ciguatoxin, a toxin elaborated by the dinoflagellate Gambierdiscus toxicus, enhances quantal acetylcholine release at the neuromuscular junction by prolonging the duration of sodium channel opening. Batrachotoxin, found in the skin of a South American frog (Phyllobates aurotaenia), and the plant alkaloids aconitine and veratridine prevent closure or inactivation of voltage-dependent sodium channels. A second important class of sodium channel blockers includes local anesthetics such as lidocaine and related antiarrhythmic agents. This quinidine-like membrane-stabilizing effect is shared with the tricyclic antidepressants and is responsible for the cardiotoxicity. Potassium channel blockers such as 4-aminopyridine are convulsants, and polypeptide toxins from scorpion


201

(charybdotoxin), bee (apamin), or snake (dendrotoxin) venoms also interfere with potassium channel activity.

The Histaminergic System The histaminergic system functions in the regulation of arousal, body temperature, locomotor activity, analgesia, regulation of biologic rhythms, feeding, drinking, and vascular dynamics.38 Many of the psychotropic drugs interact with histamine receptors. Histamine in the brain is formed from L-histidine by decarboxylation by histidine and L-amino acid decarboxylase. Unlike with the monoamines and amino acid transmitters, there does not appear to be an active reuptake process for histamine after its release. Histamine is metabolically inactivated by histamine methyltransferase. Histamine receptors are divided into four subtypes, H1, H2, H3, and H4, and belong to the family of G protein-coupled receptors. H1 receptor agonism leads to activation of phospholipase C, formation of diacylglycerol and inositol-1,4,5-triphosphate and subsequent activation of protein kinases, phospholipase A2, and release of intracellular calcium.39 H1 receptors are found in the smooth muscle of the intestines, bronchi, and blood vessels. H1 receptor activation results in smooth muscle contraction in these organ systems. H2 receptor agonism leads to activation of adenyl cyclase, increased cAMP, and activation of protein kinases.39 H2 receptors are found in gastric parietal cells and in the vascular system and CNS. H2 receptor activation leads to gastric acid secretion and vascular smooth muscle relaxation. Activation of H1 receptors on vascular endothelial cells also results in vascular smooth muscle relaxation (vasodilation). Activation of H1 receptors on vascular endothelial cells leads to local production of nitric oxide or endothelial-derived relaxing factor and prostacyclin (PGI2), both potent mediators of vasodilation.39 H3 receptors are found in the brain and the periphery and regulate histamine release. Recent evidence suggests that the H3 receptor regulates the release of several important neurotransmitters (e.g., acetylcholine, dopamine, GABA, norepinephrine, serotonin), in both the PNS and CNS. The H4 receptor is highly expressed in peripheral blood leukocytes and intestinal tissue. Antihistamines (see Chapter 39) are related structurally to histamine and competitively antagonize the effects of histamine on H1 and H2 receptor sites. H1 receptor antagonists block the bronchoconstrictive, large vessel vasoconstrictive, small vessel vasodilatory, enhanced gut motility, and increased permeability effects of histamine. H2 receptor antagonists block gastric acid secretory and vasodilatory effects of histamine. Many first-generation H1 receptor antagonists (e.g., diphenhydramine and pyrilamine) also possess anticholinergic effects, and the major signs of acute overdose are similar to those caused by classic antimuscarinic agents and are treated accordingly. They also may stimulate or depress the CNS, and some agents such as diphenhydramine possess local anesthetic and membrane-depressant effects when they are taken in large doses.

202


The Glutaminergic System Amino acids found in the brain can function as neurotransmitters and be either excitatory or inhibitory. Glutamic acid and aspartic acid are excitatory, and the main inhibitory transmitters are GABA and glycine. Glutamates are present in high concentration in the CNS. They do not cross the blood-brain barrier and are synthesized from glucose, glutamine, aspartate, and other precursors. The synthesis of glutamate is mediated by the enzyme glutamate dehydrogenase. Glutamate is released from nerve terminals by a calcium-dependent exocytosis mechanism similar to other neurotransmitters. Glutamate is inactivated by reuptake; several uptake transporters remove glutamate from the synaptic cleft into both neuronal and glial cells. Glutamate that is taken up into glial cells is oxidized through the Krebs cycle or converted to glutamine by the enzyme glutamine synthetase. Glutamine subsequently is released back into the synapse and then recycled back into the nerve terminal to be converted to glutamate. Glutamate is stored in vesicles for subsequent release. Receptors for glutamate have a wide distribution in the CNS and are present on neurons that receive input from other neurotransmitter systems.40 Glutamate receptors convey most of the fast excitatory neurotransmission in the CNS and act through both ligandgated ion channels (ionotropic) and G protein–coupled receptors (metabotropic). The ionotropic glutamate receptors are named after the agonists kainate, AMPA, and NMDA. The AMPA and the kainate receptor are collectively known as the non-NMDA receptor.41 The non-NMDA receptors predominantly mediate sodium influx with activation, whereas NMDA receptor activation primarily promotes calcium ion influx. These channels also allow sodium ion influx and potassium ion efflux with activation. Metabotropic glutamate (mGlu) receptors are G protein–coupled receptors that have been subdivided into three groups, based on sequence similarity, pharmacology, and intracellular signaling mechanisms. These receptors may be excitatory or inhibitory to postsynaptic membranes. When excitatory, activation of the receptor often is associated with impaired potassium ion efflux. When inhibitory, activation of the receptor often is associated with enhanced potassium ion efflux. At least five distinct sites of pharmacologic or regulatory significance have been identified on the NMDA receptor.42 There are two different agonist recognition sites for glutamate and glycine: a polyamine regulatory site that promotes receptor activation, and separate recognition sites for magnesium and zinc that act to inhibit flux through agonist-bound receptors. The NMDA receptor requires simultaneous binding of glutamate and glycine for activation.43 They are known as coagonists because neither glycine nor glutamate alone can open the channel. The glycine site on the NMDA receptor is pharmacologically distinct from the classic spinal inhibitory glycine receptor in that it is not blocked by strychnine. Polyamines such as spermine and spermidine increase the ability of glutamate and glycine

to open ion channels by binding on their modulatory sites.44 Thus, glutamate, glycine, and certain polyamines act in concert to open NMDA ion channels. Zinc and magnesium are endogenous blockers of the NMDA receptor and bind to different receptor sites. Magnesium, unlike zinc, exerts a voltage-dependent block on the open ion channel. Other voltage-dependent blockers of the NMDA receptor channels include dizocilpine (MK801), phencyclidine, ketamine, and dextrorphan. Ethanol acts as an allosteric inhibitor at the NMDA receptor, and it is suggested that the behavioral disinhibition produced by ethanol is mediated by an action on the NMDA receptor and that the ataxia, somnolence, and CNS depression are mediated through other receptors.45 Acute alcohol withdrawal is accompanied by excessive NMDA activity and is thought to explain some of the characteristic agitation, hallucinations, and convulsions.46 AMPA receptors are widely distributed in the CNS, and in the absence of other excitatory activity, AMPA receptors may mediate fast depolarizing responses at most excitatory synapses in the CNS. Kainate receptors activate neuronal membrane channels that are distinguishable from those associated with NMDA and AMPA receptors on the basis of their conductance and desensitization properties. Distinct kainate receptors are involved in some neuropathologic events mediated by excitatory amino acids in the CNS. Glutamate receptors may have a role in acute neuronal death in response to various insults to the nervous system, including anoxia, hypoglycemia, seizures, and mechanical trauma. The non-NMDA receptors also may be involved in neuropathologic processes. Glutamate receptor activation can cause seizures, and excitatory amino acid receptor antagonists may be of primary value for the treatment of epilepsy. Postischemic neuronal damage is attributed in part to overactivity of the excitatory amino acid neurotransmitter systems. Elevated extracellular glutamate levels result in glutamate receptor–mediated increase in postsynaptic intracellular calcium levels. Excitotoxicity, the “excitation to death” of neurons, results mainly from the intracellular calcium increase subsequent to overexcitation of neurons. This translocation of calcium leads to a cascade of events with formation of free radicals, activation of nitric oxide synthetase, and cell death. Nitric oxide is produced after stimulation of the enzyme nitric oxide synthetase. Nitric oxide is a novel neuronal messenger that acts with surrounding neurons, not by synaptic transmission but by diffusion between cells. In excess, nitric oxide is toxic to neurons. This toxicity is mediated largely by an interaction with the superoxide anion, presumably through the generation of the oxidant peroxynitrite. This cascade can be halted by administration of NMDA receptor antagonists.47 Studies show that NMDA antagonists are more effective in reducing penumbral damage after cerebral arterial occlusion. Chronic neurodegenerative disorders such as olivopontocerebellar atrophy and Huntington’s chorea are associated with disorders of excitatory amino acid transmission, as is amyotrophic lateral sclerosis. The role that NMDA receptors play in ischemic and nonischemic

CHAPTER 10

neurotoxicity is not completely understood and under investigation. Domoic acid was identified as the toxin in a major outbreak of food poisoning in Canada in 1987.48 The alga Nitzschia pungens was found to be the source of the toxin, which contaminated blue mussels. Domoic acid is a glutamate analogue and produces neurotoxicity by overstimulation of the glutaminergic system. Dietary consumption of the chickling (not chick) pea Lathyrus sativus or other potentially neurotoxic Lathyrus species is associated with lathyrism characterized by spastic paraparesis. The offending agent in the pea is thought to be β-N-oxalyl-amino-L-alanine (BOAA). The cycad Cycas circinalis has a BOAA-like constituent, β-N-methylaminoL-alanine (BMAA), and may be the cause of the motor neuron disease that occurs in Guam. Phencyclidine and ketamine are known as dissociative anesthetics because they produce a feeling of being apart from one’s environment. They are antagonists at the N-methyl-D-aspartate subtype of the glutamate receptor and act by blocking the ion channel (see Chapter 43). The primary antiepileptic action of felbamate is believed to be at the strychnine-insensitive glycine binding site at the NMDA receptor. It is shown also to weakly potentiate GABA receptor binding. Lamotrigine, another antiepileptic drug, is thought to act by inhibiting the release of glutamate. Nimodipine inhibits release of glutamate by blockade of voltage-gated calcium channels.

The GABAergic and Glycinergic Systems The amino acids GABA and glycine are the primary inhibitory neurotransmitters that mediate fast postsynaptic inhibition in the nervous system. Their action is to bind specifically to GABA and glycine receptors, respectively. Glucose is the principal precursor for GABA production, although glutamate, pyruvate, and other amino acids can act as precursors. Glutamic acid is formed from the transamination of α-ketoglutarate, formed from glucose metabolism in the Krebs cycle by GABA α-oxoglutarate transaminase. Glutamic acid decarboxylase catalyzes the decarboxylation of glutamic acid to form GABA. The cofactor is pyridoxal phosphate. Pyridoxal phosphate is synthesized from pyridoxine (vitamin B6) by the enzyme pyridoxine kinase. The action of GABA released into the synaptic cleft is inactivated by a high-affinity, sodium-dependent uptake process. Enzymatic breakdown entails transamination to succinic semialdehyde by GABA transaminase. The next step is oxidation to succinic acid by succinic semialdehyde dehydrogenase, with the succinic acid then entering the Krebs cycle. GABA receptors predominate in the brain, where they have a widespread distribution.49 Three types of receptors for GABA have been characterized. GABAA receptors open chloride channels, causing hyperpolarization and inhibition of the recipient neuronal cell. GABAA receptors are multimembered, with five subunits assembled into a functional complex. The five major binding sites are for GABA, benzodiazepines, barbiturates, picrotoxin, and the anesthetic steroid.


203

These binding domains serve to modulate the receptors to GABA stimulation. The binding of GABA is enhanced by benzodiazepines, barbiturates, certain steroids, etomidate, propofol, chloral hydrate, meprobamate, ethanol, and zolpidem (see Chapters 34, 35, and 36); these agents serve as indirect receptor agonists. The binding of GABA is inhibited indirectly by flumazenil, penicillins, aztreonam, MAO inhibitors, tricyclic antidepressants, maprotiline, amoxapine, and organochlorine insecticides. GABAB receptors belong to the G protein–coupled receptor superfamily. Activation of GABAB receptors results in presynaptic inhibition by impairing calcium ion influx and neurotransmitter release or postsynaptic inhibition by increasing potassium ion efflux and cellular hyperpolarization. GABAB receptors are activated by baclofen and γhydroxybutyrate (GHB) and antagonized by phaclofen and saclofen (see Chapters 37 and 46). GABAC receptors are the newly identified member of the GABA receptor family. They are also linked to chloride channels, with distinct physiologic and pharmacologic properties. In contrast with the fast and transient responses elicited from GABAA receptors, GABAC receptors mediate slow and sustained responses. Pharmacologically, GABAC receptors are bicuculline- and baclofen-insensitive, and they are not modulated by many GABAA receptor modulators (such as benzodiazepines and barbiturates). A number of agonists bind to the binding site and elicit GABA-like responses. Muscimol is a naturally occurring GABA analogue isolated from the hallucinogenic mushrooms A. muscaria and A. pantherina that acts as a potent, direct receptor agonist (see Chapter 23).50 Benzodiazepines enhance GABAergic transmission indirectly. Benzodiazepine binding results in an increased affinity of GABA for its receptor and an increased frequency of chloride channel opening (see Chapter 35).49 A wide variety of nonbenzodiazepines, such as β-carbolines, cyclopyrrolones (zopiclone), and imidazopyridines (zolpidem), also bind to the benzodiazepine site to enhance GABAergic transmission.51 Pure benzodiazepine overdoses usually are not fatal. However, the newer, short-acting agents may increase greatly the frequency of complication, especially when benzodiazepines are combined with other CNS depressant drugs and alcohol. The benzodiazepine antagonist flumazenil is one of several 1,4-benzodiazepine derivatives that binds with high affinity to the benzodiazepine receptor and acts as a competitive antagonist at this receptor. Thus, flumazenil is an indirect GABAA antagonist. Caution in flumazenil administration is warranted in mixed overdoses, when benzodiazepine may provide a neuroprotective or cardioprotective action. Barbiturates facilitate GABA-mediated synaptic transmission by increasing the duration of chloride channel opening with GABA binding (see Chapter 36).49,52 At pharmacologic concentrations, some barbiturates (e.g., pentobarbital) are known to allosterically increase binding of benzodiazepine and GABA to their binding sites. At high concentrations, certain barbiturates (e.g., pentobarbital) act as direct agonists and directly open

204


chloride channels.52 The allosteric regulation of GABAA receptor function by neuroactive steroids is well known, and the steroid recognition site provides a potentially important target in the development of new therapeutic agents.53 General anesthetics, including barbiturates, volatile gases, steroids, and alcohols, enhance GABAmediated chloride conductance.54 Gabapentin, an amino acid structurally related to GABA, is being used currently in the treatment of epilepsy. Gabapentin appears to have GABA-mimetic properties; it may increase GABA concentrations by stimulating glutamic acid decarboxylase, the enzyme that produces GABA from glutamate (see Chapter 40). The anticonvulsant valproic acid is an indirect GABA agonist; it increases GABA concentrations by increasing activity of glutamic acid decarboxylase and inhibiting GABA transaminase and succinic semialdehyde dehydrogenase, enzymes that degrade GABA. Vigabatrin (γ-vinyl-GABA), an antiepileptic, is an irreversible inhibitor of GABA transaminase and increases GABA concentration. Topiramate and tiagabine, both anticonvulsants, are indirect GABA agonists. Alcohol is known to augment GABA-mediated chloride flux, and ethanol may exert some of its effect by enhancing the function of the GABA receptor.55 Bicuculline, a plant alkaloid, is a competitive GABA antagonist and is selective for the GABAA receptor that controls chloride permeability. Picrotoxin found in the berries of the shrub Anamirta cocculus is a GABAA receptor channel blocker. The active principle picrotoxin works on the gating process of the channel. Penicillin is a chloride channel blocker with a net negative charge that occludes the chloride channel by interacting with the positively charged amino acid residues within the channel pore. Pyridoxal phosphate antagonists such as isoniazid and other hydrazines, such as monomethylhydrazine in the mushroom Gyromitra (Helvella) esculenta, produce seizures by impairing GABA synthesis (see Chapter 23).56 Intravenous pyridoxine is used to combat the toxicity. Cyanide inhibits glutamic acid decarboxylase, thereby decreasing GABA, and it may partly account for seizures occurring in cyanide toxicity.57 The chlorinated hydrocarbons inhibit the action of GABA by binding to the picrotoxin site on the GABAA receptor to produce seizures.58 Baclofen is an orally active GABAmimetic agent and acts as a GABAB agonist.59 It causes hyperpolarization by increasing potassium conductance and has presynaptic inhibitory functions. Baclofen in an overdose produces drowsiness, coma, seizures, respiratory depression, and arrhythmias (see Chapter 37). The sedative/hypnotic effect of GHB is mediated by GABAB receptor and specific GHB receptor agonism (see Chapter 46). Similarly, the sedative/hypnotic effects of γbutyrolactone and 1,4-butanediol, which both are readily bioconverted to GHB, are mediated by these receptors. Glycine is another inhibitory neurotransmitter that mediates fast postsynaptic inhibition in the nervous system. Like GABAA, the postsynaptic glycine receptor is linked to a chloride channel. Activation of the glycine receptor causes chloride channel opening, hyperpolarization of the postsynaptic membrane, and inhibition of neuronal firing.60 The glycine receptors are

predominantly found in the spinal cord and the brainstem. Glycine also is likely the inhibitory neurotransmitter in the reticular formation. Glycine is present in the forebrain, where it functions as a coagonist of the NMDA glutamate receptor. At this receptor, glycine promotes the actions of glutamate, the major excitatory neurotransmitter in the CNS. The pharmacology of the glycine receptor is known less extensively than that of the GABA receptors. They are defined by their antagonism by the convulsive alkaloid, strychnine, in contrast to the strychnine-insensitive glycine-binding site that is associated with the excitatory NMDA subclass of the glutamate receptor. This explains why strychnine’s effect is localized to the medulla and spinal cord only. Strychnine, an alkaloid found in the seeds of the tree Strychnos nux-vomica, increases the level of neuronal excitability by selective antagonism at glycine receptors (see Chapter 24). The clinical picture simulates that of generalized seizures and is characterized by diffuse skeletal muscle contraction, muscular rigidity, opisthotonus, trismus, rhabdomyolysis, myoglobinuria, and acute respiratory and renal failure. Strychnine is used primarily as a rodenticide and is found sometimes as an adulterant in illicit drugs such as cocaine or heroin. Barbiturates and diazepam are effective antagonists of strychnine. Calycanthus species (Carolina allspice) contain the strychnine-like toxin calycanthine, which may produce convulsions. Tetanus toxin inhibits the release of glycine from nerve endings in the brainstem and spinal cord.

TOXICITY SPECIFIC TO THE PERIPHERAL NERVOUS SYSTEM Neurotoxins almost invariably produce polyneuropathy and rarely are implicated in focal neuropathy. Neurologic dysfunction usually occurs as part of a systemic toxicity.61 The neurotoxicity may occur in isolation, however, and then need to be differentiated from other nontoxic causes of neuropathies. The development of a neuropathy is directly related to continued exposure to a particular toxin. The neuropathy often improves when the exposure is discontinued. If the neuropathy progresses after removal of a suspected toxin, then other causes should be considered (Box 10-4). Diseases of the peripheral nervous system can be classified in two ways. The first categorization depends on the distribution: focal, multifocal, diffuse, proximal, distal, symmetric, or segmental. The second system depends on the anatomic location of the pathologic process: muscle, neuromuscular junction, or peripheral nerve. Further differentiation is based on involvement of the neuron, axon, or myelin.

Symmetric Generalized Neuropathies The most common form of drug- or toxin-induced neuropathy is a symmetric distal axonopathy. The neuropathy reflects failure of axonal transport and begins distally, where the axons are most vulnerable, and

CHAPTER 10

BOX 10-4

CHARACTERISTIC FEATURES OF TOXIC NEUROPATHY

Consistent pattern of neurologic dysfunction Reproducible pathophysiologic or pathologic findings Temporal relationship between exposure and onset of the clinical finding Nonfocal disorder Neurotoxicity improves with cessation of exposure

predominantly affects long and large-diameter axons, progressing proximally. Axonopathies usually have a subacute onset with gradual progression and clinically are reflected by a symmetric, distal, diffuse, stocking and glove–type sensorimotor loss. Sensory signs and symptoms initially predominate over motor deficits. Withdrawal of the toxic insult is necessary for recovery, which often is prolonged and slow. Axonal regeneration occurs at a rate of 2 mm/day, with recovery in an order reverse to that of the initial loss (i.e., proximal before distal). Demyelinating neuropathy is characterized by lesions that occur in the myelin sheath or Schwann cells. The axons usually are spared. The onset usually is subacute, and the involvement in myelinopathy, unlike in axonopathy, is predominantly distal and motor because the heavily myelinated large motor fibers are more severely affected than the small-diameter myelinated and unmyelinated sensory fibers. The demyelination may be patchy, however, with early proximal involvement. Areflexia is characteristic, and sensory symptoms are minimal. Recovery from a myelinopathy usually is rapid, early, and complete when compared with that from an axonopathy. The buckthorn toxin, found in high concentrations in the endocarp of the fruit of Karwinskia humboldtiana, and perhexiline are the few toxins causing a peripheral myelinopathy. Toxic injury to the cell body directly is termed a neuropathy. The dorsal root ganglions are especially involved. This vulnerability is because of a poorly formed nerve-blood barrier and the fenestrated blood vessels with increased vascular perfusion. Neuronopathies rarely are the cause of toxic insults. Neuronopathies are characterized by the rapid or subacute onset of motor or sensory deficits. The neurologic defect mirrors the nerve root involved and can occur anywhere. Recovery is variable and often incomplete because of incomplete neuronal recovery. Toxic neuronopathies can be caused by mercury, pyridoxine, and doxorubicin. Acute and chronic heavy metal exposure may produce neuropathies. Metal compounds tend to be stored in bones, from where they may be gradually released into the circulation, subsequently delaying recovery time. Other system (i.e., hematopoietic, renal, and gastrointestinal) dysfunctions usually accompany the neuropathy. Arsenic produces a generalized axonal peripheral neuropathy with predominant sensory involvement (see Chapter 74). Symptoms of toxicity usually appear 5 to 10 days after ingestion, with painful dysesthesias and


205

numbness in the feet and hands. Arsenic reacts with the sulfhydryl groups on various enzymes necessary for cellular metabolism. Both inorganic and organic lead is neurotoxic. Lead intoxication produces a demyelinating neuropathy with predominantly motor involvement (see Chapter 73). Lead intoxication in children, unlike that in adults, may produce an encephalopathy rather than a peripheral neuropathy. Mercury exposure causes a subacute, diffuse, predominantly motor neuropathy (see Chapter 71). Thallium compounds have been used as rodenticides, and toxicity produces an axonal neuropathy with prominent systemic features that include alopecia and autonomic dysfunction (see Chapter 75). Aluminum has been implicated in the causation of dialysis encephalopathy, a progressive acute syndrome found in patients undergoing dialysis (see Chapter 75). A number of organic compounds also produce neuropathies. The rodenticide Vacor causes a severe, rapid-onset distal axonopathy with associated autonomic dysfunction and diabetes mellitus due to necrosis of pancreatic β cells (see Chapter 79).62 The neuropathy can be prevented by nicotinamide, and Vacor may inhibit nicotinamide dinucleotide–dependent enzyme with disruption of an axonal-dependent process. Peripheral neurotoxic organic solvents include n-hexane and methyl-N-butyl ketone, carbon disulfide, and trichlorethylene.63 n-Hexane and methyl-N-butyl ketone are metabolized to 2,5-hexanedione, the active agent that damages the peripheral nerves. Methyl ethyl ketone enhances the neurotoxic effects of n-hexane and methylN-butyl ketone without itself being neurotoxic. Trichloroethylene may cause trigeminal neuropathy through its breakdown product, dichloroacetylene. Allyl chloride, used in the manufacture of epoxy resin, produces a characteristic distal axonopathy with sensory loss and loss of ankle jerks. Acrylamide monomer, unlike its polymer, is neurotoxic and produces a distal axonopathy involving large myelinated fibers. Ethylene oxide, commonly used as a sterilizing agent, produces a distal sensorimotor axonopathy with numbness, weakness, and areflexia (see Chapter 80). Residual ethylene oxide in dialysis tubing after the sterilization process may contribute to peripheral neuropathy in patients undergoing long-term hemodialysis.64 Methyl bromide exposure causes a distal symmetric axonopathy with involvement of the pyramidal tracts and cerebellum. Polychlorinated biphenyls have been associated with outbreaks of neuropathy when cooking oil has been contaminated with tetrachlorobiphenyl (Table 10-1).65

CONCLUSION An exciting future lies ahead in neurotoxicology. The knowledge of normal brain physiology and its response to insult has grown tremendously. The number of new antidepressants has greatly increased. Clinical trials of drugs that treat ischemic and traumatic brain injury are under way. The results of these studies will further expand the understanding of neurotoxicity and lead to the development of better therapies.

206


TABLE 10-1 Selected Neurotoxins That Produce Neuropathy TOXINS

EXPOSURE RISK

Arsenic

Metallurgy, pesticides, wood preservatives, pigments, ant stakes, weed killers Lead production, solders, batteries, pigment, insecticides, auto radiators, moonshine, construction workers, folk medicine (azarcon and greta) Gold and silver extraction, dental amalgams, fungicides, environmental contamination, thermometers Manufacture of optical lenses, photoelectric cells, and costume jewelry; rodenticide Insecticides, rayon fiber production

Lead

Mercury

Thallium Carbon disulfide Acrylamide Allyl chloride Ethylene oxide Hexacarbons (e.g., hexane)

Production of acrylamide resins Epoxy resin and glycerin production Sterilizing agent, solvent, plasticizer, chemical intermediate Solvents

PATHOLOGIC FINDING Axonopathy (S > M) Axonopathy (M > S)

GI distress, psychosis, hyperkeratosis, hyperpigmentation, Mees’ lines, anemia GI distress, microcytic anemia, basophilic stippling, encephalopathy, acute tubular dysfunction, gout, hyperuricemia

Axonopathy (M > S)

GI distress, tremor, ataxia, gingivostomatitis, neuropsychiatric disturbances

Axonopathy (M > S)

GI distress, delirium, seizures, coma, alopecia, choreoathetosis, ataxia, tremor, Mees’ lines Encephalopathy, parkinsonian syndromes, nystagmus, psychosis Irritant, contact dermatitis, ataxia Irritant, pulmonary edema Convulsions, arrhythmias, leukemia

Axonopathy (MS) Axonopathy (MS) Axonopathy (S > M) Axonopathy (MS) Axonopathy (SM)

Methyl bromide

Insecticidal fumigant, fire extinguisher ingredient

Axonopathy (MS)

Trichloroethylene

Myelinopathy

Organophosphates

Typewriter correction fluid, insecticides, spot removers, paint removers High-temperature insulators, transformers, carbonless copy papers Pesticides

Vacor (PNU)

Rodenticides

Axonopathy (M > S)

Polychlorinated biphenyls (PCBs)

CLINICAL FEATURES

GI dysfunction, hyperhidrosis, autonomic dysfunction Irritant, dermatitis, tremor, seizure, coma, dementia, psychosis, extrapyramidal symptoms Extrapyramidal dysfunction, degreaser’s flush

Myelinopathy

Chloracne, hepatic transaminitis, porphyria

Axonopathy (M > S)

Cholinergic symptoms, agitation, seizures, coma Nausea, vomiting, autonomic dysfunction, insulin-dependent diabetes mellitus

GI, gastrointestinal; M, motor; S, sensory.

REFERENCES 1. Kandel ER, Schwartz JH, Jessel TM (eds): Principles of Neural Science, 3rd ed. New York, Elsevier Science, 1991. 2. Hoffman TT, Taylor P: Neurotransmission: the autonomic and somatic motor nervous systems. In Hardman JG, Limbrid LE, Gilman AG (eds): Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 115–153. 3. Hoffman BB: Catecholamines, sympathomimetic drugs, and adrenergic receptor antagonists. In Hardman JG, Limbrid LE, Gilman AG (eds): Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 1215–1268. 4. Bourne HR, Sanders DA, McCormick F: The GTPase superfamily: conserved structure and molecular mechanism. Nature 1991; 349:117–129. 5. Palmer TM, Stiles GL: Adenosine receptor. Neuropharmacology 1995;34:683–694. 6. Clark M, Post RM: Carbamazepine, but not caffeine, is highly selective for adenosine A1 binding sites. Eur J Pharmacol 1989;164:399–401. 7. Eldridge FL, Paydarfar D, Scott C, et al: Role of endogenous adenosine in recurrent generalized seizures. Exp Neurol 1989;103:179–185.

8. Shannon MW, Maher TJ: Anticonvulsant effects of intracerebroventricular adenosine in theophylline-induced seizures. Vet Hum Toxicol 1994;36:350. 9. Blake KV, Massey KL, Hendes L, et al: Relative efficacy of phenytoin and phenobarbital for the prevention of theophyllineinduced seizures in mice. Ann Emerg Med 1988;17:1024–1028. 10. Phyllis JW, O’Regan MH: The role of adenosine in the central actions of the benzodiazepines. Prog Neuropsychopharmacol Biol Psychiatry 1988;12:389–404. 11. Mackenzie AB, Suprenant A, North AB: Functional and molecular diversity of purinergic ion channel receptors. Ann NY Acad Sci 1999;868:716–729. 12. Molinoff PB, Axelrod J: Biochemistry of catecholamines. Annu Rev Biochem 1971;40:465–500. 13. Caron MG, Lefkowitz RJ: Catecholamines receptors: structure, function, and regulation. Recent Prog Horm Res 1993;48:277. 14. Felder RA, Eisner GM, Jose PA: D1 dopamine receptor signaling defect in spontaneous hypertension. Acta Physiol Scand 2000;68:245–250. 15. Hartman DS, Civelli O: Molecular attributes of dopamine receptors: new potential for antipsychotic drug development. Ann Med 1996;28:211–219. 16. Murphy MB, Murray C, Shorten GD: Drug therapy: fenoldopam— a selective peripheral dopamine-receptor agonist for the treatment of severe hypertension. N Engl J Med 2001;345:1548–1557.

CHAPTER 10

17. Mena I: Manganese poisoning. In Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology, vol 21. New York, Elsevier Science, 1977, pp 821–823. 18. Ginsberg MD: Carbon monoxide. In Spencer PS, Schaumburg HH (eds): Experimental and Clinical Neurotoxicology. Baltimore, William & Wilkins, 1980, pp 374–394. 19. Aquilonius SM, Asmark H, Enoksson P, et al: Computerised tomography in severe methanol intoxication. BMJ 1978;2:929. 20. He FS: Extrapyramidal lesions induced by mildewed cane poisoning (with report of three cases). Chung Hua I Hsueh Tsa Chih 1987;67:395–396. 21. Tanner CM, Langston JW: Do environmental toxins cause Parkinson’s disease? A critical review. Neurology 1990;322:1781–1787. 22. Granner MA, Wooten GF: Neuroleptic malignant syndrome or parkinsonism hyperpyrexia syndrome. Semin Neurol 1991; 11:228–335. 23. DEA Intelligence Division. (2002, October). Trippin’ on tryptamines: the emergence of foxy and AMT as drugs of abuse. Accessed January 6, 2004, at http://www.usdoj.gov/dea/pubs/ intel/02052/02052p.html. 24. Sanders-Bush E, Mayer SE: 5-Hydroxytryptamine (serotonin): receptor agonists and antagonists. In Hardman JG, Limbrid LE, Gilman AG (eds): Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 269–290. 25. Mill KC: Serotonin syndrome. Am Fam Med 1995;52:1475–1482. 26. Reisine T: Opiate receptors. Neuropharmacology 1995;34:463–472. 27. Gutstein HB, Akil H: Opioid analgesics. In Hardman JG, Limbrid LE, Gilman AG (eds): Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 569–619. 28. Kaiko RF, Foley KM, Grabinski PY, et al: Central nervous system excitatory effects of meperidine in cancer patients. Ann Neurol 1983;13:180–185. 29. Galzi JL, Changeux JP: Molecular organization and regulations. Neuropharmacology 1995;34:563–582. 30. Brown JH, Taylor P: Muscarinic receptor agonists and antagonists. In Hardman JG, Limbrid LE, Gilman AG (eds): Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 155–173. 31. Benson BJ, Tolo D, McIntire M: Is the intermediate syndrome in organophosphate poisoning the result of insufficient oxime therapy? J Toxicol Clin Toxicol 1992;30:347–349. 32. Haddad LM: Organophosphate poisoning: intermediate syndrome? J Toxicol Clin Toxicol 1992;30:331–332. 33. Kitchens CS, Van Mierop LH: Envenomation by the eastern coral snake (Micrurus fulvius). JAMA 1987;258:1615–1618. 34. Rauber A: Black widow spider bites. J Toxicol Clin Toxicol 1983–84;21:473. 35. Nicholson GM, Graudins A: Spiders of medical importance in the Asia-Pacific: Atracogoxin, latrotoxin and related spider neurotoxins. Clin Exp Pharmacol Physiol 2002;29:785–794. 36. Kincaid JC: Tick bite paralysis. Semin Neurol 1990;10:32–34. 37. Taylor P: Agents acting at the neuromuscular junction and autonomic ganglia. In Hardman JG, Limbrid LE, Gilman AG (eds): Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 193–213. 38. Hough LB: Cellular localization and possible functions for brain histamine: recent progress. Prof Neurobiol 1987;30:469–505. 39. Brown NJ, Roberts II LJ: Histamine, bradykinin, and their antagonists. In Hardman JG, Limbrid LE, Gilman AG (eds): Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 645–667. 40. Pin JP, Duvoisin R: The metabotrophic glutamate receptors: structure and functions. Neuropharmacology 1995;34:1219–1237.


207

41. Bettler B, Mulle C: AMPA and kainate receptors. Neuropharmacology 1995;34:123–139. 42. Mori H, Mishina M: Structure and function of the NMDA receptor channel. Neuropharmacology 1995;34:1219–1237. 43. Kleckner NW, Dingledine R: Requirements for glycine in activation of NMDA receptors expressed in Xenopus oocyte. Science 1988;241:835–837. 44. Williams K, Romano C, Dichter MA, et al: Modulation of the NMDA receptor by polyamines. Life Sci 1991;48:469–498. 45. Weight FF, Lovinger DM, White G, et al: Alcohol and anaesthetic actions on excitatory amino acid-activated ion channels. Ann N Y Acad Sci 1990;625:97–107. 46. Hoffman PL, Grant KA, Snell LD, et al: NMDA receptors: role in ethanol withdrawal seizures. Ann N Y Acad Sci 1992;654:52–60. 47. Olney JW: Excitatory amino acids and neuropsychiatric disorders. Ann Rev Pharmacol Toxicol 1990;30:47–71. 48. Perl TM, Bedard L, Kosatsky T, et al: An outbreak of toxic encephalopathy caused by eating mussels contaminated with domoic acid. N Engl J Med 1990;322:1775–1780. 49. Luddens H, Korpi ER, Seeburg PH: GABAA/benzodiazepine receptor heterogeneity: neurophysiological implications. Neuropharmacology 1995;34:245–254. 50. Krogsgaard-Larsen P, Brehm L, Schaumburg K: Muscimol, a psychoactive constituent of Amanita muscaria, as a medicinal chemical model structure. Acta Chem Scand [B] 1981;35:311–324. 51. Mohler H, Okada T: Benzodiazepine receptor: demonstration in the central nervous system. Science 1977;198:849–851. 52. Korpi ER, Mattila MJ, Wisden W, Luddens H: GABA-A receptor subtypes: clinical efficacy and selectivity of benzodiazepine site ligands. Ann Med 1997;29:275–282. 53. Majewska MD, Harrison NL, Schwartz RD, et al: Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science 1986;232:1004–1007. 54. Allan AM, Harris RA: Anesthetic and convulsant barbiturates alter γ-aminobutyric acid-stimulated chloride flux across brain membranes. J Pharmacol Exp Ther 1986;238:763–768. 55. Suzdak PD, Schwartz RD, Skolnick P, et al: Ethanol stimulates γ-aminobutyric acid receptor-mediated chloride transport in rat brain synaptoneurosomes. Proc Natl Acad Sci U S A 1986;83: 4071–4075. 56. William HL, Killah MS, Jenny EH, et al: Convulsant effects of isoniazid. JAMA 1951;152:1317–1321. 57. Gosselin RE, Smith RP, Hodge HC: Clinical Toxicology of Commercial Products, 5th ed. Baltimore, Williams & Wilkins, 1984. 58. Lummis SC, Buckinham SD, Rauh JJ, et al: Blocking actions of heptachlor at an insect central nervous system GABA receptor. Proc R Soc Lond Biol Sci 1990;240:97–106. 59. Ogata N: Pharmacology and physiology of GABAB receptors. Gen Pharmacol 1990;21:395–402. 60. Langosch D, Becker CM, Betz H: The inhibitory glycine receptor: a ligand-gated chloride channel of the central nervous system. Eur J Biochem 1990;194:1–8. 61. Schaumberg HH, Spencer PS, Thomas PK (eds): Disorder of Peripheral Nerves. Philadelphia, F. A. Davis, 1983. 62. LeWitt P: The neurotoxicity of the rat poison vacor. N Engl J Med 1980;302:73–77. 63. Spencer PS, Schaumberg HH, Sabri M, et al: The enlarging view of hexacarbon neurotoxicity. Crit Rev Toxicol 1980;7:279–356. 64. Windebank AJ, Blexrud MD: Residual ethylene oxide in hollow fiber hemodialysis units is neurotoxic in vitro. Ann Neurol 1989;26:63–68. 65. Murai Y, Kuroiwa Y: Peripheral neuropathy in chlorobiphenyl poisoning. Neurology 1971;21:1173–1176.

208


A

Drug-Associated Neuromuscular Syndromes MICHAEL BEUHLER, MD

A “neuromuscular disorder” refers to a pathophysiologic state created by an abnormal interaction between nerve and muscle. In toxicology, most neuromuscular disorders relate to an abnormal interaction between the central or peripheral nervous systems (CNS or PNS) and the motor innervation of skeletal muscles. Drugassociated neuromuscular disorders are typically adverse effects that occur during therapeutic, occupational, or recreational use or overuse of various xenobiotics. These disorders may be dose related or idiosyncratic, mild or severe, reversible or irreversible, and can occur early or late following exposure. Three drug-associated neuromuscular disorders will be extensively reviewed in this chapter. For discussion of other drug-associated neuromuscular disorders, you should refer to the specific chapter covering a particular drug. For instance, extrapyramidal movement disorders are discussed in Chapter 38, the Antipsychotic Agents. When exposure to a xenobiotic produces, with some regularity, a specific constellation of neuromuscular physical signs and symptoms, they are referred to as syndromes. Syndrome designations are often reserved for disorders that are associated with significant patient morbidity. The majority of drug-associated neuromuscular syndromes are manifested by exaggerated muscular tone and resultant hyperthermia. Although the pathophysiologic mechanisms underlying the neuromuscular hyperactivity are frequently unique, clinical signs and symptoms often have significant overlap, thus making accurate diagnosis difficult. Recognition of the unique clinical features of each syndrome will facilitate diagnosis and assist treatment. In this chapter, the neuroleptic malignant syndrome (NMS), serotonin syndrome, and malignant hyperthermia (MH) will be reviewed and the similarities and differences of their etiology, pathophysiology, clinical findings, and treatment will be highlighted.

NEUROLEPTIC MALIGNANT SYNDROME Please also see Chapter 38.

Introduction, History, and Epidemiology This syndrome was first described in 1960 when fever and rigidity were associated with haloperidol therapy.1 During the 1960s, the syndrome was increasingly recognized as a separate entity from lethal catatonia. By the 1980s, NMS had become widely accepted as a complication of neuroleptic use. During the past 10 to 15 years, the mortality rate from NMS has declined due to a wider recognition of patients at risk, earlier diagnosis, decreases in neuroleptic dosing, the use of newer and safer atypical antipsychotics, and improvements in critical care.

From retrospective studies, the incidence of NMS has been estimated to occur in 0.02% to 3% in patients treated with neuroleptics.2 Prospective studies estimate an incidence of 0.07% to 0.9%.3-5 The incidence of NMS appears to be decreasing. This is likely due to the use of lower doses of neuroleptics, the use of atypical agents (see Chapter 38), and earlier recognition with prevention of full syndrome development. Stricter criteria for diagnosis may now limit the reporting of NMS. In addition, new cases are less likely to be published in the current literature now that the syndrome is well characterized. There does not appear to be a gender or age preference for NMS, but it is more common in men and adults due to greater frequency of neuroleptic use in these patient populations. Patients with neuropsychiatric disorders such as Parkinson’s disease and catatonia and those with severe forms of functional psychiatric disorders are at greater risk for developing NMS.2 Patients with preexisting organic brain syndrome appear to have a higher risk for mortality and morbidity from NMS. NMS has been reported with several types of medications that result in decreased CNS dopamine tone. The high-potency neuroleptics such as haloperidol, fluphenazine, and thiothixene are probably more likely to cause the syndrome, but it has been reported with lower-potency neuroleptics as well. Although haloperidol has been associated with more documented cases of NMS, this may reflect more widespread use of this antipsychotic rather than greater absolute risk with this particular agent. Even the newer, atypical agents, which have a decreased propensity to produce extrapyramidal side effects (EPS) (e.g., risperidone, clozapine, olanzapine, and quetiapine), have been associated with NMS.2,6,7 Non-neuroleptic dopamine antagonists (e.g., amoxapine and metoclopramide) have caused episodes of NMS. Drugs that result in lower levels of dopamine (e.g., reserpine, tetrabenazine, and α-methyl tyrosine) have been associated with NMS. NMS has also been reported following the abrupt cessation of dopamine agonists (e.g., levodopa/carbidopa and amantadine) used for the treatment of Parkinson’s disease.8,9 There are several purported risk factors for developing NMS. They include large doses of neuroleptics and/or rapid dose escalation, a positive history of NMS, antecedent agitated behavior, dehydration or infection (e.g., pneumonia or sepsis), the presence of electrolyte disorders (e.g., hypo- or hypernatremia), and concomitant treatment with other psychotropic agents (e.g., lithium, anticholinergic agents). Lithium is thought to decrease striatal dopamine synthesis, thus theoretically predisposing to NMS.10 Lithium is associated with its own neurotoxicity that may be mistaken for NMS. Thus, the diagnosis of NMS should be made with caution for

CHAPTER 10

patients who are treated with lithium and neuroleptics simultaneously.11,12 NMS is an idiosyncratic reaction to neuroleptic therapy and is not the result of overdose. For patients with NMS, serum levels of neuroleptics are typically in the normal range. Overdose of certain traditional neuroleptics (e.g., chlorpromazine, thioridazine) may occasionally produce short-lived patient agitation and hyperthermia. The clinical course (abrupt onset over minutes to hours and duration of 1 to 2 days) is distinctly different from that of NMS (gradual onset over days and duration of 1 to 2 weeks). NMS-like symptoms had been reported for years prior to the initial use of neuroleptics. This separate syndrome with similar clinical characteristics is called lethal catatonia (or malignant catatonia). In its final or advanced stages, lethal catatonia is clinically indistinguishable from NMS. The patient often has gradual worsening of psychiatric symptoms that include moodiness and melancholia for several days preceding the full syndrome. Typically, 1 to 2 days prior to developing lethal catatonia patients develop severe agitation and mania. Following this period, they develop catatonia, labile blood pressure, muscular rigidity, and mottled skin, similar to NMS. It is often difficult to differentiate lethal catatonia from NMS. The absence of a change in antecedent antidopamine drug therapy by history and presence of prodromal psychiatric symptoms suggest a diagnosis of lethal catatonia.13

Pathophysiology of Neuroleptic Malignant Syndrome The pathophysiology of NMS has been investigated for decades but has not yet been fully elucidated. NMS is theorized to be the result of a relative dopamine blockade (specifically D2-receptor blockade) in the mesolimbic, mesocortical, nigrostriatal, and hypothalamic brain regions.2 This is largely based on the observation that the syndrome occurs in the presence of dopamine depletion or antagonist therapy, is associated with temperature abnormalities (controlled by preoptic anterior hypothalamic dopamine tracts), and motor symptoms are exaggerations of extrapyramidal neuroleptic side effects. However, there are some limitations to the dopamine antagonist or hypofunction theory. The syndrome has been reported to occur at therapeutic serum neuroleptic levels, and effects last much longer then expected based on the elimination kinetics of neuroleptics. The syndrome has been reported to continue despite a subtherapeutic concentration or absence of neuroleptic in the CNS. This is partly explained by the counterhypothesis that NMS effects persist due to dopamine receptor hypersensitivity or increased number of dopamine receptors. However, one would expect the patient to manifest signs and symptoms often associated with dopamine excess (i.e., choreoathetoid movements, hallucinations), when CNS dopamine receptors are no longer occupied and activated due to drug metabolism. Such stigmata are not commonly reported with NMS. There does, however,


209

seem to be some temporal relationship between the duration of symptoms and the triggering agent’s half-life, as demonstrated by depot injections generally being implicated in longer clinical courses than immediaterelease oral or intramuscular formulations. There is a link between serotonin (5-HT) and dopamine activity. The newer antidepressants have 5-HT2A antagonism, which is thought to increase dopamine tone in the striatum and prefrontal cortex (by disinhibition). This 5-HT antagonism is thought to limit adverse effects (e.g., EPS) and contribute to the antipsychotic drug effects. Selective serotonin reuptake inhibitors (SSRIs) aggravate haloperidol-induced dystonia and parkinsonism in monkeys (by a decrease in brain dopamine).14 Treatment of rats with agents that increase 5-HT enhances catalepsy after blockade of dopamine receptors.15 This suggests a dopamineserotonin relationship, with increased 5-HT tone causing decreased dopamine tone.16 There are several cases of EPS and NMS triggered by SSRIs in the literature.17,18

Clinical Manifestations of Neuroleptic Malignant Syndrome NMS is most often characterized by fever, muscular rigidity, altered mental status, and autonomic dysfunction.2,19 Fever and muscular rigidity are usually present but not required for diagnosis. The reported signs and symptoms of NMS syndrome are listed in Table 10A-1. Increased muscle tone is often present (97%), being described as “lead pipe rigidity,” usually by those familiar with that phrase’s linkage to NMS. The rigidity may have a cogwheeling component. Other EPS symptoms (dystonia, dysphagia, gait abnormalities) may be present. Tremor (mild to severe, fine or coarse) has been reported. Mutism may be part of the syndrome and is occasionally described associated with fearful facial expressions. Elevated temperatures are common (98%) although not universal.2,20 Other symptoms associated with NMS include diaphoresis, tachypnea, tachycardia, and altered mental status (97%).2 Urinary incontinence is uncommonly reported. Seizures are rarely reported, and should prompt investigation for another diagnosis.

Diagnosis of Neuroleptic Malignant Syndrome The diagnosis of NMS is clinical and based on suggestive history and physical findings along with a high level of suspicion in the appropriate clinical setting. By history, the patient must have recently had a dopaminergic agent started, the dose increased, or an intervention that decreased CNS dopamine tone. Several clinical diagnostic criteria are available to facilitate the diagnosis of NMS. The disadvantage of applying rigid diagnostic criteria is that borderline or atypical cases will be excluded, possibly delaying proper therapy. This is particularly important since NMS is a heterogeneous disorder that exists along a severity continuum from moderate to very severe cases. Atypical cases may not have rigidity or elevated temperature and

210


TABLE 10A-1 Signs and Symptoms of Neuroleptic Malignant Syndrome (NMS)/Serotonin Syndrome/Malignant Hyperthermia CLINICAL FEATURES

NMS

SEROTONIN SYNDROME

MALIGNANT HYPERTHERMIA

Triggering agent Onset Duration Agitation Confusion Hyperactivity Bradykinesia/stupor Myoclonus Shivering Tremor Pupils Hyperreflexia Rigidity Rigidity type Hyperpyrexia Tachypnea Tachycardia Hypertension Leukocytosis Elevated creatine phosphokinase

Neuroleptic Slow (hours to days) Long (days to weeks) Sometimes Yes No Yes No No Sometimes Mid-sized No Severe Extrapyramidal (leadpipe) Yes Yes Yes Sometimes Yes Severe

Proserotonergic agent Fast (minutes to hours) Short (1–2 days) Yes Sometimes Yes No Yes Yes/sometimes Yes Large Yes (especially lower extremities) Sometimes Pyramidal (clasp-knife) Yes Yes Yes Yes Uncommon Mild

Succinylcholine or inhaled anesthetic Very fast to fast (minutes to hours) Short (1–3 days) No Unusual No Unusual No No No Not specific No Severe Generalized Severe Yes Yes (severe) Sometimes Not typical Severe

Adapted from Gillman PK: The serotonin syndrome and its treatment. J Psychopharmacol 1999;13:100–109; Gillman K: Serotonin toxicity. www.psychotropical.com/SerotoninToxicity.doc, accessed January 15, 2005; and Wappler F, Fiege M, Schulte am Esch J: Pathophysiological role of the serotonin system in malignant hyperthermia. Br J Anaesth 2001;87(5):794–798.

can make diagnosis difficult. A flexible definition is probably in the patient’s best interest to allow for initiation of aggressive supportive treatment. In general, it is important to initially exclude any alternative diagnoses (e.g., infection) (see later section on Differential Diagnosis). There are no laboratory studies that confirm the diagnosis of NMS. The laboratory abnormalities that have been associated with NMS are relatively nonspecific. They include markedly elevated creatine phosphokinase (CPK), increased white blood cell (WBC) count, myoglobinuria, and occasionally, diffuse slowing on electroencephalography (EEG). Serum iron levels have been reported to be low with NMS and have been suggested as a useful marker. Serum iron, however, appears to decrease with inflammatory responses, and thus has no prognostic significance.21,22 There is significant variation in the time between the administration of the “triggering” medication and the onset of NMS. Reports range from days to weeks from the addition or change in the medication to development of signs and symptoms of NMS. Once the illness begins, symptoms progress slowly and peak over a period of 24 to 72 hours. The total duration of the illness varies greatly. The duration of illness appears to be longer for patients who received depot neuroleptics as compared with oral or immediate release intramuscular formulations. The disease often has a fluctuating clinical course, irrespective of the treatment. Improvement is usually observed within 48 to 96 hours of discontinuation of the triggering medication. Full recovery, however, is slow and often takes 10 or more days. Full recovery may occasionally take several weeks, and some NMS signs and symptoms improve while others persist.2 For example,

patients can have improvement of their rigidity and resolution of elevated serum CPK, but still have altered mental status and hyperthermia. Mortality appears to be related to the severity of hyperthermia and the degree of alteration of consciousness. Mortality from NMS usually results from renal failure, pulmonary embolism, respiratory failure, acute respiratory distress syndrome, cardiovascular collapse, or disseminated intravascular coagulation (DIC). This stresses the need for aggressive supportive care. Postmortem examination is unlikely to demonstrate specific CNS findings. Persistent neurologic sequelae have been reported following episodes of NMS. These persistent neurologic findings include cognitive dysfunction, catatonia, continued rigidity, dystonia, and amnesic symptoms.23,24 Medical complications (such as hypoxic encephalopathy) can result in prolonged symptomatology. The patient may also have exacerbations of underlying psychiatric illness after removal of neuroleptics and/or treatment with dopamine agonists.

SEROTONIN SYNDROME Please also see Chapter 29.

Introduction, History, and Epidemiology Although not initially recognized as a distinct clinical entity, serotonin syndrome has existed for over half a century. The first published description of the syndrome occurred in 1955 when a fatal case of “toxic encephalitis”

CHAPTER 10

was noted after meperidine was administered to a patient taking iproniazid for pulmonary tuberculosis.25 The use of L-tryptophan in conjunction with monoamine oxidase inhibitors (MAOIs) in the 1960s caused a similar illness marked by hyperactivity that was due to excess CNS serotonin levels.26,27 It was not until 1982, however, that the syndrome was fully characterized and the term serotonin syndrome appeared in the literature.28 Several studies have attempted to estimate the frequency of serotonin syndrome; all of them suffer from varying degrees of methodologic problems. Despite these study limitations, the incidence of severe serotonin syndrome is quite low during therapeutic dosing of nonMAOI agents. There have only been approximately 200 cases of serotonin syndrome reported in the literature since it was initially characterized. This low reporting, however, may not reflect a true incidence. This illness, like NMS, has a continuum of severity. Thus, the incidence of the syndrome will depend on the flexibility of clinical criteria used for diagnosis. It is likely that mild signs and symptoms of serotonin excess occur frequently with many different proserotonergic agents. The severity of these symptoms, however, is mild enough to be overlooked by both patients and treating physicians and thus will not be diagnosed as serotonin syndrome. A recent surge in popularity of SSRIs over traditional antidepressants as well as increased education (and thus recognition) of the signs and symptoms of serotonin syndrome may lead to an increased incidence of syndrome diagnosis. In addition, the recent increased use of psychoactive medications in children is expected to increase the incidence of serotonin syndrome in this age group. There does not appear to be an age or gender preference for the development of serotonin syndrome. Underlying organic brain disease may be a risk factor that predisposes patients to the development of the syndrome. The incidence of serious morbidity and mortality associated with serotonin syndrome varies greatly and is related to individual host factors (i.e., comorbid illness), drug combinations (i.e., the “dose” of serotonin stimulation), and the timeliness of diagnosis and treatment. Most cases of serotonin syndrome occur with combination therapy of more than one proserotonergic agent, but it has been reported with serotonergic monotherapy and recreational use of indoleamine and phenylethylamine derivatives (e.g., “Ecstasy”). Although serotonin syndrome is usually an adverse drug interaction that follows the combination of therapeutic doses of proserotonergic agents, it will also occur following proserotonergic drug overdose.

Pathophysiology of Serotonin Syndrome Serotonin syndrome is caused by increased CNS 5-HT receptor activation. Usually, increased 5-HT receptor activation is due to significantly elevated CNS levels of 5-HT, which occurs as a result of proserotonergic agent activity. It is helpful to think of serotonin syndrome not as an on/off phenomenon, but as a continuous spectrum of toxicity caused by increased CNS 5-HT levels. This is


211

similar to the spectrum of illness severity that exists for NMS. Unlike NMS, however, serotonin syndrome is not an idiosyncratic reaction but a dose-effect phenomenon caused by the combination of proserotonergic agents. Some investigators have advocated calling it serotonin toxicity, which is a more accurate description of the phenomenon. In many well-documented cases of serotonin syndrome, however, serum drug levels are often in the therapeutic range. Serum levels of proserotonergic drugs, however, may not correlate with endorgan concentrations or, more importantly, elevated CNS serotonergic activity. There are several different groups of 5-HT receptors found in the CNS. Most of the symptoms seen in serotonin syndrome are believed to be caused by stimulation of the postsynaptic 5-HT2A receptor.29-32 This receptor is a G protein linked to phosphoinositidespecific phospholipase C as well as a K+ channel (causes depolarization).33 Although stimulation of the 5-HT1A receptor generates stereotypical behavior in mice once thought to be analogous to serotonin syndrome in humans, it is not believed to contribute significantly to the pathologic consequences of serotonin toxicity, and specific antagonists do not provide protection against serotonin syndrome lethality in a rat model.30,31 The stimulation of 5-HT2A receptors may occur in several different ways: increased 5-HT synthesis (e.g., L-tryptophan); increased 5-HT release (e.g., amphetamines); decreased 5-HT catabolism (e.g., MAOIs); decreased 5-HT reuptake (e.g., SSRIs); direct 5-HT receptor stimulation (e.g., 5-methoxy-N,N-dimethyltrypta-mine [DMT]); and increased postsynaptic 5-HT response by secondary messenger systems (e.g., lithium). Serotonin syndrome may also be precipitated following the withdrawal of an agent with 5-HT2A antagonist effects in a patient with 5-HT receptor up-regulation/hypersensitivity or in a patient on an SSRI.34 The propensity of an agent to cause serotonin syndrome is often directly correlated with its ability to increase brain serotonin levels or to directly stimulate 5-HT2A receptors. Usually a combination of pharmaceutical agents is required to elicit serotonin syndrome, but it has been reported following overdose of single agents.35,36 For instance, serotonin syndrome was noted to occur in 14% to 16% of patients who overdosed on SSRIs in one study. In addition, overdose of MAOIs produces a toxic syndrome that significantly overlaps with serotonin syndrome. It is much more common for serotonin syndrome to occur when two agents are combined that raise brain serotonergic tone by two different mechanisms. For example, many of the severe or fatal serotonin syndrome episodes have been due to an MAOI interaction with a selective serotonin uptake inhibitor. Serotonin reuptake inhibition appears to be a very commonly encountered cause of serotonin syndrome. The SSRIs paroxetine, clomipramine (a tricyclic antidepressant [TCA]), sertraline, fluoxetine, and venlafaxine (a serotonin norepinephrine reuptake inhibitor [SNRI]) have all been implicated as causes of serotonin syndrome. Besides clomipramine, the other TCAs (e.g., imipramine, dothiepin, and amitriptyline) have a much

212


lower affinity for the 5-HT reuptake transporter.37,38 These TCAs have rarely caused serotonin syndrome but do not usually cause significant morbidity unless combined with an MAOI. It has been hypothesized that chlorpheniramine and, possibly, brompheniramine can contribute to serotonin syndrome due to SSRI properties of these drugs.37,39 Duloxetine, a novel SSRI, is also likely capable of causing serotonin syndrome. Certain synthetic opiates have SSRI activity and have been implicated as agents capable of precipitating serotonin syndrome when combined with other proserotonergic agents. These opiates include tramadol, meperidine, dextromethorphan, methadone, and pentazocine.40 Tramadol may have serotonin-releasing properties in addition to being an SSRI.41 Traditional, irreversible, nonselective MAOIs (e.g., tranylcypromine, phenelzine, and clorgyline) and the newer, reversible, nonselective MAOIs (e.g., moclobemide) are readily capable of precipitating serotonin syndrome when combined with other proserotonergic agents (see Chapter 29).40,42 Selegiline, a selective, irreversible MAOI-B inhibitor, may cause serotonin syndrome at higher doses since MAO selectivity is lost at supratherapeutic doses.43,44 Linezolid, a newer antibiotic that has reversible MAO activity, has the potential to cause a serotonin syndrome. Several drugs of abuse (e.g., hallucinogenic amphetamines, alklytryptamines, and lysergamides) can potentiate 5-HT CNS activity and result in serotonin syndrome–like toxicity, either alone or in combination with other agents. The direct serotonin receptor agonists (e.g., lysergic acid diethylamide (LSD), 2,5 dimethoxy-4 methylamphetamine (DOM), DMT, and serotonin-releasing agents (e.g., cocaine and 3,4-methylenedioxymethamphetamine [MDMA]) may produce serotonin syndrome–like toxicity.45-47 L-tryptophan is converted to serotonin in the CNS and has caused serotonin syndrome when combined with an MAOI or SSRI. Several substances have been implicated in causing serotonin syndrome whose contributing mechanism is not well understood. Lithium is believed to contribute to serotonin syndrome because it causes an inhibition of phosphatases, thus resulting in increased intracellular inositol phosphates and potentiating the secondary messenger effects of serotonin.33,48 Trazadone and nefazodone have been implicated in several cases of serotonin syndrome, even though they appear to have 5-HT2A antagonistic properties and are not particularly potent 5-HT uptake inhibitors.37,40,49 Buspirone is a direct 5-HT1A agonist and has been implicated in causing serotonin syndrome, although its effect appears weak.46,50 Sumatriptan (a 5-HT1D agonist) has been implicated as a cause of serotonin syndrome through uncertain mechanisms.39,51 It appears that 5-HT3 antagonists (e.g., ondansetron and similar antiemetics) are unlikely to cause serotonin syndrome, although this is controversial.52 Bromocriptine and L-dopa increase brain serotonin levels and can theoretically facilitate the development of serotonin syndrome.53 It is important to understand the pharmacokinetic and pharmacodynamic characteristics of certain pro-

serotonergic agents. For example, fluoxetine and its active metabolite, norfluoxetine, have long elimination half-lives.40 This means that there will be significant serotonin uptake inhibition long after the agent is stopped. Thus, a “washout” period of 4 weeks is recommended after drug discontinuation. Another example is the use of irreversible MAOIs. Patients will require 4 to 5 weeks for the effect of these enzyme inhibitors to completely resolve. Significant P-450 interactions (and the effect of genetic polymorphisms) are observed with several of the psychiatric medications and can result in potentiation and prolongation of their effect. For example, paroxetine has significant CYP2D6 inhibition, which can increase serum levels of other medications metabolized by CYP2D6.

Clinical Manifestation of Serotonin Syndrome There is a great range in the severity of the clinical signs and symptoms of serotonin toxicity. It can manifest as unpleasant side effects reported with routine SSRI use to a hyperthermic, life-threatening syndrome. Typical signs and symptoms include CNS changes (i.e., agitation, confusion, anxiety, headache, mydriasis, hallucinations, insomnia, and dizziness), autonomic hyperactivity (i.e., hypertension, hyperthermia, tachycardia, tachypnea, flushing, diaphoresis, and shivering) gastrointestinal effects (i.e., nausea, vomiting, abdominal pain, and diarrhea), and neuromuscular abnormalities (i.e., clonus, myoclonus, tremor, sweating, trismus, hyperreflexia, ocular clonus, and muscular rigidity).54-56 Although not pathognomonic, hyperreflexia, clonus (myoclonus and ocular clonus), and/or symmetric rigidity (more prominent in the lower extremities) are characteristic findings associated with serotonin syndrome.

Diagnosis of Serotonin Syndrome As with NMS, the diagnosis of serotonin syndrome is clinical and based on suggestive history and physical findings. There are no laboratory tests that confirm the diagnosis. Diagnosis is best made by excluding other etiologies (see later section on Differential Diagnosis) and application of preestablished criteria. The use of strict diagnostic criteria is not recommended because it will not allow the inclusion of atypical cases of serotonin syndrome. Absolute frequency of symptoms is impossible to determine due to the limited nature of case reports. Of note, serotonin syndrome is not a manifestation of EPS and should not be associated with dyskinesis or cogwheeling. One of the marked differences between serotonin syndrome and NMS is the time course of symptom onset and duration of illness. With serotonin syndrome, symptom onset often occurs rapidly or within minutes to hours after introduction of or an increase in dose of the proserotonergic agent. In contrast, with NMS, symptom onset occurs gradually and insidiously over days following the introduction of an antidopaminergic agent. One of the diagnostic criteria for serotonin syndrome is that

CHAPTER 10

symptoms should begin soon after starting a serotonergic agent, and in almost all situations they have started within 24 hours of the addition of the medication. The majority of episodes are mild, and relatively short-lived. Most patients recover from serotonin syndrome within 24 hours, but patients with a severe syndrome may have signs and symptoms for 2 to 3 days. Laboratory analysis is not useful for making a specific diagnosis; it appears to be better suited for eliminating alternative diagnoses. Nonspecific findings include elevated WBC count, increased CPK, and mild metabolic acidosis. In general, the CPK elevation is not usually as severe as what is observed with NMS or MH, but significant elevation is occasionally seen with critically ill individuals. Laboratory analysis may help identify drugs of abuse as well as assisting in the identification and treatment of complications associated with serotonin syndrome (e.g., hypoxia, pneumonia, rhabdomyolysis, renal failure, hepatic transaminitis, and DIC). Lifethreatening complications of serotonin syndrome commonly occur in patients with severe and prolonged neuromuscular hyperactivity and resultant hyperthermia.

MALIGNANT HYPERTHERMIA Introduction, History, and Epidemiology Malignant hyperthermia (MH) was first described in 1962.57 It is an idiosyncratic drug reaction triggered by inhaled anesthetics and/or by the depolarizing paralytic succinylcholine. It is a disease that primarily occurs in the operating room, with an incidence of about 1 in 12,000 to 1 in 40,000 general anesthetic cases.58 It is believed that the number of susceptible patients is likely higher since 50% of patients in whom the syndrome develops have had prior anesthesia without manifesting MH.59,60 It is thought that those of African descent have a much lower rate of the genetic defect than whites.61 There are several different proteins linked to the disease and several different genetic differences within each gene. For example, there have been more than 20 different abnormal ryanodine receptor genes (RYR1) identified alone. MH is different from the other two “neuromuscular” syndromes in that the pathology is maintained without further stimulation at the neuromuscular junction. It is a disease of abnormal cytosolic calcium physiology that occurs in skeletal muscle cells and results in a cascade of pathophysiologic changes that culminate in a hypermetabolic state. When it was first recognized and reported, MH was associated with significant mortality (approximately 80%). Fortunately, the mortality rate has fallen to about 5% with aggressive, early treatment with dantrolene. There is a swine model (porcine stress syndrome [PSS]) that has allowed significant research in the field. The PSS model, however, is limited; unlike humans, the genetic defect in the swine model is limited to one specific change in the ryanodine receptor. A syndrome of excessive susceptibility to stress resulting in morbidity clinically similar to MH has been


213

reported, without any of the usual MH triggers.62 In this MH-like syndrome, individuals experience elevations in temperature, labile blood pressure, acrocyanosis, muscle cramping, fasciculations and elevated CPK with certain environmental “stressors.” These “stressors” have included long car rides, bad news, increased external temperatures, medical illness and excessive activity. There may be a family history of mysterious sudden death, or of muscle cramps and easy fatigability with exercise. This has been termed the human stress syndrome, and individuals may be at higher risk for exertional heat stroke. This syndrome is believed to share a similar pathology with MH, but without the antecedent exposure to anesthetic/paralytic agents.62,63 MH gene abnormalities have been found in some patients with this stress-induced syndrome and exerciseinduced rhabdomyolysis.64-66

Pathophysiology of Malignant Hyperthermia Under normal physiologic conditions, elevated intracellular calcium levels trigger contraction. The ryanodine receptor of the sarcoplasmic reticulum is associated with the dihydropyridine receptor (DHPR, L-type calcium channel) of the cellular membrane, and a structural change of the DHPR (which occurs during depolarization) is believed to open the ryanodine receptor. This elevated intracellular calcium stimulates more calcium release from the sarcoplasmic reticulum (calciuminduced calcium release). An increase in inositol-1,4,5triphosphate is also responsible for mobilizing stored calcium through its own sarcoplasmic reticulum receptor (InsP3). MH is caused by a cascade of biochemical changes in skeletal muscle, culminating in markedly increased metabolic rates within muscle cells. Sustained muscle contraction and rigidity typically occur. Acute toxicity is marked by elevated intracellular calcium levels. Many MH patients (and the heat-intolerant swine) have a defect in this ryanodine receptor that is believed to trigger excessive calcium release from the sarcoplasmic reticulum. The specific defect may be attributed to increased rates of calcium-induced calcium release. Some (but not all) studies have hypothesized that there are higher basilar intracellular calcium concentrations within MH-prone muscle cells.67,68 This increased intracellular calcium concentration would cause increased metabolic rate and increased activity of the sarcoplasmic Ca2+/ATPase. The increased metabolic rate can occur without having contracture.58 Higher levels of cyclic adenosine monophosphate (cAMP) are found in MH patients during exercise when compared with control patients, providing additional evidence for an alteration in the secondary messenger system.69 The cell membrane sodium channel populations are different between MH patients and controls, possibly as a result of chronically elevated intracellular Ca2+ levels.70 The initial trigger that leads to elevated intracellular calcium concentrations is not well understood. For the inhaled anesthetics, it has been hypothesized that these

214


agents interact with the ryanodine channel and lower the threshold for release of calcium from the sarcoplasmic reticulum.58 For succinylcholine, cellular depolarization from motor end-plate stimulation leads to elevated intracellular calcium concentrations. Phosphodiesterase inhibitors have rarely been reported to cause MH; elevated intracellular calcium concentrations may occur from these agents’ effects on cAMP levels and the secondary messenger system. Several genetic mutations have been found to be associated with MH, but only about half of malignant hyperthermia–sensitive (MHS) families have documented RYR1 mutations.71 Another gene that has been recently implicated is the dihydropyridine receptor gene; other gene abnormalities have been suggested.72 Cases of MH have been associated with various myopathic, metabolic, and mitochondrial genetic disorders.73 Of interest, persistent CPK elevations are frequently found in asymptomatic MH individuals.72 The administration of 5-HT agonists to skeletal muscle from MH patients can trigger contractures.74-77 This suggests a link between MH and serotonin. It is believed, however, that the increase in circulating 5-HT is a secondary response to (like catecholamine increase) and not a primary cause of contractures. The use of 5-HT receptor antagonists has not prevented morbidity from triggered MH in the PSS model.78,79 It has been observed that 5-HT2 antagonists reduce the MH response in human biopsies, possibly by causing hyperpolarization or modifying IP3 levels.33,76,80 Serotonin antagonists (such as cyproheptadine) have not been used in humans for MH. Although similar to NMS in clinical appearance, MH syndrome has markedly different pathophysiology. Key differences between MH and NMS are the rapid onset of symptoms with MH versus the slower onset with NMS, and the shorter duration of illness in MH. In addition, patients with episodes of NMS have been successfully treated with inhaled anesthetics. Although it has been suggested previously that neuroleptics might be able to trigger MH, subsequent study has shown this not to be true. There is no apparent link between NMS and MH.81

Clinical Manifestation of Malignant Hyperthermia MH often begins rapidly after administration of the triggering agent (inhaled anesthetic or succinylcholine). Most of the inhaled anesthetics can trigger MH, including halothane, enflurane, isoflurane, methoxyflurane, desflurane, and servoflurane.82 Synergy between the two classes of agents has been reported. MH has also been reported to be caused by enoximone, a phosphodiesterase inhibitor.83-85 One should also consider stressors (such as trauma or procedures) as potential triggers for the syndrome. There are “safer” alternative agents that may be used for anesthesia in patients at risk for MH. These agents include propofol, benzodiazepines, nitrous oxide, and narcotics.59,86 The signs and symptoms of MH are reflective of a greatly increased metabolic rate. The earliest, most sensitive, and specific signs of MH are increased rate

of CO2 production (as either expired CO2 or partial pressure of CO2 in arterial blood [PaCO2]). Other early findings include a rapid rise in core temperature (as fast as 1º F every 5 minutes), diffuse muscle rigidity, and acidosis.58 Temperature often rapidly increases and may not be initially noticed if the patient began at a subnormal temperature. Tetanic muscle contraction within 20 minutes after the muscle relaxants are administered is often reported. Symptoms of the full syndrome include tachycardia, rigidity, poor chest wall compliance, acidosis, cyanosis, mottling, hypotension, ventricular arrhythmias, increased ventricular rate, and elevated CPK. Hyperkalemia and marked hyperthermia carry a poor prognosis. As for other hyperthermic syndromes, the incidence of secondary complications and mortality is directly correlated with the severity and duration of hyperthermia. Sometimes the initial symptoms are subtle, such as increased masseter muscle tone during intubation; masseter rigidity may make intubation difficult. Generalized rigidity shortly following the administration of inhaled anesthetics or succinylcholine is virtually pathognomonic for MH. Generalized muscle rigidity, however, may not be present. Clinical rigidity may be relatively mild compared with subsequent CPK elevation, lactate, and myoglobinuria. In some patients, particularly those with delayed or atypical cases, the only symptoms might be muscle cramping and urinary color change reflective of ongoing rhabdomyolysis seen postoperatively.87,88 While the majority of cases have rapid onset, there are reports of delayed onset (especially with desflurane). The onset of the signs and symptoms of MH may not occur until the time of paralytic reversal or later in the recovery room.89 When succinylcholine is used, it is believed to accelerate the onset of the episode. The use of nondepolarizing paralytics are believed to slow the onset of the MH episode.82 Isolated rhabdomyolysis may sometimes occur and is associated with a delayed presentation and diagnosis.90 Recurrence of symptoms is not uncommon (see later section on Malignant Hyperthermia Management). Complications of MH include electrolyte abnormalities (i.e., hyperkalemia, hypercalcemia, hypocalcemia), ventricular fibrillation, DIC, rhabdomyolysis, hypoxia, hyperthermia, pulmonary edema, cerebral edema, and encephalopathy. These complications are ultimately responsible for the mortality and morbidity of MH. Autopsy findings (other than muscle biopsies) are nonspecific. Weakness and fatigue may last for months following an episode.62

DIAGNOSIS OF HYPERTHERMIC SYNDROMES The initial diagnosis for all three syndromes is made clinically and based on a suggestive history and physical findings. Although confirmatory laboratory tests do not exist for NMS and serotonin syndrome, the diagnosis of MH can be confirmed by the in vitro halothane or caffeine contracture test. In general, specific laboratory

CHAPTER 10

and other ancillary tests are obtained to rule out other illnesses that may be confused with these hyperthermic syndromes. For instance, during the initial patient evaluation, a diligent investigation for all sources of infection should be made, including blood, urine, and cerebrospinal fluid cultures. In addition, recommended laboratory tests include CBC, electrolytes, serum creatine phosphokinase (CPK), and urinalysis. An EEG may be obtained to exclude seizure activity. The gold standard for diagnosis of MH is a muscle biopsy specimen that is then exposed to halothane and caffeine; the basis for this test is that contractions are seen at much lower concentrations of the triggering agents than in normal muscle tissue. There are two significantly different protocols in use for testing the muscle tissue: the North American Malignant Hyperthermia Group Protocol and the European Malignant Hyperthermia Group Protocol. Either of these protocols may be utilized but they have differing reported sensitivities and specificities.91,92 Both protocols have a sensitivity close to 100%, whereas the specificity for the European protocol is 82% to 93% but only 78% for the North American protocol.92 These protocols will categorize patients into one of three different groups: malignant hyperthermia negative, malignant hyperthermia sensitive (MHS), and malignant hyperthermia equivocal (MHE). Positive in vitro muscle contraction to both halothane and caffeine results in an MHS designation, whereas a positive contraction to only one agent results in an MHE designation. For maximum clinical safety, MHE is treated as MHS. The concentration of halothane and caffeine used as well as the strength of contraction should be reported. There are some significant limitations of the halothane-caffeine contracture test. Caffeine is believed to increase calcium release from the sarcoplasmic reticulum.58 The test requires an open biopsy; this combined with its poor specificity makes it ineffective as a screening test. There is a significant difference in outcome between the two protocols,91 and significant intralaboratory variability as well as variability within the same biopsy.93 False-positive results have been reported in patients with myopathies, but these patients may be at higher risk for developing MH. Abnormal in vitro muscle contraction similar to MH has also been observed in some patients that have suffered exertional heat stroke, suggesting a common pathology. The muscle biopsy has no utility in diagnosis of NMS. Although there are reports of abnormal contractions of muscle fibers to fluphenazine, this was performed at very high concentrations and has not been replicated.94 In addition, patients who have suffered from NMS have undergone general anesthesia without any problems, and no familial link has been found between the two diseases.

DIFFERENTIAL DIAGNOSIS Although these three neuromuscular syndromes are all characterized by alterations in mental status, autonomic dysfunction, and neuromuscular hyperactivity, they are


215

often readily distinguishable by history, temporal profile, and the presence of unique physical findings. The clinical signs and symptoms that can be used to differentiate these syndromes are listed in Table 10A-1. The presence of clonus (myoclonus and ocular clonus), hyperreflexia, and tremors are unique to serotonin syndrome and not present with the other two neuromuscular syndromes. Rigidity is lead pipe type and diffuse with NMS, rigor mortis–like and diffuse with MH, and clasp-knife type and more prominent in the lower extremities with serotonin syndrome. These three hyperthermic syndromes must be differentiated from other conditions associated with fever and neuromuscular hyperactivity. These include the anticholinergic and sedative-hypnotic withdrawal syndromes; poisoning by hallucinogens, salicylates, and other uncouplers (e.g., dinitrophenol), lithium, MAOIs, strychnine, nicotine, and sympathomimetics; and nontoxic etiologies, such as intracranial hemorrhage, brain tumors, CNS infections (e.g., meningoencephalitis, brain abscess), CNS vasculitis, thyrotoxicosis, addisonian crisis, heat stroke, pheochromocytoma, hypocalcemia, hypomagnesemia, tetanus, and lethal catatonia. EPS can occasionally look like early NMS, and some clinicians have proposed a spectrum of basal ganglia dopamine dysfunction, with NMS being the extreme manifestation along a continuum. The presence of EPS that are persistent and resistant to or exacerbated by anticholinergic treatment may suggest early NMS.

MANAGEMENT OF HYPERTHERMIC SYNDROMES Management of NMS, serotonin syndrome, and MH involves immediate termination of any precipitating drugs, the provision of aggressive supportive care, and the administration of adjunctive pharmacotherapies for each syndrome. Aggressive supportive care entails the control of patient agitation and neuromuscular hyperactivity, intravenous rehydration, treatment of hyperthermia, and treatment of associated complications. Gastrointestinal decontamination is not useful for NMS, MH, or serotonin syndrome due to the delay of onset of symptoms and the route of administration of the precipitating agents. The decrease in mortality observed for NMS and serotonin syndrome is most likely due to early recognition and better critical care medicine, not due to specific antidotes. In contrast, the timeliness of initiation of the antidote, dantrolene, is critical to effect a good survival for those with MH. Complications of these syndromes are similar and can include rhabdomyolysis, renal failure, aspiration pneumonitis, respiratory failure, thromboembolism, deep venous thrombosis, infection, electrolyte imbalance, DIC, hepatic dysfunction, and cardiovascular collapse. Supportive care should be aggressive and directed at preventing or treating these complications. Special attention should be directed to ventilator status (especially if there is chest wall rigidity preventing ventilation),

216


hydration, temperature, electrolytes, and possible seizures. Aggressive fluid hydration is usually warranted; if comorbidities are present, then central monitoring for fluid status may be required. Hydration and possible alkalinization of the urine will help treat the rhabdomyolysis and myoglobinuria that often results. Vasopressor support should be given as needed for hypotension, assuming that fluid resuscitation is complete. Many of the complications of these syndromes occur largely as a result of neuromuscular hyperactivity and secondary hyperthermia. Attention should be directed to careful temperature monitoring and should always rely on core temperature readings because peripheral measurements can be erroneous. Cooling measures may initially include intravenous (IV) benzodiazepines (diazepam 0.1 to 0.3 mg/kg or lorazepam 0.05 to 0.1 mg/kg), antipyretics, evaporative cooling, ice packs, cooled IV fluids, and adjunctive pharmacotherapies specific to each syndrome. For those patients with NMS and serotonin syndrome who develop severe or protracted hyperthermia (i.e., temperature greater than 40° C), the use of nondepolarizing paralytics (e.g., pancuronium) is strongly recommended.95 Neuromuscular blockade will achieve rapid, predictable, and effective reduction of rigidity and fever. In contrast, for patients with MH, treatment with dantrolene is the key to minimizing mortality from severe hyperthermia. Neuromuscular blockade will not achieve muscle relaxation with MH.

Neuroleptic Malignant Syndrome Management There are many opinions as to the “correct” treatment for NMS. Most of what we know about treatment for this syndrome is from collections of case reports, case series, or retrospective, noncontrolled studies. There have been no prospective, controlled treatment studies. Immediate discontinuation of the offending agent is central to successful treatment. One should also ensure that other non-neuroleptic dopamine-blocking agents (e.g., metoclopramide) and other syndrome-potentiating medications (e.g., lithium, anticholinergic agents) are stopped as well. Supportive care is often overlooked in a rush to use the most “up to date” treatment. Because the natural course of the illness is often characterized by waxing and waning symptoms, initial improvement may be mistakenly interpreted as a positive response to a specific treatment. Benzodiazepines and barbiturates have been used successfully in individual cases and retrospective, uncontrolled studies. In one retrospective study of 16 patients with NMS, clinical improvement was noted within 24 to 72 hours of benzodiazepine treatment initiation (e.g., lorazepam).96 Regardless, it is uncertain if benzodiazepines hasten the recovery from NMS over supportive care alone. Benzodiazepine therapy has the advantage of being generally safe with minimal side effects. The alternative sedating agents, barbiturates, may lower the blood pressure when administered rapidly, which limit their utility with the unstable patient.

Theoretically there should be some CNS benefit for either drug due to increased γ-aminobutyric acid (GABA) tone limiting central neurologic excitation and possible injury. Standard initial IV doses of benzodiazepines (diazepam 0.1 to 0.3 mg/kg or lorazepam 0.05 to 0.1 mg/kg) should be employed. Additional doses may be administered as needed to achieve the desired level of sedation and sympatholysis. Another GABA agonist, propofol (2,6 diisopropylphenol), might be effective for the short-term treatment of those patients with severe agitation and muscular rigidity. In this setting, propofol should only be administered to patients that are intubated. Propofol is complicated by potential hypotension due to its negative inotropic effects. Due to the similarity of NMS to MH, dantrolene has been utilized for the treatment of fever and muscle rigidity associated with NMS. Dantrolene is a direct skeletal muscle relaxant; it prevents calcium release from skeletal muscle sarcoplasmic reticulum by acting on the ranitidine receptor. It has very little affect on smooth and cardiac muscle. It is very effective for MH, but its efficacy in NMS has not been firmly established. Anecdotal experience suggests occasional efficacy, but case control studies have had mixed results. Dantrolene will not terminate muscular rigidity and hyperthermia as rapidly as nondepolarizing paralytic therapy. Doses utilized have ranged from 25 mg to more then 300 mg per day. It is available in an oral and IV form; a starting IV dose of 1 to 2.5 mg/kg every 6 to 12 hours is recommended, titrating the dose upward as needed. A maximum dose of 10 mg/kg/day is recommended. Side effects of dantrolene include dizziness, headache, fatigue, drowsiness, and weakness (rarely clinically significant).97 Idiosyncratic reactions from chronic use that have been reported include hepatic dysfunction and a pleuropericardial reaction. Dantrolene has not been shown (and would not be expected) to correct a central disorder of thermoregulation.98 It should probably be reserved for NMS patients with rigidity who have failed other treatments. Bromocriptine has been used at a dose of 2.5 to 15 mg given three times a day. Bromocriptine is a partial dopamine agonist/antagonist. In rat studies, it can reverse the catatonia induced by neuroleptics. Data on its efficacy are mixed; studies have been done showing both benefit and lack thereof (see Chapter 38). Some retrospective studies have demonstrated a significant reduction in mortality from NMS in those patients treated with bromocriptine as compared with supportive care alone.99,100 In addition, some patients who were treated with bromocriptine for NMS experienced recurrence of NMS symptoms when this therapy was suddenly discontinued. It has some mild side effects, namely nausea, vomiting, limited vasospasm, dyskinesias, hallucinations, and worsening psychosis. Bromocriptine does have a mild stimulatory effect on 5-HT receptors and does reduce brain serotonin turnover.101 Its indiscriminate use should be tempered with the knowledge that it might theoretically worsen serotonin syndrome.53 It should be strongly considered for treatment of unequivocal cases of NMS.

CHAPTER 10

Amantadine is a parkinsonian drug reported to be successfully used for NMS in only a few cases, making firm conclusions about its efficacy impossible.102 It has minimal dopamine agonistic properties and its benefit may actually arise from its N-methyl-D-aspartate, glutamate receptor antagonist properties.103 It has been used in divided doses from 200 to 400 mg a day. L-dopa/ carbidopa has been tried with mixed success. There is evidence that L-dopa can cause serotonin release, which could worsen serotonin syndrome. In general, other dopaminergic agents should be considered before amantadine or L-dopa are initiated. For treatment of EPS from neuroleptic use, anticholinergic agents are often employed. The theory is that decreasing cholinergic tone increases dopamine tone, thus alleviating the symptoms of dopamine receptor antagonism. However, in general, anticholinergic agents have not been shown to be of benefit for NMS. They are likely to be detrimental when the dose is increased due to their effect on heat dissipation and CNS effects. They should be stopped or possibly tapered if the patient has been on them for a prolonged period. Electroconvulsive therapy (ECT) has been reported as effective for the treatment of NMS, although controlled studies are lacking.104 Some of the early cases had morbidity associated with the procedure, but with closer monitoring these events have not recurred. ECT increases brain catecholamine (i.e., dopamine) levels, which is believed to be the reason for its successful use. The successful use of ECT for NMS utilizing general anesthesia is additional evidence that MH and NMS are different syndromes. One should consider the use of ECT for patients with protracted signs and symptoms of NMS or those with catatonia after the illness has resolved.24 The best treatment for NMS is probably early recognition, immediate discontinuation of the precipitating agent, and vigilant supportive care in an intensive care unit setting. Adjunctive pharmacologic agents may be added. Once the episode of NMS has resolved, there is often a need to restart medication in patients with mental illness. Ideally, one should wait at least 2 weeks prior to restarting neuroleptics. Doses should be given orally, initiated at the lowest possible dose, and titrated up very slowly. Atypical or low-potency antipsychotics should be utilized. Patients should be in a setting where their temperature and clinical status can be closely monitored. Risk factors such as dehydration and agitation should be addressed and treated with IV fluids and sedation with benzodiazepines.

Serotonin Syndrome Management Because serotonin toxicity exists as a disease spectrum, it is difficult to give unifying or all-inclusive treatment recommendations. As for NMS, good supportive care and immediate discontinuation of the offending/ triggering agent are the most important aspects of treatment and will achieve a good outcome in the vast majority of patients. Depending on the pharmacokinetics and severity of the reaction, treatment decisions


217

range from outpatient to intensive care unit admission. The severe serotonin reactions are usually due to MAOI interactions with another proserotonergic agent. These patients should probably be admitted to the intensive care unit due to the potential severity of the syndrome. Serotonin syndrome is due to excessive stimulation at certain CNS 5-HT receptors (most likely 5-HT2A and possibly some 5-HT1A). Treatment with 5-HT2A receptor antagonists have been effective in animal models of serotonin syndrome and in case series of patients with serotonin syndrome. Cyproheptadine, an antihistamine with serotonin antagonist effects, has been effective for the treatment of serotonin syndrome.35,105 There are no randomized, controlled trials that have demonstrated the efficacy of cyproheptadine or other 5-HT2A receptor antagonists (e.g., chlorpromazine, olanzapine, risperidone, methysergide) for the treatment of serotonin syndrome. Efficacy for these pharmacotherapies is difficult to establish since serotonin syndrome is often self-limited and has a relatively short duration. Cyproheptadine is only available as an oral formulation; the usual dose in adults is 4 to 8 mg every 1 to 4 hours, up to a maximum of 32 mg/day.48 For children, the cyproheptadine dose is 1 to 2 mg every 1 to 4 hours, up to a maximum of 12 mg/day. There often is a positive response after a single dose, but larger doses may be necessary for those with serotonin syndrome as a complication of a serotonin agonist overdose. Cyproheptadine has some sedating and anticholinergic side effects, which may become problematic at the higher recommended doses. Methysergide has blockade at 5-HT1 and 5-HT2 receptors and has been infrequently used for serotonin syndrome; it has less 5-HT2A affinity than cyproheptadine.53 The recommended methysergide dose is 2 to 6 mg orally; it is not available for parenteral use. For either agent, if charcoal was given, larger doses may be required or this treatment may need to be abandoned due to adsorption of the antidote to charcoal. Chlorpromazine has been used as treatment for serotonin syndrome with positive results. In addition to its dopamine receptor antagonist effects, chlorpromazine is a potent 5-HT2A receptor antagonist with similar potency to cyproheptadine. It has the advantage of having a parenteral formulation and can be administered either IV or intramuscularly (IM).106 A starting dose might be 50 mg IM with a repeat dose in 4 hours if necessary; dosing is usually every 6 hours.29 Hypotension is common following larger doses of chlorpromazine. Thus, intravenous fluid administration should accompany or precede this therapy. Chlorpromazine is associated with numerous side effects (sedation, anticholinergic effects, dopaminergic blockade, potential to induce seizures, cardiac conduction effects). Use of this agent, while potentially effective, may also be associated with adverse effects and complicate patient treatment. Chlorpromazine should not be used if there is any concern for NMS. Other pharmacologic agents have been used for serotonin syndrome with mixed results. Benzodiazepines have been tried with mixed results. These agents are best reserved for patients with significant muscle rigidity

218


and hyperthermia. Diazepam or lorazepam may be administered in the same doses as recommended for NMS.107 The central GABA receptors are believed to have an inhibitory influence on serotonin syndrome.46 Very limited data exist for propranolol, which has been used to treat some of the hypertensive symptoms. Propranolol is a 5-HT1A antagonist and, thus, is not expected to reverse all the signs and symptoms of the syndrome.46,108 Due to its potential for adverse hemodynamic effects, propranolol must be used with considerable caution and cannot be recommended for first-line use. Mirtazapine has been used for the treatment of serotonin syndrome and theoretically may be efficacious via its 5-HT2A antagonistic properties.109,110 Nitroglycerin has been used and has resulted in some clinical improvement anecdotally.111 There is the theoretical possibility of exacerbating serotonin syndrome if treated with bromocriptine; this drug can increase brain 5-HT levels.53,112 Animal experimental data support the use of memantine (and possibly risperidone) for serotonin syndrome, but no human experience exists.113,114 Dantrolene has been used for serotonin syndrome without documented benefit. Dantrolene may cause increased CNS 5-HT tone and, thus, its use is not recommended for treatment of serotonin syndrome.115 Intubation and paralysis should be employed as they are for NMS if muscular rigidity or hyperthermia is severe and not initially responsive to alternative measures. Restarting medications should be done after a sufficient recovery time has been allowed. Exactly how long depends on the half-life of the drug and its metabolites and the duration of ongoing drug effect. With irreversible MAOI therapy, MAO is permanently inhibited and adequate time should be allowed (3 to 5 weeks) for regeneration of the enzyme prior to reinitiation of another proserotonergic agent.48,116 When medications are restarted, they should be restarted one at a time at the lowest effective dose and slowly advanced to the target level. Additional medications can subsequently be added as needed. A reevaluation of the need for MAOI treatment and the most potent serotonin reuptake inhibitors should be performed. Agents with less proserotonergic effect should be tried initially and started at low doses.

Malignant Hyperthermia Management This syndrome has a radically different pathophysiology from NMS and serotonin syndrome. The pathology is within the skeletal muscle itself and is not secondary to enhanced nerve activity and motor end-plate stimulation. No benefit is derived from benzodiazepines and nondepolarizing paralytics. As for the other hyperthermic syndromes, when MH is suspected, the precipitating agents must be discontinued immediately. For MH, aggressive supportive care includes hyperventilation, IV fluid administration, correction of electrolyte abnormalities (e.g., hyperkalemia, hypocalcemia, hypercalcemia), rapid cooling, and treatment of associated complications as they occur (e.g., rhabdomyolysis, renal failure, respiratory failure). Bicarbonate has been

advocated, and that combined with dextrose should be beneficial to treat associated hyperkalemia. The treatment of choice is dantrolene. There is a direct correlation between survival and early administration of dantrolene in patients with MH.117 Dantrolene is believed to interact with the ryanodine skeletal muscle receptor, preventing further release of calcium from the sarcoplasmic reticulum, halting the pathologic cascade operative in MH. The starting dose of dantrolene is 2.5 mg/kg IV. This dose can be repeated every 2 to 3 minutes until a maximum of 10 mg/kg has been administered. The IV formulation is preferred in all situations of MH due to uncertain levels achieved with oral dosing. Dantrolene is occasionally used as prophylaxis for patients with a previous history of MH or with a very strong family history of anesthetic-associated deaths. In this situation it is given as a 2.5 mg/kg dose prior to anesthesia; but despite this pretreatment, patients can still develop MH, so there should be strong consideration for using “safer” agents in such patients. Once a patient has developed MH, dantrolene should be continued every 6 hours until symptoms completely resolve, because dantrolene has a half-life of 12 hours.118 When repeated doses are used, patients are much less likely to have a recurrence of symptoms. Sufficient dosing is recommended because subtherapeutic amounts of dantrolene may paradoxically open the ryanodine channel, possibly exacerbating illness.119 The use of calcium channel blockers (e.g., verapamil) with dantrolene has been associated with hyperkalemia and hypotension. The use of calcium channel antagonists for arrhythmias is thus not recommended, even though this synergistic toxicity has not been demonstrated in a dog model.120 Short-term side effects of dantrolene have included weakness, dizziness, and fatigue; clinically significant weakness appears to be rare.97 REFERENCES 1. Delay J, Pichot P, Lemperiere T, et al: Un neuroleptique majeur nonphenothiazine et non-reserpinique, l’haloperidol, dans le traitement des psychoses. Ann Med Psychol 1960;118:145–152. 2. Caroff SN, Mann SC: Neuroleptic malignant syndrome. Med Clin North Am 1993;77(1):185–202. 3. Keck PE, Pope HG, McElroy SL: Declining frequency of neuroleptic malignant syndrome in a hospital population. Am J Psychiatry 1991;148:880–882. 4. Gelenberg AJ, Bellinghansen B, Wojcik JD, et al: A prospective survey of neuroleptic malignant syndrome in a short-term psychiatric hospital. Am J Psychiatry 1988;145:517–518. 5. Keck PE, Sebastianelli J, Pope HG, et al: Frequency and presentation of neuroleptic malignant syndrome in a state psychiatric hospital. J Clin Psychiatry 1989;50:352–355. 6. Farver DK: Neuroleptic malignant syndrome induced by atypical antipsychotics. Expert Opin Drug Saf 2003;2(1):22–35. 7. Karagianis FL, Phillips LC, Hogan KP, LeDrew KK: Clozapineassociated neuroleptic malignant syndrome: two new cases and a review of the literature. Ann Pharmacother 1999;33:623–630. 8. Friedman JH, Feinberg SS, Feldman RG: A neuroleptic malignantlike syndrome due to levodopa therapy withdrawal. JAMA 1985;254(19):2792–2795. 9. Hermesh H, Sirota P, Eviatar J: Recurrent neuroleptic malignant syndrome due to haloperidol and amantadine. Biol Psychiatry 1989;25:962–965. 10. Friedman E, Gershon S: Effect of lithium on brain dopamine. Nature 1973;243:520–521.

CHAPTER 10

11. Spring G, Frankel M: New data on lithium and haloperidol incompatibility. Am J Psychiatry 1981;138(6):818–821. 12. Davis JM, Caroff SN, Mann SC: Treatment of neuroleptic malignant syndrome. Psychiatr Ann 2000;30(5):325–331. 13. Carroll BT, Taylor RE: The nondichotomy between lethal catatonia and neuroleptic malignant syndrome. J Clin Psychopharmacol 1997;17(3):235–236. 14. Korsgaard S, Gerlach J, Christensson E: Behavioral aspects of serotonin-dopamine interaction in the monkey. Eur J Pharmacol 1985;118:245–252. 15. Carter CJ, Pycock CJ: Possible importance of 5-hydroxytryptamine in neuroleptic induced catalepsy in rats [proceedings]. Br J Pharmacol 1977;60(2):267P–268P. 16. Kapur S, Remington G: Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry 1996;153(4): 466–476. 17. Halman M, Goldbloom DS: Fluoxetine and neuroleptic malignant syndrome. Biol Psychiatry 1990;28:518–521. 18. Caley CF: Extrapyramidal reactions and the selective serotoninreuptake inhibitors. Ann Pharmacother 1997;31:1481–1489. 19. Addonizio G, Susman VL, Roth SD: Neuroleptic malignant syndrome: review and analysis of 115 cases. Biol Psychiatry 1987;22: 1004–1020. 20. Totten V, Hirschenstein E, Hew P: Neuroleptic malignant syndrome presenting without initial fever: a case report. J Emerg Med 1994;12(1):43–47. 21. Taylor C, Rogers G, Goodman C, et al: Hematologic, iron-related, and acute-phase protein responses to sustained strenuous exercise. J Appl Physiol 1987;62(2):464–469. 22. Rosebush PI, Mazurek MF: Serum iron and neuroleptic malignant syndrome. Lancet 1991;338:149–150. 23. Van Harten PN, Kemperman CJF: Organic amnestic disorder: a long-term sequel after neuroleptic malignant syndrome. Biol Psychiatry 1991;29:407–410. 24. Caroff S, Mann SC, Keck PE Jr, Francis A: Residual catatonic state following neuroleptic malignant syndrome. J Clin Psychopharmacol 2000;20(2):257–259. 25. Mitchell RS: Fatal toxic encephalitis occurring during iproniazid therapy in pulmonary tuberculosis. Ann Intern Med 1955;42: 417–424. 26. Oates JA, Sjoerdsma A: Neurologic effects of tryptophan in patients receiving a monoamine oxidase inhibitor. Neurology 1960;10:1076–1078. 27. Grahame-Smith DG: Studies in vivo on the relationship between brain tryptophan, brain 5-HT synthesis and hyperactivity in rats treated with a monoamine oxidase inhibitor and L-tryptophan. J Neurochem 1971;18:1055–1066. 28. Insel TR, Roy BF, Cohen RM, et al: Possible development of the serotonin syndrome in man. Am J Psychol 1982;139:954–955. 29. Gillman PK: The serotonin syndrome and its treatment. J Psychopharmacol 1999;13:100–109. 30. Nisijima K, Shioda K, Yoshino T, et al: Diazepam and chlormethiazole attenuate the development of hyperthermia in an animal model of the serotonin syndrome. Neurochem Int 2003; 43:155–164. 31. Nisijima K, Yoshino T, Yui K, Katoh S: Potent serotonin (5-HT)2A receptor antagonists completely prevent the development of hyperthermia in an animal model of the 5-HT syndrome. Brain Res 2001;890:23–31. 32. Mazzola Pomietto P, Aulakh CS, Wozniak KM, et al: Evidence that 1-(2,5-dimethoxy-4-iodophenol)-2-aminopropane (DOI)-induced hyperthermia in rats is mediated by stimulation of 5-HT2A receptors. Psychopharmacology 1995;117:193–199. 33. Siegel GJ (ed): Basic Neurochemistry. Philadelphia, Lippincott Williams & Wilkins, 1999. 34. Zerjav-Lacombe S, Dewan V: Possible serotonin syndrome associated with clomipramine after withdrawal of clozapine. Ann Pharmacother 2001;35:180–182. 35. Horowitz Z, Mullins ME: Cyproheptadine for serotonin syndrome in an accidental pediatric sertraline ingestion. Pediatr Emerg Care 1999;15(5):325–327. 36. Isbister GK, Bowe SJ, Dawson A, Whyte IM: Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol Clin Toxicol 2004;42:277–285.


219

37. Tatsumi M, Groshan K, Blakely RD, Richelson E: Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Euro J Pharmacol 1997;340:249–258. 38. Whyte IM, Dawson AH, Buckley NA: Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. QJM 2003;96: 369–374. 39. Gillman PK: Serotonin syndrome: history and risk. Fundam Clin Pharmacol 1998;12:482–491. 40. Gillman K: Serotonin toxicity. Accessed January 15, 2005, at www.psychotropical.com/SerotoninToxicity.doc. 41. Bamigbade TA, Davidson C, Langford RM, Stamford JA: Actions of tramadol, its enantiomers and principle metabolite, Odesmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus. Br J Anaesth 1997;79:352–356. 42. Brodribb TR, Downey M, Gilbar PJ: Efficacy and adverse effects of moclobemide. Lancet 1994;343:475. 43. Zornberg GL, Bodkin JA, Cohen BM: Severe adverse interaction between pethidine and selegiline. Lancet 1991;337:246. 44. Hinds NP, Hiller CE, Wiles CM: Possible serotonin syndrome arising from an interaction between nortriptyline and selegiline in a lady with parkinsonism. J Neurol 2000;247:811. 45. Francis E, Harchelroad F: LSD/fluoxetine-induced serotonin syndrome. J Toxicol Clin Toxicol 1996;34(5):560. 46. Marsden CA, Heal DJ (ed): Central Serotonin Receptors and Psychotropic Drugs. Oxford, Blackwell Scientific, 1992. 47. Brush ED, Bird SB, Boyer EW: Monoamine oxidase inhibitor poisoning resulting from Internet misinformation on illicit substances. J Toxicol Clin Toxicol 2004;42(2):191–195. 48. Hardman JG, Limbird LE (eds): Goodman & Gillman’s The Pharmacological Basis of Therapeutics, 9th ed. New York, McGraw-Hill, 1996. 49. John L, Perreault MM, Tao T, Blew PG: Serotonin syndrome associated with nefazodone and paroxetine. Ann Emerg Med 1997;29(2):287–289. 50. Baetz M, Malcolm D: Serotonin syndrome from fluvoxamine and buspirone. Can J Psychiatry 1995;40(7):428–429. 51. Mathew NT, Tietjen GE, Lucker C: Serotonin syndrome complicating migraine pharmacotherapy. Cephalalgia 1996;16:323–327. 52. Turkel SB, Nadala JG, Wincor MZ: Possible serotonin syndrome in association with 5-HT3 antagonist agents. Psychosomatics 2001;42(3):258–260. 53. Sandyk R: L-Dopa induced “serotonin syndrome” in a parkinsonian patient on bromocriptine. J Clin Psychopharmacol 1986;6(3):194. 54. Kuisma MJ: Fatal serotonin syndrome with trismus. Ann Emerg Med 1995;26(1):108. 55. Mills KC: Serotonin syndrome: a clinical update. Crit Care Clin 1997;13(4):763–783. 56. Sternbach H: The serotonin syndrome. Am J Psychiatry 1991; 148:705–813. 57. Denborough MA, Forster JF, Lovell RR, et al: Anaesthetic deaths in a family. Br J Anaesth 1962;34:395–396. 58. Mickelson JR, Louis CF: Malignant hyperthermia: excitationcontraction coupling, Ca2+ release channel, and cell Ca2+ regulation defects. Physiol Rev 1996;76(2):537–592. 59. Nelson TE, Flewellen EH: The malignant hyperthermia syndrome. N Engl J Med 1983;309(7):416–418. 60. Britt BA, Kalow W: Malignant hyperthermia: a statistical review. Can Anaesth Soc J 1970;17(4):293–315. 61. Lane JE, Brooks AG, Logan MS, et al: An unusual case of malignant hyperthermia during desflurane anesthesia in an African-American patient. Anesth Analg 2000;91:1032–1034. 62. Jardon OM: Physiologic stress, heat stroke, malignant hyperthermia—a perspective. Milit Med 1982;147:8–14. 63. Bendahan D, Kozak-Ribbens G, Confort-Gouny S, et al: A noninvasive investigation of muscle energetics supports similarities between exertional heat stroke and malignant hyperthermia. Anesth Analg 2001;93:683–689. 64. Wappler F, Fiege M, Steinfath M, et al: Evidence for susceptibility to malignant hyperthermia in patients with exercise-induced rhabdomyolysis. Anesthesiology 2001;94:95–100. 65. Wappler F, Fiege M, Antz M, Schulte am Esch J: Hemodynamic and metabolic alterations in response to graded exercise in a

220

66. 67.

68.

69. 70. 71. 72. 73. 74.

75.

76. 77.

78.

79.

80.

81.

82. 83. 84.

85.

86.


patient susceptible to malignant hyperthermia. Anesthesiology 2000;92:268–272. Tobin JR, Jason DR, Challa VR, et al: Malignant hyperthermia and apparent heat stroke. JAMA 2001;286(2):168–169. Bendahan D, Kozak-Ribbens G, Rodet L, et al: 31Phosphorus magnetic resonance spectroscopy characterization of muscular metabolic anomalies in patients with malignant hyperthermia: application of diagnosis. Anesthesiology 1998;88(1):96–107. Lopez JR, Contreras J, Linares N, Allen PD: Hypersensitivity of malignant hyperthermia-susceptible swine skeletal muscle to caffeine is mediated by high resting myoplasmic [Ca2+]. Anesthesiology 2000;92:1799–1806. Standec A, Stefano G: Cyclic AMP in normal and malignant hyperpyrexia susceptible individuals following exercise. Br J Anaesth 1984;56:1243–1246. Fletcher JE, Wieland SJ, Karan SM, et al: Sodium channel in human malignant hyperthermia. Anesthesiology 1997;86(5): 1023–1032. Ball SP, Johnson KJ: The genetics of malignant hyperthermia. J Med Genet 1993;30(2):89–93. Gurrera RJL: Is neuroleptic malignant syndrome a neurogenic form of malignant hyperthermia? Clin Neuropharmacol 2002;25(4):183–193. Lambert C, Blanloeil Y, Horber RK, et al: Malignant hyperthermia in a patient with hypokalemic periodic paralysis. Anesth Analg 1994;79:1012–1014. Wappler F, Scholz J, von Richthofen V, et al: Attenuation of serotonin-induced contractures in skeletal muscle from malignant hyperthermia-susceptible patients with dantrolene. Acta Anesthesiol Scand 1997;41:1312. Wappler F, Scholz J, Oppermann S, et al: Ritanserin attenuates the in vitro effects of the 5-HT2 receptor agonist DOI on skeletal muscles from malignant hyperthermia susceptible patients. J Clin Anesth 1997;9:306–311. Wappler F, Fiege M, Schulte am Esch J: Pathophysiological role of the serotonin system in malignant hyperthermia. Br J Anaesth 2001;87(5):794–798. Wappler F, Roewer N, Kochling A, et al: Effects of the serotonin 2 receptor agonist DOI on skeletal muscle specimens from malignant hyperthermia-susceptible patients. Anesthesiology 1996;84(6):1280–1287. Richter A, Scholz J, Loscher W, et al: Effects of the 5-HT2 receptor antagonist ritanserin on halothane-induced increase of inositol phosphates in porcine malignant hyperthermia. Arch Pharmacol 1996;354:593–597. Löscher W, Gerdes C, Richter A: Lack of prophylactic or therapeutic efficacy of 5-HT2A receptor antagonists in halothane induced porcine malignant hyperthermia. Arch Pharmacol 1994;350:365–374. Wappler F, Scholz J, Fiege M, et al: 5-HT2 receptor antagonistmediated inhibition of halothane-induced contractures in skeletal muscle specimens from malignant hyperthermia susceptible patients. Naunyn Schmiedebergs Arch Pharmacol 1999;360:376–381. Hermesh H, Aizenberg D, Lapidot M, Munitz H: Risk of malignant hyperthermia among patients with neuroleptic malignant syndrome and their families. Am J Psychiatry 1988; 145(11):1431–1434. Allen GC, Brubaker CL: Human malignant hyperthermia associated with desflurane anesthesia. Anesth Analg 1998;86(6): 1328–1331. Fiege M, Wappler F, Weisshorn R, et al: In vitro and in vivo effects of the phosphodiesterase-iii inhibitor enoximone on malignant hyperthermia-susceptible swine. Anesthesiology 2003;98:944–949. Riess FC, Fiege M; Moshar S, et al: Rhabdomyolysis following cardiopulmonary bypass and treatment with enoximone in a patient susceptible to malignant hyperthermia. Anesthesiology 2001;94:355–357. Fiege M, Wappler F, Scholz J, et al: Effects of the phosphodiesterase-III inhibitor enoximone on skeletal muscle specimens from malignant hyperthermia susceptible patients. J Clin Anesth 2000;12:123–128. McKenzie AJ, Couchman KG, Pollock N: Propofol is a “safe” anesthetic agent in malignant hyperthermia susceptible patients. Anaesth Intensive Care 1992;20(2):165–168.

87. Fierobe L, Nivoche Y, Mantz J, et al: Perioperative severe rhabdomyolysis revealing susceptibility to malignant hyperthermia. Anesthesiology 1998;88(1):263–265. 88. Harwood T, Nelson TE: Massive postoperative rhabdomyolysis after uneventful surgery: a case report of subclinical malignant hyperthermia. Anesthesiology 1998;88(1):265–268. 89. Hoenemann CW, Halene-Holtgraeve TB, Booke M, et al: Delayed onset of malignant hyperthermia in desflurane anesthesia. Anesth Analg 2003;96:165–167. 90. Wohlfeil ER, Woehlck HJ, McElroy ND: Malignant hyperthermia triggered coincidentally after reversal of neuromuscular blockade in a patient from the Hmong people of Laos. 1998;88(6): 1667–1668. 91. Islander G, Twetman ER: Comparison between the European and North American protocols for diagnosis of malignant hyperthermia susceptibility in humans. Anesth Analg 1999;88(5): 1155–1160. 92. Allen GC, Larach MG, Kunselman AR: The sensitivity and specificity of the caffeine-halothane contracture test: a report from the North American malignant hyperthermia registry. Anesthesiology 1998;88(3):579–588. 93. Ørding H, Islander G, Bendixen D, Ranklev-Twetman E: Betweencenter variability of results of the in vitro contracture test for malignant hyperthermia susceptibility. Anesth Analg 2000;91(2): 452–457. 94. Caroff S, Rosenberg H, Gerber JC: Neuroleptic malignant syndrome and malignant hyperthermia. Lancet 1983;1(8318):244. 95. Sangal R, Dimitrijevic R: Neuroleptic malignant syndrome successful treatment with pancuronium. JAMA 1985;254(19): 2795–2796. 96. Francis A, Koch M, Chandragiri S, et al: Is lorazepam a treatment for neuroleptic malignant syndrome? CNS Spectrum 2000;5:54–57. 97. Wedel DJ, Quinlan JG, Iaizzo PA: Clinical effects of intravenously administered dantrolene. Mayo Clin Proc 1995;70:241–246. 98. Amsterdam JT, Syverud SA, Barker WJ, et al: Dantrolene sodium for treatment of heatstroke victims: lack of efficacy in a canine model. Am J Emerg Med 1986;4:399–405. 99. Sakkas P, Davis JM, Hua J, et al: Pharmacotherapy of neuroleptic malignant syndrome. Psychiatr Ann 1991;21:157–164. 100. Sakkas P, Davis JM, Janicak PG, et al: Drug treatment of the neuroleptic malignant syndrome. Psychopharmacol Bull 1991;27:381–384. 101. Hutt CS, Snider SR, Fahn S: Interaction between bromocriptine and levodopa. Neurology 1977;27:505–510. 102. McCarron MM, Boettger ML, Peck JJ: A case of neuroleptic malignant syndrome successfully treated with amantadine. J Clin Psychiatry 1982;43(9):381–382. 103. Kornhuber J, Weller M: Psychotogenicity and N-methyl-Daspartate receptor antagonism: implications for neuroprotective pharmacotherapy. Biol Psychiatry 1997;41:135–144. 104. Nisijima K, Ishiguro T: Electroconvulsive therapy for the treatment of neuroleptic malignant syndrome with psychotic symptoms: a report of five cases. J ECT 1999;15(2):158–163. 105. Graudins A, Stearman A, Chan B: Treatment of the serotonin syndrome with cyproheptadine. J Emerg Med 1998;16(4):615–619. 106. Gillman PK: Serotonin syndrome treated with chlorpromazine. J Clin Psychopharmacol 1997;17:128–129. 107. Cano-Munoz JL, Montejo-Iglesias ML, Yanez-Saez RM, GalvezBorrero IM: Possible serotonin syndrome following the combined administration of clomipramine and alprazolam. J Clin Psychiatry 1995;56(3):122. 108. Guze BH, Baxter LR: The serotonin syndrome: case responsive to propranolol. J Clin Psychopharmacol 1986;6(2):119–120. 109. Hoes MJAJM: Mirtazapine as treatment for serotonin syndrome. Pharmacopsychiatry 1996;29:81. 110. de Boer T: The pharmacologic profile of mirtazapine. J Clin Psychiatry 1996;57:19–25. 111. Brown TM: Nitroglycerine in the treatment of the serotonin syndrome. Ann Pharmacother 1996;30:191. 112. Kline SS, Mauro LS, Scala-Barnett DM, Zick D: Serotonin syndrome versus neuroleptic malignant syndrome as a cause of death. Clin Pharm 1989;8:510–514. 113. Nisijima K, Shioda K, Yoshino T, et al: Memantine, an NMDA antagonist, prevents the development of hyperthermia in an

CHAPTER 10

114. 115. 116. 117.

animal model for serotonin syndrome. Pharmacopsychiatry 2004;37:57–62. Hamilton S, Malone K: Serotonin syndrome during treatment with paroxetine and risperidone. J Clin Psychopharmacol 2000;20(1):103–105. Nisijima K, Ishiguro T: Does dantrolene influence central dopamine and serotonin metabolism in the neuroleptic malignant syndrome? A retrospective study. Biol Psychiatry 1993;33:45–48. Kolecki P: Venlafaxine induced serotonin syndrome occurring after abstinence from phenelzine for more than two weeks. J Toxicol Clin Toxicol 1997;35:211–212. Kolb ME, Horne ML, Martz R: Dantrolene in human malignant hyperthermia: a multicenter study. Anesthesiology 1982;56:254–262.


221

118. Ward A, Chaffman MO, Sorkin ME: Dantrolene, a review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in malignant hyperthermia, the neuroleptic malignant syndrome and an update on its use in muscle spasticity. Drugs 1986;32:130–168. 119. Nelson T, Lin M, Zapata-Sudo G, Sudo RT: Dantrolene sodium can increase or attenuate activity of skeletal muscle ryanodine receptor calcium release channel: clinical implications. Anesthesiology 1996;84(6):1368–1379. 120. San Juan AC, Wong KC, Port JD: Hyperkalemia after dantrolene and verapamil-dantrolene administration in dogs. Anesth Analg 1988;67:759–762.

11

Hepatic Toxicology ALISON L. JONES, BSc, MD ■ PAUL I. DARGAN, MBBS, MD

INTRODUCTION AND IMPORTANCE Many potentially toxic substances enter the body via the gastrointestinal tract. As the blood supply from the gastrointestinal tract (through the portal vein) drains into the liver, the liver comes into contact with them, and this exposure often is at a higher concentration than that received by other tissues. The liver is essential for the metabolic disposal of virtually all xenobiotics. This process is achieved mostly without injury to the liver itself or to other organs. Some compounds, such as carbon tetrachloride, are toxic themselves and/or produce metabolites that cause liver injury in a dose-dependent fashion. Most agents, however, cause liver injury only under special circumstances when toxins accumulate. Factors contributing to the build-up of such toxic substances include genetic enzyme variants (metabolizing enzymes with altered function due to gene defects), which allow greater formation of the harmful metabolite, and induction (greater production) of an enzyme, which produces more than the usual quantity of toxic substance. There also may be accumulation of toxic substances by interference with regular nontoxic metabolic pathways by substrate competition for enzymes (e.g., ethanol and trichloroethylene) or depletion of substrates used to metabolize the toxins or prevent toxic injury (e.g., glutathione). In addition there are a number of other factors that can potentially increase the risk of drug-related hepatotoxicity. Generally, women are more susceptible to drug-induced hepatotoxicity (with the exception of azathioprine hepatotoxicity, which is more common in men).1,2 Being older than 60 years of age is associated with a greater risk of druginduced hepatotoxicity (particularly with nonsteroidal anti-inflammatory drugs [NSAIDs]), whereas children appear to be more susceptible to salicylate and valproaterelated hepatotoxicity.1,3,4 Nutritional status also can be important—malnutrition probably is associated with liver glutathione depletion and a greater risk of hepatotoxicity in acetaminophen overdose.5,6 Conversely, the risk of halothane hepatotoxicity is greater in obese patients.7 Hepatocytes near the portal tract branches (zone 1) receive blood that is rich in oxygen and nutrients, but those near the hepatic vein branches (zone 3) receive blood that has lost much of its nutrients and oxygen (Fig. 11-1). Therefore, zone 3 of the liver is sensitive particularly to damage from toxic compounds. Zone 3 cells also have a higher level of some metabolic enzymes and higher lipid synthesis than zone 1, which may also explain why zone 3 tends to be the most damaged and why lipid accumulation is a common response to this damage (see the carbon tetrachloride example later). Allyl alcohol (2-propen-l-ol), however, causes zone 1 necrosis partly because this is the first area exposed to

the compound in the blood and partly because of the presence of the enzyme alcohol dehydrogenase in zone 1, which produces reactive toxic metabolites (see Fig. 11-1). Toxic substances can damage cells in target organs in many ways. The eventual pattern of response may be reversible injury or an irreversible change leading to the death (necrosis) of the cell or perhaps to carcinogenesis (cancer). Molecular mechanisms of liver injury are shown in Box 11-1.8 Toxin-induced liver injury is a major challenge, because its difficult to differentiate from hepatic disease due to other causes, including hepatic drug reactions, which may mimic almost any kind of liver disease.9,10 Failure to recognize hepatic injury that is caused by a toxin may lead to worsening of hepatic injury or even hepatic failure.

EPIDEMIOLOGY OF DRUG-RELATED HEPATOTOXICITY The epidemiology of drug hepatotoxicity is relatively poorly documented.11 There are a number of reasons for this, including the difficulty encountered in making a definitive diagnosis of drug hepatotoxicity.12 Many cases are subclinical and are never detected or detected only by chance as part of a routine biochemical workup, and many cases are not correctly identified as drug related. Clinical studies during the premarketing phase of drug

P. vulgaris endotox.

Ngaione

CCl4 Fe++

Be

HALOTH

C.V.

Br Bnz

CCl4 + Thyroid

P CZ

ACM CHCl3 + Thyroid

MZ PZ

Allyl formate FIGURE 11-1 Hepatic zones. ACM, anticentromere; C.V., centrallvein; CZ, centrilobular zone (zone 3); MZ, midlobular zone (zone 2); PZ, periportal zone (zone 1).

223

224

BOX 11-1


MOLECULAR MECHANISMS OF LIVER INJURY

Covalent binding: Free radicals have an unpaired electron centered on a carbon, nitrogen, sulfur, or oxygen atom and hence are extremely reactive, electrophilic species, which can react with a variety of cellular components. Free radicals and other reactive intermediates may be produced by metabolism, which interact with proteins and other macromolecules binding covalently to them. There is a correlation between the amount of binding and tissue damage, though this may reflect production of other damaging species. Binding to critical sites on proteins alters their function by, for example, inhibiting an enzyme or damaging a membrane, but binding could be to noncritical sites, and therefore be of no toxicologic importance. Lipid peroxidation: Lipid peroxidation is caused by the attack of a free radical on unsaturated lipids (particularly polyunsaturated fatty acids found in cell membranes), the reaction being terminated by the production of lipid alcohols, aldehydes, or malondialdehyde. Therefore, there is a cascade of peroxidative reactions, which leads to the destruction of lipid unless stopped by a protective mechanism or a chemical reaction such as disproportionation, which gives rise to a nonradical product. The structural integrity of membrane lipids is adversely affected, leading to alterations in fluidity or permeability of membranes, destabilization of lysosomes, and altered function of the endoplasmic reticulum and mitochondria. Such mechanisms are thought to be involved in liver damage caused by carbon tetrachloride and white phosphorus. Thiol group changes: Glutathione is responsible for cellular protection and if depleted, a cell is made more vulnerable to toxic substances. Reactive intermediates of toxic substances can react with glutathione either by a direct chemical reaction or by a glutathione transferase–mediated reaction. If excessive, these reactions can deplete cellular glutathione and leave essential proteins vulnerable to attack by oxidation, cross-linking, formation of disulfides, or covalent adducts. Enzyme inhibition: Sometimes inhibition of an enzyme may lead to cell death; for example, cyanide inhibits cytochrome aa3, leading to blockage of cellular respiration. This results in depletion of intracellular adenosine triphosphate (ATP)—ATP is produced by mitochondria and is the main energy source within the cell—and other vital endogenous molecules. Ischemia: Reduction of oxygen or nutrients supplied to cells results in cell damage and eventual cell death if prolonged. Ischemia may be a secondary event due to swelling of cells with reduction of

blood flow. As a result changes in subcellular skeleton and organelles may occur. This may result in ATP depletion, changes in Ca2+ concentration, damage to intracellular organelles, and DNA damage, and stimulation of apoptosis (programmed cell death) may occur. For example, phalloidin (a toxin from toxic mushrooms) causes centrilobular necrosis (see discussion on toxic mushrooms). Depletion of ATP: Depletion of ATP may be caused by many toxic substances, usually by the uncoupling of mitochondrial oxidative phosphorylation or by DNA damage that causes activation of poly(ADP-ribose) polymerase. Depletion of ATP in the cell means that active transport in and out of the cell is altered or stopped and changes in electrolytes, particularly Ca2+, lead to changes in biosynthesis within the cell, such as protein synthesis, production of glucose, and lipid synthesis. A very important mechanism of cellular damage is alteration of the intracellular Ca2+ concentration. Changes in the intracellular distribution of this ion have been implicated in the cytotoxicity of many toxic substances including carbon tetrachloride. Interference with Ca2+ homeostasis may occur as a result of inhibition of Ca2+ ATPs, direct damage to the plasma cell membrane allowing leakage of Ca2+, or depletion of intracellular ATP. Damage to intracellular organelles: Damage to intracellular organelles can result from the above mechanisms of injury; for example, carbon tetrachloride damages both smooth and rough endoplasmic reticulum, leading to disruption of protein synthesis of the whole cell. Mitochondrial damage may occur, for example, after exposure to hydrazine, leading to functional changes and rupture of mitochondria. The mitochondria are crucial to the cell, and inhibition of their electron transport chain leads to rapid cell death. DNA damage: DNA damage may result from compounds such as alkylating agents; for example, dimethyl sulphate can cause singlestrand breaks in DNA, resulting in the activation of poly(ADP-ribose) polymerase, which catalyses post-translational protein modification and is involved in polymerization reactions and DNA repair. Severe DNA damage may result from its activation and be sufficient to lead to cell death or carcinogenesis. Apoptosis: Apoptosis is programmed cell death. Some foreign compounds may stimulate such cell death by the influx of calcium into a cell. In other cases, cell death may be mediated by cytokines (e.g., interleukin-6), chemicals produced by activated white blood cells capable of mediating tissue injury.

Data from Timbrell JA: Principles of Biochemical Toxicology. London, Taylor & Francis, 1992.

development are likely to identify only agents that commonly cause hepatotoxicity and most information comes from case reports or spontaneous reporting of hepatotoxicity to drug safety authorities such as the U.S. Food and Drug Administration (FDA).11 There have been a number of studies that have attempted to identify the frequency of drug-related hepatotoxicity, but they have not used uniform criteria to define hepatotoxicity and many have not used samples that are representative of the general population. For these reasons it is likely that the true frequency of drug-related hepatotoxicity is greater than the frequency reported in the following studies. It has been estimated that drugs account for 3% to 5% of cases of jaundice admitted to hospitals and 10% of cases of acute liver failure.13-16

In a French study, all cases of symptomatic drugrelated hepatotoxicity were collected for an area with a population of 81,301 inhabitants.1 Over the 3 years studied, 34 cases were identified, 82% occurring in outpatients, with the diagnosis being made in primary care in approximately half of the cases. Two deaths were attributed to drug-related acute liver failure, whereas the other 32 patients recovered fully. The most common drugs implicated were antibiotics, psychtropics, hypolipemic agents, and NSAIDs. The crude annual incidence rate was 13.9 ± 2.4 per 100,000 and standardized annual incidence rate 8.1 ± 1.5, with a female-to-male ratio of 0.86 until 49 years of age and 2.62 at older than 50 years of age.1 When these figures were compared with spontaneous reporting figures it was estimated that

CHAPTER 11

16 times more cases were identified.1 In a retrospective cohort study in the United Kingdom, using a primary care database, the incidence rate of drug-related hepatotoxicity varied from greater than 100 per 100,000 users of isoniazid to less than 10 per 100,000 for users of omeprazole, ranitidine, NSAIDs, and amoxicillin; amoxicillin-clavulanic acid and cimetidine were associated with an intermediate risk of between 10 and 100 per 100,000.17 A further two epidemiologic studies in France suggested that the overall incidence of drugrelated hepatotoxicity has not changed significantly in the last 10 years; however, for the reasons discussed previously, these data may not be reliable.18,19 There is relatively little published information on the long-term outcome of drug-induced liver disease.12 A recent study looked at the natural history of patients with drug-induced liver disease proven through liver biopsy.20 The most common agents involved were antibiotics, NSAIDs, phenytoin, and halothane. At a median followup of 5 years (range, 1 to 19 years) 39% of patients had persistent significant abnormalities in liver blood tests and/or scans.20 Factors predicting persistence or development of chronic liver disease were fibrosis at the time of the initial biopsy and continued exposure to the drug.20

DIAGNOSIS OF TOXIN- OR DRUGINDUCED LIVER INJURY Determining the Etiological Agent(s) When assessing a patient with virtually any kind of liver disease, the best policy is to systematically evaluate the possibility of drug- or toxin-induced liver disease. The first step is to establish clearly and meticulously any drugs the patient has been taking, including over-the-counter and herbal or traditional medicine preparations. The patient may not disclose use of certain compounds for fear of admitting to their use or misuse (e.g., Ecstasy [3,4methylenedioxy-methamphetamine, MDMA], cocaine, hypnotics, antidepressants, anabolic agents, or neuroleptic drugs). It is estimated that greater than 1000 drugs have the potential for hepatotoxicity,21 and space limitations here preclude their complete tabulation. Any list of hepatotoxic drugs represents only a soon outdated snapshot, because new drugs are released into the market constantly and the nature of the premarketing studies is that they are small and hence potential for hepatotoxicity is seldom recognized until the postmarketing stage when a larger population is exposed to the drug. The reader is referred to Stricker’s book for an exhaustive list.21 However, a list of common drugs and toxins in overdosecausing hepatotoxicity is provided below and discussed in more detail later in this chapter. In addition, poisoning may result from ingestion of natural toxins or synthetic chemicals in food or drink.9,22 These also are detailed later in this chapter. Occupational exposure to hepatotoxic agents also occurs as agents with hepatotoxic potential have been used in various industries (Table 11-1). The number of occupations that give exposure to hepatotoxic agents is

Hepatic Toxicology

225

large and includes the manufacture of munitions, rubber, rocket fuels, cosmetics, processed foods, paints, insecticides, herbicides, pharmaceuticals, and chemical products (Box 11-2). The risk, however, is largely hypothetical and a clear history of exposure taking place is required to make the diagnosis. However, many instances of poisoning from exposure to carbon tetrachloride (CCl4) have resulted from the use of this volatile solvent as a dry-cleaning agent in a poorly ventilated room, particularly by those who drink ethanol to excess.22 A large number of chemicals are found in the home as components of household products (Table 11-2) or as pesticides (Table 11-3). Household products likely to contain hepatotoxic chemicals are those used for cleaning clothes and furniture and for paint removal. Despite the potential hepatotoxicity of some household products, the number of reported instances is very low. There is little evidence that hepatic injury has occurred as a result of correct use of pesticides. In contrast, accidental or deliberate overdose of a known drug or chemical (e.g., CCl4, acetaminophen [paracetamol], iron) is a very common cause of hepatotoxicity. Ingestion of organochlorine insecticides, herbicides, fungicides, copper salts, or compounds of trivalent arsenic also can lead to hepatotoxicity. Ingestion of rodenticides containing phosphorus has led to numerous cases of severe liver injury.23 Occasionally, liver damage has been caused by ingestion of rodenticides containing thallium or warfarin.9 In general, acute hepatic injury due to ingestion of pesticides has been very rare.22 Evidence must also be gathered that may point to an alternative diagnosis (e.g., alcohol intake, blood transfusions, high-risk sexual activity, intravenous drug misuse, arrhythmias). Viral serology (hepatitis A, B, C, and E, HIV, cytomegalovirus, Epstein-Barr virus) and ultrasonography often are required, particularly in cases in which the liver function tests indicate cholestasis. Other liver disease (autoimmune chronic active hepatitis, hemochromatosis, primary biliary cirrhosis, Wilson’s disease) must be excluded.24

Chronology Once the list of toxins to which the patient has been exposed has been compiled, the chronology of each treatment should be compared with that of the liver disease. As a general rule, toxins or drugs introduced within the last 6 to 12 weeks should be most suspect, although a shorter duration (1 to 7 days) may be observed in patients who have been exposed previously to the drug/chemical and have been sensitized. It is important not to exclude any that have been withdrawn before the onset of the liver injury; for example, with the amoxicillin and clavulanic acid combination, jaundice may not become apparent until 2 weeks after the treatment. Amiodarone may continue to cause liver damage long after it has been stopped. Information that strengthens the case for an iatrogenic reaction includes previous adverse effects with the drug or related analogs and presence of immunoallergic manifestations, such as drug-induced rash.

226


TABLE 11-1 Partial List of Agents Likely To Be Encountered Occupationally, with Indication of Hepatotoxic Effects in Experimental Animals and Humans

Organic, Nonhalogenated Alcohols and glycols Allyl alcohol Dioxane Ethyl alcohol Ethylene glycol Methyl alcohol Isopropyl alcohol Aldehydes, acetyls, acetates, esters Amines, aliphatic Ethanolamine Ethylenediamine Amines aromatic 4,4′-Diaminodiphenylmethane (methylene dianiline) 4-Dimethylaminobenzene Cyanides and nitriles Acetonitrile Acrylonitrile Hydrogen cyanide Hydrocarbons, aliphatic Alicyclic Cyclopropane Cyclohexane Gasoline (C8–C10) n-Heptane Hexane Turpentine Hydrocarbons, aromatic Benzene Diphenyl Naphthalene p-Terbutyl toluene Styrene Tetraline Toluene Xylene Nitroaliphatic compounds Nitroethane Nitromethane 2-Nitropropane 1-Nitropropane Nitroaromatic compounds Dinitrobenzene Dinitrophenol 2,6-Dinitrotoluene Nitrobenzene Nitrodiphenyl Picric acid (2,4,6-trinitrophenol) Tetryl Trinitrotoluene (TNT) Organic, Halogenated Haloaliphatic compounds Bromoform Bromoethene (vinyl bromide) Carbon tetrachloride Carbon tetrabromide Chloroform Chloroethane (vinyl chloride) Chloroprene 1,2-Dibromoethane 1,2-Dichloroethane Fluoroethane

EXPERIMENTAL ANIMALS

HUMANS

+ + + ± ± 0 0

? + + ± ± 0 0

Necrosis, zone 1 Necrosis, zone 3 See Chapter 32B

+ +

? ?

Degeneration Degeneration

+

+

Cholestasis

+

?

Degeneration, CA†

± ± 0

? ? 0

Degeneration Degeneration

± ± ± ± ± ± ±

0 0 0 0 0 0 0

± + 0 ± + + ± ±

± + 0 0 0 0 ± ±

Trivial steatosis Necrosis

+ + + +

+ + + +

Necrosis Necrosis Necrosis Steatosis, necrosis

+ ± + + ± + + +

+ ± + ± ± + + +

Necrosis ?Cholestasis Necrosis, CA† Degeneration

+ + + + + +

+ ? + + + +

± + + ?

? + + ?

Necrosis, zone 3 Degeneration, CA† Necrosis, zone 3, fat, CA† Necrosis, zone 3 Necrosis, zone 3, fat Degeneration, CA†, angiosarcoma hepatoportal sclerosis Degeneration Necrosis, zone 3, CA† Necrosis, CA†

LESION*

Degeneration, steatosis Steatosis, necrosis Trivial steatosis Steatosis, necrosis in fatal poisoning after ingestion

Necrosis Necrosis Necrosis

CHAPTER 11

Hepatic Toxicology

227

TABLE 11-1 Partial List of Agents Likely To Be Encountered Occupationally, with Indication of Hepatotoxic Effects in Experimental Animals and Humans (Cont’d) EXPERIMENTAL ANIMALS Haloaliphatic compounds (Continued) Halothane Methyl chloride Methylene chloride Propylene chloride Tetrachloroethane Tetrachloroethylene

HUMANS

LESION*

+ ± ± + + +

+ ± ± + + ±

1,1,2-Trichloromethane 1,1,1-Trichloromethane

+ +

+ ±

Haloaromatic compounds 2-Acetylaminofluorine Benzyl chloride Brominated biphenyls Brominated benzenes Chlordecone Chlorinated biphenyls

+ ± + + + +

+ ± ± + ± ±

+ + + + + + + + +

? ? ? ? + + ± + +

+ ± + 0 + + + + ± + – +

? ? 0 0 + + + ? ± + 0 +

Necrosis Steatosis Steatosis, necrosis

+

+

Necrosis

+

+

Diquat

+

+

Necrosis early, bile duct injury and cholestasis later Necrosis

Inorganic Arsenic Arsine Beryllium Boronhydrides

+ 0 + +

+ 0 + +

?

+

+ +

? ±

3,3′-Dichlorobenzidine 4,4′-Methylenebis (2-chloroaniline) O-Dichiorobenzene p-Dichiorobenzene Chlorinated benzenes Chlorinated naphthalanes Pentachlorophenol Nitrochloroaliphatics Nitrochloroaromatics Organic miscellaneous β-Propiolactone Carbon disulfide Decalin Dimethyl sulfate Dimethylacetamide Dimethylformamide Diphenyl oxide Ethyleneimine Furans Hydrazine Mercaptans N-Nitrosodimethylamine (dimethylnitrosamine) Pyridine Bipyridyls Paraquat

Bordeaux mixture (copper salts and lime as spray) Cadmium Chromium See Table 11-3

Necrosis, zone 3 Degeneration Degeneration Necrosis Necrosis Steatosis, degeneration, necrosis only with severe exposure Necrosis, steatosis Steatosis, degeneration, necrosis only with severe exposure Degeneration, CA† Steatosis, necrosis in animals Necrosis, zone 3 Steatosis, CA† Steatosis, necrosis in animals Steatosis in humans Degeneration, CA† Necrosis, CA† Necrosis, zone 3‡ Degeneration, CA† Necrosis, zone 3 Necrosis Degeneration, CA† Necrosis Necrosis, CA†

Degeneration Steatosis, necrosis Necrosis CA† Steatosis, necrosis Necrosis, CA†

Steatosis, necrosis angiosarcoma, CA† Granuloma in humans Zone 2 necrosis in exposed animals Granulomas, hepatoportal Steatosis Sclerosis, cirrhosis, angiosarcoma Necrosis, cirrhosis Degeneration

0, no known injury; ±, trivial injury, i.e., minor degeneration or steatosis; +, definite hepatic injury. *Ability to cause injury on ingestion or injection, not in ordinary ocupational exposure. † Hepatocarcinogenic in experimental animals. ‡ 2-Chloro-2-bromo, 1,1,1, trifluoroethane. Injury is due to idiosyncrasy.

228

BOX 11-2


SOME OCCUPATIONS THAT ENTAIL EXPOSURE TO HEPATOTOXIC CHEMICALS

Airplane makers Airplane pilots Airplane hangar employees Artificial pearl makers Burnishers Cement (rubber, plastic) makers Cementers (rubber) Chemical industry workers Chemists Chlorinated rubber makers Cobblers Color makers Degreasers Dry cleaners Dye makers Dyers Electric transformer and condenser makers Electroplaters Enamel makers and enamelers Extractors, oil and fats Fillers (plastics) Fire extinguisher makers Galvanizers Garage workers Gardeners (insecticides) Gas (illuminating) workers Glass (safety) makers Glue workers Ink makers Insecticide sprayers/makers Insulators (wire)

Lacquer makers and lacquerers Leather workers Linoleum makers Lithographers Paint remover makers and users Painters, paint makers Paraffin workers Perfume makers Petroleum refiners Pharmaceutical workers Photographic material workers Polish (metal) makers and users Printers Pyroxylen-plastics workers Rayon makers Refrigerator workers Resins (synthetic) makers Rubber workers Scourers (metal) Shoe factory workers Soap makers Spreaders (rubber works) Straw hat makers Tapers (airplanes) Thermometer makers Tobacco denicotinizers Varnish makers and users Varnish removers Waterproofers Wax makers

From Zimmerman HJ: Hepatotoxicity: Adverse Effects of Drugs and Other Chemicals on the Liver. New York, Appleton-Century-Crofts, 1978, with permission of copyright holder.

Diversity and Classification of Drugand Toxin-Induced Liver Disease The next step in diagnosis relies on comparison of the patient’s liver disease with the types of liver disease known to be associated with the drugs or toxins to which he or she has been exposed. Stricker is very useful for identifying likely therapeutic drugs causing hepatotoxicity,21 and once suspected they should be withdrawn immediately. The ultimate step in diagnosis of therapeutic drug-induced liver disease is based on the improvement in the liver disease, which usually occurs within a few days or weeks following cessation of exposure to drug. A differential white count may show eosinophilia and nonspecific autoantibodies (antinuclear, antismooth muscle) at relatively low titers that regress after interruption of the treatment, which may strengthen a diagnosis of immune-mediated drug-induced liver disease. However, specific serologic markers are available for only a minority of drugs (Table 11-4).25-29 A liver biopsy is not necessary in most cases of acute liver injury. In rare cases, it is helpful either to eliminate other causes of liver injury or to show lesions suggestive

of drug-induced hepatotoxicity, and it can be carried out even in the presence of significant coagulopathy by the transjugular approach if necessary. The standard transabdominal route is the most common, though it also can be done under laparoscopic control. This has advantages in being able to see the biopsied area and photocoagulate any bleeding points.30 The pattern of liver damage from the mechanisms in Box 11-1 shows that the liver’s response to injury is limited and includes fatty liver, necrosis (cell death), cholestasis, cirrhosis, and carcinogenesis.

FATTY LIVER This is the accumulation of triglycerides (fats) in the liver cells. Fatty liver is a common response to toxicity, often occurring as a result of interference with protein synthesis in hepatocytes, such as after exposure to hydrazine (H2N-NH2), for example.31 Normally it is a reversible process that does not lead to cell death, although it can occur in combination with liver cell death (necrosis), as is the case with CCl4 exposure.32 Two types of fatty liver or steatosis can occur. Tetracycline and

CHAPTER 11

Hepatic Toxicology

229

TABLE 11-2 Household Products That Might Be Hepatotoxic

TABLE 11-4 Serologic Markers for Immunologically Mediated Drug- or Toxin-Induced Liver Disease

PRODUCT

TOXIC AGENT

SPECIFIC SEROLOGIC MARKER

DRUG

Antifreeze Carburetor cleaner Christmas tree lights (bubbling) Drug-cleaning fluids

Chlorobenzene Chlorobenzene Methylene chloride

Antitrifluoroacetylated proteins Antimitochondrial type 6 (anti-M6) autoantibody Antiliver kidney microsomal type 2 (anti-LKM2) autoantibody Antiliver microsomal autoantibody Lymphocyte proliferation assays

Halothane hepatitis25 Iproniazid hepatitis26

Chlorinated aliphatic compounds Acetaminophen Aspirin Ethanol Ferrous salts Phenylbutazone Antimony (trivalent) Nitrobenzene Cellosolve Chlorobenzenes

Drugs hepatotoxic in overdose

Furniture polishes and waxes Mothballs Paint products Brush cleaners Paints Plasticizers, lacquers, resins Removers, paint, wax, etc.

BOX 11-3

Cresols Arsenic (trivalent) Varied Chlorinated aliphatic compounds See Table 11-3 Ethylenedichloride, phthalates Aniline Nitrobenzene Vinyl chloride Phenol Paradichlorobenzene

Pesticides Plastic menders, greasers, plasticizers, glues Shoe cleaners Spray repellent Stamping inks Toilet bowl blocks

Any unknown product should be considered potentially hepatotoxic, and all halogenated ones should be considered hepatotoxic until otherwise determined.

hypoglycin A produce microvesicular steatosis—the fat droplets are small, there are many in each hepatocyte, and the nucleus is in the center of the cell. Other substances (e.g., ethanol, methotrexate) lead to macrovesicular steatosis. Individual large fat droplets within each cell displace the nucleus to the periphery. See Box 11-3 for examples of drugs and toxins that cause steatosis.33-39 Repeated exposure to compounds that cause fatty liver, such as ethanol, may lead to cirrhosis.

TABLE 11-3 Specific Uses of Various Potentially Hepatotoxic Pesticides

Fumigants Fungicides Herbicides Insecticides Rodenticides

HALOGEN COMPOUNDS

As

Cu

+ + + + –

– + – + +

– + – + –

– – – – +

As, inorganic arsenic derivatives; Cu, copper compounds; P, white allomorph of phosphorus; Th, thallium compunds. *Dioxins present in herbicides as contaminants.

Dihydralazine hepatitis28 Immunoallergic druginduced hepatitis29

DRUGS AND TOXINS THAT CAUSE STEATOSIS

Amiodarone33 Aspirin and Reye’s syndrome34,35 Dideoxynucleoside antiviral agents36 Ethanol37 Methotrexate38 Perhexilene38 Tetracycline39 Valproate39

ACUTE HEPATITIS Acute hepatitis is the most common drug- or toxininduced lesion. A liver biopsy is rarely necessary for the diagnosis. These cases tend to be diagnosed from the maximal increase in serum alanine aminotransferase (ALT), a marker of hepatocyte damage, and alkaline phosphatase (AP), a marker of “cholestasis,” and from the ratio of ALT/AP, with each activity being expressed in multiples of the upper limit of normal (N) (Table 11-5).40 Hepatitis may occur by direct cell injury (necrosis), with disruption of intracellular function, or by indirect injury by immune-mediated membrane damage.

TABLE 11-5 Liver Function Test Criteria for Diagnosis of Acute Hepatitis40 INJURY TYPE

CRITERIA

Hepatocellular

If only ALT is increased (>2 N) or when both activities are increased, if the ALT/AP ratio is ≥ 5 (reference 6). NB: Many other medical differential diagnoses (e.g., viral hepatitis, BuddChiari syndrome, microvesicular steatosis, low output cardiac failure) may also give such a liver test profile. ALT and AP are increased and the ALT/AP ratio is between 2 and 5. AP is increased > 2 N or when both ALT and AP are increased, if the ALT/AP ratio is ≤ 2.

P,Th, DIOXINS* WARFARIN – – + – –

Tienilic acid hepatitis27

Mixed Cholestatic

ALT, alanine aminotransferase; AP, alkaline phosphatase; N, normal.

230


As mentioned previously, allyl alcohol causes periportal (zone 1) necrosis partly because alcohol dehydrogenase is present in zone 1 and partly because this is the first area exposed to the compound in the blood (see Fig. 11-1). Conversely, CCl4 and bromobenzene cause zone 3 (centrilobular) necrosis as a result of metabolic activation in that region (Fig. 11-2). Mid-zonal (zone 2) necrosis is less common than the other two types of necrosis, but it occurs with beryllium toxicity (see Fig. 11-1). The explosive trinitrotoluene (TNT) can cause massive liver necrosis involving all zones. Ischemia (impaired blood supply to the liver) also may contribute to necrosis; for example, phalloidin, a toxic substance present in poisonous mushrooms, may cause swelling of the cells lining the sinusoids and therefore reduce the oxygen and nutrients supplied to hepatocytes. Hepatitis due to direct toxicity is not associated clinically with hypersensitivity manifestations. The liver injury may have relatively high frequency, consistent with direct toxicity. Hepatitis due to immune mechanisms has a low frequency, but this may also be true in idiosyncratic hepatitis due to direct toxicity. The frequency of immunologically mediated hepatitis (as that of hepatitis due to direct toxicity) may be influenced by either genetic or acquired metabolic factors (such as microsomal enzyme induction). Immunoallergic hepatitis frequently is associated clinically with hypersensitivity manifestations, such as fever, rash, and blood eosinophilia, and a marked inflammatory infiltrate in the liver with sometime eosinophils, or granulomas. Immunoallergic hepatitis promptly recurs after inadvertent drug rechallenge. In some cases (halothane, tienilic acid, clometacin, α-methyldopa) the patient’s sera have been shown to contain antibodies directed against hepatic neoantigens (see Table 11-4).

(from NADPH cytochrome P450 reductase) CCl4

Electron

Carbon tetrachloride

• CCl3

O2

• CCl3JOJO

Trichloromethyl radical

Trichloromethyl peroxy radical

CHCl3

O

Cl-

Secondary radical

Chloroform

K

Donor

ClJCJCl Phosgene

Lipid peroxidation

Covalent binding to lipid and protein

FIGURE 11-2 Metabolic activation of carbon tetrachloride (CCl4).

DRUGS THAT CAUSE ACUTE HEPATOCELLULAR HEPATITIS AND THEIR MECHANISMS OF HEPATOTOXICITY Acetaminophen (Paracetamol) Recent reports have raised the possibility of toxicity from acetaminophen given in therapeutic doses.41,42 In most cases of apparent therapeutic toxicity in children, the patterns of liver function tests, clinical course, and plasma concentrations represent those of acetaminophen overdose (see Fig. 11-1).42 The confusion often is between therapeutic intent to treat fever or pain and therapeutic dose.42 Often parents are tempted to give extra doses of pediatric acetaminophen preparations, and the apparent therapeutic toxicity in children is probably due to overdosage.42 In adults, unlike the pediatric population, not all the cases are clear-cut overdoses.42 Other factors, such as timing, stated dose, stated product, other products/drugs (particularly those that delay gastric emptying), glutathione depletion, and enzyme induction, may be operating, not to mention inadequate treatment with N-acetylcysteine.42 This causes confusion, but the possibility remains that a few people might be more susceptible to acetaminophen at therapeutic doses. Acetaminophen overdose is discussed in detail in Chapter 47. Poisoning with acetaminophen is characterized by liver damage, though a variety of less common manifestations, including pancreatitis, renal failure, and thrombocytopenia, also can be seen.43 The mechanism of toxicity in early acetaminophen poisoning (within 15 hours) has been well understood since the 1970s, and it depends on the metabolism of acetaminophen by cytochrome P-450 mixed-function oxidases (CYP2E1 and CYP3A4 in humans) to the active N-acetyl-p-benzoquinone imine metabolite.42,44 This metabolite then causes cell death by covalent binding to hepatic proteins and enzymes once intracellular glutathione is depleted.45 Centrizonal necrosis tends to occur first.46 The antidote, N-acetylcysteine, if given at an early enough stage, particularly within the first 8 to 12 hours of ingestion, prevents hepatic cell damage by production of cysteine, which acts as a glutathione donor.45,47 The standard treatment line indicating when N-acetylcysteine should be given is lowered by 50% for chronic alcoholics and users of enzyme-inducing drugs (such as phenytoin, carbamazepine, phenobarbital, primidone, and rifampicin) because such patients are at increased risk of toxicity due to increased production of the active metabolite, which is due to CYP enzyme induction.48 Alcohol (ethanol) is actually protective if coingested with an acetaminophen overdose, but whether chronic excessive use increases the risk of hepatotoxicity when an acetaminophen overdose is taken remains controversial.49,50 In animals chronic ethanol administration causes induction of hepatic microsomal enzymes (especially CYP2E1) and so increases formation of the toxic metabolite and increases acetaminophen hepatotoxicity.49 However, because of dose-dependence and species differences in expression, activity, and inducibility of isoenzymes, it is not justifiable to extrapolate these

CHAPTER 11

results to humans.49,50 In a recent series of 553 patients with acetaminophen hepatotoxicity at a regional liver unit, there was no association between chronic alcohol consumption and the severity of hepatotoxicity.51 Factors that lead to depletion of intrahepatic glutathione probably also potentiate acetaminophen hepatotoxicity in overdose. Fasting decreased glucuronidation of acetaminophen in rats; hence, more active metabolite was present, potentiating acetaminophen-induced hepatic necrosis.52 Fasting has been claimed to predispose to toxicity in humans, and a few cases suggest that patients with glutathione depletion are at increased risk of acetaminophen poisoning.5,6 The mean half-life of acetaminophen is significantly longer in infants and children with protein-energy malnutrition.53 Patients with HIV and AIDS have been shown to have systemic glutathione deficiency54,55 and probably also have hepatic glutathione deficiency. Patients with advanced HIV have been shown to have reduced acetaminophen glucuronidation and increased formation of hepatotoxic oxidative acetaminophen metabolites.56 It therefore seems a reasonable precaution to treat malnourished patients and patients who are seropositive for HIV who have taken an overdose with N-acetylcysteine at a lower acetaminophen level using the lower treatment line. In contrast, little is known about the mechanisms of injury in late acetaminophen poisoning. Recently, a significant role of macrophages and Kupffer cells in production of cytokines and chemokines and activation of hepatic sinusoidal cells and neutrophils has been established.57,58 In addition, activated macrophages and Kupffer cells produce potentially toxic reactive oxygen species such as superoxide and peroxynitrite, capable of directly mediating tissue injury.58,59 Nitric oxide is proposed as a hepatoprotective mechanism against oxidative injury.60,61 Many studies have tried to evaluate which of many hundreds of cytokines and chemokines are important in the pathogenesis of liver injury by acetaminophen without a clear result.62,63 Such studies are complicated by the fact that the presence of cytokines does not mean they are directly involved in the pathogenesis; they may just be an epiphenomena of injury.63 Nuclear transcription factors NF-κB and IL-6 are negative regulators of hepatocyte inflammatory cytokines.64 The current hypothesis is that toxicity occurs when the tumor necrosis factor pathway is activated but only in the absence of activation of the protective negative modulating NF-κB pathway.64 In addition to their role in the pathogenesis of cell injury, tumor necrosis factor-α and other cytokines facilitate the process of regeneration and repair.65,66 Knowledge of the mechanisms of liver injury, at the cellular level, is important in the development of new treatments for acetaminophen overdose, particularly in late presenting patients who are at greatest risk of hepatotoxicity.

Cocaine It is estimated that 22 million Americans have used cocaine at least once and that 5 million Americans use it regularly.67 Fifteen percent of cocaine-use inpatients

Hepatic Toxicology

231

(not administered intravenously) have mild elevations of liver enzymes.67 Most addicts take cocaine intranasally rather than orally, as it had been assumed that the stomach hydrolyses cocaine. However, oral cocaine produces dose-related hepatotoxicity in male mice.68 Acute cocaine hepatotoxicity is caused by hyperpyrexia, hypotension, and direct toxicity of the cocaine and can cause severe hepatic dysfunction.69,70 Cocaine is metabolized by cytochrome P-450 to norocaine, which is further oxidized to N-hydroxynorocaine, norocaine nitroxide, and norocaine nitrosonium ion.71 These metabolites cause an oxidant stress and lipid peroxidation in hepatocytes.70,72 Mouse studies suggest that a hydroxyl radical produced by the reaction of nitric oxide and superoxide via peroxynitrite may be involved in the pathogenesis of cocaine hepatotoxicity.73,74 In animals, toxicity is enhanced by inducers (phenobarbital, ethanol) of cytochrome P-450 and prevented by cytochrome P-450 inhibitors (particularly CYP2A).70,71,75,76 The presence of noninjurious doses of lipopolysaccharide (LPS) appears to potentiate the hepatotoxicity of cocaine in mouse models,77 and pretreatment with N-acetylcysteine prevents this.78 Cotreatment with adrenergic antagonist drugs appears to reduce the hepatotoxicity of cocaine.79 Cocaine-induced hepatotoxic patients have a huge rise in ALT activity with 48 hours,69,80 and liver lesions are in the centrilobular zone, extending into the midlobular zone.71,81 Hepatocytes adjacent to the central vein are spared,71 although hepatic enzyme-inducing and -inhibiting agents affect the site of necrosis.82

Ecstasy (3,4-methylenedioxymethamphetamine) The social use of Ecstasy and amphetamines is widespread in Europe and the United States.83 Recreational use of this drug presents an important but often concealed cause of hepatitis or acute liver failure, particularly in young people.83 Hepatotoxicity has featured in several hundreds of cases of intoxication with Ecstasy in the literature and it is probable that many are subclinical and go undetected.84-88 The evidence to date suggests there is more than one pattern of hepatotoxicity, in which different mechanisms may be responsible. The clinical pattern varies from asymptomatic hepatitic liver function tests to acute hepatic failure due to hepatocellular necrosis, from which some patients recover but others die or require liver transplantation.83-87 Some present with cholestasis.83 Rarely, accelerated panacinar fibrosis has been observed.89 Subacute hepatitic toxicity, with cumulative damage on recurrent exposure, has been reported after recurrent ingestions over a period of time.87,89,90 Hepatotoxicity may be variously manifest at histological level as a microvesicular fatty change, small foci, or cell necrosis or massive hepatic necrosis,84,87,91 but it is most commonly due to necrosis. In humans, oxidation is the main metabolic pathway for Ecstasy,92 and this reaction is catalyzed by cytochrome P-450 CYP2D6 in yeast93 and CYP2D in rats.94 Thus, methylenedioxyamphetamine (MDA) is a main MDMA metabolite.95

232


In humans, the molecular mechanisms involved in the hepatotoxicity of MDMA remain poorly understood. Immune-mediated mechanisms have been hypothesized to play a part in Ecstasy- or amphetamine-induced liver damage, as a result of the observation that rechallenge with ecstasy produced greater liver damage, and this has occurred in some patients in the absence of hyperthermia.87,96 Liver biopsy in one patient suggested an autoimmune hepatitis-like injury, which resolved spontaneously on withdrawal of the drug.96 However, a dosedependent effect can be seen.97 Many patients with hepatotoxicity have been hyperpyrexic for several hours,86,87,98 although this has not occurred in every case. Rat livers perfused by hyperthermic solutions show oxidative stress with superoxide formation.99 Animals normally react to hyperthermia by the rapid transcription and translation of heat shock proteins, which help the cell survive thermal stress.100-102 Administration of amphetamine to rats caused hyperthermia but no induction of heat shock protein in the liver, which suggests the liver may have impaired thermotolerance when amphetamine is present.83,103 In mice (and probably in humans), high ambient temperature contributes to hepatotoxicity.97,104,105 It is also postulated that apoptosis may occur.106 Incubation of hepatocytes with d-amphetamine induced a concentration-dependent glutathione depletion, which was prevented by pretreatment with the P-450 enzyme inhibitor metyrapone in rats.94 Glutathione depletion most likely contributes to hepatotoxicity of amphetamines and ecstasy. Hepatic damage has followed the intravenous use of methamphetamine and amphetamine,107-109 but this is probably a result of viral infection by hepatitis B or C due to contaminated needles.109

Iron After overdose of iron, the amount absorbed is probably about 10%.110 All of the absorbed iron goes to the liver via the portal vein and enters cells via a receptor mediated endocytosis of transferrin-bound iron.110,111 Acute hepatic necrosis (mid zone necrosis) can result from the ingestion of large amounts of iron,23,112 particularly if there is failure to recognize the severity of poisoning and delay in administration of the antidote deferoxamine (see Chapter 72). Shortly after ingestion, evidence of severe gastrointestinal injury is noted, with nausea, vomiting, diarrhea, and melena. Symptoms may abate for a short period followed within 1 to 3 days by the third phase in which evidence of hepatic injury, jaundice, elevated aspartate transaminase (AST) and ALT and striking hypothrombinemia appear, with periportal necrosis.113,114 Evidence from case reports and animal studies suggests hepatotoxicity occurs early in the clinical course (within the first 24 to 48 hours) and has relatively high mortality.114 The lowest serum iron concentration associated with hepatotoxicity is 304 μM/L (1700 μg/dL), although it was not clear at what time post-ingestion this sample was taken.112 It has long been suspected that free radicals play a part in metal-induced hepatotoxicity because of the

powerful pro-oxidant action of iron and copper salts in vitro, which catalyze free radical reactions.115 The resulting oxyradicals have the potential to damage cellular lipids, nucleic acids, proteins, and carbohydrates, and this impairs cellular function and integrity.115 Kupffer cells have enhanced respiratory bursts.116,117 Cells have cytoprotective mechanisms (antioxidants, scavenging enzymes, repair processes) that act to counteract free radicals, thus the extent of damage depends on the balance between free radical generation and cytoprotective systems. Iron overload in vivo can result in oxidative damage to lipids in vivo, once the plasma concentration of metal exceeds a threshold level. In the liver, this lipid peroxidation is associated with impairment of membrane-dependent functions of mitochondria (oxidative metabolism) and lysosomes (membrane integrity, fluidity, pH). Although these findings do not prove causality, lipid peroxidation likely is involved, since similar functional defects are produced by metalinduced lipid peroxidation in these organelles in vitro.110 Iron impairs hepatic mitochondrial respiration, primarily through a decrease in cytochrome c oxidase activity. In iron overload, hepatocellular calcium homeostasis may be impaired through damage to mitochondrial and microsomal calcium sequestration.110 Reduced cellular adenosine triphosphate (ATP) levels, lysosomal fragility, impaired cellular calcium homeostasis, and damage to DNA all may contribute to hepatocellular injury in iron overload. Deferoxamine is the treatment of choice in significant iron poisoning, in addition to acting as an iron chelating agent it also has antioxidant properties and can reverse or arrest iron-induced lipid peroxidation.118,119 Unlike most other hepatotoxins, the periportal areas of the hepatic lobule are the primary sites of injury. This is the site for hepatic regeneration, which probably accounts for the relatively high mortality.110

Halothane Halothane is a general anesthetic that causes mild hepatotoxicity in 20% of individuals.25,120 In contrast, a very small subset of individuals develops severe halothane hepatitis, which is thought to have an immunologic basis.25,120 Halothane is transformed by cytochrome P450 via both oxidative and reductive pathways to reactive metabolites. The reductive pathway (via CYP2A6 and CYP3A4)121 forms a radical, CF3CHCl, which under certain conditions (microsomal enzyme induction and hypoxia) may lead to direct hepatotoxicity in animals. The oxidative pathway (via CYP2E1)121 forms reactive acyl chloride (CF3COCl) that binds covalently to hepatic proteins, including plasma membrane proteins. These trifluoroacetylated proteins can lead to immunization and to the severe form of hepatitis seen in rare subjects. This occurs in 1 out of every 10,000 subjects after first anesthesia within 2 weeks of the procedure. In one study, 25 (45%) of 56 patients with halothane hepatitis had autoantibodies against CYP2E1.122 Jaundice is more frequent after repeated exposure and occurs sooner; 12 days after first exposure, 7 days after second exposure, and 5 days after third exposure. Jaundice frequently is associated with fever (75%) and

CHAPTER 11

eosinophilia (40%). Sera from patients with severe halothane hepatitis contain antibodies against trifluoroacetylated plasma membrane proteins such as protein disulfide isomerase, microsomal carboxylesterase, calreticulin, Erp72, GRP 78, and Erp99.25,123,124 Halothane hepatitis is hepatocellular. It is best avoided by avoiding repeated exposure, especially over short intervals.125 Halothane was the most frequent cause of hepatotoxicity resulting in death over a 21-year period in New Zealand.126

Isoniazid (with or without Rifampicin) Major adverse reactions to antituberculosis drugs can cause significant morbidity and compromise treatment regimens for tuberculosis, and antituberculosis druginduced hepatitis is one of the most prevalent druginduced liver injuries.127 Most cases of antituberculous drug-induced hepatitis have been attributed to isoniazid. Isoniazid given alone increases serum transaminase activity in 10% of patients and causes clinical hepatotoxicity in 1%.128 Peak risk is in the second month of therapy.128 Hepatocellular damage without hypersensitivity manifestations take place. Isoniazid is metabolized to a reactive toxic metabolite in the liver.129 Isoniazid is first acetylated into acetylisoniazid by hepatic N-acetyltransferase, which is hydrolyzed into acetylhydrazine. Acetylhydrazine may be either acetylated again, into the nontoxic diacetylhydrazine, or transformed by cytochrome P-450 CYP2E1129 into the reactive acetyl radical that binds covalently to hepatic proteins.130 Approximately 40% of Caucasians and blacks, but 90% of Japanese, are rapid acetylators of isoniazid.131 Rapid acetylators form acetylhydrazine at a faster rate, but at the same time, detoxify it to diacetylhydrazine at a faster rate. Thus, slow acetylators have a higher risk of hepatotoxicity than do rapid acetylators.127,131 In addition, slow acetylators are prone to develop more severe hepatotoxicity than rapid acetylators127,132 CYP2E1 genetic polymorphism may be associated with susceptibility to antituberculous druginduced hepatitis.129 Rifampicin in therapeutic doses when given alone is seldom hepatotoxic and mainly produces cholestatic liver injury. However, in patients receiving both isoniazid and rifampicin, the incidence of hepatitis is 5% to 8%, mainly during the first month of therapy.133 Acute hepatic failure due to the combination tends to develop even earlier, after about 1 week of treatment.133 Pessayre and Mazel134 suggest that rifampicin, a microsomal enzyme inducer, increases the formation of the reactive isoniazid metabolite. Liver function tests should be monitored in patients receiving antituberculosis drugs in the first few days, within the first week, and once a month thereafter. Isoniazid should be withdrawn if ALT exceeds three times the upper limit of normal.

Nonsteroidal Anti-inflammatory Drugs Hepatotoxicity is an uncommon but potentially lethal complication of therapy with nonsteroidal antiinflammatory drugs (NSAIDs). Clinically apparent liver injury occurs in 1 to 8 cases per 100,000 patient years

Hepatic Toxicology

233

of NSAID use.135-138 Hepatotoxicity can occur with all NSAIDs but appears to be more common with diclofenac and sulindac,137,139 and most commonly within 6 to 12 weeks of initiation of therapy. Patients who have experienced hepatotoxicity to one NSAID often have the same reaction if the drug is restarted or a sister drug is given. Female patients older than 50 years of age who have autoimmune disease and those on potentially hepatotoxic drugs appear to be particularly susceptible, but whether this merely represents the population taking NSAIDs remains to be established.135 Liver function test abnormalities usually settle within 4 to 6 weeks of stopping the causative drug. However, some patients may develop liver failure and require liver transplantation.139,140 Several NSAIDs have been withdrawn from clinical use because of associated hepatotoxicity.141-143 The new more selective cyclooxygenase 2 (COX-2) inhibitors (e.g., celecoxib, rofecoxib) also are associated with hepatotoxicity.144-147 Two main mechanisms are responsible for injury, hypersensitivity and metabolic aberration. Hypersensitivity reactions often have significant antinuclear factor (ANF) or anti–smooth muscle antibody titers, lymphadenopathy, and eosinophilia. Rechallenge results in an increase in ANF titers.148 Metabolic aberrations can occur as genetic polymorphisms and alter susceptibility. It may account for the incidence of 1 to 8 in every 100,000 prescriptions. In vitro metabolism of aceclofenac reflects phenotypic variability among donor liver cells.149 Recent in vitro animal studies have shown that the mechanism of diclofenac toxicity relates both to impairment of ATP synthesis by mitochondria and to production of active metabolites, particularly n,5dihydroxydiclofenac, which causes direct cytotoxicity.150,151 Mitochondrial permeability transition also has been shown to be important in diclofenac-induced liver injury, resulting in generation of reactive oxygen species, mitochondrial swelling, and oxidation of nicotinamide adenine dinucleotide phosphate (NADP) and protein thiols.152 Other studies have shown that ferrous iron release from rat liver microsomes contributes to naproxen-induced microsomal lipid peroxidation.153 Toxicity thus relates both to impairment of ATP synthesis by mitochondria and to drug metabolism. Nearly all of the NSAIDs have been implicated in causing liver injury, and they tend to be hepatocellular in nature.139,154,155 Patients who develop NSAID-induced hepatotoxicity must be advised to stop taking NSAIDs permanently. Acetaminophen remains the analgesic of choice for these patients, even if they are jaundiced.156,157 They also may safely switch to aspirin use because the toxicity of NSAIDs relates to their diphenylamine ring molecular structure, which aspirin does not have.142

Phenytoin Phenytoin is a microsomal enzyme inducer. Its administration to patients commonly causes a rise in γ-glutamyltransferase and may cause a small rise in ALT and AP in some patients.158 Clinical hepatitis is much less common (serious idiosyncratic reactions occur in approximately 1% of patients159) and occurs within 6 weeks of therapy,

234


usually associated with fever, rash, lymphadenopathy, lymphocytosis, hepatomegaly, splenomegaly, and eosinophilia, suggesting an allergic mechanism. Phenytoin is metabolized to a 3,4-epoxide.160 An autoantibody against a 53-kD microsomal protein has been reported.158 Hepatitis is predominantly hepatocellular, but sometimes it is mixed.

Thiazolidinediones These drugs act as insulin-sensitizing agents and are used in the management of type 2 diabetes mellitus. Troglitazone was the first agent in this class to be used clinically, but it has now been withdrawn after being implicated in more than 100 cases of hepatotoxicity, including a number of deaths and cases of acute liver failure that required liver transplantation.161-172 Significant hepatotoxicity was more common in women and obese patients, but concurrent use of other drugs and preexisting liver disease did not appear to increase the risk of troglitazone-induced liver disease.165 The onset of hepatotoxicity often was delayed (mean, 4 months; range, 8 days to 12 months), but progression to acute liver failure once hepatotoxicity developed often was rapid and, in some cases, liver injury continued to progress after discontinuation of troglitazone.167-170,173 Troglitazone is metabolized by CYP3A4 and CYP2C8 to a quinine metabolite, which may cause hepatotoxicity similar to that seen with antimalarials and quinolone antibiotics.174 The hypotoxicity of troglitazone is predominantly hepatocellular, but in addition, the sulfate metabolite of troglitazone inhibits hepatobiliary transport of bile acids by competing with the bile acid export pump, so there may also be a cholestatic element.171 The other thiazolidinediones (pioglitazone and rosiglitazone) are similar structurally to troglitazone, but their metabolic pathways differ and they do not appear to have the same hepatotoxic potential as troglitazone. In large clinical trials the incidence of liver enzyme elevations with these two drugs did not differ from placebo.175,176 There have been two reports of hepatotoxicity with rosiglitazone and one related to pioglitazone; all of these patients recovered.177-179 In one case of troglitazone-related hepatotoxicity, the patient was successfully treated with rosiglitazone with no recurrence of hepatotoxicity.180 Many other drugs cause acute hepatocellular hepatitis and some of these are listed in Box 11-4.181-205

MUSHROOMS THAT CAUSE ACUTE HEPATOCELLULAR HEPATITIS Hepatotoxic mushrooms may be mistaken for edible mushrooms. Several hundred deaths per year are attributable to hepatotoxic mushrooms, especially in Europe,206 and the amount ingested need not be great (see Chapter 23). There are more than 21,000 published cases of amatoxin poisoning.201,207 Fatal mushroom poisoning is relatively rare in North America. There are many thousands of species of mushrooms, but the number of poisonous species is small. Most fatal poisonings are due to the ingestion of Amanita phalloides or the

closely related A. verna or A. virosa.206 Amatoxins are bicyclic octapeptides that bind eukaryotic DNA-dependent RNA polymerase II and inhibit transcription.208,209 A single mushroom has been estimated to contain a fatal dose.206 The toxicity results from thermostabile toxins (amatoxins and phallotoxins) present in the mushroom. They cause a syndrome of hepatorenal failure similar to that caused by CCl4 and white phosphorus. The lesion produced by mushroom poisoning is steatosis and centrizonal (zone 3) necrosis. Degenerative changes of the gastrointestinal tract, kidneys, heart, and central nervous system also occur.210 The syndrome consists of a latent period of 6 to 20 hours after ingestion of poisonous mushrooms followed by extremely severe gastrointestinal symptoms, including abdominal cramps/pain, vomiting, and diarrhea. These symptoms usually are promptly followed by cyanosis and shock. Within 1 to 2 days, hepatocellular jaundice and uremia are noted. Central nervous system abnormalities such as confusion, coma, and convulsions may occur during the first 3 days after ingestion.206 Electrocardiogram evidence of myocardial involvement may include bundle branch block and premature ventricular beats.206 Hemolytic anemia may occur. AST and ALT levels are strikingly elevated, as with those of CCl4 poisoning.210 Mortality rate is 10% to 25%.210 Death within 4 to 8 days results from hepatic failure, severe dehydration, and collapse or central nervous system complications. Death also may occur during the first 48 hours from choleriform diarrhea,210 of which children are more at risk. No specific antidote is available, but several agents have been tried, including penicillins, silymarin, thioctic acid, and antioxidants. Benzylpenicillin, N-acetylcysteine, and silymarin all are effective in animal models of Amanita poisoning.207,211-215 However, in a recently published review of 2108 patients treated for Amanita poisoning, benzylpenicillin did not appear to offer a significant benefit, whereas N-acetylcysteine and silymarin were associated with a modest benefit; these data need to be interpreted with caution as the review was retrospective and uncontrolled.207

CHEMICALS THAT CAUSE ACUTE HEPATOCELLULAR HEPATITIS Carbon Tetrachloride Poisoning Careless use or sniffing of the solvent carbon tetrachloride (CCl4) leads to centrilobular necrosis,216-221 usually accompanied by renal tubular epithelial necrosis. Alcoholic individuals are particularly susceptible. The syndrome consists of renal and hepatic failure, usually preceded by transient neurological and gastrointestinal symptoms. Immediately after exposure, dizziness, headache, visual disturbances, and confusion occur, reflecting the anesthetic properties of haloalkenes.22,216,218 Nausea, vomiting, and abdominal pain with diarrhea occur also during the first 24 hours, especially if ingestion has occurred. Evidence of hepatic disease

CHAPTER 11

BOX 11-4

Hepatic Toxicology

235

OTHER COMMON DRUGS THAT CAUSE ACUTE HEPATOCELLULAR HEPATITIS

Amoxicillin-clavulanic acid: Hepatocellular or cholestatic hepatitis.181 Allopurinol: Patients on diuretics or those with compromised renal function are most susceptible. Hepatitis occurs most frequently during the first month of treatment and is hepatocellular. Granulomas, fever, rashes, and eosinophilia suggest an allergic/ hypersensitivity mechanism.182 Amodiaquine: Hepatocellular jaundice and even acute liver failure. Amodiaquine undergoes autoxidation into a reactive quinoneimine.183,184 Aspirin: Hepatitis occurs after one to several weeks of treatment. This is a dose-related phenomenon related to intrinsic salicylate hepatotoxicity and generally occurs only when aspirin is used in full anti-inflammatory doses. Plasma salicylate concentrations greater than 25 mg/L are likely to lead to hepatic injury, whereas concentrations less than 15 mg/L rarely do. Hepatic injury often is silent, or, at least, anicteric. However, a few cases with hepatic encephalopathy have been described. Use of aspirin during viral infections favors the secondary development of Reye’s syndrome in children.185 Cyproterone acetate: Often produces mild abnormalities in liver function tests. However, it has also produced acute liver failure in elderly patients. It may also lead to hepatocellular carcinoma.186 Dantrolene: Prolonged administration of dantrolene increases serum transaminase activity in 1% to 8% of recipients and produces jaundice in 0.6%. Hepatitis usually occurs between month 2 and 5 of treatment, with a fatality rate of 28%. Hypersensitivity is uncommon.187 Dihydralazine and hydralazine: Hepatitis occurs weeks to months after treatment and is hepatocellular. Some cases of associated fever or blood eosinophilia have been described. Anti–smooth muscle, antimitochondrial, and antimicrosomal antibodies have

been observed. The antimicrosomal antibodies are directed against the cytochrome P-450 1A2 isoenzyme, which transforms dihydralazine into reactive radicals. Slow acetylators are at increased risk of developing hepatitis.188,189 Disulfiram: Disulfiram is converted into reactive metabolites and causes abnormal liver biochemistry in 25% of recipients during the first few weeks of treatment, which represents direct toxicity. However, clinically relevant effects accompanied by hypersensitivity manifestations occur within 2 months of treatment and at least 10 cases of acute liver failure have been reported.190,191 Enflurane: Hepatitis closely resembles halothane hepatitis. Enflurane is transformed into reactive acyl halide metabolites, which cause immune-mediated hepatitis.192 Fipexide: Has produced acute liver failure in three patients.193 Ketoconazole: Overt hepatitis on rechallenge with drug. May produce cirrhosis.194,195 Lamotrigine: Acute hepatitis has been reported in six patients (acute liver failure in two of these), with onset between 2 and 3 weeks of starting therapy. Liver function tests normalized in five patients when lamotrigine was stopped; the other patient had mildly abnormal liver function tests.196-198 Methyldopa: Hepatitis seen in pregnancy, sometimes with hemolytic anemia.199 Nicotinic acid/Niacin: Hepatotoxicity.200 Nifedipine: Acute hepatotoxicity accompanied by eosinophilia.201-203 Pyrazinamide: The incidence of pyrazinamide-induced hepatotoxicity is higher than that of other first-line antituberculosis drugs.204 Tacrine: Half of patients treated have abnormal liver functions tests. One case of fatal hepatic necrosis has been documented.205

usually follows the exposure by 2 to 4 days, but it can occur at 24 hours. Jaundice develops in 50% of cases of poisoning; it is hepatocellular and rapid in evolution. Renal failure begins a few days after the liver damage and peaks in the second week. It may be heralded by oliguria between the second and fourth day after exposure. Continued oliguria or anuria beyond day 4 and rising blood urea during the first and second weeks indicates the presence of tubular necrosis. Renal failure is the cause of death in most fatal cases.22,216 Pulmonary edema is observed in most patients who survive for longer than 1 week. Laboratory features include a low hemoglobin concentration and a neutrophil leucocytosis. Toward the end of the first week frank uremia secondary to renal tubular necrosis develops. There are striking elevations of AST and ALT22,222 and prolongation of the prothrombin ratio. Mortality rate was 25% prior to hemodialysis.22 N-acetylcysteine has been used successfully to treat the hepatotoxicity of CCl4.223 With chronic exposure, like in the case of ethanol, CCl4 causes micronodular and macronodular cirrhosis.

place in the developing world. It causes mid-zone necrosis and periportal steatosis.224 Mortality rate is high (50%), and renal tubular necrosis is common in such cases. Initially, there are severe, irritant effects on the gastrointestinal tract: nausea, vomiting, abdominal pain and diarrhea, and even hematemesis and shock. The vomitus and feces are phosphorescent and have a strong garlic odor, as does the breath. One third of patients die during this 8- to 24-hour stage. One third of patients recover and one third go to the next stage, which is a latent, symptom-free period for 1 to 3 days.225 The third stage is characterized by hepatic failure, renal failure, and recurrent central nervous system involvement, including restlessness, coma, and toxic psychosis. Jaundice is apparent between days 3 and 5 after poisoning and renal failure is apparent between days 1 and 4. AST and ALT levels are only moderately elevated (compared with CCl4 poisoning) and coagulopathy occurs.22,226-228

White Phosphorus Poisoning

These compounds can cause neurological, muscular, renal, and gastrointestinal manifestations. Hepatic injury (necrosis and steatosis) is a regular feature of the intoxication, but it has only a contributory role in

Suicide by deliberate ingestion of phosphorus in cockroach powder, rat poison, or firecrackers often takes

Inorganic Arsenicals, Thallium, and Borates

236


determining the outcome. Jaundice and other evidence of hepatic failure are rare, and they can be recognized only in patients who survive for a few days. Prolonged exposure causes cirrhosis.22,23,229

Sniffing of Chloroform, Trichloroethylene, or Perchloroethylene Often users who develop jaundice have histological features of necrosis and fat deposition in the liver. Features of toxicity include a syndrome usually of lesser severity than that due to CCl4 poisoning.22,230,231

Copper Clinical features of copper poisoning are similar to those of iron overdose. Even dermal application has been associated with hepatotoxicity. Copper salt ingestion causes gastrointestinal erosions, centrizonal necrosis, and renal tubular necrosis. The course resembles that of other forms of hepatorenal failure. Severe nausea, vomiting, diarrhea, and abdominal pain, accompanied by metallic taste, are followed by jaundice, high aminotransferase activities, and hepatomegaly by the second or third day after ingestion.232,233 Other chemicals associated with hepatocellular hepatitis are shown in Box 11-5.234-240

DRUGS AND TOXINS THAT CAUSE MIXED HEPATITIS Mixed hepatitis reflects both hepatocellular necrosis and cholestasis in the same patient from direct necrosis or by adverse immune response against the liver241 and causing the liver function tests abnormalities shown in Box 11-6.242-264

HMG-CoA Reductase Inhibitors (“Statins”) Hepatotoxicity from a mixed hepatocellular-cholestatic mechanism has been reported with atorvastatin, fluvastatin, lovastatin, cerivastatin (predominantly hepatocellular mechanism, now removed because of frequent rhabdomyolysis), simvastatin, and pravastatin.256-262 Elevation of liver enzymes up to three times the upper limit of normal occurs in up to 3% of patients who take these agents and is usually dose dependent and occurs within 3 months of initiating therapy.256-262 The incidence of severe hepatotoxicity is low (0.2 per 100,000), although there are a number of published cases of acute liver failure due to statins.257 There is conflicting evidence on the cross-toxicity of these agents (e.g., in one patient with simvastatin-related toxicity, pravastatin also caused hepatotoxicity but atorvastatin was not associated with hepatotoxicity).263 Although rhabdomyolysis commonly is associated with statin-fibrate combination therapy, concurrent liver injury with this combination does not appear to be more common than with statin therapy alone.264

BOX 11-5

OTHER CHEMICALS ASSOCIATED WITH HEPATOCELLULAR HEPATITIS

Polychlorinated biphenyls: In 1968, hepatic injury developed in 11% of more than 1000 people in Japan who ate food prepared with cooking oil contaminated with polychlorinated biphenyl.234-236 Nitrites and nitrates: Caused hepatic necrosis due to reaction of nitrites with secondary amines in the fish to form dimethylnitrosamine. They may be used as food preservatives.9 Beryllium: Central zone necrosis.237 Toluene: Subacute necrosis.238 Tetrachloroethane: Subacute necrosis in industrially exposed humans. Ingestion or inhalation of high concentration, however, leads to acute disease similar to that induced by CCl3.239 Insecticide poisoning (e.g., DDT and paraquat): A number of insecticides are chlorinated hydrocarbons. Ingestion of large amounts of DDT (≈6 g) and paraquat (20 g) has led to zone 3 centrizonal hepatic necrosis. Paraquat also is associated with a later selective destruction of bile ducts and cholestasis.240

BOX 11-6

DRUGS THAT CAUSE MIXED HEPATOCELLULAR AND CHOLESTATIC HEPATITIS IN THERAPEUTIC DOSES

Angiotensin-converting enzyme inhibitors242 Carbamazepine243 Chlorpropamide244 Cimetidine245 Clozapine246 Haloperidol247 Methimazole248 Nitrofurantoin249 Dextropropoxyphene250 Quinidine251 Ranitidine252 Sulfonamides249,253 Tamoxifen254 Terbinafine255 HMG-CoA reductase inhibitors (e.g., pravastatin, simvastatin, atorvastatin)256-264

ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS AND ANGIOTENSIN II RECEPTOR INHIBITORS There have been a number of reports of pure cholestatic jaundice, hepatocellular hepatitis, and a mixed hepatotoxicity with all of the angiotensin-converting enzyme (ACE) inhibitors and reports of acute liver failure associated with lisinopril and enalapril.265-272 Onset of hepatotoxicity can be delayed up to 1 to 3 years, but it generally occurs within the first 3 to 4 months and is more common after a dose increase.266,271 There is little published data on the newer angiotensin II receptor antagonists, but there have been published case reports of hepatotoxicity associated with candesartan (hepatocellular), irbesartan (cholestatic), and losartan (hepatocellular).273-277

CHAPTER 11

DRUGS AND TOXINS THAT CAUSE ACUTE CHOLESTATIC HEPATITIS Because of the close interrelation between bile ducts and hepatocytes, damage to bile ducts may be accompanied by damage to hepatocytes by the build-up of bile, which damages cell membranes in excess. A list of common agents that cause acute cholestatic hepatitis is shown in Box 11-7.278-284 Cholestasis can result from direct bile duct necrosis or by adverse immune response against the liver.241 Clinically, cholestasis presents as jaundice, pruritus, and dark urine. Biochemically, in pure cholestasis there is an increase in AP, conjugated bilirubin and γ-glutamyl transpeptidase; in mixed cholestatic-hepatitis the ALT also increases but the ALT/AP ratio is between 2 and 5.

DRUGS AND TOXINS THAT CAUSE PURE CHOLESTASIS WITHOUT HEPATITIS Bile duct injury may result from exposure to a number of compounds, particularly those that are concentrated in bile. The result of the damage is cholestasis due to debris from necrotic cells blocking the ductules. Accidental contamination of food by industrial chemicals can lead to domestic hepatotoxicity. Epping jaundice occurred in the United Kingdom after contamination of flour by a leaking container of 4,4′diaminodiphenylmethane (methylenedianiline).9 Similar injuries have been acquired occupationally with this chemical.285 Drugs that cause pure cholestasis are listed in Box 11-8.286-292

CIRRHOSIS Cirrhosis is characterized by regenerative nodules (clumps of new cells) within fibrotic tissue (amorphous tissue) forming an irregular lobulated (defined) pattern. Any repetitive injury resulting in cell death (necrosis) followed by repair mechanisms may lead to cirrhosis. This happens because the liver has only a limited capacity to regenerate.293

BOX 11-7

DRUGS THAT CAUSE ACUTE CHOLESTATIC HEPATITIS IN THERAPEUTIC DOSES

Amoxicillin-clavulanic acid (can also get acute hepatocellular hepatitis)181,278,279 Azathioprine280 Chlorpromazine281 Erythromycin282 Flucloxacillin282 Gold salts283 Penicillamine28

BOX 11-8

Hepatic Toxicology

237

DRUGS AND TOXINS THAT CAUSE PURE CHOLESTASIS WITHOUT HEPATITIS IN THERAPEUTIC DOSES

Estrogens and oral contraceptives286 Anabolic steroids287 Cyclosporin288 4,4′-methylenedianiline (Epping jaundice)289,290 Rapeseed oil-aniline (Spanish toxic oil syndrome)291,292

The classic and most common agent that causes cirrhosis is ethanol.293,294 In addition, compounds that do not appear to cause acute necrosis, such as ethionine, may cause cirrhosis after chronic exposure.295 Other drugs or chemicals that have been reported to cause cirrhosis include ketoconazole, amiodarone, and floxuridine.296-299 The main problems with cirrhosis are portal hypertensive complications (i.e., variceal bleeding) and ascites, together with encephalopathy when the liver cell mass becomes insufficient to cope.300-303

VENO-OCCLUSIVE DISEASE Rarely, a toxin may damage sinusoids and endothelial cells directly; for example, monocrotaline, a plant alkaloid, which is metabolized to a reactive molecule, causes damage and blockage of the venous return to the liver and secondary ischemic death of hepatocytes.304

DRUG- OR TOXIN-INDUCED HEPATIC TUMORS Liver tumors may be benign305 (grow in situ) or malignant (able to metastasize to other tissues). They may arise from any cell type within the liver (e.g., adenoma,305 hepatocellular carcinoma [aflatoxin,306,307 dimethylnitrosamine,308 ethanol,309 hepatitis C310], or hemangiosarcoma [vinyl chloride311,312]). Among the various mycotoxins (toxins produced by molds on nuts, oil seeds, and grains), the aflatoxins have been the subject of intensive research because they are potent carcinogens. Aflatoxin B1 is a very reactive compound (Fig. 11-3). Its carcinogenicity is associated with its biotransformation to a highly reactive, electrophilic oxide, which forms covalent bonds, adducts with DNA, ribonucleic acid (RNA), and protein (see Fig. 11-3).306,307 Damage to DNA is thought to induce tumor growth. There may be species differences due to differences in biotransformation and susceptibility to the initial biochemical lesion. Dimethylnitrosamine is evenly distributed throughout the body, but exposure to single doses causes centrilobular hepatic necrosis indicating that metabolism is an important factor in its toxicity.308 One metabolite is a highly reactive alkylating agent that methylates nucleic

238


J

O

11 10

J

11 10

O

4 6

J

J

8 7

O

5

J

O

OJCJH H

O 1

2 3

2,3-Epoxyaflatoxin B1

H

J

J O

H

J J

J9

2 3

K

K

O

O

5

1

J J

O

4 6

J

J

9 8 7

O

K

K

O

Aflatoxin B1

OJCJH

it can be difficult to identify the specific component of the CHM that is responsible for hepatotoxicity, but the genus Paeonia has been present in at least four cases of severe hepatotoxicity.357,359,361 Two studies have looked at the incidence of hepatotoxicity in patients taking these agents.362,363 In a review of 1265 patients taking CHM, one developed acute hepatitis and 106 (8.4%) developed an increase in ALT up to three times normal, which returned to normal in 95% of patients.362 In a study of 1507 patients using CHM for chronic pain, 14 had a reversible increase in ALT greater than two times normal, the risk being greater with use of glycyrrhizae radix and atractylodis macrophalae.364 Prescriptions of CHM often contain up to 25 different ingredients, so if hepatotoxicity develops it can be difficult to identify which agent is responsible.

H

FIGURE 11-3 Aflatoxin B1.

acids and proteins. The degree of methylation of DNA in vivo correlates with the risk of tumor induction in those tissues. Vinyl chloride (or vinyl chloride monomer) is the starting point in the manufacture of poly(vinyl chloride). Chronic exposure leads to a “vinyl chloride disease,” which includes skin changes, changes to the bones of the hands, and liver damage. Hemangiosarcoma is a tumor of sinusoidal cells (not hepatocytes) that also may result from chronic exposure to vinyl chloride.311,312 This again appears to occur because the epoxide intermediate and fluoroacetaldehyde bind to DNA and proteins respectively within the cell. Hemangiosarcoma has been associated also with arsenite exposure, although the mechanism is still unclear. It should be stressed that the experience in humans with carcinogenicity has not been replicated in animal models.

HERBAL AND PLANT CAUSES OF HEPATOTOXICITY Hepatic impairment from use of conventional drugs is widely acknowledged but there is less awareness of the potential hepatotoxicity of herbal preparations. Plants and herbs are considered to be harmless and commonly are used for self-medication without supervision. However, many plants and herbs can cause severe hepatotoxicity, including acute and chronic abnormalities and even cirrhotic transformation and acute liver failure (Box 11-9).313-356 This list probably represents the tip of an emerging iceberg. The diagnosis of herbal hepatotoxicity often is delayed because patients may not readily give a history of their use of herbals, so it is important that a detailed history be taken of exposure to drugs (prescribed, over the counter, and illicit/recreational), chemicals, plants, and traditional medicines in all patients with hepatotoxicity. There has been reports of hepatotoxicity related to Chinese herbal medicine (CHM), including at least three cases of acute liver failure.357-364 As discussed below,

PRINCIPLES OF MANAGEMENT FOR DRUG- OR TOXIN-INDUCED LIVER DISEASE General Management Drug- or toxin-induced hepatotoxicity must be considered in the differential diagnosis of all patients presenting with a spectrum of disease that ranges from isolated deranged liver function tests in an otherwise well patient to acute liver failure. The degree and extent of liver injury should be monitored by serial prothrombin time estimations and liver function tests, including bilirubin, aminotransferases, alkaline phosphatase, and albumin. As discussed earlier it is important to exclude all other nondrug causes of liver disease. Liver biopsy should be considered if the extent of liver damage or etiology is in doubt. Accurate clinical assessment of renal function—that is, more than simply monitoring plasma urea and electrolytes—is also required. Patients who develop hepatotoxicity must be advised to stop taking the drug or stop exposure to the toxin. Acetaminophen is the analgesic of choice for these patients, even if they are jaundiced.156,157 Meticulous supportive care is critical to good outcome. Systemic hypotension, which may reduce liver blood flow, should be avoided with judicious fluid and inotropic support.365 Hyperthermia, if present (e.g., MDMA hepatotoxicity), should be treated aggressively with cold fluids, but care should be taken to avoid provocation of hyponatremia due to antidiuretic hormone (ADH) release.366,367 The role of dantrolene is controversial.368 It acts to control calcium release at the sarcoplasmic reticulum and thus reduce “muscular” source of heat. However, hyperthermia from amphetamines or Ecstasy also is attributed to a central hyperthermic effect, and there is no evidence that dantrolene has any action on the central nervous system. There may be a role for specific 5-hydroxytryptamine (5-HT) drugs, such as cyproterone, to reduce central nervous system–induced hyperthermia. The development of acute liver failure is characterized by cerebral edema, circulatory shock, coagu-

CHAPTER 11

BOX 11-9

Hepatic Toxicology

239

PLANTS AND HERBALS ASSOCIATED WITH HEPATOTOXICITY

Germander (Teucrium chamaedrys): The diterpenoids of the plant are transformed by cytochromes P-450 3A into hepatotoxic epoxide metabolites. Mixed hepatocellular and cholestatic or acute cholestatic hepatitis results. Several cases have occurred, mainly in France, Spain, and Canada.313-316 Pyrrolizidine alkaloids: Use of plants that contain unsaturated pyrrolizidine alkaloids (PAs), such as Symphytum officinale (comfrey), Tussilago farfara, Heliotropium, Senecio, and t’u-san-ci’I (Compositae), is associated with hepatotoxicity due to venoocclusive disease. This is due to the conversion of PAs to cytotoxic pyrroles, which damage hepatic sinusoidal and endothelial cells, resulting in ischemic damage and centrilobular necrosis. Liver failure can occur in the acute phase with mortality of 20% to 40%, but complete recovery is also reported. Chronic PA veno-occlusive disease has a poor prognosis.314-323 Pennyroyal oil: Pulegone is the main component that has been shown to deplete hepatic glutathione. It is metabolized to menthofuran, which is directly toxic to hepatocytes. Both pulegone and menthofuran are metabolized via CYP2E1. Administration of Nacetylcysteine is recommended in all cases of ingestion of more than 10 mL of pennyroyal oil.324-328 Skullcap: Diterpenoid containing metabolite-mediated hepatotoxicity. 329 Teucrium polium: One reported case of acute liver failure requiring liver transplantation.330 Chaparral leaf (creosote bush, Larrea tridentata): Nineteen reported cases of hepatotoxicity (mixed-cholestatic hepatitis), occurring 3 to 52 weeks after ingestion, with resolution over 1 to 17 weeks in most patients. However, there have been two cases of acute liver failure with successful liver transplant and four cases of chronic liver disease progressing to cirrhosis.331-334 Kava (Piper methysticum): There have been at least 22 cases of acute hepatitis, including 18 cases of acute liver failure. Generally, the hepatotoxicity settles within 8 weeks, but two patients with ALF have required liver transplantation. Liver histology shows extensive hepatocellular necrosis, and additional cholestasis was identified in two cases. In one report, two patients with kava hepatotoxicity were poor metabolizers of debrisoquine, and so it is possible that CYP2D6 deficiency may increase the risk of kava hepatotoxicity.335-338

Senna fruit extracts: Commonly used as laxatives and stool softeners. Metabolite rhein anthrane is thought to cause hepatotoxicity.339 Fruit of the cycad tree: Found on Guam, contains a potent hepatotoxin that can also lead to hepatic injury when eaten.340 Senecio, Heliotropium, Crotalaria: More than 100 alkaloids have been identified and these cause centrizonal necrosis and venoocclusive disease. The clinical picture is of relatively acute or subacute hepatic failure, with ascites, jaundice, and a mortality rate of 20%.341 Camphor: Hepatitis.342,343 Mediterranean glue thistle (Atractylis gummifera): Hepatic necrosis, possibly due to interference with hepatic ADP and ATP transport inhibiting oxidative phosphorylation and induction of the mitochondrial membrane permeability transition pore resulting in apoptosis.344 Impila (Callilepsis laureola): The carboxyatractyloside component produces an acute illness with abdominal pain, vomiting, convulsions, and acute renal and liver failure (centrizonal necrosis) with profound hypoglycemia. Up to 63% patients die within 24 hours, with an overall mortality rate of 91% at 5 days.345 Cascara sagrada: Cholestatic hepatitis.346 Isabgol: Giant cell hepatitis.347 Venencapsan (horse chestnut leaf): Steatosis.348,349 Prostata: Hepatic fibrosis.350 Ma Huang (Ephedra species): There have been two case reports of severe acute hepatitis in patients using ma huang for weight loss. However, the contents of the products were not formally analyzed to confirm botanical identity.351,352 Jin Bu Huan: There have been 10 reported cases of acute hepatitis and one case of chronic hepatitis related to jin bu huang use. Levotetrahydropalmatine is the active agent and probably responsible for the hepatotoxicity, which developed at a mean of 20 weeks (range, 6 days to 52 weeks) in the reported cases. Liver biopsy in one case showed eosinophilic infiltrates and cholestasis.353-355 Greater celandine (Chelidonium majus): Ten reported cases of reversible mixed cholestasis-hepatitis within 3 months, one unintentional rechallenge resulting in a recurrence of hepatotoxicity. Commercial extracts of greater celandine contain more than 20 alkaloids and the toxic component has not been identified.356

lopathy, and renal failure, as well as liver failure with encephalopathy.369 Conservative management focuses on invasive hemodynamic monitoring and prevention of complications such as cerebral edema, infection, renal failure, and coagulopathy.369 A common cause of death from acute liver failure is cerebral edema due to raised intracranial pressure.370 Intracranial pressure may increase rapidly and waiting for clinical signs such as pupil abnormalities, bradycardia, or hypertension may result in brain death before treatment can be started. Therefore, intracerebral pressure monitoring ideally should be undertaken in all patients who fulfill liver transplant criteria.369 Controlled hypothermia has been proposed as a treatment for patients with acetaminophen-related acute liver failure.371 Jalan and coworkers actively cooled (to 32°C–33°C) seven patients with acetaminophen-related acute liver failure and increased intracranial pressure unresponsive to

treatment with mannitol and ultrafiltration. All seven showed a decrease in intracranial pressure with cooling (from 45 mm Hg [25 to 49] to 16 mm Hg [13 to 17]).371 In addition, in some reports, hypothermia associated with acetaminophen overdose appears to have provided additional protection by slowing metabolic activation of acetaminophen.372,373

Specific Therapies STEROIDS The role of steroids in cases postulated to have an immune component has not been properly evaluated, although steroids probably have rationale in cases in which rechallenge with the drug produces significant hepatotoxicity.83 Once a viral etiology has been excluded, a therapeutic trial with high-dose steroids (e.g.,

240


prednisolone 40 mg/day) is worthy of consideration in such patients. N-ACETYLCYSTEINE N-acetylcysteine (NAC; see Chapter 47) is used routinely for the management of early and late acetaminophen poisoning. Its mechanism of action is well understood in early poisoning, where it replenishes intracellular glutathione by acting as a cysteine donor.45 In late acetaminophen poisoning NAC has been shown to alter cytokine concentrations, such as interleukin-1 and tumor necrosis factor.374-376 Chemopreventive properties of NAC include reduction of oxidized thiol groups in key enzymes that permits reestablishment of calcium homeostasis, which plays a key role in apoptosis.377 NAC blocks electrophiles and scavenges reactive oxygen species, and it can restore the capacity of the intracellular proteolytic system to degrade toxic arylated proteins.378 The catheter study by Harrison and coworkers reporting that NAC acts by hemodynamic action together with prostaglandin E1 (PGE1) to increase cardiac output, oxygen delivery, and utilization has recently been challenged.379,380 Using end-tidal CO2 as a measure of oxygen uptake, Walsh and colleagues demonstrated that NAC administration alone did not lead to an increase in oxygen utilization.380 The increase in cardiac output seen was transient, lasting, at most, 20 to 30 minutes. Whether regional hyperemia in one or multiple circulations is likely to benefit patients with acute liver failure remains a critical but unanswered question.369 N-acetylcysteine also is used for CCl4 poisoning,223 and it may have a role in amatoxin mushroom poisoning.207 LIVER TRANSPLANTATION The role of liver transplantation in acute liver failure is controversial and emotive. Orthotopic or auxiliary liver transplantation has been performed successfully in patients with acute liver failure due to acetaminophen,381 Ecstasy,83,382 NSAIDs (e.g., diclofenac),383,384 iron,385 A. phalloides,386 isoniazid,387 and many other drugs and chemicals.386,387 In the United Kingdom, the presence of non– acetaminophen drug–induced acute liver failure is considered to be a poor prognostic feature. Association with two of the following four features is considered to be an indicator for emergency liver transplantation388: jaundice to encephalopathy developing over more than 1 week; age younger than 10 years or older than 40 years; serum bilirubin greater than 300 μM/L; prothrombin time greater than 50 seconds. Different criteria are used in the United Kingdom for transplantation for acetaminophen-induced liver failure.389 Ninety-two percent of patients whose peak prothrombin time exceeded 180 seconds died.390 Ninety-three percent of patients with an increasing prothrombin time between day 3 and day 4 died.390 In clinical practice, if a patient’s prothrombin time starts to improve, full recovery occurs. The O’Grady criteria (arterial blood pH of less than 7.3 or H+ of more than 50 nmol/L or prothrombin time of more than 100 seconds and serum creatinine more than

300 μM/L in patients with grade III or grade IV encephalopathy) currently provides the best guide for when to transplant for acetaminophen poisoning in the United Kingdom.391 It therefore follows that in the care of patients prior to transplantation it is important to avoid giving fresh frozen plasma (unless there is lifethreatening bleeding), vitamin K, or sedative drugs.391 Recently, the O’Grady criteria have been modified to include the post-resuscitation serum lactate concentration, and this has increased the sensitivity from 76% to 91%.392 A threshold value of 3.0 mmol/L after resuscitation even when used alone has a sensitivity of 76% and a specificity of 97% in predicting nonsurvival.392 Contraindications to transplantation may vary between transplant centers, but in the United Kingdom they include HIV-positive status, acute alcoholism (i.e., delirium tremens), serious sepsis, acute intravenous drug abuse, serious chronic psychiatric illness associated with high risk of repeat suicide attempts, and extrahepatic malignancy.391 A report of 7 years’ experience of treating acetaminophen-induced liver failure at Kings College, London, found survival rate improved from less than 50% in 1987 to 78% in 1993.393 Meticulous supportive care and transplants were believed to be responsible, among other factors. MOLECULAR ADSORBENTS RECIRCULATIONS SYSTEM Water-soluble drugs can be removed by hemodialysis or hemofiltration. However, kinetically this method of elimination is unsuitable for protein-bound drugs. The molecular adsorbents recirculations system (MARS) offers particular promise in removal of highly proteinbound drugs and in the management of acute liver failure.394 Severe phenytoin toxicity has been successfully treated with the MARS system.395 REFERENCES 1. Sgro C, Clinard F, Ouazir K: Incidence of drug-induced hepatic injuries: a French population based study. Hepatology 2002;36:451–455. 2. Romagnuolo J, Sadowski DC, Lalor E, et al: Cholestatic hepatocellular injury with azathioprine: a case report and review of the mechanisms of hepatotoxicity. Can J Gastroenterol 1998;12:479–483. 3. Halpin TJ, Holtzhauer F, Campbell RJ, et al: Reye’s syndrome and medication use. JAMA 1982;248:678–681. 4. Powell-Jackson PR, Jackson JM, Williams R, et al: Hepatotoxicity to sodium valproate. Gut 1984;25:673–681. 5. Whitcomb DC, Block GD: Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA 1994;272: 1845–1850. 6. McClements BM, Hyland M, Calander ME, Blair TL: Management of paracetamol poisoning complicated by enzyme induction due to alcohol or drugs. Lancet 1990;335:1526. 7. Brown BR: Halogenated anaesthetics and hepatotoxicity. S Afr Med J 1981;59:422–424. 8. Timbrell JA: Principles of Biochemical Toxicology. London, Taylor & Francis, 1992. 9. Zimmerman HJ: Chemical hepatic injury. In Haddad LM, Winchester JF (eds): Clinical Management of Poisoning and Drug Overdose, 3rd ed. Philadelphia, WB Saunders, 1998. 10. Farrell GC: Drug-induced liver injury. New York, Churchill Livingstone, 1994.

CHAPTER 11

11. Larrey D: Drug-induced hepatitis: epidemiologic, clinical, diagnostic and physiopathologic aspects in 1995. Rev Med Interne 1995;16:752–758. 12. Danan G: Causality assessment of drug-induced liver injury. J Hepatol 1988;7:132–136. 13. Dossing M, Andreasen PB: Drug-induced liver disease in Denmark. An analysis of 572 cases of hepatotoxicity reported to Danish Board of Adverse Reactions to Drugs. Scan J Gastroenterol 1982;17:205–211. 14. Friss H, Andreasen PB: Drug-induced hepatic injury. An analysis of 1100 cases reported to the Danish committee on Adverse Drug Reactions between 1978 and 1987. J Intern Med 1992;232:113–118. 15. Hoofnagle JH, Carithers RL Jr, Shapiro C, Ascher N: Fulminant hepatic failure: summary of a workshop. Hepatology 1995; 21:240–252. 16. Dossing M, Sonne J: Drug-induced hepatic disorders. Incidence, management and avoidance. Drug Saf 1993;9:441–449. 17. Garcia Rodriguez LA, Ruigomez A, Jick H: A review of epidemiologic research on drug-induced acute liver injury using the general practice research database in the UK. Pharmacotherapy 1997;17:721–728. 18. Biour M, Poupon R, Calmus Y, et al: Hepatotoxicity of drugs. A data bank of hepatic involvement and responsible drugs. Gastroenterol Clin Biol 1987;11:56–67. 19. Biour M, Poupon R, Grange JD, Chazouilleres O: Drug-induced hepatotoxicity. The 13th updated edition of the bibliographic database of drug-related liver injuries and responsible drugs. Gastroenterol Clin Biol 2000;24:1052-–1091. 20. Aithal PG, Day CP: The natural history of histologically proved drug-induced liver disease. Gut 1999;44:731–735. 21. Stricker BH: Drug-induced hepatic injury, 2nd ed. Amsterdam, Elsevier, 1992. 22. Zimmerman JH: Hepatotoxicity: The Adverse Effects of Drugs and Other Chemicals on the Liver. New York, Appleton-CenturyCrofts, 1978. 23. Arena JM, Drew RH (eds): Poisoning: Toxicology-SymptomsTreatment, 5th ed. Springfield, IL, Charles C Thomas, 1986. 24. Benichou C: Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol 1990;11:272–276. 25. Gut J, Christen U, Huwyler J: Mechanisms of halothane toxicity: novel insights. Pharmacol Ther 1993;58:133–155. 26. Pons C, Dansette PM, Gregeois J, et al: Human anti-mitochondria autoantibodies appearing in iproniazid-induced immunoallergic hepatitis recognize human liver monoamine oxidase B. Biochem Biophys Res Commun 1996;218:118–124. 27. Lecoeur S, Andre C, Beaune PH: Tienilic acid-induced autoimmune hepatitis: anti-liver and -kidney microsomal type 2 autoantibodies recognize a three-site conformational epitope on cytochrome P4502C9. Mol Pharmacol 1996;50:326–333. 28. Dalekos GN, Zachou K, Liaskos C, et al: Autoantibodies and defined target autoantigens in autoimmune hepatitis: an overview. Eur J Intern Med 2002;13:293–303. 29. Maria VA, Pinto L, Victorino RM: Lymphocyte reactivity to ex-vivo drug antigens in drug-induced hepatitis. J Hepatol 1994;21:151–158. 30. Helmreich-Becker I, Meyer zum Buschenfelde KH, Lohse AW: Safety and feasibility of a new minimally invasive diagnostic laparoscopy technique. Endoscopy 1998;30:756–762. 31. Sarich TC, Youssefi M, Zhou T, et al: Role of hydrazine in the mechanism of isoniazid hepatotoxicity rabbits. Arch Toxicol 1996;70:835–840. 32. Weber LW, Boll M, Stampfl A: Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit Rev Toxicol 2003;33:105–136. 33. Richer M, Roberts S: Fatal hepatotoxicity following oral administration of amiodarone. Ann Pharmacother 1995;29:582–586. 34. Kaneda M, Kashiwamura S, Ueda H, et al: Inflammatory liver steatosis caused by IL-12 and IL-18. J Interferon Cytokine Res 2003;23:155–162. 35. Trost LC, Lemasters JJ: Role of the mitochondrial permeability transition in salicylate toxicity of cultured rat hepatocytes: implications for the pathogenesis of Reye’s syndrome. Toxicol Appl Pharmacol 1997;147:431–441. 36. Koch RO, Graziadei IW, Zangerle R, et al: Acute hepatic failure and lactate acidosis associated with antiretroviral treatment for HIV. Wien Klin Wochenschr 2003;115:135–140.

Hepatic Toxicology

241

37. Maher JJ: Alcoholic steatosis and steatohepatitis. Semin Gastrointest Dis 2002;13:31–39. 38. Farrell GC: Drugs and steatohepatitis. Semin Liver Dis 2002;22:185–194. 39. Hautekeete ML, Degott C, Benhamou JP: Microvesicular steatosis of the liver. Acta Clin Belg 1990;45:311–326. 40. Pessayre D, Larrey D, Biour M: Drug-induced liver injury. In Bircher J, Benhamou J-P, McIntyre N, et al (eds): Oxford Textbook of Clinical Hepatology. Oxford, Oxford University Press, 1999, pp 1261–1315. 41. Bridger S, Henderson K, Glucksman E, et al: Deaths from low dose paracetamol poisoning. BMJ 1998;316:1724–1725. 42. Prescott LF: Therapeutic misadventure with paracetamol: fact or fiction? Am J Ther 2000;7:99–114. 43. Jones AL, Prescott LF: Unusual complications of paracetamol poisoning. QJM 1997;90:161–168. 44. Corcoran GB, Mitchell JR, Vaishnav YN, Horning EC: Evidence that acetaminophen and N-hydroxyacetaminophen for a common arylating intermediate, N-acetyl-p-benzoquinoneimine. Mol Pharmacol 1980;18:536–542. 45. Mitchell JR, Thorgeirsson SS, Potter WZ, et al: Acetaminopheninduced hepatic injury: protective role of glutathione in man and rationale for therapy. Clin Pharmacol Ther 1974;16:676–684. 46. Lesna M, Watson AJ, Douglas AP, et al: Evaluation of Paracetamolinduced damage in liver biopsies. Acute changes and followup findings. Virchows Arch A Pathol Anat Histol 1976;370: 333–344. 47. Prescott LF, Illingworth RN, Critchley JA, et al: Intravenous NAcetylcysteine: the treatment of choice for paracetamol poisoning. BMJ 1979;2:1097–1100. 48. Management of acute paracetamol poisoning. Guidelines agreed by the UK National Poisons Information Service 1998. Supplied to Accident and Emergency Centres in the United Kingdom by the Paracetamol Information Centre in collaboration with the British Association for Accident and Emergency Medicine. Norfolk, UK, Paracetamol Information Centre, 1998. 49. Prescott LF: Paracetamol, alcohol and the liver. Br J Clin Pharmacol 2000;49:291–301. 50. Jones AL, Dargan PI: Should a lower treatment line be used when treating paracetamol poisoning in chronic ethanol users: the case against. Drug Saf 2002;25:625–632. 51. Makin A, Williams R: Paracetamol hepatotoxicity and alcohol consumption in deliberate and accidental overdose. QJM 2000;93:341–349. 52. Price VF, Miller MG, Jollow DT: Mechanism of fasting-induced potentiation of acetaminophen hepatotoxicity in the rat. Biochem Pharmacol 1987;36:427–433. 53. Mehta S, Nain CK, Yadav D, et al: Disposition of acetaminophen in children with protein calorie malnutrition. Int J Clin Pharmacol Ther Toxicol 1985;23:311–315. 54. Buhl R, Jaffe HA, Holroyd KA, et al: Systemic glutathione deficiency in symptom-free HIV-seropositive individuals. Lancet 1989;2:1294–1298. 55. Helbling B, von Overbeck J, Lauterburg BH: Decreased release of glutathione into the systemic circulation of patients with HIV infection. Eur J Clin Invest 1996;26:38–44. 56. Esteban A, Perez-Mateo M, Boix V, et al: Abnormalities in the metabolism of acetaminophen in patients infected with the human immunodeficiency virus (HIV). Methods Find Exp Clin Pharmacol 1997;19:129–132. 57. Laskin DL, Pendino KJ: Macrophages and inflammatory mediators in tissue injury. Ann Rev Pharmacol Toxicol 1995;35:655–677. 58. Lawson JA, Farhood A, Hopper RD, et al: The hepatic inflammatory response after acetaminophen overdose: role of neutrophils. Toxicol Sci 2000;54:509–516. 59. Tapia G, Cornejo P, Ferreira J, et al: Acetaminophen-induced liver oxidative stress and hepatotoxicity: influence of Kupffer cell activity assessed in the isolated perfused rat liver. Redox Rep 1997;3:213–218. 60. Kuo PC, Slivka A: Nitric oxide decreases oxidant-mediated hepatocyte injury. J Surg Res 1994;56:594–600. 61. Kuo PC, Schroeder RA, Loscalzo J: Nitric oxide and acetaminophen-mediated oxidative injury: modulation of interleukin-1-induced nitric oxide synthesis in cultured rat hepatocytes. J Pharmacol Exp Ther 1997;282:1072–1083.

242


62. Takada H, Mawet E, Shiratori Y, et al: Chemotactic factors released from hepatocytes exposed to acetaminophen. Dig Dis Sci 1995;40:1831–1836. 63. Jones AL, Simpson KJ: Proinflammatory and chemokine concentrations are raised in plasma of patients with late paracetamol poisoning. J Accid Emerg Med 2000;17:69. 64. Blazka ME, Germolec DR, Simeonova P, et al: Acetaminopheninduced hepatotoxicity is associated with early changes in NF-kB and NF-IL6 DNA binding activity. J Inflamm 1996;47:138–150. 65. Devalarja R, Barve S, Hill D, McClain C: Acetaminophen hepatotoxicity: new insights. Gastroenterology 1998;114:A1234. 66. Hogaboam CM, Bone-Larson CL, Steinhauser ML, et al: Novel CXCR2-dependent liver regenerative qualities of ELR-containing CXC chemokines. FASEB J 1999;13:1565–1574. 67. Kothur R, Marsh F, Posner G: Liver function tests in nonparenteral cocaine users. Arch Intern Med 1991;151:1126–1128. 68. Labib R, Turkall R, Abdel-Rahman MS: Oral cocaine produces dose-related hepatotoxicity in male mice. Toxicol Lett 2001;125:29–37. 69. Silva MP, Roth D, Reddy KR, et al: Hepatic dysfunction accompanying acute cocaine intoxication. J Hepatol 1991;12:312–315. 70. Mallat A, Dhumeaux D: Cocaine and the liver. J Hepatol 1991;12:275–278. 71. Ndikum-Moffor FM, Schoeb TR, Roberts SM: Liver toxicity from norcocaine nitroxide, an N-oxidative metabolite of cocaine. J Pharmacol Exp Ther 1998;284:413–419. 72. Devi BG, Chan AW: Impairment of mitochondrial respiration and electron transport chain enzymes during cocaine-induced hepatic injury. Life Sci 1997;60:849–855. 73. Aoki K, Ohmori M, Takimoto M, et al: Cocaine-induced liver injury in mice is mediated by nitric oxide and reactive oxygen species. Eur J Pharmacol 1997;336:43–49. 74. Boelsterli UA, Wolf A, Goldlin C: Oxygen free radical production mediated by cocaine and its ethanol-derived metabolite, cocaethylene, in rat hepatocytes. Hepatology 1993;18:1154–1161. 75. Bornheim LM: Effect of cytochrome P450 inducers on cocainemediated hepatotoxicity. Toxicol Appl Pharmacol 1998;150:158–165. 76. Aoki K, Takimoto M, Ota H, et al: Participation of CYP2A in cocaine-induced hepatotoxicity in female mice. Pharmacol Toxicol 2000;87:26–32. 77. Labib R, Turkall R, Abdel-Rahman MS: Endotoxin potentiates cocaine-mediated hepatotoxicity by nitric oxide and reactive oxygen species. Int J Toxicol 2003;22:305–316. 78. Labib R, Abdel-Rahman MS, Turkall R: N-acetylcysteine pretreatment decreases cocaine and endotoxin induced hepatotoxicity. J Toxicol Environ Health A 2003;66:223–239. 79. Roberts SM, DeMott RP, James RC: Adrenergic modulation of hepatotoxicity. Drug Metab Rev 1997;29:329–353. 80. Perino LE, Warren GH, Levine JS: Cocaine-induced hepatotoxicity in humans. Gastroenterology 1987;93:176–180. 81. Kanel GC, Cassidy W, Shuster L, et al: Cocaine-induced liver cell injury: comparison of morphological features in man and in experimental models. Hepatology 1990;11:646–651. 82. Roth L, Harbison RD, James RC, et al: Cocaine hepatotoxicity: influence of hepatic enzyme inducing and inhibiting agents on the site of necrosis. Hepatology 1992;15:934–940. 83. Jones AL, Simpson KJ: Mechanisms and management of hepatotoxicity in ecstasy (MDMA) and amphetamine intoxications. Aliment Pharmacol Ther 1999;13:129–133. 84. Henry JA, Jeffreys KJ, Dawling S: Toxicity and deaths from 3,4methylenedioxymethamphetamine (“ecstasy”). Lancet 1992;340: 384–387. 85. De Man RA, Wilson JH, Tjen HS: Acute liver failure caused by methylenedioxymethamphetamine (“ecstasy”). Ned Tijdschr Geneeskd 1993;137:727–729. 86. Jones AL, Jarvie DR, MacDermid G, et al: Hepatocellular damage following amphetamine intoxication. Clin Toxicol 1994;32: 435–444. 87. Ellis AJ, Wendon JA, Portmann B, et al: Acute liver damage and ecstasy ingestion. Gut 1996;38:454–458. 88. Andreu V, Mas A, Bruguera M, et al: Ecstasy: a common cause of severe acute hepatotoxicity. J Hepatol 1998;29:394–397. 89. Khakoo SI, Coles CJ, Armstrong JS, et al: Hepatotoxicity and accelerated fibrosis following 3,4-methylenedioxymethamphetamine (“ecstasy”) usage. J Clin Gastroenterol 1995;20:244–247.

90. Ijzermans JN, Tilanu HW, de Man RA, et al: Ecstasy and liver transplantation. Ann Med Intern 1993;144:568. 91. Milroy CM, Clark JC, Forrest AR: Pathology of deaths associated with “ecstasy” and “eve” misuse. J Clin Pathol 1996:49:149–153. 92. Maurer HH, Moeller MR, Roesler M, et al: On the metabolism of 3,4-methylenedioxymethamphetamine (MDMA) in man. Ther Drug Monti 1993;14:148. 93. Tucker GT, Lennard MS, Ellis SW, et al: The demethylenation of methylenedioxymethamphetamine (“Ecstasy”) by debrisoquine hydroxylase (CYP2D6). Biochem Pharmacol 1994;47:1151–1156. 94. Carvalho F, Remiao F, Amado F, et al: D-Amphetamine interaction with glutathione in freshly isolated rat hepatocytes. Chem Res Toxicol 1996;9:1031–1036. 95. Carvalho M, Milhazes N, Remiao F, et al: Hepatotoxicity of 3,4methylenedioxyamphetamine and alpha methyldopamine in isolated rat hepatocytes: formation of glutathione conjugates. Arch Toxicol 2004;78:16–24. 96. Fidler H, Dhillon A, Gertner D, et al: Chronic ecstasy (3,4methylenedioxymethamphetamine) abuse: a recurrent and unpredictable cause of severe acute hepatitis. J Hepatol 1996;25:563–566. 97. Greene SL, Dargan PI, O’Connor N, et al: Multiple toxicity from 3,4-methylenedioxymethamphetamine “ecstasy.” Am J Emerg Med 2003;21:121–124. 98. Willis EJ, Findlay JM, McManus JP: Effects of hyperthermia therapy on the liver. II. Morphological observations. J Clin Pathol 1976;29:1–10. 99. Skibba JL, Stadnicka A, Kalbfleisch JH: Hyperthermic liver toxicity: a role of oxidative stress. J Surg Oncol 1989;42:103–112. 100. Cairo G, Bardella L, Schiaffonati L, et al: Synthesis of heat shock proteins in rat liver after ischaemia and hyperthermia. Hepatol 1985;5:357–361. 101. Lindquist S, Craig EA: The heat-shock proteins. Annu Rev Genet 1988;22:631–677. 102. Subjeck JR, Sciandra JJ, Chao CF, et al: Heat shock proteins and biological response to hyperthermia. Br J Cancer Suppl 1982;45:127–131. 103. Lu D, Das DK: Induction of differential heat shock gene expression in heart, lung, liver, brain and kidney by a sympathomimetic drug amphetamine. Biochem Biophys Res Comm 1993;192:808–812. 104. Carvalho M, Carvalho F, Bastos ML: Is hyperthermia the triggering factor for hepatotoxicity induced by 3,4-methylenedioxymethamphetamine (ecstasy)? An in vitro study using freshly isolated mouse hepatocytes. Arch Toxicol 2001;74:789–793. 105. Carvalho M, Carvalho F, Remião F, et al: Effect of 3,4methylenedioxymethamphetamine (“ecstasy”) on body temperature and liver antioxidant status in mice: influence of ambient temperature. Arch Toxicol 2002;76:166–172. 106. Montiel-Duarte C, Varela-Rey M, Oses-Prieto JA, et al: 3,4Methylenedioxymethamphetamine (“Ecstasy”) induced apoptosis of cultured rat liver cells. Biochim Biophys Acta 2002;1588: 26–32. 107. Harvey JK, Todd CW, Howard JW: Fatality associated with Benzedrine ingestion: a case report. Del Med J 1949;21:537–540. 108. Kalant H, Kalant OJ: Death in amphetamine users: causes and rates. Can Med Assoc J 1975;112:299–304. 109. Smith DE, Fischer CM: An analysis of 310 cases of acute high-dose methamphetamine toxicity in Haight-Ashbury. Clin Toxicol 1970;3:117–124. 110. Tenenbein M: Toxicokinetics and toxicodynamics of iron poisoning. Toxicol Lett 1998;102–103:653–656. 111. Brown RJ, Gray JD: The mechanisms of acute ferrous sulphate poisoning. Can Med Assoc J 1955;73:192–197. 112. Strom RL, Schiller P, Seeds AE, Ten Bensel R: Fatal iron poisoning in a pregnant female. Minn Med 1976;59:483–489. 113. Gleason WA, de Mellow DE, De Castro FJ, Connors JJ: Acute hepatic failure in severe iron poisoning. J Pediatr 1979;95:138–140. 114. Tenenbein M: Hepatotoxicity in acute iron poisoning. J Toxicol Clin Toxicol 2001;39:721–726. 115. Britton RS: Metal-induced hepatotoxicity. Semin Liver Dis 1996;16:3–12. 116. Videla LA, Fernandez V, Tapia G, Varela P: Oxidative stressmediated hepatotoxicity of iron and copper: role of Kupffer cells. Biometals 2003;16:103–111.

CHAPTER 11

117. Tapia G, Troncoso P, Galleano M, et al: Time course study of the influence of acute iron overload on Kupffer cell functioning and hepatotoxicity assessed in the isolated perfused rat liver. Hepatology 1998;27:1311–1316. 118. Tenenbein M: Benefits of parenteral deferoxamine for acute iron poisoning. J Toxicol Clin Toxicol 1996;34:485–489. 119. Khan S, Ramwani JJ, O’Brien PJ: Hepatocyte toxicity of mechloroethane and other alkylating anticancer drugs: role of lipid peroxidation. Biochem Pharmacol 1992;43:1963–1967. 120. Ray DC, Drummond GB: Halothane hepatitis. Br J Anaesth 1991;67:84–99. 121. Spracklin DK, Thummel KE, Kharasch ED: Human reductive halothane metabolism in vitro is catalyzed cytochrome P450 2A6 and 3A4. Drug Metab Dispos 1996;24:976–983. 122. Bourdi M, Chen W, Peter RM, et al: Human cytochrome P450 2El is a major autoantigen associated with halothane hepatitis. Chem Res Toxicol 1996;9:1159–1166. 123. Kenna JG, Satoh H, Christ DD, et al: Metabolic basis for a drug hypersensitivity: antibodies in sera from patients with halothane hepatitis recognize liver neoantigens that contain the trifluoroacetyl group derived from halothane. J Pharmacol Exp Ther 1988;245:1103–1109. 124. Vergani D, Mieli-Vergani G, Alberti A et al: Antibodies to the surface of halothane-altered rabbit hepatocytes in patients with severe halothane-associated hepatitis. N Engl J Med 1980;303:66–71. 125. Davis P, Holdsworth CD: Jaundice after multiple halothane anaesthetics administered during the treatment of carcinoma of the uterus. Gut 1973;14:566–568. 126. Pillans PI: Drug associated hepatic reactions in New Zealand: 21 years experience. N Z Med J 1996;109:315–319. 127. Huang YS, Chern HD, Su WJ, et al: Polymorphism of the Nacetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis. Hepatology 2002;35: 883–889. 128. Black M, Mitchell JR, Zimmerman HJ, et al: Isoniazid-associated hepatitis in 114 patients. Gastroenterology 1975;69:289–302. 129. Huang YS, Chern HD, Su WJ, et al: Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatology 2003;37:924–930. 130. Timbrell JA, Wright JM, Baillie TA: Monoacetylhydrazine as a metabolite of isoniazid in man. Clin Pharmacol Ther 1977;22: 602–608. 131. Ellard GA: Variations between individuals and populations in the acetylation of isoniazid and its significance for the treatment pulmonary tuberculosis. Clin Pharmacol Ther 1976;19:610–625. 132. Ohno M, Yamaguchi I, Yamamoto I, et al: Slow N-acetyltransferase 2 genotype affects the incidence of isoniazid and rifampicininduced hepatotoxicity. Int J Tuberc Lung Dis 2000;4:256–261. 133. Pessayre D, Bentata M, Degott C, et al: Isoniazid-rifampin fulminant hepatitis. A possible consequence of the enhancement of isoniazid hepatotoxicity by enzyme induction. Gasteroenterology 1977;72:284–289. 134. Pessayre D, Mazel P: Induction and inhibition of hepatic drug metabolizing enzymes by rifampin. Biochem Pharmacol 1976;25: 943–949. 135. Garcia-Rodriguez LA, Williams R, Derby LE, et al: Acute liver injury associated with nonsteroidal anti-inflammatory drugs and the role of risk factors. Arch Int Med 1994;154:311–316. 136. Manoukian AV, Carson JL: Nonsteroidal anti-inflammatory druginduced hepatic disorders. Incidence and prevention. Drug Saf 1996;15:64–71. 137. Walker AM: Quantitative studies of the risk of serious hepatic injury in persons using nonsteroidal anti-inflammatory drugs. Arthritis Rheum 1997;40:201–208. 138. Sgro C, Clinard F, Ouazir K, et al: Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology 2002;36:451–455. 139. O’Connor N, Dargan PI, Jones AL: Hepatocellular damage from non-steroidal anti-inflammatory drugs. QJM 2003;96:787–791. 140. Rodiguez-Gonzalez FJ, Montero JL, Puente J, et al: Orthotopic liver transplantation after subacute lvier failure induced by therapeutic doses of ibuprofen. Am J Gastroenterol 2002;97: 2476–2477.

Hepatic Toxicology

243

141. Koff RS: Liver disease induced by nonsteroidal anti-inflammatory drugs. In Borda IT, Koff RS (eds): A Profile of Adverse Effects. Philadelphia, Hanley and Belfus, 1992, pp 133–145. 142. Boelsterli UA, Zimmerman HJ, Kretz-Rommel A: Idiosyncratic liver toxicity of nonsteroidal anti-inflammatory drugs: molecular mechanism and pathology. Crit Rev Toxical 1995;25:207–235. 143. Rabkin JM, Smith MJ, Orloff SL, et al: Fatal fulminant hepatitis associated with bromofenac use. Ann Pharmacother 1999;33: 945–947. 144. Nachimuthu S, Volfinzon L, Gopal L: Acute hepatocellular and cholestatic injury in a patient taking celecoxib. Postgrad Med 2001;77:548–550. 145. Merlani G, Fox M, Oehen HP, et al: Fatal hepatotoxicity secondary to nimesulide. Eur J Clin Pharmacol 2001;57:321–326. 146. Alegria P, Lebre L, Chagas C: Celecoxib-induced cholestatic hepatotoxicity in a patient with cirrhosis. Ann Intern Med 2002;137:75. 147. Huster D, Schubert C, Berr F, et al: Rofecoxib-induced cholestatic hepatitis: treatment with molecular adsorbent recycling system (MARS). J Hepatol 2002;37:413. 148. Greaves RR, Agarwal A, Patch D, et al: Inadvertent diclofenac rechallenge from generic and non-generic prescribing, leading to liver transplantation for fulminant liver failure. Eur J Gastroenterol Hepatol 2001;13:71–73. 149. Ponsoda X, Pareja E, Gomez-Lechon MJ, et al: Drug biotransformation by human hepatocytes. In vitro/in vivo metabolism by cells from the same donor. J Hepatol 2001;34:19–24. 150. Masubuchi Y, Yamada S, Horie T: Possible mechanisms of hepatocyte injury induced by diphenylamine and its structurally related NSAIDS. J Pharmacol Exp Ther 2000;292:982–987. 151. Bort R, Ponsoda X, Jover R, et al: Diclofenac toxicity to hepatocytes: a role for drug metabolism in cell toxicity. J Pharmacol Exp Ther 1999;288:65–72. 152. Masubuchi Y, Nakayama S, Horie T: Role of mitochondrial permeability transition in diclofenac-induced hepatotoxicity in rats. Hepatology 2002;35:544–551. 153. Ji B, Masubuchi Y, Horie T: A possible mechanism of naproxeninduced lipid-peroxidation in rat liver microsomes. Pharmacol Toxicol 2001;89:43–48. 154. Zimmerman HJ: Update on hepatotoxicity due to classes of drugs in common clinical use: non-steroidal drugs, antiflammatory drugs, antibiotics, antihypertensives and cardiac and psychotropic agents. Semin Liver Dis 1990;10:322–338. 155. Rabinovitz M, Van Thiel DH: Hepatotoxicity of non-steroidal antiinflammatory drugs. Am J Gastroenterol 1992;87:1696–1704. 156. Prescott LJ: Effect of non-narcotic analgesics on the liver. Drugs 1986;32:129–147. 157. Jones AL: Recent advances in the management of late Paracetamol poisoning. Emerg Med 2000;12:14–21. 158. Leeder JS: Mechanisms of idiosyncratic hypersensitivity reactions to antiepileptic drugs. Epilepsia 1998;39(Suppl 7):S8–S16. 159. Smythe MA, Umstead GS: Phenytoin hepatotoxicity: a review of the literature. DICP 1989;23:13. 160. Moustafa MA, Claesen M, Adline J, et al: Evidence for an arene3,4-oxide as a metabolic intermediate in the meta- and parahydroxylation of phenytoin in the dog. Drug Metab Dispos 1983;11:574–580. 161. Watkins PB, Whitcomb RW: Hepatic dysfunction associated with troglitazone. N Engl J Med 1998;338:916–917. 162. Murphy EJ, Davern TJ, Shakil O: Troglitazone-induced fulminant hepatic failure. Dig Dis Sci 2000;45:549–553. 163. Gitlin N, Julie NL, Spurr CL: Two cases of severe clinical and histologic hepatotoxicity associated with troglitazone. Ann Intern Med 1998;129:36–38. 164. Neuschwander-Tetri A, Isley WL, Oki JC: Troglitazone induced hepatic failure leading to liver transplantation. Ann Intern Med 1998;129:38–41. 165. Kohlroser J, Mathai J, Reichheld J: Hepatotoxicity due to troglitazone: report of two cases and review of adverse events reported to the US FDA. Am J Gastroenterol 2000;95:272–276. 166. Schiano T, Dolehide K, Hart J, Baker AL: Severe but reversible hepatitis induced by troglitazone. Did Dis Sci 2000;45:1039–1042. 167. Bell DS, Ovalle F: Late onset troglitazone-induced hepatic dysfunction. Diabetes Care 2000;2:128–129.

244


168. Jagannath S, Rai R: Rapid onset subfulminant liver failure associated with troglitazone. Ann Intern Med 2000;132:677. 169. Menon KV, Angulo P, Lindor KD: Severe cholestatic hepatitis from troglitazone in a patient with non-alcoholic steatohepatitis and diabetes mellitus. Am J Gastroenterol 2001;96:1631–1634. 170. Iwase M, Yamaguchi M, Yoshinari M: A Japanese case of liver dysfunction after 19 months of troglitazone treatment. Diabetes Care 1999;22:1382–1384. 171. Funk C, Ponelle C, Scheuermann G, Pantze M: Cholestatic potential of troglitazone as a possible factor contributing to troglitazone-induced hepatotoxicity: in vivo and in vitro interaction at the cacalicular bile salt export pump in the rat. Mol Pharmacol 2001;59:627–635. 172. Shibuya M, Watanabe M, Yoshikuni F: An autopsy case of troglitazone induced fulminant hepatitis. Diabetes Care 1998;21;2140–2143. 173. Sitruk V, Mohib S, Grando-Lemiare V, et al: Acute cholestatic hepatitis induced by glimepride. Gastroenterol Clin Biol 2000;24: 1233–1234. 174. Bloomgarden ZT: American Diabetes Association 60th Scientific Sessions, 2000: thiazolidinediones, obesity and related topics. Diabetes Care 2001;24:162–166. 175. Lebovitz HE, Salzman A: Rosiglitazone liver safety update. Diabetes 2000;49:123. 176. Rubin CJ, Schneider RL: Pioglitazone liver enzyme profile is similar to placebo in US controlled clinical trials. Diabetes 2000;49:39. 177. Maeda K: Hepatocellular injury in a patient receving pioglitazone. Ann Intern Med 2001;135:306. 178. Forman LM, Simmons DA, Diamond RH: Hepatic failure in patient taking rosiglitazone. Ann Intern Med 2000;132:118–121. 179. Al-salman J, Arjomand H, Kemp DG, Mittal M: Hepatocellular injury in a patient receiving rosiglitazone. Ann Intern Med 2000;132:121–124. 180. Lenhard MJ, Funk WB: Failure to develop hepatic injury fom rosiglitazone in a patient with a history of troglitazone-induced hepatitis. Diabetes Care 2001;24:168–169. 181. Zaidi SA: Hepatitis associated with amoxicillin/clavulanic acid and/or ciprofloxacin. Am J Med Sci 2003;325:31–33. 182. Knowles SR, Shapiro LE, Shear NH: Reactive metabolites and adverse drug reactions: clinical considerations. Clin Rev Allergy Immunol 2003;24:229–238. 183. Taylor WR, White NJ: Antimalarial drug toxicity: a review. Drug Saf 2004;27:25–61. 184. Raymond JM, Dumas F, Baldit C, et al: Fatal acute hepatitis due to amodiaquine. J Clin Gastroenterol 1989;11:602–603. 185. Prescott LF: Effects of non-narcotic analgesics on the liver. Drugs 1986;32(Suppl 4):129–147. 186. Friedman G, Lamoureux E, Sherker AH: Fatal fulminant hepatic failure due to cyproterone acetate. Dig Dis Sci 1999;44:1362–1363. 187. Chan CH: Dantrolene sodium and hepatic injury. Neurology 1999;40:1427–1432. 188. Beaune PH, Lecoeur S: Immunotoxicology of the liver: adverse reactions to drugs. J Hepatol 1997;26(Suppl 2):37–42. 189. Roschlau G, Baumgarten R, Fengler JD: Dihydralazine hepatitis. Morphologic and clinical criteria for diagnosis. Zentralbl Allg Pathol 1990;136:127–134. 190. Chick J: Safety issues concerning the use of disulfiram in treating alcohol dependence. Drug Saf 1999;20:427–435. 191. Eliasson E, Stal P, Oksanen A, et al: Expression of autoantibodies to specific cytochromes P450 in case of disulfiram hepatitis. J Hepatol 1998;29:819–825. 192. Reichle FM, Conzen PF: Halogenated inhalational anaesthetics. Best Pract Res Clin Anaesthesiol 2003;17:29–46. 193. Durand F, Samuel D, Bernuau J, et al: Fipexide-induced fulminant hepatitis. Report of three cases with emergency liver transplantation. J Hepatol 1992;15:144–146. 194. Chien RN, Sheen IS, Liaw YF: Unintentional rechallenge resulting in a causative relationship between ketoconazole and acute liver injury. Int J Clin Pract 2003;57:829–830. 195. Kim TH, Kim BH, Kim YW, et al: Liver cirrhosis developed after ketoconazole-induced acute hepatic injury. J Gastroenterol Hepatol 2003;18:1426–1429. 196. Makin AJ, Fitt S, Williams R, Duncan JS: Fulminant hepatic failure induced by lamotrigine. BMJ 1995;311:292.

197. Sauve G, Bresson-Hadni S, Prost P: Acute hepatitis after lamotrigine administration. Drug Dis Sci 2000;45:1874–1877. 198. Arnon R, DeVivo D, Defelice AR, Kazlow PG: Acute hepatic failure in a child treated with lamotrigine. Pediatr Neurol 2000;18:251–252. 199. Breland BD, Hicks GS Jr: Hepatitis and hemolytic anemia associated with methyldopa therapy. Drug Intell Clin Pharm 1982;16:489–492. 200. Dalton TA, Berry RS: Hepatotoxicity associated with sustainedrelease niacin. Am J Med 1992;93:102–104. 201. Shaw DR, Misan GM, Johnson RD: Nifedipine hepatitis. Aust N Z J Med 1987;17:447–448. 202. Dorn-Beineke A, Hassan AW, Brautigam J, et al: Phenprocoumoninduced hepatitis as an immunologically mediated drug allergic complication of antithrombotic therapy. Thromb Haemost 2003;90:1210–1213. 203. Hinrichsen H, Luttges J, Kloppel G, et al: Idiosyncratic drug allergic phenprocoumon-induced hepatitis with subacute liver failure initially misdiagnosed as autoimmune hepatitis. Scand J Gastroenterol 2001;36:780–783. 204. Yee D, Valiquette C, Pelletier M, et al: Incidence of serious side effects from first-line antituberculos drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med 2003;167: 1472–1477. 205. Blackard WG Jr, Sood GK, Crowe DR, et al: Tacrine. A cause of fatal hepatotoxicity? J Clin Gastroenterol 1998;26:57–59. 206. Spoerke DG, Rumack BH (eds): Handbook of Mushroom Poisoning. Diagnosis and Treatment. Baca Raton, FL, CRC Press, 1994. 207. Enjalbert F, Rapoir S, Nouguier-Soule J, et al: Treatment of amatoxin poisoning: 20-year retrospective analysis. J Toxicol Clin Toxicol 2002;40:715–757. 208. Enjalbert F, Gallion C, Jehl F, et al: Amatoxins and phallatoxins in amanita species. HPLC determination. Mycologica 1993;85: 579–584. 209. Wieland T: The toxic peptides from amanita mushrooms. Int J Pept Protein Res 1983;22:257–276. 210. Herold R, Straub PW: Acute hepatic necrosis of hepatitis and mushroom poisoning. The value of coagulation tests in their differentiation, prognostic assessment and pathogenesis. Helv Med Acta 1978;37:5. 211. Floersheim GL, Schneeberger J, Bucher K: Curative potencies of penicillin in experimental amanita phalloides poisoning. Agents Actions 1971;2:138–141. 212. Floersheim GL, Eberhard M, Tschumi P, Duckert P: Effects of penicillin and silymarin on liver enzymes and blood clotting factors in dogs given a boiled preparation of amanita phalloides. Toxicol Appl Pharmacol 1978;46:455–462. 213. Bogle G, Tuchweber B, Trost W, Mengs U: Protection by silibinin against Amanita phalloides intoxication in beadles. Toxicol Appl Pharmacol 1984;73:355–362. 214. Locatelli C, Maccarini D, Ferruzi M, et al: Intossicazioni acute da Amanita phalloides: proposta di terapia con N-Acetilcisteina. Ann Mus Civ Rovereto 1989;4:211–212. 215. Locatelli C, Travaglia A, Sala G, et al: The role of N-acetylcysteine and forced diuresis in the treatment of phalloidea poisoning. Minerva Anestesiol 1990;56:1361–1363. 216. Dossing M, Skinhoj P: Occupational liver injury. Present state of knowledge and future perspectives. Int Arch Occup Environ Health 1985;56:11. 217. Zimmerman HJ: Effects of alcohol on other hepatotoxins. Alcohol Cin Exp Res 1986;10:3. 218. Ruprah M, Mont TG, Flannagan RJ: Acute carbon tetrachloride poisoning in 19 patients: implications for diagnosis and treatment. Lancet 1985;1:107. 219. Simmons JE, McDonald A, Seely JC, et al: Potentiation of carbon tetrachloride hepatotoxicity by inhaled methanol: time course of injury and recovery. J Toxicol Environ Health 1995;46:203–216. 220. Shibayama Y: Potentiation of carbon tetrachloride hepatotoxicity of hypoxia. Br J Exp Pathol 1986;67:909–914. 221. Slater TF, Cheeseman KH, Ingold KU: Carbon tetrachloride toxicity as a model for studying free-radical mediated liver injury. Philos Trans R Soc Lond B Biol Sci 1985;311:633–645. 222. Wroblewski F: Clinical significance of alterations in transaminase activities in serum and other body fluids. Adv Clin Chem 1958;1:313.

CHAPTER 11

223. Mathieson PW, Williams G, MacSweeney JE: Survival after massive ingestion of carbon tetrachloride treated by intravenous infusion of acetylcysteine. Hum Toxicol 1985;4:627–631. 224. Greenberger NJ, Robinson WL, Isselbacher KJ: Toxic hepatitis after the ingestion of phosphorus with subsequent recovery. Gastroenterol 1964;47:179–183. 225. Fletcher GF, Galambos JT: Phosphorus poisoning in humans. Arch Int Med 1963;112:846–852. 226. Brewer E, Haggerty RJ: Toxic hazards. Rat poisons. II. Phosphorus. N Engl J Med 1958;258:147. 227. Rodriguez-Iturbe B: Acute yellow phosphorus poisoning. N Engl J Med 1971;284:157. 228. Simon FA, Pickering LK: Acute yellow phosphorus poisoning. Smoking stool syndrome. JAMA 1976;235:1343. 229. Poklis A, Saady J: Arsenic poisoning: Acute or chronic. Suicide or murder. Am J Forensic Med Pathol 1990;11:226. 230. Clearfield JR: Hepatoreneal toxicity from sniffing spot remover (metchloroethylene). Am J Dig Dis 1970;15:851. 231. Tucker SC, Patterson TE: Hepatitis and halothane sniffing. Ann Intern Med 1974;30:667. 232. Goyer RA: Toxic effects of metals. In Klaassen CD (ed): Casarette and Doull’s Toxicology: The Basic Science of Poisons, 5th ed. New York, Macmillan, 1996, pp 691, 736. 233. Jantsch W, Kulig K, Rumack BH: Massive copper sulfate ingestion resulting in hepatotoxicity. J Toxicol Clin Toxicol 1984;22:585. 234. Kimbrough RD: The toxicity of polychlorinated polycyclic compounds and related chemicals. CRC Crit Rev Toxicol 1974;2:445. 235. Kuratsune M, Yoshimura T, Matsuzaka J, et al: Epidemiologic study of oil contaminated with a commercial brand of polychlorinated biphenyls. Environ Health Perspect 1972;1:119. 236. Safe S: Toxicology, structure-function relationship, and human and environmental health impacts of polychlorinated biphenyls: progress and problems. Environ Health Perspect 1993;100:259–268. 237. Skilleter D, Cain K, Dinsdale D, et al: Biochemical mechanisms and morphological selectivity in hepatotoxicity: studies in cultures of hepatic-parenchymal and non-parenchymal cells. Xenobiotica 1985;15:687–693. 238. Brautbar N, Williams J II: Industrial solvents and liver toxicity: risk assessment, risk factors and mechanisms. Int J Hyg Environ Health 2002;205:479–491. 239. Paolini M, Sapigni E, Mesirca R, et al: On the hepatotoxicity of 1,1,2,2-tetrachloroethane. Toxicology 1992;73:101–115. 240. Tomiyama N, Watanabe M, Takeda M, et al: A comparative study on the reliability of toxicokinetic parameters for predicting hepatotoxicity of DDT in rats receiving a single or repeated administration. Toxicol Sci 2003;28:403–413. 241. Liu ZX, Kaplowitz N: Immune-mediated drug-induced liver disease. Clin Liver Dis 2002;6:467–486. 242. Yeung E, Wong FS, Wanless IR, et al: Ramipril-associated hepatotoxicity. Arch Pathol Lab Med 2003;127:1493–1497. 243. Kalapos MP: Carbamazepine-provoked hepatotoxicity and possible aetiopathological role of glutathione in the events. Retrospective review of old data and call for new investigation. Adverse Drug React Toxicol Rev 2002;21:123–141. 244. Schneider HL, Hornbach KD, Kniaz JL: Chlorpropamide hepatotoxicity: report of a case and review of the literature. Am J Gastroenterol 1984;79:721–724. 245. Fisher AA, Le Couteur DG: Nephrotoxicity and hepatotoxicity of histamine H2 receptor antagonists. Drug Saf 2001;24:39–57. 246. Hummer M, Kurz M, Kurzthaler I, et al: Hepatotoxicity of clozapine. J Clin Psychopharmacol 1997;17:314–317. 247. Munyon WH, Salo R, Briones DF: Cytotoxic effects of neuroleptic drugs. Psychopharmacology (Berl) 1987;91:182–188. 248. Woeber KA: Methimazole-induced hepatotoxicity. Endocr Pract 2002;8:222–224. 249. Thiim M, Friedman LS: Hepatotoxicity of antibiotics and antifungals. Clin Liver Dis 2003;7:381–399. 250. Bergeron L, Guy C, Ratrema M, et al: Dextropropoxyphene hepatotoxicity: four cases and literature review. Therapie 2002;57:464–472. 251. Slezak P: Quinidine hepatotoxicity. Med J Aust 1981;1:139. 252. Devuyst O, Lefebvre C, Geubel A, et al: Acute cholestatic hepatitis with rash and hypereosinophilia associated with ranitidine treatment. Acta Clin Belg 1993;48:109–114.

Hepatic Toxicology

245

253. Zaman F, Ye G, Abreo KD, et al: Successful orthotopic liver transplantation after trimethoprim-sulfamethoxazole associated fulminant liver failure. Clin Transplant 2003;17:461–464. 254. Lasso Vega MC, Zapater P, Such J, et al: Toxic hepatitis associated with tamoxifen use. A case report and literature review. Gastroenterol Hepatol 2002;25:247–250. 255. Ajit C, Suvannasankha A, Zaeri N, et al: Terbinafine-associated hepatotoxicity. Am J Med Sci 2003;325:292–295. 256. Farmer JA, Torre-Amione G: Comparative tolerability of the HMG-CoA reductase inhibitors. Drug Saf 2000;23:197–213. 257. Ballare M, Xampanini M, Airoldi G: Hepatotoxicity of HMG-CoA reductase inhibitors. Minerva Gastroenterol Dietol 1992; 38:41–44. 258. Grimbert S, Pessayre D, Degott C: Acute hepatitis induced by the HMG-CoA reductase inhibitor lovastatin. Drug Dig Sci 1999;39:2032–2033. 259. Hartleb M, Rymarczyk C, Januszewski K: Acute cholestatic hepatitis associated with pravastatin. Am J Gastroenterol 1999;94:1388–1390. 260. Huchzermeyer H, Munzenmaier R: Lovastatin-induced acute cholestatic hepatitis. Dtsch Med Wochenschr 1995;120:252–256. 261. Gascon A, Zabala S, Iglesias E: Acute cholestasis during long term treatment with fluvastatin in a nephritic patient. Nephrol Dial Transpl 1999;14:1038. 262. Punthakee Z, Scully LJ, Guindi MM, Ooi TC: Liver fibrosis attributed to lipid-lowering medications: two cases. J Intern Med 2001;250:249–254. 263. Nakad A, Bataille L, Hamoir V: Atorvastatin-induced acute hepatitis with absence of cross-toxicity with simvastatin. Lancet 1999;53:1763–1764. 264. Athyros VG, Papageorgiou AA, Hatzikonstandinou HA: Safety and efficacy of long-term statin-fibrate combinations in patients with familial combined hyperlipidaemia. Am J Cardiol 1997; 80:608–613. 265. Rosellini SR, Costa PL, Gaudio M, et al: Hepatic injury related to enalapril. Gastroenterology 1989;97:810. 266. Hagley MT, Hulisz DT, Burns CM: Hepatotoxicity associated with angiotensin-converting enzyme inhibitors. Ann Phamacother 1993;27:228–231. 267. Larrey D, Babany G, Bernau J, et al: Fulminant hepatitis after lisinopril administration. Gastroenterology 1990;99:1832–1833. 268. Nunes AC, Amaro P, Mac F, et al: Fosinopril induced proloned cholestatic jaundice and pruritis: first case report. Eur J Gastroenterol Hepatol 2001;13:279–282. 269. Rahmat J, Gelfand RL, Gelfand M, et al: Captopril-associated cholestatic jaundice. Ann Intern Med 1985;102:56–58. 270. Hagley MT, Benak RL, Hulisz DT: Suspected cross-reactivity of enalapril and captopril induced hepatotoxicity. Ann Pharmacother 1992;26:780–781. 271. Jeserich M, Ihling C, Allgaier HP, et al: Acute liver failure due to enalapril. Herz 2000;25:689–693. 272. Todd P, Levison D, Farthing MJ: Enalapril related acute cholestatic jaundice. J R Soc Med 1990;83:271–272. 273. Andrade RJ, Lucena MI, Santella F: Hepatic injury associated with losartan. Ann Pharmacother 1998;32:1371. 274. Hariraj R, Stoner E, Jader S, et al: Drug points: prolonged cholestasis associated with irbesartan. BMJ 2000;321:547. 275. Vallejo I, Garcia Morillo S, Pamies E: Acute hepatitis induced by candesartan. Med Clin (Barc) 2000;1115:719. 276. See S, Stirling AL: Candesartan cilexitil: an angiotensin II receptor blocker. Am J Health Syst Pharm 2000;57:739–746. 277. Gonzalez-Jiminez D, Varela JM, Calderon E, et al: Candesartan and acute liver injury. Eur J Clin Pharmacol 2000;56:769–770. 278. Yap I, Gwee KA, Wee A: Augmentin-induced cholestatic jaundice—a case report. Singapore Med J 1993;34:464–465. 279. O’Donohue J, Oien KA, Donaldson P, et al: Co-amoxiclav jaundice: clinical and histological features and HLA class II association. Gut 2000;47:717–720. 280. Romagnuolo J, Sadowski DC, Lalor E, et al: Cholestatic hepatocellular injury with azathioprine: a case report and review of the mechanisms of hepatotoxicity. Can J Gastroenterol 1998;12:479–483. 281. Knodell RG: Effects of chlorpromazine on bilirubin metabolism and biliary secretion in the rat. Gastroenterology 1975;69:965–972. 282. Hautekeete ML: Hepatotoxicity of antibiotics. Acta Gastroenterol Belg 1995;58:290–296.

246


283. Basset C, Vadrot J, Denis J, et al: Prolonged cholestasis and ductopenia following gold salt therapy. Liver Int 2003;23:89–93. 284. Rosenbaum J, Katz WA, Schumacher HR: Hepatotoxicity associated with use of D-penicillamine in rheumatoid arthritis. Ann Rheum Dis 1980;39:152–154. 285. Bastian PG: Occupational hepatic caused by methylenedianiline. Med J Aust 1984;141:533. 286. Kaplowitz N, Aw TY, Simon FR, et al: Drug-induced hepatotoxicity. Ann Intern Med 1986;104:826–839. 287. Hepatic effects of 17 alpha-alkylated anabolic-androgenic ster. HIV Hotline 1998;8:2–5. 288. Stone BG, Udani M, Sanghvi A, et al: Cyclosporin A-induced cholestasis. The mechanism in a rat model. Gastroenterology 1987;93:344–351. 289. Hall AJ, Harrington JM, Waterhouse JA: The Epping jaundice outbreak: a 24 year follow up. J Epidemiol Community Health 1992;46:327–328. 290. Kopelman H, Robertson MH, Sanders PG, et al: The Epping jaundice. BMJ 1966;5486:514–516. 291. Doll R: Spanish toxic oil syndrome. Med Hist 2003;47:99. 292. A search for an animal model of the Spanish toxic oil syndrome. Food Chem Toxicol 2002;40:1551–1567. 293. Leiber CS: Alcoholic liver injury: pathogenesis and therapy in 2001. Pathol Biol (Paris) 2001;49:738–752. 294. Ugarte G, Iturriaga H, Insunza I: Some effects of ethanol on normal and pathologic livers. Prog Liver Dis 1970;3:355–370. 295. Kurihara T, Akimoto M, Kurokawa K, et al: Effects of a gastric mucosal protecting agent in rats with liver cirrhosis. J Gastroenterol Hepatol 1992;7:405–410. 296. Harrison RF, Elias E: Amiodarone-associated cirrhosis with hepatic and lymph node granulomas. Histopathology 1993;22:80–82. 297. Bach N, Schultz BL, Cohen LB, et al: Amiodarone hepatotoxicity: progression from steatosis to cirrhosis. Mt Sinai J Med 1989;56:293–296. 298. Pettavel J, Gardiol D, Bergier N, Schnyder P: Fatal liver cirrhosis associated with long-term arterial infusion of floxuridine. Lancet 1986;2:1162–1163. 299. Kim TH, Kim BH, Kim YW, et al: Liver cirrhosis developed after ketoconazole-induced acute hepatic injury. J Gastroenterol Hepatol 2003;18:1426–1429. 300. Arteel G, Marsano L, Mendez C, et al: Advances in alcoholic liver disease. Best Pract Res Clin Gastroenterol 2003;17:625–647. 301. Comar KM, Sanyal AJ: Portal hypertensive bleeding. Gastroenterol Clin North Am 2003;32:1079–1105. 302. Thalheimer U, Mela M, Patch D, et al: Prevention of variceal rebleeding. Lancet 2003;361:2244–2245. 303. Vilstrup H: Cirrhosis and bacterial infections. Rom J Gastroenterol 2003;12:297–302. 304. Copple BL, Ganey PE, Roth RA: Liver inflammation during monocrotaline hepatotoxicity. Toxicology 2003;190:155–169. 305. Biecker E, Fischer HP, Strunk H, et al: Benign hepatic tumours. Z Gastroenterol 2003;41:191–200. 306. Rogers AE: Toxicity and carcinogenicity of aflatoxins in experimental animals. In Pollack JD (ed): Reye’s Syndrome. New York, Grune & Stratton, 1974, p 135. 307. Wogan GN: Aflatoxins as risk factors for hepatocellular carcinoma in humans. Cancer Res 1992;52:1145. 308. Sell S: Cellular origin of hepatocellular carcinomas. Semin Cell Dev Biol 2002;13:419–424. 309. Naccarato R, Farinati F: Hepatocellular carcinoma, alcohol, and cirrhosis: facts and hypotheses. Dig Dis Sci 1991;36:1137–1142. 310. Blum HE: Molecular therapy and prevention of hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2003;2:11–22. 311. Kielhorn J, Melber C, Wahnschaffe U, et al: Vinyl chloride: still a cause for concern. Environ Health Perspect 2000;108:579–588. 312. Ward E, Boffetta P, Andersen A, et al: Update of the follow-up of mortality and cancer incidence among European workers employed in the vinyl chloride industry. Epidemiology 2001;12:710–718. 313. Larrey D, Vial T, Pauwels A: Hepatitis after germander (Teucrium chamaedrys) administration: another instance of herbal medicine toxicity. Ann Intern Med 1992;117:129–132. 314. Fau D, Lekehal M, Farrell G: Diterpenoids from germander, an herbal medicine, induce apoptosis in isolated rat hepatocytes. Gastroenterology 1997;113:1334–1346.

315. Lekehal M, Pessayre D, Lereau JM: Hepatotoxicity of the herbal medicine germander: metabolic activation of its furano diterpenoids by cytochrome P4503A depletes cytoskeletonassociated protein thiols and forms plasma membrane blebs in rat hepatocytes. Hepatology 1996;24:212–218. 316. De Berardinis V, Moulis C, Maurice M: Human microsomal epoxide hydrolase is the target of germander-induced autoantibodies on the surface of human hepatocytes. Mol Pharmacol 2000;58:542–551. 317. Mattocks AR, Driver HF, Barbour RH, Robins DJ: Metabolism and toxicity of synthetic analogues of macrocyclic diester pyrrolizidine alkaloids. Chem Biol Interact 1986;58:95–108. 318. Winship KA: Toxicity of comfrey. Adverse Drug React Toxicol Rev 1991;10:47–59. 319. Weston CF, Cooper BT, Davies JD: Veno-occlusive disease of the liver secondary to ingestion of comfrey. BMJ 1987;295:183. 320. Steenkamp V, Stewart M, Zuckerman M: Clinical and analytical aspects of pyrrolizidine alkaloid poisoning caused by South African traditional medicines. Ther Drug Monit 2000;22:302–306. 321. Stickel F, Egerer G, Seitz HK: Hepatotoxicity of botanicals. Public Health Nutr 2000;3:113–124. 322. DeLeve LD, McCuskey RS, Wang X: Characterization of a reproducible rat model of hepatic veno-occlusive disease. Hepatology 1999;29:1779–1791. 323. Wang X, Kanel GC, DeLeve LD: Support of sinusoidal endothelial cell glutathione prevents hepatic veno-occlusive disease in the rat. Hepatology 2000;31:428–434. 324. Anderson IB, Mullen WH, Meeker JE: Pennyroyal toxicity: measurement of toxic metabolites in two cases and review of the literature. Ann Intern Med 1996;124:726–734. 325. Bakerink JA, Gosper SM, Dimand RJ, Eldridge MW: Multiple organ failure after ingestion of pennyroyal oil from herbal tea in two infants. Pediatrics 1996;98:944–947. 326. Khojasteh-Bakht SC, Chen W, Koenigs LL: Metabolism of (R)+pulegone and (R)+-menthofuran by human liver cytochrome P450s: evidence for formation of a furan epoxide. Drug Metab Dispos 1999;27:574–580. 327. Sullivan JB Jr, Rumack BH, Thomas H Jr, et al: Pennyroyal oil poisoning and hepatotoxicity. JAMA 1979;242:2873–2874. 328. Sztajnkrycer MD, Otten EJ, Bond GR, et al: Mitigation of pennyroyal oil hepatotoxicity in the mouse. Acad Emerg Med 2003;10:1024–1028. 329. Haouzi D, Lekehal M, Moreau A, et al: Cytochrome P450generated reactive metabolites cause mitochondrial permeability transition, caspase activation, and apoptosis in rat hepatocytes. Hepatology 2000;32:303–311. 330. Mattei A, Rucay P, Samuel D: Liver transplantation for acute liver failure after herbal medicine (Teucrium polium) administration. J Hepatol 1995;22:597. 331. Batchelor WB, Heathcote J, Wanless IR: Chaparral-induced hepatic injury. Am J Gastroenterol 1995;90:831–833. 332. Sheikh NM, Philen RM, Love LA: Chaparral-associated hepatotoxicity. Arch Intern Med 1997;157:913–919. 333. Batchelor WB, Heathcote J, Wanless IR: Chaparral-induced hepatic injury. Am J Gastroenterol 1995;90:831–832. 334. Smith BC, Desmond PV: Acute hepatitis induced by ingestion of the herbal medicine chaparral. Aust N Z J Med 1993;23:526. 335. Escher M, Desmeales J, Giostra E, Mentha G: Hepatitis associated with Kava, a herbal remedy for anxiety. BMJ 2001;322:139. 336. Kraft M, Spahn TW, Menzel J: Fulminant liver failure after administration of the herbal antidepressant Kava-Kava. Dtsch Med Wochenschr 2001;126:970–972. 337. Russmann S, Lauterburg BH, Helbling A: Kava hepatotoxicity. Ann Intern Med 2001;135:68–69. 338. Strahl S, Ehret V, Dahm HH, Maier KP: Necrotizing hepatitis after taking herbal remedies. Dtsch Med Wochenschr 1998;123: 1410–1414. 339. Xing JH, Soffer EE: Adverse effects of laxatives. Dis Colon Rectum 2001;44:1201–1209. 340. Fukunishi R: Acute hepatic lesions induced by cycasin. Acta Pathol 1973;23:639. 341. Atal CK: Semisynthetic derivatives of pyrrolizidine alkaloids of pharmacodynamic importance: a review. Lloydia 1978;41: 312–326.

CHAPTER 11

342. Uc A, Bishop WP, Sanders KD: Camphor hepatotoxicity. South Med J 2000;93:596–598. 343. Jimenez JF, Brown AL, Arnold WC, Byrne WJ: Chronic camphor ingestion mimicking Reye’s syndrome. Gastroenterology 1983;84:394–398. 344. Stewart MJ, Steenkamp V: The biochemistry and toxicity of atractyloside: a review. Ther Drug Monit 2000;22:641–649. 345. Popat A, Shear NH, Malkiewicz I: The toxicity of Callilepis laureola, a South African traditional herbal medicine. Clin Biochem 2001;34:229–236. 346. Nadir A, Reddy D, Van Thiel DH: Cascara sagrada-induced intrahepatic cholestasis causing portal hypertension: case report and review of herbal hepatotoxicity. Am J Gastroenterol 2000;95:3634–3637. 347. Fraquelli M, Colli A, Cocciolo M, Conte D: Adult syncytial giant cell chronic hepatitis due to herbal remedy. J Hepatol 2000;33:505–508. 348. De Smet PA, Van den Eertwegh AJ, Lesterhuis W, et al: Hepatotoxicity associated with herbal tablets. BMJ 1996;313:92. 349. Takegoshi K, Tohyama T, Cox D: A case of Venoplant-induced hepatic injury. Gastroenterol Japan 1986;21:62–65. 350. Hamid S, Rojter S, Vierling J: Protracted cholestatic hepatitis after the use of Prostata. Ann Intern Med 1997;127:169–170. 351. Nadir A, Sangeeta A, King P, Marshall JB: Acute hepatitis associated with the use of a Chinese herbal product, Ma-Huang. Am J Gastroenterol 1996;91:1436–1438. 352. Borum ML: Fulminant exacerbation of autoimmune hepatitis after the use of ma-huang. Am J Gastroenterol 2001;96:1654–1655. 353. Picciotto A, Campo N, Brizzolara R: Chronic hepatitis induced by Jin Bu Huan. J Hepatol 1998;28:165–167. 354. Horowitz RS, Feldhaus K, Dart RC: The clinical spectrum of Jin Bu Huan toxicity. Arch Intern Med 1996;156:899–903. 355. Woolf GM, Petrovic LM, Rojter SE: Acute hepatitis associated with the Chinese herbal product Jin Bu Huan. Ann Intern Med 1994;121:729–735. 356. Benninger J, Schneider HT, Schuppan D: Acute hepatitis induced by greater celandine (Chelidonium majus). Gastroenterology 1999;117:1234–1237. 357. Yoshida EM, McLean CA, Cheng ES: Chinese herbal medicine, fulminant hepatitis and liver transplantation. Am J Gastroenterol 1996;91:2647–2648. 358. Perharic-Walton L, Murray V: Toxicity of Chinese herbal remedies. Lancet 1992;340:674. 359. Gorey JD, Wahlqvist ML, Boyce NW: Adverse reaction to a Chinese herbal remedy. Med J Aust 1992;157:484–486. 360. Pillans PI: Herbal medicines and toxic hepatitis. N Z Med J 1994;107:432–433. 361. Kane JA, Kane SP, Jain S: Hepatitis induced by traditional Chinese herbs; possible toxic components. Gut 1995;36:146–147. 362. Al-Khafaji M: Monitoring of liver enzymes in patients on Chinese medicines. JCM 2000;62:6–10. 363. McRae CA, Agarwal K, Mutimer D, Bassedine MF: Hepatitis associated with Chinese herbs. Eur J Gastroenterol Hepatol 2002;14:559–562. 364. Melchart D, Linde K, Hager S: Monitoring of liver enzymes in patients treated with traditional Chinese drugs. Complement Ther Med 1999;7:208–216. 365. Lautt WW: Intrinsic regulation of hepatic blood flow. Can J Physiol Pharmacol 1996;74:223–233. 366. Holden R, Jackson MA: Near-fatal hyponatraemia coma due to vasopressin over-secretion after “ecstasy” (3,4 MDMA). Lancet 1996;347:1052. 367. Box SA, Prescott LF, Freestone S: Hyponatraemia at a rave. Postgrad Med J 1997;73:53–54. 368. Denborough MA, Hopkinson KC: Dantrolene and “ecstasy.” Med J Aust 1997;166:165–166. 369. Ellis A, Wendon J: Circulatory, respiratory, cerebral and renal derangements in acute liver failure: pathophysiology and management. Semin Liver Dis 1996;16:379–388. 370. Lee WM: Acute liver failure. Am J Med 1994;96:S3–S9. 371. Jalan R, Damink SW, Deutz NE, et al: Moderate hypothermia for uncontrolled intracranial hypertension in acute liver failure. Lancet 1999;354:1164–1168. 372. Kritharides L, Fasset R, Singh B: Paracetamol-associated coma, metabolic acidosis, renal and hepatic failure. Intensive Care Med 1988;14:439–440.

Hepatic Toxicology

247

373. Block R, Jankowski JA, Lacoux P, Pennington CR: Does hypothermia protect against the development of hepatitis in paracetamol overdose? Anaesthesia 1992;47:789–791. 374. Aruoma OI, Halliwell B, Hey BM, Butler J: The antioxidant action of N-acetylcysteine. Its reaction with hydrogen peroxide, hydroxyl radical, superoxide and hypochlorous acid. Free Radic Biol Med 1989;6:593–597. 375. Bernuau J, Benhamou JP: Fulminant and subfulminant liver failure. In McIntyre NM, Benhamou JP, Rodes J (eds): The Oxford Textbook of Clinical Hepatology. Oxford, Oxford University Press, 1991, pp 923–942. 376. Gressier B, Cabanis A, Lebegue S, et al: Comparison of in vitro effects of two thiol-containing drugs on human neutrophils hydrogen peroxide production. Methods Find Exp Clin Pharmacol 1993;15:101–105. 377. Tee LG, Boobis AR, Davies DS: N-acetylcysteine for paracetamol overdose. Lancet 1986;1:331–332. 378. Chyka PA, Butler AY, Holliman BJ, Herman MI: Utility of acetylcysteine in treating poisonings and adverse drug reactions. Drug Saf 2000;22:123–148. 379. Harrison PM, Wendon JA, Gimson AE, et al: Improvement by acetylcysteine of haemodynamics and oxygen transport in fulminant hepatic failure. N Engl J Med 1991;324:1852–1857. 380. Walsh TS, Hopton P, Lee A: A comparison between the Fick method and indirect calorimetry for determining oxygen consumption in patients with fulminant hepatic failure. Crit Care Med 1998;26:1200–1207. 381. Bailey B, Amre DK, Gaudreault P: Fulminant hepatic failure secondary to acetaminophen poisoning: a systematic review and meta-analysis of prognostic criteria determining the need for liver transplantation. Crit Care Med 2003;31:299–305. 382. De Carlis L, De Gasperi A, Slim AO, et al: Liver transplantation for ecstasy-induced fulminant hepatic failure. Transplant Proc 2001;33:2743–2744. 383. Greaves BR, Agarwal A, Patch D, et al: Inadvertent diclofenac rechallenge from generic and non-generic prescribing leading to liver transplantation for ulminant liver failure. Eur J Gastroenterol Hepatol 2001;13:71–73. 384. Jones AL, Latham T, Shallcross TM, Simpson KJ: Fulminant hepatic failure due to diclofenac treaeted successfully by orthotopic liver transplant. Transplant Proc 1998;30:192–194. 385. Kozaki K, Egawa H, Garcia-Kennedy R, et al: Hepatic failure due to massive iron ingestion successfully treated with liver transplantation. Clin Transplant 1995;9:85–87. 386. Jackson N, Ellis A, Rhodes A, et al: Non-paracetamol drug induced acute liver failure in a specialist liver intensive care unit: a seven year experience. Hepatology 1998;28:496. 387. Bernal W: Changing patterns of causation and the use of transplantation in the UK. Semin Liver Dis 2003;23:227–237. 388. O’Grady JG, Alexander GJ, Hayllar KM, et al: Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989;97:439–445. 389. Harrison PM, O’Grady JG, Keays RT, et al: Serial prothrombin time as prognostic indicator in paracetamol induced fulminant hepatic failure. BMJ 1990;301:964–966. 390. O’Grady JG, Wendon J, Tan KC, et al: Liver transplantation after paracetamol overdose. BMJ 1991;303:221–223. 391. Jones AL: Recent advances in the management of late paracetamol poisoning. Emerg Med 2000;12:14–21. 392. Bernal W, Donaldson N, Wyncoll D, Wendon J: Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study. Lancet 2002;16:558–563. 393. Makin AJ, Wendon J, Williams R: A 7-year experience of severe acetaminophen-induced hepatotoxicity, 1987–1993. Gastroenterology 1995;109:1907–1916. 394. Sen S, Ytrebo LM, Rose C, et al: Albumin dialysis: a new therapeutic strategy for intoxication from protein-bound drugs. Intensive Care Med 2004;30:496–501. 395. Sen S, Ratnaraj N, Davies NA, et al: Treatment of phenytoin toxicity by the molecular adsorbents recirculating system (MARS). Epilepsia 2003;44:265–267.

12

Renal Toxicology

A

Acute Renal Failure MIGUEL C. FERNÁNDEZ, MD

Acute renal failure (ARF) is one of the most common and serious consequences of poisoning or drug overdose. ARF is a clinical syndrome of diverse causes (Box 12A-1) in which a relatively sudden deterioration of renal function results in the inability of the kidneys to regulate normal homeostasis. Its importance stems from the acuteness and severity of the clinical manifestations that develop and the potential for reversibility of the condition, particularly if it is recognized early and the appropriate preventive and therapeutic measures are instituted promptly. ARF can be a self-limited condition and is one example of organ failure that is totally reversible and for which replacement therapy is available. Nevertheless, ARF is principally associated with a high mortality rate because of the seriousness of the underlying conditions that lead to its onset, which are in turn aggravated by the loss of renal regulatory functions.1 Much of what we know about ARF was relatively recently elucidated.2 Human activity has often led to infection, crush injury, dehydration, massive hemorrhage, and other causes of shock and tissue injury. Historically, acute anuria was attributed to obstruction or associated with edema, earlier known as dropsy. Nonobstructive suppression or retention of urine was termed ischuria renalis in the Age of Enlightenment, which came to be attributed to either inflammation or “paralysis of the kidneys.”3 In 1909, Osler classified ARF under the general heading of acute Bright’s disease. He described a broad and vague group of cases of ARF related to burns, other trauma, and the toxicants turpentine, potassium chlorate, and carbolic acid (phenol). Acute renal lesions that affected crushed or wounded soldiers were described in the German literature during and immediately after World War I.4 In 1923, Muir used the term war nephritis and others used the term field or trench nephritis in describing variations of ARF.5 Sporadic reports of ARF in traumatized civilians began to appear in the literature thereafter and were soon followed by reports of cases of ARF that ensued after prolonged, complicated, and infected surgical procedures.6 In 1926, Haas described his poorly accepted hemodialysis invention for treatment of uremia.7 In 1941 Bywaters, and Beall reported on four patients who sustained crush injuries during the bombing of London in the Battle of Britain and developed ARF, and although they did not make a clear etiologic connection, they made the first modern description of rhabdomyolysis.8 In 1945 nephritis following mite-borne rickettsial scrub typhus

infection was described by several researchers.9,10 Detailed studies of ARF developed during efforts to elucidate the mechanism of shock in battle injuries.11 This, coupled with the further development of hemodialysis and renal replacement therapy by Kolff and Beck in 1944, led to a rapid expansion of knowledge about ARF, while hemodialysis became better accepted as further studies led to improvements of outcome in the 1950s.12-14 Literature in the 1960s concerning patients whose kidneys had failed because of the acute renal toxicity

BOX 12A-1

MAJOR CAUSES OF ACUTE RENAL FAILURE

Prerenal Failure

Extracellular circulating fluid volume contraction Gastrointestinal losses: vomiting, diarrhea Fluid sequestration: burns, pancreatitis, peritonitis, crush injury, venous ligation Renal losses: diuretics, diabetic ketoacidosis Blood loss Central or cardiac shock: congestive heart failure, myocardial infarction, tachyarrhythmias, central nervous system injury Septicemia: endotoxic shock Anoxia (requires salt depletion) Postrenal Failure

Prostatic hypertrophy, tumors, calculi, blood clots, ureteral edema, retroperitoneal fibrosis, inadvertent ureteral ligation, papillary necrosis Renal Failure

Primary damage to tubular epithelium Ischemia Nephrotoxic Drugs: aminoglycosides, methoxyflurane, cytolytic agents, phenytoin, cisplatin, bismuth, rifampin Radiopaque contrast agents Respiratory pigments: hemoglobin, myoglobin Poisons: heavy metals, carbon tetrachloride, animal toxins Intratubular precipitation: uric acid, myeloma proteins, mucoprotein, sulfas, calcium, xanthine, oxalate Primary damage to glomeruli and small renal vasculature Acute glomerulonephritis, collagen vascular disease, malignant hypertension, serum sickness, thrombotic microangiopathy Primary damage to major renal vessels Thrombosis, embolization, atheroembolism Parenchymal necrosis Cortical, papillary 249

250


of drugs and poisons emphasized removal through renal replacement therapy.13 Presently, ARF is classified into three general categories: that caused by renal hypoperfusion (prerenal), that caused by intrinsic parenchymal lesions of the kidneys (renal, or intrinsic), and that caused by obstruction of the urinary outflow passages (postrenal, or obstructive uropathy). These categories and their relative prevalence as a cause of ARF are shown in Figure 12A-1.

PATHOPHYSIOLOGY The hallmarks of ARF are the onset of progressive oliguria and azotemia, typically over a period of hours to days, stemming from a sudden decrease in glomerular filtration rate (GFR) and leading to an acute rise in blood urea nitrogen (BUN) and serum creatinine (Cr) concentrations.15 Daily urine volume less than the volume necessary to excrete the waste products of the body is termed oliguria. Azotemia exists when the blood contains a higher than normal quantity of urea or other nitrogen-containing substances. Normal human kidneys are able to maximally concentrate the urine to 1200 mOsm/L of water. To maintain normal homeostasis, an adult must excrete about 600 mOsm of solute, with urea constituting 40% to 50% of this obligatory solute load. Therefore, the daily urine excretion necessary to maintain homeostasis is about 400 to 500 mL in an adult with normal renal function who is concentrating the urine maximally and consuming a normal diet, and

ARF

Prerenal (50%–70%)

Renal (20%–30%)

Postrenal (1%–10%)

AIN (10%–15%)

ATN (80%–85%)

AGN (600

Uos 320 mOsm UNa50 mEq/L, fractional sodium excretion > 1%) and literally isosmotic concentration (320 to 350 mOsm/kg of water). Should the patient survive, in the absolute majority of cases regeneration of tubular cells sets in and restores renal function. The regenerative and repair process of the injured tubules is an early event that is activated at the very start of injury, culminates during the ensuing days, and results in the ultimate restoration of normal renal structure and function.38,39 The clinical course that ATN follows has been divided into four phases that correspond to the various phases of epithelial cell injury, necrosis, and regeneration. They are of variable duration and have considerable overlap.

Initial Phase The initial phase is the period of ischemia or exposure to the nephrotoxic agent; it continues until oliguria develops (see Fig. 12A-2). The importance of identifying this phase stems from the fact that it represents a potentially reversible stage. Its length varies and depends largely on the causative agent (may last 5 to 7 days). In

general, an abnormal sediment (cylindruria), tubular proteinuria (β2-microglobulins), lysozymuria, and a renal concentrating defect precede by several days any decrease in GFR caused by nephrotoxic agents. Other tubular dysfunctions (renal glycosuria, tubular acidosis, sodium loss) may be detectable and should be sought. The efficacy of prophylactic measures that on occasion are effective during this phase (mannitol, loop diuretics, dopamine) relates to their ability to increase renal blood flow and solute excretion. These measures may also have the capacity to convert oliguric to nonoliguric renal failure (see Fig. 12A-2 and Table 12A-1). As a rule, their efficacy in preventing ARF clinically is questionable.24 On the other hand, prostaglandins have a protective role in the renal autoregulation that is associated with vasoconstricting insults. Inhibitors of prostaglandin synthesis (NSAIDs) or inhibitors of efferent constriction (ACE inhibitors), used during this phase, can accentuate the ischemia and precipitate oliguria.28-30,40

Oliguric Phase No single pathogenetic sequence appears to account for all the varieties of ATN and the development of oliguria. The balance of evidence favors the view that excessive backleak across the damaged tubular epithelium and tubular obstruction by the sloughed cells are important. Changes in glomerular permeability and filtration rate also appear to be contributing mechanisms.1,25 The degree of involvement of any of these potential pathogenetic mechanisms varies and depends on the nature, severity, and duration of the initial nephrotoxic insult. Oliguria is present in 60% to 70% of cases encountered clinically; another 30% to 40% are diagnosed earlier and are associated with a nonoliguric ARF (see Fig. 12A-2 and Table 12A-1). The average duration of the oliguria is 1 to 2 weeks, and daily urine volume averages 150 mL. Anuria (urine output 2 mg/dL), diabetes mellitus, and total dose of radiocontrast agent injected are especially important. Adequate volume expansion with a brisk diuresis initiated before and maintained well after the procedure, coupled with use of N-acetylcysteine, and limitation of the dose of radiocontrast agents administered, is effective in circumventing the undesirable side effect of these agents.72-74 N-acetylcysteine may provide tissue protection through its antioxidative effects and by increasing intracellular glutathione concentrations.75-77 Rhabdomyolysis consequent to the overuse of many drugs, including sedative hypnotics and opiates and opioids, can result in ARF. Myoglobinuria and hyperuricosuria, due to muscle injury, in a setting of severely compromised ECFV account for the ARF that develops. Prompt recognition, with restoration of intravascular volume and alkalization of urine, can prevent progression to oliguric ARF. A similar picture can occur after overdosage with sympathetic stimulating drugs, such as cocaine, amphetamines, and phencyclidine or therapeutic use of gemfibrozil, particularly when used in combination with statin drugs.78,79 Lithium can induce renal tubular acidosis resulting in polyuria, volume depletion, and water and electrolyte abnormalities. Severe lithium poisoning can lead to acute tubular necrosis and altered renal function, albuminuria, copper metabolism, and urinary enzyme abnormalities.80 Other less common forms of ARF are due to glomerular lesions that result from a vasculitis that has been reported in association with the use of allopurinol, hydralazine, procainamide, penicillin, and sulfas. The thrombotic microangiopathy associated with certain antineoplastic agents has been mentioned. Finally, membranous glomerulopathy has been noted with the use of gold, penicillamine, and captopril.24,33,42

TREATMENT Renal replacement therapy has greatly simplified the management of ARF. Nevertheless, certain principles governing fluid and electrolyte management are important to monitor and correct in order to avoid the invasive nature of dialysis, when possible.20,81

Prerenal Failure BOX 12A-5

PRINCIPAL AGENTS ASSOCIATED WITH ACUTE INTERSTITIAL NEPHRITIS

Antimicrobials

Penicillins, cephalosporins, sulfonamides, rifampin Nonsteroidal Anti-inflammatory Drugs

Propionic acid derivatives, others Miscellaneous

Phenindione, phenytoin, thiazide diuretics, allopurinol, cimetidine

Prompt recognition of the manifestations of prerenal ARF is extremely important.38,82 Prerenal ARF represents an early and reversible change in renal hemodynamics that if left uncorrected can lead to ATN. It is characterized by symptoms of peripheral circulatory failure (low blood pressure, rapid pulse, orthostatic hypotension, dry mucous membranes); urine that is low in volume, sodium content (145 mEq/L) would indicate insufficient water replacement, whereas a decline in serum sodium level ( 12 in. in first 12 hr; systemic symptoms, including coagulation defects after crotaline bites; signs of grades I and II appear in rapid progression, with immediate systemic signs and symptoms Very severe envenomation; local reaction develops rapidly; edema may involve ipsilateral trunk; ecchymoses,necrosis, blebs, and blisters develop; at tightly restrictive fascial planes, tension may become great enough to obstruct venous or even arterial flow

II

III

IV

From Dart RC, Hurlbut KM, Garcia R, et al: Validation of a severity score for the assessment of crotalid snakebite. Ann Emerg Med 1996; 27:321.

grade 0 through IV scoring method, and (3) the snakebite severity score (see Box 21A-1 and Tables 21A-7 to 21A-9).56 The snakebite severity score (see Table 21A-8) is a research tool and was not intended for general clinical use. We use a modified minimal-moderate-severe scoring method that integrates portions of all three systems; this is detailed in Table 21A-9.32 Serial physical examinations and assessment of vital signs and clinical status, searching for tissue edema, induration and tenderness, progression of swelling, and development of systemic signs and symptoms, are essential to proper diagnosis and management of the snakebite victim. LABORATORY DIAGNOSIS Laboratory diagnosis of snake venom poisoning focuses predominantly on detection of the following: coagulopathies; hemoconcentration due to third spacing of plasma; anemia due to extravasation of erythrocytes or other sources of bleeding; rhabdomyolysis as indicated by elevated creatine phosphokinase values, elevated creatinine levels not attributable to renal failure, and myoglobinuria; and hematuria or hemoglobinuria on urinalysis. Laboratory tests to detect these potential abnormalities should be obtained on presentation and periodically thereafter. We recommend obtaining a complete blood count with platelets, prothrombin time, partial thromboplastin time, fibrinogen, and fibrin degradation (split) products on presentation and every 4 hours thereafter for at least the first 12 hours of hospitalization. This is recommended because laboratory evidence of coagulopathy may not be evident initially or can worsen after initial presentation. Frequency of obtaining these laboratory data should be determined by the clinician, depending on the patient’s clinical course, the results of the laboratory tests, and whether and when the patient receives antivenom. After administering antivenom, we prefer to obtain these laboratory data every 4 hours until values have returned to normal or to stable near-normal levels. We often screen for laboratory abnormalities caused by concurrent illnesses that can confound the care of envenomated patients. This also helps to determine whether coagulopathies are the result of an envenomation or of underlying severe liver disease. Chest radiography and electrocardiograms should be obtained for patients with preexisting cardiopulmonary diseases and for patients with cardiopulmonary signs or symptoms. We do not routinely obtain these for all

CHAPTER 21

Venomous Snakes

405

TABLE 21A-8 Crotaline Envenomation: The Snakebite Severity Score CRITERIA

POINTS*

Pulmonary System No symptoms/signs Dyspnea, minimal chest tightness, mild or vague discomfort, or respirations of 20–25/min Moderate respiratory distress (tachypnea, 26–40 breaths/min; accessory muscle use) Cyanosis, air hunger, extreme tachypnea, or respiratory insufficiency/failure Cardiovascular System No symptoms/signs Tachycardia (100–25 beats/min), palpitations, generalized weakness, benign dysrhythmia, or hypertension Tachycardia (126–75 beats/min) or hypotension, with systolic blood pressure >100 mm Hg Extreme tachycardia (>175 breaths/min), hypotension with systolic blood pressure 100 cm from bite site)

Gastrointestinal System No symptoms/signs Pain, tenesmus, or nausea Vomiting or diarrhea Repeated vomiting, diarrhea, hematemesis, or hematochezia

0 1 2 3 0 1 2 3

0 1 2 3 4 0 1 2 3

Hematologic System No symptoms/signs Coagulation parameters slightly abnormal: PT, 3.5

SYMPTOMS Usually none Nausea, vomiting, lethargy, tremor CNS depression, fatigue, diarrhea Confusion, agitation, delirium, tachycardia, hypertonia Coma, seizures, hyperthermia, hypotension

*Lithium toxicity may be manifested even at therapeutic levels, especially in the elderly, when the therapeutic level may be 0.2 mEq/L.

† Classification of Hansen and Amdisen.4 (Stages I and II: apathy, tremor, weakness, ataxia, motor agitation, rigidity, fascicular twitching, nausea, vomiting and diarrhea. Stage III: Latent convulsive movements, stupor, and coma.)

CHAPTER 30

examination may be helpful in patients who may endure a prolonged hospital course.

Laboratory and Imaging Studies Initial studies should include cardiac monitoring, electrocardiogram (ECG), assessment of oxygenation and monitoring of urine output, serum electrolytes, calcium, renal function, glucose, serum lithium level, and thyroid-stimulating hormone (TSH). Leukocytosis can be seen with therapeutic lithium use as well as intoxication. A low anion gap can also be present after acute ingestion of lithium carbonate8 possibly owing to the presence of and interference by the carbonate anion in the calculation of anion gap. In addition, in chronic poisoning, patients are likely to demonstrate evidence of renal insufficiency with elevated blood urea nitrogen and creatinine. In some cases in which the diagnosis is initially unclear, imaging of the brain may be necessary. Although some formulations of lithium may be radiopaque, radiography is not reliable for excluding ingestion.39 Many hospitals have readily available serum testing for lithium levels (normal range, ~0.6 to 1.2 mEq/L). Serum levels should ideally be drawn at least 6 to 12 hours after the last therapeutic dose to avoid misinterpretation of predistributional levels. However, these levels can still be misleading because lithium has a low therapeutic index and levels frequently do not correlate with level of toxicity. Levels as high as 10.6 mEq/L (10.6 mmol/L) have been reported without evidence of neurologic toxicity after an acute overdose40 because of the multicompartment kinetics of the drug. Furthermore, a normal level does not exclude toxicity, because serum levels do not accurately reflect the intracellular concentration or toxicity of the drug. It is important to note that some specimen tubes contain lithium heparin as an anticoagulant and can falsely elevate serum lithium results. This phenomenon has been demonstrated to factitiously elevate serum lithium levels by as much as 2.0 mEq/L in healthy volunteers.41 Others have reported these tubes producing falsely elevated levels by as much as 6 to 8 mEq/L.42 There is relatively poor correlation between serum levels and systemic toxicity, particularly after an acute or acute-on-chronic overdose. Hansen and Amdisen described 23 patients with lithium intoxication and concluded that there is no clear-cut relationship between serum lithium levels and severity of symptoms. However, 21 of their patients were suffering from chronic lithium intoxication. They suggested that levels of 1.5 to 2.5 mEq/L are associated with mild symptoms of toxicity, 2.5 to 3.5 mEq/L are considered serious, and greater than 3.5 mEq/L are considered life threatening (see Table 30-3). These levels, which were all drawn at approximately 12 hours after the last dose of lithium,43 hold relevance only for patients with chronic lithium exposure. Bailey and McGuigan prospectively studied all cases of lithium exposure brought to the attention of a poison control center over a 1-year period, and their study group included patients with acute, acute-on-chronic,

Lithium

583

and chronic exposures plus one patient with severe lithium intoxication after a chronic exposure and a peak serum level of 1.5 mEq/L.44 They noted that toxicity occurred at lower levels in patients with chronic exposures compared with those with acute-on-chronic exposures. They concluded that the Hansen and Amdisen classification is not a useful tool for predicting morbidity or mortality and does not correlate well with lithium level. Oakley and colleagues conducted a retrospective analysis of 97 cases of lithium exposure at a regional center over a 13-year period. They concluded that peak serum levels are significantly higher in patients with severe intoxication and that chronic exposure carries a substantially higher risk of severe neurotoxicity than acute exposure. Furthermore, they identified risk factors contributing independently to the development of chronic intoxication: NDI, age over 50 years, thyroid dysfunction, and baseline endogenous creatinine clearance below normal.45 Currently, most authors agree that clinical symptoms are more reliable than serum lithium levels. Additionally, management should be based on these clinical parameters rather than on drug levels.46 Clinicians are cautioned about reliance on an isolated serum lithium level. It has been suggested that erythrocyte, urine, or cerebrospinal fluid (CSF) levels of lithium might be useful in the assessment of lithium toxicity. The erythrocyte concentration does not fluctuate as much as plasma lithium levels, perhaps reflecting an intracellular lithium concentration. However, this value has not been shown to have clinical significance. CSF levels are about 40% to 50% of plasma lithium levels, but in animal studies they have demonstrated no advantage over plasma lithium levels in assessing toxicity.47 In addition to being more invasive, CSF levels do not reflect intracellular levels of lithium. Urine levels do not correlate with clinical toxicity but can be useful in the calculation of renal lithium clearance.

Differential Diagnosis Differential diagnosis of lithium toxicity includes psychosis, hypoglycemia, meningitis, encephalitis, gastroenteritis, food poisoning, drug withdrawal, intracranial bleeding, trauma, thyrotoxicosis, Parkinson’s disease, and neuroleptic malignant syndrome. Intoxication by other psychotropic drugs that may be available to the patient should be considered, such as tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), valproic acid, and antipsychotic drugs.

MANAGEMENT Supportive Measures Initial treatment of lithium toxicity includes appropriate airway management, assessment of vital signs, and continuous cardiac monitoring. Peripheral IV lines should be inserted for the administration of fluids as well

584

CENTRAL NERVOUS SYSTEM

as other general emergency treatment measures including dextrose and naloxone if needed. Hyperthermia or hypothermia should be treated appropriately. If seizures develop, they should be treated with standard measures including benzodiazepines and barbiturates (see Chapter 2A). Electrocardiographic findings such as flattened or inverse T waves and mild QT prolongation do not usually require treatment; however, severe arrhythmias should be treated with usual measures, including magnesium for marked QT prolongation or torsades de pointes. The goal of fluid therapy is to maintain GFR and urine output in order to reduce the continued reabsorption of lithium. Fluid replacement should begin with isotonic saline. A few reports have suggested marked improvement with forced diuresis using very large volumes of normal saline along with diuretics,48 achieving lithium clearance values of 39 mL/min (in patients with normal renal function).49 However, other studies have suggested less than favorable outcomes with forced diuresis, including a reduction in lithium clearance.43 Because of inconsistent results and the risk of electrolyte imbalances, forced diuresis is not recommended. On the other hand, volume resuscitation to replace fluid losses and to maintain adequate urine output is crucial to the treatment of lithium intoxication.

Decontamination There is no known antidote for lithium, so particular attention should be paid to gastric decontamination. Although it has been demonstrated in in vitro studies that lithium does not bind well to activated charcoal,50 charcoal should be given if co-ingestants are suspected. In patients with early presentation, consideration should be given to gastric lavage, especially for regular-release preparations. After ingestion of sustained-release preparations (e.g., Litho-Bid), whole bowel irrigation may be preferable. In a crossover study of healthy volunteers who were given GoLYTELY at 2 L/hr for 5 hours after lithium ingestion, there was a significant reduction in peak lithium concentrations by more than 50% and reduction in lithium absorption by 67%.51 Whole-bowel irrigation should also be considered after massive ingestion of regular-release products. Limited evidence supports the use of sodium polystyrene sulfonate (SPS; Kayexalate) to bind lithium in the gut and to enhance elimination. Animal studies have demonstrated that the SPS resin effectively binds lithium and can reduce serum lithium concentrations even after IV lithium dosing.7 Studies in healthy human volunteers have shown small but statistically significant reductions in lithium absorption after treatment with SPS, without significant changes in serum sodium or potassium levels.52,53 However, the reductions were not large enough to likely affect the clinical course of an acute overdose.52 Furthermore, there is no consensus regarding optimal dosing or whether electrolyte alterations in a sick patient population could be more pronounced. At this time, SPS is not recommended for acute lithium ingestion.

Elimination Besides hemodialysis, a variety of methods have been suggested or reported to enhance the elimination of lithium, including alkaline diuresis, IV theophylline, and dopamine. However, in addition to posing potential adverse effects, these alternative methods are not supported by clinical studies. Lithium renal clearance can be estimated using the serum and urine lithium levels. Renal lithium clearance = urine flow rate (mL/min) × urine lithium (mEq/L)/ serum lithium (mEq/L). The normal renal lithium clearance is estimated to be between 10 and 40 mL/min. Hansen and Amdisen, however, reported in their study of chronic lithium intoxicated patients that the lithium clearance of this group ranged from 0.9 to 18.4 mL/ min.43 Similar variable clearances for patients on chronic lithium therapy have been found in other studies.54 Peritoneal dialysis has been shown to achieve lithium clearance rates of between 9 and 15 mL/min.23,49 This modality might be considered in patients who have poor renal function if hemodialysis facilities are unavailable (e.g., in remote areas). Otherwise, it should not be substituted for hemodialysis. Because lithium has a small volume of distribution and minimal protein binding, hemodialysis is an appropriate method for lithium removal. Lithium clearances of 70 to 170 mL/min have been reported with hemodialysis. However, there is controversy about indications for hemodialysis. Removal of lithium from the plasma and extracellular fluid may have little effect on intracellular lithium concentrations, and toxic effects may persist even after serum levels fall. This is consistent with the clinical observation that serum lithium levels correlate poorly with signs and symptoms of toxicity. It could be argued that dialysis is most likely to be effective soon after an acute ingestion while the serum lithium level is markedly elevated and prior to intracellular redistribution. However, these patients generally experience less severe toxic effects,45 and patients with levels as high as 10.6 or higher40 may remain asymptomatic and recover with supportive measures alone. Amdisen recommended that patients with impaired renal function or those who have taken an overdose and have persistent levels greater than 1.4 mEq/L should undergo hemodialysis.6 Jaeger and coworkers studied the kinetics of lithium in intoxicated patients and concluded that no rigid indication for hemodialysis can be set. They further stated that hemodialysis is not an emergency therapy but one that should be initiated only after observation of the patient as an inpatient and based on a combination of clinical and kinetic criteria.54 Other authors have suggested that the rapid correction of lithium by hemodialysis might contribute to persistent neurologic toxicity similarly to rapid correction of hyponatremia.28 Bailey and McGuigan in a prospective study recommended hemodialysis for patients with any of the following criteria: (1) severe toxicity, (2) alteration in level of consciousness, (3) cardiac toxicity, (4) creatinine greater than 2.3 mg/dL associated with an acute lithium level greater than 2.0 mEq/L or chronic level greater

CHAPTER 30

585

100 Lithium MAP

4

90 80 70

3

60

Agitation, hypertonia, hyperreflexia resolved

50

2

40

Stop HV-CVVH

30

1

MAP (mm Hg)

Lithium concentration (mmol/L)

HV-CVVH

20 10 Mildly confused

0 0

4

8

Discharged from ICU

0

12 16 20 24 28 32 36 40 44 48

A

Time (hr)

6

Case 14 HD

Serum Li concentration (mmol/L)

than 1.5, or (5) creatinine greater than 1.7 mg/dL associated with a chronic level of 2.5 mEq/L or acute level of 4.0 mEq/L. Serum creatinine levels were obtained after several hours of hydration. The authors compared the outcomes for patients in whom dialysis was recommended but not performed to those of patients who actually received hemodialysis. Although fewer patients received dialysis than was recommended, there was no outcome difference between the two groups. They concluded that indications for hemodialysis should be based on clinical symptoms and reserved for the more severe cases.55 Clearly, there is no consensus on precisely when to dialyze. Most agree that patients exhibiting signs and symptoms of severe lithium poisoning (seizures, coma, cardiac arrhythmias) or who have renal failure should undergo hemodialysis. In addition, dialysis should be considered in acute overdose patients with clinical deterioration and patients with chronic lithium toxicity whose serum levels are greater than 3.5 mEq/L. Patients with acute or acute-on-chronic overdose with elevated levels but who are asymptomatic or minimally symptomatic and have normal renal function should be treated with IV fluids and monitored closely for deterioration. There may be rebound (Fig. 30-2) in serum levels after dialysis, and the procedure should be repeated until the serum level 6 to 8 hours after dialysis is less than 1 mEq/L. Several case reports have demonstrated success in adults and children56 for treating lithium intoxication with the use of continuous renal replacement therapy (CRRT). This includes methods such as continuous venovenous hemodialysis (CVVHD), continuous arteriovenous hemodialysis (CAVHD), continuous venovenous hemodiafiltration (CVVHDF), and continuous arteriovenous hemodiafiltration (CAVHDF). The reported lithium clearance rates for CVVHD, CVVHDF, CAVHD, and CAVHDF are given in Table 30-4.56-60 While these clearances are less than for hemodialysis, the procedures require less specialized staff and facilities and can be done continuously for several hours or days, compared with typical dialysis runs of 2 to 3 hours at a time. In addition, CVVHD is pump-driven and therefore does not rely on the patient’s arterial pressure to provide a pressure gradient. One particular case study documented success with CVVHD in a hemodynamically unstable lithium-intoxicated patient in whom hemodialysis had to be discontinued.58 CRRT has the added advantage of ease of implementation and avoidance of rebound lithium levels (see Fig. 30-2). One author suggests that the combination of hemodialysis and CVVHD may have the potential to decrease length of hospital stay and health care costs.56 CRRT procedures have been used for periods of 14 to 72 hours, with an average duration of 34.7 hours in one study.60 It is not yet clear, however, whether CRRT will shorten the length of hospital stay or change outcome when compared with intermittent hemodialysis. There are no controlled studies to date comparing safety and efficacy of CRRT over other methods of therapy for routine treatment of lithium toxicity. Continuous renal

Lithium

HD

HD

1

0.1 0

1

2

3

4

5

6

7

B

Day FIGURE 30-2 Serum lithium concentration after (A) highvolume continuous venovenous hemofiltration (HV-CVVH) vs. (B) intermittent hemodialysis (HD). Note the steady decline in lithium concentration during HV-CVVH in A in contrast with the rebound in lithium concentration after each run of hemodialysis in B. Although hemodialysis remains the gold standard for lithium elimination, other modes of continuous renal replacement therapy demonstrate promise. (Reproduced from Jaeger A, Sauder P, Kopferschmidt J, et al: When should dialysis be performed in lithium poisoning? A kinetic study in 14 cases of lithium poisoning. J Toxicol Clin Toxicol 1993;31:429–447, and van Bommel EF, Kalmeijer MD, Donssen H: Treatment of life-threatening lithium toxicity with high-volume continuous venovenous hemofiltration. Am J Nephrol 2000;20:408–411.)

replacement therapy may be considered in treating patients in facilities in which dialysis is not readily available or who are considered too unstable for immediate hemodialysis.

Disposition All patients with symptoms of lithium intoxication should be admitted to the hospital for observation in a

586


TABLE 30-4 Approximate Clearance of Lithium Based on Different Methods* METHOD OF LITHIUM CLEARANCE Normal renal clearance in healthy patient Renal clearance of patients taking lithium chronically Peritoneal dialysis Hemodialysis CVVHD CVVHDF CAVHD CAVHDF

APPROXIMATE CLEARANCE (mL/min) 10–40 mL/min 0.9–18.4 mL/min 9–15 mL/min 70–170 mL/min 23–54 mL/min 28–62 mL/min 20.5 mL/min 27–55 mL/min

*Approximate clearances are based on data from references 56 to 60. CVVHD, continuous venovenous hemodialysis; CVVHDF, continuous venovenous hemodiafiltration; CAVHD, continuous arteriovenous hemodialysis; CAVHDF, continuous arteriovenous hemodiafiltraton.

monitored setting, even in the presence of normal serum lithium levels. Patients with moderate or severe symptoms should be admitted to an intensive care unit. For patients who are asymptomatic after an acute ingestion, serial levels should be obtained at 6-hour intervals until a downward trend has been established. Patients should not be discharged until they are asymptomatic and have a serum lithium level less than 1.5 mEq/L. REFERENCES 1. Ford MD, Delaney KA, Ling LJ, et al: Clinical Toxicology. Philadelphia, WB Saunders, 2001. 2. Groleau G: Lithium toxicity. Emerg Med Clin North Am 1994;12:511. 3. Aita JF, Aita JA, Aita VA: 7-Up anti-acid lithiated lemon soda or early medicinal use of lithium. Nebr Med J 1990;75:277–279. 4. Timmer RT, Sands JM: Lithium intoxication. J Am Soc Nephrol 1999;10:666–674. 5. Schou M: Forty years of lithium treatment. Arch Gen Psychiatry 1997;54:9–13. 6. Amdisen A: Clinical features and management of lithium poisoning. Med Toxicol Adverse Drug Exp 1988;3:18. 7. Scharman FJ: Methods used to decrease lithium absorption or enhance elimination. J Toxicol Clin Toxicol 1997;35:601–608. 8. Haddad LM, Shannon MW, Winchester JF (eds): Clinical Management of Poisoning and Drug Overdose, 3rd ed. Philadelphia, WB Saunders, 1998. 9. Baldessarini RJ: Drugs and the treatment of psychiatric disorders. In Goodman LS, Gillman AG (eds): The Pharmacologic Basis of Therapeutics, 8th ed. Singapore, McGraw-Hill, 1991. 10. Waldmeier PC: Mechanisms of action of lithium in affective disorders: a status report. Pharmacol Toxicol 1990;66(Suppl): 121–132. 11. Singer I, Rotenberg D: Mechanism of lithium action. N Engl J Med 1973;289:254–260. 12. Schou M: Lithium studies: distribution between serum and tissue. Acta Pharmacol 1958;15:115–124. 13. Hayslett JP, Kashgarian M: A micropore study of the renal handling of lithium. Pflugers Arch 1979;380:159–163. 14. Amdisen A: Serum level monitoring and clinical pharmacokinetics of lithium. Clin Pharmacokinet 1977;2:73–92. 15. Dyson EH, Simpson D, Prescott LF, et al: Self poisoning and therapeutic intoxication with lithium. Hum Toxicol 1987;6:325.

16. Goodnick PJ, Fieve RR, Meltzer HL, et al: Lithium elimination half-life and duration of therapy. Clin Pharmacol Ther 1981; 29:47–50. 17. Lehmann K, Merten K: Elimination of lithium in correlation with age in normal subjects and in renal insufficiency. Int J Clin Pharmacol Ther Toxicol 1974a; 10:292. 18. Webb AL, Solomon DA, Ryan CE: Lithium levels and toxicity among hospitalized patients. Psychiatr Serv 2001;52:229–231. 19. Iqbal MM, Sohhan T, Mahmud SZ: The effect of lithium, valproic acid, and carbamazepine during pregnancy and lactation. Clin Toxicol 2001;39:381–392. 20. Tunnesen WW II, Hertz CG: Toxic effects of lithium in newborn infants: a commentary. J Pediatr 1972;81:804–807. 21. Berry N, Pradhan S, Sagar R, et al: Neuroleptic malignant syndrome in an adolescent receiving olanzapine-lithium combination therapy. Pharmacotherapy 2003;23:255–259. 22. Gill J, Singh H, Nugent K, et al: Acute lithium intoxication and neuroleptic malignant syndrome. Pharmacotherapy 2003;23: 811–815. 23. Okusa MD, Crystal LJ: Clinical manifestations and management of acute lithium intoxication. Am J Med 1994;97:383–389. 24. Movig KL, Baumgarten R, Leufkens HG, et al: Risk factors for the development of lithium-induced polyuria. Br J Psychiatry 2003; 182:319–323. 25. Von Hartitzsch B, Hoenich NA, Leigh RJ, et al: Permanent neurological sequelae despite haemodialysis for lithium intoxication. BMJ 1972;30:757–759. 26. Schou M: Long-lasting neurological sequelae after lithium intoxication. Acta Psychiat Scand 1984;70:594–602. 27. Apte SN, Langston JW: Permanent neurological deficits due to lithium toxicity. Ann Neurol 1982;13:453–455. 28. Swartz CM, Jones P: Hyperlithemia correction and persistent delirium. J Clin Pharmacol 1994;34:865–870. 29. Bendz H, Aurell M: Drug-induced diabetes insipidus: incidence, prevention and management. Drug Saf 1999;21:449–456. 30. Oksche A, Rosenthal W: The molecular basis of nephrogenic diabetes insipidus. J Mol Med 1998;76:326–337. 31. Battle DC, von Riotte AB, Gaviria M, et al: Amelioration of polyuria by amiloride in patients receiving long-term lithium therapy. N Engl J Med 1985;312:408–414. 32. Eustatia-Rutten CF, Tamsma JT, Meinders AE, et al: Lithiuminduced nephrogenic diabetes insipidus. Neth J Med 2001;58: 137–142. 33. Stoff JS, Rosa RM, Silva P, et al: Indomethacin impairs water diuresis in the DI rat: role of prostaglandins independent of ADH. Am J Physiol 1981;241:F231–F237. 34. Allen HM, Jackson RL, Winchester MD, et al: Indomethacin in the treatment of lithium-induced nephrogenic diabetes insipidus. Arch Intern Med 1989;149:1123–1125. 35. Guirguis AF, Taylor HC: Nephrogenic diabetes insipidus persisting 57 months after cessation of lithium carbonate therapy: report of a case and review of the literature. Endocr Pract 2000;6:324–328. 36. Brady HR, Horgan JH: Lithium and the heart: unanswered questions. Chest 1988;93:166–168. 37. Perrier A, Martin PY, Favre H, et al: Very severe self-poisoning lithium carbonate intoxication causing a myocardial infarction. Chest 1991;100:863–865. 38. Oakley PW, Dawson AH, Whyte IM, et al: Lithium: thyroid effects and altered renal handling. J Toxicol Clin Toxicol 2000;38:333–337. 39. Tillman DJ, Ruggles DL, Leikin JB, et al: Radiopacity study of extended-release formulations using digitalized radiography. Am J Emerg Med 1994;12:310–314. 40. Nagappan R, Parkin WG, Holdsworth SR: Acute lithium intoxication. Anaesth Intensive Care 2002;30:90–92. 41. Lee DC, Klachko MN: Falsely elevated lithium levels in plasma samples obtained in lithium containing tubes. J Toxicol Clin Toxicol 1996;34:467–469. 42. Olson KR (ed): Poisoning and Drug Overdose, 4th ed. San Francisco, McGraw-Hill, 2004. 43. Hansen HE, Amdisen A: Lithium intoxication. Q J Med 1978; 47:123–144. 44. Bailey B, McGuigan M: Lithium poisoning from a poison control center perspective. Ther Drug Monit 2000;22:650–655.

CHAPTER 30

45. Oakley PW, Whyte IM, Carter GL: Lithium toxicity: an iatrogenic problem in susceptible individuals. Aust N Z J Psychiatry 2001;35:833–840. 46. Sadosty AT, Groleau GA, Atcherson MM: The use of lithium levels in the emergency department. J Emerg Med 1999;17:887–891. 47. Cooper JR, Thomas B: Psychopharmacology: The Third Generation of Progress. New York, Raven Press, 1987. 48. Parfrey PS, Ikeman R, Anglin D, et al: Severe lithium intoxication treated by forced diuresis. Can Med Assoc J 1983;129:979–980. 49. O’Connor J, Gleeson J: Acute lithium intoxication: peritoneal dialysis or forced diuresis? NZ Med J 1982;95:790–791. 50. Favin FD, Klein-Schwartz W, Oderda GM, et al: In vitro study of lithium carbonate adsorption by activated charcoal. J Toxicol Clin Toxicol 1988;26:443–450. 51. Smith SW, Ling LJ, Halstenson CE: Whole-bowel irrigation as a treatment for acute lithium overdose. Ann Emerg Med 1991;20:536–539. 52. Belanger DR, Tierney MG, Dickinson G: Effect of sodium polystyrene sulfonate on lithium bioavailability. Ann Emerg Med 1992;21:1312–1315. 53. Tomaszewski C, Musso C, Pearson JR, et al: Lithium absorption prevented by sodium polystyrene sulfonate in volunteers. Ann Emerg Med 1992;21:1308–1311.

Lithium

587

54. Jaeger A, Sauder P, Kopferschmitt J, et al: When should dialysis be performed in lithium poisoning? A kinetic study in 14 cases of lithium poisoning. J Toxicol Clin Toxicol 1993;31:429–447. 55. Bailey B, McGuigan M: Comparison of patients hemodialyzed for lithium poisoning and those for whom dialysis was recommended by PCC but not done: what lesson can we learn? Clin Nephrol 2000;54:388–392. 56. Meyer RJ, Flynn JT, Brophy PD, et al: Hemodialysis followed by continuous hemofiltration for treatment of lithium intoxication in children. Am J Kidney Dis 2001;37:1044–1047. 57. Bellomo R, Kearly Y, Parkin G, et al: Treatment of life-threatening lithium toxicity with continuous arterio-venous hemodiafiltration. Crit Care Med 1991;19:836–837. 58. Beckmann U, Oakley PW, Dawson AH, et al: Efficacy of continuous venovenous hemodialysis in the treatment of severe lithium toxicity. J Toxicol Clin Toxicol 2001;39:393–397. 59. van Bommel EF, Kalmeijer MD, Ponssen HH: Treatment of lifethreatening lithium toxicity with high-volume continuous venovenous hemofiltration. Am J Nephrol 2000;20:408–411. 60. LeBlanc M, Raymond M, Bonnardeaux A, et al: Lithium poisoning treated by high-performance continuous arteriovenous and venovenous hemodiafiltration. Am J Kidney Dis 1996;27:365–372.

31

Ethanol KURT C. KLEINSCHMIDT, MD

At a Glance… ■

■ ■

■

■

Chronic ethanol use is associated with many medical problems including osteoporosis, electrolyte abnormalities, polyneuropathy, endocrine disorders, dementia, alcoholic heart disease, cardiac dysrhythmias, liver dysfunction, and suppression of all hematopoietic elements. The elderly and children are more prone to experience ethanol’s intoxicating effects. Benzodiazepines are the mainstay of therapy of alcohol withdrawal. Very large doses may be needed for severe withdrawal. Sympatholytic agents should not be used alone in severe withdrawal management. Delirium tremens is uncommon today. It manifests with significant autonomic hyperactivity and gross disorientation. Hyperthermia or seizures during delirium tremens is particularly associated with poor outcome. Wernicke’s encephalopathy is difficult to diagnose, so all persons with alcoholism should receive thiamine during an evaluation.

INTRODUCTION Ethanol is derived from fermentation of sugars in fruits, cereals, and vegetables. Valued for its medicinal and mood altering effects, ethanol has played a significant historical role in the medical, social, and religious rituals of humankind. While modern medical uses of ethanol are limited, it remains a popular social lubricant and is widely used in religious and social ceremonies. Ethanol is commonly abused by humans, resulting in significant medical and social morbidity. Its widespread availability also makes it a common cause of unintentional poisoning in children. In addition to alcoholic beverages, many household products such as food extracts, mouthwashes, and cough preparations contain ethanol, often in large amounts (Table 31-1).1,2 Chronic alcohol-related problems are common. Approximately 8.2 million persons in the United States are dependent on alcohol. In a primary care practice, 15% of the patients had an “at-risk” pattern of alcohol use or an alcohol-related health problem.3 Chronic use of ethanol is associated with many medical problems including physical dependence and withdrawal, neuropsychiatric problems including Wernicke’s encephalopathy, and significant effects on many body organs.

PHARMACOKINETICS Ethanol is a clear, low-molecular-weight hydrocarbon that is highly soluble in water and lipids. Its volume of

distribution (0.6 L/kg) is similar to that of water. Ethanol does not bind proteins or tissues and does not affect the binding of other agents.4 Environmental and genetic factors influence its absorption, bioavailability, metabolism, and elimination.5 The significance of these factors is difficult to assess owing to great variations among individuals. Ethanol is rapidly absorbed by passive diffusion across the lipid membranes of the stomach (≈20%) and small intestine (≈80%), reaching peak levels 20 to 60 minutes after ingestion.4-6 Various factors affect absorption (Table 31-2). Inter- and intraindividual differences in gastric emptying rate affect absorption.4 The time to maximum concentration can vary by as much as fourfold between subjects, and the maximum concentration itself can vary by twofold.4 The major factor decreasing the rate of gastric emptying, thus delaying ethanol absorption, is the presence of food.4 Decreased gastrointestinal motility also delays absorption.5 Activated charcoal binds ethanol poorly, minimally affecting its absorption.7 Ethanol is metabolized in a series of oxidative steps; initially to acetaldehyde and then to acetate. Three hepatic enzyme systems contribute to the initial metabolism to acetaldehyde: the microsomal cytochrome P-450 (CYP) isoenzyme CYP2E1, the cytosol-based enzyme alcohol dehydrogenase (ADH), and the hydrogen peroxide– dependent peroxisome catalase system (Fig. 31-1). The catalase system contributes minimally and is not discussed further.8 In the nonalcoholic person, 90% of the oxidation of ethanol to acetaldehyde is done by ADH. Multiple isoenzyme forms of ADH occur with variable frequency in different human populations. These ADH isoenzymes have different affinities for ethanol, resulting in variations in ethanol elimination rates among individuals and racial groups. The activity of ADH does not change with chronic ethanol consumption.9 However, liver ADH is degraded in the fasting state, which may result in as much as a 40% decrease in ADH activity.10 CYP2E1 (CYP2E1 is the specific isoenzyme) contributes less than 10% to the oxidation of ethanol in the

TABLE 31-1 Alcohol Content of Common Products and Medications PRODUCT Aftershave lotions Cold/allergy medications Cough preparations Glass cleaners Mouthwashes Perfumes/colognes

ETHANOL CONTENT (%) 15–80 5–16 2–25 10 15–25 25–95

589

590


TABLE 31-2 Absorption and Metabolic Factors Affecting Blood Ethanol Concentrations FACTOR

EFFECT ON BLOOD ETHANOL

REASON

Adiposity Age

Fasting state

↑ ↑ in elderly ↓ in those < 13 years of age ↑ ↓ ↑

Delayed gastric emptying Increased lung tidal volume Medications Sex

↓ ↓ Variable ↑ in females

Cigarette smoking Lean body weight (increased)

↓ ↓

Relative ↓ in Vd ↓ Vd secondary to ↑ adipose/lean body mass ratio ↑ in metabolic rate If severe alcoholic liver disease present ↑ in metabolic rate secondary to ↑ CYP2E1 oxidation ↑ Absorption secondary to faster gastric emptying and temporary ↓ in gastric ADH activity Longer exposure to gastric ADH ↑ in elimination from breath Often secondary to change in CYP2E1 activity ↑ in absorption secondary to ↓ gastric metabolism ↑ in adipose tissue ↓ in lean body weight ↑ in metabolic rate Relative ↑ in Vd

Chronic use

↑, increase; ↓, decrease; ADH, alcohol dehydrogenase; Vd, volume of distribution.

CYP2E1 NADPH

Ethanol

ADH NAD+

Acetaldehyde

Catalase H2O2 FIGURE 31-1 Pathways for ethanol oxidation to acetaldehyde. ADH, alcohol dehydrogenase; H2O2, hydrogen peroxide; NAD+, nicotinamide adenine dinucleotide, oxidized form; NADPH, nicotinamide adenine dinucleotide phosphate, reduced form.

moderate drinker. The Km (the concentration of a substrate which yields half-maximal enzyme activity) of ADH for ethanol is much lower than that for CYP2E1. The contribution of CYP2E1 to the oxidation of ethanol increases as the blood ethanol concentration rises. The activity of CYP2E1 is significantly increased in chronic drinkers.8 Unlike ADH, which requires oxidized nicotinamide adenine dinucleotide (NAD+) and generates nicotinamide adenine dinucleotide reduced form (NADH), CYP2EI requires the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) and yields nicotinamide adenine dinucleotide phosphate, oxidized form (NADP+). Oxidation of ethanol by ADH results in an increased NADH/NAD+ ratio, creating an unfavorable “redox” state for oxidative metabolism, decreasing the oxidative capacity of the liver. Interestingly, the “revved up” CYP2E1 in chronic alcoholics creates excess NADP+, which improves the redox state of the liver and enhances ADH activity.8 The next step in ethanol metabolism is the oxidation of acetaldehyde to acetate, which also yields more NADH (Fig. 31-2). The reaction is catalyzed by various acetaldehyde dehydrogenase (ALDH) isoenzymes.

These isoenzymes are very efficient, having a Km approximately 1000 times lower than that of ADH for ethanol.10 Fifty-percent of Japanese and Chinese persons have isoenzymes with decreased activity, resulting in increased levels of acetaldehyde after ingestion of ethanol.8,10 This may be the cause of the increased incidence of facial flushing, vasodilation, and tachycardia (acetaldehyde syndrome) noted in some Japanese after drinking.10 The increased acetaldehyde levels found in chronic alcoholics result from its increased production and are not due to inadequate ALDH activity.11 Acetaldehyde itself is hepatotoxic by decreasing cellular capacity to repair DNA, increasing free radical–mediated lipid peroxidation, and augmenting hepatic collagen synthesis.12 Ethanol’s bioavailability, and thus blood ethanol concentration (BEC), is affected by first pass metabolism (FPM). FPM primarily results from liver ADH. However, the mucosa of the intestinal tract, particularly the stomach, also contains ADH. Stomach ADH can contribute up to 20% of the metabolism of ethanol.13 Metabolism is affected by other factors. Persons with chronic alcoholism and severe liver disease have decreased rates of ethanol metabolism that correlate with severity of hepatic damage. This mechanism may contribute to the loss of previously attained tolerance in some persons with chronic alcoholism.11 Abnormalities of liver function tests are not associated with changes in BECs.14 Elimination involves multiple processes. Most ethanol is metabolized by the above-noted oxidative processes, resulting in carbon dioxide and water production. A small percentage of ethanol is eliminated unchanged in the breath. For example, lung volume affects levels, since ethanol is excreted unchanged in the breath. The contribution of this mechanism may be significant at high BECs.9 The elimination kinetics of ethanol are complex and not clearly defined. It was considered to be linear and to

CHAPTER 31

NAD+ Ethanol CH3CH2OH

NADH+H+ Acetaldehyde CH3CHO

NAD+

NADH+H+

Ethanol

591

Tricarboxylic acid cycle

Acetate CH3COO−

Acetyl CoA

CO2+H2O

FIGURE 31-2 Ethanol metabolism. CoA, coenzyme A; NAD+, nicotinamide adenine dinucleotide, oxidized form; NADH, nicotinamideadenine dinucleotide, reduced form.

follow zero order kinetics, that is, an absolute amount is eliminated per unit time. However, more recent work reflects that the kinetics are complicated. Elimination kinetics are difficult to evaluate because many enzyme systems with different Kms are involved, different BEC ranges have been studied, and individual variability exists in the rates of ethanol elimination. One case report described a patient with a BEC of 1500 mg% whose ethanol elimination followed first order kinetics (an absolute percentage eliminated per unit time) down to 400 mg%.15 When BECs are high, the initial availability of free enzymes plus activation of CYP2E1 contributes to a rapid decline in ethanol that is most consistent with a first order process. The contribution of CYP2E1 decreases at moderate ethanol concentrations where the more linear decline reflects saturation of alcohol dehydrogenase. Ethanol elimination slows even further at low concentrations, a pattern consistent with the final phase of first order kinetics. Because of ethanol’s complex pharmacokinetics, BECs are variable and difficult to predict (see Table 31-2). Although the absolute dose of ethanol roughly correlates with the resulting BEC, it is not associated with the time to the peak level.6 The metabolism rate correlates directly with the degree of drinking done by individuals; however, there is much overlap between groups. Metabolism rates for nondrinkers are 12 to 24 mg%/hr and for persons with alcoholism 15 to 49 mg%/hr. Not all studies have demonstrated differences between chronic and intermittent drinkers.14 The only way to definitely know an individual’s elimination rate is to obtain serial BECs. It is reasonable to assume a metabolic rate of 20 mg%/hr for unselected patients in an emergency department setting.14

aged 6 to 19 years were alcoholic beverages in 93%, whereas exposure in those younger than 6 years of age were not beverage related in 77%.17 Unlike many pediatric exposures, older children were involved with ethanol more than younger ones.17 Approximately 75% of the exposures reported to PCCs involve perfumes, colognes, and aftershave lotions; alcoholic beverages and mouthwashes make up 15% and 7% of the ingestions, respectively.2 Most emergency department visits and hospital admissions result from drinking alcoholic beverages rather than nonbeverage items.17 Intentional exposure must always be considered and the appropriate child protection network initiated if this concern exists. While the pharmacokinetics are similar, children less than 13 years of age appear to metabolize ethanol faster than do adults with alcoholism.2 Children have more severe effects at lower BECs than do adults, and fatal complications have been reported at less than 50 mg%.2 Children commonly present with marked sleepiness or coma and may also have vomiting, ataxia, and seizures.2 Ethanol-induced hypoglycemia occurs more frequently in children than in adults and has occurred with a BEC level as low 20 to 30 mg%.2 Hypoglycemia is usually associated with ingestion of alcoholic beverages but does not appear to be dose dependent.2 Seizures may occur and are often associated with hypoglycemia.2 The etiology of hypoglycemia in children versus adults is not fully understood but may be related to smaller glycogen stores.2 An estimate of the potential BEC can be obtained by using the relationship between the volume of distribution (Vd), specific gravity of ethanol (SG), and volume ingested (A):

SPECIAL POPULATIONS

For example, a concerned individual calls because a 20-kg toddler grabbed a half-ounce (15 mL) shot glass of 100-proof (50% ethanol) whiskey and drank it. The numerator determines the absolute amount of ethanol ingested (15 mL × 0.50 × 0.80 g/mL) and is divided by the volume in which it is distributed (0.6 L/kg × 20 kg). After correcting for the units used, the expected BEC is 49 mg%. This is a potentially dangerous level in so young a child, and immediate evaluation in an emergency department would be appropriate. Conversely, the formula can be rearranged to determine the amount ingested once the BEC has been determined. This information may be used to verify the history when considering the possibility of a nonaccidental exposure. Women attain higher BECs after ingesting equal amounts to men. Women generally have a smaller body mass but more fat, resulting in decreased total body

The metabolism of ethanol is not significantly different in the elderly. However, age-related increases in adipose tissue and decreases in lean body mass result in decreased total body water. This results in higher BECs than those obtained by younger individuals ingesting equal amounts of ethanol.16 Cognitive impairment and dementia may also be worsened by chronic ethanol use.16 In addition, ethanol interacts with many medications commonly used by the elderly, including central nervous system (CNS) depressants, analgesics, anticoagulants, and antidiabetic agents.16 Childhood exposure to ethanol is uncommon, representing less than 1% of contacts with poison control centers (PCCs).17 Reports of pediatric deaths due to ethanol alone are rare. In 2002, exposures in children

BEC (mg/dL) = A (mL) × %EtOH × SG (0.80 g/mL) ÷ Vd (0.6 L/kg) × body weight (kg)

592


water and a decreased volume of distribution of ethanol.18 Women have decreased gastric ADH activity compared with men, also contributing to higher BECs.13

DRUG INTERACTIONS Ethanol’s complex pharmacology results in many potential drug interactions (Table 31-3). Because of cross-tolerance between ethanol and barbiturates, alcohol-dependent individuals who are abstaining from ethanol require relatively larger doses of barbiturates for induction of anesthesia.19 Conversely, barbiturate and benzodiazepine metabolism is inhibited in actively drinking individuals, since ethanol already occupies the microsomal CYP oxidizing system. Ethanol-associated CNS sedation is additive to that produced by benzodiazepines and other sedative-hypnotics such as chloral hydrate, ethchlorvynol, meprobamate, methylqualone, and glutethamide.19 Sedation associated with phenothiazines, antihistamines, and narcotics is also enhanced by ethanol.20 The use of long-term β-blockers in persons with alcoholism may mask sympathomimetic symptoms associated with hypoglycemia or early withdrawal.20 The significance of the interaction between the H2 antagonists and ethanol is debated. All H2 blockers except famotidine inhibit gastric alcohol dehydrogenase and have been associated with increased BECs.21 Disulfiram (Antabuse) irreversibly inhibits acetaldehyde dehydrogenase. If ethanol is ingested after pretreatment with disulfiram, a 5- to 10-fold increase in acetaldehyde develops within 15 minutes. Patients experience flushing and throbbing pains of the head and

neck, which are secondary to vasodilation. In addition, abdominal cramps, nausea, vomiting, chest pain, weakness, dizziness, dyspnea, hyperventilation, tachycardia, diaphoresis, and hypotension occur.19,20,22 Symptoms last 30 minutes to several hours. This reaction develops even up to 2 weeks after disulfiram exposure.20 Toxicity can be precipitated by as few as 7 mL ethanol.22 Patients using disulfiram should be made aware of the presence of ethanol in over-the-counter products to prevent unexpected reactions. Diethyldithiocarbamate, the major metabolite of disulfiram, chelates metals and thus inactivates metalloenzymes including ADH and dopamine β-hydroxylase (DBH). The increased BECs sometimes associated with disulfiram therapy have been attributed to ADH suppression. The sometimes intractable hypotension associated with disulfiram reactions may be secondary to DBH inhibition, which causes decreased nerve terminal norepinephrine production.22 Long-term users of disulfiram have an increased incidence of depression, which may be secondary to altered dopamine metabolism owing to suppression of central nervous system DBH.19 Although other medications have been associated with disulfiram-like reactions (see Table 31-3), their effects are generally inconsistent and mild.19 Management of patients with disulfiram reactions is generally supportive. However, hypotension secondary to vomiting and vasodilation can be severe and aggressive volume resuscitation may be needed. If vasopressor support is indicated, direct α agonists such as nor-epinephrine should be used, since dopamine’s effect is blocked by disulfiram’s inhibition of DBH. Antiemetics should be considered if vomiting is present.

TABLE 31-3 Medications That Interact with Ethanol MEDICATIONS

MECHANISM OF INTERACTION

FINAL EFFECT

Acetaminophen Anesthetics (chloroform, halothane) Barbiturates Benzodiazepines Isoniazid Phenytoin Warfarin

Chronic ethanol use enhances CYP2E1 activity if (1) alcoholic is currently abstaining from drinking (2) alcoholic is currently drinking alcohol

Fulminant hepatic failure ↓ in medication levels ↑ in medication levels

Cimetidine Ranitidine

Inhibits gastric ADH, increasing ethanol bioavailability

↑ in blood ethanol concentration

Barbiturates Benzodiazepines Chloral hydrate

Synergistic with effects of ethanol

↑ in sedation ↑ in respiratory depression

Allopurinol

Synergistic with the ↑ in serum uric acid levels secondary to ethanol Disulfiram-like reaction with inhibition of acetaldehyde dehydrogenase

↑ in gouty arthritis

Cephalosporins Chloramphenicol Griseofulvin Metronidazole Quinacrine Sulfonylurea oral hypoglycemics

↑ increase; ↓ decrease; ADH, alcohol dehydrogenase.

Acetaldehyde syndrome

CHAPTER 31

The significance of the interaction between acetaminophen and ethanol in persons with chronic alcoholism is debated. Both acetaminophen and ethanol are metabolized by the CYP isoenzyme CYP2E1. Acetaminophen metabolism results in a small amount of the hepatotoxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), which is eliminated by conjugation with glutathione. Hepatic injury, however, occurs when NAPQI production overwhelms the detoxification mechanism. Conditions that result in increased NAPQI production or in decreased glutathione detoxification can cause hepatotoxicity; patients with chronic alcoholism have these conditions. Ethanol use induces the CYP2E1 isoenzyme, resulting in increased NAPQI production. Chronic ethanol use and starvation decrease glutathione availability; further contributing to potential toxicity.23,24 One retrospective series describes patients with chronic alcoholism who have developed hepatotoxicity despite having minor overdoses or even after using less than 4 g/day.23 Some authors have recommended that acetaminophen be used in decreased doses or not at all in patients with alcoholism.25 However, a randomized, double-blind, prospective comparison of acetaminophen with placebo in 201 chronic alcoholics did not find increased transaminases with acetaminophen.26

Acute Toxicity (Intoxication) It is unusual for persons with alcoholism to present for acute care with intoxication as their only medical problem. In one urban emergency department (ED) series, only 26% of patients intoxicated with ethanol had intoxication as their sole problem.14 A different ED series found that 50% of 289 patients with positive ethanol screens had at least one other drug.27 Fifty-three percent of 116 consecutive motor vehicle accident admissions to an urban trauma service had BECs greater than 100 mg%.28 A toxic dose is considered to be 5 g/kg in an adult or 3 g/kg in a child. The ethanol content of popular beverages ranges from 3% to 6% in beers to as high as 90% in some distilled liquors. One ounce of whiskey (80 proof, or 40%), 12 ounces of beer, or 4 ounces of wine are approximately equipotent and will raise the BEC 25 mg% in the average adult. The majority of states in the United States use 0.08% (80 mg%) as the legal limit for ethanol. Symptoms of intoxication begin with a perception of stimulation due to the suppression of central inhibitory mechanisms. However, as BEC rises, sedation, incoordination, ataxia, and impaired psychomotor performance appear.29 Even higher levels can result in coma and death. While BECs typically correlate with symptoms in nondrinkers (Table 31-4),30-33 chronic drinkers require higher levels to reach similar states of intoxication. The degree of intoxication also correlates with the rate of rise of the BEC. Slower ethanol ingestion results in less intoxication.30 Acute tolerance has been

593

TABLE 31-4 Signs and Symptoms of Intoxication and Blood Ethanol Concentrations in a Non-AlcoholDependent Population* ETHANOL CONCENTRATION (MG%)

SIGNS AND SYMPTOMS

400

TOXICOLOGY

Ethanol

*Correlation between signs and symptoms and blood ethanol levels show wide variability among individuals.

demonstrated with a single large ingestion of ethanol. This manifests as a greater degree of intoxication at any BEC when the level is rising compared to when the level is falling.30 Visual tracking of objects is decreased as much as 25% with a BEC of 80 mg%.34 Coma is unusual when the BEC is below 200 mg%.31 The lethal level for 50% of the non-ethanol-dependent population is 450 mg%31 although individuals have survived BECs as large as 1500 mg%.15 DIAGNOSIS OF ACUTE INTOXICATION The differential diagnosis is vast because it involves altered mentation or coma. Conditions that must routinely be considered include hypoglycemia, hypoxia, intracranial pathology, seizure, encephalopathy, uremia, cerebral infection, and shock. Many medications cause an alteration in mental status including sedativehypnotics, opioids, antidepressants, and antipsychotics. The patient’s history and physical examination should guide the selection of ancillary laboratory data. The usefulness of routine measurement of the BEC in the emergency department is controversial. Its use is appropriate in a patient with an altered mental status. However, the BEC is less likely to affect management decisions in an intoxicated individual who is awake and alert. The disposition of intoxicated patients is a clinical decision and should not be based on BEC.

594


The BEC may be obtained by using various body fluids; however, venous blood and breath samples are most commonly used. BECs are not affected by the use of ethanol in the skin preparation, despite theoretical concerns.35 The accuracy of the breath ethanol analyzer (BEA) depends on the constant equilibrium of ethanol in the blood to alveolar air at a ratio of 2100:1.4 BEA results are slightly lower than those from venous blood, especially at higher levels of ethanol, and may be affected by the patient’s ability to cooperate.36 BEA results are also consistently less than venous blood estimations in patients with poor pulmonary function, including the elderly.37 Testing within 15 to 20 minutes of the last drink or if vomitus is in the mouth may cause small false elevations. Conversely, false negatives are rare.36 MANAGEMENT OF ACUTE INTOXICATION Other causes of altered mental status must be assessed depending on the clinical situation. Hypoglycemia should routinely be considered. The threshold to perform a head computed tomographic (CT) scan must be low. Because steady improvement occurs when mental status is depressed by ethanol, a head CT scan is indicated if a patient’s sensorium does not improve during a period of observation. Fluid administration is indicated, since the intoxicated patient is frequently volume depleted secondary to ethanol-induced diuresis, vomiting, and poor oral intake. However, IV fluids do not affect blood ethanol clearance.38 Patients with alcoholism should also receive multivitamins, thiamine, and folate. The routine administration of glucose to sick alcoholic patients is rational because of the significant incidence of ketoacidosis and glycogen deficiency. Studies have not shown caffeine,39 naloxone,40 fructose,41 or flumazenil42 to hasten the reversal of intoxication. Gastric emptying is ineffective at decreasing BECs due to ethanol’s rapid absorption. Charcoal should be considered in patients who may have ingested other toxins. The timing of the disposition of an intoxicated patient is controversial. However, most would agree that patients should walk away from an acute care facility only when they actually can walk without difficulty and can demonstrate clear, appropriate thought processes. These points should be documented at the time of disposition.

Chronic Toxicity NEUROPSYCHIATRIC EFFECTS OF CHRONIC INTOXICATION In addition to the neuropsychiatric effects of acute intoxication, chronic ethanol use is associated with polyneuropathy, Wernicke’s encephalopathy, Korsakoff’s psychosis, cerebellar degeneration, dementia, and central pontine myelinolysis. Controversy exists over the etiology and management of these disorders and the relationship between them. The most common chronic neurologic symptom in alcoholics is polyneuropathy. The axonal degeneration and demyelination likely results from both nutritional

deficiencies and direct toxic ethanol effects.33 Common findings include painful dysesthesia, anesthesia, weakness, decreased pain and temperature sensation, and decreased touch and vibration sense.32,33 Disease progression is gradual, bilateral, and symmetric. The most common site of involvement is the distal legs.32,33 If severe, muscle atrophy occurs and the deep tendon reflexes are decreased. Abstinence may result in slow and incomplete recovery.33 Wernicke’s encephalopathy (WE) results from a deficiency of vitamin B1 (thiamine) and is characterized by the classic clinical triad of oculomotor abnormalities, ataxia, and global confusion. Thiamine is an enzyme cofactor in various metabolic pathways. Although WE is classically associated with alcoholism, thiamine deficiency may also occur in any nutritionally depleted state.32,33,43 Indeed, one autopsy series demonstrated that only 18% of cases occurred in persons with alcoholism.43 Thiamine deficiency occurs in persons with alcoholism because of poor diet, reduced absorption and liver storage, and decreased conversion to its active form.33,43 Glucose loading in thiamine-depleted individuals has been proposed to induce WE.43 It is common for authors to recommend that thiamine be given prior to glucose in patients with altered mental status. The usual reference44 cited in support describes four patients. None of these developed WE after a single, acute administration of glucose; however, all required hours of glucose administration. Thus, the specific order of administration of thiamine and glucose likely does not matter as long as they are given around the same time.45 Only a small minority of thiamine-deficient patients develop WE. A low serum thiamine level has poor specificity for the diagnosis. The development of clinical disease in so few thiamine-deficient individuals reflects either a genetic contribution, unknown affecting variables, or underdiagnosis.46 The diagnosis is usually established by the combination of clinical symptoms and magnetic resonance imaging revealing mammillary body shrinkage. On autopsy, findings include mammillary body shrinkage and petechial hemorrhages.33,37 WE is likely more common than generally perceived, since the diagnosis is difficult to establish. Autopsy series have demonstrated cerebral and cerebellar neuropathologic changes specific for WE in 0.8% to 2.8% of the general population and in 12% of persons with alcoholism.43 Reviews of premorbid patient symptoms from these series found stupor and coma to be the most common presentations, while WE was diagnosed in less than 20% of the patients.43,47 Based on pathologic studies and chart reviews, WE presents with the classic triad in only 10% to 33% of the patients and up to 20% have none of the three.32,43 The onset occurs over several days to many weeks. The hallmark of WE is the extraocular movement abnormalities, with horizontal nystagmus noted in 85%, bilateral lateral rectus paralysis in 54%, and paresis of conjugate gaze in 44%.48 The equilibrium loss is secondary to vestibular paresis and cerebellar dysfunction and typically produces ataxia of gait but not of the limbs.48 The global confusional state consists of

CHAPTER 31

apathy, poor concentration, spatial and temporal disorientation, and slow and irrational thinking. Most patients have a normal level of consciousness. Impairment of memory and ability to learn is present in a majority but is often difficult to demonstrate because of poor concentration skills.30 Other manifestations include hypothermia and hypotension secondary to altered temperature regulation and decreased sympathetic outflow.43 Wernicke’s encephalopathy evolves over time, with mild, subclinical episodes progressing until the clinical triad is apparent.43 The mortality for treated WE is 17% during the initial weeks after diagnosis, most of which is related to associated diseases including infections and cirrhosis.48 WE is partially reversible with the administration of thiamine. It should be considered a medical emergency because of the associated morbidity and mortality. Thiamine absorption from the gastrointestinal tract is significantly poorer in thiamine-deficient patients than in healthy controls. In addition, ethanol loading decreases thiamine absorption by 50%.49 It is recommend that patients with WE be hospitalized and receive 100 mg thiamine intravenously daily for at least 5 days.32,33 Ocular abnormalities generally reverse completely within hours to days except for a fine horizontal nystagmus on lateral gaze that persists in 60%.48 Recovery from ataxia usually takes more than a month and is complete in only 33% of patients. Virtually all patients recover from the global confusion within 2 months, although most have persistent memory difficulties.48 Abnormal thought processing is common in persons with chronic alcoholism. Neuropsychological impairment is present in 50% to 70% of detoxified persons with alcoholism.50 Diagnoses that have been applied to these patients include both Korsakoff’s psychosis (KP) and alcoholic dementia. Much overlap between dementia and KP exists and differentiation between the two is not clear. KP is classically described as an “abnormal mental state in which memory and learning are affected out of all proportion to other cognitive functions in an otherwise alert and responsive patient.”48 It is characterized by anterograde (events occurring now) and some retrograde (recent events) amnesia. Patients are alert, responsive, and can interact well socially but are apathetic and unaware of their disability.48 The term psychosis is confusing, since patients with KP do not have the gross distortion of mental capacity typically associated with a psychosis. The classic work of Victor reflected that 80% of those with WE will have KP evident once the global confusion of WE has cleared following thiamine treatment. He suggests that the memory impairment associated with WE is likely the beginning of KP—all primarily related to thiamine deficiency.48 However, not all patients with KP will have had WE. In particular, patients with nonalcoholic WE uncommonly develop severe permanent memory disorders. This argues against WE and KP being the acute and chronic phases of the same thiamine deficiency.50 KP may have a multifactorial etiology including a drinking lifestyle, multiple episodes of withdrawal, seizures, and repeated head injury.50

Ethanol

595

Management of KP includes routine nursing care, proper diet, and abstinence from alcohol. The role of thiamine is not clear. Complete recovery from KP occurs over 1 to 3 months in 20% of afflicted patients, while 25% do not recover at all.48 Alcoholic dementia has been used to describe cases in which amnesia occurs in conjunction with global intellectual decline.50 It likely has multiple etiologies including a direct toxic effect of ethanol on the CNS. Cerebral atrophy is common. Some feel the dementia is a manifestation of KP.33 Central pontine myelinolysis is also associated with alcoholism. It evolves over days to weeks and is associated with hyponatremia.33 The pontine corticobulbar white fibers undergo demyelination, causing mental confusion, dysarthria, dysphagia, facial and neck weakness, dysfunctional tongue movements, and gaze palsies.32,33 Alcoholic cerebellar degeneration affects chronic drinkers and is characterized by a gradual onset of ataxia that affects the trunk more than the limbs and the legs more than the arms.32,33 The symptoms and cerebellar abnormalities are similar to those found in WE, suggesting that these diseases may actually be parts of the same process.33 While the gait ataxia is similar to that of WE, patients with cerebellar degeneration have more limb ataxia and dysarthria and much less nystagmus.32 Various causes have been proposed, including thiamine deficiency, electrolyte abnormalities, and direct toxicity from ethanol.33 The disease stabilizes or improves with the cessation of drinking.33 OTHER EFFECTS OF CHRONIC INTOXICATION Ethanol alters many aspects of endocrine function including all levels of the hypothalamic-pituitary-adrenal axis, gonadal and carbohydrate activity, and mineral metabolism. Some of these effects may reverse with prolonged abstinence.51 Ethanol and its metabolites directly decrease testosterone production.51 Up to 50% of persons with alcoholism and cirrhosis have atrophic testes and many have gynecomastia. Women who drink moderately have more anovulatory cycles, and amenorrhea occurs more often in those with cirrhosis.51 Alcoholism is associated with osteoporosis in both men and women. Etiologies include ethanol’s direct toxicity to osteoblasts, hypogonadism, decreased calcium intake, malabsorption, increased urinary calcium excretion, minimal exercise, and an altered parathormone response to hypocalcemia.51 Acute and chronic ethanol ingestion cause stimulation of the hypothalamic-pituitary-adrenal axis. Elevated adrenocorticotropin hormone and cortisol levels in some persons with alcoholism suggest Cushing’s syndrome.31,51 These individuals have classic clinical stigmata such as central obesity and laboratory abnormalities including altered dexamethasone suppression tests.51 Glucocorticoid secretion returns to normal within a few weeks of abstinence.51 Ethanol alters fat and carbohydrate metabolism. Hepatic lipogenesis, peripheral fat mobilization, and hepatic uptake of circulating lipids are increased while hepatic lipoprotein release is decreased. The

596


Pyruvate

NADH

Acetoacetate

Lactate

NAD+

b-Hydroxybutyrate

TABLE 31-5 Alcoholic Ketoacidosis Presentation Summary SOURCE OF DATA

FINDINGS

History taking

Alcoholism Cessation or decrease of ethanol intake over prior 24–72 hours Fasted state Abdominal pain Vomiting Consciousness Status consistent with volume depletion Tachycardia Tachypnea Anion-gap metabolic acidosis pH may be acidemic, normal, or alkalemic Acidemia secondary to ketoacidosis Alkalosis secondary to tachypnea and vomiting Hypokalemia Hypophosphatemia Glucose level mildly elevated, normal, or low Serum and urinary ketones increased (elevation may be underestimated with the nitroprusside test because this test only measures acetoacetate, whereas β-hydroxybutyrate is the primary ketoacid)

+

FIGURE 31-3 Some effects of the increased NADH/NAD ratio.

altered NADH/NAD+ ratio impedes the function of the tricarboxylic acid cycle and slows fatty acid oxidation.12 These actions cause triglycerides to accumulate in hepatocytes (steatosis) and increase serum triglycerides. Hypoglycemia results from nutrition-related glycogen depletion and decreased gluconeogenic activity resulting from the altered redox ratio.12,51,52 Malnutrition leads to vitamin deficiency disorders such as pellagra, stomatitis, and scurvy. Thiamine deficiency is particularly common because its total body supply can be depleted within 33 days.46 Electrolyte disorders include hypokalemia, hypophosphatemia, and hypomagnesemia. Hypokalemia is also caused by gastrointestinal losses and urinary excretion due to altered mineralocorticoid activity.52,53 Acid–base abnormalities occur in persons with alcoholism; however, ethanol itself does not cause an acidosis. The anion-gap acidosis sometimes seen in alcoholic patients results from a combination of keto acids and lactic acid. The increased NADH/NAD+ ratio favors lactate over pyruvate production (Fig. 31-3).52,54 Metabolic alkalosis secondary to vomiting and volume contraction may occur.52 Alcoholic ketoacidosis (AKA) typically begins with abdominal pain (from gastric irritation, pancreatitis, hepatitis, etc.) and vomiting. Volume depletion occurs, and ethanol ingestion decreases as the patient becomes more ill. Comorbid conditions often cloud the typical clinical characteristics (Table 31-5). The stress-related catecholamine increase and resurgent gluconeogenesis (since the patient has stopped drinking) result in normal to mildly elevated serum glucose levels. Ketoacidosis results from acetyl CoA shunting to ketone production, increased lipolysis and free fatty acid (FFA) release, decreased peripheral tissue uptake and metabolism of ketones, and decreased urinary elimination of ketones (Fig. 31-4).54 The primary keto acids are β-hydroxybutyrate and acetoacetate. In AKA, the increased NADH/NAD+ ratio favors β-hydroxybutyrate production (see Fig. 31-3). The treatment of AKA includes volume resuscitation, thiamine and glucose supplementation, and management of associated disorders. Glucose administration causes endogenous insulin release, which suppresses FFA release and ketogenesis. Treatment of AKA results in a decreased NADH/NAD+ ratio, which decreases the βhydroxybutyrate-to-acetoacetate ratio. Because the nitroprusside test for ketones measures only acetoacetate, this is paradoxically reflected by an increasingly positive nitroprusside test for ketones. Most urine dipsticks and in-laboratory tests for ketones are still based on nitroprusside color changes. Acute ethanol ingestion causes dose-dependent suppression of pituitary antidiuretic hormone, resulting in its familiar diuretic effect. This causes free water loss

Physical examination Laboratory

without significant urinary electrolyte loss.53 The effect of chronic ethanol intake on total body water is debatable. Ethanol-induced diuresis and periodic abdominal upset and vomiting may lead to dehydration in persons with chronic alcoholism. However, chronic ethanol use may cause a lowering of the pituitary osmole receptor set-point that increases antidiuretic hormone secretion, resulting in eventual volume overload.53 Fluid supplementation of the patient with chronic alcoholism should be based on the clinical evaluation. Cardiac abnormalities associated with ethanol use include alcoholic cardiomyopathy with congestive heart failure, dysrhythmias, hypertension, and coronary artery disease. The term alcoholic heart disease is replacing the term alcoholic cardiomyopathy, since cardiomyopathy technically is the primary disease of the cardiac muscle of unknown etiology. Alcoholic heart disease is affected by genetic predisposition and the amount and length of ethanol abuse.55 Once alcoholic heart disease is present, the prognosis is poor unless patients abstain from further ethanol intake.55 The postulated pathophysiology includes changes in the sarcolemma, the Na+/K+-activated ATPase pump, calcium homeostasis, and contractile proteins.55 Changes in cardiac structure and function include four chamber dilatation, reduced left ventricular compliance and ejection fraction, mild endocardial and valve-leaflet scarring, and mural thrombi.55 Chronic, heavy ethanol use increases both systolic and diastolic blood pressures.55,56 Conversely, acute ethanol ingestion causes decreased blood pressure that may be due to a combination of decreased vascular resistance and cardiac function.57

CHAPTER 31

Ethanol

597

Decreased insulin

Increased: Catecholamines Glucagon Glucocorticoids

Lipolysis

Decreased KB metabolism by peripheral tissues

Volume depletion

Free fatty acid release

Ethanol

Acetate

Acetyl CoA

Vomiting and ethanol blockage of ADH secretion

Serum ketones

Decreased ketone elimination

* Tricarboxylic acid cycle

Decreased food intake

FIGURE 31-4 Factors causing ketonemia in alcoholic ketoacidosis. ADH, antiduretic hormone. *The tricarboxylic acid cycle is significantly slowed because intermediates are used for gluconeogenesis.

The effect of ethanol on coronary atherosclerotic disease (CAD) and on stroke is biphasic. Regular lightto-moderate alcohol intake appears to provide protection against both CAD and ischemic stroke. This protective effect may be related to an increase in high-density lipoprotein and to a decrease in low-density lipoprotein, platelet aggregation, and fibrinolytic activity.56-59 Low doses of ethanol increase nitric oxide release, augmenting vasodilation. Conversely, heavy consumption increases the risk of CAD and both hemorrhagic and ischemic stroke.56,59 Excessive alcohol use increases atherosclerotic disease by increasing blood pressure, triglycerides, and insulin resistance and by altering coagulation.56,59 Ethanol is associated with atrial and ventricular dysrhythmias. Ettinger and others described the “holiday heart syndrome” in persons with alcoholism without overt alcoholic heart disease who developed dysrhythmias. Atrial fibrillation and flutter are the most common signs; they clear with abstinence.60 This relationship was supported by a review that found ethanol caused or contributed to 63% of admissions for atrial fibrillation. Eighty-nine percent of the ethanol-related cases converted to sinus rhythm within 24 hours of admission in contrast to only 42% of those with atrial fibrillation secondary to other etiologies.61 The effects of ethanol on the gastrointestinal tract include esophagitis, gastritis, peptic ulcer disease, malabsorption, gastrointestinal bleeding secondary to numerous causes, and liver and pancreatic diseases. Ethanol-associated liver disorders include fatty infiltration, alcoholic hepatitis, and fibrosis (cirrhosis). Fatty infiltration of the liver can start within days of the onset of heavy drinking. It is due primarily to triglyceride deposition, but dietary fat intake also contributes.18 Inflammation resulting from alcoholic hepatitis hastens the deposition of collagen. Inflammation associated with fatty infiltration results in the deposition of collagen, the primary protein of fibrous tissues, into liver lipocytes. The lipocytes eventually transform into collagen-

producing cells. Cirrhosis develops when collagen production outpaces its degradation.18 Ethanol’s induction of the CYP system increases the conversion of xenobiotic compounds such as anesthetics and industrial solvents to toxic metabolites. The system also activates carcinogens that may contribute to the increased incidence of upper alimentary and respiratory tract cancers in persons with alcoholism. Acetaldehyde accumulation is associated with impaired hepatic oxygen utilization, increased free radical production, lipid peroxidation, and fibrinogenesis.12 Ethanol abuse suppresses hematopoietic elements of the bone marrow through malnutrition-related vitamin deficiency and direct ethanol toxicity. Ethanol causes decreased bone marrow cellularity, vacuolization of marrow precursor cells, and a macrocytosis independent of folate deficiency. Chronic ethanol abuse causes thrombocytopenia that resolves with abstinence; however, its effect on platelet function is not clear.62 Ethanol also causes many types of anemia including iron and folate deficiency, hemolytic, and sideroblastic. Classic folate-dependent megaloblastic anemia occurs in 4% of ambulatory persons with alcoholism and generally affects those who imbibe hard liquor, since beer is actually a good folate source.62 Folate deficiency in persons with alcoholism is secondary to poor diet, malabsorption, disruption of the enterohepatic circulation, and a direct antifolate effect of ethanol. Infection in alcoholics is associated with increased morbidity. Immunosuppression occurs with acute and chronic ethanol abuse. Acute ingestion causes decreased neutrophil delivery to infection sites and decreased adherence, whereas chronic abuse results in marrow suppression, decreased chemotaxis, and neutropenia. Neutrophil bactericidal and phagocyte activity are not affected by ethanol.63 Abstinence results in the reversal of leukopenia within a few days.62 Ethanol is also associated with decreased pulmonary macrophage mobilization, bactericidal activity, and reticuloendothelial system clearance.62

598


Addiction, Tolerance, Dependency, and Withdrawal in Chronic Intoxication Various terms are associated with inappropriate use of addicting agents. The American Psychiatric Association uses the term substance dependence instead of drug addiction.29 Substance dependence is a collection of physiologic, behavioral, and cognitive symptoms indicating that a person is continuing to use an agent despite having significant agent-related problems.29 Tolerance and physical dependence reflect physiologic adaptation at a cellular level. Larger and larger doses of an agent are required to obtain the same effect and use of the agent is necessary to maintain the desired psychological effect or prevent symptoms of withdrawal. A withdrawal syndrome occurs in physically dependent individuals who reduce or cease their ethanol intake.29 Physical dependence is not required for the diagnosis of substance dependence. Addictive drugs provide a “reward” by acting as positive reinforcers (producing euphoria) or as negative reinforcers (alleviating symptoms of withdrawal or dysphoria).29 The brain system involved in the reward mechanism becomes hypersensitized to both the direct effects of the drug and associated environmental stimuli (cues) that are not directly attributable to the drug. The hypersensitization results in pathologic wanting, or craving, independent of symptoms of withdrawal. Substance abuse incorporates recurrent and significant adverse effects related to the use of an agent including the use of the agent in dangerous situations, failure to fulfill major role obligations, legal problems, and continued use despite all the attendant problems.29 The pathophysiology of addiction is complex but interestingly is shared by different addicting agents. The center is the mesocorticolimbic dopamine systems that originate in the ventral tegmental area (VTA). Projections from the VTA go to limbic structures such as the nucleus accumbens, amygdala, and hippocampus and to the prefrontal cortex and anterior cingulate. These circuits affect reinforcement, memory, craving, and the emotional and motivational changes of the withdrawal syndrome. Addictive drugs provide a “reward” by stimulating release of dopamine from the VTA into the nucleus accumbens, causing euphoria and reinforcement of the behavior. Ethanol increases dopamine by activating the inhibitory neurotransmitter γ-aminobutyric acid (GABA) receptors or by inhibiting the stimulatory N-methyl-D-aspartate (NMDA) receptors. Chronic ethanol use enhances the function of NMDA receptors by modifying the subunits.29 Opioid and serotonin receptors have a role in the reinforcing effects of ethanol.29 Interestingly, during withdrawal, there is a decrease in dopamine levels in the nucleus accumbens. The severity of withdrawal syndrome is related to three major factors: the degree of drug exposure, duration of exposure, and (of less clarity) the history of previous withdrawal episodes.64 Persons with alcoholism with a longer history of recurrent withdrawal experience more severe withdrawal. This phenomenon has been referred to as “kindling.”64,65 “Reinstatement” is another

clinical entity that refers to the ever-shortening drinking bouts required before cycles of withdrawal.65 This sensitization is likely related to hypofunction of the GABA receptors and enhanced function of the NMDA receptors.64 PATHOPHYSIOLOGY OF INTOXICATION AND WITHDRAWAL The complex cellular mechanisms of ethanol intoxication, tolerance, dependence, and withdrawal are not completely clear. Ethanol is a relatively weak sedative. Much greater concentrations of ethanol are required to induce an effect than are required of agents such as benzodiazepines or barbiturates. This likely reflects the absence of specific receptors for ethanol.32 Ethanol alters membrane fluidity, the function of membrane structures involved in signal transduction, binding of neurotransmitters, and regulation of gene expression.32,33 Selective sites of toxicity include the receptor complex of GABA, the areas regulating excitatory amino acids, calcium channels, the central adrenergic system, dopamine and adenosine receptors, and the hypothalamic-pituitaryadrenal axis.32,33 GABA receptors are part of a large membrane protein complex that includes a GABA-activated chloride channel and closely linked benzodiazepine receptors whose effect is mediated by the same chloride channels.32,33 Ethanol causes neuronal inhibition by a direct effect on the chloride channel and indirectly by potentiating GABA.32 The physical proximity of these receptors may explain the cross-tolerance that occurs between ethanol and the benzodiazepines. Chronic ethanol use decreases the magnitude of GABA complex–mediated neuroinhibition, an effect that probably contributes to the development of tolerance.32 Decreased GABA-activated chloride channel flux during abstinence contributes to the CNS hyperexcitability of ethanol withdrawal.32 The sedating effect of benzodiazepines on patients with symptoms of ethanol withdrawal is likely due to activation of these same channels. Calcium channels and their receptors also contribute to the cellular mechanisms of tolerance and withdrawal. A few days of ethanol use causes an increase in both calcium channel flux and binding site availability that persists for several hours after drinking has ceased. Calcium channel blockers decrease tremors, seizures, and death in ethanol-dependent rodents deprived of ethanol. Calcium channel blockers attenuate some of the sympathetic symptoms of withdrawal in humans; however, they do not prevent seizures or delirium tremens.33 Ethanol affects the activity of excitatory amino acids, particularly NMDA, in certain areas of the brain.33 Ethanol decreases NMDA-receptor-associated calcium channel flux and changes the cell’s response to its activation. Of particular interest is ethanol’s inhibition of NMDA receptors in the hippocampus, an area involved in learning and memory. This is a proposed mechanism of cognitive defects and “blackouts” associated with ethanol use.32,33 Adrenergic activity affects withdrawal symptoms. The excitatory neurotransmitter norepinephrine (NE) is

CHAPTER 31

released by presynaptic vesicles. It interacts with various receptors and is then resequestered into the presynaptic terminal. Within the hypothalamus, intersynaptic NE is taken up by extraneuronal cells (possibly astrocytes) and converted to epinephrine, which is then released back into the synapse. Phenylethanolamine-Nmethyltransferase (PNMT) catalyzes this extraneuronal conversion of NE to epinephrine. Epinephrine activates presynaptic α2 receptors, which inhibit NE release. Ethanol increases PNMT activity, leading to central adrenergic inhibition. Chronic ethanol ingestion leads to compensatory down-regulation of presynaptic α2 receptors. Ethanol withdrawal is associated with decreased PNMT activity that results in less epinephrine being available to stimulate the previously downregulated α2 receptors. Since the α2 receptors provide negative feedback to the presynaptic neurons, the resulting loss of negative inhibition yields increased sympathomimetic activity.65 This pathophysiologic process explains the effect of the central α2 agonist clonidine in decreasing the sympathomimetic activity associated with withdrawal. The stimulatory central adrenergic β receptors also appear to contribute to the withdrawal syndrome. Ethanol causes uncoupling between the β receptor proteins and their second messengers, which prevents the receptor downregulation that typically occurs during sympathetic states. Increased adrenergic activity during withdrawal results in hyperstimulation of these receptors.66 This mechanism may explain the effects of atenolol in management of the withdrawal syndrome. Excess dopaminergic states are associated with psychosis, hallucinosis, cravings, and the mechanisms of reward and reinforcement.33 However, the roles of serotonin and dopamine in ethanol intoxication and withdrawal are not clearly defined.33 Adenosine is also associated with physical dependence and tolerance.33 While not a neurotransmitter itself, it modulates the effects of neurotransmitters. Acute ethanol ingestion inhibits intracellular transport of adenosine, leading to increased stimulation of extracellular membrane adenosine α2 receptors. This stimulation of the α2 receptors causes increased G protein–mediated adenylcyclase activity and increased intracellular adenosine 3’,5’-cyclic phosphate (cyclic AMP). Chronic ethanol intake eventually causes an adaptive decrease in cyclic AMP production. Adapted cells require ethanol to maintain adequate cAMP production. The adenosine nucleoside transporter also loses its sensitivity to ethanol inhibition with chronic ethanol use. Protein kinase A activity, which requires cyclic AMP, is responsible for the decreased adenosine nucleoside transporter uptake. The decrease in available cyclic AMP associated with chronic ethanol ingestion eventually results in increased adenosine transporter activity. These membrane changes reflect “tolerance” at the cellular level.33 WITHDRAWAL SYNDROMES Into the 1950s, the cause of the clinical syndrome that we now refer to as “withdrawal” was hotly debated. It was unclear whether the syndrome was due to cessation of

Ethanol

599

drinking, a direct toxic effect of ethanol, or nutritional deficiencies. Isbell and others settled the debate in 1953.67 In their study, ethanol was given daily to 10 healthy, former opiate addicts in controlled conditions that provided adequate diets and vitamins but prevented the introduction of other agents. Upon cessation of drinking, four subjects who drank for up to 34 days all developed tremor, perspiration, gastrointestinal distress, and anorexia lasting 1 to 3 days. Three of these four drank for no more than 16 days, reflecting the little time needed to develop physical dependence. The six subjects who drank between 48 and 87 days developed vomiting, diarrhea, insomnia, hyperreflexia, and fever in addition to the above symptoms. Five also had hallucinations, two had seizures, and three developed delirium tremens.67 Ethanol withdrawal developed even if the study participants did not become intoxicated as long as the amount of ethanol ingested remained large over time.67 Symptoms of ethanol withdrawal range from mild anxiety and tremors to seizures, delirium tremens (DTs), and death. Symptoms start 6 to 8 hours after a significant drop in ethanol level. Sympathetic symptoms include tremors, tachycardia, hypertension, irritability, and/or hyperreflexia. Neuropsychiatric symptoms include anxiety, agitation, hyperalertness, easy startling, insomnia, craving for rest, self-preoccupation, inattention, and mild disorientation to time with no gross confusion.30,67 The absence of significant disorientation, confusion, and autonomic instability differentiates minor withdrawal from the more serious DTs. Tremors may be minimally noticeable (shaky inside) but worsen with activity or agitation and can become so coarse that the patient many not be able to talk, walk, or eat.30 Symptoms often peak and begin to resolve within 24 hours but can last days to more than a week. Without treatment, the hyperalertness, shakiness, and insomnia can last as long as 10 to 14 days.30 A mild symptom complex occurs in 70% to 80%, while 15% to 20% become moderately ill if treatment is not provided.68 Hallucinations can occur in up to 25% of patients. Three quarters begin within 48 hours, but they may not occur until 6 to 8 days after the cessation of drinking.30 Pure visual hallucinations are five times more frequent than auditory.30 They may also rarely be tactile or olfactory. Other disorders of perception such as illusions are transient and rarely last longer than 3 days.30 An unusual manifestation of ethanol withdrawal is “acute auditory hallucinosis,” which occurred in 2% of patients in one series.30 The patients did not have significant autonomic hyperactivity. The auditory hallucinations affected only chronic alcoholics, were usually threatening in nature, and lasted a few days to 2 weeks. Patients were oriented and appropriate during the hallucinatory events. Upon recovery, patients realized that the voices were imaginary but could vividly recall the events.30 Alcoholic withdrawal seizures, or “rum fits,” are generalized and tonic–clonic. Unlike idiopathic seizures, this is an adult-onset disease, with 94% beginning after the age of 30 years.69 Electroencephalograms (EEGs) of patients with ethanol withdrawal seizures demonstrate diffuse

600


slowing that normalizes after the seizures have ceased. This is different from idiopathic seizure in patients whose baseline EEGs are abnormal.67,69 The frequency of withdrawal seizures in patients with concomitant idiopathic epilepsy is increased relative to those without epilepsy.30 Three to 12 percent of untreated withdrawal patients have seizures, with 50% occurring 13 to 24 hours after cessation of drinking and 90% within 48 hours.30,69 Seizures occurring within 12 hours of the cessation of drinking often have other contributing factors including prior ethanol tapering or head trauma.30,69 Fifty-four percent of patients with alcohol withdrawal seizures have more than one seizure, all occurring within a few hours of each other.30,69 One third of patients who have seizures eventually develop DTs if not treated,30,69 while one third of those who have DTs will have had a seizure during the current withdrawal.70 Seizures are unusual after the onset of DTs. Patients who have both withdrawal seizures and DTs typically have the seizures first. Delirium tremens begins during the postictal period in 25%, and most episodes begin within 3 days of the seizure.30 While ethanol withdrawal can cause seizures, it is proposed that ethanol itself causes seizures. One retrospective series of 308 inner-city patients with newonset seizures found that only 30% of the alcoholic patients had reduced or stopped their drinking during the 2 weeks prior to their seizures.71 It has been noted72 that even patients in the older, classic series30,69 had seizures outside the typical time frames or while still ingesting ethanol. It has been suggested that seizures in the setting of ethanol use should simply be referred to as “ethanol-related seizures.”71 Delirium tremens is an infrequent but potentially fatal syndrome. It can occur in individuals who have drunk steadily for as few as 48 days67 and develops in approximately 5% of patients with untreated ethanol withdrawal.30,73 It typically begins 3 to 5 days after ethanol intake has decreased but can start within 24 hours or as late as 14 days.30 Delirium tremens is marked by severe autonomic hyperactivity (hypertension, tachycardia, fever, tremors, diaphoresis, dilated pupils) and significant disorientation. Patients may demonstrate brief moments of insight and reality if their attention can be obtained. While 83% recover within 3 days, 10% can have relapses, with the entire process lasting up to a month.30 Patients are typically amnestic for events during the delirium.30 Prior to the 1950s, the mortality associated with DTs was as high as 50% but averaged 20% to 25%.73 A 1950s series had a 15% mortality.30 Mortality today is often quoted to be 5% to 15% in treated patients.68 However, mortality has not been well studied since the benzodiazepines have become the mainstay of therapy. Mortality likely is relatively low in patients with DTs who have received adequate doses of benzodiazepines and appropriate nursing care. Death during DTs is usually related to patients’ underlying medical conditions including pancreatitis, subarachnoid hemorrhage, gastrointestinal hemorrhage, infection, dehydration, seizure disorders, severe electrolyte abnormalities, cardiac rhythm disturbances, and liver disease.70,73 Hyperthermia or seizures in patients with DTs are particularly

associated with a poor outcome. In one series, seizures occurred in 31% of those who died versus 13% of survivors. Even more significant was that 51% of those with temperatures greater than 104° F died, compared with 8% of survivors.70 Management of Withdrawal Syndrome The treatment goals for individuals with the withdrawal syndrome are to prevent the progression of withdrawal to seizures or DTs, allay symptoms, treat underlying disorders, and prepare patients for long-term rehabilitation. Both pharmacologic and nonpharmacologic approaches have been used. Benzodiazepines are the mainstay of pharmacologic therapy. Nonpharmacologic approaches include reassurance, reality orientation, frequent monitoring of signs and symptoms, and general nursing care.74 Nonpharmacologic therapy has been effective, but it has only been used on patients with mild withdrawal symptoms and without seizures or concomitant medical problems.74,75 Patients in withdrawal should receive supplementary multivitamins, thiamine, glucose, and folate. Multivitamins are included because of malnutrition resulting from the “empty” ethanol calories. Thiamine is given by the oral, intramuscular, or intravenous routes. The safety of IV thiamine was demonstrated in a prospective series of 989 patients. Eleven had local irritation and only one developed mild generalized pruritis.76 Dextrose is given because hypoglycemia is common owing to poor oral intake, glycogen depletion, and decreased carbohydrate production. Potassium, phosphate, and magnesium supplementation may also be beneficial, but there are no data to support this. Patients with severe symptoms, altered mental status, or significant comorbid conditions should be hospitalized. Hayashida and others demonstrated that outpatient management was effective, safe, and less costly in a population with mild to moderate symptoms, no comorbid disease, and accessibility to daily follow-up.77 Social issues including homelessness and social support must also be considered when making management decisions. Benzodiazepines (BDZs) are cross-tolerant with ethanol and are the drugs of choice because of their sedative, anxiolytic, and anticonvulsive properties.78 Their efficacy was established initially in two classic papers. Sereny and Kalant performed a five-armed, randomized, doubleblind comparison of two doses of chlordiazepoxide, two doses of promazine, and placebo. Chlordiazepoxide improved study parameters more consistently than did promazine, and the latter was also associated with an increased progression to DTs.79 Kaim and others compared chlordiazepoxide, chlorpromazine, hydroxyzine, thiamine, and placebo for the treatment of withdrawal. Chlordiazepoxide was clearly the best at preventing progression of withdrawal.80 BDZs should be started at the onset of withdrawal symptoms, regardless of the blood ethanol concentration. Problems associated with the use of BDZs include excessive sedation and minor cardiovascular and respiratory depression.31 However, their safety profile is excellent.

CHAPTER 31

No trials exist that compare oral to parenteral BDZs in patients with severe withdrawal, seizures, or DTs. However, most use intravenous BDZs because they can be better titrated to effect. Intramuscular administration of lorazepam is appropriate if intravenous access cannot initially be obtained. The optimal choice of BDZ for the treatment of withdrawal is debated, especially with regard to the desirability of drug characteristics such as half-life, lipid solubility, the mechanism of metabolism and the presence of active metabolites, and abuse potential. An extensive meta-analysis found all BDZs to be equally effective in reducing signs and symptoms of withdrawal.81 However, the longer acting agents, with their active metabolites, may be more effective at preventing seizures during a fixed-dose taper owing to smoother withdrawal with fewer rebound symptoms.3,81 The potential for abuse is another consideration in BDZ choice. Faster acting agents such as lorazepam, diazepam, and alprazolam have a higher abuse potential than agents with a slower onset of action such as oxazepam or chlordiazepoxide.82 Oversedation is a concern, particularly with oral dosing. Agents with long half-lives or active metabolites may accumulate and cause extended periods of sedation.78,81 Interestingly, while oversedation is a concern, this author could not find any cases that reflected this has ever had any clinical significance in the alcohol withdrawal setting. Indeed, as noted above, the long-acting agents likely provide a “smoother” withdrawal with fewer symptom flares. This concept was supported by a comparison of diazepam and lorazepam that found the latter agent to be associated with significantly more anxiety, depression, and poorer performance on cognitive testing.83 Severe liver dysfunction slows the metabolism of BDZs eliminated by oxidation (diazepam, chlordiazepoxide) more than those eliminated by glucuronidation alone (lorazepam oxazepam).78,84 It is possible that the metabolism of long-acting agents is decreased in the presence of cirrhosis, chronic active hepatitis, and old age, and half-lives are increased by concomitant administration of disulfiram, cimetidine, or ethanol.85,86 Such patients may become oversedated, especially with oral regimens, if dosing is not adjusted appropriately.78,84-86 The significance of lipophilicity is unclear. More lipophilic agents (midazolam > diazepam

Ethanol

601

> lorazepam) penetrate the CNS faster (of unclear clinical significance) but also undergo faster redistribution back out of the CNS (shortening the duration of a single injection).78 Chlordiazepoxide continues to be one of the most commonly used agents for a fixed-dose taper. It was the first to enter the market (1960); is inexpensive; has long-acting metabolites that accumulate with multiple doses, enabling a smooth taper; and has a relatively low abuse potential. Comparisons among BDZs are shown in Table 31-6. Few conclusions can be drawn from large reviews or meta-analyses. Three meta-analyses have reached similar conclusions: that BDZs are the agents of choice and the data are not clear as to the optimal BDZ.81,87,88 Bird and Makela conducted a literature review to determine whether lorazepam should be the agent of choice over the long-acting agents and concluded that no experimental evidence documented the clinical superiority of lorazepam.78 Three treatment protocols with BDZs have been used. The most commonly used BDZ dosing method in the United States is a fixed-dose, 3- to 5-day taper of chlordiazepoxide.89 A slower taper should be considered for the BDZs that only undergo glucuronidation— lorazepam and oxazepam.31 Tapering should be done by decreasing the dose and not by increasing the interval between doses.31 Another approach is the “loading dose technique,” which takes advantage of the sustained action of the longacting agents. A high dose of a long-acting agent is given every 1 to 2 hours until the withdrawal symptoms clear or sedation occurs.90,91 For example, diazepam 20 mg orally has been used for each dose. Patients averaged four doses over 12 hours and then received no further medications. The long half-lives of diazepam’s active metabolites facilitate this approach, since therapeutic levels persist beyond 72 hours.90 A pharmacokinetic study of the diazepam loading dose technique revealed that some patients did not reach maximum concentration until 90 minutes, reflecting that the dosing intervals should be at least 90 minutes long.92 The third protocol is symptom-triggered therapy, in which patients receive medication only when symptoms exceed a threshold of severity, enabling individualized tapering regimens.89 This approach uses an assessment

TABLE 31-6 Comparison of Benzodiazepines Used for the Treatment of Withdrawal CHARACTERISTIC

CHLORDIAZEPOXIDE

DIAZEPAM

LORAZEPAM

OXAZEPAM

Routes Initial dosing regimen Liver metabolism Active metabolites Half-life (hr)†

IV, IM*, PO 15–50 mg tid/qid Oxidation Yes (Long) Range: 6–30 Average: 10

IV, IM*, PO 5–20 mg tid/qid Oxidation Yes (Long) Range: 20–70 Average: 33

IV, IM, PO 1–2 mg bid/qid Glucuronidation No (Intermediate) Range: 5–25 Average: 15

PO 15–30 mg tid/qid Glucuronidation No (Intermediate) Range: 5–20 Average: 8

IM, intramuscular; IV, intravenous; PO, oral; tab, tablet. *IM absorption is erratic, and thus this route of delivery should be avoided if possible. Inject in the deltoid muscle if administration must be IM. † Chlordiazepoxide’s and diazepam’s active metabolites have half-lives from 25 to 100 hr.

602


scale to establish severity. The most extensively studied scales are the Clinical Institute Withdrawal Assessment– Alcohol (CIWA-A) and the revised, shortened version of the same. The scales are reliable, reproducible, and valid. High scores predict increased likelihood of seizures or delirium.3,81 Symptom-triggered therapy decreases the total dose of BDZ and the duration of treatment.3,81,89 Unfortunately, studies of symptom-triggered therapy have been only in patients with mild to moderate withdrawal.81,86,89,93 Concerns over the approach include inducing drug-seeking behavior, undertreating patients, and causing “kindling” sensitization because too little treatment has been given.93 For patients with severe withdrawal, very large doses of BDZs may be required. Reported doses include 2640 mg of diazepam over 48 hours94 and 3600 mg of lorazepam over 3 days.95 A common mistake in the management of patients with severe withdrawal is to not be aggressive enough with the use of BDZs. Use of the “usual” doses may be very inadequate. Other sedative-hypnotic medications have been assessed. Barbiturates have been used extensively; however, there are few data to support them. They have a narrow safety margin, have abuse potential, and are very sedating. Barbital, a long-acting oral barbiturate, decreases symptoms comparably to BDZs.81 Phenobarbital is supported by various uncontrolled trials. It has less abuse potential than other barbiturates, can be administered by multiple routes, and is inexpensive.96 However, it has a greater risk of respiratory depression and a lower safety profile than BDZs.3,81 γ-Hydroxybutyrate (GHB) compared favorably with diazepam in a prospective series of 60 patients with mild to moderate withdrawal.97 Propofol is reported to decrease the symptoms of DTs in patients who were refractory to benzodiazepines.95,98 A problem with these and other sedatives is that they have not clearly been shown to decrease the progression of withdrawal. Anticonvulsant medications have long been used for ethanol withdrawal, with a main action of cross-tolerance with ethanol at the GABAA receptors.3,96 Various openlabel trials and anecdotal reports indicate that valproic acid is effective at reducing symptoms.96 Gabapentin relieved withdrawal symptoms in a four-patient series.99 Carbamazepine is the best studied of these agents. It is superior to placebo and at least equal to oxazepam, lorazepam, and barbital for the suppression of mild to moderate alcohol withdrawal. Compared with lorazepam, it is associated with fewer protracted symptoms, less relapse during a 3-month follow-up, and fewer adverse events such as dizziness or incoordination.3,81,96 Like the nonbenzodiazepine sedative-hypnotics, the anticonvulsant medications have not been shown to prevent the progression of withdrawal in humans. The neuroleptic phenothiazines and butyrophenones have no role in the management of withdrawal despite their ability to attenuate the signs and symptoms of withdrawal. They are less effective than BDZs in preventing delirium and have actually been associated with an increase in seizures compared with placebo.3,81 Neuroleptics can also modify the body’s ability to regulate hyperthermia and can cause hypotension.31

The sympatholytic centrally acting α2 agonists and β blockers are also used. Their primary benefit is attenuation of hyperadrenergic symptoms such as tremor, tachycardia, and hypertension while permitting normal cognitive function.81,100,101 They usually are used in conjunction with other agents. They have not been shown to prevent seizures or progression to DTs.81,101 In seriously ill patients, the reduction of sympathetic symptoms masks the progression of DTs and the worsening of associated medical problems.100,101 β Blockers may be contraindicated for medical reasons including hypoglycemia, cardiomyopathy, and chronic obstructive pulmonary disease.100 Alcohol-related seizures should be treated with BDZs. Intravenous lorazepam significantly decreased the frequency of recurrent seizures in one prospective, randomized series of 229 patients who presented following an alcohol withdrawal seizure.102 Phenytoin, valproic acid, carbamazepine, and primidone are not effective.101 In addition, except for phenytoin, these agents also cannot be rapidly loaded. REFERENCES 1. Petroni NC, Cardoni AA: Alcohol content of liquid medicinals. Clin Toxicol 1979;14:407–432. 2. Vogel C, Caraccio T, Mofenson H, et al: Alcohol intoxication in young children. J Toxicol Clin Toxicol 1995;33:25–33. 3. Kosten TR, O’Connor PG: Management of drug and alcohol withdrawal. N Engl J Med 2003;348:1786–1795. 4. Norberg A, Jones AW, Hahn RG, et al: Role of variability in explaining ethanol pharmacokinetics: research and forensic applications. Clin Pharmacokinet 2003;42:1–3. 5. Holt S, Stewart MJ, Adam RD, et al: Alcohol absorption, gastric emptying and a breathalyser. Br J Clin Pharmacol 1980;9:205–208. 6. Jones AW, Jonsson KA, Neri A: Peak blood-ethanol concentration and the time of its occurrence after rapid drinking on an empty stomach. J Forensic Sci 1991;36:376–385. 7. Minocha A, Herold DA, Barth JT, et al: Activated charcoal in oral ethanol absorption: lack of effect in humans. J Toxicol Clin Toxicol 1986;24:225–234. 8. Crabb DW, Bosron WF, Li TK: Ethanol metabolism. Pharmacol Ther 1987;34:59. 9. Bogusz M, Pach J, Stasko W: Comparative studies on the rate of ethanol elimination in acute poisoning and in controlled conditions. J Forensic Sci 1977;22:446–451. 10. Li TK, Bosron WF: Genetic variability of enzymes of alcohol metabolism in human beings. Ann Emerg Med 1986;15:997–1004. 11. Panes J, Caballeria J, Guitart R, et al: Determinants of ethanol and acetaldehyde metabolism in chronic alcoholics. Alcohol Clin Exp Res 1993;17:48–53. 12. Lieber CS: Hepatic and metabolic effects of ethanol: pathogenesis and prevention. Ann Intern Med 1994;26:325–330. 13. Caballeria J: First-pass metabolism of ethanol: its role as a determinant of blood alcohol levels after drinking. Hepatogastroenterology 1992;39(Suppl 1):62–66. 14. Gershman H, Steeper J: Rate of clearance of ethanol from the blood of intoxicated patients in the emergency department. J Emerg Med 1991;9:307–311. 15. O’Neill S, Tipton KF, Prichard JS, et al: Survival after high blood alcohol levels: association with first-order elimination kinetics. Arch Intern Med 1984;144:641–642. 16. Dufour MC, Archer L, Gordis E: Alcohol and the elderly. Clin Geriatr Med 1992;8:127–141. 17. Watson W, Litovitz T, Rodgers GC II, et al: 2002 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2003;21:353–364. 18. Lieber CS: Medical disorders of alcoholism. N Engl J Med 1995;333:1058–1065. 19. Seixas FA: Alcohol and its drug interactions. Ann Intern Med 1975;83:86–91.

CHAPTER 31

20. Interactions of drugs with alcohol. Med Lett Drugs Ther (April 3) 1981;23:33–36. 21. Gugler R: H2-antagonists and alcohol: do they interact? Drug Saf 1994;10:271–280. 22. Gilman AG, Rall TW, Nies AS, et al: The Pharmacological Basis of Therapeutics, 8th ed. New York, Pergamon, 1990. 23. Schiodt FV, Rochling FA, Casey DL, et al: Acetaminophen toxicity in an urban county hospital. N Engl J Med 1997;337:1112–1117. 24. Lee WM: Drug-induced hepatotoxicity. N Engl J Med 2003; 349:474–485. 25. Zimmerman HJ, Maddrey WC: Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure. Hepatology 1995;22:767–773. 26. Kuffner EK, Dart RC, Bogdan GM, et al: Effect of maximal daily doses of acetaminophen on the liver of alcoholic patients: a randomized, double-blind, placebo-controlled trial. Arch Intern Med 2001;161:2247–2252. 27. Bailey DN: Comprehensive toxicology screening: the frequency of finding other drugs in addition to ethanol. J Toxicol Clin Toxicol 1984;22:463–471. 28. Fantus RJ, Zautcke JL, Hickey PA, et al: Driving under the influence: a level-I trauma center’s experience. J Trauma 1991; 31:1517–1520. 29. Cami J, Farre M: Drug addiction. N Engl J Med 2003;349:975–986. 30. Victor M, Adams RD: The Effect of Alcohol on the Nervous System. Baltimore, Williams & Wilkins, 1953. 31. Adinoff B, Bone GH, Linnoila M: Acute ethanol poisoning and the ethanol withdrawal syndrome. Med Toxicol Adverse Drug Exp 1988;3:172–196. 32. Charness ME, Simon RP, Greenberg DA: Ethanol and the nervous system. N Engl J Med 1989;321:442–454. 33. Diamond I, Messing RO: Neurologic effects of alcoholism. West J Med 1994;161:279–287. 34. Bittencourt P, Wade P, Richens A, et al: Blood alcohol and eye movements. Lancet 1980;2:981. 35. McIvor RA, Cosbey SH: Effect of using alcoholic and non-alcoholic skin cleansing swabs when sampling blood for alcohol estimation using gas chromatography. Br J Clin Pract 1990;44:235–236. 36. Gibb K: Serum alcohol levels, toxicology screens, and use of the breath alcohol analyzer. Ann Emerg Med 1986;15:349–353. 37. Wilson A, Sitar DS, Molloy WD, et al: Effect of age and chronic obstructive pulmonary disease on the breathalyzer estimation of blood alcohol level. Alcohol Clin Exp Res 1987;11:440–443. 38. Li J, Mills T, Erato R: Intravenous saline has no effect on blood ethanol clearance. J Emerg Med 1999;17:1–5. 39. Nuotto E, Mattila MJ, Seppala T, et al: Coffee and caffeine and alcohol effects on psychomotor function. Clin Pharmacol Ther 1982;31:68–76. 40. Nuotto E, Palva ES, Lahdenranta U: Naloxone fails to counteract heavy alcohol intoxication. Lancet 1983;2:167. 41. Brown SS, Forrest JA, Roscoe P: A controlled trial of fructose in the treatment of acute alcoholic intoxication. Lancet 1972;2:898–899. 42. Fluckiger A, Hartmann D, Leishman B, et al: Lack of effect of the benzodiazepine antagonist flumazenil (Ro 15-1788) on the performance of healthy subjects during experimentally induced ethanol intoxication. Eur J Clin Pharmacol 1988;34:273–276. 43. Reuler JB, Girard DE, Cooney TG: Current concepts: Wernicke’s encephalopathy. N Engl J Med 1985;312:1035–1039. 44. Watson AJS, Walker JF, Tomkin GH, et al: Acute Wernicke’s encephalopathy precipitated by gluclose loading. Ir J Med Sci 1981;150:301–303. 45. Hack JB, Hoffman RS: Thiamine before glucose to prevent Wernicke’s encephalopathy: examining the conventional wisdom. JAMA 1998;279:583. 46. Wilson JD, Madison LL: Deficiency of thiamine (beriberi), pyridoxine, and riboflavin. In Isselbacher KJ (ed): Harrison’s Principles of Internal Medicine, 9th ed. New York, McGraw-Hill, 1980, pp 425–429. 47. Naik P, Lawton J: Pharmacological management of alcohol withdrawal. Br J Hosp Med 1993;50:265–269. 48. Victor M, Adams RD, Collins GH: The Wernicke-Korsakoff Syndrome. Philadelphia, FA Davis, 1971. 49. Thomson AD, Baker H, Leevy CM: Patterns of S-thiamine hydrochloride absorption in the malnourished alcoholic patient. J Lab Clin Med 1970;76:34–45.

Ethanol

603

50. Homewood J, Bond NW: Thiamin deficiency and Korsakoff’s syndrome: failure to find memory impairments following nonalcoholic Wernicke’s encephalopathy. Alcohol 1999;19:75–84. 51. Adler RA: Clinically important effects of alcohol on endocrine function. J Clin Endocrinol Metab 1992;74:957–960. 52. Halperin ML, Hammeke M, Josse RG, et al: Metabolic acidosis in the alcoholic: a pathophysiologic approach. Metabolism 1983; 32:308–315. 53. Ragland G: Electrolyte abnormalities in the alcoholic patient. Emerg Med Clin North Am 1990;8:761–773. 54. Duffens K, Marx JA: Alcoholic ketoacidosis: a review. J Emerg Med 1987;5:399–406. 55. Piano MR, Schwertz DW: Alcoholic heart disease: a review. Heart Lung 1994;23:3–17. 56. Puddey IB, Zilkens RR, Croft KD, et al: Alcohol and endothelial function: a brief review. Clin Exp Pharm Physiol 2001;28: 1020–1024. 57. Lang RM, Borow KM, Neumann A, et al: Adverse cardiac effects of acute alcohol ingestion in young adults. Ann Intern Med 1985;102:742–747. 58. Ahlawat SK, Siwach SB: Alcohol and coronary artery disease. Int J Cardiol 1994;44:157–162. 59. Reynolds K, Lewis B, Nolen JD, et al: Alcohol consumption and risk of stroke: a meta-analysis. JAMA 2003;289:579–588. 60. Ettinger PO, Wu CF, De La Cruz C II, et al: Arrhythmias and the “holiday heart”: alcohol-associated cardiac rhythm disorders. Am Heart J 1978;95:555–562. 61. Lowenstein SR, Gabow PA, Cramer J, et al: The role of alcohol in new-onset atrial fibrillation. Arch Intern Med 1983;143: 1882–1885. 62. Girard DE, Kumar KL, McAfee JH: Hematologic effects of acute and chronic alcohol abuse. Hematol Oncol Clin North Am 1987;1:321–334. 63. MacGregor RR: Alcohol and immune defense. JAMA 1986; 256:1474–1478. 64. Gonzalez LP, Veatch LM, Ticku MK, et al: Alcohol withdrawal kindling: mechanisms and implications for treatment. Alcohol Clin Exp Res 2001;25:197S–201S. 65. Linnoila M, Mefford I, Nutt D, et al: NIH conference: alcohol withdrawal and noradrenergic function. Ann Intern Med 1987; 107:875–889. 66. Rosenbloom A: Emerging treatment options in the alcohol withdrawal syndrome. J Clin Psychiatry 1988;49:28–31. 67. Isbell H, Fraser HF, Wikler A, et al: An experimental study of the etiology of rum fits and delirium tremens. Q J Stud Alcohol 1955;16:1–33. 68. Lerner WD, Fallon HJ: The alcohol withdrawal syndrome. N Engl J Med 1985;313:951–952. 69. Victor M, Brausch C: The role of abstinence in the genesis of alcoholic epilepsy. Epilepsia 1967;8:1–20. 70. Tavel ME, Davidson W, Batterton TD: A critical analysis of mortality associated with delirium tremens. Am J Med Sci 1961;242:18–29. 71. Ng SK, Hauser WA, Brust JC, et al: Alcohol consumption and withdrawal in new-onset seizures. N Engl J Med 1988;319:666–673. 72. Simon RP: Alcohol and seizures. N Engl J Med 1988;319:715–716. 73. Moore M, Gray MG: Delirium tremens: a study of cases at the Boston City Hospital, 1915–1936. N Engl J Med 1939;220:953–956. 74. Sellers EM, Naranjo CA: New strategies for the treatment of alcohol withdrawal. Psychopharmacol Bull 1986;22:88–92. 75. Sullivan JT, Swift RM, Lewis DC: Benzodiazepine requirements during alcohol withdrawal syndrome: clinical implications of using a standardized withdrawal scale. J Clin Psychopharmacol 1991;11:291–295. 76. Wrenn KD, Murphy F, Slovis CM: A toxicity study of parenteral thiamine hydrochloride. Ann Emerg Med 1989;18:867–870. 77. Hayashida M, Alterman AI, McLellan AT, et al: Comparative effectiveness and costs of inpatient and outpatient detoxification of patients with mild-to-moderate alcohol withdrawal syndrome. N Engl J Med 1989;320:358–365. 78. Bird RD, Makela EH: Alcohol withdrawal: what is the benzodiazepine of choice? Ann Pharmacother 1994;28:67–71. 79. Sereny G, Kalant H: Comparative clinical evaluation of chlordiazepoxide and promazine in treatment of alcoholwithdrawal syndrome. BMJ 1965;1:92–97.

604


80. Kaim SC, Klett CJ, Rothfeld B: Treatment of the acute alcohol withdrawal state: a comparison of four drugs. Am J Psychiatry 1969;125:1640–1646. 81. Mayo-Smith MF: Pharmocological management of alcohol withdrawal. JAMA 1997;278:144–151. 82. Griffiths RR, Wolf B: Relative abuse liability of different benzodiazepines in drug abusers. J Clin Psychopharmacol 1990;10:237–243. 83. Ritson B, Chick J: Comparison of two benzodiazepines in the treatment of alcohol withdrawal: effects on symptoms and cognitive recovery. Drug Alcohol Depend 1986;18:329–334. 84. Solomon J, Rouck LA, Koepke HH: Double-blind comparison of lorazepam and chlordiazepoxide in the treatment of the acute alcohol abstinence syndrome. Clin Ther 1983;6:52–58. 85. Miller WC II, McCurdy L: A double-blind comparison of the efficacy and safety of lorazepam and diazepam in the treatment of the acute alcohol withdrawal syndrome. Clin Ther 1984; 6:364–371. 86. Massman JE, Tipton DM: Signs and symptoms assessment: a guide for the treatment of the alcohol withdrawal syndrome. J Psychoactive Drugs 1988;20:443–444. 87. Moskowitz G, Chalmers TC, Sacks HS, et al: Deficiencies of clinical trials of alcohol withdrawal. Alcohol Clin Exp Res 1983; 7:42–46. 88. Holbrook AM, Crowther R, Lotter A, et al: Meta-analysis of benzodiazepine use in the treatment of acute alcohol withdrawal. CMAJ 1999;160:649–655. 89. Saitz R, Mayo-Smith MF, Roberts MS, et al: Individualized treatment for alcohol withdrawal: a randomized double-blind controlled trial. JAMA 1994;272:519–523. 90. Sellers EM: Alcohol, barbiturate and benzodiazepine withdrawal syndromes: clinical management. CMAJ 1988;139:113–120.

91. Lejoyeux M, Solomon J, Ades J: Benzodiazepine treatment for alcohol-dependent patients. Alcohol Alcohol 1998;33:563–575. 92. Heinala P, Piepponen T, Heikkinen H: Diazepam loading in alcohol withdrawal: clinical pharmacokinetics. Int J Clin Pharmacol Ther Toxicol 1990;28:211–217. 93. Sullivan JT: Individualized treatment of alcohol withdrawal. JAMA 1995;273:183–184. 94. Nolop KB, Natow A: Unprecedented sedative requirements during delirium tremens. Crit Care Med 1985;13:246–247. 95. McCowan C, Marik P: Refractory delirium tremens treated with propofol: a case series. Crit Care Med 2000;28:1781–1784. 96. Malcolm R, Myrick H, Brady KT, et al: Update on anticonvulsants for the treatment of alcohol withdrawal. Am J Addict 2001; 10(Suppl):16–23. 97. Addolorato G, Balducci G, Capristo E, et al: Gamma-hydroxybutyric acid (GHB) in the treatment of alcohol withdrawal syndrome: a randomized comparative study versus benzodiazepine. Alcohol Clin Exp Res 1999;23:1596–1604. 98. Coomes TR, Smith SW: Successful use of propofol in refractory delirium tremens. Ann Emerg Med 1997;30:825–828. 99. Bonnet U, Banger M, Leweke FM, et al: Treatment of alcohol withdrawal syndrome with gabapentin. Pharmacopsychiatry 1999;32:107–109. 100. Baumgartner GR, Rowen RC: Transdermal clonidine versus chlordiazepoxide in alcohol withdrawal: a randomized, controlled clinical trial. South Med J 1991;84:312–321. 101. Liskow BI, Goodwin DW: Pharmacological treatment of alcohol intoxication, withdrawal and dependence: a critical review. J Stud Alcohol 1987;48:356–370. 102. D’Onofrio G, Rathlev NK, Ulrich AS, et al: Lorazepam for the prevention of recurrent seizures related to alcohol. N Engl J Med 1999;340:915–919.

32

Methanol, Ethylene Glycol, and Other Toxic Alcohols

A

Methanol DAG JACOBSEN, MD, PHD ■ KNUT ERIK HOVDA, MD, PHD

At a Glance… ■ ■

■

■ ■ ■

Methanol or methyl alcohol is converted to the toxic metabolite formic acid, which causes acidosis and inhibits cell cytocromes. Clinical manifestations vary and are usually delayed for 12 to 24 hours: Visual disturbances, gastrointestinal symptoms, dyspnea, headache, and sometimes chest pain occur. In late stages, coma and respiratory arrest may be observed. Diagnosis is based on clinical signs, acid-base status, measurement of serum formate and/or direct serum methanol analyses, or calculation of the anion and osmolal gaps. Treatment consists of buffer, an antidote (either ethanol or fomepizole), folinic acid, and often hemodialysis. One should always consider multiple victims, especially if the source is contaminated alcohol. Permanent sequelae, such as impaired vision and brain damage, may develop if treatment is delayed.

Methanol (HCOOH, methyl alcohol, wood spirits) is a clear, colorless liquid at room temperature. It is a widely used commercial, industrial, and marine solvent and paint remover, as well as a solvent in paints, varnishes, shellacs, and photocopying fluid. It may be used as an antifreeze fluid and is commonly used in windshieldwashing fluids. In addition, it can be formulated as a solid canned fuel (4%), along with ethanol and soap, or as a liquid fuel for heating small engines used in various hobbies. In the United Kingdom, methanol is adulterated with a purple dye to distinguish it from ethanol. However, its high industrial production and its use in laboratories, schools, and industrial processes account for the fact that large volumes may be obtained and contribute to epidemic outbreaks of methanol poisoning. Methanol is also used as an adulterant to make ethyl alcohol unfit to drink when the latter is used for cleaning purposes. Because methanol can be purchased tax free and is considerably less expensive than normal alcoholic beverages, it is not surprising that chronic alcoholics may consume such compounds.1 Methanol outbreaks are therefore most common in countries with high taxes on alcohol.2 Methanol has no therapeutic properties and is considered to be only a toxicant.

TOXICOLOGY AND PHARMACOLOGY The lethal dose of methanol is variably given as 30 to 240 mL, with 1 g/kg (1.2 mL/kg) as the best estimate.3

However, with aggressive treatment, survival may be achieved despite much higher intake. Because toxicity in methanol poisoning depends on the degree of metabolic acidosis, there is really no lethal or toxic concentration of methanol if its metabolism to formic acid is blocked. The minimum dose that can cause permanent visual defects is unknown, but most probably ingestion of more than 30 mL (adults) is necessary. The main route of toxicity is ingestion, but toxicity may also occur after inhalation or skin absorption.4,5 Methanol is readily absorbed from the gastrointestinal (GI) tract after ingestion and reaches peak blood levels in 30 to 90 minutes. It is widely distributed in body tissues, with a volume of distribution of 0.6 to 0.7 L/kg.6,7 A small amount of methanol is found in the expired breath of normal persons, presumably due to endogenous metabolic production. The kidneys and lungs in untreated patients excrete less than 5% to 10% of unchanged methanol. The majority of methanol, therefore, is metabolized in the liver, by alcohol dehydrogenase to formaldehyde. Thereafter, formaldehyde is converted by the enzyme aldehyde dehydrogenase to formic acid, which is primarily responsible for the toxicity in methanol poisoning (Fig. 32A-1). This toxicity results from a combination of metabolic acidosis (H+ production) and an intrinsic toxicity of the anion formate.7 The metabolism and hence elimination of formate depends on the folate pool in the liver.8 Primates have a small

Ethanol Ethylene glycol

Methanol Fomepizole ethanol

Alcohol dehydrogenase

Formaldehyde Aldehyde dehydrogenase

Glycol aldehyde Acetaldehyde

Formic acid + Folinic acid Folic acid

Aldehyde dehydrogenase Organic acids (glycolic acid)

CO2+H2O

FIGURE 32A-1 The metabolic pathways of methanol, ethylene glycol, and ethanol.

605

606


folate reserve and are the only species that accumulate formate and thus suffer from methanol toxicity.9,10 Other animals only develop acidosis and methanol toxicity if they are made folate deficient.11 In our latest study,12 the renal elimination of formate was unexpectedly high in nonacidotic patients. Based on experimental studies demonstrating that this renal elimination depends on pH, we have postulated that increasing acidosis may, by this mechanism, also contribute to the ensuing metabolic acidosis. Thus, metabolic acidosis may itself be a trigger for increasing accumulation of formate. If correct, this adds further importance to the correction of metabolic acidosis in these patients. The elimination of methanol is usually of zero order because of saturation of alcohol dehydrogenase. Data on this elimination are limited, but elimination rates of 2.7 mmol/L/hr (8.5 mg/dL/hr)13 and 6.3 mmol/L/hr (20 mg/dL/hr)12 have been reported. If ethanol metabolism is inhibited by antidote (ethanol or fomepizole) administration, methanol elimination is of first order with a half-life of 22 to 87 hours.12 For unknown reasons, this half-life seems to increase with increasing serum methanol concentrations.12,14 In the early stage of methanol poisoning, the toxic effects are due to the increasing metabolic acidosis caused by the production of formic acid. At this stage, there is a good correlation between the degree of metabolic acidosis reflected by the base deficit or the increase in anion gap, and the formate concentration.15 In late stages, as formate accumulates, the toxicity is mainly caused by acidosis and the histotoxic effects of formate, which inhibits mitochondrial respiration.16 The resulting lactate production increases acidosis and thereby

toxicity of formate, as more formate is protonated and thereby able to penetrate the blood-brain barrier.11 Thus, a vicious hypoxic circle is initiated.17 In this late stage, the metabolic acidosis reflected by the increased anion gap usually is a combined formate and lactate acidosis.18 Why the eye is the primary target organ for methanol’s toxic effects is unknown.19,20 In the late stages, specific lesions of the basal ganglia may develop.9,21 It is not known why this structure is particularly vulnerable in late stages of methanol toxicity. Although the mechanism of these lesions is not known, it is reasonable to believe that the histotoxic effect of formate in late stages, causing a socalled hypoxic circle, is a contributing factor (Fig. 32A-2). Formate inhibits the enzyme cytochrome oxidase in the mitochondrial electron transport chain by binding to the ferric iron in the heme moiety of that enzyme. This inhibition occurs in the 5- to 30-millimolar range,16 which correlates with formate concentrations found in symptomatic patients17,18 and other primates.22,23 This inhibition of mitochondrial energy metabolism increases the production of reactive oxidative molecules and thus the likelihood of oxidative injury.24 Formate also causes depletion of glutathione, which is the major endogenous molecule protecting against oxidative stress in the retina.25 Because the retina is exposed to several sources of oxidative stress by virtue of its high intrinsic metabolic rate and its exposure to ambient radiation, retinal glutathione concentrations are relatively high compared with other organs.26 Glutathione synthesis depends on mitochondrial respiration.27 Experimental studies indicate that cones may be more sensitive than rods to long-term damage from methanol poisoning, possibly because of their greater number of mitochondria.25

Early stage of poisoning

Late stage of poisoning

Inhibition of mitochondrial respiration

Methanol

Increased formate toxicity Formaldehyde Circulatory failure

Ocular toxity

Tissue hypoxia

Circulus hypoxicus

Formic acid Acidosis Acidosis

Lactate production General toxity

FIGURE 32A-2 Circulus hypoxicus; a proposed description of the toxic effects of methanol in humans. (Modified from Jacobsen D, McMartin KE: Methanol and ethylene glycol poisonings. Mechanism of toxicity, clinical course, diagnosis and treatment. Med Toxicol 1986;1[5]: 309–334.)

CHAPTER 32


CLINICAL MANIFESTATIONS OF METHANOL INTOXICATION Symptoms of methanol poisoning may be delayed for 12 to 24 hours, or even longer if ethanol is also ingested before, concomitantly, or just after methanol consumption. This characteristic latent period is thought to result from the slow metabolism of methanol to the principal toxic product, formic acid. In contrast to ethanol (or ethylene glycol), methanol does not cause significant central nervous system (CNS) depression and ethanol-like inebriation. Early clinical features are nausea, vomiting, and abdominal pain, but these are also seen in later stages.28 A few cases may also present as acute abdomen, probably because of pancreatitis.9,29 Clinical features of systemic toxicity are usually anorexia, headache, nausea, accompanied or followed by increasing hyperventilation as metabolic acidosis progresses.9,28 The first complaint may often be shortness of breath because of hyperventilation. Some patients may also have chest pain and may therefore be admitted acutely with the diagnosis of acute myocardial infarction. Visual symptoms (of all kinds, such as blind spots, blurred vision, or “snow fields”) may appear first, or with the symptoms above. Usually ocular symptoms precede objective signs, such as dilated pupils that are partially reactive or nonreactive to light and fundoscopy showing optic disc hyperemia with blurring of the margins (pseudopapillitis).7 If treatment is not initiated at this early stage of poisoning, the patient may develop coma and respiratory and circulatory failure. Respiratory arrest is a dramatic complication associated with a mortality rate of 75%.28 The toxic effect on the basal ganglia may not be evident in the acute stage because it is concealed by pronounced CNS depression. Survivors may later manifest a parkinsonian-like syndrome.7,9,21

DIAGNOSIS In the absence of an exposure history, methanol poisoning is difficult to diagnose, especially if ethanol is co-ingested and the latency period is prolonged. Therefore, methanol poisoning should be considered in every patient presenting with a metabolic acidosis of unknown origin.18 Methanol is usually determined by gas chromatography or radioimmunoassay techniques. Formate analyses are usually not available in the clinical setting, but a recent simple enzymatic method has proven to be both sensitive and specific and may therefore replace the need for more complicated gas chromatography.30 Laboratory evaluation of suspected methanol poisoning should always include arterial blood gas analysis in addition to standard blood samples. If ethylene glycol poisoning is considered a differential diagnosis, urinalysis including microscopy should be performed in search of crystalluria (see Chapter 32B). The presence of crystals may suggest ethylene glycol, although their absence has no diagnostic value. The standard physical examination should focus on vital signs (especially respiratory rate). Visual acuity and

607

fundoscopy examinations should be performed. The objective signs of ocular toxicity of methanol include dilated pupils, which are partially reactive or nonreactive to light, and optic disc hyperemia with blurring of the disc margins (pseudopapillitis). The blurring of the disc margin may look like papillary edema, but there is no diopter difference between the fundus and the disc. Several days after the acute stage, this hyperemia turns into pallor, which is usually associated with blindness. A computed tomography scan or magnetic resonance scan of the brain may show necrosis of the putamenal areas, a finding seen late in the course of methanol poisoning.9,21 If the patient presents with a metabolic acidosis of unknown origin, especially if diabetic ketoacidosis and renal failure are ruled out, the anion and osmolal gaps should be calculated as a clue to the diagnosis. The accumulation of formate causes a metabolic acidosis with an increased anion gap.18 The “normal” range for the anion gap ([Na+ + K+] – [Cl– + HCO3-]) in unselected acutely hospitalized patients is 12 ± 8 mmol/L (mean ± 2 SD; reference range is then 4 to 20 mmol/L).31 In concentrations associated with toxicity, methanol also increases the serum osmolality, as do other alcohols. This effect can be demonstrated by calculating the difference between the measured osmolality (Om) and the calculated osmolality (Oc): Osmolal gap (OG) = Oc – Om

The calculated osmolality is determined as follows: 1.86 × Νa + glucose + urea 0.93

where all concentrations are in mmol/L. To convert from SI units, divide glucose (mg/dL) by 18 and urea (BUN in mg/dL) by 2.8. Correct for co-ingested ethanol (mg/dL/4.6). The reference range for the osmolal gap in unselected acutely admitted patients is 5 ± 14 mOsm/kg H2O (mean ± 2 SD).31 An osmolal gap above 19 (5 ± 2 SD) therefore indicates exogenous osmoles of some kind. Although the value of the osmolal gap has been questioned in recent years,32 as demonstrated by us in a recent epidemic, a decision level or cutoff value for the osmolal gap of 25 mOsm/kg H2O works very well.18 Osmometry must be performed by the freezing point depression technique and not by the vapor pressure technique, because the latter does not detect the increased osmolality caused by volatile alcohols. The osmolal contribution from methanol and other alcohols is shown in Table 32A-1. The relationships between the osmolal gap and methanol and between the anion gap and formate are presented in Figures 32A-3 and 32A-4. Note the good correlation for the patients studied. In the two patients with the highest anion gap (see Fig. 32A-4), there was a significant accumulation of lactate. Therefore, the increase of the anion gaps is slightly higher than the respective serum formate levels. It must be noted that the magnitude of the increase in the osmolal and anion gap in methanol poisoning varies with time since ingestion, as illustrated in Figure 32A-5. In early stages, or if ethanol is co-ingested, only the osmolal gap is elevated, because the metabolism of methanol to

608


45

TABLE 32A-1 Molecular Mass of Alcohols and Their Contribution to the Osmolal Gap MOLECULAR WEIGHT (DALTONS)

ALCOHOL Dietylene glycol Ethanol Ethylene glycol Isopropyl alcohol Isobutyl alcohol Methanol Propylene glycol

40 35

ANION GAP ELEVATED

106

9

46 62

22 16

– +

60

17

–

74

14

–

32 76

34 13

+ –

Anion gap (mmol/L)

OSMOLAL CONTRIBUTION (mOsm/kg H2O) per 100 mg/dL (*)

(+)

25 20 15

10 5

*A methanol concentration of 32 mmol/L (100 mg/dL) increases the osmolal gap by 32/0.93 = 34 mOsm/kg H2O. Divide by 0.93 because serum consists of 93% water.

y=1.12x+13.82 R2=0.86

0 0

10

20

30

S-formate (mmol/L) FIGURE 32A-4 S-formate versus anion gap in eight methanol poisoned patients. Equation of correlation: y = 1.12x + 13.82, R2 = 0.86. (From Hovda KE, Hunderi OH, Rudberg N, et al: Anion and osmolal gaps in the diagnosis of methanol poisoning: clinical study in 28 patients. Intensive Care Med 2004;30[9]:1842–1846.)

180 160 140 120

80

Anion gap Osmolal gap S-methanol S-formate

100 70 80 60 40 20

y=1.03x+12.71 R2=0.94

0 0

20

40

60

80

100

120

140

160

180

S-methanol (mmol/L)

Result of analyzes (mmol/L or mOsm/kgH2O)

Osmolal gap (mOsm/kgH2O)

30

60 50 40 30

20

FIGURE 32A-3 S-methanol versus osmolal gap in 28 methanolpoisoned patients. Equation of correlation: y = 1.03x + 12.71, R2 = 0.94. (From Hovda KE, Hunderi OH, Rudberg N, et al: Anion and osmolal gaps in the diagnosis of methanol poisoning: clinical study in 28 patients. Intensive Care Med 2004;30[9]:1842–1846.)

5

0

Early

formate has not yet begun. In late stages of methanol poisoning, most of the methanol is metabolized to formate. At this stage the anion gap is elevated but the osmolal gap may be normal; formate detection may then be the only way to confirm the diagnosis.30 If the diagnosis is based on the osmolal and anion gaps, it must be noted that elevated gaps also occur in ethylene glycol intoxication. Differentiating the two may be difficult, but the treatment is essentially the same. Hypocalcemia, seizures, and urine oxalate crystals indicate ethylene glycol poisoning; visual symptoms and/or optic

Intermediate

Late

Time after intake FIGURE 32A-5 Changes in osmolal and anion gaps with time in methanol poisoning. (From Hovda KE, Hunderi OH, Rudberg N, et al: Anion and osmolal gaps in the diagnosis of methanol poisoning: clinical study in 28 patients. Intensive Care Med 2004;30[9]:1842–1846.)

disc hyperemia indicate methanol poisoning.20 Differential diagnoses when both the gaps are elevated are few (Table 32A-2). A proposed algorithm for diagnosis and triage in suspected methanol poisoning is given in Figure 32A-6.

CHAPTER 32


TREATMENT OF METHANOL INTOXICATION General treatment measures include intensive supportive care and gastric decontamination. If the patient is seen soon (within 1 hour) after ingestion, which is rarely the case, gastric aspiration is recommended. Activated charcoal is probably of limited value because of limited binding. Specific treatment of methanol poisoning includes intravenous (IV) sodium bicarbonate to combat the metabolic acidosis, antidotal therapy with ethanol or fomepizole to inhibit methanol metabolism to formate, and hemodialysis to remove methanol and formate and correct the metabolic acidosis. Folinic acid, 1 mg/kg IV up to 50 mg every 4 hours, may be of value in increasing the metabolism of formate.33 If folinic acid is unavailable, folic acid, in the same dose, can be used. Metabolic acidosis should be immediately and aggressively treated by infusing sodium bicarbonate,

TABLE 32A-2 Differential Diagnoses with Elevated Osmolal (>25) and/or Anion Gap (>20) DIAGNOSIS

INCREASED OSMOLAL GAP

Methanol Ethylene glycol Isopropanol Ethanol Other alcohols Lactic acids Ketoacidosis Acidosis in alcoholics Renal failure Shock following trauma

Yes Yes Yes Yes Yes No Minimally Minimally No Minimally

INCREASED ANION GAP Yes Yes No No Rarely Yes Yes Yes Yes Yes

609

aiming for a full correction of acidosis.3 As much as 400 to 600 mEq may be required during the first few hours. It is important to realize that bicarbonate treatment also decreases the amount of undissociated formic acid, resulting in less access of formate to the CNS, and thereby less toxicity.11,12,20 Hence, metabolic acidosis resulting from methanol poisoning, in contrast to most other causes of metabolic acidosis, should always be treated with bicarbonate. Alkali treatment must be accompanied by administration of fomepizole or ethanol; otherwise, the acidosis becomes so-called bicarbonate resistant, because more formic acid will be produced from the metabolism of methanol. If a methanol level cannot readily be obtained and anion and osmolal gaps are difficult to interpret, ethanol or fomepizole therapy should be started in any patient with acidosis, symptoms, or a history of a potentially toxic alcohol ingestion. Antidotal treatment can be discontinued when the methanol level drops below about 6 mmol/L (20 mg/dL), provided that the acidbase status is normal and there are no complications. The recommended therapeutic blood ethanol level is about 22 mmol/L (100 mg/dL). However, the amount of ethanol necessary to block methanol metabolism depends on the concomitant methanol level, because there is a dynamic competition for the enzyme alcohol dehydrogenase in the liver. If the blood methanol level is known, the molar ethanol concentrations should be at least one fourth of the molar methanol concentration.7 A blood ethanol level of 100 mg/dL may be achieved by giving a bolus dose of 600 mg/kg, followed by 66 to 154 mg/kg/hr IV or orally, with the higher maintenance dose for heavy drinkers. Mixing 50 mL of absolute ethanol with 450 mL isotonic glucose yields a 10% solution if a 10% ethanol solution for IV use is unavailable. With this solution, a bolus of 8 mL/kg (over 0.5 hour), followed by 1.5 mL/kg/hr, will produce the desired ethanol

Suspected methanol poisoning

AG25

AG>20 OG>25

AG>20 OG 0.05 resulting in a pH outside the normal range despite bicarbonate infusion Inability to maintain arterial pH > 7.3 despite bicarbonate therapy Decrease in bicarbonate concentration > 5 mmol/L despite bicarbonate therapy Rise in serum creatinine by > 90 mmol/L Recently released: Initial plasma ethylene glycol concentration ≥ 50 mg/dL Data from references 23 and 61.

620


19, 46%), had a plasma glycolate concentration on admission of greater than 98 mg/dL. Renal elimination and hemodialysis are the only significant routes of ethylene glycol elimination, as long as fomepizole concentrations are maintained well above 10 μmol/L.49 Hemodialysis effectively clears glycolate, with an elimination rate of 170 ± 23 mmol/L/min and a halftime of 155 ± 474 minutes, compared with the spontaneous elimination rate of 1.8 ± 0.67 mL/L/min and half-time of 625 ± 474 min.16 In a retrospective study, Borron and colleagues demonstrated the lack of requirement of systematic dialysis in the management of ethylene glycol poisoning treated with fomepizole.41 Among 38 patients treated for suspicion of ethylene glycol exposure, 11 patients had ethylene glycol concentrations of greater than 0.2 g/L. Among these, 21% presented in coma, 34% in metabolic acidosis, and 11% with an initial plasma creatinine of greater than 110 μmol/L (1.2 mg/dL). Hemodialysis was performed in only 3 of these 11 patients, 2 with renal insufficiency and acidosis and 1 with a very high ethylene glycol concentration (134 mmol/L, or 837.5 mg/dL), but with normal renal function. Among the 7 patients with normal renal function treated with fomepizole, no subsequent deterioration was noted. Among all the 38 patients, only 1 died within a few hours after his admission, with severe multiorgan failure, whose onset started before fomepizole administration. Patients who were dialyzed were significantly more acidotic (arterial pH 7.11 vs. 7.31) than those who were not. Patients treated with fomepizole prior to the onset of significant acidosis did not require hemodialysis. Since this study, new insights have been developed with regard to hemodialysis criteria. An absolute concentration above 0.5 g/dL is no longer considered to be an independent criterion for hemodialysis in patients treated with fomepizole.49 The use of hemodialysis should be based on the presence of renal insufficiency or severe metabolic acidosis rather than unsupported criteria of serum concentrations greater than 0.5 g/L alone.62 The recommended criteria are now the existence of a significant metabolic acidosis (pH < 7.25), renal failure, or electrolyte imbalances unresponsive to conventional therapy and deteriorating vital signs despite intensive supportive care.23 Before fomepizole availability, repeated hemodialysis had been recommended in case of redistribution of ethylene glycol within 12 hours after its cessation.63 Initial serum glycolic acid concentration appears to be a good indicator for hemodialysis. However, it is not readily available in the majority of hospitals. An initial glycolic acid level higher than 10 mmol/L predicts acute renal failure, with a sensitivity of 100%, a specificity of 94%, and an efficiency of 98%.64 In a retrospective study including 41 ethylene glycol–poisoned patients, these researchers demonstrated that a glycolic acid concentration higher than 8 mmol/L is a criterion for the initiation of hemodialysis. On the contrary, ethylene glycol concentration was not predictive of acute renal failure or central nervous system toxicity, while an anion gap of greater than 20 mmol/L or pH of less than 7.30 predicts acute renal failure. There was no need to dialyze, regardless of ethylene glycol level, if the glycolic

acid level was less than or equal to 8 mmol/L in patients receiving antidotal treatment.64

CRITICAL ANALYSIS OF ETHYLENE GLYCOL TREATMENT Although ethanol and hemodialysis constituted the recommended therapy for many years, it is unlikely that applying principles of evidence-based medicine would justify such recommendations now, given the significant experience with fomepizole and dialysis.62 While it would have been desirable in the U.S. prospective trial10 to have a comparison group with the standard of practice (ethanol plus hemodialysis), this was not done for a variety of reasons. Nonetheless, until demonstration that ethanol therapy results in equivalent efficacy and outcomes, it is difficult not to recommend fomepizole. To date, there has been no randomized comparative study regarding efficacy and cost effectiveness among hemodialysis + ethanol versus hemodialysis + fomepizole or fomepizole alone. There are frequent references to the minimal cost of parenteral ethanol in comparison with the relatively high cost of fomepizole. Such comparisons generally ignore the critical issue of laboratory costs for monitoring serum ethanol and blood glucose, the increased nursing care required for patients maintained in a state of ethanol intoxication, and the requirement for intensive care (which may not be necessary in patients receiving fomepizole in the absence of extant toxicity). Considering the high cost of fomepizole (about $1000 per gram), smaller hospital centers that only occasionally see ethylene glycol poisoning might prefer to continue to stock inexpensive and readily available parenteral ethanol rather than fomepizole.65 However, it should be kept in mind that the suggested shelf life of fomepizole is 3 years and that, in some cases, the manufacturer will replace it at no charge after this period, rendering it economical even for smaller emergency departments to have this antidote in their armamentarium. Why is it worthwhile to confirm that fomepizole may obviate hemodialysis under certain conditions? First, there is a significant downside to the use of hemodialysis: it is not universally available, rendering it difficult to obtain in case of epidemic poisonings. It represents an invasive technique with risks of adverse effects, such as hemorrhage, catheter infections, and metabolic disorders (hypophosphatemia). Moreover, hemodialysis of poisoned patients often requires hospitalization in an ICU. If significant toxicity and hemodialysis can be avoided by the early administration of fomepizole, ICU admissions may be limited to a relatively brief (24-hour) period of observation (Fig. 32B-3). There are also advantages to the use of fomepizole in comparison with ethanol: fomepizole is a more potent ADH inhibitor (and not a substrate), with a wider therapeutic index, a longer duration of action, easier dosing, and more predictable kinetics. There is no need for blood fomepizole concentration monitoring, treatments are well tolerated, and there are no similar data to prove ethanol efficacy. Use of ethanol, in our estimation, should now be limited to settings where fomepizole is

CHAPTER 32


621

Admission to emergency room or intensive care unit (ICU) with suspicion of toxic alcohol poisoning

Loading dose of fomepizole

Yes

Evidence of toxic metabolism: metabolic acidosis, blurred vision (methanol), renal insufficiency or oxalate crystalluria (ethylene glycol)

No

Monitor renal function, acid/base balance, and serum EG and methanol concentrations

Indications for dialysis? (See indications in Box 32B-2)

Yes

Presence of EG or methanol

Yes

No

No

Stop fomepizole

Dialyze Continue fomepizole until serum EG or methanol concentrations become negligible +Consider transfer to general medical ward Increase dosage of fomepizole during dialysis FIGURE 32B-3 Proposed algorithm for treatment of ethylene glycol– and methanol-poisoned patients. This algorithm is based on series and case reports and has not been validated prospectively. (Adapted from Megarbane B, Borron SW, Baud FJ: Current recommendations for treatment of severe toxic alcohol poisonings. Intensive Care Med 2005;31:189–195.)

unavailable or in patients for whom fomepizole is contraindicated. Given its safety, especially in patients who may subsequently be found not to be poisoned with toxic alcohols, fomepizole is of value in emergency medicine because it permits a margin of diagnostic error. In selected exposed patients, fomepizole may obviate the need for hemodialysis. However, the risks and benefits of fomepizole must be weighed against those of hemodialysis. Accelerated blood clearance by an adequate single hemodialysis session provides for a shorter hospital stay and fewer required doses of ADH inhibitors.66 REFERENCES 1. Watson WA, Litovitz TL, Klein-Schwartz W, et al: 2003 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2004;22:325–404. 2. Wills JH, Coulston F, Harris ES, et al: Inhalation of aerosolized ethylene glycol by man. Clin Toxicol 1974;7:463–476. 3. Troisi FM: Chronic intoxication with ethylene glycol vapour. Br J Ind Med 1950;1:65. 4. Johnson B, Meggs WJ, Bentzel CJ: Emergency department hemodialysis in a case of severe ethylene glycol poisoning. Ann Emerg Med 1999;33:108–110. 5. Mundy RL, Hall LM, Teague RS: Pyrazole as an antidote for ethylene glycol poisoning. Toxicol Appl Pharmacol 1974; 28:320–322. 6. Gessner PK, Parke DV, Williams RT: Studies in detoxication. 86. The metabolism of 14C-labelled ethylene glycol. Biochem J 1961;79:482–489.

7. Jacobsen D, McMartin KE: Antidotes for methanol and ethylene glycol poisoning. J Toxicol Clin Toxicol 1997;35:127–143. 8. Cheng JT, Beysolow TD, Kaul B, et al: Clearance of ethylene glycol by kidneys and hemodialysis. J Toxicol Clin Toxicol 1987; 25:95–108. 9. Weiss B, Coen G: Effect of ethanol on ethylene glycol oxidation by mammalian liver enzymes. Enzymol Biol Clin (Basel) 1966; 6:297–304. 10. Brent J, McMartin K, Phillips S, et al: Fomepizole for the treatment of ethylene glycol poisoning. Methylpyrazole for Toxic Alcohols Study Group. N Engl J Med 1999;340:832–838. 11. Jacobsen D, Hewlett TP, Webb R, Brown ST: Ethylene glycol intoxication: evaluation of kinetics and crystalluria. Am J Med 1988;84:145–151. 12. Peterson CD, Collins AJ, Himes JM, Keane WF: Ethylene glycol poisoning: pharmacokinetics during therapy with ethanol and hemodialysis. N Engl J Med 1981;304:21–23. 13. Hoffman RS, Smilkstein MJ, Howland MA, Goldfrank LR: Osmol gaps revisited: normal values and limitations. Clin Toxicol 1993;31:81–93. 14. Clay KL, Murphy RC: On the metabolic acidosis of ethylene glycol intoxication. Toxicol Appl Pharmacol 1977;39:39–49. 15. Jacobsen D, Ovrebo S, Ostborg J, Sejersted OM: Glycolate causes the acidosis in ethylene glycol poisoning and is effectively removed by hemodialysis. Acta Med Scand 1984;216:409–416. 16. Moreau CL, Kerns W II, Tomaszewski CA, et al: Glycolate kinetics and hemodialysis in ethylene glycol poisoining. J Toxicol Clin Toxicol 1998;36:659–666. 17. Berman LB, Schreiner GE, Feys J: The nephrotoxic lesion of ethylene glycol. Ann Intern Med 1957;46:611–619. 18. Pons CA, Custer RP: Acute ethylene glycol poisoning: a clinicopathologic report of eighteen fatal cases. Am J Med Sci 1946;211:544.

622


19. Bove KE: Ethylene glycol toxicity. Am J Clin Pathol 1966;45:46–50. 20. Munro KMH, Adams JH: Acute ethylene glycol poisoning: report of a fatal case. Med Sci Law 1967;7:181–184. 21. Mair W: Cerebral computed tomography of ethylene glycol intoxication. Neuroradiology 1983;24:175–177. 22. Milles G: Ethylene glycol poisoning with suggestions for its treatment as oxalate poisoning. Arch Pathol 1946;41:631–638. 23. Barceloux DG, Krenzelok EO, Olson K, Watson W: American Academy of Clinical Toxicology practice guidelines on the treatment of ethylene glycol poisoning. J Toxicol Clin Toxicol 1999;37:537–560. 24. Hylander B, Kjellstrand CM: Prognostic factors and treatment of severe ethylene glycol intoxication. Intensive Care Med 1996;22: 546–552. 25. Kahn HS, Brotchner RJ: A recovery from ethylene glycol (antifreeze) intoxication: a case of survival and two fatalities from ethylene glycol including autopsy findings. Ann Intern Med 1950;32:284–294. 26. Davies D, Bramwell KJ, Hamilton RS, Williams SR: Ethylene glycol poisoning: case report of a record-high level and a review. J Emerg Med 1997;15:653–667. 27. Berger JR, Ayyar DR: Neurological complications of ethylene glycol intoxication. Report of a case. Arch Neurol 1981;38:724–726. 28. Spillane L, Roberts JR, Meyer AE: Multiple cranial nerve deficits after ethylene glycol poisoning. Ann Emerg Med 1991;20:208–210. 29. Blakeley KR, Rinner SE, Knochel JP: Survival of ethylene glycol poisoning with profound acidemia. N Engl J Med 1993;328:515–516. 30. Steinke W, Arendt G, Mull M, et al: Good recovery after sublethal ethylene glycol intoxication: serial EEG and CT findings. J Neurol 1989;236:170–173. 31. Eder AF, McGrath CM, Dowdy YG, et al: Ethylene glycol poisoning: toxicokinetic and analytical factors affecting laboratory diagnosis. Clin Chem 1998;44:168–177. 32. Morgan TJ, Clark C, Clague A: Artifactual elevation of measured plasma 1-lactate concentration in the presence of glycolate. Crit Care Med 1999;27:2177–2179. 33. Porter WH, Crellin M, Rutter PW, Oeltgen P: Interference by glycolic acid in the Beckman Synchron Method for lactate: a useful clue for unsuspected ethylene glycol intoxication. Clin Chem 2000;46:874–875. 34. Steinhart B: Case report: severe ethylene glycol intoxication with normal osmolal gap—“a chilling thought.” J Emerg Med 1990;8:583. 35. Hewlett TP, McMartin RE: Ethylene glycol intoxication: the value of glycolic acid determination for diagnosis and treatment. Clin Toxicol 1986;24:389. 36. Heckerling PS: Ethylene glycol poisoning with a normal anion gap due to occult bromide intoxication. Ann Emerg Med 1987; 16:1384. 37. Bjellerup P, Kallner A, Kollind M: GLC determination of serumethylene glycol, interferences in ketotic patients. J Toxicol Clin Toxicol 1994;32:85–87. 38. Standefer J, Blackwell W: Enzymatic method for measuring ethylene glycol with a centrifugal analyzer. Clin Chem 1991;37:1734–1736. 39. Baud FJ, Galliot M, Astier A, et al: Treatment of ethylene glycol poisoning with intravenous 4-methylpyrazole. N Engl J Med 1988;319:97–100. 40. Baud FJ, Bismuth C, Garnier R, et al: J Toxicol Clin Toxicol 1986;24:463–483. 41. Borron SW, Mégarbane B, Baud FJ: Fomepizole in treatment of uncomplicated ethylene glycol poisoning. Lancet 1999;354:831. 42. McMartin KE, Hedström KG, Tolf BR, et al: Studies on the metabolic interactions between 4-methylpyrazole and methanol using the monkey as an animal model. Arch Biochem Biophys 1980;199:606–614. 43. Jacobsen D, Barron SK, Sebastian CS, et al: Non-linear kinetics of 4-methylpyrazole in healthy human subjects. Eur J Clin Pharmacol 1989;37:599–604.

44. Li TK, Theorell H: Human liver alcohol dehydrogenase: inhibition by pyrazole and pyrazole analogs. Acta Chem Scand 1969;23:892–902. 45. Jacobsen D, Sebastian CS, Dies DF, et al: Kinetic interactions between 4-methylpyrazole and ethanol in healthy humans. Alcohol Clin Exp Res 1996;20:804–809. 46. Tournaud C, Kopferschmidt J, Sauder P, et al: Ethylene glycol poisoning treated with 4-methylpyrazole [abstract]. Presented at the 15th Congress of the EAPCCT, Istanbul, 1992. 47. Faissel H, Houze P, Baud FJ, Scherrmann JM: 4-methylpyrazole monitoring during hemodialysis of ethylene glycol intoxicated patients. Eur J Clin Pharmacol 1995;49:211–213. 48. Jobard E, Harry P, Turcant A, et al: 4-methylpyrazole and hemodialysis in ethylene glycol poisoning. J Toxicol Clin Toxicol 1996;34:379–381. 49. Sivilotti MLA, Burns MJ, McMartin KE, Brent J: Toxicokinetics of ethylene glycol during fomepizole therapy: implications for management. Ann Emerg Med 2000;36:114–125. 50. Jacobsen D, Sebastian CS, Barron SK, et al: Effects of 4methylpyrazole, methanol/ethylene glycol antidote, in healthy humans. J Emerg Med 1990;8:455–461. 51. Blomstrand R, Ellin A, Lôf A, Ostling-Wintzell H: Biological effects and metabolic interactions after chronic and acute administration of 4-methylpyrazole and ethanol to rats. Arch Biochem Biophys 1980;199:591–605. 52. Harry P, Jobard E, Briand M, et al: Ethylene glycol poisoning in a child treated with 4-methylpyrazole. Pediatrics 1998;102:31–33. 53. Baum CR, Langman CB, Oker EE, et al: Fomepizole treatment of ethylene glycol poisoning in an infant. Pediatrics 2000; 106:1489–1491. 54. Martin Caravati E, Heileson HL, Jones M: Treatment of severe pediatric ethylene glycol intoxication without hemodialysis. J Toxicol Clin Toxicol 2004;42:255–259. 55. Benitez JG, Swanson-Biearman B, Krenzelok EP: Nystagmus secondary to fomepizole administration in a pediatric patient. J Toxicol Clin Toxicol 2000;38:795–798. 56. Pietruszko R, Voigtlander K, Lester D: Alcohol dehydrogenase from human and horse liver: substrate specificity with diols. Biochem Pharmacol 1978;27:1296. 57. Peterson CD, Collins A, Himes JM, et al: Ethylene glycol poisoning. Pharmacokinetics during therapy with ethanol and hemodialysis. N Engl J Med 1981;304:21. 58. Roy M, Bailey B, Chalut D, et al: What are the adverse effects of ethanol used as an antidote in the treatment of suspected methanol poisoning in children? J Toxicol Clin Toxicol 2003;41:155–161. 59. Hirsch DJ, Jindal KK, Wong P, Fraser AD: A simple method to estimate the required dialysis time for cases of alcohol poisoning. Kidney Int 2001;60:2021–2024. 60. Youssef GM, Hirsch DJ: Validation of a method to predict required dialysis time for cases of methanol and ethylene glycol poisoning. Am J Kidney Dis 2005;46:509–511. 61. Ellenhorn MJ: Alcohols and glycols. In Ellenhorn MJ, Schonwald S, Ordog G, Wasserberger J (eds): Ellenhorn’s Medical Toxicology: Diagnosis and Treatment of Human Poisoning, 2nd ed. Baltimore, Williams & Wilkins, 1997, pp 1127–1166. 62. Watson WA: Ethylene glycol toxicity: closing in on rational, evidence-based treatment. Ann Emerg Med 2000;36:114–125. 63. Gabow PA, Clay K, Sullivan JB, Lepoff R: Organic acids in ethylene glycol intoxication. Ann Intern Med 1986;105:16–20. 64. Porter WH, Rutter PW, Bush BA, et al: Ethylene glycol toxicity: the role of serum glycolic acid in hemodialysis. J Toxicol Clin Toxicol 2001;39:607–615. 65. Goldfarb DS: Fomepizole for ethylene glycol poisoning. Lancet 1999;354:1646. 66. Vasavada N, Williams C, Hellman RN: Ethylene glycol intoxication: case report and pharmacokinetic perspectives. Pharmacotherapy 2003;23:1652–1658.

CHAPTER 32

C


Other Toxic Alcohols MARCO L. SIVILOTTI, MD, MSc

At a Glance… ■ ■ ■

■ ■

623

These alcohols range considerably in their degree of toxicity. Multiple routes of exposure are possible, which in turn affect the degree of toxicity. Poisoning with certain alcohols may produce early central nervous system depression and elevation of serum osmolality followed by a delayed-onset metabolic acidosis and renal failure. Fomepizole or ethanol are potential antidotes in selected cases. Isopropanol poisoning results in ketosis (acetonemia and acetonuria) without significant metabolic acidosis, and can almost always be managed supportively in a manner analogous to ethanol intoxication.

Although ethanol, methanol, and ethylene glycol account for the vast majority of toxicity from alcohols encountered in clinical practice, other members of this chemical class can also be harmful to human health. An alcohol is any compound with a hydroxyl (-OH) group attached to a carbon chain. The chemical structures of commonly encountered alcohols are shown in Table 32C-1. Since their toxicities vary considerably, they will be discussed individually.

ISOPROPANOL Isopropanol (2-propanol, isopropyl alcohol) is widely used as a solvent, rubefacient, and sterilizing agent and is found in many skin lotions, mouthwashes, rubbing alcohols, and cleaning fluids. Being readily available and less expensive than ethanol, it is often abused as an ethanol substitute. The IDLH (immediate danger to life and health) workplace standard according to the

National Institute of Occupational Safety and Health is 2000 ppm. Isopropanol is rapidly absorbed after oral ingestion into a volume of distribution of 0.7 L/kg. Peak serum concentrations occur from 30 to 120 minutes after ingestion, whereas peak concentrations of its metabolite, acetone, do not occur until 4 hours after ingestion.1 Inhalation and dermal application can also result in substantial absorption and subsequent toxicity.2-5 Isopropanol is metabolized primarily by alcohol dehydrogenase (ADH) in the liver (80%). A smaller fraction is eliminated unchanged by the kidneys. The serum elimination half-life is 2.5 to 16.2 hours, and increases substantially when ethanol or fomepizole are also present.6-12 Because isopropanol is a secondary alcohol (the hydroxyl group is attached to a carbon atom bonded to two other carbon atoms), oxidation yields a ketone (acetone), which cannot be further oxidized to an organic acid.13 Acetone is slowly eliminated by the lungs and kidneys with a half-life ranging from 7.6 to 26 hours.7,14,15 As a result, the biochemical hallmark of isopropanol metabolism is the presence of a substantial ketonemia and ketonuria without acidemia. Clinically, isopropanol ingestion resembles acute ethanol poisoning. Central nervous system (CNS) depression develops rapidly, and has generally reached its nadir within a few hours of the ingestion. Animal data suggest that the CNS depressant effects of isopropanol are two to three times more potent than ethanol, whereas its metabolite, acetone, has CNS depressant effects equivalent to ethanol.16 CNS depression can range from mild lethargy with slurred speech and ataxia to deep coma with areflexia. The fruity breath odor of ketones may be appreciated on physical examination. Other clinical findings include hemorrhagic gastritis, vomiting, abdominal pain, hemorrhagic tracheobron-

TABLE 32C-1 Chemical Structure and Molecular Weight of Selected Alcohols CHEMICAL STRUCTURE Methanol Ethanol Isopropanol Benzyl alcohol Ethylene glycol Propylene glycol Polyethylene glycols Diethylene glycol Triethylene glycol PEG-400 PEG-3350 Ethylene glycol ethers (cellosolves) Ethylene glycol monomethyl ether Ethylene glycol monoethyl ether Ethylene glycol monobutyl ether

CH3OH CH3–CH2OH CH3–CHOH–CH3 (C6H5)–CH2OH CH2OH–CH2OH CH2OH–CHOH–CH3 CH2OH–CH2–O–(CH2–CH2–O)nH n=1 n=2 n = 8–9 n = 68–84 CH3–(CH2)n–O–CH2–CH2OH, n = 0 n=0 n=1 n=3

MOLECULAR WEIGHT (DALTONS) 32 46 60 108 62 76 106 150 ~400 ~3350 76 90 118

624


chitis, tachycardia, muscle weakness, and pulmonary aspiration. Rarely, massive ingestion results in hypotension from vasodilatation and negative cardiac inotropic effects, and respiratory arrest. The duration of CNS depression may be prolonged due to the added CNS depressant effects and slower rate of elimination of the acetone metabolite. Serum isopropanol concentrations can be measured by gas chromatography, and may be reported on an “alcohol screen” in addition to methanol and ethanol (but not necessarily ethylene glycol). Serum concentrations of at least 50 to 100 mg/dL (8 to 17 mmol/L) result in intoxication, and of at least 150 mg/dL (25 mmol/L) result in coma, although tolerance can diminish these effects. Cardiovascular depression is generally seen at concentrations above 450 mg/dL (75 mmol/L). Because treatment is largely supportive and determined by clinical findings, serum isopropanol concentrations usually add little information beyond identifying and quantifying the exposure. Small concentrations of isopropanol may be detectable in the serum of patients with alcoholic, starvation, and diabetic ketoacidosis due to acetone reduction back to isopropanol.17,18 In one study, 15% of patients with diabetic ketoacidosis had detectable serum concentrations of isopropanol, ranging as high as 30 mg/dL.17 Breath analysis for ethanol by infrared absorption may detect isopropanol as an interferent.19 Some enzymatic assays may misrepresent isopropanol as ethanol. In general, the presence or absence of an osmol gap is neither sensitive nor specific and cannot be used to rule in or out a toxic alcohol ingestion (see Chapter 3). Both isopropanol and acetone will increase serum osmolality. For each 1 mg/dL of either isopropanol (molecular weight 60 daltons) or acetone (58 daltons) in the serum, the serum osmolality will increase by about 0.17 mOsm/kg. Therefore, either isopropanol or acetone contribute approximately 10 mOsm/kg at a combined concentration of 60 mg/dL (10 mmol/L), and the osmolal gap multiplied by 6 approximates the summed serum concentrations of isopropanol and acetone in mg/dL. Thus, when history, physical examination, and initial laboratory data suggest poisoning with isopropanol and conclusive measurement of this alcohol is not immediately available, the osmolal gap can be used to quantify and follow the exposure with good sensitivity, since the metabolite, acetone, is both osmotically active and uncharged. Acetone is detectable in the serum within 30 minutes, and in the urine within 3 hours after isopropyl alcohol ingestion.1 Conversely, the absence of serum acetone effectively rules out isopropanol ingestion, unless ethanol is also present. Acetone can interfere with serum creatinine assays,20-22 and persists after isopropanol is undetectable. Other laboratory findings associated with isopropanol poisoning include rhabdomyolysis, hemolytic anemia, and renal tubular acidosis. Patient management closely parallels acute ethanol ingestion. Gastrointestinal decontamination is rarely indicated due to the delay that usually occurs between ingestion and hospital presentation. Large doses of

activated charcoal have been shown to adsorb both isopropanol and acetone in vitro.23 Administration of such large doses of activated charcoal, however, is impractical in the care of poisoned patients. Thus, in circumstances where a patient can be treated immediately after a massive ingestion, small nasogastric tube aspiration is the only decontamination necessary. Supportive care must emphasize airway protection and ensure adequate tissue oxygenation. Careful monitoring and frequent reassessment are essential. As with ethanol, the pharmacokinetics are such that peak CNS effects typically occur by the time of hospital presentation. If symptoms have not developed within 2 hours after reported ingestion, they will not develop, and patients can be cleared for discharge.24 Unlike ethanol, however, the duration of CNS depression may be prolonged. Regardless, serial observation should demonstrate an improving level of consciousness with time. Indeed, a deterioration should lead the clinician to investigate alternate causes of the depressed level of consciousness. Similarly, the presence of a metabolic acidosis demands a careful evaluation of alternate diagnoses, including alcoholic ketoacidosis (see Chapter 6) and inadequate tissue perfusion following massive ingestion. Inhibition of ADH using either fomepizole or ethanol is not indicated and would only serve to prolong toxic effects.12,13 Hemodialysis, while effective at removing both isopropanol and acetone, is not necessary for the vast majority of patients. Hemodialysis should be reserved for the rare patient with severe hemodynamic compromise despite fluid resuscitation.25,26

THE HIGHER ALCOHOLS The higher saturated aliphatic alcohols may also have some toxicity. The higher liquid alcohols are butyl, amyl, ethyl, hexyl, and so on, and the solid fatty alcohols include lauryl, myristyl, cetyl, and stearyl. The liquid alcohols are used as solvents, and the solid fatty alcohols are used in cosmetics. The term fusel alcohol is used to describe the higher-order alcohols produced by natural fermentation, and are present in beer and other alcoholic beverages at concentrations as high as 2200 ppm.27 In general, the CNS potency of an alcohol increases with increasing carbon chain length.16 The order of increasing toxicity by single oral doses is as follows: ethanol, isopropanol, n-propanol, sec-butyl, nbutyl, tert-butyl, isobutyl, and amyl alcohol. n-Butyl alcohol vapors have produced conjunctivitis and keratitis. Although skin irritation is common with the liquid alcohols, percutaneous absorption does not seem to occur. Vapor inhalation may produce pulmonary injury. The amyl alcohols are more potent, and ingestion or rectal instillation of about 30 mL has proved lethal in human adults. Glycosuria and methemoglobinemia may result from ingestion of isoamyl alcohol. The primary alcohols, such as ethanol, n-propanol, nbutyl, and isobutyl alcohol, are oxidized to aldehydes and carboxylic acids. Therefore, significant metabolic acidosis may result from their ingestion. The secondary

CHAPTER 32


alcohols, such as isopropanol and sec-butyl alcohol, are converted to ketones, which may also cause CNS depression. The tertiary alcohols such as tert-butyl alcohol are metabolized slowly and incompletely, and excreted in the urine as glucuronides. Very few cases of human toxicity have been described. In general, the major clinical effects are in the CNS, particularly with vaporizing compounds, and include headache, muscle weakness, giddiness, ataxia, confusion, delirium, and coma. If these agents are ingested, GI effects predominate and consist of vomiting and diarrhea. The odor of the alcohol may be noted. Fusel alcohols may contribute to both the flavor and side effects (“hangover”) of certain alcoholic beverages. Death from higher alcohols is mainly due to respiratory failure but may also result from cardiac arrhythmias.

BENZYL ALCOHOL Benzyl alcohol (α-hydroxytoluene) is an aromatic alcohol used as an antimicrobial preservative at concentrations ranging from 0.9% to 2.0% in many multidose medication vials and parenteral solutions. It is readily oxidized in vivo to benzoic acid, and conjugated with glycine to form hippuric acid. Neonates have reduced capacity to metabolize benzoic acid, and toxicity may result from bioaccumulation of benzyl alcohol and benzoic acid with repetitive dosing. Neonates inadvertently given 100 to 240 mg/kg/day of benzyl alcohol (mostly in bacteriostatic catheter flush solutions) developed a syndrome of CNS depression, severe metabolic acidosis, gasping respiration, thrombocytopenia, hepatorenal failure, seizures, intracranial hemorrhage, bradycardia, skin breakdown, cardiovascular collapse, and death, termed the “gasping baby syndrome.”28 The evidence for causation rests on the original case-control description, elevated concentrations of serum and urine metabolites, and the disappearance of the syndrome with the removal of bacteriostatic solutions from the nursery.28,29 A reduction in kernicterus, intracranial hemorrhage, neurologic deficit, and perhaps mortality has also been associated with elimination of benzyl alcohol solutions in neonates.30-32 The daily dose of benzyl alcohol should not exceed 5 mg/kg body weight.33 Some common parenteral medications formulated with benzyl alcohol include amiodarone, atracurium, atropine sulfate, bacteriostatic water and saline for injection, bumetanide, chlordiazepoxide, diazepam, furosemide, glycopyrrolate, heparin, hydroxyzine, metoclopramide, midazolam, lorazepam, pancuronium, physostigmine, procainamide, prochlorperazine, succinylcholine, and trimethoprim-sulfamethoxazole.

PROPYLENE GLYCOL Propylene glycol (1,2-propanediol; PG) is a clear, colorless, odorless, sweet-tasting liquid that is widely used as a solvent and antimicrobial preservative. PG is considerably less toxic than ethylene glycol,34 and thus commonly used as the main ingredient in many “ethylene

625

glycol–free” antifreeze, de-icing and heat-exchanger solutions. Being generally recognized as safe by the U.S. Food and Drug Administration, it is routinely used as a solvent in pharmaceutical preparations, and as a humectant and preservative in food products. Deaths are rare following exposure to PG. Nevertheless, the relatively high concentration of PG in intravenous formulations of phenytoin (40%), diazepam (40%), chlordiazepoxide (20%), etomidate (35%), phenobarbital (70%), pentobarbital (40%), and lorazepam (80%) can result in toxicity during rapid or prolonged infusion of high doses of these medications. PG is also present in parenteral preparations of esmolol, digoxin, multivitamins, nitroglycerin, and trimethoprim-sulfamethoxazole. Toxicity following dermal exposure is possible, particularly in infants and burn patients.35,36 The use of silver sulfadiazine cream has produced serum hyperosmolality, hypoglycemia, seizures, and CNS depression from transdermal absorption of PG.36-38 The oral median lethal dose (LD50) is 20 g/kg or greater in rodents.34 The daily dose should not exceed 25 mg/kg.39 Similar to other alcohols and glycols, PG is rapidly absorbed from the gastrointestinal tract with peak serum levels after 1 to 2 hours, and distributes into a volume of 0.6 L/kg. The terminal hydoxyl group of PG is readily oxidized via ADH to form lactic acid (2-hydroxypropanoic acid), which subsequently can be converted to pyruvate and enter the Kreb’s cycle. Up to half of the parent glycol is excreted unchanged in the kidneys. The serum elimination half-life in adults is 2.3 ± 0.7 hours, but becomes saturated above 50 mg/dL, and can be up to 17 hours (or zero-order 13.5 mg/dL/hr) in neonates.36,40,41 With chronic dosing of racemic PG, Dlactate accumulates in cats.42 The significance of chirality is not known in human exposures. In an adult patient treated with continuous ethanol infusion and ethanol: PG serum concentrations of 1:2 mol/mol, zero-order elimination of 13 mg/dL/hr was observed across PG concentrations ranging from 300 to 500 mg/dL.43 PG concentrations greater than 17.7 mg/dL are required to increase the lactate concentration and increase the anion gap.44 PG concentrations of 76 mg/dL will increase the serum osmolality by about 10 mOsm/kg.45 PG can be detected by gas chromatography. PG is a potential interferent when testing for ethylene glycol, so mass spectrometry should be used to confirm glycol identity.46-48 High doses result in abrupt cardiovascular depression, cardiac conduction abnormalities including QRS widening and bradyasystole, lactic acidosis, hyperosmolality, CNS depression and seizures, hypoglycemia, deafness, and thrombophlebitis, as described in various case reports.4953 Bradycardia is vagally mediated, as evidenced by pretreatment with atropine or vagotomy in animals.54 Most toxic effects from PG are attributed to the parent glycol rather than its metabolites, suggesting that ADH inhibitor therapy is of limited benefit.55 Hemodialysis has been used in critically ill patients.56,57 The role of fomepizole is unknown.55 Continuous venovenous hemofiltration with dialysis removes PG more slowly, and one patient receiving up to 9 g PG hourly developed toxicity despite simultaneous venovenous hemofiltration.58

626


DIETHYLENE GLYCOL Diethylene glycol (2,2’-dihydroxydiethyl ether, ethylene diglycol, 2,2’-oxydiethanol, 3-oxapentane-1,5-diol) is a viscous, sweet-tasting hydroscopic liquid. It is used as a plasticizer, antifreeze, lubricant, and liquid fuel (e.g., Sterno Wick Chafing Fuel, Des Plaines, IL). Its solubility in both organic and aqueous solutions has resulted in its occasional incorporation into pharmaceutical elixirs, with tragic results. The use of diethylene glycol to dissolve the early sulfa drug sulfanilamide by the Messengill company in 1937 resulted in 105 deaths, and triggered a national outcry.59 This tragedy led to the federal Food, Drug and Cosmetic Act in 1938, which initiated the close regulation of the safety of medicinals by the Food and Drug Administration. Unfortunately, outbreaks continue to occur in developing countries following the inadvertent substitution of diethylene glycol for PG or glycerin in elixirs usually intended for children, with mortality rates of 40% to 100%.60-64 (Table 32C-2) The oral LD50 ranges from 4.9 g/kg (rabbits) to 28.2 g/kg (mice), but is only 1.1 to 2.2 g/kg in mice when given intravenously. A human infant fatality has been reported following ingestion of 3.6 g. After ingestion, diethylene glycol is rapidly absorbed, and 40% to 70% is excreted unchanged in the urine. The remainder is oxidized to 2-hydroxyethoxy acetic acid by ADH and aldehyde dehydrogenase, which may esterify under physiologic conditions to the cyclic lactone p-dioxanone, a nonacid.65,66 The parent ether link is stable in vivo, accounting for the absence of ethylene glycol, glycolate, and glyoxalate in animal toxicity studies, and the inconsistent observation of oxalate in human cases.65-68 Lactic acid accounts for a substantial portion of the metabolic acidosis.69 Pyrazole and ethanol both reduce but do not eliminate the toxicity in animal models,69 suggesting that the parent compound is also toxic. Nephrotoxicity (tubular necrosis) is the prominent feature in animal poisoning studies. Other findings include CNS depression and hemorrhage, metabolic acidosis, and fatty liver. In poisoned humans, characteristic findings include delayed-onset renal failure with

vacuolar nephropathy and acute tubular necrosis, and centrilobular hepatic necrosis following single or subacute ingestion of about 1 g/kg. In the Haiti outbreak, the maximum possible median toxic dose was 1.5 g/kg (95% confidence interval 0.25 to 4.9 g/kg).62 In serious poisonings, headache, dizziness, CNS depression, anorexia, nausea, vomiting, diarrhea, and abdominal pain are commonly seen within 24 hours after ingestion. Unlike poisoning with ethylene glycol, the metabolic acidosis is not as prominent until renal toxicity is advanced. Laboratory findings include elevated serum osmolality, hypoglycemia, elevated blood urea nitrogen and creatinine, anion gap metabolic acidosis, elevated liver function test results, and an abnormal urinalysis result with cells and casts. In addition to hepatorenal failure, other late findings include cerebral and pulmonary edema, encephalopathy progressing to coma, facial nerve paralysis, demyelinating neuropathy, seizures, hypertension, adrenal cortical hemorrhage, and pancreatitis. Although there is little reported experience in humans, both early dialysis and the inhibition of ADH is recommended for all symptomatic diethylene glycol exposures, especially patients with acidemia or renal insufficiency.67,70 Using fomepizole to inhibit ADH is rational,71 and has been used empirically in human cases.69,70 The toxicity of the parent compound suggests that fomepizole without hemodialysis is unwise. In addition to dialysis and ADH inhibition, the need for intensive care to multiple patients with multiorgan failure may overwhelm a health care system in the context of an outbreak.62,64

POLYETHYLENE GLYCOLS Triethylene glycol is the next higher molecular weight polymer after diethylene glycol in the series of polyethylene glycols. This series consists of subunits of ethylene glycol joined by an ether link. As the number of subunits increases, the polyethylene glycols are typically a mixture of varying chain lengths and are described by a number (e.g., PEG-3350). This number denotes the average molecular weight of the mixture.

TABLE 32C-2 Diethylene Glycol (DEG) Poisoning Outbreaks YEAR

COUNTRY

SOURCE (% DEG)

AGES

FATALITIES IDENTIFIED

1937 1969 1985

USA South Africa Spain

30% children Children

105 of 353 7 5

59 103 104

1985 1986 1990 1990–1992 1992 1995/1996 1998

Netherlands India Nigeria Bangladesh Argentina Haiti India

Sulfonilamide (72%) Sedatives Topical silver Sulfadiazine Wine Glycerin (18.5%) Acetaminophen Acetaminophen Propolis Acetaminophen (14%) Cough syrup (17.5%)

14 47 236 7 101 of 109 33 of 36

105 106 63 60 68 61, 62 64

Adults Adults Children Children Children Children

REFERENCES

CHAPTER 32


These compounds are liquids at room temperatures until the molecular weight exceeds 1000 daltons, after which they become solids and are termed carbowaxes. The toxicity also decreases substantially with increasing molecular weight. The higher polyethylene glycols are commonly used as excipients in medications and ointments. Intravenous lorazepam contains nearly 20% PEG-400, and burn ointments may contain over 99% PEG-300. PEG-3350 combined with an electrolyte solution (PEG-ELS) is used as a bowel evacuant for whole bowel irrigation (e.g., Go-Lytely [Braintree Laboratories, Braintree, MA] and CoLyte [Schwarz Pharma, Milwaukee, WI]). Only lower-molecular-weight polyethylene glycols are absorbed in significant quantities after ingestion. These compounds can be metabolized via ADH to mono- and diacid metabolites,72 but the majority is excreted unchanged in the urine. The ether link appears to be stable in vivo (see earlier section on Diethylene Glycol), and toxic amounts of ethylene glycol are not generated. In animals, 10 g/kg of polyethylene glycols over a wide range of molecular weights are well tolerated after single intravenous administration. Although uncommon, toxicity associated with polyethylene glycols includes CNS depression, serum hyperosmolality, anion gap metabolic acidosis, and renal failure. Triethylene glycol has been reported to cause acute toxicity after ingestion in humans.73 In this case report, intentional ingestion of nearly pure triethylene glycol resulted in coma and profound anion gap metabolic acidosis (initial arterial pH 7.03, anion gap 30 mmol/L, lactate 2 mmol/L, osmol gap 7) within 90 minutes of ingestion. In another case report, an intentional ingestion of brake fluid containing both diethylene glycol (10%) and triethylene glycol (55% vol/vol) resulted in coma, clonus, and anion gap acidosis (pH 7.34, anion gap 28 mmol/L, lactate 12 mmol/L, osmol gap 31) at least 2 hours after ingestion.69 The third report of toxicity following intentional ingestion involved the liquid contents of a lava light (18% PEG200) by a 65-year-old man who presented with confusion, nystagmus, renal failure, and acidosis (anion gap 15, creatinine 5.7 μg/dL). Burn patients absorb PEG-300 from creams applied topically and eliminate acid metabolites in urine,72 perhaps resulting in toxicity.74 For instance, serum hyperosmolality, anion gap metabolic acidosis, and acute tubular necrosis have been described in this patient population and may be attributed to PEG percutaneous absorption.74 One case of hyperosmolar metabolic acidosis in a patient administered 1.7 g lorazepam intravenously (18% PEG-400, 80% PG) was attributed to the 150 mL of polyethylene glycol excipient,57 but the coadministered 704 g of PG are a more plausible explanation.55 The relative safety of PEG3350 is illustrated by a case report of a 2-year-old child treated with 3 L/kg of whole bowel irrigation over 5 days without adverse effects.75 Treatment with ADH blockade using either fomepizole or ethanol appears to be appropriate for symptomatic ingestions of low-molecular-weight polyethylene glycols.69,73 The role of hemodialysis is not defined, but should be

627

instituted for persistent metabolic acidosis or renal insufficiency. The acute oral toxicity of the highermolecular-weight polyethylene glycols is minimal.

GLYCOL ETHERS The glycol ethers, or cellosolves, are a family of organic compounds in which at least one alkyl hydrocarbon is joined by an ether link to a diol such as ethylene glycol. Thus, the basic structure is R1-O-(CH2)x-O-R2. The most common glycol ether, accounting for about half of the annual production in North America, is ethylene glycol n-butyl ether (EGBE), in which R1 = CH3(CH2)3- (i.e., n-butyl), x = 2 (ethylene glycol), and R2 = H. Replacing R1 with methyl results in ethylene glycol methyl ether (EGME). Other commonly encountered glycol ethers are listed in Table 32C-3. Since the glycol ethers combine the solubility properties of both alcohols and ethers, they are miscible in a wide range of aqueous and organic solutions, and have numerous household and industrial applications. The first reports of human toxicity appeared in the 1930s following the introduction of EGME into the manufacture of stiffened shirt collars. Workers producing “fused collar” shirts developed toxic encephalopathy and bone marrow toxicity following chronic pulmonary and dermal exposure.76 Today, various glycol ethers are found as the primary component of automotive brake fluids, as well as in fuel injector and carburetor cleaners, degreasing agents, stain removers, carpet and fabric cleaners, inks and ink removers, leather dyes, shoe polish, leather conditioners, and many window and surface cleaning products. Their coating properties lead to their use in lacquers, paints, varnishes, and surface preparation agents. They are used extensively in the semiconductor industry, as well as the plastics, rubber, photography, and printing industries. Although the first human fatality attributed to intentional ingestion of a glycol ether was reported over 50 years ago,77 there are very few published case reports of toxicity following acute use. This is in contrast with their prevalence in the household environment. For the years of 1998 to 2000, the American Association of Poison Control Centers Toxic Exposure Surveillance System shows over 26,000 human exposures (54% age younger than 6 years) to products containing any glycol other than ethylene glycol, out of a total of 6.6 million cases reported to U.S. poison control centers. Of these, 64 (0.2%) resulted in major toxicity, and 2 deaths are listed, both in adults, presumably following intentional ingestion with suicidal intent. Indeed, toxicity was not observed in a retrospective poison control center study of 24 young children following accidental ingestion of a mouthful of products containing less than 10% glycol ethers.78 Following oral ingestion, absorption of low-molecularweight glycol ethers such as EGME and EGBE is rapid, and comparable with ethanol.79 Pulmonary absorption is also possible, particularly of the more volatile agents. Thus, methyl derivatives such as EGME (vapor pressure

628


TABLE 32C-3 Glycol Ethers NAME

ABBREVIATION

CAS NO.

SYNONYMS

STRUCTURE

Ethylene glycol methyl ether

EGME

109-86-4

CH3O-CH2CH2OH

Ethylene glycol ethyl ether

EGEE

110-80-5

Ethylene glycol n-butyl ether

EGBE

111-76-2

Diethylene glycol methyl ether

DEGME

111-77-3

Diethylene glycol n-butyl ether

DEGBE

112-34-5

2-Propylene glycol-1-methyl ether 1-Propylene glycol-2-methyl ether

α-PGME β-PGME

107-98-2 1589-47-5

Dipropylene glycol methyl ether

DPGME

34590-94-8

Ethylene glycol dimethyl ether

EGDME

110-71-4

2-methoxyethanol, Methyl Cellosolve, methyl oxitol 2-ethoxyethanol, Cellosolve, Oxitol 2-butoxyethanol, Butyl Cellosolve, 3-oxa-1-heptanol 2-(2-methoxy-ethoxy)ethanol, methoxydiglycol, methyl dioxitol, 3,6-dioxa1-heptanol 2-(2-butoxyethoxy)ethanol, butoxydiglycol, butyl dioxitol, Dowanol DB 1-methoxy-2-propanol 2-methoxy-1-propanol (4 isomers) 1,2-dimethoxyethane, Glyme, Dimethyl Cellosolve 2,5-dioxahexane

9.7 mm Hg at 25° C) are more hazardous than EGBE (vapor pressure 0.9 mm Hg). The diethylene and dipropylene glycol ethers have vapor pressures ranging from about 0.4 to 0.004 mm Hg under ambient conditions, reducing the risk for exposure, and triethylene glycol ethers or higher are essentially nontoxic via the pulmonary route.80 The glycol ethers readily diffuse across intact skin in inverse proportion to molecular weight. EGME diffuses across human skin more quickly than ethanol, then in decreasing order propylene glycol methyl ether (PGME), ethylene glycol ethyl ether (EGEE), dimethylene glycol methyl ether (DEGME), diethylene glycol ethyl ether, and EGBE.81 Both the pulmonary and dermal routes of exposure can lead to toxicity in the occupational setting.82 Once absorbed, the volume of distribution for EGBE has been estimated at 0.7 L/kg.83 The monoalkyl ethers are predominantly metabolized to alkoxyacetic acid by hepatic ADH and aldehyde dehydrogenase.80 For example, EGME is oxidized to methoxyacetic acid and EGBE to butoxyacetic acid (BAA). This metabolism is inhibited in animals by pyrazole (a fomepizole analog) or relatively low concentrations of ethanol. O-dealkylation to ethylene glycol and a monoalcohol plays a minor role in mammals. The alkoxyacetic acid and its glycine conjugate are the major urinary metabolites recovered.83 Only trivial amounts of the parent compound are eliminated in feces or breath. Despite reports of moderate increases in oxaluria in two case reports,84,85 the absence of detectable ethylene glycol, methanol, and tissue calcium oxalate crystals in most other published reports demonstrates that the toxicity of EGME and EGBE is not due to the release of ethylene glycol.77,79,85,86 Two other case reports may represent ethylene glycol ingestions.87,88 In contrast to all

C2H5O-CH2CH2OH C4H9O-CH2CH2OH CH3O-CH2CH2O-CH2CH2OH

C4H9O-CH2CH2O-CH2CH2OH CH3O-CH2CH(CH3)OH CH3O-CH(CH3)CH2OH CH3O-C3H6O-C3H6OH CH3O-CH2CH2O-CH3

the ethylene glycol monoalkyl ethers and β-PGME, ADH oxidizes secondary alcohols such as α-PGME more slowly, and O-dealkylation presumably via CYP450 can produce substantial quantities of PG.80 Because of the paucity of published reports of acute toxicity following oral ingestion, careful scrutiny of these case reports is justified, as summarized in Table 32C-4. Analogous to most other toxic alcohols, the acid metabolites appear to be more potent toxins than the parent glycol ether. Rapid onset coma may occur within 1 hour of ingestion,79 but an anion gap metabolic acidosis follows several hours later if ADH metabolism is not inhibited.79,84-86 Mild to moderate hemolysis has been observed in humans following large ingestions of EGBE,79,84,89,90 but not after inhalational exposure or with other glycol ethers. Animal models demonstrate that BAA is the proximate hemolytic agent.91 Human erythrocytes appear to be resistant to hemolysis in vitro.92 Other reported toxic effects following glycol ether ingestion are hypotension requiring pressors, mild renal dysfunction with proteinuria, lactic acidosis, and less commonly disseminated intravascular coagulopathy, acute lung injury, hepatic dysfunction, and hypochloremic metabolic acidosis. Chronic exposure can result in bone marrow suppression, encephalopathy, developmental toxicity, and subfertility. The neurologic effects range from personality changes to amnesia, headache, and lethargy, with tremor, clonus, ataxia, and dysarthria. Both erythroid and myeloid hypoplasia have been described on the bone marrow aspirates of workers exposed to higher concentrations of EGME, but not following low level exposures to EGBE.93,94 Several epidemiologic studies have reported an association between decreased fertility in female workers and exposure to EGME, EGBE (and

CHAPTER 32


629

TABLE 32C-4 Human Case Reports of Symptomatic Glycol Ether Ingestion REFERENCE

AGE (yr)

SEX

INTENTIONAL

INGESTION

77

46

M

Yes

250 mL pure EGME + some ethanol

85

41

M

Yes

100 mL pure EGME 8 hr PTA

TIME POST ARRIVAL 0 5 hr 0 12 hr

5 days 85

23

M

Yes

100 mL pure EGME 20 hr PTA

-2 hr 0

1 day 5–9 days 84

50

F

Yes

250+ mL 12% EGBE 12 hr PTA

0 3–6 days 5 days

79

23

F

Yes

250 mL 12.7% EGBE + 3.2% ethanol 1 hr PTA

0

2 hr 3 hr 6 hr

22 hr 86

1.3

F

No

10%–30% EGBE 2 hr PTA

0 2 hr 4 hr 26 hr

89

19

M

Yes

600 + mL 1 hr 25%–35% EGBE + 15%– 25% propylene glycol 20 min PTA

FEATURES

TREATMENT

Comatose, RR 28/min Dead; no methanol/some ethanol in urine Agitated, confused, restless, increased RR Restless, AG 24, Ethanol × creat 2.0 mg/dL, 3 days pH 7.18, Ca oxalate crystalluria Creat N; no methanol or EGME in urine Motor weakness Confused, Ethanol × increased RR, 3 days AG 30, creat 1.5 mg/dL, pH 7.22; no methanol, EGME, or Ca oxalate in urine Creat N 27–54 mg/day oxaluria (N) Coma inc creat, pH 7.23, oxalate crystaluria Hemolysis Extubated; BAA up to 40 g/g creat, EGBE 2 g/g creat, and oxalate 200 mg/g creat (peaks day 1 and 7) in urine Coma, AG N, creat N; EGBE 432 mg/L, ethanol 35.6 mg/L in serum EGBE 304 mg/L, ethanol 1 mg/L in serum Awake RR 28/min, AG 28, creat N, lactate 7.1 mM, pH 7.08, OG N Creat N, urine HD × 6 hr oxalate N, mild hemolysis GCS 7, AG 19, lactate 1.0 mM AG 20, no Fomepizole ethylene glycol × 1 dose in serum AG N Awake Lethargic, RR 24/min

COMMENTS Acute hemorrhagic gastritis, toxic changes renal tubules and pancreas

Proteinuria × 7 day, alopecia, dermatitis

Proteinuria × 7 day

Rapid onset coma, dopamine for hypotension, coingested ethanol appears to have delayed onset of acidosis and serum elimination of EGBE

Early hypoglycemia,late pancreatitis (mild) Hypotension on 3 pressors; DIC; propylene glycol coingestion; peak BAA 170 mg/dL, no increased elimination during hemodialysis; lactate also cleared slowly

630


TABLE 32C-4 Human Case Reports of Symptomatic Glycol Ether Ingestion—Cont’d REFERENCE

AGE (yr)

SEX

INTENTIONAL

INGESTION

TIME POST ARRIVAL 3 hr

107

59

F

Yes

20%–30% DPGME

101

51

F

Yes

240 mL 10%– 30% EGBE + 10%–40% isopropanol 1.5 hr PTA

29 hr 2 days 0

24 hr 0

4 hr 3 days

90

18

M

Yes

360 + mL 22% EGBE 3 hr PTA

0 10 hr 16 hr

21 hr 30 hr 60 hr 90

18

M

Yes

480 mL 22% EGBE 6 hr PTA

0

8 hr

FEATURES

TREATMENT COMMENTS

Coma, AG 10, lactate 5.0 mM, pH 7.36; propylene glycol 43 mg/dL

HD × 4 hr Hemolysis Coma, AG Ethanol increased, OG 12; no methanol or ethylene glycol in serum AG N Vomited, RR 24/ min, AG 15, creat 0.8 mg/dL, pH 7.31; isopropanol 3 mg/dL, acetone 3 mg/dL Obtunded Ethanol × 3 days AG 11–15, creat N, no oxaluria, no hemolysis Awake, AG N, creat 1.2 mg/dL, pH 7.34, OG N Lethargic, inc RR Creat 1.5 mg/dL, lactate 5.9 mM, pH 7.46; no ethylene glycol, peak BAA 4.9 mM, peak EGBE 0.001 mM in serum Creat 1.1 mg/dL, HD × 4.5 hr; no ethylene glycol ethanol × in serum 30 hr Awake, mild hemolysis AG N, creat N Alert, creat 1.3 mg/dL, pH 7.40, no ethylene glycol in serum OG 8, peak BAA 2 mM, EGBE 0.1 mM

Ethanol × 28 hr HD

Hypotensive eventually needing CPR; skin burns attributed to urine leak

Deteriorated shortly after ethanol begun; hyperchloremic metabolic acidosis resolved when ethanol discontinued; EGBE and BAA levels much lower than expected

Mild epigastric discomfort; ketonuria, hematuria, proteinuria

Time of peak BAA relative to HD not clear

The table summarizes published reports of serious glycol ether ingestion AG, anion gap (mM); CPR, external chest compressions; creat, serum creatinine; DIC, disseminated intravascular coagulation; HD, hemodialysis; N, normal; OG, osmolal gap; PTA, prior to hospital arrival; RR, respiratory rate.

their acetate derivatives which are deesterified in vivo to the parent glycol ether), and other ethylene and PG ethers used in photolithography during semiconductor fabrication.95-97 EGME, EGEE, and perhaps higher glycol ethers are teratogenic.98-100 The diagnosis of acute exposure to glycol ether depends on a reliable history, since laboratory testing for the parent glycol ether or its acid metabolite is generally

not possible within a clinically relevant turnaround time. CNS depression should be present on physical examination following significant poisoning. The presence of an anion gap metabolic acidosis, with or without a concurrent lactic acidosis, is an indirect marker of exposure and metabolism, but is not specific. The osmol gap is usually normal despite severe symptoms.79,90,101,102 In fact, in one patient with rapid onset coma, the serum

CHAPTER 32


concentration of EGBE was 3 mmol/L, and would therefore not be expected to increase the osmol gap appreciably. Treatment must therefore be predicated upon clinical effects such as mental status, acid-base status, and other readily apparent end-organ effects. Many of the patients in case reports were treated with ADH blockade or delayed hemodialysis, or both. Fomepizole was used in one instance.86 There are insufficient data on which to base a firm recommendation at this time. The use of an ADH inhibitor is based on the premise that the acid metabolite is the more toxic species, and is justified only if substantial amounts of the parent glycol ether remain at the time of initiation of therapy. It is difficult to interpret the human toxicokinetics of the parent glycol ether, because the reported methodologies for quantifying EGBE appear to yield inconsistent results. From these imprecise published estimates, it would appear that the glycol ether is absorbed and cleared rapidly from the serum. The available data also suggest that full-dose ethanol therapy can result in hemodynamic compromise and a hyperchloremic metabolic acidosis.101 The use of hemodialysis is recommended to correct refractory metabolic acidosis and to remove the glycol ether metabolites. Here again, the literature is unsatisfactory. The only report of serial serum BAA levels suggests that hemodialysis does not increase BAA elimination substantively.89 This observation is at odds with the low molecular weight and volume of distribution of BAA, and should be confirmed prior to reconsidering the role of hemodialysis. Pending better information, it seems prudent to recommend fomepizole or low-dose ethanol for symptomatic patients who present shortly after an intentional ingestion of a product known to contain nontrivial concentrations of glycol ethers. Hemodialysis should be offered to patients with a metabolic acidosis not responsive to fluids and sodium bicarbonate. Accidental sips of solutions with less than 10% glycol ether can be managed with home observation if the patient remains asymptomatic.78

REFERENCES 1. Lacouture PG, Heldreth DD, Shannon M, Lovejoy FH Jr: The generation of acetonemia/acetonuria following ingestion of a subtoxic dose of isopropyl alcohol. Am J Emerg Med 1989; 7(1):38–40. 2. Leeper SC, Almatari AL, Ingram JD, Ferslew KE: Topical absorption of isopropyl alcohol induced cardiac and neurologic deficits in an adult female with intact skin. Vet Hum Toxicol 2000;42(1):15–17. 3. Lewin GA, Oppenheimer PR, Wingert WA: Coma from alcohol sponging. JACEP 1977;6:165–167. 4. Martinez TT, Jaeger RW, deCastro FJ, et al: A comparison of the absorption and metabolism of isopropyl alcohol by oral, dermal and inhalation routes. Vet Hum Toxicol 1986;28(3):233–236. 5. Vivier PM, Lewander WJ, Martin HF, Linakis JG: Isopropyl alcohol intoxication in a neonate through chronic dermal exposure: a complication of a culturally-based umbilical care practice. Pediatr Emerg Care 1994;10(2):91–93. 6. Monaghan MS, Ackerman BH, Olsen KM, et al: The use of delta osmolality to predict serum isopropanol and acetone concentrations. Pharmacotherapy 1993;13(1):60–63.

631

7. Pappas AA, Ackerman BH, Olsen KM, Taylor EH: Isopropanol ingestion: a report of six episodes with isopropanol and acetone serum concentration time data. J Toxicol Clin Toxicol 1991; 29(1):11–21. 8. Parker KM, Lera TA Jr: Acute isopropanol ingestion: pharmacokinetic parameters in the infant. Am J Emerg Med 1992; 10(6):542–544. 9. Daniel DR, McAnalley BH, Garriott JC: Isopropyl alcohol metabolism after acute intoxication in humans. J Anal Toxicol 1981;5(3):110–112. 10. Gaudet MP, Fraser GL: Isopropanol ingestion: case report with pharmacokinetic analysis. Am J Emerg Med 1989;7(3):297–299. 11. Natowicz M, Donahue J, Gorman L, et al: Pharmacokinetic analysis of a case of isopropanol intoxication. Clin Chem 1985;31(2):326–328. 12. Bekka R, Borron SW, Astier A, et al: Treatment of methanol and isopropanol poisoning with intravenous fomepizole. J Toxicol Clin Toxicol 2001;39(1):59–67. 13. Su M, Hoffman RS, Nelson LS: Error in an emergency medicine textbook: isopropyl alcohol toxicity. Acad Emerg Med 2002;9(2):175. 14. Jones AW: Elimination half-life of acetone in humans: case reports and review of the literature [Review]. J Anal Toxicol 2000; 24(1):8–10. 15. Vicas IM, Beck R: Fatal inhalational isopropyl alcohol poisoning in a neonate. J Toxicol Clin Toxicol 1993;31(3):473–481. 16. Wallgren H: Relative intoxicating effects on rats of ethyl, propyl and butyl alcohols. Acta Pharmacol Toxicol 1960;16:217–222. 17. Bailey DN: Detection of isopropanol in acetonemic patients not exposed to isopropanol. J Toxicol Clin Toxicol 1990;28(4):459–466. 18. Jones AE, Summers RL: Detection of isopropyl alcohol in a patient with diabetic ketoacidosis. J Emerg Med 2000;19(2): 165–168. 19. Logan BK, Gullberg RG, Elenbaas JK: Isopropanol interference with breath alcohol analysis: a case report. J Forensic Sci 1994; 39(4):1107–1111. 20. Linden CH: Unknown alcohol [Letter; Comment]. Ann Emerg Med 1996;28(3):371. 21. Blijenberg BG, Brouwer HJ: The accuracy of creatinine methods based on the Jaffe reaction: a questionable matter. Eur J Clin Chem Clin Biochem 1994;32(12):909–913. 22. Rich J, Scheife RT, Katz N, Caplan LR: Isopropyl alcohol intoxication [Review; see comments]. Arch Neurol 1990;47(3):322–324. 23. Burkhart KK, Martinez MA: The adsorption of isopropanol and acetone by activated charcoal. J Toxicol Clin Toxicol 1992;30(3): 371–375. 24. Stremski E, Hennes H: Accidental isopropanol ingestion in children. Pediatr Emerg Care 2000;16(4):238–240. 25. Rosansky SJ: Isopropyl alcohol poisoning treated with hemodialysis: kinetics of isopropyl alcohol and acetone removal. J Toxicol Clin Toxicol 1982;19(3):265–271. 26. King LH Jr, Bradley KP, Shires DL Jr: Hemodialysis for isopropyl alcohol poisoning. JAMA 1970;211(11):1855. 27. Chen EC, David JJ: Quantitative determination of fusel alcohols in beer and fermenting wort. J Sci Food Agric 1974;25(11): 1381–1387. 28. Gershanik J, Boecler B, Ensley H, et al: The gasping syndrome and benzyl alcohol poisoning. N Engl J Med 1982;307(22):1384–1388. 29. Brown WJ, Buist NR, Gipson HT, et al: Fatal benzyl alcohol poisoning in a neonatal intensive care unit. Lancet 1982;1(8283):1250. 30. Jardine DS, Rogers K: Relationship of benzyl alcohol to kernicterus, intraventricular hemorrhage, and mortality in preterm infants. Pediatrics 1989;83(2):153–160. 31. Benda GI, Hiller JL, Reynolds JW: Benzyl alcohol toxicity: impact on neurologic handicaps among surviving very low birth weight infants. Pediatrics 1986;77(4):507–512. 32. Hiller JL, Benda GI, Rahatzad M, et al: Benzyl alcohol toxicity: impact on mortality and intraventricular hemorrhage among very low birth weight infants. Pediatrics 1986;77(4):500–506. 33. Brunson EL: Benzyl alcohol. In Kibbe AH (ed): Handbook of Pharmaceutical Excipients. Washington, DC, American Pharmaceutical Association, 2000, pp 41–43. 34. LaKind JS, McKenna EA, Hubner RP, Tardiff RG: A review of the comparative mammalian toxicity of ethylene glycol and propylene glycol [Review]. Crit Rev Toxicol 1999;29(4):331–365.

632


35. Peleg O, Bar-Oz B, Arad I: Coma in a premature infant associated with the transdermal absorption of propylene glycol. Acta Paediatr 1998;87(11):1195–1196. 36. Fligner CL, Jack R, Twiggs GA, Raisys VA: Hyperosmolality induced by propylene glycol. A complication of silver sulfadiazine therapy. JAMA 1985;253(11):1606–1609. 37. Kulick MI, Wong R, Okarma TB, et al: Prospective study of side effects associated with the use of silver sulfadiazine in severely burned patients. Ann Plast Surg 1985;14(5):407–419. 38. Kulick MI, Lewis NS, Bansal V, Warpeha R: Hyperosmolality in the burn patient: analysis of an osmolal discrepancy. J Trauma 1980;(3):223–228. 39. Dandiker Y: Propylene glycol. In Kibbe AH (ed): Handbook of Pharmaceutical Excipients. Washington, DC, American Pharmaceutical Association, 2000; pp 442–444. 40. Speth PA, Vree TB, Neilen NF, et al: Propylene glycol pharmacokinetics and effects after intravenous infusion in humans. Ther Drug Monit 1987;9(3):255–258. 41. Ruddick JA: Toxicology, metabolism, and biochemistry of 1,2propanediol [Review]. Toxicol Appl Pharmacol 1972;21(1): 102–111. 42. Christopher MM, Eckfeldt JH, Eaton JW: Propylene glycol ingestion causes D-lactic acidosis. Lab Invest 1990;62(1):114–118. 43. Brooks DE, Wallace KL: Acute propylene glycol ingestion. J Toxicol Clin Toxicol 2002;40(4):513–516. 44. Kelner MJ, Bailey DN: Propylene glycol as a cause of lactic acidosis. J Anal Toxicol 1985;9(1):40–42. 45. Hall AH, Bronstein AC, Smolinske SC, et al: Propylene glycol plasma level. Pediatrics 1985;76(4):654. 46. Tuohy KA, Nicholson WJ, Schiffman F: Agitation by sedation. Lancet 2003;361(9354):308. 47. Robinson CA Jr, Scott JW, Ketchum C: Propylene glycol interference with ethylene glycol procedures. Clin Chem 1983;29(4):727. 48. DeWitt C, Palmer R, Phillips S, Dart RC: False positive ethylene glycol level [Abstract]. J Toxicol Clin Toxicol 2003;41(5):736. 49. Bedichek E, Kirschbaum B: A case of propylene glycol toxic reaction associated with etomidate infusion. Arch Intern Med 1991;151(11):2297–2298. 50. Arbour RB: Propylene glycol toxicity related to high-dose lorazepam infusion: case report and discussion. Am J Crit Care 1999;8(1):499–506. 51. Guillot M, Bocquet G, Eckart P, et al: [Home environment and acute propylene glycol intoxication in a two-year old. An unusual case report] [French]. Arch Pediatr 2002;9(4):382–384. 52. Wilson KC, Reardon C, Farber HW: Propylene glycol toxicity in a patient receiving intravenous diazepam. N Engl J Med 2000; 343(11):815. 53. Reynolds HN, Teiken P, Regan ME, et al: Hyperlactatemia, increased osmolar gap, and renal dysfunction during continuous lorazepam infusion. Crit Care Med 2000;28(5):1631–1634. 54. Louis S, Kutt H, McDowell F: The cardiocirculatory changes caused by intravenous dilantin and its solvent. Am Heart J 1967;74(4):523–529. 55. Mullins ME, Barnes BJ: Hyperosmolar metabolic acidosis and intravenous Lorazepam [see comment]. N Engl J Med 2002;347(11):857–858. 56. Parker MG, Fraser GL, Watson DM, Riker RR: Removal of propylene glycol and correction of increased osmolar gap by hemodialysis in a patient on high dose lorazepam infusion therapy. Intens Care Med 2002;28(1):81–84. 57. Tayar J, Jabbour G, Saggi SJ: Severe hyperosmolar metabolic acidosis due to a large dose of intravenous lorazepam [see comment]. N Engl J Med 2002;346(16):1253–1254. 58. Al Khafaji AH, Dewhirst WE, Manning HL: Propylene glycol toxicity associated with lorazepam infusion in a patient receiving continuous veno-venous hemofiltration with dialysis. Anesth Analg 2002;94(6):1583–1585. 59. Wax PM: Elixirs, diluents, and the passage of the 1938 Federal Food, Drug and Cosmetic Act. Ann Intern Med 1995;122(6):456–461. 60. Hanif M, Mobarak MR, Ronan A, et al: Fatal renal failure caused by diethylene glycol in paracetamol elixir: the Bangladesh epidemic [see comment]. BMJ 1995;311(6997):88–91.

61. Junod SW: Diethylene glycol deaths in Haiti. Public Health Rep 2000;115(1):78–86. 62. O’Brien KL, Selanikio JD, Hecdivert C, et al: Epidemic of pediatric deaths from acute renal failure caused by diethylene glycol poisoning. Acute Renal Failure Investigation Team [see comment]. JAMA 1998;279(15):1175–1180. 63. Okuonghae HO, Ighogboja IS, Lawson JO, Nwana EJ: Diethylene glycol poisoning in Nigerian children [see comment]. Ann Trop Paediatr 1992;12(3):235–238. 64. Singh J, Dutta AK, Khare S, et al: Diethylene glycol poisoning in Gurgaon, India, 1998 [see comment]. Bull WHO 2001;79(2): 88–95. 65. Mathews JM, Parker MK, Matthews HB: Metabolism and disposition of diethylene glycol in rat and dog. Drug Metab Dispos 1991;19(6):1066–1070. 66. Lenk W, Lohr D, Sonnenbichler J: Pharmacokinetics and biotransformation of diethylene glycol and ethylene glycol in the rat. Xenobiotica 1989;19(9):961–979. 67. Rollins YD, Filley CM, McNutt JT, et al: Fulminant ascending paralysis as a delayed sequela of diethylene glycol (Sterno) ingestion. Neurology 2002;59(9):1460–1463. 68. Drut R, Quijano G, Jones MC, Scanferla P: [Pathologic findings in diethylene glycol poisoning.] Medicina 1994;54(1):1–5. 69. Borron SW, Baud FJ, Garnier R: Intravenous 4-methylpyrazole as an antidote for diethylene glycol and triethylene glycol poisoning: a case report. Vet Hum Toxicol 1997;39(1):26–28. 70. Brophy PD, Tenenbein M, Gardner J, et al: Childhood diethylene glycol poisoning treated with alcohol dehydrogenase inhibitor fomepizole and hemodialysis. Am J Kidney Dis 2000;35(5): 958–962. 71. Wiener HL, Richardson KE. Metabolism of diethylene glycol in male rats. Biochem Pharmacol 1989;38(3):539–541. 72. Herold DA, Keil K, Bruns DE: Oxidation of polyethylene glycols by alcohol dehydrogenase. Biochem Pharmacol 1989;38(1): 73–76. 73. Vassiliadis J, Graudins A, Dowsett RP: Triethylene glycol poisoning treated with intravenous ethanol infusion. J Toxicol Clin Toxicol 1999;37(6):773–776. 74. Bruns DE, Herold DA, Rodeheaver GT, Edlich RF: Polyethylene glycol intoxication in burn patients. Burns 1982;9(1):49–52. 75. Kaczorowski JM, Wax PM: Five days of whole-bowel irrigation in a case of pediatric iron ingestion. Ann Emerg Med 1996;27(2): 258–263. 76. Browning RG, Curry SC: Clinical toxicology of ethylene glycol monoalkyl ethers [Review]. Hum Exp Toxicol 1994;13(5): 325–335. 77. Young EG, Woolner LB: A case of fatal poisoning from 2-methoxyethanol. J Ind Hyg Toxicol 1946;28:267–268. 78. Dean BS, Krenzelok EP: Clinical evaluation of pediatric ethylene glycol monobutyl ether poisonings [see comment]. J Toxicol Clin Toxicol 1992;30(4):557–563. 79. Gijsenbergh FP, Jenco M, Veulemans H, et al: Acute butylglycol intoxication: a case report. Hum Toxicol 1989;8(3):243–245. 80. Miller RR: Metabolism and disposition of glycol ethers [Review]. Drug Metab Rev 1987;18(1):1–22. 81. Dugard PH, Walker M, Mawdsley SJ, Scott RC: Absorption of some glycol ethers through human skin in vitro. Environ Health Perspect 1984;57:193–197. 82. Ohi G, Wegman DH: Transcutaneous ethylene glycol monomethyl ether poisoning in the work setting. J Occup Med 1978;20(10):675–676. 83. Johanson G, Kronborg H, Naslund PH, Byfalt NM: Toxicokinetics of inhaled 2-butoxyethanol (ethylene glycol monobutyl ether) in man. Scand J Work Environ Health 1986;12(6):594–602. 84. Rambourg-Schepens MO, Buffet M, Bertault R, et al: Severe ethylene glycol butyl ether poisoning. Kinetics and metabolic pattern. Hum Toxicol 1988;7(2):187–189. 85. Nitter-Hauge S: Poisoning with ethylene glycol monomethyl ether. Report of two cases. Acta Med Scand 1970;188(4):277–280. 86. Osterhoudt KC: Fomepizole therapy for pediatric butoxyethanol intoxication. J Toxicol Clin Toxicol 2002;40(7):929–930. 87. Nisse P, Coquelle-Couplet V, Forceville X, Mathieu-Nolf M: Renal failure after suicidal ingestion of window cleaner: a case report. Vet Hum Toxicol 1998;40:173.

CHAPTER 32


88. Litovitz TL, Bailey KM, Schmitz BF, et al: 1990 annual report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med 1991;9(5):461–509. 89. Burkhart KK, Donovan JW: Hemodialysis following butoxyethanol ingestion. J Toxicol Clin Toxicol 1998;36(7):723–725. 90. Gualtieri JF, DeBoer L, Harris CR, Corley R: Repeated ingestion of 2-butoxyethanol: case report and literature review. J Toxicol Clin Toxicol 2003;41(1):57–62. 91. Ghanayem BI, Burka LT, Matthews HB: Metabolic basis of ethylene glycol monobutyl ether (2-butoxyethanol) toxicity: role of alcohol and aldehyde dehydrogenases. J Pharmacol Exp Ther 1987;242(1):222–231. 92. Bartnik FG, Reddy AK, Klecak G, et al: Percutaneous absorption, metabolism, and hemolytic activity of n-butoxyethanol. Fundam Appl Toxicol 1987;8(1):59–70. 93. Cullen MR, Solomon LR, Pace PE, et al: Morphologic, biochemical, and cytogenetic studies of bone marrow and circulating blood cells in painters exposed to ethylene glycol ethers. Environ Res 1992;59(1):250–264. 94. Johanson G: Toxicity review of ethylene glycol monomethyl ether and its acetate ester [Review]. Crit Rev Toxicol 2000;30(3): 307–345. 95. Correa A, Gray RH, Cohen R, et al: Ethylene glycol ethers and risks of spontaneous abortion and subfertility. Am J Epidemiol 1996;143(7):707–717. 96. Swan SH, Beaumont JJ, Hammond SK, et al: Historical cohort study of spontaneous abortion among fabrication workers in the Semiconductor Health Study: agent-level analysis. Am J Ind Med 1995;28(6):751–769. 97. Chen PC, Hsieh GY, Wang JD, Cheng TJ: Prolonged time to pregnancy in female workers exposed to ethylene glycol ethers

98. 99. 100.

101.

102. 103. 104. 105. 106.

633

in semiconductor manufacturing. Epidemiology 2002;13(2): 191–196. Saavedra D, Arteaga M, Tena M: Industrial contamination with glycol ethers resulting in teratogenic damage. Ann NY Acad Sci 1997;837:126–137. Cordier S, Szabova E, Fevotte J, et al: Congenital malformations and maternal exposure to glycol ethers in the Slovak Republic [see comment]. Epidemiology 2001;12(5):592–593. Cordier S, Bergeret A, Goujard J, et al: Congenital malformation and maternal occupational exposure to glycol ethers. Occupational Exposure and Congenital Malformations Working Group [see comment]. Epidemiology 1997;8(4):355–363. McKinney PE, Palmer RB, Blackwell W, Benson BE: Butoxyethanol ingestion with prolonged hyperchloremic metabolic acidosis treated with ethanol therapy. J Toxicol Clin Toxicol 2000;38(7):787–793. Browning RG, Curry SC: Effect of glycol ethers on plasma osmolality. Hum Exp Toxicol 1992;11(6):488–490. Bowie MD, McKenzie D: Diethylene glycol poisoning in children. South Afr Med J 1972;46(27):931–934. Cantarell MC, Fort J, Camps J, et al: Acute intoxication due to topical application of diethylene glycol. Ann Intern Med 1987;106(3):478–479. van der Linden-Cremers PM, Sangster B: [Medical sequelae of the contamination of wine with diethylene glycol] [Dutch]. Nederlands Tijdschrift voor Geneeskunde 1985;129(39):1890–1891. Pandya SK: Letter from Bombay. An unmitigated tragedy. BMJ 1988;297(6641):117–119.

33

Opioids LUKE YIP, MD ■ BRUNO MÉGARBANE, MD, PHD ■ STEPHEN W. BORRON, MD, MS

At a Glance… ■

■

■ ■ ■ ■

■ ■

Opioids elicit the same overall physiologic effects as morphine but may demonstrate conspicuous differences following an overdose. The classic “opioid toxidrome” (mental status depression, respiratory depression, miosis, and decreased bowel motility) may not be apparent following a mixed overdose. Purity and adulterants play a considerable role in the outcome and complications of heroin use. Inhalation of heated heroin vapors may result in a progressive spongiform leukoencephalopathy. Acute lung injury may occur following opioid overdose or naloxone therapy. Higher doses of naloxone may be required to antagonize the effects of high-potency opioids (e.g., fentanyl and its analogs, methadone, pentazocine, propoxyphene, and diphenoxylate). Naloxone has a short half-life, and the effects of most opioids will significantly outlast several doses of naloxone. Judicious use of naloxone infusion may obviate the need for endotracheal intubation.

HISTORY AND INTRODUCTION Opium, one of the oldest known pharmacologic agents, is derived from the poppy Papaver somniferum. The Sumerians first reported the psychotherapeutic benefits of juice from immature poppy heads about 4000 BC. Opium solutions contained morphine, codeine, and numerous other related alkaloids. In 1806, morphine was isolated from opium by Sertürner. Other alkaloids were later isolated, including codeine in 1832 by Robiquet and papaverine in 1848 by Merck. Morphine was soon recognized to be as addictive as opium. Attempts were made to increase morphine’s antinociceptive and antidiarrheal properties while decreasing tolerance and dependence. The result was Dreser’s synthesis of diacetylmorphine (heroin) in 1898. The existence of specific opioid receptors was definitively established in 1973 by Snyder and colleagues in the United States and Terenius and colleagues in Sweden. In 1975, Kosterlitz and Hughes identified two endogenous pentapeptides with morphine-like activity— the leu-enkephalin and the met-enkephalin—opening the door to the characterization of additional endogenous ligands. Work continues on opioid receptors with the aim of improving our understanding of their biopharmacology and manipulating the beneficial effects of opioids, while reducing their undesirable consequences. The term opiate specifically refers to all naturally occurring alkaloids derived from opium, including

morphine, 6-mono-acetyl-morphine, codeine, codethyline, and pholcodine. In contrast, the term opioid refers to all drugs, natural or synthetic, with morphine-like actions or actions mediated through binding to opioid receptors. This chapter focuses on the clinical issues concerning the acute and chronic toxicology of opioids and appropriate treatment relevant to current clinical practice.

EPIDEMIOLOGY The dangers of opioid overdose have been recognized for as long as the use of opium itself. Overdose from illicit opioid use has increased in many countries over the past decade,1 as has the illicit production, transportation, and consumption of opioids, especially heroin. Higher production, increasing purity, and lower prices have considerably contributed to the worldwide expansion of opioid use. Higher heroin purity enables users to smoke or snort rather than inject it, contributing to widespread popularity, illustrated by a recently reported epidemic of heroin use.2 Changes in the route of opioid administration over time may occur in relation to opioid tolerance or drug purity increase. Heroin vapor inhalation produced by heating heroin on aluminum foil is increasingly common. The majority of drug users currently entering treatment programs are noninjectors. There is a trend toward multidrug use, with attendant drug-drug interactions and the risk of polyintoxication. In 2004, the Substance Abuse and Mental Health Services Administration (SAMHSA) and the Drug Abuse Warning Network (DAWN) estimated that 19.1 million Americans ages 12 or older (about 7.9% of the population) were current illicit drug users.3 However, the prevalence of heroin use remains low in the general population when compared with alcohol, tobacco, or cannabis. Typically, less than 2% of the adult population has ever used heroin, and less than 1% is dependent on heroin. An estimated 300,000 persons in the United States suffer from heroin dependence or abuse (Fig. 33-1), and 118,000 persons have used heroin for the first time within the past 12 months with an average age of initiation at 24 years. The number of injectors has been estimated to be about 5.3 million worldwide, which appears to be constant. For 2003, the American Association of Poison Control Centers (AAPCC) reported 22,600 opioid overdoses among the 270,000 exposures to analgesics (around 8%), which resulted in 213 of 656 deaths (around 35%) attributed to this pharmacological class.4 The SAMHSA reported 709,000 hospital facility visits in 2004 related to illicit drug use, versus 638,484 in 2001 635

636


Heroin

67.8

Cocaine

27.8

Marijuana

17.6

Sedatives

17.4

Stimulants

16.1

Pain relievers

12.3

Alcohol

11.9

Hallucinogens

11.6

Tranquilizers

11.3 10.3

Inhalants 0

10 20 30 40 50 60 Percent of users with dependence on or abuse of specific substance

70

FIGURE 33-1 Comparative incidence of dependence or abuse of specific substances among past users of substances in the United States in 2004. (Courtesy of the Substance Abuse and Mental Health Services Administration, http://www.icpsr.umich.edu/SAMHDA.)

and 323,100 in 1978.3 This increase does not necessarily reflect an elevation in the number of heroin users, but rather a greater number of individuals seeking help. Emergency department admissions for opioid overdose were estimated in the United States at 93,000 per year in 2002 versus 72,000 in 1995. In contrast, heroin use is decreasing in western Europe, with a rise in the mean age, presumably in relation to the widespread introduction of opioid maintenance treatment programs and to the development of dependence on other illicit drugs (cannabis, cocaine, and amphetamines). In France, for example, traditional opiate use has decreased since 1996, when both prescribed and diverted buprenorphine appeared on the scene.5 In other countries, various locally produced opioids are used, including “homeback” in Australia and New Zealand, prepared with codeine and other opiates; “kompot” in Poland, made from poppy straw; and “black water opium” in Vietnam. Opioids represent the most lethal illicit drug, with most of the fatalities occurring in young males, resulting in 33,662 potential years of life lost and 42 years of life lost per death.6 A dependent heroin injector has a 20 to 30 times greater estimated risk for premature death than a similar-aged non–drug-using person. In 1995, opioid overdose deaths accounted for 76% of all deaths due to illicit drug use and 9% of deaths among young adults 15 to 44 years of age in Australia.2 In Glasgow, nearly a third of all deaths among young adults 15 to 35 years of age were related to opioids.7 However, after a rise in the second half of the 1980s, the number of overdose deaths has generally stabilized or declined in the majority of Western countries.1,5 Nearly two thirds of all long-term heroin users have self-overdosed on heroin at least once.8 Mortality for opioid users in maintenance treatment is reduced (about four times), in comparison to opioid users involved in opioid-related emergencies.9 Substi-

tution therapy with methadone, levomethadyl acetate, or buprenorphine may result in a substantial reduction in consumption of illicit opiate and psychoactive substances.10-12 However, deaths have been attributed to maintenance treatment as well, in relation to their overdose or misuse. Deaths have been reported in relation to buprenorphine “overdose.”13-16 Forensic studies concluded that these deaths were due to asphyxia, with the underlying cause attributed to misuse and/or coadministration of psychotropic substances. Buprenorphine is injected by some users, despite the labeling for sublingual use.17-19 However, despite an estimated 90,000 patients treated with high-dose buprenorphine (8 to 16 mg/day) in France since 1996, the number of significant reported side effects has been limited.5,20 Interestingly, it appears that a strict limitation on the number of patients per prescribing physician for buprenorphine substitution programs has been associated with very limited abuse of the product since its launch in the United States in 2002.21 Similarly, most lethal methadone intoxications are due to diverted or illegal methadone, in association with medications or other illicit drugs.22,23 Recent increases in methadone prescription under strict medical control have not increased the number of lethal methadone intoxications but may have contributed to a large decrease in overall drug intoxication deaths.24

PHARMACOLOGY The Various Opioid Molecules Morphine is still obtained from opium or extracted from poppy straw. A number of natural alkaloids are derived from Papaver somniferum, including phenanthrenes (morphine, codeine, and thebaine) and benzylisoquinolines (papaverine, noscapine). Codeine is methylmorphine. Thebaine, the precursor of several compounds such as oxycodone and naloxone, differs from morphine in the methylation of its two hydroxyl groups and the presence of double bonds in the ring. Heroin is a diacetylmorphine, in the 3 and 6 positions. Hydromorphone, oxymorphone, hydrocodone, and oxycodone are also made by modifying the morphine molecule. Synthetic opioids can be structurally divided into five classes: morphinans, phenylpiperidines, benzomorphans, methadones, and propionanilides. Levorphanol is the only commercially available opioid agonist from the morphinan series. The phenylpiperidine family includes meperidine, diphenoxylate, loperamide, fentanyl, sufentanil, alfentanil, and remifentanil. Methadone and propoxyphene are structurally related opioids. Some partial opioid antagonists are clinically used, including pentazocine (a benzomorphan derivative), nalbuphine (structurally related to naloxone and oxymorphone), buprenorphine (a semisynthetic opioid derived from thebaine), and meptazinol. Minor changes in the chemical structure may convert an agonist into an antagonist opioid, like nalorphine (derived from morphine) or naloxone and naltrexone (both derived

CHAPTER 33

from oxymorphone). These substitutions are critical in determining agonist or antagonist properties, as well as their interactions with the various opioid receptors. A simple classification scheme including all opioids, whether clinically used or not, distinguishes natural exogenous opioids, synthetic opioids, and endogenous opioids. THE EXOGENOUS NATURAL OPIOIDS This class includes opiates derived from Papaver somniferum, like morphine, as well as other animalderived peptides, like deltorphines, extracted from the skin of South American frogs belonging to the Phyllomedusa genus and characterized by a high affinity to b receptors. THE SYNTHETIC OPIOIDS This group may be subdivided into nonpeptide and peptide-like molecules. The first subgroup includes morphine derivatives, like heroin, buprenorphine, methadone, and etorphine (Fig. 33-2), as well as some b selective agonists. THE ENDOGENOUS OPIOIDS Endogenous opioids are naturally occurring peptides with various types of opioid activity. They are produced after the cleavage of high-molecular-weight precursors. This group includes endorphins, enkephalins, and dynorphins or neoendorphins. They are found at various sites and in differing quantities throughout the central and peripheral nervous system. Complex interactions with multiple opioid receptors result in modulation of the response to painful stimuli. More recently, two tetrapeptides have been described and dubbed “endomorphins” due to their high affinity to + opioid receptors, making them good candidates as endogenous ligands of these receptors.25 HO N

Me

MeCOO

O

N

Me

O MeO HO

H

Pr n MeCOO

Me Etorphin

Heroin

HO N O

Me Me

MeO HO

But

EtCO

N Me Ph Ph

Me Buprenorphine Methadone FIGURE 33-2 Chemical structures of the main opiate/opioid molecules.

Opioids

637

PHARMACODYNAMICS The clinically used opioids exert a common activity profile, mainly through + opioid receptors. The central analgesic action of opioids is the most important property used in therapeutics.26 These antinociceptive effects are mediated through spinal and supraspinal opioid receptors. Analgesia occurs without loss of consciousness. Given to patients in pain, opioids reduce the pain, while drowsiness commonly occurs and euphoria may be experienced. Given to normal painfree subjects, opioids may induce nausea, vomiting, drowsiness, apathy, or lessened physical activity. Mood alterations including euphoria, tranquility, and rewarding properties may follow opioid administration. Their mechanism is still not clearly understood but seems mediated by dopaminergic pathways, independently from those involved in physical dependence and analgesia. Pinpoint miosis is a near pathognomonic consequence of opioids on the parasympathetic innervation of pupils. The cough reflex is depressed through a direct action on the cough center in the medulla. This antitussive action represents the target effect of some opioid agents. Nausea and vomiting are caused by direct stimulation of the chemoreceptor trigger zone for emesis in the area postrema of the medulla. Opioids may be responsible for respiratory depression, mainly by a direct effect on the brainstem respiratory centers. Opioids may also depress the pontine and medullary centers involved in regulation of respiratory rhythmicity. With usual opioid doses, in the absence of underlying pulmonary or neurologic diseases, clinically significant respiratory depression is rare, unless other psychotropic or sedative medications are concomitantly used. Respiratory depression increases with the dose and is the incriminated mechanism of death following opioid overdose. All phases of respiration may be depressed, including respiratory rate and tidal and minute volumes. Following an intravenous (IV) injection of morphine, maximal respiratory depression is obtained within 5 to 10 minutes. High doses of certain opioids (fentanyl, alfentanil, remifentanil, and sufentanil) may produce acute muscular rigidity, involving the trunk and the chest wall, sometimes compromising respiration. The mechanism for this is still debated and may involve basal ganglia dopamine receptor blockade, _2-adrenergic or b opioid receptor stimulation. In patients undergoing anesthesia, muscle rigidity may necessitate the administration of neuromuscular blocking agents to facilitate mechanical ventilation. Endocrine effects have also been reported, including the inhibition of gonadotropin-releasing hormone and corticotropin-releasing factor production, inducing a diminution in concentrations of luteinizing hormone, follicle-stimulating hormone, adrenocorticotropic hormone, and `-endorphin circulating. Antidiuretic hormone release is also reduced. Opioids increase the muscular tonus of the gastrointestinal (GI) tract and diminish peristaltic contractions. They also diminish biliary, pancreatic, and intestinal secretions, but increase anal sphincter tone. Intestinal resting tone is increased and

638


spasms may result. All these effects induce desiccation of the feces, leading to constipation and the therapeutic use of some opioid compounds as antidiarrheic substances. Opioids also increase bladder external sphincter tone, resulting in urinary retention, sometimes requiring bladder catheterization. Opioid-related cardiovascular side effects are well known: mild reduction in blood pressure, risk for orthostatic hypotension, or, uncommonly, bradycardia. Only propoxyphene is associated with significant cardiovascular toxicity due to sodium channel blockade. Opioids also induce peripheral vasodilatation at therapeutic doses. The skin of the face, neck, and upper thorax may flush due to histamine liberation. The immune system also may be considered a potential therapeutic target of opioids, including central immunomodulatory activity or direct effects on immune cells. This latter effect is related to an activation of b opioid receptors expressed on peripheral blood cells. Met-enkephalin and `-endorphin may stimulate the chemotactic properties of neutrophils, monocytes, or lymphocytes. In contrast, morphine reduces the activity of natural killer lymphocytes and neutrophil activity. The latter immunosuppressive effects appear to be mediated through + receptors.27 Prolonged treatment with opioids may induce a tolerance to their effect, characterized by the loss of their effectiveness and the necessity to increase doses to obtain the same effects. Dependence on opioids is responsible for the appearance of withdrawal when the opioid therapy is abruptly stopped. Addiction results from an altered behavior with the compulsive use of opioids and an overwhelming need for their procurement and use. The molecular mechanisms of dependence and tolerance appear very complex, involving opioid and N-methyl-Daspartate receptors. These pathways are physiologic responses to opioid treatments and may be distinct from those involved in addiction. Morphine, tramadol, meperidine, fentanyl, and related opioids are used primarily for their analgesic properties. Codeine is used widely for its antitussive action. Given their dynamic and kinetic properties, methadone (with a long half-life) and buprenorphine (with partial + agonist activity) are used as maintenance therapies in heroin abusers. Naloxone, the therapeutic antagonist of reference, is used to reverse neurologic and respiratory depression induced by acute opioid poisoning.

OPIOID RECEPTORS The International Union on Receptor Nomenclature has recently recommended a nomenclature change from the historical Greek alphabet to one similar to other neurotransmitter systems, the receptors b, g, and +, becoming OP1, OP2, and OP3, respectively.28 1. The m opioid receptors (OP3). The + receptors were the first opioid binding sites described, in relation to morphine agonist activity and high affinity.29 Morphine has a 50-times higher affinity for + receptors in comparison with other opioids. Fentanyl

and other piperidyl agonists also have good affinity and selectivity for + receptors (Table 33-1). Naloxone is the only clinically used opioid receptor antagonist, with a higher affinity for the + than for the other receptors.30 Other antagonists also have good selectivity for + receptors (Fig. 33-3). + Receptors are further classified into +1 and +2 subclasses (Table 33-2). The +1 receptors found in the periaqueductal gray matter, the nucleus raphe magnus, and the locus caeruleus are postulated to have supraspinal analgesic properties. The +1 receptors are responsible for almost all opioid analgesic properties, and to some extent, their side effects. The +2 receptors, characterized by a lower affinity for opioids than +1, are responsible for the untoward side effects of opioids, including respiratory depression, delayed GI motility (nausea, vomiting, and constipation), urinary retention, bradycardia, miosis, euphoria, and physical dependence. 2. The k receptors (OP2). The g agonists produce analgesia that is unaffected by tolerance or antagonists to + receptors (see Table 33-2). The g1 receptors appear to be concentrated in the spinal cord, whereas g2 and g3 receptors appear to predominate in the supraspinal region. They may even outnumber + receptors in that region. Untoward effects of g stimulation include respiratory depression (less than +), miosis, dysphoria, and psychotomimetic effects. 3. The b receptors (OP1). The b receptors mediate spinal analgesia, specifically via thermal nociception. Both enkephalins and `-dynorphin bind to this class. The b receptors also have a cortical distribution and may have a role interacting with centrally located + receptors. Untoward side effects include respiratory depression via decreased respiratory rate.29 All these opioid receptors have now been cloned and sequenced. They each consist of seven transmembrane segments (Fig. 33-4). The molecular conformations of the opioid receptors play an important role in their activity.31,32 All the opioid receptors belong to the Gprotein–binding superfamily, with significant sequence homology between their transmembrane regions. However, important differences exist within their intracellular and extracellular segments, determining the differences in their binding properties (Table 33-3). Different mechanisms of cellular transduction are now described, depending not on the receptor type but on its localization. The G-protein structure contains three subunits (_, `, a), from which the à subunit is liberated on the binding of the _ subunit to guanosine triphosphate. The à is then able to activate various effector systems, including phospholipase C, adenylate cyclase, other channels, or transport proteins (Fig. 33-5). The main postsynaptic signal trasduction mechanism is based on the inhibition of the adenylate cyclase, mediated by inhibitory G proteins (Gi), associated with +, g, and b opioid receptors.33,34 Opening of potassium channels may result from opioid receptor stimulation, yielding membrane hyperpolarization and neuronal excitability reduction.35,36 On the presynaptic membrane, the opioid receptor activation is associated with a closure

CHAPTER 33

Opioids

639

TABLE 33-1 Opioid Pharmacological Properties a RECEPTOR, [3]HU-69,593

d RECEPTOR, [3H]NALTRINDOL

m RECEPTOR, [3H]DAMGO

Nonselective Compounds Dynorphin A Leu-enkephalin Met-enkephalin `-Endorphin Des-Tyr1-`-endorphin (–)-Naloxone (+)-Naloxone Levorphanol Dextrorphan (±)-Bremazocine Ethylketocyclazocine Etorphine Pentazocine Diprenorphine `-CNA `-FNA Naltrexone Nalbuphine Nalorphine

0.5 >1000 >1000 52 >1000 2.3 >1000 6.5 >1000 0.089 0.40 0.13 7.2 0.017 0.083 2.8 3.9 3.9 1.1

>1000 4.0 1.7 1.0 >1000 17 >1000 5.0 >1000 2.3 101 1.4 31 0.23 115 48 149 >1000 148

32 3.4 0.65 1.0 >1000 0.93 >1000 0.086 >1000 0.75 3.1 0.23 5.7 0.072 0.90 0.33 1.0 11 0.97

m-Selective Compounds CTOP Dermorphin Methadone DAMGO PLO17 Morphiceptin Codeine Fentanyl Sufentanil Lofentanil Naloxonazine Morphine

>1000 >1000 >1000 >1000 >1000 >1000 >1000 255 75 5.9 11 538

>1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 50 5.5 8.6 >1000

0.18 0.33 0.72 2.0 30 56 79 0.39 0.15 0.68 0.054 14

k-Selective Compounds Norbinaltorphimine Spiradoline U-50,488 U-69,593 ICI 204,488 d-Selective Compounds DPDPE D-Ala2-deltorphin II DSLET BW 3734 DADL SIOM Naltrindole NTB BNTX

0.027 0.036 0.12 0.59 0.71 >1000 >1000 >1000 17 >1000 >1000 66 13 55

65 >1000 >1000 >1000 >1000 14 3.3 4.8 0.013 0.74 1.7 0.02 0.013 0.66

2.2 21 >1000 >1000 >1000 >1000 >1000 39 26 16 33 64 12 18

Receptor affinity (Ki) were obtained using competition with [3H]naltrindol (b), [3H]U69,593 (g), and [3H]DAMGO (+) in the presence of the indicated molecules. `-CNA, `-chlornaltrexamine; `-FNA, `-funaltrexamine; CTOP, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2; SIOM, 7-spiroindinooxymorphone. Data from Raynor K, Kong H, Chen Y, et al: Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors. Mol Pharmacol 1994;45(2):330–334.

of N-type calcium channels, resulting in a reduction of intracellular calcium concentration at the end of the synapse and leading to the blockage of presynaptic vesicle fusion with the terminal membrane and the reduction in neurotransmitter release.37

PHARMACOKINETICS Opioids are available in numerous formulations, allowing various routes of administration, including oral, parenteral, transdermal (fentanyl), transmucosal (morphine

640


FIGURE 33-3 Selective + opioid receptor agonists and antagonists.

N

N

O

N

K

HO

H

OH

O

PLO17

DAMGO

TyrJProJtJMePheJDJProJNH2

TyrJDJAlaJGlyJN(Me)PheJGlyJoI

Fentanyl

Morphine

CH2CHKCH2 CH2CHKCH2

HO

N

N HO

OH O

HO

O

O

Naloxone

K

K

N N

N

K

OH

O

OH

Naloxonazin

HO N OH O

OH

H

H

NJCH2J OK

HO

O

Naltrexone

H

C KC

NHCO

CO2CH3 H

b-FNA

TABLE 33-2 The Different Opioid Receptor Type and Subtypes RECEPTORS

AGONISTS*

ANTAGONISTS

+ +1

Morphine, methadone, DAMGO Meptazinol

CTOP Naloxonazin

+2

Metkephamid

b

DSLET

b1 b2 g g1 g2 g3

DPDPE Deltorphin Dynorphin A, ethylketocyclazocine U50,488H, spiradolin Bremazocin Nalorphin

SPECIFIC REPORTED EFFECTS OF EACH RECEPTOR SUBTYPE

Naltrindol, NTB, BNTX

Nor-binaltorphimin (nor-BNI)

Sedation, euphoria Supraspinal analgesia, peripheral analgesia, euphoria, prolactin release Spinal analgesia, respiratory depression, physical dependence, gastrointestinal effects, bradycardia, puritis, dopamine, and growth hormone release Modulation of + receptor function and dopaminergic neurons Spinal and supraspinal analgesia Supraspinal analgesia Sedation, gastrointestinal effects Spinal analgesia, diuresis, miosis Psychotomimesis, dysphoria Supraspinal analgesia

*Leverphanol and etorphin are nonspecific agonists of the three opioid receptor types, whereas naloxone and naltrexone are nonselective antagonists of these three receptor types.

and hydromorphone), epidural, intrathecal, intranasal, and even intrapulmonary (by smoking) administration. In opioid overdoses, dosage, duration, and route of administration may influence symptoms and their duration. Thus, considering opioid pharmacokinetic properties is useful in understanding their toxicologic

consequences and choosing the best methods of treatment. Variable reduction in bioavailability results from first pass metabolism when absorbed through the GI tract. Morphine bioavailability by the oral route is only 25%, in contrast to codeine at 60%. Buprenorphine undergoes

CHAPTER 33

P G

A

A

R S

A

E M

S L A L S I

A

K I

T A L Y C V A S A V G L V N G L L V M F V I G Y T

P C A S

S A N A G A S

P G

Y L

A S Q F S T L P T A L A A L A D L N F I T N I Y A T

R K M

K

I

A V

A

A A G

G G

P

V V C

T W P F L E L C K

G

P Y

M

L Q S

G D R P R

Q L P

A G

F L P

A

A N A D S

F

W Y

E

P

P S

W

G A S A

I

D T V

D R

D V T L

R

P

A

P

Opioids

641

E M

D P L V V R A L H

T F K W V I V F L L V H A I C I F A F F V L I P P G W V V A Y N M F V P I G Y A G N I I L F V V C L A S F I S T L S S T V A G V N V W I C T L T C Y G V P V L F A Y L I N I M V L V L L M L V S M M L D R T R A K C D R K L Q L R R I A P F E Y R R L T R K N R C S S R F P C F V K R H P D D K C R V K A L E L L S G G S K R P D S P S D S P T C A T V R E R A T A E R A R S F A V L S Y D I

T V A M I M V

C

A TMH 5

TMH 3

TMH 6 Phe 5.43 Tyr 3.33

TMH 4 Phe 5.47

His 6.52

Trp 4.50

Trp 6.48

Phe 6.44

B FIGURE 33-4 A, Molecular representation of opioid receptors. All receptors exhibit seven transmembrane segments with differences determining specific binding properties. B, As an example, we represented the aromatic and polar residues of the b receptors, which are specific for its binding sites.

extensive first pass metabolism after oral administration, making the sublingual route mandatory for a bioavailability of 50%.38 Protein binding and any interaction that alters it also play a vital role in pharmacodynamics. The range of protein-bound opioid varies from a low of 7% for

codeine to greater than 90% for methadone and buprenorphine. Depression in albumin and other serum proteins (_- or `-globulin) resulting in decreased binding may produce higher levels of free opioid with possible opioid toxicity. Changes in serum pH may also alter protein binding of opiates. Transport system

642


TABLE 33-3 Selective Activity of the Main Opiate/Opioid on the Different Opioid Receptors MOLECULES

ACTIVITY

+ RECEPTOR

Morphine Methadone Etorphin Fentanyl Sufentanyl Buprenorphine Nalorphin Pentazocin Naloxone Naltrexone

Agonist Agonist Agonist Agonist Agonist Agonist–antagonist Agonist–antagonist Agonist–antagonist Antagonist Antagonist

+++ +++ +++ +++ +++ P ––– P ––– –––

Endogenous Peptides* Met- et Leu-enkephalins `-endorphin Dynorphin A Dynorphin B _-neoendorphin

Agonist Agonist Agonist Agonist Agonist

++ +++ ++ + +

b RECEPTOR

g RECEPTOR +

+++

+++

+ ?

+ –– + ++ –– –––

– – +++ +++ + +

+++ +++ +++

*Enkephalins and endorphins are considered the endogenous ligands of + and b receptors; dynorphin A activity is related to g receptors. +, agonist; –, antagonist; P, partial agonist; ?, not determined.

proteins, such as P-glycoproteins, may also influence tissue distribution. Crossing the blood-brain barrier is dependent on lipid solubility and polarity and influences clinical effects. Heroin (diacetylmorphine) enters the brain more readily than both of its metabolites, 6monoacetylmorphine (6-MAM) and morphine, explaining its greater addictive potential. Opioids generally undergo hepatic metabolism with some form of conjugation, hydrolysis, oxidation, or dealkylation. Some of the resulting metabolites have been implicated in the activity or recognized toxic side effects of various opioids. Examples of this include the metabolism of codeine to morphine, morphine to the more active morphine-6-glucuronide, buprenorphine to norbuprenorphine, meperidine to the potentially neurotoxic normeperidine, and propoxyphene to the potentially cardiotoxic norpropoxyphene. Figure 33-6 illustrates the metabolism of buprenorphine, which undergoes extensive cytochrome P-450 3A4-mediated N-dealkylation to norbuprenorphine and then glucuronidation.39 Cytochrome genotype appears to be an important parameter in opioid efficacy or toxicity. Small doses of codeine, which is bioactivated into morphine by cytochrome P-450 2D6, may be responsible for lifethreatening intoxication in patients with allele patterns inducing ultrarapid metabolism, in combination with inhibition of cytochrome P-450 3A4 activity and a transient reduction in renal function.40 Excretion of opiates occurs primarily via the renal route, with about 90% of the opioid metabolites eventually being excreted in the urine, usually via glomerular filtration. A small amount may end up in the GI tract via enterohepatic circulation. The urinary detection of opioids or metabolites is a routinely used diagnostic test. The presence of 6-MAM in the urine is a reliable marker of recent heroin consumption, because humans cannot acetylate morphine but only deacetylate heroin. Renal failure leads to toxic effects via accumulated drug or active metabolites (morphine-6-

glucuronide or normeperidine). Hepatic dysfunction results in delayed liver metabolism of certain opioids (meperidine, pentazocine, and propoxyphene), leading to accumulation and development of central nervous system (CNS) or respiratory depression. Drug interactions may occur at various sites affecting the absorption, metabolism (induction of hepatic enzymes), and elimination of opioids (competition for renal excretion) contributing to the potentiation or reduction of their effects. Acceleration of metabolism in the liver, which results from phenytoin induction, may result in diminished activity (methadone) or an increase in potentially toxic metabolites (normeperidine). The discontinuation of an interacting drug may play just as important a role as the addition of one in changing the bioavailability and activity of opioids. These interactions may lead to the onset of overdose or withdrawal symptoms. Interaction between buprenorphine and benzodiazepines, which is suspected to be one of the mechanisms of buprenorphine-related toxicity or fatality,41 has been attributed to a pharmacodynamic mechanism.42

TOXICOLOGY In general, a drug classified as an opiate or opioid elicits the same overall physiologic effects as morphine, the prototype of this group. However, there are conspicuous differences among these agents, which will be specifically addressed. Varying degrees of the classic “opiate toxidrome” (i.e., mental status depression, respiratory depression, miosis, and decreased bowel motility) may manifest in patients administered opioids.

Central Nervous System Effects A dose of 5 to 10 mg of morphine usually produces analgesia without altering mood or mental status in a patient. Sometimes dysphoria rather than euphoria may

CHAPTER 33

Ca2;

K;

;

:

ai

ai

bg

: ATP

AMPc

PLC

Ca2;

PIP2

;

; Ca2;

aq

; IP3

;

643

FIGURE 33-5 Regulation of the different cellular effectors by the opioid receptors MAPK (mitogenactivated protein kinases), AC (adenylate cyclase), PLC (phospholipase C), IP3 (inositol 1,4,5 triphosphate), and PIP2 (phosphatidylinositol 4,5 biphosphate).

Ca2;

AC

;

Opioids

MAPK Ca2;

HO O NJ H3CO

HO C CH3 CH2OH CH3

Hydroxylation

N-dealkylation

CH3 M1

CYP3A5,3A4,3A7,2C8

HO

HO

O

N-dealkylation

O NJ

HO O

Hydroxylation

NH

NH CYP3A5,3A4,3A7,2C8

H3CO

CYP3A4,3A5

H3CO

HO C CH3

HO C CH3 CH3 CH3 CH3

Bup

Norbup

CH3 CH3 CH3

Hydroxylation

H3CO

HO C CH3 CH2OH CH3 CH3 M3

HO

HO OH

OH

N-dealkylation

O

O NJ

H3CO

NH H3CO



M2 M4 (or M5) FIGURE 33-6 Liver metabolism of buprenorphine (Bup), as demonstrated in vitro, using liver microsomes. Various cytochromes P-450 (CYP) are involved, resulting in the production of a predominant active metabolite, the norbuprenorphine (Norbup). Other metabolites (M1 to M5) are also produced, but their role and importance in vivo are unknown. (From Chang Y, Moody DE, McCance-Katz EF: Novel metabolites of buprenorphine detected in human liver microsomes and human urine. Drug Metab Dispos 2006;34(3):440–448.

644


manifest, resulting in mild anxiety or a fear reaction. Nausea is frequently reported, whereas vomiting is occasionally observed. The clinical effects of morphine are accentuated with increasing doses (e.g., analgesia is stronger, lethargy and drowsiness progress to sleepiness and coma). Slurred speech and significant motor incoordination are usually absent. Morphine and most of its congeners cause pupillary constriction. This effect is predominantly a central effect and is accentuated following an overdose. Not all patients taking opioids present with miosis. Patients taking meperidine or propoxyphene regularly maintain normal pupillary size, and patients taking pentazocine may not develop miosis.43 Mydriasis may occur in severely poisoned patients secondary to hypoxic or anoxic brain injury. Combination drug use such as cocaine and heroin (“speedball”), scopolamine-adulterated heroin, and Lomotil (diphenoxylate hydrochloride and atropine sulfate; Pfizer, New York, NY) or the presence of adulterants may produce variable pupil size depending on the relative contribution by each agent. Cerebral circulation does not appear to be altered by therapeutic doses of morphine, unless respiratory depression and carbon dioxide retention result in cerebral vasodilation.44 Seizures are rare adverse drug events associated with most therapeutic opioid dosing. In an acute opioid overdose, seizures are most likely to be caused by hypoxia. Morphine-induced seizures have only been reported in neonates,45 and seizures should be anticipated in patients with meperidine, propoxyphene, or tramadol toxicity.

Respiratory Effects Respiratory failure is the most serious consequence from opioid overdose. Opioids reduce ventilation by diminishing the sensitivity of the medullary chemoreceptors in the respiratory centers to an increase in carbon dioxide tension (PaCO2) and depress the ventilatory response to hypoxia.46 The combined diminution in hypercapnic and hypoxic drive leaves virtually no stimulus to breathe, and apnea ensues. Even small doses of morphine depress respiration by directly affecting the brainstem respiratory centers. Morphine-induced respiratory depression initially relates more closely to changes in tidal volume and a reduction of respiratory rate with escalating doses.30,44 The peak respiratory depressant effect is usually noted within 7 minutes of IV morphine administration, and may be delayed for up to 30 minutes if the drug is administered intramuscularly. Normal carbon dioxide sensitivity usually returns within 2 to 3 hours, while minute volume may remain below normal for up to 5 hours following a therapeutic dose.47

Cardiovascular Effects Therapeutic opioid doses cause arteriolar and venous dilation and may result in a mild decrease in blood pressure.48 This change in blood pressure is clinically insignificant while the patient is supine, but significant orthostatic changes are common.49 Hypotension appears to be mediated by histamine release50 and may be related to the nonspecific ability of certain opioids to activate mast cell

G protein,51 which induces degranulation of histaminecontaining vesicles. The combination of H1 and H2 antagonists appears to be effective in ameliorating the hemodynamic effects of opioids.52 Not all opioids are equivalent in their ability to release histamine. In one study, meperidine produced the most, and fentanyl the least, hypotension and elevation of plasma histamine levels.53 Bradycardia is unusual, but a reduction in heart rate is common as a result of the associated reduction in CNS stimulation. Myocardial damage (necrotizing angiitis) in opiate overdose associated with prolonged hypoxic coma may be mediated by cellular components released during rhabdomyolysis, direct toxic effects, or hypersensitivity to the opioids or adulterants.54

Gastrointestinal Effects Therapeutic use of opioids, morphine in particular, produces significant nausea and vomiting.55 It is mediated through agonism at dopamine-2 receptor subtypes within the chemoreceptor trigger zone of the medulla. Opioid-induced constipation is an adverse drug event of both the therapeutic and recreational use of opioids. It is mediated by +2 receptors within the smooth muscle of the intestinal wall. Morphine and related drugs may cause a delay in the passage of gastric contents through the pylorus up to 12 hours and marked decrease in intestinal peristalsis.

SPECIFIC OPIOIDS Heroin Heroin has two to five times the analgesic potency of morphine, with similar effects on the CNS.56 Virtually all street heroin in the United States is produced in clandestine laboratories and is adulterated prior to distribution. The purity of street heroin is between 5% and 90%, and is usually less than 50%.57 Adulterants may include noscapine, caffeine, procaine, various sugars, phenobarbital, methaqualone, quinine, and acetaminophen in combination with caffeine.58,59 Heroin is generally bought by the “bag” (25 mg) or quarter gram and may also be mixed with other drugs of abuse (e.g., “speed ball”). Purity and adulterants may play a considerable role in the outcome and complications of heroin use. Interindividual variation in sensitivity and tolerance makes correlation of serum heroin levels with clinical symptoms difficult. Heroin is available as either a hydrochloride salt or a base, with the base being the prevalent form in most regions of the world. The hydrochloride salt form is typically a white or beige powder and is highly water soluble, which allows simple IV administration. Heroin base is often brown or black in color, and “black tar heroin” is one designation referring to an impure form available in the United States. Heroin base is virtually insoluble in water, and requires heating until it liquefies prior to IV administration. This process involves heating the powder in a spoon or bottle cap until it is dissolved, passing the heroin through cotton or a cigarette filter

CHAPTER 33

into a syringe, and boiling the cotton or filters to extract additional drug. The filtered heroin and the extract are injected IV or subcutaneously (“skin popping”). Some drug users may become acutely ill with a benign febrile, leukocytic syndrome following an IV injection. This condition is known as “cotton fever,” and its etiology has been attributed to bacteremia following injection of Enterobacter agglomerans that has colonized in the cotton or cigarette filters.60 Heroin may also be taken intranasally (snorted) and by inhalation of heated vapors. Inhalation of heated vapors is known as “chasing the dragon,” “Chinesing,” or “Chinese blowing,” and involves placing heroin base on aluminum foil, heating it from below with a flame, and inhaling the thick white pyrolysate through a straw. The bioavailability of heroin administered by this route is comparable with that of heroin administered by other routes, and the clinical and toxicological effects are dose dependent.61,62 Physiologically, the effects of heroin are identical to those described for morphine.63,64 The plasma half-life of heroin is 5 to 15 minutes. Heroin is initially deacetylated in the liver and plasma and then is renally excreted as a conjugate, with small amounts of morphine, diacetylmorphine, and 6-MAM.65 The initial heroin rush is probably due to its high lipid solubility and rapid penetration into the CNS.56 The majority of its lasting effects are attributable to its metabolites 6-MAM and morphine.49 Fatal overdoses with heroin have been reported with serum morphine concentrations of 0.1 to 1.8 +g/mL.66 Acute lung injury (noncardiogenic pulmonary edema) as a complication of heroin overdose was first described by William Osler during an autopsy.67 Its presentation and clinical course following nonfatal heroin overdoses were first described in 1953,68 and later in case series and reports.69 Patients with acute lung injury may present early on in their course; within 2 hours of parenteral heroin use and up to 4 hours following intranasal heroin use.66,69,70 Typically, the patient awakens from an opioid coma, either spontaneously or following an opioid antagonist, and over the subsequent several minutes to hours develops hypoxemia and pulmonary rales. Classic frothy, pink sputum is occasionally observed in the patient’s airway. Acute lung injury was reported in 48% of hospitalized heroin overdose patients71 and was noted in 50% to 90% of heroin overdose patients at postmortem examinations, many of whom died in a prehospital setting.72,73 Postmortem studies of patients who succumbed to heroin-induced acute lung injury showed no gross cardiac pathology.74 The mechanism for acute lung injury may be multifactorial and includes profound hypoxemia, hypersensitivity reactions, immune complex deposition in the alveolar capillary membrane, histamine-induced capillary leakage, neurogenic sympathetic discharge, and transient lymphatic pumping irregularities.70-72,75-79 A consequence of “chasing the dragon” is a progressive spongiform leukoencephalopathy and was first reported from the Netherlands.80 The initial symptoms include pronounced motor restlessness (e.g., compulsion to move), apathy, bradyphrenia, soft (pseudobulbar)

Opioids

645

speech, disturbed cerebellar speech, and ataxia. After 2 to 4 weeks some patients developed rapid worsening of the cerebellar symptoms (e.g., gait disturbance). Hyperactive deep tendon reflexes and pathologic reflexes with hypertonic hemiplegia or tetraplegia developed. Some patients developed tremor of the head and shoulders, and others developed myoclonic jerks or choreoathetoid movements. In most cases palmomental, snout, and oculomandibular reflexes became evident. Patients who did not deteriorate remained stable with subsequent partial improvement. Within the next 2 to 4 weeks some patients further progressed in their clinical course and developed stretching spasms, profuse perspiration, central pyrexia, and blindness. The spastic paresis became hypotonic and resulted in areflexia. Some patients developed akinetic mutism. All patients who had progress to this stage died, most because of respiratory difficulties. The mortality rate was 25%. Survivors have stabilized with severe deficits or shown modest degrees of improvement.81,82 Heroin toxicity may be associated with cardiac conduction abnormalities and dysrhythmias,83-85 which may be the result of metabolic derangements associated with hypoxia, a direct effect of heroin or its metabolites or of adulterants.54,86,87 Quinine-adulterated heroin has been associated with dysrhythmias,88,89 amblyopia,90 and thrombocytopenia.91 Patients exposed to heroin that has been adulterated with scopolamine may present in acute anticholinergic crisis.92 Surreptitious addition of cocaine to heroin may cause significant myocardial ischemia or infarction.93 Other reported adulterants include thallium,94 lead,95 amphetamines,96 chloroquine,97 and strychnine.98

Codeine Codeine (methylmorphine) is available as a sole ingredient and in combination with aspirin or acetaminophen. Codeine is rapidly absorbed by the oral route, producing a peak plasma level within 1 hour of a therapeutic dose.99 Ten percent of codeine is metabolized to morphine.100 Both codeine and morphine appear in the urine within 24 to 72 hours, with only morphine being detected in the urine at 96 hours.99 The effect of codeine on the CNS is comparable but less pronounced than that of morphine. An IV codeine phosphate dose of 750 to 900 mg produces symptoms similar to those seen with acute heroin overdose.101 Fatal ingestions with codeine alone are rare. The estimated lethal dose in a nonabuser is 800 mg, with a serum codeine concentration of 0.14 to 4.8 mg/dL.102,103

Fentanyl Fentanyl is a synthetic opioid with rapid onset of action and short duration of action, and has a potency 100 times that of morphine. It is highly lipid soluble and has a volume of distribution of 60 to 300 L.104 Legitimate fentanyl use is limited to anesthesia and conscious sedation, and it has been abused mostly by medical and paramedical personnel because of limited access since it was first introduced. Numerous fentanyl analogs (e.g., _-

646


methylfentanyl [“China White”], 3-methylfentanyl, _methyl-acetyl-fentanyl, _-methyl-fentanyl acrylate, and benzyl fentanyl) have been illicitly synthesized and distributed on the street as heroin substitutes.105-109 They can be 200 to 6000 times more potent than morphine. Toxic effects may be experienced with very small amounts. Typically, the patients present comatose and apneic. In such cases, unsuspecting users administer their usual “dose” of heroin, which surreptitiously contains variable amounts of an illicit fentanyl analog. A number of “heroin-related” deaths have been attributed to these agents secondary to marked increased potency compared with heroin.106-108 Rapid IV injection of certain high-potency opioids (e.g., fentanyl) may result in acute muscular rigidity primarily involving the trunk, and may impair chest wall movement and exacerbate hypoventilation. Similar effects contribute to lethality during epidemics of fentanyl-adulterated heroin.107 Although motor activity resembling seizures has been associated with fentanyl use,110-112 simultaneous electroencephalogram recording during fentanyl induction of general anesthesia did not show epileptiform activity.113-116 This suggests a myoclonic rather than epileptic nature of the observed muscle activity.115 Fentanyl is available as a patch; a transdermal delivery system establishes a depot of drug in the upper skin layers, where it is available for systemic absorption. After removal of the patch, drug absorption from the dermal reservoir continues and the effective fentanyl half-life is 17 hours, versus 2 to 4 hours associated with the IV route (Duragesic [fentanyl], Janssen Pharmaceutica, Piscataway, NJ). The availability of a transdermal fentanyl delivery system provides a widening pool of individuals with access. Prescribed transdermal fentanyl patches can be sold or stolen. Disabling myoclonus has been reported after several days of fentanyl therapy by the transdermal delivery system.117 Misuse and abuse of the fentanyl patch has been reported in the form of simultaneous application of multiple patches, ingestion, inhalation, and IV injection of the transdermal fentanyl patch contents, which has resulted in respiratory arrest and death.118-124

Meperidine Meperidine is a synthetic opioid and is chemically different from the traditional opiates. Although considered to possess strong analgesic properties when given by the parenteral route, it is less than half as effective if given by the oral route.125 It appears to be a common drug of abuse among medical personnel, with few reports of meperidine poisoning or fatalities.126-128 Meperidine is metabolized in the liver primarily by Ndemethylation to normeperidine, an active metabolite with half the analgesic and euphoric potency of meperidine, and twice the neurotoxic properties.129,130 Excretion is primarily through the kidneys as conjugated metabolites.131 Meperidine and normeperidine may be detected in either urine or serum.131 Meperidine toxicity

has been attributed to the accumulation of normeperidine in patients with renal impairment, which has an elimination half-life of 14 to 24 hours.132-134 However, when meperidine is used in large doses and at frequent dosing intervals, seizures may occur in patients with normal renal function.135-138 Meperidine also interacts with serotonin receptors by blocking presynaptic reuptake of serotonin. A potentially fatal form of serotonin syndrome may occur in patients on monoamine oxidase inhibitors (MAOIs) and is treated with meperidine.139 Meperidine is the prototype for a series of homologs that are used as heroin substitutes. In a process to synthesize a meperidine analog, 1-methyl-4-phenylpropionoxypiperidine (MPPP), as a heroin substitute, a clandestine drug laboratory inadvertently introduced 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by incorrect heating of the synthetic mixture. When MPTP is introduced into the body, monoamine oxidaseB in glial cells metabolizes MPTP to MPP+, which selectively destroys dopamine-containing cells in the substantia nigra by inhibiting mitochondrial oxidative phosphorylation.140,141 MPTP contaminant led to an epidemic of severe parkinsonism among IV drug abusers (“frozen addicts”) within days of repeated injections.142-144

Diphenoxylate and Loperamide Diphenoxylate is structurally similar to meperidine, with limited absorption from the GI tract that contributes to its strong local constipating effects, and is used in the management of diarrhea. Diphenoxylate (2.5 mg) is formulated with 0.025 mg of atropine sulfate (Lomotil). In therapeutic doses, the drug has no significant CNS effects. However, the standard adult formulation may result in significant systemic absorption and toxicity in children. One half tablet of Lomotil has been reported to cause serious toxicity in children.145-147 Signs and symptoms arising from a toxic ingestion may be delayed, prolonged, or recurrent.147 This is related to the delayed gastric emptying effects inherent to both opioids and anticholinergics, and more important, the accumulation of the hepatic metabolite difenoxin, which is a significantly more potent opioid than diphenoxylate and possesses a longer serum half-life.148,149 Loperamide, an over-the-counter antidiarrheal agent, is another meperidine analog with limited absorption from the GI tract, and appears to have a high safety profile.150

Methadone Methadone is a synthetic opioid commonly used in the treatment of chronic pain or detoxification, or as a maintenance substitute for opioid addiction, and is also sold on the streets.151,152 Methadone is well absorbed from the GI tract, resulting in a peak plasma level within 2 to 4 hours, with peak effect occurring within 2 hours.153 It has an average half-life of 25 hours and may be

CHAPTER 33

as long as 52 hours during long-term maintenance therapy.154 Methadone and its inactive metabolite, an N-demethylated pyrolidine, may be detected in either urine or plasma.155 Its analgesic, sedative, euphoric, and respiratory depressive effects are comparable with those seen with analogous doses of morphine.156,157 In a nontolerant person, a 40- to 50-mg dose may produce coma and respiratory depression.155,158 Rapid escalation of methadone doses have been associated with choreoathetoid movements and may be due to enhanced striatal dopamine release.159 Unintentional pediatric poisoning with fatal consequences has occurred in situations in which parents on methadone maintenance treatment had improperly stored their methadone at home.160 A protracted clinical course is expected following an overdose. There is a possible association between patients on very high doses of methadone and having torsades de pointes, particularly in a setting of additional dysrhythmia risk factors (e.g., hypokalemia).161 In these patients the mean daily methadone dose was 397 ± 283 mg and their mean QTc interval was 615 ± 77 msec.

Opioids

647

rates.5 In the United States, restricted conditions for drug prescription (no more than 30 patients per qualifying certified physician) have resulted in little abuse since its launch.21 As with other opioids, buprenorphine intoxication includes coma, respiratory depression, and pinpoint pupils. Several deaths have been associated with buprenorphine misuse or psychotropic drug coingestion, including benzodiazepines.14 However, forensic determination of the exact role of buprenorphine in the death process appears difficult, because other factors may be involved (and potentially unknown), including substitution modality and concomitant intake of other drugs.20 Moreover, the exact mechanism of interaction between buprenorphine and benzodiazepines (often implicated in buprenorphine deaths) is unknown.165 The clinical role of drugs that interact with CYP3A4 and that may modify production of norbuprenorphine (an active metabolite with more potent respiratory depressant effects) is unknown.

Propoxyphene Buprenorphine Buprenorphine is a semisynthetic, highly lipophilic opioid, with 25 to 50 times more potent analgesic activity than morphine.162 Sublingual buprenorphine is well absorbed, with 60% to 70% of the bioavailability of the IV route. Buprenorphine is mainly metabolized in the liver by CYP3A4 to an active dealkylated metabolite, norbuprenorphine. There is no direct relation of buprenorphine’s clinical effects with plasma concentrations. Buprenorphine is a partial + receptor agonist and a weak g receptor antagonist, with ceiling effects. Doseeffect relationships, both in animals and humans, suggest a plateau of respiratory effects.163 Buprenorphine shows a very slow dissociation from opioid receptors, and consequently, has a long duration of action. These pharmacologic properties appear to be of utmost importance regarding its safety for use in substitution treatment. They confer a low level of physical dependence and mild withdrawal symptoms on cessation after prolonged administration. Although respiratory depression can be prevented by prior administration of naloxone, buprenorphine is weakly antagonized by naloxone given after buprenorphine.164 Buprenorphine 8 to 16 mg/day has been used in France as a maintenance treatment for opioid-dependent patients since 1996. In 2002, buprenorphine was approved by the Food and Drug Administration for the treatment of opioid addiction in certified physicians’ offices. A mixture of buprenorphine and naloxone named Suboxone (Reckitt Benckiser Healthcare, Ltd., Hull, UK) is also available, designed to discourage IV use. Since the advent of office-based availability, buprenorphine has been successfully used for opioid detoxification, with a good safety profile.10,11 In France, the introduction of high-dose buprenorphine coincided with a decrease in opiate/opioid poisoning mortality

Propoxyphene is structurally related to methadone, and toxicity has resulted in significant morbidity and mortality.166-168 It is available alone or in combination with aspirin or acetaminophen. Oral administration is followed by rapid absorption, with peak serum levels occurring within 1 hour.169 The plasma half-lives of propoxyphene and its main active hepatic metabolite norpropoxyphene are 6 to 12 hours and 37 hours, respectively. Norpropoxyphene is also the primary metabolite excreted in the urine and is believe to play a role in the prolonged clinical course following an overdose.170,171 Prominent cardiovascular effects may occur with propoxyphene toxicity and manifest by widecomplex dysrhythmias and negative contractility through sodium channel antagonism similar to that of type IA antidysrhythmic agents. Propoxyphene appears to be responsible for both CNS (e.g., respiratory depression and seizures) and cardiac toxicity (e.g., QRS prolongation, negative inotropy, and dysrhythmias), whereas norpropoxyphene contributed only to the cardiotoxicity.172 The clinical course following an overdose may be severe and rapidly progressive, with cardiac dysrhythmias, circulatory collapse, seizures, and respiratory arrest developing within 1 hour.173-178 Propoxyphene toxicity may result in focal and generalized seizures.176,178 The minimum toxic dose reported is 10 mg/kg, and 20 mg/kg is considered potentially fatal,179 but tolerance develops with chronic use. Doses of 1000 to 2000 mg may be ingested or injected with minimal signs of intoxication in chronic propoxyphene abusers and heroin addicts.178,180-182 Blood levels in fatal overdose cases range from 0.1 to 2.5 mg/dL.167,168

Pentazocine Pentazocine is a synthetic analgesic class with both agonist and weak antagonist activity at the opioid

648


receptors.183 The physiologic effects of pentazocine are similar to morphine, and with one third of its analgesic potency.183 When administered by the oral route, peak plasma pentazocine levels occur within 1 hour.184 Pentazocine is extensively metabolized in the liver,183,184 with the parent compound and metabolites detectable in either urine or plasma.183 Anxiety, dysphoria, and hallucinations may be more common with pentazocine than with other opiate derivatives.183 Pentazocine (Talwin, Sandoz, Princeton, NJ) is associated with a fairly specific scenario of parenteral abuse when used in combination with the antihistamine tripelennamine (Pyribenzamine, Novartis, Basel, Switzerland), a blue capsule. This combination forms a street product known as “T’s and blues” and, once solubilized and injected, was used as a heroin substitute that was previously popular among addicts because of its heroinlike “rush” and lower cost.185-187 Newer combination street products, such as pentazocine with methylphenidate, have been reported.188 Acute toxicity results in the typical opiate intoxication syndrome, as well as dyspnea, hyperirritability, hypertension, and seizures. It is believed that these effects may be directly related to the tripelennamine dose.186,189,190 In an effort to curtail IV pentazocine abuse, the oral preparation was reformulated to contain 0.5 mg of naloxone (Talwin-NX, Sandoz, Princeton, NJ).191 The naloxone component is inactivated when taken orally, and avoids withdrawal symptoms. However, when TalwinNX is parenterally administered, pentazocine’s effects are antagonized by naloxone, which causes withdrawal in opiate-dependent individuals. Because pentazocine’s duration of action exceeds that of naloxone, delayed respiratory depression may occur.

Dextromethorphan Dextromethorphan, an analog of codeine and the optical isomer of levorphanol (a potent opioid analgesic), is found in a large number of nonprescription cough and cold remedies. Within the therapeutic dose, dextromethorphan lacks analgesic, euphoriant, and physical dependence properties.192 Dextromethorphan is formulated as the hydrobromide salt. It is available as a single ingredient or in combination with decongestants (sympathomimetics) and antihistamines. Dextromethorphan is well absorbed from the GI tract, with peak plasma levels occurring 2.5 and 6 hours after ingestion of regular and sustained-release preparations, respectively. The therapeutic effect lasts 3 to 6 hours, with a corresponding plasma half-life of 2 to 4 hours. The predominant antitussive effect is attributed to the active metabolite dextrorphan.193 Over-the-counter access appears to be the primary reason for its popularity in abuse, although its abuse pattern seems to be self-limiting due to adverse drug events, such as lethargy, somnambulism, and ataxia, after a few weeks of abuse.194 Dextromethorphan abuse appears to be associated with a psychological rather than a physiologic dependence syndrome.192 Recreation dextromethorphan abusers report increased perceptual awareness, altered time perception, euphoria, and visual

hallucinations.194-196 Long-term dextromethorphan use may result in bromide toxicity.197 Since dextromethorphan frequently appears in combination products, the contribution of these co-ingestants should be considered in assessing overdose or abuse cases. Dextromethorphan blocks presynaptic serotonin reuptake and may elicit the serotonin syndrome in patients on MAOI therapy.198,199 Interaction between dextrorphan and the “m receptor” produces a phencyclidine-like dysphoria.200 The metabolism of dextromethorphan to dextrorphan is dependent on CYP2D6 activity, an enzyme with a significant genetic polymorphism. Patients who express extensive metabolizer polymorphism appear to experience more drugrelated psychoactive effects, whereas patients with poor metabolizers experience more adverse effects related to the parent compound.201 Occasionally, a patient may experience choreoathetoid or dystonia-like movements while on dextromethorphan.202

Tramadol Tramadol is structurally similar to morphine and has both opioid and nonopioid mechanisms responsible for its clinical effects. It is a centrally acting analgesic with moderate affinity for + opioid receptors. However, the metabolite O-demethyl tramadol appears to have a higher affinity than the parent compound for the same receptors. In therapeutic doses, tramadol does not appear to produce significant respiratory depression or have significant cardiovascular effects. Most of the analgesic effects are attributed to the nonopioid properties of the drug. Tramadol may exert its analgesic effect by blocking the reuptake of biogenic amines (e.g., norepinephrine and serotonin) at synapses in the descending neural pathways, which inhibits pain responses in the spinal cord.203 Serotonin syndrome may develop in patients concurrently taking tramadol and serotonin reuptake inhibitor medication.204,205 Seizures may occur during therapeutic dosing.206

BODY PACKERS The transportation of illicit drugs by internal concealment is an important means of international smuggling, with accounts of body packing worldwide. Body packers are sometimes called “mules,” “swallowers,” “internal carriers,” or “couriers.” These are people who transport large numbers of meticulously prepared illicit drug packets in their GI tracts across borders with the intent to sell or receive compensation for transporting the drug. Typically, the packets contain either concentrated cocaine or heroin. If one of these packets ruptures, the amount of drug released may cause life-threatening toxicity.207,208

CLINICAL MANIFESTATIONS Mental status depression, respiratory depression, miosis, and decreased bowel motility are the hallmarks of opiate intoxication, with the magnitude and duration of toxicity

CHAPTER 33

dependent on the dose and individual degree of tolerance. The clinical effects of an overdose with any one of the agents in this class are similar. However, as discussed, there are important differences between certain drugs. Overdoses resulting in toxicity often have a prolonged clinical course, partially due to an opioidinduced decrease in GI motility and prolonged half-life of the drug or its active metabolites. Miosis is considered a consistent finding in opioid poisoning, with the exception of meperidine, porpoxyphene, petazocin, dextromethorphan use, in case of a mixed overdose with an anticholinergic or sympathomimetic drug, or when severe acidemia, hypoxemia, hypotension, or a CNS structural disorder is present. Patients presenting with CNS depression following an opioid overdose represent the most seriously intoxicated patients. However, codeine, meperidine, and dextromethorphan intoxications are remarkable for CNS hyperirritability, resulting in a mixed syndrome of stupor and delirium. In addition, patients with meperidine toxicity may also have tachypnea, dysphoric and hallucinogenic episodes, tremors, muscular twitching, and spasticity,126,132,133,135 whereas patients with dextromethorphan toxicity may also manifest restlessness and clonus.196,209-212 Acute lung injury after heroin overdose may not be unique. It has been reported with overdoses of opioids that include methadone, propoxyphene, codeine, buprenorphine, and nalbuphine.76,102,103,189,213-222 Acute lung injury may not develop until 24 hours following methadone overdose.70,71,223,224 Patients with heroin-induced acute lung injury typically have normal capillary wedge pressures and elevated pulmonary arterial pressures.224,225 In contrast, elevated systemic, pulmonary arterial, and pulmonary capillary wedge pressures and total systemic vascular resistance are seen with pentazocine intoxication.226 These effects are believed to result from transient endogenous catecholamine release.227 Signs and symptoms of heroin-induced acute lung injury usually resolve within 24 to 36 hours.69,228,229 Persistent pulmonary symptoms beyond 24 to 48 hours may indicate aspiration or bacterial pneumonitis, with atelectasis, fibrosis, bronchiectasis, granulomatous disease, or pneumomediastinum.230 Adulterants in street drugs are potential pulmonary toxicants.231 The injection of adulterants such as talc (magnesium trisilicate) has produced granulomatosis in small pulmonary arteries, resulting in pulmonary thrombosis, pulmonary hypertension, and acute cor pulmonale.189,190,230,232 Other potential pulmonary complications associated with IV opioid use include pulmonary arteritis, septic emboli, lung abscess, bacterial pneumonia, aspiration pneumonitis, pulmonary edema, and respiratory arrest. Seizures and focal neurologic signs are usually absent following opiate intoxication233 unless precipitated by severe hypoxia, dysrhythmia and hypotension, an intracranial process (e.g., brain abscess and subarachnoid hemorrhage), hypersensitive immune vascular injury or vasculitis, proconvulsive adulterants, meperidine, propoxyphene, pentazocine (T’s and blues), or tramadol use.176,178,186,234-242 Normeperidine neurotoxicity may manifest as delirium, tremor, myoclonus, or seizures.

Opioids

649

Meperidine- and propoxyphene-related seizures may be more frequent in chronic drug abusers with renal dysfunction. Hypotension may occur following opiate overdose, although pentazocine intoxication may result in hypertension.186 Heroin and propoxyphene toxicity may be associated with nonspecific ST-segment and T-wave changes, first-degree atrioventricular block, atrial fibrillation, prolonged QTc intervals, and ventricular dysrhythmias.83-85,173-175 Cardiovascular findings may be exacerbated by electrolyte abnormalities, metabolic derangements associated with hypoxia, or adulterants (e.g., quinine) in street drugs. The anticholinergic and opioid effects may be significantly delayed, prolonged, or recurrent following a Lomotil overdose.147,243 The relevance of delayed toxicity is highlighted by a patient with an asymptomatic presentation 8 hours postingestion who was observed for several hours and discharged. This patient returned to the emergency department 18 hours postingestion with severe atropinism.243 Toxicity may manifest as a biphasic clinical syndrome, and patients may manifest anticholinergic toxicity (CNS excitement, hypertension, fever, flushed dry skin) before, during, or after opioid effects. However, opioid effects (CNS and respiratory depression with miosis) may predominate or occur without any signs of atropinism. Cardiopulmonary arrest has been reported to occur 12 hours after Lomotil ingestion.244 Patients presenting after a tramadol overdose may exhibit lethargy, nausea, tachycardia, agitation, seizures, coma, hypertension, and respiratory depression.240 Tramadol-associated seizures are brief, and significant respiratory depression is uncommon. Interaction between meperidine and MAOIs, dextromethorphan and MAOIs, and tramadol and selective serotonin reuptake inhibitors may result in the serotonin syndrome.245-246 Patients with severe serotonin syndrome exhibit rapid onset of altered mental status, muscle rigidity, hyperthermia, autonomic dysfunction, coma, seizures, and death. Rhabdomyolysis, hyperkalemia, myoglobinuria, and renal failure may complicate the clinical course of an acute opioid overdose or opioid dependence.86,247,248 Rhabdomyolysis has been reported following IV, inhalational, and intranasal heroin abuse.249 Acute renal failure may be due to direct insult by the abused substance, adulterants in the street drugs, and prolonged coma.86,247,248 Chronic parental drug use may result in glomerulonephritis and renal amyloidosis and has been associated with concurrent bacterial infections.250-253 Body packers are typically asymptomatic, but are at risk for delayed and prolonged toxicity from packet rupture.254 Symptomatic patients will exhibit the typical signs and symptoms of opiate intoxication. Body packers may also present with or develop signs and symptoms of intestinal obstruction, and occasionally intestinal perforation and peritonitis.255 Clandestine laboratories have produced exceedingly potent and toxic drugs as new manufacturing methods have been developed to circumvent the use of controlled or unavailable precursor compounds. As government

650


authorities stringently regulate these products and their precursors, new drugs and methods are designed to take their place.105 Since these drugs may contain a wide variety of active ingredients, adulterants, and contaminants, the clinical syndromes seen in the abuser may be only partly related to the opioid component.

DIAGNOSIS Laboratory Studies Laboratory studies such as complete blood count, serum electrolytes, blood urea nitrogen, creatinine, creatine phosphokinase, urinalysis, arterial blood gas, electrocardiography, imaging studies, and lumbar puncture should be obtained as clinically indicated. Laboratory investigations should also include infections associated with IV drug abuse (e.g., endocarditis, aspergillosis, bacterial meningitis, cutaneous abscess, mycotic aneurism, intracranial abscess, epidural abscess, transverse myelitis, viral hepatitis, wound botulism, tetanus, osteomyelitis, and acquired immunodeficiency syndrome).

MANAGEMENT Opioid toxicity should be part of the differential diagnosis in all comatose patients. However, the classic “opioid toxidrome” may not be apparent following a mixed overdose. Respiratory support is paramount in the management of patients with opioid toxicity; and the patient should be managed according to current advanced cardiac life support guidelines. Priorities include assessment and establishment of effective ventilation and oxygenation, followed by ensuring adequate hemodynamic support. Initial support with a bag-valve-mask (BVM) device is appropriate, along with 100% oxygen supplementation. Oral or nasal airway placement may be helpful, and caution is advised with their use given the potential for vomiting and/or aspiration. A suction apparatus should be available for immediate use at the patient’s bedside. Ventilatory support can usually be safely provided with a BVM device while awaiting the reversal of respiratory depression by an opioid antagonist. Endotracheal intubation is indicated in severely compromised patients in whom there is a real risk for aspiration or in patients who do not satisfactorily respond to opioid antagonists. GI decontamination should be considered after vital signs have been stabilized. Opioids may cause decreased GI motility, and this suggests there may be some benefit to GI decontamination several hours postingestion. Gastric lavage may be of benefit in patients who are critically ill, do not respond to naloxone, are suspect of polypharmacy overdose, or have overdosed on Lomotil; retrieval of Lomotil pills as late as 27 hours postingestion has been reported.147 In the obtunded patient, endotracheal intubation should be performed prior to the placement of the orogastric tube to minimize the risk of aspiration. Early administration of activated charcoal has been advocated as the sole GI decontamination procedure. Although the clinical benefits of multiple

oral doses of activated charcoal remain to be established, it has potential benefit because of the prolonged absorption phase typically encountered with opioid overdoses. Patients should be closely monitored for the presence of bowel sounds and passing of charcoal-laden stool. Repeat charcoal doses should not be used in the absence of active bowel sounds or in the presence of an ileus. Ipecac-induced emesis in patients with opioid overdose is not recommended given the potential for rapid deterioration and the risk for aspiration. Naloxone is a pure competitive opioid antagonist at the +, g, and b receptors, and has a greater affinity for the + receptor than for the g or b receptors. It can reverse the analgesia, respiratory depression, miosis, hyporeflexia, and cardiovascular effects of opiate toxicity256,257 and is effective in terminating opioidinduced vomiting. The goal of naloxone therapy is to reestablish adequate spontaneous ventilation and maintain adequate airway reflexes without precipitating an acute withdrawal syndrome.258 Naloxone is relatively contraindicated in the pregnant patient, in whom precipitation of acute narcotic withdrawal may induce premature labor or miscarriage. However, this does not preclude judicious naloxone use in pregnant patients with severe respiratory depression. A judicious starting dose for IV naloxone may be 0.05 to 0.1 mg if the patient is possibly opioid dependent. Otherwise, an initial 2-mg dose can be administered. The recommended pediatric naloxone dose is 0.1 mg/kg, up to 2 mg. For high-potency opioids (e.g., fentanyl and its analogs) or opioids with a greater affinity for the g or b receptor (e.g., pentazocine, propoxyphene) a larger than usual dose of naloxone may be needed to successfully antagonize the opioid effects.259 Repeat IV naloxone boluses up to 10 to 20 mg should be considered if there is a history of opioid exposure, a strong clinical suspicion based on presenting signs and symptoms, or a partial response to the initial naloxone dose. Submental, intranasal, intralingual, endotracheal, intraosseous, intramuscular, and subcutaneous routes of naloxone administration are acceptable alternatives when vascular access is not readily available.260-264 However, intramuscular and subcutaneous injections are less desirable in the emergent situation. Repeat naloxone boluses may be required every 20 to 60 minutes because of its short elimination half-life (60 to 90 minutes) compared with that of most opioids.265 A continuous naloxone infusion may be considered in patients who have a positive response and require repeated bolus doses because of recurrent respiratory depression.266-268 A therapeutic naloxone infusion may be made up by multiplying the effective naloxone bolus dose by 6.6, adding that quantity to 1000 mL normal saline, and infusing the solution at 100 mL/hr. The infusion is titrated to maintain adequate spontaneous ventilation without precipitating acute opioid withdrawal and is empirically continued for 12 to 24 hours. The patient should be admitted to an intensive care setting where the patient will be frequently assessed during this time. After discontinuing the naloxone therapy, the patient should be carefully observed for 2 to 4 hours for recurrent respiratory depression. In the event of acute iatrogenic opioid withdrawal, allow the

CHAPTER 33

effect of naloxone to abate and avoid administering additional opioids. Clinical experience has demonstrated naloxone to be an extremely safe drug. It has been administered at a bolus dose of 5.4 mg/kg followed by infusion at 4 mg/kg/hr for 23 hours in the treatment of acute spinal cord injury.269 Although naloxone is ordinarily a safe drug, there have been reports ascribing acute lung injury,222,270-275 hypertension, cardiac dysrhythmias, and death to naloxone therapy.276-279 Typically, the patient has a depressed consciousness and respiration. After naloxone administration, the patient awakens and over minutes to hours is noted to become hypoxic with an adequate respiratory rate and to develop pulmonary edema. Pink, frothy sputum may be evident in the nasopharyngeal area. Acute naloxone-induced withdrawal has been associated with massive CNS sympathetic discharge, which may be a precipitating factor in the development of “neurogenic” pulmonary edema.280-282 It appears that the pulmonary injury is at the alveolarcapillary membrane, resulting in manifestations consistent with acute respiratory distress syndrome.77,218 Abrupt heroin withdrawal precipitated by naloxone may contribute to the development of acute lung injury. However, it cannot be the only effect. Naloxone does not appear to directly alter the vascular permeability of the lung.283 Pulmonary edema was reported in 50% to 90% of the autopsies performed on heroin overdose patients, many of whom were declared dead in the prehospital setting and never received naloxone.72,73 In addition, opioid antagonist was unavailable when the initial cases of pulmonary edema were reported. A mechanical effect in which negative intrathoracic pressure generated by attempted inspiration against a closed glottis creates a large pressure gradient across the alveolar membrane and draws fluid into the alveolar space may be responsible for the observed association between naloxone administration and acute lung injury, similar to ventilator-associated pulmonary edema (Müller maneuver) prior to the advent of demand ventilators and neuromuscular blockers.284 Opioid poisoning may result in glottic laxity, prevent adequate air entry during inspiration, and may be especially prominent at the time of naloxone administration. This may result in breathing being reinstituted prior to the return of adequate upper airway function. Naloxone is effective in reversing diphenoxylate (Lomotil)-induced opioid toxicity, but recurrence of respiratory and CNS depression is common.243 All patients with significant diphenoxylate overdose should be admitted for monitored observation in the hospital for at least 24 hours.147 Naloxone has been reported to reverse, though inconsistently, the CNS effects of ethanol, benzodiazepines, clonidine, chlorpromazine, and valproic acid following an overdose.285-288 Naloxone administration may “unmask” cocaine toxicity in patients using “speedballs”289 or anticholinergic toxicity in patients using heroin and scopolamine.290 Hypotension may respond to naloxone therapy, but may require fluid resuscitation and vasopressors. Overzealous fluid resuscitation should be avoided because of the risk for pulmonary edema. Cardiac

Opioids

651

dysrhythmias should be managed according to current advance cardiac life support guidelines. Sodium bicarbonate may be useful in treating cardiotoxicity from drugs with “quinidine-like effects” (type IA antidysrhythmics) that impair sodium channel functioning, manifested by widened QRS complexes, dysrhythmias, and hypotension. Sodium bicarbonate has been reported to be effective in narrowing the QRS complex in the setting of propoxyphene-induced wide complex dysrhythmias.291 Sodium bicarbonate (1 to 2 mEq/kg) may be administered as an IV bolus over a period of 1 to 2 minutes. Greater amounts may be required to treat unstable ventricular dysrhythmias. Sodium bicarbonate boluses can then be repeated as needed with the end point of stabilizing or narrowing the QRS interval. Excessive alkalemia (pH greater than 7.55) and hypernatremia should be avoided. Management of seizures should follow current treatment guidelines and should include benzodiazepines or barbiturates. Adjunct naloxone therapy may be effective in propoxyphene-292 but not meperidine- or tramadolrelated seizures. Experimental evidence suggests naloxone may potentiate normeperidine-induced seizures by inhibiting an anticonvulsant effect of meperidine.293 Naloxone appears to potentiate the anticonvulsant effects of benzodiazepines and barbiturates, and may antagonize the effects of phenytoin.294 Seizure has been reported immediately following naloxone administration for tramadol overdose.240,295 The tramadol package insert cautions against naloxone use in overdose situations. The management of serotonin syndrome is primarily supportive. Sedation, paralysis, intubation and ventilation, anticonvulsants, antihypertensives, and aggressive rapid cooling may all be necessary. There has been some success with nonspecific serotonin antagonist cyproheptadine (4 to 8 mg every 8 hours orally).296 The occurrence of acute lung injury appears to be clinically unpredictable,70,71,76,297 and it has been suggested that a man in his late thirties who is a relatively inexperienced heroin user and has a Glasgow Coma Scale score of 4 to 5, has a respiratory rate of 6, and requires naloxone to maintain his respiratory drive in the prehospital setting would have a high likelihood of developing acute lung injury.298 It has been recommended to observe all patients for at least 24 hours following emergence from an opioid overdose. However, some clinicians suggest that 4 hours patient observation may be sufficient following a pure IV heroin or shortacting opioid overdose.69,299 An even shorter observation of at least 1 hour in an emergency department has been investigated and may be acceptable, and remains to be validated.300 This study suggests that patients with presumed opioid overdose can be safely discharged 1 hour after naloxone administration if they (1) can mobilize as usual, (2) have oxygen saturation on room air greater than 92%, (3) have a respiratory rate between 10 and 20 breaths per minute, (4) have a temperature between 35.0° C and 37.5° C, (5) have a heart rate between 50 and 100 beats per minute, and (6) have a Glasgow Coma Scale score of 15. The management of acute lung injury should include adequate ventilation, oxygenation, and positive-pressure

652


ventilation as needed. Inotropic and chronotorpic agents and preload- and afterload-reducing agents appear to be of little value. In one case series, the majority of patients only required supplemental oxygen, and 33% of patients required mechanical ventilation.69 Asymptomatic body packers may be managed conservatively by the prograde route provided the condition of packaging does not appear to be compromised. Some clinicians suggest whole bowel irrigation with polyethylene glycol electrolyte lavage solution based on retrospective case series and case reports.207,301-303 A proposed method, based on more than 100 cases of cocaine body packers, together with more than 10 years’ experience, suggests a safe and efficient method for the medical management of asymptomatic body packers. This same method may be applied to heroin body packers and involves the oral administration of a watersoluble contrast solution followed by serial abdominal radiographs (Box 33-1).304,305 Body packers who develop opiate toxicity can often be managed with continuous naloxone infusion, activated charcoal, and whole bowel irrigation. Surgical intervention is indicated for patients with intestinal obstruction or perforation, and may be indicated when packets fail to progress through the GI tract after conservative management. Endoscopic retrieval of a few packets that are retained in the stomach may be considered, and should be performed by an experienced endoscopist. Pruritis is a common opioid adverse drug event. It may be localized or general and range from mild to severe. Antihistamines are usually ineffective, but naloxone has frequently been found to offer relief. Ondansetron has been reported to provide relief in refractory cases.307 Treatment of spongiform leukoencephalopathy is supportive, and antioxidant therapy with coenzyme Q (30 mg four times daily), vitamin E (2000 mg daily), and vitamin C (2000 mg daily) has been advocated.310 Constipation may be ameliorated by oral naloxone. Enteral naloxone is poorly absorbed, and opioid with-

BOX 33-1

MANAGEMENT OF ASYMPTOMATIC BODY PACKERS

Abdominal radiographs with oral contrast: 1. Administer an oral dose of water-soluble contrast (e.g., Gastrografin): 1 mL/kg. 2. Perform abdominal radiographs (supine and upright) at least 5 hours after oral contrast administration. 3. If radiographs are positive, administer an oral dose of 100 mL mineral oil twice daily. 4. Perform daily abdominal radiographs and after a spontaneous bowel movement. 5. All bowel movements are checked for drug packets. 6. The patient may be discharged after passage of two packet-free bowel movements and negative abdominal radiographs. Patients are permitted to feed normally and vascular access should be maintained.

drawal symptoms are usually not evident when the oral dose of naloxone does not exceed hepatic glucuronidase capacity.308 Methylnal-trexone is a quaternary ammonium molecule and is unable to cross the bloodbrain barrier. It antagonizes the effects of opioids on the GI tract without precipitating opioid withdrawal.309 Forced diuresis and manipulation of urine pH have not been demonstrated to be of clinical benefit in opioid overdose. Hemodialysis may be indicated in patients with compromised renal function and are toxic from opioids or its metabolites (e.g., normeperidine) that depend on renal elimination.310

OTHER OPIOID ANTAGONISTS Nalmefene is effective for the reversal of opioid-induced CNS effects and may be administered orally or intravenously. Its half-life and dose-dependent duration of action are 4 to 8 hours following IV administration.311,312 The initial adult dose is 0.5 mg for those who are not opioid dependent and 0.1 mg for those suspected of having opioid dependency. If there is an incomplete response or no response, additional doses can be given at 2- to 5-minutes intervals. A total dose of 1.5 mg may be necessary to exclude the possibility of opioid poisoning. Nalmefene has proven safety and efficacy in the management of meperidine-induced sedation and opiate overdose in the emergency department.313-315 The principal advantage over naloxone is its considerably longer duration of antagonistic action, which translates into fewer complications arising from fluctuations in the level of consciousness, reduced incidence of resedation, better long-term control of longer-acting opiate ingestions, and fewer indications for naloxone infusions. Withdrawal syndrome precipitated by the use of nalmefene would also be prolonged. Naltrexone is a potent, long-acting, pure opiate antagonist that is effective orally. Its use is primarily limited as adjunctive therapy for opioid detoxification. Naltrexone may induce a withdrawal syndrome lasting up to 72 hours.

DISPOSITION The minimum observation period following a patient’s emergence from an opioid overdose remains to be determined. Data seem to suggest that observation for 1 to 4 hours may be sufficient following a pure IV heroin or short-acting opioid overdose.69,299,300 Factors that favor extended observation or hospital admission include exposure to agents with long half-lives (e.g., methadone, L-_-acetylmethadol, propoxyphene, diphenoxylate, and buprenorphine); agents whose toxicity may be delayed, prolonged, or recurrent (e.g., diphenoxylate); large amounts of ingestant or co-ingestant; low tolerance to opioids (as compared to that of the chronic abuser); respiratory or cardiovascular instability; and comorbid conditions. Although administering an opioid antagonist can have a temporizing effect, overdose on an opioid with a long half-life (e.g., methadone) will significantly

CHAPTER 33

outlast several doses of naloxone and may require a continuous naloxone infusion or the use of nalmefene. Because of the potential for delayed onset and recurrent respiratory and CNS depression following naloxone therapy, it is recommended to observe patients for at least 24 hours. Patients who are on high-dose methadone therapy and have a prolonged QTc interval on ECG should be admitted to an intensive care unit because of its association with torsades de pointes and risk for sudden death.161

ACKNOWLEDGMENT Michael Schwartz, MD, contributed to this chapter in a previous edition.

REFERENCES 1. World Health Organization: Opioid overdose. Trends, risk factors, interventions and priorities for action. In Social Change and Mental Health. Geneva, Switzerland, World Health Organization, 1998. 2. Hall W, Darke S: Trends in opiate overdose deaths in Australia 1979–1995. Drug Alcohol Depend 1998;52(1):71–77. 3. Substance Abuse and Mental Health Services Administration: Results from the 2004 National Survey on Drug Use and Health: national findings. Rochville, MD, Substance Abuse and Mental Health Services Administration, 2005. 4. Watson WA, Litovitz TL, Klein-Schwartz W, et al: 2003 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2004;22(5):335–404. 5. Gueye PN, Megarbane B, Borron SW, et al: Trends in opiate and opioid poisonings in addicts in north-east Paris and suburbs, 1995–99. Addiction 2002;97(10):1295–1304. 6. Single E, Rehm J, Robson L, Truong MV: The relative risks and etiologic fractions of different causes of death and disease attributable to alcohol, tobacco and illicit drug use in Canada. CMAJ 2000;162(12):1669–1675. 7. Frischer M, Goldberg D, Rahman M, Berney L: Mortality and survival among a cohort of drug injectors in Glasgow, 1982–1994. Addiction 1997;92(4):419–427. 8. White JM, Irvine RJ: Mechanisms of fatal opioid overdose. Addiction 1999;94(7):961–972. 9. Risser D, Honigschnabl S, Stichenwirth M, et al: Mortality of opiate users in Vienna, Austria. Drug Alcohol Depend 2001;64(3): 251–256. 10. Gowing L, Ali R, White J: Buprenorphine for the management of opioid withdrawal. Cochrane Database Syst Rev 2004(4):CD002025. 11. Johnson RE, Chutuape MA, Strain EC, et al: A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med 2000;343(18):1290–1297. 12. Mattick RP, Kimber J, Breen C, Davoli M: Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev 2003(2): CD002207. 13. Gaulier JM, Marquet P, Lacassie E, et al: Fatal intoxication following self-administration of a massive dose of buprenorphine. J Forensic Sci 2000;45(1):226–228. 14. Kintz P: Deaths involving buprenorphine: a compendium of French cases. Forensic Sci Int 2001;121(1–2):65–69. 15. Kintz P: A new series of 13 buprenorphine-related deaths. Clin Biochem 2002:35(7):513–516. 16. Tracqui A, Kintz P, Ludes B: Buprenorphine-related deaths among drug addicts in France: a report on 20 fatalities. J Anal Toxicol 1998;22(6):430–434. 17. Comer SD, Collins ED, Fischman MW: Intravenous buprenorphine self-administration by detoxified heroin abusers. J Pharmacol Exp Ther 2002:301(1):266–276.

Opioids

653

18. Obadia Y, Perrin V, Feroni I, et al: Injecting misuse of buprenorphine among French drug users. Addiction 2001;96(2):267–272. 19. Thirion X, Lapierre V, Micallef J, et al: Buprenorphine prescription by general practitioners in a French region. Drug Alcohol Depend 2002;65(2):197–204. 20. Pirnay S, Borron SW, Giudicelli CP, et al: A critical review of the causes of death among post-mortem toxicological investigations: analysis of 34 buprenorphine-associated and 35 methadoneassociated deaths. Addiction 2004;99(8):978–988. 21. Cicero TJ, Inciardi JA: Potential for abuse of buprenorphine in office-based treatment of opioid dependence. N Engl J Med 2005;353(17):1863–1865. 22. Bryant WK, Galea S, Tracy M, et al: Overdose deaths attributed to methadone and heroin in New York City, 1990–1998. Addiction 2004;99(7):846–854. 23. Perret G, Deglon JJ, Kreek MJ, et al: Lethal methadone intoxications in Geneva, Switzerland, from 1994 to 1998. Addiction 2000;95(11):1647–1653. 24. Seymour A, Black M, Jay J, et al: The role of methadone in drug related deaths in the west of Scotland. Addiction 2003: 98(7):995–1002. 25. Zadina JE, Hackler L, Ge LJ, Kastin AJ: A potent and selective endogenous agonist for the mu-opiate receptor. Nature 1997; 386(6624):499–502. 26. Reisine T, Pasternak G: Opioid analgesics and antagonists. In Hardman J, Limbird LE, Gilman AG, et al (eds): Goodman & Gilman’s The Pharmacological Basis of Therapeutics. New York, McGraw-Hill, 1996, pp 521–555. 27. Gaveriaux-Ruff C, Matthes HW, Peluso J, Kieffer BL: Abolition of morphine-immunosuppresion in mice lacking the mu-opioid receptor gene. Proc Natl Acad Sci U S A 1998;95(11):6326–6230. 28. Dhawan BN, Cesselin F, Raghubir R, et al: International Union of Pharmacology. XII. Classification of opioid receptors. Pharmacol Rev 1996;48(4):567–592. 29. Shook JE, Watkins WD, Camporesi EM: Differential roles of opioid receptors in respiration, respiratory disease, and opiateinduced respiratory depression. Am Rev Respir Dis 1990;142(4): 895–909. 30. Emmerson PJ, Liu MR, Woods JH, Medzihradsky F: Binding affinity and selectivity of opioids at mu, delta and kappa receptors in monkey brain membranes. J Pharmacol Exp Ther 1994;271(3): 1630–1637. 31. Janecka A, Fichna J, Janecki T: Opioid receptors and their ligands. Curr Top Med Chem 2004;4(1):1–17. 32. Salvadori S, Temussi PA: Antagonism in opioid peptides: the role of conformation. Curr Top Med Chem 2004;4(1):145–157. 33. Ueda H, Harada H, Nozaki M, et al: Reconstitution of rat brain mu opioid receptors with purified guanine nucleotide-binding regulatory proteins, Gi and Go. Proc Natl Acad Sci U S A 1988;85(18):7013–7017. 34. Yasuda K, Raynor K, Kong H, et al: Cloning and functional comparison of kappa and delta opioid receptors from mouse brain. Proc Natl Acad Sci U S A 1993;90(14):6736–6740. 35. Grudt TJ, Williams JT: Kappa-opioid receptors also increase potassium conductance. Proc Natl Acad Sci U S A 1993;90(23): 11429–11432. 36. North RA, Williams JT, Surprenant A, Christie MJ: Mu and delta receptors belong to a family of receptors that are coupled to potassium channels. Proc Natl Acad Sci U S A 1987;84(15): 5487–5491. 37. Schoffelmeer AN, Van Vliet BJ, De Vries TJ, et al: Regulation of brain neurotransmitter release and of adenylate cyclase activity by opioid receptors. Biochem Soc Trans 1992;20(2):449–453. 38. Elkader A, Sproule B: Buprenorphine: clinical pharmacokinetics in the treatment of opioid dependence. Clin Pharmacokinet 2005;44(7):661–680. 39. Chang Y, Moody DF, McCance-Kate EF: Novel metabolites of buprenorphine detected in human liver microsomes and human urine. Drug Metab Dispos 2006;34(3):440–448. 40. Gasche Y, Daali Y, Fathi M, et al: Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med 2004;351(27): 2827–2831. 41. Borron SW, Monier C, Risede P, Baud FJ: Flunitrazepam variably alters morphine, buprenorphine, and methadone lethality in the rat. Hum Exp Toxicol 2002;21(11):599–605.

654


42. Kilicarslan T, Sellers EM: Lack of interaction of buprenorphine with flunitrazepam metabolism. Am J Psychiatry 2000;157(7): 1164–1166. 43. Ghoneim MM, Dhanaraj J, Choi WW: Comparison of four opioid analgesics as supplements to nitrous oxide anesthesia. Anesth Analg 1984;63(4):405–412. 44. Eckenhoff JE, Oech SR: The effects of narcotics and antagonists upon respiration and circulation in man. A review. Clin Pharmacol Ther 1960;1:483–524. 45. Koren G, Butt W, Pape K, Chinyanga H: Morphine-induced seizures in newborn infants. Vet Hum Toxicol 1985;27(6):519–520. 46. Weil JV, McCullough RE, Kline JS, Sodal IE: Diminished ventilatory response to hypoxia and hypercapnia after morphine in normal man. N Engl J Med 1975;292(21):1103–1106. 47. Eckenhoff JE, Helrich M, Hege MJ, Jones RE: Respiratory hazards of opiates and other narcotic analgesics. Surg Gynecol Obstet 1955;101(6):701–708. 48. Ward JM, McGrath RL, Weil JV: Effects of morphine on the peripheral vascular response to sympathetic stimulation. Am J Cardiol 1972;29(5):659–666. 49. Zelis R, Mansour EJ, Capone RJ, Mason DT: The cardiovascular effects of morphine. The peripheral capacitance and resistance vessels in human subjects. J Clin Invest 1974;54(6):1247–1258. 50. Fahmy NR, Sunder N, Soter NA: Role of histamine in the hemodynamic and plasma catecholamine responses to morphine. Clin Pharmacol Ther 1983;33(5):615–620. 51. Barke KE, Hough LB: Opiates, mast cells and histamine release. Life Sci 1993;53(18):1391–1399. 52. Philbin DM, Moss J, Akins CW, et al: The use of H1 and H2 histamine antagonists with morphine anesthesia: a double-blind study. Anesthesiology 1981;55(3):292–296. 53. Flacke JW, Flacke WE, Bloor BC, et al: Histamine release by four narcotics: a double-blind study in humans. Anesth Analg 1987;66(8):723–730. 54. Melandri R, Re G, Lanzarini C, et al: Myocardial damage and rhabdomyolysis associated with prolonged hypoxic coma following opiate overdose. J Toxicol Clin Toxicol 1996;34(2):199–203. 55. Cepeda MS, Gonzalez F, Granados V, et al: Incidence of nausea and vomiting in outpatients undergoing general anesthesia in relation to selection of intraoperative opioid. J Clin Anesth 1996;8(4):324–328. 56. Lasagna L: The clinical evaluation of morphine and its substitutes as analgesics. Pharmacol Rev 1964;16:47–83. 57. Darke S, Hall W, Weatherburn D, Lind B: Fluctuations in heroin purity and the incidence of fatal heroin overdose. Drug Alcohol Depend 1999;54(2):155–161. 58. Griffiths P, Gossop M, Powis B, Strang J: Transitions in patterns of heroin administration: a study of heroin chasers and heroin injectors. Addiction 1994;89(3):301–309. 59. Kaa E: Impurities, adulterants and diluents of illicit heroin. Changes during a 12-year period. Forensic Sci Int 1994;64(2–3): 171–179. 60. Ferguson R, Feeney C, Chirurgi VA: Enterobacter agglomerans– associated cotton fever. Arch Intern Med 1993;153(20): 2381–2382. 61. Hendriks VM, van den Brink W, Blanken P, et al: Heroin selfadministration by means of “chasing the dragon”: pharmacodynamics and bioavailability of inhaled heroin. Eur Neuropsychopharmacol 2001;11(3):241–252. 62. Jenkins AJ, Keenan RM, Henningfield JE, Cone EJ: Pharmacokinetics and pharmacodynamics of smoked heroin. J Anal Toxicol 1994;18(6):317–330. 63. Elliott HW, Parker KD, Wright JA, Nomof N: Actions and metabolism of heroin administered by continuous intravenous infusion to man. Clin Pharmacol Ther 1971;12(5):806–814. 64. Tress KH, El-Sobky AA: Cardiovascular, respiratory and temperature responses to intravenous heroin (diamorphine) in dependent and non-dependent humans. Br J Clin Pharmacol 1980; 10(5):477–485. 65. Boerner U: The metabolism of morphine and heroin in man. Drug Metab Rev 1975;4(1):39–73. 66. Nakamura GR: Toxicologic assessments in acute heroin fatalities. Clin Toxicol 1978;13(1):75–87. 67. Osler W: Oedema of left lung—Morphia poisoning. Montreal Gen Hosp Rep 1880;1:291–293.

68. Troen P: Pulmonary edema in acute opium intoxication. N Engl J Med 1953;248:364–366. 69. Sporer KA, Dorn E: Heroin-related noncardiogenic pulmonary edema: a case series. Chest 2001;120(5):1628–1632. 70. Steinberg AD, Karliner JS: The clinical spectrum of heroin pulmonary edema. Arch Intern Med 1968;122(2):122–127. 71. Duberstein JL, Kaufman DM: A clinical study of an epidemic of heroin intoxication and heroin-induced pulmonary edema. Am J Med 1971;51(6):704–714. 72. Helpern M, Rho YM: Deaths from narcotism in New York City. Incidence, circumstances, and postmortem findings. NY State J Med 1966;66(18):2391–2408. 73. Hine CH, Wright JA, Allison DJ, et al: Analysis of fatalities from acute narcotism in a major urban area. J Forensic Sci 1982;27(2): 372–384. 74. Levine SB, Grimes ET: Pulmonary edema and heroin overdose in Vietnam. Arch Pathol 1973;95(5):330–332. 75. Dettmeyer R, Schmidt P, Musshoff F, et al: Pulmonary edema in fatal heroin overdose: immunohistological investigations with IgE, collagen IV and laminin–no increase of defects of alveolar-capillary membranes. Forensic Sci Int 2000;110(2):87–96. 76. Frand UI, Shim CS, Williams MH Jr: Heroin-induced pulmonary edema. Sequential studies of pulmonary function. Ann Intern Med 1972;77(1):29–35. 77. Katz S, Aberman A, Frand UI, et al: Heroin pulmonary edema. Evidence for increased pulmonary capillary permeability. Am Rev Respir Dis 1972;106(3):472–474. 78. Paranthaman SK, Khan F: Acute cardiomyopathy with recurrent pulmonary edema and hypotension following heroin overdosage. Chest 1976;69(1):117–119. 79. Smith WR, Glauser FL, Dearden LC, et al: Deposits of immunoglobulin and complement in the pulmonary tissue of patients with “heroin lung.” Chest 1978;73(4):471–476. 80. Wolters EC, van Wijngaarden GK, Stam FC, et al: Leucoencephalopathy after inhaling “heroin” pyrolysate. Lancet 1982; 2(8310):1233–1237. 81. Tan TP, Algra PR, Valk J, Wolters EC: Toxic leukoencephalopathy after inhalation of poisoned heroin: MR findings. Am J Neuroradiol 1994;15(1):175–178. 82. Weber W, Henkes H, Moller P, et al: Toxic spongiform leucoencephalopathy after inhaling heroin vapour. Eur Radiol 1998; 8(5):749–755. 83. Glauser FL, Downie RL, Smith WR: Electrocardiographic abnormalities in acute heroin overdosage. Bull Narc 1977;29(1):85–89. 84. Labi M: Paroxysmal atrial fibrillation in heroin intoxication. Ann Intern Med 1969;71(5):951–959. 85. Lipski J, Stimmel B, Donoso D: The effect of heroin and multiple drug abuse on the electrocardiogram. Am Heart J 1973;86(5): 663–668. 86. Pearce CJ, Cox JG: Heroin and hyperkalaemia. Lancet 1980; 2(8200):923. 87. Perry DC: Editorial. Heroin and cocaine adulteration. Clin Toxicol 1975;8(2):239–243. 88. Lupovich P, Pilewski R, Sapira JD, Juselius R: Cardiotoxicity of quinine as adulterant in drugs. JAMA 1970;212(7):1216. 89. Shesser R, Jotte R, Olshaker J: The contribution of impurities to the acute morbidity of illegal drug use. Am J Emerg Med 1991;9(4):336–342. 90. Brust JC, Richter RW: Quinine amblyopia related to heroin addiction. Ann Intern Med 1971;74(1):84–86. 91. Christie DJ, Walker RH, Kolins MD, et al: Quinine-induced thrombocytopenia following intravenous use of heroin. Arch Intern Med 1983;143(6):1174–1175. 92. Scopolamine poisoning among heroin users—New York City, Newark, Philadelphia, and Baltimore, 1995 and 1996. Morb Mortal Wkly Rep MMWR 1996;45(22):457–460. 93. Hollander JE, Lozano M Jr: Cocaine-associated myocardial infarction secondary to a contaminant. Am J Emerg Med 1993;11(6):681–682. 94. Questel F, Dugarin J, Dally S: Thallium-contaminated heroin. Ann Intern Med 1996;124(6):616. 95. Parras F, Patier JL, Ezpeleta C: Lead-contaminated heroin as a source of inorganic-lead intoxication. N Engl J Med 1987; 316(12):755. 96. Choudry N, Doe J: Inadvertent abuse of amphetamines in street heroin. Lancet 1986;2(8510):817.

CHAPTER 33

97. O’Gorman P, Patel S, Notcutt S, Wicking J: Adulteration of “street” heroin with chloroquine. Lancet 1987;1(8535):746. 98. Hoffman R: The toxic emergency: strychnine. Emerg Med 1994;26:111–112. 99. Solomon MD: A study of codeine metabolism. Clin Toxicol 1974;7(3):255–257. 100. Adler TK, Fujimoto JM, Way EL, Baker EM: The metabolic fate of codeine in man. J Pharmacol Exp Ther 1955;114(3):251–262. 101. Huffman DH, Ferguson RL: Acute codeine overdose: correspondence between clinical course and codeine metabolism. Johns Hopkins Med J 1975;136(4):183–186. 102. Peat MA, Sengupta A: Toxicological investigations of cases of death involving codeine and dihydrocodeine. Forensic Sci 1977;9(1):21–32. 103. Wright JA, Baselt RC, Hine CH: Blood codeine concentrations in fatalities associated with codeine. Clin Toxicol 1975;8(4):457–463. 104. Fung DL, Eisele JH: Fentanyl pharmacokinetics in awake volunteers. J Clin Pharmacol 1980;20(11–12):652–658. 105. Buchanan JF, Brown CR: “Designer drugs.” A problem in clinical toxicology. Med Toxicol Adverse Drug Exp 1988;3(1):1–17. 106. Hibbs J, Perper J, Winek CL: An outbreak of designer drug– related deaths in Pennsylvania. JAMA 1991;265(8):1011–1013. 107. Kram TC, Cooper DA, Allen AC: Behind the identification of China White. Anal Chem 1981;53(12):1379A–1386A. 108. Martin M, Hecker J, Clark R, et al: China White epidemic: an eastern United States emergency department experience. Ann Emerg Med 1991;20(2):158–164. 109. Ziporyn T: A growing industry and menace: makeshift laboratory’s designer drugs. JAMA 1986;256(22):3061–3063. 110. Rao TL, Mummaneni N, El-Etr AA: Convulsions: an unusual response to intravenous fentanyl administration. Anesth Analg 1982;61(12):1020–1021. 111. Safwat AM, Daniel D: Grand mal seizure after fentanyl administration. Anesthesiology 1983;59(1):78. 112. Sebel PS, Bovill JG: Fentanyl and convulsions. Anesth Analg 1983;62(9):858–859. 113. Murkin JM, Moldenhauer CC, Hug CC Jr, Epstein CM: Absence of seizures during induction of anesthesia with high-dose fentanyl. Anesth Analg 1984;63(5):489–494. 114. Scott JC, Sarnquist FH: Seizure-like movements during a fentanyl infusion with absence of seizure activity in a simultaneous EEG recording. Anesthesiology 1985;62(6):812–814. 115. Smith NT, Benthuysen JL, Bickford RG, et al: Seizures during opioid anesthetic induction—are they opioid-induced rigidity? Anesthesiology 1989;71(6):852–862. 116. Sprung J, Schedewie HK: Apparent focal motor seizure with a jacksonian march induced by fentanyl: a case report and review of the literature. J Clin Anesth 1992;4(2):139–143. 117. Adair JC, el-Nachef A, Cutler P: Fentanyl neurotoxicity. Ann Emerg Med 1996;27(6):791–792. 118. Arvanitis ML, Satonik RC: Transdermal fentanyl abuse and misuse. Am J Emerg Med 2002;20(1):58–59. 119. DeSio JM, Bacon DR, Peer G, Lema MJ: Intravenous abuse of transdermal fentanyl therapy in a chronic pain patient. Anesthesiology 1993;79(5):1139–1141. 120. Edinboro LE, Poklis A, Trautman D, et al: Fatal fentanyl intoxication following excessive transdermal application. J Forensic Sci 1997;42(4):741–743. 121. Kramer C, Tawney M: A fatal overdose of transdermally administered fentanyl. J Am Osteopath Assoc 1998;98(7): 385–386. 122. Marquardt KA, Tharratt RS: Inhalation abuse of fentanyl patch. J Toxicol Clin Toxicol 1994;32(1):75–78. 123. Reeves MD, Ginifer CJ: Fatal intravenous misuse of transdermal fentanyl. Med J Aust 2002;177(10):552–553. 124. Tharp AM, Winecker RE, Winston DC: Fatal intravenous fentanyl abuse: four cases involving extraction of fentanyl from transdermal patches. Am J Forensic Med Pathol 2004; 25(2):178–181. 125. Stambaugh JE, Wainer IW, Sanstead JK, Hemphill DM: The clinical pharmacology of meperidine—comparison of routes of administration. J Clin Pharmacol 1976;16(5–6):245–256. 126. Green RC Jr, Carroll GJ, Buxton WD: Drug addiction among physicians. The Virginia experience. JAMA 1976;236(12): 1372–1375.

Opioids

655

127. Putnam PL, Ellinwood EH Jr: Narcotic addiction among physicians: a ten-year follow-up. Am J Psychiatry 1966:122(7): 745–748. 128. Ward CF, Ward GC, Saidman LJ: Drug abuse in anesthesia training programs. A survey: 1970 through 1980. JAMA 1983;250(7): 922–925. 129. Hershey LA: Meperidine and central neurotoxicity. Ann Intern Med 1983;98(4):548–549. 130. Miller JW, Anderson HH: The effect of N-demethylation on certain pharmacologic actions of morphine, codeine, and meperidine in the mouse. J Pharmacol Exp Ther 1954;112(2):191–196. 131. Mather LE, Tucker GT, Pflug AE, et al: Meperidine kinetics in man. Intravenous injection in surgical patients and volunteers. Clin Pharmacol Ther 1975;17(1):21–30. 132. Kaiko RF, Foley KM, Grabinski PY, et al: Central nervous system excitatory effects of meperidine in cancer patients. Ann Neurol 1983;13(2):180–185. 133. Morisy L, Platt D: Hazards of high-dose meperidine. JAMA 1986;255(4):467–468. 134. Szeto HH, Inturrisi CE, Houde R, et al: Accumulation of normeperidine, an active metabolite of meperidine, in patients with renal failure of cancer. Ann Intern Med 1977;86(6):738–741. 135. Goetting MG, Thirman MJ: Neurotoxicity of meperidine. Ann Emerg Med 1985;14(10):1007–1009. 136. Marinella MA: Meperidine-induced generalized seizures with normal renal function. South Med J 1997;90(5):556–558. 137. Mauro VF, Bonfiglio MF, Spunt AL: Meperidine-induced seizure in a patient without renal dysfunction or sickle cell anemia. Clin Pharm 1986;5(10):837–839. 138. McHugh GJ: Norpethidine accumulation and generalized seizure during pethidine patient-controlled analgesia. Anaesth Intensive Care 1999;27(3):289–291. 139. Browne B, Linter S: Monoamine oxidase inhibitors and narcotic analgesics. A critical review of the implications for treatment. Br J Psychiatry 1987;151:210–212. 140. Nicklas WJ, Youngster SK, Kindt MV, Heikkila RE: MPTP, MPP+ and mitochondrial function. Life Sci 1987;40(8):721–729. 141. Uhl GR, Javitch JA, Snyder SH: Normal MPTP binding in parkinsonian substantial nigra: evidence for extraneuronal toxin conversion in human brain. Lancet 1985;1(8435):956–957. 142. Ballard PA, Tetrud JW, Langston JW: Permanent human parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): seven cases. Neurology 1985;35(7):949–956. 143. Burns RS, LeWitt PA, Ebert MH, et al: The clinical syndrome of striatal dopamine deficiency. Parkinsonism induced by 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP). N Engl J Med 1985; 312(22):1418–1421. 144. Langston JW, Ballard P, Tetrud JW, Irwin I: Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 1983;219(4587):979–980. 145. Henderson W, Psaila A: Lomotil poisoning. Lancet 1969;1(7589): 307–308. 146. Penfold D, Volans GN: Overdose from Lomotil. BMJ 1977; 2(6099):1401–1402. 147. Rumack BH, Temple AR: Lomotil poisoning. Pediatrics 1974;53(4):495–500. 148. Karim A, Ranney RE, Evensen KL, Clark ML: Pharmacokinetics and metabolism of diphenoxylate in man. Clin Pharmacol Ther 1972;13(3):407–419. 149. Rubens R, Verhaegen H, Brugmans J, Schuermans V: Difenoxine (R 15403), the active metabolite of diphenoxylate (R 1132). 5. Clinical comparison of difenoxine and diphenoxylate in volunteers and in patients with chronic diarrhea. Double-blind cross-over assessments. Arzneimittelforschung 1972;22(3):526–529. 150. Litovitz T, Clancy C, Korberly B, et al: Surveillance of loperamide ingestions: an analysis of 216 poison center reports. J Toxicol Clin Toxicol 1997;35(1):11–19. 151. Aronow R, Brenner SL, Woolley PV Jr: An apparent epidemic: methadone poisoning in children. Clin Toxicol 1973;6(2): 175–181. 152. Persky VW, Goldfrank LR: Methadone overdoses in a New York City hospital. JACEP 1976;5(2):111–113. 153. Berkowitz BA: The relationship of pharmacokinetics to pharmacological activity: morphine, methadone and naloxone. Clin Pharmacokinet 1976;1(3):219–230.

656


154. Anggard E, Nilsson MI, Holmstrend J, Gunne LM: Pharmacokinetics of methadone during maintenance therapy: pulse labeling with deuterated methadone in the steady state. Eur J Clin Pharmacol 1979;16(1):53–57. 155. Garriott JC, Sturner WQ, Mason MF: Toxicologic findings in six fatalities involving methadone. Clin Toxicol 1973;6(2):163–173. 156. Kreek MJ: Medical complications in methadone patients. Ann N Y Acad Sci 1978;311:110–134. 157. Norris JV, Don HF: Prolonged depression of respiratory rate following methadone analgesia. Anesthesiology 1976;45(3): 361–362. 158. Gordon E: Treatment of methadone poisoning. JAMA 1972;220(5):728–731. 159. Bonnet U, Banger M, Wolstein J, Gastpar M: Choreoathetoid movements associated with rapid adjustment to methadone. Pharmacopsychiatry 1998;31(4):143–145. 160. Binchy JM, Molyneux EM, Manning J: Accidental ingestion of methadone by children in Merseyside. BMJ 1994;308(6940): 1335–1336. 161. Krantz MJ, Lewkowiez L, Hays H, et al: Torsade de pointes associated with very-high-dose methadone. Ann Intern Med 2002;137(6):501–504. 162. Cowan A, Doxey JC, Harry EJ: The animal pharmacology of buprenorphine, an oripavine analgesic agent. Br J Pharmacol 1977;60(4):547–554. 163. Walsh SL, Preston KL, Stitzer ML, et al: Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther 1994;55(5):569–580. 164. Gal TJ: Naloxone reversal of buprenorphine-induced respiratory depression. Clin Pharmacol Ther 1989;45(1):66–71. 165. Megarbane B, Pirnay S, Borron SW, et al: Flunitrazepam does not alter cerebral distribution of buprenorphine in the rat. Toxicol Lett 2005;157(3):211–219. 166. Carson DJ: Fatal dextropropoxyphene poisoning in Northern Ireland. Review of 30 cases. Lancet 1977;1(8017):894–897. 167. Hudson P, Barringer M, McBay AJ: Fatal poisoning with propoxyphene: report from 100 consecutive cases. South Med J 1977;70(8):938–942. 168. Sturner WQ, Garriott JC: Deaths involving propoxyphene. A study of 41 cases over a two-year period. JAMA 1973;223(10): 1125–1130. 169. Wolen RL, Gruber CM Jr, Kiplinger GF, Scholz NE: Concentration of propoxyphene in human plasma following oral, intramuscular, and intravenous administration. Toxicol Appl Pharmacol 1971;19(3):480–492. 170. Bellville JW, Seed JC: A comparison of the respiratory depressant effects of dextropropoxyphene and codeine in man. Clin Pharmacol Ther 1968;9(4):428–434. 171. Verebely K, Inturrisi CE: Disposition of propoxyphene and norpropoxyphene in man after a single oral dose. Clin Pharmacol Ther 1974;15(3):302–309. 172. Lund-Jacobsen H: Cardio-respiratory toxicity of propoxyphene and norpropoxyphene in conscious rabbits. Acta Pharmacol Toxicol (Copenh) 1978;42(3):171–178. 173. Bogartz LJ, Miller WC: Pulmonary edema associated with propoxyphene intoxication. JAMA 1971;215(2):259–262. 174. Gary NE, Maher JF, DeMyttenaere MH, et al: Acute propoxyphene hydrochloride intoxication. Arch Intern Med 1968;121(5):453–457. 175. Gustafson A, Gustafsson B: Acute poisoning with dextropropoxyphene. Clinical symptoms and plasma concentrations. Acta Med Scand 1976;200(4):241–248. 176. McCarthy WH, Keenan RL: Propoxyphene hydrochloride poisoning. Report of the first fatality. JAMA 1964;187:460–461. 177. Sloth Madsen P, Strom J, Reiz S, Bredgaard Sorensen M: Acute propoxyphene self-poisoning in 222 consecutive patients. Acta Anaesthesiol Scand 1984;28(6):661–665. 178. Tennant FS Jr: Complications of propoxyphene abuse. Arch Intern Med 1973;132(2):191–194. 179. Strom J: Acute propoxyphene self-poisoning—with special reference to propoxyphene cardiotoxicity and treatment. Dan Med Bull 1989;36(4):316–336. 180. D’Abadie NB, Lenton JD: Propoxyphene dependence: problems in management. South Med J 1984;77(3):299–301. 181. Miller RR, Feingold A, Paxinos J: Propoxyphene hydrochloride. A critical review. JAMA 1970;213(6):996–1006.

182. Woody GE, Tennant FS, McLellan AT, et al: Lack of toxicity of high dose propoxyphene napsylate when used for maintenance treatment of addiction. NIDA Res Monogr 1979;27:435–440. 183. Brogden RN, Speight TM, Avery GS: Pentazocine: a review of its pharmacological properties, therapeutic efficacy and dependence liability. Drugs 1973;5(1):6–91. 184. Ehrnebo M, Boreus LO, Lonroth U: Bioavailability and first-pass metabolism of oral pentazocine in man. Clin Pharmacol Ther 1977;22(6):888–892. 185. Challoner KR, McCarron MM, Newton EJ: Pentazocine (Talwin) intoxication: report of 57 cases. J Emerg Med 1990;8(1):67–74. 186. De Bard ML, Jagger JA: “T’s and B’s”—Midwestern heroin substitute. Clin Toxicol 1981;18(9):1117–1123. 187. Stahl SM, Kasser IS: Pentazocine overdose. Ann Emerg Med 1983;12(1):28–31. 188. Carter HS, Watson WA: IV pentazocine/methylphenidate abuse— the clinical toxicity of another Ts and blues combination. J Toxicol Clin Toxicol 1994;32(5):541–547. 189. Bhargava HN: Mechanism of toxicity and rationale for use of the combination of pentazocine and pyribenzamine in morphinedependent subjects. Clin Toxicol 1981;18(2):175–188. 190. Farber HW, Falls R, Glauser FL: Transient pulmonary hypertension from the intravenous injection of crushed, suspended pentazocine tablets. Chest 1981;80(2):178–182. 191. Poklis A: Decline in abuse of pentazocine/tripelennamine (T’s and Blues) associated with the addition of naloxone to pentazocine tablets. Drug Alcohol Depend 1984;14(2): 135–140. 192. Bem JL, Peck R: Dextromethorphan. An overview of safety issues. Drug Saf 1992;7(3):190–199. 193. Silvasti M, Karttunen P, Tukiainen H, et al: Pharmacokinetics of dextromethorphan and dextrorphan: a single dose comparison of three preparations in human volunteers. Int J Clin Pharmacol Ther Toxicol 1987;25(9):493–497. 194. McCarthy JP: Some less familiar drugs of abuse. Med J Aust 1971;2(21):1078–1081. 195. Murray S, Brewerton T: Abuse of over-the-counter dextromethorphan by teenagers. South Med J 1993;86(10):1151–1153. 196. Wolfe TR, Caravati EM: Massive dextromethorphan ingestion and abuse. Am J Emerg Med 1995;13(2):174–176. 197. Ng YY, Lin WL, Chen TW, et al: Spurious hyperchloremia and decreased anion gap in a patient with dextromethorphan bromide. Am J Nephrol 1992;12(4):268–270. 198. Rivers N: Possible lethal reaction between Nardil and dextromethorphan. Can Med Assoc J 1970;103:85. 199. Sovner R, Wolfe J: Interaction between dextromethorphan and monoamine oxidase inhibitor therapy with isocarboxazid. N Engl J Med 1988;319(25):1671. 200. Szekely JI, Sharpe LG, Jaffe JH: Induction of phencyclidine-like behavior in rats by dextrorphan but not dextromethorphan. Pharmacol Biochem Behav 1991;40(2):381–386. 201. Zawertailo LA, Kaplan HL, Busto UE, et al: Psychotropic effects of dextromethorphan are altered by the CYP2D6 polymorphism: a pilot study. J Clin Psychopharmacol 1998;18(4):332–337. 202. Graudins A, Fern RP: Acute dystonia in a child associated with therapeutic ingestion of a dextromethorphan containing cough and cold syrup. J Toxicol Clin Toxicol 1996;34(3):351–352. 203. Raffa RB, Friderichs E, Reimann W, et al: Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an “atypical” opioid analgesic. J Pharmacol Exp Ther 1992;260(1):275–285. 204. Kesavan S, Sobala GM: Serotonin syndrome with fluoxetine plus tramadol. J R Soc Med 1999;92(9):474–475. 205. Lantz MS, Buchalter EN, Giambanco V: Serotonin syndrome following the administration of tramadol with paroxetine. Int J Geriatr Psychiatry 1998;13(5):343–345. 206. Nightingale SL: From the Food and Drug Administration. JAMA 1996;275(16):1224. 207. Traub SJ, Hoffman RS, Nelson LS: Body packing—the internal concealment of illicit drugs. N Engl J Med 2003;349(26): 2519–2526. 208. Wetli CV, Rao A, Rao VJ: Fatal heroin body packing. Am J Forensic Med Pathol 1997;18(3):312–318. 209. Katona B, Wason S: Dextromethorphan danger. N Engl J Med 1986;314(15):993.

CHAPTER 33

210. Pender ES, Parks BR: Toxicity with dextromethorphan-containing preparations: a literature review and report of two additional cases. Pediatr Emerg Care 1991;7(3):163–165. 211. Schneider SM, Michelson EA, Boucek CD, Ilkhanipour K: Dextromethorphan poisoning reversed by naloxone. Am J Emerg Med 1991;9(3):237–238. 212. Shaul WL, Wandell M, Robertson WO: Dextromethorphan toxicity: reversal by naloxone. Pediatrics 1977;59(1):117–118. 213. Gould DB: Buprenorphine causes pulmonary edema just like all other mu-opioid narcotics. Upper airway obstruction, negative alveolar pressure. Chest 1995;107(5):1478–1479. 214. Jaffe RB, Koschmann EB: Intravenous drug abuse. Pulmonary, cardiac, and vascular complications. Am J Roentgenol Radium Ther Nucl Med 1970;109(1):107–120. 215. Kjeldgaard JM, Hahn GW, Heckenlively JR, Genton E: Methadoneinduced pulmonary edema. JAMA 1971;218(6):882–883. 216. Pearson MA, Poklis A, Morrison RR: A fatality due to the ingestion of (methyl morphine) codeine. Clin Toxicol 1979;15(3):267–271. 217. Schaaf JT, Spivack ML, Rath GS, Snider GL: Pulmonary edema and adult respiratory distress syndrome following methadone abuse. Am Rev Respir Dis 1973;107(6):1047–1051. 218. Sklar J, Timms RM: Codeine-induced pulmonary edema. Chest 1977;72(2):230–231. 219. Stadnyk A, Grossman RF: Nalbuphine-induced pulmonary edema. Chest 1986;90(5):773–774. 220. Thammakumpee G, Sumpatanukule P: Noncardiogenic pulmonary edema induced by sublingual buprenorphine. Chest 1994;106(1):306–308. 221. Winek CL, Collom WD, Wecht CH: Codeine fatality from cough syrup. Clin Toxicol 1970;3(1):97–100. 222. Zyroff J, Slovis TL, Nagler J: Pulmonary edema induced by oral methadone. Radiology 1974;112(3):567–568. 223. Presant S, Knight L, Klassen G: Methadone-induced pulmonary edema. Can Med Assoc J 1975;113(10):966–967. 224. Wilen SB, Ulreich S, Rabinowitz JG: Roentgenographic manifestations of methadone-induced pulmonary edema. Radiology 1975;114(1):51–55. 225. Gopinathan K, Saroja J, Spears R: Hemodynamic studies in heroin induced acute pulmonary edema. Circulation 1970;42:44. 226. Lee G, DeMaria AN, Amsterdam EA, et al: Comparative effects of morphine, meperidine and pentazocine on cardiocirculatory dynamics in patients with acute myocardial infarction. Am J Med 1976;60(7):949–955. 227. Tammisto T, Jaattela A, Nikki P, Takki S, et al: Effect of pentazocine and pethidine on plasma catecholamine levels. Ann Clin Res 1971;3(1):22–29. 228. Addington W: The pulmonary edema of heroin toxicity—an example of stiff lung syndrome. Clinical Conference in Pulmonary Disease. Chest 1972;62:199–205. 229. Morrison WJ, Wetherill W, Zyroff J: The acute pulmonary edema of heroin intoxication. Radiology 1970;97(2):347–351. 230. Pare JA, Fraser RG, Hogg JC, et al: Pulmonary “mainline” granulomatosis: talcosis of intravenous methadone abuse. Medicine (Baltimore) 1979;58(3):229–239. 231. Glassroth J, Adams GD, Schnoll S: The impact of substance abuse on the respiratory system. Chest 1987;91(4):596–602. 232. Sieniewicz DJ, Nidecker AC: Conglomerate pulmonary disease: a form of talcosis in intravenous methadone abusers. Am J Roentgenol 1980;135(4):697–702. 233. Sternbach G, Moran J, Eliastam M: Heroin addiction: acute presentation of medical complications. Ann Emerg Med 1980; 9(3):161–169. 234. Angiitis in drug abusers. N Engl J Med 1971;284(2):111–113. 235. Amine AR: Neurosurgical complications of heroin addiction: brain abscess and mycotic aneurysm. Surg Neurol 1977;7(6):385–386. 236. Brust JC, Richter RW: Stroke associated with addiction to heroin. J Neurol Neurosurg Psychiatry 1976;39(2):194–199. 237. Jensen R, Olsen TS, Winther BB: Severe non-occlusive ischemic stroke in young heroin addicts. Acta Neurol Scand 1990;81(4): 354–357. 238. King J, Richards M, Tress B: Cerebral arteritis associated with heroin abuse. Med J Aust 1978;2(9):444–445. 239. Niehaus L, Meyer BU: Bilateral borderzone brain infarctions in association with heroin abuse. J Neurol Sci 1998;160(2):180–182.

Opioids

657

240. Spiller HA, Gorman SE, Villalobos D, et al: Prospective multicenter evaluation of tramadol exposure. J Toxicol Clin Toxicol 1997;35(4):361–364. 241. Vila N, Chamorro A: Ballistic movements due to ischemic infarcts after intravenous heroin overdose: report of two cases. Clin Neurol Neurosurg 1997;99(4):259–262. 242. Woods BT, Strewler GJ: Hemiparesis occurring six hours after intravenous heroin injection. Neurology 1972;22(8):863–866. 243. McCarron MM, Challoner KR, Thompson GA: Diphenoxylateatropine (Lomotil) overdose in children: an update (report of eight cases and review of the literature). Pediatrics 1991;87(5): 694–700. 244. Cutler EA, Barrett GA, Craven PW, Cramblett HG: Delayed cardiopulmonary arrest after Lomotil ingestion. Pediatrics 1980; 65(1):157–158. 245. Dunkley EJ, Isbister GK, Sibbritt D, et al: The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM 2003;96(9):635–642. 246. Sternbach H: The serotonin syndrome. Am J Psychiatry 1991; 148(6):705–713. 247. Richter RW, Challenor YB, Pearson J, et al: Acute myoglobinuria associated with heroin addiction. JAMA 1971;216(7):1172–1176. 248. Schwartzfarb L, Singh G, Marcus D: Heroin-associated rhabdomyolysis with cardiac involvement. Arch Intern Med 1977;137(9): 1255–1257. 249. D’Agostino RS, Arnett EN: Acute myoglobinuria and heroin snorting. JAMA 1979;241(3):277. 250. Cunningham EE, Brentjens JR, Zielezny MA, et al: Heroin nephropathy. A clinicopathologic and epidemiologic study. Am J Med 1980;68(1):47–53. 251. Cunningham EE, Venuto RC, Zielezny MA: Adulterants in heroin/cocaine: implications concerning heroin-associated nephropathy. Drug Alcohol Depend 1984;14(1):19–22. 252. Cunningham EE, Zielezny MA, Venuto RC: Heroin-associated nephropathy. A nationwide problem. JAMA 1983;250(21):2935–2936. 253. Dubrow A, Mittman N, Ghali V, Flamenbaum W: The changing spectrum of heroin-associated nephropathy. Am J Kidney Dis 1985;5(1):36–41. 254. Utecht MJ, Stone AF, McCarron MM: Heroin body packers. J Emerg Med 1993;11(1):33–40. 255. Hutchins KD, Pierre-Louis PJ, Zaretski L, et al: Heroin body packing: three fatal cases of intestinal perforation. J Forensic Sci 2000;45(1):42–47. 256. Handal KA, Schauben JL, Salamone FR: Naloxone. Ann Emerg Med 1983;12(7):438–445. 257. Hantson P, Evenepoel M, Ziade D, et al: Adverse cardiac manifestations following dextropropoxyphene overdose: can naloxone be helpful? Ann Emerg Med 1995;25(2):263–266. 258. American Heart Association in collaboration with the International Liaison Committee on Resuscitation: Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 8: advanced challenges in resuscitation: section 2: toxicology in ECC. Circulation 2000;102(8 Suppl):I223–I228. 259. Moore RA, Rumack BH, Conner CS, Peterson RG: Naloxone: underdosage after narcotic poisoning. Am J Dis Child 1980; 134(2):156–158. 260. Barton ED, Ramos J, Colwell C, et al: Intranasal administration of naloxone by paramedics. Prehosp Emerg Care 2002;6(1):54–58. 261. Maio RF, Gaukel B, Freeman B: Intralingual naloxone injection for narcotic-induced respiratory depression. Ann Emerg Med 1987;16(5):572–573. 262. Salvucci AA Jr, Eckstein M, Iscovich AL: Submental injection of naloxone. Ann Emerg Med 1995;25(5):719–720. 263. Tandberg D, Abercrombie D: Treatment of heroin overdose with endotracheal naloxone. Ann Emerg Med 1982;11(8):443–445. 264. Wanger K, Brough L, Macmillan I, et al: Intravenous vs subcutaneous naloxone for out-of-hospital management of presumed opioid overdose. Acad Emerg Med 1998;5(4):293–299. 265. Longnecker DE, Grazis PA, Eggers GW Jr: Naloxone for antagonism of morphine-induced respiratory depression. Anesth Analg 1973;52(3):447–453. 266. Goldfrank L, Weisman RS, Errick JK, Lo MW: A dosing nomogram for continuous infusion intravenous naloxone. Ann Emerg Med 1986;15(5):566–570.

658


267. Lewis JM, Klein-Schwartz W, Benson BE, et al: Continuous naloxone infusion in pediatric narcotic overdose. Am J Dis Child 1984;138(10):944–946. 268. Romac DR: Safety of prolonged, high-dose infusion of naloxone hydrochloride for severe methadone overdose. Clin Pharm 1986;5(3):251–254. 269. Bracken MB, Shepard MJ, Collins WF, et al: A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med 1990;322(20):1405–1411. 270. Brimacombe J, Archdeacon J, Newell S, Martin J: Two cases of naloxone-induced pulmonary oedema—the possible use of phentolamine in management. Anaesth Intensive Care 1991; 19(4):578–580. 271. Flacke JW, Flacke WE, Williams GD: Acute pulmonary edema following naloxone reversal of high-dose morphine anesthesia. Anesthesiology 1977;47(4):376–378. 272. Olsen KS: Naloxone administration and laryngospasm followed by pulmonary edema. Intensive Care Med 1990;16(5):340–341. 273. Prough DS, Roy R, Bumgarner J, Shannon G: Acute pulmonary edema in healthy teenagers following conservative doses of intravenous naloxone. Anesthesiology 1984;60(5):485–486. 274. Schwartz JA, Koenigsberg MD: Naloxone-induced pulmonary edema. Ann Emerg Med 1987;16(11):1294–1296. 275. Taff RH: Pulmonary edema following naloxone administration in a patient without heart disease. Anesthesiology 1983;59(6): 576–577. 276. Andree RA: Sudden death following naloxone administration. Anesth Analg 1980;59(10):782–784. 277. Cuss FM, Colaco CB, Baron JH: Cardiac arrest after reversal of effects of opiates with naloxone. BMJ 1984;288(6414):363–364. 278. Michaelis LL, Hickey PR, Clark TA, Dixon WM: Ventricular irritability associated with the use of naloxone hydrochloride. Two case reports and laboratory assessment of the effect of the drug on cardiac excitability. Ann Thorac Surg 1974;18(6):608–614. 279. Tanaka GY: Hypertensive reaction to naloxone [Letter]. JAMA 1974;228(1):25–26. 280. Mills CA, Flacke JW, Flacke WE, et al: Narcotic reversal in hypercapnic dogs: comparison of naloxone and nalbuphine. Can J Anaesth 1990;37(2):238–244. 281. Mills CA, Flacke JW, Miller JD, et al: Cardiovascular effects of fentanyl reversal by naloxone at varying arterial carbon dioxide tensions in dogs. Anesth Analg 1988;67(8):730–736. 282. Pallasch TJ, Gill CJ: Naloxone-associated morbidity and mortality. Oral Surg Oral Med Oral Pathol 1981;52(6):602–603. 283. Silverstein JH, Gintautas J, Tadoori P, Abadir AR: Effects of naloxone on pulmonary capillary permeability. Prog Clin Biol Res 1990;328:389–392. 284. Kollef MH, Pluss J: Noncardiogenic pulmonary edema following upper airway obstruction. 7 cases and a review of the literature. Medicine (Baltimore) 1991;70(2):91–98. 285. Chandavasu O, Chatkupt S: Central nervous system depression from chlorpromazine poisoning: successful treatment with naloxone. J Pediatr 1985;106(3):515–516. 286. Jefferys DB, Flanagan RJ, Volans GN: Reversal of ethanol-induced coma with naloxone. Lancet 1980;1(8163):308–309. 287. Kulig K, Duffy J, Rumack BH, et al: Naloxone for treatment of clonidine overdose. JAMA 1982;247(12):1697. 288. Montero FJ: Naloxone in the reversal of coma induced by sodium valproate. Ann Emerg Med 1999;33(3):357–358. 289. Merigian KS: Cocaine-induced ventricular arrhythmias and rapid atrial fibrillation temporally related to naloxone administration. Am J Emerg Med 1993;11(1):96–97. 290. Hamilton RJ, Perrone J, Hoffman R, et al: A descriptive study of an epidemic of poisoning caused by heroin adulterated with scopolamine. J Toxicol Clin Toxicol 2000;38(6):597–608. 291. Stork CM, Redd JT, Fine K, Hoffman RS: Propoxyphene-induced wide QRS complex dysrhythmia responsive to sodium bicarbonate—a case report. J Toxicol Clin Toxicol 1995;33(2): 179–183.

292. Gilbert PE, Martin WR: Antagonism of the convulsant effects of heroin, d-propoxyphene, meperidine, normeperidine and thebaine by naloxone in mice. J Pharmacol Exp Ther 1975; 192(3):538–541. 293. Cowan A, Geller EB, Adler MW: Classification of opioids on the basis of change in seizure threshold in rats. Science 1979;206(4417):465–467. 294. Jackson HC, Nutt DJ: Investigation of the involvement of opioid receptors in the action of anticonvulsants. Psychopharmacology (Berl) 1993;111(4):486–490. 295. Van Derburgh K, Hantsch C, Meredith T: Is naloxone contraindicated in tramadol overdose? [Abstract]. J Toxicol Clin Toxicol 1998;36:435. 296. Graudins A, Stearman A, Chan B: Treatment of the serotonin syndrome with cyproheptadine. J Emerg Med 1998;16(4):615–619. 297. Frand UI, Shim CS, Williams MH Jr: Methadone-induced pulmonary edema. Ann Intern Med 1972;76(6):975–979. 298. Sterrett C, Brownfield J, Korn CS, et al: Patterns of presentation in heroin overdose resulting in pulmonary edema. Am J Emerg Med 2003;21(1):32–34. 299. Smith DA, Leake L, Loflin JR, Yealy DM: Is admission after intravenous heroin overdose necessary? Ann Emerg Med 1992; 21(11):1326–1330. 300. Christenson J, Etherington J, Grafstein E, et al: Early discharge of patients with presumed opioid overdose: development of a clinical prediction rule. Acad Emerg Med 2000;7(10): 1110–1118. 301. Farmer JW, Chan SB: Whole body irrigation for contraband bodypackers. J Clin Gastroenterol 2003;37(2):147–150. 302. Hoffman RS, Smilkstein MJ, Goldfrank LR: Whole bowel irrigation and the cocaine body-packer: a new approach to a common problem. Am J Emerg Med 1990;8(6):523–527. 303. Traub SJ, Kohn GL, Hoffman RS, Nelson LS: Pediatric “body packing.” Arch Pediatr Adolesc Med 2003;157(2):174–177. 304. Marc B, Baud FJ, Aelion MJ, et al: The cocaine body-packer syndrome: evaluation of a method of contrast study of the bowel. J Forensic Sci 1990;35(2):345–355. 305. Marc B, Baud F: Paraffin and body-packers. Lancet 1999; 353(9148):238–239. 306. Larijani GE, Goldberg ME, Rogers KH: Treatment of opioidinduced pruritus with ondansetron: report of four patients. Pharmacotherapy 1996;16(5):958–960. 307. Kriegstein AR, Shungu DC, Millar WS, et al: Leukoencephalopathy and raised brain lactate from heroin vapor inhalation (“chasing the dragon”). Neurology 1999;53(8):1765–1773. 308. Meissner W, Schmidt U, Hartmann M, et al: Oral naloxone reverses opioid-associated constipation. Pain 2000;84(1):105–109. 309. Yuan CS, Foss JF, O’Connor M, et al: Methylnaltrexone for reversal of constipation due to chronic methadone use: a randomized controlled trial. JAMA 2000;283(3):367–372. 310. Hassan H, Bastani B, Gellens M: Successful treatment of normeperidine neurotoxicity by hemodialysis. Am J Kidney Dis 2000;35(1):146–149. 311. Dixon R, Howes J, Gentile J, et al: Nalmefene: intravenous safety and kinetics of a new opioid antagonist. Clin Pharmacol Ther 1986;39(1):49–53. 312. Gal TJ, DiFazio CA: Prolonged antagonism of opioid action with intravenous nalmefene in man. Anesthesiology 1986;64(2): 175–180. 313. Barsan WG, Seger D, Danzl DF, et al: Duration of antagonistic effects of nalmefene and naloxone in opiate-induced sedation for emergency department procedures. Am J Emerg Med 1989;7(2):155–161. 314. Kaplan JL, Marx JA: Effectiveness and safety of intravenous nalmefene for emergency department patients with suspected narcotic overdose: a pilot study. Ann Emerg Med 1993;22(2): 187–190. 315. Kaplan JL, Marx JA, Calabro JJ, et al: Double-blind, randomized study of nalmefene and naloxone in emergency department patients with suspected narcotic overdose. Ann Emerg Med 1999;34(1):42–50.

34

Sedative-Hypnotics JOHN G. BENITEZ, MD, MPH, FACMT, FACPM ■ LINDA G. ALLISON, MD, MPH ■ SHARON TERNULLO, BS, PHARMD, CSPI

At a Glance…

Sedative-hypnotic is a term that describes different medications that sedate or calm a person or induce drowsiness and sleep. The substances covered in this chapter are all chemically different from benzodiazepines and barbiturates (see Chapters 35 and 36). This chapter will focus on the multiple, diverse sedative-hypnotic drugs that are not structurally similar (Fig. 34-1).

K J

J

J JJ

J

JJ

K

JJ

O

H2N

O

NH2

Meprobamate

Methoqualone

K

N

J

OK N

K

N

Cl

O

J

J

H3C

N

N

O

CH3 N

J

J

Methprylone

N

N

N

Zaleplon

Zolpidem

J

OH OH

Cl

N

CH3

Chloral hydrate

Zopiclone

Cl

J

ClJ

N

O

CH3

N

Cl

CH3

CH3

CH3 O

N

O

J

J N

N

CH3

N H

H3C

O H3C

CH3

K

J

K

O

CH3 O

CH3

N O

J

CH3

J J

INTRODUCTION AND HISTORY

K

■

Sedatives and hypnotics were among the earliest medications to be introduced into medical practice. Chloral hydrate was synthesized in 1832 and first used clinically starting in 1869. Deaths from this agent were reported as early as 1890.1 Chloral hydrate, urethane, and paraldehyde were used prior to the introduction of barbital in 1903 and phenobarbital in 1912. As the physical dependence, withdrawal, and abuse potential of these agents began to be appreciated, a search was made for sedative-hypnotics that minimized these risks. Chlorpromazine, the first phenothiazine, was introduced in the early 1950s, and meprobamate, a biscarbamate ester, was introduced in 1955. Other sedativehypnotics were introduced during this time period that were presumed to have more selectivity and less abuse potential, including glutethimide, methyprylon (piperidinediones), chlormezanone, ethinamate (urethane derivative), ethchlorvynol, and methaqualone (quinazolines and their derivatives).2-5

All sedative-hypnotics are not the same. Central nervous system depression is their main effect. Additive CNS effects occur with other CNS depressants. There is no specific antidote for any of the sedative-hypnotics. Plasma concentrations of these agents do not assist in management. Hemodialysis does not help in clinical management.

K

■ ■ ■ ■ ■

OH ClJ Cl Trichlorol ethanol

K

O

O

Cl

OH

CH3

HN

J K

K

J J J

O

S

K

Cl

O

CH

N

K

H3C

CH3

OK

Chlormezanone Ethchlorvynol Glutethimide FIGURE 34-1 Chemical structures of sedative-hypnotics described in this chapter. (All structures drawn and identified using ChemIDplus, accessed at http://chem.sis.nlm.nih.gov/chemidplus/.)

659

660


Because of the high abuse potential, tolerance, and acute toxicity of the early sedatives and hypnotics, their use was eventually discontinued. Ethinamate, chlormezanone, methyprylon, paraldehyde, and methaqualone were withdrawn in the 1980s and 1990s. These agents had dependence and abstinence syndromes at least equal to those of the barbiturates, and intoxication was more difficult to manage. During the 1980s to 1990s, selective benzodiazepine receptor agonists were identified and synthesized, including zolpidem, zaleplon, zopiclone (not available in the United States), and alpidem. Zopiclone was first introduced in France in 1987. It was the first cyclopyrrolone hypnotic and was chemically unrelated to other existing sedatives. Ultimately, zolpidem and zaleplon were marketed in the United States. Alpidem was not marketed in the United States due to inconsistent results during clinical trials and was withdrawn from the French market in 1993 due to reports of hepatic toxicity.6,7 Sedative-hypnotics are used worldwide, but overall use has steadily decreased since the 1980s. Over the years, barbiturate and benzodiazepine use has increased, replacing the older sedative-hypnotics. In the United States, American Association of Poison Control Centers (AAPCC) data show that exposures to sedative-hypnotics (nonbarbiturates and nonbenzodiazepines) decreased from 2000 to 2003 (Fig. 34-2). Exposures to chloral hydrate, however, remain steady, with approximately 220 toxic exposures reported per year. Fewer than five deaths per year from these agents were reported to U.S. poison centers from 2000 to 2003 (Fig. 34-3).8 In Australia, the ratio of female-to-male overdoses was 1.5 to 1. Most overdoses were from the barbiturate or benzodiazepine class, with a small percentage in the “other” class, but specific agents were not described.9 Chloral hydrate was noted in 0.3% of admissions and 3.5% of deaths from self-poisoning between 1987 and 1992.10 Chloral hydrate was 4.5 times as likely (odds ratio [OR] 4.5, confidence interval 2–10, 95%) to be used for self-poisoning and had a high likelihood of death (OR

58.1) between 1989 and 1992. In London, 3.1% of overdoses were with sedative-hypnotics, excluding benzodiazepines and barbiturates, during 1984 to 1988. The female-to-male ratio was 1.3:1 for all overdoses.11,12 Chlormethiazole was the most popular medication for ethanol withdrawal in Great Britain during the mid1980s, but its use was discontinued secondary to drug interactions. The drug exhibits cross-tolerance with ethanol, and with long-term use alcoholics readily transferred dependence and often used it while continuing to drink, resulting in a significantly increased mortality rate. There were 95.7 deaths per million prescriptions for this drug, which was twice that of chloral hydrate. By comparison, the newer less toxic alternatives zolpidem and zopiclone resulted in approximately 2 deaths per million prescriptions each.4,5 During the late 1960s and early 1970s, 22% of overdose fatalities were due to glutethimide. Mortality approaches 20% after glutethimide-only overdoses and 17% in mixed ingestions, and is greater than any other drug in the sedative-hypnotic group.13 Meprobamate was the second most commonly prescribed sedative in the United States after barbiturates during this same time period, and was available in combination dosage forms containing anticholinergics, conjugated estrogens, antianginal agents, and antidepressants.14,15 In France, mortality from meprobamate overdose was approximately 2.6%.16 Until 1992, the drug was sold over the counter in some European countries, including Belgium. Moving it to prescription status decreased the number of meprobamate poisoning cases requiring admission from 120 to 18 per year.17

STRUCTURE AND STRUCTURE-ACTIVITY RELATIONSHIPS The exact mechanism of action is unknown or unclear for many sedative-hypnotics. Some affect the γ-aminobutyric acid (GABA) chloride channel but differently from

Chloral hydrate Ethchlorvynol Glutethimide

250 225

Meprobamate Methaqualone

200

Number

175 150 125 100 75 50 25 0 2000

2001

2002

2003

FIGURE 34-2 Human exposures to selected sedative-hypnotics, 2000–2003, United States. (Data from WebTESS, American Association of Poison Control Centers, http://webtess.aapcc.org, accessed June 2004.)

CHAPTER 34

5

Number

4 3

Chloral hydrate Ethchlorvynol Glutethimide Meprobamate Methaqualone

2 1 0

2000 2001 2002 2003 FIGURE 34-3 Human deaths attributed to selected sedativehypnotics, 2000–2003, United States. (Data from WebTESS, American Association of Poison Control Centers, http://webtess., aapcc.org, accessed June 2004.)

benzodiazepines and barbiturates. The primary metabolite of chloral hydrate is trichloroethanol (TCE), which seems to produce the main sedative-hypnotic effect. TCE affects the GABAA receptor–ion channel complex similar to other sedative-hypnotic agents by altering chloride currents and decreasing excitability of neurons, but only when GABA is present. In addition, TCE inhibits ion currents activated by excitatory amino acids. This combined effect leads to central nervous system (CNS) sedation.18 TCE also sensitizes the myocardium to endogenous catecholamines and may induce arrhythmias, similar to other halogenated hydrocarbons.19-21 Chlormethiazole similarly affects GABAA-evoked currents in a dose-dependent fashion. It modulates the GABA receptor via a site separate from that of the benzodiazepines. At low doses it potentiates GABAevoked responses; at high doses it directly activates the GABA receptor. Chlormethiazole prolongs the GABA channel burst duration similar to that of the barbiturates. In addition, chlormethiazole potentiates glycine-evoked currents. This potentially explains its efficacy in treating status epilepticus resistant to therapy with benzodiazepines or barbiturates.22 It does not seem to have any direct interaction with the N-methyl-D-aspartate receptor.4 Meprobamate potentiates GABA at the GABAA receptors and also activates the chloride channel in the absence of GABA.23 Zaleplon, zolpidem, and zopiclone are selective GABAA benzodiazepine receptor agonists (type 1 omega-1).7,24 It is unknown at this time how this receptor site mediates pharmacologic activities.25-27 The mechanisms of action for ethchlorvynol, glutethimide, and methyprylon are unknown. Glutethimide has an active metabolite, 4-hydroxy-2-ethyl-2-phenylglutarimide.

SPECIFIC DRUGS The pharmacology and toxicology of the different sedative-hypnotics will be considered individually for

Sedative-Hypnotics

661

similar agents. The diagnosis and treatment sections consider all drugs together due to the similar diagnostic approach and management of all of these agents.

General Comments on Pharmacology and Pharmacokinetics Absorption varies greatly between the sedative-hypnotic agents; some have significant first pass clearance. Due to their high lipid solubility, many of these agents can be described by a two- or even three-compartment model of distribution and eventual elimination. The initial plasma elimination reflects partitioning into fat stores, and the later slow elimination reflects gradual release from fat stores back into the plasma. All are extensively metabolized in the liver along complex multiple pathways and all are enzyme inducers. Specific pathways of metabolism have not been fully elucidated. Many agents have at least one active metabolite.1,7,14,15,24,28,29 The pharmacokinetic parameters of selected agents are summarized in Table 34-1. It is noteworthy that with the exception of the newer agents, zaleplon and zolpidem, data from various studies with the older agents are inconsistent. See Table 34-2 for a summary of important drug interactions.

General Comments on Toxicology The sedative-hypnotics generally produce drowsiness and sedation, hence their classification. Overdose of these agents is associated with sedation, dizziness, hypothermia, and hypotension that can progress to coma and respiratory depression. Patients may vomit and aspirate, leading to pneumonia or even death. In all of these patients, respiratory depression may lead to hypoxia, which could result in devastating neurologic injury if not recognized and treated. There are a few exceptions to this general picture, and there are a few additional findings with specific agents, which are described under the individual agents.

Adverse Effects Physical dependence and cross-tolerance exists between many of these agents, and withdrawal symptoms have been reported after chronic use and abuse. Maternal administration has resulted in respiratory depression or withdrawal in neonates exposed for many of these agents, including chlormethiazole and ethchlorvynol.30,31

Chloral Hydrate/Trichloroethanol PHARMACOLOGY AND PHARMACOKINETICS See Table 34-1. SPECIAL POPULATIONS For chloral hydrate, toxicity has been particularly pronounced in neonates due to accumulation and persistence of TCE for several days after chloral hydrate has been discontinued. Because TCE competes with bilirubin for protein binding sites and metabolic (glucuronidation)

662


TABLE 34-1 Pharmacokinetic Parameters of Selected Agents HALF-LIFE (hr) Chloral hydrate (Noctec)

Vd

Rapid reduction to TCE TCE 7–11, Avg 8

RENAL EXCRETION

METABOLISM

PROTEIN BIOAVAILBINDING % ABILITY

PEAK (hr)

Less than 10% parent compound

Liver extensive

70%–80%

0.3–1

Chlormethiazole 2.6–8.9 (investigational in USA)

0.28 L/kg

0.1–5%

Chlormezanone 19–24 (Trancopal) (TEN reactions led to discontinuation in 1996) Ethchlorvynol 10–25 (Placidyl) Ethinamate 1.9–2.5 (discontinued 1990 in USA) Glutethimide Parent (Doriden) 11.6–13.5 Meprobamate 9–11 (Equanil, Miltown) Methaqualone 10–43 (Mandrax) Avg 16 (discontinued in 1983 in USA) Methyprylon 9.2 (Noludar) (discontinued by Roche in 1988) Paraldehyde 7.4 (removed from U.S. market) Zaleplon 1 (Sonata) Zopiclone 3.5–6

1.2 L/kg

40% less than 3% unchanged

4 L/kg

Less than 10%

Zolpidem (Ambien)

1.2–4

36% 1.6 L/kg

Less than 2% unchanged 0.5–0.8 L/kg 10%–20% Feces 1%–4%

Metabolized to trichloroethanol active metabolite and trichloroacetic acid Hepatic 70%–80% 2 inactive metabolites Stomach-hydrolyzed Liver: hydrolysis and oxidation with nonglucuronide conjugation

1–2

0.5–1.0 47%–59%

1–6

90% liver to inactive metabolites Site of metabolism to phenolic derivatives unknown

0–30%

2–3

2 identified P-450 enzyme system, some dose dependency

1.73 L/kg

0% unchanged

1.4 L/kg

Less than 1% active, 71% inactive 4–5% parent Extensive metabolites

Liver: 70%–80% to acetaldehyde 30% exhaled via lungs CYP3A4 4 inactive metabolites Extensive:1 active (N-oxide) 1: N-desmethyl (inactive) Extensive No active metabolites

Less than 1% active, 79%–96% inactive

48%–64%

2–3 active metabolites

3% unchanged 60% metabolites

0.54 L/kg

10%–15% 0.5 increase in liver disease

Extensive hydroxylation and glucuronidation

0.97 L/kg

1.5 L/kg

56%–64%

Parent highly protein bound 38%

67%–99%

1–2

Assumed at least 90%

2

45%

Well absorbed IM PO:93% PR:80% 30% first 1.1 pass effect 80% 1–1.5

89%–92%

70%

60%

1.6–2

IM, intramuscularly; PO, orally; PR, rectally; TCE, trichloroethanol; TEN, toxic epidermal necrolysis; Vd, volume of distribution.

systems, resulting in both impaired transport and elimination, it should be used with caution in neonates. There have been reports of indirect hyperbilirubinemia, apnea, and difficulty in weaning neonates from mechanical ventilation after chloral hydrate therapy.32 DRUG INTERACTIONS The prototypical drug interaction for this class of medications has been the interaction between chloral hydrate and ethanol. Chloral hydrate is rapidly converted to TCE.21 TCE successfully competes with ethanol for the dehydrogenase enzymes that metabolize ethanol, thereby decreasing elimination of ethanol. Ethanol stimulates NADH production and therefore increases the rate of chloral hydrate reduction to TCE by liver

alcohol dehydrogenase. This dual mechanism results in an increased production of TCE and decreased elimination of ethanol that is the basis for the toxicity of the “Mickey Finn.”33 Other interactions with chloral hydrate are based on its ability to induce microsomal enzymes and displace other agents such as furosemide and warfarin from plasma protein binding sites.1,20 Chloral hydrate increases myocardial sensitivity to catecholamines, with the potential for inducing recalcitrant and fatal dysrhythmias when these agents are used. See section on Management below.21 TOXICOLOGY: MANIFESTATIONS For chloral hydrate, cardiac toxicity is a hallmark of severe overdose, manifested by atrial and ventricular

CHAPTER 34

Sedative-Hypnotics

663

TABLE 34-2 Summary of Important Drug Interactions SEDATIVE

INTERACTING MEDICATION

MECHANISM

RESULT

Chloral hydrate

Ethanol

Accumulation of trichloroethanol and elevated ethanol levels Cardiovascular toxicity

Cimetidine Warfarin Warfarin Ethanol Cimetidine

Competition for alcohol dehydrogenase system Displacement of furesemide from protein binding sites Displacement of warfarin from protein binding sites Decreased metabolism Microsomal enzyme induction Microsomal enzyme induction Microsomal enzyme induction Enzyme inhibition

Rifampin

Enzyme induction

Ritonavir Rifampin (*both phenytoin and carbamazepine could potentially interact as well) Ketoconazole Sertraline, venlafaxine, bupropion, desipramine, fluoxetine Oral contraceptives Cigarette smoking Erythromycin

Decreased metabolism Induction of CYP3A4

50% increase in half-life Decreased prothrombin time Decreased prothrombin time Variable; increased sedation Increased plasma concentration of zaleplon by 85% Decreased Cpmax and AUC by 80% and increased clearance fivefold Increased serum concentrations Decreased serum concentrations

Inhibition of metabolism Unknown

Decreased clearance by 40%–65% Hallucinations

Increased clearance Increased clearance Decreased plasma clearance or increased oral bioavailability Induction of CYP3A4

Decreased half-life of zolpidem Decreased half-life Increased plasma concentrations and AUC Decreased plasma concentrations of zopiclone

Furosemide Warfarin Chlromethiazole Ethchlorvynol Glutethimide Meprobamate Zaleplon

Zolpidem

Zopiclone

Rifampin (*both phenytoin and carbamazepine could potentially interact as well)

Increased risk of bleeding

AUC, area under the curve; Cpmax, maximum plasma concentration of the drug.

dysrhythmias, including unifocal and multifocal ventricular premature contractions, bigeminy, torsades de pointes, ventricular fibrillation, and asystole.1,19-21 When ethanol and chloral hydrate are ingested together (a Mickey Finn), the CNS depressant actions of both are enhanced, leading to the so-called “knock-out drop” effect, or rapid, decreased level of consciousness; some persons also experience vasodilation, tachycardia, facial flushing, headache, and hypotension.33

bronchial secretions.34 A direct effect on thermoregulatory centers contributes to significant hypothermia. The addition of alcohol to chlormethiazole leads to a deep coma, severe respiratory depression, and increased mortality.5

Chlormezanone

PHARMACOLOGY AND PHARMACOKINETICS Chlormethiazole exhibits a 10-fold increase in bioavailability if co-ingested with alcohol and in patients with cirrhosis, presumably from an impaired first pass effect. Low serum albumin in alcoholics leads to decreased protein binding, allowing for an increased free drug serum concentration. This may account for the high death rate in alcoholics who continue to drink while taking chlormethiazole.12

PHARMACOLOGY AND PHARMACOKINETICS Chlormezanone is rapidly absorbed and metabolized into at least six compounds, which are excreted in the urine. In one series of eight elderly patients, oral absorption of chlormezanone was delayed but not reduced, and the half-life was prolonged to 54 hours. The volume of distribution calculated from these data was approximately 85 L, which is consistent with other agents of this class. The half-life following an overdose without evidence of shock has been estimated at 29 to 35 hours.35 Chlormezanone is similar to baclofen in chemical structure, and its metabolite exerts a similar muscle relaxant effect.36

DRUG INTERACTIONS Ethanol and imipramine produce additive clinical effects.25

DRUG INTERACTIONS Ethanol and imipramine produce additive clinical effects.25

TOXICOLOGY: MANIFESTATIONS The coma associated with chlormethiazole overdose may be prolonged and has been reported to last from 40 to 92 hours. Victims also have increased salivation and

TOXICOLOGY: MANIFESTATIONS Chlormezanone overdose signs and symptoms are similar to those of other sedatives; metabolic acidosis has also been noted. In addition, drug-induced hepatitis may

Chlormethiazole

664


occur, with abrupt elevation of liver enzymes, prolonged prothrombin time, elevated bilirubin, and hypoglycemia. Diffuse hydropic degeneration and necrosis of hepatocytes with pericentral vein congestion are noted on liver biopsy.37-39 Central anticholinergic syndrome has been reported in chlormezanone overdose both as a result of single agent ingestion and in combination with ofloxacin and diphenhydramine.40 ADVERSE EFFECTS Even with the recommended dose of chlormezanone, a hypersensitivity reaction can result in a transient hepatitis, which is associated with eosinophilia, cholestasis, and mild periportal infiltration. A fixed skin eruption may also occur at normal doses.37-39

Ethchlorvynol PHARMACOLOGY AND PHARMACOKINETICS Ethchlorvynol is rapidly absorbed after oral administration. It is highly lipophilic, and concentrates in adipose tissue and the CNS.41 Because of this high lipid solubility, it exhibits a biphasic elimination, with a secondary plasma peak occurring between 7 and 14 hours postingestion, reflecting gradual elimination from extensive body stores. This may explain the large variation in the duration of coma reported after large ingestions (50 to 300 hours). Ethchlorvynol is metabolized by hepatic glucuronidation and/or hydroxylation. Some of the volatile oil is eliminated via the lung. It is unknown whether the parent compound or the metabolite of the drug is responsible for the pungent breath odor that is noticed in intoxicated patients. Ethchlorvynol may accumulate in circulating and developing blood cells; severe pancytopenia has been reported.42 DRUG INTERACTIONS Ethanol and imipramine produce additive clinical effects.25 Ethchlorvynol is a microsomal enzyme inducer that enhances the metabolism of warfarin, decreasing its effectiveness.43 TOXICOLOGY: MANIFESTATIONS Ethchlorvynol overdose presents with the typical symptoms, but bradycardia rather than tachycardia may be present. A distinctive pungent aromatic odor may be noted on the breath. There is a direct relationship between the dose and the duration and level of coma, but no such relationship exists between dose and the occurrence or level of hypothermia. Interestingly, however, the level of coma does not change appreciably after hemodialysis and a reduction in the ethchlorvynol level. Deep prolonged coma may last from 10 to 288 hours, with a mean of 119 hours. Deep tendon reflexes are usually absent, and there may be loss of the corneal and pupillary light reflexes. The prolonged coma places victims at risk for complications such as gram-negative pneumonia, pressure ischemia and neuropathy, thrombophlebitis, and thromboembolism. Pressure necrosis similar to that reported for barbiturates,

glutethimide, opiates, and carbon monoxide has been noted.44 An autopsy performed on one patient who had severe multisystem disease revealed bilateral bronchopneumonia, pulmonary embolism, thrombophlebitis of the ovarian vein, renal infarct, focal hepatic necrosis, acute cystitis, marked cerebral edema, and passive congestion of viscera.45 Intravenous injection, and possibly oral ingestion, of ethchlorvynol may lead to noncardiogenic pulmonary edema. Noncardiogenic pulmonary edema appears to be mediated by cyclooxygenase products since it can be blunted by the prior administration of nonsteroidal anti-inflammatory agents.46,47 After intravenous injection, patients experience a mintlike taste, marked shortness of breath, and nonproductive cough; physical findings include diffuse end-inspiratory rales and a normal cardiac examination. Other findings include hypoxemia, respiratory acidosis, bilateral alveolar infiltrates on chest x-ray without cardiomegaly, and a normal electrocardiogram.48,49

Glutethimide PHARMACOLOGY AND PHARMACOKINETICS Absorption of glutethimide is slow and erratic due to its poor solubility. The absorption is hastened and increased with concurrent ethanol ingestion.13 The apparent volume of distribution for glutethimide is greater than that of body water.28 Due to its high lipid solubility, 80% of the parenterally administered drug appears to be sequestered in the gastrointestinal tract, adipose tissue, and the central nervous system. Less than 2% is found in the blood.50 The majority of the metabolites undergo enterohepatic circulation in animals, with slow urinary excretion. At least one metabolite, 4hydroxy-2-ethyl-2-phenylglutarimide (4-HG), contributes to toxicity.51 In mice, 4-HG is approximately twice as potent as the parent compound in producing death.41,52 The drug is 90% conjugated in the liver as two glucoronides with delayed excretion. As with other highly lipophilic agents, it is eliminated following a biphasic elimination curve. Further complicating elimination is the racemic nature of the drug, with each enantiomer being metabolized differently.41 DRUG INTERACTIONS Ethanol and imipramine produce additive clinical effects.25 Glutethimide is a microsomal enzyme inducer that enhances the metabolism of warfarin, decreasing its effectiveness.43 Glutethimide potentiates codeine’s sedative effect, with increased risk for death when both are taken together.53 TOXICOLOGY: MANIFESTATIONS Intoxication with glutethimide results in a prolonged coma with variations in coma depth and sudden apnea, but little correlation between blood levels and the patient’s clinical condition.53 Cerebral edema and seizures appear to be more common than with other sedativehypnotics. Acute renal failure is rare but has been reported.13 Anticholinergic activity of glutethimide

CHAPTER 34

probably contributes to reduced gastric motility and delayed gastrointestinal transit, urinary retention, mydriasis, and some of the hallucinations and delusions reported in acute ingestions of the drug.54 In the 1970s, there were reports of neonatal withdrawal from glutethimide. Infants born to mothers addicted to glutethimide responded well initially, then had recurrence of symptoms about 5 days later, including overactivity, restlessness, tremors, hyper-reflexia, hypotonus, vasomotor instability, incessant crying, and general irritability. The infants usually responded to treatment with benzodiazepines, phenobarbital, and morphine/methadone/ paregoric over 6 to 7 weeks.55

Meprobamate PHARMACOLOGY AND PHARMACOKINETICS Meprobamate has a low solubility in water, is resistant to gastric and intestinal juices, and decreases gastric motility; bezoar formation is more likely than with other sedative-hypnotics. The metabolism of meprobamate is induced by ethanol.15 Meprobamate has characteristics of a drug whose elimination might be increased by hemoperfusion, including a low intrinsic clearance, a relatively low volume of distribution, and charcoal adsorption.56 Carisoprodol is a muscle relaxant (half-life of 100 minutes) that is converted to meprobamate (halflife of 11.3 hours).57,58 DRUG INTERACTIONS Ethanol and imipramine produce additive clinical effects.25 TOXICOLOGY: MANIFESTATIONS Meprobamate intoxication may be difficult to distinguish from other sedatives, but some differences may be noted. Fluctuating coma and seizures may occur, although the drug has been reported to have anticonvulsant activities. Cardiac dysrhythmias include both tachycardia and bradycardia; hypotension can be profound and protracted, and is attributed to direct action on the CNS vasomotor center. Pulmonary edema has been reported, as has bullous skin lesions. Meprobamate deaths have been attributable to shock, pulmonary edema, or complications such as pneumonia or sepsis. Carisoprodol overdose presents with the same clinical picture.16,57,58

Methaqualone PHARMACOLOGY AND PHARMACOKINETICS See Table 34-1. TOXICOLOGY: MANIFESTATIONS Methaqualone is no longer available either as a single drug or in combination with diphenhydramine (Mandrax) in the United States or United Kingdom; however, some is available on the black market and is used to adulterate heroin. Patients presenting with a methaqualone overdose exhibit a range of neurologic symptoms, including lethargy to coma, slurred speech, and gait disturbance. Sensorimotor abnormalities

Sedative-Hypnotics

665

include hyperacusis, blurred vision, ophthalmoplegia, hallucinations, and paresthesias. Increased muscular tone and rigidity, hyper-reflexia, clonus, myoclonus, and seizures may occur, leading to rhabdomyolysis and hyperthermia. In general, hypotension and respiratory depression occur less frequently with methaqualone than with other drugs in this class, but can be exacerbated by co-ingestion of additional depressants or ethanol. Markedly increased tracheobronchial secretions and salivation are also seen in intoxication. One case of unilateral pulmonary edema has been reported. Retinal hemorrhages, purpura, and gastrointestinal hemorrhages can occur. Studies in animal models noted that the drug inhibits adenosine diphosphate (ADP) and decreases both collagen- and ADP-induced platelet aggregation.59 Many of these findings may be related to or exacerbated by diphenhydramine combined with methaqualone in a preparation available earlier.59-62

Methyprylon PHARMACOLOGY AND PHARMACOKINETICS Methyprylon is structurally and pharmacologically related to glutethimide, but is more water soluble and therefore has nearly complete gastrointestinal absorption. Its distribution and elimination are generally described as a two-compartment model. Hepatic metabolism is via the P-450 dehydrogenase system, with production of at least four metabolites. A second oxidative pathway has also been identified with multiple metabolites. The elimination half-lives of methyprylon reported in the literature vary greatly (4 to 50 hours).63 DRUG INTERACTIONS Ethanol and imipramine produce additive clinical effects.25 TOXICOLOGY: MANIFESTATIONS Patients with methyprylon overdose may demonstrate inconsistent findings. Various studies have reported cases with no hypotension, moderate to severe hypotension that was recurrent, no decrease in peripheral reflexes except in mixed ingestions, hyperreflexia and seizure activity, hyperreflexia and areflexia, pinpoint, sluggish pupils, or fixed and dilated pupils. The one fatal case in the literature was deeply comatose, cyanotic, and hypotensive, and presented approximately 18 hours postingestion. Other cases that presented earlier, but with equally severe initial findings recovered with supportive treatment or supportive treatment plus hemodialysis.63-70

Zaleplon, Zolpidem, and Zopiclone PHARMACOLOGY AND PHARMACOKINETICS The kinetics of zaleplon, zolpidem, and zopiclone have been characterized to a greater extent than the preceding agents. Neither zaleplon nor zolpidem appear to exhibit dose-dependent kinetics within the therapeutic range. Zaleplon has a more rapid elimination than zolpidem.7 Zolpidem has a rapid absorption, rapid distribution into the CNS, and rapid onset of activity.71

666


Zolpidem is metabolized in the liver by four different P-450 pathways. Sixty-one percent of the drug is metabolized through the 3A4 enzyme system, 22% through 2C9, 14% through 1A2, and less than 3% through the combined 2D6 and 2C19 pathways.72 Because it is less lipophilic than other similar agents, it is cleared from the CNS more rapidly.6 Zopiclone has a high bioavailability, which suggests absence of a significant first pass effect. Thirteen metabolites through seven pathways have been identified. A low volume of distribution, confirmed by autopsy results, indicates that the agent has no particular preferential distribution into solid organs.73 The drug’s elimination follows a two-compartment model.74 The half-life of its primary active metabolite is approximately equal to the half-life of the parent drug. The half-life of zopiclone is longer in patients with cirrhosis and in elderly patients, so the dosage should be reduced by half in these patients. The half-life of the drug is also prolonged in patients with renal disease, but the changes are slight and probably not clinically significant.25,75,76 SPECIAL POPULATIONS Zopiclone dosage should be reduced by half in elderly patients and those with severe liver insufficiency.75 DRUG INTERACTIONS Ethanol and imipramine appear to have no effect on the kinetics or pharmacodynamics of zopiclone.25 Rifampin has been shown to enhance the metabolism of zaleplon, zolpidem, and zopiclone due to its potent induction of cytochrome P-450, resulting in decreased maximum peak concentration, reduction of the area under the curve (AUC), and increased total clearance. This potential effect also exists for other inducers of the cytochrome isoenzymes, such as phenytoin and carbamazepine.77-79 Zaleplon appears to have no significant pharmacokinetic drug interactions with digoxin, ibuprofen, warfarin, imipramine, or paroxetine; however, additive psychomotor effects have been reported when it is combined with imipramine, paroxetine, or thioridazine. Cimetidine increases the plasma concentration of zaleplon by 85%.77,80-83 Erythromycin has been shown to increase the AUC and peak concentrations of zopiclone, but the differences are not likely to be of clinical significance.84 Ranitidine did not increase drowsiness when used in patients receiving a single dose of zopiclone as a preoperative medication.85 No pharmacokinetic interactions have been observed between digoxin, warfarin, or ranitidine and zolpidem.86,87 The half-life of zolpidem is reduced by smoking and oral contraceptive use; this is not likely to be clinically significant.88 There is an increase in peak serum concentration and a decrease in time to peak concentration of zolpidem in patients who also take sertraline, but this is also unlikely to be of routine clinical significance.89 Ketoconazole decreases the clearance of zolpidem by approximately 40%; itraconazole and fluconazole produce only small changes in the drug’s elimination kinetics. Ritonavir also reduces the clearance of zolpidem.72,90 Decreased psychomotor performance has been observed with the

combination of chlorpromazine and zolpidem, but no pharmacokinetic interaction was found with single-dose administration.87 There is an increased risk for hallucinations with concurrent use of zolpidem and select antidepressants, including bupropion, fluoxetine, sertraline, venlafaxine, and desipramine. The mechanism of this interaction has not been established.91 TOXICOLOGY: MANIFESTATIONS Two cases of zaleplon overdose have been reported, and both patients recovered uneventfully. Zolpidem overdose usually presents with a mild clinical picture, including drowsiness and vomiting. Some patients experience gait abnormalities, blurred vision, mydriasis, visual hallucinations, and memory impairment. More severe symptoms are consistent with multiple-drug overdose, including respiratory depression or failure and hypotension.92-97 Fatalities have occurred with zolpidem taken with co-ingestants such as morphine, hydrocodone, meprobamate, lidocaine, and carisoprodol.93,97,98 ADVERSE EFFECTS Withdrawal symptoms after chronic use have been reported with zopiclone and zolpidem but are not generally life threatening. Hallucinations and sensory distortion may occur with therapeutic doses of zolpidem. Amnesic psychotic reactions and agitation with disorganization of thoughts may occur.6,97,99-101

DIAGNOSIS Laboratory Testing A toxicology screen may confirm the presence of these agents, but will generally not be helpful in establishing the level of toxicity and planning treatment; severity of toxicity is generally a clinical diagnosis. General laboratory testing should include a complete blood count, serum electrolytes, blood urea nitrogen (BUN), creatinine, liver enzymes, and arterial blood gas. Pulse oximetry should be monitored. Therapeutic serum chlormezanone levels are normally 4 to 6 mg/L, with levels greater than 50 mg/L considered toxic. Ethchlorvynol levels are directly proportional to the amount ingested, but they do not correlate with clinical symptoms.45 Meprobamate levels of 3 to 10 mg/dL are associated with mild to moderate signs of toxicity, 10 to 20 mg/dL with deeper coma, and greater than 20 mg/dL with severe toxicity and increased fatality rate. Rising levels may indicate continued absorption, which would suggest the formation of concretions in the gastrointestinal tract. Methaqualone levels of 2 to 5 μg/dL are generally considered to be in the toxic range.62 Multiple complications have been associated with methaqualone, and therefore baseline laboratory evaluation should include a complete blood count, liver enzymes, coagulation studies, platelet count, serum creatine phosphokinase (CPK), BUN, creatinine, and electrolytes. Coagulation abnormalities, with prolonged prothrombin and partial

CHAPTER 34

thromboplastin times, inhibition of platelet aggregation, and decreases in factors V and VII may lead to bleeding problems. Rhabdomyolysis and hyperthermia may affect renal function.59,62 Methyprylon levels of greater than 3.0 mg/dL are associated with coma, and levels less than 3.0 mg/dL are generally associated with somnolence. Other symptoms do not demonstrate a correlation between dose and severity.63,70 Most laboratory values are not affected in methyprylon overdose, although slight transient elevations of liver enzymes have been noted.65,68

Other Diagnostic Testing Additional testing, such as electrocardiography (ECG) and chest radiography should be performed as indicated in specific clinical situations. Chloral hydrate is radiopaque and may be seen on radiography.102 Methaqualone ECG abnormalities are reversible and include right bundle branch block and nonspecific T wave abnormalities.59,62 On examination, a pear-like odor to the breath may be noted in chloral hydrate overdose, and a pungent, vinyl-like odor may be associated with ethchlorvynol overdose.

Differential Diagnosis The differential diagnosis of these agents typically includes other CNS depressant drugs, CNS lesions, other endocrine or infectious processes, and fluid and electrolyte abnormalities. Organophosphate poisoning is included in the differential diagnosis of methaqualone overdose because of the copious secretions associated with this agent.

MANAGEMENT Supportive Measures The standard “ABCs” approach is appropriate in cases of sedative-hypnotic overdose. For comatose patients, the main goal is supporting the airway, ventilation, and cardiovascular system. Vital signs must be monitored frequently, including respirations, pulse, blood pressure, and temperature. Unresponsive patients should be intubated to protect the airway and to ensure adequate respirations and ventilation. Ventilation/oxygenation should be monitored with pulse oximetry and arterial blood gas, making adjustments in fraction of inspired oxygen (FIO2) or rate of ventilation as indicated. Aggressive management of the respiratory status decreases the risk factors for cardiac arrest. Hypotension may be treated with isotonic fluid boluses; vasopressors and inotropes should be used as indicated. Cardiac dysrhythmias should be treated according to advanced cardiac life support (ACLS) protocols with the exception of chloral hydrate (see Specific Treatment). Seizures may be treated with benzodiazepines. Normal body temperature should be maintained; warming blankets

Sedative-Hypnotics

667

may be sufficient, but use of warmed IV fluids, radiant warming, and other methods may also be required. This is especially important if the patient is hypothermic and develops cardiac dysrhythmias; patients may not respond to usual ACLS protocols during hypothermia. One must anticipate the sequelae of coma and immobilization. The overall incidence and severity of pneumonia is directly proportional to the duration of coma; gram-negative organisms are frequently the cause of pneumonia in these patients. Patients may develop pressure ischemia and neuropathy from prolonged immobilization; such patients should be repositioned frequently. Victims are also at risk for thrombophlebitis and thromboembolism.

Decontamination Gastric lavage should be considered in patients presenting with mixed ingestions or a potentially lethal ingestion of a single drug if they present within 1 to 2 hours of ingestion. Activated charcoal 1 g/kg may decrease absorption and should be administered. Multiple-dose activated charcoal has been advocated for meprobamate and glutethimide ingestions to prevent ongoing absorption from concretions and delayed motility and to interrupt enterohepatic circulation; however, its efficacy in these ingestions is unproved. Gastric lavage, multiple-dose activated charcoal, and whole bowel irrigation should be considered with meprobamate because of the tendency toward bezoar formation. Recovery of a bezoar weighing only 25 g could be clinically significant because the minimum lethal dose is approximately 20 g. However, it is important to evaluate whether ileus is present before instituting these measures.56,103-105

Laboratory Monitoring Arterial blood gases and pH provide information about ventilation and acid–base status. Mixed respiratory and metabolic acidosis may be seen due to hypoventilation, immobilization, hypotension, and hypothermia. Monitoring for complications related to prolonged coma and immobilization should be considered.45 One should monitor for rhabdomyolysis and hyperthermia in cases of myoclonus and seizures, including serum CPK, creatinine, BUN, and electrolytes. Special attention should be focused on maintaining renal function. One should monitor liver enzymes, platelet count, and coagulation times after methaqualone ingestion.62

Antidote There are no specific antidotes currently available for sedative-hypnotic overdoses. Flumazenil has been reported to reverse the effects of chloral hydrate, but there are concerns that it may also precipitate seizures in chloral hydrate overdose, so it should be used with caution, if at all.105 Flumazenil may reverse CNS depression from severe zolpidem toxicity and zaleplon overdose.106

668


Specific Treatment Chloral hydrate and trichloroethanol sensitize the myocardium to endogenous catecholamines. Naloxone and flumazenil may precipitate ventricular dysrhythmias. Ventricular dysrhythmias associated with chloral hydrate overdose may be treated with β blockers: propranolol (adults 1.0 to 2.0 mg IV bolus followed by 1.0 to 2.0 mg/hr infusion, children 0.01 to 0.1 mg/kg, maximum 1 mg) or esmolol (adults 500 μg/kg IV slow bolus over 2 minutes followed by 25 to 100 μg/kg/min, children 100 to 500 μg/kg given over 1 minute, followed by infusion of 25 to 100 μg/kg/min, titrated to dysrhythmias cessation). Torsades de points may be treated with IV magnesium or overdrive pacing. Platelets, fresh frozen plasma, and vitamin K should be administered for uncontrolled bleeding after methaqualone ingestion.62

Elimination Enhancement In general, there is no convincing evidence to support the use of hemodialysis or hemoperfusion in the treatment of sedative-hypnotic overdose. Historically, these methods have been attempted for severe chloral hydrate (TCE) poisoning or inadequate response to supportive care, but clinical improvement has not correlated with reduced levels of drug.107 There is no evidence to support the use of hemodialysis or hemoperfusion in treating chlormethiazole, glutethimide, or chlormezanone overdoses.108,109 The use of forced diuresis, hemodialysis, peritoneal dialysis, and hemoperfusion in accelerating the removal of ethchlorvynol remains somewhat controversial. Although these modalities have been shown to reduce the half-life of ethchlorvynol, they have not been shown to shorten the duration of coma, or to reduce morbidity or mortality.45,110 Hemodialysis and hemoperfusion can enhance the elimination of meprobamate, but these invasive methods are rarely indicated when aggressive decontamination and supportive measures are used.103 Hemodialysis and hemoperfusion do not alter the clinical outcome of methaqualone overdose, but do increase clearance.111 Although dialysis has been used in cases of severe methyprylon overdoses, reports of clinical improvement and elimination of the active drug have been inconsistent. Most cases can be managed with supportive care. Osmotic diuresis has also been used, but there is little evidence that this is helpful.63,65,68,70 There is no experience with hemodialysis for zaleplon or zopiclone overdose. Zolpidem is not dialyzable.76

Disposition Symptomatic patients should be admitted and monitored for 24 hours, or until symptoms resolve; asymptomatic patients for 2 to 6 hours. Patients who are comatose, hypotensive, hypothermic, or show signs of cardiac instability should be admitted to the intensive care unit for supportive care and close monitoring. It may take a day or up to a week to stabilize the patient, depending on

level of coma, respiratory compromise, and development of complications. The patient may be discharged to home or psychiatric care when he or she is stable. The prolonged deep coma and severe respiratory depression associated with ethchlorvynol overdose may last up to 17 days. Patients who improve initially should be observed for at least 24 hours due to the biphasic distribution of ethchlorvynol.45 Patients who have ingested significant amounts of chloral hydrate should be admitted for observation and their cardiac status monitored for at least 24 hours. Asymptomatic patients with suspected ingestions should be monitored for 6 to 8 hours. Because of the gastric irritation and vomiting associated with chloral hydrate overdose, the patient should be followed for later development of esophageal stricture.20 Asymptomatic patients should be monitored for 6 to 8 hours after meprobamate or glutethimide ingestion. Patients with mild symptoms should be observed for 12 to 24 hours; those with more severe symptoms require longer observation and support due to the biphasic recurrence of toxic symptoms after an initial resolution.51,109 Infants born to mothers who have received chlormethiazole should be monitored for 36 to 48 hours for development of respiratory depression or apnea.30 Neonatal withdrawal symptoms may persist for up to 45 days in infants born to mothers addicted to glutethimide.67 REFERENCES 1. Graham SR, Day RO, Lee R, Fulde GWO: Overdose with chloral hydrate: a pharmacological and therapeutic review. Med J Aust 1988;149:686–688. 2. Charney DS, Mihic SJ, Harris RA: Hypnotics and sedatives. In Hardman JG, Limbird LC (eds): Goodman & Gilman: The Pharmacologic Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 399–427. 3. Bailey D, Shaw R: Interpretation of blood glutethimide, meprobamate, and methyprylon concentrations in nonfatal and fatal intoxications involving a single drug. J Toxicol Clin Toxicol 1983;20(2):113–145. 4. Green AR, Cross AJ: The neuroprotective actions of chlormethiazole. Prog Neurobiol 1994;44:463–484. 5. McInnes GT: Chlormethiazole and alcohol: a lethal cocktail. BMJ 1987;294(6572):592. 6. Durand A, Thenot JP, Bianchetti B, et al: Comparative pharmacokinetic profile of two imidazopyridine drugs: zolpidem and alpidem. Drug Metab Rev 1992;24(2):239–266. 7. Greenblatt DJ, Harmatz JS, von Moltke LL, et al: Comparative kinetics and dynamics of zaleplon, zolpidem, and placebo. Clin Pharmacol Ther 1998;64(5):553–561. 8. WebTESS, American Association of Poison Control Centers: http://webtess.aapcc.org, accessed June 2004. 9. McGrath J: A survey of deliberate self-poisoning. Med J Aust 1989;150:317–324. 10. Buckley NA, Whyte IM, Dawson AH, et al: Self-poisoning in Newcastle, 1987–1992. Med J Aust 1995;162:190–193. 11. Buckley NA, Whyte IM, Dawson AH, et al: Correlations between prescriptions and drugs taken in self-poisoning. Implications for prescribers and drug regulation. Med J Aust 1995;162:194–197. 12. Fuller GN, Rea AJ, Payne JF, Lant AF: Parasuicide in central London 1984–1988. J R Soc Med 1989;82:653–656. 13. Arieff A, Friedman E: Coma following non-narcotic drug overdosage: management of 208 adult patients. Am J Med Sci 1973;266(6):405–426. 14. Breimer DD: Clinical pharmacokinetics of hypnotics. Clin Pharmacokinet 1977;2:93–109. 15. Gomolin I: Meprobamate. Clin Toxicol 1981;18(6):757–760.

CHAPTER 34

16. Kintz P, Tracqui A, Mangin P, et al: Meprobamate self-poisoning. Am J Forensic Med Pathol 1988;9(2):139–140. 17. Lambert WE, De Leenheer AP, Van Bocxlaer JF, et al: Meprobamate intoxication: rare and difficult to find. Clin Toxicol 1992; 30(4):683–684. 18. Peoples RW, Weight FF: Trichloroethanol potentiation of γaminobutyric acid-activated chloride current in mouse hippocampal neurones. Br J Pharmacol 1994;113:555–563. 19. Brown AM, Cade JF: Cardiac arrhythmias after chloral hydrate overdose. Med J Aust 1980;1:28–29. 20. Bowyer K, Glasser SP: Chloral hydrate overdose and cardiac arrhythmias. Chest 1980;77:232–235. 21. Sing K, Erickson T, Amitai Y, Hryhorczuk D: Chloral hydrate toxicity from oral and intravenous administration. Clin Toxicol 1996;34(1):101–106. 22. Hales TG, Lambert JJ: Modulation of GABAA and glycine receptors by chlormethiazole. Eur J Pharmacol 1992;210:239–246 23. Rho JM, Donevan SD, Rogawski MA: Barbiturate-like actions of the propanediol dicarbamates felbamate and meprobamate. J Pharmacol Exp Ther 1997;280(3):1383–1391. 24. Sanger DJ, Morel E, Perrault G: Comparison of the pharmacological profiles of the hypnotic drugs, zaleplon and zolpidem. Eur J Pharmacol 1996;313(1–2):35–42. 25. Goa KL, Heel RC: Zopiclone: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy as an hypnotic. Drugs 1986;32:48–65. 26. Trifiletti RR, Snyder SH: Anxiolytic cyclopyrrolones zopiclone and suriclone bind to a novel sited linked allosterically to benzodiazepines receptors. Mol Pharmacol 1984;26:458–469. 27. Depoortere M, Zivkovic B, Lloyd KG, et al: Zolpidem, a novel nonbenzodiazepine hypnotic. I. Neuropharmacological and behavioral effects. J Pharmacol Exp Ther 1986;237(2):649–658. 28. Curry SH, Riddall JS, Gordon MB, et al: Disposition of glutethimide in man. Clin Pharmacol Ther 1971;12(5):849–856. 29. Gwilt PR, Pankaskie MC, Thornburg JE, et al: Pharmacokinetics of methyprylon following a single oral dose. J Pharm Sci 1985; 74(9):1001–1003. 30. Johnson RA: Adverse neonatal reaction to maternal administration of intravenous chlormethiazole and diazoxide. BMJ 1976;1(6015):943. 31. Rumack BH, Walravens PA: Neonatal withdrawal following maternal ingestion of ethchlorvynol (Placidyl). Pediatrics 1973;52(5):714–716. 32. Birner G, Rutkowska A, Dekant W: N-acetyl-S (1,2,2trichlorovinyl)-L-cysteine and 2,2,2-trichloroethanol; two novel metabolites of tetrachloroethene in humans after occupational exposure. Drug Metab Dispos 1996;24:41–48. 33. Sellers EM, Lang B, Koch-Weser J, et al: Interaction of chloral hydrate and ethanol in man. Clin Pharmacol Ther 1971;13:37–49. 34. Illingworth RN, Stewart MJ, Jarvie DR: Severe poisoning with chlormethiazole. BMJ 1979;2(6195):902–903. 35. Bernard N, Fauvel JP, Pozet N, et al: Pharmacokinetics of chlormezanone in elderly patients. Eur J Clin Pharmacol 1991;40: 603-607. 36. Bor-Shyang S, Ching-Yih L, Kuan-Wen, C, et al: Severe hepatocellular damage induced by chlormezanone overdose. Am J Gastroenterol 1995;90:833–835. 37. Sheu BS, Lin CY, Chen KW, et al: Severe hepatocellular damage induced by chlormezanone overdose. Am J Gastroenterol 1995;90:833–835. 38. Armstrong D, Braithwaite RA, Vale JA: Chlormezanone poisoning. BMJ (Clin Res Ed) 1983;286:845–846. 39. Ohsawa T, Konishi K: Hepatitis associated with chlormezanone. Drug Intell Clin Pharm 1986;20:506. 40. Koppel C, Hopfe T, Menzel J: Central anticholinergic syndrome after ofloxacin overdose and therapeutic doses of diphenhydramine and chlormezanone. Clin Toxicol 1990;28(2):249–253. 41. Bertino J, Reed M: Barbiturate and nonbarbiturate sedative hypnotic intoxication in children. Pediatr Clin North Am 1986;33(3):703–723. 42. Klock J: Hemolysis and pancytopenia in ethchlorvynol overdose. Ann Intern Med 1974;81(1):131–132. 43. Yell RP: Ethchlorvynol overdose. Am J Emerg Med 1990;8(5): 246–250.

Sedative-Hypnotics

669

44. Chamberlain JM, Klein-Schwartz W, Gorman R: Pressure necrosis following ethchlorvynol overdose. Am J Emerg Med 1990;8(5): 467–468. 45. Teehan BP, Maher JF, Carey JJ, et al: Acute ethchlorvynol (Placidyl) intoxication. Ann Intern Med 1970;72:875–882. 46. Yagi K, Baudendistel LJ, Dahms TE: Ibuprofen reduces ethchlorvynol lung injury: possible role of blood flow distribution. J Appl Phys 1992;72(3):1156–1165. 47. Zanaboni PB, Bradley JD, Webster RO, Dahms TE: Cyclooxygenase inhibitors prevent ethchlorvynol-induced injury in rat and rabbit lungs. J Appl Phys 1991;71(1):43–49. 48. Reed CR, Glauser FL: Drug-induced noncardiogenic pulmonary edema. Chest 1991;100:1120–1124. 49. Glauser, FL, Smith WR, Caldwell A, et al: Ethchlorvynol (Placidyl®)induced pulmonary edema. Ann Intern Med 1976;34:46–48. 50. Keberle H, Hoffmann K, Bernhard K: The metabolism of glutethimide (Doriden). Experientia 1962;18:105–111. 51. Decker WJ, Thompson HL, Arneson LA: Glutethimide rebound. Lancet 1970;1(7650):778–779. 52. Jones AH, Mayberry JF: Chronic glutethimide abuse. Br J Clin Pract 1986;40:213. 53. Bailey D, Shaw R: Blood concentrations and clinical findings in nonfatal and fatal intoxications involving glutethimide and codeine. Clin Toxicol 1985–1986;23(7,8):557–570. 54. Campbell R, Schaffer CB, Tupin J: Catatonia associated with glutethimide withdrawal. J Clin Psychiatry 1983;44(1):32–33. 55. Reveri M, Pyati SP, Pildes RS: Neonatal withdrawal symptoms associated with glutethimide (Doriden) addiction in the mother during pregnancy. Clin Pediatr 1977;16(5):424–425. 56. Jacobsen D, Wiik-Larson E, Saltvedt E, et al: Meprobamate kinetics during and after terminated hemoperfusion in acute intoxications. Clin Toxicol 1987;25(4):317–331. 57. Lin JL, Lim PS, Lai BC, Lin WL: Continuous arteriovenous hemoperfusion in meprobamate poisoning. Clin Toxicol 1993;31(4): 645–652. 58. Hassan E: Treatment of meprobamate overdose with repeated oral doses of activated charcoal. Ann Emerg Med 1986;15(1): 73–76. 59. Mills DG: Effects of methaqualone on blood platelet function. Clin Pharmacol Ther 1978;23(6):685–691. 60. Trese M: Retinal hemorrhage caused by overdose of methaqualone. Am J Ophthalmol 1981;91(2):201–203. 61. Oh TE, Gordon TP, Burden PW: Unilateral pulmonary oedema and “Mandrax” poisoning. Anaesthesia 1978;33(8):719–721. 62. Matthew H, Proudfoot AT, Brown SS, Smith ACA: Mandrax poisoning: conservative management of 116 patients. BMJ 1968;2:101–102. 63. Contos DA, Dixon KF, Guthrie RM, et al: Nonlinear elimination of methylprylon (Noludar) in an overdosed patient: correlation of clinical effects with plasma concentration. J Pharm Sci 1991; 80(8):768–771. 64. Pancorbo AS, Palagi PA, Piecoro JJ, Wilson HD: Hemodialysis in methyprylon overdose: some pharmacokinetic considerations. JAMA 1977;237:470–471. 65. Mandelbaum JM, Simon NM: Severe methyprylon intoxication treated by hemodialysis. JAMA 1971;216:139–140. 66. Xanthaky G, Freireich AW, Matusiak W, Lukash L: Hemodialysis in methyprylon poisoning. JAMA 1966;198(11):190–191. 67. Yudis M, Swartz C, Onesti G, et al: Hemodialysis for methyprylon (Noludar) poisoning. Ann Intern Med 1968;68(6):1301–1304. 68. Burnstein N, Stauss HK: Attempted suicide with methyprylon. JAMA 1965;194(10):1139–1140. 69. Reidt WU: Fatal poisoning with methyprylon (Noludar), a nonbarbiturate sedative. N Engl J Med 1956;255(5):231–232. 70. Bailey DN, Jatlow PI: Methyprylon overdose: interpretation of serum drug concentrations. Clin Toxicol 1973;6(4):563–569. 71. Kurta DL, Myers LB, Krenzelok EP: Zolpidem (Ambien) a pediatric case series. Clin Toxicol 1997;35(5):453–457. 72. von Moltke LL, Greenblatt DJ, Granda BW, et al: Zolpidem metabolism in vitro: responsible cytochromes, chemical inhibitors, and in vivo correlations. Br J Clin Pharmacol 1999;48:89–97. 73. Pounder DJ, Davies JI: Zopiclone poisoning: tissue distribution and potential for postmortem diffusion. Forensic Sci Int 1994;65:177–183.

670


74. Gaillot J, Heusse D, Houghton GW, et al: Pharmacokinetics and metabolism of zopiclone. Pharmacology 1983;27(Suppl 2):76–91. 75. Gaillot H, Le Roux Y, Houghton GW, et al: Critical factors for pharmacokinetics of zopiclone in the elderly and in patients with liver and renal insufficiency. Sleep 1987;10(Suppl 1):7–21. 76. Marc-Aurele J, Caille G, Bourgoin J: Comparison of zopiclone pharmacokinetics in patients with impaired renal function and normal subjects. Effect of hemodialysis. Sleep 1987;10(Suppl 1): 22–26. 77. Dooley M, Plosker GL: Zaleplon: a review of its use in the treatment of insomnia. Drugs 2000;60(2):413–445. 78. Villikka K, Kivisto KT, Lamberg TS, et al: Concentrations and effects of zopiclone are greatly reduced by rifampicin. Br J Clin Pharmacol 1997;43:471–474. 79. Villikka K, Kivisto KT, Luurila H, et al: Rifampin reduces plasma concentrations and effects of zolpidem. Clin Pharm Ther 1997;62(6):629–634. 80. Garcia PS, Carcas A, Zapater P, et al: Absence of an interaction between ibuprofen and zaleplon. Am J Health Syst Pharm 2000;57:1137–1141. 81. Garcia PS, Paty I, Leister CA, et al: Effect of zaleplon on digoxin pharmacokinetics and pharmacodynamics. Am J Health Syst Pharm 2000;57:2267–2270. 82. Hetta J, Broman JE, Darwish M, et al: Psychomotor effects of zaleplon and thioridazine coadministration. Eur J Clin Pharmacol 2000;56:211–217. 83. Sonata Product Information Sheet. Philadelphia, Wyeth-Ayerst Phamaceuticals Inc., 2003. 84. Aranko K, Luurila H, Backman JT, et al: The effect of erythromycin on the pharmacokinetics and pharmacodynamics of zopiclone. Br J Clin Pharmacol 1994;38:363–367. 85. Wilson CM, Robinson FP, Thompson EM, et al: Effect of pretreatment with ranitidine on the hypnotic action of single doses of midazolam, temazepam and zopiclone: a clinical study. Br J Anaesth 1986;58:483–486. 86. Hullhoven R, Desager JP, Harvengt C, et al: Lack of interaction between zolpidem and H2 antagonists, cimetidine and ranitidine. Int J Clin Pharmacol Res 1988;8:471–476. 87. Ambien Product Information Sheet. New York, Sanofi-Synthelabo, Inc., 2004. 88. Olubodun JO, Ochs HR, Truten V, et al: Zolpidem pharmacokinetic properties in young females: influence of smoking and oral contraceptive use. J Clin Pharmacol 2002;42:1142–1146. 89. Allard S, Sainati SM, Roth-Schecter BF: Coadministration of shortterm zolpidem with sertraline in healthy women. J Clin Pharmacol 1999;39:184–191. 90. Greenblatt DJ, von Moltke LL, Harmatz JS, et al: Kinetic and dynamic interactions study of zolpidem with ketoconazole, itraconazole, and fluconazole. Clin Pharmacol Ther 1998;64: 661–671. 91. Elko CJ, Burgess JL, Robertson WO: Zolpidem-associated hallucinations and serotonin reuptake inhibition: a possible interaction. Clin Toxicol 1998;36:195–203.

92. Gock SB, Wong SH, Nuwayhid N, et al: Acute zolpidem overdose — report of two cases. J Anal Toxicol 1999;23(6):559–562. 93. Winek CL, Wahba WW, Janssen JK, et al: Acute overdose of zolpidem. Forensic Sci Int 1996;78(3):165–168. 94. Hamad A, Sharma N: Acute zolpidem overdose leading to coma and respiratory failure. Intensive Care Med 2001;27(7):1239. 95. Tracqui A, Knitz P, Mangin P: A fatality involving two unusual compounds—zolpidem and acepromazine. Am J Forensic Med Pathol 1993;14(4):309–312. 96. Lichtenwalner M, Tully R: A fatality involving zolpidem. J Anal Toxicol 1997;21(7):567–569. 97. Garnier R, Guerault E, Muzard D, et al: Acute zolpidem poisoning—analysis of 344 cases. J Toxicol Clin Toxicol 1994; 32(4):391–404. 98. Meeker JE, Som CW, Macapagal EC: Zolpidem tissue concentrations in a multiple drug related death involving Ambien. J Anal Toxicol 1995;19:531–534. 99. Iruela LM, Ibanez-Roho V, Baca E: Zolpidem-induced macropsia in anorexic woman. Lancet 1993;342:443–444. 100. Pitner JK, Gardner M, Neville M, et al: Zolpidem-induced psychosis in an older woman. J Am Geriatr Soc 1997;45(4):533–534. 101. Hoyler CL, Tekell JL, Silva JA: Zolpidem-induced agitation and disorganization. Gen Hosp Psychiatry 1996;18:452–453. 102. Maes V, Huyghens L, Dekeyser J, et al: Acute and chronic intoxication with carbromal preparations. Clin Toxicol 1985;23:341. 103. Hassan E: Treatment of meprobamate overdose with repeated oral doses of activated charcoal. Ann Emerg Med 1986;15(1): 73–76. 104. Felby S: Concentrations of meprobamate in the blood and liver following fatal meprobamate poisoning. Acta Pharmacol Toxicol 1970;28:334–337. 105. Donovan KL, Fisher DJ: Reversal of chloral hydrate overdose with flumazenil. BMJ 1989;298(6682):1253. 106. Lheureux P, Debailleul G, De Witt O, Askensasi R: Zolpidem intoxication mimicking narcotic overdose: response to flumazenil. Hum Exp Toxicol 1990;9(2):105–107. 107. Stalker NE, Gambertoglio JG, Fukumitsu CJ, et al: Acute massive chloral hydrate intoxication treated with hemodialysis: a clinical pharmacokinetic analysis. J Clin Pharmacol 1978;18(2–3): 136–142. 108. Chazan JA, Cohen JJ: Clinical spectrum of glutethimide intoxication: hemodialysis reevaluated. JAMA 1969;208(5): 837–839. 109. Chazan JA, Garella S: Glutethimide intoxication: a prospective study of 70 patients treated conservatively without hemodialysis. Arch Intern Med 1971;128:215–218. 110. Benowitz N, Abloin C, Tozer T, et al: Resin hemoperfusion in ethchlorvynol overdose. Clin Pharmacol Ther 1980;27(2):346–242. 111. Baggish D, Gra S, Jatlow P, Bia MJ: Treatment of methaqualone overdose with resin perfusion. Yale J Biol Med 1981;54(2): 147–150.

35

Benzodiazepines SUSAN E. FARRELL, MD ■ TANIA M. FATOVICH, MD

At a Glance… ■

■ ■ ■ ■

■

Benzodiazepines are widely prescribed and used for sedative, hypnotic, amnestic, anxiolytic, anticonvulsant, and muscle relaxant properties. Benzodiazepines are relatively safe in isolated overdose but may be dangerous when co-ingested with other agents. Laboratory testing is of limited value in overdose. Treatment of overdose is primarily supportive. Flumazenil, a competitive antagonist at the γ-aminobutyric acid A receptor, will reverse the toxic effects of benzodiazepines but should be used with caution in benzodiazepine poisoning. Patients with benzodiazepine overdose that remain asymptomatic after 4 to 6 hours of observation are medically safe for psychiatric evaluation and disposition.

INTRODUCTION AND RELEVANT HISTORY The first commercially marketed benzodiazepine, chlordiazepoxide, was accidentally synthesized in 1955 by Roche Laboratories in Nutley, New Jersey. The scope of its pharmacologic properties and clinical applications, however, were not appreciated until 1957, when it was noted to possess effective sedative, hypnotic, and anticonvulsant properties.1 Subsequent to its clinical release as Librium (Roche Pharmaceuticals of Hoffman-La Roche, Inc., Nutley, NJ) in 1960, chlordiazepoxide spawned an era of widespread benzodiazepine use that still persists today. Diazepam, perhaps the best known and most commercially successful of all the benzodiazepines, was synthesized in 1959 and marketed as Valium (Roche Pharmaceuticals of Hoffman-La Roche, Inc. Nutley, NJ) in 1963. Since the early 1960s, more than 3000 benzodiazepines have been developed, more than 120 have been tested for biologic activity, and approximately 50 different benzodiazepines are currently marketed worldwide. Fourteen benzodiazepines are currently available for clinical use in the United States. They are classified as schedule IV drugs by the Food and Drug Administration (FDA). These agents and a few related compounds available outside the United States are listed in Table 35-1. Benzodiazepines have various sedative, hypnotic, amnestic, anxiolytic, anticonvulsant, and muscle relaxant properties. All benzodiazepines are effective in the treatment of anxiety and insomnia. However, individual drugs are approved by the FDA and marketed for specific indications on the basis of their clinical and pharmacologic characteristics. For example, alprazolam may have significant antidepressant activity in addition to its sedative properties. Benzodiazepines such as alprazolam

and clonazepam have gained use in the treatment of social phobias and panic disorders,2,3 and clonazepam and lorazepam may be effective in place of, or in combination with, a neuroleptic and lithium for the treatment of acute mania in bipolar disorder.4 Reports also describe the efficacy of benzodiazepines for the initial treatment of catatonia5-8 and neuroleptic-induced akathisia and dystonias.9 In addition, short-acting benzodiazepines such as temazepam and triazolam have found new uses in the prevention and treatment of jet lag.10,11 Their action is presumed to be through the readjustment of sleep patterns and body temperature, and they shorten the time to resynchronize activity rhythms when used in conjunction with regular exercise. In the past several years, certain benzodiazepines have also been reported to be of benefit in the treatment of pain syndromes,12 by both decreasing situational anxiety in the setting of acute pain and relieving muscle tension related to some chronic musculoskeletal pain syndromes. Finally, benzodiazepines are also increasingly used in the treatment of cancer patients for the relief of anticipatory anxiety and nausea, insomnia, chemotherapy-induced emesis, neuralgias, and psychiatric disorders secondary to high-dose steroids.13 Since their introduction, the benzodiazepines have enjoyed a meteoric rise in popularity and have largely replaced other sedative-hypnotics. Their extraordinary acceptance in clinical medicine has been based on their safety, efficacy, minimal side effects, relatively low addiction potential, and the medical and public demand for sedative and anxiolytic agents. In 1979, the U.S. National Household survey reported that 11% of the adult population in the United States had taken an anxiolytic on one or more occasions in the previous year.14 Benzodiazepine use peaked in the late 1970s and mid1980s. Since that time, the annual prevalence of benzodiazepine use in the United States has declined, from a prevalence of 13% in 1981 to 8.3% in 1990.15 Similar declining rates in benzodiazepine prescriptions have been reported in Australia, Great Britain, and Canada. This decline has largely been attributed to widespread negative publicity and concern about potential misuse, abuse, and long-term side effects, particularly dependence and withdrawal. Benzodiazepine prescriptions vary by age. In a recent nationwide U.S. survey, 5% of children were prescribed benzodiazepines, a rate that has remained stable from 1987 to 1996.16 Data from a Canadian study of benzodiazepine prescriptions dispensed for the elderly demonstrated rates that decreased from 25.1% in 1993 to 22.5% in 1998. Prescription rates, however, were still significantly higher for older patients: approximately 20% for those 65 to 69 years of age, and approximately 30% for those at least 85 years of age.17 671

672


TABLE 35-1 Benzodiazepines Available in the United States YEAR OF INTRODUCTION

RECOMMENDED ADULT DOSE*

AVAILABLE DOSAGE FORMS

FDA-APPROVED INDICATIONS

RATE OF ORAL ABSORPTION

Oral: 0.75–4 mg/day divided tid Oral: 15–100 mg/day divided tid to qid

0.25-, 0.5-, 1-mg tablets

Intermediate

Oral:7.5–20 mg/day divided tid Oral: 7.5–60 mg/day divided qd to qid Oral: 6–40 mg/day divided qd to qid IV: 0.1 mg/kg per dose

0.5-, 1-, 2-mg tablets

Anxiety Anxious depression Alcohol withdrawal Anxiety Preoperative sedation Seizure disorder

Oral: 15–30 mg/day hs Oral: 80–160 mg/day divided tid to qid Oral: 1–10 mg/day divided bid to tid IM: 0.5 mg/kg IV: 0.05 mg/kg Oral: not available IM: 0.07–0.08 mg/kg IV: Begin 1–2.5 mg, titrate to effect; 0.05 mg/kg total Oral: 30–120 mg/day divided tid to qid

15-, 30-mg capsules 20-, 40-mg capsules

1977

Oral: 20–60 mg/day divided bid

Restoril

1981

Halcion

1983

Oral: 15–30 mg qhs Oral: 0.125–0.5 mg qhs

5-, 10-mg capsules 10-mg tablets 15-, 30-mg capsules 0.125-, 0.25-, 0.5mg capsules

GENERIC NAME

TRADE NAME

Alprazolam

Xanax

1981

Chlordiazepoxide

Librium

1960

Clonazepam

Klonopin

1974

Clorazepate

Tranxene

1972

Diazepam

Valium

1963

Flurazepam

Dalmane

1970

Halazepam

Paxipam

1981

Lorazepam

Ativan

1977

Midazolam

Versed

1986

Oxazepam

Serax

1963

Prazepam

Centrax

Temazepam Triazolam

5-, 10-, 25-mg tablets or capsules

2.75-, 7.5-, 15-mg capsules 2-, 5-, 10-mg tablets

Intermediate

Intermediate

Anxiety Rapid Alcohol withdrawal Anxiety/insomnia Rapid Alcohol withdrawal Muscle spasm/ seizures Preoperative sedation Insomnia Rapid Anxiety

Intermediate to slow

0.5-, 1-, 2-mg tablets

Anxiety/insomnia Intermediate Anxious depression Preoperative sedation Preoperative Rapid† sedation Anesthesia induction Conscious sedation

10-, 15-, 30-mg capsules 15-mg tablets

Anxiety Alcohol withdrawal Anxious depression Anxiety

Ultraslow

Insomnia

Slow

Insomnia

Intermediate

Slow

IM, intramuscularly; IV, intravenously. *Maximum dose not established. † Oral form of midazolam is not yet commercially available, but may administer parenteral formulation orally at 0.3 to 0.7 mg/kg (typically in children).

Because of their widespread availability, benzodiazepines are also among the most frequently misused drugs. Dependence and abuse by the general population, however, are minor when compared to those of alcohol, cocaine, or opiates. As a class, benzodiazepines are not powerful euphoriants and are therefore not frequently abused as a primary agent. Secondary drug abuse is common, however, usually in the form of self-medication, to decrease the adverse side effects of stimulants or hallucinogens, to ameliorate the

unpleasant symptoms of withdrawal from more highly addictive substances, or to substitute for the drug of primary dependence when it is not available. Benzodiazepines are often used by intravenous drug abusers. This combination of intravenous drug use and benzodiazepine abuse has been correlated with increased incidence of needle sharing, polydrug use, psychosocial dysfunction, depression, anxiety, and poor health.18 The U.S. Treatment Outcome prospective study reported that 73% of heroin abusers also used benzodi-

CHAPTER 35

5

R3

N R4 R′2

FIGURE 35-1 The general chemical structure of benzodiazepines.

N

CH3

J

J

CH3

N

N

N

N

N N Cl

Alprazolam (Xanax)

Triazolam (Halcion)

H

O

N

O

N

N

Diazepam (Valium)

OH N

Cl

J

Cl

Cl

K

CH3

J

Cl

N

K

All benzodiazepines are organic bases composed of a benzene ring fused to a seven-membered diazepine ring26 (Figs. 35-1 and 35-2) All of the important benzodiazepines have a 5-aryl substituent and various substitutions at the R1 and R4 positions of the diazepine ring. The aryl ring at position R5 confers greater potency of the molecule. Specific benzodiazepine agonists vary in the substitutions at the R1, R2, R3, R4, R7, and R2′ positions. Substitution of a keto group at R5 and a methyl group at R4 creates the benzodiazepine antagonist flumazenil. Despite the myriad benzodiazepine

R2

R7

J

STRUCTURE AND STRUCTURE-ACTIVITY RELATIONSHIPS

673

R1 N

J

azepines on their entry into treatment.18 A 1999 study found a similarly high prevalence of benzodiazepine abuse among patients entering a methadone treatment clinic, with lifetime and current prevalences of 66.3% and 50.8%, respectively.19 In an attempt to limit such widespread availability and the incidence of misuse and abuse, various laws regulating the prescribing of benzodiazepines have been enacted, with mixed results.20 For example, in 1989, the State of New York enacted a regulation that required prescriptions for benzodiazepines to be written in triplicate, with mandatory reporting of prescriptions to the New York State Department of Health. The purpose of the regulation was to decrease improper prescribing practices, to restrict overall use of benzodiazepines, and to help eliminate fraud and illegal misdirection of the drugs. As a result of this regulation, benzodiazepine prescriptions decreased by 2 million, but were accompanied by a concurrent increase in the use of other anxiolytics.21,22 The number of elderly patients using benzodiazepines was reduced by 33%, and the number of prescriptions written was reduced by 45%.23 Weintraub compared the use of benzodiazepine alternatives in New York to prescribing practices in other unlegislated areas, and concluded that “an undesirable increase has occurred in the prescribing of less acceptable medications.”24 Other unintended consequences of this legislation included an increase in patient visits to an urban psychiatric emergency department for a recurrence of previously controlled psychiatric symptoms or acute benzodiazepine withdrawal. Sales of distilled spirits also increased during the first 4 months after the law was implemented. Similar findings have been reported in European studies.25 A more recent study reported another unintended effect of the New York ruling. A marked decrease in new benzodiazepine prescriptions was found among patients discharged from the hospital after cardiac- or cancerrelated admissions, 72.5% and 69.4%, respectively.20 Over the past decade, six states have enacted legislation to restrict benzodiazepine prescribing. Although benzodiazepines have a low likelihood for producing fatal central nervous system (CNS) depression and are, thus, remarkably safe as compared with older sedative-hypnotics, their potential for addiction and abuse is still well-recognized and a matter of medical and legal controversy.

Benzodiazepines

Cl

Lorazepam (Ativan)

FIGURE 35-2 The four most prescribed benzodiazepines in the United States.

compounds available, all derivatives can be expected to have similar qualitative pharmacologic and clinical effects when adjusted for differences in potency. Variations in the pharmacokinetics of an individual drug’s onset, duration of action, and metabolism make it more suitable for certain indications.

PHARMACOLOGY Benzodiazepines produce their sedative, hypnotic, anxiolytic, and anticonvulsant effects through their ability to potentiate the activity of γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the CNS. GABA is involved in sleep induction, control of neuronal excitation and epileptic potentials, anxiety, memory, hypnosis, and modulation of the hypothalamic-pituitary axis. GABA is found in high concentrations in the basal ganglia, hippocampus, cerebellum, hypothalamus, and substantia gelatinosa of the dorsal horn of the spinal cord.27 Three types of GABA receptors have been defined. GABAA is a hetero-oligomeric chloride channel composed of five subunits of various types, which is modulated by chemicals such as benzodiazepines,

674


barbiturates, ethanol, and steroids. GABAB is a seven trans-membrane receptor coupled to G proteins, which activate the second messenger system of phospholipase C and adenylate cyclase, leading to the opening of calcium and potassium channels. It is also a hetero-oligomeric receptor, composed of subunits R1a, R1b, and R2. Baclofen is an agonist at the GABAB receptor. GABAC is an ionotropic chloride channel, similar to GABAA. In fact, GABAC receptors may actually be homomeric GABAA receptors, composed entirely of one subunit type, unlike GABAA. Although both GABAA and GABAC are chloride channels, they are architecturally, pharmacologically, biochemically, and physiologically different. Benzodiazepines do not modulate GABAC.28 GABAA receptors are made up of five subunits. To date, eight subunit families and 18 subunit types have been identified: α1-6, β1-3, γ1-3, δ, ε, π, θ, ρ1–3. Nearly all GABAA receptors in the brain are composed of a combination of α, β, and γ subunits. This structural diversity of the GABAA receptor accounts for the variations in its channel functioning and affinity for GABA and its related receptor ligands, such as benzodiazepines, localization in the brain, and pharmacology. This compares to the GABAC receptor, which is composed of only ρ subunits and is located primarily in the retina and neuroendocrine cells in the gut.29,30 The molecular structure of the GABAA receptor and the activity of benzodiazepines are intimately related. Although the theoretically possible combination of GABAA subunits is greater than 500,000, the most prevalent receptor combinations in the brain contain α1, α2, α3, and α5 subunits, any β subunit type, and γ2. The combination of α1β2γ2 is especially prevalent. These subunits are encoded as a cluster on chromosome 5 of the genome, such that their expression is regulated in a coherent manner.31 Benzodiazepine recognition sites, termed benzodiazepine receptor (BZ) types I and II, are located on the GABAA receptor. Because these sites are also binding sites for nonbenzodiazepine ligands, they have been termed w1 and w2 receptors. A “peripheral type” benzodiazepine receptor, or “P” site, has also been identified in most peripheral tissues and glial cells in the brain. It is unrelated to central benzodiazepine receptors, but may be involved in the modulation of central benzodiazepine effects, the synthesis of neurosteroids, and steroid hormones in peripheral glands.32-34 Benzodiazepine receptor ligands can act as agonists, antagonists, or inverse agonists at the GABAA receptor. In other words, binding of these ligands may increase, decrease, or block the effects of GABA at GABAA receptors, respectively. Recent studies now show that the ω1 and ω2 receptors actually correspond to the interface of the α subunits and the γ2 subunit on the GABAA receptor complex.35 Specifically, ω1 receptors correspond to the interface at the α1 subunit, and ω2 receptors correspond to the interface at the α2, α3, or α5 subunit on GABAA.36 This interface is the active binding site for benzodiazepines, which bind at the α subunit. After benzodiazepine binding, a conformational change, mediated through the γ2 subunit, occurs at the β subunit, enhancing the

binding of GABA at the β subunit. The chloride ion channel opens, hyperpolarizing the cell, and limiting excitatory impulses. Benzodiazepines potentiate GABA effects by increasing the frequency of channel opening (Fig. 35-3). They are positive modulators of the GABA receptor. In the absence of GABA, however, benzodiazepines have no direct effect on GABAA receptor function; benzodiazepine effects depend on the presynaptic release of GABA. Although classic benzodiazepines act at all αγ2 interfaces of the GABAA receptor complex, animal studies, which target individual subunit formation through genetic single point mutations and knockouts, have elucidated the important relationship between the phamacologic effects of benzodiazepine agonists and the subunit composition of individual GABAA receptors.29,37 For example, GABAA receptors, which contain α1 subunits, mediate the sedative and amnestic effects produced by benzodiazepines. The anticonvulsant effects of these drugs are also partially mediated by α1-containing receptors. Anxiolysis and muscle tone are mediated through α2-containing GABAA receptors, which comprise only 15% of all GABAA receptors, but are particularly dense in the amygdala and the dorsal horn cells of the spinal cord. GABAA receptors, which are the active binding sites of benzodiazepines, are extremely heterogeneous receptor complexes. It is this complexity that accounts for the variety of effects of GABAA-related modulators. Classic benzodiazepines act at all GABAA receptors, accounting for their many side effects. The creation of drugs that act at specific receptor subunits will allow for selective therapeutic effects devoid of the side effects, which are common to the benzodiazepines. For example, zopiclone, zolpidem, alpidem, and zaleplon, nonbenzodiazepine sedatives, preferentially bind to α1 GABAA receptors, accounting for their therapeutic efficacy as hypnotics.29,37 Future research into the development of subtype-selective drugs with specific activity mediated at specific GABAA receptor subunits is certain to enhance the therapy of many neuropsychiatric disorders, which involve GABA regulation. Endogenous benzodiazepine-like substances, diazepambinding inhibitors, have been recently isolated. Although the actual source of diazepam-binding inhibitors is controversial, research into their role in neuroendocrine function,34 panic disorder,38 anxiety,39 memory and learning,40 and hepatic encephalopathy,41,42 may further elucidate the normal regulatory functions of GABA.

PHARMACOKINETICS Although some benzodiazepines form water-soluble salts at acidic pH, at physiologic pH all are moderately to highly lipid-soluble molecules that are rapidly and completely absorbed from the proximal small bowel (see Tables 35-1 and 35-2). Significant differences in lipid solubility affect the rate of gastrointestinal absorption and subsequent distribution. Highly lipophilic benzodiazepines, such as diazepam and flurazepam, are rapidly

CHAPTER 35

Benzodiazepines

675

TABLE 35-2 Absorption Rates of Orally Administered Benzodiazepines

Presynaptic GABA-ergic Neuron

TIME OF PEAK PLASMA CONCENTRATION

Glutamate Glutamic acid decarboxylase

BA

Mitochondria

GA

Synaptic vesicle

BZD

BZD

GABA

ABZD

ABZD

GABA Cl:

:

Cl

Gamma

Chl

GABA receptor Beta

nel

han

ec

orid

BZD Alpha receptor

:

Cl

Subsynaptic membrane

Subsynaptic membrane

Rapid Desmethyldiazepam (from clorazepate [Tranxene]) Diazepam (Valium) Flurazepam (Dalmane) Midazolam* (Versed)

3.0 hr

*Oral form midazolam not yet commercially available.

Postsynaptic neuron GABA-ergic synapse FIGURE 35-3 Benzodiazepine receptors and the GABAergic synapse. Central nervous system neurotransmission occurs via a complex circuitry consisting of multiple connections, pathways, feedback mechanisms, and inhibitory/disinhibitory neurons, all under the control of neurotransmitters and neuroinhibitors. The body’s most important neuroinhibitor, γ-aminobutyric acid (GABA), is synthesized in nerve endings of presynaptic GABAergic neurons from glutamate, under the influence of the enzyme glutamic acid decarboxylase. GABA is stored in synaptic vesicles located in presynaptic nerve endings and is released into the synapse to function as a neuroinhibitor. GABA activity is terminated by diffusion out of the synapse or reuptake into presynaptic nerve endings. Specific GABA receptors have been identified on the subsynaptic membrane of postsynaptic neurons. GABA receptors are adjacent to and coupled with chloride ion channels in such a way that activation of a GABA receptor “opens” the associated channel, increasing chloride ion influx. The end result is hyperpolarization of the cell membrane and decreased neuronal excitability. The activity of GABA or its functional relationship to GABA receptors may be related to GABA modulin, an endogenous peptide located in synaptic membranes. The benzodiazepine receptor is located on a subunit of the benzodiazepine-GABA pharmacophore, spatially adjacent to the GABA receptor. Binding of benzodiazepines to the benzodiazepine receptor subunit induces a change in the receptor complex, which facilitates GABA binding to the GABA receptor subunit, increasing the frequency of chloride ion channel opening. Benzodiazepine antagonists competitively block specific benzodiazepine receptor sites and either block the benzodiazepine binding or displace already bound drug, thereby offsetting any benzodiazepine-enhanced GABAergic transmission. GABA, γ-aminobutyric acid; BZD, benzodiazepine; ABZD, benzodiazepine antagonist.

absorbed, and less lipophilic compounds, such as oxazepam and temazepam, are more slowly absorbed.26,43 The rate of oral absorption is influenced by other factors, such as the co-ingestion of ethanol44 (enhanced absorption), or co-ingestion of food or antacids45 (slowed). Depending on the drug preparation and the presence of co-ingestants, the time from ingestion to appearance of the drug in the systemic circulation is approximately 10 to 20 minutes. In general, the time to maximal serum concentration (Tmax) is inversely related to the maximal serum concentration (Cmax) and may be influenced by the aforementioned factors.46 Certain benzodiazepines, such as clorazepate, flurazepam, and prazepam, do not reach the systemic circulation in clinically significant amounts. Clorazepate is rapidly decarboxylated in the acidic environment of the stomach to its active metabolite, N-desmethyldiazepam (nordiazepam), which is then absorbed completely. Flurazepam and prazepam undergo first pass metabolism in the liver and reach the systemic circulation only as metabolites. Benzodiazepine absorption from intramuscular injection is variable. Lorazepam and midazolam are the only benzodiazepines rapidly and completely absorbed after intramuscular administration. Chlordiazepoxide absorption is particularly slow and erratic; plasma concentration may not peak for 6 to 12 hours. Diazepam is inconsistently absorbed after intramuscular administration. Serum levels of diazepam and chlordiazepoxide are more rapidly achieved by the oral route than by intramuscular administration.

676


After absorption, benzodiazepines are highly protein bound, ranging from 70% to 99%. Protein binding is greatest with highly lipid-soluble drugs (e.g., diazepam 99% bound) and least with more water-soluble agents (e.g., alprazolam 70% bound). Only unbound drug is available to cross the blood-brain barrier and interact with CNS receptors. Drug concentrations in the cerebrospinal fluid are generally 2% to 4% of plasma levels, roughly equivalent to the concentration of free drug in the plasma. Alterations in protein binding affect the amount of free drug available to the CNS at sites of action, and the subsequent clinical effects. All benzodiazepines distribute widely and rapidly to highly perfused organs. Their volume of distribution ranges from 0.3 to 5.5 L/kg, and tissue concentrations within the brain, liver, and spleen typically exceed that of the serum. Because penetration into the CNS is rapid, the onset of clinical effects is limited more by the rate of systemic absorption of individual compounds than by their rate of distribution. After initial distribution within the central compartment, benzodiazepines slowly redistribute to less perfused tissues, such as adipose and muscle. The rate of initial distribution and redistribution, and thus onset and offset of clinical effect, correlates with the individual drug lipophilicity. Benzodiazepine activity is terminated by at least three mechanisms. Two of these are pharmacokinetic, and the third is a function of alterations of the GABA(A)/ benzodiazepine recognition site. The rate of redistribution of drug from the central compartment to the peripheral compartment is the most important determinant of the duration of clinical effect. The second mechanism responsible for the duration of action is hepatic metabolism and renal excretion. The third mechanism is acute tolerance that occurs at the level of the receptor. The duration of action of benzodiazepines is a function of the CNS elimination half-life, which correlates with drug lipophilicity. During single-dose administration, the most lipophilic benzodiazepines have the shortest duration of action due to their rapid and extensive redistribution. They have the longest calculated plasma half-lives after redistribution because they remain in clinically inactive peripheral storage compartments (fat, muscle) for prolonged periods. In contrast, drugs that are less lipophilic have a longer duration of action, but a shorter plasma half-life due to slower redistribution from the CNS. This is illustrated by comparing the clinical anticonvulsant activity of lorazepam and diazepam. Lorazepam, a drug of relatively low lipophilicity, has more prolonged anticonvulsant activity than the highly lipophilic diazepam. The benzodiazepine midazolam is extremely lipophilic and rapidly metabolized in the liver. It has an extremely rapid onset but short duration of action due to both rapid redistribution and hepatic metabolism. Benzodiazepines may be classified into four different groups based on plasma elimination half-lives of the parent in combination with its active metabolites (see Tables 35-1 and 35-3).

TABLE 35-3 Classification of Benzodiazepines According to Plasma Half-Life Short Flurazepam (Dalmane) Midazolam (Versed) Triazolam (Halcion)

HALF-LIFE 1–4 hr 2–5 hr 2–6 hr

Intermediate Alprazolam (Xanax) Chlordiazepoxide (Librium) Halazepam (Paxipam) Lorazepam (Ativan) Oxazepam (Serax) Temazepam (Restoril) Estazulam (Prosem)

6–20 5–20 10–20 10–20 5–15 5–20 10–20

hr hr hr hr hr hr hr

Long Flunitrazepam (Rohypnol) Clonazepam (Klonopin) Diazepam (Valium) Nitrazepam (Mogadon)

20–50 20–30 20–70 17–50

hr hr hr hr

Very Long Clorazepate† (Tranxene) Desalkylflurazepam* Desmethyldiazepam* Prazepam† (Centrax)

30–200 45–300 30–200 30–200

hr hr hr hr

*Active metabolite of primary benzodiazepine compounds. † Prodrug or drug precursor that does not reach the system circulation in clinical significant amounts. Compounds are metabolized in the gastrointestinal tract or liver before systemic absorption and appear in the serum as desmethyldiazepam.

During prolonged administration, the plasma half-life is a more reliable predictor of clinical response (intensity and duration) to the highly lipophilic agents. Repeated doses of lipid-soluble benzodiazepines cause the eventual saturation of peripheral fat stores during redistribution. As they become saturated, the concentration gradient from plasma to peripheral lipid compartment decreases, increasing the drug concentration and duration of action at CNS receptor sites. In addition, the lipid stores act as a depot for the drug and its active metabolites, resulting in prolonged release of drug and persistence of drug effects.45 Benzodiazepines with longer elimination half-lives have a greater potential for accumulation after multiple doses and are more likely to exhibit prolonged “washout” periods after termination of multiple-dose therapy. In contrast, these agents are less likely to be associated with rebound side effects upon termination of treatment.46 Hepatic biotransformation via phase I oxidation or phase II conjugation accounts for virtually all benzodiazepine metabolism and clearance in humans. Oxidative metabolism occurs primarily at the cytochrome families CYP3A, CYP2D, and CYP2C.47 These drugs undergo aliphatic hydroxylation or N-demethylation to pharmacologically active intermediates, and/or conjugation to inactive glucuronides, sulfates, and acetylated compounds; these inactive compounds are subsequently renally excreted (Fig. 35-4).

CHAPTER 35

Chlordiazepoxide (Librium), [I]

Benzodiazepines

Desmethylchlordiazepoxide,* [I] Valium Demoxepam,* [L]

CIorazepate† (Tranxene), [S]

Desmethyldiazepam* (nordiazepam), [L]

(minor)

(major)

Temazepam* (Restoni), [T] Oxazepam* (Serax), [I]

Prazepam† (Centrax), [S]

ACETYLATION AND EXCRETION

N-hydroxymethyl flurazepam,* [S]

7-Amine derivative, [L]

(major)

N-desalkyl flurazepam,* [L]

b-Hydroxy derivative,* [I]

Triazolam (Halcion), [S]

a-Hydroxy triazolam,* [S]

Alprazolam (Xanax), [I]

a-Hydroxy alprazolam,* [S]

Midazolam (Versed), [S]

1-Hydroxy midazolam,* [S]

CIonazepam (minor) (Klonopin), [L]

GLUCURONIDATION AND EXCRETION

Halazepam (Paxipam), [I]

Flurazepam (Dalmane), [S]

677

3-Hydroxy cIonazepam,* [S]

FIGURE 35-4 Major metabolic pathways of benzodiazepines approved for use in the United States. [S], conversion half-life of less than 6 hours; [I], conversion half-life of 6 to 20 hours; [L], conversion half-life of greater than 20 hours; *, active metabolite; †, prodrug or drug precursor, which does not reach the systemic circulation in clinically significant amounts. Shaded areas denote processes that proceed via phase II metabolism.

Several benzodiazepines are biotransformed to active metabolites, which possess half-lives that far exceed those of the parent compound. In such instances, persistent clinical effects are a consequence of the metabolite, its blood concentration, lipophilicity, and affinity for the GABAA/benzodiazepine receptor complex. For example, flurazepam has a plasma half-life of 1 to 4 hours, but its pharmacologically active metabolite, desalkylflurazepam, has a serum half-life of 45 to 300 hours. Due to biotransformation to active metabolites with slow elimination, the duration of action of most benzodiazepines often bears little resemblance to the elimination half-life of the administered (parent) drug. For those agents that are biotransformed to inactive metabolites (e.g., lorazepam and oxazepam) or active metabolites that are subsequently rapidly eliminated (e.g., temazepam and triazolam), the duration of action will be more closely correlated with their clinical duration of action. Elimination of benzodiazepine metabolites usually occurs via renal clearance. Tolerance can develop rapidly to nearly all of the clinical effects of benzodiazepines, although the effect on anxiolytic properties is limited. Several studies have been performed to evaluate the mechanism of tolerance. Mice made tolerant to lorazepam exhibited decreased benzodiazepine-receptor binding and GABAA function, consistent with down-regulation of the receptor. Subsequent discontinuation of lorazepam was accompanied by increased motor activity, receptor binding, and function, consistent with up-regulation. Lorazepam-tolerant mice

also had markedly reduced levels of messenger RNA for some subunits of the GABAA/benzodiazepine receptor.48 Tolerance to chronic lorazepam was attenuated in mice, and the down-regulation of the GABAA receptor reversed when the benzodiazepine antagonist flumazenil was administered concomitantly with lorazepam.49 Tolerance is likely due to acute uncoupling of the benzodiazepine effect at the GABA receptor, as well as changes in gene expression for certain subunits of the GABA receptor, particularly the α1 and γ2 subunits, in conjunction with up-regulation of genes encoding less common subunits, such as α4 and α5.31,33 The incidence of tolerance is unclear. In one retrospective study of 191 patients that received longterm benzodiazepine therapy, 92% had not needed to increase their dose of benzodiazepine, despite drug treatment for a mean of 5.6 years.50 Conversely, the development of tolerance to these medications has limited their long-term utility as sedatives and anticonvulsants. Interventions to prevent or reduce tolerance are under study and consist of intermittent dosing, tapering schedules, use of benzodiazepine antagonists, or coadministration of anticonvulsants.49

Special Populations GERIATRICS The clinical responses of elderly patients to benzodiazepines are altered as a result of age-related changes in both pharmacokinetics and pharmacodynamics. Aging is

678


associated with an increased volume of distribution, increased plasma half-life, and decreased hepatic clearance of some benzodiazepines. Advanced age is associated with diminished hepatic oxidative metabolism, serum protein-binding (i.e., hypoalbuminemia), and glomerular filtration, all of which place the elderly at increased risk for complications due to benzodiazepine accumulation. At the receptor level, positron emission tomography has not demonstrated a diminution in benzodiazepinebinding potentials in elderly persons.51 However, elderly men experienced increased sensitivity to the sedative, hypnotic, and psychomotor effects of alprazolam when compared with younger men, despite similar serum benzodiazepine concentrations.52 The increased sensitivity to benzodiazepines may be due to a combination of agerelated changes in the rate of acute tolerance, higher concentrations of drug in the brain due to altered bloodbrain barrier permeability, enhanced benzodiazepine receptor binding, increased receptor functionality, or less homeostatic reserve to compensate for drug effect. Short-acting agents, which undergo less hepatic biotransformation, have few active metabolites, and have less capacity for bioaccumulation are the benzodiazepines of choice in this population. HEPATIC AND RENAL IMPAIRMENT Because benzodiazepines are primarily metabolized by the liver, their pharmacokinetics may be altered in patients with cirrhosis.45,46,53 In general, agents that undergo phase I biotransformation may accumulate in cirrhotic patients due to increased volumes of distribution, decreased protein binding, prolonged half-life, and decreased oxidative clearance.45 Dose adjustment is usually unnecessary for agents, which are biotransformed by phase II glucuronidation alone. Elimination of benzodiazepine metabolites occurs via renal clearance. Patients with renal insufficiency may be at risk for the accumulation of active metabolites. PREGNANCY Benzodiazepines readily cross the placenta and may accumulate in the fetus, with serum concentrations that exceed those achieved in the mother. High doses of benzodiazepines administered during the immediate prepartum period may produce a floppy baby syndrome in newborn infants. This syndrome may be attributed to the persistence of long-acting benzodiazepine metabolites in neonatal serum.54,55 The incidence may decrease when benzodiazepines, which undergo only phase II metabolism, are administered.56 Most benzodiazepines are categorized as class D in pregnancy by the FDA, indicating that these drugs have caused or are expected to cause an increased incidence of human fetal malformations with maternal use. The teratogenic potential of benzodiazepines is unknown, and categorization comes from early human data that are inconsistent. Fetal benzodiazepine dependence occurs, and subsequent withdrawal may be delayed up to 10 days postpartum due to diminished neonatal benzodiazepine clearance.57 Benzodiazepines and their metabolites are

excreted in breast milk in clinically significant amounts58 and may sedate a nursing neonate. Because the metabolic capability of neonates is immature,59 benzodiazepines metabolized by phase I pathways may persist for extended periods. Breast-feeding should be avoided if benzodiazepines are to be administered to lactating women. OTHER There are ethnic-associated differences in the metabolism of certain benzodiazepines. For instance, East Asian populations exhibit slower phase I activity of the P-450 oxidative enzyme system (particularly the CYP2C family) and may be more sensitive to the clinical effects of benzodiazepines.47,60 Gender-specific sensitivity to benzodiazepine effects has been reported in association with concomitantly administered progesterone in postmenopausal women.61 This is likely a pharmacodynamic effect, because progesterone and its metabolites are steroid hormones, which modulate activity at the GABA(A) receptor. Finally, obese patients may have an increased sensitivity to benzodiazepine effects associated with multiple doses.62

Drug Interactions Benzodiazepine drug interactions can be pharmacodynamic or pharmacokinetic; they may be associated with effects at the GABAA/benzodiazepine recognition site or associated with benzodiazepine absorption and hepatic metabolism. Benzodiazepines potentiate the CNS-depressant effects of ethanol and numerous other drugs. Many of these interactions occur at the GABAA receptor, where ethanol, barbiturates, propofol, some general anesthetics, and other sedative-hypnotics (e.g., meprobamate, zaleplon, zolpidem, and zopiclone) also have binding sites and act as positive GABA modulators. Methylxanthines and some antibiotics diminish benzodiazepine-induced sedation. Since phase I biotransformation is a primary metabolic pathway for many benzodiazepines (e.g., diazepam, alprazolam, and temazepam), drugs that induce or inhibit the function of the P-450 CYP3A4 and CYP2D or 2C enzyme families can enhance or diminish the normal metabolism of benzodiazepines. The result may be shortened elimination half-life and reduced efficacy, or prolonged duration of action and oversedation.47,63 Phase II conjugation reactions are effected to a lesser degree, inhibited by probenecid and induced by oral contraceptive agents.47 These alterations in conjugative enzyme function will not produce significant clinical effects as related to benzodiazepines. Certain drugs also inhibit renal tubular secretion of benzodiazepine metabolites. Probenecid inhibits the tubular secretion of organic bases, and has been shown to decrease the renal clearance of N-desmethyladinazolam, the active metabolite of adinazolam.64 The coadministration of probenecid with adinazolam was associated with a decrease in psychomotor skill performance in healthy volunteers, and was presumed to be secondary to N-desmethyladinazolam accumulation.

CHAPTER 35

TOXICOLOGY Clinical Manifestations ACUTE The acute clinical manifestations of benzodiazepines are mainly those of CNS depression. Patients with a pure benzodiazepine overdose display mild to moderate sedation, often with dysarthria and ataxia, without serious neurologic, cardiovascular, or respiratory impairment. CHRONIC The long-term effects of benzodiazepines on the GABAA receptor and GABA physiology are not known. Research into the neurochemical effects of chronic benzodiazepine use indicates the possibility of subtle and delayed effects on cognitive function and memory acquisition. The reversibility of these effects is unclear. In one study of long-term benzodiazepine users who were detoxified from benzodiazepines, some cognitive defects persisted for up to 6 months.

Adverse Effects Therapeutic doses of benzodiazepines cause various degrees of sedation, drowsiness, lightheadedness, lethargy, and lassitude in virtually all patients, especially when therapy is initiated. Dysarthria, ataxia, motor incoordination, impairment of cognition, and amnesia may also occur. Uncommonly, fatigue, headache, blurred vision, vertigo, nausea and vomiting, diarrhea, arthralgias, chest pain, and incontinence have been reported. The frequency and severity of side effects increase with age. Uncommon side effects of rapid intravenous benzodiazepine administration include respiratory arrest, cardiac arrest, hypotension, and phlebitis at the site of injection. Severe adverse reactions are more common in the elderly, patients with severe cardiopulmonary disease, and those taking cardiorespiratory depressant medications. Other extremely rare side effects reported after benzodiazepine overdose include neuromuscular blockade; hematologic, renal, and hepatic toxicity; acute rhabdomyolysis; anaphylaxis; dermatitis; and acute respiratory distress syndrome. Postoperative exposure to benzodiazepines may increase the risk for delirium in recovering surgical patients. Long- and short-acting benzodiazepines have different side effect profiles.65 Long-acting benzodiazepines are associated with residual sedation and daytime drowsiness and may cause greater respiratory depression in patients with pulmonary disease. In addition, longand intermediate-acting benzodiazepines are considered to have reinforcing properties that may lead to their persistent use and potential for abuse.65 In comparison, short-acting benzodiazepines (those used as hypnotics) are more commonly associated with daytime anxiety and rebound insomnia upon discontinuation. The anxiolytic benzodiazepines have been reported to unmask bizarre, uninhibited behavior in some patients, as well as hostility, rage, paranoia, and depression. These reactions occur more frequently in elderly patients or

Benzodiazepines

679

those with overt or latent psychoses and organic brain syndrome. Such disinhibition or dyscontrol reactions are quite rare and usually are related to the patient’s preexisting expectations and pretreatment level of aggression and hostility.66 Rates of benzodiazepine usage increase with age, and elderly patients thus account for a disproportionately large percentage of benzodiazepine prescriptions. In addition, the elderly are more likely to be long-term users of these drugs. These facts, in combination with age-related differences in benzodiazepine pharmacokinetics and pharmacodynamics, place this population at greater risk for adverse side effects, namely, excess sedation, falls, and cognitive impairment. Multiple studies demonstrate adverse effects suffered by elderly benzodiazepine users.67-69 Chronic use and higher-than-recommended dosages are associated with an increased risk for accelerated decline in physical performance in community-dwelling elderly women.70 In one review of 11 epidemiologic studies, at least a 50% increase in the risk for hip fracture secondary to falls was associated with benzodiazepine use, especially during the initiation of therapy and at higher doses.71 After adjustment for covariates, the risk for hip fracture was also increased with benzodiazepine dosage regimens greater than or equal to 3 mg/day of diazepam equivalents, during initiation (first 2 weeks) of benzodiazepine therapy, and continuous benzodiazepine use for greater than 1 month.72 Short-acting benzodiazepines were not found to be safer than long-acting agents in these studies. Benzodiazepines, particularly long-acting agents, are the drug class most commonly associated with cognitive impairment in elderly people, often producing confusion, forgetfulness, slowing of thought processes, and loss of the ability to care for oneself.73 In a 4-year longitudinal study, chronic elderly benzodiazepine users had a greater risk for cognitive decline, independent of age, sex, education, ethanol, and other psychotropic drug use.74 A subgroup of elderly patients with neurodegenerative processes, such as dementia, may be at greater risk for cognitive impairment.69,75 Although a recent study notes the difficulty of quantifying benzodiazepine exposure in relation to adverse events,76 and outcomes of cognitive studies depend on the battery of tests applied to the study patients, it is still prudent to be cautious when using benzodiazepines in the elderly. Low doses should be administered for brief periods, and patients should be closely monitored for the development of side effects. If excess sedation, confusion, agitation, or other signs of cognitive impairment develop in an elderly patient taking benzodiazepines, the drug should be discontinued immediately pending further clinical investigation. The benzodiazepine effect may be overlooked by family and physicians and wrongly attributed to senility or a worsening of an underlying disease process. Benzodiazepine use in pregnancy may be associated with teratogenic effects and fetal loss. A syndrome of benzodiazepine embryopathy was reported in the 1980s, consisting of growth retardation, dysmorphic features, and CNS dysfunction, after oxazepam exposure.45 These

680


findings may be linked to potential benzodiazepineinduced regulation of GABAA subunit expression in the embryo. For example, mice, which lack β3 subunits, have an associated cleft palate. A recent review of the teratogenicity of benzodiazepines concluded that current data are insufficient to make informed decisions regarding benzodiazepine use in pregnancy, but suggest that diazepam and chlordiazepoxide, but not alprazolam, are safe.77 These drugs, however, are still categorized as pregnancy class D by the FDA. In an animal model, fetal exposure to benzodiazepines alters function and stressor-induced responsiveness of the GABAA receptor in the brains of the exposed adult animals. It is hypothesized that the GABA receptor has a developmental role in integrated stress responses, in addition to developmental changes in nonneural systems. Research is ongoing into the effect of prenatal exposure to benzodiazepines on the development of both the neurologic and immunologic systems. Central GABAA receptors and “peripheral” benzodiazepine receptors may interact with exogenous benzodiazepines in a way that adversely affects fetal development of these systems. Fetal benzodiazepine dependence and subsequent neonatal withdrawal can occur. The syndrome resembles neonatal narcotic withdrawal; symptoms include hypertonicity, irritability, tremors, hyperreflexia, tachypnea, and weight loss.57 Benzodiazepine administration to ill neonates may be associated with an increased risk for respiratory depression and hypotension.78 Early animal data suggested that benzodiazepine use may influence the risk for selected cancers. However, no association between the use of these drugs and the incidence of cancers, including breast, large bowel, malignant melanoma, lung, endometrium, or ovarian. has been proven.79,80

Acute Overdose Numerous clinical reports support the relatively benign nature and uncomplicated course of benzodiazepine overdose.44,81,82 In contrast to older sedative-hypnotic drugs, benzodiazepines have a high therapeutic index. Deaths attributable to benzodiazepines taken alone are extremely rare,1,81,82 and often involve short-acting benzodiazepines.83 For instance, death has been associated with isolated ingestions of flunitrazepam, flurazepam, nitrazepam, and triazolam. CNS depression is the hallmark of benzodiazepine overdose. Patients become acutely drowsy, stuporous, and ataxic, or may present in low-grade coma without focal neurologic abnormalities. These patients can generally be aroused from this state with verbal or painful stimulation. In one series of 38 patients with pure benzodiazepine overdose, 16 were awake and none were more symptomatic than grade 0 coma (asleep but arousable).84 In a series of 93 cases of diazepam overdose, patients required only supportive therapy, and no patient who ingested benzodiazepines alone required hospital admission.84 Occasionally, patients may manifest mild hypothermia, bradycardia, and hypotension.

Profound and significant coma, hypotension, respiratory depression, or hypothermia is extremely uncommon in oral overdose, unless other drugs have also been ingested. Although prolonged deep coma, cyclic coma, and focal neurologic signs85 have been reported with benzodiazepine overdose, such clinical scenarios are distinctly unusual. Most acutely poisoned patients become easily arousable or awaken within 12 to 36 hours. The duration of coma, however, may be prolonged in elderly and nonhabituated patients. After recovery of consciousness, it is typical for overdosed patients to feel dizzy, depressed, and apathetic for an extended period of time. Recovery may also be prolonged for those who develop complications (e.g., aspiration pneumonia). When they do occur, deaths are almost always due to benzodiazepines taken in combination with other drugs. The risk for toxicity is substantially increased when coingested with other CNS depressants.82 In this series, the combination of benzodiazepines and barbiturates was noted to be particularly dangerous, and 50% of these overdose patients required mechanical ventilation. Ethanol, identified as a co-ingestant in 38% of benzodiazepine overdoses,44 also enhances the CNS toxicity of benzodiazepines.86 These clinical outcomes are predictable, based on the synergistic effects of these drugs at the GABAA/benzodiazepine receptor complex.

DIAGNOSIS Laboratory Testing Qualitative urine screening for the presence of parent benzodiazepines or their metabolites provides rapid, useful information in the evaluation of patients with an unknown cause of CNS depression. Qualitative screening techniques, however, are fallible and should not be used in isolation to make clinical treatment decisions. Most laboratories perform initial screens for benzodiazepines with diagnostic immunoassays, the results of which are confirmed by gas or high-pressure liquid chromatography and/or mass spectrometry. Quantitative plasma measurements are not available in most hospitals, and provide no significant therapeutic direction to the treating physician.81,84,87,88 Plasma concentrations of benzodiazepines correlate very poorly with the severity of toxic effects (e.g., degree of CNS depression) or mortality. Various urine immunoassay screens are available and are standardized against the detection of a single benzodiazepine compound, usually oxazepam. Other structurally similar benzodiazepines are subsequently detected through immunologic cross-reactivity with the compound that is used as the standard. The concentration of benzodiazepine metabolites in urine can vary by several orders of magnitude, depending on the ingested drug, drug dose, and time of sample collection relative to dosing. Therefore, the sensitivity for detecting any individual benzodiazepine may vary significantly. Laboratory detection of benzodiazepines depends on the particular toxicologic screen used. For example, the

CHAPTER 35

enzyme-multiplied immunoassay technique (EMIT) screen cross-reacts with chlordiazepoxide, clonazepam, demoxepam, desalkylflurazepam, desmethyldiazepam, flurazepam, lorazepam, oxazepam, prazepam, and temazepam.89 However, several of these compounds are inconsistently detected unless they are present in extremely high concentrations. Enzymatic hydrolysis may improve the yield of EMIT screens.90 Triazolobenzodiazepine derivatives, such as alprazolam or triazolam,91 may be particularly difficult to detect in small but clinically significant ingestions because they possess poor immunologic cross-reactivity with oxazepam. The radioimmunoassay screening test, Abuscreen (Roche Diagnostic Systems, Inc., Somerville, NJ), identifies alprazolam, chlordiazepoxide, demoxepam, clorazepate, diazepam, temazepam, desmethyldiazepam, desalkylflurazepam, halazepam, lorazepam, midazolam, and prazepam but does not detect clonazepam or flurazepam.92 Various urine screens have been compared in their ability to accurately detect benzodiazepines.93,94 The metabolites that most commonly produce false-negative results were lorazepam and 7-aminoclonazepam. None of the screens were able to detect α-hydroxytriazolam or α-hydroxyalprazolam. Although some urine screens have sensitivities of 90% to 98%, as compared with gas chromatography/mass spectrophotometry, the range in sensitivities is 80% to 100%.95 In summary, the crossreactivity lists quoted by screen manufacturers may be incomplete, and it is important to realize that some commonly used screens may produce negative results despite a clinically significant benzodiazepine ingestion. In addition, positive screens for benzodiazepines may not correlate with clinical toxicity and may reflect the presence of an inactive metabolite (e.g., Ndesmethyldiazepam) that cross-reacts with the screen. False-positive benzodiazepine screens have been reported in the urine of patients using the nonsteroidal anti-inflammatory agent oxaprozin.96,97 Its urinary metabolite is probably responsible for these results. Similar false-positive results have been reported for etodolac, naproxen sodium, fenoprofen calcium, and tolmetin sodium.94 False-positive screens have also been reported in the presence of sertraline.98, 99 In this era of drug screening for legal and management decisions in the workplace, it is important to be aware of the limitations of some screening technologies. Although some research toxicology laboratories have the capacity to measure quantitative benzodiazepine levels, their measurement is not useful in the management of acute overdose. Therapeutic diazepam levels range between 0.5 and 2.0 μg/mL, while levels of 5 to 20 μg/mL are generally regarded as toxic. Yet, many patients with “toxic” levels may exhibit no or only mild clinical toxicity. Quantitative measurement of serum benzodiazepines and their metabolites may be useful for differentiating acute from chronic ingestions or for medicolegal or forensic cases. Other sources of tissue used for benzodiazepine detection include hair100,101 and oral fluids.95 Both sources may yield false-negative results and lack the sensitivity to be used as screening tests. Forensic studies

Benzodiazepines

681

have also examined benzodiazepine detection in postmortem samples of bile and bone, with fairly good yield.102,103

Other Diagnostic Testing Other diagnostic testing should be performed as necessary to identify or exclude coexisting conditions, which may also require treatment. Such testing often includes, but is not limited to, computed tomography of the head, laboratory testing for ethanol and other toxicants for which qualitative or quantitative testing may be beneficial, measurements of serum electrolytes and glucose, as well as electroencephalography for subclinical status epilepticus. Arterial blood gas analysis and capnography may be performed to assess the adequacy of respiration in those patients with CNS depression.

Differential Diagnosis Patients with a pure benzodiazepine overdose display mild to moderate sedation, often with dysarthria and ataxia, without serious focal neurologic, cardiovascular, or respiratory derangement. There are no specific diagnostic clinical features unique to benzodiazepine overdose. Toxicity from benzodiazepines produces signs and symptoms that are similar to many toxicologic and nontoxicologic entities. The CNS depressant effects may be similar to effects produced by alcohols, antiepileptics, antipsychotics, barbiturates, carbon monoxide and other gases, lithium, opiates, other sedative-hypnotics, and skeletal muscle relaxants. CNS infection, traumatic head injury, cerebrovascular accidents, and metabolic disturbances should be considered and ruled out with appropriate testing.

MANAGEMENT Supportive Measures and Laboratory Testing Treatment for benzodiazepine overdose is primarily supportive. Patients with significant CNS or respiratory depression should have their airways protected, breathing assisted, and cardiovascular support provided supportive as necessary. All patients should have continuous cardiac monitoring, an intravenous line established, and electrocardiography performed. Supplemental oxygen, continuous pulse oximetry, and parenteral thiamine, dextrose (or rapid fingerstick glucose determination), and naloxone should be considered for patients with altered mental status or seizures. Semi-comatose patients should be placed in the left lateral, head-down position to minimize the risk for aspiration. Frequent vital sign and neurologic evaluations are necessary. Routine laboratory analysis should include a complete blood count and measurement of electrolytes, blood urea nitrogen, creatinine, glucose concentrations, and pregnancy testing for women of childbearing age. Serum acetaminophen and

682


salicylate concentrations should be performed for all intentional overdose patients. Co-ingestion of other toxic substances, concurrent trauma, or other underlying medical conditions significantly alter the diagnostic and therapeutic approach. Urine screening may confirm the presence of benzodiazepines or their metabolites. Negative screening does not rule out the presence of certain benzodiazepines, as mentioned above.

Decontamination and Enhanced Elimination Techniques Single-dose administration of activated charcoal (1 g/kg orally or by nasogastric tube) is the preferred method of gastrointestinal decontamination and may be beneficial if administered within 1 hour of drug ingestion. Orogastric lavage is not recommended for isolated benzodiazepine overdose since the risk for death is very low in this patient population. The clinical benefit of activated charcoal administration beyond 1 hour following benzodiazepine ingestion is likely low.

Antidotes Flumazenil (Romazicon [Roche Pharmaceuticals of Hoffman-La Roche, Inc., Nutley, NJ]) was synthesized in 1979 and is the benzodiazepine antagonist available in the United States. It is a 1,4-imidazobenzodiazepine, a derivative of the antibiotic anthramycin,104 which contains a diazepine ring that binds at the benzodiazepine receptor complex (Fig. 35-5). Flumazenil is administered intravenously. It has also been studied as a potential reversal agent after subcutaneous,105 sublingual, intramuscular, rectal,106 submucosal,107 intranasal,108 and endotracheal administration.109 Orally administered flumazenil has been studied in the treatment of epilepsy110-112 and hepatic encephalopathy.113 Flumazenil has a volume of distribution of 1.1 L/kg, is 40% to 50% protein bound, and is highly lipid soluble.104 It has a distribution half-life of 5 minutes and rapidly crosses the blood-brain barrier to reverse benzodiazepine-induced sedation within 1 to 2 minutes after intravenous administration. The mean half-life of flumazenil is 57 minutes; therefore, resedation may occur within 1 to 2 hours after administration, requiring subsequent doses. Flumazenil is hepatically metabolized by conjugation, and the metabolite is renally excreted. In oral dosage form, flumazenil is rapidly absorbed but has low bioavailability secondary to significant first pass metabolism in the liver. The dose of flumazenil is 0.2 IV per dose, to a total of 3 mg, in adults and 0.01 mg/kg IV per dose, to a total of O

K

N

JCJOCH2CH3 F

K O

N CH3

FIGURE 35-5 The chemical structure of flumazenil (Ro 15-1788), a specific benzodiazepine antagonist.

0.05 mg/kg or 1 mg, in children. A continuous infusion of flumasenil has been used in both children114 and adults.115 The adult dose of flumazenil is 0.2 mg intravenously over 30 seconds, followed by 0.3 and 0.5 mg at 1-minute intervals to a maximum dose of 3 mg. Alternatively, flumazenil may be administered in 0.2-mg aliquots intravenously every 30 to 60 seconds until a dose of 3 mg is reached. Flumazenil rapidly reverses the sedative, anxiolytic, anticonvulsant, ataxic, anesthetic, and muscle relaxant effects of benzodiazepines in animals and humans.116 It restores an electroencephalogram to the baseline waking state in patients who have been administered benzodiazepines,117,118 and is an effective antidote for benzodiazepine overdose.119 Patients with benzodiazepine-induced coma respond dramatically within 1 to 5 minutes after flumazenil administration.120,121 A number of benzodiazepine effects have been reversed by flumazenil, which include respiratory depression,122 midazolam-induced laryngospasm,123 first-degree atrioventricular block in alprazolam overdose,124 lorazepam-induced acute delirium,125 and midazolam-associated myoclonic movements in fullterm newborns.126 Incomplete or partial antagonism of benzodiazepineinduced sedation has been reported121 but may be secondary to co-ingestion of other sedative-hypnotics or concomitant medical causes of depressed consciousness. In addition, residual memory deficits may persist. Finally, orally administered flumazenil may only partially reverse the effects of benzodiazepines.127 Flumazenil acts as an antagonist, competitively removing both positive and negative GABA modulators from the benzodiazepine recognition site. It binds at the same αγ2 interface on the GABA(A) complex where benzodiazepines bind and interacts with amino acid residues that are not associated with benzodiazepine binding. At high doses, it is reported to have agonist-like anticonvulsant activity. However, it is also reported to have weak inverse agonist properties.128 Based on its mechanism of action, flumazenil has been used to reverse sedation in cases of hepatic encephalopathy.129 Anecdotal reports also describe partial reversal of ethanol- and carbamazepine-induced CNS depression. When administered to normal volunteers, flumazenil has produced dizziness, facial erythema, anxiety, and headache. Symptoms are often mild and disappear within several minutes. Flumazenil has been shown to further increase intracranial pressure when administered to head-injured patients with elevated intracranial pressure. Reports of ventricular dysrhythmias have been associated with its administration.114 Additionally, flumazenil has been noted to precipitate seizures in epileptic patients who take benzodiazepines for seizure control and in patients who have co-ingested drugs that lower the seizure threshold.130,131 Older case series demonstrated an increased risk for seizures after flumazenil administration to patients who had ingested cyclic antidepressants. A more recent study, however, did not show such serious complications occurring in this setting. The lack of seizure precipitation in this latter study may have been due to slow incremental flumazenil dosing or smaller total doses of the antagonist.132 Flumazenil has

CHAPTER 35

also precipitated acute benzodiazepine withdrawal and seizures in dependent persons. For these reasons, the role of flumazenil in patients who present with suspected benzodiazepine overdose and CNS depression or undifferentiated drug coma is controversial. Flumazenil has been used in the pediatric population for both reversal of sedation and for empiric treatment in the unconscious patient. Pediatric case reports of flumazenil-associated seizures have also been reported,133 one in the setting of iatrogenic apnea induced by diazepam and treated with flumazenil after an infant presented with febrile seizures.134 The Flumazenil Pediatric Study Group suggests flumazenil dosing of 0.01 mg/kg infusion (max 0.2 mg) each minute to a maximum of 0.05 mg/kg (or 1 mg) for reversal of sedation.135 As mentioned, flumazenil has the potential to precipitate withdrawal symptoms in benzodiazepinedependent individuals.136 In animal studies, the severity of withdrawal depends on the specific benzodiazepine used, the dose and duration of treatment, and the dose of flumazenil administered.137 Abrupt withdrawal symptoms are usually more severe when induced by flumazenil administration. Although the potential toxicity of benzodiazepines is relatively low and aggressive therapy for pure overdose is rarely required, flumazenil offers several important potential uses in clinical medicine. Its use can help to confirm a suspected diagnosis of benzodiazepine overdose and obviate the need for other diagnostic testing (e.g., cranial computed tomography and lumbar puncture). Flumazenil may reverse overdose of zolpidem and zopiclone, and may be indicated for benzodiazepineassociated respiratory depression, particularly if intubation and mechanical ventilation would otherwise be indicated. Flumazenil may be useful postoperatively to reverse the effects of preoperative sedation or to reverse iatrogenic overdose when benzodiazepines are used for conscious sedation. Flumazenil may be used in select circumstances with experienced practitioners in these settings. The use of flumazenil for undifferentiated coma, even when administered slowly, is dangerous and not recommended. Despite its potential usefulness, flumazenil should not become “routine” antidote in the treatment of coma secondary to overdose.

Elimination There are no practical ways to significantly enhance the elimination of benzodiazepines. Forced diuresis is of no value. Extracorporeal removal techniques are not recommended as part of treatment for benzodiazepine poisoning since these agents have large volumes of distribution and high plasma protein binding.

Disposition Most patients with isolated benzodiazepine overdose develop minimal to mild toxicity and are medically safe after an observation period of 4 to 6 hours in the emergency department. Patients who are able to safely ambulate after observation may be discharged

Benzodiazepines

683

after appropriate psychiatric consultation. Patients who develop more significant CNS depression or have continued evidence of mild toxicity at 6 hours should be admitted to a monitored bed for continued observation.

REFERENCES 1. Greenblatt DJ, Shader RI: Drug therapy. Benzodiazepines. N Engl J Med 1974;291:1011–1015. 2. Johnson MR, Lydiard RB, Ballenger JC: Panic disorder. Pathophysiology and drug treatment. Drugs 1995;49:328–344. 3. Blanco C, Schneier FR, Schmidt A, et al: Pharmacological treatment of social anxiety disorder: a meta-analysis. Depress Anxiety 2003;18:29–40. 4. Practice guidelines for the treatment of patients with bipolar disorder. Am J Psychiatry 1994;151:1–36. 5. Ungvari GS, Leung CM, Wong MK, Lau J: Benzodiazepines in the treatment of catatonic syndrome. Acta Psychiatr Scand 1994;89:285–288. 6. Rosenfeld MJ, Friedman JH: Catatonia responsive to lorazepam: a case report. Mov Disord 1999;14:161–162. 7. Ungvari GS, Kau LS, Wai-Kwong T, Shing NF: The pharmacological treatment of catatonia: an overview. Eur Arch Psychiatry Clin Neurosci 2001;251(Suppl 1):31–34. 8. Pommepuy N, Januel D: Catatonia: resurgence of a concept. A review of the international literature. Encephale 2002;28 (6 Pt 1):481–492. 9. Rosebush PI, Mazurek MF: Do benzodiazepines modify the incidence of neuroloptic-induced dystonia? [Letter]. Am J Psychiatry 1993;150:528. 10. Redfern P, Minors D, Waterhouse J: Circadian rhythms, jet lag, and chronobiotics: an overview. Chronobiol Int 1994; 11:253–265. 11. Buxton OM, Copinschi G, Van Onderbergen A, et al: A benzodiazepine hypnotic facilitates adaptation of circadian rhythms and sleep-wake homeostasis to an eight hour delay shift simulating westward jet lag. Sleep 2000;23:915–927. 12. Dellemijn PLI, Fields HL: Do benzodiazepines have a role in chronic pain management? Pain 1994;57:137–152. 13. Greenberg DB: Strategic use of benzodiazepines in cancer patients. Oncology 1991;5:83–88. 14. Livingston MG: Benzodiazepine dependence. Br J Hosp Med 1994;51:281–286. 15. Woods JH, Winger G: Current benzodiazepine issues. Psychopharmacology 1995;118:107–115. 16. Olfson M, Marcus SC, Weissman MM, Jensen P: National trends in the use of psychotropic medications by children. J Am Acad Child Adolesc Psychiatry 2002;41:514–521. 17. Tu K, Mamdani MM, Hux JE, Tu J: Progressive trends in the prevalence of benzodiazepine prescribing in older people in Ontario, Canada. J Am Geriatr Soc 2001;49:1341–1345. 18. Darke S: Benzodiazepine use among injecting drug users: problems and implications. Addiction 1994;89:379–382. 19. Gelkopf M, Bleich A, Hayward R, et al: Characteristics of benzodiazepine abuse in methadone maintenance treatment patients: a 1-year prospective study in an Israeli clinic. Drug Alcohol Depend 1999;55:6368. 20. Wagner AK, Soumerai SB, Zhang F, et al: Effects of state surveillance on new post-hospitalization benzodiazepine use. Int J Qual Health Care 2003;15:423–431. 21. Schwartz HI, Blank K: Regulation of benzodiazepine prescribing practices: clinical implications. Gen Hosp Psychiatry 1991; 13:219–224. 22. Schwartz HI: Negative clinical consequences of triplicate prescription regulation of benzodiazepines. NY State J Med 1991;91(Suppl 11):9–12. 23. McNutt LA, Coles FB, McAuliffe T, et al: Impact of regulation on benzodiazepine prescribing to a low income elderly population, New York State. J Clin Epidemiol 1994;47:613–625. 24. Weintraub M, Singh S, Byrne L, et al: Consequences of the 1989 New York State triplicate benzodiazepine prescription regulations. JAMA 1991;266:2392–2397.

684


25. Linden M, Gothe H: Benzodiazepine substitution in medical practice. Analysis of pharmacoepidemiologic data based on expert interviews. Pharmacopsychiatry 1993;26:107–113. 26. Charney DS, Mihic SJ, Harris RA: Hypnotics and sedatives. In Hardman JG, Limbrid LE, Gilman AG (eds): Goodman & Gilman’s the Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 399–427. 27. Goodchild CS: GABA receptors and benzodiazepines. Br J Anaesth 1993;71:127–133. 28. Chebib M: The “ABC” of GABA receptors: a brief review. Clin Exp Pharm Phys 1999;26:937–940. 29. Enz R: GABAC receptors: a molecular view. Biol Chem 2001;382:1111–1122. 30. Möhler H, Fritshy JM, Rudolph U: A new benzodiazepine pharmacology. Pharm Exp Ther 2002;300:2–8. 31. Doble A: New insights into the mechanism of action of hypnotics. J Psychopharm 1999;13(Suppl 1):11–20. 32. Whitehouse BJ: Benzodiazepines and steroidogenesis. J Endocrinol 1992;134:1–3. 33. Sanger DJ, Benavides J, Perrault G, et al: BZ-omega receptor subtypes—activity of various benzodiazepines may be due to different activity at various subtypes. Neurosci Biobehav Rev 1994;18:355–372. 34. Arvat E, Giordano R, Grottoli S, Ghigo E: Benzodiazepines and anterior pituitary function. J Endocrinol Invest 2002; 25:735–747. 35. Griebel G, Perrault G, Letang V, et al: New evidence that the pharmacological effects of benzodiazepine receptor ligands can be associated with activities at different BZ(?) receptor subtypes. Psychopharmacology 1999;146:205–213. 36. Sanger DJ, Griebel G, Perrault G, et al: Discriminative stimulus effects of drugs acting at GABAA receptors; differential profiles and receptor selectivity. Pharm Biochem Behav 1999; 64:269–273. 37. Rudolph U, Crestani F, Möhler H: GABAA receptor subtypes: dissecting their pharmacological functions. Trends Pharm Sci 2001;22:188–194. 38. Nutt DJ, Smith CF, Bennett R, Jackson HC: Investigations on the “set-point” theory of benzodiazepine receptor function. Adv Biochem Psychopharmacol 1992;47:419–429. 39. Malizia AL, Coupland NJ, Nutt DJ: Benzodiazepine receptor function in anxiety disorders. Adv Biochem Psychopharmacol 1995;48:115–133. 40. Izquierdo I, Medina JH: GABAa receptor modulation of memory: the role of endogenous benzodiazepines. Trends Pharmacol Sci 1991;12:260–265. 41. Rothstein JD: Benzodiazepine-receptor ligands and hepatic encephalopathy: a causal relationship? Hepatology 1994;19:248–250. 42. Mullen KD: Benzodiazepine compounds and hepatic encephalopathy. N Engl J Med 1991;325:509–511. 43. Baselt RC: Disposition of Toxic Drugs and Chemicals in Man, 7th ed. Foster City, CA, Biomedical Publications, 2004. 44. Finkle BS, McCloskey KL, Goodman LS: Diazepam and drugassociated deaths: a survey in the United States and Canada. JAMA 1979;242:429–434. 45. Bailey L, Ward M, Musa MN: Clinical pharmacokinetics of benzodiazepines. J Clin Pharmacol 1994;34:804–811. 46. Greenblatt DJ: Benzodiazepine hypnotics: sorting the pharmacokinetic facts. J Clin Psychiatry 1991;52(Suppl 9):4–10. 47. Obach RS: Drug-drug interactions: an important negative attribute in drugs. Drugs Today 2003;39:301–338. 48. Miller LG: Chronic benzodiazepine administration: from the patient to the gene. J Clin Pharmacol 1991;31:492–495. 49. Miller LG, Koff JM: Interaction of central and peripheral benzodiazepine sites in benzodiazepine tolerance and discontinuation. Prog Neuropsychopharmacol Biol Psychiatry 1994;18:847–857. 50. Logan KE, Lawrie SM: Long term use of hypnotics and anxiolytics [Letter]. BMJ 1994;309:27–28. 51. Suhara T, Inoue O, Kobayashi K, et al: No age-related changes in human benzodiazepine receptor binding measured by PET with [11C]Ro 15-4513. Neurosci Lett 1993;159:207–210. 52. Bertz RJ, Kroboth PD, Kroboth FJ, et al: Alprazolam in young and elderly men: sensitivity and tolerance to psychomotor,

53. 54. 55. 56. 57. 58. 59. 60. 61. 62.

63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74.

75. 76.

sedative and memory effects. J Pharmacol Exp Ther 1997;281: 1317–1329. Kroboth PD, Maxwell RA, Fleishaker JC, et al: Comparison of adinazolam pharmacokinetics and effects in healthy and cirrhotic subjects. J Clin Pharmacol 1991;31:580–586. Spreight ANP: Floppy-infant syndrome and maternal diazepam and/or nitrazepam. Lancet 1977;2:878. Whitelaw AGL, Cummings AJ, McFadyen IR: Effect of maternal lorazepam on the neonate. BMJ 1981;282:1106–1108. Drury KAD: Floppy-infant syndrome: is oxazepam the answer? Lancet 1977;2:1126. Smith DE, Wesson DR: Benzodiazepine dependency syndromes. In Smith DE, Wesson DR (eds): The Benzodiazepines: Current Standards for Medical Practice. Lancaster, UK, MTP Press, 1985. Cole AP, Hailey DM: Diazepam and active metabolites in breast milk and their transfer to the neonate. Arch Dis Child 1975;50:741–742. Kaplan SA: Pharmacokinetics of the benzodiazepines. In Priest RG, Vianna Filho U, Amrein R, Skreta M (eds): Benzodiazepines Today and Tomorrow. Lancaster, UK, MTP Press, 1980. Ajir K, Smith M, Keh-Ming L, et al: The pharmacokinetics and pharmacodynamics of adinazolam: multi-ethnic comparisons. Psychopharmacology 1997;129:265–270. McAuley JW, Reynolds IJ, Kroboth FJ, et al: Orally administered progesterone enhances sensitivity to triazolam in postmenopausal women. J Clin Psychopharmacol 1995;15:3–11. Derry CL, Kroboth PD, Pittenger AL, et al: Pharmacokinetics and pharmacodynamics of triazolam after two intermittent doses in obese and normal-weight men. J Clin Psychopharmacol 1995;15:197–205. Dresser GK, Bailey DG: A basic conceptual and practical overview of interactions with highly prescribed drugs. Can J Clin Pharmacol 2002;9:191–198. Golden PL, Warner PE, Fleishaker JC, et al: Effects of probenecid on the pharmacokinetics and pharmacodynamics of adinazolam in humans. Clin Pharmacol Ther 1994;56:133–141. Mendelson WB: Clinical distinctions between long-acting and short-acting benzodiazepines. J Clin Psychiatry 1992;53(Suppl): 4–7. Rothschild AJ: Disinhibition, amnestic reactions, and other adverse reactions secondary to triazolam: a review of the literature. J Clin Psychiatry 1992;53(Suppl):69–79. Dealberto MJ, Mcavay GJ, Seenan T, Berkman L: Psychotropic drug use and cognitive decline among older men and women. Int J Geriatr Psychiatry 1997;12:567–574. Paterniti S, Dufouil C, Bisserbe JC, Alperovitch A: Anxiety, depression, psychotropic drug use and cognitive impairment. Psychol Med 1999;29:421–428. Pat McAndrews M, Weiss RT, Sandor P, et al: Cognitive effects of long-term benzodiazepine use in older adults. Hum Psychopharmacol 2003;18:51–57. Gray SL, Penninx BW, Blough DK, et al: Benzodiazepine use and physical performance in community-dwelling older women. J Am Geriatr Soc 2003;51:1563–1570. Cumming RG, LeCouteur DG: Benzodiazepines and risk of hip fractures in older people: a review of the evidence. CNS Drugs 2003;17:825–837. Wang PS, Bohn RL, Glynn RJ, et al: Hazardous benzodiazepine regimens in the elderly: effects of half-life, dosage, and duration on risk of hip fracture. Am J Psychiatry 2001;158:892–898. Larson EB, Kukill WA, Buchner D, Reifler BV: Adverse drug reactions associated with cognitive impairment in elderly persons. Ann Intern Med 1987;107:169–173. Paterniti S, Dufouil C, Alperovitch A: Long-term benzodiazepine use and cognitive decline in the elderly: the Epidemiology of Vascular Aging Study. J Clin Psychopharmacol 2002;22:285–293. Allard J, Artero S, Ritchie K: Consumption of psychotropic medication in the elderly: a re-evaluation of its effect on cognitive performance. Int J Geriatr Psychiatry 2003;18:874–878. Ray WA, Thapa PB, Gideon P: Misclassification of current benzodiazepine exposure by use of a single baseline measurement and its effects upon studies of injuries. Pharmacoepidemiol Drug Saf 2002;11:663–669.

CHAPTER 35

77. Iqbal MM, Sobhan T, Ryals T: Effects of commonly used benzodiazepines on the fetus, the neonate, and the nursing infant. Psychiatr Serv 2002;53:39–49. 78. Ng E, Klinger G, Shah V, Taddio A: Safety of benzodiazepines in newborns. Ann Pharmacother 2002;36:1150–1155. 79. Rosenberg L, Palmer JR, Zauber AG, et al: Relation of benzodiazepine use to the risk of selected cancers: breast, large bowel, malignant melanoma, lung, endometrium, ovary, non-Hodgkin’s lymphoma, testis, Hodgkin’s disease, thyroid, and liver. Am J Epidemiol 1995;141:1153–1160. 80. Dublin S, Rossing MA, Heckbert SR, et al: Risk of epithelial ovarian cancer in relation to use of antidepressants, benzodiazepines, and other centrally acting medications. Cancer Causes Control 2002;13:35–45. 81. Busto U, Kaplan HL, Sellers EM: Benzodiazepine-associated emergencies in Toronto. Am J Psychiatry 1980;137:224–227. 82. Greenblatt DJ, Allen MD, Noel BJ, et al: Acute overdosage with benzodiazepine derivatives. Clin Pharmacol Ther 1977;21:497–514. 83. Martin CD, Chan SC: Distribution of temazepam in body fluids and tissues in lethal overdose. J Anal Toxicol 1986;10:77–78. 84. Jatlow P, Dobular K, Bailey D: Serum diazepam concentrations in overdose: their significance. Am J Clin Pathol 1979;72:571–579. 85. Deleu D, Keyser J: Flunitrazepam intoxication simulating a structural brainstem lesion. J Neurol Neurosurg Psychiatry 1987;50:236–237. 86. Sellers EM, Busto U: Benzodiazepines and ethanol: assessment of the effects and consequences of psychotropic drug interactions. J Clin Pharmacol 1982;22:249–262. 87. Allen-Divoll M, Greenblatt DJ, Lacasse Y: Pharmacokinetic study of lorazepam overdosage. Am J Psychiatry 1980;137:1414–1415. 88. Bailey DN: Blood concentrations and clinical findings following overdose of chlordiazepoxide alone and chlordiazepoxide plus ethanol. Clin Toxicol 1984;22:433–446. 89. Package insert, EMIT. Urine immunoassay. Sylva Company, Palo Alto, CA, August 1985. 90. Borrey D, Meyer E, Duchateau L, et al: Enzymatic hydrolysis improves the sensitivity of emit screening for urinary benzodiazepines. Clin Chem 2002;48:2047–2049. 91. Fraser AD: Urinary screening for alprazolam, triazolam and their metabolites with the EMIT®d.a.u.TM benzodiazepine metabolite assay. J Anal Toxicol 1987;11:263–266. 92. Package insert, Abuscreen-Radioimmunoassay for benzodiazepines. Roche Diagnostic Systems, Nutley, NJ, July 1987. 93. Fitzgerald RL, Rexin DA, Herold DA: Detecting benzodiazepines: immunoassays compared with negative chemical ionization gas chromatography/mass spectrometry. Clin Chem 1994;40:373–380. 94. Peace MR, Poklis JL, Tarnai LD, Poklis A: An evaluation of the OnTrak Testcup-er® on-site urine drug-testing device for drugs commonly encountered from emergency departments. J Anal Toxicol 2002;26:500–503. 95. Gronholm M, Lillsunde P: A comparison between on-site immunoassay drug-testing devices and laboratory results. Forensic Sci Int 2002;121:37–46. 96. Pulini M: False-positive benzodiazepine urine test due to oxaprozin [Letter]. JAMA 1995;273:1905–1906. 97. Fraser AD, Howell P: Oxaprozin cross-reactivity in three commercial immunoassays for benzodiazepines in urine. J Anal Toxicol 1998;22:50–54. 98. Gear JL: False-positive toxicology screens. J Am Acad Child Adolesc Psychiatry 1996;35:1571–1572. 99. Fitzgerald RL, Herold DA: Improved CEDIA benzodiazepine assay eliminates sertraline crossreactivity. J Anal Toxicol 1997;21:32–35. 100. Sramek JJ, Baumgartner WA, Ahrens TN, et al: Detection of benzodiazepines in human hair by radioimmunoassay. Ann Pharmacother 1992;26:469–472. 101. Yegles M, Mersch F, Wennig R: Detection of benzodiazepines and other psychotropic drugs in human hair by GC/MS. Forensic Sci Int 1997;84:211–218. 102. Gorczynski LY, Melbye FJ: Detection of benzodiazepines in different tissue, including bone, using a quantitative ELISA assay. J Forensic Sci 2001;46:916–918. 103. Vanbinst R, Koenig J, Di Fazio V, Hassoun A: Bile analysis of drugs in postmortem cases. Forensic Sci Int 2002;128:35–40.

Benzodiazepines

685

104. Longmire AW, Seger DL: Topics in clinical pharmacology: flumazenil, a benzodiazepine antagonist. Am J Med Sci 1993;306:49–52. 105. Luger TJ, Morawetz RF, Mitterschiffthaler G: Additional subcutaneous administration of flumazenil does not shorten recovery time after midazolam. Br J Anaesth 1990;64:53–58. 106. Heniff MS, Moore GP, Trout A, et al: Comparison of routes of flumazenil administration to reverse midazolam-induced respiratory depression in a canine model. Acad Emerg Med 1997;4: 1115–1118. 107. Oliver FM, Sweatdown TW, Unkel JH, et al: Comparative pharmacokinetics of submucosal vs. intravenous flumazenil (Romazicon) in an animal model. Pediatr Dent 2000;22:489–493. 108. Scheepers LD, Montgomery CJ, Kinaham AM, et al: Plasma concentration of flumazenil following intranasal administration in children. Can J Anaesth 2000;47:120–124. 109. Weiner AL, McKay CA Jr: Endotracheal administration of flumazenil. Am J Emerg Med 1998;16:436–437. 110. Scollo-Lavizzari G: The clinical anti-convulsant effects of flumazenil, a benzodiazepine antagonist. Eur J Anaesthesiol Suppl 1988;2:129–138. 111. Sharief MK, Sander JW, Shorvon SD: The effect of oral flumazenil on interictal epileptic activity: results of a double-blind, placebo-controlled study. Epilepsy Res 1993;15:53–60. 112. Reisner-Keller LA, Pham Z: Oral flumazenil in the treatment of epilepsy. Ann Pharmacother 1995;29:530–531. 113. Blei AT: Diagnosis and treatment of hepatic encephalopathy. Baillieres Clin Gastroenterol 2000;14:959–974. 114. Sugarman JM, Paul RI: Flumazenil: a review. Pediatr Emerg Care 1994;10:37–43. 115. Guglielminotti J, Maury E, Alzieu M, et al: Prolonged sedation requiring mechanical ventilation and continuous flumazenil infusion after routine doses of clonazepam for alcohol withdrawal syndrome. Intensive Care Med 1999;25:1435–1436. 116. Darragh A, Lambe R, Scully M, et al: Investigation in man of the efficacy of a benzodiazepine antagonist, Ro15-1788. Lancet 1981;2:8–10. 117. Laurian S, Gailard M, Le PK, et al: Effects of a benzodiazepine antagonist on the diazepam-induced electrical brain activity modifications. Neuropsychobiology 1984;11:55–58. 118. Wojna V, Guerrero L, Guzman J, Cotto M: Effect of flumazenil on electroencephalographic patterns induced by midazolam. P R Health Sci J 2000;19:353–356. 119. Hofer P, Scollo-Lavizzari G: Benzodiazepine antagonist Ro 15-1788 in self-poisoning: diagnostic and therapeutic use. Arch Intern Med 1985;145:663–664. 120. Scollo-Lavizzari G: First clinical investigation of the benzodiazepine antagonist Ro 15-1788 in comatose patients. Eur Neurol 1983;22:7–11. 121. Chern CH, Chern TL, Hu SC, et al: Complete and partial response to flumazenil in patients with suspected benzodiazepine overdose [Letter]. Am J Emerg Med 1995;13:372–375. 122. Gross JB, Blouin RT, Zandsberg S, et al: Effect of flumazenil on ventilatory drive during sedation with midazolam and alfentanil. Anesthesiology 1996;85:713–720. 123. Davis DP, Hamilton RS, Webster TH: Reversal of midazolaminduced laryngospasm with flumazenil. Ann Emerg Med 1998;32:263–265. 124. Mullins ME: First degree atrio-ventricular block in alprazolam overdose reversed by flumazenil. J Pharm Pharmacol 1999; 51:367–370. 125. Olshaker JS, Flanigan J: Flumazenil reversal of lorazepam-induced acute delirium. J Emerg Med 2003;24:181–183. 126. Zaw W, Knoppert DC, da Silva O: Flumazenil’s reversal of myoclonic-like movements associated with midazolam in term newborns. Pharmacotherapy 2001;21:642–646. 127. Girdler NM, Lyne JP, Wallace R, et al: A randomised, controlled trial of cognitive and psychomotor recovery from midazolam sedation following reversal with oral flumazenil. Anaesthesia 2002;57:868–876. 128. Philip BK: Drug reversal: benzodiazepine receptors and antagonists. J Clin Anesth 1993;5(Suppl 1):46–51. 129. Hoffman EJ, Warren EW: Flumazenil: a benzodiazepine antagonist. Clin Pharm 1993;12:641–656.

686


130. Haverkos GP, DiSalvo RP, Imhoff TE: Fatal seizures after flumazenil administration in a patient with mixed overdose. Ann Pharmacother 1994;28:1347–1349. 131. Spivey WH: Flumazenil and seizures: analysis of 43 cases. Clin Ther 1992;14:292–305. 132. Weinbroum A, Rudick V, Sorkine P, et al: Use of flumazenil in the treatment of drug overdose: a double-blind and open clinical study in 110 patients. Crit Care Med 1995;24:199–206. 133. McDuffee AT, Tobias JD: Seizure after flumazenil administration in a pediatric patient. Pediatr Emerg Care 1995;11:186–187. 134. Davis CO, Wax PM: Flumazenil associated seizure in an 11-monthold child. J Emerg Med 1996;14:331–333.

135. Shannon M, Albers G, Burkhart K, et al: Safety and efficacy of flumazenil in the reversal of benzodiazepine-induced conscious sedation. The Flumazenil Pediatric Study Group. Curr Opin Pediatr 1996;8:243–247. 136. Cumin R, Bonetti EP, Scherchlicht R, et al: Use of the specific benzodiazepine antagonist, Ro 15-1788, in studies of physiological dependence on benzodiazepines. Experientia 1982;38:833–834. 137. Investigational drug brochure, intravenous flumazenil (Ro 151788). Hoffmann-La Roche, Nutley, NJ, March 1987.

36

Barbiturates RICHARD LYNTON, MD

■

■ ■ ■

■

■ ■

The barbiturates are a family of sedative-hypnotics. Their clinical use has fallen dramatically over the past 3 decades as benzodiazepines and other safer sedative-hypnotics have been created. Barbiturates are associated with significant morbidity and mortality, the result of their ability to produce profound central nervous system and myocardial depression. There are nine barbiturates in clinical use, each having a unique pharmacokinetic profile. Barbiturate use is associated with a number of significant drug interactions. Tolerance and dependence with barbiturates can lead to significant addiction as well as an abstinence syndrome (withdrawal) with acute discontinuation. Barbiturate overdose produces a syndrome of central nervous system depression; severe intoxication may lead to hemodynamic instability. Other manifestations, for example, skin changes (“barb blisters”), are less common. Treatment of barbiturate overdose begins with supportive care that includes airway and blood pressure support The elimination of phenobarbital can be enhanced through three measures: multiple-dose activated charcoal, urine alkalinization, and hemodialysis. Hemodialysis and other extracorporeal drug removal techniques are generally reserved for patients with severe phenobarbital toxicity (serum concentration > 100 μg/L). These elimination techniques are not effective with other barbiturates.

Over the past 30 years, barbiturates as a class have slowly been replaced by safer sedative-hypnotics such as benzodiazepines. Their role to toxicologists as drugs in overdose settings are therefore significantly less, as shown in cumulative data from poison centers in North America (Fig. 36-1). Barbiturate overdose now results in less morbidity and mortality when compared with more commonly used benzodiazepines. However, barbiturates continue to be important in sedation, anesthesia, and seizure control, and as an adjunct in headache treatment. With such widespread use, the barbiturates continue to have overdose potential.

HISTORY In 1864, research assistant Adolph von Baeyer in Ghent, Belgium, produced barbituric acid, a cyclic diureide, from the condensation of malonic acid and urea.1 Barbituric acid itself does not possess any central nervous system (CNS) properties. The hypnotic and CNS-depressant effects of its congeners were discovered after various substitutions were made to it.

PHARMACOLOGY AND PHARMACOKINETICS Table 36-1 shows the general formula of barbituric acid and where the substitutions occur that give each chemical its characteristics. Most barbiturates carry oxygen at carbon position 2 on the ring and hence are called oxybarbiturates. Barbiturates where sulfur replaces oxygen are called thiobarbiturates; of these, only thiopental is currently in use in the United States.

TESS data 250

60,000

50,000

Benzodiazepine death Barbiturate death Benzodiazepine Barbiturates

200

40,000 150 30,000

Deaths

■

In 1903, Fisher and von Mehring introduced diethylbarbituric acid or barbital as the first barbiturate to enter medicine, under the trade name Veronal. In 1912, phenobarbital, under the trade name Luminal, was independently and simultaneously brought to medicine by Loewe, Juliusburger, and Impens.1-3 In the mid-20th century, barbiturates became the most popular class of sedative-hypnotics. During this time they also became popular substances of abuse, along with other sedative-hypnotics of that era; collectively these agents were known as “downers.” Sold on the street with such names as “red devils,” barbiturates were taken either alone or with ethanol to produce a pleasurable feeling of intoxication. The death of actress Marilyn Monroe was attributed to barbiturates; an empty bottle of Nembutal was found at her side. As safer sedative-hypnotics for those with insomnia or other sleep disturbances were created, use of barbiturates declined quickly; they are rarely used for these purposes any longer. Finally, among advocates of euthanasia and suicide, barbiturates remain one of the most commonly recommended drugs.

Exposures

At a Glance…

100 20,000 50 10,000

0

0

1998

1999

2000

2001

2002

Year FIGURE 36-1 Toxic Exposure Surveillance System (TESS) Data. (Data from references 65 through 69.)

687

688


TABLE 36-1 Barbiturate Classification GENERAL FORMULA AND SUBSTITUTED DERIVATIVES

O

N

K

R3 C

R5a OK C

★

C R5b N

CK O

H

BARBITURATE

DURATION OF ACTION (hr)

PLASMA HALF-LIFE (hr)

TRADE NAME

pKa

R5a

R5b

R3

Pentothal Brevital

7.6 7.9

0.3 0.3

6–46

Ethyl Allyl

1-Methylbutyl 1-Methyl-2-pentynyl

H CH3

Nembutal Seconal

7.96 7.90

3.0 3.0

21–42 20–28

Ethyl Allyl

1-Methylbutyl 1-Methylbutyl

H H

Amobarbital Butabarbital

Amytal Butisol

7.75 7.74

3–6 3–6

15–40 34–42

Ethyl Ethyl

Isopentyl sec-Butyl

H H

Long-Acting Barbiturates Barbital Mephobarbital Phenobarbital Primidone

Veronal Mebaral Luminal Mysoline

7.74 8.5 7.24 —

6–12 6–12 6–12 6–12

48 48–52 48–144 6–22

Ethyl Ethyl Ethyl Ethyl

Ethyl Phenyl Phenyl Phenyl

H CH3 H H

Short-Acting Barbiturates ULTRASHORT

Thiopental Methohexital SHORT

Pentobarbital Secobarbital INTERMEDIATE

*S苷 Substitution for O苷 in thiopental, H2 substitution for O苷 in primidone.

Lipid solubility is important in barbiturate pharmacokinetics. In general, increased lipid solubility decreases drug latency of onset and duration of action, and increases metabolic degradation rate and hypnotic potency. Methylation of one or both of the nitrogens increases drug affinity for lipids and hence decreases duration of action; methohexital is an example of such a drug. Other methylated barbiturates are demethylated in the body, producing long-acting compounds; mephobarbital conversion to phenobarbital is such an example. Sulfur in general makes thiobarbiturates more lipid soluble than oxybarbiturates; this explains thiopental’s rapid onset and short duration. The anticonvulsant activity of barbiturates is produced by discrete moieties such as a phenyl group at carbon 5 or alkyl groups on both nitrogen atoms.1,4 Barbiturates are well absorbed orally as sodium salts. Other routes of administration include rectal (particularly in children) and intravenous. Barbiturates distribute throughout all body compartments, including the blood-brain barrier, and can cross the placenta, depending on their lipid solubility, protein binding, and extent of ionization. Barbiturates are metabolized by either oxidation at carbon 5, n-dealkylation, cleavage of the barbituric acid

ring, or desulfuration as in the case of thiobarbiturates. Of these, oxidation is the most important, yielding polar compounds that appear in urine as free compounds or glucoronide conjugates. Barbital, because of its low lipid solubility, is one of the few barbiturates that rely almost exclusively on renal elimination for removal of drug from the body.1 Primidone is unique in that it is oxidized to phenobarbital and phenylethylmalonamide, the latter having no anticonvulsant activity.5 In neonates the half-life of phenobarbital is very long (45 to 409 hours) but decreases with age. Primidone conversion to its active metabolites generally does not occurs with neonates.6

THERAPEUTIC USES OF BARBITURATES Table 36-2 displays some of the currently used barbiturates and their indications. Barbiturates continue to play an important role in seizure treatment. Phenobarbital is used as maintenance therapy for patients with seizure disorders. It is useful for both generalized tonicclonic seizures and simple partial seizures. Several, including phenobarbital and pentobarbital, are useful for treating status epilepticus in the intensive care unit

CHAPTER 36

Barbiturates

689

TABLE 36-2 Common Barbiturates and Their Uses BARBITURATE

SCHEDULE

INDICATION

PREPARATIONS

Thiopental

III

250, 400, and 500 mg intectable 1, 2.5, 5 g injectable

Methohexital Secobarbital

IV II

Amobarbital

II

Butabarbital

II (secobarbital/phenobarbital combination) III IV

Anesthetic Pediatric sedation ICP management Status epilepticus Anesthetic Insomnia Status epilepticus Insomnia Narcoanalysis Schizophrenia aid Sedation, anxiety Sedation Seizure prophylaxis Insomnia Status epilepticus Barbiturate withdrawal Coma induction Seizure prophylaxis Barbiturate withdrawal Sedation, anxiety Psychomotor seizure prophylaxis Refractory tonic-clonic seizures

32, 50 and 100 mg tablets

Mephobarbital Pentobarbital

II III (suppositories)

Phenobarbital

IV

Primidone

500 mg, 2.5 g, 5 g injectable 100 mg capsule 500 mg injectable 50 mg capsules 30 mg/5 mL elixir 30 and 50 mg tablets

18.2 mg/5 mL elixir 50, 100 mg capsules 50 mg/mL injectable 30, 60, 120, 200 mg suppositories 20 mg/5 mL elixir 15, 16, 30, 32, 60 65, and 100 mg tablets 30, 60, 65, and 130 mg/mL

ICP, intracranial pressure. Adapted from McEvoy G (ed): AHFS Drug Information 2004. Bethesda, MD, American Society of Health-System Pharmacists, 2004.

where a “barbiturate coma” can be employed in attempts to treat refractory seizures. Pentobarbital as a second-tier agent for the treatment of refractory intracranial hypertension is also commonly used.7,8 However, a recent Cochrane review found no evidence of improved outcome when barbiturates were used to treat increased intracranial pressure in severely head-injured patients.9 Several over-the-counter (OTC) and prescription medications contain barbiturates (e.g., butalbital in combination with acetaminophen, codeine, aspirin, or caffeine) that are used to treat migraine headaches. Barbiturates are also used to treat insomnia and anxiety states; as hypnotics, they are also used to provide general anesthesia as in the case of thiopental and methohexital. Less well known uses for barbiturates include primidone for the treatment of essential hand tremor10 and phenobarbital for cyclic vomiting,11 to prevent and treat hyperbilirubinemia in neonates,12 or as an intervention for chronic anovulation.13 There is anecdotal evidence that pentobarbital may be useful for treating γ-hydroxybutyrate (GHB) and γ-butyrolactone withdrawal.14,15 Phenobarbital, thiopental, and methohexital have all been useful for sedation and immobilization in young children and can be given by different routes. Barbiturate use is contraindicated in patients with porphyrias.16

TOLERANCE, ABUSE, AND DEPENDENCE The abuse potential of barbiturates results from pharmacologic characteristics such as rapid onset and lipid solubility that facilitates entry across the blood-brain

barrier. Barbiturates bind to γ-aminobutyric acid A [GABAA] through an ionotropic or ligand gated mechanism that mediates fast synaptic transmission, causing a conformational change in the GABAA channel and an influx of chloride that goes on to activate proteins essential in producing CNS-depressant effects.17 In the presence of a depressant such as a barbiturate, stimulatory effects will increase neurologically to keep the body in homeostasis. Over time, if that drug becomes unavailable due to abrupt cessation in use, unfavorable neuroexcitation symptoms predominate, such as tremors, anxiety, insomnia, tachycardia, hypertension, and even seizures. These symptoms usually resolve once the drug is reintroduced, creating an environment for dependence potential. Tolerance also manifests because of pharmacokinetic and pharmocodynamic properties of barbiturates. Because they are microsomal inducers, enhanced metabolism and resulting decreased drug at the site of action can produce tolerance within days. A reduced response in the face of unchanged or higher drug concentration through cellular adaptive changes can develop over weeks to months.18 Patients who use medications with butalbital for treatment of migraines are particularly at risk for abuse. Care should be taken when treating these patients and in consideration of withdrawal from the medication. There is anecdotal evidence that withdrawal seizures, personality changes, and psychotic behavior can occur.19 A syndrome of a rebound headache commonly occurs in these patients, which worsens as the dose of butalbital is increased to prevent headache induction. This syndrome has been treated with a long-acting barbiturate such

690


as phenobarbital. Patients generally require inpatient monitoring until they are symptom free.20,21 There is an ongoing debate whether butalbital should be removed from the U.S. formulary, given its relative lack of therapeutic value.22,23

DRUG INTERACTIONS AND ADVERSE DRUG REACTIONS One of the potential common drug interactions with barbiturates occurs when they are given in conjunction with other sedative-hypnotics. Benzodiazepines, alcohol, anesthetics such as propofol and etomidate, glutethimide, and zolpidem, to name a few, all can have a synergistic effect with serious consequences if dosage adjustments are not made. Certain herbs used in conjunction with phenobarbital appear to lower seizure threshold. These include thujonecontaining herbs such as wormwood and sage, and gamolenic acid–containing herbs such as evening primrose oil and borage.24 Table 36-3 lists some important drug-herb interactions. Anticonvulsant hypersensitivity syndrome (AHS) is a rare life-threatening adverse drug reaction seen with phenobarbital and primidone use. The syndrome usually occurs 1 to 8 weeks after initiation of the drug and may present with fever, cervical adenopathy, pharyngitis, skin findings ranging from skin eruption to Stevens-Johnson syndrome, and systemic injury. There is anecdotal evidence suggesting that severe cases of AHS may respond to steroids and immunoglobulin therapy.25,26 Other findings seen with barbiturate hypersensitivity include urticaria, erythema multiforme, leukocytoclastic vasculitis, bullous eruption, and fixed drug eruptions.27 At therapeutic doses, barbiturates have also been implicated in toxic epidermal necrolysis, and when abused by injection through skin-popping, tender erythematous plaques can lead to deep ulcers caused by the alkalinity of barbiturates.28 Tubular interstitial nephritis has been seen with phenobarbital therapy.29 Barbiturates are known to cause

the syndrome of inappropriate antidiuretic hormone as well.30 Barbiturates have been implicated in cytochrome P-450 interactions. Phenobarbital is known to be a potent inducer of CYP1A2, 2A6, 2C8, 2C9, 2C19, and 3A4. Phenobarbital is also a known substrate for CYP2E1; it may be a substrate for CYP2C9 and 2C19 as well. Vulnerable populations such as children, pregnant women, the elderly, and patients with genetic polymorphisms can be adversely affected. Care must also be taken when using phenobarbital as an anticonvulsant in combination with other anticonvulsants.31 Phenobarbital increases oral contraceptive, warfarin, theophylline, and corticosteroid metabolism. Valproate is known to increase serum phenobarbital concentrations by inhibiting p-hydroxylation and n-glucosidation, significantly reducing its clearance.32 Primidone and phenobarbital are known to cause hypocalcemia; however, primidone has been shown to shorten the QT interval.33 Thiopental has been implicated in treatment-resistant hypokalemia, with severe rebound hyperkalemia occurring in patients treated with barbiturate coma for traumatic brain injury and subarachnoid hemorrhage.34 There are also data implicating them in gingival hyperplasia35 and various embryonic malformations in mothers receiving long-standing therapy for epilepsy36; this may result from folate antagonism.37 Adverse drug reactions can occur in infants whose mothers are breastfeeding while taking phenobarbital or primidone. Although no clear consensus exists for recommendations to this specific subpopulation of anticonvulsant users, lactation should be regarded as potentially unsafe, and such mothers should observe infants for sedation or poor suckling.38 To those who must be maintained on antiseizure medication such as phenobarbital, monthly levels are recommended.39 Primidone has been implicated in the development of rare cases of hyperammonemia.40 Another rare reported effect includes shoulder-hand syndrome.41,42 Phenobarbital and primidone have also been implicated in the development of bone disorders. Patients

TABLE 36-3 Common Herbs and Their Potential Barbiturate Interactions HERB

USE

EFFECT ON BARBITURATE

Kava

Relaxation beverage Uterine relaxation Anxiety, insomnia Depression Food additive Local irritant (mace) Nervous restlessness, insomnia Treat asthma Rubefacient URI treatment Treat muscle spasms, asthma, newborn colic, sedative Sedative, pain relief, vasodilator

Synergistic CNS depression in animal studies

Valerian St. John’s Wort Cayenne Passion flower Tylophora indica Eucalyptus Catnip Calamus

Increased CNS depression Decreased efficacy of barbiturates Increased or decreased effect of barbiturates Increased CNS depression Increased sedation Decreased sedative and depressant effects Increased CNS depression and psychomotor retardation Increased sedation, potentiates the hypnotic effect of barbiturates

CNS, central nervous system; URI, upper respiratory infection. Adapted from Thomson MICROMEDEX: MICROMEDEX Healthcare Series, I. Greenwood Village, CO, Thomson MICROMEDEX, 2007.

CHAPTER 36

taking these medications chronically demonstrate a drop in bone mineral density. Although low 25-hydroxyvitamin levels have been noted, the exact etiology of osteopenia is unclear. At-risk patients include postmenopausal women, older men, children, and institutionalized patients.43,44

Barbiturates are sedatives and as such their physiologic effects are depressive. The differential diagnosis of barbiturate overdose includes other drugs and toxins that produce CNS and cardiovascular depression, such as other sedative-hypnotics, toxic alcohols, cellular asphyxiants, and other psychotropic agents. Medical conditions such as hypoglycemia must always be ruled out in any patient presenting with an altered level of consciousness. Manifestations of acute barbiturate toxicity can be divided into (1) mild intoxication (victims are somnolent but arousable with slurred speech, unsteady gait, and nystagmus); (2) moderate intoxication (victims have depressed level of consciousness, decreased deep tendon reflexes, and slowed respirations), and (3) severe intoxication (victims are unresponsive to painful stimuli; respiratory, cardiovascular, and neurologic collapse occur).45 Four grades of coma from barbiturate overdose are shown in Table 36-4.46 Cardiovascular effects most commonly include hypotension, but cardiovascular collapse and cardiac arrest are also possible. In severe overdoses, respiratory depression and apnea may occur. Hypothermia is commonly seen after barbiturate overdose.47-49 Along with clonidine, guanfacine, GHB and its congenors, and narcotics, barbiturates are among the few drugs associated with significant hypothermia. Barbiturate overdose victims can also present with renal failure due to acute tubular necrosis. Several case reports describe massive crystalluria from primidone overdose50,51; however, this has also been seen during maintenance therapy.52

691

TABLE 36-4 Stages of Coma in Barbiturate Overdose GRADE

FEATURES

I

Patient is comatose, the patient withdraws from painful stimuli, and the reflexes are intact. Patient is comatose and fails to respond to painful stimuli, but the reflexes are intact and the vital signs are stable. Patient is comatose and fails to respond to painful stimuli, deep tendon reflexes are absent, but vital signs are stable. Patient is comatose and fails to respond to painful stimuli, deep tendon reflexes are absent, and vital signs are unstable, with respiratory and cardiovascular depression.

II

CLINICAL PRESENTATION OF BARBITURATE OVERDOSE

Barbiturates

III IV

Muscle necrosis and calcification associated with acute renal failure have also been described.53 Barbiturate blisters, also known as coma blisters, although not specific for barbiturate overdose, have been seen. They are noted in patients profoundly poisoned with associated neurologic sequale such as loss of consciousness, hence the latter name. They typically appear as blanchable erythematous patches at pressure points of normal skin within 24 hours of coma. A biopsy of the lesion shows intraepidermal or subepidermal blisters with characteristic necrosis of sweat glands. Over the next 2 to 3 days these patches become blisters or erosions, but they usually heal spontaneously over 1 to 2 weeks28 (Fig. 36-2).

EVALUATION AND MANAGEMENT As with most drug overdoses, the mainstay of treatment and good outcome is attention to supportive care principles. Since respiratory and CNS depression are the most common findings, attention to the airway and prevention of hypoxia are of the utmost importance.

FIGURE 36-2 Coma blisters. (From Bolognia J, Jorizzo JL, Rapini RP [eds]: Dermatology, Vol 1. St. Louis, Mosby, 2003.)

692


Given the risk for cardiovascular compromise and hypothermia, attention should be directed to vital signs as soon as possible. Also, ruling out hypoglycemia is essential; missing this diagnosis can have grave consequences. Activated charcoal should be given in a dose of 50 to 60 g (1 g/kg in children). For patients who have a compromised airway, endotracheal intubation is advised prior to giving charcoal. With very large overdoses, antecedent gastric lavage may be considered; however, it should be performed cautiously, given the morbidity associated with this procedure. Laboratory evaluation should include basic electrolytes and glucose. Screening assays employing semiquantitative immunoassays of serum and urine are readily available. Serum barbiturate levels can be useful in gauging the clinical course or therapy. In patients who have taken primidone, it is important to measure serum concentrations of phenobarbital, its active metabolite. The therapeutic range for phenobarbital is generally considered 15 to 40 μg/mL. Toxic effects from phenobarbital can be seen at 50 μg/mL.54 Parenthetically, cross-reaction among various barbiturates and nonbarbiturates have been reported, requiring special consideration of a false-positive result.55,56 Urine alkalinization is of theoretical value in the treatment of phenobarbital overdose but not overdose of other barbiturates. According to the theory of ion trapping, phenobarbital, as a weak acid, will be poorly reabsorbed by the renal tubules if it can be ionized in the milieu of an alkaline urine. The administration of sodium bicarbonate is therefore typically recommended to produce such an alkaline environment. However, having a pKa of 7.4, phenobarbital is difficult to ionize without producing profound changes in urine pH; such alkalinization is rarely achieved in clinical practice without the unwanted effects of metabolic alkalosis or hypernatremia. Given the risks versus benefits, routine urinary alkalinization in barbiturate overdose is no longer recommended.57 Multiple-dose activated charcoal (MDAC) has been shown to be more effective in decreasing phenobarbital half-life, increasing its total body clearance in adults and neonates.57-60 Working by the principle of “gastrointestinal dialysis,” MDAC reduces the elimination halflife of phenobarbital by more than 50%; this effect occurs even when the drug has been administered intravenously. However, while MDAC greatly accelerates phenobarbital elimination, its clinical value in the treatment of phenobarbital overdose has been questioned. In a seminal study by Pond and colleagues, MDAC, while greatly reducing the elimination half-life of phenobarbital in a cohort of severely poisoned patients, was ineffective in reducing length of intensive care unit stay and other measures of therapeutic benefit.61 In a more recent study of 30 patients equally divided into three groups who received MDAC only, urine alkalinization alone, or both, clinical parameters, including the duration of assisted ventilation, intubation, and coma, were all appreciably reduced the greatest in the group that only received MDAC.62

Extracorporeal removal by hemodialysis or hemoperfusion is also effective in removing the barbiturates, although they are reserved for the most severe cases. Hemoperfusion is thought to be more effective in barbiturate clearance; however, it has a high rate of adverse effects, is less available than hemodialysis, and, in the era of the high-flux hemodialysis apparatus, does not produce substantially greater clearance rates.63 As a result, hemodialysis has become the extracorporeal treatment of choice for severe phenobarbital overdose. It is important to note that while phenobarbital is readily removed by hemodialysis, other barbiturates are not. Exchange transfusion has been reported to be useful in an underweight newborn with phenobarbital intoxication.64 Indications for hemodialysis after phenobarbital have not been clearly established. Prevailing recommendations call for the procedure in all patients with serum phenobarbital concentrations of 100 μg/mL or greater. This recommendation is based on the clinical observation that as serum phenobarbital concentrations reach and exceed this range, victims are more likely to develop signs of life-threatening intoxication, including severe hypotension and, in the face of fluid support, pulmonary edema. Unfortunately, victims with serum phenobarbital concentrations in this range are often too hypotensive to become ideal hemodialysis candidates. Given the ease and efficacy of hemodialysis in patients with severe barbiturate overdose, its early use should always be considered. All patients with a barbiturate overdose will need to be admitted. Disposition will depend on clinical affects. Patients with severe mental status depression will need intensive care unit admission, possible intubation with mechanical ventilation, and close monitoring. Less poisoned patients must also be watched closely, in an inpatient setting. In all intentional overdose patients, disposition should include a psychiatric evaluation. REFERENCES 1. Goodman L, Gilman AG (eds): The Pharmacological Basis of Therapeutics, 5th ed. New York, Macmillan, 1975. 2. Ball C, Westhorpe R: The history of intravenous anaesthesia: the barbiturates. Part 1. Anaesth Intensive Care 2001;29(2):97. 3. Ball C, Westhorpe R: The history of intravenous anaesthesia: the barbiturates. Part 2. Anaesth Intensive Care 2001;29(3):219. 4. Hardman J, Limbird LE (eds): Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001. 5. Baselt R: Disposition of Toxic Drugs and Chemicals in Man, 6th ed. Foster City, CA, Biomedical Publications, 2002. 6. Battino D, Estienne M, Avanzini G: Clinical pharmacokinetics of antiepileptic drugs in paediatric patients. Part I: Phenobarbital, primidone, valproic acid, ethosuximide and mesuximide. Clin Pharmacokinet 1995;29(4):257–286. 7. Censullo JL, Sebastian S: Pentobarbital sodium coma for refractory intracranial hypertension. J Neurosci Nurs 2003;35(5): 252–262. 8. Claassen J: Treatment of refractory status epilepticus with pentobarbital, propofol or midazolam: a systematic review. Epilepsia 2002;43(2):146–153. 9. Roberts I: Barbiturates for acute traumatic brain injury. Cochrane Database Syst Rev 2000(2):CD000033. 10. Chen JJ, Swope DM: Essential tremor: diagnosis and treatment. Pharmacotherapy 2003;23(9):1105–1122.

CHAPTER 36

11. Gokhale R, Huttenlocher PR, Brady L, Kirschner BS: Use of barbiturates in the treatment of cyclic vomiting during childhood. J Pediatr Gastroenterol Nutr 1997;25(1):64–67. 12. Dennery PA: Pharmacological interventions for the treatment of neonatal jaundice. Semin Neonatol 2002;7(2):111–119. 13. Gocze PM, Szabo I, Porpaczy Z, Freeman DA: Barbiturates inhibit progesterone synthesis in cultured Leydig tumor cells and human granulosa cells. Gynecol Endocrinol 1999;13(5):305–310. 14. Sivilotti ML, Burns MJ, Aaron CK, Greenberg MJ: Pentobarbital for severe gamma-butyrolactone withdrawal. Ann Emerg Med 2001;38(6):660–665. 15. Rosenberg MH, Deerfield LJ, Baruch EM: Two cases of severe gamma-hydroxybutyrate withdrawal delirium on a psychiatric unit: recommendations for management. Am J Drug Alcohol Abuse 2003;29(2):487–496. 16. Krauss B, Green SM: Sedation and analgesia for procedures in children. N Engl J Med 2000;342(13):938–945. 17. Cami J, Farre M: Drug addiction. N Engl J Med 2003;349(10): 975–986. 18. Silberstein SD, McCrory DC: Butalbital in the treatment of headache: history, pharmacology, and efficacy. Headache 2001;41(10):953–967. 19. Raja M, Altavista MC, Azzoni A, Albanese A: Severe barbiturate withdrawal syndrome in migrainous patients. Headache 1996; 36(2):119–121. 20. Loder E, Biondi D: Oral phenobarbital loading: a safe and effective method of withdrawing patients with headache from butalbital compounds. Headache 2003;43(8):904–909. 21. Sands GH: A protocol for butalbital, aspirin and caffeine (BAC) detoxification in headache patients. Headache 1990;30(8): 491–496. 22. Young WB, Siow HC: Should butalbital-containing analgesics be banned? Yes. Curr Pain Headache Rep 2002;6(2):151–155. 23. Solomon S: Butalbital-containing agents: should they be banned? No. Curr Pain Headache Rep 2002;6(2):147–150. 24. Miller LG: Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med 1998;158(20):2200–2211. 25. Mostella J, Pieroni R, Jones R, Finch CK: Anticonvulsant hypersensitivity syndrome: treatment with corticosteroids and intravenous immunoglobulin. South Med J 2004;97(3):319–321. 26. Bessmertny O, Pham T: Antiepileptic hypersensitivity syndrome: clinicians beware and be aware. Curr Allergy Asthma Rep 2002;2(1):34–39. 27. McKenna JK, Leiferman KM: Dermatologic drug reactions. Immunol Allergy Clin North Am 2004;24:399–423. 28. Bolognia J, Jorizzo JL, Rapini RP (eds): Dermatology, 1st ed, Vol 1. St. Louis, CV Mosby, 2003. 29. Sawaishi Y, Komatsu K, Takeda O, et al: A case of tubulo-interstitial nephritis with exfoliative dermatitis and hepatitis due to phenobarbital hypersensitivity. Eur J Pediatr 1992;151(1):69–72. 30. Asconape JJ: Some common issues in the use of antiepileptic drugs. Semin Neurol 2002;22(1):27–39. 31. Patsalos PN, Froscher W, Pisani F, van Rijn CM : The importance of drug interactions in epilepsy therapy. Epilepsia 2002;43(4): 365–385. 32. Yukawa E: Investigation of phenobarbital-carbamazepine-valproic acid interactions using population pharmacokinetic analysis for optimisation of antiepileptic drug therapy: an overview. Drug Metab Drug Interact 2000;16(2):86–98. 33. Loukeris K, Mauri D, Pazarlis P: QT length and heart function in primidone hypocalcaemia. Acta Cardiol 2002;57(5):367–369. 34. Cairns CJ, Thomas B, Fletcher S, et al: Life-threatening hyperkalaemia following therapeutic barbiturate coma. Intensive Care Med 2002;28(9):1357–1360. 35. Sinha S, Kamath V, Arunodaya GR, Taly AB: Phenobarbitone induced gingival hyperplasia. J Neurol Neurosurg Psychiatry 2002;73(5):601. 36. Holmes LB, Harvey EA, Coull BA, et al: The teratogenicity of anticonvulsant drugs. N Engl J Med 2001;344(15):1132–1138. 37. Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA: Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med 2000;343(22):1608–1614.

Barbiturates

693

38. Hagg S, Spigset O: Anticonvulsant use during lactation. Drug Saf 2000;22(6):425–440. 39. Pennell PB: Antiepileptic drug pharmacokinetics during pregnancy and lactation. Neurology 2003;61(6 Suppl 2):35–42. 40. Katano H, Fukushima T, Karasawa K, et al: Primidone-induced hyperammonemic encephalopathy in a patient with cerebral astrocytoma. J Clin Neurosci 2002;9(1):79–81. 41. Rovetta G, Baratto L, Farinelli G, Monteforte P: Three-month follow-up of shoulder-hand syndrome induced by phenobarbital and treated with gabapentin. Int J Tissue React 2001;23(1):39–43. 42. De Santis A, Ceccarelli G, Cesana BM, et al: Shoulder-hand syndrome in neurosurgical patients treated with barbiturates: a long term evaluation. J Neurosurg Sci 2000;44(2):69–76. 43. Pack AM, Morrell MJ: Adverse effects of antiepileptic drugs on bone structure: epidemiology, mechanisms and therapeutic implications. CNS Drugs 2001;15(8):633–642. 44. Farhat G, Yamout B, Mikati MA, et al: Effect of antiepileptic drugs on bone density in ambulatory patients. Neurology 2002;58(9): 1348–1353. 45. Lindberg MC, Cunningham A, Lindberg NH: Acute phenobarbital intoxication. South Med J 1992;85(8):803–807. 46. Arieff AI, Friedman EA: Coma following nonnarcotic drug overdosage: management of 208 adult patients. Am J Med Sci 1973; 266(6):405–426. 47. Fell RH, Gunning AJ, Bardhan KD, Triger DR: Severe hypothermia as a result of barbiturate overdose complicated by cardiac arrest. Lancet 1968;1(7539):392–394. 48. Rosenberg J, Benowitz NL, Pond S: Pharmacokinetics of drug overdose. Clin Pharmacokinet 1981;6(3):161–192. 49. Hernandez E, Praga M, Alcazar JM, et al: Hemodialysis for treatment of accidental hypothermia. Nephron 1993;63(2):214–216. 50. van Heijst AN, de Jong W, Seldenrijk R, van Dijk A: Coma and crystalluria: a massive primidone intoxication treated with haemoperfusion. J Toxicol Clin Toxicol 1983;20(4):307–318. 51. Lehmann DF: Primidone crystalluria following overdose: a report of a case and an analysis of the literature. Med Toxicol Adverse Drug Exp 1987;2(5):383–387. 52. Sigg T, Leikin JB: Massive crystalluria in a patient taking primidone. Ann Emerg Med 1999;33(6):726–727. 53. Clark JG, Sumerling MD: Muscle necrosis and calcification in acute renal failure due to barbiturate intoxication. BMJ 1966;5507:214–215. 54. Warner A, Privitera M, Bates D: Standards of laboratory practice: antiepileptic drug monitoring. National Academy of Clinical Biochemistry. Clin Chem 1998;44(5):1085–1095. 55. Drost RH, Plomp TA, Maes RA: EMIT-st drug detection system for screening of barbiturates and benzodiazepines in serum. J Toxicol Clin Toxicol 1982;19(3):303–312. 56. Nordt SP: Butalbital cross-reactivity to an Emit assay for phenobarbital. Ann Pharmacother 1997;31(2):254–255. 57. Proudfoot AT, Krenzelok EP, Vale JA: Position paper on urine alkalinization. J Toxicol Clin Toxicol 2004;42(1):1–26. 58. Frenia ML, Schauben JL, Wears RL, et al: Multiple-dose activated charcoal compared to urinary alkalinization for the enhancement of phenobarbital elimination. J Toxicol Clin Toxicol 1996;34(2): 169–175. 59. Veerman M, Espejo MG, Christopher MA, Knight M: Use of activated charcoal to reduce elevated serum phenobarbital concentration in a neonate. J Toxicol Clin Toxicol 1991;29(1):53–58. 60. Bradberry SM, Vale JA: Multiple-dose activated charcoal: a review of relevant clinical studies. J Toxicol Clin Toxicol 1995;33(5):407–416. 61. Pond SM, Olson KR, Osterloh JD, Tong TG: Randomized study of the treatment of phenobarbital overdose with repeated doses of activated charcoal. JAMA 1984;251(23):3104–3108. 62. Mohammed Ebid AH, Abdel-Rahman HM: Pharmacokinetics of phenobarbital during certain enhanced elimination modalities to evaluate their clinical efficacy in management of drug overdose. Ther Drug Monit 2001;23(3):209–216. 63. Palmer BF: Effectiveness of hemodialysis in the extracorporeal therapy of phenobarbital overdose. Am J Kidney Dis 2000;36(3): 640–643. 64. Sancak R, Kucukoduk S, Tasdemir HA, Belet N: Exchange transfusion treatment in a newborn with phenobarbital intoxication. Pediatr Emerg Care 1999;15(4):268–270.

694


65. Watson WA, Litovitz TL, Rodgers GC Jr, et al: 2002 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2003;21(5): 353–421. 66. Litovitz TL, Klein-Schwartz W, Rodgers GC Jr, et al: 2001 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2002;20(5): 391–452. 67. Litovitz TL, Klein-Schwartz W, White S, et al: 2000 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2001;19(5): 337–395.

68. Litovitz TL, Klein-Schwartz W, White S, et al: 1999 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2000;18(5): 517–574. 69. Litovitz TL, Klein-Schwartz W, Caravati EM, et al: 1998 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 1999;17(5): 435–487.

37

Muscle Relaxants MATTHEW D. SZTAJNKRYCER, MD, PHD

At a Glance… ■

■ ■ ■

The skeletal muscle relaxants comprise a structurally and pharmacologically heterogeneous group of compounds, all of which are purported to decrease skeletal muscle tone. Central nervous system depression is the predominant finding in acute toxicity. Cardiac conduction abnormalities and dysrhythmias are rare, with the exception of orphenadrine. Management is primarily supportive, focusing on central nervous system and cardiopulmonary support.

Muscle tone reflects a complex interplay among the central nervous system, spinal cord, and musculoskeletal system. Skeletal muscle relaxants comprise a structurally and pharmacologically heterogeneous group of compounds, all of which are purported to decrease skeletal muscle tone. Mechanistically, this may occur at the level of the central nervous system, spinal cord, or musculoskeletal system. These agents are prescribed for acute post-traumatic muscle spasm (e.g., acute lumbar strain) or the management of spasticity associated with chronic neuropathologic processes (e.g., multiple sclerosis, cerebral palsy, spinal cord injury). Dantrolene is also used in the treatment of severe muscle hypertonia due to malignant hyperthermia, neuroleptic malignant syndrome (NMS), and tetanus. Significant abuse potential exists for several of these agents.1,2 Carisoprodol has additionally been used to modify the effects of other abused drugs, including benzodiazepines, alcohol, and cocaine.3 In addition to the benzodiazepines (see Chapter 35), 10 skeletal muscle relaxants have clinical and toxicologic significance (Table 37-1). An 11th agent, chlormezanone, was voluntarily recalled from worldwide markets in 1996 due to severe hypersensitivity reactions. According to the American Association of Poison Control Centers, 21,793 exposures were reported in 2003. Of these, 4084 resulted in moderate toxicity, 1024 resulted in major toxicity, and 59 resulted in death. A total of 2490 exposures occurred in children 5 years old or younger, and 14,019 occurred in patients over the age of 19.

STRUCTURE Baclofen (Lioresal, para-chlorophenyl-γ-aminobutyric acid; Novartis, East Hanover, NJ) differs from GABA (γ-aminobutyric acid) solely due to the presence of an additional phenylchloride group. Carisoprodol (Rela

[Schering-Plough, Kenilworth, NJ], Soma [Wallace, Somerset, NJ], n-isopropyl-meprobamate) is structurally similar to the sedative-hypnotic agent meprobamate (see Chapter 34). Cyclobenzaprine (Flexeril, McNeil, Chattanooga, TN) is a tricyclic amine, structurally related to amitriptyline (see Chapter 27), while orphenadrine (Norflex, 3M Pharmaceuticals, St. Paul, MN) is structurally related to diphenhydramine (see Chapter 39). Dantrolene (Dantrium, Procter & Gamble, Cincinnati, OH) and metaxalone (Skelaxin, Mallinckrodt, Hazelwood, MO) are structurally related to phenytoin (see Chapter 40), while tizanidine (Zanaflex, Acorda Therapeutics, Hawthorn, NY) is an imidazoline derivative similar to clonidine (see Chapter 62). Chlorzoxazone (Parafon Forte, Ortho-McNeil Pharmaceutical, Raritan, NJ), methocarbamol (Robaxin, Wyeth-Ayerst, Collegeville, PA), and the chemically related chlorphenesin (Maolate, Upjohn, Pfizer, Inc., New York, NY) are unrelated to other agents.

PHARMACOLOGY With the exception of dantrolene, the skeletal muscle relaxants act centrally, in part through central nervous system (CNS) modulation of interneurons, modifying pain perception without affecting pain threshold.4 Baclofen, a GABAB agonist, acts predominantly at presynaptic sites, as well as by decreasing spinal γ motor neuron activity.5 Carisoprodol acts pharmacologically through its primary metabolite meprobamate, increasing chloride ion flux through the GABAA receptor complex. At high concentrations, meprobamate is capable of blocking N-methyl-D-aspartate (NMDA)–receptor mediated calcium currents.6 Cyclobenzaprine possesses antimuscarinic, antihistaminic, and sedative properties with (in contrast to the tricyclic antidepressants) only weak inhibition of presynaptic norepinephrine and serotonin reuptake. Skeletal muscle activity is attributed to brainstem-mediated inhibition of α and γ motor neurons.7 Although orphenadrine demonstrates peripheral antimuscarinic properties, NMDA receptor blockade, and sodium channel blockade, its skeletal muscle relaxant properties appear to be centrally mediated.8 Orphenadrine-mediated dopamine release may be partly responsible for its abuse potential.9 Tizanidine, a centrally acting α2 agonist, is believed to reduce spasticity by increasing presynaptic inhibition of motor neurons.10 Dantrolene is unique among the muscle relaxants, acting directly on skeletal muscle. It functions by inhibiting calcium release from the sarcoplasmic reticulum, decreasing the force of skeletal muscle contraction without affecting cardiac or smooth muscle.11 695

0.54 (pediatric)

Dantrolene

Vd, volume of distribution.

2.4

6

Cyclobenzaprine

Tizanidine

Small

Chlorzoxazone

Large

1.27

Chlorphenesin

Orphenadrine

1

Carisoprodol

1–2

1.3

Baclofen

Metaxalone Methocarbamol

Vd (L/kg)

AGENT

1.5

2–4

3.3–4.3 1

4–8

4–6

3–4

1.9

1–4

2

TIME TO PEAK LEVEL (hr)

2.1–4.1

14

2.4–9.2 1.2–2.2

8–10

24–72

1.1

3–4

1.5–6

2–6

ELIMINATION

TABLE 37-1 Selected Pharmacologic Properties of Muscle Relaxants

3-(2-hydroxyphenoxy)-1, 2-propanediol-1-carbamate 3-(4-hydroxy-2 methoxyphenoxy)1,2 propanediol-1-carbamate N-monodemethyl orphenadrine Orphenadrine-N-oxide O-methylbenzhydrol conjugate O-methylbenzhydroxyacetic acid conjugate Metabolite 3 (DS-200-717) Metabolite 4 (DS-201-341)

Glucuronide conjugate Cyclobenzaprine-N-oxide Norcyclobenzaprine, bis-10, 11-dihydroxy-nortriptyline 3-hydroxy-cyclobenzaprine 5-hydroxy-dantrolene

6-hydroxy-chlorzoxazone

Meprobamate, hydroxycarisoprodol Hydroxymeprobamate

Deaminated metabolites

METABOLITES

Renal insufficiency, hepatic insufficiency

Porphyria

Liver insufficiency Women Age > 35 years Amyotrophic lateral sclerosis

Renal insufficiency, hepatic insufficiency, Asthamtics (secondary to tartrazine) Porphyria

Renal insufficiency, hepatic insufficiency

Renal insufficiency

SPECIAL POPULATIONS

Oral contraceptives, phenytoin

Calcium channel antagonists Vecuronium Theophyllline

Isoniazid Disulfiram Guanethidine Tramadol

NSAIDs Levodopa

DRUG INTERACTIONS

696 CENTRAL NERVOUS SYSTEM

CHAPTER 37

PHARMACOKINETICS The heterogeneous nature of the muscle relaxants results in a wide range of pharmacokinetic properties (see Table 37-1). Baclofen is rapidly and completely absorbed from the gastrointestinal tract with therapeutic dosing. Absorption is both decreased and prolonged as ingested dose increases. Although penetration of the blood-brain barrier is limited at therapeutic doses, baclofen demonstrates central effects at higher doses.12 Carisoprodol is rapidly absorbed after ingestion.13 Cyclobenzaprine is slowly but completely absorbed after ingestion, while 70% of an ingested dantrolene dose is absorbed. Orphenadrine is readily absorbed after ingestion, demonstrating 100% bioavailability. Peak orphenadrine plasma levels may be delayed in overdose.14 Metabolism of the muscle relaxants is primarily hepatic, and elimination is primarily renal. Less than 1% of ingested carisoprodol and chlorzoxazone are eliminated unchanged in the urine, while 85% of baclofen is excreted unchanged. After extensive first pass hepatic metabolism, 50% of an ingested cyclobenzaprine dose is excreted in the urine. Substantial enterohepatic recirculation occurs, with 15% excreted in the bile unchanged.15 Orphenadrine and tizanidine also demonstrate significant enterohepatic recirculation. The elimination half-life of cyclobenzaprine is 1 to 3 days, substantially longer than that of the other muscle relaxants. Approximately 60% of an ingested orphenadrine dose is excreted in the urine, with up to 30% excreted unchanged in the setting of urinary acidification.

Selected At-Risk Patient Populations With the exception of cyclobenzaprine, safety in pregnancy is uncertain (category C). Cyclobenzaprine is presumed safe in pregnancy (category B). Carisoprodol is concentrated in breast milk and is considered unsafe in lactation. Methocarbamol is considered safe in lactation, and the safety of the remaining agents is unknown. Baclofen and tizanidine should be used cautiously in patients with renal insufficiency.16 Tizanidine and dantrolene are contraindicated in the setting of liver disease. Dantrolene should also be used cautiously in women and individuals over the age of 35 due to an increased risk for idiosyncratic hepatotoxicity (see Adverse Effects with Therapeutic Use), and in patients with amyotrophic lateral sclerosis due to potential worsening of neuromuscular weakness.17 Orphenadrine and carisoprodol are associated with acute porphyria and are contraindicated in patients with porphyria.

Adverse Drug Interactions All skeletal muscle relaxants have the potential for adverse drug interactions with other CNS depressants. Concomitant baclofen and levodopa administration has resulted in hallucinations and worsening of parkinsonian symptoms.18 Chlorzoxazone metabolism is decreased with concomitant disulfiram administration

Muscle Relaxants

697

and in slow acetylators on isoniazid.19,20 Due to structural similarities with the tricyclic antidepressants, potential adverse interactions have been suggested for cyclobenzaprine and guanethidine or tramadol. Animal studies have demonstrated potentially lethal interactions between dantrolene and verapamil or theophylline.21,22 In the former, dantrolene administration to verapamilpretreated swine resulted in profound myocardial depression, hyperkalemia (8.0 ± 0.7 mEq/L), and cardiac arrest preceded by complete heart block in 50% of the experimental group. In the latter, rat studies demonstrated increased theophylline mortality from concomitant therapeutic dantrolene doses in the absence of increased seizure frequency. Dantrolene prolonged neuromuscular blockade in a patient receiving vecuronium.23 Oral contraceptive use has been associated with decreased tizanidine clearance, while tizanidine use is associated with decreased phenytoin clearance.24

TOXICOLOGY Adverse Effects with Therapeutic Use Numerous adverse effects have been associated with therapeutic use of the muscle relaxants (Table 37-2). CNS depression has been noted with all the agents, although it is less commonly associated with dantrolene. Additional CNS findings associated with baclofen therapy include movement disorders, memory impairment, muscle weakness, flapping tremor, nystagmus, diplopia, and dysarthria. Increased seizure activity, including status epilepticus, has been observed in patients with preexisting seizure disorders. Chlorzoxazone use is associated with opisthotonus and torticollis, while visual blurring and sensorineural hearing loss have been described with therapeutic use of intravenous and oral dantrolene, respectively. Neuropsychiatric effects, including mania, depression, psychosis, confusion, and amnesia, have been described with all skeletal muscle relaxants. Cardiovascular complaints associated with baclofen administration include palpitations, flushing, bradycardia, hypotension, and hypertension. Facial flushing and orthostatic hypotension have been reported with carisoprodol use. Cyclobenzaprine, methocarbamol, and chlorphenesin are associated with hypotension, palpitations, and syncope. Although possessing only 2% to 10% of clonidine’s antihypertensive potency, mild hypotension, symptomatic orthostatic hypotension, and syncope have been described with tizanidine use. Pericarditis, pleural effusions, and pleural fibrosis have been described with chronic therapeutic dantrolene use.25 Gastrointestinal complaints typically include nausea, vomiting, abdominal pain, and diarrhea or constipation. Idiosyncratic, potentially fatal hepatotoxicity is associated with chronic chlorzoxazone and dantrolene use. Onset of chlorzoxazone-associated hepatotoxicity is variable, typically occurring within weeks of initiation of therapy, but occasionally occurring after 5 or more months. Although reversible, centrilobular hepatotoxi-

698


TABLE 37-2 Clinical Toxicity of the Muscle Relaxants AGENT

CHRONIC EXPOSURE

ACUTE INTOXICATION

Baclofen

Neuropsychiatric dysfunction, GI upset, uinary retention, morbilliform rash, palpitations, physical dependence Sedation, nausea, vomiting, orthostatic hypotension, allergic reactions, physical dependence CNS depression, neuropsychiatric dysfunction, allergic reactions CNS depression, amnesia, parasthesias, opisthotonis, torticollis, urticaria, nausea/vomiting, idiosyncratic hepatitis CNS depression, antimuscarinic syndrome, hypotension, palpitations, syncope CNS depression, neuropsychiatric dysfunction, idiosyncratic heptotoxicity, pericarditis, pleural effusions, muscle weakness CNS depression, neuropsychiatric dysfunction, syncope

Coma, respiratory depression, seizures, hypothermia Coma, nystagmus, seizures, cardiovascular instability CNS depression

Carisoprodol Chlorphenesin Chlorzoxazone Cyclobenzaprine Dantrolene Metaxalone Methocarbamol Orphenadrine

Tizanidine

CNS depression, neuropsychiatric dysfunction, syncope, hypotension, hypersensitivity reactions Antimuscarinic syndrome

CNS depression, syncope, urinary retention, orthostatic hypotension

Coma, GI distress, hypotonia, hypotension Antimuscarinic syndrome, coma Severe muscle weakness, CNS depression, hypotension CNS depression, nephrotoxicity, seizures, muscular rigidity CNS depression, seizures Antimuscarinic syndrome, coma, seizures, cardiac conduction abnormalities, ventricular dysrhythmias, hypoglycemia, pulmonary hemorrhage Coma, hypotonia, miosis, bradycardia, apnea, hypothermia

CNS, central nervous system; GI, gastrointestinal.

city has recurred upon rechallenge to chlorzoxazone.26 Risk factors for fatal hepatic necrosis after dantrolene use include age greater than 30 years, chronic use greater than 2 months, female gender, doses greater than 300 mg/day, high bilirubin levels, and concomitant illness.27,28 Urinary retention has been associated with baclofen, cyclobenzaprine, orphenadrine, and tizanidine. Dantrolene and baclofen use is associated with acneiform and morbilliform rashes, respectively. Cyclobenzaprine and orphenadrine are associated with central and peripheral antimuscarinic symptoms. Profound muscle weakness can occur with dantrolene use, resulting in diminished protective airway reflexes.29 Severe allergic reactions have been reported with carisoprodol and chlorphenesin, associated with the additives sodium metabisulfite and tartrazine, respectively.

Acute Intoxication Severe baclofen poisoning is characterized by coma, respiratory depression, bradycardia, and hypotension. Other CNS findings include hyporeflexia and encephalopathy.30,31 Seizure activity has been observed after oral and intrathecal overdose, including generalized tonic–clonic activity, focal motor seizures, and status epilepticus. Two of eight patients in a case series of recreational abuse and 5 patients in a series of 12 overdoses developed seizures.31,32 Seizure activity is believed secondary to the inhibitory effects of baclofen at presynaptic GABAB receptors and resultant inhibition of presynaptic GABA release, and may be delayed as long as 12 hours after acute ingestion. Cardiovascular findings are typically limited to bradycardia and hypotension, although cardiac conduction disturbances including first-

and second-degree AV block and QTc prolongation have rarely been reported in overdose. Mechanical ventilation was required in 10 of 12 patients after acute baclofen overdose in one case series.31 Accidental intrathecal bolus administration of 10 mg resulted in coma and respiratory arrest within 80 minutes.33 Mild hypothermia is common in overdose. Minimum adult oral lethal doses in case reports range from 1000 to 2500 mg, while acute ingestions of 300 to 970 mg have resulted in severe poisoning. In overdose, elimination half-life increases to 8.6 hours, with one report suggesting an elimination half-life of 34.5 hours.34 Acute carisoprodol toxicity presents similarly to meprobamate, with potentially abrupt onset of coma, cardiovascular instability, and death. Coma may persist for several days, and cerebral and pulmonary edema have been noted in severe overdose. Sixteen of 50 patients in a case series of meprobamate intoxications required mechanical ventilation.35 Hypotension is likely multifactorial, related to CNS depression, direct effects on the CNS vasomotor center, and myocardial depression.36 Ingestion of 700 mg by a toddler was associated with severe toxicity, and ingestion of 3.5 g by a 5-year-old resulted in death.37,38 Antimuscarinic findings predominate in acute cyclobenzaprine poisoning. CNS findings range from agitated delirium to coma. Symptoms typically occur within 4 hours of ingestion, although they may be delayed up to 12 hours. In one case series, sinus tachycardia occurred in one third of patients and CNS depression in 54%.39 Three percent of patients required mechanical ventilation. Despite chemical similarity to the tricyclic antidepressants, impaired cardiac conduction, ventricular dysrhythmias, and seizures have only rarely been reported. Less than 1% of patients manifested

CHAPTER 37

dysrhythmias other than sinus tachycardia, none of which were life threatening. While one case report suggested a minimum lethal adult dose of 100 mg, a case series suggested that adult ingestions of less than 100 mg were asymptomatic, and no deaths were reported after ingestions of up to 1000 mg.39,40 Severe orphenadrine intoxication is associated with respiratory and CNS depression, ranging from lethargy to coma. Antimuscarinic findings are noted in overdose, including mydriasis and sinus tachycardia, and may predominate in milder toxicity. Unlike cyclobenzaprine, orphenadrine poisoning is associated with seizures (including status epilepticus), cardiac conduction abnormalities, ventricular dysrhythmias, and cardiac arrest.41-43 Life-threatening symptoms may appear precipitously, necessitating prompt, aggressive management. Additional manifestations of severe toxicity include hypoglycemia (especially in children), hypokalemia, hypothermia, pulmonary hemorrhage, and disseminated intravascular coagulation (DIC).44 A 3-year-old child died after ingestion of 400 mg of orphenadrine, and a 23-month-old child developed severe toxicity after ingestion of 300 mg.42,43 Acute tizanidine toxicity presents similarly to clonidine, with decreased level of consciousness, hypotonia, hyporeflexia, hypotension, bradycardia, miosis, respiratory depression, apnea, and hypothermia (see Chapter 62). A 3-year retrospective review of 45 cases demonstrated lethargy in 38 patients (84%), bradycardia in 14 (31%), hypotension in 8 (18%), agitation in 7 (16%), and coma in 2 (4%).45 The minimum adult ingested doses associated with hypotension and coma were 28 and 120 mg, respectively. In acute overdose, chlorzoxazone toxicity presents as varying degrees of CNS depression, gastrointestinal distress, and hypotonia. Coma, flacidity, hyporeflexia, and subsequent secondary respiratory failure have been described. With the exception of hypotension, cardiovascular toxicity has not been described. Acute dantrolene overdose is not well described in the literature.46,47 Severe muscle weakness may occur, with CNS depression occurring less frequently. Hypotension has been reported. Metaxalone overdose manifests predominantly as CNS depression, ranging from sedation to coma. Seizures may rarely occur, as may nephrotoxicity, and elevated hepatic transaminases. In one case report, severe muscular rigidity with subsequent prolonged weakness required placement in an extended care facility.48 Findings in acute methocarbamol and chlorphenesin overdose are similar to metaxalone, with CNS depression and rare seizures noted. Cardiotoxicity is extremely rare in isolated ingestions.

Withdrawal Chronic carisoprodol use is associated with tolerance, dependence, and a withdrawal syndrome, attributed to the metabolite meprobamate.49 Symptoms are analogous to those seen with withdrawal from other sedativehypnotic agents, with death reported after sudden withdrawal.50 After long-term baclofen use, a withdrawal syn-

Muscle Relaxants

699

drome has been described, manifesting as hallucinations, agitated delirium, and seizures, typically within 12 to 96 hours of discontinuation.51,52 Withdrawal may last as long as 8 days. This syndrome is particularly severe after abrupt discontinuation of intrathecal infusion, manifesting as an NMS-like syndrome. Severe dysautonomia, spasticity and rigidity, marked hyperthermia (43ºC), tachycardia, rhabdomyolysis, agitated delirium, seizures, and DIC have been reported. In one case, an infant born to a paraplegic mother receiving chronic baclofen therapy developed status epilepticus resistant to multiple antiepileptic agents 7 days postdelivery. The seizures abated within 30 minutes of receiving baclofen.53

DIAGNOSIS Diagnosis of skeletal muscle relaxant poisoning is based on history and clinical examination. Although analytic laboratory monitoring methods exist to confirm exposure to these agents, they are not routinely available, nor do specific levels correlate with outcome. Baclofen may be detected in serum using either high-performance liquid chromatography or gas chromatography/mass spectrometry technology. Therapeutic serum concentrations range from 80 to 395 ng/mL. Postmortem levels of 17 μg/mL have been reported 12 hours after ingestion.54 Cyclobenzaprine has been reported to crossreact with the Syva EMIT (Dade-Behring, Deerfield, IL) technique and Abbott Adx tricyclic antidepressant (TCA) immunoassay (Abbott Laboratories, North Chicago, IL), and migrates similarly to amitriptyline on the Toxilab thin layer chromatography (TLC) system (Varian, Inc., Palo Alto, CA).55 Therapeutic blood concentrations range from 10 to 40 ng/mL, with postmortem levels of 260 to 300 ng/mL reported.55,56 Therapeutic blood levels of orphenadrine are less than 0.2 μg/mL, while moderate effects have been described at levels of 5.1 μg/mL and severe effects at 12.3 μg/mL. Postmortem levels have ranged from 7 to 33 μg/mL.42,57 Therapeutic serum levels for carisoprodol range from 4 to 7 mg/L, while coma has been reported with a serum level of 13.4 mg/L 19 hours after ingestion, and death has been reported with a level of 36 mg/L 4.5 hours after ingestion.58 No specific laboratory analyses are routinely indicated, and clinical investigations are directed toward identification of end-organ toxicity. Creatine phosphokinase, electrolytes, and urine output should be monitored in patients with prolonged seizures or coma. Serum glucose should be rapidly determined in patients presenting with altered mental status. Coagulation studies and hepatic transaminase levels are indicated in orphenadrine intoxication, while hepatic and renal studies are indicated in metaxalone toxicity. Acetaminophen levels may be indicated in patients presenting after acute intentional ingestion. Electrocardiographic monitoring should be considered to detect the presence of conduction abnormalities and dysrhythmias. Computed tomography of the head and electroencephalographic assessment may be indicated to evaluate altered mental status, prolonged coma, and status epilepticus.

700

BOX 37-1


DIFFERENTIAL DIAGNOSIS OF MUSCLE RELAXANT INTOXICATION

Antidepressants Antihistamines Antiepileptic agents Barbiturates Benzodiazepines Buspirone Carbon monoxide Cyanide Ethanol Ethylene glycol γ-hydroxybutyrate (GHB) Ketamine Lithium Hydrogen sulfide Imidazolines Isoniazid Isopropanol Organophosphate and carbamate pesticides Phencyclidine Sedative-hypnotic agents Solvents Zolpidem

tachycardia. Hypotension should initially be treated with intravenous crystalloid boluses, provided no contraindication exists. Inotropic support is indicated for patients failing to respond to fluid boluses. Atropine is the first-line agent for symptomatic bradycardia. Cardiac dysrhythmias are treated according to standard guidelines, except as noted below. Benzodiazepines are firstline agents for patients with psychomotor agitation or seizures. Benzodiazepine-resistant seizures may be treated with barbiturates. Administration of oral or intrathecal baclofen may be required for seizures associated with baclofen withdrawal.53 Core body temperature should be monitored due to the potential for hypothermia (baclofen) or hyperthermia (agitation, seizures, antimuscarinic syndrome, or sedative-hypnotic withdrawal syndrome). Activated charcoal administration may be considered for patients presenting within 1 hour from time of ingestion, in accordance with the published guidelines of the American Academy of Clinical Toxicology and European Association of Poisons Centres and Clinical Toxicologists. Agents with delayed gastric emptying secondary to anticholinergic properties may benefit from activated charcoal beyond this time frame, although data are sparse. Whole bowel irrigation may be considered after ingestion of sustained-release preparations. Hemodialysis is not beneficial in the management of skeletal muscle relaxant toxicity.

Differential Diagnosis

Agent-Specific Management Strategies

Signs and symptoms of skeletal muscle relaxant poisoning are nonspecific, reflecting the CNS depressant effects of the agents (Box 37-1). The differential diagnosis for cyclobenzaprine and orphenadrine also includes sympathomimetic agents, antihistamines, antipsychotic agents, antispasmodic agents, cyclic antidepressants, and antimuscarinic plants and preparations. Toxicologic causes of altered mental status and seizures include cyanide, carbon monoxide, organophosphates and carbamates, buproprion, camphor, isoniazid, lithium, meperidine, propoxyphene, phencyclidine, oral hypoglycemics, phenothiazines, venlafaxine, and cyclic antidepressants. Toxicologic causes of cardiac conduction abnormalities include antidysrhythmics, antidepressants, antihistamines, antimuscarinic agents, β-adrenergic antagonists, propoxyphene, phenothiazines, and cocaine. The differential diagnosis for tizanidine intoxication includes opiates and opioids, clonidine and imidazolines, organophosphates and carbamates, and olanzapine.

Physostigmine has reversed baclofen-induced coma and orphenadrine-associated CNS toxicity, but is not universally effective, and has been associated with cardiac arrest59-62 (Table 37-3). As a result, physostigmine use is limited to severe toxicity unresponsive to meticulous supportive care. Although flumazenil has successfully reversed coma and stupor in chlorzoxazone and carisoprodol intoxications, respectively, routine use cannot be recommended due to concern of flumazenilinduced seizures.63,64 Given similarities to clonidine, naloxone may have a role in the management of tizanidine-associated CNS depression, bradycardia, and hypotension.65 Cyproheptadine has been used in the management of intrathecal baclofen withdrawal.66 Atropine appears beneficial in the management of baclofen-associated bradycardia and hypotension.67 QRS prolongation associated with orphenadrine and cyclobenzaprine toxicity is initially managed with sodium bicarbonate, analogous to tricyclic antidepressant toxicity (see Chapter 27). Ventricular dysrhythmias unresponsive to sodium bicarbonate therapy are treated with lidocaine. Physostigmine has reversed orphenadrineassociated ventricular tachycardia.68 Quinidine, disopyramide, and procainamide are contraindicated due to their effects on sodium channels. Multidose activated charcoal may be beneficial in the management of cyclobenzaprine and orphenadrine, which demonstrate enterohepatic recirculation, although outcome data are lacking. Hemoperfusion may be of benefit in carisoprodol toxicity, due to its

MANAGEMENT Management of skeletal muscle relaxant toxicity is primarily supportive, focusing on respiratory, CNS, and cardiovascular monitoring and support. Given the potential for profound CNS and respiratory depression, early aggressive airway management is paramount in patient management. Cardiovascular toxicity predominantly presents as hypotension, bradycardia, or

CHAPTER 37

Muscle Relaxants

701

TABLE 37-3 Specialized Treatment Recommendation for Muscle Relaxant Toxicity ANTIDOTAL AGENT

MUSCLE RELAXANT

INDICATION

DOSE

Atropine

Baclofen Tizanidine

Bradycardia and hypotension

Physostigmine

Baclofen Cyclobenzaprine Orphenadrine Carisoprodol

Severe antimuscarinic syndrome

Adult: 0.5–1 mg IV every 5 min (maximum dose 3 mg) Pediatrics: 0.02 mg/kg every 5 min minimum 0.1 mg, maximum dose 1 mg in children, 2 mg in adolescents) Adult: 1–2 mg IV over 5 min (may repeat once) Pediatrics: 0.02 mg/kg IV (maximum dose 0.5 mg) Adult: 0.2 mg IV over 30 s every 1 min (maximum dose 5 mg) Pediatrics: 0.01 mg/kg IV over 30 s every 1 min (maximum dose 1 mg) Adult: 0.4–2 mg IV (maximum dose 10 mg) Pediatrics ≤ 20 kg: 0.01 mg/kg, then 0.1 mg/kg if needed Pediatrics > 20 kg: 0.4–2 mg IV (maximum dose 10 mg) Adult: 4–8 mg PO every 1–4 hr until therapeutic response (maximum dose 32 mg/day) Pediatrics: 0.25 mg/kg/day PO divided every 6 hr (maximum dose 12 mg/day)

Flumazenil

CNS depression

Chlorzoxazone Naloxone

Tizanidine

CNS depression

Cyprohepatidine

Baclofen

Withdrawal

CNS, central nervous system; IV, intravenously; PO, orally.

ability to effectively remove the primary metabolite, meprobamate.69 Brisk diuresis may increase the elimination of baclofen, which is predominantly excreted in an unchanged form.

Patient Disposition Asymptomatic or mildly symptomatic patients presenting after ingestion of a non-sustained-release preparation may be medically cleared after a 6-hour observation period. In the case of cyclobenzaprine and orphenadrine, an observation period of 6 to 12 hours has been suggested. Due to the potential for CNS and respiratory depression, significantly intoxicated patients should be admitted to a monitored setting. Hemodynamically unstable patients require continuous cardiopulmonary monitoring in an intensive care setting. Patients may be medically cleared for hospital discharge after signs and symptoms of toxicity have resolved. REFERENCES 1. Schifano F, Marra R, Magni G: Orphenadrine abuse. South Med J 1988;8:546–547. 2. Bailey DN, Briggs JR: Carisoprodol: an unrecognized drug of abuse. Am J Clin Pathol 2002;117:396–400. 3. Reeves RR, Carter OS, Pinkofsky HB: Use of carisoprodol by substance abusers to modify the effects of illicit drugs. South Med J 1999;92:441. 4. De Lee JC, Rockwood CA: Skeletal muscle spasm and a review of muscle relaxants. Curr Ther Res 1980;27:64–74. 5. Gerkin R, Curry SC, Vance MV, et al: First-order elimination kinetics following baclofen overdose. Ann Emerg Med 1986;15:843–846. 6. Rho JM, Donevan SD, Rogawski MA: Barbiturate-like actions of the propanediol dicarbamates felbamate and meprobamate. J Pharmacol Exp Ther 1997;280:1383–1391.

7. Share NN, McFarlane CS: Cyclobenzaprine: a novel centrally acting skeletal muscle relaxant. Neuropharmacology 1975;12:675–684. 8. Product information: Norflex®, orphenadrine. 3M Pharmaceuticals, Northridge CA, 1998. 9. Cami J, Farre M: Mechanisms of disease: drug addiction. N Engl J Med 2003;349:975–986. 10. Coward DM: Tizanidine: neuropharmacology and mechanism of action. Neurology 1994;44(Suppl 9):6–10. 11. Ward A, Chaffman MO, Sorkin EM: Dantrolene. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in malignant hyperthermia, the neuroleptic malignant syndrome and an update of its use in muscle spasticity. Drugs 1986;32:130–168. 12. Nugent S, Katz MD, Little TE: Baclofen overdose with cardiac conduction abnormalities: care report and review of the literature. J Toxicol Clin Toxicol 1986;24:321–328. 13. Hurlbut KM: Skeletal muscle relaxants—central acting. Micromedex Healthcare Series, Vol 117. Greenwood Village, CO, Thomson Healthcare Inc., September 2003. 14. Ellison T, Snyder A, Bolger J, et al: Metabolism of orphenadrine citrate in man. J Pharmacol Exp Ther 1971;176:284–295. 15. Hucker HB, Stauffer SC, Balletto AJ, et al: Physiological disposition and metabolism of cyclobenzaprine in the rat, dog, rhesus monkey, and man. Drug Metab Dispos 1978;6:659–672. 16. Skausig OB, Korsgaard S: Hallucinations and baclofen. Lancet 1977;1(8024):1258. 17. Rivera VM, Breitbach WB, Swanke L: Dantrolene in amyotrophic lateral sclerosis. JAMA 1975;233:863–864. 18. Lees AJ, Shaw KM, Stern GM: Baclofen in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1978;41:707–708. 19. Kharasch ED, Thummel KE, Mhyre J, et al: Single-dose disulfiram inhibition of chlorzoxazone metabolism: a clinical probe for P450 2E1. Clin Pharmacol Ther 1993;53:643–650. 20. Zand R, Nelson SD, Slattery JT, et al: Inhibition and induction of cytochrome P4502E1-catalyzed oxidation by isoniazid in humans. Clin Pharmacol Ther 1993;54:142–149. 21. Tayeb OS: A serious interaction of dantrolene and theophylline. Vet Hum Toxicol 1990;32:442–443. 22. Saltzman LS, Kates RA, Corke BC, et al: Hyperkalemia and cardiovascular collapse after verapamil and dantrolene administration in swine. Anesth Analg 1984;63:473–478.

702


23. Driessen JJ, Wuis EW, Gielen MJ: Prolonged vecuronium neuromuscular blockade in a patient receiving orally administered dantrolene. Anesthesiology 1985;62:523–524. 24. Ueno K, Miyai K, Mitsuzane K: Phenytoin-tizanidine interaction. Ann Pharmacother 1991;25:1273. 25. Mahoney JM, Bachtel MD: Pleural effusion associated with chronic dantrolene administration. Ann Pharmacother 1994;28:587–589. 26. Powers BJ, Cattau EL Jr, Zimmerman HJ: Chlorzoxazone hepatotoxic reactions. Arch Intern Med 1986;146:1183–1186. 27. Chan CH: Dantrolene sodium and hepatic injury. Neurology 1990;40:1427–1432. 28. Utili R, Boitnott JK, Zimmerman HJ: Dantrolene-associated hepatic injury: incidence and character. Gastroenterology 1977;72:610–616. 29. Watson CB, Reierson N, Norfleet EA: Clinically significant muscle weakness induced by oral dantrolene sodium prophylaxis for malignant hyperthermia. Anesthesiology 1986;65:312–314. 30. Lee TH, Chen SS, Su SL: Baclofen intoxication: report of four cases and review of literature. Clin Neuropharmacol 1992;15:56–62. 31. Nugent S, Katz MD, Little TE: Baclofen overdose with cardiac conduction abnormalities: case report and review of the literature. Clin Toxicol 1986;2:321–328. 32. Perry HE, Wright RO, Shannon MW, et al: Baclofen overdose: drug experimentation in a group of adolescents. Pediatrics 1998;101:1045–1048. 33. Saltuari L, Baumgartner H, Kofler M, et al: Failure of physostigmine in treatment of acute severe intrathecal baclofen intoxication. N Engl J Med 1990;322:1533. 34. Ghose K, Holmes K: Complications of baclofen overdosage. Postgrad Med J 1980;56:865–867. 35. Allen MD, Greenblatt DJ, Noel BJ: Meprobamate overdosage: a continuing problem. Clin Toxicol 1977;11:501–515. 36. Blumberg AG, Rosett HL, Dobrow A: Severe hypotensive reactions following meprobamate overdosage. Ann Intern Med 1959;51:607–612. 37. Green DI, Caravati EM: Coma in a toddler from low-dose carisoprodol. J Toxicol Clin Toxicol 2001;39:503. 38. Adams HR, Kerzee T, Morehead CD: Carisoprodol-related death in a child. J Forensic Sci 1975;20:200–202. 39. Spiller HA, Winter ML, Mann KV, et al: Five year multicenter retrospective review of cyclobenzaprine toxicity. J Emerg Med 1995;13:781–785. 40. Hurlbut KM, Rumack BH: Cyclobenzaprine. Micromedex Healthcare Series Vol 117. Greenwood Village, CO, Thomson Micromedex, September 2003. 41. Garza MB, Osterhoudt KC, Rutstein R: Central anticholinergic syndrome from orphenadrine in a 3 year old. Pediatr Emerg Care 2000;16:97–98. 42. Gill DG, Sowerby HA: Orphenadrine poisoning in childhood. Practitioner 1975;214:542–544. 43. Sangster B, van Heijst A, Zimmerman A: Intoxication by orphenadrine HCl: mechanism and therapy. Acta Pharmacol Toxicol 1977;41(Suppl 2):129–136. 44. Bozza-Marrubini M, Frigerio A, Ghezzi R, et al: Two cases of severe orphenadrine poisoning with atypical features. Acta Pharmacol Toxicol 1977;41(Suppl 2):137–152. 45. Adamson LA, Spiller HA, Bosse GM: Tizanidine (Zanaflex®) exposure. J Toxicol Clin Toxicol 2003;41:664.

46. Paloucek FP, Erickson TE, Lundquist S, et al: Oral dantrolene ingestion: a case series. Vet Hum Toxicol 1991;33:362. 47. Robillart A, Bopp P, Vailly B, et al: Cardiac failure caused by an overdose of dantrolene [French]. Ann Fr Anesth Reanim 1986;5:617–619. 48. Snyder LK, Sint T, Kirk MA: Metaxalone induced muscular rigidity. J Toxicol Clin Toxicol 2001;39:503. 49. Littrell RA, Sage T, Miller W: Meprobamate dependence secondary to carisoprodol (Soma) use. Am J Drug Alcohol Abuse 1993;19:133–134. 50. Swanson LA, Okada T: Death after withdrawal of meprobamate JAMA 1963;184:780–781. 51. Kao LW, Amin Y, Kirk MA, et al: Intrathecal baclofen withdrawal mimicking sepsis. J Emerg Med 2003;24:423–427. 52. Alden TD, Lytle RA, Park TS, et al: Intrathecal baclofen withdrawal: a case report and review of the literature. Childs Nerv Syst 2002;18:522–525. 53. Ratnayaka BDM, Dhaliwal H, Watkin S: Neonatal convulsions after withdrawal of baclofen. BMJ 2001;323:85. 54. Fraser AD, MacNeil W, Isner F: Toxicological analysis of a fatal baclofen (Lioresal) ingestion. J Forensic Sci 1991;36:1596–1602. 55. Hucker HB, Stauffer SC, Albert KS, et al: Plasma levels and bioavailability of cyclobenzaprine in human subjects. J Clin Pharmacol 1977;17:719–727. 56. Levine B, Jones R, Smith ML, et al: A multiple drug intoxication involving cyclobenzaprine and ibuprofen. Am J Forensic Med Pathol 1993;14:246–248. 57. Clarke B, Mair J, Rudolf M: Acute poisoning with orphenadrine. Lancet 1985;1:1386. 58. Adams H, Kerzee T, Morehead C: Carisoprodol-related death in a child. J Forensic Sci 1975;20:200–202. 59. Rushman S, McLaren I: Management of intra-thecal baclofen overdose. Intensive Care Med 1999;25:239. 60. Saltuari L, Baumgartner H, Kofler M, et al: Failure of physostigmine in treatment of acute severe intrathecal baclofen intoxication. N Engl J Med 1990;322:1533–1534. 61. Delhass EM, Brouwers JR: Intrathecal baclofen overdose: report of 7 events in 5 patients and review of the literature. Int J Clin Pharmacol Ther Toxicol 1991;29:274–280. 62. Snyder BD, Kane M, Plocher D: Orphenadrine overdose treated with physostigmine. N Engl J Med 1976;295:1435. 63. Roberge RJ, Atchley B, Ryan K, et al: Two chlorzoxazone (Parafon Forte) overdoses and coma in one patient: reversal with flumazenil. Am J Emerg Med 1998;16:393–395. 64. Roberge RJ, Lin E, Krenzelok EP: Flumazenil reversal of carisoprodol (soma) intoxication. J Emerg Med 2000;18:61–64. 65. Seger DL: Clonidine toxicity revisited. J Toxicol Clin Toxicol 2002;40:145–155. 66. Meythaler JM, Roper JF, Brunner RC: Cyproheptadine for intrathecal baclofen withdrawal. Arch Phys Med Rehabil 2003;84:638–642. 67. Cohen MB, Gailey R, McCoy GC: Atropine in the treatment of baclofen overdose. Am J Emerg Med 1986;4:552–553. 68. Danze LK, Langdorf MI: Reversal of orphenadrine-induced ventricular tachycardia with physostigmine. J Emerg Med 1991;9:453–457. 69. Lin JL, Lim PS, Lain PC, et al: Continuous arteriovenous hemoperfusion in meprobamate poisoning. J Toxicol Clin Toxicol 1993;31:645–652.

38

Antipsychotic Agents MICHAEL LEVINE, MD ■ MICHAEL J. BURNS, MD

At a Glance… ■

■

■ ■ ■

The toxic effects of antipsychotic agents are often an amplification of their pharmacologic effects; overdose findings can be predicted by knowledge of relative receptor binding affinities. The presence of central nervous system or respiratory depression, miosis, sinus tachycardia, anticholinergic findings, and extrapyramidal signs should suggest antipsychotic agent poisoning. Clinical effects occur within 1 to 4 hours following antipsychotic agent overdose. Timely supportive care should ensure a good outcome for the vast majority of patients with antipsychotic poisoning. The optimal treatment of neuroleptic malignant syndrome requires prompt recognition, immediate withdrawal of antipsychotic agents, and the provision of good supportive care.

INTRODUCTION AND RELEVANT HISTORY Prior to 1952, drug therapy for schizophrenia was ineffective and often involved the nonspecific use of sedativehypnotics (e.g., barbiturates) to calm patients during periods of agitation. The discovery of the traditional antipsychotics (e.g., chlorpromazine and haloperidol) in the early 1950s revolutionized the treatment of schizophrenia. These agents provided specific and effective therapy for the positive signs and symptoms (e.g., delusions, disorganized behavior, hallucinations) of psychosis. Subsequent to their introduction, however, it was realized that traditional agents were associated with disabling extrapyramidal motor and neuroendocrine (e.g., hyperprolactinemia) side effects, and were dangerous in overdose (significant cardiac and neurotoxicity). In addition, it became apparent that these agents were not effective for the negative signs and symptoms (e.g., alogia, avolition, and social withdrawal) and neurocognitive deficits of schizophrenia. This led to the development of second-generation or atypical antipsychotic agents in the 1990s. Atypical agents produce minimal extrapyramidal side effects (EPS) at clinically effective antipsychotic doses and are effective for the negative signs and symptoms and neurocognitive deficits of schizophrenia. Atypical agents, however, are also associated with a variety of adverse effects (e.g., glucose intolerance, weight gain, prolonged QTc interval) that limit efficacy and patient compliance. In 2002, further advance in drug therapy for schizophrenia was marked by the release of the third-generation antipsychotic aripiprazole. It is anticipated that this novel antipsychotic and the class it represents will provide

equal or greater antipsychotic efficacy combined with a lower incidence and severity of side effects.

Terminology The term antipsychotic is somewhat of a misnomer because these agents are often used for purposes other than treating psychoses: They are also used as preanesthetics and for the treatment of the manic phase of bipolar disorder, agitated behavior, drug-induced hallucinations, nausea and vomiting, migraine and tension headaches, hiccups, pruritus, Tourette’s syndrome, and various extrapyramidal movement disorders (e.g., tics, chorea, and hemiballismus).1 Historically, this class of agents was termed major tranquilizers due to their ability to calm agitated patients. To think of these agents as simple sedatives, however, is overly simplistic. Until recently, the term neuroleptic was synonymous with and preferred to antipsychotic, because all traditional antipsychotics produce EPS at therapeutic doses. The introduction of agents that produce minimal EPS, or atypical antipsychotics, has allowed separation of antipsychotic from neuroleptic effects, and prevents the ready interchange of terms. Consequently, the term antipsychotic is more commonly used.

Epidemiology Toxicity from the antipsychotic drugs may be dose related and occur following unintentional or intentional overdose, or may be idiosyncratic and occur as unanticipated adverse effects during therapeutic administration. Dose-related toxicity will vary according to agent, patient age and habituation, and comorbid conditions. Toxic effects are often an overextension of an agent’s pharmacologic effects.1 Because of a large toxic-totherapeutic ratio, fatalities rarely occur. Death, when it occurs, is usually a consequence of polysubstance overdose. The agents with the greatest individual toxicity or highest fatal toxicity index (most deaths caused per prescription written) are the low-potency traditional agents, such as chlorpromazine, loxapine, mesoridazine, and thioridazine.2-4 These agents, however, are now implicated in fewer deaths from antipsychotic agents in the United States due to their lower frequency of usage. In 2004, there were 42,833 antipsychotic agent exposures reported to U.S. poison centers, of which 38,315 (89%) were due to atypical antipsychotics and 4518 (11%) were due to phenothiazines.5 Major toxicity and death occurred in 5.5% and 0.2% of atypical agent exposures and 4.1% and 0.4% of phenothiazine exposures, respectively.5 While antipsychotic drugs often have a wide margin of safety, these drugs are commonly used, have a 703

704


large number of adverse effects, and can produce significant toxicity in the nonhabituated host or those at the extremes of age.

CLASSIFICATION AND STRUCTUREACTIVITY RELATIONSHIPS Antipsychotics can be classified by structure, pharmacologic profile, and whether they are typical (traditional or conventional) or atypical (novel, second and third generation). Classification by structure is challenging since antipsychotics are a structurally diverse group of heterocyclic compounds. Currently more than 50 neuroleptics are available worldwide, with numerous others in various stages of development.1 Chemical classes include benzamide, benzepine, butyrophenone (phenylbutylpiperidine), diphenylbutylpiperidine, indole, phenothiazine, quinolinone, rauwolfia alkaloid, and thioxanthene derivatives (Table 38-1).1 The phenothiazines and thioxanthenes are traditional tricyclic antipsychotic agents for which structure predicts function. These agents have two benzene rings linked by a sulfur atom and either a nitrogen (phenothiazines) or carbon (thioxanthenes) atom double bonded to the side chain at position 10 of the central ring (Fig. 38-1).1 The presence of an electron-withdrawing group at position 2 increases antipsychotic efficacy and potency. Phenothiazines and thioxanthenes are subdivided into three groups (aliphatic, piperidine, and piperazine), based on the side chain substitution at position 10 on the central ring (see Fig. 38-1). The nature of the substitution influences pharmacologic activity. The aliphatic and piperidine subclasses have a higher antipsychotic potency and incidence of EPS, but a lower incidence of sedation, hypotension, and anticholinergic effects than do the piperazine class.1 In general, the antihistaminergic and anticholinergic properties of the phenothiazines and thioxanthenes are derived from the presence of a tertiary amino group in the side chain connected by two or three carbons to position 10 of the central ring (see Fig. 38-1 and Chapter 39).1 Aside from the phenothiazine and thioxanthene classes, structure-activity relationships have not been well characterized for most antipsychotics. Therefore, classification based on chemical structure has limited clinical utility for most agents. A more clinically useful method of antipsychotic agent classification is to identify agents by their relative receptor-binding profiles (Table 38-2). Because clinical toxicity of antipsychotics results from exaggerated pharmacologic activity, knowledge of the agent’s binding affinity at various receptors allows one to predict adverse effects in both therapeutic and overdose situations.6-8 The most commonly used method of classifying antipsychotics is to identify them as typical or atypical. This classification is clinically based. Agents are considered atypical if they (1) produce minimal EPS at clinically effective antipsychotic doses; (2) have a low propensity to cause tardive dyskinesia (TD) with long-term treatment; and (3) are effective for treating both the positive and negative signs and symptoms of schizophrenia.6-10 Interestingly, this clinically determined classification

system is rooted in receptor binding. Drug atypia is defined by unique, relative receptor-binding profiles (see Pharmacology section). In the preclinical area, knowledge of an agent’s relative receptor-binding affinities can be used to predict whether it will be atypical or typical.

PHARMACOLOGY All antipsychotic agents bind and block presynaptic (autoreceptors) and postsynaptic D2 receptors in the central nervous system (CNS).1 Initially, this receptor antagonism stimulates increased presynaptic production and release of dopamine. With continued antipsychotic treatment, however, depolarization inactivation occurs at the synapse, and decreased production and release occurs simultaneous with continued postsynaptic receptor blockade. Partial receptor agonists and agents with lower receptor affinity (e.g., atypical agents) are less likely to lead to depolarization inactivation at the synapse. Antipsychotic agents block D2-subtype receptors in nigrostriatal (basal ganglia), tuberoinfundibular (hypothalamus to pituitary), mesocortical, and mesolimbic pathways of the brain.1,6,8,9 These agents also antagonize D2 receptors in the medulla oblongata and the anterior hypothalamus. Blockade of the D2 receptors in the area postrema (chemotactic trigger zone) is responsible for the antiemetic activity of antipsychotics. Antipsychotic efficacy is mediated by a drug’s ability to block mesocortical and mesolimbic D2 receptors; all antipsychotics share this property.1,6,8,9 For most neuroleptics, there is a strong correlation between the affinity (potency) at D2 receptors and daily dose necessary to treat the positive symptoms of schizophrenia (see Tables 38-1 and 38-2).1,8,11 Based on in vivo studies utilizing positron emission tomography, the therapeutic effects of neuroleptics correlate with 70% or greater D2 receptor occupancy in the mesolimbic pathway.12 Antagonism of the D2 receptors in other brain regions, however, accounts for many of the undesired side effects of antipsychotics. For example, antagonism of the D2 receptors in the tuberoinfundibular pathway in the pituitary gland causes hyperprolactinemia, which can result in galactorrhea, gynecomastia, menstrual changes, and sexual dysfunction.1,6 Antagonism of the nigrostriatal D2 receptors produces EPS (e.g., acute dystonia, parkinsonism, akathisia). Agents with higher D2 receptor affinity (e.g., fluphenazine, haloperidol, and thiothixene) have a high likelihood for producing EPS.6 In contrast, agents with minimal D2 receptor affinity (i.e., clozapine, quetiapine) or those that selectively inhibit the limbic D2 receptors over the nigrostriatal D2 receptors (e.g., sulpiride, remoxipride) are less likely to produce EPS.6,7,10 Unfortunately, for most traditional antipsychotics, basal ganglia D2 receptor blockade occurs in the same dose range necessary for limbic D2 blockage.12 This produces a high incidence of EPS at therapeutic doses for traditional antipsychotics.1,6 Regulation of core body temperature involves dopamine. D2 receptor blockade by antipsychotics in the anterior hypothalamus (preoptic area) can alter the core temperature set point, block thermosensitive neuronal

CHAPTER 38

Antipsychotic Agents

705

TABLE 38-1 Classification and Dosing of Antipsychotic Agents STRUCTURAL CLASS Typical Agents Butyrophenone (phenylbutylpiperidine)

Diphenylbutylpiperidine Indole Phenothiazine Aliphatic

Piperazine

Piperidine

Thioxanthene

Atypical Agents Benzamides

Benzepine Dibenzodiazepine Dibenzooxazepine Thienobenzodiazepine Dibenzothiazepine Dibenzothiazepine Indole Benzisoxazole Imidazolidinone Benzisothiazole Quinolinone

GENERIC NAME (TRADE NAME)

DAILY DOSE RANGE (mg)

Droperidol (Inapsine) Haloperidol (Haldol) Other: benperidol, bromperidol, melperone, pipamperone, trifluperidol Pimozide (Orap) Other: fluspirilene, penfluridol Molindone (Moban) Other: oxypertine

1.25–30 1–30 1–20 15–225

Chlorpromazine (Thorazine) Promazine (Sparine) Promethazine (Phenergan) Triflupromazine (Vesprin) Acetophenazine (Tindal) Fluphenazine (Prolixin) Perphenazine (Trilafon) Prochlorperazine (Compazine) Trifluoperazine (Stelazine) Thiethylperazine (Torecan) Mesoridazine (Serentil) Thioridazine (Mellaril, Millazine) Other: diethazine, ethopropazine, levomepromazine, perazine, pipotiazine thiopropazate, thioproperazine, pericyazine Chlorprothixene (Taractan) Clopenthixol Flupenthixol Thiothixene (Navane) Zuclopenthixol (Cisordinal, Clopixol)

25–2000 50–1000 25–150 5–90 40–400 0.5–30 4–64 10–150 2–40 10–30 30–400 20–800

Amisulpiride Raclopride Remoxipride Sulpiride Sultopride Other: epidepride, eticlopride levosulpiride, nemonapride, tiapride

100–1200 5–8 150–600 100–1600 100–1200

Clozapine (Clozaril, Leponex) Loxapine (Loxitane) Olanzapine (Zyprexa) Quetiapine (Seroquel) Zotepine Other: butaclamol, fluperlapine, clothiapine, metiapine, savoxepine

150–900 20–250 5–20 300–600 100–300

Risperidone (Risperdal) Sertindole (Serlect) Ziprasidone (Zeldox) Other: iloperidone Aripiprazole (Abilify, Abitat)

inputs, and inhibit centrally mediated thermoregulatory responses.1 Thus, either hypothermia or hyperthermia can occur from antipsychotic therapy. D2 receptor antagonism in the hypothalamus and the nigrostriatum mediates the neuroleptic malignant syndrome (NMS), a fulminant hyperthermic adverse reaction associated with antipsychotic therapy. Decreased tolerance to heat and fatal heat stroke have been described in patients who

30–600 — 4 6–60 10–50

2–16 12–24 40–160 10–30

take phenothiazines.9 Antipsychotics have also been used successfully to treat hyperthermia associated with cocaine and amphetamines.10-12 In addition to their D2 receptor antagonism, most antipsychotics are competitive antagonists at a wide variety of other neuroreceptors. Since the D2 receptor binding affinity determines the daily (therapeutic) dose, the relative binding affinity at other neuroreceptor

706


6

5 S

and mucous membranes, hyperpyrexia, ileus, mydriasis, tachycardia, and urinary retention). Sialorrhea, a feature unique to clozapine, is likely mediated by its partial agonism at M1 and M4 receptors.6 Significant antagonism of the α1-adrenergic receptor (e.g., aliphatic and piperidine phenothiazines, clozapine, risperidone, ziprasidone, olanzapine, and sertindole) results in orthostatic hypotension, reflex tachycardia, nasal congestion, and miosis.1 Blockade of the α2-adrenergic receptor by certain agents (e.g., clozapine and risperidone) may produce sympathomimetic effects (e.g., tachycardia). The ability of certain agents (e.g., loxapine, clozapine) to block neuronal reuptake of norepinephrine and antagonize GABAA receptors partly accounts for the high prevalence of seizures with these drugs. High relative binding affinities at M1 and 5-HT1A- and 5-HT2Aserotonin receptors are inversely related to the likelihood of producing EPS.1,13,15,16 Although drug atypia is defined clinically, it also appears to be determined by one or more of several different pharmacologic mechanisms. Atypical agents belong to one of four distinct receptor-binding groups: (1) D2 and D3 receptor antagonists (e.g., amisulpiride, remoxipride, raclopride, sulpiride); (2) D2, α1, and 5-

4 3

7 10 N

8 9

2 1

R2

R1 FIGURE 38-1 Phenothiazine structure.

sites compared with that at D2 receptors predicts the likelihood of producing clinical effects from other neuroreceptors (see Table 38-2).6,13 Knowledge of relative binding affinities can be used to predict clinical effects at both therapeutic doses and overdoses.6,13 For instance, high relative antagonism at the H1-histamine receptor (e.g., aliphatic and piperidine phenothiazines, clozapine, loxapine, olanzapine, and quetiapine) results in sedation, hypotension, and appetite stimulation.1,6,13,14 Significant blockade of the M1-muscarinic receptor (e.g., aliphatic and piperidine phenothiazines, clozapine, and olanzapine) produces anticholinergic effects (e.g., agitation, hallucinations, delirium, blurred vision, dry skin

TABLE 38-2 Relative Neuroreceptor Affinities for Antipsychotics* RECEPTOR NEUROLEPTIC AGENT

D2

†

H1

a1

a2

M1

5-HT2A

OTHER RECEPTOR BINDING

Typical Agents Chlorpromazine Fluphenazine Haloperidol Loxapine Mesoridazine Molindone Perphenazine Pimozide Prochlorperazine Thioridazine Thiothixene Trifluoperazine

2+ 3+ 2+ 1+ 2+ 1+ 3+ 2+ 2+ 2+ 3+ 3+

2+ 0 0 3+ 3+ 0 1+ 0 1+ 2+ 0 0

3+ 0 1+ 3+ 3+ 0 1+ 1+ 1+ 3+ 0 1+

0 0 0 0

1+ 0 0 2+ 1+ 0 0 0 0 3+ 0 0

3+ 0 1+ 3+

D1,3,4

Atypical Agents (Ami)sulpiride Aripiprazole

2+ 3+‡

0 2+

0 2+

0 0

0 0

0 3+

Clozapine

1+

3+

3+

3+

3+

3+

Olanzapine Quetiapine Remoxipride Risperidone Sertindole Ziprasidone

2+ 1+ 1+ 3+ 3+ 3+

2+ 3+ 0 0 0 0

2+ 3+ 0 2+ 1+ 3+

0 0 1+ 0 0

3+ 3+ 0 0 0 0

3+ 1+ 0 3+ 3+ 3+

Zotepine

2+

2+

0

2+

0

3+

1+

0 0

*Relative neuroreceptor affinity is the neuroreceptor affinity at receptor X/dopamine D2 receptor affinity. † Binding affinity (potency) at D2 receptor correlates inversely with the daily dose of antipsychotic agent. ‡ High binding affinity but partial agonist at receptor. 0, minimal to none; 1+, low; 2+, moderate; 3+, high; 4+, very high. NE, norepinephrine. Data from references 1, 6–8, 57, 58, and 181.

D1,4, σ D4, blocks NE reuptake

0 1+ 0 2+ 0 1+ D3 D3,4, 5-HT1A,2C,7, blocks 5-HT reuptake D1,4, M2-5, 5HT2C,2D,3,6,7, blocks NE reuptake D1,3,4, M2-5, 5HT1C,3,6 5-HT1A, D1 σ D1,4 5HT1C,2C 5HT1A,1C,1D,2C,D1 blocks NE, 5-HT reuptake D1,3,4, 5-HT2C, blocks NE reuptake

CHAPTER 38

HT2A receptor antagonists (e.g., ziprasidone, sertindole, risperidone), also known as the serotonin-dopamine antagonists; (3) broad-spectrum, multireceptor antagonists (e.g., clozapine, olanzapine, quetiapine); and (4) D2 and 5-HT1A receptor partial agonists (e.g., aripiprazole), also known as dopamine and serotonin system stabilizers.7 Characteristics associated with drug atypia include low D2 receptor potency (high milligram drug dosing); low D2 receptor occupancy (less than 70%) in the mesolimbic and nigrostriatal areas at therapeutic doses; partial agonist activity at D2 receptors; high affinities for M1, D1, D3, α2, 5-HT1A, and 5-HT2A receptors relative to the D2 receptor; multiple neuroreceptor antagonism; and a low likelihood of raising serum prolactin concentrations.6-8,10,12,14,16 CNS serotonin antagonism is now recognized as an important mechanism of antipsychotic action and minimizing the likelihood of EPS.1,14-18 Normally, serotonergic fibers inhibit dopamine release in the nigrostriatum and prefrontal cortex. Thus, blockade of the 5-HT2A receptors in the CNS increases dopamine release in the striatum and prefrontal cortex. Antipsychotics that have high relative 5-HT2A receptor antagonism (5-HT2A/D2 binding ratio greater than 1) (e.g., amperozide, clozapine, risperidone, sertindole, ziprasidone) have enhanced efficacy for treating the negative signs and symptoms of schizophrenia and provide a lower EPS liability.16-18 Agents with partial agonist activity at 5-HT1A autoreceptors (e.g., ziprasidone, aripiprazole) have similar beneficial effects.

Pathophysiology CARDIAC EFFECTS The aliphatic and piperidine phenothiazines (e.g., chlorpromazine, thioridazine, and mesoridazine) have direct negative inotropic and quinidine-like (type IA) antiarrhythmic effects on cardiac myocytes.1 These agents block voltage-gated fast sodium channels; blockade is enhanced at less negative membrane potentials and faster heart rates.1,19 Thus, conduction disturbances will be augmented for drugs that also produce tachycardia (e.g., those with anticholinergic properties) or tissue acidemia (e.g., as a result of drug-associated seizure or shock). In addition, certain antipsychotic agents antagonize delayed-rectifier, voltage-gated potassium channels (encoded by the HERG gene) responsible for membrane repolarization during phase 3 of the action potential.1,20,21 Potassium channel antagonism is concentration, voltage, and reverse frequency dependent; block is augmented at higher drug tissue concentrations, less negative membrane potentials, and slower heart rates.20,21 Potassium channel blockade may induce early after depolarization and triggered ventricular activity (e.g., torsades de pointes [TdP]). Some neuroleptics, (e.g., haloperidol, mesoridazine, pimozide, and thioridazine) are also calcium channel antagonists.22 The cardiac channel effects of antipsychotics produce a depressed rate of phase 0 depolarization, decreased amplitude and duration of phase 2, and prolongation of phase 3. In addition, early after-depolarizations that result from the


707

blockade of the rectifying potassium channels can trigger ventricular arrhythmias (e.g., TdP). CARDIOVASCULAR Hypotension results from α1-adrenergic antagonism and loss of peripheral vasomotor tone, α2-adrenergic antagonism and loss of central vasomotor tone, and direct membrane-depressant cardiac effects. Membranedepressant effects result in impaired cardiac conduction and contractility.1 Cardiovascular effects are dose related. Tachycardia occurs as a vasomotor reflex to hypotension or from anticholinergic drug effects. SEIZURES All antipsychotic agents appear to lower the seizure threshold and produce dose-related electroencephalographic (EEG) abnormalities that are similar to discharge patterns observed in epileptic patients.1,23-27 The degree of EEG changes and incidence of seizures are greatest with certain agents (e.g., clozapine, loxapine, and aliphatic and piperidine phenothiazines).1,23-29 The mechanisms of seizure production are not well elucidated but appear to involve GABAA receptor antagonism, norepinephrine reuptake inhibition, and disrupted ionic flow through neuronal membrane channels. EXTRAPYRAMIDAL SIDE EFFECTS All EPS result from D2 receptor blockade by antipsychotics in basal ganglia nuclei.1,6,14,30,31 This leads to a disruption of neurotransmission in numerous basal ganglia and thalamocortical pathways critical for coordinated movement. These pathways utilize acetylcholine, serotonin, glutamate, γ-aminobutyric acid (GABA), and various neuropeptides for communication.16,17,32 Drug-induced parkinsonism is a result of decreased nigrostriatal dopaminergic activity with resultant striatal cholinergic excess.1,6,30,31 Akathisia is likely produced by D2 receptor blockade in mesocortical pathways.1,6,30,31 The pathophysiology of acute dystonic reactions (ADRs) is still unknown. One attractive theory posits that dystonia is the manifestation of an acute compensatory response to nigrostriatal D2 receptor blockade produced by antipsychotics. The acute administration of antipsychotics provokes increased dopamine synthesis and release from nigrostriatal neurons and postsynaptic receptor up-regulation.30,31,33,34 As brain concentrations of the neuroleptic decline hours to days after a dose, a state of dopamine excess develops and hyperkinesis or dystonia results. TD is likely secondary to an increased number and up-regulated dopamine receptor as a compensatory response to chronic D2 receptor blockade by antipsychotics in the nigrostriatum.1,6,30,31,33,34 TD signifies a state of dopaminergic supersensitivity and cholinergic underactivity in the basal ganglia. NMS appears to involve dopaminergic hypoactivity in the CNS. Blockade of D2 receptors in the striatum and hypothalamus results in muscular rigidity (similar to parkinsonism) and altered thermoregulation, respectively.35-37 Fever occurs largely from increased heat production from muscular rigidity but is also due to impaired heat dissipation and an altered set point of

708


core temperature in the hypothalamus.1,35-37 Blockade of D2 receptors in the mesolimbic and mesocortical regions produces altered mentation. Blockade of D2 receptors in peripheral sympathetic nerve terminals and the vasculature may cause autonomic disturbances.38,39 The pathophysiology of NMS may involve iron. Iron is a positive modulator of dopamine receptor activity, and low serum iron levels often displayed in those with NMS may lead to a decreased number of dopamine receptors in the brain.40,41

PHARMACOKINETICS Although most classes of antipsychotics have similar pharmacokinetics, there is substantial interindividual variability. Following oral administration, absorption is generally rapid and nearly complete. Because of extensive first-pass hepatic and intestinal metabolism, however, bioavailability is erratic and unpredictable (range 10% to 70%).1,42,43 Peak plasma concentrations occur within 1 to 6 hours after oral administration. Intramuscular (IM) administration increases bioavailability by a factor of 4 to 10.1 Peak plasma concentrations occur within 30 to 60 minutes after IM administration of immediate-release preparations but are delayed up to 24 hours following IM administration of depot preparations.1,42,43 Following an oral overdose, absorption occurs more rapidly but peak plasma concentrations are delayed; clinical effects may occur earlier and last longer. The depot (sustained-release) injectable preparations are created by esterifying the hydroxyl group of the antipsychotic with a long-chain fatty acid (e.g., enanthate or decanoate) and dissolving it in a sesame oil vehicle.1 Most antipsychotics are highly protein bound (75% to 99%) and lipophilic. These drugs have large volumes of distribution (usual range 10 to 40 L/kg) and tend to accumulate in brain and other tissues.1,42,43 Removal of these agents by hemodialysis or hemoperfusion is impossible. Antipsychotic agents are largely and extensively eliminated by hepatic metabolism. Less than 1% of an ingested dose is excreted unchanged by the kidney. Hepatic metabolism occurs via flavin-containing monooxygenase or cytochrome P-450 mixed-function oxidase systems or by hydroxylation, sulfoxidation, N-dealkylation, and conjugation.42,43 Hepatic metabolites are not easily measured but often remain pharmacologically active and will extend the parent drug’s effects after therapeutic doses or overdose. Thus, there is often a poor correlation between serum concentration and clinical effects.42-44 Metabolites are variably excreted in the urine and stool after conjugation and enterohepatic circulation, respectively. Elimination half-lives of most antipsychotic agents range from 20 to 40 hours after oral dosing. Depot IM preparations have elimination half-lives of 7 to 21 days.1,42 With newer sustainedrelease preparations (e.g., Risperdal Consta, Janssen, LP, Titusville, NJ), steady-state plasma concentrations are maintained for 4 to 6 weeks after the last IM injection.45

Risperdal Contra contains an aqueous suspension of risperidone mixed with a biodegradable copolymer. The pharmacokinetic profile of common neuroleptic drugs is presented in Table 38-3.

Special Populations PREGNANCY AND BREAST-FEEDING Due to their high lipophilicity, most antipsychotics readily enter the fetal circulation across the placenta and are readily secreted into breast milk.1 Data that establish the safety of antipsychotics during pregnancy are lacking, and these drugs are thus considered pregnancy class C; their use in pregnant women is warranted only if the benefits to the mother justify the potential risks to the fetus. While most manufacturers recommend against the use of antipsychotics during breast feeding, toxic effects and impaired development have not been demonstrated to date in infants who have been breastfed by women regularly taking antipsychotics.46 RENAL IMPAIRMENT Most of the antipsychotics are metabolized almost exclusively in the liver before excretion and are not significantly affected by alterations in renal function. Risperidone and the benzamide derivatives (e.g., sulpiride and remoxipride), however, require dosage alterations for patients in renal failure because large amounts of these drugs are excreted unchanged by the kidneys.43 HEPATIC IMPAIRMENT Patients with advanced hepatic disease (e.g., cirrhosis) and conditions that impair hepatic blood flow (e.g., congestive heart failure) have diminished clearance of antipsychotic agents. Thus, dose reduction is recommended for this group of patients during chronic therapy.43 The presence of hepatic disease, however, is unlikely to affect clinical outcome following acute overdose in this group of patients. AGE Infants and geriatric patients have reduced capacity to metabolize and eliminate antipsychotic agents, whereas children tend to metabolize these drugs more rapidly than adults.1 In general, however, elderly and pediatric patients are more sensitive to the effects of neuroleptics than are young adults. Thus, patients at the extremes of age have a greater tendency to develop anticholinergic stigmata, EPS, sedation, confusion, and postural hypotension. The safety and efficacy of many antipsychotics have not been adequately studied in pediatric patients. GENETIC POLYMORPHISMS There is large interindividual variation in the hepatic biotransformation of antipsychotic agents, which largely reflects CYP enzyme polymorphisms. For instance, 5% to 10% of white individuals are CYP2D6 “poor metabolizers,” which may result in certain antipsychotic drug concentrations (e.g., risperidone, haloperidol, thioridazine) that are up to 10-fold higher than those in

CHAPTER 38


709

TABLE 38-3 Pharmacokinetics of Various Antipsychotics

ANTIPSYCHOTIC AGENT

TIME TO PEAK AFTER ORAL DOSING (hr)

ELIMINATION HALF-LIFE (hr)

PROTEIN BINDING (%)

Vd (L/KG)

ROUTE OF METABOLISM

CYP2D6 CYP2D6 CYP3A4 Hepatic CYP1A2 CYP2D6 CYP3A4 CYP2D6 Hepatic Hepatic CYP3A4 CYP1A2 CYP2D6 Hepatic

Typical Agents Chlorpromazine Haloperidol

2–4 1–6

8–35 17–36

90–95 92

7–20 10–35

Fluphenazine Loxapine

2–5 1–6

5–27 2–8

90–95 91–99

220 NA

8–21 17–27 9–16 28–214

90–95 >90 93 99

10–35 13–32 9–19 11–62

Perphenazine Prochlorperazine Promethazine Pimozide

2–6 1.5–5 3.3 6–8

Thioridazine Thiothixene

2–4 1–3

9–36 12–36

99 90–95

18 NA

Atypical Agents Aripiprazole

3–5

75

99

4.9

Clozapine

1–4

10–105

92–96

Iloperidone Olanzapine

2–3.5 5–6

5–14 20–70

93 93

NA 10–20

Quetiapine Remoxipride Risperidone Sertindole

1–2 1–2 1–1.5 10

4–10 4–7 3–24 24–200

83 80 90 >99

10 0.7 1–1.5 20–40

Sulpiride Ziprasidone

3–6 5

5–14 4–10

40 >99

2.7 2

2–5

CYP3A4 CYP2D6 CYP1A2 CYP3A4 Hepatic CYP1A2 CYP2D6 CYP3A4 Hepatic, renal CYP2D6 CYP3A4 CYP2D6 Hepatic, renal CYP3A4

ACTIVE METABOLITE

Yes Yes Yes Yes No No Yes Yes Yes No Yes Yes No Yes No Yes Yes No No

NA, data not available. Pharmacokinetic data obtained from references 1, 8, 10, 42–44, and 182.

“normal” CYP2D6 individuals.47,48 Dose adjustment for these patients is unknown. Theoretically, these patients are at greater risk for adverse drug interactions.

Drug Interactions The coadministration of antipsychotics with other drugs has the potential for numerous clinically significant pharmacodynamic and pharmacokinetic interactions.49 The CNS and respiratory depressant effects of neuroleptics are potentiated when co-ingested with alcohols, antihistamines, opiates, other psychotropics, and sedativehypnotics. Fatal cardiopulmonary arrest has occurred when therapeutic doses of clozapine have been taken with lorazepam.50 Exaggerated anticholinergic effects could occur when certain antipsychotics are coadministered with tricyclic antidepressants, antihistamines, antiparkinson agents, and some skeletal muscle relaxants (e.g., cyclobenzaprine). Hypotension could occur when antipsychotics with α1-adrenergic antagonistic effects are co-ingested with antihypertensives with similar properties (e.g., prazosin, hydralazine). QT prolongation may occur when cardioactive agents are coadministered with certain antipsychotics (e.g., droperidol,

haloperidol, thioridazine). The combination of lithium and neuroleptic agents can produce a syndrome similar to NMS.51,52 Since many neuroleptics are metabolized by the CYP2D6, CYP1A2, and CYP3A4 enzymes, their clearance can be significantly altered when coadministered with inhibitors or inducers of these enzymes (see Table 38-3). A thorough knowledge of the neuroleptic’s unique receptor-binding profile and hepatic metabolism will facilitate recognition and treatment of clinically significant drug interactions.

TOXICOLOGY Clinical Manifestations Following Overdose Isolated antipsychotic agent overdose is rarely fatal; most patients who overdose on these agents will remain asymptomatic or develop only mild toxicity.5 Ingested doses that produce acute toxicity and lethality are highly variable; many patients have survived ingestions reported to be lethal in others.53 Toxicity largely depends on age,

710


habituation, and comorbid illness of the patient, agent identity, and time to treatment. Tolerance develops to the sedative effects of antipsychotics over a period of days to weeks.1 Thus, nonhabituated adults and young children (rarely prescribed these agents) are more sensitive to the toxic effects of antipsychotics than those who have ingested the drug chronically. The ingestion of a single tablet of chlorpromazine, clozapine, loxapine, mesoridazine, olanzapine, quetiapine, or thioridazine may cause CNS and respiratory depression in young children.53–58 Multireceptor, low-potency agents (e.g., clozapine, loxapine, chlorpromazine, thioridazine, and mesidorazine) are more toxic than more selective, highpotency agents (e.g., fluphenazine, haloperidol).1-5 When death occurs, it usually results from respiratory arrest (prior to medical intervention), arrhythmias, or aspiration-induced respiratory failure.2 Clinical effects begin within 30 to 90 minutes and peak within 2 to 6 hours of ingestion. Delayed onset and peak toxicity are possible after ingestion of drugs that slow gastrointestinal motility (e.g., anticholinergic drugs). Resolution of serious toxicity usually occurs by 24 to 48 hours. The toxic effects are similar in adults and children. CNS depression is the most common finding following overdose.3,54-64 CNS effects range from lethargy, slurred speech, ataxia, and confusion in mild intoxication, to mild coma with respiratory depression in moderate intoxication, to deep coma with apnea and loss of brainstem and deep tendon reflexes in severe intoxication. Paradoxical agitation and delirium may occur with mixed overdoses and those involving antipsychotic agents with anticholinergic properties (e.g., chlorpromazine, clozapine, mesidorazine, olanzapine, and thioridazine). Respiratory depression that necessitates endotracheal intubation is uncommon but occurs with greater frequency in children, polydrug overdoses, and sedating, multireceptor, low-potency antipsychotics (e.g., aliphatic and piperidine phenothiazines, clozapine, olanzapine, and quetiapine). Apnea and sudden infant death syndrome have been associated with the use of antipsychotic agents.65 Pulmonary edema can rarely occur.66 Seizures are uncommon in overdose, reported in about 1% of patients in large series.3,57 Seizures, however, appear to occur with greater frequency after ingestion of chlorpromazine, clozapine, loxapine, mesoridazine, and thioridazine. A seizure incidence of 60% and 10% have been reported following loxapine and clozapine overdose, respectively.28,57,60 Loxapine-induced seizures can be recurrent and severe, resulting in rhabdomyolysis, myoglobinuria, and acute renal failure.28 Anticholinergic manifestations (peripheral and central) are frequent following overdoses of thioridazine, mesoridazine, chlorpromazine, clozapine, and olanzapine. These effects include dry, flushed skin; dry mucous membranes; mydriasis; sinus tachycardia; decreased bowel sounds; urinary retention; myoclonic jerking and tremulousness; hyperthermia; agitation; delirium; and coma. Both hyperthermia and hypothermia have been described following antipsychotic overdose. Neuro-

muscular hyperactivity, seizures, the inability to sweat, and cutaneous vasodilation at high ambient temperature increase the likelihood of drug-associated hyperthermia. Coma, hypotension, suppressed shivering capability, and cutaneous vasodilation at low ambient temperatures increase the likelihood of drug-associated hypothermia. Miosis or mydriasis may occur with antipsychotic overdose. Miosis is more likely to occur in seriously poisoned patients with both atypical and typical agents; it has been described in 75% of adults and 72% of children after phenothiazine overdose.57,60,61,63,67 The most common cardiovascular manifestations of antipsychotic overdose are sinus tachycardia and orthostatic hypotension.57,59,60,63 Other cardiovascular effects occur uncommonly and include hypertension, sinus bradycardia, conduction abnormalities, and supraventricular and ventricular tachyarrhythmias. Electrocardiographic (ECG) abnormalities include prolongation of the PR, QRS, and QT intervals, nonspecific ST-T wave changes, depressed ST segments, T wave abnormalities (widening, flattening, notching, and inversion), increased U wave amplitude, rightward shift of the terminal 40 milliseconds of the QRS (i.e., the presence of R in aVR), atrioventricular, bundle branch, fascicular, and intraventricular blocks, and supraventricular and ventricular arrhythmias.3,68-72 Other than sinus tachycardia, repolarization abnormalities are the earliest and most common ECG abnormalities.68-72 Serious cardiotoxicity is more common with the aliphatic and piperidine phenothiazines and less common with atypical agents.3,57 TdP ventricular tachycardia has been reported after overdose of droperidol, haloperidol, mesoridazine, pimozide, and thioridazine.72-77 Cardiovascular and ECG abnormalities should be apparent within several hours of an acute overdose. Although EPS are often idiosyncratic reactions that follow therapeutic neuroleptic doses, these effects may also be dose related, and have occurred following overdose with many neuroleptics.54,59,64 EPS can be the presenting manifestation in a child following accidental neuroleptic poisoning.54,64,78

Adverse Effects All antipsychotics, typical or atypical, are associated with numerous adverse effects. Adverse effects may be idiosyncratic or dose related, can occur early or late in the course of therapy, and are often the result of receptor antagonism.1 Neurologic and cardiovascular side effects occur most commonly. EXTRAPYRAMIDAL SIDE EFFECTS EPS are a group of sustained movement disorders that can occur in approximately 30% of patients treated with antipsychotic agents and often lead to medication noncompliance in those with psychosis.1,79 All antipsychotics can produce EPS, but the incidence is significantly reduced for newer generation, atypical agents. The incidence of EPS is similar to that with placebo during chronic therapy with clozapine, olanzapine, quetiapine, ziprasidone, and aripiprazole.14,34,79-81 There are six EPS

CHAPTER 38

syndromes. They can be divided into the reversible syndromes that occur within hours to days (e.g., acute dystonia, akathisia) or days to weeks (e.g., parkinsonism, NMS) and the potentially irreversible syndromes that occur after months to years of therapy (e.g., TD, focal perioral tremor).1 Acute dystonia is a hyperkinetic movement disorder characterized by intermittent, uncoordinated, spasmodic, or sustained involuntary contractions of muscles of the face, tongue, neck, trunk, and extremities. Clinical manifestations include facial grimacing, trismus, blepharospasm, oculogyric crisis, tongue protrusion, buccolingual crisis, retrocollis, torticollis, opisthotonus, abnormal postures and gait, tortipelvis, and respiratory difficulty. ADRs, although distressing to patients, are rarely life threatening. Pharyngeal and laryngeal muscle spasm has produced respiratory distress and asphyxia.82 ADRs usually occur soon after initiation of antipsychotic therapy or after an increase in dose. Fifty percent occur within 48 hours and 90% within the first 5 days of treatment.83,84 The peak incidence occurs when antipsychotic concentrations are declining in the serum. In one study of pediatric patients, ADRs occurred 5 to 50 hours (mean 23 hours) after the first therapeutic dose and 1 to 20 hours (mean 5 hours) after single accidental ingestion of phenothiazines.85 The incidence of ADRs varies according to the agent’s identity, dose, route of administration, and duration of therapy, and the presence of individual risk factors. The incidence is lowest with agents that have low D2 receptor potency and/or high relative potency at 5-HT2, 5-HT1A, M1, α2, or D4 receptors (atypical agents). Incidence rates of 25%, 16%, 8.3%, 3.5%, and less than 1% have been described for IM fluphenazine decanoate, haloperidol, thiothixene, chlorpromazine, and atypical agents, respectively.33,83,84 Individual risk factors include male gender, young age (peak range 5 to 45 years), a family history or personal history of ADRs, or a recent history of cocaine or alcohol use.33,83,84,86,87 Akathisia is a condition of subjective unease and motor restlessness that occurs within minutes to days of initiation or increase of antipsychotic drug dosing.14,81 It is usually observed within the first 3 months of treatment.1 Akathisia may be misinterpreted as anxiety or agitation related to an underlying psychiatric condition. Akathisia is characterized by the inability to sit still and the overwhelming need to continuously move the legs or get up and walk or pace. Patients are frequently anxious, agitated, or unable to concentrate. About 30% of patients ingesting traditional agents develop akathisia.1,8,10,14,81 The incidence is less with atypical agents, with an incidence range of 5% to 15%.88,89 Akathisia is more likely to occur with the use of higherpotency D2 antagonists, larger doses, rapid dose escalation, and parenteral antipsychotic administration.14,81,88 Parkinsonism is a reversible, intermediate-stage EPS that typically occurs gradually over days to weeks and is evident by 2 to 3 months of therapy.1 Parkinsonism is characterized by muscle rigidity (cogwheel type), bradykinesia or akinesia, mask facies, shuffling gait, tremor (e.g., pill rolling), and cognitive impairment.


711

Antipsychotic-induced parkinsonism occurs in 13% of patients who take antipsychotic agents chronically.6,14 Antipsychotic-induced parkinsonism occurs in all age groups but occurs with greater frequency in the elderly. Other risk factors for its occurrence include female sex, the presence of organic brain injury, use of high-potency agents, and long duration of therapy.1,6,14,81 The rabbit syndrome is an uncommon reversible late-onset EPS characterized by perioral lip tremor. It usually occurs after months or years of antipsychotic treatment and is considered a variant of parkinsonism.1 TD is a hyperkinetic, late-onset EPS that typically occurs after 2 years of antipsychotic therapy and only rarely before 6 months.1,14,81 It is characterized by involuntary, painless, stereotyped, repetitive movements of orofacial structures and, occasionally, the trunk and arms. These movements include chewing; tongue protrusion; lip smacking, sucking, and pursing; facial grimacing; grunting; rapid eye blinking; and occasionally choreoathetosis of the trunk and limbs. TD is associated with all antipsychotic agents, but the incidence is significantly lower with atypical agents, particularly clozapine. TD develops in 15% to 25% of patients on long-term antipsychotic therapy. An annual incidence of 3% to 5% is described with traditional antipsychotics, whereas atypical agents have an annual incidence of less than 2%.90 TD occurs in patients of all ages (including children) but occurs more commonly in women older than 50 years.91 TD is frequently elicited in patients who have their drug discontinued or dose lowered after years of therapy.1,91 NMS is an uncommon but potentially fatal idiosyncratic complication of antipsychotic drug therapy. NMS is often considered an extreme, severe form of EPS92–95 (see also Chapter 10A). NMS usually occurs early in the course of treatment or soon after a change in dose but may appear at any time during therapy. It is estimated that NMS occurs in 2 out of every 1000 patients treated with neuroleptics.95 While NMS has been associated with all antipsychotic agents, most cases have been secondary to the high-potency agents haloperidol and fluphenazine, particularly their depot formulations. NMS is not a result of overdose and usually occurs with antipsychotic serum concentrations in the therapeutic range. Potential risk factors for development of NMS include rapid initiation of antipsychotic therapy; use of high-potency agents and depot preparations; dehydration; severe patient agitation or catatonia; requirement of restraints or patient seclusion; preexisting organic brain disease, mental retardation, or affective disorder; a history of NMS or electroconvulsive therapy (ECT); poorly controlled EPS; and concomitant use of predisposing drugs, namely lithium, anticholinergic agents, and antiparkinson agents.92-98 NMS occurs more commonly in men (2:1 male:female ratio), with a mean age of 40 years.92-98 NMS typically develops over a period of 24 to 72 hours and is commonly characterized by the tetrad of altered consciousness, fever (temperature greater than 38° C), muscular rigidity, and autonomic dysfunction.92-98 Altered mental status includes lethargy, agitation, mutism,

712


stupor, and coma. Muscular rigidity is lead pipe and cogwheel type, similar to parkinsonism.1 Autonomic dysfunction includes fever, tachycardia, tachypnea, hypertension or hypotension, diaphoresis, sialorrhea, pallor, flushing, urinary incontinence, and cardiac arrhythmias. Other common findings include EPS (e.g., tremor, bradykinesia, akinesia, festinating gait, chorea, dystonia, dysphagia, dysarthria, aphonia), mutism, seizures, abnormal reflexes, dyspnea, and hypoxemia. Laboratory abnormalities include elevated serum creatine phosphokinase (greater than three times normal) in up to 97% of cases, leukocytosis, elevated levels of hepatic transaminases, hyper- or hyponatremia, metabolic acidosis, myoglobinuria, elevated serum blood urea nitrogen and creatinine, and decreased serum iron levels.40,41,92-99 Medical complications of NMS include rhabdomyolysis, myoglobinuric renal failure, aspiration pneumonitis, pulmonary edema, pulmonary embolism, respiratory failure, sepsis, coagulopathy, disseminated intravascular coagulation, seizures, myocardial infarction, cardiac arrhythmias, peripheral neuropathy, necrotizing enterocolitis, and periarticular ossification.92-99 The presence of fever and muscle rigidity is usually required for diagnosis, but their absence has been associated with certain NMS variants. NMS is best considered a heterogeneous syndrome with variable signs, symptoms, and severity.93-95 Most cases of NMS seem to follow a sequence of development. Mental status changes and muscular rigidity precede autonomic dysfunction and fever in over 80% of cases.100 Early recognition of confusion, catatonia, or worsening EPS may facilitate timely treatment and halt progression to the fulminant syndrome.100 Once antipsychotics are discontinued, the signs and symptoms of NMS resolve over a period of 1 to 61 days, with a mean duration of approximately 10 days.94-97 The clinical course is nearly twice as long in patients who have received IM depot preparations.94-97 NMS was initially characterized as malignant due to its frequent fatal outcome. Mortality rate, once estimated to range from 17% to 28%, now ranges from 0 to 11.6%.92-102 SEIZURES Seizures are usually generalized and major motor type. Risk factors for seizures include a history of organic brain disease, epilepsy, drug-associated seizures, or ECT, an abnormal baseline EEG, polypharmacy, initiation of antipsychotic therapy, rapid dose titration and/or use of large antipsychotic doses, and the use of certain antipsychotic agents.23-29 Seizures occur most commonly with chlorpromazine, clozapine, and loxapine; the risk is dose dependent with these agents.25,28,29,57 A 0.5% incidence of seizures has been reported with low to moderate doses of chlorpromazine (30 to 900 mg/day) and 9% incidence with daily doses greater than 1 g.23 A seizure incidence of 1.8% has been reported with moderate doses of clozapine (300 to 600 mg/day), whereas those taking greater than 600 mg/day have an incidence of 4.4%.24,27,29 Seizures are unlikely to occur during therapeutic dosing with other antipsychotics;

the incidence is comparable with that of placebo (less than 1%).24 CARDIOVASCULAR Although repolarization abnormalities (e.g., prolongation of the QT interval) and arrhythmias are dose dependent and have been reported most frequently with antipsychotic overdose, these findings can also occur with therapeutic doses of these agents. QT prolongation has been associated with therapeutic dosing and overdose of aliphatic and piperidine phenothiazines, droperidol, haloperidol, loxapine, pimozide, quetiapine, risperidone, sertindole, and ziprasidone.3,28,68-77,103-117 The U.S. manufacturer of sertindole (Abbott Laboratories, North Chicago, IL) withdrew its new drug application for consideration by the Food and Drug Administration (FDA) due to concern that therapeutic dosing would be associated with TdP and sudden death. The rare association of ventricular arrhythmia (e.g., TdP) with therapeutic doses of droperidol (typically large doses) caused the FDA to issue a “black box” warning to U.S. health care practitioners in December 2001.115 Sudden unexplained death has been described in otherwise healthy patients taking therapeutic doses of many antipsychotic drugs.104,115-117 These deaths are presumed to be the result of malignant ventricular arrhythmias (e.g., TdP).116,117 In one series of sudden death from antipsychotics, more than half were associated with thioridazine.104 Myocarditis and cardiomyopathy have rarely been associated with the therapeutic use of antipsychotic agents. Ten cases of myocarditis, some with eosinophilic cellular infiltrates, have been described in association with clozapine; this adverse effect is rare, idiosyncratic, often occurs within 1 to 2 weeks of starting therapy, is likely the result of acute hypersensitivity, and may be fatal.118,119 METABOLIC Recently, the therapeutic use of the benzepines (e.g., clozapine, olanzapine, and quetiapine) and aripiprazole has been associated with an increased risk for developing type 2 diabetes mellitus or diabetic ketoacidosis (DKA).120-124 Numerous cases of fatal DKA or hyperglycemic hyperosmolar nonketotic coma have been reported in patients taking either clozapine or olanzapine.125-129 African Americans appear to be affected disproportionately as compared with other races.130 Hypertriglyceridemia has also been reported in patients taking olanzapine, clozapine, and quetiapine.131-134 Nonalcoholic steatohepatitis has been associated with the therapeutic use of olanzapine and risperidone, and pancreatitis has been associated with the use of clozapine.135,136 Asymptomatic elevations of hepatic transaminases (both cholestatic and hepatitic pattern) have been reported with most neuroleptics.137-139 These elevations are usually idiosyncratic, self-limiting, and typically occur during the first 3 months of therapy. Most atypical antipsychotics produce increased appetite and weight gain; these side effects occur most commonly

CHAPTER 38

with benzepine agents and are likely associated with the increased risk for acquired diabetes mellitus.1,14,57 Priapism, allergic dermatitis, photosensitivity, cholestatic jaundice, and pigmentation of the skin, cornea, lens, and retina have been associated with therapeutic phenothiazine use.1 HEMATOLOGIC TOXICITY Agranulocytosis (absolute neutrophil count of less than 500 per cubic millimeter) is a life-threatening idiosyncratic reaction that can rarely occur with phenothiazine and clozapine therapy. Agranulocytosis occurs in approximately 1 in 10,000 patients taking chlorpromazine and 1 in 100 patients taking clozapine.140-143 Early recognition (by regular white blood cell monitoring) and treatment (use of granulocyte colony-stimulating factor [G-CSF]) of clozapine-associated agranulocytosis has reduced its mortality to 3% to 4%.130 Prompt treatment with the use of G-CSF and granulocytemacrophage colony-stimulating factor (GM-CSF) has reduced the duration of granulocytopenia from a mean of 16 days to 8 days.144 Agranulocytosis has also been reported with the use of olanzapine, quetiapine, and risperidone.145-147 Clozapine has been associated with an increased risk for thromboembolic disease.148

DIAGNOSIS The diagnosis of antipsychotic poisoning is based on a positive history of ingestion, suggestive physical findings, and supporting evidence from the ECG, laboratory, and other adjunctive tests. Physical findings that suggest antipsychotic agent toxicity include CNS and/or respiratory depression, anticholinergic stigmata, miosis, hypotension, and EPS. The presence of sinus tachycardia and/or repolarization abnormalities on ECG supports a history of antipsychotic agent poisoning. Phenothiazines and butyrophenones are radiopaque and often visible on abdominal radiographs. The use of abdominal radiography as a diagnostic aid is not recommended, however, since a normal radiograph does not rule out significant ingestion of these or other antipsychotic agents. Similarly, although the Forrest, ferric chloride, and Phenistix colorimetric urine tests can be positive in the setting of phenothiazine ingestion, the tests are both insensitive and nonspecific.149 Thus, they should not be used to confirm or rule out ingestion of either phenothiazine or nonphenothiazine antipsychotics. Comprehensive screening of urine (using gas chromatography and mass spectrometry) may be used to qualitatively confirm the presence of most antipsychotics. Comprehensive testing, however, is not routinely available at most hospitals, and results are often delayed beyond 4 to 6 hours. In addition, comprehensive tests have other limitations. False-negative results may occur with newer atypical agents or if testing is performed too early or late following exposure. For instance, a falsenegative screen is likely to occur for a patient who


713

presents with EPS more than 24 hours after ingestion of a single antipsychotic tablet. Quantitative drug concentrations can also be performed for most antipsychotic agents (usually from the drug manufacturer). Serum drug concentrations, however, will not guide therapy; they do not correlate well with clinical toxicity and are not readily available. It should be recognized that certain antipsychotics (e.g., chlorpromazine, mesoridazine, quetiapine, and thioridazine) will often produce falsepositive results for tricyclic antidepressants on many commercial immunoassay screens for drugs of abuse.150 The diagnosis of NMS is clinical and based on a positive history of antipsychotic exposure and suggestive physical findings. The adoption and use of standardized criteria to make the diagnosis is recommended (Box 38-1).35,95,151,152 Fever and muscular rigidity should be present to make the diagnosis of NMS, and the diagnosis should not be made before other medical illnesses (e.g., CNS infection) have been excluded.

Differential Diagnosis Toxicity from antipsychotic agents produces signs and symptoms that are similar to many toxicologic and nontoxicologic entities. The CNS and cardiovascular manifestations of antipsychotic overdose may be similar to effects produced by alcohols, antiarrhythmics, anticholinergics, antiepileptics, antihistamines, barbiturates, cyclic antidepressants, lithium, opiates, sedative-hypnotics, and skeletal muscle relaxants. Toxicity from chlorpromazine, loxapine, mesoridazine and thioridazine can be clinically indistinguishable from that of cyclic antidepressants. CNS infection, traumatic head injury, cerebrovascular accidents, and metabolic disturbances should be considered and ruled out with appropriate testing. ADRs must be differentiated from anticholinergic, antiepileptic, and strychnine poisoning, CNS or oropharyngeal infections, hypocalcemia, hypomagnesemia, temporomandibular joint dislocations, cerebrovascular accidents, and conversion disorders. Akathisia may be mistaken for acute anxiety or agitation associated with underlying psychosis.1 NMS must be differentiated from the anticholinergic, serotonin, and sedative-hypnotic withdrawal syndromes; poisoning by hallucinogens, lithium, monoamine oxidase inhibitors, strychnine, and sympathomimetics; and intracranial hemorrhage, thyrotoxicosis, heat stroke, pheochromocytoma, malignant hyperthermia, and lethal catatonia. Malignant hyperthermia should not be confused with NMS. Malignant hyperthermia is a rare, inherited disorder of skeletal muscle calcium metabolism. Exposure to certain anesthetic agents (e.g., succinylcholine, halothane) or stress precipitates enhanced release and impaired reuptake of calcium from the sarcoplasmic reticulum in skeletal muscle cells. The result is excessive excitationcontraction coupling and a syndrome of muscle rigidity and fever that may appear clinically similar to NMS. Unlike NMS, malignant hyperthermia is associated with general anesthesia and not antipsychotics.

714

BOX 38-1


USEFUL DIAGNOSTIC CRITERIA FOR NEUROLEPTIC MALIGNANT SYNDROME (NMS)

Criterion 1*

Criterion 2†

Criterion 3‡

A. Treatment with neuroleptic agents within 7 days of symptom onset (2–4 weeks for depot agents)

A. Major: 1. Fever 2. Rigidity 3. Elevated CPK concentration B. Minor: 1. Tachycardia 2. Abnormal arterial blood pressure 3. Tachypnea 4. Altered mental status 5. Diaphoresis 6. Leukocytosis

A. Development of muscle rigidity and fever associated with the use of neuroleptics

B. Fever > 38° C

C. Muscle rigidity

D. Five of the following: 1. Change in mental status 2. Tachycardia 3. Hypertension or hypotension 4. Tachypnea or hypoxia 5. Diaphoresis or sialorrhea 6. Tremor 7. Incontinence 8. Increased CPK or myoglobinuria 9. Leukocytosis 10. Metabolic acidosis

C. The presence of all three major criteria, or two major and three minor criteria indicate a high likelihood of NMS D. Symptoms are supported by an appropriate clinical history

B. At least two of the following: Change in level of consciousness Mutism Tachycardia Hypertension or labile blood pressure Diaphoresis Dysphagia Tremor Incontinence Leukocytosis Laboratory evidence of muscle injury (e.g., elevated CPK) C. Symptoms in A and B are not due to another substance or to a neurologic or general medical condition D. Symptoms in A and B are not better accounted for by a mental disorder

CPK, creatine phosphokinase. *Data from reference 95. † Data from reference 152. ‡ Data from reference 151.

MANAGEMENT Overdose OVERVIEW Treatment for antipsychotic agent poisoning is mainly supportive.58 Patients with significant CNS or respiratory depression should have their airway protected, breathing assisted, and cardiovascular support provided as necessary. All patients should have continuous cardiac monitoring, an intravenous (IV) line established, and an ECG performed. Supplemental oxygen, continuous pulse oximetry, and parenteral thiamine, dextrose (or rapid fingerstick glucose determination), and naloxone should be considered for patients with altered mental status or seizures. Semicomatose patients should be placed in the left lateral, head-down position to minimize the risk for aspiration. Frequent vital sign and neurologic evaluations are necessary. Routine laboratory analysis should include a complete blood count and measure-

ment of electrolytes, blood urea nitrogen, creatinine, glucose concentrations, and pregnancy testing for women of childbearing age. Serum acetaminophen and salicylate concentrations should be performed for all intentional overdose patients. For patients with seizures or hyperthermia, laboratory evaluation should also include an arterial blood gas, urinalysis, and measurement of serum creatine phosphokinase, calcium, and magnesium concentrations. A complete blood count should also be obtained on any patient who presents with a fever while taking clozapine or chlorpromazine. SEIZURES Seizures are often self-limited and may not require specific treatment. If prolonged or recurrent, seizures should be treated with benzodiazepines (e.g., lorazepam 0.05 to 0.1 mg/kg IV). Barbiturates (e.g., phenobarbital 10 to 20 mg/kg IV) are reserved for seizures refractory to benzodiazepine therapy. Pentobarbital coma may rarely be necessary for patients with status epilepticus

CHAPTER 38

associated with certain antipsychotics (e.g., loxapine). The efficacy and safety of phenytoin treatment for antipsychotic-associated seizures is unknown. Measurements of blood glucose concentration and core temperature are imperative for those with seizures. CARDIOVASCULAR Hypotension is treated initially by placing the patient in the Trendelenberg position and administering IV crystalloid boluses (10 to 40 mL/kg). α-Adrenergic agonists (e.g., norepinephrine, phenylephrine) are the preferred vasopressors for treatment of refractory hypotension. Dopamine, an indirect-acting vasopressor, may be ineffective and is not recommended as a first-line agent for hypotension. Central venous, peripheral arterial, or pulmonary arterial catheter monitoring is recommended for patients requiring prolonged vasopressor therapy. Intraventricular conduction delay (e.g., prolonged QRS on ECG) and ventricular arrhythmias should be treated with sodium bicarbonate (1 to 2 mEq/kg IV bolus followed by intermittent boluses or continuous infusion).153 Lidocaine (1 to 1.5 mg/kg IV) is an acceptable alternative or second-line agent for ventricular arrhythmias.154 Types Ia (e.g., quinidine, procainamide), Ic (e.g., propafenone), II, III (e.g., amiodarone), and IV antiarrhythmic agents should be avoided in patients with cardiac conduction disturbances and/or ventricular arrhythmias. Their use may potentiate such cardiotoxicity.154 TdP ventricular tachycardia should be treated in the standard fashion (e.g., IV magnesium and/or lidocaine, overdrive pacing with isoproterenol or electrical pacing, correction of electrolyte disturbances).155-158 Sinus tachycardia associated with antipsychotic poisoning does not require specific treatment.


715

decontamination. Orogastric lavage is not routinely recommended since the risk for death following acute neuroleptic overdose is very low. If performed, gastric lavage should be followed by the administration of activated charcoal. Due to slowed gut motility and delayed drug absorption produced by the anticholinergic effects of many antipsychotics, activated charcoal administration is still recommended when patients present several hours after an overdose. The clinical benefit of this recommendation, however, is likely minimal. Forced emesis, use of cathartics, whole bowel irrigation, and multiple-dose activated charcoal are not recommended for antipsychotic poisoning due to their low likelihood to provide clinical benefit. Extracorporeal removal techniques are not recommended as part of treatment for antipsychotic poisoning since these agents have large volumes of distribution and high plasma protein binding.

Extrapyramidal Side Effects ADRS Treatment of ADRs may rarely require supplemental oxygen and assisted ventilation for patients with respiratory difficulty from laryngeal and pharyngeal dystonia. The usual treatment is parenteral administration of either diphenhydramine (1 mg/kg IV or IM) or benztropine (1 to 2 mg IV or IM in adults, or 0.02 to 0.05 mg/kg in pediatric patients). ADRs typically respond within 5 to 10 minutes of IV anticholinergic administration, but repeat dosing may be necessary for its complete resolution. If dystonia does not respond to anticholinergic therapy, diazepam (0.1 mg/kg IV) or lorazepam (0.05 to 1.0 mg/kg IV) may be effective. Following parenteral therapy, an oral anticholinergic agent should be administered for the next 48 to 72 hours to prevent dystonia recurrence.161

ANTICHOLINERGIC SYNDROME Physostigmine may be used to control agitation and reverse delirium in patients with the anticholinergic syndrome (ACS) from certain antipsychotics (see Chapter 39). It has been used successfully for patients with ACS associated with chlorpromazine, clozapine, olanzapine, and thioridazine.57,60,159,160 Physostigmine is safe provided that the ECG does not demonstrate cardiac conduction disturbances (e.g., prolonged PR or QRS intervals).159 Physostigmine should be given slowly IV (0.02 mg/kg in children, or 2 mg in adults) over 3 minutes. Because the clinical duration of action of physostigmine is short (20 to 90 minutes) compared with that of antipsychotic agents, resolution of the anticholinergic stigmata after physostigmine administration should not alter patient disposition. Agitation associated with the ACS from antipsychotics may also be treated with benzodiazepines.

AKATHISIA No treatment for akathisia is uniformly effective.88 Anticholinergic drugs significantly reduce the incidence of akathisia when administered prior to or concomitant with antipsychotic agents.162 Although recommended as first-line treatment for established akathisia, anticholinergic therapy often fails to provide consistent and adequate symptom relief.81,163 Alternatively, benzodiazepines may provide effective symptom relief.88 Patients who develop akathisia but require chronic antipsychotic treatment may benefit from reduction of the antipsychotic dose, substitution with another atypical agent, administration of propranolol (10 mg orally three times per day), clonidine (0.1 mg orally three times per day), cyproheptadine (16 mg/day), anticholinergic agents (e.g., benztropine or diphenhydramine), or benzodiazepines (e.g., diazepam).88,164-167

DECONTAMINATION AND ENHANCED ELIMINATION Gastrointestinal decontamination should be initiated rapidly after patient stabilization. Single-dose administration of activated charcoal (1 g/kg orally or by nasogastric tube) is the preferred method of gastrointestinal

PARKINSONISM Drug-induced parkinsonism may be minimized by using low doses of traditional antipsychotics, changing to an atypical agent, or adding either an anticholinergic agent (e.g., benztropine or diphenhydramine) or one that enhances dopaminergic activity (e.g., amantadine).81

716


TARDIVE DYSKINESIA Once tardive dyskinesia (TD) develops, it is difficult to treat and may be irreversible. The best treatment is to minimize its risk for occurrence.168 Antipsychotic drugs should be administered at the lowest possible effective doses, and periodic reevaluation should be performed to determine the continued need for antipsychotic therapy and evaluate for the earliest signs of TD.81,168 Because TD is a progressively irreversible disorder, early detection and prompt antipsychotic withdrawal will increase the likelihood of complete recovery. Atypical agents should preferentially be used for long-term therapy since they have a lower propensity for producing TD. Anticholinergic agents will exacerbate TD and should not be used.1 While higher doses of antipsychotic agents will temporarily relieve the symptoms of TD, this treatment is discouraged because it will further enhance dopamine receptor dysfunction and lead to worsening dyskinesia.1,81,168 NEUROLEPTIC MALIGNANT SYNDROME Successful treatment of neuroleptic malignant syndrome (NMS) requires prompt recognition, immediate withdrawal of antipsychotic and NMS-potentiating drugs (e.g., lithium or anticholinergics), exclusion of other medical conditions that could simulate or complicate NMS, and the provision of good supportive care. Good supportive care necessitates the provision of adequate ventilation and oxygenation, rehydration, aggressive temperature reduction, nutritional support, low-dose heparin to prevent thromboembolic disease, antibiotics to treat concurrent infection, and treatment of cardiopulmonary, metabolic, and renal complications.99 Gastrointestinal decontamination is not necessary since NMS is associated with therapeutic dosing of antipsychotic agents. Empirical antibiotic administration is prudent due to the difficulty in differentiating NMS from a systemic infectious process and the high incidence of concurrent infection. Prophylactic intubation should be strongly considered for patients with excessive sialorrhea, swallowing dysfunction, coma, hypoxia, acidosis, or muscular rigidity associated with their hyperthermia. The role of specific pharmacotherapies for NMS is controversial since most data on individual agent efficacy comes from retrospective studies and case reports. Although each therapy has been reported effective anecdotally in the management of NMS, none has been consistently beneficial or clearly superior to supportive care alone.94,95,99,169 Specific treatment measures include dantrolene, nondepolarizing neuromuscular paralysis, benzodiazepines, bromocriptine, amantadine, levodopa/ carbidopa, nifedipine, nitroprusside, and ECT. Anticholinergic agents are not recommended for treatment of NMS; they are considered ineffective and may worsen hyperthermia.37,94,95 One retrospective study in children and adolescents with NMS, however, noted a reduction in the duration of illness associated with the use of anticholinergic agents.97 Dantrolene is a hydantoin derivative that inhibits the release of ionized calcium from the sarcoplasmic reticulum. It causes direct muscle relaxation by

uncoupling excitation-contraction in the skeletal muscle. It is used to control NMS-associated rigidity and hyperthermia. It can be administered orally or intravenously. While the initial dosing is 1 to 2.5 mg/kg every 6 hours, doses up to 10 mg/kg/day are considered safe.94,95,170,171 Dantrolene should be continued until the signs and symptoms of NMS resolve. Bromocriptine, a dopamine receptor agonist, is given orally three times daily (2.5 to 10 mg/dose).94,95,99 Amantadine, which enhances presynaptic dopamine release, is given orally two times per day (100 to 200 mg per dose).94,95,99 Levodopa/carbidopa, which increases presynaptic dopamine stores, is given orally three to four times daily (25/250 mg per dose). Dopamine agonists are given alone or in conjunction with dantrolene or other muscle relaxants. For both dantrolene and dopamine agonist therapy, it is recommended that treatment be tapered over a period of days.92,172 Signs of NMS have returned when pharmacotherapies have been abruptly discontinued.173 In one retrospective analysis of 67 cases of NMS, dantrolene or bromocriptine reduced mean times to improvement and complete resolution of toxicity as compared with supportive care alone.174 Mean response time to clinical improvement was 1.0 day for bromocriptine, 1.7 days for dantrolene, and 6.8 days for supportive care alone. Mean time to complete resolution was 9.0 days for dantrolene, 9.8 days for bromocriptine, and 15.8 days for supportive care alone. A prospective nonrandomized study of 20 patients with NMS, however, demonstrated a more prolonged illness and greater complication rates with bromocriptine or dantrolene treatment as compared with supportive care alone.175 The mean duration of illness was 9.9 days for patients receiving bromocriptine/dantrolene versus 6.8 days for patients receiving supportive care. In retrospective analyses, dopamine agonists have been reported to reduce NMS mortality rates significantly, from 21% to 9.2%.176,177 The addition of dantrolene to bromocriptine treatment does not offer additional survival advantage. ECT has been employed successfully for NMS. In one review of 29 patients, a positive response occurred in 83% of patients.178 Some suggest that the mortality rate of NMS patients treated with ECT is lower than that of patients treated supportively.178 ECT should be reserved for severely affected patients since this therapy has been associated with cardiac arrhythmias, cerebral edema, and death.95 Prompt reduction of NMS-associated muscle rigidity and hyperthermia can be expected to minimize the risk for rhabdomyolysis, renal failure, pneumonia, respiratory failure, disseminated intravascular coagulation, and cardiovascular collapse. These complications are responsible for most NMS-associated deaths, and, thus, their prevention is paramount. Since NMS-associated hyperthermia occurs primarily from muscular rigidity, rapid peripheral muscle relaxation is imperative. Dantrolene and bromocriptine take a day or more to achieve fever reduction. Nondepolarizing neuromuscular paralysis will provide rapid, predictable, and effective resolution of rigidity and fever and should be the first-

CHAPTER 38

line treatment for patients who have severe hyperthermia (e.g., core temperature greater than or equal to 40° C). Pancuronium administration has been effective for the rapid control of fever and rigidity in patients with severe NMS.179 For patients with less severe NMS, a logical first approach to the management of fever and rigidity is the administration of benzodiazepines (e.g., diazepam 0.1 to 0.4 mg/kg or lorazepam 0.05 to 0.1 mg/kg IV) coupled with antipyretics, evaporative cooling, ice packs, and cooled IV fluids.180 The addition of dopamine agonist therapy and dantrolene may be helpful. If muscle rigidity persists and core temperature reaches 40° C despite these therapies, neuromuscular paralysis with a nondepolarizing paralytic agent is recommended. The level of intervention depends on the severity of illness.

Disposition Most patients with pure neuroleptic overdose develop only mild toxicity and are medically safe for psychiatric evaluation and disposition after an observation period of 4 to 6 hours in the emergency department. Patients who have continued evidence of mild toxicity (e.g., sinus tachycardia, mild CNS depression, QTc prolongation) at 6 hours should be admitted to a monitored bed for continued observation. Patients with evidence of moderate or severe toxicity at any time (e.g., significant CNS and/or respiratory depression, cardiac arrhythmias or conduction disturbances, acidosis, prolonged hypotension, seizures, ACS) should be admitted to the intensive care unit for supportive care. Due to its significant associated morbidity, all patients suspected of having NMS should be admitted initially to the intensive care unit. REFERENCES 1. Baldessarini RJ, Tarazi FI: Drugs and the treatment of psychiatric disorders: psychosis and mania. In Hardman JG, Limbrid LE, Gilman AG (eds): Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 485–520. 2. Buckley N, McManus P: Fatal toxicity of drugs used in the treatment of psychotic illnesses. Br J Psychiatry 1998;172:461–464. 3. Buckley NA, Whyte IM, Dawson AH: Thioridazine has greater cardiotoxicity in overdose than other neuroleptics, J Toxicol Clin Toxicol 1995;33:199–204. 4. Schreinzer D, Frey R, Stimpfl T, et al: Different fatal toxicity of neuroleptics identified by autopsy. Eur Neuropsychopharmacol 2001;11:117–124. 5. Watson WA, Litovitz TL, Rodger GC, et al: 2004 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2005; 23:589–666. 6. Richelson E: Receptor pharmacology of neuroleptics: relation to clinical effects. J Clin Psychiatry 1999;60(Suppl 10):5–14. 7. Blin O: A comparative review of new antipsychotics. Can J Psychiatry 1999;44:235–244. 8. Jibson MD, Tandon R: New atypical antipsychotic medications. J Psychiatr Res 1998;32:215–218. 9. Tandon R, Milner K, Jibson MD: Antipsychotics from theory to practice: integrating clinical and basic data. J Clin Psychiatry 1999;60(Suppl 8):21–28. 10. Borison RL: Recent advances in the pharmacotherapy of schizophrenia. Harvard Rev Psychiatry 1997;4:255–271.


717

11. Seeman P, Lee T, Chau-Wong M, Wong K: Antipsychotic drug doses and neuroleptic dopamine receptors. Nature 1976;261:717–719. 12. Farde L, Nordstrom AL, Wiesel FA, et al: Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry 1992;49:538–544. 13. Black JL, Richelson E: Antipsychotic drugs: prediction of side effect profiles based on neuroreceptor data derived from human brain tissue. Mayo Clin Proc 1987;62:369–372. 14. Casey DE: The relationship of pharmacology to side effects. J Clin Psychiatry 1997;58(Suppl 10):55–62. 15. Meltzer HY, Li Z, Kaneda Y, et al: Serotonin receptors: their key role in drugs to treat schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2003;27:1159–1172. 16. Kapur S, Remington G: Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry 1996;153:466–476. 17. Kinon BJ, Lieberman JA: Mechanisms of action of atypical antipsychotic drugs: a critical analysis. Psychopharmacology 1996;124:2–34. 18. Risch SC: Pathophysiology of schizophrenia and the role of newer antipsychotics. Pharmacotherapy 1996;16(Suppl):11–14. 19. Ogata N, Narahashi T: Block of sodium channels by psychotropic drugs in single guinea-pig cardiac myocytes. Br J Pharmacol 1989; 97:905–913. 20. Drolet B, Cincet F, Rail J, et al: Thioridazine lengthens repolarization of cardiac ventricular myocytes by blocking the delayed rectifier potassium current. J Pharmacol Exp Ther 1999; 288:1261–1268. 21. Rampe D, Murawsky K, Grau J, Lewis EW: The antipsychotic agent sertindole is a high affinity antagonist of the human cardiac potassium channel HERG. J Pharmacol Exp Ther 1998;286: 788–793. 22. Gould RJ, Murphy KMM, Reynolds IJ, et al: Antischizophrenic drugs of the diphenylbutylpiperidine type act as calcium channel antagonists. Proc Natl Acad Sci U S A 1983;86:5122–5125. 23. Logothetis J: Spontaneous epileptic seizures and electroencephalographic changes in the course of phenothiazine therapy. Neurology 1967;17:869. 24. Cold JA, Wills BG, Froemming JH: Seizure activity associated with antipsychotic therapy. DICP 1990;24:601–606. 25. Hedges D, Jeppson K, Whitehead P: Antipsychotic medication and seizures: a review. Drugs Today (Barc) 2003;39:551–557. 26. Pisani F, Oteri G, Costa C, et al: Effects of psychotropic drugs on seizure threshold. Drug Saf 2002;25:91–110. 27. Alldredge BK: Seizure risk associated with psychotropic drugs: clinical and pharmacokinetic considerations. Neurology 1999; 53(Suppl 2):68–75. 28. Peterson C: Seizures induced by acute loxapine overdose. Am J Psychiatry 1981;138:1089–1091. 29. Devinsky D, Honigfeld G, Patin J: Clozapine-related seizures. Neurology 1991;41:369–371. 30. Marsden CD, Jenner P: The pathophysiology of extrapyramidal side-effects of neuroleptic drugs. Psychol Med 1980;10:55–72. 31. Baldessarini RJ, Tarsy D: Dopamine and the pathophysiology of dyskinesia induced by antipsychotic drugs. Ann Rev Neurosci 1980;3:23–41. 32. Carlsson A, Walters N, Carlsson ML: Neurotransmitter interactions in schizophrenia—therapeutic implications. Biol Psychiatry 1999;46:1388–1395. 33. Rupniak NMJ, Jenner P, Marsden CD: Acute dystonia induced by neuroleptic drugs. Psychopharmacology 1986;88:403–419. 34. Kolbe H, Clow A, Jenner P, et al: Neuroleptic-induced acute dystonic reactions may be due to enhanced dopamine release or to supersensitive postsynaptic receptors. Neurology 1981; 31:434–439. 35. Mann SC, Caroff SN, Lazarus A: Pathogenesis of neuroleptic malignant syndrome. Psychiatr Ann 1991;21:175–180. 36. Henderson VW, Wooten GF: Neuroleptic malignant syndrome: a pathophysiologic role for the dopamine receptor blockade? Neurology 1981;1331:132–137. 37. Ebadi M, Pfeiffer RF, Murrin LC: Pathogenesis and treatment of neuroleptic malignant syndrome. Gen Pharmacol 1990; 21:367–386.

718


38. Lindvall O, Bjorklung A, Skagerberg G: Dopamine-containing neurons in the spinal cord: anatomy of some functional aspects. Ann Neurol 1983;14:255–260. 39. Stoof JC, Kebabian JW: Two dopamine receptors: biochemistry, physiology and pharmacology. Life Sci 1984;34:2281–2286. 40. Rosebush PI, Mazurak MF: Serum iron and neuroleptic malignant syndrome. Lancet 1991;338:149–151. 41. Garcia FM, Duarte J, Perez A, et al: Low serum iron and neuroleptic malignant syndrome. Ann Pharmacother 1993;27:101–102. 42. Javid JI: Clinical pharmacokinetics of antipsychotics. J Pharmacol 1994;34:286–295. 43. Ereshefsky L: Pharmacokinetics and drug interactions: update for new antipsychotics. J Clin Psychiatry 1996;57(Suppl 11):12–25. 44. Fang J, Gorrod JW: Metabolism, pharmacogenetics, and metabolic drug-drug interactions of antipsychotic drugs. Cell Mol Neurobiol 1999;19:491–510. 45. Micromedex Healthcare Series, Vol. 123. DRUGDEX drug evaluations, Risperdal Consta. Greenwood Village, CO, Thomson MICROMEDEX, 2004. Accessed December 29, 2004. 46. Howard L, Webb R, Abel K: Safety of antipsychotic drugs for pregnant and breastfeeding women with non-affective psychosis [Editorial]. BMJ 2004;329:933–934. 47. Dahl ML: Cytochrome p450 phenotyping/genotyping in patients receiving antipsychotics: useful aid to prescribing? Clin Pharmacokinet 2002;41:453–470. 48. Ozaki N: Pharmacogenetics of antipsychotics. Nagoya J Med Sci 2004;67:1–7. 49. Goff DC, Baldessarini RJ: Drug interactions with antipsychotic agents. J Clin Psychopharmacol 1993;13:57–67. 50. Klimke A, Klieser E: Sudden death after intravenous application of lorazepam in a patient treated with clozapine. Am J Psychiatry 1994;151:780. 51. Berry N, Pradhan S, Sagar R, et al: Neuroleptic malignant syndrome in an adolescent receiving olanzapine-lithium combination therapy. Pharmacotherapy 2003;23:255–259. 52. Joseph JK, Thomas K: Lithium toxicity—a risk factor for neuroleptic malignant syndrome. J Assoc Physicians India 1991;39:572–573. 53. Trenton A, Currier G, Zwemer F: Fatalities associated with therapeutic use and overdose of atypical antipsychotics. CNS Drugs 2003;17:307–324. 54. Mady S, Wax P, Wang D, et al: Pediatric clozapine intoxication. Am J Emerg Med 1996;14:462–463. 55. Yip L, Dart RC, Graham K: Olanzapine toxicity in a toddler [Letter]. Pediatrics 1998;102:1494. 56. Bond GR, Thompson JD: Olanzapine pediatric overdose [Letter]. Ann Emerg Med 1999;34:292–293. 57. Burns MJ: The pharmacology and toxicology of atypical antipsychotic agents. J Toxicol Clin Toxicol 2001;39:1–14. 58. Parsons M, Buckley NA: Antipsychotic drugs in overdose: practical management guidelines. CNS Drugs 1997;6:427–441. 59. Acri AA, Henretig FM: Effects of risperidone in overdose. Am J Emerg Med 1998;16:498–501. 60. LeBlaye I, Donatini B, Hall M, et al: Acute overdosage with clozapine: a review of the available clinical experience. Pharm Med 1992;6:169–178. 61. O’Malley GCF, Seifert S, Heard K, et al: Olanzapine overdose mimicking opioid intoxication. Ann Emerg Med 1999;34:279–281. 62. Harmon TJ, Benitez JG, Krenzelok EP, et al: Loss of consciousness from acute quetiapine overdosage. J Toxicol Clin Toxicol 1998;36:599–602. 63. Barry D, Meyskens FL, Becker CE: Phenothiazine poisoning: a review of 48 cases. Calif Med 1973;118:1–5. 64. Bonin MM, Burkhart KK: Olanzapine overdose in a 1-year old male. Pediatr Emerg Care 1999;15:266–267. 65. Dyer KS, Woolf AD: Use of phenothiazines as sedatives in children: what are the risks? Drug Saf 1999;21:81–90. 66. Li C, Gefter WB: Acute pulmonary edema induced by overdosage of phenothiazines. Chest 1992;101:102–104. 67. Mitchell AA, Lovejoy FH, Goldman P: Drug ingestions associated with miosis in comatose children. J Pediatr 1976;89:303. 68. Elkayam U, Frishman W: Cardiovascular effects of phenothiazines. Am Heart J 1980;100:397–401. 69. Fowler ND, McCall D, Chou T, et al: Electrocardiographic changes and cardiac arrhythmias in patients receiving psychotropic drugs. Am J Cardiol 1981;37:223–230.

70. Fletcher GF, Kazamias TM, Wenger NK: Cardiotoxic effects of Mellaril: conduction disturbances and supraventricular arrhythmias. Am Heart J 1961;78:135–138. 71. Thornton CC, Wendkos MH: EKG T-wave distortions among thioridazine-treated psychiatric inpatients. Dis Nerv Syst 1971; 32:320–323. 72. Frye MA, Coudreaut MF, Hakeman SM, et al: Continuous droperidol infusion for management of agitated delirium in an intensive care unit. Psychosomatics 1995;36:301–305. 73. Riker RR, Fraser GL, Cox PM: Continuous infusion of haloperidol controls agitation in critically ill patients. Crit Care Med 1994;22:433–440. 74. Krahenbuhl SI, Sauter B, Kupferschmidt H, et al: Reversible QT prolongation with torsades de pointes in a patient with pimozide intoxication. Am J Med Sci 1995;309:315–316. 75. Hulisz DT, Dasa SL, Black LD, et al: Complete heart block and torsade de pointes associated with thioridazine poisoning. Pharmacotherapy 1994;14:239–245. 76. Wilt JL, Minnema AM, Johnson RF, et al: Torsade de pointes associated with the use of intravenous haloperidol. Ann Intern Med 1993;119:391–394. 77. Sharma ND, Rosman HS, Padhi D, Tisdale JE: Torsades de pointes associated with intravenous haloperidol in critically ill patients. Am J Cardiol 1998;81:238–240. 78. Cheslik TA, Erramouspe J: Extrapyramidal symptoms following accidental ingestion of risperidone in a child. Ann Pharmacother 1996;30:360–363. 79. Muscettola G, Barbato G, Pampallona S, et al: Extrapyramidal syndromes in neuroleptic-treated patients: prevalence, risk factors, and association with tardive dyskinesia. J Clin Psychopharmacol 1999;19:203–208. 80. Balestrieri M, Vampini C, Bellantuono C: Efficacy and safety of novel antipsychotics: a critical review. Hum Psychopharmacol Clin Exp 2000;15:499–512. 81. Cortese L, Pourcher-Bouchard E, Williams R: Assessment and management of antipsychotic-induced adverse events. Can J Psychiatry 1998;43(Suppl 1):15–20. 82. Koek RJ, Edmond HP: Acute laryngeal dystonic reactions to neuroleptics. Psychosomatics 1989;30:359–364. 83. Swett C: Drug-induced dystonia. Am J Psychiatry 1982;132:532–534. 84. Ayd FJ: A survey of drug-induced extrapyramidal reactions. JAMA 1961;175:1054–1060. 85. Gupta JM, Lovejoy FH: Acute phenothiazine toxicity in childhood: a five-year survey. Pediatrics 1967;39:771. 86. Hegarty AM, Lipton RB, Merriam AE, et al: Cocaine as a risk factor for acute dystonic reactions. Neurology 1991;41:1670–1672. 87. Freed E: Alcohol-triggered neuroleptic-induced tremor, rigidity and dystonia. Med J Aust 1981;2:44–45. 88. Nelson DE: Akathisia—a brief review. Scott Med J 2001;46:133–134. 89. Kurz M, Hummer M, Oberbauer H, Fleischhacker WW: Extrapyramidal side effects of clozapine and haloperidol. Psychopharmacology 1995;118:52–56. 90. Kobayashi RM: Drug therapy of tardive dyskinesia. N Engl J Med 1977;296:257. 91. Yassa R, Ananth J, Cordozo S, et al: Tardive dyskinesia in an outpatient population: prevalence and predisposing factors. Can J Psychiatry 1983;28:391–394. 92. Nierenberg D, Disch M, Manheimer E, et al: Facilitating prompt diagnosis and treatment of the neuroleptic malignant syndrome. Clin Pharmacol Ther 1991;50:580–586. 93. Levinson DF, Simpson GM: Neuroleptic-induced extrapyramidal symptoms with fever: heterogeneity of the “neuroleptic malignant syndrome.” Arch Gen Psychiatry 1986;43:839–848. 94. Addonizio G, Susman VL, Roth SD: Neuroleptic malignant syndrome: review and analysis of 115 cases. Biol Psychiatry 1987;22:1004–1020. 95. Caroff SN, Mann SC: Neuroleptic malignant syndrome. Med Clin North Am 1993;77:185–202. 96. Shalev A, Munitz H: The neuroleptic malignant syndrome: agent and host interaction. Acta Psychiatr Scand 1986;73:337–347. 97. Silva RR, Munoz DM, Alpert M, et al: Neuroleptic malignant syndrome in children and adolescents. J Am Acad Adolesc Psychiatry 1999;38:187–194. 98. Pearlman CA: Neuroleptic malignant syndrome: a review of the literature. J Clin Psychopharmacol 1986;6:257–273.

CHAPTER 38

99. Pelonero AL, Levenson JL, Pandurangi AK: Neuroleptic malignant syndrome: a review. Psychiatr Serv 1998;49:1163–1172. 101. Velamoor VR, Norman RMG, Caroff SN, et al: Progression of symptoms in neuroleptic malignant syndrome. J Nerv Ment Dis 1994;182:168–173. 102. Keck PE, Pope HG, McElroy SL: Declining frequency of neuroleptic malignant syndrome in a hospital population. Am J Psychiatry 1991;148:880–882. 103. Kellam AMP: The (frequently) neuroleptic (potentially) malignant syndrome. Br J Psychiatry 1990;157:169–173. 104. Ravin DS, Levenson JW: Fatal cardiac event following initiation of risperidone therapy. Ann Pharmacother 1997;31(7–8):867–870. 105. Mehtonen OP, Aranko K, Malkonen L, et al: A survey of sudden death associated with the use of antipsychotic or antidepressant drugs: 49 cases in Finland. Acta Psychiatr Scand 1991;84:58–64. 106. Hollister LE, Kosek JV: Sudden death during treatment with phenothiazine derivatives. JAMA 1965;192:1035–1038. 107. Lee AM, Knoll JL, Suppes R: The atypical antipsychotic sertindole: a case series. J Clin Psychiatry 1997;58:410–416. 108. Brown K, Levy H, Brenner C, et al: Overdose of risperidone. Ann Emerg Med 1993;22:1908–1910. 109. Lynch S, Fill S, Hoffman RS: Intentional quetiapine (Seroquel) overdose [Abstract]. J Toxicol Clin Toxicol 1999;37:631. 110. Hustey FM: Acute quetiapine poisoning. J Emerg Med 1999;17:995–997. 111. Kopala LC, Day C, Dillman B, Gardner D: A case of risperidone overdose in early schizophrenia: a review of potential complications. J Psychiatry Neurosci 1998;23:305–308. 112. Flugelman MY, Tal A, Pollack S, et al: Psychotropic drugs and long QT syndromes: case reports. J Clin Psychiatry 1985;46:290–291. 113. Aunsholt NA: Prolonged QT interval and hypokalemia caused by haloperidol. Acta Psychiatr Scand 1989;79:411–412. 114. Lawrence KR, Nasraway SA: Conduction disturbances associated with administration of butyrophenone antipsychotics in the critically ill: a review of the literature. Pharmacotherapy 1997;17:531–537. 115. Lischke V, Behne M, Doelken P, et al: Droperidol causes a dosedependent prolongation of the QT interval. Anesth Analg 1994;79:983–986. 116. MedWatch 2001 Safety Information Summaries: Inapsine (Droperidol). Accessed January 16, 2005, from http://www. fda.gov/medwatch/safety/2001/safety01.htm#inapsi. 117. Glassman AH, Bigger JT Jr: Antipsychotic drugs: prolonged QT interval, torsades de pointes, and sudden death. Am J Psychiatry 2001;158:1774–1782. 118. Haddad PM, Anderson IM: Antipsychotic-related QTc prolongation, torsades de pointes and sudden death. Drugs 2002; 62:1649–1671. 119. Anonymous: Clozapine and myocarditis. WHO Drug Information 1994;8:212–213. 120. Merrill DB, Dec GW, Goff DC: Adverse cardiac effects associated with clozapine. J Clin Psychopharmacol 2005;25:32–41. 121. Lebovitz HE: Metabolic consequences of atypical antipsychotic drugs. Psychiatr Q 2003;74:277–290. 122. Liebzeit KA: New onset diabetes and atypical antipsychotics. Eur Neuropsychopharmacol 2001;11:25–32. 123. Gianfrancesco F, White R, Ruey-hua W, et al: Antipsychoticinduced type 2 diabetes: evidence from a large health plan database. J Clin Psychopharmacol 2003;23:328–335. 124. Citrone LL, Jaffe AB: Relationship of atypical antipsychotics with development of diabetes mellitus. Ann Pharmacother 2003;37: 1849–1857. 125. Torrey EF, Swalwell CI: Fatal olanzapine-induced ketoacidosis. Am J Psychiatry 2003;160:2241. 126. Koller EA, Doraiswamy PM: Olanzapine-associated diabetes mellitus. Pharmacotherapy 2002;22:841–852. 127. Avella J, Wetli CV, Wilson JC, et al: Fatal olanzapine-induced hyperglycemia. Am J Forensic Med Pathol 2004;25:172–175. 128. Meatherall R, Younes J: Fatality from olanzapine-induced hyperglycemia. J Forensic Sci 2002;47:893–896. 129. Wehring HJ, Kelly DL, Love RC, et al: Deaths from diabetic ketoacidosis after long-term clozapine treatment. Am J Psychiatry 2003;160:2241–2242. 130. Koller E, Schneider B, Bennett K, et al: Clozapine-associated diabetes. Am J Med 2001;15:716–723.


719

131. Iqbal MM, Rahman A, Husain K, et al: Clozapine: a clinical review of adverse effects and management. Ann Clin Psychiatry 2003;15:33–48. 132. Haupt DW, Newcomer JW: Hyperglycemia and antipsychotic medications. J Clin Psychiatry 2001;62(Suppl 27):15–26. 133. Meyer JM: Novel antipsychotics and severe hyperlipidemia. J Clin Psychopharmacol 2001;21:369–374. 134. Domon SE, Webber JC: Hyperglycemia and hypertriglyceridemia secondary to olanzapine. J Clin Adolesc Psychopharmacol 2001;11:285–288. 135. Kingsbury SJ, Fayek M, Trufasiu D: The apparent effects of ziprasidone on plasma lipids and glucose. J Clin Psychiatry 2001;62:347–349. 136. Haberfellner EM, Honsig T: Nonalcoholic steatohepatitis: a possible side effect of atypical antipsychotics. J Clin Psychiatry 2003;64:851. 137. Koller EA, Cross JT, Doraiswamy PM: Pancreatitis associated with atypical antipsychotics: from the Food and Drug Administration’s Med Watch surveillance system and published reports. Pharmacotherapy 2003;23:1123–1130. 138. Selem K, Kaplowitz N: Hepatotoxicity of psychotropic drugs. Hepatology 1999;29:1347–1351. 139. Hummer M, Kurz M, Kurzthalaer I, et al: Hepatotoxicity of clozapine. J Clin Psychopharmacol 1997;17:314–317. 140. Whitworth AB, Liensberger D, Fleischhacker WW: Transient increase of liver enzymes induced by risperidone: two case reports [Letter]. J Clin Psychopharmacol 1999;19:475–476. 141. Trayle WH: Phenothiazine-induced agranulocytosis [Letter]. JAMA 1986;256:1957. 142. Wren P, Frizzell LA, Keltner NL, et al: Three potentially fatal adverse effects of psychotropic medications. Perspect Psychiatr Care 2003;39:75–81. 143. Litvak R, Kaelbling R: Agranulocytosis, leukopenia and psychotropic drugs. Arch Gen Psychiatry 1971;24:265–267. 144. Alvir J, Lieberman J, Safferman A, et al: Clozapine-induced agranulocytosis; incidence and risk factors in the United States. N Engl J Med 1993;329:162–167. 145. Gerson SL: G-CSF and the management of clozapine-induced agranulocytosis. J Clin Psychiatry 1994;55(Suppl B):139–142. 146. Steinwachs A, Grohmann R, Pedrosa F, et al: Two cases of olanzapine-induced reversible neutropenia. Pharmacopsychiatry 1999;32:154–156. 147. Ruhe HG, Becker HE, Jessurun P: Agranulocytosis and granulocytopenia associated with quetiapine. Acta Psychiatr Scand 2001;104:311–313. 148. Dernovsek Z, Tavcar P: Risperidone-induced leucopenia and neutropenia. Br J Psychiatry 1997;171:393–394. 149. Hagg S, Spigset O, Soderstrom TG: Association of venous thromboembolism and clozapine. Lancet 2000;355:1155–1156. 150. Forrest FM, Forrest IS, Mason AS: Review of rapid urine tests for phenothiazine and related drugs. Am J Psychiatry 1961;118: 300–307. 151. Sloan KL, Haver VM, Saxon AJ: Quetiapine and false-positive urine drug testing for tricyclic antidepressants [Letter]. Am J Psychiatry 2000;157:148–149. 152. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC, American Psychiatric Association, 1994, pp 739–742. 153. Adnet P, Lestavel P, Krivosic-Horber R: Neuroleptic malignant syndrome. Br J Anaesth 2000;85:129–135. 154. Albertson TE, Dawson A, de Latorre FJ, et al: TOX-ACLS: toxicologic-oriented advanced cardiac life support. Ann Emerg Med 2001;37(Suppl 4):78–90. 155. Kawamura T, Kodama I, Toyama J, et al: Combined application of class I antiarrhythmic drugs causes “additive,” “reductive,” or “synergistic” sodium channel block in cardiac muscles. Cardiovasc Res 1990;24:925–931. 156. Tranum BL, Murphy ML: Successful treatment of ventricular tachycardia associated with thioridazine (Mellaril). South Med J 1969;62:357–358. 157. Lumpkin J, Watanabe AS, Rumack BH, et al: Phenothiazineinduced ventricular tachycardia following acute overdose. JACEP 1979;8:476–478. 158. Pietro DA: Thioridazine-associated ventricular tachycardia and isoproterenol [Letter]. Ann Intern Med 1981;94:411.

720


159. Kemper A, Dunlop R, Pietro D: Thioridazine-induced torsades de pointes successful therapy with isoproterenol. JAMA 1983;249: 2931–2934. 160. Burns MJ, Linden CH, Graudins A, et al: A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Ann Emerg Med 2000;35:374–381. 161. Schuster P, Gabriel E, Luefferie B, et al: Reversal by physostigmine of clozapine-induced delirium. Clin Toxicol 1977;10:437–441. 162. Corre K, Neimann J, Bessen H: Extended therapy for acute dystonic reactions. Ann Emerg Med 1984;13:194–197. 163. Vinson DR, Drotts DL: Diphenhydramine for the prevention of akathisia induced by prochlorperazine: a randomized, controlled trial. Ann Emerg Med 2001;37:125–131. 164. Lima AR, Weiser KV, Bacaltchuk J, Barnes TR: Anticholinergics for neuroleptic-induced akathisia. Cochrane Database Syst Rev 2004;1:CD003727. 165. Adler L, Angrist B, Peselow E, et al: A controlled assessment of propranolol in the treatment of neuroleptic-induced akathisia. Br J Psychiatry 1983;149:42–45. 166. Zubenko GS, Cohen BM, Lipinski JF, et al: Use of clonidine in treating neuroleptic-induced akathisia [Letter]. Psychiatry Res 1985;13:253. 167. Fischel T, Hermesh H, Aizenberg D, et al: Cyproheptadine versus propranolol for the treatment of acute neuroleptic-induced akathisia: a comparative double-blind study. J Clin Psychopharmacol 2001;21:612–615. 168. Miller CH, Fleischhacker WW: Managing antipsychotic-induced acute and chronic akathisia. Drug Saf 2000;22:73–81. 169. Sachdev PS: The current status of tardive dyskinesia. Aust N Z J Psychiatry 2000;34:355–369. 170. Susman VL: Clinical management of neuroleptic malignant syndrome. Psychiatr Q 2001;72:325–336. 171. Guze BH, Baxter LR: Neuroleptic malignant syndrome. N Engl J Med 1985;313:163–166.

172. Krause T, Gerbershagen MU, Fiege M, et al: Dantrolene—a review of its pharmacology, therapeutic use and new developments. Anaesthesia 2004;59:364–373. 173. Velamoor VR, Swamy GN, Parmar Late-RS, et al: Management of suspected neuroleptic malignant syndrome. Can J Psychiatry 1995;40:545–550. 174. Dhib-Jalbut S, Hesselbrock R, Mouradian MM, et al: Bromocriptine treatment of neuroleptic malignant syndrome. J Clin Psychiatry 1987;48:69–73. 175. Rosenberg MR, Green M: Neuroleptic malignant syndrome: review of response to therapy. Arch Intern Med 1989;149:1927–1931. 176. Rosebush PI, Stewart TD, Marzurek MF: The treatment of neuroleptic malignant syndrome: are dantrolene and bromocriptine useful adjuncts to supportive care? Br J Psychiatry 1991; 159:709–712. 177. Sakkas P, Davis JM, Hua J, et al: Pharmacotherapy of neuroleptic malignant syndrome. Psychiatr Ann 1991;21:157–164. 178. Sakkas P, Davis JM, Janicak PG, et al: Drug treatment of the neuroleptic malignant syndrome. Psychopharmacol Bull 1991;27: 381–384. 179. Davis JM, Janicak PG, Sakkas P, et al: Electroconvulsive therapy in the treatment of the neuroleptic malignant syndrome. Convuls Ther 1991;7:111–120. 180. Sangai R, Dimitrijevic R: Neuroleptic malignant syndrome: successful treatment with pancuronium. JAMA 1985;254:2795–2796. 181. Khaldarov V: Benzodiazepines for treatment of neuroleptic malignant syndrome. Hosp Physician 2000;36:51–55. 182. Burris KD, Molski FR, Xu C, et al: Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther 2002;302:381–389. 183. Baselt RC: Disposition of Toxic Drugs and Chemicals in Man, 7th ed. Foster City, CA, Biomedical Publications, 2004.

39

Anticholinergics and Antihistamines MARK A. KIRK, MD ■ ALEXANDER B. BAER, MD

At a Glance… ■

■

■ ■

Anticholinergic and sedating antihistamine agent poisoning is common and should be included in the differential diagnosis of any patient with an altered mental status and sinus tachycardia, particularly those with agitated delirium. The diagnosis of the anticholinergic syndrome is based on the clinical examination; the absence of patient sweating is a key physical finding. The majority of patients with anticholinergic poisoning have a good outcome with supportive care. Treatment with physostigmine is indicated for select patients with agitated delirium and the absence of conduction disturbances on the electrocardiogram.

INTRODUCTION AND RELEVANT HISTORY Anticholinergic drugs and plants have a distinct place in world history. Marc Anthony’s military troops were neutralized and defeated after ingesting hallucinogenic anticholinergic plants. In 1676, a witness wrote of British soldiers’ antics after they had consumed salad containing Datura stramonium. His account is a vivid description of anticholinergic poisoning1: . . . some of them eat plentiful of it [James-town weed], the Effect of which was a very pleasant Comedy; for they turn’d natural Fools upon it for several Days: One would blow up a Feather in the Air: another wou’d dart Straws at it with much Fury; and another stark naked was sitting up in a Corner, like a Monkey, grinning and making Mows at them; a Fourth would fondly kiss, and paw his Companions, and snear in their faces . . . and after Eleven Days return’d to themselves again, not remembring any thing that had pass’d. In the world of crime, scopolamine has been “truth serum,” “date-rape drug,” and “knockout drops” for great detective novels. In the real world, it has produced temporary psychosis so that victims could be robbed. Analgesia for broken bones and cure for the common cold are only a few of the historical uses of anticholinergic drugs. These drugs continue to contribute to modern medicine. Today, many classes of prescription and over-thecounter medications have anticholinergic properties. Anticholinergic effects are the desired therapeutic actions for some medications but may occur as unintended or exaggerated adverse drug effects for others. In addition to medications, a number of plants and mush-

rooms contain anticholinergic alkaloids. Some may be ingested deliberately for their mind-altering effects. Others may be added to illicit drugs to enhance the drug experience but produce inadvertent effects. For instance, scopolamine-tainted heroin2,3 and atropineadulterated cocaine4 has led to hospitalizations for anticholinergic poisoning. Anticholinergic toxicity has also been associated with the use of herbal supplements.5 Antihistamines are a diverse group of medications, most with potent anticholinergic effects and numerous other pharmacologic activities. The clinical syndrome of anticholinergic poisoning is one of the most common and readily recognized toxidromes. The ability to identify the signs and symptoms of this syndrome and differentiate it from other drug intoxications and medical illnesses is a basic skill that is necessary for all health care practitioners that care for poisoned patients.

CLASSIFICATION AND STRUCTURE Anticholinergics Anticholinergic (antimuscarinic) agents may be classified by their source (natural, semisynthetic, or synthetic) or structure (tertiary amine or quaternary ammonium compounds). The naturally occurring agents, atropine (d,lhyoscyamine) and scopolamine (l-hyoscine), are tropane alkaloids of the belladonna (family Solanaceae) plants.6 Specifically, atropine and scopolamine are esters of tropic acid (aromatic acid) and tropine and scopine (organic bases), respectively (Fig. 39-1). Semisynthetic derivatives are created by the addition of a different organic base to tropic acid or a methyl group to the base’s nitrogen. Synthetic derivatives have a wide variety of structures but maintain the ester bond in close proximity to a nitrogen to preserve anticholinergic activity. In general, anticholinergic activity requires the presence of a tertiary or quaternary amino group linked by two or three carbons to an ester, ether, or nitrogen and one or more aromatic rings (see Fig. 39-1). Embedded in each anticholinergic compound is a portion that resembles the structure of acetylcholine, which allows for competitive binding at muscarinic receptors. The most potent antimuscarinic agents have an ester and -OH group in close proximity to the amino group. Antimuscarinic compounds contain a tertiary amine or quaternary ammonium structure. The tertiary amines are readily absorbed from the gastrointestinal (GI) tract and freely cross the blood-brain barrier (BBB). Quaternary ammonium compounds, however, have a charge on their nitrogen and are, thus, not well absorbed from the GI tract and penetrate the BBB poorly. Quaternary deriv721

722


FIGURE 39-1 Structures of some anticholinergic agents.

H3C CH3N

H3C

CH3N

N;

J

J CH2OH

OH

CH2OH

O

O

K

K

O

O

K

O

CH3

O

Scopolamine

O

Atropine

Ipratropium

N;

CH3

J

ArJXJCJCJN

CH3

K

O

J J

J J

CH3

H3C

O

Acetylcholine

Muscarinic antagonist structure (Ar is aryl, X is an ester, ether, or nitrogen link)

atives, however, have more potency at both muscarinic and nicotinic receptors. The charge, like that of acetylcholine, enables greater attraction to the anionic active site of target receptors.

Antihistamines H1-receptor antagonists are typically divided into six structural classes. They include ethanolamines (diphenhydramine), ethylenediamines (pyrilamine), alkylamines (chlorpheniramine), piperazines (hydroxyzine), phenothiazines (promethazine), and piperidines (loratadine, acrivastine, cetirizine, and fexofenadine). Although potent antihistamines, doxepin (a dibenzoxepine) and other tricyclic antidepressants (TCAs) are classified by their other drug effects and considered separately (see Chapter 27). Except for the novel class of piperidines, all first-generation agents readily cross the BBB and are often referred to as sedating antihistamines. First-generation H1-receptor antagonists have a tertiary amino group connected by two or three carbons to a nitrogen or ether link and then two to three aromatic rings (Fig. 39-2).7 Like histamine, antihistamines have a β-aminoethyl side chain. Unlike histamine, antihistamines have substitutions on their amino group and more than a single aromatic ring. As shown in Figures 39-1 and 39-2, sedating antihistamines possess the structural characteristics necessary to bind and competitively antagonize muscarinic receptors (tertiary amine linked by an ethyl group to an aromatic ring). This large overlap of structure accounts for a large overlap in pharmacologic and toxic effects and is why these agents are considered together.

Agents That Produce the Anticholinergic Syndrome Both pharmaceutical agents and plants may cause significant anticholinergic toxicity (Box 39-1). For many medications, such as the GI antispasmodics or the local

mydriatics, the anticholinergic properties produce the desired therapeutic effect for the drug. Hence, many of the primary pharmacologic effects are not considered toxic. The desired therapeutic effects of other medications (e.g., antipsychotics and antiparkinsonian drugs), however, are not the anticholinergic manifestations. Thus, mydriasis, constipation, tachycardia, and dry mouth are frequently considered adverse effects. The more potent the anticholinergic binding relative to other drug effects, the more likely the antimuscarinic side effects will occur with therapeutic drug dosing. Combining medications with anticholinergic properties produces synergistic effects.8-10 For example, when antiparkinsonian medications are administered in combination with phenothiazines to prevent the occurrence of undesirable extrapyramidal reactions, this greatly increases the incidence of toxic confusional states.11 Small changes in the dose of either drug may precipitate the central anticholinergic syndrome in a previously unaffected individual.12 Many over-the-counter medications have anticholinergic properties and can precipitate the anticholinergic syndrome when ingested by an unknowing layperson who is already prescribed an agent with antimuscarinic activity. For example, the combined use of oral diphenhydramine with topical application of Caladryl lotion (calamine lotion and diphenhydramine [Parke-Davis, Morris Plains, NJ]) has produced central anticholinergic toxicity in children.13-15 An unusual form of toxicity involves the use of transdermal scopolamine patches.16 Several cases of the central anticholinergic syndrome have been reported in adults and children using the patches for treatment of motion sickness. Accidental instillation of the drug into the eyes has occurred after manipulation of the patch. This has resulted in a unilateral fixed dilated pupil or bilateral fixed dilated pupils without focal neurologic changes.17,18 This finding is also known as the “cornpicker’s pupil” and has been described in cornfield workers who have unintentionally rubbed pulverized jimsonweed in their eyes during harvesting.19 An additional

CHAPTER 39

Cl

S

723

FIGURE 39-2 Structures of some H1-histamine antagonists.

N

J

N Histamine

CH3

Promethazine

CH3

N

CH3

J

NH

J

N

N

J

J

J

Diphenydramine

H3C

N

J

J

J

CH3 N CH3

N CH3

J

J

N

O

H2NJ

Anticholinergics and Antihistamines

CH3

CH3

Chlorpheniramine

Tripelenamine

Ar1 XJCJCJN Ar2 H1-antagonist structure (Ar is aryl, X is a nitrogen, carbon, or ether link)

BOX 39-1

EXAMPLES OF AGENTS WITH ANTICHOLINERGIC PROPERTIES

Plants and Mushrooms

Antihistamines

Atropa belladonna (Deadly nightshade) Datura stramomium (Jimsonweed) Mandrigora officinarum (Mandrake) Hyoscyamine niger (Henbane) Amanita muscaria (Fly agaric) Amanita pantherina (Panther)

Brompheniramine (Dimetane) Chlorpheniramine (Ornade, Chlor-Trimeton) Cyclizine (Marezine) Dimenhydrinate (Dramamine) Diphenhydramine (Benadryl, Caladryl) Hydroxyzine (Atarax) Meclizine (Antivert)

Belladonna Alkaloids and Related Synthetic Compounds

Atropine Scopolamine Glycopyrrolate (Robinul) Antispasmodics

Clidinium bromide (Librax) Dicyclomine (Bentyl) Propantheline bromide (Pro-Banthíne) Methantheline bromide (Banthíne) Flavoxate (Urispas) Oxybutynin (Ditropan)

Antipsychotics

Chlorpromazine (Thorazine) Clozapine (Clozaril) Loxapine (Loxitane) Mesoridazine (Serentil) Olanzapine (Zyprexa) Thioridazine (Mallaril) Over-the-Counter Sleep Aids

Diphenhyramine (Benadryl) Doxylamine (Unisom)

Antiparkinsonism Medications

Cyclic Antidepressants

Benztropine mesylate (Cogentin) Biperiden (Akineton) Trihexyphenidyl (Artane)

Amitriptyline (Elavil) Clomipramine (Anafranil) Doxepin (Sinequan) Imipramine (Tofranil)

Local Mydriatics

Cyclopentolate (Cyclogyl) Homatropine (Isopto Homatropine) Tropicamide (Mydriacyl) Muscle Relaxants

Others

Amantadine (Symmetrel) Carbamazepine (Tegretol) Cyproheptadine (Periactin) Ipratropium (Atrovent)

Cyclobenzaprine (Flexeril) Orphenadrine (Norflex)

method of systemic anticholinergic toxicity involves the absorption of ophthalmologic agents or nasal decongestants through the conjunctiva, nasal mucosa, or GI tract.20,21

Scopolamine eyedrops have allegedly been used deliberately to disorient subsequent victims of theft.22 The victim is often found naked, disoriented, hallucinating, and amnestic to the events before hospital-

724


ization. Scopolamine was believed to have been placed in a beverage ingested by the victim.23 Many toxicologic laboratories do not routinely screen for scopolamine; therefore, these patients had negative results on toxicologic screens. Both anticholinergic pharmaceuticals and plants may be abused. Central anticholinergic effects of intentional ingestion may produce euphoria and hallucinogenic effects.24 It has been proposed that a physiologic dependence and the development of withdrawal symptoms exist when the agent is withheld.24 Among the most frequently reported anticholinergic drugs abused are the antiparkinsonian agents trihexyphenidyl and benztropine mesylate.25 These drugs have potent dopamine reuptake inhibition. The resulting dopamine excess is a proposed mechanism for craving of many abused drugs.25,26 Drug seekers may feign extrapyramidal symptoms to receive additional anticholinergic agents.24,27-30 Many types of plants contain alkaloids that produce anticholinergic stigmata in humans. Most of these are found in the family Solanaceae, which include the genera Atropa, Datura, Hyoscyamus, Lycium, and Solanum. The principal alkaloids found in these plants include solanine, atropine (a racemic mixture of d- and l-hyoscyamine, of which only the levorotatory isomer is pharmacologically active), and scopolamine (l-hyoscine). The mushrooms Amanita muscaria and Amanita pantherina have rarely been reported to cause anticholinergic or cholinergic toxicity. Anticholinergic effects can be severe but are rarely the prominent finding with poisoning by these mushrooms (see Chapter 23).31 The alkaloid content of each species and each plant varies greatly and depends on many parameters such as the time of year, the available moisture, and the temperature. For this reason, it is very difficult to determine predicted toxicity in relation to the amount and the origin of the plant material. Recreational abusers of anticholinergic mushrooms and D. stramonium (jimsonweed) are unable to titrate the dose of ingested substance because of this tremendous biologic variability and, therefore, are prone to severe anticholinergic poisoning.

PHARMACOLOGY Anticholinergics Acetylcholine is an endogenous neurotransmitter found in various synaptic sites and neuroeffector junctions (e.g., secretory glands and smooth and cardiac muscle) in the central and peripheral nervous systems.6 The actions of acetylcholine are mediated by muscarinic and nicotinic cholinergic receptors. Muscarinic receptor sites are in the brain (e.g., cerebral cortex, thalamus, hippocampus, reticular activating system), postganglionic parasympathetic nervous system, and select postganglionic sympathetic nervous system sites (e.g., sweat glands). Nicotinic receptors are located at the skeletal muscle motor end plate and spinal cord and autonomic ganglia.32 There are five subtypes of muscarinic receptors (M1–5) and all are transmembrane proteins that interact

with G proteins.32 Acetylcholine binds to and activates muscarinic receptors, and the result is stimulation or inhibition of cellular function. Nicotinic receptors are ligand-gated cation channels in autonomic ganglia and postsynaptic membranes. Their activation results in increased permeability to sodium and calcium ions, depolarization, and excitation. Nicotinic receptor activation is responsible for enhanced autonomic neurotransmission and skeletal muscle contraction. Acetylcholine is inactivated when metabolized at the synaptic cleft by the enzyme acetylcholinesterase. Anticholinergic drugs block acetylcholine’s action by competitively binding to and blocking muscarinic receptors. Receptor blockade and clinical effects are dose dependent. Clinical effects, however, are nonuniform since there is variable sensitivity of the neuroeffector organ sites to blockade by muscarinic receptor antagonists.6 Differential sensitivity is largely from the variable parasympathetic tone of each organ system but is also influenced by the effects of other neuronal inputs and the ability of the drug to reach the end organ. In general, small doses of anticholinergic drugs decrease secretions of the sweat, bronchial, and salivary glands. Larger doses produce mydriasis, cycloplegia, and increased heart rate from blockade of the sphincter muscle of the iris, ciliary muscle of the lens, and vagus nerve innervation to the heart, respectively. Even larger doses cause urinary retention and ileus from depressed bladder tone and GI motility, respectively. These classic peripheral anticholinergic effects are caused by blocking postganglionic cholinergic nerves and predominate in most cases of acute poisoning.33 Cholinergic neurons are spread widely through the cerebral cortex and subcortical areas.32 Because of this ubiquitous distribution, they likely have a role in regulation and modulation of other neurotransmitters.34 Central cholinergic pathways are important to memory, wake-sleep cycle, alertness, and orientation and for fine-tuning motor movements. Central anticholinergic syndrome refers to an acute psychosis or delirium resulting from inhibition of central cholinergic transmission. The degree of central anticholinergic activity is related to a medication’s ability to cross the BBB. Muscarinic antagonists are highly selective for muscarinic over nicotinic sites. Thus, the nicotinic receptors at autonomic ganglia and the motor end plates are unaffected by drugs that block muscarinic receptors.

Antihistamines Histamine is a mediator of the allergic response, a regulator of gastric acid secretion, and a central nervous system (CNS) neurotransmitter.35 Four distinct receptors have been identified (H1, H2, H3, H4). Stimulation of H1 receptors constricts bronchioles, dilates peripheral vasculature, increases vascular permeability, and triggers proinflammatory effects through B cells, T cells, monocytes, and lymphocytes.36 H1 receptors have also been detected in the brain, GI tract, and genitourinary tract. H2 receptors are primarily regulators of gastric acid secretion but are also present in the brain, lymphoid

CHAPTER 39

cells, and uterus. In the CNS, histamine (H1 and H2) modulates activities such as arousal, thermoregulation, and neuroendocrine and vegetative functions that are controlled by the neocortex, hypothalamus, and hippocampus.35 H3 receptors are expressed in the brain and the bronchial smooth muscle and are presynaptic regulators of synthesis and release of histamine into the synapse. The recently characterized H4 receptor is expressed on mononuclear cells, neutrophils, eosinophils, mast cells, and resting cluster of differentiation CD4 T lymphocytes. The antihistamines are reversible competitive inhibitors of H1-histamine receptors.35 Except for the newer, second-generation piperidines, all first-generation agents readily cross the BBB and produce both CNS excitation and depression. All H1 antagonists inhibit both the early vasodilatory effects and later vasoconstrictive effects of histamine. In addition, these agents block histamine-mediated increases in capillary permeability, pruritus, and salivary, lacrimal, and other exocrine secretions. First-generation antihistamines (but not second-generation agents) are also competitive antagonists at both central and peripheral muscarinic receptors and produce clinical effects that are often clinically indistinguishable from those of other anticholinergic drugs. Therapeutic antimuscarinic effects are likely responsible for the prevention of motion


725

sickness with these agents. In addition, antihistamines alter cortical neurons and block fast-sodium channels. These effects cause CNS symptoms, local anesthetic effects, and cardiac conduction abnormalities.37,38 Diphenhydramine and orphenadrine have been associated with QRS prolongation following overdose.38 Promethazine and other phenothiazines have α1-adrenergic blocking effects, which may result in hypotension. The piperidines block the outward potassium rectifier current of cardiac cells, and may result in QTc prolongation and torsades de pointes–type cardiac dysrhythmias. Some H1 antagonists affect serotonin receptors. Specifically, cyproheptadine is a competitive antagonist at 5-HT1- and 5-HT2-serotonin receptors.39

PHARMACOKINETICS Relevant pharmacokinetic parameters for the anticholinergic and antihistaminergic agents are listed in Table 39-1. Clinical toxicity is usually evident within 1 to 4 hours after ingestion of these agents, but the severity and duration of toxic effects are highly variable. The pharmacokinetic parameters of these agents may change significantly after overdose. Anticholinergic agents decrease gut motility and may produce delayed, erratic, and prolonged absorption with excessive doses.

TABLE 39-1 Pharmacokinetic Parameters of Common Anticholinergic and Antihistaminergic Compounds*

GENERIC NAME (TRADE NAME) Anticholinergic Agents dl-Hyoscyamine (Atropine)

Benztropine (Cogentin) Biperiden (Akineton) Cyclobenzaprine (Flexeril, Lisseril) Dicyclomine (Bentyl) Orphenadrine (Disipal, Norflex, Norgesic) Oxybutynin (Cystrin, Ditropan, Tropax) Scopolamine (Hyoscine, Transderm Scop, Donnatol) Trihexylphenidyl (Artane, Bentex, Broflex, Parkinane)

ROUTES OF ADMINISTRATION AND THERAPEUTIC DOSING FOR ADULTS


1–2


PROTEIN BINDING (%)

Vd (L/kg)

4.9–23

2.3–3.9 Hepatic

Yes

—

—

—

—

—

ACTIVE METABOLITE

Oral: 0.3–1.2 mg q 4–6 hr ETT: 0.6–2 mg Ophtho: 1 drop of 1%–2% solution up to tid IM/IV 0.04 mg/kg (0.5–1 mg, up to 3 mg) Oral/IV/IM: 1–2 mg bid to tid Oral/IV/IM: 2–16 mg/day

1.5

18–24

—

20–28

Hepatic

—

Oral: 10–20 mg bid to tid

3.8

24

97

—

Hepatic

Yes

Oral/IM: 10–40 mg tid to qid Oral/IM/IV: 25–100 mg bid to tid

1.5–2

5

—

—

Renal

—

13–20

20

4.3–7.8 Hepatic; renal (8%)

Yes

—

3

3–4

ROUTE OF METABOLISM

Oral: 5–20 mg/day divided qd to qid

1–2

2–5

—

1.3–2.8 Hepatic

Yes

Oral/IM: 0.01–0.5 mg single dose; Transdermal patch: 1.5 mg q 3 days Oral: 2–15 mg/day, divided qd to bid

1

2–6

10

1.4–2.0 Hepatic

No

24–41

—

—

—

1–2

Hepatic

726


TABLE 39-1 Pharmacokinetic Parameters of Common Anticholinergic and Antihistaminergic Compounds* (Cont’d)

GENERIC NAME (TRADE NAME)

ROUTES OF ADMINISTRATION AND THERAPEUTIC DOSING FOR ADULTS

Sedating H1 Antihistamines Brompheniramine Oral/IM/IV 4 mg 4–6 hr (Dimetane, Puretane) Chlorpheniramine Oral/IM: 0.5–8 mg qd to tid Clemastine (Tavist) Oral:1–2 mg qd to tid Cyclizine (Marezine) Oral/IM: 50 mg q 4–6 hr Cyproheptadine Oral: 4 mg tid (Periactin) Diphenhydramine Oral/IM/IV: 25–50 mg tid (Benadryl) to qid; 1 mg/kg/dose Doxylamine Oral: 12.5–25 mg q 4–6 hr (Bendectin, Diclectin, Unisom, Nyquil) Hydroxyzine (Atarax, Oral/IM: 25–100 mg tid Vistaril) to qid Meclizine (Antivert, Oral: 12.5–50 mg/day, Bonamine, Bonine, divided bid to tid Dramamine) Promethazine Oral/IM/IV rectal: 12.5– (Phenergan, Remsed, 25 mg tid Zipan) Pyrilamine (MidolOral: 25 mg tid to qid PMS, Robitussin Night Relief) Tripelennamine Oral: 25–50 mg bid to qid (Pyribenzamine) Triprolidine (Actifed) Oral: 1.25–2.5 mg q 4–6 hr Nonsedating H1 Antihistamines Acrivastine (Duact, Semprex-D) Cetirizine (Zyrtec) Desloratadine (Clarinex) Loratadine (Alavert, Claritin) Fexofenadine (Allegra) H2 Antihistamines Cimetidine (Tagamet)



PROTEIN BINDING (%)

Vd (L/kg)

ROUTE OF METABOLISM

Yes

ACTIVE METABOLITE

3–5

25

—

9–15

2–3

12–43

72

5.9

Hepatic (90%); renal (10%) Hepatic

2–3 2 —

21 7–24 —

— 75 —

7–16 13–21 —

Hepatic Hepatic Hepatic

Yes Yes —

1–4

3–14

78–98

3–4

Hepatic

Yes

Yes

1–4

10

—

2.7

Hepatic; renal

—

2

13–27

—

13–31

Hepatic

Yes

4

—

—

—

Hepatic

No

93

7–19

Hepatic

Yes

—

—

—

Hepatic

—

2–3

2.9–5.3

—

9–12

Hepatic

—

2

1.2–3.3

—

6–9

Hepatic

—

Oral: 4–12 mg qd to qid

1–2

1.7–3.5

50

0.6

Yes

Oral: 5–10 mg qd

1

6.5–10

93–98

0.58

Oral: 5 mg qd

3–6

21–27

82–87

10–30

Renal (67%); hepatic; fecal Renal (70%); hepatic; fecal (10%) Hepatic

Oral: 10 mg qd

2

3–20

97

32–261 Hepatic

Yes

Oral: 60 mg bid

2–4

9–20

60–70

12

No

1.4

2–3 —

9–19

0.5–3

1–4

18–26

Famotidine (Pepcid)

Oral/IM/IV: 1200–2400 mg/ day, divided bid to tid Oral: 20–40 mg qd to bid

1–2

2–4

15–22

Nizatidine (Axid)

Oral: 150–300 qd to bid

0.5–3

1.3–1.7

30

Ranitidine (Zantac)

Oral: 150–300 mg qd to bid

0.5–2.0

2.1

15

Fecal (80%); renal (10%)

Renal (35%–60%); hepatic (30%) 1–1.3 Renal (25%–70%); hepatic (30%–35%) 1.2–1.8 Renal (70%); renal (10%) 1.5 Renal (60%); hepatic (30%)

No Yes

No —

No No

*Pharmacokinetic data may be inaccurate when applied to overdose situation. Anticholinergic agent–induced decreased gut motility may create delayed and prolonged absorption following oral ingestion. —,data not available; bid, twice daily; ETT, endotracheal tube; IM, intramuscularly; IV, intravenously; Ophtho, ophthalmic. Pharmacokinetic data obtained from references 94 and 95.

CHAPTER 39

SPECIAL POPULATIONS: PREGNANCY AND LACTATION Most anticholinergic and antihistaminergic drugs are categorized as Class B or C by the U.S. Food and Drug Administration. Although largely unknown, most agents are likely secreted into breast milk as suggested by their large volumes of distribution. DIPHENHYDRAMINE There is one case-control study in which there was a slight statistical association between cleft palate and diphenhydramine exposure in the first trimester. Other than this single study, the vast majority of animal and human data support the safe usage of diphenhydramine in pregnancy. Diphenhydramine is excreted into human breast milk, and the manufacturer concludes that the drug is contraindicated in nursing mothers.40 CIMETIDINE Although the use of cimetidine in pregnancy has not been associated with congenital malformations, multiple animal studies and one human study of nonpregnant patients suggest an antiandrogen effect in the form of decreased prostate, seminal vesicle, and testes size and decreased human libido. Cimetidine is excreted into breast milk, but the effect on the infant is unknown.40 ATROPINE Atropine readily crosses the placenta. No fetal or neonatal adverse effects were noted in two human studies in which atropine was used to reduce gastric secretions before cesarean section. The largest study of fetal exposure to atropine demonstrated no associated congenital anomalies. Another smaller study, however, demonstrated a possible association of atropine exposure to neonatal limb reduction, but other factors could have contributed as well.40

TOXICOLOGY Clinical Manifestations Although anticholinergic agents often have activity at sites other than muscarinic receptors, the major clinical toxicity from these agents is the anticholinergic syndrome. Manifestations are divided into peripheral and central antimuscarinic effects (Box 39-2). Peripheral manifestations include (1) thirst, dry mucous membranes and hot, dry skin from inhibition of secretions from salivary glands, bronchioles, and sweat glands; (2) skin flushing from dilation of cutaneous blood vessels, especially those of the face; (3) hyperpyrexia from the inability to sweat and neuromuscular hyper-reactivity; (4) mydriasis, poor pupillary light response, and blurred vision from pupillary sphincter and ciliary muscle paralysis; (5) tachycardia from vagolytic effects; (6) urinary retention from inhibition of ureter and bladder contraction; and (7) decreased bowel sounds from inhibition of gastric emptying and GI motility. Sinus


BOX 39-2

727

SYMPTOMS/SIGNS OF ANTICHOLINERGIC TOXICITY

Peripheral (Muscarinic Blockade)

Tachycardia Dry, flushed skin Dry mucous membranes Dilated pupils Hyperpyrexia Urinary retention Decreased bowel sounds Hypertension Hypotension (late finding) Central Anticholinergic Syndrome

Confusion Disorientation Loss of short-term memory Ataxia Psychomotor agitation Picking and grasping movements Extrapyramidal reactions Visual/auditory hallucinations Frank psychosis Coma Seizures Respiratory failure Cardiovascular collapse

tachycardia is one of the earliest and most reliable signs of muscarinic receptor blockade.41 Thus, the absence of tachycardia early after anticholinergic poisoning suggests inaccurate history or co-ingestion of a cardiotoxic agent. The urinary bladder may be palpable from bladder atony, and impaired bowel motility may produce an ileus and delayed and prolonged drug absorption. This latter effect may result in prolonged symptoms secondary to protracted drug absorption. Anticholinergic delirium, or the central anticholinergic syndrome, is characterized by patient hyperactivity; tremulousness; disorientation; short-term memory impairment; agitation; delirium; visual and auditory hallucinosis; slurred, nonsensical, or incoherent speech; meaningless motor activity such as repetitive picking at bed clothes or grabbing at nonexistent objects; removal of clothing; seizures; and coma.8-10,42-44 In overdose, both central and peripheral anticholinergic signs are commonly present. Indeed, the famous mnemonic, “Mad as a hatter, red as a beet, dry as a bone, blind as a bat, and hot as a hare” describes the syndrome well. The central anticholinergic syndrome may occasionally occur without evidence of peripheral signs.45-48 Although one study reported that “isolated” central anticholinergic signs and symptoms were present in 17% of their patients with the anticholinergic syndrome, dry skin was preserved in those with central sign predominance.49 Thus, “isolated” central anticholinergic syndrome will likely have at least some peripheral signs of poisoning present and should be more appropriately termed central predominance anticholinergic syndrome.

728


Central predominance anticholinergic syndrome seems more likely to occur in the very young and old, those with underlying organic brain syndrome, those with exaggerated antimuscarinic responses to therapeutic doses, and late following an acute overdose (when peripheral effects have decreased in intensity).10 Anticholinergic agents may produce seizures following both therapeutic and excessive doses. Seizures are more commonly dose related and, thus, occur more frequently in overdose. Anticholinergic-induced seizures are usually short lived and require no specific therapy. However, large overdoses of diphenhydramine, pyrilamine, hydroxyzine, orphenadrine, cyclic antidepressants, and carbamazepine have caused prolonged or repeated seizures. The mechanism of anticholinergic-induced seizures remains unclear. The majority of seizures related to anticholinergic toxicity seem to be associated with medications having other toxic manifestations rather than purely anticholinergic drugs. Seizures have been reported with antihistamine, cyclic antidepressant, phenothiazine, and carbamazepine poisonings but are infrequently reported in jimsonweed abusers and atropine-poisoned infants. Interestingly, researchers have suggested that histamine may have a role as a natural anticonvulsant. Positron emission tomography has demonstrated possible H1 receptors’ coalescence around epileptogenic foci in brain, and this may inhibit generalization of epileptic discharges in the brain.50 Histamine and its precursor, histidine, seem to act as anticonvulsants in the mammalian brain by their actions on presynaptic H3 receptors and postsynaptic H1 receptors.51-54 H1 antagonists have been shown to decrease the seizure threshold in rats and mice by heat and electrical stimuli to the brain, respectively.52,53 Similarly, antihistamines increase electroencephalographic abnormalities and are suspected of producing seizures in epileptic patients. Retrospective data have suggested that phenothiazines, a class of antihistamine, decrease the seizure threshold.55,56 Doxepin and other cyclic antidepressants are potent histamine blockers that frequently cause seizures when taken in serious overdoses. In addition, seizure activity from some medications with anticholinergic activity is due to interactions at γ-aminobutyric acid (GABA) receptors (cyclic antidepressants) or adenosine receptors (carbamazepine). Sinus tachycardia is the most common arrhythmia in anticholinergic poisoning and occurs by blocking vagal effects on M2-muscarinic receptors on the sinoatrial node pacemaker.6 Sinus tachycardia is most prevalent in young, healthy adults who normally have high resting vagal tone.6 Tachycardia may not be as evident in the very young and old. Some anticholinergic agents cause life-threatening cardiac arrhythmias by mechanisms other than muscarinic blockade. Medications with anticholinergic effects and the potential to cause quinidinelike conduction abnormalities include cyclic antidepressants, phenothiazines, diphenhydramine, chlorpheniramine, orphenadrine, pyrilamine, and class IA antiarrhythmics.38 These drugs have sodium channel–blocking properties that not only slow conduction but also

decrease myocardial contractility. Phenothiazines also block rectifying potassium channels and may prolong the QT interval and cause torsades de pointes or other ventricular dysrhythmias. Rhabdomyolysis is an occasional complication of anticholinergic poisoning, particularly for patients that have psychomotor agitation.57 Drug-induced rhabdomyolysis from anticholinergic poisoning is due to excess energy use or inadequate oxygen and nutrient delivery to the muscle, which causes myocyte breakdown. Patients at greatest risk are those who have repetitive or prolonged seizures, coma, compartment syndrome, hyperthermia, or severe agitation requiring restraint. Death from anticholinergic or antihistamine poisoning is most often from cardiac arrhythmia and is frequently associated with seizures. Death is not likely to occur from antimuscarinic receptor antagonism but rather the sodium and potassium channel–blocking effects of these drugs.58

Diagnosis The diagnosis of anticholinergic or sedating antihistamine poisoning is based on a positive history of ingestion and physical findings consistent with the anticholinergic syndrome. When a history of ingestion is not available from the patient due to delirium or obtundation, patient belongings and the exposure environment should be searched for clues to diagnosis. Any knowledge of a patient’s past medical history, particularly a list of medications, may greatly assist diagnosis. Any history obtainable from friends or relatives about abuse of drugs or hallucinogenic plants (particularly jimsonweed and mushrooms) may be of value. A history of recent travel and the use of scopolamine patches should be sought. In a mixed ingestion, the physical findings may be variable and make the diagnosis more challenging. Electrocardiographic (ECG), laboratory, and other adjunctive tests are not often helpful to confirm or refute the diagnosis of anticholinergic poisoning. An ECG often demonstrates sinus tachycardia alone. The presence of repolarization abnormalities (e.g., nonspecific ST-T changes, QT prolongation) is consistent with certain agents (e.g., diphenhydramine). As with many poisonings, a toxicology screen has limited value. Agents that produce anticholinergic toxicity are not often part of a routine immunoassay screen.23 Comprehensive qualitative screening techniques (e.g., gas chromatography/mass spectrometry) and quantitative assays are not readily available and do not routinely guide treatment. These tests may be useful for confirmation of the presence of a drug after treatment has been initiated. Toxicology screens are more useful to identify other causes of altered mental status or to identify unsuspected co-ingestions (e.g., acetaminophen). As stated, the diagnosis and treatment of the anticholinergic syndrome is guided by the clinical examination. This cause of delirium can be missed if the physician fails to recognize associated peripheral signs or inappropriately dismisses the diagnosis because common

CHAPTER 39

peripheral anticholinergic signs (e.g,, sinus tachycardia and mydriasis) are absent. Anticholinergic delirium has been misdiagnosed as dementia or psychotic depression in elderly patients and varicella encephalitis in children.45,47

DIFFERENTIAL DIAGNOSIS OF ANTICHOLINERGIC POISONING The constellation of symptoms that identify the anticholinergic syndrome can be mimicked, in part, by many other toxins and medical conditions (Box 39-3). Distinguishing it from adrenergic excess (sympathomimetic poisoning, thyrotoxicosis, or pheochromocytoma) can be difficult. The pupillary, cardiovascular, and CNS effects of sympathomimetic poisons are similar to those produced by anticholinergic poisoning. Sweating frequently accompanies adrenergic stimulation, whereas dry skin and mucous membranes are characteristic of anticholinergic poisoning. Paranoid hallucinations and violent behavior often accompany adrenergic-induced

BOX 39-3

TOXINS AND MEDICAL CONDITIONS EASILY CONFUSED WITH THE ANTICHOLINERGIC SYNDROME

Toxins

Adrenergic poisons Amphetamines Caffeine Cocaine Methylphenidate Pseudoephedrine Theophylline Autonomic dysfunction Disulfiram reactions Neuroleptic malignant syndrome Serotonin syndrome Withdrawal from ethanol or benzodiazepines Central hallucinogen poisoning Lysergic acid diethylamide Mescaline Phencyclidine Psilocybin mushrooms Lithium poisoning Salicylate poisoning Steroid-induced psychosis Medical Conditions

Adrenergic excess Pheochromocytoma Thyrotoxicosis Central nervous system infection Cerebral vasculitis Dehydration Heat stroke Hypoglycemia Hypoxia Psychiatric illnesses Sepsis


729

hallucinations, whereas anticholinergic poisoning causes mumbling speech, picking at sheets, and disorientation. Urinary retention may also be helpful in distinguishing anticholinergic from sympathomimetic poisoning. The anticholinergic syndrome has similarities to the autonomic dysfunction and altered mental status that occurs with ethanol or sedative-hypnotic withdrawal, serotonin syndrome, neuroleptic malignant syndrome, or a disulfiram reaction. The absence of sweat with the anticholinergic syndrome is a key differentiating feature from these other drug-associated syndromes. Chronic salicylate poisoning can appear similar to anticholinergic poisoning because patients often present with altered mental status, tachycardia, and fever. Medical conditions can also mimic the anticholinergic syndrome. Hypoxia or hypoglycemia causes delirium, agitation, or CNS depression. Dry, hot skin and altered sensorium due to heat stroke, dehydration, or sepsis can be mistaken for anticholinergic toxicity. Central anticholinergic effects in the absence of peripheral signs can be similar to those caused by some hallucinogenic substances, steroidinduced psychosis, vascular or infectious CNS disease, sepsis, or psychiatric illnesses.

TREATMENT OF ANTICHOLINERGIC TOXICITY General Management The majority of patients poisoned by anticholinergic agents are adequately treated with supportive care and observation. Anticholinergics inhibit GI motility and can cause prolonged, erratic, or delayed drug absorption. After a large overdose of benztropine, a patient demonstrated erratic absorption and repeated worsening of anticholinergic symptoms over 9 days.59 Because of slowed GI absorption, gastric emptying procedures may be useful even when patients present many hours after toxicant ingestion. Administration of charcoal is effective for preventing further drug absorption. Repeated doses of activated charcoal may play a role in preventing continued absorption, although the development of ileus limits its use. There is no role for enhanced elimination techniques (e.g., hemodialysis or hemoperfusion) with anticholinergic agents and antihistamines due to their large volumes of distribution and high protein binding (see Table 39-1). A search for and removal of a transdermal patch should be initiated in all patients with altered mental status that could be attributed to the anticholinergic syndrome.

Treatment of Agitation Anticholinergic-induced delirium ranges from mild confusion to severe agitation and possibly violence. Controlling agitation is necessary for adequate patient assessment and to prevent rhabdomyolysis, hyperthermia, and physical injury. Physical and chemical re-

730


straints are indicated for the treatment of severe agitation. Benzodiazepines may be tried initially to control patient agitation, but they are often ineffective when anticholinergic-associated agitation is severe.60 Adjunctive therapy with haloperidol or other neuroleptics is not recommended to control agitation since these agents can impair thermoregulation. Provided no contraindications for its use exist (see Antidote Theraphy), physostigmine has been shown to be both safe and effective for the treatment of agitated delirium in the setting of known or suspected anticholinergic syndrome.49 As compared with benzodiazepine therapy, physostigmine treats patient delirium better, controls patient agitation more effectively, may decrease the need for mechanical ventilation, and shortens the course of neurologic morbidity.49 When the diagnosis is initially suspected but uncertain, physostigmine may obviate the need for further testing (e.g., head computed tomography and lumbar puncture) upon resolution of delirium.49

Treatment of Seizures Although the mechanism of seizures is not well understood for this class of agents, drug-associated seizures are generally best treated with benzodiazepines (e.g., diazepam or lorazepam) followed by barbiturates (e.g., phenobarbital) when necessary. Data from case reports suggest that physostigmine may be effective for seizure termination, but clinical experience is limited and efficacy not well established.61,62 The administration of physostigmine for seizures from this class of agents is not recommended, particularly since seizures are a known major adverse effect from physostigmine.

Treatment of Rhabdomyolysis Agitation and excessive neuronal stimulation increase the risk of rhabdomyolysis. Controlling agitation and seizures is important to prevent rhabdomyolysis. Serial measurements of creatine phosphokinase in blood and determination of occult blood positivity in the urine will help identify those at risk for developing acute renal failure from rhabdomyolysis. Ensuring adequate urine output with intravenous (IV) fluids is the mainstay of treatment for preventing acute tubular necrosis.57 The efficacy of mannitol and urine alkalinization has not been established for the routine treatment of rhabdomyolysis.63

Treatment of Cardiovascular Toxicity Sinus tachycardia is the most common toxic cardiovascular effect from anticholinergic poisoning but rarely requires intervention. A large number of drugs with anticholinergic effects cause QRS prolongation and dysrhythmias by blocking fast-sodium channels (type 1a activity).64-66 IV sodium bicarbonate improves impaired conduction from fast-sodium channel blockers such as cyclic antidepressants, diphenhydramine, and orphenadrine.38,67 Rarely, myocardial pump failure occurs with large overdoses. Case reports have demonstrated that

refractory shock can occur despite aggressive medical intervention. Patients with such profound cardiovascular toxicity have been successfully resuscitated after cardiac bypass or intra-aortic balloon pump procedures.68

Antidote Therapy Although its use is controversial, physostigmine is a well-recognized antidote that can be used to treat the anticholinergic syndrome. Physostigmine, a naturally occurring alkaloid obtained from the West African vine Physostigma venosum, is a reversible, carbamate cholinesterase inhibitor.6 After a single dose of physostigmine, the action of acetylcholine is potentiated at postganglionic parasympathetic and central cholinergic neuroreceptors, and the competitive blockade by anticholinergic agents is reversed by mass action. As a tertiary amine, physostigmine readily crosses the BBB and is capable of reversing central anticholinergic effects (e.g., agitation, hallucinations, delirium, and coma).69-73 Peripherally, physostigmine may reverse the tachycardia, mydriasis, ileus, and urinary retention that occur secondary to muscarinic blockade. Physostigmine is a nonspecific analeptic. Its administration results in cholinergic modulation of other CNS neurotransmitter pathways by poorly understood mechanisms. The sedating effects of drugs without anticholinergic activity have responded to physostigmine administration through nonspecific arousal.73 Because of this, physostigmine was employed as part of a “coma cocktail” in the 1970s and often administered to patients with undifferentiated drug-induced coma. When used for this indication, physostigmine was neither consistently effective nor safe. Physostigmine resulted in an unacceptable high incidence of side effects (e.g., seizures, cholinergic crisis, bradyarrhythmias, and asystole), particularly when used for TCA poisoning.60 In one clinical series, 2 of 21 patients who received physostigmine had seizures after its administration, and 2 developed cholinergic symptoms (hypersalivation in 1 patient, bradycardia and hypotension in the other). The author of this series concluded that physostigmine has “little part to play in routine management” because patients with anticholinergic symptoms usually fare well with supportive therapy alone.74 In another clinical series of 26 patients (of which 17 had ingested a TCA), seizures occurred in 3 (12%) patients and bradycardia in 1 patient given physostigmine.75 In a recent retrospective chart review of 39 adults who were administered physostigmine for the anticholinergic syndrome, 1 (2.6%) developed a brief seizure. However, this individual had presented after a 1- to 2-minute seizure, so it is impossible to say that physostigmine caused the seizure.76 In a retrospective study that compared treatment of physostigmine with benzodiazepines in a group of 52 patients with anticholinergic delirium, physostigmine was more effective for the control of agitation and reversing delirium.49 One case report described a patient poisoned by D. stramonium (jimsonweed), who developed atrial fibrillation and a short run of ventricular tachycardia 45 minutes after administration of physostigmine.77 In an

CHAPTER 39

AU: Unclear what you mean by ‘dangerous for use’. Do you mean for any use?

additional case report, an 85-year-old man developed ventricular ectopy 30 minutes after receiving 1 mg of physostigmine.78 Physostigmine is no longer indicated in the treatment of cyclic antidepressant poisoning, and evidence strongly suggests that it is dangerous for use.74,75,79,80 A series of 41 patients taking intentional overdoses of maprotiline showed that 6 of 7 patients treated with physostigmine developed seizures.74 The investigators concluded that the use of physostigmine should be abandoned in overdoses of maprotiline and other cyclic antidepressants. The danger of physostigmine administration is further illustrated in another cases series of two patients with acute severe TCA poisoning. The administration of physostigmine was temporally associated with the occurrence of bradyasystole.80 The potential risks associated with physostigmine are greater than the benefits gained from its use in cyclic antidepressant toxicity. There is a long history of clinical use of physostigmine as an antidote. It is apparent that when used inappropriately (e.g., nondifferentiated drug-induced coma, known or suspected TCA poisoning, rapid IV administration), it is associated with an unacceptably high incidence of side effects. Conversely, when used appropriately, it is both safe and effective and the preferred treatment for the anticholinergic syndrome. The use of physostigmine is indicated for the treatment of patient agitation and delirium in known or suspected anticholinergic syndrome, particularly when patients are dangerous to themselves or others. Although efficacy is not wellestablished, physostigmine may also be appropriate for narrow complex supraventricular arrhythmias in the setting of the anticholinergic syndrome that result in hemodynamic instability (hypotension, myocardial ischemia, or congestive heart failure) when other attempts to control heart rate have failed or are believed to be too risky in a particular patient. Neostigmine, a quaternary cholinesterase inhibitor that does not cross the BBB, may play a selective role for severe ileus or intestinal pseudo-obstruction associated with anticholinergic drugs.81 Absolute contraindications for the use of physostigmine include any evidence of cardiac conduction disturbances on ECG (e.g., prolonged PR or QRS intervals) or known or suspected acute cyclic antidepressant poisoning. Although physostigmine has been previously recommended for the treatment of ventricular tachyarrhythmias and seizures associated with the anticholinergic syndrome, these should be considered relative, if not absolute, contraindications for use of this antidote. Conversely, although contraindications for the use of physostigmine have historically included the presence of patient asthma, ischemic heart disease, peripheral vascular disease, and mechanical obstruction of the GI or urogenital tract, these contraindications are theoretical, unsubstantiated, and no longer considered true.6,82 The suggested doses of physostigmine are as follows: For children: a dose of 0.02 mg/kg slowly IV over 3 to 5 minutes. For adults: 1 to 2 mg slowly IV; may be repeated every 10 minutes until cessation of the life-threatening


731

condition. Schneck has recommended an IV infusion of 2 mg in 100 mL of normal saline infused over 10 minutes to avoid adverse effects from too rapid administration.34 In one study of adults, the mean initial dose necessary to treat agitated delirium associated with the anticholinergic syndrome was 2.2 mg (range, 0.5 to 6 mg) with a mean initial response time of approximately 11 minutes.49 The duration of action is usually 20 to 60 minutes, and recurrence of anticholinergic symptoms may require repeated doses. In this same study, relapse of symptoms occurred in 78% of patients with a mean relapse time of 100 minutes.49 Adverse effects are more likely after repeated doses. Cholinergic excess due to physostigmine use is not often life threatening. It has been suggested that atropine should be available and given in half the dose of physostigmine should severe cholinergic toxicity develop.70 The use of glycopyrrolate, a pure peripheral anticholinergic agent, has been proposed as an alternative to atropine to treat the cholinergic toxicity of physostigmine. Whenever physostigmine is used, it should (1) be given very slowly (over 3 to 10 minutes) IV; (2) not be given merely to “wake the patient up”; (3) be used only in a setting where advanced life support is available; (4) be used only when central and peripheral anticholinergic findings are present; (5) be used only in the absence of cardiac conduction abnormalities suggesting sodium channel blockade; and (6) always be preceded and followed by proper supportive care.

SPECIAL CONSIDERATIONS FOR ANTIHISTAMINE AND ANTICHOLINERGIC TOXICITY Nonsedating Piperidine Antihistamines Acrivastine, cetirizine, fexofenadine, desloratadine, and loratadine are currently marketed in the United States as nonsedating piperidine antihistamines. In therapeutic doses, their lack of CNS effects is secondary to an inability to cross the BBB.39 Acrivastine, the active metabolite of triprolidine, was given to humans for 1 week at 100 times the recommended dose without cardiovascular effects.83 Cetirizine, the carboxylated metabolite of hydroxyzine, lacked cardiovascular toxicity and sedation in overdose.84 Fexofenadine, the metabolite of terfenadine, has a safety profile similar to placebo with no significant drug interactions, cardiotoxicity, or sedation.85 In vitro, loratadine significantly inhibited the potassium rectifier current.86 Loratadine, when given with nefazodone, resulted in significantly increased QT interval in humans.87 Desloratadine, the active metabolite of loratadine, does not seem to effect the potassium rectifier current.88,89 This finding was likely from the inhibition of the CYP3A4-mediated metabolism of loratadine, leading to increased concentrations. From a historical perspective, terfenadine and astemizole were withdrawn from the market in the late 1990s because of the high incidence of ventricular dys-

732


rhythmias. Terfenadine and astemizole inhibit the delayed potassium rectifier current and thus slow repolarization.90 Accumulation of these drugs in the serum as occurred with overdose or impaired metabolism from coadministration of CYP3A4 inhibitors, was manifested clinically as prolongation of the QT interval and torsades de pointes. Agents that inhibit CYP3A4 metabolism of terfenadine include erythromycin, clarithromycin, ketoconazole, fluconazole, itraconazole, and grapefruit juice. Underlying liver disease in the absence of P-450 inhibitors can also cause cardiac toxic effects.

H2 Receptor Blockers The H2 blockers are competitive antagonists at H2 receptors and block gastric acid secretion. These agents are used to treat peptic acid diseases and include cimetidine, ranitidine, famotidine, and nizatidine. They are highly selective receptor antagonists and do not block H1 receptors or have antimuscarinic activity. Blocking central H2 receptors alters neurotransmitter function and causes delirium, confusion, agitation, and seizures. Confusion is more likely to occur in elderly patients and those who have elevated blood concentrations of these agents after acute deterioration of renal and hepatic function.91 Only cimetidine causes significant inhibition of hepatic microsomal mixed-function oxidases that may impair metabolism of other drugs. Acute overdose of the specific H2 receptor antagonists typically causes only minor toxic effects such as drowsiness and mild bradycardia.92 More serious effects such as hypotension or bradycardia are likely to occur with IV overdoses and not with ingestion of the drug. Other effects rarely reported include hypersensitivity hepatitis, bone marrow suppression, and renal failure with long-term therapeutic doses.

Chemical Weapons Anticholinergic chemicals have been used both as an agent and an antidote in chemical warfare. 3-Quinuclidinyl benzylate (QNB) was first developed for the treatment of GI illness but later turned over to the U.S. Army because of the multiple cases of delirium at very low doses. QNB is a competitive antagonist at the muscarinic receptors in the central and peripheral nervous systems. The reader is referred to Chapter 105E for a detailed discussion of this agent Atropine is a component, along with pralidoxime, of the Mark I kits developed as an antidote for nerve agent poisoning. There are multiple cases of anticholinergic poisoning from unjustified injections in the Scud missile attacks on Israel in 1991. There were 208 unjustified injections of atropine accounting for 47% of all the injuries during this 8-day barrage of surface-to-surface missiles93 (see Chapter 105A).

DISPOSITION Clinical toxicity is usually evident within 1 to 4 hours after ingestion, but the severity and duration of toxic

effects are highly variable. The potential for prolonged toxin absorption and, thus, prolonged toxicity from anticholinergic agents must be considered when determining patient disposition. Patient discharge or medical clearance is reserved for patients who do not develop toxic effects or who develop mild toxic effects initially that resolve during a 6-hour period of observation (provided that GI ileus and significant co-ingestants with delayed toxicity are not present). No patient should be discharged without suicide assessment, substance abuse counseling, or poison prevention counseling. Those patients who manifest mild toxicity (e.g., ataxia, lethargy, mild agitation, sinus tachycardia, repolarization abnormalities on ECG) should be admitted to a monitored bed for continued observation. Patients with moderate to severe toxicity (e.g., significant CNS depression or agitation, respiratory depression, hypotension, seizures, acid–base disturbances, nonsinus arrhythmias, and cardiac conduction disturbances) should be admitted to an intensive care unit for aggressive supportive care. In addition, patients who are given large doses of benzodiazepines for the control of agitation require intensive care unit observation. Patients whose agitation and delirium resolve following the administration of physostigmine still require hospital admission due to the short duration of antidotal activity and, consequently, high incidence of recrudescent toxicity. When the appropriate disposition of a patient is in question, consultation with a medical toxicologist or poison control center is recommended. REFERENCES 1. Labianca DA, Reeves WJ: Scopolamine: a potent chemical weapon. J Chem Educ 1984;61:678–680. 2. Beaver K, Gavin T: Treatment of acute anticholinergic poisoning with physostigmine. Am J Emerg Med 1998;16(5):505–507. 3. Centers for Disease Control and Prevention: Scopolamine poisoning among heroin users—New York City, Newark, Philadelphia, and Baltimore, 1995 and 1996. MMWR Morb Mortal Wkly Rep 1996; 45:457–460. 4. Weiner A, Bayer M, McKay C, et al: Anticholinergic poisoning with adulterated intranasal cocaine. Am J Emerg Med 1998;16(5): 517–520. 5. Chan T: Anticholinergic poisoning due to Chinese herbal medicines. Vet Hum Toxicol 1995;37(2):156–157. 6. Brown JH, Taylor P: Muscarinic receptor agonists and antagonists. In Hardman JG, Limbird LE (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New York, McGraw-Hill, 1996, pp 141–160. 7. Brown N, Roberts L: Histamine, bradykinin, and their antagonists. In Hardman JG, Limbird LE (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New York, McGraw-Hill, 2001, pp 645–667. 8. Hall RC, Fox J, Stickney SK, Gardner ER: Anticholinergic delirium: etiology, presentation, diagnosis and management. J Psychedelic Drugs 1978;10:237–241. 9. Hall RC, Feinsilver DL, Holt RE: Anticholinergic psychosis: differential diagnosis and management. Psychosomatics 1981; 22:581–587. 10. Hvizdos AJ, Bennet JA, Wells BG, et al: Anticholinergic psychosis in a patient receiving usual doses of haloperidol, desipramine, and benztropine. Clin Pharm 1983;2:174–178. 11. Cole J: Atropine-like delirium and anticholinergic substances. Am J Psychiatry 1972;128:898–899. 12. Forrester PA: An anticholinergic effect of general anaesthetics on cerebrocortical neurones. Br J Pharmacol 1975;55:275–278.

CHAPTER 39

13. Woodward GA, Baldassano RN: Topical diphenhydramine toxicity in a five year old with varicella. Pediatric Emerg Care 1988; 4:18–20. 14. Reilly JF, Weisse ME: Topically induced diphenhydramine toxicity. J Emerg Med 1990;8:59–61. 15. Filloux F: Toxic encephalopathy caused by topically applied diphenhydramine. J Pediatr 1986;108:1018–1020. 16. Wilkinson JA: Side effects of transdermal scopolamine. J Emerg Med 1987;5:389–392. 17. Price BH: Anisocoria from scopolamine patches. JAMA 1985; 253:1561. 18. Patterson JH, Ives T, Greganti MA: Transient bilateral pupillary dilation from scopolamine discs. Drug Intell Clin Pharm 1986;20:986–987. 19. Thompson H: Cornpicker’s pupil: Jimson weed mydriasis. J Iowa Med Soc 1971;61(8):475–477. 20. Reid D, Fulton JD: Tachycardia precipitated by topical homatropine. BMJ 1989;299:795–796. 21. Fitzgerald DA, Hanson RM, West C: Seizures associated with 1% cyclopentolate eyedrops. J Paediatr Child Health 1990;26:106–107. 22. Brizer DA, Manning DW: Delirium induced by poisoning with anticholinergic agents. Am J Psychiatry 1982;139:1343–1344. 23. Goldfrank L, Flomenbaum N, Lewin N, et al: Anticholinergic poisoning. Clin Toxicol 1982;19:17–25. 24. Dilsalver SC: Antimuscarinic agents as substance of abuse: a review. J Clin Psychopharmacol 1988;8:14–22. 25. Smith JM: Abuse of the antiparkinson drugs: a review of the literature. J Clin Psychiatry 1980;41:351–354. 26. Modell JG, Tandon R, Beresford TP: Dopaminergic activity of the antimuscarinic antiparkinsonian agents. J Clin Psychopharmacol 1989;9:347–351. 27. Land W, Pinsky D, Salzman C: Abuse and misuse of anticholinergic medications. Hosp Commun Psychiatry 1991;42:580–581. 28. MacVicar K: Abuse of antiparkinsonian drugs by psychiatric patients. Am J Psychiatry 1977;134:809–811. 29. Pullen GP, Best NR, Maguire J: Anticholinergic drug abuse: a common problem. BMJ 1984;289:612–613. 30. Crawshaw JA, Mullen PA: A study of benzhexol abuse. Br J Psychiatry 1984;145:300–303. 31. Benjamin MB: Mushroom poisoning in infants and children: the Amanita Pantherina/Muscaria Group. Clin Toxicol 1992;30:13–22. 32. Taylor P, Brown JH: Acetylcholine. In Siegel GJ (ed): Basic Neurochemistry: Molecular, Cellular, and Medical Aspects. New York, Raven, 1989, pp 203–231. 33. Cuello AC, Sofroniew MV: The anatomy of the CNS cholinergic neurons. Trends Neurosci 1984;7:74–78. 34. Schneck HJ, Rupreht J: Central anticholinergic syndrome in anesthesia and intensive care. Acta Anaesthesiol Belg 1989;40: 219–228. 35. Green JP: Histamine. In Siegel GJ (ed): Basic Neurochemistry: Molecular, Cellular, and Medical Aspects. New York, Raven, 1994, pp 309–318. 36. Gefland EW: Role of histamine in the pathophysiology of asthma: immunomodulatory and anti-inflammatory activities of the H1receptor antagonists. Am J Med 2002;113(9A):2s–7s. 37. Sastry BS, Phillis JW: Depression of rat cerebral cortical neurons by H1 and H2 histamine receptor agonists. Eur J Pharmacol 1976;38:269–273. 38. Clark RF, Vance MV: Massive diphenhydramine poisoning resulting in a wide-complex tachycardia: successful treatment with sodium bicarbonate. Ann Emerg Med 1992;21:318–321. 39. Simons FE, Simons KJ: The pharmacology and use of H1-receptorantagonist drugs. N Engl J Med 1994;330:1663–1670. 40. Briggs G, Freeman R, Yaffe S: Drugs in Pregnancy and Lactation, 6th ed. Philadelphia, Lippincott Williams & Wilkins, 2002. 41. Greenblatt DJ, Shader RI: Anticholinergics. N Engl J Med 1973;288:1215–1217. 42. Gowdy JM: Stramonium intoxication: review of symptomatology in 212 cases. JAMA 1972;221:585–587. 43. Perry PJ, Wilding DC, Juhl RP: Anticholinergic psychosis. Am J Hosp Pharm 1978;35:725–727. 44. Fisher CM: Visual hallucinations on eye closure associated with atropine toxicity. A neurological analysis and comparison with other visual hallucinations. Can J Neurol Sci 1991;18:18–27.


733

45. Johnson AL, Hollister LE, Berger PA: The anticholinergic intoxication syndrome: diagnosis and treatment. J Clin Psychiatry 1981;42:313–316. 46. Klein-Schwartz W, Oderda GM: Jimson weed intoxication in adolescents and young adults. Am J Dis Child 1984;138:737–739. 47. Moreau A, Jones BD, Banno V: Chronic central anticholinergic toxicity in manic depressive illness mimicking dementia. Can J Psychiatry 1986;31:339–340. 48. Richmond M, Seger D: Central anticholinergic syndrome in a child: a case report. J Emerg Med 1985;3:453–456. 49. Burns M, Linden C, Graudins A, et al: A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Ann Emerg Med 1999;35(4):374–381. 50. Tuomisto L, Tacke U: Is histamine an anticonvulsive inhibitory transmitter? Neuropharmacology 1986;25:955–958. 51. Chen Z, Li W-D, Zhu L-J, et al: Effects of histidine, a precursor of histamine, on phenylenetetrazole-induced seizures in rats. Acta Pharmacol Sin 2002;23(4):361–366. 52. Yokoyama H, Sato M, Iinuma K, et al: Centrally acting histamine H1 antagonists promote the development of amygdala kindling in rats. Neurosci Lett 1996;217:194–196. 53. Yokoyama H, Onodera K, Iinuma K, Watanabe T: 2-Thiazolylethylamine, a selective histamine H1 agonist, decreases seizure susceptibility in mice. Pharmacol Biochem Behav 1994;47: 503–507. 54. Scherkl R, Hashem A, Frey H: Histamine in brain—its role in regulation of seizure susceptibility. Epilepsy Res 1991;10:111–118. 55. Markowitz J, Brown R: Seizures with neuroleptics and antidepressants. Gen Hosp Psychiatry 1987;9:135–141. 56. Donlon P, Tupin J: Successful suicides with thioridazine and mesoridazine. Ach Gen Psychiatry 1977;34:955–957. 57. Curry SC, Chang D, Conner D: Drug- and toxin-induced rhabdomyolysis. Ann Emerg Med 1989;18:1068–1084. 58. Glauser J: Tricyclic antidepressant poisoning. Cleve Clin J Med 2000;67(10):709–713. 59. Fahy P, Arnold P, Curry SC, Bond R: Serial serum drug concentrations and prolonged anticholinergic toxicity after benztropine (Cogentin) overdose. Am J Emerg Med 1989;7:199–202. 60. Manoguerra AS, Ruiz E: Physostigmine treatment of anticholinergic poisoning. J Am Coll Emerg Physicians 1976;5:125–127. 61. Magera BE, Betlach CJ, Sweatt AP, Derrick CW: Hydroxyzine intoxication in a 13-month-old child. Pediatrics 1981;67:280–283. 62. Gillick JS: Atropine toxicity in a neonate. Br J Anaesth 1974; 46:793–794. 63. Homsi E, Barreiro M, Orlando J, Higra E: Prophylaxis of acute renal failure in patients with rhabdomyolysis. Ren Fail 1997; 19(2):283–288. 64. Lindsay CA, Williams GD, Levin DL: Fatal adult respiratory distress syndrome after diphenhydramine toxicity in a child: a case report. Crit Care Med 1995;23:777–781. 65. Danze LK, Langdorf MI: Reversal of orphenadrine-induced ventricular tachycardia with physostigmine. J Emerg Med 1991; 9:453–457. 66. Farrell M, Heinrichs M, Tilelli JA: Response of life threatening dimenhydrinate intoxication to sodium bicarbonate administration. Clin Toxicol 1991;29:527–535. 67. Sharma A, Hexdall A, Chang E, et al: Diphenhydramine-induced wide complex dysrhythmia responds to treatment with sodium bicarbonate. Am J Emerg Med 2003;21(3):212–215. 68. Freedberg RS, Friedman GR, Palu RN, Feit F: Cardiogenic shock due to antihistamine overdose: reversal with intra-aortic balloon counterpulsation. JAMA 1987;257:660–661. 69. Granacher RP, Baldessarini RJ, Messner E: Physostigmine treatment of delirium induced by anticholinergics. Am Fam Physician 1976;13:99. 70. Rumack BH: Anticholinergic poisoning: Treatment with physostigmine. Pediatrics 1973;52:449–451. 71. Burks JS, Walker JE, Rumack BH, Oh JE: Tricyclic antidepressant poisoning. Reversal of coma, choreoathetosis, and myoclonus by physostigmine. JAMA 1974;230:1405–1407. 72. Duvoisin RC, Katz R: Reversal of central anticholinergic syndrome in man by physostigmine. JAMA 1968;206:1963. 73. Nattel S, Bayne L, Ruedy J: Physostigmine in coma due to drug overdose. Clin Pharmacol Ther 1979;25:96.

734


74. Knudsen K, Heath A: Effects of self poisoning with maprotiline. BMJ 1984;288:601–603. 75. Walker WE, Levy RC, Henenson IB: Physostigmine—its use and abuse. J Am Coll Emerg Physicians 1976;5:335. 76. Schneir A, Offerman S, Ly B, et al: Complications of diagnostic physostigmine administration to emergency department patients. Ann Emerg Med 2003;42(1):14–19. 77. Levy R: Arrhythmias following physostigmine administration in Jimson weed poisoning. J Am Coll Emerg Physicians 1977;6:107. 78. Dysken MW, Janowsky DS: Dose-related physostigmine induced ventricular arrhythmia: case report. J Clin Psychiatry 1985;46: 446–447. 79. Munoz RA, Kuplic JB: Large overdoses of tricyclic antidepressants treated with physostigmine salicylate. Psychosomatics 1975;16: 77–78. 80. Pentel P, Peterson CD: Asytole complicating physostigmine treatment of tricyclic antidepressant overdose. Ann Emerg Med 1980;9:588–590. 81. Isbister G, Oakley P, Whyte I, Dawson A: Treatment of anticholinergic-induced ileus with neostigmine. Ann Emerg Med 2001; 38(6):689–693. 82. Nilsson E, Meretoja OA, Neuvonen P: Hemodynamic responses to physostigmine in patients with a drug overdose. Anesth Analg 1983;62:885–888. 83. Berlin J, King A, Tutsch K, et al: A phase II study of vinblastine in combination with acrivastine in patients with advanced renal cell carcinoma. Invest New Drugs 1994;12:137–141. 84. Spiller H, Villalobos D, Benson B, et al: Retrospective evaluation of cetirizine (Zyrtec) ingestion [Letter]. Clin Toxicol 2002;40(4): 525–526.

85. Mason J, Reynolds R, Rao N: The systemic safety of fexofenadine HCl. Clin Exp Allergy 1999;29(Suppl 3):163–170. 86. Crumb W: Loratadine blockage of K (+) channels in human hear, comparison with terfenadine under physiological conditions. J Pharmacol Exp Ther 2000;292:261–264. 87. Abernathy D, Barbey J, Franc J, et al: Loratadine and terfenadine interaction with nefazodone, both antihistamines are associated with QTc prolongation. Clin Pharmacol Ther 2001;69:96–103. 88. Kreutner W, Chiu J, Barnett A: Preclinical pharmacology of desloratadine, a selective and nonsedating histamine H1 receptor antagonist. Second communication, lack of central nervous system and cardiovascular effects. Arzneimittelforschung 2000;50:441–448. 89. Paakkari I: Cardiotoxicity of new antihistamines and cisapride [Review]. Toxicol Lett 2002;127:279–284. 90. Berul CI, Morad M: Regulation of potassium channels by nonsedating antihistamines. Circulation 1995;91:2220–2225. 91. Schentag JJ: Cimetidine-associated mental confusion: further studies in 36 severely ill patients. Ther Drug Monit 1980; 2:133–142. 92. Krenzelok EP, Litovitz T, Lippold KP: Cimetidine toxicity: an assessment of 881 cases. Ann Emerg Med 1987;16:1217–1221. 93. Bleich A, Dycian A, Koslowsky M, et al: Psychiatric implications of missile attacks on a civilian population. JAMA 1992;268(5): 613–615. 94. Baselt RC: Disposition of Toxic Drugs and Chemicals in Man, 7th ed. Foster City, CA, Biomedical Publications, 2004. 95. Thummal KE, Shen DD: Design and optimization of dosage regimens. In Hardman JG, Limbird LE, Gilman AG (eds): Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 1924–2023.

40

Anticonvulsants DONNA SEGER, MD


■ ■

Many anticonvulsants are used to treat nonconvulsive disorders such as mood disorders. Drugs that are hepatically metabolized via the cytochrome system interact with other drugs metabolized via the same system. Data on overdose is minimal for most newer anticonvulsants. Unless otherwise stated, treatment is supportive. Gastrointestinal decontamination recommendations supported by the American Academy of Clinical Toxicology/European Association of Poison Control Centres and Clinical Toxicologists are as follows: ■ Gastric lavage may be considered if the patient is obtunded within an hour of ingestion. ■ Whole-bowel irrigation may be considered when tablets are sustained release or enteric coated.

types, causes few adverse effects, and interacts with few drugs.4

Sudden Unexpected Death Sudden unexpected death (SUD) is increased in patients with epilepsy and reflects population rates, not drug effect. Mechanism and role of AC in SUD are unknown and may depend on the unique circumstances.5

Teratogenicity Major malformation, growth retardation, and hypoplasia of the midface and fingers is called anticonvulsant embryopathy. The incidence of embryopathy correlates with exposure to the anticonvulsant drug.6 Its incidence is not increased in infants whose mother had epilepsy but did not take anticonvulsant drugs during pregnancy.

Anticonvulsant Hypersensitivity Syndrome Prior to 1993, the only drugs available to treat epilepsy— phenobarbital, primidone, phenytoin, carbamazepine, and valproate—caused significant side effects. Many patients taking these drugs still had refractory seizures. Since 1993, eight new anticonvulsants with better side effect profiles and less hepatic enzyme induction have been approved. However, they are more expensive than the traditional drugs and may not be more cost effective.1

EPILEPSY AND DRUG DEVELOPMENT Epilepsy is a chronic neurologic condition in which the patient suffers recurrent, unprovoked seizures.2 Seizures, a paroxysmal transient disturbance of brain function, affect 1% of the world’s population. Side effects of anticonvulsants (ACs) and the 25% of the epileptic population who are not seizure-free have driven the development of new ACs that are less toxic and more efficacious.3

Choice of Drug The ideal AC has the following pharmacokinetic characteristics: rapid absorption after oral ingestion, high bioavailability, rapid achievement of steadystate concentrations, minimal protein binding, linear kinetics, long elimination half-life that allows twice a day dosing, minimal hepatic metabolism, primary renal excretion, and constant interpatient pharmacokinetics. The ideal drug is also effective for a wide range of seizure

Anticonvulsant hypersensitivity syndrome (AHS), a rare, life-threatening syndrome consisting of rash and internal organ (most frequently liver) involvement, occurs within 8 weeks of initiation of an AC and is not related to dose or serum concentration of the drug. AHS occurs in one in 1000 to 10,000 exposures and is most frequently caused by the aromatic AC (phenobarbital, phenytoin, carbamazepine). Its cause is unknown. Treatment is discontinuation of the anticonvulsant and aggressive supportive care. The syndrome is associated with substantial morbidity and mortality, including fulminant hepatic failure and death.7

PHENOBARBITAL Pharmacology Phenobarbital (PB) inhibits seizures by potentiating synaptic inhibition through two separate actions on the γ-aminobutyric acid (GABAA) receptor—that is, enhanced effects of GABA-evoked chloride currents, and direct activation of the receptor at supratherapeutic concentrations.8

Pharmacokinetics PB is slowly absorbed, with peak concentrations occurring several hours after a single dose. It is 40% to 60% bound to plasma proteins. Up to 23% of the dose is eliminated unchanged by pH-dependent renal excretion. The remainder of the drug is metabolized primarily by hepatic CYP2C9.8 735

736


Toxicology

Pharmacokinetics

ACUTE TOXICITY (OVERDOSE) Central nervous system (CNS) depression is caused by the effects of the drug on the reticular activating system and the cerebellum. Vasodilation, decreased sympathetic output, and negative inotropic cardiac effects cause hypotension. Decreased consciousness, respiratory depression, hypotension, and hypothermia follow overdose. Less severe toxicity is manifest by slurred speech, ataxia, nystagmus, and confusion. The patient may appear intoxicated. Pupils may be constricted or dilated. Brainstem and deep tendon reflexes are usually depressed or absent. Bullous skin lesions may also be seen.9 Owing to PBs rapid CNS redistribution, patients may become more alert despite persistently elevated serum drug concentrations. Fatalities result from cardiorespiratory arrest or (direct) myocardial depression.

Limited phenytoin solubility (i.e., dissolution rate decreases with increasing dose) causes prolonged absorption and delays peak serum concentrations, which have been reported to occur days after ingestion of a large dose. After a 400-mg dose, peak serum concentrations occur in 8 hours. The drug is 90% protein bound with a volume of distribution of 0.6 to 0.7 L/kg. Half-life is 20 to 30 hours. Metabolism is hepatic. Inactive metabolites and 5% of the parent drug are renally excreted.13,14 Metabolism is dose dependent. At therapeutic serum concentrations, elimination is first order (i.e., rate of drug metabolism increases as the concentration of the drug increases). In the upper therapeutic and toxic serum concentrations, the hydroxylation reaction reaches maximum velocity and elimination is zero order (i.e., rate of metabolism is constant).13-15 Absorption from bone is rapid following intraosseous administration. Pharmacokinetics approximate those following intravenous administration.16

CHRONIC TOXICITY Sedation and impaired cognition occurs in both children and adults.9 ADVERSE EFFECTS Children manifest altered sleep, fussiness, irritability, and hyperactivity.

Diagnosis The relationship between plasma concentration and adverse effects depends on the development of tolerance. Side effects usually disappear with continued use even when serum concentrations are supratherapeutic. The usual therapeutic serum concentration is 15 to 40 μg/mL. Concentrations greater than 60 μg/mL are associated with significant toxicity in the nontolerant individual.9

Management Administration of multiple-dose activated charcoal (MDAC) and urinary alkalinization to a pH of 7.5 to 8.0 increases elimination of the parent compound. Although both MDAC and urinary alkalinization decrease elimination half-life, treatment with these modalities may neither shorten the clinical course nor change outcome. Hemoperfusion and hemodialysis increase clearance of the drug, although they are rarely needed for this overdose.10,11 A serum PB concentration of greater than 100 to 125 μg/mL is an indication for extracorporeal drug removal.

PHENYTOIN Pharmacology Phenytoin (PHT) causes voltage-frequency and usedependent block of sodium channels, inhibits calcium channels, and stimulates the Na+/K+-ATPase pump.12

Toxicology ACUTE TOXICITY (OVERDOSE) Initial cerebellar symptoms (nystagmus, ataxia, and drowsiness) are followed by basal ganglia signs (movement disorders) as serum concentrations exceed 20 mg/L. At higher concentrations, the CNS becomes depressed, ultimately producing coma. PHT overdose does not cause cardiac toxicity. The occurrence of paradoxical seizures following overdose has not been confirmed. Treatment is supportive.17 CHRONIC TOXICITY Chronic PHT toxicity may occur during therapeutic ingestion owing to (1) small increases in maintenance doses that saturate enzyme systems, leading to zero order kinetics; (2) decrease in protein binding of the drug (e.g., addition of another drug); or (3) drug-induced alteration in hepatic metabolism. Although head computed tomography (CT) may demonstrate cerebellar atrophy and cerebellar tissue loss in patients chronically receiving phenytoin, seizures can cause the same changes.18 ADVERSE EFFECTS Adverse effects of PHT usually occur when serum concentrations are greater than 15 mg/L. Gingival hyperplasia and folic acid deficiency are among the most common and are dose related. Rash, acne, lupus-like syndrome, Stevens-Johnson syndrome, thyroid function inhibition, hirsutism, hypertrichosis, benign intracranial hypertension (pseudotumor cerebri), carbohydrate intolerance, peripheral neuropathy, osteomalacia, and altered vitamin D metabolism (increased alkaline phosphatase) may occur. The most serious adverse effect is a hypersensitivity syndrome manifested by fever, rash, lymphadenopathy, hepatitis, and eosinophilia. Death

CHAPTER 40

typically occurs from fulminant hepatic failure. Elevated liver enzymes should be monitored closely to distinguish transient enzyme elevation from progression to hepatic failure.19

Diagnosis Symptoms correlate with free rather than total phenytoin concentrations; free concentrations are usually not available. Therapeutic serum concentrations (10 to 20 mg/L) equate with a free PHT concentration of 1.0 to 2.0 mg/L. Symptoms of toxicity occur when free PHT concentrations are greater than 5 mg/L.20

Management Treatment of acute overdose and chronic PHT toxicity is supportive. The drug’s prolonged elimination half-life may cause prolonged symptoms. The main concern in patients with PHT toxicity is ataxia causing a fall and resultant injury. The patient must be in the appropriate setting for observation.17

Intravenous Phenytoin PHT is administered intravenously when a therapeutic concentration is needed as rapidly as possible (e.g., subtherapeutic concentrations following a seizure). Propylene glycol is necessary to maintain solubility and stability of parenteral PHT, but it can cause hypotension and bradycardia if administered too rapidly. In concentrations of 6 to 10 mg/L of normal saline (NS), PHT maintains solubility for about 1 hour. Oral loading results in delayed therapeutic concentrations, since limited PHT absorption (with a large dose) prolongs the time needed to reach therapeutic concentration.21 An IV dose of 15 to 18 mg/kg produces therapeutic serum concentrations lasting 12 to 24 hours. Distribution to the brain is rapid, and anticonvulsant activity begins within 3 to 5 minutes after IV infusion. If serum concentration of phenytoin is known, each 100 mg of IV phenytoin will increase serum concentration approximating 1.2 mg/L.21 Rapid IV administration of the drug (because of propylene glycol) and high PHT solution concentrations can cause cardiovascular toxicity. A PHT concentration of 4 to 10 mg/mL NS can be safely administered at a rate of 50 mg/min in patients younger than 50 years of age, and a concentration of 4 mg/mL NS (1 g phenytoin in 250 mL NS) at a rate of 25 mg/min in patients less than 50 years of age. Patients should be on a cardiac monitor. A constant infusion pump should monitor intravenous piggyback delivery. PHT should not be administered to patients with marked bradycardia, second- or thirddegree heart block, active severe arteriosclerotic heart disease (ASHD), or hypotension. Fatalities have occurred in elderly patients with ASHD and in younger patients when the IV delivery rate or phenytoin concentration was greater than recommended.23,24

Anticonvulsants

737

If the total dose administered is greater than 1 g, ataxia, dizziness, and confusion may occur despite appropriate administration rate and concentration. The infusion should be stopped if systemic side effects occur.23 Solvent alkalinity may cause burning and aching of the arm if infused into a small vein and buffering capacity of the blood is exceeded. Decreasing the rate or concentration may alleviate the symptoms. Soft tissue and vascular injury have occurred in elderly women with cardiovascular disease. A 20-gauge IV catheter and administration rate less than 25 mg/min may decrease the risk of injuries.25

FOSPHENYTOIN Pharmacology Fosphenytoin (FOS) is a disodium phosphate ester prodrug of PHT that is water-soluble and therefore does not require propylene glycol. Phosphatases present in the liver, red blood cells, and other tissues remove the phosphate molecule and convert FOS to active PHT in 8.4 minutes following intravenous administration.26

Pharmacokinetics Maximal serum concentration is reached within 10 to 20 minutes of starting the infusion. Therapeutic PHT concentrations (10 to 20 mg/mL) occur within 10 minutes of infusions administered at a rate of 100 mg/min and within 30 minutes of infusions administered at less than 100 mg/min.27 ADVERSE EFFECTS Nystagmus, headache, ataxia, and somnolence are the most frequent symptoms. Paresthesias and perineal and generalized pruritus have been reported in 30% to 60% of patients.

Diagnosis Determination of FOS concentrations is of no value, since the drug is not clinically active. However, serum PHT levels are useful in guiding therapy.

Intravenous PHT vs. Intravenous FOS FOS may be administered more rapidly than PHT. However, owing to the need for observation and other medical issues in patients who have just had a seizure, emergency department (ED) time is not decreased by administration of FOS. The adverse effect profile of FOS is different from that of PHT but not necessarily better. A significant number of people suffer perineal pruritus. FOS is more expensive than PHT. Cost analysis does not justify administration of FOS over PHT.28,29

738


CARBAMAZEPINE Pharmacology Carbamazepine (CBMZ) inhibits sodium channels, interferes with release of glutamate (and possibly other neurotransmitters), and inhibits muscarinic and nicotinic acetylcholine receptors, N-methyl-D-aspartate (NMDA) receptors, and CNS adenosine receptors.30

Pharmacokinetics CBMZ is an iminostilbene derivative that is chemically and structurally similar to imipramine, yet shares few of its pharmacologic properties. Absorption is slow, and peak serum concentrations usually occur within 4 to 8 hours but may be as late as 12 hours after ingestion.31,32 A serum therapeutic concentration is 4 to 12 μg/mL. The drug is 75% protein bound and has a volume of distribution of 0.79 to 1.19 L/kg. It is metabolized by liver cytochrome P4503A4 to an active metabolite (10,11epoxide) with a half-life of 10 to 20 hours. The epoxide concentration is 10% to 15% of the parent compound in adults and 20% in children. The epoxide may be responsible for the neurotoxicity of the drug. Because CMBZ induces its own metabolism, its half-life after an isolated single dose (35 hours) is much longer than the half-life of the drug at steady state (10 to 20 hours). Autoinduction takes about a month. Elimination of the parent compound follows zero order kinetics, and 3% of the parent compound is excreted unchanged in the urine. The epoxide is metabolized to inactive compounds, which are excreted in the urine.32,33

Toxicology ACUTE TOXICITY (OVERDOSE) Delayed and erratic absorption due to CMBZ’s anticholinergic properties and low water solubility can cause delayed clinical deterioration and a cyclic clinical course. Peak serum concentrations may occur 72 hours after ingestion of immediate-release (IR) and 96 hours after ingestion of controlled-release (CR) formulations. Half-life may be prolonged (39 hours) after an isolated ingestion or shorter when chronic therapeutic ingestion has induced metabolism.31,32 Symptoms of toxicity include coma, respiratory failure, ataxia, nystagmus, mydriasis, ileus, hypertonicity, increased deep tendon reflexes, movement disorders, and anticholinergic toxidrome. Seizures are more likely to occur in patients with high serum drug concentrations and an underlying seizure disorder. Left ventricular dysfunction with heart failure has been reported. Complete heart block (without hemodynamic compromise) has been reported in children. Cardiac arrhythmias are rarely seen. Laboratory abnormalities include hyponatremia, hyperglycemia, and transient elevation of serum liver enzymes.34-38

CHRONIC TOXICITY CBMZ-induced bradycardia (including complete heart block) may occur in elderly patients with a defective conduction system or sick sinus syndrome. Benign cardiac conduction disturbances have been found in up to 57% of patients with CBMZ toxicity. Patients over 50 years of age should have an electrocardiogram (ECG) performed prior to initiation of CBMZ therapy.37,38 ADVERSE EFFECTS Adverse effects occur in 25% of patients ingesting CBMZ. A mild transient leukopenia that may occur during the first month of treatment is unrelated to aplastic anemia, which occurs in 1 in 575,000 patients taking CBMZ. Hematologic monitoring is recommended. Discontinuation of the drug is not required for the mild liver enzyme elevation that occurs in up to 10% of patients taking CBMZ.

Diagnosis Although serum CBMZ concentrations do not accurately correlate with the clinical severity of the poisoning, serum concentrations greater than 40 mg/L are associated with an increased risk of serious complications such as coma, seizures, respiratory failure, and cardiac conduction defects. Serum concentrations greater than 60 to 80 mg/mL may be associated with a fatal outcome. The seriousness of toxicity should be judged by the clinical status of the patient, not by the serum CBMZ concentration.37,38 Because of its ringed structure, CBMZ can cause a false-positive tricyclic antidepressant (TCA) result on the urine drug screen (UDS). Both CBMZ and carbamazepine 10,11-epoxide are measured by the standard enzyme multiplied immunoassay test (EMIT). A ratio of parent compound to epoxide greater than 2.5 is suggestive of continuing gastrointestinal (GI) absorption.39

Management Gastric lavage may be considered if the patient is obtunded within 1 hour of ingestion of CBMZ. Prolonged absorption is possible. MDAC may decrease half-life but may not decrease time to recovery or change outcome. The benefit:risk ratio of MDAC administration in a sleepy patient or a patient who may require intubation must be assessed in each case. Similarly, although charcoal hemoperfusion (CHP) decreases the half-life of both CBMZ and the epoxide, the efficacy of charcoal hemoperfusion has not been compared with administration of multiple doses of activated charcoal or supportive care. If extracorporeal removal is considered in a life-threatening overdose, hemodialysis usually is the treatment of choice, since CHP cartridges are not readily available.40-42

CHAPTER 40

VALPROATE Pharmacology Valproate (VPA) has a number of indirect actions on the GABAergic system, causing increased GABA concentration. VPA reduces release of γ-hydroxybutyrate (an eliptogenic amino acid) and blocks cell firing induced by NMDA glutamate receptors. In rat brain sections, VPA increases brain endogenous opioid. Active metabolites may add to the drug’s antiepileptic actions.43-46

Pharmacokinetics VPA is a simple eight-carbon, branch-chained fatty acid. It is rapidly and completely absorbed, with peak serum concentrations occurring 1 to 4 hours after ingestion. The drug is extensively metabolized in the liver by glucuronic acid conjugation and mitochondrial βoxidation, which may be inhibited by long-term or highdose VPA therapy. VPA enters the mitochondria by a transport system that uses L-carnitine as a cofactor. Cytosolic ω-oxidation plays a smaller role in metabolism. Protein binding is determined by serum concentration with 90% of the drug protein bound at concentrations of 40 μg/mL. Concentrations greater than 150 μg/mL saturate protein binding sites, and less than 70% of the drug is protein bound. VPA has a small volume of distribution (0.13 to 0.23 L/kg) The half-life of VPA is 8 to 21 hours but may be up to 42 hours after overdose. In therapeutic concentrations and following overdose, elimination kinetics of the parent compound appear to be first order. Less than 3% of the drug is excreted unchanged in urine and feces.47,48

Toxicology ACUTE TOXICITY (OVERDOSE) If the enteric-coated or CR formulation has been ingested, peak serum concentration may be delayed for 12 to 16 hours. Patients who have ingested these formulations cannot be medically cleared until the clinical picture and serum concentration are assessed at the end of this time period.49 CNS depression, ranging from drowsiness to coma, is the most frequent sign following overdose. Serum concentrations greater than 850 μg/mL uniformly cause coma. Respiratory depression, hypotension, hypoglycemia, hypocalcemia, hypernatremia, hypophosphatemia, and anion-gap metabolic acidosis may persist for days. Serum aminotransferases, ammonia, amylase, and lactate may be elevated. Pancreatitis may occur. Thrombocytopenia, the most common hematologic toxicity, may be clinically significant and severe.49 VPA increases renal ammonia production and blocks hepatic ammonia metabolism. Resultant hyperammonemia may increase intracellular osmolarity, which promotes influx of water into the cell and causes cerebral edema. Hyperammonemia (in the absence of liver failure) and cerebral edema have been reported following VPA overdose. Whether increased ammonia is

Anticonvulsants

739

the cause of cerebral edema and the resultant increased intracranial pressure is unknown.50 CHRONIC TOXICITY Increased serum liver enzymes and bilirubin occur in up to 60% of patients with therapeutic VPA serum concentrations. Liver enzymes normalize with dose reduction or discontinuation of the drug. Hepatic failure, histologically evident as microvesicular steatosis, occurs in 1 in 20,000 patients. VPA-induced hepatotoxicity may be either intrinsic (reversible, reproducible, and dose dependent) and benign, occurring in 44% or patients, or idiosyncratic (unpredictable, not dose dependent, long latent period) and fatal. Children less than 3 years of age who are receiving multiple antiepileptic agents and have additional medical problems are at highest risk for fatal hepatotoxicity (incidence of 1 in 500). Liver enzymes and ammonia should be checked in children therapeutically ingesting VPA who demonstrate somnolence, lethargy, or even coma.51 Asymptomatic hyperammonemia without hepatic damage occurs in 20% of patients taking this drug. The origin of the ammonia is hepatic, a result of impaired urea cycle function and inability to metabolize nitrogen loads. The mechanism of this impairment is unknown. Carnitine deficiency may play a role in impaired urea production.50 Thirty-six cases of VPA-associated pancreatitis, including nine deaths, have been reported. Patients receiving multiple anticonvulsants may be at highest risk for developing pancreatitis. The cause of the pancreatitis is unknown. Abdominal pain, lethargy, or coma may be the presenting symptoms. Thrombocytopenia, usually transient despite continuing the drug, has rarely induced bone marrow toxicity.52 ADVERSE EFFECTS Fifteen percent of patients experience GI side effects such as anorexia, nausea, and diarrhea. CNS effects of sedation, ataxia, and tremor also occur.

Diagnosis Serum concentration does not correlate well with either seizure control or toxicity. Therapeutic concentrations are 50 to 100 μg/mL. The incidence of adverse side effects increases at concentrations greater than 120 μg/mL. EMIT will yield higher values of serum VPA than will the gas-liquid chromatographic assay, requiring consistent analytic methodology. VPA is eliminated partly as ketone bodies and may cause a false-positive test result for ketones in the urine.

Management Administration of high-dose naloxone has been reported to reverse VPA-induced CNS depression, possibly by reversal of VPA-induced release of endogenous opioids or reversal of VPA blockade of GABA uptake.53

740


Because of delayed peak serum concentrations, serial concentrations should be obtained. Whole-bowel irrigation may be considered if the patient ingests Depakote or an extended-release preparation and presents within 5 hours of ingestion. Serum ammonia concentrations should be obtained in all patients with an altered level of consciousness. Serum glucose, calcium, phosphate, and platelets must be monitored.54 β-Oxidation, the primary metabolic pathway, may be decreased following overdose. Hypocarnitinemia, which inhibits β-oxidation, may occur following long-term VPA therapy. The clinical relevance of hypocarnitinemia in patients with seizures on chronic VPA therapy or in overdose patients is unknown. L-Carnitine has been administered to overdose patients in an attempt to increase VPA metabolism via β-oxidation. L-Carnitine causes few adverse side effects. However, its administration is experimental.55 Hemoperfusion (HP) and hemodiafiltration without HP have been performed to treat severe VPA overdose. Although the significant protein binding should not make it amenable to dialysis, the hypothesis is that unbound (free) drug is markedly increased in overdose. None of the extracorporeal means of detoxification have been compared with supportive care to determine whether these measures improve outcome.56

FELBAMATE Introduction Shortly after U.S. Food and Drug Administration (FDA) approval, it became apparent that felbamate was not well tolerated owing to GI complaints, insomnia, weight loss, dizziness, fatigue, ataxia, and lethargy. Felbamateinduced aplastic anemia (with an incidence 100 times higher than in the general population) and hepatic failure caused many physicians to discontinue the drug. Unfortunately, acute withdrawal of felbamate precipitated status epilepticus in some patients, causing some fatalities.57,58 Currently, felbamate is recommended only when other treatment regimens have failed. It remains on the market with a black box warning for aplastic anemia and hepatic failure and is not considered a first-line anticonvulsant.1

Pharmacology Felbamate decreases the sodium current, enhances inhibitory actions of GABA, and blocks NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. There is no effect on benzodiazepine receptors or GABA receptor binding.1,59

Pharmacokinetics Felbamate is a dicarbamate derivative structurally related to meprobamate. The drug is 90% bioavailable after ingestion. Time to peak plasma level is 1 to 4 hours.

Volume of distribution is 0.75 L/kg. It is 25% bound to plasma protein, and elimination half-life is 20 hours. Forty to fifty percent is excreted unchanged in the urine.59

Toxicology ACUTE TOXICITY (OVERDOSE) Somnolence and GI symptoms may occur. Following overdose of felbamate and VPA, massive felbamate crystalluria and acute renal failure occurred. Crystalluria may have been caused by felbamate alone or in combination with VPA.60 CHRONIC TOXICITY Fatal hepatitis and aplastic anemia are potential lifethreatening effects. ADVERSE EFFECTS Weight gain, weakness, malaise, influenza-like symptoms, palpitations, tachycardia, agitation, psychological disturbance, aggressive reaction, pruritus, and StevensJohnson syndrome have been reported.

Diagnosis Liver enzymes and white blood counts must be monitored when felbamate is taken. Although there is no recommended therapeutic range for felbamate, plasma concentrations as high as 140 μg/mL have been tolerated without significant adverse effects.61 Acute overdose is treated with supportive care; there is no means of enhancing the drug’s removal.

GABAPENTIN Pharmacology Structurally related to GABA, gabapentin does not bind to GABA receptors but is thought to enhance the release or actions of GABA. Unlike GABA, gabapentin readily crosses the blood-brain barrier. Gabapentin inhibits voltage-dependent sodium currents.12

Pharmacokinetics Bioavailability is dose-dependent owing to facilitated transport during absorption by the L-amino acid transporter. The transport system becomes saturated at higher doses, limiting absorption. (The drug is presumed to be transported across the blood-brain barrier in the same way.) Oral bioavailability is 60% after a 300 mg dose and decreases to 35% when the dosage is 1600 mg three times a day. It is neither metabolized (and therefore does not induce hepatic enzymes) nor bound to plasma proteins. Gabapentin half-life is 5 to 7 hours. Kinetics are linear. Since gabapentin is eliminated by the kidneys, its renal clearance is dependent on creatinine clearance; the dose should be adjusted in patients with renal impairment.62

CHAPTER 40

Toxicology ACUTE TOXICITY (OVERDOSE) Serious toxicity has not been reported after gabapentin overdose, probably because of its limited bioavailability.63 ADVERSE REACTIONS Side effects of dizziness, somnolence, fatigue, ataxia, headache, tremor, diplopia, nausea and vomiting, and rhinitis are usually transient and disappear with prolonged therapy.64 CARCINOGENICITY While the drug was being developed, preclinical studies temporarily ended owing to increased incidence of pancreatic acinar cell tumors in male Wistar rats fed high doses of gabapentin. The tumors did not occur in female rats, mice, or monkeys. Human pancreatic cancer tends to be ductal. The relevance of the tumors in animals to human carcinogenesis is unknown.64

Diagnosis In adults receiving 900 to 1800 mg/day, plasma concentrations range from 2.7 to 4.1 μg/mL following a single dose and from 4.0 to 8.5 μg/mL following multiple doses.

Management The treatment of gabapentin overdose is supportive. There is no established role for forced diuresis to enhance its urinary elimination.

LAMOTRIGINE Pharmacology Lamotrigine (LTG) stabilizes presynaptic neuronal membranes by blocking voltage-dependent sodium channels and thereby preventing the release of excitatory amino acids, especially glutamate and aspartate. Although LTG is a weak inhibitor of dihydrofolate reductase, antifolate drugs have not been shown to possess anticonvulsant activity.65

Anticonvulsants

741

hours. LTG does not induce or inhibit hepatic enzymes. LTG increases symptoms when added to carbamazepine through pharmacodynamic rather than pharmacokinetic interactions.66

Toxicology ACUTE TOXICITY (OVERDOSE) Serious toxicity has not been reported in adults. In a single case report, ataxia and rotational nystagmus were described. An analysis of serum concentrations suggests the elimination pharmacokinetics are first order. Seizures and coma have been reported in children ingesting LTG; all recovered without sequelae.67,68 ADVERSE REACTIONS Hypersensitivity reactions evidenced by multiorgan dysfunction and hepatic abnormalities, with and without the presence of a rash, have been reported. All patients who developed LTG-associated hypersensitivity syndrome were concomitantly taking ACs. Supratherapeutic dosing of LTG has also been associated with hypersensitivity reaction.68 Rashes, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reaction occur in up to 25% of children less than 16 years of age and 0.3% (3/1000) of adults. Rarely, death has occurred. Rash usually occurs within 2 to 8 weeks of initiation of the drug, but isolated cases occurring after prolonged treatment (6 months) have been reported. Risk factors include coadministering VPA and exceeding the recommended initial doses of LTG or escalating the dose. LTG should be discontinued at the first sign of a rash. Other reported side effects are headache, nausea, vomiting, dizziness, diplopia, ataxia, and tremor.69

Diagnosis At therapeutic doses, trough plasma concentrations are 2 to 4 mg/L. Maximum reported concentration following overdose is 35.8 mg/L. Serum concentrations are of no clinical value following overdose.67 Treatment of overdose is supportive.

TOPIRAMATE

Pharmacokinetics

Pharmacology

The drug is well absorbed; bioavailability is 98%. Its halflife is 22 to 36 hours. Being 55% protein bound, LTG is metabolized by hepatic glucuronidation, which is a target for enzyme inducers and inhibitors. Not surprisingly, metabolism of LTG is markedly increased by inducing drugs. Less than 10% is excreted unchanged.65

Topiramate, a sulfamate-substituted monosaccharide, is structurally distinct from other ACs. Topiramate causes a state-dependent blockade of sodium channels and potentiates GABA-mediated neuroinhibition by acting at a unique modulatory site. It enhances GABA-mediated chloride influx into neurons (similarly to diazepam), increasing the frequency at which GABA activates GABAA receptors. The drug itself does not interact with GABA binding sites or BZDP binding sites on GABAA. Topiramate also causes blockade of glutamate-mediated neuroexcitation. It is a weak carbonic anhydrase inhibitor.70

DRUG INTERACTIONS Hepatic drug enzyme inducers such as carbamazepine, phenytoin, and phenobarbital reduce the half-life of LTG by 15 hours. Sodium valproate reduces the clearance of LTG by 21% and increases its half-life to 59

742


Pharmacokinetics Topiramate is rapidly and completely absorbed from the GI tract and is minimally protein bound (9% to 17%) but extensively bound to erythrocytes until the binding sites are saturated. The drug’s half-life is 19 to 23 hours. Hepatic metabolism is minimal, and there are no active metabolites. The drug is primarily (70%) excreted in the urine.70

Toxicology ACUTE TOXICITY (OVERDOSE) Coma, status epilepticus, and hyperchloremic metabolic acidosis have been reported following acute overdose.71 ADVERSE EFFECTS CNS side effects (sedation) and cognitive side effects (trouble concentrating and finding words, decreased attention span) are worse with rapid titration of topiramate. Weight loss, ataxia, dizziness, nystagmus, tremor, and fatigue may occur. Since the drug is a carbonic anhydrase inhibitor, exchange of hydrogen ion for sodium ion and reabsorption of bicarbonate is decreased at the proximal renal tubule. Metabolic acidosis can therefore develop. Carbonic anhydrase inhibitors also decrease urinary citrate. Both decreased urinary citrate and acidosis increase the chance of calcium phosphate stones.72,73 Treatment of topiramate overdose is supportive; there are no antidotes.

TIAGABINE Pharmacology Tiagabine (TGB) prolongs the action of GABA by selectively inhibiting GABA transporters in the glia and neurons. TGB does not affect voltage-gated sodium or calcium channels.74

Pharmacokinetics TGB is oxidized via the cytochrome P-450 system but does not affect hepatic enzyme function and therefore does not affect other drug metabolism. Its half-life is 5 to 8 hours although it may be decreased to 3 hours by inducing drugs.1,75

Toxicology ACUTE TOXICITY (OVERDOSE) TGB overdose may precipitate seizures and nonconvulsive status.76 ADVERSE REACTIONS Side effects associated with therapeutic use include dizziness, headache, asthenia, and tremor. Visual field defects (VFDs) have been reported. Whether VFDs are

completely reversible when the drug is discontinued is unclear.77

Diagnosis Therapeutic monitoring of plasma concentration is not recommended, since there is no clinical correlation between plasma concentrations and clinical course. Treatment of TGB overdose is supportive.

VIGABATRIN (VGB) Introduction Early experiments revealed that brain microvacuoles developed in some animal species taking vigabatrin (VGB). An extensive clinical monitoring program since 1982 throughout the United States and Europe has not revealed evidence of VGB-related CNS vacuolation in humans.78

Pharmacology VGB is a structural analog of GABA and an irreversible inhibitor of GABA transaminase, the enzyme primarily responsible for GABA catabolism. VGB also reduces GABA reuptake activity. Both mechanisms increase brain GABA concentrations.

Pharmacokinetics The bioavailability of VGB is 90%, and volume of distribution is 0.8L/kg. The drug is not protein bound, has negligible hepatic metabolism, and is primarily cleared by the kidneys. Its half-life is 5 to 7 hours. The pharmacologic half-life is much longer than the elimination half-life, with the duration of action being 5 to 7 days.79

Toxicology ACUTE TOXICITY (OVERDOSE) Symptoms following overdose include drowsiness, decreased level of consciousness, and coma. Respiratory depression, bradycardia, hypotension, agitation, irritability, confusion, and abnormal behavior have also been reported.80 ADVERSE REACTIONS Mood and behavior changes such as depression, psychosis, and acute encephalopathy may occur. Sedation, fatigue, headache, and weight gain are usually mild and short lasting.

Diagnosis There is no correlation between plasma concentration and seizure control or adverse effects. Treatment of overdose is supportive.

CHAPTER 40

LEVETIRACETAM Pharmacology Levetiracetam is structurally unrelated to other antiepileptic drugs. It does not affect the GABA system, nor does it block sodium or calcium channels. In vitro, the drug binds to brain cell membranes in reversible, saturable, and stereoselective fashion.81

Pharmacokinetics Levetiracetam is rapidly and completely absorbed, and peak plasma concentrations occur in an hour. Minimal protein binding and lack of hepatic metabolism prevent drug interactions. Sixty-six percent is excreted unchanged in the urine, of which 27% is excreted as inactive metabolites. The drug’s volume of distribution is 0.5 to 0.7 L/kg. Its half-life in adults is 6 to 8 hours; in the elderly, 10 to 12 hours; and in children, 6 hours. Because it is primarily renally excreted, dosage adjustments are necessary for patients with renal impairment.81,82

Toxicology ACUTE TOXICITY (OVERDOSE) Levetiracetam may cause CNS and respiratory depression. Recovery is rapid with supportive care. Elimination kinetics are first order following overdose. Treatment of overdose is supportive.83

ZONISAMIDE Pharmacology Zonisamide (ZNS) is a sulfonamide. The drug blocks sodium channels and T-type calcium channels and is a weak carbonic anhydrase inhibitor.82,84

Pharmacokinetics Peak plasma concentrations are achieved in 2.4 to 3.6 hours after ingestion. Japanese studies have reported linear pharmacokinetics, whereas U.S. studies have reported nonlinear pharmacokinetics with first order clearance. CYP3A4 is the isoenzyme that metabolizes the drug. The drug’s elimination half-life is 63 hours. The drug is excreted in the urine as unchanged drug, as an acetylation product, and as the glucuronide of a metabolite.84

Toxicology CHRONIC TOXICITY Carbonic anhydrase inhibitors decrease urinary citrate, an inhibitor of stone formation. Whether ZNS increases the risk of nephrolithiasis is unknown. In 2001, oligohidrosis and hyperthermia were reported in 38 patients in Japan and 2 patients in the

Anticonvulsants

743

United States. Pediatric patients may be at increased risk for this dangerous adverse effect.85 ZNS may contribute to psychosis during polytherapy. The incidence of psychotic episodes in epileptic patients taking ZNS is higher than the prevalence of epileptic psychosis in those not receiving the drug.86 SIDE EFFECTS Drowsiness (24%), ataxia (13%), anorexia, dizziness, forgetfulness, slowness of thought, and irritability are usually mild and transient.

OXCARBAZEPINE Pharmacology Oxcarbazepine (OXZ) is the 10-keto analog of carbamazepine. Similarly to CBMZ, oxcarbazepine blocks voltage-sensitive sodium channels, causing stabilization of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and inhibition of the spread of discharges. The drug also increases potassium conductance, decreases glutaminergic transmission, and modulates the calcium channel.87

Pharmacokinetics OXZ is well absorbed; its absorption is not affected by food. Peak serum concentrations occur 4 to 6 hours after ingestion. It is rapidly metabolized in the liver to an active, nontoxic metabolite, which is widely distributed in the brain and lipophilic tissues and is responsible for the pharmacologic action of the drug. Metabolite halflife is 8 to 10 hours and is not affected by other ACs. Compared with CBMZ, OXZ has fewer side effects owing to lack of toxicity of the metabolite. OXZ is 38% bound to plasma protein. Since the active drug is excreted by the kidneys, the dose may need to be reduced in patients with renal impairment.88

Toxicology ADVERSE EFFECTS Duration and frequency of side effects are less than for CBMZ. Side effects include fatigue, headache, dizziness, ataxia, and nausea. Skin rash occurs in up to 10% of patients and is the main reason for discontinuation of the drug. OXZ may be administered to patients who have developed a rash while taking carbamazepine. Crossreactivity is about 25%. Clinically insignificant hyponatremia occurs in 20% of patients.89 DRUG INTERACTIONS An advantage of OXZ is that it causes few drug interactions. If OXZ is substituted for carbamazepine, deinduction can occur.

744


REFERENCES 1. LaRoche SM, Helmers SL: The new antiepileptic drugs: clinical applications. JAMA 2004;291:605–614. 2. Kwan P, Brodie MJ: Early identification of refractory epilepsy. N Engl J Med 2000;342:314–319. 3. Diaz-Arrastia R, Agostini MA, Van Ness PC: Evolving treatment strategies for epilepsy. JAMA 2002;287:2917–2920. 4. Perucca E: Marketed new antiepileptic drugs: are they better than old-generation agents? Ther Drug Monit 2002;24:74–80. 5. Lathers CM, Schraeder PL: Clinical pharmacology: drugs as a benefit and/or risk in sudden unexpected death in epilepsy? J Clin Pharmacol 2002;42:123–136. 6. Holmes LB, Harvey EA, Coull BA, et al: The teratogenicity of anticonvulsant drugs. N Engl J Med 2001;344:1132–1138. 7. Knowles SR, Shapiro LE, Shear NH: Anticonvulsant hypersensitivity syndrome: incidence, prevention and management. Drug Saf 1999;21:489–501. 8. Rho JM, Donevan SD, Rogawski MA: Direct activation of GABAA receptors by barbiturates in cultured rat hippocampal neurons. J Physiol 1996;497:509–522. 9. Shubin H, Weil MH: The mechanism of shock following suicidal doses of barbiturates, narcotics and tranquilizer drugs, with observations on the effects of treatment. Am J Med 1965; 38:853–863. 10. Pond SM, Olson KR, Osterloh JD, et al: Randomized study of the treatment of phenobarbital overdose with repeated doses of activated charcoal. JAMA 1984;251:3104–3108. 11. Frenia ML, Schauben JL, Wears RL, et al: Multiple-dose activated charcoal compared to urinary alkalinization for the enhancement of phenobarbital elimination. J Toxicol Clin Toxicol 1996; 34:169–175. 12. Russell RJ, Parks B: Anticonvulsant medications. Pediatr Ann 1999;28:238–245. 13. McNamara J: Drugs effective in the therapy of the epilepsies. In Hardman J, Limbird L (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 436–444. 14. Jung D, Powell JR, Walson P, et al: Effect of dose on phenytoin absorption. Clin Pharmacol Ther 1980;28:479–485. 15. Dichter MA: Old and new mechanisms of antiepileptic drug actions. Epilepsy Res Suppl 1993;10:9–17. 16. Walsh-Kelly CM, Berens RJ, Glaeser PW, et al: Intraosseous infusion of phenytoin. Am J Emerg Med 1986;4:523–524. 17. Wyte CD, Berk WA: Severe oral phenytoin overdose does not cause cardiovascular morbidity. Ann Emerg Med 1991;20:508–512. 18. Masur H, Elger CE, Ludolph AC, et al: Cerebellar atrophy following acute intoxication with phenytoin. Neurology 1989; 39:432–423. 19. Flowers FP, Araujo OE, Hamm KA: Phenytoin hypersensitivity syndrome. J Emerg Med 1987;5:103–108. 20. Gordon MF, Gerstenblitt D: The use of free phenytoin levels in averting phenytoin toxicity. N Y State J Med 1990;90:469. 21. Donovan PJ, Cline D: Phenytoin administration by constant intravenous infusion: selective rates of administration. Ann Emerg Med 1991;20:139–142. 22. Carducci B, Hedges JR, Beal JC, et al: Emergency phenytoin loading by constant intravenous infusion. Ann Emerg Med 1984;13:1027–1031. 23. Earnest MP, Marx JA, Drury LR: Complications of intravenous phenytoin for acute treatment of seizures: recommendations for usage. JAMA 1983;249:762–765. 24. York R, Coleridge ST: Cardiopulmonary arrest following intravenous phenytoin loading. Am J Emerg Med 1988;6:255–259. 25. Spengler RF, Arrowsmith JB, Kilarski DJ, et al: Severe soft-tissue injury following intravenous infusion of phenytoin. Arch Intern Med 1988;148:1329–1333. 26. DeToledo JC, Ramsay RE: Fosphenytoin and phenytoin in patients with status epilepticus. Drug Saf 2000;22:459–466. 27. Browne TR, Kugler AR, Eldon MA: Pharmacology and pharmacokinetics of fosphenytoin. Neurology 1996;46(6 Suppl 1):S3–S7. 28. Rudis MI, Touchette DR, Swadron SP, et al: Cost-effectiveness of oral phenytoin, intravenous phenytoin, and intravenous fosphenytoin in the emergency department. Ann Emerg Med 2004;43:386–397.

29. Swadron SP, Rudis MI, Azimian K, et al: A comparison of phenytoin-loading techniques in the emergency department. Acad Emerg Med 2004;11:244–252. 30. Yoshimura R, Yanagihara N, Terao T, et al: Inhibition by carbamazepine of various ion channels: mediated catecholamine secretion in cultured bovine adrenal medullary cells. Naunyn Schmiedebergs Arch Pharmacol 1995;352:297–303. 31. Graudins A, Peden G, Dowsett RP: Massive overdose with controlled-release carbamazepine resulting in delayed peak serum concentrations and life-threatening toxicity. Emerg Med (Fremantle) 2002;14:89–94. 32. Winnicka RI, Topacinski B, Szymczak WM, et al: Carbamazepine poisoning: elimination kinetics and quantitative relationship with carbamazepine 10,11-epoxide. J Toxicol Clin Toxicol 2002; 40:759–765. 33. Graves NM, Brundage RC, Wen Y, et al: Population pharmacokinetics of carbamazepine in adults with epilepsy. Pharmacotherapy 1998;18:273–281. 34. Seymour JF: Carbamazepine overdose. Drug Saf 1993;8:81–88. 35. Apfelbaum JD, Cavarati EM, Kerns WP II, et al: Cardiovascular effects of carbamazepine toxicity. Ann Emerg Med 1995;25:631–635. 36. Lifshitz M, Gavrilov V, Sofer S: Signs and symptoms of carbamazepine overdose in young children. Pediatr Emerg Care 2000;16:26–27. 37. Stremski ES, Brady WB, Prasad K, et al: Pediatric carbamazepine intoxication. Ann Emerg Med 1995;25:624–630. 38. Hojer J, Malmlund HO, Berg A: Clinical features in 28 consecutive cases of laboratory confirmed massive poisoning with carbamazepine alone. J Toxicol Clin Toxicol 1993;31:449–458. 39. Matos ME, Burns MM, Shannon MW: False-positive tricyclic antidepressant drug screen results leading to the diagnosis of carbamazepine intoxication. Pediatrics 2000;105:E66. 40. Boldy DA, Heath A, Ruddock S, et al: Activated charcoal for carbamazepine poisoning. Lancet 1987;1:1027. 41. Wason S, Baker RC, Carolan P, et al: Carbamazepine overdose: the effects of multiple-dose activated charcoal. J Toxicol Clin Toxicol 1992;30:39–48. 42. Tapolyai M, Campbell M, Dailey K, et al: Hemodialysis is as effective as hemoperfusion for drug removal in carbamazepine poisoning. Nephron 2002;90:213–215. 43. Andersen GO, Ritland S: Life threatening intoxication with sodium valproate. J Toxicol Clin Toxicol 1995;33:279–284. 44. Albus H, Williamson R: Electrophysiologic analysis of the actions of valproate on pyramidal neurons in the rat hippocampal slice. Epilepsia 1998;39:124–129. 45. Loscher W: Effects of the antiepileptic drug valproate on metabolism and function of inhibitory and excitatory amino acids in the brain. Neurochem Res 1993;18:485–502. 46. Asai M, Talavera E, Massarini A, et al: Valproic acid–induced rapid changes of met-enkephalin levels in rat brain. Neuropeptides 1994;27:203–210. 47. Dupuis RE, Lichtman SN, Pollack GM: Acute valproic acid overdose: clinical course and pharmacokinetic disposition of valproic acid and metabolites. Drug Saf 1990;5:65–70. 48. Rho JM, Sankar R: The pharmacologic basis of antiepileptic drug action. Epilepsia 1999;40:1471–1483. 49. Spiller HA, Krenzelok EP, Klein-Schwartz W, et al: Multicenter case series of valproic acid ingestion: serum concentrations and toxicity. J Toxicol Clin Toxicol 2000;38:755–760. 50. Patsalos PN, Wilson SJ, Popovik M, et al: The prevalence of valproic acid–associated hyperammonaemia in patients with intractable epilepsy. J Epilepsy 1993;6:228–232. 51. Bryant AE III, Dreifuss FE: Valproic acid hepatic fatalities. 3. U.S. experience since 1986. Neurology 1996;46:465–469. 52. Yazdani K, Lippmann M, Gala I: Fatal pancreatitis associated with valproic acid. Medicine 2002;81:305–310. 53. Alberto G, Erickson T, Popiel R, et al: Central nervous system manifestations of a valproic acid overdose responsive to naloxone. Ann Emerg Med 1989;18:889–891. 54. Ingels M, Beauchamp J, Clark RF, et al: Delayed valproic acid toxicity: a retrospective case series. Ann Emerg Med 2002; 39:616–621. 55. Ishikura H, Matsuo N, Matsubara M, et al: Valproic acid overdose and L-carnitine therapy. J Anal Toxicol 1996;20:55–58.

CHAPTER 40

56. Kane SL, Constantiner M, Staubus AE, et al: High-flux hemodialysis without hemoperfusion is effective in acute valproic acid overdose. Ann Pharmacother 2000;34:1146–1151. 57. Leppik IE: Felbamate. Epilepsia 1995;36(Suppl 2):S66–S72. 58. Welty TE, Privitera M, Shukla R: Increased seizure frequency associated with felbamate withdrawal in adults. Arch Neurol 1998;55:641–645. 59. Hachad H, Ragueneau-Majlessi I, Levy RH: New antiepileptic drugs: review on drug interactions. Ther Drug Monit 2002; 24:91–103. 60. Rengstorff DS, Milstone AP, Seger DL, et al: Felbamate overdose complicated by massive crystalluria and acute renal failure. J Toxicol Clin Toxicol 2000;38:667–669. 61. Harden CL, Trifiletti R, Kutt H: Felbamate levels in patients with epilepsy. Epilepsia 1996;37:280–283. 62. Fisher JH, Andrews CO, Taber JE, et al: Multidose evaluation of gabapentin pharmacokinetics in patients with epilepsy. Epilepsia 1995;36(Suppl 4):121. 63. Fischer JH, Barr AN, Rogers SL, et al: Lack of serious toxicity following gabapentin overdose. Neurology 1994;44:982–983. 64. U.S. Gabapentin Study Group No. 5: Gabapentin as add-on therapy in refractory partial epilepsy: a double-blind, placebocontrolled, parallel-group study. Neurology 1993;43:2292–2298. 65. Goa KL, Ross SR, Chrisp P: Lamotrigine: a review of its pharmacological properties and clinical efficacy in epilepsy. Drugs 1993;46:152–176. 66. Yuen AW, Land G, Weatherby BC, et al: Sodium valproate acutely inhibits lamotrigine metabolism. Br J Clin Pharmacol 1992; 33:511–513. 67. O’Donnell J, Bateman DN: Lamotrigine overdose in an adult. J Toxicol Clin Toxicol 2000;38:659–660. 68. Briassoulis G, Kalabalikis P, Tomiolaki M, et al: Lamotrigine childhood overdose. Pediatr Neurol 1998;19:239–242. 69. Schlumberger E, Chavez F, Palacios L, et al: Lamotrigine in treatment of 120 children with epilepsy. Epilepsia 1994;35:359–367. 70. Garnett WR: Clinical pharmacology of topiramate: a review. Epilepsia 2000;41(Suppl 1):S61–S65. 71. Fakhoury T, Murray L, Seger D, et al: Topiramate overdose: clinical and laboratory features. Epilepsy Behav 2002;3:185–189.

Anticonvulsants

745

72. Stowe CD, Bollinger T, James LP, et al: Acute mental status changes and hyperchloremic metabolic acidosis with long-term topiramate therapy. Pharmacotherapy 2000;20:105. 73. Wasserstein AG, Rak I, Reife RA: Nephrolithiasis during treatment with topiramate. Epilepsia 1995;36(Suppl 3):S153. 74. Suzdak PD, Jansen JA: A review of the preclinical pharmacology of tiagabine: a potent and selective anticonvulsant GABA uptake inhibitor. Epilepsia 1995;36:612–626. 75. Leach JP, Brodie MJ: Tiagabine. Lancet 1998;351:203–207. 76. Ostrovskiy D, Spanaki MV, Morris GL II: Tiagabine overdose can induce convulsive status epilepticus. Epilepsia 2002;43:773–774. 77. Kaufman KR, Lepore FE, Keyser BJ: Visual fields and tiagabine: a quandary. Seizure 2001;10:525–529. 78. Gidal BE, Privitera MD, Sheth RD, et al: Vigabatrin: a novel therapy for seizure disorders. Ann Pharmacother 1999;33:1277–1286. 79. Hoke JF, Yuh L, Antony KK, et al: Pharmacokinetics of vigabatrin following single and multiple oral doses in normal volunteers. J Clin Pharmacol 1993;33:458–462. 80. Davie MB, Cook MJ, Ng C: Vigabatrin overdose. Med J Aust 1996;165:403. 81. Patsalos PN: Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacol Ther 2000;85:77. 82. Perucca E, Bialer M: The clinical pharmacokinetics of the newer antiepileptic drugs: focus on topiramate, zonisamide and tiagabine. Clin Pharmacokinet 1996;31:29–46. 83. Barrueto F II, Williams K, Howland MA, et al: A case of levetiracetam poisoning with clinical and toxicokinetic data. J Toxicol Clin Toxicol 2002;40:881–884. 84. Mimaki T: Clinical pharmacology and therapeutic drug monitoring of zonisamide. Ther Drug Monit 1998;20:593–597. 85. Oommen KJ, Mathews S: Zonisamide: a new antiepileptic drug. Clin Neuropharmacol 1999;22:192. 86. Miyamoto T, Kohsaka M, Koyama T: Psychotic episodes during zonisamide treatment. Seizure 2000;9:65–70. 87. Shorvon S: Oxcarbazepine: a review. Seizure 2000;9:75–79. 88. Tecoma ES: Oxcarbazepine. Epilepsia 1994;40(Suppl 5):S37–S46. 89. Rouan MC, Lecaillon JB, Godbillon J, et al: The effect of renal impairment on the pharmacokinetics of oxcarbazepine and its metabolites. Eur J Clin Pharmacol 1994;47:161–167.

41

Marijuana JOÃO DELGADO, MD


Marijuana is the most commonly used illicit drug in the United States. Marijuana intoxication is self-limited and typically produces mild symptoms. There is no specific antidote—treatment of intoxication is supportive.

INTRODUCTION AND RELEVANT HISTORY Marijuana is by far the most extensively used illicit drug in the United States. The hemp plant, Cannabis sativa, from which it is prepared, has been used for centuries not only for its psychoactive resin but also for hemp fiber and rope. The cannabinoid Δ9-tetrahydrocannabinol (THC) is the principal psychoactive constituent and is found in highest concentration in the leaves and the flowering tops of the plant. In addition, the plant contains hundreds of other chemicals, including several cannabinoids. Marijuana and its synthetic analogs (e.g., dronabinol) have also been used medicinally to treat a variety of chronic conditions. The term marijuana refers to dried, tobacco-like preparations of the leaves, stems, and flowers. The THC content of marijuana is variable and may range from 0.4% to 20%, depending on cultivation techniques. The average THC content of confiscated marijuana has increased over the past two decades from under 2% in the late 1970s to 7.79% in 2005.1 A typical marijuana cigarette contains 500 to 1000 mg of plant material, which is equivalent to approximately 25 to 50 mg of THC. Hashish is the resin extracted from the tops of the flowering plants and has a THC concentration that may exceed 10%. Hash oil is an organic solvent extract of cannabis that may have a THC concentration of 20% or higher. The modern phase of therapeutic cannabis use began in 1842, when O’Shaughnessy reported on its effectiveness as an analgesic and anticonvulsant.2 Cannabis was subsequently touted as a treatment for psychiatric illnesses, insomnia, poor appetite, opium addiction, chronic alcoholism, delirium tremens, and a wide variety of painful disorders. However, as synthetic analgesics and sedatives became available, the medical use of cannabis faded. The Marijuana Tax Act of 1937 officially eliminated it from medical practice in the United States. Current therapeutic uses of cannabinoids include alleviating chemotherapy-induced nausea and vomiting and attenuation of anorexia and nausea associated with AIDS. In general, enthusiasm for the medicinal use of marijuana has been tempered by inconsistent clinical

trial results, modest therapeutic effectiveness, the adverse health consequences of delivery by smoking, undesirable side effects, and the superiority of already marketed drugs. Those advocating the use of marijuana for medicinal purposes argue that THC is delivered more effectively in smoke than in oral preparations, that marijuana is less expensive than synthetic THC, and that marijuana produces few if any harmful side effects. The most common form of marijuana use in the United States is in cigarettes. Generally, smoke is inhaled deeply and held in the lungs for 15 to 30 seconds, which results in rapid intoxication or “high.” Other psychoactive substances, such as phencyclidine or cocaine, may be mixed with marijuana and then smoked. Ingestion is the second most common means of intoxication and is typically accomplished by baking marijuana inside cookies or brownies. In contrast to inhalation, the effects after ingestion occur more gradually and the level of intoxication is not as readily controlled as with inhalation. Illicit intravenous injection of crude marijuana plant extracts remains an unusual practice. The gummy consistency of the plant resin and its poor water solubility limit its use via this route.

EPIDEMIOLOGY The National Institute on Drug Abuse (NIDA) funds an ongoing national research and reporting program called the Monitoring the Future Study, in which secondary school students, college students, and young adults are surveyed annually about drug use.3 This study has consistently shown that alcohol is the most frequently used substance in all subgroups, and marijuana is the most frequently used illicit substance. The most recent data show that nearly one half of 12th graders have used marijuana at least once and that 22% are current users.4 Another large national survey indicates that 37% of the U.S. population (83 million people) has used marijuana at least once and 14.6 million are currently using marijuana.5 Such widespread use has significant public health implications. For example, workers who smoke marijuana frequently have higher rates of absenteeism and miss more days of work due to illness than nonsmokers.6 Perhaps more concerning is marijuana’s role as a “gateway” drug, meaning that marijuana users are more likely to move on to other more harmful drugs, such as cocaine, heroin, and amphetamines.7

STRUCTURE Cannabinoids are aryl-substituted monoterpenes unique to the genus Cannabis. C. sativa contains over 60 cannabi747

748


J

CH3 OH

H3C H3C

J

H H O

CH3

FIGURE 41-1 Chemical structure of 1-trans-Δ9-tetrahydrocannabinol.

noids, the most pharmacologically potent of which is THC (Fig. 41-1).

PHARMACOLOGY AND PATHOPHYSIOLOGY THC produces numerous pharmacologic and behavioral effects through its action on the CB1 cannabinoid receptor. This receptor is a member of a large family of receptors that are coupled to G proteins and modulate adenylate cyclase.8 CB1 receptors are distributed primarily in axons and nerve terminals. Their presynaptic localization suggests a modulatory role on neurotransmitter release. In fact, THC is known to inhibit the release of a variety of neurotransmitters, including acetylcholine, dopamine, γ-aminobutyric acid, L-glutamate, serotonin, and norepinephrine.9 A number of arachidonic acid derivatives have been shown to serve as endogenous CB1 ligands. These derivatives include arachidonolyl-glycerol (Ara-G1) and anandamide.10,11 The establishment of a cannabinoid receptor and several endogenous ligands with biosynthetic and degradative pathways suggests the possible presence of a distinct neurochemical system. A peripheral cannabinoid receptor, designated CB2, has been identified in macrophages but its role remains unknown.12 The highest density of cannabinoid receptors is found in the cerebral cortex, particularly the frontal areas, cerebellum, basal ganglia, hypothalamus, and hippocampus.9 This distribution explains the prominent effects of THC on memory, cognition, and motor function. Scarce levels of CB1 receptors in the brainstem regions are thought to account for the low lethality of cannabinoids. Binding has also been found in the Blymphocyte-rich areas, including the marginal zone of the spleen, the nodular corona of Peyer’s patches, and the cortex of lymph nodes.13 Pharmacologic effects begin rapidly and generally peak within 30 minutes of smoking a marijuana cigarette. Behavioral and physiologic effects generally return to baseline levels 4 to 6 hours after smoking. However, impairment of various performance measures related to complex tasks, such as driving a car or flying an airplane, has been demonstrated immediately after marijuana use and persisting for as long as 24 hours.14,15 Marijuana is classified as a schedule I controlled substance (“no currently accepted medical use”) by the U.S. Drug Enforcement Administration, whereas pharmaceutical THC is classified as a schedule III controlled substance. The THC analogs dronabinol, levonantradol, nabilone, and nabitan have been used to treat chemotherapy-

induced nausea and vomiting.16 A systematic review of the medical literature determined that cannabinoids appear to be more effective than conventional antiemetics in treating mild to moderate nausea but were associated with significant side effects that limited their usefulness.17 The development of 5-HT3 receptor antagonists, such granisetron and ondasetron, has further limited the use of THC for this indication. Dronabinol is approved by the Food and Drug Administration for chemotherapyassociated nausea and vomiting refractory to conventional antiemetics. The recommended dose is 5 to 15 mg/m2. Dronabinol is also approved for appetite stimulation in patients with AIDS wasting syndrome.18 The typical starting dose for appetite stimulation is 2.5 mg twice a day. Dronabinol is marketed under the trade name Marinol (Solvay Pharmaceuticals, Inc., Marietta, GA) Although THC has analgesic properties, it is no more effective than codeine and produces considerable side effects in the effective analgesic dose range.19 Marijuana, THC, and several synthetic derivatives have been shown to lower intraocular pressure in patients with glaucoma but are not widely used for this indication.20 A topical preparation of marijuana intended for the treatment of glaucoma is marketed as Canasol in Jamaica (Medi-Grace Ltd., Kingston, Jamaica).21 Extensive animal studies have shown that THC is capable of producing both proconvulsant and anticonvulsant effects. Cannabidiol, in particular, showed some promise as an anticonvulsant in animal studies.22 However, its efficacy was not sufficient to warrant clinical use in humans. Recently, there has been an interest in using Cannabis for tremor and spasticity associated with multiple sclerosis. Clinical trials have not shown improvement in objective measures of tremor or spasticity despite the perception by participants of an improvement of their symptoms.23,24

PHARMACOKINETICS THC is readily absorbed when marijuana is smoked, with peak serum concentrations obtained within 10 to 20 minutes. Peak clinical effects occur within 30 minutes of smoking.25 Heavy marijuana smokers absorb THC more efficiently (23% to 27% bioavailability) than light smokers (10% to 14% bioavailability).26 Although oral ingestion of marijuana produces similar pharmacologic effects, THC is absorbed more slowly and erratically than when smoked. Oral bioavailability is only 6% to 10% because of extensive first pass metabolism. Peak plasma THC concentrations occur 1 to 3 hours after ingestion and are much lower than those achieved by smoking. THC is highly protein bound (97% to 99%) and lipophilic, with an apparent volume of distribution of 4 to 14 L/kg.25 THC is metabolized first to hydroxylated metabolites, followed by conversion to carboxylic acids. The metabolites are subsequently excreted as conjugates. The initial hydroxylated metabolites of THC (i.e., 11-hydroxy-THC and 8-β-hydroxy-THC) are active but do not achieve appreciable plasma concentrations and are not likely to contribute to the acute behavioral

CHAPTER 41

effects of marijuana.25 Approximately 15% and 50% of THC is excreted in urine and feces, respectively, over several days.27 The urinary elimination half-life of THC averages 5 days in heavy users of marijuana as compared with 20 to 57 hours for infrequent users.25,28 The primary urinary metabolite is conjugated 11-nor-9-carboxy-Δ9− THC, which has a urinary elimination half-life of 3 days in heavy users.29 Only trace amounts of THC are excreted in urine unchanged. Blood concentrations of THC peak before behavioral effects and do not correlate well with pharmacologic effects.30 Peak behavioral effects lag behind the time of peak plasma THC levels by 10 to 30 minutes for smoking and 1 to 3 hours for ingestion; significant effects may last for 4 to 8 hours.25,31,32 In clinical settings, blood and urine levels of THC and metabolites are only useful for determining whether or not an individual has used marijuana and not in determining degree of resulting impairment.

TOXICOLOGY Overall, toxicity arising from cannabinoid use is mild. Even when large doses are used, the effects are not usually prolonged or life threatening. Exceptions to this rule are ingestions involving small children, who may become severely obtunded after ingesting hashish or marijuana, and individuals who experience severe allergic reactions to Cannabis, both of which are rare occurrences.33,34

Psychological and Neurologic Effects Marijuana’s effects on central nervous system functions such as behavior, cognition, perception, and performance are its most important physiologic effects. Individuals who consume low to moderate quantities generally report a feeling of well-being and pleasant relaxation, euphoria, a dreamlike state, alteration of time and space perception, and a heightening of their senses. Smoking a large quantity of marijuana can produce a range of effects including mild anxiety, paranoid behavior, acute psychosis, problems in dealing with reality, and obsessional thought content characterized by delusions, hallucinations, illusions, and bizarre behavior. These adverse effects sometimes occur in inexperienced users even after low doses. Cognitive functioning, such as speaking, problem solving, and memory recall, are affected by marijuana use.35 Marijuana’s interference with short-term memory is thought to be a major cause of poor cognitive performance during marijuana intoxication. Information learned while intoxicated is less well recalled than in a sober state. Impairment of complex motor functions also occurs in intoxicated individuals.35 Some parameters that affect driving performance continue to be impaired even several hours after a marijuana user no longer feels high. Epidemiologic data suggest that drivers who recently used Cannabis are approximately three to seven times

Marijuana

749

more likely to have caused a crash than sober drivers.36 This impairment is exacerbated by the common combination of marijuana with alcohol. Adverse psychological reactions to marijuana use occur relatively frequently.37 The exaggeration of the more usual marijuana response, in which an individual loses perspective (i.e., the realization that what he or she is experiencing is a transient drug-induced distortion of reality), may produce anxiety. This reaction appears to occur primarily in inexperienced users, although unexpectedly higher doses of the drug can cause such a response even in experienced users. Symptoms usually resolve in a few hours as the immediate effects of acute intoxication recede. Typically, only authoritative assurance and limiting sensory input are required. Uncommon cannabinoid-induced symptoms may include severe panic and anxiety states, paranoia, depression, personality changes, confusional states, and psychoses, which are indistinguishable from primary psychiatric syndromes unless the drug-induced etiology is known. Whether marijuana use can precipitate permanent psychiatric illness in individuals who have no underlying predisposition remains controversial. Marijuana has also been linked to transient ischemic attacks and strokes, but definitive evidence of a causative role is lacking.38,39 There is no convincing evidence that cannabinoids are neurotoxic to humans.40

Respiratory Effects Inhalation of marijuana smoke is associated with rhinitis, pharyngitis, laryngitis, cough, hoarseness, and bronchitis, which are symptoms commonly reported by tobacco smokers as well. Interestingly, marijuana smoke also produces bronchodilatation in both normal and asthmatic patients. Prolonged marijuana use is associated with chronic bronchitis and changes in respiratory tract cells.41 In contrast to tobacco smoke, which affects primarily the smaller airways and the alveoli, marijuana smoke is associated with large airways disease.42,43 Longitudinal data suggest an additive effect of marijuana plus tobacco with respect to symptom prevalence. Uncommon adverse effects include pneumothorax and pneumomediastinum from the Valsalva maneuver that marijuana users frequently employ in an attempt to increase THC absorption by the lung; partial upper airway obstruction from marijuana smoke–induced uvulitis; and pulmonary aspergillosis.44-46 As with tobacco smoke, marijuana smoke has a high content of particulate matter, or tar. Compared to tobacco smoke, marijuana smoke contains threefold more tar and results in fivefold higher carbon monoxide concentrations.47 No large-scale epidemiologic studies have been carried out to determine if there is a relationship between smoking marijuana and the incidence of lung cancer. Nevertheless, there is good reason for concern about the possibility that lung cancer might result from prolonged use. Several reports have noted a higher-than-expected incidence of head and neck squamous cell carcinoma.48 Like tobacco smoke residuals, so-called tar Cannabis residuals, when applied to the skin

750


of experimental animals, produce tumors. Analysis of marijuana smoke has also revealed high concentrations of carcinogenic hydrocarbons.

Cardiovascular Effects Dose-related sinus tachycardia is the most common cardiovascular effect observed after the administration of THC, regardless of route.49 Orthostatic hypotension may occur with higher doses. Electrocardiographic changes in intoxicated individuals include nonspecific ST-T changes as well as occasional premature ventricular contractions. One report implicated marijuana use in causing atrial fibrillation.50 The cardiovascular effects are caused primarily by stimulation of the autonomic nervous system with involvement of both the parasympathetic and sympathetic pathways. These effects are not likely to have serious consequences in young, healthy adults but may be significant in patients with preexisting cardiovascular disease. For example, one study found that the risk of having a myocardial infarction increases fourfold in the hour following marijuana use.51 No longterm cardiovascular effects have been described to date.

Reproductive Effects No definitive evidence shows that marijuana use alters reproductive function in either gender to such an extent that reproduction is compromised. Changes in sex hormone levels after heavy marijuana use have been described, but these effects have not been consistently demonstrated. For example, one study found depressed testosterone levels in heavy marijuana users but another found no difference in levels of testosterone, luteinizing hormone, follicle-stimulating hormone, prolactin, or cortisol.52,53 Even when lower testosterone levels have been noted, the levels have been within normal limits. Whether long-term use of marijuana might result in persistently depressed levels of serum testosterone is unknown. An increased incidence of gynecomastia and elevated estrogen levels have been noted in some men who use marijuana chronically. Studies of the semen of male long-term users found abnormalities in count, motility, and structural characteristics of the sperm examined.54,55 In men with already marginal fertility, decreased fertility might well result, although definitive evidence of this has not emerged. Marijuana use does not appear to affect the ovulatory cycle in women.56

Pregnancy and Fetal Development In laboratory animals, exposure to high doses of THC results in an increased number of stillbirths and decreased litter size.57 Malformations in offspring have also been described, but these occur only when dams received very high doses of THC during the initial stages of organogenesis. Many of these studies conducted with high doses of THC more likely reflect maternal toxicity rather than direct effects on embryonic and fetal development.58

The effects of maternal marijuana use on fetal development and the outcome of pregnancy are difficult to study in humans because these effects are confounded by alcohol and drug use, smoking, nutritional status, and socioeconomic status. A reduction in birth weight of infants born to women who used marijuana during pregnancy has been noted in some studies but not in others.59 In general, marijuana users are more likely than nonusers to have had an unplanned pregnancy, premature labor, and abruptio placentae, and their children are more likely to have lower birth weight and congenital features compatible with fetal alcohol syndrome or other major malformations.60-62 Because women who smoke marijuana frequently smoke tobacco, drink alcohol, and abuse other drugs, it is difficult to isolate a marijuana effect. The long-term consequences of prenatal marijuana exposure are not clear. Some alterations in language skills are observed at 2 years of age, and verbal ability and memory were different between marijuana-exposed and nonexposed 4-yearolds.63,64 However, these differences were not observed in 5- and 6-year-olds.

Immune System The presence of a unique subpopulation of cannabinoid receptors in macrophages suggests that cannabinoids are capable of affecting the immune system. Although there has been concern that cannabinoids could contribute to immunosuppression, particularly in already compromised individuals, convincing evidence is lacking in humans.65,66 Marijuana smoke has been shown to alter numerous immune parameters in vitro. Described changes in macrophages include suppression of superoxide production, altered morphology, diminished phagocytic and spreading ability, increased interleukin-1 production, suppression of extrinsic antivirus activity, and alteration of tumor necrosis factor levels.67-73 Studies examining cellular and humoral responses have produced inconsistent results, with some showing differences in immunoglobulin production and alteration in CD4 to CD8 ratios, while others have not been able to demonstrate differences.74,75 Perhaps most concerning is the observation that cannabinoids may decrease host resistance to infection. While these effects are unlikely to affect normal hosts, they may be significant in compromised hosts.

Tolerance and Dependence The development of tolerance to the effects of marijuana is well established.76 Marijuana dependence, defined as experiencing physical symptoms (such as irritability, restlessness, sleep disturbance, nausea, and diarrhea) on cessation of use may occur in settings of heavy use.77 It is estimated that more than 200,000 individuals in the United States seek treatment for marijuana dependence each year.78 The gradual release of accumulated THC from fat stores creates a “tapered dose” effect and is thought to account for the relatively mild manifestations of marijuana withdrawal.

CHAPTER 41

EFFECTS OF MARIJUANA IN COMBINATION WITH ALCOHOL AND OTHER DRUGS Marijuana is most commonly used along with ethanol. Several studies have reported that concomitant marijuana and ethanol use produces either additive or supraadditive effects on psychomotor performance.79,80 One study, however, reported that marijuana attenuates plasma ethanol levels, with a resultant decrease in the duration of subjective effects for both agents.81 Concomitant use of intranasal cocaine and marijuana smoke enhances the tachycardia observed with marijuana alone. The duration of the effects of marijuana and cocaine are unaltered when both drugs were given together; however, marijuana pretreatment reduces the time required for the onset of cocaine effects and decreases the duration of negative cocaine effects. Moreover, marijuana pretreatment increases cocaine levels almost twofold.82 These observations are thought to occur because marijuana-induced dilation attenuates the vasoconstrictive properties of cocaine, enhancing the absorption of the latter. Simultaneous use of marijuana and amphetamines increases the intensity and duration of a subjective high.

DIAGNOSIS The clinical features of acute marijuana intoxication are nondescript. Conjunctival hyperemia, nasopharyngeal irritation, tachycardia, and difficulty with short-term memory with its attendant effects on fluency of speech and performance of complex tasks, may be noted. Acute anxiety reactions as well as an acute toxic psychosis with hallucinations, delusions, illusions, and agitation are primarily observed in inexperienced individuals or in those who take large doses. Symptoms, even when severe, generally subside within 4 to 6 hours. In individuals with underlying schizophrenia, marijuana may exacerbate existing symptoms or precipitate a relapse.37 Urine immunoassay is the easiest way to confirm marijuana use. Although a marijuana-induced toxic psychosis that lasted days has been described, symptoms that persist beyond a few hours after marijuana use are more likely to indicate the presence of a cointoxicant or an underlying psychiatric disorder.

Laboratory Testing The typical means of detecting marijuana use is through measurement of the THC metabolite 11-nor-Δ9-THC carboxylic acid in urine using an immunoassay screen. Common cutoff limits for commercially available kits are 20, 50, and 100 ng/mL. When the results from the initial screen are confirmed by gas chromatography/mass spectrometry, the results are extremely reliable, with sensitivity and specificity approaching 100%. Therapeutic use of synthetic THC may result in a positive urine screen.

Marijuana

751

The length of time that marijuana metabolites can be detected in urine depends on the cutoff limit, the amount absorbed, and the frequency of use. Using a urine screen with a 50 ng/mL cutoff, THC may be detected for 1 to 3 days after acute marijuana use. Lower detection cutoffs permit detection for as long as a week or more.83 Heavy users may have detectable cannabinoids in urine for weeks following last use. The reason for this is that THC accumulates in fat stores and upon cessation gradually redistributes back to blood and is then eliminated. Obese individuals who have large lipid stores of THC and lose weight rapidly may have detectable THC in their urine despite a prolonged period of abstinence. A number of purported methods to defeat urinary assays have been described. These include dilution, bleach, lemon juice, potassium nitrite, niacin, salt, tetrahydrozoline, and vinegar. Marijuana use may be distinguished from dronabinol use by measuring urinary Δ9-tetrahydrocannabivirin, which is a THC analog found only in plant material.84 Passive inhalation of marijuana smoke may lead to low concentrations of THC and the 11-carboxy metabolite in both serum (up to 20 ng/mL) and urine (up to 40 ng/mL).85 However, this requires such an intense exposure to ambient marijuana smoke that it would be unlikely to occur outside research settings. Passive exposure to marijuana smoke ordinarily does not trigger a positive immunoassay nor does it produce psychotomimetic effects.25,86 A group of rock concert attendees who were in an area where marijuana was smoked did not have detectable THC metabolites using a radioimmunoassay with a detection limit of 50 ng/mL.87 Ingestion of hemp seed oil and other hemp seed food products has resulted in positive urine screens.88 Antenatal exposure to cannabinoids may be documented by testing urine as soon as possible after birth. When routine urine testing is negative but clinical suspicion remains high, meconium may be tested for Cannabis and other illicit substances. In fact, meconium is more sensitive than urine or hair testing in determining antenatal exposure to cannabinoids and may indicate exposure as remote as the second trimester.89 Methods for meconium analysis for the presence of THC have been described.90 Federal regulations require that workers employed in certain transportation-related occupations, such as aviation, mass transit, railroads, and trucking, undergo drug and alcohol testing. The Department of Transportation develops and publishes the rules that govern the testing of these transportation workers. The Department of Transportation cutoff concentration for THC is 50 ng/mL for initial screening and 15 ng/mL for confirmatory testing.

MANAGEMENT Treatment of marijuana intoxication is supportive. Anxiety associated with inexperience or excessive dosescan generally be managed with a quiet, protective environment, reassurance, and mild sedation with

752


benzodiazepines, if needed. Patients who experience psychotic symptoms should be treated with antipsychotic medications. Activated charcoal may help prevent the absorption of THC after ingestion but data are not available on its effectiveness. Because THC toxicity is rarely life threatening, gastric emptying is not recommended. Patients who present with anxiety or a toxic psychosis may be discharged when their symptoms have abated. Admission is almost never required.

Elimination THC is not amenable to enhanced elimination techniques due to high protein binding and a large volume of distribution.

14. 15. 16. 17. 18.

19.

Prevention and Addiction Treatment No prevention model has been successful on a broad scale. Although recent data suggest that the prevalence of marijuana use in school-aged children may be declining, it is unknown which public health measures or policies, if any, are responsible for this decline.4 The standard treatment modality for marijuana use has been psychotherapy similar to that of a 12-step Alcoholics Anonymous model. This approach, coupled with urine monitoring, can be effective in terminating marijuana use. However, as with most other drugs of abuse, relapse is common. REFERENCES 1. The University of Mississippi Potency Monitoring Project, 2002. http://www.dea.gov/concern/18862/marijuan.htm. 2. O’Shaughnessy WB: On the preparation of Indian hemp and gunjah. Trans Med Phys Soc Bombay 1842;8:421–461. 3. Johnston LD, O’Malley PM, Bachman JG: National survey results on drug use from the Monitoring the Future Study, 1975–1995. Washington, DC, US Department of Health and Human Services, 1995. 4. Johnston LD, O’Malley PM, Bachman JG, Schulenberg JE: Monitoring the Future National Survey results on drug use, 1975–2003. Volume I: Secondary school students (National Institutes of Health Publication No. 04-5507). Bethesda, MD, National Institute on Drug Abuse, 2004. 5. Substance Abuse and Mental Health Services Administration: Results from the 2002 National Survey on Drug Use and Health: national findings (Department of Health and Human Services Publication No. SMA 03-3836). Rockville, MD, Department of Health and Human Services, 2003. 6. Polen MR, Sidney S, Tekawa IS, et al: Health care use by frequent marijuana smokers who do not smoke tobacco. West J Med 1993;158:596–601. 7. Ferguson DM, Horwood LJ: Does cannabis use encourage other forms of illicit drug use? Addiction 2000;95:505–520. 8. Matsuda LA, Lolait SJ, Brownstein MJ, et al: Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990;346:561–564. 9. Iversen L: Cannabis and the brain. Brain 2003;126:1252–1270. 10. Axelrod J, Felder CC: Cannabinoid receptors and their endogenous agonist anandamide. Neurochem Res 1998;23:575–581. 11. Calignano A, La Rana G, Giuffrida A, Piomelli D: Control of pain initiation by endogenous cannabinoids. Nature 1998;394:277–281. 12. Munro S, Thomas KL, Abu-Shaar M: Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993;365:61–64. 13. Lynn A, Herkenham M: Localization of cannabinoid receptors and nonsaturable high-density cannabinoid binding sites in

20. 21. 22. 23. 24.

25. 26.

27. 28. 29. 30. 31. 32. 33. 34. 35.

36. 37. 38.

peripheral tissues of the rat: Implications for receptor-mediated immune modulation by cannabinoids. J Pharmacol Exp Ther 1994;268:1612–1623. Leirer VO Yesavage JA, Morrow DG: Marijuana, aging and task difficulty effects on pilot performance. Aviat Space Environ Med 1989;60:1145–1152. Kurzthaler I, Hummer M, Miller C, et al: Effects of cannabis on cognitive functions and driving ability. J Clin Psychiatry 1999; 60:395–399. Joy JE, Watson SJ, Benson JA: The Medical Value of Marijuana and Related Substances in Marijuana and Medicine: Assessing the Science Base. Washington, DC, National Academy Press, 1999. Tramèr MR, Carroll D, Campbell FA, et al: Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ 2001;323:16–21. Regelson W, Butler JR, Schulz J, et al: Δ9-Tetrahydrocannabinol as an effective antidepressant and appetite-stimulating agent in advanced cancer patients. In Braude MC, Szara S (eds): The Pharmacology of Marihuana. New York, Raven, 1976. Campbell FA, Tramèr MR, Carroll D, et al: Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review. BMJ 2001;323:1–6. Adler MW, Geller EB: Ocular effects of cannabinoids. In Mechoulam R (ed): Cannabinoids as Therapeutic Agents. Boca Raton, FL, CRC Press, 1986. West ME, Homi J: Cannabis as a medicine. Br J Anaesth 1996; 76:167. Karler R, Turkanis SA: The cannabinoids as potential antiepileptics. J Clin Pharmacol 1981;21(Suppl):417–448. Fox P, Bain PG, Glickman S, et al: The effect of cannabis on tremor in patients with multiple sclerosis. Neurology 2004;62:1105–1109. Zajicek J, Fox P, Sanders H, et al: Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS Study): multicentre randomized placebo-controlled trial. Lancet 2003;362:1517–1526. Baselt RC: Disposition of toxic drugs and chemicals in man, 7th ed. Foster City, CA, Biomedical Publications, 2004, pp 1083–1088. Ohlsson A, Agurell S, Londgren J, et al: Pharmacokinetics studies of delta-1-tetrahydrocannabinol in man. In Barnett G, Chiang C (eds): Pharmacokinetics and Pharmacodynamics of Psychoactive Drugs. Foster City, CA, Biomedical Publications,1985. Wall ME, Sadler BM, Brine D, et al: Metabolism, disposition, and kinetics of Δ9-tetrahydrocannabinol in men and women. Clin Pharmacol Ther 1983;34:352–363. Johansson E, Halldin MM, Agurell S, et al: Terminal elimination plasma half-life of delta9-tetrahydrocannabinol (delta9-THC) in heavy users of marijuana. Eur J Clin Pharmacol 1989;37:273–277. Johansson E, Halldin MM: Urinary excretion half-life of delta Ltetrahydrocannabinol-7-oic acid in heavy marijuana users after smoking. J Anal Toxicol 1989;13:218–223. Huestis MA, Sampson AH, Holicky BJ, et al: Characterization of the absorption phase of marijuana smoking. Clin Pharmacol Ther 1992;52:31–41. Hollister LE, Gillespie HK, Ohlsson A, et al: Do plasma concentrations of delta-9-tetrahydrocannabinol reflect the degree of intoxication? J Clin Pharm 1981;21(Suppl):171–177. Chiang CN, Barnett G: Marijuana effect and delta-9-tetrahydrocannabinol plasma level. Clin Pharm Ther 1984;36:234–238. MacNab A, Anderson E, Susak L: Ingestion of cannabis: a cause of coma in children. Pediatr Emerg Care 1989;5:238–239. Stadtmauer G, Beyer K, Bardina L, Sicherer SH: Anaphylaxis to ingestion of hempseed (Cannabis sativa). J All Clin Immunol 2003;112:216–217. Chait LD, Pierri J: Effects of smoked marijuana on human performance: a critical review. In Murphy L, Bartke A (eds): Marijuana/Cannabinoids: Neurobiology and Neurophysiology. Boca Raton, FL, CRC Press, 1992. Ramaekers JG, Berghaus G, van Laar M, Drummer OH: Dose related risk of motor vehicle crashes after cannabis use. Drug Alcohol Depend 2004;73:109–119. Johns A: Psychiatric effects of cannabis. Br J Psychiatry 2001;179: 116–122. Mouzak A, Agathos P, Kerezoudi E, et al: Transient ischemic attack in heavy cannabis smokers: how safe is it? Eur Neurol 2000;44:44–44.

CHAPTER 41

39. Russmann S, Winkler A, Lovblad KO, et al: Lethal ischemic stroke after cisplatin-based chemotherapy for testicular carcinoma and cannabis. Eur Neurol 2002;48:178–180. 40. Zimmer L, Morgan JP: Marijuana Myths, Marijuana Facts. New York, Lindemith Center, 1997. 41. Gong H, Fligiel S, Tashkin DP, Barbers RG: Tracheobronchial changes in habitual, heavy smokers of marijuana with and without tobacco. Am Rev Respir Dis 1987;136:142–149. 42. Tashkin DP, Calvarese BM, Simmons MS, Shapiro BJ: Respiratory status of seventy-four habitual marijuana smokers. Chest 1980;78:699–706. 43. Tashkin DP, Coulson AH, Clark VA, et al: Respiratory symptoms and lung function in habitual heavy smokers of marijuana alone, smokers of marijuana and tobacco, smokers of tobacco alone, and nonsmokers. Am Rev Respir Dis 1987;135:209–216. 44. Birrer RB, Calderon J: Pneumothorax, pneumomediastinum and pneumopericardium following Valsalva’s maneuver during marijuana smoking. NY State J Med 1984;84:619–620. 45. Boyce SH, Quigley MA: Uvulitis and partial upper airway obstruction following cannabis inhalation. Emerg Med 2002;14:106–108. 46. Levitz SM, Diamond RD: Aspergillosis and marijuana. Ann Intern Med 1991;115:578–579. 47. Wu TC, Tashkin DP, Djahed B, Rose JE: Pulmonary hazards of smoking marijuana as compared with tobacco. N Engl J Med 1988;318:347–351. 48. Zhang ZF, Morgenstern H, Spitz MR, et al: Marijuana use and increased risk of squamous cell carcinoma of the head and neck. Cancer Epidemiol Biomarkers Prev 1999;6:1071–1078. 49. Jones RT: Cardiovascular system effects of marijuana. J Clin Pharmacol 2002;42(11 Suppl):58–63. 50. Kosior DA, Filipiak KJ, Stolarz P, Opolski G: Paroxysmal atrial fibrillation following marijuana intoxication: a two-case report of possible association. Int J Cardiol 2001;78:183–184. 51. Mittleman MA, Lewis RA, Maclure M, et al: Triggering myocardial infarction by marijuana. Circulation 2001;103:2805–2809. 52. Kolodny R, Leasin P, Tora G, et al: Depression of plasma testosterone with acute marihuana administration. In Braude MC, Szara S (eds): The Pharmacology of Marihuana. New York, Raven, 1976. 53. Block R, Farinpour R, Schlechte J: Effects of chronic marijuana use on testosterone, luteinizing hormone, follicle stimulating hormone, prolactin and cortisol in men and women. Drug Alcohol Depend 1991;28:121–128. 54. Hembree W, Nahas GG, Zeidenberg P, Huang HFS: Changes in human spermatozoa associated with high dose marihuana smoking. In Nahas GG, Paton WDM (eds): Marihuana: Biological Effects. New York, Pergamon, 1979. 55. Issidorides MR: Observations in chronic hashish users: nuclear aberrations in blood and sperm and abnormal acrosomes in spermatozoa. In Nahas GG, Paton WDM (eds): Marihuana: Biological Effects. New York, Pergamon, 1979. 56. Mendelson JH, Mello NK: Effects of marijuana on neuroendocrine hormones in human males and females. In Braude MC, Ludford JP (eds): Marijuana Effects on the Endocrine and Reproductive Systems. Washington, DC, US Government Printing Office, 1984. 57. Wenger T, Croix D, Tramu G, Leonardelli J: Effects of Δ9-tetrahydrocannabinol on pregnancy, puberty, and the neuroendocrine system. In Murphy L, Bartke A (eds): Marijuana/Cannabinoids: Neurobiology and Neurophysiology. Boca Raton, FL, CRC Press, 1992. 58. Abel EL: Effects of prenatal exposure to cannabinoids. In Pinkert TM (ed): Current Research on the Consequences of Maternal Drug Abuse. Washington, DC, U.S. Government Printing Office, 1985. 59. Fried PA, O’Connell CM: A comparison of the effects of prenatal exposure to tobacco, alcohol, cannabis and caffeine on birth size and subsequent growth. Neurotoxicol Teratol 1987;9:79–85. 60. Hingston R, Zuckerman B, Frank DS, et al: Effects on fetal development of maternal marijuana use during pregnancy. In Harvey DJ (ed): Marijuana ‘84: Proceedings of the Oxford Symposium on Marijuana. Oxford, IRL Press, 1984. 61. Gibson GT, Baghurst PA, Colley DP: Maternal alcohol, tobacco and cannabis consumption and the outcome of pregnancy. Aust N Z J Obstet Gynaecol 1983;23:15–19.

Marijuana

753

62. Linn S, Schoenbaum SC, Monson RR, et al: The association of marijuana use with outcome of pregnancy. Am J Public Health 1983;73:1161–1164. 63. Fried PA, O’Connell CM, Watkinson B: 60- and 72-month followup of children prenatally exposed to marijuana, cigarettes, and alcohol: cognitive and language assessment. J Dev Behav Pediatr 1992;13:383–391. 64. Day N, Richardson G, Goldschmidt L, et al: Effect of prenatal marijuana exposure on the cognitive development of offspring at age three. Neurotoxicol Teratol 1994;16:169–175. 65. Morahan PS, Klykken PC, Smith SH, et al: Effects of cannabinoids on host resistance to Listeria monocytogenes and herpes simplex virus. Infect Immun 1979;23:670–674. 66. Ashfaq MK, Watson ES, ElSohly HN: The effect of subacute marijuana smoke inhalation on experimentally induced dermonecrosis by S. aureus infection. Immunopharmacol Immunotoxicol 1987;9:319–331. 67. Davies P, Somberger GC, Huber GL: Effects of experimental marijuana and tobacco smoke inhalation on alveolar macrophages. Lab Invest 1979;41:220–223. 68. Cabral GA, Stinnett AL, Bailey J, et al: Chronic marijuana smoke alters alveolar macrophage morphology and protein expression. Pharmacol Biochem Behav 1991;40:643–649. 69. Lopez-Cepero M, Friedman M, Klein T, Friedman H: Tetrahydrocannabinol induced suppression of macrophages spreading and phagocytic activity in vivo. J Leukoc Biol 1986;39:679–686. 70. Spector S, Lancz G: Suppression of human macrophage function in vitro by Δ9-tetrahydrocannabinol. J Leukoc Biol 1991;50: 423–426. 71. Shivers SC, Newton C, Friedman H, Klein TW: Δ9-Tetrahydrocannabinol (THC) modulates IL-1 bioactivity in human monocyte/macrophage cell lines. Life Sci 1994;54:1281–1289. 72. Cabral GA, Vasquez R: Δ9-Tetrahydrocannabinol suppresses macrophage extrinsic antiherpes virus activity. Proc Soc Exp Biol Med 1992;199:255–263. 73. Fischer-Stenger K, Pettit DAD, Cabral GA: Δ9-Tetrahydrocannabinol inhibition of tumor necrosis factor-α: suppression of post-translational events. J Pharmacol Exp Ther 1993;267: 1558–1565. 74. Wallace JM, Tashkin DP, Oishi JS, Barbers RG: Peripheral blood lymphocyte subpopulations and mitogen responsiveness in tobacco and marijuana smokers. J Psychoactive Drugs 1988;20:9–14. 75. Nahas GG, Ossweman EF: Altered serum immunoglobulin concentration in chronic marijuana smokers. In Friedman H, Spector S, Klein TW (eds): Drug of Abuse, Immunity, and Immunodeficiency. New York, Plenum, 1991. 76. Tennant FS: The clinical syndrome of marijuana dependence. Psychiatr Ann 1986;16:225–234. 77. Weller RA, Halikas JA: Objective criteria for the diagnosis of marijuana abuse. J Nerv Ment Dis 1980;168:98–103. 78. Office of Applied Studies: Results from the 2001 National Household Survey on Drug Abuse: Volume II. Technical Appendices and Selected Data Tables (Department of Health and Human Services Publication No. SMA 02-3759). Rockville, MD, Substance Abuse and Mental Health Services Administration, 2002. 79. Bird KD, Boleyn T, Chesher GB, et al: Intercannabinoid and cannabinoid-ethanol interactions and their effects on human performance. Psychopharmacology 1980;71:181–188. 80. Sutton L: The effects of alcohol, marijuana and their combination on driving ability. J Stud Alcohol 1983;44:438–445. 81. Lukas SE, Benedikt R, Mendelson JH, et al: Marihuana attenuates the rise in plasma ethanol levels in human subjects. Neuropsychopharmacology 1992;7:77–81. 82. Lukas S, Sholar M, Kouri E, et al: Marihuana smoking increases plasma cocaine levels and subjective reports of euphoria in male volunteers. Pharmacol Biochem Behav 1994;48:715–721. 83. Huestis MA, Mitchell JM, Cone EJ: Detection times of marijuana metabolites in urine by immunoassay and GC/MS. J Anal Toxicol 1995;19:443–449. 84. ElSohly MA, DeWit H, Wachtel SR, et al: Δ9-Tetrahydrocannabivarin as a marker for the ingestion of marijuana versus Marinol: results of a clinical study. J Anal Toxicol 2001;25:565–571. 85. Stein IN: Marijuana testing. West J Med 1988;148:78.

754


86. Morland J, Bugge A. Shuterud B, et al: Cannabinoids in blood and urine after passive inhalation of cannabis smoke. J Forensic Sci 1985;30:997–1002. 87. Toussi A: Side-stream inhalation of marijuana: the Grateful Dead experience. Ann Emerg Med 1996;27:816–817. 88. Alt A, Reinhartdt G: Positive cannabis results in urine and blood samples after consumption of hemp food products. J Anal Toxicol

1998;22:80–81. 89. Bar-Oz B, Klein J, Karaskov T, Koren G: Comparison of meconium and neonatal hair analysis for detection of gestational exposure to drugs of abuse. Arch Dis Childhood 2003;88:F98–F100. 90. Moore C, Negrusz A, Lewis D: Determination of drugs of abuse in meconium. J Chromatogr B Biomed Sci Appl 1998;713:137–146.

42

Cocaine TIMOTHY E. ALBERTSON, MD, MPH, PHD ■ ANDREW CHAN, MD ■ R. STEVEN THARRATT, MD, MPVM

At a Glance… ■

■ ■

■

■

Cocaine is the most frequent cause of emergency department visits and death associated with illicit drug use in the United States. The major routes of administration of cocaine are sniffing, injecting, and smoking (free-base or “crack” cocaine). Local anesthetic effects and the blockade of catecholamine and serotonin uptake define cocaine’s principal mechanisms of action. Toxicity is manifested primarily by behavioral alterations, hyperthermia, seizures, and cardiac abnormalities. Less commonly, gastrointestinal, liver, kidney, muscle, renal, and pulmonary damage have been reported. Treatment is primarily supportive in nature.

INTRODUCTION AND RELEVANT HISTORY Cocaine continues to be a significant drug of abuse in the United States, as well as in many other parts of the world. It is often associated with drug-related emergency department (ED) visits, intensive care unit (ICU) admissions, and death.1-3 Cocaine is frequently detected on drug screens performed on reckless or impaired drivers4 and trauma patients that present to EDs.5,6 Although the central nervous and cardiovascular systems are most commonly affected by cocaine, the drug can have toxic manifestations in nearly every organ system. Due to the prevalence and medical significance of cocaine toxicity, health care providers must be knowledgeable of and alert for cocaine toxicity. Cocaine, an alkaloid that is derived from the leaves of Erythroxylum coca, has an interesting history that interfaces with the history of medicine and drug abuse. The first recorded medicinal uses were reported by Spanish physicians in 1596.7 Cocaine was first isolated from coca leaves in 1859 by Albert Nieman, a graduate student at the University of Göttingen.8 By 1863, Angelo Mariani was marketing a wine in France that was fortified with about 6 mg per ounce of the cocaine alkaloid extract.8 In the United States, the Parke-Davis Company was selling a fluid extract containing 0.5 mg/mL of a crude cocaine by 1880.8 By 1884, Sigmund Freud had proposed that cocaine be used for the treatment of depression, cachexia, and asthma and also as a local anesthetic.9 That same year, cocaine was also first used in eye surgery, a field that was revolutionized by the discovery of this drug. William Steward Halsted, the father of modern American surgery, first used cocaine in regional nerve blocks also in 1884. Unfortunately, Halsted,

like Freud, became heavily dependent on cocaine.9 In 1885, the Georgia pharmacist John Styth Pemberton registered the cocaine-containing “French Wine Cola” in the United States; later, he renamed the product CocaCola.3,8 Coca-Cola was initially a mixture of extracts from the cocaine-containing coca leaf and the caffeinecontaining African kola nut. The soft drink was first introduced in 1892 as a brain tonic for elderly people who were easily tired; it was also marketed as a cure for all nervous afflictions.3 By 1893, fatalities from the use of cocaine had been reported. In 1895, a series of six fatalities was reported in the Lancet.6,10 In 1909, more than 10 tons of cocaine was imported into the United States without legal restraint. Multiple over-the-counter medical products and elixirs containing various amounts of cocaine were created. A product for nasal application called Dr. Tucker’s Asthma Specific contained 420 mg of cocaine per ounce.8 The passage of the Harrison Narcotics Act of 1914 finally banned nonprescription use of cocaine-containing products. Subsequently, a significant reduction in the use of cocaine occurred in the United States. Although amphetamines surpassed cocaine as the most prevalent stimulant of abuse in the 1950s, the use of cocaine surged again in the 1970s. Cocaine currently remains the most commonly abused stimulant and illicit drug of abuse.1,9,11 The Controlled Substances Act of 1970 prohibited the manufacture, distribution, and possession of cocaine in the United States, except for increasingly limited medical uses.9 It has since been designated as a schedule II drug by the U.S. Drug Enforcement Agency (DEA). By the 1980s, chunks of an alkaloidal cocaine called “crack” had become widely available. Cocaine is still used medicinally as a local anesthetic. Topical application of the hydrochloride (1%, 4%, or 10% solution) to the eyes or upper respiratory tract mucosa provides local anesthesia and vasoconstriction with a single agent.12

EPIDEMIOLOGY Cocaine use and dependence remains an epidemic in the United States. The widespread availability of a highly pure, relatively inexpensive, easy-to-use, and highly addictive formulation crack cocaine has ensured the continued American addiction to this illicit drug.13,14 In 1999, it was estimated that 25 million Americans had used cocaine at least once, 3.7 million used it within the past year, and 1.5 million were current regular users.1,14 Each year, the number of new users steadily increases, with 900,000 new users estimated in 2000.15 The prevalence of cocaine use is greatest in Americans 18 755

756


to 25 years of age. Approximately 11% of Americans older than 12 years have used cocaine, with 7% of adults between 18 and 34 years of age having used it within the previous year.3 According to the Drug Abuse Warning Network, cocaine continues to be the most frequent cause of ED visits associated with illicit drug use in the United States; it accounted for 30% of all such ED visits in 2002 (approximately 200,000 ED visits).1 In addition, from 1995 to 2002, cocaine-related ED visits have increased by 33%.1 Death after cocaine use is one of the five leading causes of death in the 15- to 44-year-old age group.16 Between 1990 and 1992, as many as 26.7% of all deaths in New York City were associated with the presence of cocaine or a cocaine metabolite in the blood or urine.16 More than 30% of these deaths were attributed to cocaine directly, and 65% involved traumatic injuries associated with cocaine.16 Cocaine overdose appears from surveys of users to be less associated with crack cocaine smoking than with intravenous use.17 Accidental overdose deaths have slightly decreased from its peak between 1993 and 1995 in New York.18 Regardless, cocaine alone or in combination with alcohol and or an opiate was determined to be the cause of death in 69.5% of these cases.18 In a study of intravenous drug users in San Francisco, the use of heroin and cocaine together (“speedballs”) was frequently associated with overdose.19 A survey of cocaine users in Brazil noted that 20% had experienced one or more episodes of overdose.20 In Tennessee in 1993, more than 25% of reckless drivers who did not smell of alcohol were found to be intoxicated with cocaine alone or in combination with marijuana.4 Again, both the direct effects of cocaine and related trauma contribute to the high rate of cocaineassociated deaths.3,6,16 In 2001, cocaine was the most frequent cause of drug-related deaths reported to medical examiners in the United States.2,14 Cocaine remains a major drug of abuse, with the majority coming into the United States from South and Central America.21 The DEA noted that in 2002, federal drug seizures of cocaine in Florida alone amounted to 26,258 kg.21 Acute and chronic cocaine toxicity represents a major challenge to the clinician. Cocaine’s ability to cause significant multiorgan system dysfunction contributes to this challenge. Preventive care and new carefully tested approaches to therapy can help reduce the incidence and improve the outcome of patients with this modern affliction.

STRUCTURE/STRUCTURE-ACTIVITY RELATIONSHIPS Cocaine is a naturally occurring drug; it is the principal active alkaloid that is derived from the leaves of the shrub Erythroxylum coca, found in South and Central America, India, and Java, and also from Erythroxylum novogranatense, found in South America. Coca leaves may be chewed or ingested as a tea (mate de coca).3 This is how the ancient Incas used and native South Americans still

currently use cocaine. Each coca leaf contains 0.1% to 0.9% cocaine by weight.3,22 A partly purified product, cocaine sulfate (also known as pasta, basuco, basa, pitillo, and paste) is made when coca leaves are mixed with water and dilute sulfuric acid. Coca paste is commonly mixed with tobacco and smoked in South America.3,22 Coca paste is often further refined to cocaine hydrochloride (an odorless, white, crystalline powder) by repetitive mixings with various solvents (e.g., kerosene, methyl alcohol, and sulfuric acid). Refined cocaine hydrochloride powder is 30% to 40% pure.3,22 Cocaine hydrochloride is freely soluble in water and can be injected intravenously or readily absorbed across all mucous membranes. Alternatively, the free base of cocaine can be made by dissolving the hydrochloride salt in a solvent and separating and drying the precipitate. Cocaine free base is not water soluble and, thus, cannot be injected intravenously or readily absorbed across mucosal surfaces.3,13,22 Cocaine base, however, is lipophilic and rapidly absorbed across the alveolar-capillary and blood-brain barrier. Free-basing is a process of converting cocaine hydrochloride back to cocaine base for smoking. Traditionally, free base was made by dissolving the hydrochloride salt in water, adding ammonia to remove the hydrochloride, adding ether to solubilize the base, and then letting the ether evaporate from the base.3,13 An alternative form of cocaine free base, crack is made by dissolving the hydrochloride salt in water, adding sodium bicarbonate (baking soda) to remove the hydrochloride, heating the mixture until the water evaporates, and cooling the free base into a soft mass that subsequently dries into a hard rock.3,13 Cocaine free base has a relatively low melting point as compared with the hydrochloride form (98° C versus 197° C) and is stable to pyrrolysis.3,14 Thus, the free base can be heated, vaporized, and inhaled (smoked). The base is commonly smoked in a glass or regular pipe or mixed with tobacco or marijuana in cigarette form. If the ether is not fully evaporated from the free base prior to smoking, airway burns are a possibility.13 The hydrochloride form of cocaine breaks down with pyrrolysis.9 The term crack comes from the popping sound that occurs when the rock is smoked.3,13,14 Due to ease of production, relative inexpense, ease of use, and rapid onset of effects after use, crack has become a very popular means of cocaine abuse.13,19 It also appears to be the most potent and addictive form of cocaine.13,14 Crack and free-base cocaine are 85% to 90% pure, whereas cocaine hydrochloride preparations are often adulterated with one or more of several compounds (e.g., sucrose, mannitol, lactose, quinine, caffeine, amphetamine, phencyclidine, talc, procaine, lidocaine, or strychnine).23 The stimulant cocaine (benzoylmethylecgonine, C17H21NO4) is an ester of benzoic acid and the amino alcohol base methylecgonine (Fig. 42-1).12 Its molecular weight is 303.4. In its natural form, cocaine is a weak base with a pKa of 8.6.24 The ester structure of cocaine predicts rapid hydrolysis by esterases and a short duration of action. Its structure is similar to other estertype local anesthetics.12

CHAPTER 42

+

J

HJN

O CH3

K

Cl –

– OCH 3

K

O

O

FIGURE 42-1 The chemical structure of the alkaloid cocaine hydrochloride.

PHARMACOLOGY Cocaine produces its clinical effects predominantly from reuptake blockade and enhanced presynaptic release of catecholamines (e.g., norepinephrine and dopamine) and serotonin from central and peripheral nerve terminals.3,24 Reuptake blockade of norepinephrine in the sympathetic nervous system innervation to the adrenal gland results in postsynaptic medullary release of catecholamines (predominantly epinephrine) and systemic sympathetic effects.25 Reuptake inhibition of dopamine in the central nervous system (CNS) produces stimulation of both D1- and D2-dopamine receptors in mesocortical, mesolimbic (e.g., nucleus accumbens), and basal ganglia areas of the brain; this accounts for the euphoric, psychostimulatory, and motor effects from cocaine.12,26 Cocaine also enhances release of the excitatory amino acids glutamate and aspartate in the limbic system, which adds to its psychostimulatory effects.27,28 Reuptake inhibition with repetitive cocaine use leads to accelerated catabolism and depletion of presynaptic catecholamines and serotonin. In addition, compensatory processes work to down-regulate the overstimulated neuronal pathways. Cocaine craving and movement disorders (e.g., parkinsonism) likely occur from depletion of dopaminergic stores or a downregulated dopamine pathway.12 Cocaine also causes marked local anesthetic effects from the blockade of membrane sodium channels (see Chapter 63).11,12,24 Sodium channel blockade is concentration, frequency, pH, and voltage dependent; block is greater at higher frequencies of stimulation, lower pH, and more positive membrane potentials.12 Vasoconstrictive effects of cocaine will increase local drug concentration and membrane effects.12 Cocaine may also inhibit potassium channels and sodium-calcium exchange mechanisms in some cellular membranes.29

PHARMACOKINETICS Cocaine is readily absorbed across all mucous membranes.3,12,14 The onset of action and peak effects depend on the dose and route of absorption. Mucosal and oral administration of cocaine result in a slower absorption, slower onset of action, later peak effect, and longer duration of action than the inhalation and intravenous routes.14 Although absorption is rapid after ingestion, the oral bioavailability of both the hydrochloride and

Cocaine

757

free-base forms are only 30% to 40%.3 After nasal insufflations of cocaine, the onset of effects occurs within 1 to 5 minutes.3,14 Constriction of nasal vessels inhibits and prolongs drug absorption, such that the duration of effects are extended, peak levels are blunted, and dosedependent toxicity is reduced.13,30 When cocaine is snorted, chewed, or ingested, peak levels and effects occur within 30 to 120 minutes.3,24,30 The inhalation route produces a more rapid increase in plasma and brain cocaine levels and more intense euphoria than the nasal and oral routes; the cardiovascular effects are similar to those produced by an equivalent intravenous dose of cocaine.22 When inhaled and injected intravenously, the onset of action occurs within seconds, and peak effects occur within 3 to 5 minutes. The duration of effects typically lasts 5 to 15 minutes after inhalation and 20 to 60 minutes after intravenous use of cocaine.12,14,30 The rapid decrease in plasma and brain cocaine concentrations that follow an initial surge (i.e., brief duration of euphoria) probably accounts for the desire to reuse within 10 to 30 minutes of inhalant (crack) use.12 Although dependent on dose and route of administration, peak cocaine blood concentrations of 200 to 600 mg/mL are seen with typical doses (0.2 to 2 mg/kg or 10 to 140 mg).24,30 Peak blood concentrations of several thousand milligrams per milliliter have been reported in intoxicated patients.24,30 Blood cocaine concentrations averaged 4600 mg/mL in one study of 37 cocaine-related fatalities.31 Cocaine has a volume of distribution of 2 to 3 L/kg.24,30 About 35% to 45% of cocaine is rapidly metabolized by nonenzymatic hydrolysis to benzoylecgonine. Another 32% to 49% of cocaine is metabolized to ecgonine methyl ester by enzymatic hydrolysis with hepatic and plasma esterases (e.g., pseudocholinesterase). A small amount of the benzoylecgonine is metabolized on to ecgonine in a 24-hour period. Although these metabolites tend not to be very active, a small percentage of cocaine, particularly after toxic exposure, undergoes hepatic microsomal oxidative metabolism (N-demethylation) to norcocaine, a potentially active metabolite, and then to N-hydroxynorcocaine, a metabolite potentially toxic to the liver.24,30 Endogenous (genetic) loss or induced (e.g., by organophosphate pesticide exposure) loss of cholinesterase activity in a patient may result in a delay in metabolism of cocaine and may increase the toxic risk of a given exposure. Blood or plasma samples must be frozen, or fluoride or cholinesterase inhibitors must be added to samples, to prevent cocaine from being hydrolyzed to ecgonine methyl ester by serum cholinesterases. The serum half-life of cocaine is approximately 30 to 90 minutes. The fact that only 1% to 9% of cocaine appears in the urine unchanged (dependent on urine pH) makes the analysis of the major cocaine metabolites benzoylecgonine and ecgonine more useful for diagnostic and forensic purposes. Benzoylecgonine and ecgonine have serum half-lives of approximately 4 to 6 hours and 3 to 4 hours, respectively.12,24,30 Intravenous use of cocaine alone or in combination with heroin, benzodiazepines, or other sedative-hypnotics

758


is commonly seen. As previously noted, the intravenous use of heroin in combination with cocaine is called “speedballing” and is thought to be responsible for 12% to 15% of toxic cocaine episodes managed in EDs in the United States.1 The combined use of ethanol and cocaine facilitates the formation of cocaethylene.32 This potent cocaine metabolite has a half-life of approximately 2 hours. Animal studies and human epidemiologic studies suggest that cocaethylene is more toxic to the brain and heart than cocaine or its usual metabolites.33 The risk of sudden death is 21.5-fold greater with the combined use of ethanol and cocaine than with cocaine use alone.33 The exact contribution of cocaethylene to this increased toxicity in humans is controversial.34 In a randomized, double-blind trial, daily oral cocaine treatment at doses without subjective effects or signs of toxicity significantly decreased physiologic responses to intravenous cocaine.35 Whether this is a form of tachyphylaxis is not clear.

TOXICOLOGY The toxicity of cocaine comes from the extension of its pharmacology and mechanisms of action. Acute toxicity is frequently noted from CNS and sympathetic nervous system overstimulation. Toxic cardiac manifestations are likely from cocaine’s effect on sodium and potassium exchange channels along with its catecholaminergic effects. In addition to acute toxic effects, binge use depletes central and peripheral nervous system catecholamines and serotonin, resulting in depression and potential reduced vascular tone. Cocaine withdrawal may represent an extension of this type of depleted state. The toxicity associated with cocaine abuse often results in ED and ICU admissions.

CLINICAL MANIFESTATIONS Cocaine is capable of inducing toxicities in many organ systems. Both acute and chronic abnormalities have been reported with cocaine exposures. Studies have not established the exact prevalence or incidence of the toxicities, which are summarized in Table 42-1.

Cardiovascular Cocaine use and abuse is frequently associated with a wide array of cardiovascular complications.14,36,37 Acute and chronic cardiovascular toxicity results from an exaggeration of both β- and α-adrenergic receptor stimulation, augmented myocardial cellular calcium influx and elevation of cytosolic free calcium concentrations, and increased secondary messenger (e.g., phospholipase C, inositol triphosphate) activation.37 Chest pain is the most frequent presenting complaint of patients who have used cocaine and is responsible for approximately 16% of cocaine admissions to EDs.5,14,38-41 Although most of cocaine-associated chest pain is

noncardiac in origin, ruling out myocardial ischemia is the principal concern when such patients present to the ED.14,41 This is because acute myocardial infarction (MI) is the most frequently reported cardiac consequence of cocaine abuse.41,42 Prospective studies have shown that approximately 6% of patients with cocaineassociated chest pain that present to the ED have an MI by enzyme analysis.41,43 The risk for MI is increased 24-fold in the hour following use of cocaine.14,44 Cocaineassociated MI is not route, dose, or duration dependent; it occurs following all routes of administration, with a wide range of doses, and occurs in both first-time and long-term users.14,41 Cocaine-associated MI cannot be distinguished from noncardiac chest pain on the basis of chest pain location, quality, duration, associated symptoms, or the presence of traditional risk factors for atherosclerosis.14,41,43 A recent retrospective study of patients with cocaine-associated chest pain found that a 9- to 12-hour period of ED observation without evidence of ischemic or cardiac complications predicted a very low risk for death or MI for a 30-day period after ED discharge.45 Several mechanisms may lead to cocaine-induced MI.46 These include increased myocardial oxygen demand in the setting of limited myocardial oxygen supply, coronary artery vasoconstriction, enhanced platelet aggregation, in situ coronary artery thrombosis formation, left ventricular hypertrophy, and accelerated atherosclerosis.14,37,41,46 Increased oxygen demand is created by cocaine-induced tachycardia, enhanced contractility, and increased blood pressure (enhanced afterload). Decreased oxygen supply is the result of coronary vasoconstriction, which is greatest in diseased coronary artery segments.47 Cocaine-induced coronary artery vasoconstriction is mediated by α-adrenergic stimulation, as evidenced by its reversal after administration of the α-adrenergic receptor antagonist phentolamine and exacerbation with β-adrenergic antagonist therapy.48,49 Cocaine potentiates vasoconstriction by stimulating release of endothelin and thromboxane (vasoconstrictors) and impairing release of nitric oxide and prostacyclin (vasodilators) from endothelial cells.50,51 Coronary artery spasm leading to MI has been widely reported in cocaine users.38 Both epicardial and microvascular cardiac flow is impaired by cocaine.52 Enhanced platelet activity occurs from α-adrenergic-mediated increases in platelet aggregation and increased releases of thromboxane and adenosine diphosphate.53,54 In situ thrombosis formation may occur from cocaine-induced vasoconstriction and resultant disruption in the endothelial surface (i.e., plaque rupture).55 In addition, concentrations of antithrombin III and protein C are decreased and concentrations of tissue plasminogen activator inhibitor are increased after cocaine use.3,56 Cocaine may promote atherosclerosis by enhancing endothelial cell permeability to low-density lipoprotein and enhancing endothelial cell expression of adhesion molecules and leukocyte migration to their surface.14,57,58 Most patients with cocaine-associated MI are young (mean age 38 years), nonwhite (72%) tobacco smokers (91%). They have a history of cocaine use within the past

CHAPTER 42

Cocaine

759

TABLE 42-1 Major Noninfectious Medical Complications Associated with Cocaine Use COMPLICATION

FREQUENCY AND MAGNITUDE OF EVENTS*

Respiratory BAROTRAUMA

Pneumothorax Pneumopericardium Pneumomediastinum Subcutaneous emphysema Pulmonary hemorrhage/infarct Diffuse alveolar hemorrhage Pulmonary edema Exacerbation of asthma Eosinophilic lung disease Recurrent transient pulmonary infiltrates with peripheral eosinophilia Chronic diffuse interstitial pneumonia with mild fibrosis Sudden infant death syndrome (SIDS) Pulmonary hypertension “Crack lung” with transient pulmonary infiltrates Nasal septum perforation/aspiration Bronchiolitis obliterans organizing pneumonia Airway burns/tracheal stenosis Sinusitis Epiglottitis Bronchitis Pulmonary cellulose granulomas in lung Panlobar emphysema Foreign body aspiration/needle Alveolar accumulation of carbonaceous material Central nervous system respiratory stimulant effect

COMPLICATION

FREQUENCY AND MAGNITUDE OF EVENTS*

Cardiac Chest pain Myocardial infarction Arrhythmias Cardiomyopathy Myocarditis Hypertension Sudden death

+++ +++ ++ ++ + +++ ++

+

Psychiatric Anxiety Depression Paranoia Delirium Psychosis Suicide

++ ++ ++ ++ ++ +++

+ +

Obstetric Low birth weight Placental abruption

++

+ + +++ ++ + +

++ + + + + + ++ + + + ++ ++

NEUROGENIC PULMONARY EDEMA

+++

Respiratory depression— overdose/postictal Abnormal hypoxic response in infants of cocaine-abusing mother

+++

Neurologic Headaches Strokes Seizures Cerebral infarcts Cerebral hemorrhage Cerebral vasculitis Gastrointestinal, Renal, and Other Renal failure Rhabdomyolysis Hyperthermia Disseminated vasculitis Bowel ischemia/colitis Thrombocytopenia/platelet aggregation Hepatitis

+ + ++ ++ +++ ++ ++ + + ++ + + ++ + +

+

*Estimated. +, rarely reported; ++, commonly reported; +++, frequently seen with chronic use or overdose.

24 hours (88%), have a history of repeated use of cocaine (mean duration of use of 5 years), and do not have other traditional risk factors for atherosclerosis.37,14,41,43,44 Q-wave and non-Q-wave infarctions are seen with equal frequency.14 Although most patients have the onset of pain within an hour of cocaine use, MI has been reported several days after use.42-44 MI has also been associated with therapeutic doses and use of cocaine and in the setting of cocaine withdrawal.41,42 Angiographic studies of these patients have demonstrated both atherosclerotic and normal coronary arteries with about equal frequency.13,14,59 Left ventricular hypertrophy, hypertension, and coronary atherosclerosis are thought to occur as a result of chronic cocaine use. Accelerated atherosclerosis is found in animals that are administered cocaine chronically and in 40% of autopsies of young patients who used cocaine regularly.3,60

Early cardiovascular complications occur in up to 36% of patients with cocaine-associated MI.14,41,60 Ventricular arrhythmias occur in 4% to 17%, congestive heart failure in 5% to 7%, and death in less than 2%.14,60 Most complications (90%) occur within 12 hours of hospital arrival, and death is extremely unlikely for those patients who are alive on hospital arrival.41,60 The cardiovascular toxicity of cocaine is potentiated by concomitant cigarette smoking or use of alcohol. Similar to cocaine, cigarette smoking produces coronary vasoconstriction by an α-adrenergic mechanism.61 Simultaneous use of cocaine and cigarettes produces synergistic increases in blood pressure, heart rate, and coronary vasoconstriction.41,61 When cocaine is used concomitantly with alcohol, the heart rate increase is greater than when each drug is used alone.62 Patients who die of a combined overdose of cocaine and ethanol

760


have lower blood cocaine concentrations than those who die from cocaine alone.14,63 The hepatic transesterification product cocaethylene is considered to be largely responsible for the synergistic toxicity that occurs when cocaine and ethanol are used in close proximity.64 Animal models have demonstrated that cocaethylene is more lethal than cocaine.14,65 Cocaethylene increases myocardial oxygen demand by producing hypertension and increased vascular resistance; it does not have direct effects on coronary blood flow.66 A number of clinical reports have described left ventricular hypertrophy, systolic dysfunction, dilated cardiomyopathy and myocarditis from long-term use of cocaine. Myocardial hypertrophy is frequently discovered at autopsy in patients who die from cocaine toxicity.67 Seven percent of long-term abusers of cocaine demonstrate left ventricular systolic dysfunction by radionuclide ventriculography.14,68 Numerous mechanisms may explain cocaine-associated cardiomyopathy. Repetitive elevations of plasma catecholamines as occur with repetitive cocaine use may produce subendocardial contraction band necrosis, mononuclear cell myocardial infiltration, myocytolysis, myocarditis, and resultant fibrosis.69 These effects may be reversible with discontinuation of cocaine use. Alternatively, cocaine-induced cardiomyopathy may be the result of repetitive episodes of ischemia or infarction, long-standing hypertension, an immune-mediated or hypersensitivity reaction to cocaine, altered myocyte collagen production, or from the toxic effects of cocaine adulterants or contaminants, including heavy metals such as manganese.14,37 Because of cocaine’s local anesthetic properties and its effects on catecholamines, it is not surprising that both cardiac conduction disturbances and arrhythmias are common in patients who abuse cocaine. Although sinus bradycardia, complete heart block, and bundle branch block have been described, supraventricular and ventricular tachyarrhythmias occur most commonly.14,37 At low doses, sinus bradycardia and ectopic rhythms may occur.70 At high doses, cocaine produces direct sodium and potassium channel blockade, prolonged QRS and QTc intervals and ST-T wave changes on electrocardiograms (ECGs), and resultant intraventricular conduction delays and reentrant ventricular dysrhythmias (e.g., ventricular tachycardia and torsades de pointes).14,29,37,70 Enhanced sympathetic stimulation will increase myocardial intracellular calcium concentrations, enhance automaticity, produce afterdepolarizations, and possibly lead to ectopic rhythms (e.g., tachyarrhythmias).14,37 Cardiac conduction abnormalities and arrhythmias occur most commonly in the context of myocardial ischemia, profound metabolic acidosis, seizures, hypoxia, or hypotension.14,37,71 These latter effects minimally play a potentiating role and may often be the primary cause of cardiac toxicity from cocaine. Acute aortic dissection and rupture and papillary muscle rupture have been associated with cocaine use in otherwise healthy patients.72 Endocarditis is a frequent complication of intravenous drug use, and thus is seen in the patient abusing intravenous cocaine.73

Central Nervous System Neurologic complaints occur in 17% to 42% of patients with cocaine-related medical problems necessitating ED treatment in the United States.3,5,39,40 Altered mental status, anxiety, paranoid behavior, dizziness, headaches, paresthesias, tremors, seizures, strokes, transient ischemic attacks, and coma represent the majority of these neurologic complaints.74 Cocaine-associated strokes may be ischemic or hemorrhagic. The mechanisms of cerebrovascular accidents are multifactorial and include cerebral vasoconstriction, thrombosis, vasculitis, and loss of vasomotor autoregulation in the setting of acute hypertension, and embolism of particulate matter.3,74-77 Increased activity of platelets and other mediators of thrombosis potentiate the likelihood of an ischemic stroke. Cocaine-induced agitated delirium may result from disrupted dopaminergic function and is often associated with fulminant hyperthermia, rhabdomyolysis, and sudden death.78 Seizures are a very common manifestation of cocaine toxicity and have been reported in up to 9% of ED patients with cocaine toxicity.39 Drug-induced seizures are frequently caused by stimulants. Cocaine-induced seizures accounted for the increase in all drug-induced seizure cases from 4% in 1981 to 23% in 1988.79 Although not fully elucidated, the mechanism of cocaine-induced seizures involves interaction of the drug with voltagedependent sodium channels and numerous neurotransmitter systems. It appears that 5-HT2-serotonergic, D1-dopaminergic, α1- and α2-adrenergic, GABAA, and glutamatergic receptors are all involved in cocaineinduced seizures.80 Human and animal data suggest that cocaine-induced seizures are usually generalized, single seizures without long-lasting neurologic consequences.81,82 The majority of cocaine-related seizures are associated with intravenous injection or inhalation of cocaine. In one study, Pascual-Leone and colleagues found that when habitual cocaine abuse was associated with seizures, computed tomography and electroencephalography frequently showed diffuse brain atrophy and diffuse slowing, respectively.81 Multiple or focal seizures are often seen with acute intracerebral complications (e.g., hemorrhage) or with the toxic manifestations of other medications.81 Recurrent generalized seizures have been reported in children after mucosal application of the topical anesthetic tetracaine-adrenaline-cocaine. Seizures may be a major determinant of cocaine lethality.83 This justifies aggressive immediate treatment of sustained cocaine-induced seizures with the correction of seizure-associated metabolic acidosis and hypoxemia. Repetitive or prolonged seizures attributed to the use of cocaine indicate the need for further diagnostic workup that includes computed tomography of the brain and, possibly, lumbar puncture. Cerebral vasculitis, headaches, toxic encephalopathies, transient ischemic events, migraine-like events, and a wide array of extrapyramidal side effects (e.g., acute dystonic reactions, Tourette’s syndrome, akathisia, choreoathetosis, tardive dyskinesia) have been reported

CHAPTER 42

with both acute and chronic use of cocaine.3,13,84,85 Choreoathetoid movements associated with crack use have been termed “crack dancing.”85 Extrapyramidal movement disorders occur from dopamine disturbances in the basal ganglia; choreoathetosis is from an overabundance of dopamine, and acute dystonia from dopamine deficiency. As expected, cerebral hemorrhage, cerebral infarction, and cerebral vasculitis are associated with significant morbidity and mortality among cocaine users. Kaku and Lowenstein reported that 34% of patients between the ages of 15 and 44 years with a diagnosis of ischemic or hemorrhagic stroke had associated drug abuse. Cocaine and amphetamines accounted for the largest percentage of cases.86 Psychological dependence and a cocaine withdrawal or abstinence syndrome have been reported.12,24 The cocaine abstinence syndrome has been described as having three phases.24 The first phase is a “crash” that lasts up to 4 days and is characterized by dysphoria, depression, irritability, anxiety, and insomnia followed by hypersomnolence, exhaustion, and drug craving. The second phase lasts from 1 to 10 weeks and is characterized by anergia, anxiety, listlessness, and drug craving. The third phase, which has been called the “extinction phase,” may last indefinitely and is associated with normalization of mood and actions but also episodic drug craving that is often triggered by environmental cues.24 Acute psychiatric disturbances, including agitation, anxiety, depression, psychosis, paranoia, and suicidal ideation have been widely reported in cocaine users.87 The cocaine “washed out” syndrome is similar to the “crash” associated with the abstinence syndrome and occurs soon after a several day binge of cocaine.12 Patients are lethargic with normal vital signs and sleep deeply for a period of 24 to 48 hours. The syndrome is considered to result from an acute depletion of catecholamines that follows a several day binge of cocaine.

Pulmonary Cocaine can produce a wide range of pulmonary complications (see Table 42-1).88,89 Cocaine-induced pulmonary disturbances occur in up to 25% of users and often result in ED and ICU admissions.3,90 Primary respiratory depression or reduced respiratory drive has been associated with toxic cocaine exposures. This has occurred both in conjunction with and independent of cardiac arrhythmias and seizure-induced cardiovascular collapse. Cocaine smoking is associated with significant barotrauma and may result in pneumothorax, pneumomediastinum, pneumopericardium, and subcutaneous air.3,89 The self-application of a Valsalva maneuver (to increase positive airway or intrapleural pressures) by cocaine smokers seeking enhancement of its euphoric effects may precipitate barotraumatic complications. High positive airway pressures can also be generated by an “assistant” who blows back into the cocaine pipe being used. Thermal injury from smoking cocaine may also contribute to the development of barotrauma.

Cocaine

761

Noncardiogenic pulmonary edema is associated with cocaine use.88,89,91 Although pulmonary edema may be cardiogenic and occur secondary to acute or chronic left ventricular failure from increased vascular resistance, the majority of cases appear to be caused by a noncardiogenic “capillary leak” syndrome.92 Both neurogenic and non-neurogenic mechanisms for cocaine-induced noncardiogenic pulmonary edema can be postulated. Cocaine may directly injure pulmonary endothelium and increase local capillary permeability.91 Exacerbation of reversible airway diseases, including asthma, has been reported in association with the use of cocaine. These exacerbations may be the consequences of heat or of exposure to the impurities in cocaine, since its catecholamine effects would not be expected to produce airway bronchospasm.23,88,89 An increase in bronchial hyperactivity has been seen in patients who inhaled “rebujo” (vaporized heroin and cocaine on aluminum foil compound) compared with controls using lung function tests before and after methacholine challenge.93 Dyspnea is a frequent presenting complaint of patients with cocaine-induced toxicity, occurring in 3% to 22% of cases in various series.3,5,39,40 Hemoptysis, bronchitis, and expectoration of carbonaceous sputum are frequent complaints of cocaine users in the ED. An increased incidence of pulmonary hypertension, pulmonary infarction, pulmonary hemorrhage, and pulmonary foreign body granulomas have been reported in cocaine users.3,89 Bronchiolitis obliterans and organizing pneumonia (BOOP) associated with fever and dyspnea may also occur.88,89,94 Loss of a functional alveolocapillary interface as measured by a reduction in carbon monoxide diffusion capacity has been observed in studies of frequent cocaine users.88 The interpretation of this finding is complicated by other pulmonary exposures to tobacco and marijuana in the population studied. Other studies have suggested that the reduction can be attributed to tobacco use alone.95 A specific syndrome known as “crack lung” is a hypersensitivity pneumonitis associated with the smoking of cocaine; it is characterized by fever, chest pain, dyspnea, wheezing, hemoptysis, productive cough, and diffuse interstitial and alveolar infiltrates.3,89,96 Clinically inapparent alveolar hemorrhage has been demonstrated to occur frequently in crack cocaine users.97 Again, whether these manifestations of pulmonary toxicities are related to cocaine exposure itself, to the inhalation of superheated adulterants, or to exposure to combustion products is unknown.

Hyperthermia The majority of cocaine deaths are associated with druginduced hyperthermia.98-100 Cocaine may produce hyperthermia from increased heat production (e.g., psychomotor agitation, neuromuscular hyperactivity, seizures), impaired heat dissipation (e.g., cutaneous vasoconstriction), and altered thermoregulation (e.g., hypothalamic dysfunction). Although psychomotor

762


agitation and seizures are the principal etiologies of hyperthermia, temperature elevations from cocaine have been reported in their absence.59,60,101,102 Altered thermoregulation may be the result of an altered core temperature set point from D2-dopamine or 5-HT2serotonin receptor agonism effects in the hypothalamus.60,102 In general, the duration and severity of hyperthermia from drug-associated heatstroke are correlated closely with mortality.98 Patient dehydration and high ambient temperature will increase the lethal effects of cocaine and other drugs. Interestingly, in one study, it was shown that mortality from cocaine in New York City increased at higher ambient temperatures.103 Like exertional heatstroke, hyperthermia from cocaine toxicity may precipitate a cascade of complications that includes agitated delirium, coma, seizures, cerebral edema, rhabdomyolysis, acute renal failure, hepatocellular necrosis, disseminated intravascular coagulation, metabolic acidosis, and cardiovascular collapse.98,101,102,104 Rectal temperatures as high as 45.6° C (104° F to 114.1° F) have been reported.102

Rhabdomyolysis and Renal Failure Similar to the vascular beds of other organ systems, cocaine produces vasoconstriction as well as thrombosis of both large and small skeletal muscle and renal vessels; ischemia and cell death may ensue with the amount of tissue injury dependent on the size of the occluded vessel.3,105 Cocaine-associated rhabdomyolysis may result from ischemia, seizures, and trauma.101,104 Approximately one third of patients with cocaine-associated rhabdomyolysis develop acute renal failure.101 Renal failure usually occurs from acute tubular necrosis, either from direct cocaine-induced renal cortical vasoconstriction or from rhabdomyolysis with myoglobinuria and renal tubular obstruction. The presence of profound hypotension, hyperpyrexia, and marked elevations of serum creatine kinase levels at admission are useful for predicting renal failure.101 Cocaine-induced rhabdomyolysis is often associated with seizures, coma, hypotension, arrhythmia, or cardiac arrest. In one series, six of seven patients who developed cocaine-induced rhabdomyolysis, disseminated intravascular coagulation, and renal failure died.101 The systemic release of tissue thromboplastin from local ischemic injury may partly precipitate disseminated intravascular coagulation.3,101 Chest wall, skeletal muscle rhabdomyolysis is felt to account for the majority of cocaine-associated chest pain and is often mistaken for myocardial ischemia.3,14,41

Head and Neck Although rarely life-threatening, head and neck complications of cocaine toxicity are not uncommon. An ophthalmologic condition called “crack eye” has been described; it is characterized by pain, photophobia, lacrimation, chemosis, and hyperemia in association with corneal epithelial defects. In addition, microbial keratitis may complicate the syndrome of crack eye, leading to potential long-term corneal alterations.106 Central retinal

artery occlusion and blindness have been associated with cocaine use.107 Chronic sinusitis as a result of cocaine abuse, including osteolytic sinusitis and secondary bilateral optic nerve involvement, has been described.108 Midline granulomas and loss of olfaction have also been reported with cocaine use. Acute epiglottitis has followed crack cocaine inhalation. It is not known whether epiglottitis is a direct effect of cocaine or is induced by the inhalation of hot gases. Cocaine-induced dental erosions and gingival necrosis have been reported.109 A perforated nasal septum is commonly noted with chronic nasal inhalation of cocaine. At least one case of the pulmonary aspiration of a fragment of nasal septum has been described.88

Gastrointestinal Gastrointestinal (GI) tract ischemic injury may occur when cocaine is used by all routes of administration.3 The fear of GI tract injury is heightened when “body stuffers” (people who ingest a relatively small amount of loosely wrapped drugs to avoid arrest) or “body packers” or “mules” (people who ingest large amounts of wellwrapped drugs to smuggle them across borders) ingest the drug. Cocaine ingestion has been associated with bowel obstruction, ischemia, necrosis, and perforation.110-112 Although it commonly occurs in the small bowel, obstruction and perforation may occur in the esophagus.113 Ischemia and perforation occur in the small or large bowel and are usually focal and segmental.3 Patients with cocaine-induced bowel ischemia will often manifest constant pain in the midabdomen and may have associated low-grade fever and leukocytosis.3,114 Symptomatic body stuffers or body packers may present with a seizure, vomiting, abdominal pain, an adrenergic crisis, or cardiac arrest.115,116 Acute pyloric and GI perforations have been reported after prolonged crack cocaine smoking.111 The intense vasoconstriction from stimulation of α-adrenergic receptors in the mesenteric vasculature is believed to contribute to focal tissue ischemia and perforation. Thermal injury of the esophagus has been reported after smoking free-base cocaine.112 Nontraumatic splenic infarction, hemorrhage, and hematomas have been reported from cocaine use.3,117

Pregnancy Significant alteration in menstrual cycle function, including amenorrhea and infertility, have been noted with cocaine abuse.118 If the female cocaine user becomes pregnant, increased risk for placental abruption exists.119 Cocaine causes uterine contractions, decreased uterine blood flow, and constriction of placental blood flow.3,120 As a result, premature rupture of membranes, spontaneous abortion, pregnancy-induced hypertension, intrauterine growth retardation, precipitous delivery, and fetal death have been associated with cocaine use.119 A meta-analysis suggests that increased congenital malformations of the limbs, the GI tract, and the cardiovascular and neurologic systems occur in children of cocaine users.121 Congenital urinary tract anomalies

CHAPTER 42

and bilateral cleft lip may be associated with maternal cocaine use.119,121,122 Abnormal ventilatory patterns and increased incidence of sudden infant death syndrome have been reported with maternal cocaine use.123,124 Other neurobehavioral abnormalities in the neonate, including tremulousness and an increased startle reflex (“crack baby” behavior), have been noted after maternal cocaine use.119,124 Infants born to women who were heavy cocaine users during pregnancy demonstrate altered “executive” functioning at 9.5 to 12.5 months of age.124 Brain dopamine and serotonin concentrations and pathways are abnormal at birth in rats that have significant prenatal exposure to cocaine. These neurotransmitter concentrations return to normal as the rat ages.125 The duration and long-term implications of these neurobehavioral abnormalities are unknown. Both cocaine and cocaethylene are found in breast milk and may be transferred to breast-fed infants.126

Urologic Effects Several cases of impotence and priapism from acute cocaine use have been reported. Intranasal, intraurethral, and topical application (to the glans penis) of cocaine have all been reported to cause priapism.127 The risk for priapism is greater when cocaine is used in combination with trazodone.128

Hepatic Oxidative processes centered around the tropane nitrogen are responsible for about 10% of cocaine metabolism, using the cytochrome P-450 enzyme system within the liver.30,129 This minor pathway appears to be responsible for hepatic toxicity. It produces norcocaine, norcocaine nitroxide, hydrogen peroxide, and superoxide radicals.129,130 These products are thought to reduce hepatocyte nicotinamide-adenine dinucleotide phosphate (NADPH) and glutathione levels.129 The formation of lipid peroxidation and the resultant superoxide or hydroxyl radical injury are believed to lead to the intrinsic hepatotoxicity seen with cocaine abuse.129 A case of fulminant liver failure that recovered after snorting large doses of cocaine has been reported with centrilobular necrosis.131 Agents that deplete NADPH and intracellular glutathione (e.g., acetaminophen) can enhance the risk for cocaine hepatotoxicity. Human cocaine hepatotoxicity is seen most frequently as necrosis in zone 3 of the liver that corresponds to the cytochrome P-450 distribution.129,130 Although many case reports of cocaine-induced hepatotoxicity exist and hepatocyte tissue cultures confirm intrinsic toxicity, the clinical incidence of cocaine hepatotoxicity is unknown, but is probably low. The explanation for the low frequency of hepatitis secondary to cocaine toxicity is as yet unknown, and the determination of its exact incidence is complicated by the high prevalence of viral and alcohol-induced liver disease in this patient population. Most instances of toxic hepatitis (manifested as hepatic transaminitis) attributed to cocaine will occur in the setting of fulminant hyperthermia and multiorgan dysfunction.

Cocaine

763

Hematologic The association of disseminated intravascular coagulation, rhabdomyolysis, and renal failure has been discussed.101 Severe destructive thrombocytopenia unrelated to retroviral infection has been reported in a small series of both intravenous and inhalation cocaine users.132 Cocaine-associated thrombocytopenia has been described and has a clinical course similar to that of immunopathic thrombocytopenic purpura. In one series, five of six patients with thrombocytopenia responded favorably to corticosteroids. The sixth patient had a partial response to corticosteroids and a complete response to splenectomy.132 Whether this thrombocytopenia reflects a direct or an indirect immunologic stimulus from cocaine or a contaminant is not known. In addition, increased platelet aggregation is believed to contribute to thrombocytopenia in some cocaine users. In a study of 19 patients presenting to an ED with acute cocaine use, hemoglobin and hematocrit levels were significantly elevated, but no evidence of erythrocytosis was seen. Male patients presenting with chest pain were more likely than females to demonstrate these effects.133

Endocrine Thyroid function tests are not significantly different from normal values in heavy users of cocaine. Hyperprolactinemia with resultant galactorrhea has been described in chronic cocaine abusers. Higher peak and trough levels of prolactin-releasing factor have also been reported in male cocaine users with hyperprolactinemia.118 In one study, prolactin levels remained elevated for 4 weeks in men and women during hospitalization for cocaine withdrawal.69 The persistent elevation of prolactin was attributed to cocaine-induced derangement in the dopaminergic neural regulatory systems. In this same study, levels of plasma luteinizing hormone, testosterone, and cortisol were found to be within the normal range. Chronic cocaine use also alters plasma growth hormone levels, dexamethasone suppression of cortisol, and thyroid-stimulating hormone response to thyroid-releasing hormone.134 Many of these neuroendocrine abnormalities are augmented when cocaine abuse is combined with ethyl alcohol.135 The clinical importance of these findings is unclear, but they may account for the impotence and gynecomastia reported in men who chronically abuse cocaine.

DIAGNOSIS The diagnosis of cocaine toxicity is based on a suggestive history, physical findings consistent with the known toxicity of cocaine (e.g., sympathomimetic effects), and laboratory testing that confirms the presence of cocaine. The physical examination may need to include a thorough cavity search (e.g., vaginal and rectal examinations) when body packing or body stuffing is suspected.

764


Laboratory Testing If the history of use is clear and symptoms or signs of intoxication are mild, laboratory testing is often unnecessary. If patients have moderate to severe toxic effects, routine laboratory investigations should include a complete blood count; measurements of electrolytes, blood urea nitrogen, creatinine, glucose, creatine phosphokinase (CPK), or troponin T or I; and a urinalysis. The diagnosis of acute MI in the setting of cocaineassociated chest pain is most accurately made with serial measurements of troponin T or I.41 Troponin measurements are more specific than CPK-MB measurements; the latter can be falsely elevated with concomitant cocaine-associated rhabdomyolysis.14,41,136 Patients with agitated delirium, seizures, hyperthermia, or severe rhabdomyolysis should have liver function tests, calcium, phosphate, and coagulation (e.g., prothrombin time, international normalized ratio, disseminated intravascular coagulation [DIC] screen) parameters measured. Arterial blood gas analysis and lactate concentrations may be helpful for patients with significant toxicity. Analysis of both blood and urine for cocaine and its metabolites can be readily and routinely performed at most hospitals. Testing of saliva, hair, meconium, gastric aspirates, and breast milk can also be performed, if necessary. An enzyme-linked immunoassay directed against benzoylecgonine is useful for the rapid, qualitative screening of samples for cocaine and its metabolites. This method usually detects benzoylecgonine in body fluids at or above a concentration of 300 ng/mL.30 False-positive results are rare. Other screening tests include thin-layer and high-pressure liquid chromatography. Gas chromatography followed by mass spectrometry (GC-MS) of urine or blood represents one of the most sensitive and specific assays available for identifying cocaine and its metabolites and can be used to confirm the presence of cocaine in a body fluid specimen. Quantification of cocaine and its major metabolites in saliva using GC-MS have been reported.137 Typically, cocaine metabolites will be detected in the urine for 48 to 72 hours after cocaine use. Rarely, heavy use may allow metabolite detection for up to 22 days.138,139 Quantification of cocaine and its metabolites from body fluids is generally not recommended because no correlation has been found between cocaine or metabolite levels and the severity of clinical effects and mortality.85,140 Cocaine concentrations in tissues of patients who die from cocaine intoxication vary greatly, depending on the dose, route of administration, period of survival, and manner of storage of specimens prior to analysis.30

Other Laboratory Testing A chest radiograph and ECG should be performed on all patients with chest pain, cardiopulmonary complaints, or moderate to severe toxicity from cocaine. Arrhythmias, conduction disturbances, and repolarization abnormalities (e.g., prolonged QRS and QTc intervals) can be readily identified on the ECG. The ability to detect acute MI on the ECG, however, is significantly more limited.

The ECG is abnormal in 56% to 84% of patients with cocaine-associated chest pain, yet its sensitivity and positive predictive value for detecting acute MI are only 36% and 18%, respectively.41,43,141,142 Up to 43% of patients with cocaine-associated chest pain that are determined subsequently not to have an MI meet ECG criteria for thrombolytic therapy.41,43,141 A normal ECG has greater diagnostic utility for those with cocaine-associated chest pain. The specificity and negative predictive value of the ECG for ruling out acute MI are 90% and 96%, respectively.141 A normal ECG in a patient with cocaine-associated chest pain, however, cannot be used to rule out MI.43 Chest radiography is used to facilitate diagnosis of pneumothorax, pneumopericardium, pneumomediastinum, pneumonia, “crack lung,” pulmonary edema, or pulmonary hemorrhage or infarct. Abdominal plain films may be useful as a screening tool to detect the presence of foreign bodies in a suspected body packer. Plain abdominal radiography has a sensitivity of 85% to 90%.115,143 In contrast, plain abdominal radiography is not useful or recommended to detect the presence of drug packets in a “body stuffer.”144 Contrast-enhanced computed tomography (CT) or barium-enhanced radiography are recommended when plain radiography is negative and clinical suspicion for ingested or retained packets is high.115 The incidence of false-positive and -negative results with contrast-enhanced radiography has been reported to be 4%.145 Head CT imaging should be performed for patients with recurrent seizures, headache, or altered mental status associated with cocaine to rule out intracerebral hemorrhage. Lumbar puncture may be necessary to rule out subarachnoid hemorrhage. Chest and abdominal CT imaging with oral and intravenous contrast may be necessary for patients with significant chest, back, and abdominal pain to evaluate for the presence of a vascular catastrophe (e.g., aortic dissection) or pulmonary, renal, or GI tract hemorrhage, ischemia, or infarct.

Differential Diagnosis Cocaine may produce effects similar to those of other toxicants, such as sympathomimetic drugs (e.g., amphetamines, methylxanthines, nicotine, ephedrine, β- and α-adrenergic agonists, monoamine oxidase inhibitors), central hallucinogens (e.g., tryptamine derivatives, phencyclidine, lysergic acid diethylamide, hallucinogenic amphetamines), drug withdrawal states (e.g., alcohol and sedative-hypnotic withdrawal), metabolic poisons (e.g., salicylates, dinitrophenol), psychotropics (e.g., cyclic antidepressants, lithium, antipsychotics, amantadine), membrane-active drugs (e.g., local anesthetics and antiarrhythmics), and certain drug-associated syndromes (e.g., malignant hyperthermia, serotonin syndrome, and neuroleptic malignant syndrome). Certain medical emergencies may present in a similar manner, such as endocrinologic disorders (e.g., pheochromocytoma, thyrotoxicosis, hypoglycemia), infections (e.g., meningoencephalitis, sepsis, tetanus), neuropsychiatric disorders (e.g., paranoid schizophrenia, bipolar disorder, intra-

CHAPTER 42

cerebral hemorrhage, head trauma, status epilepticus), and environmental disorders (e.g., exertional and nonexertional heatstroke).

MANAGEMENT Table 42-2 outlines an algorithm for the general approach to patients with suspected cocaine toxicity. Prospective human studies evaluating different treatment options for such patients are lacking. Thus, recommendations are based on the findings from animal studies and small series of human poisonings with cocaine. The initial management strategy is to institute airway, breathing, and circulatory support as necessary. Supplemental oxygen, vascular access, and continuous cardiac and respiratory monitoring should be provided rapidly. All patients with altered mental status and seizures should have their serum glucose checked or be given dextrose infusion for possible neuroglycopenia. A critical component to successful management is to obtain a core (i.e., rectal) temperature early and treat hyperthermia promptly. Aggressive control of seizures and psychomotor agitation are equally important, particularly since these manifestations often precipitate cocaine-associated hyperthermia. After initial supportive care has been provided, subsequent treatment will depend on the signs, symptoms, and organ system(s) affected. Early GI decontamination should be strongly considered for patients who have ingested cocaine. Activated charcoal with or without a cathartic is administered (1 g/kg body weight) initially; other GI decontamination modalities (e.g., whole bowel irrigation) are also recommended for body stuffers and packers.115,146 Specific measures for each complication are discussed below. Even patients with cocaine-induced brain death have been successfully stabilized so that organs can be harvested for transplantation.147 Given the relatively large volume of distribution and short elimination half-life, enhanced elimination techniques (e.g., urine acidification, hemodialysis) are unlikely to improve the clearance of cocaine and are also not necessary. These approaches have not been formally studied in humans. No specific antidotes exist. However, efforts to develop immunologic ways to bind or neutralize cocaine with antibodies, FAB fragments, vaccines, and specific dopamine receptor antagonists are ongoing and would have potential utility in treating both acute toxicity and drug addiction.148,149

Cardiovascular Toxicity As a result of the relatively short half-life of cocaine and its metabolites, supportive care with minimal pharmacologic intervention is usually adequate for most patients with acute cocaine-related cardiovascular toxicity. Hypertension and sinus tachycardia usually respond to sedation alone. Nonspecific sympatholysis with benzodiazepines is recommended as first-line treatment.14,41,150-152 When hypertension and tachycardia do not respond to sedation and are associated with end-organ dysfunction

Cocaine

765

(e.g., myocardial ischemia, confusion, headache, congestive heart failure), treatment with nitroprusside, calcium channel blockers (e.g., verapamil), or nonselective α-adrenergic agents (e.g., phentolamine) are recommended.14,41,48,151,152 The use of a β-adrenergic antagonist therapy alone is generally contraindicated for treatment of cocaine toxicity. These agents may result in unopposed α-adrenergic stimulation and worsened end-organ toxicity (e.g., increased coronary vasospasm, worsening hypertension).14,41,49,151,152 Patients with cocaine toxicity may present with palpitations and supraventricular tachycardia. Treatment of the patient with no evidence of coronary artery disease includes observation, sedation with benzodiazepines, and the occasional judicious use of calcium channel blockers (e.g., verapamil or diltiazem) for heart rate control.153 Adenosine may be used but its efficacy is questionable due the transient nature of its effects as compared with the sympathomimetic effects of cocaine. Synchronized cardioversion may be necessary for unstable patients with arrhythmias. The use of β-adrenergic antagonists is contraindicated in these patients for the reasons stated above. Although the data are controversial, the use of labetalol is usually not recommended since it is largely a β-adrenergic antagonist (β- to α-effect of 6 to 1).14,41,151,152,154,155 Ventricular arrhythmias are best treated with lidocaine, sodium bicarbonate, and nonspecific sedation with benzodiazepines.14,41,151,152 The correction of hypoxia and metabolic and electrolyte abnormalities are critically important. Sodium bicarbonate (1-2 mEq/kg intravenous boluses) administration is recommended as a first-line treatment for ventricular or wide-complex arrhythmias immediately after cocaine use, when the fast sodiumchannel (type I) blocking effects of cocaine are most likely to be operative.14,41,151,152 Sodium bicarbonate has been shown to reverse cocaine-induced QRS complex prolongation in animal studies and human case reports.71,156,157 Lidocaine is recommended as first-line treatment when ventricular arrhythmias are attributed to cocaine-induced myocardial ischemia.14,41,151,157,158 Although lidocaine itself is a fast-sodium channel blocker, lidocaine competitively antagonizes the sodium channel-blocking activity of cocaine.157 Unlike cocaine, which has slow on-off sodium channel-binding kinetics, lidocaine has rapid on-off binding kinetics at the sodium channel.157 Lidocaine does not prolong action potential duration or the QRS interval, and its presence could partly reverse the prolongation that occurs in the presence of toxic concentrations of cocaine. Based on most animal and human clinical data, lidocaine is likely safe and effective for use in cocaine poisoning.157,158 Intravascular volume replacement, diuretics, cardiotonic and inotropic agents, and careful vasopressor support have all been utilized in cocaine-induced cardiomyopathy with congestive heart failure.14 Monitoring of central venous or pulmonary artery wedge pressure may be necessary for titration of these agents. Short-term use of intra-aortic balloon pumps also has been reported to augment cardiac function during transient myocardial dysfunction. General supportive care is important in

766


TABLE 42-2 Cocaine Toxicity and Treatment Decision Algorithm SUSPECTED COCAINE TOXICITY MILD COCAINE TOXICITY

SEVERE COCAINE TOXICITY

EVALUATE FOR OTHER AGENTS

Psychologic support Decontamination of oral ingestions/ administration of activated charcoal Observe

Immediate Supportive Care Airway control Oxygenation Vascular access

Initiate specific treatment for additional agents Consider interactions with cocaine Monitor for early and late toxicities of other agents

Decontaminate/Antagonists In oral exposures, administer activated charcoal Consider whole-bowel lavage with polyethylene glycol solutions for “body packers” Consider empiric dextrose, thiamine, and naloxone Avoid using benzodiazepine antagonists (e.g., flumazenil) Terminate Seizures Benzodiazepines (e.g., diazepam, lorazepam) Barbiturates (e.g., pentobarbital, phenobarbital) Correct Immediate Metabolic, Oxygenation, and Electrolyte Abnormalities Correct Local Tissue Ischemia, Improve Perfusion Local α-Adrenergic Blockers for Cocaine (e.g., phenoxybenzamine, phentolamine) Treat Hyperthermia Second-Level Evaluations to Check for Persistent Abnormalities PERSISTENT HYPOTENSION

CNS ABNORMALITIES

SUPPORTIVE CARE

Intravascular volume resuscitation Acute cardiopulmonary support Central hemodynamic monitoring

Seizures Strokes Bleeds Terminate seizures

Psychologic and pharmacologic support for cocaine abstinence and long-term recovery

VENTRICULAR ARRHYTHMIA

PULMONARY EDEMA/RESPIRATORY FAILURE

Antiarrhythmics (e.g., lidocaine) Electrolyte correction Acid-base correction RENAL FAILURE

Hemodialysis Intravascular volume HYPERTENSION

Sedation (e.g., diazepam) Calcium channel blockers (e.g., nifedipine, nicardipine) Nitroprusside CORONARY ARTERY ISCHEMIA

Antiplatelet agents (e.g., aspirin) Calcium channel blockers (e.g., nifedipine, diltiazem, nicardipine) α-Adrenergic blockers (e.g., phentolamine)

Ventilator Oxygen PEEP Electrolyte Abnormalities Correct hypokalemia (e.g., potassium chloride) Correct hypocalcemia (e.g., calcium gluconate) RHABDOMYOLYSIS

Alkalinize urine (e.g., IV bicarbonate) Calcium replacement (e.g., calcium gluconate) Intravascular volume

CHAPTER 42

Cocaine

767

TABLE 42-2 Cocaine Toxicity and Treatment Decision Algorithm (Con’t) SUSPECTED COCAINE TOXICITY MILD COCAINE TOXICITY

SEVERE COCAINE TOXICITY


β-Adrenergic blockers (e.g., esmolol, metoprolol) may be contraindicated (see text) Nitrates (e.g., nitroglycerin) Sedation (e.g., diazepam) CNS, central nervous system; PEEP, positive end-expiratory pressure; IV, intravenous.

maintaining cardiovascular function during cocaineinduced cardiac toxicities. Discontinuation of cocaine use appears to be the most prudent way of reversing or limiting the progression of cocaine-induced chronic cardiomyopathy.

Myocardial Ischemia Recommendations are based on two recent reviews of cocaine-induced myocardial ischemia and the recently revised consensus guidelines on emergency cardiovascular care from the American Heart Association in collaboration with the International Liaison Committee on Resuscitation.14,41,151,152 Patients with suspected cocaineinduced myocardial ischemia or MI should be treated initially with oxygen, parenteral benzodiazepines, aspirin, and nitrates. Both benzodiazepines and nitroglycerin have been shown to improve hemodynamics (reduce rate-pressure product) and resolve chest pain in patients with cocaine-associated chest pain and suspected myocardial ischemia.41,150,159 As previously noted, use of β-adrenergic antagonists is contraindicated because they may result in unopposed α-adrenergic effects and exacerbate coronary vasoconstriction associated with cocaine.14,41,49,151,152,154 The specific use of labetalol, although not recommended, cannot be considered an absolute contraindication based on the scientific data available to date.151,152 In humans undergoing cardiac catheterization and given intranasal cocaine, labetalol reversed cocaine-induced increases in mean arterial pressure but had no effect on cocaine-induced vasoconstriction of coronary arteries.155 The use of calcium channel blockers (specifically, verapamil), the α-blocker phentolamine, and heparin therapy are considered second-line therapies for cocaine-induced coronary ischemia.41,151-153 Both verapamil and phentolamine have been shown to reverse coronary artery vasoconstriction in human volunteers given intranasal cocaine immediately prior to cardiac catheterization.48,153 If medical management does not eliminate cocaineinduced myocardial ischemia, primary percutaneous intervention (diagnostic and therapeutic cardiac catheterization) is recommended over rapid reperfusion with thrombolytic therapy.14,41 The increased risk for cerebrovascular hemorrhage with cocaine-induced toxicity

requires that the use of thrombolytics in this patient population be carried out with extreme care.14,41 Thrombolytic therapy has not been proven safe or effective in patients with cocaine-associated MI.160 In addition, it is usually difficult to base treatment decisions in this patient population on ECG criteria for an MI, which are both insensitive and nonspecific. In general, the mortality of cocaine-induced MI patients that make it to the hospital alive is less than 2%.14,41 The morbidity and mortality are likely to be increased with the use of thrombolytic therapy. Major intracerebral hemorrhage has been reported in more than 5% of published cases of cocaine-induced MI treated with thrombolytic therapy. Thrombolysis should only be considered when the diagnosis of cocaine-induced MI is firm and cardiac catheterization is not available. As mentioned, the use of lidocaine is recommended for ventricular arrhythmias felt secondary to myocardial ischemia. In review of the use of lidocaine in 29 patients with cocaine-associated MIs, no enhanced cocaine toxicity was seen.158

Central Nervous System Toxicity Sedation with benzodiazepines (e.g., diazepam) is the first-line treatment for CNS agitation associated with cocaine; large doses may be necessary.99,100,161 Although controversial, the adjunctive use of neuroleptics (e.g., droperidol, haloperidol, or ziprasidone) may be effective for the control CNS agitation produced by cocaine. Successful treatment of cocaine-induced hyperthermia requires early recognition, rapid cooling, and aggressive supportive care.98-100,102 Cooling methods include rehydration with cooled intravenous fluids; cool water mist and fans (evaporative and convective cooling); ice packs; ice water baths; and ice water, gastric, peritoneal, rectal, or bladder lavage. Since cocaine-induced hyperthermia is predominantly secondary to increased muscle activity, prompt peripheral muscle relaxation is essential to minimize morbidity and mortality. Sedation with benzodiazepines may be tried initially for mild cases of hyperthermia. Nondepolarizing neuromuscular paralysis (e.g., pancuronium), however, which provides rapid, predictable, and effective termination of motor hyperactivity, should be instituted for severe or refractory hyperthermia.98,100,102 When canines given intravenous

768


lethal doses of cocaine are ventilated and pretreated with pancuronium, hyperthermia, metabolic acidosis, and mortality can be prevented.99 Seizures associated with cocaine are generally best treated with benzodiazepines (e.g., lorazepam) followed by barbiturates (e.g., phenobarbital, pentobarbital), if necessary. The efficacy and safety of phenytoin has not been established. Animal studies suggest that other antiepileptics (e.g., felbamate and gabapentin) may also be effective for cocaine-induced seizures.162 Treatment for other neurologic complications of cocaine abuse is supportive. Subarachnoid hemorrhage and intracerebral bleeding may be associated with an underlying cerebral saccular aneurysm or vascular malformation and may require neurosurgical intervention. Transient ischemic attacks and ischemic cerebrovascular accidents are treated symptomatically and may require empiric therapy with aspirin and heparin. The use of thrombolytic therapy for acute ischemic strokes associated with cocaine has not been studied and is theoretically dangerous. Migraine-like headaches produced by cocaine have been reported to improve with ergotamine treatment. However, there is theoretical concern about the use of another vasospastic agent such as ergotamine in view of the vasospastic side effects of cocaine itself. The use of serotonergic agonists (e.g., triptans) for cocaine-induced migraine headaches has not been reported.

Pulmonary Complications The management of pulmonary complications associated with cocaine use is supportive.89 Supplemental oxygen, bronchodilator therapy, steroids, and mechanical support may be necessary for cocaine-induced bronchospasm. Oxygen, diuretics, and intubation with or without positive end-expiratory pressure (PEEP) have been used successfully and may be necessary for patients with cocaine-induced pulmonary edema.89 In addition to PEEP, the lengthening of inspiratory time intervals can also to increase the functional residual capacity and may also enhance oxygenation. Empiric treatment with corticosteroids for BOOP and eosinophilic pulmonary syndromes is recommended, but efficacy has been variable.88,89 Patients with pneumomediastinum or pneumopericardium should be admitted and observed for the subsequent development of a pneumothorax.89 Chest tube placement is necessary for patients with large pneumothoraces or those who do not resolve or worsen with high-flow oxygen. It is important to inform patients that barotraumatic complications may recur with repeated use of crack cocaine.89

Rhabdomyolysis and Renal Failure Treatment of cocaine-induced rhabdomyolysis and renal failure is supportive. Aggressive rehydration is recommended to correct hypovolemia and prevent myoglobin precipitation in the renal tubules. Isotonic normal saline is recommended initially to establish and maintain a

urine flow of at least 2 mL/kg/hr. Careful monitoring of electrolytes (e.g., phosphate, calcium, potassium) is necessary. Although not proven effective, most experts recommend the administration of bicarbonate-rich fluids to alkalinize the urine (urine pH > 7) and prevent myoglobin precipitation in the renal tubules. Hemodialysis may be necessary for acute renal failure.

Body Stuffers and Packers Whole bowel irrigation, endoscopy, surgery, cathartics, and repeat doses of activated charcoal have been used to treat patients who have ingested packets of cocaine.115,143,145,146,163-165 In a series of 34 body stuffers in Chicago, 74% remained asymptomatic, 18% had mild symptoms, 4% had moderate symptoms, and 4% had severe symptoms leading to death. Abdominal radiography, decontamination, and benzodiazepines appeared to be useful.166 In another series of patients, approximately 3% of patients that ingested cocaine packets required surgical removal for obstruction or toxic effects.167 Asymptomatic body packers and stuffers may be treated conservatively with simple observation in an ICU until spontaneous passage of the packets has occurred.115,116,167 Alternatively, GI tract decontamination with activated charcoal (to bind any cocaine that may leak out of the packets) coupled with whole bowel irrigation may be performed to enhance passage of the packets (see Chapter 2B). Whole bowel irrigation should be continued until complete clearance of the drug packets has occurred from the GI tract. Abdominal imaging with contrast and the passage of several packetfree stools is used to confirm passage of all cocaine packets.115,145 Symptomatic body stuffers should be treated similarly to other symptomatic cocaine-intoxicated patients. In addition, GI tract decontamination with activated charcoal is important for these patients to limit further cocaine absorption.115,146 Symptomatic body packers, either from mechanical bowel obstruction or perforation or from cocaine poisoning, require immediate surgical removal of drug packets.115,116 Although endoscopy has been used to remove cocaine packets from the stomach or proximal small bowel, operative removal is still recommended due to the risk for packet rupture during endoscopic removal.115

DISPOSITION The level (intensive care or floor) and duration of medical care are dependent on the severity and duration of toxicity. If signs and symptoms of toxicity are mild to moderate and resolve after a 4- to 6-hour observation period in the ED, patients may be medically discharged. Patients with altered mental status, persistent abnormal vital signs, nonsinus rhythms, or significant end-organ toxicity (e.g., rhabdomyolysis) should be admitted for further care and observation. Patients with cocaineassociated chest pain who are not at high risk for acute coronary syndrome may be admitted to a 9- to 12-hour chest pain observation unit.45 These patients may

CHAPTER 42

subsequently be discharged with close follow-up if they “rule out” for MI by troponin testing and cardiovascular complications do not occur during their 12-hour observation.45 Body packers and stuffers usually require ICU admission for observation and treatment.115 After clinical toxicity has resolved, referral for psychiatric follow-up care may be needed, as may serologic testing for viral hepatitis and human immunodeficiency virus. Evaluation for complications attendant to intravenous drug abuse (e.g., endocarditis, sexually transmitted diseases, etc.) should also be considered.168 REFERENCES 1. Substance Abuse and Mental Health Services Administration, Office of Applied Studies: Emergency department trends from the Drug Abuse Warning Network: final estimates 1995–2002, DAWN series: D-24. DHHS publication no. (SMA) 03-3780. Rockville, MD, Department of Health and Human Services, 2003. 2. Substance Abuse and Mental Health Services Administration, Office of Applied Studies: Mortality data from the Drug Abuse Warning Network, 2002. DAWN Series D-25, DHHS publication no. (SMA) 04-3875. Rockville, MD, Department of Health and Human Services, 2004. 3. Shanti CM, Lucas CE: Cocaine and the critical care challenge. Crit Care Med 2003;31:1851–1859. 4. Brookoff D, Cook CS, Williams C, et al: Testing reckless drivers for cocaine and marijuana. N Engl J Med 1994;331:518–522. 5. Rich JA, Singer DE: Cocaine-related symptoms in patients presenting to an urban emergency department. Ann Emerg Med 1991;20:616–621. 6. Loiselle JM, Baker MD, Templeton JM Jr, et al: Substance abuse in adolescent trauma. Ann Emerg Med 1993;22:1530–1534. 7. Cregler LL, Mark H: Medical complications of cocaine abuse. N Engl J Med 1986;315:1495–1500. 8. Karch SB: The history of cocaine toxicity. Hum Pathol 1989;20:1037–1039. 9. Warner EA: Cocaine abuse. Ann Intern Med 1993;119:226–235. 10. Garland O: Fatal acute poisoning by cocaine. Lancet 1895;2: 1104–1105. 11. Gawin FH, Ellinwood EH Jr: Cocaine and other stimulants. Actions, abuse, and treatment. N Engl J Med 1988;318:1173–1182. 12. Catterall W, Mackie K: Local anesthetics. In Hardman JG, Limbird LE, Gilman AG (eds): Goodman & Gilman’s The Pharmacologic Basis of Therapeutics, 10th edition. New York, McGraw-Hill, 2001, pp 367–384, 634–638. 13. Boghdadi MS, Henning RJ: Cocaine: pathophysiology and clinical toxicology. Heart Lung 1997;26:466–481. 14. Lange RA, Hillis LD: Cardiovascular complications of cocaine use. N Engl J Med 2001;345:351–358. 15. Office of Applied Studies: 2002 National Survey on Drug Use & Health, trends in initiation of substance abuse. Accessed April 2004 from http://oas.samhsa.gov/nhsda/2k2nsduh/Results/ 2k2results.htm#chap6. 16. Marzuk PM, Tardiff K, Leon AC, et al: Fatal injuries after cocaine use as a leading cause of death among young adults in New York City. N Engl J Med 1995;332:1753–1757. 17. Pottieger AE, Tressell PA, Inciardi JA, et al: Cocaine use patterns and overdose. J Psychoactive Drugs 1992;24:399–410. 18. Coffin PO, Galea S, Ahern J, et al: Opiates, cocaine and alcohol combinations in accidental drug overdose deaths in New York City, 1990–98. Addiction 2003;98:739–747. 19. Ochoa KC, Hahn JA, Seal KH, et al: Overdosing among young injection drug users in San Francisco. Addict Behav 2001;26:453–460. 20. Mesquita F, Kral A, Reingold A, et al: Overdoses among cocaine users in Brazil. Addiction 2001;96:1809–1813. 21. Drug Enforcement Agency: Florida: Drug Situation: Cocaine Statistics. Accessed December 2003 from http://www.dea.gov/ pubs/states/florida.html. 22. Gay GR, Inaba DS, Sheppard CW, et al: Cocaine: history, epidemiology, human pharmacology, and treatment. Clin Toxicol 1975;8:149–178.

Cocaine

769

23. Shannon M: Clinical toxicity of cocaine adulterants. Ann Emerg Med 1988;17:1243–1247. 24. Benowitz NL: Clinical pharmacology and toxicology of cocaine. Pharmacol Toxicol 1993;72:3–12. 25. Tella SR, Schindler CW, Goldberg SR: Cocaine: cardiovascular effects in relation to inhibition of peripheral neuronal monoamine uptake and central stimulation of the sympathoadrenal system. J Pharmacol Exp Ther 1993;267:153–162. 26. Leshner AI: Molecular mechanisms of cocaine addiction. N Engl J Med 1996;335:128–129. 27. Reid MS, Hsu K, Berger SP: Cocaine and amphetamine preferentially stimulate glutamate release in the limbic system: studies on the involvement of dopamine. Synapse 1997;27:95–105. 28. Smith JA, Mo Q, Guo H, et al: Cocaine increases extraneuronal levels of aspartate and glutamate in the nucleus accumbens. Brain Res 1995;683:264–269. 29. Perera R, Kraebber A, Schwartz MJ: Prolonged QT interval and cocaine use. J Electrocardiol 1997;30:337–339. 30. Baselt RC: Disposition of Toxic Drugs and Chemicals in Man, 5th ed. Foster City, CA, Chemical Toxicology Institute, 2000, pp 205–210. 31. Spiehler VR, Reed D: Brain concentrations of cocaine and benzoylecgonine in fatal cases. J Forensic Sci 1985;30:1003–1011. 32. Rose JS: Cocaethylene: a current understanding of the active metabolite of cocaine and ethanol. Am J Emerg Med 1994;12: 489–490. 33. Henning RJ, Wilson LD, Glauser JM: Cocaine plus ethanol is more cardiotoxic than cocaine or ethanol alone. Crit Care Med 1994;22:1896–1906. 34. Cami J, Farre M, Gonzalez ML, et al: Cocaine metabolism in humans after use of alcohol. Clinical and research implications. Recent Dev Alcohol 1998;14:437–455. 35. Walsh SL, Haberny KA, Bigelow GE: Modulation of intravenous cocaine effects by chronic oral cocaine in humans. Psychopharmacology (Berl) 2000;150:361–373. 36. Knuepfer MM: Cardiovascular disorders associated with cocaine use: myths and truths. Pharmacol Ther 2003;97:181–222. 37. Mouhaffel AH, Madu EC, Satmary WA, et al: Cardiovascular complications of cocaine. Chest 1995;107:1426–1434. 38. Hollander JE, Hoffman RS, Burstein JL, et al: Cocaine-associated myocardial infarction. Mortality and complications. CocaineAssociated Myocardial Infarction Study Group. Arch Intern Med 1995;155:1081–1086. 39. Derlet RW, Albertson TE: Emergency department presentation of cocaine intoxication. Ann Emerg Med 1989;18:182–186. 40. Brody SL, Slovis CM, Wrenn KD: Cocaine-related medical problems: consecutive series of 233 patients. Am J Med 1990; 88:325–331. 41. Hollander JE: The management of cocaine-associated myocardial ischemia. N Engl J Med 1995;333:1267–1272. 42. Osula S, Stockton P, Abdelaziz MM, et al: Intratracheal cocaine induced myocardial infarction: an unusual complication of fibreoptic bronchoscopy. Thorax 2003;58:733–734. 43. Hollander JE, Hoffman RS, Gennis P, et al: Prospective multicenter evaluation of cocaine associated chest pain. Acad Emerg Med 1994;1:330–339. 44. Mittleman MA, Mintzer D, Maclure M, et al: Triggering of myocardial infarction by cocaine. Circulation 1999;99:2737–2741. 45. Weber JE, Shofer FS, Larkin GL, et al: Validation of a brief observation period for patients with cocaine-associated chest pain. N Engl J Med 2003;348:510–517. 46. Kloner RA, Rezkalla SH: Cocaine and the heart. N Engl J Med 2003;348:487–488. 47. Flores ED, Lange TA, Cigarroa RG, Hillis LD: Effect of cocaine on coronary artery dimensions in atherosclerotic coronary artery disease: enhanced vasoconstriction at sites of significant stenoses. J Am Coll Cardiol 1990;16:74–79. 48. Lange RA, Cigarroa RG, Yancy CW Jr, et al: Cocaine-induced coronary-artery vasoconstriction. N Engl J Med 1989;321: 1557–1562. 49. Lange RA, Cigarroa RG, Flores ED, et al: Potentiation of cocaineinduced coronary vasoconstriction by beta-adrenergic blockade. Ann Intern Med 1990;112:897–903. 50. Wilbert-Lampen U, Seliger C, Zilker T, Arendt RM: Cocaine increases the endothelial release of immunoreactive endothelin

770

51. 52.

53. 54. 55. 56. 57. 58. 59. 60. 61.

62. 63.

64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74.


and its concentrations in human plasma and urine: reversal by coincubation with sigma-receptors antagonists. Circulation 1998;98:385–390. Mo W, Singh AK, Arruda JA, Dunea TG: Role of nitric oxide in cocaine-induced acute hypertension. Am J Hypertens 1998;11: 708–714. Weber JE, Hollander JE, Murphy SA, et al: Quantitative comparison of coronary artery flow and myocardial perfusion in patients with acute myocardial infarction in the presence and absence of recent cocaine use. J Thromb Thrombolysis 2002;14: 239–245. Rezkalla SH, Mazza JJ, Kloner RA, et al: The effects of cocaine on human platelets in healthy subjects. Am J Cardiol 1993;72: 243–246. Togna G, Tempesta E, Togna AR, et al: Platelet responsiveness and biosynthesis of thromboxane and prostacyclin in response to in vitro cocaine treatment. Haemostasis 1985;15:100–107. Stenberg RG, Winniford MD, Hillis LD, et al: Simultaneous acute thrombosis of two major coronary arteries following intravenous cocaine use. Arch Pathol Lab Med 1989;113:521–524. Moliterno DJ, Lange RA, Gerard RD, et al: Influence of intranasal cocaine on plasma constituents associated with endogenous thrombosis and thrombolysis. Am J Med 1994;96:492–496. Kolodgie FD, Wilson PS, Mergner WJ, Virmani R: Cocaineinduced increase in the permeability function of human vascular endothelial cell monolayers. Exp Mol Pathol 1999;66:109–122. Gan X, Zhang L, Berger O, et al: Cocaine enhances brain endothelial adhesion molecules and leukocyte migration. Clin Immunol 1999;91:68–76. Minor RL Jr, Scott BD, Brown DD, Winniford MD: Cocaineinduced myocardial infarction in patients with normal coronary arteries. Ann Intern Med 1991;115:797–806. Hollander JE, Hoffman RS, Burstein JL, et al: Cocaine-associated myocardial infarction: mortality and complications. Arch Intern Med 1995;155:1081–1086. Winniford MD, Wheelan KR, Kremers MS, et al: Smoking-induced coronary vasoconstriction in patients with atherosclerotic coronary artery disease: evidence for adrenergically mediated alterations in coronary artery tone. Circulation 1986;73:662–667. Foltin RW, Fischman MW, Levin FR: Cardiovascular effects of cocaine in humans: laboratory studies. Drug Alcohol Depend 1995;37:193–210. Escobedo LG, Ruttenber AJ, Agocs MM, et al: Emerging patterns of cocaine use and the epidemic of cocaine overdose deaths in Dade Country, Florida. Arch Pathol Lab Med 1991;115: 9800–9805. Hearn WL, Flynn DD, Hime GW, et al: Cocaethylene: a unique cocaine metabolite displays high affinity for the dopamine transporter. J Neurochem 1991;56:698–701. Hearn WL, Rose S, Wagner J, et al: Cocaethylene is more potent than cocaine in mediating lethality. Pharmacol Biochem Behav 1991;39:531–533. Wilson LD, French S: Cocaethylene’s effects on coronary artery blood flow and cardiac function in a canine model. J Toxicol Clin Toxicol 2002;40:535–546. Karch SB, Green GS, Young S: Myocardial hypertrophy and coronary artery disease in male cocaine users. J Forensic Sci 1995;40:591–595. Bertolet BD, Freund G, Martin CA, Perchalski EL, et al: Unrecognized left ventricular dysfunction in an apparently healthy cocaine abuse population. Clin Cardiol 1990;13:323–328. Tazelaar HD, Karch SB, Stephens BE, Billingham ME: Cocaine and the heart. Hum Pathol 1987;18:195–199. Mehta A, Jain AC, Mehta MC: Electrocardiographic effects of intravenous cocaine: an experimental study in a canine model. J Cardiovasc Pharmacol 2003;41:25–30. Wang RY: pH-dependent cocaine-induced cardiotoxicity. Am J Emerg Med 1999;17:364–369. Perron AD, Gibbs M: Thoracic aortic dissection secondary to crack cocaine ingestion. Am J Emerg Med 1997;15:507–509. Chambers HF, Morris DL, Tauber MG, Modin G: Cocaine use and the risk for endocarditis in intravenous drug users. Ann Intern Med 1987;106:833–836. Spivey WH, Euerle B: Neurologic complications of cocaine abuse. Ann Emerg Med 1990;19:1422–1428.

75. Qureschi AI, Akbar MS, Czander E, et al: Crack cocaine use and stroke in young patients. Neurology 1997;48:341–345. 76. Kaufman MJ, Levin JM, Ross MH, et al: Cocaine-induced cerebral vasoconstriction detected in humans with magnetic resonance angiography. JAMA 1998;279:376–380. 77. Merkel PA, Koroshetz WJ, Irizarry MC, et al: Cocaine-associated cerebral vasculitis. Semin Arthritis Rheum 1995;25:172–183. 78. Ruttenber AJ, Lawler-Heavner J, Yin M, et al: Fatal excited delirium following cocaine use: epidemiologic findings provide new evidence for mechanisms of cocaine toxicity. J Forensic Sci 1997;42:25–31. 79. Olson KR, Kearney TE, Dyer JE, et al: Seizures associated with poisoning and drug overdose. Am J Emerg Med 1993;11:565–568. 80. Lason W: Neurochemical and pharmacological aspects of cocaineinduced seizures. Pol J Pharmacol 2001;53:57–60. 81. Pascual-Leone A, Dhuna A, Altafullah I, et al: Cocaine-induced seizures. Neurology 1990;40:404–407. 82. Dhuna A, Pascual-Leone A, Langendorf F, et al: Epileptogenic properties of cocaine in humans. Neurotoxicology 1991;12: 621–626. 83. Jonsson S, O’Meara M, Young JB: Acute cocaine poisoning. Importance of treating seizures and acidosis. Am J Med 1983;75:1061–1064. 84. Kaye BR, Fainstat M: Cerebral vasculitis associated with cocaine abuse. JAMA 1987;258:2104–2106. 85. Daras M, Koppel BS, Atos-Radzion E: Cocaine-induced choreoathetoid movements (“crack dancing”). Neurology 1994;44:751–752. 86. Kaku DA, Lowenstein DH: Emergence of recreational drug abuse as a major risk factor for stroke in young adults. Ann Intern Med 1990;113:821–827. 87. Lowenstein DH, Massa SM, Rowbotham MC, et al: Acute neurologic and psychiatric complications associated with cocaine abuse. Am J Med 1987;83:841–846. 88. Albertson TE, Walby WF, Derlet RW: Stimulant-induced pulmonary toxicity. Chest 1995;108:1140–1149. 89. Haim DY, Lippmann ML, Goldberg SK, Walkenstein MD: The pulmonary complications of crack cocaine. Chest 1995;107: 233–240. 90. Cruz R, Davis M, O’Neil H, et al: Pulmonary manifestations of inhaled street drugs. Heart Lung 1998;27:297–305. 91. Cucco RA, Yoo OH, Gregler L, et al: Non-fatal pulmonary edema after “freebase” cocaine smoking. Am Rev Respir Dis 1987;136: 174–181. 92. Lang SA, Maron MD: Hemodynamic basis for cocaine-induced pulmonary edema in dogs. J Appl Physiol 1991;71:1166–1170. 93. Boto de los Bueis A, Pereira Vega A, Sanchez Ramos JL, et al: Bronchial hyperreactivity in patients who inhale heroin mixed with cocaine vaporized on aluminum foil. Chest 2002;121: 1223–1230. 94. Patel RC, Dutta D, Schonfeld SA: Free-base cocaine use associated with bronchiolitis obliterans organizing pneumonia. Ann Intern Med 1987;107:186–187. 95. Kleerup EC, Koyal SN, Marques-Magallanes JA, et al: Chronic and acute effects of “crack” cocaine on diffusing capacity, membrane diffusion, and pulmonary capillary blood volume in the lung. Chest 2002;122:629–638. 96. Forrester JM, Steele AW, Waldron JA, et al: Crack lung: an acute pulmonary syndrome with a spectrum of clinical and histopathologic findings. Am Rev Respir Dis 1990;142:462–467. 97. Baldwin GC, Choi R, Roth MD, et al: Evidence of chronic damage to the pulmonary microcirculation in habitual users of alkaloidal (“crack”) cocaine. Chest 2002;121:1231–1238. 98. Rosenberg J, Pentel P, Pond S, et al: Hyperthermia associated with drug intoxication. Crit Care Med 1986;14:964–969. 99. Catravas JD, Waters IW: Acute cocaine intoxication in the conscious dog: studies on the mechanism of lethality. J Pharmacol Exp Ther 1981;217:350–356. 100. Guinn MM, Bedford JA, Wilson MC: Antagonism of intravenous cocaine lethality in nonhuman primates. Clin Toxicol 1980;16: 499–508. 101. Roth D, Alarcon FJ, Fernandez JA, et al: Acute rhabdomyolysis associated with cocaine intoxication. N Engl J Med 1988;319: 673–677. 102. Callaway CW, Clark RF: Hyperthermia in psychostimulant overdose. Ann Emerg Med 1994;24:68–76.

CHAPTER 42

103. Marzuk PM, Tardiff K, Leon AC, et al: Ambient temperature and mortality from unintentional cocaine overdose. JAMA 1998;279: 1795–1800. 104. Merigian KS, Roberts JR: Cocaine intoxication: hyperpyrexia, rhabdomyolysis and acute renal failure. J Toxicol Clin Toxicol 1987;25:135–148. 105. Kramer RK, Turner RC: Renal infarction associated with cocaine use and latent protein C deficiency. South Med J 1993;86: 1436–1438. 106. Strominger MB, Sachs R, Hersh PS: Microbial keratitis with crack cocaine. Arch Ophthalmol 1990;108:1672. 107. Devenyi P, Schneiderman JF, Devenyi RG, Lawby L: Cocaineinduced central retinal artery occlusion. Can Med Assoc J 1988;138:129–130. 108. Newman NM, DiLoreto DA, Ho JT, et al: Bilateral optic neuropathy and osteolytic sinusitis. Complications of cocaine abuse. JAMA 1988;259:72–74. 109. Quart AM, Small CB, Klein RS: The cocaine connection. Users imperil their gingiva. J Am Dent Assoc 1991;122:85–87. 110. Yang RD, Han MW, McCarthy JH: Ischemic colitis in a crack abuser. Dig Dis Sci 1991;36:238–240. 111. Cheng CL, Svesko V: Acute pyloric perforation after prolonged crack smoking. Ann Emerg Med 1994;23:126–128. 112. Lee HS, LaMaute HR, Pizzi WF, et al: Acute gastrointestinal perforations associated with use of crack. Ann Surg 1990;211:15–17. 113. Cohen ME, Kegel JG: Candy cocaine esophagus. Chest 2002;121:1701–1703. 114. Herrine SK, Park PK, Wechsler RJ: Acute mesenteric ischemia following intranasal cocaine use. Dig Dis Sci 1998;43:586–589. 115. Traub SJ, Hoffman RS, Nelson LS: Body packing of illicit drugs. N Engl J Med 2003;349:2519–2526. 116. Caruana DS, Weinbach B, Goerg D, et al.: Cocaine-packet ingestion. Diagnosis, management, and natural history. Ann Intern Med 1984;100:73–74. 117. Homler HJ: Nontraumatic splenic hematoma related to cocaine abuse. West J Med 1995;163:160–161. 118. Mendelson JH, Mello NK, Teoh SK, et al: Cocaine effects on pulsatile secretion of anterior pituitary, gonadal, and adrenal hormones. J Clin Endocrinol Metab 1989;69:1256–1260. 119. Slutsker L: Risks associated with cocaine use during pregnancy. Obstet Gynecol 1992;79:778–789. 120. Hurd WW, Betz AL, Dombrowski MP, et al: Cocaine augments contractility of the pregnant human uterus by both adrenergic and nonadrenergic mechanisms. Am J Obstet Gynecol 1998;178: 1077–1081. 121. Kain ZN, Kain TS, Scarpelli EM: Cocaine exposure in utero: perinatal development and neonatal manifestations—review. J Toxicol Clin Toxicol 1992;30:607–636. 122. Markov D, Jacquemyn Y, Leroy Y: Bilateral cleft lip and palate associated with increased nuchal translucency and maternal cocaine abuse at 14 weeks of gestation. Clin Exp Obstet Gynecol 2003;30:109–110. 123. Durand DJ, Espinoza AM, Nickerson BG: Association between prenatal cocaine exposure and sudden infant death syndrome. J Pediatr 1990;117:909–911. 124. Noland JS, Singer LT, Mehta SK, et al: Prenatal cocaine/polydrug exposure and infant performance on an executive functioning task. Dev Neuropsychol 2003;24:499–517. 125. Keller RW Jr, Snyder-Keller A: Prenatal cocaine exposure. Ann NY Acad Sci 2000;909:217–232. 126. Bailey DN: Cocaine and cocaethylene binding to human milk. Am J Clin Pathol 1998;110:491–494. 127. Fiorelli RL, Manfrey SJ, Belkoff LH, et al: Priapism associated with intranasal cocaine abuse. J Urol 1990;143:584–585. 128. Myrick H, Markowitz JS, Henderson S: Priapism following trazodone overdose with cocaine use. Ann Clin Psychiatry 1998;10:81–83. 129. Kloss MW, Rosen GM, Rauckman EJ: Cocaine-mediated hepatotoxicity. A critical review. Biochem Pharmacol 1984;33:169–173. 130. Wanless IR, Dore S, Gopinath N, et al: Histopathology of cocaine hepatotoxicity. Report of four patients. Gastroenterology 1990;98:497–501. 131. Campos Franco J, Martinez Rey C, Perez Becerra E, et al: [Cocaine related fulminant liver failure.] Ann Med Interna 2002;19: 365–367.

Cocaine

771

132. Leissinger CA: Severe thrombocytopenia associated with cocaine use. Ann Intern Med 1990;112:708–710. 133. Weber JE, Larkin GL, Boe CT, et al: Effect of cocaine use on bone marrow-mediated erythropoiesis. Acad Emerg Med 2003;10: 705–708. 134. Di Paolo T, Rouillard C, Morissette M, et al: Endocrine and neurochemical actions of cocaine. Can J Physiol Pharmacol 1989;67:1177–1181. 135. Farre M, de la Torre R, Gonzalez ML, et al: Cocaine and alcohol interactions in humans: neuroendocrine effects and cocaethylene metabolism. J Pharmacol Exp Ther 1997;283:164–176. 136. Hollander JE, Levitt MA, Young GP, et al: The effect of cocaine on the specificity of cardiac markers. Am Heart J 1998;135:245–252. 137. Ambre J: The urinary excretion of cocaine and metabolites in humans: a kinetic analysis of published data. J Anal Toxicol 1985;9:241–245. 138. Weiss RD: Protracted elimination of cocaine metabolites in longterm high-dose cocaine abuse. Am J Med 1988;85:879–880. 139. Campora P, Bermejo AM, Tabernero MJ, et al: Quantitation of cocaine and its major metabolites in human saliva using gas chromatography-positive chemical ionization-mass spectrometry (GC-PCI-MS). J Anal Toxicol 2003;27:270–274. 140. Blaho K, Logan B, Winbery S, et al: Blood cocaine and metabolite concentrations, clinical findings, and outcome of patients presenting to an ED. Am J Emerg Med 2000;18:593–598. 141. Gitter MJ, Goldsmith SR, Dunbar DN, Sharkey SW: Cocaine and chest pain: clinical features and outcome of patients hospitalized to rule out myocardial infarction. Ann Intern Med 1991;115: 277–282. 142. Zimmerman JK, Dellinger RP, Majid PA: Cocaine-associated chest pain. Ann Emerg Med 1991;20:611–615. 143. McCarron MM, Wood JD: The cocaine “body-packer” syndrome: diagnosis and treatment. JAMA 1983;250:1417–1420. 144. Hoffman RS, Chiang WK, Weisman RS, et al: Prospective evaluation of “crack-vial” ingestions. Vet Hum Toxicol 1990;32: 164–166. 145. Marc B, Baud FJ, Aelion MJ, et al: The cocaine body-packer syndrome: evaluation of a method of contrast study of the bowel. J Forensic Sci 1990;35:345–355. 146. Tomaszewski C, McKinney P, Phillips S: Prevention of toxicity from oral cocaine by activated charcoal in mice. Ann Emerg Med 1993;22:1804–1806. 147. Caballero F, Lopez-Navidad A, Gomez M, et al: Successful transplantation of organs from a donor who died from acute cocaine intoxication. Clin Transplant 2003;17:89–92. 148. Kantak KM: Vaccines against drugs of abuse: a viable treatment option? Drugs 2003;63:341–352. 149. Deng SX, de Prada P, Landry DW: Anticocaine catalytic antibodies. J Immunol Methods 2002;269:299–310. 150. Baumann BM, Perrone J, Hornig SE, et al: Randomized, doubleblind, placebo-controlled trial of diazepam, nitroglycerin, or both for treatment of patients with potential cocaine-associated acute coronary syndrome. Acad Emerg Med 2000;7:878–885. 151. The American Heart Association in collaboration with the International Liaison Committee on Resuscitation: Guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care: toxicology in ECC. Circulation 2000;102(Suppl I): 223–228. 152. Albertson TE, Dawson A, de Latorre F, et al: TOX-ACLS: toxicologic-oriented advanced cardiac life support. Ann Emerg Med 2001;37(Suppl):78–90. 153. Negus BH, Willard JE, Hillis LD, et al: Alleviation of cocaineinduced coronary vasoconstriction with intravenous verapamil. Am J Cardiol 1994;73:510–513. 154. Sand IC, Brody SL, Wrenn KD, et al: Experience with esmolol for the treatment of cocaine associated cardiovascular complications. Am J Emerg Med 1991;9:161–163. 155. Boehrer JE, Moliterno DJ, Willard JE, et al: Influence of labetalol on cocaine-induced coronary vasoconstriction in humans. Am J Med 1993;94:608–610. 156. Beckman KJ, Parker RB, Hariman RJ, et al: Hemodynamic and electrophysiological actions of cocaine: effects of sodium bicarbonate as an antidote in dogs. Circulation 1991;83:1799–1807. 157. Winecoff AP, Hariman RJ, Grawe JJ, et al: Reversal of the electrocardiographic effects of cocaine by lidocaine. Part 1.

772

158. 159. 160.

161. 162.


Comparison with sodium bicarbonate and quinidine. Pharmacotherapy 1994;14:698–703. Shih RD, Hollander JE, Burstein JL, et al: Clinical safety of lidocaine in patients with cocaine-associated myocardial infarction. Ann Emerg Med 1995;26:702–706. Brogan WC III, Lange RA, Kim AS, et al: Alleviation of cocaineinduced coronary vasoconstriction by nitroglycerin. J Am Coll Cardiol 1991;18:581–586. Hollander JE, Burstein JL, Hoffman RS, et al: Cocaine-associated myocardial infarction. Clinical safety of thrombolytic therapy. Cocaine Associated Myocardial Infarction (CAMI) Study Group. Chest 1995;107:1237–1241. Derlet RW, Albertson TE: Diazepam in the prevention of seizures and death in cocaine-intoxicated rats. Ann Emerg Med 1989;18:542–546. Gasior M, Ungard JT, Witkin JM: Preclinical evaluation of newly approved and potential antiepileptic drugs against cocaineinduced seizures. J Pharmacol Exp Ther 1999;290:1148–1156.

163. Schaper A, Hofmann R, Ebbecke M, et al: [Cocaine-body-packing. Infrequent indication for laparotomy.] Chirurg 2003;74:626–631. 164. Klein C, Balash Y, Pollak L, et al: Body packer: cocaine intoxication, causing death, masked by concomitant administration of major tranquilizers. Eur J Neurol 2000;7:555–558. 165. Swan MC, Byrom R, Nicolaou M, et al: Cocaine by internal mail: two surgical cases. J R Soc Med 2003;96:188–189. 166. June R, Aks SE, Keys N, et al: Medical outcome of cocaine bodystuffers. J Emerg Med 2000;18:221–224. 167. Aldrighetti L, Paganelli M, Giacomelli M, et al: Conservative management of cocaine-packet ingestion: experience in Milan, the main Italian smuggling center of South American cocaine. Panminerva Med 1996;38:111–116. 168. Feist-Price S, Logan TK, Leukefeld C, et al: Targeting HIV prevention on African American crack and injection drug users. Subst Use Misuse 2003;38:1259–1284.

43

Dissociative Agents: Phencyclidine, Ketamine, and Dextromethorphan IVAN E. LIANG, MD ■ EDWARD W. BOYER, MD, PHD

■

■ ■ ■

Phencyclidine (phenylcyclohexyl piperidine, or PCP), ketamine [2-(O-chlorophenyl)-2-methylamino cyclohexanone], and dextromethorphan [(+)-3-methoxy-17methyl-9a,13a,14a-morphinan] (Fig. 43-1) are structurally related chemicals that are abused for their dissociative properties. Because these drugs are often used in club settings, the prevalence of their use may have increased dramatically over the past decade. Intoxication with these agents produces a syndrome of sympathetic activation, central nervous system depression, and hallucinations.

EPIDEMIOLOGY

Phencyclidine, ketamine, and dextromethorphan exert their psychotomimetic effects by antagonizing with high affinity the N-methyl-D-aspartate (NMDA) receptors in limbic and cortical structures, inhibiting the release of excitatory amino acid neurotransmitters.8,9 Dissociative drugs bind to the Ca2+ cation channel of the NMDA receptor to modulate glutamate neurotransmission, the end result of which is the production of specific neurobehavioral findings such as dissociative, “out-ofbody” experiences.7,9 When used for licit purposes such as procedural sedation, these experiences are known as “emergence reactions.” NMDA receptor antagonism may selectively interrupt association pathways of the brain before producing somesthetic sensory blockade, and may also selectively depress the thalamoneocortical system before depressing the reticular activating and limbic systems. Dissociative agents also produce dosedependent reuptake blockade of norepinephrine, dopamine, and serotonin, which contributes to the psychomotor, sympathomimetic, and psychotomimetic effects associated with these agents.9 In recreational doses, PCP, H3CO

J J

NH

J

J

J

Cl

J

N

J

J

O

J

J J

J

Accurate estimation of the abuse prevalence of phencyclidine, ketamine, and dextromethorphan is difficult. Because these substances are frequently taken in conjunction with other drugs, individuals suffering the effects of multiple drug use may present with a confusing clinical picture that prevents clinicians from accurately identifying the substances used. Nonetheless, the Drug Abuse Warning Network (DAWN) in 2003 identified a dramatic increase in the use of phencyclidine in several metropolitan areas. Data from the American Association of Poison Control Centers’ Toxic Exposure Surveillance System (TESS) in 2002 identified 918 phencyclidine exposures with 6 deaths.1 The DAWN data also observed significant increases in ketamine reports that were likely related to its abuse in party settings such as in raves and circuit parties. In 2002, TESS reported 342 ketamine exposures. Similarly, dextromethorphan was identified by DAWN as having a significantly increased prevalence of abuse. Data from TESS suggest that abuse or misuse of

NEUROPHARMACOLOGY

J

■

Phencyclidine, ketamine, and dextromethorphan are structurally related chemicals referred to as dissociative agents. The dissociative agents produce their psychotomimetic effects by antagonizing N-methyl-D-aspartate receptors in the central nervous system. Clinical effects of overdose include euphoria, a trance-like state, nystagmus, and, occasionally, violent behavior; hyperthermia, rhabdomyolysis, metabolic acidosis, and cardiovascular collapse may ensue. Coma and seizures may occur in severe overdose. Patients are often anesthetic and may be unaware of serious injuries. All of the dissociative agents may produce a positive urine toxicology screen for phencyclidine. Treatment for dissociative agent overdose is supportive. Benzodiazepines or haloperidol are preferred agents for chemical restraint.

J

■

the drug by adolescents between ages 13 and 19 has increased more than 300% over a 3-year period.2 Dextromethorphan abuse has been observed in children as young as 11.3 Dissociative agents are widely available in pill, powder, and injectable form. Phencyclidine is more commonly sold as a powder, but has been recently reported as an additive to marijuana cigarettes in metropolitan areas. Ketamine is difficult to synthesize; therefore, it is diverted from pharmaceutical or veterinary sources in injectable or powdered formulations.4 Abused dextromethorphan is commonly diverted from over-the-counter cough and cold products that are widely available in stores.4 Even individuals not intending to take dissociative agents may inadvertently receive them since ketamine and dextromethorphan are commonly used as adulterants in tablets purportedly containing methylenedioxymethamphetamine (MDMA, or “Ecstasy”).5-7

K

At a Glance…

H

J N

CH3

Phencyclidine (PCP) Ketamine Dextromethorphan FIGURE 43-1 Chemical structure of dissociative agents.

773

774


ketamine, and dextromethorphan (large via its active metabolite, dextrorphan) bind with high affinity to nonopiate σ receptors, which may contribute to their antinoceptive and sedative activities. As a nonanalgesic opiate, dextromethorphan produces antitussic activity by selectively binding to δ receptors without exhibiting classic opiate effects that occur from binding to μ and κ opiate receptors. In high doses, PCP and ketamine also bind to opioid and nicotine and muscarinic acetylcholine receptors.

PHENCYCLIDINE Phencyclidine (PCP, “angel dust,” “PeaCe Pill”) was originally marketed in 1957 as a preinduction anesthetic agent that was not associated with cardiorespiratory depression.10 Many patients in their postoperative course, however, developed extreme agitation and dysphoria.10 Phencyclidine therefore was removed from the marketplace, although it was reintroduced as the veterinary product Senylan (Parke-Davis, Detroit, MI). Phencyclidine emerged as a hallucinogen in the 1960s but did not reach full popularity until the 1970s.11,12 It was classified as a schedule I substance in 1978, and its use declined during the 1980s.13 Over the past 5 years, however, increasing numbers of PCP abusers appear to smoke the drug with another substance such as marijuana.14-17

Pharmacology Phencyclidine is a highly lipophilic, water-soluble weak base. It is rapidly absorbed following oral, intranasal, intramuscular, intravenous, pulmonary, or rectal administration. Absorption is minimal in the stomach, but occurs rapidly in the duodenum and jejunum.15,16 Onset of effects occurs within 30 to 60 minutes when ingested, but may be as rapid as 2 minutes after smoking.15 Acute toxicity often persists for 4 to 6 hours, and generally resolves within 48 hours.16 At oral doses of between 5 and 10 mg, toxic psychoses and violent behavior are described.18 Oral doses greater than 10 mg are associated with schizophreniform reactions, although the doseresponse relationship is incompletely defined.18 Phencyclidine distributes widely in tissues.16,18 It possesses an unusual enterogastric circulation in which significant amounts of the drug are actively secreted into the stomach and then reabsorbed in the small intestine.15 The concentration of PCP in gastric fluid may be 50 times higher than in the serum.15 The concentration in the brain may be up to nine times that of the serum.15,16 The slightly acidic milieu of the cerebrospinal fluid (CSF) induces ion trapping of the compound, an effect that explains the prolonged neurologic effects of the drug.16 The apparent volume of distribution of phencyclidine is 6.3 L/kg, and the drug is 78% protein bound.15 The large volume of distribution and lipophilicity contribute to PCP’s persistence in the body and its long duration of action. Phencyclidine is hepatically metabolized in a

stepwise manner, first by oxidative hydroxylation to an inactive metabolite that undergoes glucuronidation. This water-soluble derivative is the major metabolite that is renally eliminated. Significant first pass metabolism occurs after ingestion, an effect that is not observed following pulmonary or parenteral administration.15 More than 90% of users excrete metabolites in the urine for up to 7 days after exposure, while chronic abusers do so for up to 4 weeks after last use.19 Ten percent of an ingested dose is excreted unchanged in the urine.

Clinical Effects No therapeutic indications are described for PCP, although NMDA antagonists may have theoretical utility in preventing neuronal injury following cerebral hypoxic/ischemic insult.20,21 Phencyclidine exhibits a broad variety of clinical effects, some of which are unpredictable but which are generally dose related.21 Violent behavior, rotatory nystagmus, hypertension, anesthesia, and analgesia are the most characteristic signs of intoxication.21,22 At elevated doses, PCP will produce a dissociative condition characterized by a catatonic, trancelike state but may include a sense of euphoria, omnipotence, tremendous strength, and sexual prowess.23 Seizures are described at high doses, and coma may occur, persisting for up to 10 days.22 Lower doses of phencyclidine will produce ataxia, slurred speech, profuse diaphoresis, and neuromuscular rigidity.21 The most common causes of death from PCP overdose involve trauma or occur as the sequela of physical restraint of severely agitated patients, with attendant hypothermia, rhabdomyolysis, metabolic acidosis, and cardiovascular collapse.24 The neurologic examination may reveal horizontal, vertical, or rotatory nystagmus, a prominent finding that occurs in over half of all intoxicated patients.21,22 Pupils may be miotic and reactive, and reflexes are briskly hyperactive. Increased muscle strength is commonplace, and several attendants may be required to restrain agitated patients. Patients are anesthetic and are often unaware of injuries, a quality that results from the dissociative effects of the drug.22 Prominent psychiatric effects of phencyclidine include violent, aggressive behavior that, when combined with a sense of tremendous strength, is troublesome for caretakers.21 Patients may also demonstrate mania, but catatonia and visual hallucinations are common.25 Physiologic dependence on PCP in the absence of clear physiologic symptoms is described, as is an abstinence syndrome characterized by depression, anxiety, and irritability.26 Long-term PCP abuse is associated with diminished abstract thought and incidental memory.26 A temperature greater than 38.8ºC (101.8ºF) was identified in 2.6% of patient in one series of PCP intoxications.22 Hyperthermia in PCP overdose may arise from isometric muscle contraction and may portend significant morbidity.27 Elevations in serum transmamines, rhabdomyolysis, clotting abnormalities, hepatic injury, and renal failure probably arise as a consequence of poorly treated hyperthermia and muscle trauma.

CHAPTER 43

Dissociative Agents: Phencyclidine, Ketamine, and Dextromethorphan

Diagnosis The diagnosis of phencyclidine poisoning can be inferred from history and physical examination findings, and is confirmed by laboratory testing. Rotatory nystagmus is an important clinical clue to establishing the diagnosis.21,22 Because PCP is lipophilic and may be detected in the urine for up to 4 weeks, urine is the preferred specimen for detection.19 If present, PCP should elicit a positive result on qualitative urine toxicologic screen. Quantitative measurement of phencyclidine in plasma is not recommended because clinical signs and symptoms do not correlate well with plasma concentrations. Patients in whom phencyclidine intoxication is suspected should have electrolytes, blood urea nitrogen, creatinine, transaminases, coagulation times, glucose, and serum creatine phosphokinase concentrations measured. Hyperthermic patients deserve measurement of arterial pH. Clinicians should remain vigilant for electrolyte disturbances, metabolic acidosis, and renal failure.

KETAMINE Initially developed as a veterinary anesthetic, ketamine is structurally similar to PCP (see Fig. 43-1). Ketamine is often diverted from veterinary or pharmaceutical sources and is sold either in powdered or liquid form or as an adulterant in club drug (“Ecstasy”) pills.

Pharmacology The pharmacology of ketamine is similar to that of phencyclidine. Ketamine can be administered via oral, intranasal, intramuscular, intravenous, and rectal routes.28 Ketamine is a weakly basic amino compound (pKa of 7.5) with close structural similarity to phencyclidine.28 It is commercially available as 1:1 racemic mixtures of the S(+) and R(-) enantiomers of the hydrochloride salt. Ketamine undergoes rapid absorption via all routes and distributes within 7 to 10 minutes of intravenous administration into highly perfused tissues such as the brain, heart, and lungs. Concentrations in these organs may be four to five times greater than corresponding plasma levels. Ketamine then undergoes a second redistribution into muscle and, eventually, adipose with a distribution half-life of approximately 10 to 15 minutes.8,28-30 Ketamine and its metabolites are moderately protein bound in the serum 60%, 50%, and 69% for ketamine, norketamine, and dehydronorketamine, respectively, in human serum.31 Volumes of distribution of ketamine have been reported ranging from 2 to 5 L/kg.29 Ketamine undergoes significant first-pass metabolism via hepatic N-demethylation by CYP2D6 to produce norketamine, a compound with one third the activity of the parent compound.28,32,33 This metabolite is subsequently hydroxylated and conjugated to water-soluble compounds that undergo renal elimination. Approximately 90% of an administered ketamine dose is eliminated as the conjugated hydroxyl metabolite; about

775

4% is excreted unchanged. Interestingly, the elimination half-life is approximately 2.5 to 3 hours in adults, but only 1 to 2 hours in children.29,33 The onset of effects depends on the method of administration. In general, anesthetic or therapeutic doses of ketamine are between 1 and 2 mg/kg (approximately 1 mg for a 70-kg patient) for intravenous administration; the dose of ketamine used for recreational purposes is somewhat lower.29 Recreational doses begin at approximately 25 mg and are titrated upward to clinical effect. One method of titration, for example, involves insufflating approximately 25-mg “bumps” of ketamine until the user can no longer feel his or her legs. Clinical effects often resolve within 10 minutes of intraparenteral dosing, but may persist for up to 90 minutes after oral administration.32

Clinical Effects Recommended doses of 1 to 2 mg/kg intravenously, up to 4 mg/kg intramuscularly, and 7 mg/kg orally will produce anesthesia and analgesia accompanied by catalepsy with minimal purposeful response to noxious stimuli. The eyes often remain open, with a slow nystagmic gaze; corneal and light responses often remain normal.34 Hypertonic and occasionally purposeful movements may be intermittently noted.34 Subanesthetic doses will produce a spectrum of symptoms, but will often interfere with normal cognition and appropriate responses to environment.34 Ketamine evokes a number of physiologic responses besides anesthesia.28,30 The drug increases sympathetic outflow and effect that can be blunted by sedation with benzodiazepines.28,30 Ketamine produces elevated cerebrospinal fluid and intraocular pressures, although this effect may be abolished by maintenance of normocapnia and/or benzodiazepine administration.28 The salivary and tracheal-bronchial secretions that accompany ketamine administration are due to the drug’s cholinergic characteristics.28 Despite these secretions, ketamine has been associated with decreases in airway resistance and bronchospasm.28 Respiratory failure from massive doses of ketamine has been described, although this finding occurred in multiple drug use.28 Hallucinations that occur as ketamine anesthesia decreases are described as “emergence reactions” and are the reason for which the drug is diverted to illicit use.7,35 Drug users frequently describe cosmic, religious, or near death experiences, visualization of psychedelic colors, and out-of-body experiences that can be characterized as ranging from pleasurable to nightmarish.7 During the episode, patients may be mildly agitated, sympathomimetic, or frankly psychotic and delirious. Incidence of emergence reactions is low among children, but has been reported to be as high as 30% in adults.35

Diagnosis Establishing the diagnosis of ketamine intoxication requires the recognition of subtle physical examination findings. When used illicitly, ketamine does not, in general,

776


produce the extreme agitation of phencyclidine.35 Instead, intoxicated patients may demonstrate a distinctive, plodding gait as the legs dissociate from the remainder of the body.7 Patients may lose fine motor control and experience nausea and vomiting with movement. They may deliver pronouncements that are confusing to sober observers.7 In addition to the acute dissociative effects, ketamine is associated with dystonia, paranoia, and rhabdomyolysis.35 This latter finding occurs almost exclusively in patients who receive physical restraints without chemical sedation. Dependence on ketamine has been described. The chronic effects of ketamine abuse include poor concentration, inhibited learning capabilities, and decreased memory. Ketamine users have described “flashbacks” up to several months after use of the drug.7 In addition, habitual users describe tolerance to established doses of ketamine, which can be explained by the ability of ketamine to induce the expression of cytochrome P-450 enzyme subtypes.28 The diagnosis of ketamine intoxication may be confused by the observation that ketamine produces a false-positive result on qualitative urine assays for phencyclidine.36

DEXTROMETHORPHAN The easy availability of dextromethorphan in over-thecounter preparations contributes to its increasing abuse by younger adults. Data from the TESS database suggest that abuse or misuse of the drug has increased more than 300% over a 3-year period in adolescents between the ages of 13 and 19.2 Abused dextromethorphan products are sometimes known by users as “Triple C” from the three Cs whose imprint is used to identify some products that are preferred for abuse, but gelcap formulations of dextromethorphan are also called “Skittles” or “Red Hots” because of the similarity in appearance between the drug and the popular candies.37,38 Unwitting users may not recognize that some over-the-counter dextromethorphan formulations may contain acetaminophen or anticholinergic agents, which cause their own toxicity.

Pharmacology Dextromethorphan is available in oral formulation; it is well absorbed following ingestion with maximum serum concentrations at 2.5 hours.39 The major metabolite of dextromethorphan, dextrorphan, achieves peak plasma concentrations at 1.6 to 1.7 hours following ingestion.40 The volume of distribution of dextromethorphan in humans is not firmly established, but is thought to be large (5.0 to 6.7 L/kg).29 Dextromethorphan and its metabolites undergo renal elimination, with less than 0.1% of the drug being eliminated in the feces.29 The half-life of the parent compound is approximately 2 to 4 hours in individuals with normal metabolism. Dextromethorphan is metabolized by cytochrome CYP2D6. In humans, CYP2D6 is a genetically polymorphic enzyme responsible for metabolizing numerous

substances.41 Rapid metabolizers—those individuals with extensive CYP2D6 activity and, hence, increased rates of dextromethorphan metabolism—constitute about 85% of the U.S. population. Dextromethorphan undergoes 3-demethylation to dextrorphan and, to a lesser extent, N-demethylation to 3-methoxymorphinan.40,41 Both of these metabolites are further demethylated to 3-hydroxymorphinan. Dextrorphan is the active metabolite that produces neurobehavioral effects, while dextromethorphan does not exhibit the same actions. Dextromethorphan is therefore a prodrug, and the metabolic conversion of dextromethorphan to dextrorphan is an important determinant of the abuse potential of dextromethorphan in an individual. Experienced dextromethorphan users describe tachyphylaxis to the drug, but whether this effect is from alterations in cytochrome function or other effects is not known.

Clinical Effects The dose of ingested dextromethorphan determines the neurobehavioral outcome. Recreational users of dextromethorphan describe several intensities of effect from the drug, known as “plateaus.”42 The first plateau is a mild stimulant effect similar to that of methylenedioxyamphetamine. The second plateau is described as similar to a combination of concurrent ethanol and marijuana intoxication, although some users describe hallucinations as occurring at this stage.43 The third level is a dissociative, “out-of-body” state like that produced by a low recreational dose of ketamine, and the fourth plateau is a fully dissociative condition similar to that produced by ketamine intoxication.42 Neurobehavioral effects begin within 30 to 60 minutes of ingestion and persist for approximately 6 hours. To produce nominal effects from dextromethorphan—the first plateau—online drug encyclopedias such as Erowid (www.erowid.org) describe a dose of between 100 and 200 mg (1.5–2.5 mg/kg). The second plateau may be achieved with 200 to 400 mg (2.5–7.5 mg/kg), and the third plateau can be achieved with 300 to 600 mg (7.5–15 mg/kg) of the drug. An ingested dose of 600 to 1500 (>15 mg/kg) mg of dextromethorphan may produce a full-blown dissociative state. These doses depend on several factors, such as an individual’s CYP2D6 subtype and body weight as well as the degree of tolerance to dextromethorphan. The clinical presentation of dextromethorphan intoxication therefore depends on the ingested dose. Minimally intoxicated persons may develop tachycardia, hypertension, vomiting, mydriasis, diaphoresis, nystagmus, euphoria, loss of motor coordination, and giggling or laughing.42 In addition to the above findings, persons with moderate intoxication may demonstrate hallucinations and a distinctive, plodding ataxic gait that has been compared to “zombie-like” walking.43 Severely intoxicated individuals in a dissociated state may be agitated or somnolent.38,42,44,45 Extremely agitated patients may develop hyperthermia and metabolic acidosis. Experienced dextromethorphan users describe a rapidly developing and persistent tolerance to the drug.42 Dependence on dextromethorphan is rarely described.46-48

CHAPTER 43


Although dextromethorphan is not thought to have addictive properties, susceptible individuals may develop craving and habitual use of the drug.44,49 An abstinence syndrome may be associated with cessation of dextromethorphan abuse that is characterized by dysphoria and intense cravings.46,48,50,51 Toxic psychosis and cognitive deterioration may arise from chronic use of the drug.46,50,51 Toxicity in the setting of dextromethorphan abuse can arise from additional sources. Over-the-counter cough formulations frequently contain, in addition to dextromethorphan, other pharmaceutical agents such as chlorpheniramine, acetaminophen, or pseudoephedrine.52 Chlorpheniramine is an H1 receptor antagonist. Consequently, individuals who have abused chlorpheniraminecontaining dextromethorphan formulations may also exhibit anticholinergic signs and symptoms, such as tachycardia; warm, dry, flushed skin; dry mucosa; mydriasis; agitated delirium; urinary retention; and gastrointestinal dysmotility (see Chapter 39). Severe chlorpheniramine intoxication has also been associated with seizure activity, rhabdomyolysis, and hyperthermia.38 Pseudoephedrine intoxication may mimic that of chlorpheniramine except that patients may exhibit diaphoresis. In contrast, overdose of acetaminophen, an antipyretic and analgesic that is a component of over 100 cough and cold preparations, produces delayed hepatic injury and, potentially, death. Lastly, because dextromethorphan is produced as the crystalline hydrobromide salt, bromism is a rare consequence that has been identified in heavy chronic abusers of dextromethorphan.53 Drug interactions exist between dextromethorphan and other substances, the best characterized of which is serotonin syndrome. Dextromethorphan and its active metabolite, dextrorphan, block reuptake of serotonin in central nerve terminals. This condition typically occurs from the interaction between dextromethorphan and selective serotonin reuptake inhibitors or monoamine oxidase inhibitors, but concurrent administration of antibiotics (e.g., linezolide), opiate analgesics (e.g., meperidine and tramadol), or drugs of abuse (e.g., Syrian rue) could precipitate the condition.54 Patients with serotonin syndrome may demonstrate the clinical triad of mental status changes, autonomic instability, and muscular hypertonicity55 (see Chapters 10A and 29).

Diagnosis The diagnosis of dextromethorphan intoxication relies on epidemiologic, historical, and physical examination findings. Younger adolescents may be at increased risk for dextromethorphan abuse.56 In addition, data from the National Institute on Drug Abuse’s Community Epidemiology Working Group and other sources suggests that pharmaceutical abuse may be more prevalent among females.57-59 On history, patients may report the abuse of dextromethorphan-containing products. The diagnosis of dextromethorphan intoxication is otherwise made on clinical grounds, with attention directed to signs and symptoms of dissociative use: tachycardia, hypertension, diaphoresis, ataxia, nystagmus, and, potentially, hallucinations, but clinicians should remain

777

aware that specific findings depend on the degree to which individuals are intoxicated. The differential diagnosis of dextromethorphan intoxication includes other potentially serious toxidromes. Patients with ataxia, nystagmus, and mental status changes may suffer from ketamine or phencyclidine abuse, lithium intoxication, phenytoin or carbamazepine poisoning, serotonin syndrome, Wernicke-Korsakoff syndrome, and sedativehypnotic, including ethanol, abstinence syndromes.48 Although dextromethorphan does not produce true positive results on toxic screens or cross-react with the opiate portion of the screen, the molecule may produce false-positive results on qualitative urine assays for phencyclidine.60,61

TREATMENT Supportive management is often sufficient to care for dissociative agent overdose.38,45,62 Because airway reflexes are preserved in dissociative agent toxicity, relatively few patients require orotracheal intubation and airway support. Excessive airway secretions can be controlled by atropine or glycopyrrolate; clinicians should be aware that phencyclidine may hyperstimulate oropharyngeal musculature, and care should be taken to prevent laryngospasm during passage of an orotracheal tube. Basic emergency measures that include measurement of vital signs and intravascular access should be performed immediately. All patients should receive intravenous saline solution; this therapy corrects dehydration and prevents renal failure secondary to rhabdomyolysis from muscle breakdown. Hypertension and tachycardia may respond well to sedating agents such as diazepam, but nitroprusside may be necessary in patients who fail chemical sedation. Patients should receive sedation if necessary. Auditory, tactile, and visual stimuli should be minimized. The technique of “talking down” a patient, often applied effectively to ketamine and dextromethorphan overdose, is generally ineffective in PCP poisoning; the practice may even provoke hostile behavior in PCP-poisoned patients. Combative or hostile patients should receive chemical sedation with either benzodiazepines or phenothiazines. The preferred agent is intravenous lorazepam (initial dose 0.1 mg/kg, total dose titrated to desired level of sedation). However, intramuscular haloperidol (5 to 10 mg) has been demonstrated to improve schizophreniform symptoms seen in PCP poisoning. Notably, phenothiazines may produce unintended adverse reactions such as anticholinergic reactions, dystonia, or seizure activity. These adverse reactions are, however, rare. Physical restraints are highly undesirable and may contribute to mortality by enforcing isometric muscle contractions that are associated with severe lactic acidosis and hyperthermia.27 If used, physical restraints must be rapidly replaced with chemical sedation. Hyperthermia and metabolic acidosis arise from excess muscle activity; treatment of these findings may require neuromuscular blockage and mechanical ventilation. Although benzodiazepines have a beneficial

778


effect in moderate cases, severely ill, hyperthermic patients (T ≥ 40º C) should receive immediate paralysis with nondepolarizing agents such as vecuronium followed by orotracheal intubation and ventilation. Clinicians should avoid succinylcholine because of the risks of arrhythmia from rhabdomyolysis-associated hyperkalemia. There is no role for antipyretics in the management of hyperthermia from dissociative agent overdose; the increase in body temperature is due to muscular activity, not an alteration in the hypothalamic temperature set point. Activated charcoal is indicated in cases of recent dextromethorphan ingestion (e.g., less than 1 hour after ingestion), but is of unclear benefit in PCP or ketamine toxicity since these agents are infrequently administered via oral routes. Because PCP is actively secreted in the stomach, multiple-dose activated charcoal may offer some benefit, although its efficacy has not been rigorously established. Continuous gastric suctioning has also been recommended for evacuating PCP-laden secretions. Close monitoring of electrolytes is warranted since continuous suctioning may remove potassium, hydrogen, and other essential ions. There are no antidotes for dissociative agent poisoning. Respiratory depression, rarely described in severe dextromethorphan intoxication, intermittently responds to high-dose intravenous naloxone.48 Clinicians should consider physostigmine to reverse anticholinergic signs if present. Laboratory assessment of intoxicated individuals should include measurement of serum electrolytes, hepatic and renal function, acid–base status, serum creatinine phosphokinase, a toxic screen, and urinalysis. In addition, physicians should always measure the serum acetaminophen concentration and treat potentially toxic concentrations or hepatic injury with N-acetylcysteine.

REFERENCES 1. Litovitz T, Klein-Schwartz W, Caravati E: 2002 Annual report of the American Association of Poison Control Centers toxic exposure surveillance system. Am J Emerg Med 2003;22:517–575. 2. Watson W: TESS Dextromethorphan Data. Washington, DC, American Association of Poison Control Centers, 2003. 3. Boyer EW: 2003 Poisoning Data. Boston, Massachusetts Poison Control Center, 2003. 4. Anonymous: Trouble in the medicine chest (I): Rx drug abuse growing. Prevention Alert 2003;6. 5. Boyer E, Quang L, Woolf A, Shannon M, Magnani B: Dextromethorphan and ecstasy pills. JAMA 2001;285:409–410. 6. Baggott M, Heifets B, Jones R, Mendelson J, et al: Chemical analysis of ecstasy pills. JAMA 2000;284:2190. 7. Boyer EW, Woolf AW: What’s new on the street. Clin Pediatr Emerg Med 2000;1:12–15. 8. Kohrs R, Durieux M: Ketamine: teaching an old drug new tricks. Anesth Analg 1998;87:1186–1193. 9. Lindefors N, Barati S, O’Connor W: Differential effects of single and repeated ketamine administration on dopamine, serotonin, and GABA transmission in rat medial prefrontal cortex. Brain Res 1997;759:205. 10. Pradhan S: Phencyclidine (PCP): some human studies. Neurosci Behav Physiol 1984;8:493–501. 11. Lundberg G, Gupta R, Montgomery M: Phencyclidine (PCP): patterns seen in street drug analysis. J Toxicol Clin Toxicol 1976;9:503–510.

12. Rainey J, Crowder M: Prevalence of phencyclidine in street drug preparations. N Engl J Med 1974;290:466–467. 13. Bailey D: Phencyclidine detection during toxicology testing of a university medical patient population. J Toxicol Clin Toxicol 1987;25:517–526. 14. O’Brien M: Emerging trends in drug use. Presented at the CEWG Annual Conference, Atlanta, GA, December 9–12, 2003. Bethesda, MD, National Institute on Drug Abuse. 15. Showalter C, Thornton W: Clinical pharmacology of phencyclidine toxicity. Am J Psychiatry 1977;134:1234–1238. 16. Misra A, Pontani R, Bartolomeo J: Persistence of phencyclidine and metabolites in brain and adipose tissue and implications for long-lasting behavioral effects. Res Commun Chem Pathol Pharmacol 1979;24:431–435. 17. Holland J, Nelson L, Ravikumar P: Embalming-fluid soaked marijuana: a new high or new guise for PCP? J Psychoactive Drugs 1998;30:215–219. 18. Cook C, Brine D, Quin G: Phencyclidine and phenylcyclohexane disposition after smoking phencyclidine. Clin Pharmacol Ther 1982;31:635–641. 19. Simpson G, Khajawall A: Urinary phencyclidine excretion in chronic abusers. J Toxicol Clin Toxicol 1982;19:1051–1059. 20. Liden C, Lovejoy F: Phencyclidine: nine cases of poisoning. JAMA 1975;234:513–516. 21. McCarron M, Schulze B, Thompson G: Acute phencyclidine intoxication: clinical patterns, complications, and treatment. Ann Emerg Med 1981;10:290–297. 22. McCarron M, Schulze B, Thompson G: Acute phencyclidine intoxication: incidence of clinical findings in 1000 cases. Ann Emerg Med 1981;10:232–242. 23. Burns R, Lerner S: Perspectives: acute phencyclidine intoxication. Clin Toxicol 1976;9:477–501. 24. Heilig S, Diller J, Nelson F: A study of 44 PCP related deaths. Int J Addiction 1982;17:1175–1184. 25. Balster R: Clinical implications of behavioral pharmacol-ogy research on phencyclidine. NIDA Res Monogr 1986;64:148–162. 26. Rawson R, Tennant F, McCann M: Characteristics of 68 chronic phencyclidine users who sought treatment. Drug Alcohol Depend 1981;8:223–227. 27. Hick J, Smith S, Lynch M: Metabolic acidosis in restraint-associated cardiac arrest: a case series. Acad Emerg Med 1999;6:239–245. 28. White P: Ketamine: its pharmacology and therapeutic uses. Anesthesiology 1982;56:119–136. 29. Baselt R, Cravey R: Disposition of Toxic Drugs and Chemicals in Man. Chicago, Yearbook Medical Publishers, 1989. 30. Reich D, Silvay G: Ketamine: an update on the first twenty-five years of clinical experience. Can J Anaesth 1989;36:186–197. 31. Hajazi Y, Boulieu R: Protein binding of ketamine and its active metabolites to human serum. Eur J Clin Pharmacol 2002;58: 37–40. 32. Grant I, Nimmo W, Clements J: Pharmacokinetics and analgesic effects of intramuscular and oral ketamine. Br J Anaesth 1981;53:805–810. 33. Grant I, Nimmo W, Clements J: Ketamine disposition in children and adults. Br J Anaesth 1983;55:1107–1111. 34. Weiner A, Vieira L, McKay C, Bayer M: Ketamine abusers presenting to the emergency department: a case series. J Emerg Med 2000;18:447–451. 35. Green S, Li J: Ketamine in adults: what emergency physicians need to know about patient selection and emergence reactions. Acad Emerg Med 2000;7:278–281. 36. Shannon M: Recent ketamine administration can produce urine toxic screen which is falsely positive for phencyclidine. Pediatr Emerg Care 1998;14:180. 37. Boyer EW: Dextromethorphan abuse. Pediatr Emerg Care 2004; 20:858–863. 38. Kirages T, Sule H, Mycyk M: Severe manifestations of coricidin intoxication. Am J Emerg Med 2003;21:648–651. 39. Barnhart J, Massad E: Determination of dextromethorphan in serum by gas chromatography. J Chromatogr 1979;163:390–395. 40. Silvasti M, Karttunen P, Tukiannen H: Pharmacokinetics of dextromethorphan and dextrorphan: a single dose comparison of three preparations in human volunteers. Int J Clin Pharmacol Ther 1987;9:493–497.

CHAPTER 43


41. Schadel M, Wu D, Otton S, et al: Pharmacokinetics of dextromethorphan and metabolites in humans: influence of the CYP2D6 phenotype and quinidine inhibition. J Clin Psychopharmacol 1995;15:263–269. 42. White W: DXM FAQ. Vol. 2004: Erowid, www.erowid.org, 1995. 43. Anonymous: RFG’s guide to DXM (dextromethorphan). Vol. 2004: DXM Harm Reduction Project, www.dextromethorphan.ws, 2004. 44. Banerji S, Anderson I: Abuse of Coricidin HBP Cough & Cold: episodes recorded by a poison center. Am J Health System Pharmacy 2001;58:1811–1814. 45. Graudins A, Ferm R: Acute dystonia in a child associated with therapeutic ingestion of a dextromethorphan-containing cough and cold syrup. J Toxicol Clin Toxicol 1996;34:351–352. 46. Hinsberger A, Sharma V: Cognitive deterioration from long-term abuse of dextromethorphan: a case report. J Psychiatry Neurosci 1994;19:375–377. 47. Fleming P: Dependence on dextromethorphan. BMJ 1986; 293:597. 48. Wolfe T, Caravati E: Massive dextromethorphan ingestion and abuse. Am J Emerg Med 1995;13:174–176. 49. Nicholson K, Hayes B, Balster R: Evaluation of the reinforcing properties and phencyclidine-like discriminative stimulus effects of dextromethorphan and dextrorphan in rates and rhesus monkeys. Psychopharmacology 1999;146:49–59. 50. Dodds A: Toxic psychosis due to dextromethorphan. Med J Aust 1967;2:231. 51. Schadel M, Sellers E: Psychosis with Vicks Formula 44-D abuse. Can Med Assoc J 1992;147:843–844.

779

52. Helfer J, Kim O: Psychoactive abuse potential of Robitussin-DM. Am J Psychiatry 1990;147:672–673. 53. Ng Y, Lin W, Chen T, Tsai S: Spurious hyperchloremia and decreased anion gap in a patient with dextromethorphan bromide. Am J Nephrol 1992;12:268–270. 54. Bowdle T: Adverse effects of opioid agonists and agonistantagonists in anaesthesia. Drug Saf 1998;19:173–189. 55. Shannon M: Methylenedioxymethamphetamine. Pediatr Emerg Care 2000;16:377–380. 56. Baker D, Borys D: Coricidin use and abuse in Texas during 1998 and 1999. J Toxicol Clin Toxicol 2000;38:533. 57. Anonymous: Group discussion: pharmaceutical abuse. Presented at the CEWG Annual Conference, Atlanta, GA, December 9–12, 2003. Bethesda, MD: National Institute on Drug Abuse. 58. Cutler S: Philadelphia report. Presented at the CEWG Annual Conference, Atlanta, GA, December 9–12, 2003. Bethesda, MD: National Institute on Drug Abuse. 59. Dooley D: Boston report. Presented at the CEWG Annual Meeting, Atlanta, GA, December 9–12, 2003. Bethesda, MD: National Institute on Drug Abuse. 60. Darboe M, Keenan G, Richards T: The abuse of dextromethorphan: a pilot study of the community of Waynesboro, PA. Adolescence 1996;31:633–644. 61. Schier J, Diaz J: Avoid unfavorable consequences: dextromethorphan can bring about a false-positive phencyclidine urine drug screen. J Emerg Med 2000;18:379–380. 62. Henretig F, Cugini D, Dubin D: Dextromethorphan overdose in children. Vet Hum Toxicol 1988;3:364.

44

Amphetamines and Derivatives TIMOTHY E. ALBERTSON, MD, MPH, PHD ■ NICHOLAS J. KENYON, MD ■ BRIAN MORRISSEY, MD

At a Glance… ■

■ ■

■ ■

Amphetamine abuse and toxicity account for significant morbidity, mortality, and emergency medicine and intensive care unit admissions. The impact of amphetamine toxicity is amplified by its association with violent crime and trauma. The ability of the various amphetamine-related compounds to cause significant behavioral and multiple organ system dysfunction contributes to the clinical challenge. After decontamination, treatment is primarily supportive. Community education and prevention approaches can reduce the incidence of this increasing problem.

enhanced intellectual performance with use of the inhaler.4,5 Because of reports of medical complications, amphetamines became prescription drugs in the United States in 1938; however, inhalers initially remained available without prescription. Limited use and abuse of amphetamine and related compounds continued until World War II, when they were extensively used by the Allies and the Axis powers as stimulants in combat. DAmphetamine is still used by the U.S. military as a “go pill” for sustained operations and during deployments, and often followed by a benzodiazepine as a “no go pill.” The psychologically addicting characteristics were first realized when amphetamine abuse became epidemic in

BOX 44-1

INTRODUCTION AND RELEVANT HISTORY Amphetamines and related stimulant compounds represent an increasingly important class of recreational drugs of abuse in the United States as well as in many other parts of the world. In some locales, they rival cocaine as a cause of drug-related Emergency Department (ED) and intensive care unit (ICU) admissions. Although altered mental status, psychiatric disorders, and cardiovascular symptoms are most commonly encountered with amphetamine use, toxic manifestations in nearly every organ system have been reported (Box 44-1). The amphetamine-like compounds have a long medical history. Related phenylisopropylamines including the alkaloids ephedrine, obtained from Ephedra mahuang, and norpseudoephedrine, or cathine, obtained from Catha edulis, have been used for more than 5000 years in China and 600 years in East Africa, respectively.1 Ephedrine was classified as a food additive in the United States. Because of this classification, the Food and Drug Administration (FDA) had little regulatory jurisdiction over it. Documentation of increasing cases of toxicity and deaths associated with its use resulted in an FDA ban of ephedrine in April 2004. Although racemic β-phenylisopropylamine was first synthesized in 1887, initial investigations into the pharmacology of amphetamine derived from the basic phenylethylamine structure (Fig. 44-1) were not reported until 1930 by Piness.2,3 Early medicinal uses of amphetamine included the treatment of rhinitis and asthma.1 The Smith, Kline and French Pharmaceutical Company introduced the Benzedrine Nasal Inhaler in the United States in 1932. Each inhaler contained 250 mg of synthetic racemic amphetamine base with menthol and various other aromatics.4 Abuse of amphetamines was quickly noted and increased with a 1936 report claiming

MAJOR SIGNS, SYMPTOMS, AND NONINFECTIOUS MEDICAL COMPLICATIONS ASSOCIATED WITH USE OF AMPHETAMINES AND RELATED COMPOUNDS

Cardiac

Chest pain Myocardial infarction Palpitations Arrhythmias Cardiomyopathy Myocarditis Hypertension Sudden death

Neurologic

+++ + ++ ++ + + ++ +

Headaches Seizures Cerebral infarcts/strokes Cerebral vasculitis Cerebral edema Mydriasis Cerebral hemorrhage Subarachnoid Intraventricular Intracerebral

+++ ++ ++ +++

Pulmonary edema Dyspnea Bronchitis Pulmonary hypertension Hemoptysis Pleuritic chest pain Asthma exacerbations Pulmonary granuloma

Psychiatric

Anxiety Depression Paranoia Delirium/ hallucinations Psychosis Suicide Aggressive behavior Euphoria/ hyperactivity Irritability

+ ++ ++ ++ + ++ ++ ++ +++ ++

Respiratory

+++ ++ ++ ++

+ ++ + + + ++ + +

++ Other

Hyperpyrexia Renal failure Ischemic colitis Obstetric complications Anorexia/weight loss Rhabdomyolysis Nausea/vomiting Disseminated vasculitis

++ + + ++ +++ ++ + +

Estimated frequency of events: +, reported rare case; ++, commonly reported; +++, frequently seen or reported with chronic use or overdose.

781

782


Phenylethylamine 2 3 4 5

1

b

a

Amphetamine

Methamphetamine

NH2

NH2

NH

CH3

6

CH3

CH3

3,4-Methylenedioxymethamphetamine (MDMA)

Ephedrine

OH

NH

O NH CH3

CH3

O

CH3

CH3 3,4-Methylenedioxyamphetamine (MDA)

O O

4-Methyl-2,5Dimethoxyphenylethylamine (DOM/STP)

H3CO

NH2

NH2

CH3 CH3 H3C H3CO

FIGURE 44-1 Chemical structures of several amphetamine-like compounds. The basic phenylethylamine structure is labeled. Both α and β side chain positions and the phenyl ring itself can be modified to alter the pharmacologic effects of these related compounds.

several countries including Japan and Sweden after World War II.6 The 1950s and 1960s brought widespread abuse of amphetamines to the United States. Abuse was initially limited to use as an anorectic or as a stimulant in an effort to improve intellectual and physical performance or to combat fatigue.7 A second pattern of abuse emerged later, with recreational use of amphetamines in an attempt to achieve a euphoric state.7 In addition to oral use, nasal and intravenous routes were popularized at this time. Large amounts of amphetamines were legally produced in the United States, peaking in 1965 with more than 10 billion pills (10,000 kg) manufactured.7 Much of this amphetamine was diverted from legitimate pharmaceutical sales, mainly for the treatment of obesity, to illicit street use. Additional amphetamine-like compounds that have emerged have limited proven medical uses and varying abuse potential (Box 44-2). Compounds such as methamphetamine, propylhexedrine, aminorex fumarate, fenfluramine, and methylphenidate (Ritalin) are a few of these agents. After the passage of the Controlled Substances Act of 1970, manufacture and distribution of amphetamines were better regulated in the United States, and legal production was markedly reduced.7 The use of the phenethylamine derivative and amphetamine-like compound methylphenidate (Ritalin) has increased over the last 20 years primarily for the treatment of attention-deficit hyperactivity disorder (ADHD) in children and increasingly in adults. Toxic effects are similar to those of other amphetamines with agitation, tachycardia, and lethargy being the most

BOX 44-2

AMPHETAMINES AND RELATED COMPOUNDS

Aminorex fumarate Amphetamine Benzphetamine 4-Bromo-2,5-methoxyphenylethylamine (2-CB/MFT) Cathinone (khat) Cinnamedrine Desoxyphedrine Dextroamphetamine Diethylpropion 4-Bromo-2,5-dimethoxyamphetamine (DOB) 4-Methyl-2,5-dimethoxyamphetamine (DOM/STP) Fenfluramine Mescaline (3,4,5-trimethoxyphenylethylamine) 3,4-Methylenedioxyamphetamine (MDA) 3,4-Methylenedioxyethamphetamine (MDEA) 3,4-Methylenedioxymethamphetamine (MDMA) Methamphetamine Methcathinone Methylphenidate Methoxyamphetamine (PMA) Pemoline Phendimetrazine Phenmetrazine Phentermine Phenylephrine Phenylethylamine Phenylpropanolamine Propylhexadrine Pseudoephedrine

common symptoms.8 Exposures in children tend to be due to dosing errors or ingestion of a sibling’s drug. Teenage and adult exposures tend to be associated with abuse or suicide attempts. With reduced amounts of diverted pharmaceuticalgrade amphetamines such as D-amphetamine (Dexedrine), large-scale illegal manufacture and illegal importation of amphetamines began. Methamphetamine is synthesized easily in crude street laboratories from readily available precursors such as L-ephedrine.6 Methamphetamine provides illicit users with equal or longer acting stimulant and euphoric action than that of D-amphetamine. During the past 20 years, “designer” illicit amphetamines have enjoyed popularity on the street (see Box 44-2).

EPIDEMIOLOGY Colorful names have been used to refer to methamphetamines on the street, including “meth,” “speed,” “crystal,” and “crank.” Studies in the late 1980s established the illicit manufacture of methamphetamine to be a 3 billion dollar per year industry in the United States, localized primarily in Hawaii, California, Oregon, and Texas.1 By the early 1990s, the crude techniques had given way to illicit manufacturers who were able to synthesize very pure methamphetamine. A 99% to 100% pure form of methamphetamine called “ice” (because of

CHAPTER 44

its purity) demonstrates increased volatility when heated. Inhaling these volatile vapors, or “smoking meth,” provides the same “rush” as IV use of methamphetamine. Increasing use has been noted in many western states, and nearly epidemic use is reported in some parts of Hawaii and California. Death associated with amphetamine use has been frequently reported the past 25 years to the present.9-11 These deaths are often associated with assault, suicide, or homicide.9,10 Cocaine was involved in one fifth and methamphetamine in about one eighth of all homicides in San Diego County in 1987.12 By 1989, methamphetamine accounted for 60% of illicit drug seizures by San Diego County law enforcement agencies and 40% of all drug rehabilitation referrals in the area.13 A large university teaching hospital in San Diego found an increase in the detection of amphetamine compounds on toxicology screens from 3% to 10% of all tests during a 7- to 8-year period.14 Predominantly men (56%) between the ages of 21 and 30 years (61%) had positive results.14 Between 1986 and 1988, a 1.7-fold increase in ED visits for methamphetamine abuse was reported nationwide.13 White males that are unemployed and of low income are most likely to use methamphetamine.15 Abuse of methcathinone, a cathinone-methamphetamine analog easily made as an oxidative product of ephedrine, has been widely reported in Russia and most recently in the midwestern United States. p-Methoxyamphetamine (PMA) is a substituted synthetic amphetamine used in the recreational drug culture including at “raves.” A number of fatal overdoses of this drug have been reported in South Australia and the United States.16-18 Stimulants are used differently in different regions. In California in 2003, the DEA identified methamphetamine as the primary drug threat, with MDMA (“ecstasy”) as the most popular “club” or “rave” drug.19 The 2002 federal drug seizures in California alone included 9551 kg of cocaine and 311.2 kg of methamphetamine along with the destruction of 1718 clandestine drug laboratories. In contrast, in Florida in 2002, 26,258 kg of cocaine and only 103.1 kg of methamphetamine were seized. A 2000 report noted that more than 35 million individuals abuse amphetamines compared with approximately 15 million who regularly abuse cocaine worldwide.20

Amphetamines and Derivatives

783

acting compound with more profound euphoric action. The appetite suppression effect is unchanged.

PHARMACOLOGY AND PATHOPHYSIOLOGY Amphetamines have complicated and diverse pharmacologic mechanisms. They work primarily (as indirect sympathomimetics) by affecting the release of catecholamines at the neuronal presynaptic terminal.1-3 Amphetamines and related compounds work indirectly to cause neuronal stimulation by increasing postsynaptic catecholamines. This is accomplished by blocking the presynaptic uptake transport activity from the synaptic cleft, by blocking presynaptic vesicular storage, and by reducing cytoplasmic destruction of catecholamines by inhibiting mitochondrial monoamine oxidase.1-3 Together these activities increase the rate of postsynaptic receptor stimulation. Both central and peripheral norepinephrine and dopamine neurotransmitters are affected. Some amphetamine-related compounds (e.g., ephedrine) are thought also to have the ability to directly stimulate sympathetic receptors (direct sympathomimetics), but this is probably not a major mechanism of action for most of these compounds.7 Amphetamines lack the local anesthetic effects of cocaine on cardiac and nervous tissue. The catecholamine toxicity of amphetamines is similar qualitatively to that of cocaine. Increased norepinephrine postsynaptically causes sympathetic nervous system stimulation. This results in bronchodilation and increased heart rate, cardiac output, pupil size, and blood pressure, all of which are seen in the fight-or-flight response.1 The central nervous system (CNS) effects of amphetamine appear to be mediated primarily by dopaminergic alterations, which cause changes in mood, excitation, motor movements, and appetite.1 Some evidence suggests that repeated high-dose amphetamine exposure in both adults and fetuses or neonates results in long-lasting destruction or depletion of central dopamine neurons.1 Further alteration in mood, psychotic behavior, and aggressiveness may be the result of CNS serotonin release or reuptake blockade.2 The extent to which serotonin neurotransmission alterations function in the clinical manifestations of amphetamine toxicity is controversial.1-3

STRUCTURE AND STRUCTURE-ACTIVITY RELATIONSHIPS

PHARMACOKINETICS

As noted above, the various “designer” illicit amphetamines (see Box 44-2) have additional hallucinogenic properties gained by methoxyl group substitutions on the phenyl ring, especially at the 3,4 position (see Fig. 44-1). These drugs include agents such as 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), and 2,5-dimethoxy-4-methylamphetamine (DOM). These agents have had intermittent popularity on the streets of various communities. The addition of the methyl group on the nitrogen of Damphetamine generates methamphetamine, a longer

Amphetamines are weak bases with pKa values around 8.8 to 10.4. For example, amphetamine has a pKa of 9.9.7,21 Amphetamines are easily absorbed across most biologic membranes including gut, airway, nasopharynx, muscle, and vagina. Peak plasma concentrations occur in minutes by the intravenous route, in about 30 minutes by the intramuscular or topical nasal route, and within 2 to 3 hours after ingestion.7 Tissue redistribution is extensive, and the high lipid solubility of the amphetamines leads to increased concentrations relative to serum in the liver, kidneys, and lungs. This results in

784


large volumes of distribution ranging from 3 to 6 L/kg for amphetamine, phentermine, and phenylephrine and 12 to 33 L/kg for fenfluramine and methylphenidate.7 Cerebrospinal fluid levels are about 80% of plasma levels at steady state. Therapeutic levels of amphetamine itself range between 30 and 40 ng/mL (0.030 to 0.040 mg/L), and death is associated with average levels of 8600 (range, 500 to 44,000) ng/mL in the blood.7,21 Wide variations in doses and blood levels are reported to cause toxicity. This is in part related to the tolerance to amphetamines that can develop. The serum half-lives of various amphetamine-related compounds are urine pH dependent and range between 7 and 34 hours.21 The more acidic the urine, the shorter the half-life because of reduced renal reabsorption of ionized urinary amphetamines. This leads to increased renal clearance of the iodized amphetamines. Both active and inactive metabolites exist. Metabolism that results in aromatic hydroxylation, aliphatic hydroxylation, and n-dealkylation of amphetamines can give rise to active metabolites such as the potent hallucinogen p-hydroxyamphetamine.7 Other metabolic pathways, including deamination and subsequent side chain oxidation, produce inactive amphetamine derivatives.7 Glucuronide and glycine conjugation pathways result in urinary excretion of metabolites.21 As much as 30% of amphetamine is excreted unchanged in the urine, whereas between 86% and 97% of ephedrine, pseudoephedrine, and phenylpropanolamine is excreted unchanged.7,21

Methylphenidate is metabolized by various pathways to ritalinic acid, p-hydroxymethylphenidate, or lactam. Increasing evidence suggests that the co-ingestion of ethanol and methylphenidate results in the novel metabolite ethylphenidate that may contribute to its toxicity.22,23 Concomitant use of drugs such as the opiates (“speedballing”) can increase the overall toxicity of amphetamines. However, major alterations of the metabolic pathways of amphetamine have not been postulated as an explanation for the increased toxicity.21 Simultaneous use of methamphetamine and ethanol has more psychological and cardiac effects than use of methamphetamine alone. This response also is presumed to be pharmacodynamic in nature rather than a result of any specific pharmacokinetic interaction.24

TOXICOLOGY The amphetamines can cause toxic effects to every organ system. Both acute and chronic and direct and indirect abnormalities have been reported. Figure 44-2 summarizes the clinical presentation of acute amphetamine toxicity. The exact prevalence and incidence of the toxicities summarized in Box 44-1 have not been determined and probably vary with route, dose, and length of exposure to each of the amphetamine-related agents.

Altered consciousness Dilated pupils Nausea/vomiting Confusion Aggressive behavior Stroke Psychosis Seizures Coma

Tachypnea Pulmonary edema Pleuritic chest pain Hemoptysis

Ulcers Ischemic colitis Anorexia/weight loss

FIGURE 44-2 Major signs and symptoms associated with acute amphetamine toxicity.

Tachycardia Hypertension Hypotension Dysrhythmias (atrial or ventricular)

Renal failure

Rhabdomyolysis DIC Hyperpyrexia Obstetrical complications

CHAPTER 44

Central Nervous System Toxicity The CNS is the target organ for the pharmacologic effects of most amphetamine-related compounds. As such, significant CNS toxicity can result from use of amphetamines. With the resurgence of amphetamines as drugs of abuse in the 1960s, it was quickly recognized that the initial sensation of extreme physical and mental powers following amphetamine use could rapidly deteriorate with high doses or chronic moderate doses to recurrent affective lability, confusion, and hallucinations.25,26 In a series of 127 amphetaminepoisoned patients presenting to an ED, 57% were determined to have altered mental status.27 Agitation, suicidal ideation, hallucinations, delusions, confusion, and despondent affect were the most common major signs and symptoms noted. The presenting manifestations of headache affected 4%, seizure 3%, and paresthesia 2%.27 An additional 10% were unresponsive.27 Tolerance to the autonomic effects of amphetamine has been reported for body temperature, blood pressure, heart rate, and respirations. The anorectic effects of amphetamines exhibit tolerance as well.28 In contrast, the motor stimulant and stereotypic behavior effects of amphetamine display progressive enhancement with repeated intermittent administration.28 This is termed behavioral sensitization or reverse tolerance. Researchers have postulated that the acute paranoid delusional psychosis associated with amphetamine use may produce a psychosis similar to schizophrenia that persists through behavioral sensitization long after elimination of the amphetamine.29 Whether this represents emergence of an underlying psychiatric disorder or simply a lowering of the threshold for druginduced psychosis is not known.30,31 When challenged with large doses of IV methamphetamine, patients dependent on amphetamine developed drug-induced psychosis.31 This same dose of methamphetamine failed to produce drug-induced psychosis in non–amphetamine users.31 Drug-induced psychotic states have been reported with abuse of most of the stimulant amphetaminerelated compounds, including cathinone, pemoline, and phenmetrazine.32-34 Psychosis is common with derivatives of amphetamine that are hallucinogens, such as mescaline, DOM, MDA, p-methoxyamphetamine, and MDMA.33 Although tolerance to the hallucinogenic properties of these agents has been noted, prolonged psychotic reactions are also well documented.33 Acute severe hallucinations with bizarre and risky behavior due to the use of agents such as MDA, MDMA, and 3,4methylenedioxyethamphetamine have resulted in traumatic deaths.35 Mild to moderate amphetamineinduced agitated behavior and psychosis can be treated with benzodiazepines (e.g., diazepam or lorazepam), but severe symptoms should be treated with high-potency antipsychotic agents (e.g., haloperidol, droperidol, or thiothixene).7,27,36 Minimizing sensory stimuli with low doses of benzodiazepines in combination with low doses of antipsychotic agents has been a useful approach to amphetamine-induced psychosis.


785

In addition to behavioral effects including agitation, hallucinations, and psychosis, amphetamine use is associated with several other neurologic toxicities. Amphetamine-induced changes in sexual function and performance including enhancement and inhibition are complicated and have been reviewed.37 Cases of juvenile parkinsonism associated with MDMA have been reported.38 Positron-emission tomography (PET) scans suggest that amphetamine compounds have profiles of binding to the dopamine transporter and changes in synaptic dopamine levels similar to cocaine.39 The chorea of patients with Huntington’s disease is exacerbated by use of amphetamines.40 The dopaminergic receptor blocker haloperidol was shown to inhibit the amphetamine-induced exacerbation of the choreoathetoid movements.40 Choreoathetoid movement disorders have also been seen with acute and chronic amphetamine exposures in patients who do not have Huntington’s disease.41,42 Treatment of acute amphetamine-induced choreoathetoid movement disorders includes supportive care, gastrointestinal decontamination with activated charcoal, and administration of haloperidol.41 Seizures have been reported with severe intoxications of amphetamine and related compounds.27,43-45 The seizures have been isolated or associated with hyperpyrexia, coma, metabolic acidosis, and shock. IV benzodiazepines (e.g., diazepam, lorazepam), phenytoin, and barbiturates (e.g., pentobarbital, amobarbital) have been used to terminate amphetamine-induced seizures.7,44 Intracerebral hemorrhage is associated with the use of amphetamines and related compounds. Amphetaminerelated cerebral hemorrhage has occurred in patients with arteriovenous malformations46 and drug-induced cerebral vasculitis.47-50 Both oral and IV amphetamine exposures have resulted in cases of cerebral vasculitis.47-51 Traditional approaches to intracerebral hemorrhage have focused on supportive care, correction of the hypotension, use of corticosteroids, and employment of antifibrinolytic agents such as ε-aminocaproic acid.47-50 Treatment directed at the vasculitis in these cases has included use of dexamethasone and cyclophosphamide therapy.47,48 The efficacy of these agents in the treatment of amphetamine-associated vasculitis is unknown. Ischemic strokes have been reported with amphetamine compounds taken orally, intravenously, and by inhalation.52 Supportive care and hypervolemic hemodilution therapy using albumin or 10% dextran 40 has been advocated after angiographic demonstration of cerebral artery spasm and occlusion.52 Elective extracranial/intracranial bypass was performed in at least one case of amphetamine-associated occlusive stroke, but its efficacy is unproved.52 A case of transient cortical blindness in an infant exposed to methamphetamine has been reported.53 The blindness resolved within 12 hours without specific therapy. It was postulated to represent a manifestation of amphetamine-induced cerebral vasospasm.53 Methamphetamine neurotoxicity in human abuse is thought to be in part due to necrotic and apoptotic mechanisms.54 The central nervous system is the main

786


target of the pharmacologic actions of the amphetamines and is also the most frequent organ system to manifest amphetamine-induced toxicity.

Cardiovascular System Toxicity In a retrospective study of patients with amphetamine toxicity presenting to an ED, hypertension and tachycardia were commonly encountered. The same study found that patients complained of chest pain 9% and palpitations 3% of the time.27 Direct pharmacologic effects of the amphetamines most likely account for the frequently encountered hypertension and the tachycardia. In a double-blind, placebo-controlled study of eight healthy adults, modest doses of MDMA increased heart rate, blood pressure, and myocardial oxygen consumption in a magnitude similar to that of dobutamine without causing the positive inotropic effects of dobutamine.55 Hypertension and agitated behavior associated with amphetamine use are initially approached by minimizing stimulus or sensory inputs and by using sedating agents. If more specific treatment is needed, the use of IV nitroprusside or oral or IV calcium channel blockers (e.g., nifedipine or nicardipine) may be indicated. β blockers should not be used in the treatment of amphetamine-induced hypertension without concomitant α blockade, because unopposed α blockade can produce intense vasospasm and paradoxical hypertension. Appetite suppressants and amphetamine derivatives have been associated with an increased risk of cardiac valvular insufficiency.56-58 The use of fenfluramine or dexfenfluramine for 4 months or longer was associated with an increased risk of valvular changes.59 Fenfluramine has been used with the phenylethylamine derivative phentermine (Fen-Phen) extensively to suppress appetite. By 1997, reports of aortic mitral regurgitation associated with the use of these drugs surfaced. The mechanism of this effect is unknown; incidence estimates vary from less than 1% to greater than 20% after exposure to Fen-Phen for more than 4 months.60,61 Some echocardiographic improvement with cessation of use has been noted. These findings coupled with evidence of associated pulmonary hypertension resulted in the removal of fenfluramine from the market. Ectopic ventricular beats as well as supraventricular and ventricular tachyarrhythmias have been reported with amphetamine use. Direct catecholamine effects and ischemic effects secondary to coronary vasospasm generated by amphetamine use are probably responsible for the arrhythmias.62 Although not normally studied, short-acting β-adrenergic receptor blockers (e.g., esmolol), calcium channel blockers (e.g., verapamil, diltiazem), or lidocaine can be used to treat these arrhythmias. Correction of hypoxia and electrolyte abnormalities also is required. Myocardial infarction associated with amphetamine use is thought to be secondary to direct cardiac toxicity (myocarditis), vasospasm, and thrombus formation.62,63 Cardiac irritability and myocardial infarction in a 13-yearold has been reported after amphetamine overdose.64 In

addition to treatment with nitrates and analgesics, at least one report describes the use of thrombolytics in treating amphetamine-induced myocardial infarctions.63 Profound hypotension, bradycardia, and metabolic acidosis have occurred with massive amphetamine overdoses. Treatment includes aggressive hemodynamic support with intravascular volume replacement and vasopressor agents (e.g., norepinephrine or phenylephrine). Direct-acting catecholamines (norepinephrine or phenylephrine rather than dopamine) are preferred because massive overdoses may result in a relative catecholamine-depleted state. Both acute and chronic cardiomyopathies have been associated with amphetamine use. This effect is thought to be secondary to direct amphetamine toxicity and indirect hypertension.65 Treatment includes avoidance of amphetamines, use of diuretics and digoxin, and afterload reduction (e.g., nitroprusside acutely and angiotensin-converting enzyme inhibitors such as captopril for long-term use).66 IV amphetamine use is associated with bacterial endocarditis, which can lead to abnormal cardiac valves, dilated cardiomyopathy, and formation of mycotic aneurysms. Acute aortic dissection, necrotizing angiitis, and both visceral and cerebral aneurysms have also been reported to occur in amphetamine users.62,67 Arterial or tissue-extravasated amphetamine quickly leads to tissue ischemia. Immediate intra-arterial or local tissue injection of α-adrenergic blocking agents such as phentolamine or phenoxybenzamine is indicated to reverse the local vasopressor effects of amphetamines. General supportive or symptomatic care is most important to maintain the cardiac system during acute amphetamine toxicity.

Pulmonary System Toxicity Respiratory symptoms including chest pain and dyspnea have been presenting complaints of patients with amphetamine toxicity presenting to an ED.27 The actual incidence of respiratory toxicity with amphetamines is not known. The incidence and types of toxicity may vary, depending on the amphetamine compound and the route of exposure. One review examined pulmonary effects of exposure to amphetamine-related compounds.68 Although amphetamines are often snorted, inhaled, and smoked, the literature does not note an association with barotrauma. On the other hand, a few case reports have associated cocaine, which has similar routes of administration, with barotrauma.68 Despite increased use of inhaled or smoked methamphetamine, no extensive reports of exacerbation of reactive airway disease have been noted. In comparison, the association between asthma and cocaine, which has similar pharmacologic properties and patterns of abuse to methamphetamine, is much stronger. One death due to asthma has been reported with the use of the hallucinogenic amphetamine MDMA.35 In that case, a young man was found dead clutching an inhaler and had pathologic features of asthma at postmortem examination. The contribution of his MDMA use to his

CHAPTER 44

asthma death is speculative. Thirteen patients in two small case series have noted obstructive findings associated with 20% to 60% reductions in carbon monoxide diffusion capacity after IV methylphenidate use.69,70 These patients showed variable responses to β-adrenergic agonist bronchodilators (e.g., albuterol) and were noted to have panlobular emphysema. Foreign particle embolization from IV dosing of methylphenidate was postulated as the cause rather than a direct drug effect, as similar findings have been found with other IV drugs (e.g., methadone).68,71 Case reports describe acute noncardiogenic pulmonary edema associated with amphetamine toxicity.68 Not only smoking but also ingesting amphetamines has been associated with the development of pulmonary edema.72 At least one death with pulmonary edema has been related to the use of MDMA.35 Animal data suggest, at least in part, a direct amphetamine toxicity leading to leaky pulmonary capillaries partly mediated by freeradical and oxidant injury.73 Alternatively, edema may occur owing to indirect neurogenic (e.g., seizure) or cardiovascular (e.g., shock, hydrostatic leak) consequences. Although noncardiogenic pulmonary edema with cocaine abuse is reported more frequently in the literature than with amphetamine abuse, its mechanism also has not been determined and may be similar.68 The literature has for some time described amphetamine use associated with pulmonary hypertension. Users of IV amphetamines obtained from nasal inhalers available until the 1960s were noted to have pulmonary artery foreign body granulomas and muscle hypertrophy.4,68 Long-term inhalation of methamphetamine and propylhexedrine also has been associated with marked pulmonary hypertension at autopsy in at least one case and in a second case of sudden death.74,75 Proposed mechanisms include direct toxic endothelial injury caused by the drugs or their contaminants, recurrent hypoxic insults, direct spasm in genetically determined sensitive hosts, vasculitis, and dysregulation of the mediators of vascular tone such as nitric oxide. The amphetamine-like anorectic agents fenfluramine and aminorex fumarate have also been associated with several European reports of pulmonary hypertension.68 Pulmonary artery vasodilation and remodeling agents have been used for these drug-induced cases of pulmonary hypertension, along with the avoidance of stimulants and supportive care, including supplemental oxygen for hypoxic patients. With the increased incidence of smoking methamphetamine, the authors have noted pulmonary toxicities similar to those reported with the use of the stimulant crack cocaine. These include hemoptysis, alveolar hemorrhage, and alveolar accumulation of carbonaceous material associated with cough, bronchitis, sinusitis, and thermal epiglottitis.68 Basic airway management and supportive care are the only approaches to these complications. In severe cases of amphetamine-induced pulmonary edema, aggressive mechanical ventilatory support with the addition of positive end-expiratory pressure and high levels of inspired oxygen flow often are required.


787

Systemic Toxicity Severe systemic toxicity has been reported with overdoses of amphetamine-related compounds. A pattern of fulminant hyperthermia, convulsions, disseminated intravascular coagulation (DIC), hepatocellular damage, rhabdomyolysis, acute renal failure, arrhythmias, and refractory hypotension has been seen with use of MDMA.43 Hyperthermia, shock, pulmonary edema, rhabdomyolysis, acute renal failure, and DIC have been encountered with use of “designer” amphetamines as well as with phenmetrazine and methamphetamine.43,45,76-78 In certain parts of the country, trauma may have a high association with methamphetamine. Severe metabolic acidosis associated with methamphetamine use has exaggerated the estimated severity of the injury in trauma patients.79 Aggressive cooling, cardiopulmonary support, large amounts of intravascular volume replacement, electrolyte replacement, temperature control measures, and early extracorporeal hemodialysis are needed to overcome the amphetamine-induced hyperthermia with severe rhabdomyolysis in these patients.43,76 If cooling and sedation do not control the hyperthermia, then neuromuscular blockade and mechanical ventilation may be needed.77 This combination of severe systemic toxicity from amphetamines appears to predict a poor outcome. Hepatotoxicity with hepatocellular damage has occurred with use of MDMA and other amphetamines.80-82 Postulated mechanisms for the hepatotoxicity include direct toxic effects, lipid peroxidation, necrotizing angiitis, contaminants, hypotension, and genetic variations in metabolism, which create toxic intermediates. Treatment consists of supportive care and avoidance of amphetamines. At least one liver transplant has been attempted.43 To further complicate this issue, a case of thrombocytopenic purpura after MDMA-induced acute liver failure has been reported.83 In addition to the severe systemic toxicities described above, reversible ischemic colitis induced by methamphetamine abuse has been reported. Abdominal pain was the presenting complaint in 4% of amphetaminepoisoned patients presenting to an ED.27 The exact incidence of amphetamine-related ischemic bowel and hemorrhagic colitis in abusers of amphetamines is unknown.84 Diagnostic efforts to rule out necrotic bowel would be prudent in amphetamine-associated cases of persistent abdominal pain, particularly with bloody stools. Giant gastric and duodenal ulcers are strongly associated with methamphetamine use.85 Skin changes including lichenoid drug eruptions and burns complicated by “rave” use of amphetamine derivatives have been noted.86,87

Obstetric and Prenatal Toxicity Gestational exposure to amphetamines has been postulated but not proved to have lasting effects on neonates.88 After illicit amphetamine exposure, infants have had hypoglycemia, sweating, poor feeding, poor visual tracking, and seizures.88 As with cocaine exposure,

788


fetal amphetamine exposure was associated with intrauterine growth retardation, decreased head circumference, preterm delivery with fetal distress, anemia, and placental abruption in one study.88 An amphetamine withdrawal pattern similar to that of cocaine withdrawal was noted in these infants. This pattern consisted of abnormal sleep patterns, tremors, hypertonia, highpitched cry, poor feeding, vomiting, sneezing, frantic sucking, and tachycardia.89 Although long-term behavioral and neurologic follow-up of these infants is not yet available, early reports suggest that chaotic lifestyles with minor neurologic abnormalities continue for these infants after discharge from the hospital.88 Other studies have reported reduced birth weight with methamphetamine exposure relative to normal populations but no increase in other adverse outcomes.89 In a report of eight cases of fetal and infant deaths, blood levels of methamphetamine averaged 0.36 μg/mL (range, 0.03 to 1.20 μg/mL).90 A large retrospective study in the United States and Canada of vasoactive compounds such as pseudoephedrine, phenylpropanolamine, ephedrine, and methylenedioxymethamphetamine exposure during the first 2.5 months of pregnancy resulted in doubling the risk of gastroschisis and small intestinal atresia.91 Combination exposure to vasoactive drugs and 20 or more cigarettes per day increased the risk with an odds ratio of 3.6 (1.3 to 10.3) for gastroschisis and 4.2 (1.1 to 16.2) for small bowel atresia.91 One hypothesis is that these small intestine defects are the result of vascular disruption by toxins in early gestation. Pregnant women exposed to amphetamines are at increased risk of serious obstetric complications, including intracranial hemorrhage, seizures, and amniotic fluid embolism.89 No specific therapy has been identified for neonates or pregnant women heavily exposed to amphetamines. Identification of at-risk women before pregnancy and during prenatal care would afford an opportunity to educate. Unfortunately, many pregnant women using amphetamines do not seek prenatal care and may be unable or unwilling to reduce their gestational exposures.

DIAGNOSIS The clinician should consider the diagnosis of toxicity from amphetamine-related compounds in the differential diagnosis when behavioral stimulation is coupled to evidence of catecholamine excess. Inadvertent exposure to amphetamines can occur in pediatric patients, particularly around adults participating in illegal manufacture and distribution. Urine screening tests primarily utilizing immunoassay techniques exist for amphetamine-related compounds and are often part of “drug abuse” screens.92 Confirmation of urine and blood samples is made by a gas chromatography coupled with mass spectroscopy (GCMS) analysis.93 Urine can remain positive for greater than 48 hours after exposure depending on route, rate of absorption, urine pH, and hydration status.94 Many

laboratories used to monitor persons in sensitive occupations have thresholds for reporting positive amphetamine results in the urine. Drug detected below these thresholds is not reported. Some laboratories require the D-isomer of methamphetamine to be present along with detectable amphetamine (a metabolite) to report a urine sample positive for methamphetamine. For example, selegiline is metabolized to L-amphetamine and L-methamphetamine (both have minimal toxicity) and will be reported as positive for methamphetamine unless an isomer analysis is performed.95 Other drugs such as clobenzorex, a Mexican anorectic drug, are metabolized to actual D-amphetamine and will give a positive result on confirmation by GC-MS analysis.96 Infrared transmission spectroscopy has been used to detect methamphetamines.97 A rapid-detection, nonaqueous capillary electrophoresis-fluorescence spectroscopy method for MDMA has been reported.98 The use of hair analysis for amphetamine-related compounds has also been reported but is of little use clinically because of interlaboratory variability.99-102

MANAGEMENT An algorithm for the general approach to a suspected amphetamine-poisoned patient is shown in Table 44-1. No prospective human trials have evaluated different treatment options. Most recommendations are based on animal studies or case reports of humans. For example, the efficacy of activated charcoal in treating oral methamphetamine exposure has been demonstrated in a study in mice but lacks human trials.103 Early recommendations to acidify the urine in amphetamine overdoses were based on a single case.104 The risks of systemic acidification and the potential problems for the kidneys when rhabdomyolysis is present have prevented this recommendation from being widely adopted until controlled trials have demonstrated improved patient outcomes. Clinicians must be aware of the problem of contaminants in addition to the direct toxic effects of amphetamines. A cluster of at least 14 cases of acute lead poisoning was found in IV methamphetamine users in Oregon in 1988. Amphetamine products manufactured in clandestine laboratories may be grossly contaminated with toxic heavy metals and chemicals. In addition, the authors have noticed a cluster of 20 cases of acute botulism poisoning associated with illicit drug use.105,106 General supportive care; decontamination of the gastrointestinal tract with activated charcoal for ingestions; and control of behavior, seizures, arrhythmias, and temperature remain the mainstay of therapy for amphetamine-poisoned patients. An animal model failed to demonstrate the utility of multiple doses of activated charcoal after IV methamphetamine.107 In the absence of renal failure, dialysis and hemoperfusion have no role in amphetamine overdose. Specific measures when available for each complication associated with amphetamine use have been mentioned above. Vaccines and antibodies directed against methamphetamine are currently under development to treat overdoses and long-term drug

TABLE 44-1 Amphetamine and Related Compound Toxicity and Treatment and Decision Algorithm Suspected Amphetamine Toxicity

MILD AMPHETAMINE TOXICITY

Evaluate Decontamination of oral ingestions/activated charcoal Observe Psychologic support/environmental control Health care maintenance HIV testing Hepatitis screening, etc.

SEVERE AMPHETAMINE TOXICITY


Immediate Supportive Care Airway control Oxygenation Vascular access Appropriate monitoring

Initiate specific treatment for additional agents Consider interactions with amphetamine Monitor for early and late toxicities of other agents

Decontaminate/Antagonists Oral ingestion/activated charcoal Consider empirical 50% dextrose, thiamine, naloxone Avoid benzodiazepine antagonists Terminate Seizures Benzodiazepines (e.g., diazepam, lorazepam) Barbiturates (e.g., pentobarbital, phenobarbital) Control Severe Psychotic Agitation Minimize sensory stimulation Benzodiazepines (e.g., diazepam, lorazepam) Butyrophenones (e.g., droperidol, haloperidol) Protect from aggressive or self-destructive behavior Correct Immediate Metabolic, Oxygenation, and Electrolyte Abnormalities Avoid acidification of the urine Local a blockers for Exuded or Intra-Arterial Amphetamines (e.g., Phenoxybenzamine, Phentolamine) Treat Hyperthermia Passive/active cooling measure Treat Arrhythmias Antiarrhythmic (e.g., lidocaine) Supraventricular arrhythmias (e.g., esmolol) Electrolyte correction Acid–base/oxygenation correction Second-Level Evaluations to Check for Persistent Abnormalities

Persistent Hypotension

Supportive Care

Intravascular volume resuscitation Acute cardiopulmonary support Central hemodynamic monitoring

Observation/monitoring Psychologic and pharmacologic support for amphetamine abstinence and long-term recovery Health maintenance/education (e.g., HIV and hepatitis testing) Coronary Artery Ishemia Calcium channel blockers (e.g., nifedipine, diltiazem) β blockers (e.g., esmolol, metoprolol) Nitrates (e.g., nitroglycerin) Hypertension Sedation (e.g., diazepam, haloperidol) Calcium channel blockers (e.g., nifedipine, nicardipine) β blockers (e.g., esmolol) Nitroprusside Electrolyte Abnormalities Correct hypokalemia (e.g., potassium chloride) Correct hypocalcemia (e.g., calcium gluconate) Correct hypoglycemia (e.g., dextrose as D50)

Pulmonary Edema/Respiratory Failure Ventilator Oxygen Positive end-expiratory pressure Rhabdomyolysis Alkalize urine (e.g., intravenous bicarbonate) Calcium replacement (e.g., calcium gluconate) Intravascular volume Renal Failure/Rhabdomyolysis/Renal Ischemia Hemodialysis Intravascular volume

Central Nervous System Abnormality Seizures Strokes Bleeds Vasculitis Agitation

790


abuse.108 Infectious diseases should be considered. Patients should be evaluated for complications attendant to IV drug abuse such as bacterial endocarditis, viral hepatitis, and human immunodeficiency virus. Once the acute symptoms of amphetamine poisoning have passed, treating physicians should consider referring patients for rehabilitation or psychiatric care to break up the destructive drug abuse pattern. REFERENCES 1. Cho AK: Ice: a new dosage form of an old drug. Science 1990;249:631–634. 2. Gawin FH, Ellinwood EH Jr: Cocaine and other stimulants: actions, abuse, and treatment. N Engl J Med 1988;318:1173–1182. 3. Piness G, Miller H, Alles GA: Clinical observations on phenylaminoethanol sulfate. JAMA 1930;94:790–791. 4. Anderson RJ, Reed WG, Hillis LD, et al: History, epidemiology, and medical complications of nasal inhaler abuse. J Toxicol Clin Toxicol 1982;19:95–107. 5. Myerson A: Effect of benzedrine sulphate on mood and fatigue in normal and in neurotic persons. Arch Neurol Psychiatry 1936;36:816–822. 6. Derlet RW, Heischober B: Methamphetamine. Stimulant of the 1990s? West J Med 1990;153:625–628. 7. Linden CH, Kulig KW, Rumack BH: Amphetamines. Top Emerg Med 1985;7:18–32. 8. Klein-Schwartz W: Abuse and toxicity of methylphenidate. Curr Opin Pediatr 2002;14:219–223. 9. Ellinwood EH Jr: Assault and homicide associated with amphetamine abuse. Am J Psychiatry 1971;127:1170–1175. 10. Kalant H, Kalant OJ: Death in amphetamine users: causes and rates. Can Med Assoc J 1975;112:299–304. 11. Katsumata S, Sato K, Kashiwade H, et al: Sudden death due presumably to internal use of methamphetamine. Forensic Sci Int 1993;62:209–215. 12. Bailey DN, Shaw RF: Cocaine- and methamphetamine-related deaths in San Diego County (1987): homicides and accidental overdoses. J Forensic Sci 1989;34:407–422. 13. Beebe DK, Walley E: Smokable methamphetamine (“ice”): an old drug in a different form. Am Fam Physician 1995;51:449–453. 14. Bailey DN: Amphetamine detection during toxicology screening of a university medical center patient population. J Toxicol Clin Toxicol 1987;25:399–409. 15. Wermuth L: Methamphetamine use: hazards and social influences. J Drug Educ 2000;30:423–433. 16. Caldicott DG, Edwards NA, Kruys A, et al: Dancing with “death”: p-methoxyamphetamine overdose and its acute management. J Toxicol Clin Toxicol 2003;41:143–154. 17. Kraner JC, McCoy DJ, Evans MA, et al: Fatalities caused by the MDMA-related drug paramethoxyamphetamine (PMA). J Anal Toxicol 2001;25:645–648. 18. Martin TL: Three cases of fatal paramethoxyamphetamine overdose. J Anal Toxicol 2001;25:649–651. 19. U.S. Drug Enforcement Agency: http://www.dea.gov/pubs/ states/california.html. Accessed 1/6/05. 20. Rawson RA, Gonzales R, Brethen P: Treatment of methamphetamine use disorders: an update. J Subst Abuse Treat 2002;23: 145–150. 21. Baselt RC, Cravey RH: Amphetamine. In Disposition of Toxic Drugs and Chemicals in Man. Foster City, CA, Chemical Toxicology Insitute, 1995, pp 44–47. 22. Markowitz JS, DeVane CL, Boulton DW, et al: Ethylphenidate formation in human subjects after the administration of a single dose of methylphenidate and ethanol. Drug Metab Dispos 2000;28:620–624. 23. Markowitz JS, Logan BK, Diamond F, Patrick KS: Detection of the novel metabolite ethylphenidate after methylphenidate overdose with alcohol coingestion. J Clin Psychopharmacol 1999;19:362–366. 24. Mendelson J, Jones RT, Upton R, Jacob P III: Methamphetamine and ethanol interactions in humans. Clin Pharmacol Ther 1995;57:559–568.

25. Kramer JC, Fischman VS, Littlefield DC: Amphetamine abuse: pattern and effects of high doses taken intravenously. JAMA 1967;201:305–309. 26. Smith DE, Fischer CM: An analysis of 310 cases of acute high-dose methamphetamine toxicity in Haight-Ashbury. Clin Toxicol 1970;3:117–124. 27. Derlet RW, Rice P, Horowitz BZ, Lord RV: Amphetamine toxicity: experience with 127 cases. J Emerg Med 1989;7:157–161. 28. Robinson TE, Becker JB: Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res 1986;396:157–198. 29. Sato M: A lasting vulnerability to psychosis in patients with previous methamphetamine psychosis. Ann N Y Acad Sci 1992;654:160–170. 30. Ellinwood EH: Amphetamine Psychosis. 1. Description of the individuals and process. J Nerv Ment Dis 1967;144:273-–283. 31. Bell DS: The experimental reproduction of amphetamine psychosis. Arch Gen Psychiatry 1973;29:35–40. 32. Polchert SE, Morse RM: Pemoline abuse. JAMA 1985;254:946–947. 33. Castellani S, Petrie W, Ellinwood E: Drug-induced psychosis: neurobiological mechanisms. In Alterman A (ed): Substance Abuse and Psychopathology. New York, Plenum Press, 1985, pp 173–210. 34. Schechter MD, Glennon RA: Cathinone, cocaine and methamphetamine: similarity of behavioral effects. Pharmacol Biochem Behav 1985;22:913–916. 35. Dowling GP, McDonough ET, Bost RO: “Eve” and “Ecstasy”: a report of five deaths associated with the use of MDEA and MDMA. JAMA 1987;257:1615–1617. 36. Dubin WR, Weiss KJ, Dorn JM: Pharmacotherapy of psychiatric emergencies. J Clin Psychopharmacol 1986;6:210–222. 37. Meston CM, Gorzalka BB: Psychoactive drugs and human sexual behavior: the role of serotonergic activity. J Psychoactive Drugs 1992;24:1–40. 38. Kuniyoshi SM, Jankovic J: MDMA and parkinsonism. N Engl J Med 2003;349:96–97. 39. Fowler JS, Volkow ND: PET imaging studies in drug abuse. J Toxicol Clin Toxicol 1998;36:163–174. 40. Klawans HL, Weiner WJ: The pharmacology of choreatic movement disorders. Prog Neurobiol 1976;6:49–80. 41. Rhee KJ, Albertson TE, Douglas JC: Choreoathetoid disorder associated with amphetamine-like drugs. Am J Emerg Med 1988;6:131–133. 42. Lundh H, Tunving K: An extrapyramidal choreiform syndrome caused by amphetamine addiction. J Neurol Neurosurg Psychiatry 1981;44:728–730. 43. Henry JA, Jeffreys KJ, Dawling S: Toxicity and deaths from 3,4methylenedioxymethamphetamine (“ecstasy”). Lancet 1992;340: 384–387. 44. Simpson D, Rumack B: Methylenedioxyamphetamine clinical description of overdose, death, and review of pharmacology. Arch Intern Med 1987;141:1507–1509. 45. Chan P, Chen JH, Lee MH, Deng JF: Fatal and nonfatal methamphetamine intoxication in the intensive care unit. J Toxicol Clin Toxicol 1994;32:147–155. 46. Lukes SA: Intracerebral hemorrhage from an arteriovenous malformation after amphetamine injection. Arch Neurol 1983; 40:60–61. 47. Salanova V, Taubner R: Intracerebral haemorrhage and vasculitis secondary to amphetamine use. Postgrad Med J 1984;60:429–430. 48. Matick H, Anderson D, Brumlik J: Cerebral vasculitis associated with oral amphetamine overdose. Arch Neurol 1983;40:253–254. 49. Hughes JC, McCabe M, Evans RJ: Intracranial haemorrhage associated with ingestion of “ecstasy.” Arch Emerg Med 1993;10:372–374. 50. Conci F, D’Angelo V, Tampieri D, Vecchi G: Intracerebral hemorrhage and angiographic beading following amphetamine abuse. Ital J Neurol Sci 1988;9:77–81. 51. Brorholt-Petersen JU, Christensen HR: (Fatal intracerebral hemorrhage after amphetamine intake). Ugeskr Laeger 2000; 162:4156–4157. 52. Rothrock JF, Rubenstein R, Lyden PD: Ischemic stroke associated with methamphetamine inhalation. Neurology 1988;38:589–592.

CHAPTER 44

53. Gospe SM Jr: Transient cortical blindness in an infant exposed to methamphetamine. Ann Emerg Med 1995;26:380–382. 54. Davidson C, Gow AJ, Lee TH, Ellinwood EH: Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment. Brain Res Brain Res Rev 2001;36:1–22. 55. Lester SJ, Baggott M, Welm S, et al: Cardiovascular effects of 3,4methylenedioxymethamphetamine. A double-blind, placebocontrolled trial. Ann Intern Med 2000;133:969–973. 56. Khan MA, Herzog CA, St Peter JV, et al: The prevalence of cardiac valvular insufficiency assessed by transthoracic echocardiography in obese patients treated with appetite-suppressant drugs. N Engl J Med 1998;339:713–718. 57. Weissman NJ, Tighe JF Jr, Gottdiener JS, Gwynne JT: An assessment of heart-valve abnormalities in obese patients taking dexfenfluramine, sustained-release dexfenfluramine, or placebo. Sustained-Release Dexfenfluramine Study Group. N Engl J Med 1998;339:725–732. 58. Devereux RB: Appetite suppressants and valvular heart disease. N Engl J Med 1998;339:765–766. 59. Jick H, Vasilakis C, Weinrauch LA, et al: A population-based study of appetite-suppressant drugs and the risk of cardiac-valve regurgitation. N Engl J Med 1998;339:719–724. 60. Gardin JM, Schumacher D, Constantine G, et al: Valvular abnormalities and cardiovascular status following exposure to dexfenfluramine or phentermine/fenfluramine. JAMA 2000;283:1703–1709. 61. Wee CC, Phillips RS, Aurigemma G, et al: Risk for valvular heart disease among users of fenfluramine and dexfenfluramine who underwent echocardiography before use of medication. Ann Intern Med 1998;129:870–874. 62. Davis GG, Swalwell CI: Acute aortic dissections and ruptured berry aneurysms associated with methamphetamine abuse. J Forensic Sci 1994;39:1481–1485. 63. Furst SR, Fallon SP, Reznik GN, Shah PK: Myocardial infarction after inhalation of methamphetamine (letter). N Engl J Med 1990;323:1147–1148. 64. Sztajnkrycer MD, Hariharan S, Bond GR: Cardiac irritability and myocardial infarction in a 13-year-old girl following recreational amphetamine overdose. Pediatr Emerg Care 2002;18:E11–E15. 65. Frishman WH, Del Vecchio A, Sanal S, Ismail A: Cardiovascular manifestations of substance abuse. 2. Alcohol, amphetamines, heroin, cannabis, and caffeine. Heart Dis 2003;5:253–271. 66. Hong R, Matsuyama E, Nur K: Cardiomyopathy associated with the smoking of crystal methamphetamine. JAMA 1991;265: 1152–1154. 67. Swalwell CI, Davis GG: Methamphetamine as a risk factor for acute aortic dissection. J Forensic Sci 1999;44:23–26. 68. Albertson TE, Walby WF, Derlet RW: Stimulant-induced pulmonary toxicity. Chest 1995;108:1140–1149. 69. Schmidt RA, Glenny RW, Godwin JD, et al: Panlobular emphysema in young intravenous Ritalin abusers. Am Rev Respir Dis 1991;143:649–656. 70. Sherman CB, Hudson LD, Pierson DJ: Severe precocious emphysema in intravenous methylphenidate (Ritalin) abusers. Chest 1987;92:1085–1087. 71. Pare JP, Cote G, Fraser RS: Long-term follow-up of drug abusers with intravenous talcosis. Am Rev Respir Dis 1989;139:233–241. 72. Maury E, Darondel JM, Buisinne A, et al: Acute pulmonary edema following amphetamine ingestion. Intensive Care Med 1999; 25:332–333. 73. Huang KL, Shaw KP, Wang D, et al: Free radicals mediate amphetamine-induced acute pulmonary edema in isolated rat lung. Life Sci 2002;71:1237–1244. 74. Nishida N, Ikeda N, Kudo K, Esaki R: Sudden unexpected death of a methamphetamine abuser with cardiopulmonary abnormalities: a case report. Med Sci Law 2003;43:267–271. 75. Schaiberger PH, Kennedy TC, Miller FC, et al: Pulmonary hypertension associated with long-term inhalation of “crank” methamphetamine. Chest 1993;104:614–616. 76. Kendrick WC, Hull AR, Knochel JP: Rhabdomyolysis and shock after intravenous amphetamine administration. Ann Intern Med 1977;86:381–387. 77. Callaway CW, Clark RF: Hyperthermia in psychostimulant overdose. Ann Emerg Med 1994;24:68–76.


791

78. Wallace ME, Squires R: Fatal massive amphetamine ingestion associated with hyperpyrexia. J Am Board Fam Pract 2000;13: 302–304. 79. Burchell SA, Ho HC, Yu M, Margulies DR: Effects of methamphetamine on trauma patients: a cause of severe metabolic acidosis? Crit Care Med 2000;28:2112–2115. 80. Jones AL, Jarvie DR, McDermid G, Proudfoot AT: Hepatocellular damage following amphetamine intoxication. J Toxicol Clin Toxicol 1994;32:435–444. 81. Andreu V, Mas A, Bruguera M, et al: Ecstasy: a common cause of severe acute hepatotoxicity. J Hepatol 1998;29:394–397. 82. Shannon M: Methylenedioxymethamphetamine (MDMA, “Ecstasy”). Pediatr Emerg Care 2000;16:377–380. 83. Schirren CA, Berghaus TM, Sackmann M: Thrombotic thrombocytopenic purpura after Ecstasy-induced acute liver failure. Ann Intern Med 1999;130:163. 84. Johnson TD, Berenson MM: Methamphetamine-induced ischemic colitis. J Clin Gastroenterol 1991;13:687–689. 85. Pecha RE, Prindiville T, Pecha BS, et al: Association of cocaine and methamphetamine use with giant gastroduodenal ulcers. Am J Gastroenterol 1996;91:2523–2527. 86. Deloach-Banta LJ: Lichenoid drug eruption: crystal methamphetamine or adulterants? Cutis 1994;53:97–98. 87. Cadier MA, Clarke JA: Ecstasy and Whizz at a rave resulting in a major burn plus complications. Burns 1993;19:239–240. 88. Dixon SD: Effects of transplacental exposure to cocaine and methamphetamine on the neonate. West J Med 1989;150: 436–442. 89. Catanzarite VA, Stein DA: “Crystal” and pregnancy—methamphetamine-associated maternal deaths. West J Med 1995;162:454–457. 90. Stewart JL, Meeker JE: Fetal and infant deaths associated with maternal methamphetamine abuse. J Anal Toxicol 1997;21:515–517. 91. Werler MM, Sheehan JE, Mitchell AA: Association of vasoconstrictive exposures with risks of gastroschisis and small intestinal atresia. Epidemiology 2003;14:349–354. 92. Lekskulchai V, Mokkhavesa C: Evaluation of Roche Abuscreen ONLINE amphetamine immunoassay for screening of new amphetamine analogues. J Anal Toxicol 2001;25:471–475. 93. Valentine JL, Middleton R: GC-MS identification of sympathomimetic amine drugs in urine: rapid methodology applicable for emergency clinical toxicology. J Anal Toxicol 2000;24:211–222. 94. Smith-Kielland A, Skuterud B, Morland J: Urinary excretion of amphetamine after termination of drug abuse. J Anal Toxicol 1997;21:325–359. 95. Meeker JE, Reynolds PC: Postmortem tissue methamphetamine concentrations following selegiline administration. J Anal Toxicol 1990;14:330–331. 96. Tarver JA: Amphetamine-positive drug screens from use of clobenzorex hydrochlorate. J Anal Toxicol 1994;18:183. 97. Chappell JS: Infrared discrimination of enantiomerically enriched and racemic samples of methamphetamine salts. Analyst 1997;122:755–760. 98. Fang C, Chung YL, Liu JT, Lin CH: Rapid analysis of 3,4methylenedioxymethamphetamine: a comparison of nonaqueous capillary electrophoresis/fluorescence detection with GC/MS. Forensic Sci Int 2002;125:142–148. 99. Nakahara Y, Kikura R: Hair analysis for drugs of abuse. 18. 3,4Methylenedioxymethamphetamine (MDMA) disposition in hair roots and use in identification of acute MDMA poisoning. Biol Pharm Bull 1997;20:969–972. 100. Rohrich J, Kauert G: Determination of amphetamine and methylenedioxy-amphetamine-derivatives in hair. Forensic Sci Int 1997;84:179–188. 101. Kronstrand R, Grundin R, Jonsson J: Incidence of opiates, amphetamines, and cocaine in hair and blood in fatal cases of heroin overdose. Forensic Sci Int 1998;92:29–38. 102. Kintz P, Cirimele V: Interlaboratory comparison of quantitative determination of amphetamine and related compounds in hair samples. Forensic Sci Int 1997;84:151–156. 103. McKinney PE, Tomaszewski C, Phillips S, et al: Methamphetamine toxicity prevented by activated charcoal in a mouse model. Ann Emerg Med 1994;24:220–223. 104. Gary NE, Saidi P: Methamphetamine intoxication: a speedy new treatment. Am J Med 1978;64:537–540.

792


105. Lead poisoning associated with intravenous-methamphetamine use—Oregon, 1988. MMWR Morb Mortal Wkly Rep 1989;38: 830–831. 106. Sandrock CE, Murin S: Clinical predictors of respiratory failure and long-term outcome in black tar heroin-associated wound botulism. Chest 2001;120:562–566.

107. Hutchaleelaha A, Mayersohn M: Influence of activated charcoal on the disposition kinetics of methamphetamine enantiomers in the rat following intravenous dosing. J Pharm Sci 1996;85: 541–545. 108. Kantak KM: Vaccines against drugs of abuse: a viable treatment option? Drugs 2003;63:341–352.

45

Hallucinogens STEPHEN J. TRAUB, MD

At a Glance… ■

■

■ ■ ■

■

■

Most hallucinogens are indoleamine or phenylethylamine derivatives that are structurally similar to the neurotransmitter serotonin. Hallucinogens commonly used today include lysergic acid diethylamide, mescaline, 5-methoxy-N,N-diisopropyltryptamine (“foxy methoxy”), and psilocybin (in “magic mushrooms”). Hallucinogens produce disturbances of perception, mood, and thought. Occasionally, hallucinogens produce negative experiences, often referred to as a “bad trip.” Treatment of hallucinogen toxicity is primarily supportive; agitation often necessitates “talking the patient down” and/or treatment with benzodiazepines. Hallucinogen persisting perceptual disorder, more commonly known as “flashbacks,” is a syndrome whereby previous users of LSD experience perceptual distortions despite abstinence from the drug. Hallucinogens rarely cause life-threatening alterations in physiology, but severe impairments in judgment may lead to severe disability or death.

The term hallucination is derived from the Latin word hallucinari, which means “to wander in mind.” Hallucinations are false sensory perceptions that occur in the absence of real external stimuli; hallucinogens are substances that produce these perceptions. Many drugs may produce hallucinations, but those classified as hallucinogens or “psychedelics” produce disturbances of perception, mood, and thought as their primary effect with each use.

HISTORY Although most commonly associated with the “psychedelic” era of San Francisco’s Haight-Ashbury district during the 1960s, hallucinogens have a rich history and have been used by humans for millennia.1 Hallucinogens have been and still are regularly used as integral parts of religious rituals. The Aztecs consumed psilocybin-containing mushrooms (teonanacatl, or “flesh of the gods”) during their ceremonies. Mescaline, the major active alkaloid of the peyote cactus (Lophophora williamsii), is still used in religious ceremonies by Native American tribes in the Desert Southwest of the United States. The modern era of hallucinogen use was inadvertently ushered in by Albert Hoffman of Sandoz Laboratories in 1943. Hoffman was working with synthetic ergot derivatives in an attempt to create new vasoactive medications when he inadvertently absorbed

one of them, lysergic acid diethylemide (LSD), percutaneously. Soon afterward, he reportedly began to experience sensations we now recognize as characteristic of hallucinogen use: The external world became changed as in a dream. Objects appeared to gain in relief; they assumed unusual dimensions; and colors became more glowing. Even self-perception and the sense of time were changed. When the eyes were closed, colored pictures flashed past in a quickly changing kaleidoscope. After a few hours, the not unpleasant inebriation, which had been experienced whilst I was fully conscious, disappeared.2 Sandoz later marketed LSD as Delysid. It was touted as a cure for several psychiatric ailments, including alcoholism3 and, interestingly, schizophrenia.4 It was also used regularly by psychiatrists for analytical psychotherapy5,6 and as an adjunct to treat those with terminal illness. LSD, however, was prohibited from use in the United States in 1966, and the drug was classified as a schedule I substance by the Drug Enforcement Agency as part of the Controlled Substances Act of 1970. This dramatically curtailed further human research with hallucinogenic drugs. The use of hallucinogens as a means to “expand the mind” was popularized in the 1960s. In 1960, Dr. Timothy Leary, a Harvard psychologist, used psilocybin for the first time. His interest in this drug led to the development of the Harvard Psilocybin Project, in which hallucinogens were given to volunteers. Leary first tried LSD in 1962, and shortly thereafter began touting its benefits. He was (not coincidentally) fired from his Harvard position in 1963 but went on to become one of the strongest public advocates of hallucinogen use. The popularity of LSD and other hallucinogens grew during the rest of that decade, until it reached its height of popularity in the late 1960s. At the same time that Leary was urging people to “tune in, turn on, and drop out,” however, more established institutions began paying attention to—and expressing alarm at—the “epidemic” of hallucinogen use. A review of LSD in the New England Journal of Medicine in 1968 opened with the statement that “no drug use by man has stimulated greater public debate than lysergic acid diethylamide,” and opined that “the widespread use of LSD, or similar drugs waiting in the psychedelic wings, could lead to a whole generation of psychedelic dropouts, incapable of and uninterested in addressing themselves to the important sociologic problems that challenge our times. If this happened, the very structure of this democratic society would be threatened.”7 793

794


EPIDEMIOLOGY Although the use of LSD and other hallucinogens has decreased since the 1960s, it has not disappeared. According to a 1999 report by the National Institutes of Health National Institute on Drug Abuse, approximately 10% of the U.S. population aged 12 and older has experimented with hallucinogens.8 Use generally begins between ages 15 and 19, peaks at age 19, and becomes less common after age 30.9 Whites are more likely than African Americans or Hispanics to report hallucinogen use9 and are less likely to perceive that LSD is a dangerous drug. A recent report from the Drug Abuse Warning Network (DAWN) notes a significant decline in emergency department (ED) visits related to LSD from 1994 to 2001.10 DAWN estimates that in 2001, LSD was associated with 2821 ED visits in the coterminous United States; this represents a 45% decline from that reported in 1994. In 2001, LSD accounted for only 11% of ED visits associated with club drugs and 0.4% of all drug-related ED visits. Still, adolescents (12 to 17 years of age) and young adults (18 to 25 years) account for 34% and 48% of all ED visits related to LSD, respectively. Members of previous generations may have relied on friends to tell them about their experiences with hallucinogenic drugs before trying them. Today, however, websites such as Erowid (www.erowid.org) and Lycaeum (www.lycaeum.org) contain information and descriptions (many very positive) of the effects of hallucinogen use. These websites are attractive to adolescents and young adults and may serve to reinforce the use of hallucinogenic drug use in this group of patients.

CLASSIFICATION There are several classes of hallucinogens that are commonly used today. They include the indoleamines, phenylethylamines, piperazines, arylcyclohexylamines, tetrahydrocannabinoids, anticholinergics, and diterpene alkaloids (Table 45-1). The indoleamines include lysergamides (e.g., LSD) and alkyltryptamines (e.g., N,N-dimethyltryptamine [DMT], psilocybin, and bufotenine). The phenylethylamines include mescaline, dimethoxymethylamphetamine, methylenedioxymethamphetamine, and other amphetamine derivatives. Piperazines are structurally similar to phenylalkylamines and include benzylpiperazine and trifluromethylphenylpiperazine. The synthetic amphetamine and piperazine derivatives are discussed in Chapter 44. The arylcyclohexylamines include phencyclidine, ketamine, and dextromethorphan and are discussed in Chapter 43. Tetrahyrocannabinoids include marijuana and hashish and are discussed in Chapter 41. The anticholinergics include belladonna alkaloids and a wide variety of pharmaceutical agents (see Chapter 39). The diterpene alkaloids are found in the plant Salvia divinorum. This chapter will largely discuss the two primary hallucinogen classes, indoleamines and phenylalkylamines, as well as diterpene alkaloids.

Lysergamides The lysergamides or ergolines include the synthetic Dlysergic acid diethylamide and naturally occurring indole alkaloids from the morning glory and Hawaiian baby wood rose plants. LSD is synthesized from lysergic acid and diethylamine; the former is derived from the wheat or rye fungus Claviceps purpurea. Seeds from the morning glory plants Ipomoea violaceae and Rivea corymbosa (Mexican ololiuqui), the Hawaiian baby woodrose (Argyreia nervosa), and the Hawaiian woodrose (Merremia tuberose) contain D-lysergic acid amide and D-isolysergic acid amide; these indole alkaloids have about one tenth the potency of LSD.11 LSD is the most potent hallucinogenic drug known, with psychedelic effects occurring with doses as little as 25 to 50 μg.12 The psychedelic effects from morning glory occur after ingestion of approximately 250 seeds.11

Tryptamines The alkyltryptamines include both synthetic and naturally occurring compounds. These agents include DMT, αmethyl- and α-ethyltryptamine (AMT and AET), 5methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT, “foxy methoxy,” or “methoxy”), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), psilocin, psilocybin, and bufotenine (5-hydroxydimethyltryptamine [5-OH-DMT]). Both bufotenine and 5-MeO-DMT are present in the secretions and skin of the cane toads, Bufo genus. The toad Bufo alvarius (Colorado River toad) produces the hallucinogen 5-MeO-DMT.13 AMT and 5-MeO-DIPT are relatively new, potent, synthetic, hallucinogenic tryptamines popularized by their easy access via the Internet and as club drugs.14,15 These drugs were recently made schedule I by the Drug Enforcement Administration.14 DMT is another hallucinogenic tryptamine that is produced synthetically (known as the “businessman’s trip”) and found naturally in the bark of the yackee plant (Vivola calophylla). In Brazil, DMT is known as yurema and is basic to the Brazilian Indian Kariri religion.16 DMT is prepared as snuff from the seeds, leaves, and pods of Piptadenia peregrina, Prestonia amazenicum, Anadenanthera peregrina (yopo tree), and Mimosa hostilis. The dose of tryptamines necessary to produce hallucinations varies according to the agent and route of exposure. Hallucinogenic effects have been demonstrated with oral doses of 4 to 10 mg for 5-MeODIPT, 100 mg for AMT, and 0.2 to 0.4 mg/kg IV for DMT.14,15,17 Another naturally occurring, hallucinogenic alkaloid is ibogaine, which is derived from the shrub Tabernanthe igoba. Psilocybin and psilocin are found naturally in mushrooms that belong mainly to the genera Psilocybe, Conocybe, Gymnopilus, Lycoperdon, Pluteus, Panaeolus, and Stropharia (see Chapter 23).16,18,19 Some specific mushrooms containing psilocybin and/or psilocin include Psilocybe mexicana, Psilocybe cubensis, Stropharia cubensis, Psilocybe semilanceata, Psilocybe pelliculosa, Panaeolus subbalteatus, Psilocybe cyanescens, Gymnopilus spectabilis, and Psilocybe baeocystis. Psilocybin mushrooms are usually

CHAPTER 45

Hallucinogens

795

TABLE 45-1 Classes of Hallucinogens CHEMICAL NAMES

PLANTS OR NATURAL SOURCES; SYNTHETIC AGENTS; ”SLANG NAMES”

Indoleamines LYSERGAMIDES (ERGOLINES) D-Lysergic

acid diethylamide

D-Lysergic

acid amide

LSD; Delysid; “acid,” “blotter,” “stamps,” “dots,” “trips,” “paper,” “a-bombs,” “pyramids” Ipomoea violaceae (morning glory), Rivea corymbosa (Mexican ololiuqui), Argyreia nervosa (Hawaiian baby woodrose), Merremia tuberose (Hawaiian woodrose)

ALKYTRYPTAMINES

α-methyltryptamine N,N-dimethyltryptamine (DMT) 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) Psilocybin (4-phophoryloxy-DMT) Psilocin (4-OH-DMT) 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) Bufotenine (5-OH-DMT) Diethyltryptamine Ibogaine Phenylethylamines Mescaline (3,4,5-trimethoxyphenethylamine) 3,4-methylenedioxymethamphetamine (MDMA) 3,4-methylenedioxyethamphetamine (MDEA) Methylenedioxyamphetamine (MDA) 4-bromo-2,5-dimethoxyamphetamine (DOM) Paramethoxyamphetamine (PMA) Arylcyclohexylamines (Piperidine Derivatives) Phencyclidine (PCP) Ketamine Dextromethorphan Piperazines Benzylpiperazine (BZP) Trifluoromethylphenylpiperazine (TFMPP) Methylenedioxybenzylpiperazine (MDBP) m-chlorophenylpiperazine (mCPP) p-methoxyphenylpiperazine (MeOPP)

AMT; “alpha” Piptadenia peregrine, Anadenanthera peregrina, Prestonia amazenicum, Mimosa hostilis, Vivola calophylla; “businessman’s trip” Bufo alvarius Psilocybe sp, Panaeolus sp, Conocybe sp, Inocybe sp, Gymnopilus sp, Lycoperdon sp, Pluteus genus; “magic mushrooms,” “shrooms,” “alice” “Foxy methoxy,” “foxy” Ch’an Su DET Tabernanthe igoba Peyote cactus (Lophophora williamsii) Ecstasy; “XTC,” “X,” “E,” ”Adam,” ”the hug drug” “Eve” “Serenity, tranquility, and peace” [STP]

Angel dust; ”hog,” “wacky weed,” “T,” ”killer weed” Ketalar, ketaject, ketanest, “special K,” ”K,” “K-hole,” ”vitamin K” “DXM,” “dex,” “robotripping,” “CCC,” “skittles,” “red devils” “Legal E,” “legal X,” “A2”

Tetrahydrocannabinoids Tetrahydrocannabinol (Δ9-THC, Δ1-THC)

Dronabinol (Marinol); Cannabis sativa (marijuana, hashish)

Diterpene Alkaloids Salvinorin A, C Myrisicin, saffrole

Salvia divinorum; sage Myristica fragrans (nutmeg, mace)

Anticholinergic Agents Atropine (D,L-hyoscyamine) Scopolamine (L-hyoscine)

Atropa belladonna (deadly nightshade), Datura stramonium (jimson weed) Transderm Scop; Datura stramonium (jimson weed), Hyoscyamus niger (henbane)

found in moist warm climates but are widely distributed across the United States. These mushrooms grow overnight in cow pastures after a rainfall. Characteristically, the stalks of some psilocybin mushrooms turn blue with handling secondary to oxidation.18 Psilocybin is quite stable; both dried mushrooms and boiled extract retain their hallucinogenic potency. Concentrations of psilocybin vary greatly from mushroom to mushroom (both within and between species), by season, and by location.19 The initial hallucinogenic effects (e.g.,

detachment and relaxation) of psilocybin are evident with as little as 4 mg of toxin.18,19 There is a dosage effect, with a dose of 12 mg or more producing vivid hallucinations. Due to the varied psilocybin content of each mushroom, it may take the ingestion of from 3 to 60 mushrooms to achieve the desired effect. In general, 4 to 8 mg of psilocybin is present in 20 g of fresh and 2 g of dried mushroom. Psilocybin sold on the street may be nonspecific mushrooms adulterated with LSD or other substances.

796


J

N

N

CH3 Lyseric acid diethylamide (LSD) :

OPO32

J

CH3

J J

N

CH3

N H Psilocybin

J J

J

CH3

HO

N

J

CH3

N H Bufotenine

CH3O

J J

J

CH3O

NH2

J

The neurotransmitter serotonin (5-hydroxytryptamine [5-HT]) is thought to play a major role in the pharmacology of most hallucinogens.26 The two major classes of hallucinogens, indoleamines and phenylalkylamines, display similar euphoric and psychedelic effects, are cross-tolerant, and are close structural analogs to serotonin (Fig. 45-1).27,28 These observations suggest that these hallucinogens share a common mechanism of

J J

STRUCTURE, STRUCTURE-ACTIVITY RELATIONSHIPS, AND PHARMACOLOGY

J

Salvia divinorum is a perennial herb in the mint family native to certain areas of the Sierra Mazateca region of Oaxaca, Mexico.23-25 Salvia is used medicinally and for divination by Mazatec Indians. Numerous species of Salvia are found in North and South America. Salvia is grown locally as sage or imported from Mexico. The active component of S. divinorum is salvinorin A and C, neoclerodane diterpenes (terpenoid essential oils). The hallucinogenic dose of Salvia is 10 to 20 fresh leaves chewed or two to five dried leaves smoked or vaporized. This is equivalent to inhaling 200 to 500 μg of salvinorin A.24,25 Thus, salvinorin A is a very potent hallucinogen, similar to LSD.

O

J

Salvinorin A and C

J J HJN J

J

Both nutmeg and mace are narcotic hallucinogens derived from a tall evergreen tree, Myristica fragrans, native to the Molucca Islands of the South Pacific and now cultivated on Grenada and Trinidad. Nutmeg is the dried seed kernel of the fruit and mace is derived from the fleshy outer covering of the seed.21,22 Nutmeg and mace are commonly used as spices. The volatile oils present in nutmeg and mace contain the active ingredients, which include myristicin, saffrole, and terpenes. The toxic dose of nutmeg is one to three whole nutmegs, or 5 to 15 g of the ground spice. To produce toxicity from ingestion of nutmeg, the seeds must first be crushed to release the active oils.

NH2 N H Serotonin

J

Nutmeg

J J

J

Mescaline is the active phenylethylamine alkaloid from the peyote cactus (Lophophora williamsii), which is found in the deserts of the southwestern United States and Mexico. Peyote is a spineless cactus, which forms buttons with seven to ten ribs. The cactus contains about 6% mescaline when dried. Peyote buttons are the round fleshy tubercles from the cactus. One peyote button contains about 40 to 50 mg of mescaline. The average hallucinogenic dose of synthetic mescaline is 5 mg/kg body weight or 4 to 12 peyote buttons.20 The legal use of peyote and mescaline in the United States is limited to Indian tribes in the Native American Church, who use peyote as part of religious ceremonies.

HO

J

Phenylethylamines

OCH3 Mescaline FIGURE 45-1 Chemical structures of serotonin and select hallucinogens.

action that involves serotonin. Evidence for this is solidified by numerous human studies that demonstrate a strong correlation between the relative affinity that these compounds have for 5-HT2A receptors and their potency as hallucinogens.29-31 When normal subjects are pretreated with adequate doses of the 5-HT2A antagonists ketanserin or risperidone, the hallucinogenic effects of psilocybin are completely blocked.32 These findings suggest further that the 5-HT2A receptor mediates the psychedelic effects of indoleamines and phenylethylamines. The importance of receptor subtype selectivity is underscored by the fact that drugs and medications that increase overall serotonergic tone (such as the serotonin selective reuptake inhibitors) do not produce the same clinical effects as hallucinogens. Partial agonist activity at 5-HT2A receptors is central to the hallucinatory effects of these agents, and binding at other serotonin receptor subtypes likely modulates these effects. Both hallucinogen classes are also agonists at 5-HT2C receptors.26 In addition, the indoleamines are agonists at 5-HT1A and dopamine D2 receptors.33 Interestingly, LSD has the structures of both serotonin and dopamine embedded in its nucleus; this latter finding may explain its dopamine receptor agonist properties.

CHAPTER 45

In general, addition of methyl hydroxyl groups to the benzene ring of the tryptamines or phenylethylamines increases lipophilicity, central nervous system (CNS) penetration, and hallucinogenic potency. For instance, addition of a methyl hydroxy group to bufotenine creates 5-MeO-DMT, a hallucinogen with greater CNS potency. Addition of methyl hydroxy groups to the benzene ring of phenylethylamines (e.g., mescaline) markedly increases CNS penetration and effects. Anatomically, the regions of the brain that appear to be the major targets of hallucinogens are the olfactory bulb, locus ceruleus, dorsal raphe nucleus, nucleus accumbens, and cerebral cortex (in particular, the medial prefrontal cortex).26,34,35 These brain regions are heavily concentrated with 5-HT2A receptors. These brain areas receive and process a large amount of sensory inputs from the body and environment and transfer this information to the cerebral cortex via extensive cortical projections.36,37 The cerebral cortex is responsible for final processing and interpretation of neuronal data. Hallucinogens facilitate neuronal activation in the aforementioned brain areas in response to external stimuli. They activate afferent inputs to the cortex while also filtering out tonic inhibitory influences; the end result is asynchronous neuronal activation of numerous cortical regions. Although serotonin pathways are integral to hallucinogen effects, other neurotransmitters are involved, and include glutamate, norepinephrine, dopamine, and γ-aminobutyric acid (GABA).26,38 Hallucinogen binding to central 5-HT2A receptors activates release of norepinephrine from the locus ceruleus, serotonin from raphe nuclei, GABA from specific cortical interneurons, and glutamate from multiple cortical areas.26 Enhanced glutamate activity is diffuse and asynchronous and results in cognitive, perceptual, and affective distortions. Tolerance to hallucinogens develops rapidly after regular use of these drugs.39,40 This is likely due, at least in part, to a rapid down-regulation of 5-HT2A receptors.41,42 Cross-tolerance between hallucinogens is also reported.27,28 Tolerance occurs to the euphoric and psychedelic effects, but not to autonomic effects. Although some users elect to use hallucinogens extensively, this class of drugs is not considered physiologically addicting. Tolerance does develop to the psychedelic effects, but no withdrawal syndrome has been observed. A recent review43 noted that there are no studies in which animals are trained to self-administer hallucinogens; animal self-administration is an important predictor of addiction. In rhesus monkeys, LSD was actually a negative reinforcer.44 The hallucinogenic mint S. divinorum contains the psychoactive neoclerodane diterpenes salvinorin A and C. These bioactive compounds are structurally distinct from other naturally occurring hallucinogens (e.g., indoleamines and phenylalkylamines) and do not bind 5-HT2 receptors. Rather, salvinorin A and C are potent, selective, opioid, κ receptor agonists and activate the dynorphin peptide system to induce analgesia, sedation, and perceptual distortion.23,45-48

Hallucinogens

797

PHARMACOKINETICS Formulations and Route of Administration Most hallucinogens are ingested but may also be chewed and absorbed orally, administered sublingually, insufflated, smoked, or injected intramuscularly or intravenously. LSD is a clear or white, odorless, tasteless powder. The powder is formulated as capsules, tiny tablets (“microdots”), and small gelatin squares (“windowpanes”) or applied to postage stamp–sized sheets (“blotter acid”) or sugar cubes.49 Each unit dose varies from 50 to 300 μg or more.12 LSD is typically ingested but may be smoked or injected. Exposure to natural lysergamides (e.g., morning glory) occurs following ingestion of seeds. The hallucinogenic tryptamines are typically ingested with the exception of DMT and 5-methoxy-DMT; these latter compounds are often insufflated, smoked, or injected IV. S. divinorum is administered in many ways; it is smoked (roll dried leaves into a “joint”), ingested (“oral infusion”), or chewed (“the quid”) and absorbed sublingually or from the buccal mucosa. Bufotenine can be isolated from secretions of the parotid and sebaceous glands of Bufo toads. “Toad licking” has been touted by some as a means to intoxication with this hallucinogen. This is misguided for two reasons. First, N,N-hydroxydimethyltryptamine is not well absorbed from the gastrointestinal (GI) tract and does not readily cross the blood-brain barrier; hallucinations will not result from toad licking. Second, several species of toads secrete potent cardioactive steroids or bufadienolides (e.g., bufalin) from their skin glands. Thus, toad licking may result in serious cardiac toxicity without a hallucinogenic effect.50

Absorption, Peak Clinical Effects, and Duration of Clinical Effects Certain pharmacokinetic parameters and clinical characteristics for select hallucinogens are provided in Tables 45-2 and 45-3. The time of onset and duration of clinical effects from hallucinogens vary according to the route of exposure and agent administered. In general, most hallucinogens are rapidly absorbed and distributed to the CNS after ingestion; clinical effects begin within 30 to 60 minutes after ingestion, peak by 2 to 4 hours, and last 4 to 8 hours. Certain agents have a very rapid onset and short duration of effects (e.g., DMT), whereas others may have effects that last 12 to 24 hours or more (e.g., mescaline, nutmeg, and ibogaine).

Metabolism and Excretion Most agents are extensively metabolized in the liver (by N-demethylation, hydroxylation, and glucuronidation) to inactive metabolites (see Table 45-2). Mescaline is also excreted unchanged in the urine.

798


TABLE 45-2 Pharmacokinetics of Select Hallucinogens

HALLUCINOGEN LSD Psilocybin DMT Mescaline

TIME TO PEAK SERUM CONCENTRATION AFTER ORAL DOSING (hr)


3–5 1–2 1.5 2

PROTEIN BINDING (%)

2–4 1.8–4.5 0.5–1.5 6

Vd (L/kg)

80–90 *

0.27 2.5–5 38–53

ROUTE OF METABOLISM

ACTIVE METABOLITE

Hepatic Hepatic Hepatic Renal (55%–60%); hepatic

No Yes (psilocin) No No

*Data not available. DMT, N,N-dimethyltryptamine; LSD, lysergic acid diethylamide; Vd, volume of distribution. Pharmacokinetic data obtained from references 18 and 55.

TABLE 45-3 Time of Onset and Duration of Effects of Select Hallucinogens HALLUCINOGEN

HUMAN RECREATIONAL DOSE

LSD

Oral: 25–250 μg (3 μg/kg) IV: 140 μg (2 μg/kg) Nasal insufflation: 100 mg

AMT DMT

Smoke: 30–150 mg IV/IM: 0.2–0.4 mg/kg

5-MeO-DMT 5-MeO-DIPT

IV or smoked: 5–10 mg Oral: 5–30 mg

Psilocybin

Oral: 4–12 mg (0.02 mg/kg); 20–30 fresh mushrooms or 1–2 g dried mushroom* Oral: 200–600 mg (5 mg/kg) Oral: 5–15 g ground spice; 1–3 nutmegs Oral: 1 mg Smoked: 200–500 μg

Mescaline Nutmeg Salvia divinorum

TIME OF ONSET OF CLINICAL EFFECTS

DURATION OF CLINICAL EFFECTS (hr)

Oral: 0.5–1 hr

4–12

Smoke, nasal: 5 min Oral: 15 min IV: 1–5 min IM: 10 min Oral: 30–60 min IV: 1–5 min Oral: 20 min Smoke: 10 min Oral: 20–30 min

8–16

45–60 min 2–4 hr 15 min

0.5–1 0.33–0.5 3–6 4–6 10–12 24 1–3

*The recreational dose of mushroom varies by mushroom genus and species, season, geographic location, and habituation of the user. AMT, α-methyltryptamine; DMT, N,N-dimethyltryptamine; 5-MeO-DIPT, 5-methoxy-N,N-diisopropyltryptamine; 5-MeO-DMT, 5-methoxy-N,Ndimethyltryptamine; IM, intramuscularly, IV, intravenously; LSD, lysergic acid diethylamide; Adapted from references 2, 18, 19, 43, and 55, and from Shulgin AT: Profiles of psychedelic drugs. Psilocybin. J Psychedelic Drugs 1980,12:79.

TOXICOLOGY Physiologic Disturbances In addition to their CNS effects, most hallucinogens produce a variety of autonomic (parasympathetic and sympathetic) effects that include mydriasis, tachycardia, hypertension, cutaneous flushing, salivation, lacrimation, hyper-reflexia, nausea, vomiting, abdominal cramps, hyperthermia, and tachypnea. These effects may occur directly from the drug or indirectly from the anxiety and CNS stimulation produced by the hallucinogen. The sympathomimetic effects from hallucinogens, for instance, may be mediated by stimulation of noradrenergic neurons in the locus ceruleus. Physiologic effects occur concurrently with the CNS disturbances. Other nonspecific effects include dizziness, ataxia, vertigo, weakness, headache, and paresthesias. Seizures have been rarely reported. Nutmeg, mescaline, and psilocybin ingestion

have a greater frequency of GI adverse effects (i.e., nausea, vomiting, epigastric cramps) than those associated with other hallucinogens.18,51 An anticholinergic-type syndrome has been associated with nutmeg intoxication.52 Although life-threatening physiologic disturbances are unusual, one series of eight patients with massive LSD overdose developed hyperthermia, coma, respiratory arrest, and coagulopathy.53

Central Nervous System Psychedelic Effects Acute perceptual distortions are the common thread that links the hallucinogens. Inanimate objects may begin to pulsate or move. Concrete physical boundaries, such as a wall or a person’s face, may appear to waver or even blend in with the surroundings; users frequently perceive that inanimate objects are “melting.” Geometric patterns are frequently described, and may be readily

CHAPTER 45

“visible” even when the eyes are closed. An object that moves across the user’s visual field may leave a “trail” that persists for several seconds. Synesthesias (the melding of sensory modalities) may occur, in which users may hear colors or see sounds. Sensory inputs such as sights or noises may seem more striking, and ordinary thoughts may seem quite profound. The user’s sense of time may be markedly distorted, or completely lost. Time contraction is common such that the user overestimates chronologic time. Most people who knowingly ingest hallucinogens welcome these perceptual distortions and find the experience quite pleasant. Occasionally, however, users have a profoundly dysphoric experience when using hallucinogens, typically referred to as a “bad trip.” The reason why one experience with hallucinogens is good and another bad is not entirely clear. Drug dose, the user’s environment, and the user’s attitude when taking the drug may all play a role. An interesting but uncontrolled convenience study of LSD users compared a group of 25 users with positive experiences with 25 users with negative experiences. There were no historical or clinical variables that accurately predicted a bad trip. Those with bad trips were not more likely to have a previous psychiatric diagnosis.54

Dose-Response Characteristics The usual recreational doses that produce hallucinogenic effects in humans are listed in Table 45-3. Psychedelic effects are dose related, such that low doses produce mild illusions and perceptual distortions whereas large doses may produce severe neurovegetative disturbances, extreme anxiety or dysphoria, disorientation, or the inability to discriminate between reality and illusion (true hallucinations).18 In general, hallucinogens have a remarkably low likelihood for producing significant acute morbidity and mortality. For instance, LSD has a therapeutic index of approximately 1000.55

“Flashbacks”: Hallucinogen Persisting Perception Disorder Perceptual distortions may recur months or years after hallucinogen abstinence. Commonly referred to as “flashbacks,” these perceptual distortions are formally known as hallucinogen persisting perception disorder (HPPD). HPPD is a recognized psychiatric diagnosis in which distressing “geometric hallucinations, false perceptions of movement in the peripheral visual fields, flashes of color, intensified colors, trails of images of moving objects, positive afterimages, halos around objects, macropsia, and micropsia”56 cannot be ascribed to an acute drug intoxication or another psychiatric illness or condition. The physiologic basis of HPPD is incompletely understood. Various theories have been proposed, including an LSD-induced decrease in tonic inhibitory tone in visual areas of the brain57 and/or LSD-induced sensitization of areas of visual processing within the brain.58 A genetic predisposition has also been postulated.59

Hallucinogens

799

Although several quantitative studies have addressed HPPD, this literature suffers from methodologic flaws, and firm conclusions are difficult to draw.60 Various pharmacologic treatments have been proposed to treat HPPD, which include clonidine61,62 and clonazepam.63,64 Interestingly, risperidone (which possesses antagonist activity at the 5-HT2 receptor) has been reported to exacerbate this condition,65 as have the serotonin selective reuptake inhibitors.66

Hallucinogen-Induced Psychiatric Disorders Prolonged perceptual distortions and hallucinosis that last a few days may occasionally occur after hallucinogen use. In addition, hallucinogens may induce acute anxiety, panic disorder, major depression, or schizophrenic episodes in susceptible individuals. There is some evidence that repeated hallucinogen use is a risk factor for the development of chronic or persistent thought disturbances.67 One case series described four patients diagnosed with schizophrenia within a few years of ingesting LSD between 50 and 300 times.68 The lack of a control group in this study significantly limits their findings. In addition, all of the patients were in their early 20s and an age at which first psychotic breaks occur in those who subsequently develop chronic schizophrenia. Another paper compared 46 schizophrenics and 46 controls and found no statistical difference in drug use in general, but a trend toward more LSD use among schizophrenics.69 A poorly chosen control group (all controls were employed, students, or hospital volunteers) significantly limits this study’s findings. Subsequent reviews of this subject70,71 have noted the flawed methodology of these and other similar reports, and concluded that there is no significant association between hallucinogen use and chronic thought disorders.

Chromosomal Abnormalities Reports suggesting that LSD use led to chromosomal damage both in vitro72 and in vivo73 surfaced in the late 1960s and early 1970s and received sensational media attention. Subsequent reports,74-77 however, disputed the link between LSD use and chromosomal damage. The belief that LSD damages human chromosomes is no longer widely held.

Morbidity and Mortality Due to Impaired Judgment Hallucinogens are generally thought to be “safe” drugs, in that they do not produce the potentially lifethreatening alterations in physiology that one might see with opiates, barbiturates, or cocaine. It should be noted, however, that significant injury or death may result from decisions that are made when hallucinogens have markedly impaired the user’s judgment. People under the influence of hallucinogens have mistakenly believed they could fly78 or have stared directly into the sun79-81 with disastrous consequences.

800


DIAGNOSIS The diagnosis of hallucinogen intoxication is made clinically and based on a positive history of exposure and suggestive physical findings. Most patients should be able to provide a history of hallucinogen use. Suggestive physical findings include mild to moderate sympathomimetic and GI effects coupled with a patient with ongoing perceptual and sensory illusions (e.g., visual distortions). Hallucinogens do not produce any characteristic abnormalities of the electrolytes or the complete blood count, so these basic ancillary tests are unlikely to aid in the diagnosis. Standard urinary toxicology (immunoassay) screens do not detect LSD or most other hallucinogens; specialized urinary testing kits for LSD are commercially available but not stocked by most hospitals. Even when available, false-positive test results82-85 limit the utility of such kits (Box 45-1). It should be understood that drugs of abuse screens designed to detect amphetamines and PCP are both insensitive and nonspecific for detection of designer drugs that are frequently abused. Confirmatory testing by gas chromatography/mass spectroscopy or highpressure liquid chromatography is sensitive and specific, but the results of such testing often take days to return. In the absence of a clear history of hallucinogen use, patients who have ingested this class of drugs are best approached as an undifferentiated patient with an alteration in mental status. A thorough history and physical examination should be obtained. Comprehensive ancillary testing, both basic (blood glucose level, serum electrolytes, complete blood count) and advanced (computed tomography of the head, lumbar puncture) should be considered.

Differential Diagnosis The manifestations of hallucinogen intoxication may be similar to intoxication with anticholinergic, sympatho-

BOX 45-1

SUBSTANCES THAT MAY CAUSE FALSE-POSITIVE URINARY LSD TESTING

Ambroxol (mucolytic) Amitryptyline Brompheniramine Bupivacaine Diphenhydramine Doxepin Doxylamine Ergonovine Fentanyl Imipramine Lidocaine Methylphenidate Metoclopramide Prilocaine Ranitidine Tramadol

mimetic (e.g., cocaine, amphetamines, methylxanthines), and other psychotropic (e.g., lithium) agents; withdrawal from alcohol or sedative-hypnotics; functional psychiatric disorders (e.g., acute panic disorder, schizophrenia); CNS or systemic infections; traumatic head injury; cerebrovascular accidents; and several metabolic disturbances (e.g., uremia, hepatic encephalopathy, hyponatremia, or hypoglycemia). In addition, the various hallucinogenic classes may be difficult, if not impossible, to differentiate from each other clinically. Patients may be differentiated from anticholinergic agent toxicity by the absence of delirium, repetitive picking behavior, urinary retention, ileus, or dry skin. Patients may be differentiated from amphetamine poisoning by the absence of stereotypic behavior (e.g., formication, lip smacking, and teeth grinding). Unlike those with hallucinogen intoxication, patients with functional psychoses are alert and oriented, have auditory hallucinations predominantly, lack synesthesias, and cannot differentiate their illusion from reality (true hallucinosis).

MANAGEMENT Most patients with hallucinogen intoxication have an uncomplicated course and do not require medical treatment. For those patients who require hospital evaluation due to unexpected adverse clinical effects, treatment is largely supportive. Although uncharacteristic for hallucinogen poisoning, patients with significant CNS or respiratory depression should have their airway protected, breathing assisted, and cardiovascular support provided as necessary. Supplemental oxygen, continuous pulse oximetry, and parenteral thiamine, dextrose (or rapid fingerstick glucose determination), and naloxone should be considered for patients with altered mental status or seizures. Significant CNS or respiratory depression, seizures, and hypotension are unlikely findings after hallucinogen use; their presence should prompt a search for another process. Hypertension, when present, is usually mild and rarely requires treatment. In the event that the clinician is concerned about hypertension in an agitated, hallucinating patient, a benzodiazepine (i.e., lorazepam, 1 to 2 mg IV) is an appropriate first intervention. GI decontamination is not routinely necessary for hallucinogen poisoning unless there is concern for coingestants. Since hallucinogens are rapidly absorbed after ingestion, the effectiveness of GI decontamination is marginal. In addition, since uncomplicated hallucinogen poisoning usually resolves without sequelae, the risks involved in performing decontamination procedures, particularly in the anxious patient, may outweigh any benefits. If GI decontamination is performed, singledose administration of activated charcoal (1 g/kg orally or by nasogastric tube) is the preferred method. Orogastric lavage is not recommended for this group of patients due to lack of efficacy and associated procedural morbidity. Gastric emptying procedures have not been found to have an effect on the severity and duration of

CHAPTER 45

symptoms when performed on series of patients intoxicated with hallucinogenic mushrooms.86,87 Patients that are anxious, frightened, or agitated due to negative or punitive distortions (a bad trip) should be provided rest and reassurance in a dark, quiet environment; this approach has been advocated successfully for over 30 years.88 In the event that concurrent sedation is indicated, benzodiazepines are the preferred pharmacotherapy, providing safe, nonspecific sympatholysis.89 The use of atypical antipsychotic agents, which specifically antagonize 5-HT2 receptors (e.g., ziprasidone, risperidone, clozapine), are theoretically attractive for the treatment of bad trips but have not been adequately studied.

DISPOSITION Most patients with hallucinogen poisoning develop only mild toxicity and are medically safe for psychiatric evaluation (if necessary) and disposition after an observation period of 4 to 6 hours in the ED. Patients who have continued evidence of agitation, perceptual distortions, and physiologic disturbances at 6 hours should be admitted to a monitored bed for continued observation. REFERENCES 1. Bruhn JG, De Smet PA, El-Seedi HR, Beck O: Mescaline use for 5700 years. Lancet 2002;359(9320):1866. 2. Erowid website: LSD. Accessed February 28, 2005, at http:// www.erowid.org/chemicals/lsd/lsd.shtml 3. Mangini M: Treatment of alcoholism using psychedelic drugs: a review of the program of research. J Psychoactive Drugs 1998;30(4):381–418. 4. Itil TM, Keskiner S, Holden JM: The use of LSD and ditran in the treatment of therapy resistant schizophrenics (symptom provocation approach). Dis Nerv Syst 1969;30(2 Suppl):93–103. 5. Neill JR: “More than medical significance”: LSD and American psychiatry 1953 to 1966. J Psychoactive Drugs 1987;19(1):39–45. 6. Novak SJ: LSD before Leary. Sidney Cohen’s critique of 1950s psychedelic drug research. Isis 1997;88(1):87–110. 7. Louria DB: Lysergic acid diethylamide. N Engl J Med 1968;278:435–438. 8. National Institutes of Health, National Institute on Drug Abuse: Sixth Triennial Report to Congress. Bethesda, MD, National Institute on Drug Abuse, 1999. 9. Chilcoat HD, Schutz CG: Age-specific patterns of hallucinogen use in the US population: an analysis using generalized additive models. Drug Alcohol Depend 1996;43(3):143–153. 10. Drug Abuse Warning Network: The DAWN Report, Club Drugs, 2001 Update. Rockville, MD, Office of Applied Studies, Substance Abuse and Mental Health Services Administration, Drug Abuse Warning Network, 2001 (March 2002 update). Accessed October 2004 at www.drugabusestatistics.samhsa.gov 11. Ingram AL: Morning glory seed reaction. JAMA 1964;190:107–108. 12. O’Brien CP: Drug addiction and drug abuse. In Hardman JG, Limbird LE, Gilman AG (eds): Goodman & Gilman’s the Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 557–577. 13. Weil AT, Davis W: Bufo alvarius: a potent hallucinogen of animal origin. J Ethnopharmacol 1994;41(1–2):1–8. 14. Meatherall R, Sharma P: Foxy, a designer tryptamine hallucinogen. J Anal Toxicol 2003;27(5):313–317. 15. Long H, Nelson LS, Hoffman RS: Alpha-methyltryptamine revisited via easy internet access. Vet Hum Toxicol 2003;45:149. 16. Schultes RE: Hallucinogens of plant origin. Science 1969;163: 245–254.

Hallucinogens

801

17. Strassman RJ: Human psychopharmacology of N,N-dimethyltryptamine. Behav Brain Res 1996;73:121–124. 18. Spoerke DG, Rumack BH: Handbook of mushroom poisoning: diagnosis and treatment. Boca Raton, FL, CRC Press, 1994. 19. Benjamin DR: Mushrooms: poisons and panaceas. New York, W.H. Freeman & Company, 1995. 20. Schultes RE, Hofmann A: Plants of the Gods. Rochester, VT, Healing Arts Press, 1992. 21. Mack RB: Toxic encounters of the dangerous kind. NC Med J 1982;43:439. 22. Kalbhen DA: Nutmeg as a narcotic. Angew Chem Internat Edit 1971;10:370–374. 23. Giroud C, Felber F, Augsburger M, et al: Salvia divinorum: an hallucinogenic mint which might become a new recreational drug in Switzerland. Forensic Sci Int 2000;112:143–150. 24. Valdes LJ, Chang HM, Visger DC, Koreeda M: Savinorin C, a new neoclerodane diterpene from a bioactive fraction of the hallucinogenic Mexican mint Salvia divinorum. Org Lett 2001;3: 3935–3937. 25. Bigham AK, Munro TA, Rizzacasa MA, Robins-Browne RM: Divinatorins A-C, new neoclerodane diterpenoids from the controlled sage Salvia divinorum. J Nat Prod 2003;66:1242–1244. 26. Aghajanian G, Marek G: Serotonin and hallucinogens. Neuropsychopharmacology 1999;21(Suppl 1):16–23. 27. Balestireri A, Fontanari D: Acquired and crossed tolerance to mescaline, LSD-25, and BOL-148. Arch Gen Psychiatry 1959;1: 279–282. 28. Isbell H, Wolbach AE, Wikler A, Miner EJ: Cross tolerance between LSD and psilocybin. Psychopharmacology (Berl) 1961;2:147–159. 29. Glennon RA, Titeler M, McKenney JD: Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sci 1984;35(25):2505–2511. 30. Sadzot B, Baraban JM, Glennon RA, et al: Hallucinogenic drug interactions at human brain 5-HT2 receptors: implications for treating LSD-induced hallucinogenesis. Psychopharmacology (Berl) 1989;98(4):495–499. 31. Titeler M, Lyon RA, Glennon RA: Radioligand binding evidence implicates the brain 5-HT2 receptor as a site of action for LSD and phenylisopropylamine hallucinogens. Psychopharmacology (Berl) 1988;94(2):213–216. 32. Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Babler A, et al: Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport 1998;9(17):3897–3902. 33. Winter JC, Filipink RA, Timineri D, et al: The paradox of 5methoxy-N,N-dimethyltryptamine: an indoleamine hallucinogen that induces stimulus control via 5-HT1A receptors. Pharmacol Biochem Behav 2000;65:75–82. 34. Aghajanian GK: Mescaline and LSD facilitate the activation of locus coeruleus neurons by peripheral stimuli. Brain Res 1980;186(2):492–498. 35. McKenna DJ, Mathis CA, Shulgin AT, et al: Autoradiographic localization of binding sites for 125I-DOI, a new psychotomimetic radioligand, in the rat brain. Eur J Pharmacol 1987;137(2–3): 289–290. 36. Aston-Jones G, Bloom FE: Norepinephrine-containing locus coeruleus neurons in behaving rats’ exhibit pronounced responses to non-noxious environmental stimuli. J Neurosci 1981;1(8):887–900. 37. Cedarbaum JM, Aghajanian GK: Activation of locus coeruleus neurons by peripheral stimuli: modulation by a collateral inhibitory mechanism. Life Sci 1978;23(13):1383–1392. 38. Winter JC, Eckler JR, Rabin RA: Serotonergic/glutamatergic interactions: the effects of mGlu(2/3) receptor ligands in rats trained with LSD and PCP as discriminative stimuli. Psychopharmacology (Berl) 2004;172(2):233–270. 39. Isbell H, Belleville RE, Fraser HF, et al: Studies on lysergic acid diethylamide (LSD-25): 1. Effects in former morphine addicts and development of tolerance during chronic intoxication. Arch Neurol Psychiatry 1956;76:468–478. 40. Angrist B, Rotrosen J, Gershon S: Assessment of tolerance to the hallucinogenic effects of DOM. Psychopharmacologia 1974;36(3): 203–207. 41. Buckholtz NS, Zhou DF, Freedman DX: Serotonin2 agonist administration down-regulates rat brain serotonin2 receptors. Life Sci 1988;42(24):2439–2445.

802


42. Buckholtz NS, Freedman DX, Middaugh LD: Daily LSD administration selectively decreases serotonin2 receptor binding in rat brain. Eur J Pharmacol 1985;109(3):421–425. 43. Nichols DE: Hallucinogens. Pharmacol Ther 2004;101(2):131–181. 44. Hoffmeister F: Negative reinforcing properties of some psychotropic drugs in drug-naive rhesus monkeys. J Pharmacol Exp Ther 1975;192(2):468–477. 45. Valdes LJ 3rd: Salvia divinorum and the unique diterpene hallucinogen, Salvinorin (divinorin) A. J Psychoactive Drugs 1994;26(3):277–283. 46. Chavkin C, Sud S, Jin W, et al: Salvinorin A, an active component of the hallucinogenic sage Salvia divinorum is a highly efficacious κ-opioid receptor agonist: structural and functional considerations. J Pharmacol Exp Ther 2004;308(3):1197–1203. 47. Butelman ER, Harris TJ, Kreek MJ: The plant-derived hallucinogen, salvinorin A, produces kappa-opioid agonist-like discriminative effects in rhesus monkeys. Psychopharmacology (Berl) 2004;172(2):220–224. 48. Roth BL, Baner K, Westkaemper R, et al: Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proc Natl Acad Sci U S A 2002;99(18):11934–11939. 49. Kilmer SD: The isolation and identification of lysergic acid diethylamide (LSD) from sugar cubes and a liquid substrate. J Forensic Sci 1994;39(3):860–862. 50. Hitt M, Ettinger DD: Toad toxicity. N Engl J Med 1986;314(23): 1517–1518. 51. Stein U, Greyer H, Hentschel H: Nutmeg (myristicin) poisoning— report on a fatal case and a series of cases recorded by a poison information centre. Forensic Sci Int 2001;118(1):87–90. 52. Lavy G: Nutmeg intoxication in pregnancy. A case report. J Reprod Med 1987;32(1):63–64. 53. Klock J, Boermer V, Berher C: Coma, hyperthermia and bleeding associated with massive LSD overdose: a report of 8 cases. Clin Toxicol 1975;8:191–203. 54. Ungerleider JT, Fisher DD, Fuller M, et al: The “bad trip”—the etiology of the adverse LSD reaction. Am J Psychiatry 1968; 124(11):1483–1490. 55. Baselt RF: Disposition of Toxic Drugs and Chemicals in Man. Foster City, CA, Biomedical Publications, 2004. 56. American Psychological Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed, text revision. Washington, DC, American Pyschological Association, 2000. 57. Abraham HD, Aldridge AM: Adverse consequences of lysergic acid diethylamide. Addiction 1993;88(10):1327–1334. 58. Phillips TJ: Behavior genetics of drug sensitization. Crit Rev Neurobiol 1997;11:21–31. 59. Abraham HD: Visual phenomenology of the LSD flashback. Arch Gen Psychiatry 1983;40(8):884–889. 60. Halpern JH, Pope HG Jr: Hallucinogen persisting perception disorder: what do we know after 50 years? Drug Alcohol Depend 2003;69(2):109–119. 61. Lerner AG, Finkel B, Oyffe I, et al: Clonidine treatment for hallucinogen persisting perception disorder. Am J Psychiatry 1998;155(10):1460. 62. Lerner AG, Gelkopf M, Oyffe I, et al: LSD-induced hallucinogen persisting perception disorder treatment with clonidine: an open pilot study. Int Clin Psychopharmacol 2000;15(1):35–37. 63. Lerner AG, Skladman I, Kodesh A, et al: LSD-induced hallucinogen persisting perception disorder treated with clonazepam: two case reports. Isr J Psychiatry Relat Sci 2001;38(2):133–136. 64. Lerner AG, Gelkopf M, Skladman I, et al: Clonazepam treatment of lysergic acid diethylamide-induced hallucinogen persisting perception disorder with anxiety features. Int Clin Psychopharmacol 2003;18(2):101–105.

65. Morehead DB: Exacerbation of hallucinogen-persisting perception disorder with risperidone. J Clin Psychopharmacol 1997;17(4): 327–328. 66. Markel H, Lee A, Holmes RD, et al: LSD flashback syndrome exacerbated by selective serotonin reuptake inhibitor antidepressants in adolescents. J Pediatr 1994;125:817–819. 67. McLellan AT, Woody GE, O’Brien CP: Development of psychiatric illness in drug abusers: possible role of drug preference. N Engl J Med 1979;301:1310–1314. 68. Glass GS, Bowers MB Jr: Chronic psychosis associated with longterm psychotomimetic drug abuse. Arch Gen Psychiatry 1970; 23(2):97–103. 69. Breakey W, Goodell H, Lorenz PC, et al: Hallucinogenic drugs as precipitants of schizophrenia. Psychol Med 1974;4:255–261. 70. Strassman RJ: Adverse reactions to psychedelic drugs. A review of the literature. J Nerv Ment Dis 1984;172(10):577–595. 71. Halpern JH, Pope HG Jr: Do hallucinogens cause residual neuropsychological toxicity? Drug Alcohol Depend 1999;53(3):247–256. 72. Cohen MM, Marinello M, Bark N: Chromosomal damage in human leudocytes induced by lysergic acid diethylamide (LSD25). Science 1967;155:1417–1419. 73. Corey MJ, Andrews JC, McLeao MJ, et al: Chromosome studies on patients (in vivo) and in cells (in vitro) treated with LSD-25. N Engl J Med 1970;282:939–942. 74. Robinson JT, Chitham RG, Greenwood RM, Taylor JW: Chromosome aberrations and LSD. A controlled study in 50 psychiatric patients. Br J Psychiatry 1974;125(0):238–244. 75. Tjio JH, Pahnke WN, Kurland AA: LSD and chromosomes. A controlled experiment. JAMA 1969;210(5):849–856. 76. Muneer RS: Effects of LSD on human chromosomes. Mutat Res 1978;51(3):403–410. 77. Cohen MM, Shiloh Y: Genetic toxicology of lysergic acid diethylamide (LSD-25). Mutat Res 1977–1978;47(3–4):183–209. 78. Reynolds PC, Jindrich EJ: A mescaline associated fatality. J Anal Toxicol 1985;9(4):183–184. 79. Fuller DG: Severe solar maculopathy associated with the use of lysergic acid diethylamide LSD). Am J Ophthalmol 1976;81(4): 413–416. 80. Ewald RA: Sun gazing associated with the use of LSD. Ann Ophthalmol 1971;3(1):15–17. 81. Schatz H, Mendelblatt F: Solar retinopathy from sun-gazing under the influence of LSD. Br J Ophthalmol 1973;57(4):270–273. 82. Rohrich J, Zorntlein S, Lotz J, et al: False-positive LSD testing in urine samples from intensive care patients. J Anal Toxicol 1998; 22(5):393–395. 83. Gagajewski A, Davis GK, Kloss J, et al: False-positive lysergic acid diethylamide immunoassay screen associated with fentanyl medication. Clin Chem 2002;48(1):205–206. 84. Grobosch T, Lemm-Ahlers U: Immunoassay screening of lysergic acid diethylamide (LSD) and its confirmation by HPLC and fluorescence detection following LSD ImmunElute extraction. J Anal Toxicol 2002;26(3):181–186. 85. Wiegand RF, Kletter KL, Stout PR, et al: Comparison of EMIT II, CEDIA, and DPC RIA assays for the detection of lysergic acid diethylamide in forensic urine samples. J Anal Toxicol 2002; 26(7):519–523. 86. Young RE, Hutchison S, Milroy R, Kesson CM: The rising price of mushrooms. Lancet 1982;1:213. 87. Peden NR, Pringle SD, Crooks J: The problem of psilocybin mushroom abuse. Hum Toxicol 1982;1:417. 88. Martin CM: Caring for the “bad trip.” A review of current status of LSD. Hawaii Med J 1970;29(7):555–560. 89. Miller PK, Gay GR, Ferris KC, Anderson S: Treatment of acute adverse psychedelic reactions: “I’ve tripped and I can’t get down.” J Psychoactive Drugs 1992;24:277–279.

46

GHB and Related Compounds LAWRENCE S. QUANG, MD

At a Glance… ■

■

■

■

■

GHB, a schedule I drug, is a potent central nervous system depressant that is abused illicitly for its sedative, euphoric, and hallucinogenic effects. GHB has also been popular as a sports and dietary health supplement for its growth hormone–releasing, anxiolytic, and soporific effects as well as numerous other unproven “natural health benefits.” GBL and 1,4-BD are chemical precursors that are converted in vivo to GHB via simple enzymatic biotransformation steps; GVL, GHV, and THF are GHB structural analogs with anecdotal case reports of abuse and overdose. Acute toxicity from GHB and its chemical precursors and analogs consists primarily of central nervous system and respiratory depression; chronic abuse of GHB, GBL, and 1,4-BD has resulted in chemical dependency and a severe withdrawal state upon abrupt cessation. Treatment of acute GHB overdose and its withdrawal state consists of aggressive supportive care.

Despite the known dangers of illicit γ-hydroxybutyric acid (GHB) abuse, greatly publicized by the harmful, illicit, and unlawful use of GHB by high-profile celebrities, such as professional basketball player Tom Gugliotta,1 Hollywood actor Nick Nolte,2 and Max Factor heir Andrew Luster,3,4 GHB has developed into a favorite party drug in popular culture during the past 15 years.5-8 GHB and its many chemical precursors and structural analogs, most notably γ-butyrolactone (GBL) and 1,4-butanediol (1,4-BD), have become fashionable and trendy recreational drugs during the past decade as reports of its “natural” euphoric and hallucinogenic properties popularized its illicit abuse. GHB, GBL, and 1,4-BD represent an emerging group of drugs among the broad class of recreational drugs known as “club drugs.” According to the National Institute on Drug Abuse/ National Institutes of Health, the term club drugs derived from the association of these drugs with dance clubs and all-night dance parties called “raves,” and include other such drugs as N-methyl-3,4-methylenedioxymethamphetamine (see Chapter 44), ketamine (see Chapter 43), flunitrazepam (see Chapter 35), methamphetamine, (see Chapter 44), and lysergic acid diethylamide (see Chapter 45).9 Like most club drugs, GHB, GBL, and 1,4BD are physically and psychologically addictive, with acute and chronic toxicity that may be severe or lethal. However, GHB, GBL, and 1,4-BD possess many epidemiologic characteristics and pharmacologic properties that are distinctive from other club drugs. Ironically, before their recent emergence as popular recreational club drugs, GHB, GBL, and 1,4-BD had a relatively quiescent

history of medical research and licit therapeutic use spanning more than six decades. This chapter will review the unique history and complex evolution of GHB into a contemporary drug of abuse as well as its pharmacology, toxicology, and clinical diagnosis, management, and disposition.

RELEVANT HISTORY Of the three principal GHB analogs, GBL was discovered first, in 1947, 13 years before GHB and 19 years before 1,4-BD.10,11 GHB was subsequently discovered in 1960 by the French scientist Henri Laborit, who synthesized it as a structural analog of the inhibitory neurotransmitter γ-aminobutyric acid (GABA), which was capable of traversing the blood-brain barrier (BBB) after peripheral administration.12-14 Three years after its laboratory synthesis, GHB was discovered to be a naturally occurring neurochemical in the mammalian brain.15,16 In 1966, Sprince and colleagues were the first investigators to make the association of 1,4-BD with GHB. Noting the close structural similarity of 1,4-BD with GHB, they demonstrated that 1,4-BD could produce an anesthetic response similar to that of GHB and GBL. In this rodent study, GHB, GBL, and 1,4-BD all produced an anesthetic state that was characterized by the loss of voluntary movement, righting reflex, struggle response, and body and limb tone, as well as myoclonic jerking. They further demonstrated that the electroencephalographic (EEG) tracings of GHB, GBL, and 1,4-BD had very similar wave patterns.17 As a result of these discoveries, GHB found its first clinical application as an anesthetic agent in the early 1960s.12-14 Several clinical studies in the 1960s, involving a total of 376 patients, confirmed the potential of GHB to serve as an adjuvant to anesthesia.18,19 However, those same studies also documented several adverse reactions to GHB anesthesia, including the occurrence of gross muscular movements when rapidly administered, as well as inadequate analgesia (abrupt rise in systolic and diastolic pressure during surgical incision), emergence delirium, and bradycardia. Although GHB continues to be investigated and used as an anesthetic adjuvant abroad,20-22 it has never gained widespread acceptance in the United States for this clinical application. In the decades since its initial scientific discovery as a GABA-mimetic neurochemical, GHB has been diverted from an investigational drug with legitimate research applications and licit medical uses to the toxic ingredient in banned nutritional supplements and illicit recreational drugs. An important milestone in this devolution occurred in 1977, when Takahara and colleagues reported that an intravenous dose of 2.5 g of GHB resulted in a 803


significant increase in plasma growth hormone (GH) and REM sleep in six healthy male subjects.23 This discovery launched concerted efforts to study and develop GHB as a potential therapeutic agent for sleep disorders such as narcolepsy. However, as an unintended and misappropriated consequence of this and similar other studies, GHB became popular as a sports supplement and “natural” soporific. Subsequently, in the late 1980s, GHB was introduced to the health and dietary supplement market with dubious claims that it could metabolize fat, enhance muscle building, and improve sleep. However, it was quickly associated with severe adverse effects and deaths as overzealous self-administration of GHB-containing nutritional supplements resulted in a well-characterized toxidrome of coma, cardiorespiratory depression, apnea, seizure-like activity, and, in several instances, death.5,6,7 Accordingly, the U.S. Food and Drug Administration (FDA) intervened in November 1990 to prohibit over-the-counter (OTC) sale of GHB in nutritional supplements.7 However, GHB purveyors easily circumvented the FDA ban on OTC sale of GHB-containing products by substituting GBL for GHB as the active ingredient. Predictably, toxic effects similar to GHB, including deaths, were reported and confirmed to be attributable to GBL soon after its substitution into dietary health supplements.8,24-34 Consequently, the FDA issued a recall of GBL-containing health supplements in February 1999, which was easily evaded by the substitution of GBL with 1,4-BD.35,36 Predictably, the consequences of 1,4-BD misuse and abuse were clinically similar to that of GHB and GBL, including death.35-42 In the midst of its emergence as an illicit drug, GHB received both orphan drug and investigational new drug (IND) status from the FDA for clinical trials as a therapeutic agent for narcolepsy. Confounding and nearly preventing its clinical development as a narcolepsy treatment, GHB also developed forensic notoriety as a chemical submission agent used in the commission of drug-facilitated sexual assault, or “date rape.” After several highly publicized GHB-related date rape deaths, the Hillory J. Farias and Samantha Reid Date-Rape Prohibition Act (Public Law 106-72) was legislated by Congress and signed into law by President Clinton on March 11, 2000.43,44 Under this federal statute, GHB received dual scheduling as a schedule III drug for IND use in clinical trials for narcolepsy and as a schedule I drug for illicit purposes. GBL, which has numerous legitimate uses as an industrial solvent, was recognized as a federal list I chemical under this federal statute. Under this law, authority was granted to federal law enforcement agencies to monitor the commercial and industrial sale and distribution of GBL for potential diversionary activity. There was no specific mention of 1,4-BD in this federal law, but 1,4-BD, which also has many legitimate uses as an industrial solvent, was classified by the FDA as a class I health hazard in response to several 1,4-BDrelated deaths in 1999.29,37,38,42 This FDA categorization recognized 1,4-BD to be a potentially life-threatening health hazard but did not impose any regulatory actions on its commercial sale or distribution.

EPIDEMIOLOGY National statistics from the American Association of Poison Control Centers–Toxic Exposure Surveillance System (AAPCC-TESS), Drug Abuse Warning Network (DAWN), and Monitoring the Future Study (MTFS) have demonstrated a trend of escalating GHB abuse and poisoning throughout the past decade. In 2002, 1386 exposures with GHB and its analogs and precursors were reported to the AAPCC-TESS, representing more than a twofold increase from approximately 600 GHB cases reported in 1996. Among these, 1181 exposures (85%) required treatment in a health care facility and resulted in 272 major outcomes and 3 deaths.45 Eighty-five percent of these exposures involved individuals over the age of 19. According to DAWN, emergency department (ED) episodes related to GHB increased significantly from 1994 to 1999, and GHB mentions increased dramatically from 1997 to 2000 (Fig. 46-1).46 Since 2000, trends in ED mentions of GHB appear to have leveled off, with GHB mentions lower in 2002 than in 2000 (Fig. 46-2). ED mentions of GHB appeared to have peaked in 2000, but there was nevertheless a significant long-term increase in ED episodes for GHB from 1995 to 2002 (2197% increase, from 145 to 3330). Almost half (46%) of these ED mentions of GHB were attributed to patients age 20 to 25, nearly 90% were white, and two thirds were male. In 2001, the estimated rate of GHB ED mentions per 100,000 population, by metropolitan area, was highest for San Francisco (9.3%), Dallas (6.7%), New Orleans (5.6%), and Atlanta (4.6%), and GHB abuse increased in 9 of the 21 cities monitored in 2001.47 Overdose was the predominant reason for ED contact in episodes involving GHB (88%), and the recreational pursuit of its psychic effects was the predominant motive for use among patients with adverse events from GHB (46%). 6,000

4969

5,000

ED mentions for GHB

804

4,000

3178

3340

3330

3,000

2,000

1282 1,000

638

762

145 0

1995 1996 1997 1998 1999 2000 2001 2002 Year FIGURE 46-1 Emergency department trends for GHB. Final estimates from the Drug Abuse Warning Network (DAWN), 1995–2002. (Compiled from the Substance Abuse and Mental Health Services Administration, Office of Applied Studies: Emergency Department Trends from DAWN, Final Estimates 1995–2002, DAWN Series: D-24. DHHS Publication No. SMA 033780. Rockville, MD, Department of Health and Human Services, 2003.)

CHAPTER 46

GHB and Related Compounds

805

A

B

C FIGURE 46-2 A, GHB powder, GHB powder dissolved in a water vial and in water bottles, and GHB capsules and drinking solutions. B, GBL in various dietary supplements. C, 1,4-Butanediol in various dietary supplements and in a 55-gallon drum confiscated by the Drug Enforcement Agency.

Seventy-four percent of ED visits for GHB intoxication involved another club drug. Alcohol was the most frequently mentioned co-ingestant in visits that involved GHB (54%), followed by marijuana (14%) and 3,4methylenedioxymethamphetamine (MDMA, or “Ecstasy,” 12%).48 While most GHB abusers are young adults, adolescents have also abused GHB, and the 2002 MTFS reported an annual prevalence rate of GHB use of 0.8%, 1.4%, and 1.5% in grades 8, 10, and 12, respectively.49 These prevalence rates have shown little change since they were first measured for GHB in 2000. Although epidemiologic data are unavailable for each specific GHB analog, the rising abuse of GHB documented by AAPCC-TESS, DAWN, and MTFS likely reflects a parallel increase in GHB analog abuse as well. The illicit use of GHB and its precursors appears to have plateaued in the United States, but recent international statistics have reported GHB abuse to be on the rise worldwide. The escalating international abuse of GHB has resulted in its scheduling by the United Nations (UN). On March 20, 2001, the UN’s Commission on Narcotic Drugs, at the recommendation of the World Health Organization, added GHB to schedule IV of the 1971 Convention on Psychotropic Substances.50,51 Schedule IV mandates international licensing for manu-

facture, trade, and distribution of GHB and requires all nation signatories of this treaty to comply with prohibition of and restrictions on export and import of GHB, and to “adopt measures for the repression of acts contrary to these laws and regulations.” However, since the implementation of this international GHB schedule in 2001, most of the literature reporting toxicity from acute overdoses with GHB has emerged from outside the United States, including the United Kingdom,52 Spain,53 Switzerland,54 the Netherlands,55 and Australia and New Zealand.56,57 In Spain, GHB was responsible for 3.1% of all toxicologic emergencies in an urban public hospital ED during a 15-month study period and ranked second in illicit drugs requiring emergency consultation.53 Conversely, while European and Asian countries have reported recent rises in acute poisonings from GHB and its chemical precursors and structural analogs, virtually all of the reports of GHB dependence and withdrawal have emerged from the United States. Illicit use of GHB and its analogs have primarily occurred in one of four settings: in the recreational setting of dance raves or night clubs, in the athletic setting of bodybuilding gyms and fitness centers, in the home consumer setting of individuals seeking its “natural health benefits,” and in the criminal setting of drug-

806


facilitated sexual assault. At raves and nightclubs, GHB is used to achieve effects that have been equated to a combination of alcohol (euphoria, disinhibition, and anxiolysis) and ecstasy (enhanced sensuality, emotional warmth).51 Current street names for GHB and its precursors and analogs include liquid ecstasy, liquid E, Fantasy, grievous bodily harm, Georgia home boy, great hormones at bedtime, great human benefit, organic quaalude, liquid X, soap, salty water, easy lay, and liquid FX.42,58-61 In gyms and health food stores, GHB is sold as a performance-enhancing additive in bodybuilding formulas and drinks that are promoted as growth hormone releasers and muscle builders. GHB and its analogs have also been sold to home consumers as “natural” health food and nutritional supplements purporting to enhance weight loss, sexual potency, baldness reversal, and eyesight improvement, and to decrease aging, depres-sion, insomnia, and alcohol, and drug addiction.62 Products containing GHB, GBL, or 1,4-BD and marketed for these purposes—Somatomax PM, Natural Sleep-500, Renewtrient, Revivarant or Revivarant G, Blue Nitro or Blue Nitro Vitality, GH Revitalizer, Gamma G, Remforce, Invigorate, Jolt, Renewtrient, Verve Revitalize Plus, Serenity, Enliven, GHRE, SomatoPro, NRG3, Thunder Nectar, Weight Belt Cleaner, Inner G, Serenity, Soma Solutions, Blue Nitro, and others—are generally no longer sold because of law enforcement pressure; however, comparable products with similar brand names are available (see Fig. 46-1).38,42,58-61 Criminally, GHB has been employed in the commission of date rape, and the Drug Enforcement Agency (DEA) has documented 15 drug-facilitated sexual assaults involving 30 victims under the influence of GHB.58 In the only known published study on the prevalence of drugs used in cases of alleged sexual assault, urine specimens from 1179 cases were submitted to forensic toxicologists nationwide to test specifically for date rape drugs. Approximately 711 samples (60%) tested positive for one or more drugs, and GHB was specifically detected in 48 of these positive samples (6.75%).63 Presently, the major distributors of street GHB are clandestine laboratories, both domestic and foreign, that manufacture GHB using a relatively simple synthesis procedure with commercially available, easily accessible, and inexpensive solvents (GBL) and reagents (a base, such as sodium hydroxide). An alternative source for GHB has been home synthesis via recipes and kits that have been available thorough the Internet and mail order.38,64 Once synthesized, GHB is a clear and odorless liquid that is often distributed in “spring water” bottles and dispensed to the user by the water-bottle cap, with a “capful” being the most common dosage unit.58,59 GBL and 1,4-BD have been directly substituted for GHB in such packaging. In many instances, these illicit preparations are disguised by adding food coloring and flavoring agents and stored in water or sports drink bottles or in unsuspecting packaging such as eye-dropper bottles, glass vials, and mouthwash bottles. At nightclubs, bars, and “rave” parties, GHB is often sold for $5 to $20 per capful, which is orally consumed in an average dose

of 1 to 5 g.58-61 When consumed by the capful, one 55-gallon drum of GBL can yield 240,000 capfuls, potentially yielding $1.9 million per 55-gallon drum.59 While oral ingestion of liquid GHB is the most common route of consumption, capsule and tablet forms are also available, as is powdered GHB, which is snorted or dissolved in a liquid.61 Because of its salty taste, powdered or liquid GHB is typically mixed into a beverage. The quality, purity, and concentrations of GHB in these illicit preparations are usually so varied that the user is often unaware of the actual dose that is being consumed. An important epidemiologic trend in GHB abuse is the increased use of analogs. To evade law enforcement detection, GHB distributors have recently developed and distributed new analogs, which are abused in substitution of GHB or used to synthesize GHB. The list of GHB analogs known to be used for these purposes continues to evolve and expand. At present, this list includes GBL, 1,4-BD, GHV, GVL, and THF.58-61,65 Both GBL and 1,4-BD are well documented to be abused as chemical precursors of GHB, which will rapidly metabolize to GHB after ingestion. Although rarely reported in cases of acute GHB poisoning, THF is also a chemical precursor of GHB. GVL is abused as a substitute for GHB because it metabolizes to GHV, an analog with physiologic effects similar to GHB. Among the GHB analogs, only GBL is used as a precursor ingredient for the illicit synthesis of GHB. GHB analogs are usually distributed as liquids and orally consumed. Despite federal anti-GHB legislation, GHB analogs remain legally available in products not intended for human consumption, since GBL, 1,4-BD, GVL, and THF have legitimate uses as solvents for industrial production of polyurethane, pesticides, elastic fibers, coatings on metals and plastics, and other manufacturing products. Exploiting this legal loophole, GHB purveyors have recently diverted these analogs into thinly veiled household products sold as “fish tank cleaner,” “ink stain remover,” “ink cartridge cleaner,” and “nail enamel remover” for approximately $100 per bottle.

STRUCTURE AND STRUCTURE-ACTIVITY RELATIONSHIPS GHB has several endogenous structural analogs and chemical precursors as well as several well-characterized synthetic structural analogs and precursors. The chemical structures, structure-activity relationships, and biotransformation steps of GHB and its numerous endogenous and synthetic analogs are shown in Figure 46-3. The structure-activity relationships of GHB and these analogs have been methodically examined with the use of [3H]GHB binding studies by Bourguignon and colleagues and are summarized in Table 46-1.66-68

PHARMACOLOGY GHB has a dual pharmacologic profile, with the intrinsic neuropharmacology of endogenous GHB distinct and divergent from that of exogenously administered GHB.

CHAPTER 46


O

807

OH

OH

1,4-Butanediol Tetrahydrofuran 4

1

K

Gamma-valerolactone

O

O

2

Gamma-butyrolactone

OH

O

O

3

K

CH3

K

O

J

O

OH

2-Hydroxy tetrahydrofuran

H

Gamma-hydroxybutyraldehyde

6

K

OH

O

6

OH

OH

OH CH3

5

K

O

Gamma-hydroxybutyric acid

Gamma-hydroxyvaleric acid 7 9

8

O

OH

OH

O

Trans-4-Hydroxycrotonic acid

Krebs cycle

Succinic acid 11

O

K OH OH

O

NH2

K

OH

OH

O

Succinic semialdehyde 12

K

OH

K

K

K

OH

H

O

10

K

O

OH

4,5-Dihydroxyhexanoic acid Gamma-aminobutyric acid FIGURE 46-3 Chemical structures, biotransformation reactions, and metabolic steps of gamma-hydroxybutyric acid and its chemical precursors and analogues. Numbered enzymes/reactions include 1, tetrahydrofuran hydroxylase; 2, 2-hydroxy tetrahydrofuran dehydrogenase; 3, 2-hydroxy tetrahydrofuran isomerase; 4, alcohol dehydrogenase; 5, aldehyde dehydrogenase; 6, nonezymatic hydrolysis or peripheral tissue and serum lactonases; 7, GHB dehydrogenase or hydroxyacid-oxoacid transhydrogenase; 8, succinic semialdehyde reductase; 9, β-oxidation; 10, succinic semialdehyde dehydrogenase, 11, GABA transaminase; and 12, an uncharacterized reaction (involving 2-carbon condensation?) forming 4,5-dihydroxyhexanoic acid from succinic semialdehyde.

The principal difference between their profiles is that the intrinsic neuropharmacologic activity of endogenous GHB appears to be mediated by the GHB receptor, while the neuropharmacologic activity of exogenously administered GHB is likely mediated by the GABA(B) receptor. Whereas other pharmacologic aspects of endogenous GHB are presently well characterized, research on exogenous GHB neuropharmacology is only in its nascent stages. Therefore, while other pharmacologic differences probably exist between endogenous and exogenous GHB, they are under investigation and have yet to be clarified.

Endogenous GHB Although the precise physiologic function of endogenous GHB is unknown, GHB is a putative neurotransmitter or neuromodulator because it possesses the requisite pharmacologic properties for recognition as such: 1. It has a discrete regional and subcellular distribution in the central nervous system (CNS).69-72

2. It has subcellular systems for synthesis, vesicular uptake, and storage in presynaptic terminals.71,73-92 3. It is released in a Ca2+-dependent manner following depolarization of neurons.71,93-95 4. Subsequent to neuronal release, GHB binds to GHBspecific receptors and modulates neurotransmitter systems.71,96-118 5. Following neuronal release, GHB activity is terminated by active uptake from the synaptic cleft for metabolism by specific cytosolic and mitochondrial enzymes.71,119-140 6. Localized application of GHB can produce a response that mimics the action of endogenous GHB released by nerve stimulation (i.e., synaptic mimicry).141-146 These pharmacologic properties of GHB are major preconditions if GHB is to play a role in interneuronal signaling or neuromodulation. GHB is heterogeneously distributed throughout the mammalian CNS, with its highest concentrations found in the hippocampus, basal ganglia, hypothalamus, striatum, and substantia nigra.69-71 GHB is concentrated in the cytosolic and

808


TABLE 46-1 Structure-Activity Relationships of Substituted GHB and Structurally Related Synthetic Compounds GHB RECEPTOR BINDING (% INHIBITION) N0. AND NAME OF GHB DERIVATIVE Endogenous Structural Analogs 1 GABA 2 Trans-4-hydroxycrotonic acid (T-HCA)

SUBSTITUTION/MODIFICATION ON GHB MOLECULE

AT 10 μmol/L

γ-NH2 Unsaturation of GHB by double bond between α and β carbon

NA 64

Lactone ring of GHB Unsaturation of GBL by double bond between α and β carbon Substitution of —C-OH for —C-OOH

NA NA

Lengthening of GHB chain by one carbon γ-CH3

8 γ-phenyl-GHB

γ

9 γ-(p-chlorophenyl)-GHB

γ

CI

NR

10 γ-(p-methoxyphenyl)-GHB

γ

OCH3

NR

11 γ-benzyl-GHB

γ

CH3

12 γ-benzyl-GHB (R enantiomer)

γ

CH3

13 γ-benzyl-GHB (S enantiomer)

γ

CH3

14 γ-(p-methoxybenzyl)-GHB (NCS 435)

γ

CH3

Endogenous Precursors 3 γ-butyrolactone (GBL) 4 γ-crotonolactone (GCL) 5 1,4-Butanediol (1,4-BD) Synthetic Structural Analogs 6 5-Hydroxyvaleric acid 7 γ-methyl-GHB

Synthetic Structural Precursors 15 γ-valerolactone (GVL) 16 Tetrahydrofuran (THF)

OCH3

Addition of γ-CH3 on GBL; precursor of γ-methyl-GHB Cyclic ether ring precursor of GBL and GHB

AT 1 μmol/L

IC50, μmol/L

44

2.9

53 63

22 12

NR NR

56

13

6.8

NR

NR

2.3

NR

NR

1.8

NR

NR

25.0

NR

NR

0.1

NA

NA NA

The names and structures of endogenous and synthetic GHB analogues and precursors are presented with respect to their substitutions and modifications on the GHB molecule:

O HO

γ

β 3

4

α

1

OH

2

The structure-activity relationships of these endogenous and synthetic GHB analogs and precursors have been examined by binding studies with [3H]GHB. The GHB analogs and precursors in this table have been tested at concentrations of 1 and 10 μmol/L for their ability to inhibit [3H]GHB (25 μmol/L) binding to GHB receptors on rat brain membrane preparations. The IC50 concentrations were available for the most active compounds. Not depicted in the table, GHB itself produced 55% and 35% inhibition of [3H]GHB binding at concentrations of 10 and 1 μmol/L, respectively, and shows an IC50 value of 6.6 μmol/L. The GHB derivatives that demonstrated a greater potency than GHB (IC50 < 6.6 μmol/L) for inhibiting [3H]GHB binding to GHB receptors were the endogenous structural analog T-HCA (IC50 2.9 μmol/L) and the synthetic structural analogs γ-benzyl-GHB (IC50 2.3 μmol/L), R-γ-benzyl-GHB (IC50 1.8 μmol/L), and γ-(p-methoxybenzyl)-GHB (NCS 435, IC50 0.1 μmol/L). Of note, none of the endogenous or synthetic GHB ring analogs (GBL, GCL, GVL, THF) were recognized by the GHB receptor, evidence that the open form of ring analogs is necessary for GHB receptor binding. Also, the endogenous precursor 1,4-BD and the endogenous structural analog GABA were recognized by the GHB receptor. IC50, inhibition concentration of 50%; NA, no affinity; NR, not reported.

CHAPTER 46

synaptosomal fractions in studies of the subcellular distribution of GHB in rat brain, signifying a mechanism for its presynaptic synthesis and accumulation.127 As summarized in Figure 46-3, the subcellular presynaptic synthesis of endogenous GHB involves three precursors (GABA, GBL, and 1,4-BD) and five enzymes (GABA-transaminase [GABA-T], succinic semialdehyde reductase [SSR], alcohol dehydrogenase [ADH], aldehyde dehydrogenase, and serum and peripheral tissue lactonases). The major precursor of endogenous brain GHB is GABA,71,77,78 which is converted to succinic semialdehyde (SSA) by the brain mitochondrial enzyme, GABA-T. SSA can enter into one of two subsequent biotransformation pathways. In the major pathway, SSA is oxidized by the mitochondrial enzyme succinic semialdehyde dehydrogenase (SSADH) to succinic acid. Production of succinic acid by SSADH allows entry of the GABA carbon skeleton into the tricarboxylic acid cycle for catabolism to H2O and CO2.71-74,77,78 Alternatively, in the minor pathway, SSA is reduced by the neuronal cytosolic enzyme SSR to GHB. The vast majority of GABA enters the mitochondrial oxidative pathway to produce succinic acid by SSADH, because only about 0.05% (in vitro) to 0.16% (in vivo) of the metabolic flux coming from GABA enters the cytosolic reductive pathway to form GHB by SSR.74,85 Thus, GHB formation is colocalized in GABAergic neurons, or in neurons that can synthesize GABA, which are regionally most prominent in the cerebellum, colliculi, median hypothalamus, and hippocampus.80,82,84,85 The second source for subcellular presynaptic synthesis of endogenous GHB is the precursor 1,4-BD, which is present at brain concentrations of about 1/10 of those of GHB.86 1,4-BD is the dihydroxy alcohol precursor of GHB, which undergoes in vivo biotransformation by oxidation of one alcohol group on the molecule to γ-hydroxybutyraldehyde by liver ADH followed by the subsequent formation of GHB either by liver aldehyde dehydrogenase or auto-oxidation.17,73,86-88 The potential sources of the small endogenous concentrations of 1,4-BD found in the mammalian brain are the polyamines ornithine, spermine, spermidine, and putrescine.89 The third source for subcellular presynaptic synthesis of endogenous GHB is the precursor GBL, which is also present at brain concentrations (200 pmol/g tissue weight) of about 1/10 of those of GHB.75,90 GBL can undergo rapid in vivo biotransformation to GHB by serum or peripheral tissue lactonases.91 However, in contrast to ADH and aldehyde dehydrogenase, no lactonase activity has been described in the brain cell.92 Therefore, the role of GBL as a brain precursor to endogenous GHB is enigmatic. Nevertheless, the equilibrium of GBL and GHB in the mammalian brain might be explained by a chemical nonenzymatic hydrolysis rather than an enzymatic process.71 Although the existence of a putative GHB-specific receptor has been speculated96-98 and disputed for some time, its existence was recently verified by the cloning of a G protein–coupled receptor in the rat that is activated by endogenous GHB.99 This newly cloned receptor exhibits no binding affinity for GABA, baclofen, or


809

glutamate, which have no capacity to displace radioactive GHB from this binding site, but it does exhibit binding affinity for the GHB structural derivative γ-p-phenylhydroxybutyrate (see discussion of GHB analogs earlier under Structure and Structure-Activity Relationships) and the GHB β-oxidation derivative trans-4-hydroxycrotonic acid and its γ-p-chloro-phenyl and γ-p-nitro-phenyl substitute derivatives. Interestingly, however, this receptor exhibited no binding affinity for the GHB receptorspecific antagonist NCS 382. This observation, in combination with the study’s additional finding that three distinct bands were present on Northern blot analysis of total RNA extracted from several rat organs (including brain), suggests the existence of a family of GHB receptors in the brain with NCS 382–sensitive and –insensitive subtypes identified. GHB modulates several neurotransmitter systems. GHB appears to exert a dose-related effect on both the GABAergic and dopaminergic systems. The administration of low-dose GHB inhibits GABA release in the thalamus, thereby implicating a role for GHB in producing absence seizures,101 and decreases the extracellular GABA concentration in the frontal cortex.102 However, higher doses of GHB have been shown to enhance GABA concentrations in the frontal cortex.102 The accentuation of GABA neurotransmission produced by high-dose GHB might underlie the CNS-depressant effect of GHB in experimental animals and overdose patients (see later section on Exogenous GHB). GHB also exerts a prominent modulatory effect on dopamine neurotransmission. Acute administration of GHB inhibits dopamine release and results in the accumulation of dopamine in the presynaptic cells. This effect has been shown to be mediated by GHB inhibition of dopamine neuron firing in the substantia nigra and mesolimbic regions103-105 and the subsequent autoreceptor-mediated stimulation of tyrosine hydroxylase activity, resulting in increased presynaptic dopamine production.106,107 The attenuation of dopamine neurotransmission following GHB administration may be the pharmacologic basis for the loss of locomotor activity in experimental animals and overdose patients. Interestingly, it also has been proposed that GHB can produce a biphasic effect on dopamine neurotransmission that is dose and time dependent. While attenuated dopaminergic activity is the primary response after GHB administration, several investigators have demonstrated a second phase of GHB modulation that ensues after the initial decrement in dopamine release, when dopamine neurotransmission is enhanced in the striatum and corticolimbic structures.71,104,108 Such a biphasic, secondary increase of dopaminergic neurotransmission might represent the pharmacologic basis for its reported euphoric effect and the reward mechanism responsible for its abuse potential. Other systems modulated by GHB include the serotonin system, cholinergic system, and opioid system. GHB modulates the serotonin system by increasing its turnover rate, without altering total brain serotonin levels, likely by elevating presynaptic tryptophan concentrations.71,109,110 GBL, but not GHB itself, has been shown to increase total brain acetylcholine concen-

810


trations by decreasing firing of cholinergic neurons.111-113 Such an increase in brain acetylcholine might underlie the pharmacologic basis for the reported analeptic effect of GHB in narcolepsy. Despite having no binding affinity for opioid receptors, GHB has been reported to stimulate an increase in release of endogenous opioids in various brain regions.104,114-116 Furthermore, despite naloxone having no affinity for the GHB receptor, the administration of the opioid antagonists naloxone and naltrexone can attenuate or reverse the electrophysiologic and behavioral actions of GHB on dopamine neuron firing and catalepsy in experimental animals.117,118 After its release from GHBergic presynaptic membranes, GHB activity is terminated by an active vesicular uptake system driven by the vesicular inhibitory amino acid transporter (the same transporter that mediates the vesicular uptake of GABA and glycine) or by an active cellular uptake from the synaptic cleft by means of a high affinity Na+-dependent transport protein specific for GHB and its analogs.96,119,120 Once within the cell, the degradation of endogenous GHB in the mammalian brain can occur via four pathways leading to (1) succinic acid (which enters the tricarboxylic acid cycle, and represents the most quantitatively significant degradative pathway), (2) GABA, (3) trans-4-hydroxycrotonic acid, or (4) 4,5-dihydroxyhexanoic acid (see Fig. 46-3).

Exogenous GHB Although accumulating evidence favors the role of endogenous GHB as a neuromodulator, because it is synthesized, stored, and released at particular synapses that express GHB-specific receptors, the study of the pharmacologic profile of exogenous GHB is still in its infancy, having only recently been impelled by the increasing problem of GHB abuse. Nevertheless, accumulating data suggest that the GABAB receptor is a major component of the neural substrate mediating the pharmacologic, behavioral, clinical, and toxicologic actions of exogenous GHB and its precursors, particularly when the brain GHB concentration exceeds its physiologic concentration by two to three orders of magnitude, saturating GHB-specific receptors and producing GABAB receptor-mediated brain perturbations.147-153 Thus, data accumulated since 2001 support the role of the GABAB receptor in mediating acute and chronic toxicity from GHB and its precursor 1,4-BD. Under conditions of excess exogenous administration or endogenous production (see Human Inborn Error of Metabolism, 4hydroxybutric aciduria/SSADH deficiency),154 it is theorized that GHB may act both directly as a partial GABAB receptor agonist and indirectly through a GHBderived GABA pool. GHB itself is a weak GABAB receptor agonist with an affinity in the mmol/L range, which far exceeds the 1 to 4 μmol/L physiologic concentrations of GHB in the brain.147,155,156 Therefore, the supraphysiologic concentration of GHB that could accumulate after its exogenous administration may exert its effects through a weak, direct agonistic effect on GABAB receptormediated mechanisms. Alternatively, GHB could act as an indirect agonist of the GABAB receptor by its biotrans-

(b)

GHB (a)

GABA

(c)

GHB receptor

GABAB receptor FIGURE 46-4 Schematic model of GHB receptor pharmacology. a, Physiologic concentrations of GHB in the human and mammalian brain (nanomolar to micromolar) activate the GHB receptor, which exists as NCS 382–sensitive and –insensitive subtypes. b, Supraphysiologic concentrations of GHB (high micromolar to millimolar) might be metabolized to a concentration of GABA sufficient enough to activate the GABAB receptor. c, Supraphysiologic concentrations of GHB may alternatively result in the direct binding of GHB itself to the GABAB receptor. (From Wong CGT, Gibson KM, Snead OC III: From the street to the brain: neurobiology of the recreational drug γ-hydroxybutyric acid. Trends Pharmacol Sci 2004;25[1]:29–34.)

formation to GABA.71 This hypothesis is supported by the previous observation that inordinately high concentrations of GHB (high μmol/L to low mmol/L) are needed to produce enough GHB-derived GABA to induce displacement and induce GABAB receptors.157 In summary, it appears that the pharmacologic and toxicologic effects of supraphysiologic concentrations of GHB, either from exogenous administration (overdose) or endogenous production (inherited SSADH deficiency), are due to saturation of GHB receptors, direct and indirect activation of GABAB receptors, and/or a combination of these effects (Fig. 46-4).

PHARMACOKINETICS Human pharmacokinetic data are available only for GHB and are summarized in Table 46-2,158-161 but such data are lacking for its precursors and analogs, GBL, 1,4BD, GVL, GHV, and THF. Following oral administration, GHB is rapidly absorbed from the gastrointestinal tract and reaches peak plasma concentrations within 1 hour of dosing. Due to a probable first-pass mechanism, GHB has a low oral bioavailability (less than 30%). GHB does not bind to plasma proteins, readily crosses the placenta and the blood-brain barrier, and has an apparent volume of distribution of 202 to 384 mL/kg. Orally administered GHB exhibits nonlinear elimination pharmacokinetics, with elimination from the human body being dose dependent. As the oral dose is increased, there is a disproportionate increase in systemic exposure, and the elimination half-life is increased. However, plasma GHB was nondetectable or only at negligible concentrations 8 hours after oral administration of 9 g (2.5 times the coma-inducing dose). In general, only 1% to 7% of an oral GHB dose is renally eliminated as parent compound in human urine. Therefore, metabolism is the major elimination pathway for GHB.

CHAPTER 46


811

TABLE 46-2 Pharmacokinetic Parameters for GHB (Sodium Oxybate) in Healthy Volunteers after Oral Dosing GHB ADMINISTRATION STUDY POPULATION

Healthy volunteers1 Healthy volunteers3 Healthy volunteers3 Healthy volunteers (male)5 Healthy volunteers (female)5 Healthy volunteers (fed)5 Healthy volunteers (fasted)5 Healthy volunteers3

ROUTE

DOSE

DURATION

Cmax (μg/mL)

Tmax (hr)

T1/2 (hr)

8

Oral

12.5 mg/kg 25 mg/kg 50 mg/kg

Single Single Single

23 23 23

0.42 0.5 0.75

0.45 0.37 0.38

15.1 21.2 26.1

15

Oral

3g

Single

83.8

0.50

0.74

136

4.3

260

12

Oral

4.5 g

Single

146

0.50

0.76

302

3.1

190

18

Oral

4.5 g

Single

88.3

1.25

0.65

241

3.8

202

18

Oral

4.5 g

Single

83.0

1.14

0.61

233

4.2

218

36

Oral

4.5 g

Single

60.1

2.00

0.68

188

6.2

384

36

Oral

Single

142

0.75

0.57

288

3.7

190

12

Oral

Single

64.6

0.50

0.57

178

5.7

248

Single

60.1

0.64

0.59

138

6.6

325

Oral

4.5 g 4.5 g (2 × 2.25 g) 4.5 g (2 × 2.25 g) 9.0 g (2 × 4.5 g)

Single

142

0.72

0.83

518

3.6

249

Oral

25 mg/kg

Single

39.4

0.33– 0.75

0.5

NR

N

Healthy volunteers3 12 Healthy volunteers (fasted)6 8

AUCinf (mL/min·kg)

CL/F (mL/min·kg) 14 9 7

NR

Vz/F (mL/kg) NR NR NR

NR

AUC, area under the curve from time zero to time infinity; CL/F, plasma clearance divided by absolute bioavailability; Cmax, peak plasma concentration; NR, not reported; T1/2, elimination half-life; Tmax, corresponding peak time; Vz/F, volume of distribution divided by absolute bioavailability.

Special Populations Human pharmacokinetic data for GHB in special patient populations with narcolepsy, alcoholism, and liver cirrhosis as well as those undergoing general surgery and cesarean section are summarized in Table 46-3.162-168 There are no significant variations in the kinetics of GHB between males and females (see Table 46-2)159 or between healthy human volunteers and narcoleptic patients162,163 and alcohol-dependent patients165 (see Tables 46-2 and 46-3). However, compared with healthy adult volunteers, the mean oral clearance and elimination half-life were markedly reduced and significantly prolonged, respectively, in patients with biopsy-proven liver cirrhosis164 (see Tables 46-2 and 46-3).

Pharmacologic Agents ANESTHESIA GHB found its first clinical application as an anesthetic agent in the early 1960s. Several clinical studies in the 1960s, involving a total of 376 patients, confirmed the potential of GHB to serve as an adjuvant to anesthesia.169,170 However, those same studies also documented several adverse reactions to GHB anesthesia, including the occurrence of gross muscular movements when rapidly administered, as well as inadequate

analgesia (abrupt rise in systolic and diastolic pressure during surgical incision), emergence delirium, and bradycardia. Although GHB continues to be used and investigated as an anesthetic adjuvant abroad,171-173 it has never gained widespread acceptance in the United States for this clinical application. At present, GHB use as an anesthetic agent is limited to France, as well as Germany and Austria.174 NARCOLEPSY The clinical development of GHB in the United States began in 1994, when the National Organization of Rare Disorders and the FDA Orphan Products Development Division encouraged the development of GHB as a treatment for narcolepsy based on the promising results of several preliminary clinical studies.175-179 After the safety and efficacy of GHB as a narcolepsy treatment were established by two randomized, double-blind, placebo-controlled studies,180-183 the FDA approved GHB (sodium oxybate, Xyrem [Jazz Pharmaceuticals, Palo Alto, CA]) as a treatment for narcolepsy-related cataplexy on July 17, 2002. ALCOHOL DEPENDENCE AND WITHDRAWAL GHB has been widely used in Italy to treat alcohol dependence and withdrawal since 1988.184 The use of a GHB pharmaceutical for this clinical indication was

812


TABLE 46-3 Pharmacokinetic Parameters for GHB (Sodium Oxybate) in Select Patient Populations after Oral or Intravenous Administration GHB ADMINISTRATION STUDY POPULATION Narcoleptic patients9 Narcoleptic patients10 Liver disease (child’s class A patients)11 Liver disease (child’s class C patients)11 Alcoholicdependent patients12

Surgical patients13 Surgical patients or sedation14 Cesarian section patients15

DOSE

DURATION

Cmax (μg/mL)

Tmax (hr)

T1/2 (hr)

Single 8 weeks

90.0 104

0.75 0.50

0.67 0.67

226 254

4.0 3.5

226 197

Oral

4.5 g 4.5 g 6g (2 × 3 g)

Single

91.2

0.59

0.88

295

4.2

307

8

Oral

25 mg/kg (1.75 g)

Single

68

0.75

0.53

85

4.5

198

8

Oral

Single

47

0.75

0.93

94.1

4.1

285

Single

54

0.5

0.45

52

9.6

NR

10

Oral

13 doses

55

0.5

0.43

52

9.2

NR

Single

45

0.75

0.58

90.3

5.3

NR

NR

~0.5

ND

ND

ND

NR

~0.67

ND

ND

ND

NR

ND

ND

ND

ND

N

ROUTE

13

Oral

6

3

IV

6

IV

25 mg/kg (1.75 g) 25 mg/kg (1.75 g) 25 mg/kg (1.75 g) 50 mg/kg (3.5 g) 50 mg/kg (3.5 g) 30–100 mg/kg bolus (2.1–7 g)

14

IV

26.7–50 mg/kg Single (1.9–3.5 g) infusion

Single NR Single bolus and infusion NR NR

AUCinf (mL/min·kg)

CL/F (mL/min·kg)

Vz/F (mL/kg)

AUC, area under the curve from time zero to time infinity; CL/F, plasma clearance divided by absolute bioavailability; Cmax, peak plasma concentration; ND, not determined; NR, not reported; T1/2, elimination half-life; Tmax, corresponding peak time; Vz/F, volume of distribution divided by absolute bioavailability.

based on two randomized, double-blind, placebocontrolled clinical trials conducted by Gallimberti and colleagues. In the first trial, 23 patients who met the Diagnostic and Statistical Manual of Mental Disorders (DSMIIIR) criteria for alcohol withdrawal syndrome were recruited for treatment with GHB 50 mg/kg/day (n = 11) or placebo (n = 12).185 GHB treatment resulted in a significant decrease in the Alcohol Withdrawal Score.185 This was followed by a second randomized, double-blind clinical trial with 71 alcoholic patients who were randomized to receive GHB 50 mg/kg/day (n = 36) or placebo (n = 35). After the study period and a 3-month follow-up period, GHB-treated patients significantly increased their days of abstinence and reduced the number of drinks they consumed daily. Furthermore, GHB-treated patients reported a significant reduction in Alcohol Craving Scale scores.186 Similar results were also reported by fellow Italian investigators in clinical studies.187,188 As a result of these clinical trials, GHB is widely used in Italy today to treat alcohol dependence at the dosage of 50 mg/kg/day in three or more divided doses.184 EXPERIMENTAL THERAPIES Presently, GHB is undergoing clinical and preclinical investigations for diverse indications. Although GHB received FDA approval for treating narcolepsy-related cataplexy, it failed to receive approval for treatment of

excessive daytime sleepiness. Therefore, GHB is presently undergoing clinical reevaluation for this narcolepsy indication. Pilot studies have shown promising results, since the nocturnal administration of sodium oxybate in narcoleptic patients recently produced significant improvements in sleep architecture, which coincided with significant improvements in daytime functioning.189 GHB is also presently being evaluated as a treatment for fibromyalgia, with several recent clinical studies reporting GHB capable of effectively reducing the symptoms of pain, fatigue, and sleep abnormalities characteristic of this disorder.190,191 Preclinically, interesting and compelling data recently have been generated to demonstrate the potential use of GHB as a neuroprotective agent in stroke192-195 and traumatic brain196 and spinal cord injury,197 as well as an angiogenesis inhibitor in tumors.198,199 DRUG INTERACTIONS The potential for drug interactions by an inhibitory effect of GHB on human hepatic microsomal cytochrome P-450 (CYP) isozymes has been assessed in vitro with pooled human liver microsomal fractions. In these studies, the activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A were not inhibited by GHB at concentrations of 3 to 300 μmol/L. Therefore, metabolic interactions of GHB with drugs metabolized through these pathways are not anticipated.200

CHAPTER 46

TOXICOLOGY Clinical Manifestations Toxicity from GHB and its analogs have occurred in the settings of acute overdose/poisoning, withdrawal after abrupt cessation from chronic misuse, and human inborn error of SSADH expression. ACUTE OVERDOSE Clinical experience accumulated during the past 15 years with acute toxicity from GHB overdose has resulted in a fairly homogeneous and easily recognized pattern of symptoms and signs. The hallmark of this “GHB toxidrome” is CNS and respiratory depression of relatively short duration.5,6,7,8,24-42 There is a doseresponse relationship such that the level of CNS and respiratory depression progressively worsens with increasing doses, with doses of greater than 50 mg/kg leading to coma, apnea, and death. These dose-response relationships are summarized in Table 46-4. Respiratory depression is particularly prominent in the published cases of pediatric GHB/GBL poisonings. Among the seven published case reports of pediatric GHB/GBL poisonings, apnea occurred in six patients.31-33,201 Other adverse clinical effects from acute GHB overdose are summarized by systems in Box 46-1. The occurrence of generalized clonic seizures is controversial because they have been inconsistently reported in acute GHB, GBL, and 1,4-BD overdoses. It is possible that such motor


813

activity may actually represent myoclonic movements mistaken for seizure activity. Such myoclonic activity has been clearly documented during anesthesia induction with GHB and occurs without epileptiform EEG patterns. It is further possible that such seizures may be attributable to hypoxia, co-ingestion with a stimulant drug, or withdrawal. Nevertheless, GHB has been clearly established to produce absence seizures in laboratory animals so that seizures may be a plausible adverse effect from acute GHB overdose. Deaths from GHB ingestion

BOX 46-1

CLINICAL EFFECTS OF GHB AND ITS PRODRUGS AND ANALOGS

Central Nervous System

Euphoria Hallucinations Headache Ataxia Confusion Amnesia Hypotonia Somnolence Unconsciousness Coma Agitation/combativeness Delirium Seizure/myoclonic jerking Respiratory

TABLE 46-4 In Vivo and In Vitro Dose-Response Effects of GHB DOSE OR CONCENTRATION OF GHB Oral Dose (Humans) 10 mg/kg 20–30 mg/kg 50–60 mg/kg Systemic Dose (Rodents) 10–50 mg/kg 75–200 mg/kg 200–300 mg/kg >300 mg/kg 1.7 g/kg

CLINICAL OR PHYSIOLOGIC EFFECT

Short-term amnesia Sleep and drowsiness Coma, cardiorespiratory depression, seizures Memory impairment Absence seizures, EEG spikeand-wave discharges Stupor, EEG slowing Coma, EEG burst suppression LD50

In Vitro Concentration Nanomolar to low micromolar Activation of GHB receptor Low micromolar Alter GABA and glutamate release Millimolar Activation of GABA(B) receptor, possible conversion to physiologically active concentrations of GABA EEG, electroencephalographic; GABA, γ-aminobutyric acid. Adapted from Wong CGT, Gibson KM, Snead OC III: From the street to the brain: neurobiology of the recreational drug γ-hydroxybutyric acid. Trends Pharmacol Sci 2004;25(1):29–34.

Respiratory depression Apnea Cheyne-Stokes respirations Cardiovascular

Bradycardia Hypotension Right bundle branch block (pediatric) ST-segment elevation (pediatric) P-wave inversion (pediatric) U waves (adult) Gastrointestinal

Excessive salivation Vomiting Metabolic

Metabolic acidosis Respiratory acidosis Other

Miosis Hypothermia Diaphoresis Urinary incontinence Acute psychosis Withdrawal syndrome Wernickle-Korsakoff syndrome From Shannon M, Quang LS: Gamma-hydroxybutyrate, gammabutyrolactone, and 1,4-butanediol: a case report and review of the literature. Pediatr Emerg Care 2000;16(6):435–440.

814


have occurred, with the majority of these incidents involving polysubstance ingestion with either alcohol or a narcotic. Co-ingestion of 1,4-BD with alcohol is particularly dangerous because both substances are competitive substrates for the metabolizing enzyme ADH. Because ADH has a greater substrate affinity for alcohol than 1,4-BD, the adverse effects from ADHmediated biotransformation of 1,4-BD to GHB will be delayed in this co-ingestion.40 When co-ingested with GHB or GBL, alcohol has been shown to produce additive or potentiated toxicity as well. Lastly, given the proscriptive status of GHB and its analogs, improperly performed “kitchen synthesis” of GHB has resulted in caustic oral burns and subsequent esophageal strictures when the neutralization process for potassium hydroxide (a key ingredient for home synthesis of GHB from GBL) was inadequately performed.202 WITHDRAWAL SYNDROME The GHB withdrawal syndrome, which occurs after the abrupt cessation of chronic, high-dose abuse, is a rapidly emerging clinical disorder.42,203-233 As of this writing, there are 87 published case reports of GHB withdrawal in the clinical literature. Eight of these cases predated 2000,203–211 with the first case report published in 1994.203 The remaining 79 case reports of GHB withdrawal were published after 2000, which represents nearly a 10-fold increase in incidence during the past 5 years.42,211-233 The clinical experience derived from the sum of case reports has begun to yield a preliminary characterization of the GHB withdrawal state. Most of the patients experiencing the GHB withdrawal state have been males, with a mean age in the early thirties. Among these 87 case reports of withdrawal, GHB, GBL, and 1,4-BD were responsible for 72 (82.8%), 11 (12.6%), and 4 (4.6%) cases, respectively. While most individuals did not know their exact daily dose, they were estimated to be about 48 g and 27 g for GHB and GBL, respectively, with an average daily dosing interval of 4 to 5 hours. The mean duration of misuse was just over 1 year. The onset of withdrawal symptoms occurred within a mean of 46 hours after the last dose of GHB, and the mean duration of the withdrawal syndrome was 9 days. The clinical features of the GHB withdrawal syndrome were similar to ethanol withdrawal and included, in the relative order of frequency of occurrence, tremor, tachycardia, anxiety, restlessness, hallucinations (primarily visual and auditory), delirium, insomnia, delusions, paranoia, diaphoresis, hypertension, nausea or vomiting, and psychosis. Two seizures have been reported in GHB withdrawal, one of which was associated with death.223,233 HUMAN INBORN ERROR OF METABOLISM (4-HYDROXYBUTYRIC ACIDURIA/SUCCINIC SEMIALDEHYDE DEHYDROGENASE DEFICIENCY) Although acute poisoning from illicit GHB use has been seen by clinicians only in the past 15 years, chronic GHB poisoning from an inherited defect of GABA metabolism has been recognized by molecular biologists and geneticists for nearly 25 years. In 1981, Jakobs and

colleagues were the first to describe a 20-month-old boy of related Turkish parents with developmental delay (absent speech), motor retardation, hypotonia, and ataxia, in association with elevated concentrations of GHB in urine, serum, and cerebrospinal fluid.135 Based on the well-defined metabolic pathway of GABA, Jakobs and colleagues postulated that an enzyme defect of SSADH was responsible. Subsequent investigators verified this theory by demonstrating that the conversion of radiolabeled SSA to CO2 (via the tricarboxylic acid [TCA] cycle) in intact cultured lymphoblasts of patients was only 2.4% to 6.2% of control values.234,235 In patients with 4-hydroxybutyric aciduria, SSADH residual activity in these cells was significantly reduced or absent compared with controls.236-244 Parental and sibling white blood cell extracts demonstrated a “gene-dose effect,” with reduction of SSADH activity to approximately 50% of controls. These patterns of patient and parent SSADH activity were consistent with an autosomal-recessive mode of inheritance. As a result of this error of GABA catabolism, Gibson and colleagues reported urine GHB concentrations of 130 to 7600 mmol/mol creatinine (normal less than 2), plasma GHB concentrations of 98 to 1500 μmol/L (normal less than 3), and cerebrospinal fluid GHB concentrations of 263 to 830 μmol/L (normal less than 3) in their large case series. Presently, more than 350 patients have been diagnosed with 4-hydroxybutyric aciduria or SSADH deficiency.245 Recently, Trettel and colleagues mapped the gene encoding for SSADH to chromosome 6p22.246 Shortly thereafter, Chambliss and colleagues identified two exon-skipping point mutations in the SSADH genes of four patients. These genetic defects alter highly conserved sequences at intron/exon boundaries, preventing the RNA splicing apparatus from recognizing the normal splice junction. These RNA splicing errors consequently result in SSADH deficiency.247 Clinical diagnosis can be rather challenging due to some variability of the phenotypic expression of this disease, but in general, clinical findings in patients include psychomotor retardation, absent/delayed speech, mental delay, hypotonia, ataxia, hyporeflexia, seizures/EEG abnormalities, oculomotor apraxia, hyperkinesis, choreoathetosis, aggressive behavior, and somnolence.248,249

DIAGNOSIS Laboratory Testing GENERAL CONSIDERATIONS GHB poisoning is generally diagnosed based on clinical history and presentation and confirmed by laboratory testing. Laboratory testing for GHB and its analogs is confounded by several limiting considerations. First, there is a relatively small window of opportunity to recover GHB from biologic fluids. Following oral administration of GHB at toxic doses (12.5 to 50 mg/kg), GHB is almost completely eliminated from blood and urine within 2 to 8 and 8 to 12 hours of administration, respectively.158-167 Second, immunoassay urine drug screens generally

CHAPTER 46

employed by hospitals do not detect GHB and its analogs. Third, while numerous qualitative and quantitative analytical methods have been developed to detect GHB in recent years, they are not routinely available at most hospitals. Fourth, even when theses analytical methods are available to the clinician, they are presently incapable of distinguishing between GHB and its numerous analogs. Fifth, even if a laboratory test is available to confirm and/or quantify the presence of GHB or its analogs, this information is unlikely to alter management or disposition of the GHB-intoxicated patient. Lastly, accurate interpretation of quantitative GHB analysis must also take into consideration complex confounding factors such as specimen collection and storage, spontaneous GHB and GBL chemical interconversion, and endogenous GHB production. SPECIMEN COLLECTION AND STORAGE GHB concentrations from collected biologic fluids can be spuriously elevated if improperly collected and stored. Whole blood specimens undergoing laboratory analysis for GHB should be collected and stored in purple-top anticoagulant ethylenediaminetetraacetic acid (EDTA) tubes, avoiding yellow-top anticoagulantcitrate buffer tubes, which artificially generate GHB.250 Cold storage and use of sodium fluoride or sodium azide preservatives in urine specimens have been shown to minimize spurious GHB concentrations.251,252

Spontaneous Chemical Interconversion The proper identification of GHB versus one of its many analogs, especially GBL, is also complicated by a spontaneous chemical interconversion of GHB and GBL that can occur in aqueous solutions. Generally, this GHB-GBL interconversion is pH dependent, with GHB exhibiting greater stability than GBL in a variety of aqueous solutions. In aqueous solution with water, spontaneous interconversion of GBL to GHB occurs at a ratio of 2:1 within 202 days in pure water, within 9 days in acidic solution (pH 2.0), and within 15 minutes in alkaline solution (pH 12.0). Conversely, spontaneous interconversion of GHB to GBL occurred at a ratio of 1:2 only in acidic solution (pH 2.0) and did not occur at all in pure water or in alkaline solution (pH 12.0).253 Thus, aqueous solutions of alkaline pH 7.0 favor the spontaneous hydrolysis of GBL to GHB and true equilibrium between GHB and GBL occurring at approximately pH 2.0. ENDOGENOUS GHB PRODUCTION In clinical cases that have forensic implications (determination of cause of death) or medicolegal allegations (GHB use for chemical submission/date rape), the endogenous production of GHB must be carefully considered and an analytical chemist/toxicologist consulted. Endogenous production of GHB can occur spontaneously in postmortem biologic specimens and is dependent on both preservative use and storage temperature.254 Little to no endogenous production of


815

GHB will occur in postmortem blood preserved with sodium fluoride 10 mg/mL and stored at either room temperature or refrigeration at 4° C. Conversely, 50% higher endogenous GHB formation can occur when postmortem blood was not preserved but stored under refrigeration. Furthermore, when stored at room temperature, endogenous GHB production nearly doubled the value of those unpreserved specimens stored under refrigeration. Therefore, both preservative use and refrigeration of blood specimens will reduce the confounding influence of endogenous GHB production. While virtually all studies do not show elevation of endogenous GHB in postmortem urine, one investigator has reported elevations of endogenous GHB in both postmortem blood and urine specimens.255 In clinical cases when there is a medicolegal allegation of sexual assault facilitated by surreptitious placement of GHB into a beverage, it is important to consider that GBL has been discovered to be a natural constituent of a variety of wines. GBL has been detected in extracts from samples of unadulterated red and white wines at concentrations of 5 μg/mL and was easily quantified using a simple chloroform extraction technique followed by gas chromatography/mass spectrometry (GC/MS) analysis.256 It was additionally demonstrated that grape juice did not contain GBL, suggesting that GBL may be a natural by-product of the wine fermentation process. The observation that many varieties of wine may contain GBL reinforces the need to run proper controls in the forensic analysis of GBL. Hence, during the analysis of allegedly adulterated wine samples, it is important to conduct appropriate comparative quantitative analyses to assess accurately whether the amount of GBL present is at a naturally occurring or elevated level before rendering a decision that the material has been tainted. QUALITATIVE SCREENING METHODS AND QUANTITATIVE CONFIRMATION METHODS The dramatic surge in GHB abuse during the 1990s led to rapid advances in the laboratory detection of GHB, which can be useful to the clinician despite the myriad complexities associated with accurate GHB laboratory analysis and interpretation. Presently, at least two rapid colorimetric assays have been commercially developed for rapid screening of the presence of GHB.257,258 Both rely on the chemical conversion of GHB to GBL and are reported to be capable of producing qualitative results with 0.25 to 1.0 mL of urine within 5 to 10 minutes and with a sensitivity of 0.1 to 0.5 mg/mL. Such qualitative screening methods require confirmation by quantitative methods, which are the most sensitive and reliable methods. Typically, this quantitative confirmation analysis is performed commercially using a GC/MS technique, for which over two dozen methods have been developed for analysis of GHB.259 A GC/MS technique was recently used in a clinical study examining the correlation of serum and urine GHB concentrations in 16 patients with a clinical suspicion of GHB-like drug overdose and a Glasgow Coma Scale (GCS) score of 8 or lower.260 All 16

816


suspected severe GHB overdose patients had significant serum and urine GHB concentrations, which ranged from 45 to 295 mg/L (median 180 mg/L) and 432 to 2407 mg/L (median 1263 mg/L), respectively. Patients who developed a GCS score of 3 had serum concentrations that ranged from 72 to 300 mg/L (median 193 mg/L). Although these GC/MS serum GHB concentrations correlated well with the occurrence of GHB toxicity, they did not correlate with the degree of coma or the time to awakening. Lastly, routine urine organic acid analysis may also accurately detect GHB in the overdose setting when available at a hospital.261

Other Diagnostic Testing Additional diagnostic laboratory testing should be performed as clinically indicated, particularly when the clinician is confronted with a conflicting or complicated clinical picture due to polysubstance ingestion. Because GHB is commonly ingested with ethanol, which exacerbates and/or prolongs the clinical toxicity of GHB, a serum ethanol concentration should be checked in all patients with suspected GHB poisoning. Also, MDMA is a relatively common co-ingestant, which is detectable in routine immunoassay urine drug screens. A 12-lead electrocardiogram is indicated, because GHB may produce cardiac effects (see Table 46-4), but primarily to rule out co-ingestion or intoxication with another potential cardiotoxic agents. A chest x-ray is indicated if there is clinical evidence of aspiration, which the severely GHB-intoxicated patient is at risk for, and which can increase the risk for morbidity and mortality. In cases of prolonged unconsciousness, a serum creatine phosphokinase and basic metabolic panel should be obtained and renal function monitored due to the risk for development of rhabdomyolysis. Other adjunct diagnostic studies for the comatose patient, such as a head computed tomography scan and lumbar puncture, may be deferred if there is a strong clinical index of suspicion for GHB poisoning.

Differential Diagnosis The differential diagnosis for diminished mental status/ coma and respiratory depression, the hallmarks of GHB poisoning, is exhaustive and includes trauma, medical conditions (such as CNS infection or masses, stroke, and hypoglycemia), and other medication overdoses (such as benzodiazepines, barbiturates, opioids, central α2-adrenergic agonists, anticonvulsants, and ethanol or toxic alcohols). However, while no true pathognomonic sign exists for GHB poisoning, the occurrence of extreme combativeness or agitation during noxious stimuli (such as an attempt on oroendotracheal intubation), followed by relapse into coma, may aid the clinician in differentiating this overdose from other sedative-hypnotic agents. Often, there is a history of GHB ingestion offered by friends, bystanders, or emergency services personnel at the scene, or the patient may be found in possession with containers or products whose label verifies the ingestion of GHB or one of its analogs.

MANAGEMENT Supportive Measures The medical management of symptomatic acute overdoses with GHB and its analogs, as well as their withdrawal syndrome, generally only requires vigilant monitoring and anticipatory supportive care. With supportive measures, 54% of patients were treated and released in the majority of episodes involving GHB according to 2002 ED trends reported by DAWN.48 Recovery with supportive care is often spontaneous and abrupt, since patients have regained consciousness within 1 to 6 hours and without adverse sequelae. At present, there are less data and experience available for the management of the GHB withdrawal syndrome. ACUTE OVERDOSE Box 46-2 summarizes the medical management principles for the patient with symptomatic acute overdose with GHB and its analogs. Airway assessment and support is the first priority. A patent airway should be ensured, initially with proper positioning, suctioning of oral secretions, and placement of a temporizing oropharyngeal or nasopharyngeal airway if needed, and supplemental O2 delivered. Bag-valve mask ventilation followed by endotracheal intubation and mechanical ventilation will be required for patients with loss of airway protective reflexes (coma or severe obtundation), respiratory distress (aspiration pneumonitis), or apnea. When invasive airway management is required, rapid sequence intubation protocols should be applied in order to facilitate a prompt intubation and minimize the occurrence of complications. Intravenous access should be secured and a crystalloid solution administered if hypotensive. Atropine and benzodiazepines are clinically indicated if bradycardia and seizures occur, respectively. As with any patient presenting with coma, dextrose,

BOX 46-2

MEDICAL MANAGEMENT AND DISPOSITION OF OVERDOSES FROM GHB AND ITS PRODRUGS AND ANALOGS

Airway support Suction airway Supplemental oxygen Endotracheal intubation Mechanical ventilation Activated charcoal Intravenous access Cardiorespiratory monitoring Atropine for symptomatic bradycardia Benzodiazepines for seizures Discharge if clinically stable after 6 hours of observation Admit if initially presented comatose or if clinically intoxicated after 6 hours of observation From Shannon M, Quang LS: Gamma-hydroxybutyrate, gammabutyrolactone, and 1,4-butanediol: a case report and review of the literature. Pediatr Emerg Care 2000;16(6):435–440.

CHAPTER 46

naloxone, and thiamine may be administered as clinically warranted. WITHDRAWAL SYNDROME Because the withdrawal syndrome from GHB and its analogs has been reported to be clinically similar to the ethanol withdrawal syndrome, it is managed in much the same manner. In general, high doses of benzodiazepines are used to manage the common withdrawal symptoms of dysautonomia (tachycardia, hypertension), anxiety, agitation, hallucinations, and pyschosis. The limited clinical literature on the GHB withdrawal syndrome also reports cases that are refractory to high-dose benzodiazepines. In such case reports, benzodiazepines have been augmented with and/or substituted by barbiturates (pentobarbital or phenobarbital), anticonvulsants (valproic acid, carbamazepine, gabapentin), chloral hydrate, baclofen, clonidine, β-blockers (propanolol or labetolol), propofol, bromocriptine, trazadone, or antipsychotics.203–233 At present, no GHB withdrawal treatment regimen has undergone rigorous prospective clinical study.

Decontamination Induced emesis with syrup of ipecac is contraindicated due to the high likelihood for rapid onset of CNS depression. Although there are no studies demonstrating adsorption of GHB or its analogs to oral activated charcoal (AC), gastrointestinal decontamination with single-dose oral AC may be beneficial if it can be administered in a timely manner. Given the rapid absorption of liquid preparations of GHB and its analogs, decontamination with AC should be initiated within 30 minutes of most ingestions or within 60 minutes of a polydrug ingestion. Accurate assessment for airway integrity and provision of an invasive airway, if clinically indicated, should precede the administration of oral AC.

Laboratory Monitoring Continuous cardiorespiratory, pulse oximetry, and blood pressure monitoring are required for the patient with a symptomatic acute overdose or the withdrawal syndrome from GHB and its analogs.

Antidotes Two pharmacologic antidotes, physostigmine and 4methylpyrazole (4-MP, fomepizole), have been reported to reverse the clinical effects of acute GHB and 1,4-BD overdose, respectively. At present, the administration of these antidotal agents has not been validated with rigorous prospective clinical trials. PHYSOSTIGMINE There are several case reports of the successful administration of physostigmine, a carbamate inhibitor of acetylcholinesterase, to reverse GHB-induced sedation in the ED setting. Caldicott and Kuhn reported the reversal of GHB intoxication with physostigmine.262 Their notion that GHB may be reversed with physostigmine


817

was based on two studies where “GHB reversal” was produced in surgical patients receiving GHB as an anesthestic adjuvant.263,264 In the two anesthesia case series and in the Caldicott and Kuhn case series, it is likely that investigators may have confused physostigmine “reversal” with the clinical course of GHB, since physotigimine was administered to patients at a time when GHB clinical effects can be expected to wane. Furthermore, pharmacologic studies have found no relationship between GHB and acetylcholine-mediated neurotransmission in the CNS.265 Therefore, at present, there is a lack of sufficient data to recommend empirical administration of physostigmine as an antidote in the setting of symptomatic acute overdose with GHB or its analogs. 4-METHYLPYRAZOLE 4-Methylpyrazole (4-MP) is a pharmacologically plausible antidotal agent for 1,4-BD overdose. A potent competitive antagonist for ADH, 4-MP would be expected to block the biotransformation of 1,4-BD to GHB, and there are many in vitro and in vivo experimental data to support the use of 4-MP to block 1,4-BD toxicity.266-271 Furthermore, there is a case report of the successful administration of 4-MP to treat 1,4-BD poisoning.272 Following a 30-mL ingestion of a homemade 1,4-BD solution, a 43-year-old man developed generalized seizures and coma. This patient awoke shortly after the administration of the initial 4-MP dose of intravenous 10 mg/kg. However, initial GC/MS plasma 1,4-BD and GHB concentrations were 24 and 222 mg/L, respectively. These analytical data are inconsistent with the proposed pharmacologic antidotal mechanism of 4-MP, which is to block 1,4-BD biotransformation to the toxic compound GHB. Although basic investigations support the use of 4-MP in the setting of early 1,4-BD acute overdose,150,272-274 the empirical administration of 4-MP as an antidote cannot be recommended until more rigorous clinically derived data are available.

Elimination Given the known pharmacokinetic profile of GHB, it is unlikely that gastric lavage, whole bowel irrigation, or other extracorporeal methods of enhanced elimination will be useful in the management of acute overdoses with GHB or its analogs.

Disposition Box 46-2 summarizes the disposition of a patient with an acute overdose of GHB or its analogs. Patients should be observed in the ED for 6 hours and may be discharged if they remain asymptomatic. If a patient arrives at the ED with a clinical presentation consistent with an acute overdose of GHB or its analogs, or develops these symptoms during ED observation, inpatient admission is indicated. Disposition of a patient with a GHB polydrug ingestion, particularly when a narcotic or ethanol is involved, requires caution because most GHB-related deaths have been associated with these co-ingestions. In the case of ethanol, animal studies and clinical case

818


reports have documented potentiated toxicity, prolonged toxicity, and in the case of 1,4-BD, delayed GHB toxicity.

ACKNOWLEDGMENTS I wish to thank Hai Thong Nguyen, MD, attending physician, Ste. Anne Hospital, Montreal, Quebec (Veterans Affairs, Canada), for his valuable assistance in translating the French-written GHB papers cited in this manuscript (references 12 through 14). Preparation of this chapter was supported in part by National Institutes of Health/National Institute on Drug Abuse Grant 1RO3 DA14951. REFERENCES 1. Close Call. Retrieved January 2005 from http://espn.go.com/ magazine/vol3no7gugliotta.html. 2. CBS News: Nick Nolte cops a plea. Retrieved January 2005 from http://www.cbsnews.com/stories/2002/10/24/entertainment/ main526796.shtml. 3. CNN: Max Factor heir returns to face prison term. Retrieved January 2005 from http://www.cnn.com/2003/LAW/06/19/ max.factor.heir/. 4. CBS News: Fugitive Max Factor heir caught. Retrieved January 2005 from http://www.cbsnews.com/stories/2003/06/19/ national/main559376.shtml. 5. Centers for Disease Control and Prevention: Multistate outbreak of poisonings associated with illicit use of gamma hydroxybutyrate. MMWR 1990;39:861–863. 6. Dyer JE: Gamma-hydroxybutyrate: a health food product producing coma and seizure-like activity. Am J Emerg Med 1991;9:321–324. 7. Food and Drug Administration: Gamma hydroxybutyric acid. Press Release P90-53. Rockville, MD, Food and Drug Administration, November 8, 1990. 8. Higgins TF, Borron SW: Coma and respiratory arrest after exposure to butyrolactone. J Emerg Med 1996;14:435–437. 9. National Institute on Drug Abuse: Club Drugs. Retrieved January 2005 from http://www.drugabuse.gov/drugpages/clubdrugs. html. 10. Giacamino NJ, McCawley EL: On the toxic reactions of unsaturated lactones and their saturated analogs. Fed Proc 1947;6:331–332. 11. Rubin BA, Giarman NJ: The therapy of experimental influenza in mice with antibiotic lactones and related compounds. Yale J Biol Med 1947;19:1017–1024. 12. Laborit H, Jouany JM, Gerard J, et al: Generalities concerning the experimental study and clinical use of gamma hydroxybutyrate of Na [French]. Agressologie 1960;1:397–406. 13. Laborit H, Buchard F, laborit G, et al: Use of sodium 4-hydroxybutyrate in anesthesia and resuscitation [French]. Agressologie 1960;1:549–560. 14. Laborit H, Jouany JM, Gerard J, et al: Summary of an experimental and clinical study on a metabolic substrate with inhibitory central action: sodium 4-hydroxybutyrate [French]. Presse Med 1960;68:1867–1869. 15. Bessman SP, Fishbein WN: Gamma hydroxybutyrate a new metabolite in brain [Letter]. FASEB J 1963;22:334. 16. Bessman SP, Fishbein WN: Gamma-hydroxybutyrate, a normal brain metabolite. Nature 1963;200:1207–1208. 17. Sprince H, Josephs JA, Wilpizeski CR: Neuropharmacological effects of 1,4-butanediol and related congeners compared with those of gamma-hydroxybutyrate and gamma-butyrolactone. Life Sci 1966;5:2041–2052. 18. Blumenfeld M, Suntay RG, Harmel MH: Sodium gammahydroxybutyric acid: a new anaesthetic adjuvant. Anesth Analg 1962;41:721–726. 19. Solway J, Sadove MS: 4-Hydroxybutyrate: a clinical study. Anesth Analg 1965;44:532–539, 1965.

20. Kleinschmidt S, Grundmann U, Janneck U, et al: Total intravenous anesthesia using propofol, gamma-hydroxybutyrate or midazolam in combination with sufentanil for patients undergoing coronary artery bypass surgery. Eur J Anaesthesiol 1997; 14:590–599. 21. Kleinschmidt S, Grundmann U, Knocke T, et al: Total intravenous anaesthesia with gamma-hydroxybutyrate (GHB) and sufentanil in patients undergoing coronary artery bypass graft surgery: a comparison in patients with unimpaired and impaired left ventricular function. Eur J Anaesthesiol 1998;15:559–564. 22. Kleinschmidt S, Schellhase C, Mertzufft F: Continuous sedation during spinal anaesthesia: gamma-hydroxybutyrate vs propofol. Eur J Anaesthesiol 1999;16:23–30. 23. Takahara J, Yunoki S, Yakushiji W, et al: GHB Stimulatory effects of gamma-hydroxybutyric acid on growth hormone and prolactin release in humans. J Clin Endocrinol Metab 1977;44(5): 1014–1017. 24. Rambourg-Schepens MO, Buffet M, Durak C, et al: Gamma butyrolactone poisoning and its similarities to gamma-hydroxybutyric acid: two case reports. Vet Hum Toxicol 1997;39:234–235. 25. LoVecchio F, Curry SC, Bagnasco T: Butyrolactone-induced central nervous system depression after ingestion of Renewtrient, a “dietary supplement.” N Engl J Med 1998;339:847–848. 26. Centers for Disease Control and Prevention: Adverse effects associated with ingestion of gamma-butyrolactone. Minnesota, New Mexico, and Texas, 1998–1999. MMWR 1999;48(7):137–140. 27. Hardy CJ, Slifman NR, Klontz KC, et al: Adverse events reported with the use of gamma-butyrolactone products marketed as dietary supplements [Abstract]. J Toxicol Clin Toxicol 1999;37(5):650. 28. Food and Drug Administration: FDA Talk Paper: FDA warns about products containing gamma butyrolactone or GBL and asks companies to issue a recall. Retrieved January 2005 from http://www.fda.gov/bbs/topics/ANSWERS/ANS00937.html. 29. Food and Drug Administration: FDA Talk Paper: FDA warns about GBL-related products. Retrieved January 2005 from http:// www.fda.gov/bbs/topics/ANSWERS/ANS00953.html. 30. Kohrs FP, Porter WH: Gamma-hydroxybutyrate intoxication and overdose. Ann Emerg Med 1999;33(4):475–476. 31. Winickoff JP, Houck CS, Rothman EL, et al: Experience and reason: Verve and Jolt: Deadly new internet drugs. Pediatrics 2000;106(4):829–830. 32. Leblanc F, Blais R: Gamma butyrolactone exposure from nail polish remover [Abstract]. J Toxicol Clin Toxicol 2000;38(5):535. 33. Boyer EW, Fearon D, Anderson AC, et al: Child neglect leading to gamma-hydroxybutyrate ingestion [Abstract]. J Toxicol Clin Toxicol 2000;38(5):534–535. 34. Vandevenne L, Beckers J, Van de Velde E, et al: A case of gammabutyrolactone overdose [Abstract]. J Toxicol Clin Toxicol 2000; 38(2):227. 35. Eckstein M, Henderson SO, DelaCruz P, et al: Gamma hydroxybutyrate (GHB): report of a mass intoxication and review of the literature. Prehosp Emerg Care 1999;3(4):357–361. 36. Cisek J, Holstege C, Rose R: Seizure associated with butanediol ingestion [Abstract]. J Toxicol Clin Toxicol 1999;37(5):650. 37. Food and Drug Administration: Medwatch—More on GBL, GHB, BD. Retrieved January 2005 from http://www.fda.gov/ medwatch/SAFETY/1999/gblghb.htm. 38. Shannon M, Quang LS: Gamma-hydroxybutyrate, gammabutyrolactone, and 1,4-butanediol: a case report and review of the literature. Pediatr Emerg Care 2000;16(6):435–440. 39. Ingels M, Rangan C, Bellezzo J, et al: Coma and respiratory depression following the ingestion of GHB and it precursors: three cases. J Emerg Med 2000;19(1):47–50. 40. Schneidereit T, Burkhart K, Donovan JW, et al: Butanediol toxicity delayed by preingestion of ethanol. Int J Med Toxicol 2000; 3(1):1–3. 41. Kraner J, Plassard J, McCoy D, et al: Fatal overdose from ingestion of 1,4-butanediol, a GHB precursor [Abstract]. J Toxicol Clin Toxicol 2000;38(5):534. 42. Zvosec DL, Smith SW, McCutcheon JD, et al: Adverse events, including death, associated with the use of 1,4-butanediol. N Engl J Med 2001;344(2):87–94. 43. Drug Enforcement Agency, Department of Justice: Schedules of controlled substances: addition of gamma hydroxybutyric acid to schedule I. Fed Reg 2000;65:13235–13238.

CHAPTER 46

44. Drug Enforcement Administration, Department of Justice: Placement of gamma-butyrolactone in List I of the Controlled Substances Act (21 U.S.C. 802 (34)): final rule. Fed Reg 2000;65(79):21645–21647. 45. Watson WA, Litovitz TL, Klein-Schwartz W, et al: 2003 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2004; 22(5):335–404. 46. Substance Abuse and Mental Health Services Administration, Office of Applied Studies: Emergency department trends from the Drug Abuse Warning Network, final estimates 1995–2002, DAWN Series: D-24. DHHS publication no. (SMA) 03-3780. Rockville, MD, Department of Health and Human Services, 2003. 47. Community Epidemiology Work Group, National Institutes of Health, National Institute on Drug Abuse: Epidemiologic trends in drug abuse, advance report, June 2001. Retrieved July 2004 from http://www.nida.nih.gove/CEWG/AdvanceRep/601ADV/ 601adv.html. 48. Substance Abuse and Mental Health Services Administration, Office of Applied Studies: The DAWN report: club drugs 2001 update. Drug Abuse Warning Network. Rockville, MD, Department of Health and Human Services, March 2002. 49. Johnston LD, O’Malley PM, Bachman JG: Monitoring the future national results on adolescent drug use: overview of key findings, 2002. NIH publication no. 03-5374. Bethesda, MD, National Institute on Drug Abuse, 2003. 50. United Nations Commission on Narcotic Drugs: Implementation of the international drug control treaties: changes in the scope of control of substances. Retrieved December 2004 from http:// www.unodc.org/pdf/document_2001-01-29_1.pdf. 51. Galloway GP, Frederick-Osbourne SL, Seymour R, et al: Abuse and therapeutic potential of gamma-hydroxybutyric acid. Alcohol 2000;20:263–269. 52. Elliot SP: Nonfatal instances of intoxication with gammahydroxybutyrate in the United Kingdom. Ther Drug Monit 2004;26(4):432–440. 53. Miro O, Nogue S, Espinosa G, et al: Trends in illicit drug emergencies: the emerging role of gamma-hydroxybutyrate. J Toxicol Clin Toxicol 2002;40(2):129–135. 54. Liechti ME, Kupferschmidt H: γ-Hydroxybutyrate (GHB) and γ-butyrolactone (GBL): analysis of overdose cases reported to the Swiss Toxicological Information Centre. Swiss Med Wkly 2004;134:534–537. 55. Bosman IJ, Lusthof KJ: Forensic cases involving the use of GHB in the Netherlands. Forensic Sci Int 2003;133(1–2):17–21. 56. Caldicott DGE, Chow FY, Burns BJ, et al: Fatalities associated with the use of γ-hydroxybutyrate and its analogues in Australasia. Med J Aust 2004;181(6):310–313. 57. Brown TCK: Epidemic of γ-hydroxybutyrate (GHB) ingestion. Med J Aust 2004;181(6):343. 58. Drug Enforcement Administration, Office of Diversion Control, Drug and Chemical Evaluation Section: Fact sheet: gamma hydroxybutyric acid (GHB, liquid X, goop, Georgia home boy). DEA/ODE #(000811). Washington, DC, Drug Enforcement Administration, August 11, 2000. 59. Drug Enforcement Agency, U.S. Department of Justice: GHB/GBL. Retrieved March 2005 from http://www.usdoj.gov/ dea/concern/drug_trafficking.html. 60. National Drug Intelligence Center, U.S. Department of Justice: Information bulletin: GHB analogs: GBL, BD, GHV, and GVL. Product no. 2002-L0424-003. Washington, DC, National Drug Intelligence Center, August 2002. 61. National Drug Intelligence Center, U.S. Department of Justice: Intelligence bulletin: GHB trafficking and abuse. Product no. 2004L0424-015. Washington, DC, National Drug Intelligence Center, September 2004. 62. Zvosec DL, Smith SW: Unsupported “efficacy” claims of gamma hydroxybutyrate (GHB). Acad Emerg Med 2003;10(1):95–96. 63. ElSohly MA, Salamone SJ: Prevalence of drugs used in cases of alleged sexual assault. J Anal Toxicol 1999;23:141–146. 64. Henretig F, Vassalluzo C, Osterhoudt K, et al: “Rave by net”: gamma-hydroxybutyrate (GHB) toxicity from kits sold to minors via the internet [Abstract]. J Toxicol Clin Toxicol 1998; 36:503.


819

65. Cartigny B, Azaroual N, Imbenotte M, et al: 1H NMR spectroscopic investigation of serum and urine in a case of acute tetrahydrofuran poisoning. J Anal Toxicol 2001;25:270–274. 66. Benavides J, Rumigny JF, Bourguignon JJ, et al: A high-affinity, Na+-dependent uptake system for gamma-hydroxybutyrate in membrane vesicles prepared from rat brain. J Neurochem 1982;38(6):1570–1575. 67. Bourguignon JJ, Schoenfelder A, Schmitt M, et al: Analogues of γ-hydroxybutyric acid. Synthesis and binding studies. J Med Chem 1988;31(5):893–897. 68. Bourguignon JJ, Schmitt M, Didier B: Design and structureactivity relationship analysis of ligands of gamma-hydroxybutyric acid receptors. Alcohol 2000;20:227–236. 69. Vayer P, Maitre M: Regional differences in depolarization-induced release of γ-hydroxybutyrate from rat brain slices. Neurosci Lett 1988;87:99–103. 70. Mamelak M: Gammahydroxybutyrate: an endogenous regulator of energy metabolism. Neurosci Biobehav Rev 1989;13:187–198. 71. Maitre M: The γ-hydroxybutyrate signaling system in brain: organization and functional implications. Prog Neurobiol 1997; 51:337–361. 72. Snead OC: γ-Hydroxybutyric acid in subcellular fractions of rat brain. J Neurochem 1987;48:196–201. 73. Roth RH, Giarman NJ: Evidence that central nervous system depression by 1,4-butanediol is mediated through a metabolite, gamma-hydroxybutyrate. Biochem Pharmacol 1968;17:735–739. 74. Gold BI, Roth RH: Kinetics of in vivo conversion of γ[3H]aminobutyric acid to γ-[3H]hydroxybutyric acid by rat brain. J Neurochem 1977;28:1069–1073. 75. Snead OC 3rd, Furner R, Liu CC: In vivo conversion of gammaaminobutyric acid and 1,4-butanediol to gamma-hydroxybutyric acid in rat brain. Studies using stable isotopes. Biochem Pharmacol 1989;38(24):4375–4380. 76. Eli M, Cattabeni F: Endogenous γ-gammahydroxybutyrate in rat brain areas: postmortem changes and effects of drugs interfering with γ-aminobutyric acid metabolism. J Neurochem 1983;41:524–530. 77. Wong CG, Chan KF, Gibson KM, et al: γ-Hydroxybutyric acid: neurobiology and toxicology of a recreational drug. Toxicol Rev 2004;23(1):3–20. 78. Wong CG, Gibson KM, Snead OC 3rd: From the street to the brain: neurobiology of the recreational drug γ-hydroxybutyric acid. Trends Pharmacol Sci 2004;25(1):29–34. 79. Rumigny JF, Cash C, Mandel P, et al: Evidence that a specific succinic semialdehyde reductase is responsible for γ-hydroxybutyrate synthesis in brain tissue slices. FEBS Lett 1981;134:96–98. 80. Cash CD, Maitre M, Mandel P: Purification from human brain and some properties of two NADPH-linked aldehyde reductases which reduce succinic semialdehyde to 4-hydroxybutyrate. J Neurochem 1979;33:1169–1175. 81. Vayer P, Schmitt M, Bourguignon JJ, et al: Evidence for a role of high Km aldehyde reductase in the degradation of endogenous γ-hydroxybutyrate from rat brain. FEBS Lett 1985;190:55–60. 82. Weissmann-Nanopoulos D, Belin MF, Mandel P, et al: Immunocytochemical evidence for the presence of enzymes synthesizing GABA and GHB in the same neuron. Neurochem Int 1984;6:333–338. 83. Weissmann-Nanopoulos D, Rumigny JF, Mandel P, et al: Immunocytochemical localization in rat brain of the enzyme that synthesizes γ-hydroxybutyric acid. Neurochem Int 1982;4:523–529. 84. Rumigny JF, Cash C, Mandel P, et al: Ontogeny and distribution of specific succinic semialdehyde reductase apoenzyme in the rat brain. Neurochem Res 1982;7:555–561. 85. Rumigny JF, Maitre M, Cash C, et al: Regional and subcellular localization in rat brain of the enzymes that can synthesize γhydroxybutyric acid. J Neurochem 1981;36:1433–1438. 86. Barker SA, Snead OC, Poldrugo F, et al: Identification and quantitation of 1,4-butanediol in mammalian tissues: an alternative biosynthesis pathway for gamma-hydroxybutyric acid. Biochem Pharmacol 1985;34:1849–1852. 87. Pietruszko R, Voigtlander K, Lester D: Alcohol dehydrogenase from human and horse liver-substrate specificity with diols. Biochem Pharmacol 1978;27:1296–1297. 88. Maxwell R, Roth RH: Conversion of 1,4-butanediol to gammahydroxybutyric acid in rat brain and in peripheral tissue. Biochem Pharmacol 1972;21:1521–1533.

820


89. Tillakaratne NJ, Medina-Kauwe L, Gibson KM: Gammaaminobutyric acid (GABA) metabolism in mammalian neural and nonneural tissues. Comp Biochem Physiol A 1995;112(2): 247–263. 90. Doherty JD, Hattox SE, Snead OC, et al: A sensitive method for quantitation of γ-hydroxybutyric acid and γ-butyrolactone in brain by electron capture gas chromatography. Anal Biochem 1975;69:268–277. 91. Roth RH, Delgado JMR, Giarman NJ: Gamma-butyrolactone and gamma-hydroxybutyric acid. II. The pharmacologically active form. Int J Neuropharmacol 1966;5:421–428. 92. Fishbein WN, Bessman SP: Purification and properties of an enzyme in human blood and rat liver microsomes catalyzing the formation and hydrolysis of γ-lactones. J Biol Chem 1966;241: 4835–4841. 93. Maitre M, Mandel P: Liberation de γ-hydroxybutyrate calciumdependente après depolarisation de coupes de cerveau de rat. C R Acad Sci Paris 1982;295:741–743. 94. Maitre M, Cash C, Weissmann-Nanopoulos D, et al: Depolarization-evoked release of γ-hydroxybutyrate from rat brain slices. J Neurochem 1983;41:287–290. 95. Vayer P, Maitre M: Regional differences in depolarization-induced release of γ-hydroxybutyrate from rat brain slices. Neurosci Lett 1988;87:99–103. 96. Benavides J, Rumigny JF, Bourguignon JJ, et al: High affinity binding sites for gamma-hydroxybutyric acid in rat brain. Life Sci 1982;30:953–961. 97. Maitre M, Rumigny JF, Benavides J, et al: High affinity binding site for gamma-hydroxybutyric acid in rat brain. Adv Biochem Psychopharmacol 1983;37:441–453. 98. Snead OC, Liu CC: Gamma-hydroxybutyric acid binding sites in rat and human brain synaptosomal membranes. Biochem Pharmacol 1984;33:2587–2590. 99. Andriamampandry C, Taleb O, Viry S, et al: Cloning and characterization of a rat brain receptor that binds the endogenous neuromodulator γ-hydroxybutyrate (GHB). FASEB J 2003;17: 1691–1693. 100. Vayer P, Maitre M: γ-Hydroxybutyrate stimulation of the formation of cyclic GMP and inositol phosphates in rat hippocampal slices. J Neurochem 1989;52:1382–1387. 101. Banerjee PK, Snead OC III: Presynaptic gamma-hydroxybutyric acid (GHB) and gamma-aminobutyric acidB (GABAB) receptormediated release of GABA and glutamate (GLU) in rat thalamic ventrobasal nucleus (VB): a possible mechanism for the generation of absence-like seizures induced by GHB. J Pharmacol Exp Ther 1995;273:1534–1543. 102. Gobaille S, Hechler V, Andriamampandry C, et al: γ-Hydroxybutyrate modulates synthesis and and extracellular concentration of γ-aminobutyratic acid in discrete rat brain regions in vivo. J Pharmacol Exp Ther 1999;290:303–309. 103. Roth RH, Doherty JD, Walters JR: Gamma-hydroxybutyrate: a role in the regulation of central dopaminergic neurons? Brain Res 1980;189:556–560. 104. Hechler V, Gobaille S, Bourguignon J, et al : Extracellular events induced by gamma-hydroxybutyrate in striatum: a microdialysis study. J Neurochem 1991;56:938–944. 105. Howard SG, Feigenbaum JJ: Effect of γ-hydroxybutyrate on central dopamine release in vivo. Biochem Pharmacol 1997;53: 103–110. 106. Walter JR, Roth RH: Effect of gamma-hydroxybutyrate on dopamine and dopamine metabolites in the rat striatum. Biochem Pharmacol 1972;21:2111–2121. 107. Morgenroth V, Walters JR, Roth R: Dopaminergic neurons— alteration in the kinetic properties of tyrosine hydroxylase after cessation of impulse flow. Biochem Pharmacol 1976;25:655–661. 108. Nissbrandt H, Elverfors A, Enberg G: Pharmacologiclly induced cessation of burst activity in nigral dopamine neurons: significance for the terminal dopamine efflux. Synapse 1994;17:217–224. 109. Waldmeier PC, Fehr B: Effects of baclofen and γ-hydroxybutyrate on rat striatal and mesolimbic 5-HT metabolism. Eur J Pharmacol 1978;49:177–184. 110. Hedner T, Lundborg P: Effect of gammahydroxubutyric acid on serotonin synthesis, concentration and metabolism in the developing rat brain. J Neural Trans 1983;57:39–48.

111. Giarman NJ, Schmidt KF: Some neurochemical aspects of the depressant action of gamma-butyrolactone on the central nervous system 1. Br J Pharmacol 1963;20:563–568. 112. Sethy VH, Roth RH, Walters JR, et al: Effect of anesthetic doses of γ-hydroxybutyrate on the acetylcholine content of rat brain. Naunyn Schmiedebergs Arch Pharmacol 1976;295:9–14. 113. Ladinsky H, Consolo S, Zatta A, et al: Mode of action of gammabutyrolactone on the central cholinergic system. Naunyn Schmiedebergs Arch Pharmacol 1983;322:42–48. 114. Feigenbaum JJ, Simatov R: Lack of effect of γ-hydroxybutyrate on μ, κ, and δ opioid receptor binding. Neurosci Lett 1996;212:5–8. 115. Larson W, Przewlocka B, Przewlocka R: The effect of gammahydroxybutyrate and anticonvulsants on opioid peptide content in the rat brain. Life Sci 1983;33:599–602. 116. Gobaille S, Schmidt C, Cupo A, et al: Characterization of methionine-enkephalin release in the rat striatum by in vivo dialysis: effects of gamma-hydroxy butyrate on cellular and extracellular methionine enkephalin levels. Neuroscience 1994;60: 637–648. 117. Snead OC III, Bearden LJ: Naloxone overcomes the dopaminergic, EEG, and behavioral effects of γ-hydroxybutyrate. Neurology 1980;30:832–838. 118. Feigenbaum JJ, Howard SG: Naloxone reverses the inhibitory effects of γ-hydroxybutyrate on central DA release in vivo in awake animals: a microdialysis study. Neurosci Lett 1997;224:71–74. 119. Muller C, Viry S, Miehe M, et al: Evidence for a gammahydroxybutyrate (GHB) uptake by rat brain synaptic vesicles. J Neurochem 2002;80(5):899–904. 120. Hechler V, Bourguignon JJ, Wermuth CG, et al: γ-Hydroxybutyrate uptake by rat brain striatal slices. Neurochem Res 1985;10: 387–396. 121. Chambliss KL, Gibson KM: Succinic semialdehyde dehydrogenase from mammalian brain: subunit analysis using polyclonal antiserum. Int J Biochem 1992;24:1493–1499. 122. Margolis RK: The effect of γ-hydroxybutyric acid on amino-acid levels in brain. Biochem Pharmacol 1969;18:1243–1246. 123. Doherty JD, Stout RW, Roth RH: Metabolism of [1-14C]γhydroxybutyric acid by rat brain after intraventricular injection. Biochem Pharmacol 1975;24:469–474. 124. Della Pietra G, Illiano G, Capano V, et al: In vivo conversion of γ-hydroxybutyrate into γ-aminobutyrate. Nature 1966;210: 733–734. 125. De Feudis FV, Collier B: Conversion of γ-hydroxybutyrate to γ-aminobutyrate by mouse brain in vivo. Experientia 1970;26: 1072–1073. 126. Vayer P, Mandel P, Maitre M: Conversion of γ-hydroxybutyrate to γ-aminobutyrate in vitro. J Neurochem 1985;45:810–814. 127. Snead OC: γ-Hydroxybutyric acid in subcellular fractions of rat brain. J Neurochem 1987;48:196–201. 128. Chan-Palay V, Wu JY, Palay SL: Immunocytochemical localization of γ-aminobutyric acid transaminase at cellular and ultrastructural levels. Proc Natl Acad Sci U S A 1979;76:2067–2071. 129. Walsh JM, Clark JB: Studies on the control of 4-aminobutyrate metabolism in synaptosomal and free rat brain mitochondria. Biochem J 1976;160:147–157. 130. Bloch-Tardy M, Buzenet A, Fages C, et al: Two forms of GABA-T in pig brain. Purification and properties. Neurochem Res 1980;5: 1147–1154. 131. Vincent SR, Kimura H, McGreer EG: The histochemical localization of GABA transaminase in the efferents of the striatum. Brain Res 1981;222:198–203. 132. Walkenstein SS, Wiser R, Gudmundsen C, et al: Metabolism of γ-hydroxybutyratic acid. Biochem Biophys Acta 1964;86:640–642. 133. Niwa T, Maeda K, Asada H, et al: Gas chromatographic-mass spectrometric analysis of organic acids in renal tissue biopsy: 4hydroxybutyric acid and 4-hydroxy-2-butenoic acid. J Chromatogr 1982;230:1–6. 134. Vayer P, Ehrhardt JD, Gobaille S, et al: Gamma hydroxybutyrate distribution and turnover rates in discrete brain regions of the rat. Neurochem Int 1988;12:53–59. 135. Jakobs C, Bojasch M, Monch E, et al: Urinary excretion of gammahydroxybutyric acid in a patient with neurologic abnormalities. The probability of a new inborn error of metabolism. Clin Chim Acta 1981;111:169–178.

CHAPTER 46

136. Hechler V, Schmitt M, Bourguignon JJ, et al: Trans-gammahydroxycrotonic acid binding sites in brain: evidence for a subpopulation of of gamma-hydroxybutyrate sites. Neurosci Lett 1990;110:204–209. 137. Hechler V, Peter P, Gobaille S, et al: Gamma-hydroxybutyrate ligands possess antidopaminergic and neuroleptic-like activities. J Pharmacol Exp Ther 1993;264:1406–1414. 138. Kaufman EE, Nelson T, Fales HM, et al: Isolation and characterization of a hydroxyacid-oxoacid transhydrogenase from rat kidney mitchondria. J Biol Chem 1988;263:16872–16879. 139. Brown GK, Cromby CH, Manning NJ, et al: Urinary organic acids in succinic semialdehyde dehydrogenase deficiency: evidence of alpha-oxidation of 4-hydroxybutyric acid, interaction of succinic semialdehyde with pyruvate dehydrogenase and possible secondary inhibition of mitochondrial beta-oxidation. J Inherit Metab Dis 1987;10:367–375. 140. Gibson KM, Jakobs C: Disorders of beta- and gamma-amino acids in free and peptide-linked forms. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease. New York, McGraw-Hill, 2001, pp 2079–2105. 141. Olpe HR, Koella WP: Inhibition of nigral and neocortical cells by γ-hydroxybutyrate: a microiontophoretic investigation. Eur J Pharmacol 1979;53:359–364. 142. Kozhechkin SX: Microiontophoretic study of the mechanism of action of gamma-hydroxybutyric acid. Bull Exp Biol Med 1980;88:1293–1296. 143. Hosli L, Hosli E, Lehmann R, et al: Action of γ-hydroxybutyrate and GABA on neurons of cultured rat central nervous system. Neurosci Lett 1983;37:257–260. 144. Snead OC, Liu CC: GABAA receptor function in the gammahydroxybutyrate model of generalized absence seizures. Neuropharmacology 1993;32:401–409. 145. Williams SR, Turner JP, Crunelli V: Gamma-hydroxybutyrate promotes oscillatory activity of rat and cat thalamocortical neurons by a tonic GABAB receptor-mediated hyperpolarization. Neuroscience 1995;66:133–141. 146. Xie X, Smart TG: γ-Hydroxybutyrate hyperpolarizes hippocampal neurons by activating GABAB receptors. Eur J Pharmacol 1992;212:291–294. 147. Lingenhoehl K, Brom R, Heid J, et al: γ-Hydroxybutyrate is a weak agonist at recombinant GABAB receptors. Neuropharmacology 1999;38:1667–1673. 148. Emri Z, Antal K, Crunelli C, et al: Gamma-hydroxybutyric acid decreases thalamic sensory excitatory postsynaptic potentials by an action on presynaptic GABAB receptors. Neurosci Lett 1996;216:121–124. 149. Erhardt S, Andersson B, Nissbrandt H, et al: Inhibition of firing rate and changes in the firing pattern of nigral dopamine neurons by γ-hydroxybutyratic acid (GHBA) are specifically induced by activation of GABAB receptors. Naunyn Schmiedebergs Arch Pharmacol 1998;357:611–619. 150. Quang LS, Desai MC, Kraner JC, et al: Enzyme and receptor antagonists for preventing toxicity from the gamma-hydroxybutyric acid precursor 1,4-butanediol in CD-1 mice. Ann NY Acad Sci 2002;965:461–472. 151. Carai MAM, Colombo G, Reali R, et al: Central effects of 1,4butanediol are mediated by GABAB receptors via its conversion into γ-hydroxybutyric acid. Eur J Pharmacol 2002;441:157–163. 152. Carai MAM, Colombo G, Brunetti G, et al: Role of GABAB receptors in the sedative/hypnotic effect of γ-hydroxybutyric acid. Eur J Pharmacol 2001;428:315–321. 153. Carai MAM, Colombo G, Gessa GL: Resuscitative effect of a GABAB receptor antagonist on γ-hydroxybutyric acid (GHB) mortality in mice. Ann Emerg Med 2005;45:614–619. 154. Hogema BM, Taylor M, Jakobs C, et al: Pharmacologic rescue of lethal seizures in mice deficient in succinic semialdehyde dehydrogenase. Nat Genet 2001;29:212–216. 155. Mathivet P, Bernasconi R, Froestl W, et al: Binding characteristics of gamma-hydroxybutyric acid as a weak but selective GABAB receptor agonist. Eur J Pharmacol 1997;321:67–75. 156. Doherty JD, Hattox SE, Snead OC: Identification of endogenous γ-hydroxybutyrate in human and bovine brain and its regional distribution in human, guinea pig, and rhesus monkey brain. J Pharmacol Exp Ther 1978;207:130–139.


821

157. Hechler V, Ratomponirina C, Maitre M: Gamma-hydroxybutyrate conversion into GABA induces displacement of GABAB binding that is blocked by valproate and ethosuxisimide. J Pharmacol Exp Ther 1997;281:753–760. 158. Palatini P, Tedeschi L, Frison G, et al: Dose-dependent absorption and elimination of gamma-hydroxybutyric acid in healthy volunteers. Eur J Clin Pharmacol 1993;45:353–356. 159. Orphan Medical, Inc.: NDA #21-196 Xyrem (sodium oxybate) oral solution. Peripheral and Central Nervous System Drugs Advisory Committee Briefing Booklet for June 6, 2001, presentation. Minnetonka, MN, Orphan Medical, Inc., 2001, pp 201–220. 160. Borgen LA, Okerholm R, Morrison D, et al: The influence of gender and food on the pharmacokinetics of sodium oxybate oral solution in healthy subjects. J Clin Pharmacol 2003;43:59–65. 161. Brenneisen R, ElSohly MA, Murphy TP, et al: Pharmacokinetics and excretion of gamma-hydroxybutyrate (GHB) in healthy subjects. J Anal Toxicol 2004;28(8):625–630. 162. Borgen LA, Okerholm RA, Lai A, et al: The pharmacokinetics of sodium oxybate oral solution following acute and chronic administration to narcoleptic patients. J Clin Pharmacol 2004;44:253–257. 163. Scharf MB, Lai AA, Branigan B, et al: Pharmacokinetics of gammahydroxybutyrate (GHB) in narcoleptic patients. Sleep 1998;21(5):507–514. 164. Ferrara SD, Tedeschi L, Frison G, et al: Effect of moderate or severe liver dysfunction on the pharmacokinetics of γ-hydroxybutyric acid. Eur J Clin Pharmacol 1996;50(4):305–310. 165. Ferrara SD, Zotti S, Tedeschi L, et al: Pharmacokinetics of gammahydroxybutyrate in alcohol dependent patients after single and repeated oral doses. Br J Clin Pharmacol 1992;34:231–235. 166. Vree TB, Baars AM, Van Der Kleijn E: Capacity-limited elimination of 4-hydroxybutyrate (Gamma OH®), ethanol and vinylbital (Bykonox®). Pharmaceutisch Weekblad 1975;110(50): 1257–1262. 167. Vree TB, Damsma J, Van den Bogert AG, van Der Kleijn E: Pharmocokinetics of 4-hydroxybutyric acid in man, rhesus monkey and dog. Anaesthesiol Intensive Med 1978;110:21–39. 168. van den Bogert AG, Vree TB, van den Kleijn E, et al: Placenta transfer of 4-hydroxybutyric acid in man. Anaesthesiol Intensive Med 1978;110:55–65. 169. Blumenfeld M, Suntay RG, Harmel MH: Sodium gammahydroxybutyric acid: a new anaesthetic adjuvant. Anesth Analg 1962;41:721–726. 170. Solway J, Sadove MS: 4-Hydroxybutyrate: a clinical study. Anesth Analg 1965;44:532–539. 171. Kleinschmidt S, Grundmann U, Janneck U, et al: Total intravenous anesthesia using propofol, gamma-hydroxybutyrate or midazolam in combination with sufentanil for patients undergoing coronary artery bypass surgery. Eur J Anaesthesiol 1997;14:590–599. 172. Kleinschmidt S, Grundmann U, Knocke T, et al: Total intravenous anaesthesia with gamma-hydroxybutyrate (GHB) and sufentanil in patients undergoing coronary artery bypass graft surgery: a comparison in patients with unimpaired and impaired left ventricular function. Eur J Anaesthesiol 1998;15:559–564. 173. Kleinschmidt S, Schellhase C, Mertzufft F: Continuous sedation during spinal anaesthesia: gamma-hydroxybutyrate vs propofol. Eur J Anaesthesiol 1999;16:23–30. 174. European Monitoring Centre for Drugs and Drug Addiction: Report on the risk assessment of GHB in the framework of the joint action on new synthetic drugs. Retrieved April 2005 from http://www.emcdda.eu.int/?nnodeid=2821. 175. Broughton R, Mamelak M: The treatment of narcolepsy-cataplexy with nocturnal γ-hydroxybutyrate. Can J Neurol Sci 1979;6:1–6. 176. Scharf M, Brown D, Woods M, et al: The effects and effectiveness of γ-hydroxybutyrate in patients with narcolepsy. J Clin Psychiatry 1985;46:222–225. 177. Bedard MA, Montplaisir J, Godbout R, et al: Nocturnal γ-hydroxybutyrate: effect on periodic leg movements and sleep organization of narcoleptic patients. Clin Neuropharmacol 1989;12:29–36. 178. Scrima L, Hartman PG, Johnson FH, et al: The effects of γ-hydroxybutyrate on the sleep of narcolepsy patients: a doubleblind study. Sleep 1990;13:479–490.

822


179. Lammers GJ, Arends J, Declerck AC, et al: γ-Hydroxybutyrate and narcolepsy: a double-blind placebo-controlled study. Sleep 1993;6:216–220. 180. U.S. Xyrem Multicenter Study Group: A randomized, doubleblind, placebo-controlled multicenter trial comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy. Sleep 2002;25:42–49. 181. Orphan Medical, Inc.: Xyrem physician’s monograph. Minnetonka, MN, Orphan Medical, Inc., 2002. 182. U.S. Xyrem Multicenter Study Group: The abrupt cessation of therapeutically administered sodium oxybate (GHB) does not cause withdrawal symptoms. J Toxicol Clin Toxicol 2003;41:131–135. 183. U.S. Xyrem Multicenter Study Group. A 12-month, open-label, multi-center extension trial of orally administered sodium oxybate for the treatment of narcolepsy. Sleep 2003;26:31–35. 184. Gallimberti L, Spella MR, Soncini CA, et al: Gamma-hydroxybutric acid in the treatment of alcohol and heroine dependence. Alcohol 2000;20:257–262. 185. Gallimberti L, Canton G, Gentile N, et al: Gamma-hydroxybutyric acid for treatment of alcohol withdrawal syndrome. Lancet 1989;2:787–789. 186. Gallimberti L, Ferri M, Ferrara SD, et al: Gamma-hydroxybutyric acid in the treatment of alcohol dependence: a double blind study. Alcohol Clin Exp Res 1992;16:673–676. 187. Addolorato G, Cibin M, Capristo E, et al: Maintaining abstinence from alcohol with gamma-hydroxybutyric acid. Lancet 1999; 351(9095):38. 188. Addolorato G, Castelli E, Stefanini GF, et al: An open multicentric study evaluating 4-hydroxybutyric acid sodium salt in the mediumterm treatment of 179 alcohol dependent subjects. Alcohol Alcoholism 1996;31:341–345. 189. Mamelak M, Black J, Montplaisir J, et al: A pilot study on the effects of sodium oxybate on sleep architecture and daytime alertness in narcolepsy. Sleep 2004;27(7):1327–1334. 190. Scharf MB, Baumann M, Berkowitz DV: The effects of sodium oxybate on clinical symptoms and sleep patterns in patients with fibromyalgia. J Rheumatol 2003;30:1070–1074. 191. Scharf MB, Hauck M, Stover R, et al: Effect of gammahydroxybutyrate on pain, fatigue, and the alpha sleep anomaly in patients with fibromyalgia. Preliminary report. J Rheumatol 1998;25:1986–1990. 192. Ottani A, Saltini S, Bartiromo M, et al: Effect of gammahydroxybutyrate in two rat models of focal cerebral damage. Brain Res 2003;986(1–2):181–190. 193. Vergoni AV, Ottani A, Botticelli AR, et al: Neuroprotective effect of gamma-hydroxybutyrate in transient global cerebral ischemia in the rat. Eur J Pharmacol 2000;397(1):75–84. 194. Quang LS, Sadasivan S, Maher TJ, et al: Neuroprotective effect of gamma-hydroxybutyrate and its chemical precursors, gammabutyrolactone and 1,4-butanediol, in the rodent model of focal cerebral ischemia by permanent middle cerebral artery occlusion [Abstract]. Acad Emerg Med 2003;10(5):438. 195. Quang LS, Sadasivan S, Maher TJ: Neuroprotective effects of gamma-hydroxybutyrate and its precursors 1,4-butanediol and gamma-butyrolactone in MCAo cerebral ischemia [Abstract]. FASEB J 2003;17(4–5):391.12. 196. Yosunkaya A, Ustun ME, Bariskaner H, et al: Effect of gammahydroxybutyric acid on tissue Na+, K-ATPase levels after experimental head trauma. Acta Anaesthesiol Scand 2004;48(5): 631–636. 197. Guney O, Bengi Celik J, Arazi M et al: Effects of gammahydroxybutyrate on cerebrospinal fluid lactate and glucose levels after spinal cord trauma. J Clin Neurosci 2004;11(5):517–520. 198. Yonekura K, Basaki Y, Chikahisa L, et al: UFT and its metabolites inhibit the angiogenesis induced by murine renal cell carcinoma, as determined by a dorsal air sac assay in mice. Clin Cancer Res 1999;5:2185–2191. 199. Basaki Y, Chikahisa L, Aoyagi K, et al. Gamma-hydroxybutyric acid and 5-fluorouracil, metabolites of UFT, inhibit the angiogenesis induced by vascular endothelial growth factor. Angiogenesis 2001;4(3):163–173. 200. Orphan Medical, Inc.: Covance study no. 6627-129, Xyrem (sodium oxybate) oral solution NDA #21-196. Briefing Booklet for the Peripheral and Central Nervous System Drugs Advisory

201. 202. 203. 204. 205.

206. 207. 208. 209. 210.

211. 212. 213. 214. 215. 216. 217. 218. 219. 220. 221. 222. 223. 224. 225. 226. 227. 228.

Committee Meeting for June 6, 2001, presentation. Minnetonka, MN, Orphan Medical, Inc., 2001. Suner S, Szlatenyi CS, Wang RY: Pediatric gamma hydroxybutyrate intoxication. Acad Emerg Med 1997;4(11):1041–1045. Dyer JE, Reed JH: Alkali burns from illicit manufacture of GHB [Abstract]. J Toxicol Clin Toxicol 1997;35:553. Galloway GP, Frederick SL, Staggers F Jr: Physical dependence on sodium oxybate [Letter]. Lancet 1994;343:57. Friedman J, Westlake R, Furman M: “Grievous bodily harm”: gamma hydroxybutyrate abuse leading to Wernicke-Korsakoff syndrome. Neurology 1996;46:469–471. Addolorato G, Caputo F, Stefanini GF, et al: Gammahydroxybutyric acid in the treatment of alcohol dependence: possible craving development for the drug [see comment]. Addiction 1997;92(8):1035–1036. Galloway GP, Frederick-Osborne SL, Seymour R, et al: Gammahydroxybutyrate: an emerging drug of abuse that causes physical dependence. Addiction 1997;92:89–96. Dyer JE, Andrews KM: Gamma hydroxybutyrate withdrawal. J Toxicol Clin Toxicol 1997;92:89–96. Galloway GP, Frederick SL, Staggers FE Jr, et al: Gammahydroxybutyrate: an emerging drug of abuse that causes physical dependence. Addiction 1997;92:89–96. Hernandez M, McDaniel CH, Costanza CD, et al: GHB-induced delirium: a case report and review of the literature of gamma hydroxybutyric acid. Am J Drug Alcohol Abuse 1998;24:179–183. Addolorato G, Caputo F, Capristo E, et al: A case of gammahydroxybutyric acid withdrawal syndrome during alcohol addiction treatment: utility of diazepam administration. Clin Neuropharmacol 1999;22(1):60–62. Price G: In-patient detoxification after GHB dependence. Br J Psychiatry 2000;177:181. Craig K, Gomez HF, McManus JL, et al: Severe gammahydroxybutyrate withdrawal: a case report and literature review. J Emerg Med 2000;18(1):64–70. Hutto B, Fairchild A, Bright R: γ-Hydroxybutyrate withdrawal and chloral hydrate. Am J Psychiatry 2000;157:10. Miglani JS, Kim KY, Chahil R: Gamma-hydroxybutyrate withdrawal delirium: a case report. Gen Hosp Psychiatry 2000;22:213–215. Price G: In-patient detoxification after GHB dependence. Br J Psychiatry 2000;177:181. Greene T, Dougherty T: Gamma-butyrolactone withdrawal presenting as acute psychosis. J Toxicol Clin Toxicol 2000;37:651. Sharma AN, Nelson L, Hoffman RS: Severe gamma-butyrolactone withdrawal. J Toxicol Clin Toxicol 2000;38:535. Catalano MC, Glass JM, Catalano G, et al: Gamma butyrolactone (GBL) withdrawal syndromes. Psychosomatics 2001;42(1):83–88. Mullins ME, Fitzmaurice SC: Lack of efficacy of benzodiazepines in treating gamma-hydroxybutyrate withdrawal. J Emerg Med 2001;20(4):418–420. Sharma AN, Lombardi MH: Management of gamma-hydroxybutyrate withdrawal. Ann Emerg Med 2001;38(5):605–607. Su M, Traub SJ, Hussain E, et al: 1,4-Butanediol withdrawal complicated by urinary retention. J Toxicol Clin Toxicol 2001;39:542. Bowles TM, Sommi RW, Amiri M: Successful management of prolonged γ-hydroxybutyrate and alcohol withdrawal. Pharmacotherapy 2001;21(2):254–257. Dyer JE, Roth B, Hyma BA: Gamma-hydroxybutyrate withdrawal syndrome. Ann Emerg Med 2001;37(2):147–153. Mahr G, Bishop CL, Orringer DJ: Prolonged withdrawal from extreme gamma-hydroxybutyrate (GHB) abuse. Psychosomatics 2001;42(5):439–440. McDaniel CH, Miotto KA: Gamma hydroxybutyrate (GHB) and gamma butyrolactone (GBL) withdrawal: five case studies. J Psychoactive Drugs 2001;33(2):143–149. Miotto K, Darakjian J, Basch J, et al: Gamma-hydroxybutyric acid: patterns of use, effects and withdrawal. Am J Addict 2001;10: 232–241. Schneir AB, Ly BT, Clark RF: A case of withdrawal from the GHB precursors gamma-butyrolactone and 1,4-butanediol. J Emerg Med 2001;21(1):31–33. Sivilotti ML, Burns MJ, Aaron CK, et al: Pentobarbital for severe gamma-butyrolactone withdrawal. Ann Emerg Med 2001;38(6): 660–665.

CHAPTER 46

229. Mycyk MB, Wilemon C, Aks SE: Two cases of withdrawal from 1,4butanediol use. Ann Emerg Med 2001;38(3):345–346. 230. Chin RL: A case of severe withdrawal from gamma-hydroxybutyrate. Ann Emerg Med 2001;37(5):551–552. 231. Harold AH, Sneed KB: Treatment of a young adult taking gammabutyrolactone (GBL) in a primary care clinic. J Am Board Fam Pract 2002;15(2):161–163. 232. Zvosec DL, Smith SW: γ-Hydroxybutyrate addiction and withdrawal: From the γ-hydroxybutyrate addiction study. Ann Emerg Med 2004;44(4):pS91. 233. Chew G, Fernando A 3rd: Epileptic seizure in GHB withdrawal. Aust Psychiatry 2004;12(4):410–411. 234. De Vivo DC, Gibson KM, Resor LD, et al: 4-Hydroxybutyric acidemia: clinical features, pathogenetic mechanisms, and treatment strategies. Ann Neurol 1988;24(2):304. 235. Pattarelli PP, Nyhan WL, Gibson KM: Oxidation of [U-14C] succinic semialdehyde in cultured human lymphoblasts: measurement of residual succinic semialdehyde dehydrogenase activity in 11 patients with 4-hydroxybutyric aciduria. Pediatr Res 1988; 24(4):455–460. 236. Haan EA, Brown GK, Mitchell D, et al: Succinic semialdehyde dehydrogenase deficiency—a further case. J Inherit Metab Dis 1985;8:99. 237. Jakobs C, Smit LM, Kneer J, et al: The first adult case with 4hydroxybutyric aciduria. J Inherit Metab Dis 1990;13:341–344. 238. Gibson KM, Sweetman L, Nyhan WL, et al: Defective succinic semialdehyde dehydrogenase activity in 4-hydroxybutyric aciduria. Eur J Pediatr 1984;142:257–259. 239. Gibson KM, Lee CF, Chambliss KL, et al: 4-Hydroxybutyric aciduria: application of a fluorometric assay to the determination of succinic semialdehyde dehydrogenase activity in extracts of cultured human lymphoblasts [Letter]. Clin Chim Acta 1991;196: 219–222. 240. Gibson KM, Goodman SI, Frerman FE, et al: Succinic semialdehyde dehydrogenase deficiency associated with combined 4-hydroxbutyric and dicarboxylic acidurias: potential for clinical misdiagnosis based on urinary organic acid profiling. J Pediatr 1989;114(4):607–610. 241. Gibson KM, Doskey AE, Jakobs C, et al: Differing clinical presentation of succinic semialdehyde dehydrogenase deficiency in adolescent siblings from Lifu Island, New Caledonia. J Inherit Metab Dis 1997;20:370–374. 242. Gibson KM, Hoffman G, Nyhan WL, et al: 4-Hydroxybutyric aciduria in a patient without ataxia or convulsions. Eur J Pediatr 1988;147:529–531. 243. Gibson KM, Sweetman L, Nyhan WL, et al: Succinic semialdehyde dehydrogenase deficiency: an inborn error of gamma-aminobutyric acid metabolism. Clin Chim Acta 1983;133:33–42. 244. Gibson KM, Jansen I, Sweetman L, et al: 4-Hydroxybutyric aciduria: a new inborn error of metabolism. III. Enzymology and inheritance. J Inherit Metab Dis 1984;7(Suppl 1):95–96. 245. Gibson KM: 4-Hydroxybutyric aciduria: In Tunnicliff G, Cash CD (eds): Gamma-hydroxybutyrate: Molecular, Functional and Clinical Aspects. New York, Taylor & Francis, 2002, pp 197–217. 246. Trettel F, Malaspina P, Jodice C, et al: Human succinic semialdehyde dehydrogenase: molecular cloning and chromosomal localization. Adv Exp Med Biol 1996;414:253–260. 247. Chambliss KL, Hinson DD, Trettel F, et al: Two exon-skipping mutations as the molecular basis of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria). Am J Hum Genet 1998;63:399–408. 248. Rating D, Hanefeld F, Siemes H, et al: 4-hydroxybutyric aciduria: a new inborn error of metabolism. I. Clinical review. J Inherit Metab Dis 1984;7(Suppl 1):90–92. 249. Gibson KM, Christensen E, Jakobs C, et al: The clinical phenotype of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria): case reports of 23 new patients. Pediatrics 1997;99(4):567–574. 250. LeBeau M, Montgomery MA, Jufer RA, et al: Elevated GHB in citrate-buffered blood [Letter]. J Anal Toxicol 2000;24:383–384. 251. LeBeau MA, Miller ML, Levine B: Effect of storage temperature on endogenous GHB levels in urine. Forensic Sci Int 2001; 119(2):161–167.


823

252. Kerrigan S: In vitro production of gamma-hydroxybutyrate in antemortem urine samples. J Anal Toxicol 2002;26(8):571–574. 253. Ciolino LA, Mesmer MZ, Satzger D, et al: The chemical interconversion of GHB and GBL: forensic issues and implications. J Forensic Sci 2001;46(6):1315–1323. 254. Stephens BG, Coleman DE, Baselt RC, et al: In vitro stability of endogenous gamma-hydroxybutyrate in postmortem blood [Letter]. J Forensic Sci 1999;44(1):231–232. 255. Elliot S: The presence of gamma-hydroxybutyric acid (GHB) in postmortem biological fluids [Letter]. J Anal Toxicol 2001;25:152. 256. Vose J, Tighe T, Schwartz M, et al: Detection of gammabutyrolactone (GBL) as a natural component in wine. J Forensic Sci 2001;46(5):1164–1167. 257. Baddock N, Zotti R: Rapid screening test for gammahydroxybutyric acid (GHB, fantasy) in urine [Letter]. Ther Drug Monit 1999;21(3):376–377. 258. Alston WC II, Ng K: Rapid colorimetric screening test for γ-hydroxybutyric acid (liquid X) in human urine. Forensic Sci Int 2002;126:114–117. 259. Morris-Kukoski CL: γ-Hydroxybutyrate: bridging the clinicalanalytical gap. Toxicol Rev 2004;23(1):33–43. 260. Sporer KA, Chin RL, Dyer JE, et al: γ-Hydroxybutyrate serum levels and clinical syndrome after severe overdose. Ann Emerg Med 2003;42:3–8. 261. Quang LS, Levy HM, Law T, et al: Laboratory diagnosis of 1,4-BD and GHB overdose by routine urine organic acid analysis. J Toxicol Clin Toxicol 2005;43(4):1–3. 262. Caldicott DGE, Kuhn M: Gamma-hydroxybutyrate overdose and physostigmine: teaching new tricks to an old drug. Ann Emerg Med 2001;37(1):99–102. 263. Henderson RS, Holmes CM: Reversal of the anesthetic action of sodium gamma-hydroxybutyrate. Anaesth Intensive Care 1976; 4(4):351–354. 264. Holmes CM, Henderson RS: The elimination of pollution by a non inhalational technique. Anaesth Intensive Care 1978;6(2): 120–124. 265. Persson B, Henning M: Central cardiovascular effects of gammahydroxybutyric acid; interactions with noradrenaline, serotonin, dopamine and acetylcholine transmission. Acta Pharmacol Toxicol (Copenh) 1980;47:335–346. 266. McCabe ER, Layne EC, Sayler DF, et al: Synergy of ethanol and a natural soporific-gamma hydroxybutyrate. Science 1971; 171(969):404–406. 267. Poldrugo F, Snead OC: 1,4-Butanediol, gamma-hydroxybutyric acid, and ethanol: relationship and interaction. Neuropharmacology 1984;23:109–113. 268. Poldrugo F, Snead OC, Barker S: Chronic alcohol administration produces an increase in liver 1,4-butanediol concentration [Letter]. Alcohol Alcohol 1985;20(2):251–253. 269. Poldrugo F, Snead OC: 1,4-Butanediol and ethanol compete for degradation in rat brain and liver in vitro. Alcohol 1986;3(6): 367–370. 270. Poldrugo F, Snead OC: Ethanol blocks the conversion of 1,4butanediol to gamma-hydroxybutyric acid in vivo. Neurosci Abstr 1983;9:1234. 271. Poldrugo F, Barker S, Basa M, et al: Ethanol potentiates the toxic effects of 1,4-butanediol. Alcohol Clin Exp Res 1985;9(6): 493–497. 272. Quang LS, Shannon MW, Woolf AD, et al: Pretreatment of CD-1 mice with 4-methylpyrazole blocks toxicity from the gammahydroxybutyrate precursor, 1,4-butanediol. Life Sci 2002;71: 771–778. 273. Quang LS, Desai MC, Shannon MW, et al: 4-methylpyrazole decreases 1,4-butanediol toxicity by blocking its in vivo biotransformation to gamma-hydroxybutyric acid. Ann N Y Acad Sci 2004;1025:528–537. 274. Carai MA, Colombo G, Quang LS, et al: Resuscitative treatments on 1,4-butanediol mortality in mice. Ann Emerg Med 2006;47: 184–189.

S E C T I O N

C

ANALGESICS

47

Acetaminophen STEVEN D. SALHANICK, MD ■ MICHAEL W. SHANNON, MD, MPH

At a Glance… ■

■ ■ ■

■ ■

■

■

Acetaminophen toxicity is a frequent cause of hepatic toxicity and should be considered in the differential diagnosis of any patient presenting with acute hepatic failure. Toxicity is resultant of the metabolism of the drug in overdose. Onset of hepatic toxicity is delayed 12 to 36 hours after acute overdose. Therapy after acute overdose is based on the level of drug if this can be measured 4 to 24 hours after overdose, according to the Rumack-Mathews nomogram. Subacute and late-presenting cases cannot be managed according to the nomogram. Acute overdose that is thought to put the patient at high risk for developing hepatic toxicity is treated with N-acetylcysteine administered as a loading dose of 140 mg/kg followed by 17 maintenance doses at 70 mg/kg. Shorter courses of therapy are routine in Europe, Canada, Australia, and elsewhere, and have been administered in the United States as well. The efficacy of N-acetylcysteine therapy declines beginning 8 hours after acute overdose; therefore, therapy should be started within 8 hours of overdose. Patients with acute ingestion and nontoxic levels do not require therapy. Short courses of therapy in other cases may be required if potential toxicity is unclear.

Acetaminophen (paracetamol, APAP) is a widely used analgesic and antipyretic agent. Use of APAP as an antipyretic was first reported by von Mehring in 1893, in fact preceding the medicinal use of salicylates.1 Despite its effectiveness, an undesirable side effect profile led to discouragement of its use. It is likely that an impure preparation was used, accounting for the adverse effects.2 Related compounds including acetanilide (marketed as Antifebrin) were in use since the late 1880s. APAP was subsequently abandoned until the late

1940s, when Brodie and Axelrod published their data indicating that APAP was in fact a metabolite of acetanilide and was responsible for the analgesic and antipyretic effects.2 Subsequent to these investigations, APAP was substituted for phenacetin in the combination product Trigesic in 1950. Trigesic was withdrawn from the market in 1951 after reports of agranulocytosis associated with its use. APAP was never clearly implicated as causal. APAP use was essentially abandoned in the United States until the advent of Tylenol in 1955. However, aspirin was more widely prescribed until the early 1970s.2 APAP, marketed as Panadol in the United Kingdom in 1956, increased in popularity throughout the 1960s and 1970s in a fashion parallel to that in the United States.2 Currently, APAP poisoning represents the most frequent poisoning reported to U.S. poison centers, is the cause of the majority of poisoning deaths reported to U.S. poison centers, and is the most frequent cause of acute hepatic failure in the United States.3-5

PHARMACOLOGY Despite its widespread use, APAP’s mechanism of action remains elusive. Cyclooxygenase inhibition has been long postulated, but APAP has been shown to be a poor inhibitor of COX-1 and COX-2, the two well-described cyclooxygenases involved in the early inflammatory response. Furthermore, unlike nonsteroidal anti-inflammatory drugs, APAP has not shown antiplatelet activity.6-8 Chandrasekharan and colleagues recently demonstrated the presence of a COX-3 enzyme that is inhibited by APAP. The COX-3 enzyme is primarily expressed in the central nervous system, implying a central location of action for APAP.6 COX-3 inhibition by APAP is weak, however; therefore, that COX-3 inhibition does not fully explain the analgesic and antipyretic actions of APAP.8 825

826

ANALGESICS

PHARMACOKINETICS APAP in therapeutic doses is rapidly and nearly completely absorbed. Absorption occurs primarily in the small bowel with the rate of absorption consequently dependent on the rate of gastric emptying. APAP is distributed throughout the body, having a volume of distribution of 0.95 L/kg. Half-life is approximately 1.5 to 2 hours.9 Hepatic metabolism produces two major metabolites, the sulfate conjugate and the glucuronide conjugate. Approximately 5% of APAP is excreted unchanged, while approximately 4% to 5% undergoes reductive metabolism by the cytochrome P-450 (CYP) system, principally CYP2E1 and CYP1A2 to N-acetyl-parabenzoquinone-imine (NAPQI). NAPQI is subsequently bound to intracellular thiols, principally glutathione, and is excreted as the cysteine and mercapturic acid conjugates in urine9 (Fig. 47-1). This reductive metabolism and its products are implicated in the toxicity of APAP. Glucuronide conjugation occurs to a much lesser degree in young children and neonates than in adults, and sulfate conjugation predominates; the plasma halflife may also be prolonged in young children.10 Patients with severe liver dysfunction may have decreased excretion of APAP as well.11 The urinary excretion of APAP is via glomerular filtration with a significant fraction of tubular reabsorption. The glucuronide and sulfate conjugates are actively secreted by the tubules, with renal clearance rates of 130 and 170 mL/min, respectively.12 Patients with renal failure accumulate metabolites, although the plasma halflife of APAP is unaffected.11 APAP readily crosses the placenta and is risk category B in pregnancy, meaning that safety is presumed based on animal studies.13 Maternal pharmacokinetics are similar to those of humans in the nonpregnant state.14,15 Several studies have investigated the effects of APAP in therapeutic doses and overdose in all trimesters.16-22 APAP toxicity appears to occur in utero. One report describes plasma levels in an infant delivered by cesarean section similar to maternal levels following maternal APAP overdose.23 Therapeutic dosing has not been shown to have any negative effects on pregnancy or the fetus. APAP is excreted in breast milk in milk:plasma ratios reported to range from 1:0.50 to 1:1.42.24 Pharmacologic agents that can theoretically affect APAP pharmacokinetics include those that delay gastric emptying, notably the anticholinergic agents. Several case reports describe delay in absorption following APAP overdose with co-ingestants that delay gastric emptying.25-27 Absorption of liquid preparations is slightly more rapid.9 No significant drug interactions are known to occur with APAP following therapeutic dosing.

TOXICOLOGY Death due to hepatic failure following APAP overdose was first reported in 1966.28,29 Research into the cause of toxicity ensued, and in 1974 Mitchell and Jollow published their work that provided the basis for the widely

accepted theory of free radical arylation of hepatic proteins as causative.30-33 These investigators demonstrated in vivo and in vitro that radiolabeled acetaminophen was recovered bound to proteins in the hepatocyte following administration of high doses of acettaminophen. Furthermore, they found that glutathione depletion preceded other signs of hepatic injury and that glutathione precursors administered prior to experimental poisoning were hepatoprotective. This work formed the basis for N-acetylcysteine (NAC) antidotal therapy. Later studies identified the metabolite responsible for binding to be NAPQI.34,35 Further work has gone into determining the critical protein or proteins responsible for hepatic failure. At present, approximately 28 proteins subject to arylation have been identified.36,37 Binding is highly selective, however. Several specific proteins account for the majority of binding, specifically the cytosolic 56- to 58-kD acetaminophen binding protein, the 100-kD N-10-formyl-tetrahydrofolate dehydrogenase, and 50- and 54-kD mitochondrial dehydrogenases.38 Several investigators have worked extensively to determine the critical protein or proteins that, when arylated, result in cell death. No decrease in protein function has been determined that could likely account for the cell death. Most enzymes show only modest reduction in function postpoisoning, with the most prominent being glutamine synthetase, which has a 50% reduction in activity.37 These and other inconsistencies of the NAPQI binding hypothesis have led to consistent challenges to this hypothesis.37,39 Covalent binding does not always correlate with severity of injury.37 Inhibition of Kupffer cell activity alters or abolishes toxicity despite a high degree of covalent binding.40,41 High levels of covalent binding will occur in young female rats with no detectable hepatic injury.42 3’-Hydroxyacetanilide, a regioisomer of APAP administered in similar doses, results in a high degree of protein covalent binding without toxicity as well.43,44 Also, the critical protein or proteins have never been identified in nearly 30 years of investigation. A complete review of the criticism of the NAPQI theory is beyond the scope of this chapter; however, these and other inconsistencies have led to the investigation of several other causes of toxicity. Wendel and co-workers proposed the hypothesis that reactive oxygen species formed during the CYP metabolism of APAP produce massive lipid peroxidation, and they produced data to strongly support this contention.45-47 The data were challenged on the basis that due to technical difficulties in the measurement of products of lipid peroxidation, the animal model used by Wendel’s group was particularly susceptible to lipid peroxidation and that it was not therefore relevant.48 Other investigators have not reproduced the work using other models.37 Oxidant stress due to the action of reactive oxygen species has been proposed due to the generation of these species from a variety of sources, including injured mitochondria, activated Kupffer cells, infiltrating neutrophils, and xanthine oxidase.37 Evidence supporting each of these mechanisms exists, but the question

CHAPTER 47

Acetaminophen

NHCOCH3

NHCOCH3

Acetanilid

OC2H5

827

Phenacetin NH2 NHCOCH3 Aniline

Methemoglobin-forming and other toxic metabolites

OH Acetaminophen

~93%

~5%

~2%

NHCOCH3

NHCOCH3

Direct renal excretion

K

K

Methemoglobin-forming and other toxic metabolites

or

O NAPQI

Conjugated acetaminophen

Adequate glutathione or glutathione substitute? Renal excretion Yes

No

NHCOCH3

NHCOCH3

Reduced glutathione

Hepatocyte macromolecules

OH

OH

Mercapturic acid/ cysteine conjugate

Cell death

Renal excretion FIGURE 47-1 Metabolism of acetaminophen and other coal tar analgesics. NAPQI, N-acetyl-p-benzoquinoneimine; R, glucuronide or sulfate.

remains as to whether oxidant stress is a cause of hepatocyte injury or occurs as a result of hepatocyte injury. Peroxynitrate formation occurs when nitric oxide is formed in the presence of superoxide anions, a reactive oxygen species.49 Peroxynitrate is a powerful oxidant and produces nitrotyrosine adducts in tissue, which have been demonstrated by immunohistochemistry in hepatic tissue following experimental APAP overdose. Time course of nitrotyrosine adducts indicates that they bind concurrently or immediately preceding hepatocyte

injury. Furthermore, peroxynitrate can deplete cellular glutathione stores.37 Finally, early mitochondrial dysfunction is an important early finding in all models of APAP overdose and may occur as soon as 15 minutes after APAP exposure.50-55 Mitochondrial dysfunction is implicated as playing a role in nearly every aspect of the pathogenesis of APAP toxicity, including failure of energy substrate, increase in reactive oxygen species, and increased cytosolic calcium concentrations. The cause of this early failure is not

828

ANALGESICS

known. Reactive metabolite arylation of mitochondrial proteins has not been demonstrated to have a significant enough effect to be accepted as causal.37 Early mitochondrial failure remains a crucial missing piece of the puzzle of APAP-induced hepatic injury. One mechanism that has been proposed in the past and is currently undergoing investigation is the concept of hypoxia as causal regarding the early mitochondrial failure.56,57 Centrilobular hepatocytes are relatively hypoxic at baseline. Mitochondria are susceptible to a lack of available oxygen due to the use of oxygen for drug metabolism. Early work has shown promise but mixed results with regard to APAP poisoning.57 Hypoxia has been demonstrated in a more convincing fashion in relation to other centrilobular toxins, including ethanol and carbon tetrachloride.58-62 Another proposed mechanism of mitochondrial failure involves mitochondrial permeability transition (MPT), a state where the inner mitochondrial membrane becomes depolarized due to increased ion permeability. The proposed mechanism involves NAPQI binding to vicinal thiols in the membrane pore responsible for MPT. Other quinones known to bind vicinal thiols have been demonstrated to induce MPT. NAPQI has not been demonstrated to have this effect, however.63 Recently, attention has been turned to the delay in fulminant hepatic failure following overdose. Humans and animals typically will have a delay following metabolism of APAP before the rise in transaminases occurs. This phenomenon has been referred to as stage 1 and stage 2 of toxicity.64 Stage 1 is the metabolism phase of poisoning, where plasma drug level declines and serologic and clinical evidence for hepatotoxicity is absent. Stage 2 refers to the hepatic injury phase that occurs 12 to 36 hours after drug metabolism is complete. Current investigation is focused on the identification of inflammatory mediators that may be responsible for the second stage.37 It is important to note that the exact cause of the initiating events, while clearly related to metabolism, remains in question. An immune response to arylated proteins has not been demonstrated. Kupffer cell involvement is thought to be imperative in toxicity.

CLINICAL MANIFESTATIONS Acute human toxicity has traditionally been divided into four clinical phases (Box 47-1). Initially, patients may be asymptomatic or may develop nausea and vomiting. Transaminases may begin to rise by 16 hours after overdose.65 Between 24 and 72 hours, signs of hepatic insult become prominent. Transaminases begin or continue to rise, the patient may develop right upper quadrant pain, and signs of hepatic synthetic failure (i.e., elevated prothrombin time) may appear, as may evidence of cholestasis with elevated bilirubin. Renal injury will become evident in a small fraction of patients at this point.66 A few reports of renal injury without hepatic failure exist, but these are exceedingly rare and not well documented.67 Most cases include some degree of hepatic injury. Between 72 and 96 hours, hepatic and

BOX 47-1

PHASES OF ACETAMINOPHEN POISONING

Phase 1 (0.5 –24 hr)

Anorexia, nausea, and vomiting are frequently present. Malaise and diaphoresis may be present. Transaminases may be elevated. Patients may appear normal. Phase II (24–72 hr)

Anorexia, nausea, and vomiting become less pronounced. Right upper quadrant pain may be present. Transaminase levels continue to increase. Bilirubin level may be elevated. Prothrombin time may be prolonged. Renal function may deteriorate. Phase III (72–96 hr)

Characterized by the sequelae of hepatic necrosis: jaundice, coagulation defects, renal failure, and hepatic encephalopathy. Liver biopsy reveals centrilobular necrosis. Death due to multiorgan failure may result. Phase IV (4–14 days)

If patients survive, complete resolution of hepatic dysfunction occurs and the liver heals without evidence of fibrosis.

renal failure may worsen. Death occurs due to hepatic failure. Early hepatic transplant may allow survival at this point. Alternatively, hepatic injury may resolve and transaminases may return to normal over the ensuing 4 to 14 days. Complete regeneration of the liver is the rule. Renal insult will resolve as well.67 APAP toxicity following supratherapeutic administration, often referred to as chronic toxicity, has been observed in both children and adults. The patients manifest essentially the same course of toxicity. One case of hepatic fibrosis following chronic administration of supratherapeutic doses has been reported.68 More recently, chronic administration of therapeutic amounts of acetaminophen has been shown to cause hepatocellular injury. Injury was relatively mild and resolved with discontinuation of the drug.69 Case reports exist implicating APAP in analgesic nephropathy.11 However, epidemiologic data do not support the contention that chronic therapeutic administration leads to renal injury.70-72 APAP hypersensitivity is exceedingly rare.11

DIAGNOSIS The diagnosis of APAP poisoning is based primarily on history and laboratory screening, given the nonspecific nature of the initial presentation and the delay in manifestations of hepatotoxicity. Nausea and vomiting are consistent with early toxicity. A serum APAP concentration should be sent when any patient presents with a history of intentional overdose of any substance due to the wide availability of the drug and the 5% incidence of undeclared ingestion. Because the manifestations of hepatic injury are delayed, the decision to initiate

CHAPTER 47

therapy is based on the risk of developing hepatotoxicity. In the setting of the acute ingestion at a single point in time, the decision to treat is relatively straightforward. An accurate time of ingestion must first be established. Establishment of the risk for toxicity is based on the Rumack-Matthews nomogram (Fig. 47-2). The nomogram was developed in 1975 by retrospective review of 64 patients following acute APAP overdose. Patients were found to have a 60% chance of developing severe hepatotoxicity if the plasma level was above the line drawn from the 200 μg/mL level at 4 hours to the 50 μg/mL level at 12 hours. Severe hepatotoxicity was defined as an aspartate aminotransferase (AST) level of greater that 1000 IU/L.73 It is important to recognize that the nomogram is not applicable to modes of ingestion other than the acute single overdose. Furthermore, the nomogram is not applicable prior to 4 hours or after 24 hours. Levels prior to 4 hours may be markedly elevated because APAP may not have distributed from the vascular compartment to the tissues. It is also important to recognize that the nomogram comprises a series of data points rather than representing the elimination half-life of APAP in overdose. Rarely, patients following a massive overdose causing levels in the range of 800 to 1000 μg/mL will present with severe acidosis and coma.74 The mechanism of this presentation is not understood. Animal and in vitro data indicate reversible binding of APAP to mitochondrial proteins inhibiting respiration, and this mechanism has been suggested to be the cause of the acidosis seen in these massive overdoses.56,75 Patients presenting late or following ingestion over a prolonged period of time present a more difficult diagnosis because the nomogram cannot be used. A

829

careful history of ingestion should be sought. APAP level should be measured to confirm ingestion, but the level cannot be used to determine risk for resultant hepatotoxicity. Transaminase values should be obtained and elevation should be assumed due to APAP poisoning unless proven otherwise. The differential diagnosis includes all causes of hepatic centrilobular necrosis. Principal are other toxic causes, including hepatotoxic mushrooms, carbon tetrachloride, halothane and other inhaled anesthetics, brominated and chlorinated benzenes, and dioxane. Shock, vascular obstruction, and other causes of acute hepatic ischemia will also produce a centrilobular necrosis with the resultant clinical picture consistent with acute APAP poisoning. APAP poisoning may be worsened in patients with cardiac insufficiency.76

MANAGEMENT Supportive Measures Initial supportive measures should be those applicable to any poisoned patient. If the patient presents late in the course of poisoning, then resuscitative measures may be necessary. These should include standard measures to control airway, ventilation, and hemodynamic status. Supportive care for the patient with hepatic failure from APAP poisoning does not differ from that due to any other cause of hepatic failure. Acute renal failure may require dialysis.

Decontamination Activated charcoal should be given unless the clinician is certain that the time of ingestion is so remote that there is no chance that any APAP remains in the gut. Every patient who presents within 6 hours of ingestion, or for whom the time of ingestion is in question, should therefore be treated with activated charcoal. Multipledose charcoal is not indicated following APAP ingestion. Activated charcoal will bind and reduce the absorption of NAC if given simultaneously; however, no clinical detriment has been shown by this practice.77-79 NAC should never be delayed beyond 8 hours following ingestion to facilitate decontamination, and concurrent administration of charcoal likely will not be detrimental.

300 Serum acetaminophen concentration (μg/mL)

Acetaminophen

200 150 100

50 25

Laboratory Monitoring 10 Lower limit for possible-risk group Lower limit for probable-risk group Lower limit for high-risk group

5

0

4

8

12

16

20

24

Time after acetaminophen ingestion (hr) FIGURE 47-2 Acetaminophen (APAP) overdose treatment nomogram. (Adapted from Smilkstein MJ, Knapp GL, Kully KW, et al: Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose: analysis of the National Multicenter Study [1976 to 1985]. N Engl J Med 1988;319:1557.)

Initial management should include obtaining baseline serum transaminase levels, blood urea nitrogen, creatinine, and prothrombin time along with the APAP level. Appropriate screening for co-ingestants should be dictated by the clinical situation. If there is no laboratory evidence of hepatic injury, then daily transaminase levels should suffice for laboratory monitoring. Should any abnormalities in transaminase levels appear at any time, then evidence of synthetic failure should be sought. Serial prothrombin time should be added to the serial transaminases. The frequency of laboratory evaluation

830

ANALGESICS

should be dictated by the clinical situation. A modest rise in transaminase levels (less than 500 IU/L) does not warrant more than daily monitoring. As levels approach 1000 IU/L, more frequent (i.e., every 6 to 12 hours) laboratory monitoring should be instituted. With any signs of synthetic failure the evaluation should be expanded to include data with prognostic value. Renal function tests should be followed due to the renal dysfunction that occurs infrequently. Should the patient develop signs of hepatic failure, he or she should be admitted to an intensive care unit and monitored closely for developing acidosis and renal and hepatic failure. This is important because the prognostic factors associated with death include a metabolic acidosis (arterial pH less than 7.3), renal insufficiency (serum creatinine greater than 3.3), or hepatic synthetic failure (International Normalized Ratio [INR] greater than 2 at 24 hours, 4 at 48 hours, or 6 at 72 hours).80 Recently, attention has been drawn to the use of blood lactate as an early predictor of hepatic failure. Blood lactate greater than 3.5 mmol/L or 3.0 mmol/L after fluid resuscitation was predictive of mortality and has been suggested as criteria to list for transplantation.81 Prothrombin time and INR may be elevated following APAP ingestion without evidence of hepatocellular injury. Inhibition of factor VII by high levels of APAP and the anticoagulant effects of NAC have been proposed as mechanisms.82,83 This early elevation in INR has no prognostic value.

Antidotes NAC is the current antidote employed worldwide for the treatment of APAP toxicity. The rationale for NAC therapy is based on the theory that glutathione depletion leads to a state where the toxic free radical NAPQI can injure cellular macromolecules. NAC is given as both a glutathione precursor to provide substrate for NAPQI binding as well as a sulfate precursor to help drive the metabolism of APAP down the sulfonation pathway.73

Dosing The standard course of NAC therapy in the United States is to administer a loading dose of 140 mg/kg followed by 17 maintenance doses of 70 mg/kg every 4 hours. This regimen was developed in the 1970s by Rumack and colleagues based on their observations of patients suffering from APAP overdose and applying the theory of NAC as a binding substrate for NAPQI.73 The amount of NAC administered is based on the theoretical molar amount of NAPQI formation. The duration of therapy is based on the period of time required to metabolize APAP. The duration is purposefully long because some patients display a markedly extended half-life. Standard practice in Europe, Canada, Australia, and other countries is to administer NAC for 20 to 36 hours. Rates of fulminant hepatic failure, death, and transplantation are not significantly different, prompting several investigators in the United States to begin trials of shorter courses of NAC following the acute single overdose.84,85

NAC therapy is typically given orally in the United States, while in other countries, intravenous (IV) administration is the preferred route. There are several reasons for this discrepancy. Proponents of oral administration cite the theoretical advantage that oral NAC is presented to the liver in high concentration because it is initially circulated via the portal system. No data exist to support this contention, however. IV NAC can and should be given to patients in the United States, however, if the patient is unable to tolerate the medication orally. The oral preparation sold in the United States is sterile and can be given by the IV route. As with oral administration, NAC should be given as a 5% solution in saline. A 22-μm filter typically used for blood administration should be used. NAC dosing is identical to the oral protocol: 140 mg/kg loading dose followed by 17 maintenance doses of 70 mg/kg. The rate of administration is related to complications. Anaphylactoid reactions are reported in approximately 6% of patients when the loading dose is administered over 15 to 30 minutes.86,87 Typically, these resolve with cessation of administration.86 Restarting administration at a lower rate following the administration of diphenhydramine is sufficient treatment. Administration at slower rates reduces the rate of anaphylactoid reaction. Consequently, administering IV NAC over the course of 1 hour is a reasonably conservative practice. More recently, an intravenous form of NAC was approved by the U.S. Food and Drug Administration. The approved dosing protocol applies only to acute ingestion and is given over 21 hours. A loading dose of 150 mg/kg is given over 1 hour, followed by 50 mg/kg over 4 hours, followed by 100 mg/kg over 16 hours. Patients who ingest APAP over a period greater than several hours due to repeat attempts or therapeutic misadventure and patients who present greater than 24 hours after ingestion present a more difficult decision with regard to initiating treatment. Generally, if the patient gives a history of overdose, has a measurable APAP level, and/or has a rise in AST or alanine transaminase, then NAC should be initiated. If the patient remains without biochemical evidence of toxicity by 24 hours, it is reasonable to discontinue therapy. Therapy should continue if there is evidence of toxicity. The decision to treat patients who have ingested an overdose at one time point is aided by the use of the Rumack-Matthews nomogram (see Fig. 47-2). It is important to note that this is the only clinical scenario in which the nomogram is applicable. The nomogram was constructed using a series of data points, which represent the presenting plasma level of APAP versus time. A line is drawn through those points representing patients with a greater than 60% likelihood of developing an AST greater than 1000 IU/L. A second line was arbitrarily lowered in order to allow for error in history of the time of ingestion and is the treatment level most commonly in use in the United States. Most physicians outside the United States use the first line as indication for therapy. The lines are drawn from a time point of 4 hours after ingestion. This is because levels during the absorptive phase following ingestion are not reliable in terms of

CHAPTER 47

prognosis. APAP levels obtained prior to 4 hours after ingestion should not be used to base treatment decisions. Furthermore, levels obtained after 24 hours similarly have not been determined to have prognostic value. Patients presenting following ingestion should have a level checked as close to 4 hours after the ingestion as possible. Treatment should be based on that level. If the level is above the lowest treatment line, a course of NAC therapy is indicated. If it is below the line, no therapy is needed. A caveat to this rule occurs following co-ingestion of drugs that slow gastric motility, particularly anticholinergics such as diphenhydramine. Case reports indicate that delayed absorption may result in a 4-hour level that is not considered treatable followed by a 6- or 8-hour level that is toxic.88 In this case a second level should be determined at 6 hours to ensure that the level is trending down and that levels subsequent to the initial 4-hour level will be unlikely to be in the treatable range. If the patient presents 8 or more hours after the ingestion or if a level will not be available before that time, treatment based on history of ingestion alone while awaiting an APAP level is indicated due to the decreasing efficacy of NAC therapy following delay to treatment greater than 8 hours.89 Patients who present greater than 24 hours after the ingestion pose a more difficult decision to treat because the nomogram is not directly applicable to their treatment. It is reasonable practice to treat patients with persistently elevated APAP levels who present later than 24 hours after ingestion because it is reasonable to assume that the level was in a toxic range at prior to the 24-hour mark. Notably, this is an assumption only, and such levels have no prognostic significance. Patients who present greater than 24 hours after ingestion without an elevated APAP level pose a more difficult treatment decision because it is impossible to know if they had a level placing them at risk for hepatic injury during first 24 hours. Consequently, a reasonable practice is to administer a course of therapy for 24 hours and to follow transaminase levels. Patients will likely begin to display elevated transaminase levels by 36 hours after ingestion.65,90 If they show no signs of hepatic injury, therapy may be discontinued. Also, any patients with evidence of hepatic injury at the time of presentation warrant therapy. Patients whose evidence of liver injury can clearly be attributed to a cause other than APAP toxicity who do not show progression of liver injury after 24 hours may have NAC therapy discontinued. It is important to note that NAC therapy is effective at any point after poisoning and that if hepatic injury occurs, therapy is continued until evidence of hepatic dysfunction has resolved and transaminase values are declining and near normal. Therapy should never be stopped following the prescribed 18 doses when evidence of hepatic injury is still present. The reason for this apparent discrepancy is that NAC therapy is proven effective in reducing mortality when started and continued during any point in the course of APAPinduced hepatic injury.91 Lack of a measurable APAP level is not an indication to withhold NAC therapy because late-presenting patients without measurable APAP levels are clearly benefited by NAC therapy. The

Acetaminophen

831

reasons for this are unclear. Several theories have been advanced. “Extrahepatic” effects such as free radical scavenging have been suggested, but experimental evidence is lacking. NAC has been shown to increase hepatic blood flow and oxygen extraction.92-94 It is following these observations that have led to the advent of NAC therapy for other causes of hepatic failure. Other suggested antidotes include the CYP inhibitor cimetidine. Cimetidine was recognized early on as an inhibitor of the CYP system, and its use as an antidote for APAP poisoning was considered. Early animal data showed promise.95 Human experience was less promising and met with little enthusiasm.96 One argument against cimetidine is that it does not affect the specific CYP isoforms involved in the metabolism of APAP. Specific CYP2E1 inhibitors such as 4-methyl-pyrrizole and disulfiram have been investigated in animals with positive results.97,98 Human data do not yet exist.

Elimination Dialysis has been used to enhance elimination following APAP poisoning. Its use has largely been abandoned following the advent of NAC therapy due to the effectiveness of this treatment. However, a role for dialysis has been suggested in cases of massive overdose where the patient presents with coma, acidosis, and levels near 1000 μg/mL, at which point the risk for mortality is very high. There are no data addressing the effectiveness of this intervention. Liver dialysis has been reported to be of benefit in an uncontrolled case series of four patients.99 More data will be needed to determine benefit of liver dialysis.

DISPOSITION Patients presenting with a history of APAP ingestion should be screened for co-ingestants in the usual fashion. A careful physical examination aimed at identifying a toxidrome suggestive of co-ingestants should be performed. Serum APAP level should be determined at 4 hours postingestion or as soon as possible after the 4-hour mark. Levels prior to 4 hours are of no prognostic significance. Patients with a single time of ingestion between 4 and 24 hours prior to presentation may be treated according to the Rumack-Matthews nomogram. Patients ingesting APAP at more than one time point warrant an abbreviated course of therapy while monitoring transaminase levels. Any patient with evidence of hepatic injury should have therapy continued until evidence of hepatic injury is resolved. Patients not meeting these criteria do not warrant therapy. As with any ingestion, a careful investigation of the circumstances surrounding the ingestion should be performed. It is important to educate any patient who has overdosed due to misuse of APAP. Intentional overdoses warrant psychiatric evaluation before the patient is discharged from medical care. Patients who suffer hepatic injury and recover may be safely discharged from care because no sequelae will occur once the injury is resolved.

832

ANALGESICS

The question of referral to a center capable of transplantation often arises. Given the rapidity of demise in patients who suffer hepatic injury, referral should be discussed with the appropriate personnel at the referral center when the patient begins to display evidence of hepatic functional impairment in order to allow the transplant service adequate time to assess the patient and place him or her on a transplant list. Patients who have only elevation in transaminase levels and a transient, slight elevation in prothrombin time and INR can be managed expectantly with NAC therapy alone. Patients who undergo transplantation will need careful follow-up care as with any transplant patient. REFERENCES 1. Mehring JV: Beitrage zur Kenntniss der Antipyretica. Ther Monatsschr 1893;7:577. 2. Spooner JB, Harvey JG: The history and usage of paracetamol. J Int Med Res 1976;4(4 Suppl):1–6. 3. Ostapowicz G, Fontana RJ, Schiodt FV, et al: Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002;137(12):947–954. [Summary for patients in Ann Intern Med 2002;137(12):I24; PMID: 12484742.] 4. Litovitz TL, Klein-Schwartz W, Rodgers GC Jr, et al: 2001 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2002;20(5): 391–452. 5. Larson AM, Polson J, Fontana RJ, et al: Acetaminophen-induced acute liver failure: Results of a United States multicenter prospective study. Hepatology 2005;42(6):1364–1372. 6. Chandrasekharan NV, Dai H, Roos KL, et al: COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/ antipyretic drugs: cloning, structure, and expression [see comment]. Proc Natl Acad Sci U S A 2002;99(21):13926–13931. 7. Botting RM: Mechanism of action of acetaminophen: is there a cyclooxygenase 3? Clin Infect Dis 2000;31(Suppl 5):202–210. 8. Schwab JM, Schluesener HJ, Laufer S: COX-3: just another COX or the solitary elusive target of paracetamol? Lancet 2003;361 (9362):981–982. 9. Forrest JA, Clements JA, Prescott LF: Clinical pharmacokinetics of paracetamol. Clin Pharmacokinet 1982;7(2):93–107. 10. Prescott LF: Kinetics and metabolism of paracetamol and phenacetin. Br J Clin Pharmacol 1980;10(Suppl 2):291–298. 11. Clissold SP: Paracetamol and phenacetin. Drugs 1986;32(Suppl 4): 46–59. 12. Morris ME, Levy G: Renal clearance and serum protein binding of acetaminophen and its major conjugates in humans. J Pharm Sci 1984;73(8):1038–1041. 13. Levy G, Garrettson LK, Soda DM: Evidence of placental transfer of acetaminophen [Letter]. Pediatrics 1975;55(6):895. 14. Beaulac-Baillargeon L, Rocheleau S: Paracetamol pharmacokinetics during the first trimester of human pregnancy. Eur J Clin Pharmacol 1994;46(5):451–454. 15. Rayburn W, Shukla U, Stetson P, et al: Acetaminophen pharmacokinetics: comparison between pregnant and nonpregnant women. Am J Obstet Gynecol 1986;155(6):1353–1356. 16. Byer AJ, Traylor TR, Semmer JR: Acetaminophen overdose in the third trimester of pregnancy. JAMA 1982;247(22):3114–3115. 17. Friedman S, Gatti M, Baker T: Cesarean section after maternal acetaminophen overdose. Anesth Analg 1993;77(3):632–634. 18. Ludmir J, Main DM, Landon MB, et al: Maternal acetaminophen overdose at 15 weeks of gestation. Obstet Gynecol 1986;67(5): 750–751. 19. McElhatton PR, Sullivan FM, Volans GN: Paracetamol overdose in pregnancy: analysis of the outcomes of 300 cases referred to the Teratology Information Service. Reprod Toxicol 1997;11(1): 85–94. 20. Riggs BS, Bronstien AC, Kulig K, et al: Acute acetaminophen overdose during pregnancy. Obstet Gynecol 1989;74(2):247–253.

21. Rosevear SK, Hope PL: Favourable neonatal outcome following maternal paracetamol overdose and severe fetal distress. Case report. Br J Obstet Gynaecol 1989;96(4):491–493. 22. Stokes IM: Paracetamol overdose in the second trimester of pregnancy. Case report. Br J Obstet Gynaecol 1984;91(3):286–288. 23. Wang PH, Yang MJ, Lee WL, et al: Acetaminophen poisoning in late pregnancy. A case report. J Reprod Med 1997;42(6):367–371. 24. Findlay JW, DeAngelis RL, Kearney MF, et al: Analgesic drugs in breast milk and plasma. Clin Pharmacol Ther 1981;29(5):625–633. 25. Tighe TV, Walter FG: Delayed toxic acetaminophen level after initial four hour nontoxic level. J Toxicol Clin Toxicol 1994;32(4): 431–434. 26. Bartle WR, Paradiso FP, Derry JE, Livingstone DJ: Delayed acetaminophen toxicity despite acetylcysteine use. Drug Intell Clin Pharmacol 1989;23:509. 27. Augenstien WL, Kulig KW, Rumack BH: Delayed rise in serum drug levels in overdose patients despite multiple dose charcoal and after charcoal stools. Vet Hum Toxicol 1987;29:491. 28. Thomson JS, Prescott LF: Liver damage and impaired glucose tolerance after paracetamol overdosage. BMJ 1966;5512:506–507. 29. Davidson DG, Eastham WN: Acute liver necrosis following overdose of paracetamol. BMJ 1966;5512:497–499. 30. Mitchell JR, Jollow DJ, Potter WZ, et al: Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J Pharmacol Exp Ther 1973;187(1):185–194. 31. Mitchell JR, et al: Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J Pharmacol Exp Ther 1973; 187(1):211–217. 32. Mitchell JR, Thorgiersson SS, Potter WZ, et al: Acetaminopheninduced hepatic injury: protective role of glutathione in man and rationale for therapy. Clin Pharmacol Ther 1974;16(4): 676–684. 33. Jollow DJ, Mitchell JR, Potter WZ, et al: Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J Pharmacol Exp Ther 1973;187(1):195–202. 34. Dahlin DC, Miwa FT, Lu AY, et al: N-acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proc Natl Acad Sci U S A 1984;81(5):1327–1331. 35. Nelson SD: Molecular mechanisms of the hepatotoxicity caused by acetaminophen. Semin Liver Dis 1990;10(4):267–278. 36. Qiu Y, Benet LZ, Burlingame AL: Identification of the hepatic protein targets of reactive metabolites of acetaminophen in vivo in mice using two-dimensional gel electrophoresis and mass spectrometry. J Biol Chem 1998;273(28):17940–17953. 37. Jaeschke H, Knight TR, Bajt ML: The role of oxidant stress and reactive nitrogen species in acetaminophen hepatotoxicity. Toxicol Lett 2003;144(3):279–288. 38. Cohen SD, Khairallah EA: Selective protein arylation and acetaminophen-induced hepatotoxicity. Drug Metab Rev 1997; 29(1–2):59–77 [erratum in Drug Metab Rev 1997;29(4):1285]. 39. Smith CV, Lauterberg BH, Mitchell JR: Covalent binding and acute lethal injury in vivo: how has the original hypothesis survived a decade of critical examination? In Wilkinson GR, Rawlins MD (eds): Drug Metabolism and Disposition: Considerations in Clinical Pharmacology. Lancaster, UK, MTP Press, 1985, pp 161–181. 40. Michael SL, Rumford NR, Mayeux PR, et al: Pretreatment of mice with macrophage inactivators decreases acetaminophen hepatotoxicity and the formation of reactive oxygen and nitrogen species. Hepatology 1999;30(1):186–195. 41. Laskin DL, Gardiner CR, Price VF, et al: Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen. Hepatology 1995;21(4):1045–1050. 42. Tarloff JB, Khaifallah EA, Cohen SD, et al: Sex- and age-dependent acetaminophen hepato- and nephrotoxicity in Sprague-Dawley rats: role of tissue accumulation, nonprotein sulfhydryl depletion, and covalent binding. Fund Appl Toxicol 1996;30(1):13–22. 43. Tirmenstein MA, Nelson SD: Subcellular binding and effects on calcium homeostasis produced by acetaminophen and a nonhepatotoxic regioisomer, 3′-hydroxyacetanilide, in mouse liver. J Biol Chem 1989;264(17):9814–9819. 44. Myers TG, Dietz EC, Anderson NL, et al: A comparative study of mouse liver proteins arylated by reactive metabolites of acetaminophen and its nonhepatotoxic regioisomer, 3′-hydroxyacetanilide. Chem Res Toxicol 1995;8(3):403–413.

CHAPTER 47

45. Wendel A, Feuerstein S: Drug-induced lipid peroxidation in mice. I. Modulation by monooxygenase activity, glutathione and selenium status. Biochem Pharmacol 1981;30(18):2513–2520. 46. Wendel A, Jaeschke H, Gloger M: Drug-induced lipid peroxidation in mice. II. Protection against paracetamol-induced liver necrosis by intravenous liposomally entrapped glutathione. Biochem Pharmacol 1982;31(22):3601–3605. 47. Wendel A, Feuerstein S, Konz KH: Acute paracetamol intoxication of starved mice leads to lipid peroxidation in vivo. Biochem Pharmacol 1979;28(13):2051–2055. 48. Mitchell JR, Smith CV, Hughes H, et al: Overview of alkylation and peroxidation mechanisms in acute lethal hepatocellular injury by chemically reactive metabolites. Semin Liver Dis 1981;1(2):143–150. 49. Squadrito GL, Pryor WA: Oxidative chemistry of nitric oxide: the roles of superoxide, peroxynitrite, and carbon dioxide. Free Radic Biol Med 1998;25(4–5):392–403. 50. Burcham PC, Harman AW: Mitochondrial dysfunction in paracetamol hepatotoxicity: in vitro studies in isolated mouse hepatocytes. Toxicol Lett 1990;50(1):37–48. 51. Ruepp SU, Tonge RP, Shaw J, et al: Genomics and proteomics analysis of acetaminophen toxicity in mouse liver. Toxicol Sci 2002;65(1):135–150. 52. Walker RM, Racz WJ, McElligott TF: Scanning electron microscopic examination of acetaminophen-induced hepatotoxicity and congestion in mice. Am J Pathol 1983;113(3):321–330. 53. Donnelly PJ, Walker RM, Racz WJ: Inhibition of mitochondrial respiration in vivo is an early event in acetaminophen-induced hepatotoxicity. Arch Toxicol 1994;68(2):110–118. 54. Katyare SS, Satav JG: Impaired mitochondrial oxidative energy metabolism following paracetamol-induced hepatotoxicity in the rat. Br J Pharmacol 1989;96(1):51–58. 55. Meyers LL, Beierschmidt WP, Khairallah EA, et al: Acetaminophen-induced inhibition of hepatic mitochondrial respiration in mice. Toxicol Appl Pharmacol 1988;93(3):378–387. 56. Marzella L, Muhvich K, Myers RA: Effect of hyperoxia on liver necrosis induced by hepatotoxins. Virchows Arch 1986;51(6): 497–507. 57. Salhanick SD, Belikoff B, Orlow D, et al: Hyperbaric oxygen reduces acetaminophen toxicity and increases HIF-1alpha expression. Acad Emerg Med 2006;13(7):707–714. 58. Burkhart KK, Hall AH, Gerace R, Rumack BH: Hyperbaric oxygen treatment for carbon tetrachloride poisoning. Drug Saf 1991; 6(5):332–338. 59. Arteel GE, Iimuro Y, Yin M, et al: Chronic enteral ethanol treatment causes hypoxia in rat liver tissue in vivo. Hepatology 1997;25(4):920–926. 60. Arteel GE, Raleigh JA, Bradford BU, et al: Acute alcohol produces hypoxia directly in rat liver tissue in vivo: role of Kupffer cells. Am J Physiol 1996;271(3 Pt 1):G494–G500. 61. Cohen SD, Khairallah EA: Selective protein arylation and acetaminophen-induced hepatotoxicity. Drug Metab Rev 1997;29 (1–2):59–77 [erratum in Drug Metab Rev 1997;29(4):1285]. 62. Lieber CS: Alcohol and the liver: 1994 update. Gastroenterology 1994;106:1085–1105. 63. James LP, Mayeux PR, Hinson JA: Acetaminophen-induced hepatotoxicity. Drug Metab Dispos 2003;31(12):1499–1506. 64. Bessems JG, Vermeulen NP: Paracetamol (acetaminophen)induced toxicity: molecular and biochemical mechanisms, analogues and protective approaches. Crit Rev Toxicol 2001;31(1):55–138. 65. Singer AJ, Carracio TR, Mofenson HC: The temporal profile of increased transaminase levels in patients with acetaminopheninduced liver dysfunction. Ann Emerg Med 1995;26(1):49–53. 66. Boutis K, Shannon M: Nephrotoxicity after acute severe acetaminophen poisoning in adolescents. J Toxicol Clin Toxicol 2001; 39(5):441–445. 67. Blakely P, McDonald BR: Acute renal failure due to acetaminophen ingestion: a case report and review of the literature. J Am Soc Nephrol 1995;6(1):48–53. 68. O’Dell JR, Zetterman RK, Burnett DA: Centrilobular hepatic fibrosis following acetaminophen-induced hepatic necrosis in an alcoholic. JAMA 1986;255(19):2636–2637. 69. Watkins PB, Kaplowitz N, Slattery JT, et al: Aminotranferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA 2006;296(1):87–93.

Acetaminophen

833

70. Barrett BJ: Acetaminophen and adverse chronic renal outcomes: an appraisal of the epidemiologic evidence. Am J Kidney Dis 1996;28(1 Suppl 1):14–19. 71. Blantz RC: Acetaminophen: acute and chronic effects on renal function. Am J Kidney Dis 1996;28(1 Suppl 1):3–6. 72. Buckalew VM Jr: Habitual use of acetaminophen as a risk factor for chronic renal failure: a comparison with phenacetin. Am J Kidney Dis 1996;28(1 Suppl 1):7–13. 73. Rumack BH: Acetaminophen hepatotoxicity: the first 35 years. J Toxicol Clin Toxicol 2002;40(1):3–20. 74. Flanagan RJ, Mant TG: Coma and metabolic acidosis early in severe acute paracetamol poisoning. Hum Toxicol 1986;5(3): 179–182. 75. Esterline RL, Ray SD, Ji S: Reversible and irreversible inhibition of hepatic mitochondrial respiration by acetaminophen and its toxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). Biochem Pharmacol 1989;38(14):2387–2390. 76. Bonkovsky HL, et al: Acute hepatic and renal toxicity from low doses of acetaminophen in the absence of alcohol abuse or malnutrition: evidence for increased susceptibility to drug toxicity due to cardiopulmonary and renal insufficiency. Hepatology 1994; 19(5):1141–1148. 77. Ekins BR, Ford DC, Thompson MI, et al: The effect of activated charcoal on N-acetylcysteine absorption in normal subjects. Am J Emerg Med 1987;5(6):483–487. 78. Spiller HA, Krenzelok EP, Grande GA, et al: A prospective evaluation of the effect of activated charcoal before oral Nacetylcysteine in acetaminophen overdose [see comment]. Ann Emerg Med 1994;23(3):519–523. 79. Smilkstein MJ: A new loading dose for N-acetylcysteine? The answer is no [see comment]. Ann Emerg Med 1994;24(3): 538–539. 80. Makin AJ, Williams R: Acetaminophen-induced hepatotoxicity: predisposing factors and treatments. Adv Intern Med 1997;42: 453–483. 81. Bernal W, Donaldson N, Wyncoll D, et al: Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study [see comment]. Lancet 2002;359(9306): 558–563. 82. Whyte IM, Buckley NA, Reith DM, et al: Acetaminophen causes an increased International Normalized Ratio by reducing functional factor VII. Ther Drug Monit 2000;22(6):742–748. 83. Schmidt LE, Knudsen TT, Dalhoff K, et al: Effect of acetylcysteine on prothrombin index in paracetamol poisoning without hepatocellular injury [see comment]. Lancet 2002;360(9340):1151–1152. 84. Yip L, Dart RC: A 20-hour treatment for acute acetaminophen overdose. N Engl J Med 2003;348(24):2471–2472. 85. Woo OF, Mueller RD, Olson KR, et al: Shorter duration of oral Nacetylcysteine therapy for acute acetaminophen overdose. Ann Emerg Med 2000;35(4):363–368. 86. Schmidt LE, Dalhoff K: Risk factors in the development of adverse reactions to N-acetylcysteine in patients with paracetamol poisoning. Br J Clin Pharmacol 2001;51(1):87–91. 87. Appelboam AV, Dargan PI, Knighton J: Fatal anaphylactoid reaction to N-acetylcysteine: caution in patients with asthma. Emerg Med J 2002;19(6):594–595. 88. Ho SY, Arellano M, Zolkowski-Wynne J: Delayed increase in acetaminophen concentration after Tylenol PM overdose. Am J Emerg Med 1999;17(3):315–317. 89. Smilkstein MJ, Knapp GL, Kulig KW, et al: Efficacy of oral Nacetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985) [see comment]. N Engl J Med 1988;319(24):1557–1562. 90. Prescott LF: Paracetamol overdosage. Pharmacological considerations and clinical management. Drugs 1983;25(3):290–314. 91. Keays R, Harrison PM, Wendon JA, et al: Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. BMJ 1991;303(6809):1026–1029. 92. Harrison PM, Wendon JA, Gimson AE, et al: Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure. N Engl J Med 1991;324(26):1852–1857. 93. Devlin J, Ellis AE, McPeake J, et al: N-acetylcysteine improves indocyanine green extraction and oxygen transport during hepatic dysfunction [see comment]. Crit Care Med 1997;25(2):236–242.

834

ANALGESICS

94. Spies CD, Reinhart K, Witt I, et al: Influence of N-acetylcysteine on indirect indicators of tissue oxygenation in septic shock patients: results from a prospective, randomized, double-blind study. Crit Care Med 1994;22(11):1738–1746. 95. Speeg KV: Potential use of cimetidine for treatment of acetaminophen overdose. Pharmacotherapy 1987;7(6 Pt 2 Suppl): 125–133. 96. Critchley JA, Dyson EH, Scott AW, et al: Is there a place for cimetidine or ethanol in the treatment of paracetamol poisoning? Lancet 1983;1(8338):1375–1376.

97. Brennan RJ, Mankes RF, Lefevre R, et al: 4-Methylpyrazole blocks acetaminophen hepatotoxicity in the rat. Ann Emerg Med 1994;23(3):487–494. 98. Eszter Hazai LV, Monostory K: Reduction of toxic metabolite formation of acetaminophen. Biochem Biophys Res Commun 2002;291(4):1089–1094. 99. Akdogan M, El-Sahwi K, Ahmed U, et al: Experience with liver dialysis in acetaminophen induced fulminant hepatic failure: a preliminary report. Turk J Gastroenterol 2003;14(3):164–167.

48

Salicylates FERGUS KERR, MBBS, MPH ■ EDWARD P. KRENZELOK, PHARMD

At a Glance… ■

■

■ ■ ■

■

Salicylate poisoning may be a difficult diagnosis to make, particularly in the chronic setting, where salicylism is often unrecognized or mistaken for other illnesses. Serial assessments of a patient’s physical examination, acid–base state, and serum salicylate concentrations are essential to guide appropriate treatment. Activated charcoal is the preferred method of gastrointestinal decontamination. Fluid, electrolyte, and metabolic abnormalities occur commonly and should be treated promptly. Urinary alkalinization enhances salicylate elimination and should be instituted in all symptomatic patients and those with serum salicylate concentrations greater than or equal to 30 mg/dL. Hemodialysis is recommended for seriously poisoned patients.

INTRODUCTION AND RELEVANT HISTORY Salicylates have been used since ancient times. Hippocrates, Galen, and medieval herbalists relied on salicylate-containing plants for their palliative properties. The medicinal properties of willow bark (Salix alba vulgaris) have been appreciated by native peoples for centuries. In the mid-19th century, the active ingredient of willow bark, salicylic acid, was isolated and subsequently synthesized from phenol. It gained widespread use in compounded pharmaceuticals as a pain reliever, anti-inflammatory, and antipyretic. In the latter portion of the 19th century, the Bayer company in Germany developed a salicylic acid derivative, aspirin (or acetylsalicylic acid), for commercial use. Aspirin and its chemically related analogs (all known as salicylates) have since been prescribed widely by the medical profession and used extensively in numerous pharmaceuticals for nonprescription use by the public. Since the 1960s, the development of analgesic, antipyretic, and anti-inflammatory alternatives (e.g., acetaminophen, ibuprofen) to salicylates has curtailed their use for these purposes. More recently, aspirin has become widely used as an antiplatelet agent in the treatment of cardio- and cerebrovascular disease. Because of its ubiquitous use and availability, aspirin continues to result in a significant number of acute and chronic poisonings.

EPIDEMIOLOGY Salicylate poisoning (salicylism) can be accidental or intentional and acute or chronic. Salicylate poisoning occurs largely as an accidental overdose in the pediatric

age group or intentional overdose with suicidal intent in the adult and teenage population. Therapeutic misadventure (misuse or error) can result in poisoning at any age. Although acute intoxication is more common, chronic salicylism also occurs with regularity. Untreated, both forms of poisoning can result in significant morbidity and mortality, particularly in the elderly population. A review of salicylate exposures reported to the American Association of Poison Control Centers Toxic Exposure Surveillance System (AAPCC TESS) for the 10-year period of 1993 through 2002 reveals that 26.3% of all salicylate exposures occurred in children younger than 6 years (Fig. 48-1). Although a significant number of exposures occurred in the pediatric age group (birth–19 years of age), only five fatalities related to accidental overdose were reported—0.003% of all salicylate exposures reported to American poison centers. During this time period, 468 fatalities were attributed to salicylate poisoning. The mean age of those with fatal outcomes was 47.25 years. Most salicylate fatalities occur in older adults who intentionally ingest salicylates acutely in combination with other pharmaceuticals with suicidal intent. Based on poison center data, the number of salicylaterelated poisonings in children younger than 6 years has declined steadily from 1993 through 2002. This is especially noteworthy since the number of pediatric salicylate exposures decreased by nearly 10% since 1993

Unknown 3.8%

>19 years 36.0%

99%), which significantly reduces their ability to diffuse across the blood-brain barrier and into the central nervous system (CNS). In advanced salicylate poisoning, the development of metabolic acidosis (acidemia) significantly increases the fraction of nonionized salicylate and results in greater CNS penetration and elevated cerebral spinal fluid (CSF) concentrations. High CSF concentrations are associated with CNS toxicity and greater morbidity. Salicylates cross the placenta readily and pose a significant risk to the fetus after maternal overdose. Salicylates are also found in breast milk but present a threat to the breast-fed infant only when the mother is taking large daily doses. The infant is prone to toxicity due to immature metabolism and, thus, impaired ability to eliminate salicylates and their metabolites. Metabolism and Excretion After gastrointestinal absorption, aspirin is hydrolyzed rapidly by nonspecific plasma esterases to the pharmacologically and toxicologically active chemical salicylic acid. This is a first-order process with a half-life of 15 to 20 minutes.11 At therapeutic doses, salicylic acid then undergoes hepatic biotransformation and renal elimination via first-order processes1,12,13: 1. Glucuronidation → salicyl phenolic (10%) and salicyl acyl (5%) glucuronides 2. Oxidation → gentisic acid (500 mg/kg) poisoning.18 These categories are not absolute and should be utilized in conjunction with the patient’s clinical condition. Physical findings can also be used to grade the severity of salicylate poisoning.18 The physical examination should focus on the vital signs, neurologic and cardiovascular examinations, and state of hydration. Early in the course of an acute salicylate overdose, symptoms and signs may be mild and subtle. Hence, it is important to evaluate patients serially, rather than relying on a single initial assessment as an indicator of clinical severity. Traditionally, cases of mild poisoning are said to demonstrate hyperpnea and/or tachypnea, mild lethargy or ataxia, tinnitus, and mild nausea and/or vomiting. Moderate toxicity is characterized by more prominent tachypnea, tachycardia, orthostatic hypotension, and neurologic disturbances (e.g., slurred speech, disorientation, confusion). Severe poisoning is represented by stupor or coma, seizures, respiratory depression, and hyperpyrexia. It is vital to remember, however, that salicylate poisoning is a dynamic process, and regular assessments and management appraisals are required. It is unwise to rigidly categorize such patients. Finally, the severity of salicylate poisoning can be assessed with various laboratory parameters. Historically, the use of serum salicylate concentrations alone was used by some to assess severity of salicylate poisoning. In 1960, Done studied 38 patients (29 of whom were children), who presented after an acute aspirin overdose.15 Based on their clinical symptoms and signs and their plasma levels, he created a nomogram that plots salicylate concentrations at differing times in an attempt to estimate the degree of intoxication—asymptomatic, mild, moderate, or severe—and hence predict expected symptoms. Measurements made before 6 hours were considered misleading since the drug may still be in the absorptive phase. In practice, plasma salicylate concentrations do not correlate well with features of acute toxicity, especially in those patients who are assessed as moderately or severely intoxicated.14 The nomogram has been demonstrated to be unrepresentative of toxicity.58,59 More specifically, the nomogram is not useful in the following circumstances: salicylate ingestion over a prolonged time (chronic ingestion), a sustained-release preparation or oil

of wintergreen ingestion, the presence of renal insufficiency, an unknown time of ingestion, and an acidemic patient.60 Furthermore, the nomogram is based on the misconception that salicylates are eliminated via firstorder kinetics.60 Due to these limitations, most toxicologists do not utilize the nomogram to determine severity of salicylate poisoning. For those with chronic salicylate poisoning, more severe toxicity is typically manifested at lower plasma salicylate concentrations as compared with acute intoxication. For these patients as well, clinical features correlate poorly with concentrations and the Done nomogram is of no use. Use of laboratory data other than salicylate concentrations will allow a better assessment of the severity of salicylate poisoning. In particular, concurrent measurements of plasma (arterial or venous) and urine pH identify the presence of a systemic acid-base disturbance and allow for estimation of the phase and severity of salicylism.61 Early or mild poisoning is represented by alkalemia (plasma pH >7.4) and alkaluria (urine pH >6); intermediate or moderate poisoning by alkalemia and paradoxical aciduria (urine pH 30 mg/dL). The latest recommendations from the American Academy of Clinical Toxicology and the European Association of Poison Control Centres and Clinical Toxicologists Position Statement is that “Based on volunteer and clinical studies, urine alkalinization should be considered as first line treatment for patients with moderately severe salicylate poisoning who do not meet the criteria for hemodialysis.”79 The procedure for performing urine alkalinization in salicylate poisoning is described in Box 48-2. Effective alkalinization of the urine may be very difficult to achieve. More recently, the effectiveness of urinary alkalinization has been confirmed by Higgins and colleagues.81 They reported two separate episodes of salicylate poisoning in the same patient. In the first poisoning episode, hemodialysis was used without alkalinization; in the second, alkalinization was performed without hemodialysis. When urinary alkalinization was performed, the salicylate level fell by 45% 5 hours after admission as compared with a fall of only 4% in the 4 hours prior to hemodialysis where alkalinization had not been attempted. The use of sodium bicarbonate in salicylate-poisoned patients is associated with certain side effects and has some contraindications. Adverse effects of alkalinization include the creation of severe alkalemia (arterial pH > 7.55) and electrolyte disturbances (e.g., hypocalcemia, hypokalemia, hypernatremia) that may lead to arrhythmia or seizure, and to a lesser extent, fluid overload and congestive heart failure. Theoretical contraindications to the use of sodium bicarbonate include the presence of cerebral or pulmonary edema, oliguric renal failure, and an arterial pH of more than 7.55. The use of acetazolamide to alkalinize the urine is contraindicated, since it produces metabolic acidosis through renal elimination of bicarbonate, which may worsen salicylism and result in increased tissue penetration of salicylate. Tromethamine is not preferable to the use of bicarbonate when alkalinization is required.

Extracorporeal Techniques Salicylates are readily removed by extracorporeal means due to a small Vd (approximately 0.2 L/kg) and low molecular weight. At supratherapeutic levels, extracorporeal removal of salicylate is further facilitated by increased concentrations of free drug in the plasma. A number of extracorporeal removal techniques (e.g., exchange transfusion, peritoneal dialysis, hemoperfusion, hemodiafiltration, and hemodialysis) have been utilized in severe poisoning to decrease morbidity and mortality. As compared with hemodialysis, hemoperfusion provides a greater clearance of salicylate from plasma. Hemodialysis, however, is the preferred technique due to its superior safety, familiarity, and ability to correct fluid, electrolyte, and acid-base disturbances (see Chapter 2C).82 Hemodialysis can reduce the salicylate elimination half-life to 2 to 3 hours.82 Continuous veno-

846

BOX 48-2

ANALGESICS

PROCEDURE FOR PERFORMING URINE ALKALINIZATION IN SALICYLATE POISONING79

Baseline Biochemical Assessment

Measure plasma creatinine and electrolytes. Measure plasma glucose. Measure arterial acid-base status. Clinical Preliminaries

Establish an intravenous line. Insert a central venous line, if appropriate. Insert a bladder catheter. Correct any fluid deficit. Correct hypokalemia, if indicated. Measure urine pH using narrow-range indicator paper (use fresh urine because pH will change as carbon dioxide blows off on standing) or pH meter. Achieving Alkalinization

In an adult, give sodium bicarbonate 225 mmol or mEq (225 mL of an 8.4% [1mEq/mL] solution) intravenously over 1 hour. In a child, give sodium bicarbonate 25–50 mmol (25 mL of an 8.4% solution) intravenously over 1 hour. The period of administration of the loading dose of sodium bicarbonate may be shortened and/or the dose increased if there is preexisting acidemia. The goals of alkalinization are to achieve a blood pH of 7.50 and urine pH of 8.0. Maintaining Urine Alkalinization

Give additional boluses of intravenous sodium bicarbonate to maintain urine pH in the range 7.5–8.5. This can be achieved by administering a continuous infusion of 100–150 mmol or mEq NaHCO3 mixed in 1 L D5W at 150–200 mL/hr or two times maintenance IV requirements. Monitor

Urine pH every 15–30 minutes. Plasma potassium hourly. Central venous pressure hourly. Acid-base status hourly (note: arterial pH should not exceed 7.55). Plasma salicylate concentrations hourly. Urine output—should not exceed 200 mL/hr. Discontinue Urine Alkalinization

When plasma salicylate concentrations fall below 30 mg/dL in an adult or 25 mg/dL in a child.

venous hemodiafiltration (CVVHDF) is an alternative extracorporeal technique to hemodialysis. CVVHDF may be a more tangible option for patients who are too unstable to undergo hemodialysis or for whom hemodialysis is not available. Although its efficacy is not as well established as for hemodialysis, CVVHDF has provided significant reductions in salicylate levels for poisoned patients.83 Exchange transfusion has been used successfully for salicylate-poisoned infants, where hemodialysis is not technically feasible in this patient population.84 Manikian and colleagues described the successful double-volume exchange transfusion in a 4-month-old (5-kg) male infant with severe salicylate poisoning.85 The decision to perform hemodialysis is usually made on clinical parameters rather than plasma salicylate concentrations. Clinical indications for hemodialysis include the presence of coma, seizures, cerebral or pulmonary edema, renal failure, refractory acid-base disturbances, or clinical worsening despite treatment. Little information exists on which to base this decision, and in each case an individual assessment is best. The

sole reliance on the plasma salicylate concentration is not advised. Serious consideration for hemodialysis, however, should be given to acutely poisoned patients with salicylate concentrations of at least 100 mg/dL or chronic patients with salicylate concentrations of at least 60 mg/dL. Early consultation with a renal medicine specialist is prudent to avoid any possible bureaucratic delays in establishing dialysis. Once initiated, hemodialysis should be continued until clinical improvement, correction of major acid-base disturbances, or a return to nontoxic salicylate levels occurs. Since greater morbidity and mortality are associated with chronic salicylism, hemodialysis is recommended at lower salicylate levels as compared with acutely poisoned patients.

DISPOSITION Disposition decisions for salicylate-poisoned patients necessitate an assessment of the actual and predicted severity of illness, the initial salicylate concentration, the trend of that concentration, and the patient’s clinical

CHAPTER 48

state. Symptomatic patients should be admitted to the hospital, regardless of the amount ingested or of the plasma concentration. Mildly poisoned patients may be managed safely on a regular medical floor or short-stay observation unit, if available. Moderately or severely poisoned patients should be admitted to an intensive care unit. Patients with normal and falling concentrations, who are asymptomatic, and have normal acidbase status, electrolytes, and renal function may be medically discharged, provided there are no psychiatric issues that need to be addressed. REFERENCES 1. Roberts LJ II, Morrow JD: Analgesic-antipyretic and antiinflammatory agents and drugs employed in the treatment of gout. In Hardman JG, Limbrid LE, Gilman AG (eds): Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 687–731. 2. Rowland M, Riegelman S, Harris PA, et al: Absorption kinetics of aspirin in man following oral administration of an aqueous solution. J Pharm Sci 1972;61:379–385. 3. Needs CJ, Brooks PM: Clinical pharmacokinetics of salicylates. Clin Pharmacokinet 1985;10:164–177. 4. Wortzman DJ, Grunfeld A: Delayed absorption following entericcoated aspirin overdose. Ann Emerg Med 1987;16:434–436. 5. Brune K, Nuernberg A, Schneider HT: Biliary elimination of aspirin after oral and intravenous administration in patients. In Variability in Response to Anti-Rheumatic Drugs. Basel, Switzerland, Birkhauser Verlag, 1993, pp 51–57. 6. Davies MG, Briffa DV, Greaves MW: Systemic toxicity from topically applied salicylic acid. BMJ 1979;1:661. 7. Brubacher JR, Hoffman RS: Salicylism from topical salicylates: review of the literature. Clin Toxicol 1996;34:431–436. 8. Watson JE, Tagupa ET: Suicide attempt by means of aspirin enema. Ann Pharmacother 1994;28:467–468. 9. Levy G, Yaffe SJ: Relationship between dose and apparent volume of distribution of salicylate in children. Pediatrics 1974;54:713–717. 10. Kwong TC: Salicylate measurement: clinical usefulness and methodology. CRC Crit Rev Clin Lab Sci 1987;25:137–159. 11. Rowland M, Riegelman S: Pharmacokinetics of acetylsalicylic acid and salicylic acid after intravenous administration in man. J Pharm Sci 1968;57:717–720. 12. Levy G, Tsuchiya T: Salicylate accumulation kinetics in man. N Engl J Med 1972;287:430–432. 13. Levy G, Tsuchiya T, Amsel LP: Limited capacity for salicyl phenolic glucuronide formation and its effect on the kinetics of salicylate elimination in man. Clin Pharmacol Ther 1972;13:258–268. 14. Dugandzic RM, Tierney MG, Dickinson GE, et al: Evaluation of the validity of the Done nomogram in the management of acute salicylate intoxication. Ann Emerg Med 1989;18:1186–1190. 15. Done AK: Salicylate intoxication—significance of measurements of salicylate in blood in cases of acute ingestion. Pediatrics 1960;26:800–807. 16. Gabow PA, Anderson RJ, Potts DE, Schrier RW: Acid-base disturbances in the salicylate-intoxicated adult. Arch Intern Med 1978;138:1481–1484. 17. Winters RW, White JS, Hughes MC, Ordway NC: Disturbances of acid-base equilibrium in salicylate intoxication. Pediatrics 1959;23:260–285. 18. Temple AR: Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern Med 1981;141:364–369. 19. Chapman BC, Proudfoot AT: Adult salicylate poisoning: deaths and outcome in patients with high plasma salicylate concentrations. QJM 1989;72:699–707. 20. Tenney SM, Miller RM: The respiratory and circulatory actions of salicylate. Am J Med 1965;19:498–508. 21. Cameron IR, Semple SJR: The central respiratory stimulation action of salicylates. Clin Sci 1968;35:391–401. 22. McQueen DS, Ritchie IM, Birrell GJ: Arterial chemoreceptor involvement in salicylate-induced hyperventilation in rats. Br J Pharmacol 1989;98:413–424.

Salicylates

847

23. Kaplan EH, Kennedy J, Davis J: Effects of salicylate and other benzoates on oxidative enzymes of the tricarboxylic acid cycle in rat tissue homogenates. Arch Biochem Biophys 1954;51:47–61. 24. Miyahara JT, Karler R: Effect of salicylate on oxidative phosphorylation and respiration of mitochondrial fragment. Biochem J 1965;97:194–198. 25. Bartels PD, Lund-Jacobsen H: Blood lactate and ketone body concentrations in salicylate intoxication. Hum Toxicol 1986;5: 363–366. 26. Schwartz R, Landy G, Taller D: Organic acid excretion in salicylate intoxication. J Pediatr 1965;66:658–666. 27. Hill JB: Salicylate intoxication. N Engl J Med 1973;288:1110–1113. 28. Done AK: Treatment of salicylate poisoning: Review of personal and published experiences. Clin Toxicol 1968;1:451–467. 29. Temple AR: Pathophysiology of aspirin overdosage toxicity, with implications for management. Pediatrics 1978;62:873–876. 30. Robin ED, Davis RP, Rees SB: Salicylate intoxication with special reference to the development of hypokalemia. Am J Med 1959;26:869–882. 31. Lawson AAH, Proudfoot AT, Brown SS, et al: Forced diuresis in the treatment of acute salicylate poisoning in adults. QJM 1969;38:31–48. 32. Fox GN: Hypocalcemia complicating bicarbonate therapy for salicylate poisoning. West J Med 1984;141:108–109. 33. Reid IR: Transient hypercalcemia following overdoses of soluble aspirin tablets. Aust N Z J Med 1985;15:364. 34. Temple AR, George DJ, Done AK, Thompson JA: Salicylate poisoning complicated by fluid retention. Clin Toxicol 1976; 9:61–68. 35. Anderson RJ, Potts DE, Gabow PA, et al: Unrecognized adult salicylate intoxication. Ann Intern Med 1976;85:745–748. 36. Zitnik RJ, Cooper JA: Pulmonary disease due to antirheumatic agents. Clin Chest Med 1990;11:139–150. 37. Walters JS, Woodring JH, Stelling CB, Rosenbaum HD: Salicylateinduced pulmonary edema. Radiology 1983;146:289–293. 38. Fisher CJ, Albertson TE, Foulke GE: Salicylate-induced pulmonary edema. Clinical characteristics in children. Am J Emerg Med 1985;3:33–37. 39. Gaudreault P, Temple AR, Lovejoy FH: The relative severity of acute versus chronic salicylate poisoning in children: a clinical comparison. Pediatrics 1982;70:566–569. 40. Hill JB: Experimental salicylate poisoning: observations on the effects of altering blood pH on tissue and plasma salicylate concentrations. Pediatrics 1971;47:658–665. 41. Farrand RJ, Green JH, Haworth C: Enteric-coated aspirin overdose and gastric perforation. BMJ 1975;4:85–86. 42. Robertson RP: Eicosanoids as pluripotential modulators of pancreatic islet function. Diabetes 1988;37:367–370. 43. Smith MJH: The metabolic bases of the major symptoms in acute salicylate intoxication. Clin Toxicol 1968;1:387–407. 44. Rich RR, Johnson JS: Salicylate hepatotoxicity in patients with juvenile rheumatoid arthritis. Arthritis Rheum 1973;16:1–9. 45. Wolfe JD, Metzger AL, Goldstein RC: Aspirin hepatitis. Ann Intern Med 1974;80:74–76. 46. Kimberly RP, Plotz PH: Aspirin-induced depression of renal function. N Engl J Med 1977;296:418–424. 47. Rupp DJ, Seaton RD, Weigmann TB: Acute polyuric renal failure after aspirin intoxication. Arch Intern Med 1983;143:1237–1238. 48. Mongan E, Kelly P, Nils K, et al: Tinnitus as an indication of therapeutic serum salicylate levels. JAMA 1973;226:142–145. 49. Ramsden RT, Latif A, O’Malley S: Electrocochleographic changes in acute salicylate overdosage. J Laryngol Otol 1985;99:1269–1273. 50. Ralston ME, Pearigen PD, Ponaman ML, Erickson LC: Transient myocardial dysfunction in a child with salicylate toxicity. J Emerg Med 1995;5:657–659. 51. Rejent TA, Baik S: Fatal in utero salicylism. J Forensic Sci 1985;30:942–944. 52. Palatnick W, Tenenbein M: Aspirin poisoning during pregnancy: increased fetal sensitivity. Am J Perinatol 1998;15:39–41. 53. Levy G, Garrettson LK: Kinetics of salicylate elimination by newborn infants of mothers who ingested aspirin before delivery. Pediatrics 1974;53:201–210. 54. Levy G, Procknal JA, Garrettson LK: Distribution of salicylate between neonatal and maternal serum at diffusion equilibrium. Clin Pharmacol Ther 1975;18:210–214.

848

ANALGESICS

55. Montgomery H, Porter JC, Bradley RD: Salicylate intoxication causing a severe systemic inflammatory response and rhabdomyolysis. Am J Emerg Med 1994;12:531–532. 56. Vadas P, Schouten BD, Stefanski E, et al: Association of hyperphospholipasemia A2 with multiple system organ dysfunction due to salicylate intoxication. Crit Care Med 1993;21:1087–1091. 57. Botma M, Colquhoun-Flannery W, Leighton S: Laryngeal oedema caused by accidental ingestion of oil of wintergreen. Int J Pediatr Otorhinolaryngol 2001;58:229–232. 58. Hurlbut KM, Fish S, Kulig K, et al: Micromedex Healthcare Series Vol. 118. Expires December 2003. Englewood, CO. 59. Kwong TC: Salicylate measurement: clinical usefulness and methodology. CRC Crit Rev Clin Lab Sci 1987;25:137–159. 60. Yip L, Dart RC, Gabow PA: Concepts and controversies in salicylate toxicity. Emerg Med Clin North Am 1994;12:351–364. 61. Linden CH, Rumack GH: The legitimate analgesics: aspirin and acetaminophen. In: Hanson W Jr (ed): Toxic Emergencies. New York, Churchill Livingstone, 1984, p 118. 62. Krenzelok EP, Guharoy SL, Johnson DR: Toxicology screening in the emergency department: ethanol, barbiturates and salicylates. Am J Emerg Med 1984;2:331–332. 63. Greenberg MI, Hendrickson RG: Deleterious effects of endotracheal intubation in salicylate poisoning [Letter]. Ann Emerg Med 2003;41:583–584. 64. Krenzelok EP, McGuigan M, Lheureux P: AACT/EAPCCT position statement: ipecac syrup. J Toxicol Clin Toxicol 1997; 35:699–709. 65. Vale JA: AACT/EAPCCT position statement: gastric lavage. J Toxicol Clin Toxicol 1997;35:711–719. 66. Juurlink DN, McGuigan MA: Gastrointestinal decontamination for enteric-coated aspirin overdose: what to do depends on who you ask. Clin Toxicol 2000;38:465–470. 67. Prescott LF: Clinical features and management of analgesic poisoning. Hum Toxicol 1984;3(Suppl):75–84. 68. Chyka PA, Seger D: AACT/EAPCCT position statement: activated charcoal. J Toxicol Clin Toxicol 1997;35:721–741. 69. Filippone GA, Fish SS, Lacoutre PG, et al: Reversible adsorption (desorption) of aspirin from activated charcoal. Arch Intern Med 1987;147:1390–1392. 70. Dargan PI, Wallace CI, Jones AL: An evidence based flowchart to guide the management of acute salicylate (aspirin) overdose. Emerg Med J 2002;19:206–209.

71. Kirshenbaum LA, Mathews SC, Sitar DS: Whole-bowel irrigation versus activated charcoal in sorbitol for the ingestion of modifiedrelease pharmaceuticals. Clin Pharmacol Ther 1989;46:264–271. 72. Tenenbein M. AACT/EAPCCT position statement: whole bowel irrigation. J Toxicol Clin Toxicol 1997;35:753–762. 73. Kirshenbaum LA, Mathews SC, Sitar DS, Tenenbein M: Does multidose charcoal therapy enhance salicylate excretion? Arch Intern Med 1990;150:1281–1283. 74. Johnson D, Eppler J, Giesbrecht E, et al: Effect of multi-dose activated charcoal on the clearance of high-dose intravenous aspirin in a porcine model. Ann Emerg Med 1995;26:569–574. 75. Hillman RJ, Prescott LF: Treatment of salicylate poisoning with repeat oral charcoal. BMJ 1985;291:1472. 76. Vale JA, Krenzelok EP, Barceloux DG: AACT/EAPCCT position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. J Toxicol Clin Toxicol 1999;37:731–751. 77. Smith PK, Gleason HL, Stoll CG, et al: Studies on the pharmacology of salicylates. J Pharmacol Exp Ther 1946;87:253. 78. Prescott LF, Balali-Mood M, Critchley JAJH, et al: Diuresis or urinary alkalinisation for salicylate poisoning? BMJ 1982;285: 1383–1386. 79. Proudfoot AT, Krenzelok EP, Vale JA: Position paper on urine alkalization. J Toxicol Clin Toxicol 2004;42:1–26. 80. Vree TB, Van Ewijk-Beneken Kolmer EWJ, Verwey-Van Wissen CPWGM, Hekster YA: Effect of urinary pH on the pharmacokinetics of salicylic acid, with its glycine and glucuronide conjugates in human. Int J Clin Pharmacol Ther 1994;32:550–558. 81. Higgins RM, Connolly JO, Hendry BM: Alkalinization and hemodialysis in severe salicylate poisoning: comparison of elimination techniques in the same patient. Clin Nephrol 1998;50:178–183. 82. Jacobsen D, Wiik-Larsen E, Bredesen JE: Haemodialysis or haemoperfusion in severe salicylate poisoning? Hum Toxicol 1988;7:161–163. 83. Wrathall G, Sinclair R, Moore A, Pogson D: Three case reports of the use of haemodiafiltration in the treatment of salicylate overdose. Hum Exp Toxicol 2001;20:491–495. 84. Leikin SL, Emmanouilides GC: The use of exchange transfusion in salicylate intoxication. J Pediatr 1960;57:715–720. 85. Manikian A, Stone S, Hamilton R, et al: Exchange transfusion in severe infant salicylism. Vet Hum Toxicol 2002;40:224–227.

49

The Triptans ANTHONY J. TOMASSONI, MD, MS ■ CARL A. GERMANN, MD


■

■

■

■

Triptans have improved safety and side effect profiles in the treatment of migraine relative to older ergot derivatives. Triptans activate the 5-HT1B and 5-HT1D receptors within the trigeminovascular system, including serotonin receptors on cerebral vessels and, to a lesser extent, on coronary arteries. Triptans are contraindicated in patients with ischemic heart disease because of concerns about vasospasm of coronary vessels that could lead to myocardial ischemia. If a patient taking triptans experiences chest pain that may be ischemic in origin, further triptan use should be avoided and appropriate evaluation initiated. Second-generation triptans have improved pharmacokinetics and may reduce the likelihood of chest pain in migraineurs; however, differences between these medications and firstgeneration triptans are subtle. Risk for precipitating serotonin syndrome may be increased by combining triptan therapy with other serotonergic medications.

The development of the triptans nicely illustrates the process of stepwise drug design. The medicinal properties of serotonin agonists have been recognized for hundreds of years.1 Long ago, midwives used the vasoconstrictive effects of ergot to accelerate labor or reduce postpartum bleeding. Liquid extracts of ergot have also been used to treat “vascular headaches” in Europe and the United States for more than 100 years. However, the use of early ergot-derived medications frequently resulted in undesirable effects, including severe peripheral vasoconstriction, emesis, paresthesias, and psychosis. Human experience with related compounds has been well documented since the outbreaks of ergotism in the Middle Ages, then known as St. Anthony’s fire. When contaminated rye enters the food supply, generally in the form of bread, epidemic ergotism may result. Vivid descriptions of individuals afflicted with gangrene of the extremities, burning neuropathic pain, and autoamputation survive to document this form of ergotism. An even more dramatic form of ergotism may result in psychosis, seizures, and death. It has been hypothesized that those accused of witchcraft in Salem, Massachusetts, in the late 1600s were stricken with this second form of ergotism. Ironically, it was in that same century that the cause of St. Anthony’s fire was traced to ergot (Claviceps purpurea), a fungus that grows on the kernels of rye during damp, cold weather.2 Before the availability of the triptans, ergotamines were used extensively for relieving migraine pain. Ergotamine was first isolated by Arthur Stoll of Sandoz (Novartis) in 1918. The drug was then found effective in the treatment of migraine headache in the 1930s. Further research at Sandoz resulted in the synthesis

of ergonovine, lysergic acid diethylamide, and other serotonin agonist and antagonist drugs.2,3 Armed with improved understanding of the potential role of serotonin in migraine headache developed during the 1970s, efforts to synthesize a safer, more selective, serotonin agonist were undertaken. This resulted in the introduction of sumatriptan in the early 1990s. Subsequent second-generation triptans seek to improve on the properties of sumatriptan by offering more rapid relief, longer duration of action, improved bioavailability and availability to the central nervous system (CNS), and reduced side effects. Since sumatriptan became available in 1992, six additional triptans have been introduced in the United States (Table 49-1). Several theories and models have been advanced to explain the pathophysiology of migraine headache, but no unified model explains all the symptoms of a migraine headache. It seems possible that more than one mechanism may be responsible, and this may explain interindividual variations in response to migraine medications. Reductions in serotonin levels have been noted during migraine headaches. Of note, the triptans are structurally similar to serotonin (5-hydroxytryptamine [5-HT]) (Fig. 49-1) The number of migraineurs in the United States has been estimated as approximately 23 million.4 GlaxoSmithKline reports that their sumatriptan products have been used to treat more than 646 million migraines over the past decade, approximately equal to treating one migraine headache every second.5 Of note, there are many similarities, but also significant differences between these selective serotonin agonists. Therefore, patients may be advised that if one of these drugs does not offer sufficient relief from their migraine pain, it is often worthwhile to try another drug from this class with different pharmacologic or pharmacokinetic characteristics. However, the overall efficacy rate for all orally administered triptans is approximately 65%.6 Little has been reported regarding substantial overdose of these medications; however, adverse effects associated with therapeutic use of the triptans are well described.

STRUCTURE Sumatriptan is 3-[2-(dimethylamino) ethyl]-N-methyl1H-indole-5-methanesulfonamide. Structures of serotonin and the triptans available in the United States may be compared in Figure 49-1. When compared with sumatriptan, the second-generation agents are characterized by enhanced lipophilicity and greater 5-HT1 receptor selectivity. These chemical properties are associated with pharmacokinetic and pharmacodynamic improvements such as improved oral bioavailability, 849

850

ANALGESICS

TABLE 49-1 Some Available Triptans and Dates of Approval by the U.S. Food and Drug Administration (FDA) GENERIC NAME

TRADE NAME

FORMULATION

DATE OF FDA APPROVAL

Sumatriptan

Imitrex Imigran Imitrex Imigran Imitrex Imigran Zomig Amerge Naramig Maxalt Maxalt-MLT Zomig-ZMT Axert Frova Relpax Zomig

Injections

December 28, 1992

Tablets

June 1, 1995

Nasal spray

August 26, 1997

Tablets Tablets

November 25, 1997 February 10, 1998

Tablets Orally dissolvable tablets Orally dissolvable tablets Tablets Tablets Tablets Nasal spray

June 29, 1998

Sumatriptan Sumatriptan Zolmitriptan Naratriptan Rizatriptan Zolmitriptan Almotriptan Frovatriptan Eletriptan Zolmitriptan

February 13, 2001 May 17, 2001 November 8, 2001 December 26, 2002 September 30, 2003

Some triptans were available in Europe before FDA approval in the United States.57 From http://www.fda.gov, Drug Approvals.

H N

H3C O H N

S N

O

N

H N

H

OH NH

CH3 N

K

H3C N H

NH2

H3C

HN Ergotamine

Methysergide

O

CH3

K

O

H3C N S H

N

J

N

O

N

N N

N

CH3

CH3

H N

CH3

CH3

Sumatriptan

Zolmitriptan

NH2 HO

J

CH3

N

H

H N S H3C O O

H N

K

CH3

J

N

CH3

K

Almotriptan

NH

H N

J

S

K

O

O

O

H N

J

N

H N

K

K

K

Frovatriptan

O

CH3

O

O

CH3

Eletriptan

H N

H K

K

K

K

O

OK

N

N CH3

Rizatriptan Naratriptan Serotonin FIGURE 49-1 Comparative structures of serotonin and selected antimigraine drugs. [Modified from Hart C: Forged in St. Anthony’s fire: drugs for migraine. Mod Drug Discovery 1999;2(2):20–21, 23–24, 28, 31.]

rapid absorption to achieve maximum plasma levels faster (shorter time to maximum concentration [Tmax]), longer elimination half-lives (t1/2), better CNS penetration, and/or reduced cardiac effects. Improved central penetration and increased receptor affinity and selectivity for the 5-HT1D (neuronal) receptor permit lower total oral dosing and reduced peripheral exposure to the coronary vasoconstrictor 5-HT1B (vascular)

receptor, reducing the incidence and severity of chest pain that occurs with sumatriptan. Frovatriptan has a high affinity for the 5-HT1B receptor when compared with other second-generation triptan agonists.7,8 The chemical structure of frovatriptan conforms to structure-activity relationships established for 5-HT1 receptor agonists. These include a nuclear indole heterocycle and a 3-alkylamine structure (incorporated into an

CHAPTER 49

indole-fused cyclohexylamine moiety in frovatriptan). The 3-alkylamine function facilitates formulation of the triptans as water-soluble salts of acids. Of note, the 3-alkylamine feature serves as a substrate for MAO-A catabolism, except in the case of naratriptan.7 New agents that target the 5-HT1F receptor are under investigation. Such agents may lack the vascular contractile effects of the current triptans that target 5-HT1B/1D receptors.9

PHARMACOLOGY At least seven classes of 5-HT receptors with different biologic effects have been identified. These classes are noted as 5-HT1 through 5-HT7. Except for the 5-HT3 receptor, which is linked to an ion channel, all are G protein linked. The 5-HT1 receptor class differs from the others in that it is inhibitory via adenylate cyclase, while the other receptor classes are excitatory. In general, 5-HT1 receptors are the site of action of the migraine-abortive triptans and dihydroergotamine, which function as agonists at this receptor. In contrast, some migraine-preventative treatments such as amitriptyline and methysergide have 5-HT2 antagonist activity. 5HT2 receptors are excitatory via phosphatidyl hydrolysis. 5-HT3 antagonists have antiemetic activity.3 All triptans activate the 5-HT1B and 5-HT1D receptors and, to a lesser extent, the 5-HT1A and 5-HT1F receptors.10 Inhibition of vasodilation of meningeal vessels occurs via the 5-HT1B receptor. Triptans are believed to relieve migraine, in part, by stimulating 5-HT1B receptors on meningeal, dural, cerebral, or pial vessels to cause vasoconstriction, which counteracts the pain-inducing vasodilation involved in migraine. Inhibition of trigeminal nuclei cell excitability in the brainstem occurs via 5-HT(1B/1D) receptor agonism; direct inhibition of these receptors is reported to have an antimigraine effect. Additionally, stimulation of presynaptic 5-HT1D receptors inhibits both dural vasodi-

The Triptans

851

lation and inflammation.7,8 Triptans have low or no affinity for α- or β-adrenergic, cholinergic, or dopaminergic receptors.11,12 Anatomic studies using antibodies selective for human 5-HT1B or 5-HT1D receptors found that 5-HT1B receptors are located primarily in the cranial circulation but are also found in the coronary circulation.13,14 While triptans constrict meningeal arteries more potently than they constrict coronary arteries, there have been concerns regarding potential myocardial ischemia secondary to induced coronary vasoconstriction. A summary of affinities of the triptans for receptor types is provided in Table 49-2. Of interest, data have demonstrated potent antiinflammatory effects in bacterial meningitis with administration of triptans to rats. Leukocyte influx into the cerebrospinal fluid was reduced, as was intracranial pressure and the formation of brain edema. Survival and clinical score were increased. That these findings may eventually be applicable to humans is suggested by clinically observed activation of the trigeminovascular system.15

PHARMACOKINETICS Since this class of compounds was developed for affinity at specific receptors, there are only minor pharmacodynamic differences between the triptans. Despite significant pharmacokinetic improvements in the newer members of this class, only modest improvements have resulted in their ability to treat migraine. Pharmacokinetic relationships between the triptans are displayed in Table 49-3. Sumatriptan has low oral bioavailability (14%) due to first pass metabolism and incomplete absorption and, relative to newer triptans, a short elimination half-life of approximately 2 hours when administered subcutaneously or intranasally (approximately 2.5 hours when administered orally). Protein binding is approximately 14% to 21%; therefore, the effect of sumatriptan on the protein binding of other

TABLE 49-2 Affinities of Some Ergopeptides and Triptans for Serotonin Receptor Types RECEPTOR TYPE DRUG Ergotamine* Dihydroergotamine Sumatriptan Zolmetriptan Naratriptan Rizatriptan Eletriptan Almotriptan Frovatriptan

5-HT1A

5-HT1B

5-HT1D

+ +++ +

+ ++ ++ + + + ++ ++

+ +++ ++ + + + ++ ++

+ + +

5-HT1E

5-HT1F

5-HT2A

5-HT2B

+ +

+ +

+

+ + + + +

+

++

++ -

+

Of note, ergotamines also have activity at noradrenergic α and β receptors and on dopamine D1 and D2 receptors. *The published data for the ergopeptides relate mainly to dihydroergotamine, but the literature infers that the situation for ergotamine is generally similar. +, degree of agonist activity at the receptor from low (+) to high (+++); –, inactive. Adapted from references 3 and 58.

1.4–3.8

1.0–2.0

2.0–4.0

Almotriptan

Eletriptan

Frovatriptan

2.8

3.5 0.2

1

2.5

TMAX (hr) DURING ATTACK

Low

High

Unknown

High

Moderate

Moderate

Low

LIPOPHILICITY

25

3.6–5.5

3.2–3.7

5.0–6.3 5

2–3

2.5–3 2.5–3 2.82

2–2.5 2 2

t1/2 (hr)

24 (m)–30 (f)

50

70–80

63 (m)–74 (f)

45–47

40–48 40–48 42

14 17 96–97

BIOAVAILIBILITY (%)

Hepatic; CYP3A4, 2D6; MAO-A; 15% active metabolite 26%–35% excreted renally unchanged Hepatic CYP3A4, 1A2; 15% active metabolite Hepatic; CYP1A2; MAO-A; 26%–35% excreted renally unchanged

50%–70% excreted renally unchanged; CYP

Hepatic; MAO-A; 30% renally unchanged

Hepatic (1 active and 2 inactive metabolites; CYP1A2; MAO-A)

Hepatic; MAO-A; 60% renal

ELIMINATION ROUTE, METABOLISM

28–31

14

25

14–21

PROTEIN BINDING (%)

170

110–140

7

2.4

Vd (L/kg)

CYP, cytochrome P-450 system; (f), female; IN, intranasal spray; (m), male; MOA, monoamine oxidase; PO, oral; SQ, subcutaneous injection; tab, tablet; t1/2, half-life; Tmax, time to peak plasma concentration. Adapted from references 58 through 62.

1.5–3 0.2

1–1.2 1.6–2.5

2 3.3 2

2.5 1 0.2–0.25

TMAX (hr) OUTSIDE ATTACK

2.5 mg PO 1 mg SQ

Naratriptan

PO tab PO melt

Rizatriptan

2.5 mg PO 2.5 mg ZMT 2.5 mg IN

Zolmitriptan

50 mg PO 20 mg IN 6 mg SQ

Sumatriptan

DRUG, FORMULATION, AND DOSE

TABLE 49-3 Comparative Pharmacokinetics of Some Triptans

852 ANALGESICS

CHAPTER 49

drugs may be minor. The mean volume of distribution of sumatriptan after subcutaneous administration is 2.7 L/kg, and its total plasma clearance is approximately 1200 mL/min. Newer triptans have improved oral bioavailability. The absorption rate of rizatriptan is comparatively fastest when measured by the time to peak plasma concentration, and rizatriptan has been reported to result in more rapid relief of cephalalgia when compared with sumatriptan and zolmitriptan. Eletriptan and naratriptan have somewhat longer half-lives than sumatriptan, while frovatriptan has the longest half-life (up to 25 hours) of the triptans approved in the United States. Plasma levels of frovatriptan may be higher in elderly patients and in females.8,16

SPECIAL POPULATIONS All triptans are 5-HT1B agonists and thus are contraindicated in patients with ischemic heart disease, uncontrolled hypertension, and cerebrovascular disease. Prudence dictates that patients should also be screened for conditions leading to accelerated atherosclerosis and coronary artery spasm. Related conditions may include family history of coronary artery disease or heart attacks, risk factors for coronary artery disease, longstanding or uncontrolled diabetes, hypercholesterolemia and hyperlipidemia, smoking, and physiologic or surgical menopause. Clinical trials in the pediatric population have yielded positive results that triptans decrease symptoms of migraine, but often in the context of high placebo response rates. Although dosing for sumatriptan in younger patients has been reported, the manufacturer indicates that the use of sumatriptan injection, tablets, and nasal spray in those younger than 18 years is not recommended.16 In fact, a myocardial infarction has been reported in a 14-year-old boy following the use of oral sumatriptan with clinical signs occurring within 1 day of drug administration.16 While studies have demonstrated that adolescents may find triptans efficacious and tolerable, clinical data regarding the frequency of events in the pediatric population is still lacking.17-19 Since elderly patients may have decreased hepatic or renal function, since they may be more sensitive to druginduced increases in blood pressure, and since they may be at higher risk for coronary artery disease, the use of triptans in the elderly is not advisable. Triptans are category C drugs and should not be recommended for use by pregnant women. Review of data available from clinical trials, postmarketing monitoring, and the Sumatriptan Pregnancy Registry suggest no currently measurable increased risk for birth defects after prenatal exposure to sumatriptan. Sample sizes remain too small to draw definitive conclusions. Although use of triptans during pregnancy cannot be encouraged, data are reassuring where inadvertent exposure to sumatriptan has occurred during pregnancy.20,21

The Triptans

853

DRUG INTERACTIONS Triptans and ergotamines both stimulate serotonergic receptors; therefore, their combined use is not recommended. Monoamine oxidase (MAO) inhibitors, especially MAO-A inhibitors, can slow the metabolism of triptans and are thus contraindicated when using these medications. Also, the vasoconstrictive effects of the triptans may be additive to those of catecholamines. There have also been numerous case reports of suspected serotonin syndrome when MAO inhibitors and triptans are used concurrently.22-24 Given the fact that little reliable information exists regarding the combination of these two medicines, use of triptans should continue to be avoided in patients taking MAO inhibitors until further data demonstrating safety become available. It is plausible that the combination of triptans and selective serotonin reuptake inhibitors may precipitate serotonin syndrome. Although serotonin syndrome has been reported with combinations of psychotropic medications, neurologists have considered the potential of triptans combined with selective serotonin reuptake inhibitors (SSRIs) to produce this syndrome as well. In general, clinical experiences and published reports indicate a low risk for serotonin syndrome with the combined use of an SSRI and a triptan.23 However, considering the large volumes of SSRIs and other serotonergic drugs in use, the paucity of data regarding serotonin syndrome as a consequence of drug interactions with triptans suggests that further study is indicated to ascertain the relative risk of precipitating serotonin syndrome through drug interactions. Some documented and potential (but less likely) drug-drug interactions with triptans are listed in Table 49-4 and Box 49-1.

TOXICOLOGY Triptans differ from each other in terms of tolerability but not in terms of safety.10 Animal overdose of sumatriptan has resulted in seizures, tremor, paralysis, behavioral changes, ptosis, erythema of the extremities, abnormal respiration, cyanosis, ataxia, mydriasis, salivation, lacrimation, and death.16 Clinical manifestations of triptans have been largely compiled from clinical experience, case reports, and systematic retrospective and prospective research. Therefore, the information that follows is derived primarily from observations of patients using an appropriate therapeutic dose. The most frequent side effects, often called “triptan sensations,” are taste disturbances, tingling, paresthesias, and sensations of warmth in the head, neck, chest, and limbs.10 Other symptoms may include drowsiness, dizziness, flushing, and neck pain or tightness. The most serious adverse consequences of triptan use involve the cardiovascular system. These insults are presumably due to coronary and cerebral vessels narrowing secondary to 5-HT1B receptor activation. All triptans narrow coronary arteries by about 10% to 20% at

854

ANALGESICS

TABLE 49-4 Some Potential Drug Interactions with Triptans INTERACTION TYPE

AGENT AND MECHANISM

EFFECT

Macrolide antibiotics: inhibition of CYP3A4 Monoamine oxidase A inhibitor

Increased almotriptan or eletriptan level Increased 5-HT1 agonism by sumatriptan, zolmitriptan, or rizatriptan Increased zolmitriptan level 15% reduction in area under the curve for naratriptan Sumatriptan delays acetaminophen absorption

Pharmacokinetic

Propranolol: inhibition of CYP1A2 Dihydroergotamine Acetaminophen Pharmacodynamic Ergopeptide Methysergide Serotonin reuptake inhibitors Loxapine

Vasospasm; postpartum cerebral angiopathy Myocardial infarction reported with sumatriptan Increased serotonin concentration loading to serotonin syndrome (uncommon) Dystonia and movement disorder

The magnitude of these effects may be variable ranging from theoretical only or clinically insignificant to potentially life threatening. Compiled from Eadie MJ: Clinically significant drug interactions with agents specific for migraine attacks. CNS Drugs 2001;15(2):105–118.

BOX 49-1

POTENTIAL INTERACTIONS WITH THE TRIPTANS THAT ARE UNLIKELY TO OCCUR IN PRACTICE*

With Sumatriptan

With Zolmitriptan

Butorphanol nasal Flunarazine Propranolol Naproxen Naratriptan Pizotifen

Ergotamine Pizotifen Dihydroergotamine Acetaminophen Metoclopramide Fluoxetine Selegiline

With Naratriptan

Ergotamine *Given the relative newness of the triptans it is likely that additional drugdrug interactions may come to light. From Eadie MJ: Clinically significant drug interactions with agents specific for migraine attacks. CNS Drugs 2001;15(2):105–118.

conventional doses.25-27 Numerous studies have established the coronary vasoconstrictive effects of triptans.25,27-29 This constriction of coronary arteries may cause chest symptoms that closely mimic angina pectoris.10 However, the chest pain reported by 3% to 5% of patients taking oral triptans has generally not been associated with electrocardiographic changes and is unlikely to be due to cardiac ischemia.30-32 In fact, in vitro data have shown that at therapeutic concentrations, triptans have little potential to cause clinically significant constriction of nondiseased coronary arteries.11 Large retrospective studies show no increase in risk for myocardial infarction with triptan use in a general population of migraine sufferers.33,34 Noncardiac explanations for chest pain associated with the use of triptans include pulmonary vasoconstriction, esophageal spasm, muscle spasm, and anxiety.30,35,36 In June 2002, the American Headache Society convened the Triptan Cardiovascular Safety Expert Panel to evaluate the evidence on triptan-associated cardio-

vascular risk and to formulate a consensus regarding the safety of triptans.37 This consensus stated that chest symptoms occurring during the use of triptans are usually nonserious and usually not attributed to ischemia.37 Also, while serious cardiovascular adverse events have occurred after the use of triptans, their incidence in both clinical trials and clinical practice appears to be extremely low.37 Most of these data, however, are derived from clinical trials that typically excluded patients with cardiovascular risk factors or known ischemic heart disease. Therefore, the panel concluded that the cardiovascular risk-benefit profile of triptans favors their use in the absence of contraindications and that in patients at low risk for coronary artery disease, triptans can be safely prescribed without the need for prior cardiac status evaluation.37 Triptan effects on diseased coronary arteries have not been well studied. It is plausible that even a small amount of induced vasoconstriction in patients with obstructive coronary artery disease may potentiate myocardial ischemia. Indeed, in rare instances triptan therapy has been associated with severe cardiovascular events.10,38-42 There have also been published reports of atrial fibrillation, ventricular tachycardia, and ventricular fibrillation following doses of sumatriptan.40,43-47 A majority of these episodes were reported to occur within 35 minutes of triptan administration. The evidence of increased risk for myocardial ischemia and infarction is largely based on the known pathophysiology of triptans and isolated case reports rather than epidemiologic data.30 There is a paucity of data to support a correlative risk of ischemic stroke with triptan use.33,34,48 A study performed by Hall and colleagues showed no association between triptan prescription and stroke risk in 13,664 patients.48 In another study of 12,339 patients who used injectable sumatriptan, there was an incidence of 1.08 strokes per 100,000 treated migraine episodes, which correlates with the natural occurrence of migraine and stroke.34 It is also conceivable that some reports of stroke associated with triptans may have resulted from misiden-

CHAPTER 49

tification of the primary cause of headache (i.e., some patients complaining of headache who received triptans may have had a primary stroke that was only definitively diagnosed after triptan administration). Triptan-induced vasoconstriction has also been thought to induce ischemic colitis. There have been at least 11 reported cases associating triptan use with ischemic colitis.49-51 However, no association was found in a large-scale prospective trial of the safety of subcutaneous sumatriptan.34 Further studies are needed to explore this relationship because there is insufficient evidence thus far associating triptans and ischemic bowel disease. Serotonin syndrome may result from the combined use of triptans with SSRIs. A handful of case reports describe such events.22-24 However, in one large prospective study combining SSRIs with triptans, there were no significant adverse neurologic events within 24 hours.52 Serotonin syndrome consists of a triad of altered mental status, dysautonomia, and neuromuscular changes. There have been only a handful of case reports describing triptan overdose. Most of these articles report a paucity of adverse events with overuse.43,53,54 There are no published reports of death secondary to human overdose with triptans to date. However, there is one report of a woman with no underlying cardiovascular disease who presumably died secondary to complications of prolonged cardiac arrest following a single dose of oral sumatriptan.40 Ocular toxicity consisting of corneal opacity and defects in the corneal epithelium has been reported in dogs at 30 days after daily administration of oral sumatriptan at three to five times the human daily exposure rate.16 Withdrawal of triptans following overuse (approximately 10 days per month for at least several months) may result in rebound (triptan-induced) headache. Triptan use should be limited to 3 days per week. Rebound headache may be characterized by refractoriness to preventive medication, and increasing attack frequency may be the first sign. Withdrawal headaches have also been described. Patients undergoing triptan withdrawal have been reported to request less symptomatic medication than patients undergoing withdrawal from ergot or analgesic medications, suggesting that their headaches were less severe than patients in the other study groups. Substituting medications that do not share cross-tolerance, or discontinuing the medication after the “washout” period is complete, may prove effective. Some patients may require inpatient therapy and/or psychiatric and social assessment and support.55,56

DIAGNOSIS Because adverse effects reported with triptan use are also associated with migraine headaches, effects of the drugs may be difficult to distinguish from those of the disease. Any adverse events, including myocardial ischemia, that occur more than a few hours after triptan use generally do not fit within the period of pharmacokinetic activity of these medications.30 It may be prudent to exercise

The Triptans

855

longer periods of observation after potential adverse effects in the case of those triptans that have longer duration of action (i.e., frovatriptan and eletriptan), active metabolites, and elimination times.

MANAGEMENT Treatment of symptoms following therapeutic doses or potentially toxic doses largely involves supportive measures along with management of any potential cardiovascular or neurologic effects. Benzodiazepines can be useful to control agitation and muscle spasticity associated with serotonin syndrome. Nitroprusside can be used to treat hypertension if end-organ damage is suspected. Labetalol, nitroglycerine, and phentolamine may be used as alternatives with a goal of 20% to 25% reduction in mean arterial pressure.

Decontamination Activated charcoal is regarded as most effective in adsorbing unabsorbed drug from the gastrointestinal tract if given within 1 hour of ingestion after oral overdose. Some absorption of orally administered triptans might also be prevented by early gastric lavage, although the efficacy of this procedure may be no better than oral activated charcoal alone. In the event of massive triptan ingestion, a toxicologist should be consulted regarding decontamination procedures and management. No specific antidote exists.

Laboratory Studies No specific laboratory work is generally indicated for inadvertent exposure to small amounts of triptans in asymptomatic patients. Specific drug levels are not clinically useful. For patients experiencing chest pain, a 12-lead electrocardiogram and continuous electrical monitoring should be performed if symptoms suggest myocardial ischemia or dysrrhythmia. Serial cardiac enzymes may be considered. Since hepatic metabolism and renal excretion are important mechanisms of triptan and triptan metabolite formation and clearance, measures of hepatic and renal function might be useful, especially where presystemic “first pass” clearance of orally administered triptans is concerned. Patients with large exposures may be at risk for sequelae, including seizures and acidosis; laboratory studies should be obtained accordingly.

Disposition There is a paucity of information regarding risk stratification of patients with triptan overdoses. Should a patient who is exposed to triptans experience chest pain that is believed to be ischemic in origin, further triptan use should be avoided until proper risk stratification can be completed. A 3-year retrospective study of unintentional pediatric exposures to single-agent triptan acute ingestions has

856

ANALGESICS

been reported. Exposures to oral formulations of sumatriptan, zolmitriptan, naratriptan, and rizatriptan were documented in children younger than 7 years. Of 32 cases that met inclusion criteria, 26 patients ingested one or two adult doses, three patients ingested three or more doses, and three ingested an unknown amount. Five patients reported at least one effect (vomiting, nausea, abdominal pain, and/or drowsiness). Four of those five patients were treated in the emergency department, and three of the five received activated charcoal. None of the patients required admission or other treatment. Of those five symptomatic patients, one ingested a single tablet, one ingested two tablets, and the others ingested three or four tablets. All of those patients were asymptomatic at the time of follow-up phone call. This limited review suggests that while children who ingest only one to two adult doses of the triptans studied are likely to do well and might be observed at home, more experience and further investigation is needed to establish safe triage and observation guidelines.63 Review of limited data available in the literature suggests that some patients who overuse triptans in the setting of acute accidental exposure or overuse do well. However, in the current absence of sufficient data to risk stratify patients with triptan overdose, it is safest to observe or admit patients with large triptan overdoses, comorbid conditions, and abnormal vital signs, as well as symptomatic patients or those with exposure to multiple serotonergic medications, since the consequences of serotonin syndrome or massive triptan overdose may be severe. Those with supratherapeutic exposure to triptans with long half-lives should, at a minimum, be observed for an extended period until such time as further data become available to assist with risk stratification of patients taking excess doses of such triptans. REFERENCES 1. De Costa C: St Anthony’s fire and living ligatures: a short history of ergometrine. Lancet 2002;359:1768–1770. 2. Hart C: Forged in St. Anthony’s fire: drugs for migraine. Mod Drug Discovery 1999;2(2):20–21, 23–24, 28, 31. 3. Silberstein SD: The pharmacology of ergotamine and dihydroergotamine. Headache 1997;37(Suppl 1):15–25. 4. Stewart WF, Lipton RB, Celentano DD, Reed ML: Prevalence of migraine headache in the United States: relation to age, income, race, and other sociodemographic factors. JAMA 1992;267(1):64–69. 5. GlaxoSmithKline: Press release: Imitrex® (sumatriptan succinate) tablets now available in an innovative formulation for migraine sufferers: new formulation designed to rapidly release in the stomach. Research Triangle Park, NC, GlaxoSmithKline, February 4, 2004. 6. Lipton RB: The triptans and beyond. Addendum to agenda, program for the 1998 American Association for the Study of Headache, Scottsdale Symposium, Scottsdale, AZ, 1998. 7. Deleu D, Hanssens Y: Current and emerging second-generation triptans in acute migraine therapy: a comparative review. J Clin Pharmacol 2000;40:687–700. 8. Tfelt-Hansen P, De Vries P, Saxena PR: Triptans in migraine. Drugs 2000;60:1259–1287. 9. Cohen ML, Schenck K: 5-Hydroxytryptamine1F receptors do not participate in vasoconstriction: lack of vasoconstriction to LY344864, a selective serotonin1F receptor agonist in rabbit saphenous vein. J Pharmacol Exp Ther 1999;290:935–939. 10. Goadsby PJ, Lipton RB, Ferrari MD: Drug therapy: migraine— current understanding and treatment. N Engl J Med 2002;346(4):257–270.

11. Maassen VanDenBrink A, Saxena PR: Coronary vasoconstrictor potential of triptans: a review of in vitro pharmacologic data. Headache 2004;44(Suppl 1):13–19. 12. Hargreaves RJ, Shepheard SL: Pathophysiology of migraine—new insights. Can J Neurol Sci 1999;26(Suppl):12–19. 13. Smith D, Shaw D, Hopkins R, et al: Development and characterizations of human 5-HT1B or 5-HT1D receptor specific antibodies as unique research tools. J Neurosci Methods 1998;80:155–161. 14. Longmore J, Shaw D, Smith D, et al: Differential distribution of 5HT1D and 5-HT1B immunoreactivity within the human trigemino-cerebrovascular system: implications for the discovery of new antimigraine drugs. Cephalalgia 1997;17:833–842. 15. Hoffmann O, Keilwerth N, Bille MB, et al: Triptans reduce the inflammatory response in bacterial meningitis. J Cereb Blood Flow Metab 2002;22(8):988–996. 16. GlaxoSmithKline: Imitrex®. In Physicians’ Desk Reference. Montvale, NJ, Thomson PDR, 2005, pp 1513–1526. 17. Winner P: Triptans for migraine in adolescents. Headache 2002;42:675–679. 18. Rothner AD, Winner P, Nett R, et al: One-year tolerability and efficacy of sumatriptan nasal spray in adolescents with migraine: results of a multicenter, open-label study. Clin Ther 2000; 22(12):1533–1546. 19. Winner P, Rothner AD, Saper J, et al: A randomized, double-blind, placebo-controlled study of sumatriptan nasal spray in the treatment of acute migraine in adolescents. Pediatrics 2000; 106(5):989–997. 20. Loder E: Safety of sumatriptan in pregnancy: a review of the data so far. CNS Drugs 2003;17(1):1–7. 21. Ephross SA, Verp MS: Sumatriptan exposure during pregnancy: what have we learned about the risk of birth defects? Obstet Gynecol 2003;101(4 Suppl):83–84. 22. Bodner RA, Lynch T, Lewis L, et al: Serotonin syndrome. Neurology 1995;45:219–223. 23. Matthew NT, Tietjen Gem Lucker C: Serotonin syndrome complicating migraine pharmacotherapy. Cephalalgia 1999;16:323–327. 24. Gardner DM, Lynd LD: Sumatriptan contraindications and the serotonin syndrome. Ann Pharmacother 1998;32:33–38. 25. Maassen VanDenBrink A, Reekers M, Bax WA, et al: Coronary sideeffect potential of current and prospective antimigraine drugs. Circulation 1998;98:25–30. 26. Tepper SJ: Safety and rational use of the triptans. Med Clin North Am 2001;85:959–970. 27. MacIntrye PD, Bhargava B, Hogg KJ, et al: Effect of subcutaneous sumatriptan, a selective 5-HT1 agonist, on the systemic, pulmonary, and coronary circulation. Circulation 1993;87:401–405. 28. Goldstein JA, Massey KD, Kirby S, et al: Effects of high-dose intravenous eletriptan on coronary artery diameter. Cephalalgia 2004;24(7):515–521. 29. Parsons AA, Raval P, Smith S: Effects of the novel high-affinity 5HT(1B/1D)-receptor ligand frovatriptan in human isolated basilar and coronary arteries. J Cardiovasc Pharmacol 1998;32(2): 220–224. 30. Jamieson DG: The safety of triptans in the treatment of patients with migraine. Am J Med 2002;112:135–140. 31. Visser WH, Jaspers NM, de Vriend RH, et al: Chest symptoms after sumatriptan: a two year clinical practice review in 735 consecutive migraine patients. Cephalalgia 1996;16:554–559. 32. Tfelt-Hansen P: Efficacy and adverse events of subcutaneous, oral and intranasal sumatriptan used for migraine treatment: a systematic review based on number needed to treat. Cephalalgia 1998;18:532–538. 33. Velentgas P, Cole P, Mo J, et al: Severe vascular events in migraine patients. Headache 2004;44:642–651. 34. O’Quinn S, Davis RL, Gutterman DL, et al: Prospective large-scale study of the tolerability of subcutaneous sumatriptan for acute treatment of migraine. Cephalalgia 1999;19:223–231. 35. Cortijo J, Marti-Cabrera M, Bernabeu E, et al: Characteristics of 5-HT receptors on human pulmonary artery, and vein: functional and binding studies. Br J Pharmacol 1997;122:1455–1463. 36. Houghton LA, Foster JM, Whorwell PJ, et al: Is chest pain after sumatriptan oesophageal in origin? Lancet 1994;244:985–986. 37. The Triptan Cardiovascular Safety Expert Panel: Consensus statement: cardiovascular safety profile of triptans (5-HT1B/1D

CHAPTER 49

38. 39. 40. 41. 42. 43.

44. 45. 46. 47. 48. 49. 50.

agonists) in the acute treatment of migraine. Headache 2004; 44:414–425. Humphrey PPA, Feniuk W, Perren MJ, et al: Serotonin and migraine. Ann N Y Acad Sci 1990;600:587–598. Abbrescia VD, Pearlstein L, Kotler M: Sumatriptan-associated myocardial infarction: report of a case with attention to potential risk factors. J Am Osteopath Assoc 1997;97:162–164. Laine K, Raasakka T, Mantynen J, et al: Fatal cardiac arrhythmia after oral sumatriptan. Headache 1999;39:511–512. Mueller L, Gallagher RM, Ciervo CA: Vasospasm-induced myocardial infarction with sumatriptan. Headache 1996;36:329–331. O’Connor P, Gladstone P: Oral sumatriptan-associated transmural myocardial infarction. Neurology 1995;45:2274–2276. Centonze V, Bassi A, Causarano V, et al: Sumatriptan overuse in episodic cluster headache: lack of adverse events, rebound syndromes, drug dependence and tachyphylaxis. Funct Neurol 2000;15(3):167–170. Main ML, Ramaswamy K, Andrews TC: Cardiac arrest and myocardial infarction immediately after sumatriptan injection [letter]. Ann Intern Med 1998;128:874. Kelly KM: Cardiac arrest following use of sumatriptan. Neurology 1995;45:1211–1213. Morgan DR, Trimble M, McVeigh GE: Atrial fibrillation associated with sumatriptan. BMJ 2000;321:275. Curtain T, Brooks AP, Roberts JA: Cardiorespiratory distress after sumatriptan given by injection [letter]. BMJ 1992;305:713–714. Hall GC, Brown MM, Jingoing M, et al: Triptans in migraine: the risks of stroke, cardiovascular disease, and death in practice. Neurology 2004;62:563–568. Knudsen JF, Friedman B, Chen M, et al: Ischemic colitis and sumatriptan use. Arch Intern Med 1998;158:1946–1948. Liu JJ, Ardolf JC: Sumatriptan-associated mesenteric ischemia [letter]. Ann Intern Med 2000;132:597.

The Triptans

857

51. Naik M, Potluri R, Almasri E, et al: Sumatriptan-associated ischemic colitis. Dig Dis Sci 2002;47:2015–2016. 52. Putnam GP, O’Quinn S, Bolden-Watson CP, et al: Migraine polypharmacy and the tolerability of sumatriptan: a large-scale, prospective study. Cephalalgia 1999;19:668–675. 53. Turhal NS: Sumatriptan overdose in episodic cluster headache: a case report of overuse without event. Cephalalgia 2001;21:700. 54. Ottervanger JP, Valkenburg HA, Grobbee DE, et al: Pattern of sumatriptan use and overuse in general practice. Eur J Clin Pharmacol 1996;50(5):353–355. 55. Silberstein SD, Liu D: Drug overuse and rebound headache. Curr Pain Headache Rep 2002;6:240–247. 56. Katsarva Z, Fritsche G, Muessig M, et al: Clinical features of withdrawal headache following overuse of triptans and other headache drugs. Neurology 2001;57(9):1694–1698. 57. A Catalog of FDA Approved Drug Products. Available at http://www.fda.gov. Accessed May 10, 2006. 58. Eadie MJ: Clinically significant drug interactions with agents specific for migraine attacks. CNS Drugs 2001;15(2):105–118. 59. Bigal ME, Bordini CA, Antoniazzi AL, Speciali JG: The triptan formulations: a critical evaluation. Arq Neuropsiquiatr 2003; 61(2A):313–320. 60. Jhee SS, Shiovitz T, Crawford AW, Cutler NR: Pharmacokinetics and pharmacodymanics of the triptan antimigraine agents: a comparative review. Clin Pharmacol 2001;40(3):189–205. 61. Millson DS, Stewart JT, Rapoport AM: Migraine pharmacotherapy with oral triptans: a rational approach to clinical management. Exp Opin Pharmacother 2000;1(3):391–404. 62. Armstrong SC, Cozza KL: Med-psych drug-drug interactions update: triptans. Psychosomatics 2002;43(6):502–504. 63. Borys D, Hill K, Morgan D: Triptans in pediatric overdose: is medical treatment necessary? [abstract]. J Toxicol Clin Toxicol 2002;40(5):665.

50

Colchicine J. WARD DONOVAN, MD

At a Glance… ■ ■ ■ ■

■

■ ■ ■

Colchicine has a narrow therapeutic index and serious toxicity; fatalities can occur even with therapeutic doses. Colchicine is contraindicated in hepatic disease or renal failure, and should be avoided with macrolide antibiotics. The latent period of 4 to 12 hours after an overdose may mislead clinicians into discharging the patient prematurely. Toxicity develops in a first phase of severe gastroenteritis with hypovolemia; a second phase of bone marrow depression, cardiac and respiratory failure, hepatorenal syndrome, coagulopathy, and weakness; and a third phase of recovery with alopecia and rebound leukocytosis. Initial treatment includes gastric decontamination (even in late presentation), respiratory support, aggressive fluid replacement, and vasopressor use as needed. Elimination may be enhanced by multiple dosing of activated charcoal, but hemodialysis has no effect. Colchicine-specific Fab fragments show promise for future therapy, but are not currently available. Granulocyte colony-stimulating factor may aid in recovery from leukopenia.

INTRODUCTION AND RELEVANT HISTORY

CLASSIFICATION AND STRUCTURE The alkaloid colchicine has the chemical formula N(5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo [a]heptalen-7-yl) acetamide. The structure is shown in Figure 50-1.5 Pharmaceutical colchicine is available as 0.5- and 0.6-mg tablets and as a parenteral solution of 0.5 mg/mL. Colchicum species are cultivated and are popular as houseplants. The species C. autumnale has long, tubular purple or white flowers with seeds, and plants emerge from an underground corm or bulb (see Chapter 24); colchicine is present at a concentration of approximately 1% in the flowers of this plant.6

PHARMACOKINETICS Colchicine is rapidly absorbed from the gastrointestinal (GI) tract, reaching peak plasma levels within 0.5 to 2 hours.1 Oral bioavailability has been estimated to be 25% to 44%.2,6 Because higher doses depress jejunal and ileal function, prolonged absorption may occur in toxic doses.2 However, this was not observed in one study of human poisoning cases.7 Approximately 50% of circulating colchicine is bound to plasma proteins. Initial distribution half-lives range from 45 to 90 minutes, and distribution is complete after 3 to 6 hours.8 The reported volume of distribution has varied across a wide range; it has been estimated to be 2.2 to 8.5 L/kg with therapeutic doses and 21 L/kg in patients with toxic effects.6,8 A range of 12% to 44% of colchicine is excreted unchanged in the urine with therapeutic doses, similar to the 30% excretion found in overdose. In patients with liver disease, a larger fraction

CH3O CH3O

JNHCOCH3

J CH3O

J

Colchicine is an alkaloid that can be extracted from two plants of the lily family, Colchicum autumnale (autumn crocus, meadow saffron) and Gloriosa superba (glory lily), and is used as an anti-inflammatory agent in gouty arthritis. Colchicum was first recognized as a poison in the 3rd century BC by the Egyptian Dioscorides.1 In the 6th century AD, Alexander of Trallis first recommended colchicum as a cathartic in the treatment of joint pain.2 It was advocated as a diuretic in the New Edinburgh Dispensatory in 1788 and recommended as specific therapy for gout in medical texts of the early 1800s. It was probably introduced into the United States as therapy for gout by Benjamin Franklin.1 In 1820, colchicine was isolated from the C. autumnale tuber and rapidly gained popularity. It is now used to treat acute gouty arthritis, primary biliary cirrhosis, amyloidosis, Behçet’s disease, and condyloma acuminata, as prophylaxis for familial Mediterranean fever, and experimentally to study cell division in cytogenetics because of its antimitotic activity.3 The infrequency of colchicine toxicity is reflected in the annual report by the American Association of Poison Control Centers (AAPCC). In 2003, there were 213 colchicine exposures reported to the AAPCC, of which only 4 resulted in major toxicity and 4 resulted in death.4

Nevertheless, toxic effects may be encountered after accidental, suicidal, or therapeutic use of colchicine tablets. The tubers of the glory lily have also been mistakenly ingested due to their similarity to sweet potatoes. Large volumes of the plants are required to cause toxicity, but the effects are similar to those observed with tablet ingestion.

K

O

CH3O FIGURE 50-1 Chemical structure of colchicine.

859

860

ANALGESICS

of the drug is excreted unchanged. Metabolism is primarily via deacetylation in the liver mediated by cytochrome P-450 (CYP) 3A4, followed by biliary excretion. Significant enterohepatic recirculation occurs, as demonstrated by the presence of the parent drug and metabolites in large amounts in bile and intestinal secretions. The terminal plasma elimination half-life in therapeutic doses has ranged from 9.3 to 41 hours.2,6-8 This is similar to half-lives of 10.6 to 31.7 hours in toxic ingestions. However, serum concentrations were essentially unchanged for 3 days in one case of colchicine co-ingested with drugs that prolonged drug absorption and caused renal and hepatic failure.8

DRUG INTERACTIONS The CYP3A4 inhibitors cimetidine and ketoconazole can cause an increase in colchicine elimination half-life.2 Likewise, the macrolide antibiotics erythromycin and clarithromycin have the potential for inhibiting the CYP3A4 isoenzyme and, thus, decreasing hepatic metabolism of colchicine. Any known inhibitor of CYP3A4 has the potential for impairing colchicine metabolism and potentiating toxicity from this agent (see Chapter 5). The macrolide antibiotics, including josamycin, also inhibit P-glycoprotein, a transporter involved in cellular efflux and biliary elimination of drugs.8 Thus, the coadministration of macrolides has been reported to cause serious colchicine toxicity.8,9 Cyclosporine toxicity has resulted with concomitant use of colchicine.

PATHOPHYSIOLOGY Colchicine binds to intracellular tubulin, a structural protein necessary for normal cellular motility, shape, endocytosis and exocytosis, axonal transport, and cell division. As a result of tubulin binding, microtubule polymerization is inhibited, spindle formation cannot occur, and cell mitosis is inhibited in metaphase.10 Those cells with the highest turnover rate, such as intestinal epithelium, bone marrow, and hair follicles, are affected the earliest and to the greatest extent. By inhibiting tubulin polymerization, colchicine affects microtubule function and interferes with the transport of intracellular nutrients and organelles. Failed microtubule function may explain some aspects of the multiorgan failure seen in colchicine toxicity, particularly cardiac failure.11 There may be a direct toxic effect on the myocardial cells with impairment of impulse generation and cardiac conduction. Alternatively, depressed cardiac conduction and inotropy associated with severe colchicine toxicity may be due to profound acidosis and electrolyte derangements.3 The action of colchicine in gout is largely due to impaired phagocytosis of urate crystals by leukocytes; these effects probably result from failed microtubule function in leukocytes and their inability to alter cellular shape and engulf crystals.

RANGE OF TOXIC EFFECTS For acute gouty arthritis, the usual colchicine dose is 0.5 to 1.0 mg every 2 to 3 hours until relief or GI symptoms occur. Because GI warning symptoms do not occur with IV dosing, the recommended IV dose is half of the equivalent oral dose to a maximum of 2 to 4 mg per acute episode.2 There is a significant risk for death when this cumulative IV dose is exceeded.12 Maintenance colchicine therapy is usually provided as daily doses of 0.5 to 2 mg for adults and 0.5 mg per day for children. Colchicine is contraindicated in patients with combined hepatorenal disease, creatinine clearances below 10 mL/min, or extrahepatic biliary obstruction.5 Because of reduced elimination in those with renal impairment, doses should be no larger than 0.6 mg/day if the creatinine clearance is less than 50 mL/min or serum creatinine is greater than 1.6 mg/dL.13 Fatalities have occurred with total doses of 8 to 11 mg given therapeutically over several days.2 Ingestions of 0.5 to 0.8 mg/kg result in severe toxic effects, and doses greater than 0.8 mg/kg or a total of 40 mg are considered to be uniformly fatal.2,14 However, outcome is dependent on the duration between exposure and treatment, and the use of appropriate aggressive therapy.15 Severe toxic effects followed by survival have occurred with doses of 50 to 60 mg (greater than 1 mg/kg).2,10 In children, the fatal dose may be as low as 0.37 mg/kg.15 Colchicine-containing plants rarely produce severe toxicity due to the low concentrations of toxin, but large ingestions can be fatal.16 Ten grams of tuber contain about 6 mg of colchicine, and 100 to 125 g of tubers (60 to 95 mg of colchicine) have produced severe toxic effects.17 Colchicine plasma levels do not correlate well with the severity of toxicity and are not clinically useful. For instance, in acute ingestions, plasma concentrations that are associated with GI effects alone have ranged from 11 to 63 ng/mL within 4 hours of exposure.7 In contrast, a level of 24 ng/mL was noted 27 hours after acute colchicine ingestion in a patient with severe hemodynamic instability.11 In addition, reported colchicine plasma levels have ranged from 11 to 66 ng/mL in fatal cases.8 Because of enterohepatic recirculation, the drug accumulates in the bile in levels as high as over 5000 ng/mL. Thus, the bile may be the best source for analysis in forensic cases.18

CLINICAL MANIFESTATIONS The clinical manifestations of colchicine overdose involve multiple organ systems, including GI, respiratory, hematologic, cardiovascular, renal, and neurologic. After a latent period of 4 to 12 hours, signs and symptoms of toxicity occur in three phases.19 The first phase is manifested largely by GI signs and symptoms with fluid losses, electrolyte imbalance, and hypovolemic shock. Life-threatening complications occur during the second stage, or from 24 to 72 hours after exposure. At this

CHAPTER 50

time, cardiac insufficiency, arrhythmias, bone marrow depression, renal failure, hepatic injury, respiratory distress, coagulopathy, and neuromuscular abnormalities are present. This phase can last for 5 to 7 days and is followed by a recovery phase marked by a rebound leukocytosis and alopecia. The duration and features of each phase are outlined in Table 50-1, and details of each involved organ system are discussed separately.

Gastrointestinal Nausea, vomiting, diarrhea, and burning abdominal pain are the initial symptoms of colchicine toxicity. The presence of GI symptoms can serve a protective effect by warning of the potential for further toxicity with continued use of the drug. In addition, the presence of early GI effects may be the earliest indicator of impending severe toxic effects that will occur after acute overdose. Severe dehydration, hypovolemia, and cardiovascular collapse can result if aggressive treatment is not instituted. GI effects are not prominent after IV use, suggesting a local action of colchicine on gut epithelial cells. Hepatocellular damage (with associated elevations of transaminases and alkaline phosphatase) and hepatomegaly can also occur with colchicine toxicity, but fulminant hepatic failure occurs very rarely.10 Pancreatitis and a paralytic ileus also frequently occur.

Cardiovascular Hypotension occurs due to volume losses, extravasation of fluid into extracellular spaces, and myocardial depression. Development of cardiogenic shock due to a postulated direct myocardial injury is a poor prognostic sign.20 Colchicine is also thought to impair cardiac conduction, leading to arrhythmias and even late asystole.19 Marked electrocardiographic changes indicative

Colchicine

861

of myocardial injury can occur, with ST and T wave changes.17 Elevation of serum troponin I may be indicative of acute myocardial injury and the risk for cardiovascular collapse.21

Respiratory Respiratory distress occurs in about one third of cases and is a result of generalized muscle weakness and acute respiratory distress syndrome (ARDS).5 Colchicine is also thought to have a direct toxic effect on the lungs, causing capillary leakage. Prolonged hypotension, sepsis, and multiorgan failure probably also play a major role in this syndrome.

Neurologic Mental status depression may progress to delirium, seizures, and coma. Peripheral neuropathy, loss of deep tendon reflexes, and ascending paralysis can also occur late in the course.2,19,20 Myelin degeneration is thought to be the cause of these neuropathic effects.5

Hematologic The first phase of acute toxicity includes a peripheral leukocytosis, followed by bone marrow depression in the second phase. Severe leukopenia, thrombocytopenia, and a consumptive coagulopathy peak at 4 to 7 days postingestion.10 Disseminated intravascular coagulation and sepsis often complicate this phase. Hematologic studies show hypoprothrombinemia, decreased fibrinogen, and increased fibrin split products. At 8 to 10 days postingestion, bone marrow recovery is apparent, and a rebound leukocytosis occurs during the recovery phase. Neutropenia may occur without other toxic effects after several days of therapeutic use.22

TABLE 50-1 Phases of Colchicine Toxicity PHASE

COMPLICATION

TREATMENT

I (0–12 hr)

GI symptoms Volume depletion

Gastric lavage to ensure removal of all pills from stomach IV fluid replacement; treatment of shock with use of pressure if needed

II (2–7 days)

Peripheral leukocytosis Respiratory distress, ARDS, hypoxemia

III (1–2 wk)

Cardiovascular shock Thrombocytopenia, DIC Myelosuppression, neutropenia Hyponatremia, hypocalcemia, hypophosphatemia Metabolic acidosis Rhabdomyolysis, myoglobinuria, oliguric renal failure Rebound leukocytosis, alopecia

Supplemental oxygen, ET intubation and mechanical ventilation, PEEP Monitor, CVP, Swan-Ganz, fluids, pressors Replacement therapy with blood products Blood cultures, treament with antibiotics Electrolyte replacement Maintain volume status; treatment with HCO3 if necessary Fluids, diuretics to maintain urine output

ARDS, acute respiratory distress syndrome; CVP, central venous pressure; DIC, disseminated intravascular coagulopathy; ET, endotracheal; GI, gastrointestinal; IV, intravenous; PEEP, positive end-expiratory pressure.

862

ANALGESICS

Renal Renal failure is common in severe colchicine toxicity, probably secondary to hypovolemia, hypoxia, and myoglobinuria.5 The typical clinical findings are an oliguria responsive to fluids, hematuria, and proteinuria.17 There is no evidence of direct renal toxicity, although colchicine does concentrate in the kidneys.7

Metabolic/Electrolytes A lactic acid, anion-gap metabolic acidosis is common, again due to hypotension and hypovolemia. This is exacerbated by inhibition of intracellular metabolism and accumulation of organic acids.19 Hypophosphatemia, hyponatremia, hypocalcemia, and hypomagnesemia occur, primarily due to fluid losses. Hypocalcemia is also thought to be due to direct suppression of bone resorption by colchicine.2

Musculoskeletal A direct myopathic effect of colchicine can lead to muscle weakness, necrosis, and rhabdomyolysis, especially with chronic colchicine use.10 Reported cases have been associated with preexisting renal failure, and either acute or long-term colchicine in low therapeutic doses.23,24 Typically, there is rhabdomyolysis with elevated creatine kinase and aminotransferases.24 The diagnosis is aided by electromyography and muscle biopsy. If respiratory failure occurs, pulmonary function testing is recommended to determine if skeletal muscle weakness is a significant contributing factor. The myopathy is usually rapidly resolved with discontinuation of colchicine.

Dermatologic Scalp hair loss is common and typically occurs during the recovery phase, but it can occur anytime between 6 and 30 days postingestion.2,10 Hair growth almost always recovers several weeks after exposure. A vesiculating, erythematous rash resembling toxic epidermal necrolysis has been reported in rare cases, with histopathology showing subepidermal bullae and apoptosis of keratinocytes.25

Miscellaneous Colchicine has been associated with delayed corneal ulcer healing, azoospermia, and oligospermia.26

DIAGNOSIS The diagnosis should be suspected in anyone with access to colchicine and displaying the typical colchicine toxidrome of gastroenteritis, hypotension, lactic acidosis, and prerenal azotemia. In the early phases of colchicine toxicity, the diagnosis could be mistaken for sepsis, nonsteroidal anti-inflammatory drug or iron toxicity, or pancreatitis.27 Findings associated with the later phase of colchicine toxicity (e.g., peripheral neuropathy and

alopecia) could be mistaken for heavy metal poisoning. Differentiation from both is possible by the presence of severe bone marrow suppression in the second phase of colchicine toxicity. Laboratory monitoring should include frequent measurements of electrolytes (including calcium, magnesium, and phosphate), platelets, and creatine kinase; complete blood count; prothrombin time; serum troponin I; renal and liver function tests; and urinalysis for myoglobinuria. If coagulopathy is suspected, fibrinogen and fibrin split products should be monitored. In severe or persistent hypotension, echocardiography and pulmonary catheter monitoring is warranted.21 Colchicine measurements are not clinically useful except to establish or confirm the diagnosis.

TREATMENT Initial Supportive Measures Treatment for colchicine poisoning is mainly supportive. Patients with significant central nervous system or respiratory depression should have their airway protected, breathing assisted, and cardiovascular support provided as necessary. Initial therapy for hypotension includes aggressive replacement of fluid losses with IV crystalloid (20 to 60 mL/kg of normal saline or lactated Ringer’s solution); vasopressors are indicated for hemodynamic instability that is not fluid responsive or severe. If the vasopressor therapy is necessary, it should be guided by Swan-Ganz catheter placement and measurement of hemodynamic parameters. This is important, given the propensity for myocardial depression, hypovolemia, alterations in systemic vascular resistance, and ARDS. Respiratory failure may require mechanical ventilation with positive end-expiratory pressure. Transfusions of whole blood, fresh frozen plasma, vitamin K, and platelets may be necessary to treat coagulopathies. Because of frequent sepsis complicating neutropenia, the use of broad-spectrum antibiotics should be considered for febrile patients.

Decontamination Gastric decontamination is warranted if the patient presents during the latent period prior to the onset of gastroenteritis and a potentially toxic amount (greater than 5 to 10 mg in adults) has been ingested. Adsorption of colchicine by activated charcoal has not been studied but is thought to be effective. Even late decontamination should be performed, because large residual amounts of colchicine have been found in the stomach many hours after ingestion. The known enterohepatic recirculation of colchicine also supports late and repeated doses of activated charcoal, but paralytic ileus may complicate this approach.15 In such cases, duodenal tube suction could be utilized. Cathartics should not be routinely employed due to the expected onset of spontaneous diarrhea, and whole bowel irrigation would also be of limited value for this reason.

CHAPTER 50

Antidotes Colchicine-specific Fab fragments have been developed and used with success in studies in laboratory animals.11 The Fab fragments are prepared from the antiserum of goats immunized with colchicine, and their infusion results in reversal of colchicine binding to tubulin. This investigational agent has been successfully employed in a case of severe toxicity in a human without any adverse effects.11 Administration of the Fab fragments resulted in a rapid reversal of life-threatening hemodynamic instability, although bone marrow suppression did not significantly improve. The dose given was 480 mg of colchicine-specific Fab fragments, with half given over 1 hour and the remainder over the ensuing 6 hours.11 However, this agent remains an investigational antidote and is available only in France, in very limited quantities. Granulocyte colony-stimulating factor (G-CSF) has been used in colchicine toxicity in an attempt to accelerate production of neutrophils within the bone marrow.10,28 In such cases, an accelerated leukocytosis was observed within 1 to 2 days, but at a time when rebound leukocytosis may naturally occur. Because colchicine-induced bone marrow suppression is shortlived, use of G-CSF should be considered only in lifethreatening sepsis during the second phase of toxicity.

Enhanced Elimination As discussed with decontamination, repeated doses of activated charcoal should theoretically enhance colchicine elimination because of its enterohepatic recirculation, but this has not been tested. This treatment would be problematic in some cases due to the presence of emesis and, possibly, paralytic ileus. With its large volume of distribution, high protein binding, and relatively small fraction of renal excretion, it is unlikely that forced diuresis, hemodialysis, exchange transfusion, or hemoperfusion would be effective for drug removal.13 Hemodialysis may be necessary to treat the associated renal failure.

Disposition Because of its narrow therapeutic index and latent phase, any patient should be observed for 8 to 12 hours after acute ingestion of colchicine. The onset of GI symptoms or leukocytosis warrants hospital admission until at least the second phase of toxicity has ended. REFERENCES 1. Mack RB: Achilles and his evil squeeze: colchicine poisoning. NC Med J 1991;52:581–583. 2. Putterman C, Chetrit EB, Caraco Y, et al: Colchicine intoxication: clinical pharmacology, risk factors, features, and management. Semin Arthritis Rheum 1991;21:143–155.

Colchicine

863

3. Maxwell MJ, Muthu P, Pritty PE: Accidental colchicine overdose. A case report and literature review. Emerg Med J 2002;19:265–266 4. Watson WA, Litovitz TL, Klein-Schwartz W, et al: 2003 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2004;22:335–404. 5. Hood RL: Colchicine poisoning. J Emerg Med 1992;12:171–177. 6. Baselt RC: Disposition of Toxic Drugs and Chemicals in Man, 7th ed. Foster City, CA, Biomedical Publications, 2004, pp 266–267. 7. Rochdi M, Sabouraud A, Baud FJ: Toxicokinetics of colchicine in humans: analysis of tissue, plasma and urine data in ten cases. Hum Exp Toxicol 1992;11:510–516. 8. Borron SW, Scherrmann JM, Baud FJ: Markedly altered colchicine kinetics in a fatal intoxication: examination of contributing factors. Hum Exp Toxicol 1996;15:885–890. 9. Rollot F, Pajot O, Chauvelot-Moachon L, et al: Acute colchicine intoxication during clarithromycin administration. Ann Pharmacother 2004;38:2074–2077. 10. Folpini A, Furfori P: Colchicine toxicity clinical features and treatment: massive overdose case report. Clin Toxicol 1995;33:71–77. 11. Baud FJ, Sabouraud A, Vicaut E, et al: Brief report: treatment of severe colchicine overdose with colchicine-specific Fab fragments. N Engl J Med 1995;332:642–643. 12. Bonnelo RA, Villalba ML, Karwoski CB, Beitz J: Deaths associated with inappropriate intravenous colchicine administration. J Emerg Med 2002;22:385–387. 13. Wallace SL, Singer JZ, Duncan GJ, et al: Renal function predicts colchicine toxicity: guidelines for the prophylactic use of colchicine in gout. J Rheumatol 1999;18:264–269. 14. Bismuth C, Baud F, Dally S, et al: Standardized prognosis evaluation in acute toxicology: its benefit in colchicine, paraquat, and digitalis poisonings. J Toxicol Clin Exp 1986;6:33–38. 15. Atas B, Caksen H, Tuncer O, et al: Four children with colchicine poisoning. Hum Exp Toxicol 2004;23:353–356. 16. Brncic N, Viskovic I, Peric R, et al: Accidental plant poisoning with Colchicum autumnale: report of two cases. Croat Med J 1990;42:673–675. 17. Mendis S: Colchicine cardiotoxicity following ingestion of Gloriosa superba tubers. Postgrad Med J 1989;65:752–755. 18. Devaux M, Hubert N, Demarly C: Colchicine poisoning: case report of two suicides. Forensic Sci Int 2004;143:219–222. 19. Stapczynski JS, Rothstein RJ, Gaye WA, et al: Colchicine overdose: report of two cases and review of the literature. Ann Emerg Med 1981;10:364–369. 20. De Deyn PP, Cauterick C, Saxena V, et al: Chronic colchicineinduced myopathy and neuropathy. Acta Neurol Belg 1995;95: 29–32. 21. Mullins ME, Robertson DG, Norton RL: Troponin I as a marker of cardiac toxicity in acute colchicine overdose. Am J Emerg Med 2000;18;743–744. 22. Dixon AJ, Wall GC: Probable colchicine-induced neutropenia not related to intentional overdose. Ann Pharmacother 2001;35: 192–195. 23. Tanios MA, Gamal HE, Epstein SK, Hassoun PM: Severe respiratory muscle weakness related to long-term colchicine therapy. Respir Care 2004;49:189–191. 24. Wilbur K, Makowsky M: Colchicine myotoxicity: case reports and literature review. Pharmacotherapy 2004;24:1784–1792. 25. Arroyo MP, Sanders S, Yee H, et al: Toxic epidermal necrolysis-like reaction secondary to colchicines overdose. Br J Dermatol 2004;150:581–588. 26. Alster Y, Varssano D, Loewenstein A, et al: Delay of corneal wound healing in patients treated with colchicine. Ophthalmology 1997; 104:118–119. 27. Guven AG, Bahat E, Akman S, et al: Late diagnosis of severe colchicines intoxication. Pediatrics 2002;109:971–973. 28. Harris R, Marx G: Colchicine-induced bone marrow suppression: treatment with granulocyte colony stimulating factor. J Emerg Med 2000;18:435–440.

51

Nonsteroidal Anti-Inflammatory Drugs J. WARD DONOVAN, MD

At a Glance… ■

■

■ ■

■

Acute nonsteroidal anti-inflammatory drug toxicity may produce gastrointestinal (nausea, vomiting), neurologic (lethargy, coma, hallucinations, seizures), and metabolic (acidosis, renal failure) effects. Nonsteroidal anti-inflammatory drug toxicity should be included in the differential diagnosis of an anion gap metabolic acidosis, which can be severe (pH < 7.1) in large overdoses. Absorption and onset of effects are rapid (1 to 4 hours) following acute overdose. Cyclooxygenase-2 nonsteroidal anti-inflammatory drugs have fewer adverse gastrointestinal effects with chronic use, but have similar toxic effects in overdose and have a risk for inducing adverse cardiovascular events in chronic use due to their prothrombic effects. Management is supportive and must include rehydration to prevent and reverse the renal and metabolic effects.

INTRODUCTION AND RELEVANT HISTORY Nonsteroidal anti-inflammatory drugs (NSAIDs) were first developed in the late 19th century; they achieved widespread use even before the marketing of acetylsalicylic acid. The first NSAIDs were the pyrazolones, phenazone and amidopyrine; phenylbutazone, of the same class, was not introduced until after World War II. Other NSAIDs were identified in the late 1950s and the 1960s, and they have undergone an explosive increase in use over the past 30 years. Ibuprofen was first introduced in the United States in 1974 and was approved for over-thecounter use in 1984. The widespread availability of NSAIDs has naturally resulted in a marked increase in the number of overdoses and reported adverse effects. In the 4-year period 1985 through 1988, 55,800 cases of ibuprofen exposure were reported to the American Association of Poison Control Centers (AAPCC), but 71,043 ibuprofen exposures and a total of 97,123 NSAID exposures were reported in 2003 alone.1,2 Ibuprofen exposures account for more than 5% of the total cases reported to the London Poisons Information Centre.3 NSAIDs are now the most commonly utilized class of medications in the world, accounting for more than 4% of all prescriptions, with 73 million prescriptions written per year.4,5 Piroxicam, with its extended plasma half-life, potency, and safety, has become one of the most widely prescribed NSAIDs in the world.6 Despite their extensive use, NSAIDs are among the safest pharmaceuticals in use. Adverse drug reaction frequency is reported as only 24.4 per million prescrip-

tions, with fatal adverse reactions of 1.1 per million prescriptions.7 Symptoms were absent or minor in 33.6% of cases with known outcomes reported to the AAPCC.2 However, the potential does exist for serious illness and even death in a few cases, as reflected in the 578 reported serious outcomes and 47 deaths involving NSAIDs in the United States in 2003. NSAIDs are now a common cause of renal failure, and at some regional poison treatment centers, mefenamic acid has accounted for the majority of reported drug-induced seizures.8,9 Chinese herbal medications have been found to contain NSAIDs, and their use has caused renal failure and aplastic anemia.10

STRUCTURE AND STRUCTURAL RELATIONSHIPS The NSAIDs are a heterogeneous group of chemicals that share similar therapeutic properties. These acids are classified as subgroups of one of two families: the carboxylic or enolic acids. The carboxylic acids are further subdivided into arylacetic (phenylacetic) acids, propionic acids, fenamic acids, isoxazoles, and carbocylic and heterocyclic acetic acids. The enolic acetic acids are subdivided into pyrazolones and oxicams (Box 51-1). Aspirin, a salicylic acid of the carboxylic family, is discussed in Chapter 48. The structures of various NSAIDs are shown in Figure 51-1.11 NSAIDs are also classified by their activity as a specific or nonspecific inhibitor of the cyclooxygenase isoenzymes COX-1 and COX-2. Selective inhibition of COX-2, which affects inflammatory responses, is desirable, while inhibition of COX-1, affecting gastric mucosal protection, is not. Selective COX-2 inhibitors celecoxib and rofecoxib have up to a 200 to 300 times greater selectivity for COX-2 than COX-1.12 The novel coxibs etoricoxib, valdecoxib, parecoxib, and lumiracoxib have even greater COX-2 selectivity, with the possibility of using increased doses to improve efficacy.13 However, they have renal side effects similar to those of the nonselective NSAIDs, thereby limiting the use of higher doses. Some other NSAIDs also have a modest degree of COX-2 selectivity, particularly etodolac, nabumetone, and meloxicam.12 A potential disadvantage of the COX-2 inhibitors are that they are prothrombotic, whereas COX-1 inhibition has antithrombotic activity.14

PHARMACOLOGY: MECHANISM OF ACTION The primary mechanism of action of NSAIDs is via inhibition of prostaglandin synthesis. Prostaglandins are derived from phospholipids in cell membranes synthesized 865

866

BOX 51-1

ANALGESICS

CLASSIFICATION OF NSAIDS

Salicylic Acids

Propionic Acids

Acetylsalicylic acid (aspirin) Choline salicylate (arthropan) Diflunisal (Dolobid) Magnesium salicylate (Doan’s, Magan) Salicylamide Salsalate (Disalcid) Sodium salicylate Sodium thiosalicylate Trolamine salicylate (Aspercreme, Myoflex Crème)

Carprofen Ibuprofen (Advil, Nuprin, Motrin) Naproxen (Naprosyn, Anaprox) Fenbufen Flurbiprofen (Ansaid) Fenoprofen (Nalfon) Indoprofen Ketoprofen (Orudis) Loxoprofen Oxaprozin (Daypro) Pirprofen Suprofen (Suprol) Tiaprofenic acid

Phenylacetic Acids

Diclofenac (Voltaren) Carbocyclic and Heterocyclic Acetic Acids

Aceclofenac Acemetacin Bromfenac (Duract) Diclofenac Etodolac (Lodine) Indomethacin (Indocin) Ketorolac (Toradol) Nabumetone Sulindac (Clinoril) Tolmetin (Tolectin) Zomepirac Fenamic Acids

Benzydamine (Tantum, Difflam, Andolex, Opalgyne) Floctafenine Flufenamic acid Mefenamic acid (Ponstel) Meclofenamate (Meclomen)

from arachidonic acid. This synthesis is mediated by the enzyme cyclooxygenase, which is reversibly inhibited by NSAIDs. Thus, NSAIDs block the conversion of arachidonic acid to the various prostaglandins, which are involved in renin release, local vascular tone, regional circulation, water homeostasis, and potassium balance. The prostaglandin pathway and functions are outlined in Figure 51-2. Prostaglandin E2 (PGE2), PGD2, PGF2, and prostacyclin (PGI2) promote salt and water excretion, and the renal vasodilatory action of PGE2, PGD2, and prostacyclin enhances this effect. It is thought that PGE2 and prostacyclin also stimulate renin release.15 In addition, prostaglandins antagonize the effects of antidiuretic hormone.16 The net effect of NSAIDs is decreased inhibition of prostaglandins, decreased renal blood flow, and decreased glomerular filtration rate, leading to sodium, potassium, and water retention (Fig. 51-3). PGE2 also inhibits lymphocytes and other cells involved in inflammation and allergic response, and this

Furanones

Rofecoxib (Vioxx) Isoxazoles

Valdecoxib (Bextra) Pyrazoles

Celecoxib (Celebrex) Pyrazolones

Azapropazone Fenprazone Phenylbutazone (Butazolidin) Oxyphenbutazone (Oxalid) Oxicams

Isoxacam Lornoxicam Piroxicam (Feldene) Meloxicam (Mobic) Sudoxicam

may play a role in the development of interstitial nephritis and hepatotoxic effects in some patients using NSAIDs.16,17 This has occurred most with fenoprofen and the carbocyclic and heterocyclic acetic acids. Other actions of NSAIDs are inhibition of platelet activation and mast cell mediation. The former contributes to prolonged bleeding, and the latter may be involved in NSAID-induced anaphylactic reactions and idiosyncratic hypersensitivity reactions. Also, prostaglandins, particularly prostacyclin, are formed in gastric tissue and exert gastric mucosal protective actions. Inhibition of this action by NSAIDs as well as their direct disruption of the gastric mucosal barrier can cause gastritis and gastrointestinal (GI) bleeding. The selective COX-2 inhibitors have less likelihood of adverse GI events, and large clinical trials have validated this theory.18 However, by decreasing vasodilatory and antiaggregatory prostacyclin production, COX-2 inhibitors may be prothrombotic. This is discussed further under cardiopulmonary effects.

CHAPTER 51

Nonsteroidal Anti-Inflammatory Drugs

867

FIGURE 51-1 Chemical structures of various nonsteroidal anti-inflammatory drugs. A, Ibuprofen, a propionic acid. B, Rofecoxib, a furanone. C, Acetylsalicylic acid, an acetylated salicylate. D, Meloxicam, an oxicam or enolcarboxamide. E, Valdecoxib, an isoxazole. F, Indomethacin, an acetic acid. G, Salsalate, a nonacetylated salicylate. (From Brent J, Wallace KL, Burkhart KK, et al [eds]: Critical Care Toxicology. Philadelphia, Mosby, 2005.)

A

D

C

B

E

F

G

Phospholipids (found in cell membranes)

Arachidonic acid (an “eicosanoid”) Cyclooxygenase and O2 (inhibited by NSAIDs) PGG2 Peroxidase (-) free radical PGH2

PGE2 ( vasodilation; diuresis and natriuresis; NaCl/water excretion; lymphocytes)

PGF2a ( NaCl/water excretion; vasoconstriction)

FIGURE 51-2 Prostaglandin pathway and function.

Prostacyclin or PgI2 ( vasodilation; renin release; platelet aggregation)

PGD2 (mast cell mediator and bronchoconstriction; vasodilation in resistance vessels)

Thromboxane A2 ( platelet activation and intravascular aggregation; vasoconstriction)

868

ANALGESICS

Absorption

Arachidonic acid Prostaglandin NSAID Synthetase Prostaglandins

Renal blood flow

Chloride absorption

Renin

ADH effect

Aldosterone GFR

Sodium retention

Potassium retention

Water retention

BUN Edema creatinine hypertension Hyperkalemia Hyponatremia FIGURE 51-3 The net effect of NSAIDs with prostaglandins. ADH, antidiuretic hormone; BUN, blood urea nitrogen; GFR, glomerular filtration rate.

PHARMACOKINETICS The carboxylic acid and enolic acid NSAIDs share similar pharmacokinetics, pharmacodynamic properties, and metabolic pathways. However, there are some clinically significant differences in rates of absorption and elimination and in drug interactions (Table 51-1).19,20

Therapeutic oral doses for most NSAIDs are absorbed almost completely, producing peak levels within 1 to 2 hours. Exceptions to this are oxaprozin, mefenamic acid, and diflunisal, which have delays of peak levels of up to 3 to 4 hours. The presence of food can delay the absorption of all NSAIDs.20 In overdose, some delay may take place in achievement of peak serum levels. Five patients in a series of 29 patients with mefenamic acid overdoses had increasing serum levels after admission, which peaked at 8 to 12 hours postingestion.8

Distribution The NSAIDs are extensively protein bound (98% to 99%), primarily to albumin. Sulindac and indomethacin have slightly lower degrees of binding, in the range of 90% to 93%.6,20 Principally because of their high protein binding, apparent volumes of distribution are low, ranging from 0.10 to 0.36 L/kg.6,20 Acute renal insufficiency, liver disease, and hypoalbuminemic states can decrease plasma protein binding and increase volumes of distribution.20 Plasma protein binding can also decrease when NSAIDs are taken in high doses.

Metabolism The elimination of NSAIDs is primarily by hepatic biotransformation to metabolites, which are excreted in

TABLE 51-1 Pharmacokinetics of NSAIDs Vd (L/kg)

RENAL EXCRETION OF UNCHANGED DRUG (%)

Nonselective COX Inhibitors Benzydamine 4–6 Diclofenac 1–3 Diflunisal 2–3 Etodolac 1.5 Fenoprofen 1–2 Flurbiprofen 1–2 Ibuprofen 0.1–1.5 Indomethacin 1–2 Ketoprofen 0.5–2.4 Ketorolac 1 Meclofenamate 0.5–2.4 Mefenamic acid 2–3 Nabumetone — Naproxen 2 Oxaprozin 3–5 Phenylbutazone 2 Piroxicam 2 Sulindac 1 Tolmetin 0.5–1.4 Zomepirac 1

1.57 0.12–0.17 0.10 0.36 0.12 0.10 0.11–0.19 0.12 0.11 0.15–0.33 — 1.34 — 0.10 0.14–0.18 0.24 0.12–0.15 2.44 0.10–1.44 1.84

— 65 yr), renal or liver dysfunction

None

Elimination exclusively by renal excretion

Nausea, anorexia

Gastrointestinal symptoms (10%)

No effect on CYP450 enzymes

896

ANTIMICROBIAL, CHEMOTHERAPEUTIC, AND IMMUNOSUPPRESSIVE AGENTS

TABLE 53-1 Currently Available Antiretroviral Drugs (See Text for References)—cont’d

SUBSTANCE NAME

TRADE NAME

Zanamivir

Relenza

Pyrofosfate Analogs Foscarnet Foscavir

Others Ribavirin

Rebetol, Copegus

Ribavirin

Virazole

Cidofovir

Vistide

Palivizumab

Synagis

RECOMMENDED DAILY DOSE (mg)*

ORAL AVAILTmax ABILITY (%) (hr)

Inhaled 10–20 mg daily 10–20 for adults and children > 12 yr

60 mg/kg intravenously tid, or 90 mg/kg intravenously bid

PROTEIN BINDING

Poorly absorbed following oral administration bioavailability about 2%

10–20

0.4–0.7

>75 kg: 600 mg po 50 bid (generally + interferon); renal

Biliary > renal (10%–15% unchanged)

Renal

Renal

Renal

Renal Renal

ELIMINATION

55 (parent) 25 (DNL) 30 (parent) 29 (DXL) 15–24 (parent) 45 (IDL) 20–200

2 (parent)

4–15

3–12 (parent) 9 (PM) 7 (HC)

2–3 2 (PAM) 1.5 (parent) 58–73

TERMINAL PLASMA HALF-LIFE (hr)

Desacetylvinblastine* Uncharacterized 6-hydroxypaclitaxel

Biliary > renal Biliary > renal Biliary > renal

23 20–150 3-–20

Fluorodeoxyuridine monophosphate* Respiratory, renal 16 min (parent) Alpha-fluoro-beta-alanine Polyglutamated derivatives* Renal > biliary 8–15 (parent) 7-hydroxymethotrexate* 2, 4-diamino-N(10)-methylpteroic acid

Mono- and dicarboxylic acid derivatives

Idarubicinol (IDL)*

Doxorubicinol (DXL)*

Daunorubicinol (DNL)*

Methanesulfonic acid Phenylacetic acid mustard (PAM)* Hydroxylated derivatives Hydrolytic derivatives* (e.g., Monohydroxymonochloro cisdiammine platinum [II]) 4-Hydroxycyclophosphamide (HC), Phosphoramide mustard (PM)* 4-Ketocylcophosphamide Carboxyphosphamide Acrolein* 4-Hydroxyifosfamide Ifosphoramide mustard* Dechloroethylifosfamide derivatives 4-Ketoifosfamide 4-Carboxyifosfamide Acrolein* Hydrolytic derivatives

METABOLITES

TABLE 56A-1 Pharmacologic Parameters Pertaining to Selected Chemotherapeutic Agents Discussed in This Chapter.

CHAPTER 56 Chemotherapeutic Agents and Thalidomide 929

930


lead to the disruption of cellular protein activity. In the urinary bladder and in high concentration, acrolein can cause a hemorrhagic cystitis. This is prevented by hydrating the patient to promote urinary flow and to lower the urinary acrolein level and by administering the thiol agent sodium 2-mercaptoethane sulfonate (MESNA) during high-dose cyclophosphamide therapy (>120 mg/kg) before bone marrow transplantation. Another example of a toxic metabolite is when MTX is administered at a dose higher than 1 g/m2. MTX is metabolized by aldehyde oxidase to 7-hydroxymethotrexate (7OHMTX), which is not active as a folate analog and is eliminated uneventfully in the urine. However, this metabolite is less soluble than MTX and tends to precipitate in acidic pH. During high-dose MTX therapy, appreciable levels of 7OHMTX can be achieved to cause precipitation in the renal tubules with resultant necrosis and renal failure.

TOXICOLOGIC MANIFESTATIONS The toxicologic effects of the chemotherapeutic agents in the body are most apparent in cells with a high turnover rate, such as those in the epithelium, bone marrow, and hair follicle. This is because these agents were designed to limit cancerous cell growth by exploiting their high rate of mitosis. Thus, patients with toxicity will present with mucositis, alopecia, and leukopenia. The occurrence of these events posttreatment will vary by agent, but can be expected at about 3 to 5 days for mucosal epithelial loss and 7 to 13 days for the nadir effect of leukopenia. The mucosal epithelial loss can lead to gastrointestinal bleeding and serve as a source for sepsis from the entry of gut bacteria into the systemic circulation. MTX, 5FU, bleomycin, and doxorubicin are highly associated with mucosal ulcerations during therapy. The white blood cell count usually returns to baseline at 21 to 24 days. For some agents, the nadir of the leukopenia can be delayed by weeks (e.g., carmustine) or the duration of bone marrow suppression is much more sustained and can last for months to years after the exposure (e.g., busulfan). During this period of myelosuppression, patients may require blood product replacement, use of granulocyte colonystimulating factors,6,7 reverse isolation, and antibiotic therapy to protect them from overwhelming sepsis. Granulocyte colony-stimulating factor has been demonstrated to improve neutrophil count response, improve rate of recovery from neutropenia, decrease duration of febrile neutropenia, and decrease hospital length of stay in patients undergoing chemotherapy. Additional findings common to overdoses of chemotherapeutic agents include nausea, vomiting, and hyperuricemia. The onset of nausea and vomiting is within 6 hours of exposure, and the effect can last for as long as 24 hours. Chemotherapeutic agents are highly emetogenic, especially cisplatin, mechlorethamine, and doxorubicin because of their ability to stimulate the emetic center located in the medulla from various pathways. These

include the chemoreceptor trigger zone (CTZ), which can be affected by constituents in the blood or CSF, and the solitary tract nucleus, which receives vagal and sympathetic innervation by the enterochromaffin cells in the intestinal mucosa. The vagal and sympathetic afferents can stimulate the emetic center by way of the CTZ as well. Because serotonin is involved in many of these pathways, ondansetron is an effective antiemetic agent for chemotherapeutic agent–induced vomiting. In order to assist patients with protracted emesis from these agents, the pharmacologic inhibition of the other neurotransmitters involved in these pathways (e.g., dopamine) is often necessary, requiring combination drug therapy. Certain chemotherapeutic agents cause unique toxicologic manifestations and they are further discussed in the advancing sections.

Cardiac The chemotherapeutic agents causing cardiotoxicity in a dose-dependent fashion are cyclophosphamide and the anthracycline antibiotics. The pyrimidine analog 5FU appears to be associated with manifestations consistent with coronary vasopasm during high-dose continuous infusion therapy.8 Doxorubicin and daunorubicin are the original anthracycline agents, and their use is limited by their oxidative-induced damage to myocardial tissue, which can lead to irreversible congestive cardiomyopathy. Cardiomyopathy is a significant and consequential effect of anthracycline therapy because it is irreversible, can lead to congestive heart failure, and is associated with a 48% mortality rate.9 The availability of structural analogs (e.g., epirubicin and idarubicin) and liposomal encapsulated formulations of the original anthracyclines allows for the continued use of this class of agents with less toxicity to the host. For example, the cumulative dose for doxorubicin and epirubicin to cause a 20% incidence of congestive cardiomyopathy is 550 mg/m2 and 720 mg/m2, respectively.10,11 Daunorubicin and mitoxantrone are associated with a 2% incidence at the cumulative doses of 600 mg/m2 and 140 mg/m2, respectively. In addition to cardiomyopathy, which is a delayed effect, the anthracycline agents can cause immediate manifestations of cardiac toxicity. These immediate effects, occurring within 24 hours of administration, include dysrhythmias, ST segment and T wave changes on the electrocardiogram, diminished left ventricular ejection fraction leading to congestive heart failure, pericarditis, myocarditis, and sudden death.12-15 The repolarization changes on the electrocardiogram are observed in about 40% of patients receiving doxorubicin therapy, and are transient and not associated with either total dose or peak serum levels.13,16,17 The onset of cardiomyopathy is heralded by manifestations consistent with biventricular heart failure and its timing, since the last course of treatment can be quite variable, ranging from months to years. Although this period is usually 1 to 4 months, it tends be longer for the less toxic anthracycline analogs.18-20 Cyclophosphamide’s toxic effects on the heart are described in patients receiving high-dose therapy for

CHAPTER 56

bone marrow transplantation and in the overdose setting.21 These patients can develop congestive heart failure, hemorrhagic pericarditis, or cardiac tamponade resulting in death within days of exposure.22,23 Patients receiving a mean cyclophosphamide dose of 174 mg/kg were observed to have greater reductions in QRS voltage and increases in left ventricular mass index compared with patients treated at a lower dose.24 These findings were attributed to myocardial swelling from either edema or hemorrhage.25 Patients at increased risk for cardiac effects from cyclophosphamide therapy include those who are older than 50 years, have a history of cardiac dysfunction,26 or received treatment with anthracycline agents or thoracic radiotherapy. 5FU is associated with myocardial ischemia and cardiogenic shock when administered as a high-dose continuous infusion.27 The incidence of cardiac symptoms in patients receiving high-dose continuous infusion therapy was observed to be about 10%, which was 10fold higher than patients receiving bolus therapy.8 In some of these patients, diminished QRS voltage and ventricular wall motion normalized within 48 hours of discontinuation of 5FU treatment. These manifestations are attributed to increased myocardial oxygen demand28 and coronary vasospasm,29 which may be a response to endothelial damage caused by the metabolite fluoroacetate.30 Patients with coronary artery disease or prior thoracic radiotherapy are at risk for these events during 5FU therapy, and they should be treated by discontinuation of 5FU and with coronary artery vasodilators (e.g., nitrates, calcium channel blockers) for myocardial ischemia.

Neurologic The chemotherapeutic agents can cause a variety of neurologic effects, including central nervous system (CNS) and peripheral nervous system disorders, from the systemic administration of an excessive dose. Altered mental status and seizures are commonly observed during overdoses from the nitrogen mustards, MTX, and vincristine. The inappropriate IT administration of vincristine or MTX (by dose) can result in seizures as well. The putative neurotoxin from chlorambucil and ifosfamide overdoses is chloroacetaldehyde, which is produced by N-dechloroacetylation in the liver.31-33 The seizures from chlorambucil overdoses typically present within 6 hours of exposure and are generalized tonicclonic activity, which can last for 24 hours.34,35 Vincristine-induced seizures occur much later than those caused by the nitrogen mustards; typically at 1 to 7 days after exposure. Patients with underlying seizure disorders, delayed drug elimination,36-39 or altered drug pharmacokinetics (e.g., nephrotic syndrome) (salloum) are at risk for seizures during treatment with these agents. Vincristine toxicity can cause hypothalamic stimulation as well as central autonomic instability. The former can lead to fevers and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).40 The duration of the fevers can be protracted, lasting for 1 week after the exposure, and serum electrolyte abnormalities may not present until 10 days after drug

Chemotherapeutic Agents and Thalidomide

931

exposure. The manifestations of central autonomic instability include bowel ileus, constipation, atony of the urinary bladder, hypertension, and hypotension.38 Other chemotherapeutic agents associated with altered mental status include L-asparaginase, 5FU, and procarbazine.41 5FU is associated with cerebellar ataxia in less than 5% of treated patients, and the mechanism remains to be determined.42 The neurologic effects from MTX toxicity are variable and depend on the nature of the exposure. Chemical arachnoiditis occurs within hours of IT treatment and manifests as cephalgias, meningismus, pleocytosis, sterile CSF, and increased CSF protein and CSF MTX levels. The early administration of systemic steroids may limit the inflammatory response that is believed to occur during this process. A CSF MTX level higher than 100 μmol/L during IT therapy suggests either an excessive amount of MTX administered or a CSF outflow obstruction.43 Transverse myelopathy can occur from the lumbar subarachnoid administration of MTX and is typically not a reversible process, which is unlike that of chemical arachnoiditis. Neurobehavioral disorders and depressed mental status presenting months to years after treatment is characteristic of MTX-induced leukoencephalopathy. The overall incidence of this disorder is variable, ranging from 10% to 70%, and patients with increased age, intraventricular or IT administration of MTX, or prior cranial radiation appear to be at risk for developing this finding.44 Computed tomography scan and magnetic resonance imaging of the brain can demonstrate findings consistent with demyelination and necrosis of the white matter.45 IT overdoses with MTX occur infrequently and are associated with devastating outcomes, including permanent neurologic deficits and death. IT therapy is used to prevent CNS spread of cancerous cells in patients with acute lymphoblastic leukemia. The common cause of IT errors is confusing IV for IT medication, which can occur with similarly named drugs, multiple medications at the bedside, or when varying doses by different routes of administration are available for the same medication.46 This latter reason accounts for some MTX IT overdoses because the higher IV dose was administered as the IT dose. The manifestations of toxicity present within minutes of the drug’s administration, and include pain in the lower extremities, cephalgia, meningismus, and depressed level of consciousness. An electroencephalograph can demonstrate diffuse alterations in electrical activity.47 IT overdoses with vincristine also have occurred, and the clinical outcome is more devastating than other chemotherapeutic agents administered in a similar manner.48-50 Patients present with findings consistent with an ascending myelopathy, and the outcome is typically fatal or includes permanent neurologic sequelae. Peripheral neuropathies are observed with cisplatin and vincristine toxicities and occur in a dose-dependent fashion. The neuropathy is classic in its clinical presentation, ascending in nature, and can involve both sensory and motor components. The incidence of paresthesia with vincristine therapy is about 60% at a dose of 12 to 25 μg/kg and increases sixfold at a dose of

932


75 μg/kg.51 The occurrence of neuropathies is higher for vincristine than vinblastine. The onset of symptoms during therapy ranges from 2 to 8 weeks after treatment, and limits the dosing regimen for vincristine.52 For the vinca alkaloids, the loss of the Achilles tendon reflex is an early finding that can be expected to resolve within 7 weeks upon discontinuation of further therapy.53 Cranial nerve (III–VII and X) and laryngeal nerve involvement have been described in association with the vinca alkaloids.41,54 In comparison to vincristine, paclitaxel (taxol)-induced neuropathies have more of a sensory deficit and a shorter recovery period. This may be related to the difference in the mechanism of activity of these two agents on microtubule synthesis. The peripheral neuropathy associated with cisplatin toxicity is primarily a sensory disorder, and it is potentiated by the concomitant use of other neurotoxic agents, such as paclitaxel. The patient will present with paresthesia, and loss of vibratory sense and proprioception. Other clinical findings associated with cisplatin toxicity include tinnitus, high-frequency hearing loss, and retinopathy.55

Renal Chemotherapeutic agents can cause renal toxicity either directly or indirectly, resulting from the accumulation of breakdown products of cell death (i.e., uric acid). Acute uric acid nephropathy is commonly observed during the use of these agents for the treatment of leukemia or lymphoma. MTX is associated with renal insufficiency at doses higher than 500 mg/m2 (100 mg/kg). Prior to the institution of prophylactic measures, such as hydration and urinary alkalinization, MTX was associated with renal insufficiency in 30% of the patients receiving therapy, and mortality in patients with severe renal failure.56 The cause is the precipitation of the 7OHMTX metabolite in the renal tubules to cause acute tubular necrosis. This metabolite is less soluble than MTX and crystallizes in renal tubules in an acidic environment. The solubility of 7OHMTX at pH 5.5 is 2 mmol/L and increases at a higher pH. Cisplatin is another agent that causes renal tubular necrosis in a dose-dependent manner, and when repeat doses are administered in close succession. Protein unbound cisplatin freely enters into renal tubular cells, accumulating in the corticomedullary region of the kidney to cause distal and proximal tubular necrosis. Pretreatment with sodium chloride reduced the level of cisplatin and cisplatin metabolites in the kidney tissue and urine of treated animals.57 When the cisplatin dose is higher than 50 mg/m2, the frequency of renal failure is about 30%. The time of onset for the increase in serum blood urea nitrogen (BUN) and creatinine is about 1 to 2 weeks after treatment, which is slightly delayed compared to MTX. Hypomagnesemia and hypocalcemia are observed during cisplatin toxicity and may be attributed to renal loss from tubular injury.58 Patients at risk for renal toxicity from these agents include the elderly, those with underlying renal disease, and those receiving concomitant therapy with nephrotoxic agents (e.g., aminoglycosides).

DIAGNOSIS The diagnosis of a patient with an overdose from a chemotherapeutic agent is based on the presence of clinical manifestations consistent with the toxicity of the agent, historic evidence of the exposure, and laboratory findings supporting the exposure or toxicity. In most instances, the event will be clearly evident based on the history alone because these agents are typically administered in the controlled setting of a hospital. However, for agents associated with delayed onset of clinical toxicity or toxicity from chronic exposure, a heightened level of awareness will be necessary to establish the relationship between exposure and clinical findings.20 The mechanisms responsible for the unintentional administration of chemotherapeutic agents involve either errors in dosage regimens or drug preparations, and they should be investigated in situations where the exposure is not apparent but suspected.59 Some of the reasons for the dosage regimen errors include inappropriate dosage, misinterpretation of the protocol, and incorrect number for current treatment cycle. Such occurrences result from the lack of familiarity with the treatment protocol, errors in prescribing, errors in administration, errors in interpretation of the written order, and lack of familiarity with the patient’s medical background. Two common examples of errors in administration include doxorubicin (correct, 100 mg/m2 for over 4 days in divided doses; incorrect, 100 mg/m2 daily for 4 days) and vincristine (correct, IV dose [0.06 mg/kg]; incorrect, administered IT). A systemic approach to prevent medical errors with chemotherapeutic agents is discussed elsewhere.60 Patient risk factors for toxicity from these agents need to be considered during the assessment because these may explain the clinical findings. These include inability to eliminate or metabolize the drug (i.e., renal or hepatic insufficiency), pre-existing disorder (e.g., seizures, congestive heart failure, coronary artery disease) of the target organ of toxicity, the presence of third space fluid compartments (e.g., peritoneal, pleural) that can sequester the drug or metabolite, and concomitant treatments (e.g., medications or radiotherapy) that can potentiate the target organ’s toxicity. Drug levels for this class of agents are not routinely available in the clinical setting to assist in confirming the diagnosis of toxicity. However, analytical assays to measure MTX, busulfan,5 cisplatin (platinum),58 and vincristine61 are available, and the levels of these agents can be used to assess for exposure. Some of the chemotherapeutic agents are associated with unique manifestations of toxicity such that when these are present, the agents should be suspected. For example, the anthracyclines are associated with congestive heart failure and cardiomyopathy; cisplatin with renal insufficiency, ototoxicity, and peripheral neuropathy; the vinca alkaloids with peripheral neuropathy, SIADH, and central autonomic instability; and ifosfamide with seizures. Certain studies can assist the diagnostic process by either confirming the findings on clinical examination

CHAPTER 56

or by evaluating for other disorders that may present with similar findings. For example, myocardial biopsies can evaluate for infectious and ischemic causes of cardiomyopathy when anthracycline toxicity is being considered. Although this procedure is infrequently used for this purpose, it is still used in conjunction with the left ventricular ejection fraction to determine the course of anthracycline treatment in select cases. The electroretinogram can identify retinal disorders of the post-photoreceptor neural function that is described in patients with visual loss and color aberrations from cisplatin toxicity.55 Other studies include audiometry to evaluate for high-frequency hearing loss from cisplatin toxicity; brain computed axial tomography or magnetic resonance imaging to evaluate for leukoencephalopathy from MTX, hemorrhage, and metastatic lesions; and nerve conduction studies to evaluate for sensorimotor deficits attributed to a peripheral neuropathy. Druginduced peripheral neuropathies in cancer patients need to be differentiated from paraneoplastic syndromes.62

MANAGEMENT The initial approach toward the patient with a chemotherapeutic agent overdose requires the stabilization of immediate life-threatening findings. These include dysrhythmias, congestive heart failure, seizures, and complications of pancytopenia (e.g., sepsis). Furosemide, inotropic agents, and fluid restriction can be used to treat heart failure. Uncontrolled hypertension can be managed with a peripheral vasodilating agent, such as a calcium channel blocker. This may be necessary because vincristine toxicity central autonomic instability can occur in this setting. Seizures can be treated with benzodiazepines, barbiturates, and phenytoin. For busulfan, phenytoin is used in a prophylactic manner during highdose therapy (>16 mg/kg). Methylene blue (50 mg IV as a 1% solution) is used to treat encephalopathy from ifosfamide, and it was attributed to an improved patient outcome in a small case series.63 Blood product replacement may be necessary because of either anemia or thrombocytopenia. In order to protect febrile neutropenic patients from overwhelming sepsis, granulocyte colonystimulating factor, reverse isolation, and broad-spectrum antibiotics will be necessary. There are two events when decontamination is important, and they are oral and IT exposures. The application of gut decontamination is limited to only a few chemotherapeutic agents because of their availability as oral formulations. These include MTX, busulfan, melphalan, and chlorambucil. The oral administration of activated charcoal is indicated when patients present in a timely manner following the ingestion. Repeat doses of activated charcoal can be used in the setting of delayed MTX elimination (e.g., renal failure) to limit enterohepatic recirculation of the drug.64 As for IT overexposures, it is imperative to decontaminate immediately the cerebrospinal space so that the maximal amount of drug can be removed. IT decontamination consists of CSF drainage, lavage of the cerebrospinal


933

space, and ventriculolumbar perfusion.47 The volume of CSF that can be safely removed at one time is dependent on the age of the patient. For an adult, up to 75 mL can be removed and replaced with an equal volume of Ringer’s lactate. Cerebrospinal space lavage is accomplished by exchanging CSF with isotonic saline or lactated Ringer’s mixed with fresh-frozen plasma to minimize protein loss from the CSF. Patients need to be adequately hydrated to promote renal perfusion because they are at risk for volume depletion from gastrointestinal fluid loss. Specific approaches to limit renal toxicity by stabilizing either parent drug or metabolite are recommended for cisplatin and MTX. Sodium chloride promotes the anionic state of cisplatin and decreases urine platinum concentrations to limit renal toxicity.65,66 Therapy with 0.9% saline hydration and osmotic diuresis with mannitol to achieve a urinary output of 1 to 3 mL/kg/hr for 6 to 24 hours is recommended. It is important to maintain urinary output because platinum renal elimination is dependent on urine flow and not on creatinine clearance.67 For MTX, the patient needs to be adequately hydrated and the urine alkalinized to limit renal toxicity from the precipitation of drug metabolite.68 The urine pH should be maintained at >7.0, which can be accomplished with a sodium bicarbonate infusion. Baseline studies should be obtained upon initial evaluation of the patient, and they include complete blood count, serum electrolytes, BUN, creatinine, liver function tests (i.e., aspartate transaminase, alanine transaminase, lactate dehydrogenase, alkaline phosphatase, bilirubin), prothrombin time/partial thromboblastin time, urine analysis, and electrocardiogram. If the woman may be pregnant, a pregnancy test is necessary to evaluate the consequences of the exposure to the pregnancy. Trace elements such as magnesium should be monitored in the setting of cisplatin toxicity because renal wasting can lead to hypomagnesemia. In general, hematologic indices should be followed weekly for up to 2 weeks after hospital discharge of the patient because myelosuppression may not present until weeks after the exposure. For many of the chemotherapeutic agents, patients with an excessive exposure will require intensive management for their condition. This will include close and constant monitoring for existing and evolving toxicities (e.g., cardiac, CNS, renal), or treatment with either rescue agents or the use of enhanced elimination therapy. Thus, these patients need to be admitted to the area in the hospital that can provide them with the appropriate level of care. Drug levels are infrequently monitored during chemotherapy and thus are not available in the routine clinical setting. However, MTX is an exception, and drug levels are monitored to assist patient management in the course of therapy. A serum MTX level should be obtained initially and repeated at 24 and 48 hours to determine the risk for toxicity and the duration of leucovorin treatment. An MTX half-life greater than 3.5 hours within the first 24 hours of exposure or a serum MTX level greater than 5 μmol/L at 28 hours postexposure is associated with increased risk for toxicity.

934


MTX CSF levels can assist in evaluating symptomatic patients at risk for neurotoxicity (e.g., prior meningeal disease) from either an overdose or a CSF outflow obstruction. In both cases, the CSF MTX level would be elevated. The common clinical method for measuring MTX is the fluorescence polarization immunoassay (TDx), which has a level of sensitivity of 0.01 μmol/L and can accept various biologic specimens (e.g., plasma, serum, urine, and CSF). The notable interferents with this method are MTX metabolites, such as 7OHMTX and DAMPA.

Rescue Agents Rescue agents or chemoprotectants69 are medications that limit host toxicity from the effects of drugs used in chemotherapy. The role for rescue agents in the management of patients with chemotherapeutic agent toxicity is limited because of the few drugs available and the need to use them in a timely manner. These rescue agents were designed for pretreatment and not posttreatment therapy. Thus, when an exposure is recognized, it is important to administer the rescue agent immediately once the decision is made to use it. Rescue agents are available for MTX (folinic acid, carboxypeptidase), cisplatin (amifostine, thiosulfate), and the anthracycline antibiotics (dexrazoxane). Although glutamic acid is not considered a rescue agent because of its nonspecific activity, it has been used during vincristine therapy to limit peripheral neuropathy based on animal evidence.70 Patients treated with glutamic acid were observed to have improved deep tendon reflex and sensory responses,71 and a shorter duration of myelosuppression.72 The therapy is benign and should be offered to overdosed patients. The dose for glutamic acid is 500 mg every 8 hours, by mouth or IV. Folinic acid (leucovorin) is used to limit the toxic effects of MTX on host cells by allowing for the continuation of biochemical processes that are dependent on tetrahydrofolate. Tetrahydrofolate is necessary for single carbon transfer reactions that are critical to the formation of certain amino acids, purine nucleotides, and thymidylate. The latter two products are necessary for the synthesis of DNA and RNA. MTX blocks the reduction of dihydrofolate to tetrahydrofolate by inhibiting DHFR. The addition of reduced folate analogs (e.g., folinic acid [5-formyl-5,6,7,8-tetrahydro-folic acid]) allows for continued cell function and survival by bypassing this enzymatic blockade. The beneficial effects of folinic acid have been demonstrated to decrease gastrointestinal mucosal disruption and bone marrow– suppressive effects during high-dose MTX therapy. The use of folinic acid is indicated when the serum MTX level is anticipated to be greater than 0.01 μmol/L, which can occur during high-dose MTX therapy, in the overdosed patient or in a patient with delayed MTX elimination. Although the effective MTX concentration to inhibit DHFR is 0.5 μmol/L, it is generally accepted that a level of 0.01 μmol/L is not likely to have any toxicologic effects, and folinic acid rescue treatment is recommended until this level is achieved. The IV route of administration is

preferred for folinic acid in the acute setting or in the patient with toxic manifestations. This is because of the efficiency of drug administration and the limitations associated with the oral route in this setting. These include incomplete gut absorption73 and lack of compliance, which can result in the patient with mucosal ulcerations. The dose of folinic acid is from 15 to 25 mg orally, and up to 1000 mg/m2 IV, and is administered every 6 to 8 hours. When 100 mg/m2 folinic acid was administered IV over 4 hours, it achieved a steady-state reduced folate level of 4 μmol/L.74 Folinic acid should be administered IV during IT MTX overexposures to limit systemic toxicity from the distribution of MTX from the cerebrospinal space to the systemic circulation. Folinic acid is not to be administered intrathecally for IT MTX overdoses because this route of administration was associated with a fatal outcome.75 Serum MTX levels should be monitored daily to determine adjustments in dose and therapeutic end point during the use of folinic acid. Folinic acid therapy is benign, and treatment should not be delayed in anticipation of a serum MTX level in patients with an MTX overdose. Carboxypeptidase (NSC-641273) is a bacterial enzyme that effectively deactivates MTX by cleaving the glutamyl residue. This rescue agent is under investigatory use to degrade MTX during situations of host toxicity. Carboxypeptidase has been used systemically (i.e., IV) and in the cerebrospinal space for IT overdoses with success.43 This agent is made available through the National Institutes of Health, and the indications for use include renal failure and an elevated serum MTX level76 or IT overdoses (protocol number 92-C-0137). The contact information is as follows: Clinical Studies Support Center/National Cancer Institute, telephone (888) 6241937, fax (301) 881-8239, website http://ccr.ncifcrf.gov/ trials/cssc/patients/search.asp, and e-mail address ncicssc @mail.nih.gov. A limitation to the use of carboxypeptidase is host sensitization, which has not been previously described. Amifostine (Ethyol, MedImmune Oncology, Inc., Gaithersburg, MD), and sodium thiosulfate are thiol agents that have been clinically used to limit cisplatininduced nephrotoxicity. Although only amifostine is approved by the Food and Drug Administration to protect against nephrotoxicity, the mechanism by which these thiol agents work to counteract cisplatin are different. Thiol agents have long been studied for their protective effects from cisplatin toxicity. Several mechanisms are proposed by which these agents elicit their protection, and they include binding to reactive cisplatin intermediates, scavenging for free radicals, or regenerating intracellular glutathione.77 Amifostine is an organic thiol agent and is activated by intracellular alkaline phosphatase. It is most effective when administered prior to cisplatin, and may offer additional beneficial effects by limiting myelosuppression, mucositis, and neuro-toxicity.78,79 Amifostine administration can cause hypotension; thus, the patient needs adequate hydration and frequent blood pressure monitoring during the use of this drug. Sodium thiosulfate works by binding to extracellular protein unbound platinum species, which limits the metal’s

CHAPTER 56

deposition in the renal tubules to cause damage.58 There is some evidence that thiosulfate may limit neurotoxicity from cisplatin as well.80,81 Thiosulfate needs to be administered soon after cisplatin exposure to obtain maximal benefit, and as an infusion because of its short plasma half-life (approximately 20 minutes). When thiosulfate was administered as an IV bolus of 4 g/m2 and continued as an infusion of 12 g/m2 over 6 hours, it was shown to limit renal toxicity in patients receiving cisplatin at a dose as high as 270 mg/m2.82,83 BNP7787 is a disulfide of MESNA and is being investigated as another thiol rescue agent for cisplatin toxicity. In controlled animal trials, BNP7787 was shown to limit cisplatin-induced nephrotoxicity and myelosuppression.84 Dexrazoxane is used to limit cardiotoxicity during doxorubicin therapy of women with breast cancer and who are receiving doses higher than 300 mg/m2. This agent is a cyclic analog of ethylenediaminetetra-acetic acid (EDTA) and forms an intracellular intermediate to chelate iron to interrupt the formation of free radicals responsible for cardiotoxicity. Dexrazoxane treatment is associated with improved left ventricular ejection fraction and decreased incidence of congestive heart failure following doxorubicin therapy.85 During chemotherapy, dexrazoxane is administered 30 minutes prior to doxorubicin treatment, and in a dose ratio of 10:1. Although further investigations are necessary to define the role of this rescue agent in the overdose setting, its use may benefit patients with doxorubicin overdoses, and the oncologist should be consulted on this topic. Amifostine86 and monohyroxyethylrutoside87 are being considered as new rescue agents to protect patients from the cardiotoxic effects of the anthracycline agents.

Enhanced Elimination The application of enhanced elimination for patients with chemotherapeutic agent overdoses is based on the limited experience and variable success with a few agents. These include busulfan, ifosfamide, cisplatin, doxorubicin, mitoxantrone, MTX, and vincristine. The factors significantly contributing to the effectiveness of these approaches include timeliness of intervention and the extent of either tissue binding or tissue distribution by the chemotherapeutic agent. The protein-binding capacity of the agent is important when hemodialysis is being considered. Hemodialysis has been used to enhance the elimination of busulfan in renal failure patients during therapy88,89 and in an overdosed patient. This procedure may be effective for ifosfamide exposures90 as well. In a 4.6-kg infant who received a four fold overdose of busulfan tablets, hemodialysis was instituted at 9 hours following exposure and continued for 3 hours at a flow rate of 68.3 mL/min.5 During hemodialysis, the plasma half-life for busulfan was 1 hour and the clearance was 61 mL/min/kg, which were improved from the pretreatment values of 1.6 hours and 41 mL/min/kg, respectively. Hemoperfusion is the preferred method for the enhanced elimination of MTX because of its greater efficiency compared to hemodialysis.91 Hemodialysis


935

should be reserved for patients with both an elevated serum MTX level and renal failure because MTX is efficiently eliminated by normal functioning kidneys.92,93 At 24 hours, about 85% of MTX administered IV is eliminated by the body. Delayed endogenous clearance of MTX occurs when the creatinine clearance is less than 60 mL/m2/min. Hemoperfusion may be effective in removing doxorubicin because it was shown to increase doxorubicin clearance by 20-fold in animal experiments,94 and to rapidly decrease serum drug levels in patients with doxorubicin overdoses.95 However, hemoperfusion was less successful in removing mitoxantrone in an overdosed patient even though it was initiated within hours of the drug’s administration.96 The lack of efficacy in this latter situation may be attributed to this drug’s extensive tissue-binding capacity or tissue distribution. Plasmapheresis is best used to enhance the elimination of chemotherapeutic agents with a high capacity for protein binding. Plasmapheresis is the preferred approach to remove cisplatin because it was shown to be more effective than hemodialysis,52,97-99 and associated with improved symptoms following a decline in plasma drug level.52 In an event where a patient received 400 mg/m2 of cisplatin, plasmapheresis was initiated the day after drug exposure and continued for 12 days for a total of nine sessions. The plasma cisplatin level declined from 2470 ng/mL to 216 ng/mL, and the patient’s mental status improved after the fifth session.52 Plasmapheresis should be initiated soon after the exposure to limit further distribution of cisplatin into the intracellular space, but can still be of benefit when administered days after the initial exposure.67 For vincristine overdoses, plasmapheresis100,101 and exchange transfusion72 have been demonstrated to lower plasma drug levels and, possibly, shorten the duration of toxicity. Plasmapheresis and exchange transfusion were initiated at 6 hours postexposure, and drug levels decreased from pretreatment levels by 23% and 65%, respectively. It is important to institute these procedures soon after exposure to maximize removal of the drug while it remains in the blood compartment.

SUMMARY Chemotherapeutic agent overdoses are associated with high morbidity and mortality because of the cell-specific mechanism of action and the narrow therapeutic window of the drugs in this class. The causes of the exposure are typically iatrogenic and involve several mechanisms that can be categorized as errors in either dosage regimen or drug preparation. The manifestations of toxicity common to these agents include pancytopenia, nausea, vomiting, mucositis, and alopecia. The presence of additional clinical findings, such as cardiac dysrhythmias and failure, renal insufficiency, seizures, peripheral neuropathies, and electrolyte abnormalities will vary by the chemotherapeutic agent. The management of these patients includes stabilization of immediate life-threatening disorders, decontamination,

936


administration of rescue agents, and institution of enhanced elimination. Despite all of these modalities, prevention remains the best treatment for these patients. This chapter was written by Richard Y. Wang in his private capacity. No official support or endorsement by the CDC is intended or should be inferred. REFERENCES 1. Einhorn J: Nitrogen mustard: the origin of chemotherapy for cancer. Int J Radiat Oncol Biol Phys 1985;11(7):1375–1378. 2. Angier RB, Boothe JH, Hutching BL, et al: The structure and synthesis of the liver L. casei factor. Science 1946;103:667–669. 3. Du XL, Osborne C, Goodwin JS: Population-based assessment of hospitalizations for toxicity from chemotherapy in older women with breast cancer. J Clin Oncol 2002;20(24):4636–4642. 4. Royal W 3rd, Dupont B, McGuire D, et al: Topotecan in the treatment of acquired immunodeficiency syndrome-related progressive multifocal leukoencephalopathy. J Neurovirol 2003; 9(3):411–419. 5. Stein J, Davidovitz M, Yaniv I, et al: Accidental busulfan overdose: enhanced drug clearance with hemodialysis in a child with WiskottAldrich syndrome. Bone Marrow Transplant 2001;27(5):551–553. 6. Steger GG, Mader RM, Gnant MF, et al: GM-CSF in the treatment of a patient with severe methotrexate intoxication. J Intern Med 1993;233(6):499–502. 7. Jirillo A, Gioga G, Bonciarelli G, Dalla Valle G: Accidental overdose of melphalan per os in a 69-year-old woman treated for advanced endometrial carcinoma. Tumori 1998;84(5):611. 8. de Forni M, Malet-Martino MC, Jaillais P, et al: Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study. J Clin Oncol 1992;10(11):1795–1801. 9. Pratt CB, Ransom JL, Evans WE: Age-related adriamycin cardiotoxicity in children. Cancer Treat Rep 1978;62(9):1381–1385. 10. Von Hoff DD, Layard MW, Basa P, et al: Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979;91(5):710–717. 11. Michelotti A, Venturini M, Tibaldi C, et al: Single agent epirubicin as first line chemotherapy for metastatic breast cancer patients. Breast Cancer Res Treat 2000;59(2):133–139. 12. Bristow MR: Toxic cardiomyopathy due to doxorubicin. Hosp Pract (Off Ed) 1982;17(12):101–108, 110–111. 13. Steinberg JS, Cohen AJ, Wasserman AG, et al: Acute arrhythmogenicity of doxorubicin administration. Cancer 1987;60(6): 1213–1218. 14. Wortman JE, Lucas VS Jr, Schuster E, et al: Sudden death during doxorubicin administration. Cancer 1979;44(5):1588–1591. 15. Schwartz CL, Hobbie WL, Truesdell S, et al: Corrected QT interval prolongation in anthracycline-treated survivors of childhood cancer. J Clin Oncol 1993;11(10):1906–1910. 16. Lefrak EA, Pitha J, Rosenheim S, et al: A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer 1973;32(2):302–314. 17. Von Hoff DD, Rozencweig M, Piccart M: The cardiotoxicity of anticancer agents. Semin Oncol 1982;9(1):23–33. 18. Jensen BV, Skovsgaard T, Nielsen SL: Functional monitoring of anthracycline cardiotoxicity: a prospective, blinded, long-term observational study of outcome in 120 patients. Ann Oncol 2002;13(5):699–709. 19. Siegert W, Hiddemann W, Koppensteiner R, et al: Accidental overdose of mitoxantrone in three patients. Med Oncol Tumor Pharmacother 1989;6(4):275–278. 20. Gbadamosi J, Munchau A, Weiller C, Schafer H: Severe heart failure in a young multiple sclerosis patient. J Neurol 2003; 250(2):241–242. 21. Roush W: Dana-Farber death sends a warning to research hospitals. Science 1995;269(5222):295–296. 22. Mills BA, Roberts RW: Cyclophosphamide-induced cardiomyopathy: a report of two cases and review of the English literature. Cancer 1979;43(6):2223–2226. 23. Appelbaum F, Strauchen JA, Graw RG Jr, et al: Acute lethal carditis caused by high-dose combination chemotherapy. A unique clinical and pathological entity. Lancet 1976;1(7950):58–62.

24. Braverman AC, Antin JH, Plappert MT, et al: Cyclophosphamide cardiotoxicity in bone marrow transplantation: a prospective evaluation of new dosing regimens. J Clin Oncol 1991;9(7): 1215–1223. 25. Kumar S, Gupta RK, Bhake AS, Samal N: Cardiotoxic effects of high doses of cyclophosphamide in albino rats. Arch Int Pharmacodyn Ther 1992;319:58–65. 26. Steinherz LJ, Steinherz PG, Mangiacasale D, et al: Cardiac changes with cyclophosphamide. Med Pediatr Oncol 1981;9(5):417–422. 27. Tsavaris N, Kosmas C, Vadiaka M, et al: Cardiotoxicity following different doses and schedules of 5-fluorouracil administration for malignancy—a survey of 427 patients. Med Sci Monit 2002;8(6): PI51–PI57. 28. Millart H, Brabant L, Lorenzato M, et al: The effects of 5fluorouracil on contractility and oxygen uptake of the isolated perfused rat heart. Anticancer Res 1992;12(2):571–576. 29. Gorgulu S, Celik S, Tezel T: A case of coronary spasm induced by 5-fluorouracil. Acta Cardiol 2002;57(5):381–383. 30. Arellano M, Malet-Martino M, Martino R, Gires P: The anti-cancer drug 5-fluorouracil is metabolized by the isolated perfused rat liver and in rats into highly toxic fluoroacetate. Br J Cancer 1998;77(1):79–86. 31. Brock N, Stekar J, Pohl J, et al: Acrolein, the causative factor of urotoxic side-effects of cyclophosphamide, ifosfamide, trofosfamide and sufosfamide. Arzneimittelforschung 1979;29(4):659–661. 32. Kupfer A, Aeschlimann C, Wermuth B, Cerny T: Prophylaxis and reversal of ifosfamide encephalopathy with methylene-blue. Lancet 1994;343(8900):763–764. 33. Goren MP, Wright RK, Pratt CB, Pell FE: Dechloroethylation of ifosfamide and neurotoxicity. Lancet 1986;2(8517):1219–1220. 34. Ammenti A, Reitter B, Muller-Wiefel DE: Chlorambucil neurotoxicity: report of two cases. Helv Paediatr Acta 1980;35(3):281–287. 35. Byrne TN Jr, Moseley TA 3rd, Finer MA: Myoclonic seizures following chlorambucil overdose. Ann Neurol 1981;9(2):191–194. 36. Hurwitz RL, Mahoney DH Jr, Armstrong DL, Browder TM: Reversible encephalopathy and seizures as a result of conventional vincristine administration. Med Pediatr Oncol 1988;16(3):216–219. 37. Johnson FL, Bernstein ID, Hartmann JR, Chard RL Jr: Seizures associated with vincristine sulfate therapy. J Pediatr 1973;82(4): 699–702. 38. Kaufman IA, Kung FH, Koenig HM, Giammona ST: Overdosage with vincristine. J Pediatr 1976;89(4):671–674. 39. Stones DK: Vincristine overdosage in paediatric patients. Med Pediatr Oncol 1998;30(3):193. 40. Rosenthal S, Kaufman S: Vincristine neurotoxicity. Ann Intern Med 1974;80(6):733–737. 41. Weiss HD, Walker MD, Wiernik PH: Neurotoxicity of commonly used antineoplastic agents. N Engl J Med 1974;291(2):75–81 42. Pirzada NA, Ali II, Dafer RM: Fluorouracil-induced neurotoxicity. Ann Pharmacother 2000;34(1):35–38. 43. O’Marcaigh AS, Johnson CM, Smithson WA, et al: Successful treatment of intrathecal methotrexate overdose by using ventriculolumbar perfusion and intrathecal instillation of carboxypeptidase G2. Mayo Clin Proc 1996;71(2):161–165. 44. Gowan GM, Herrington JD, Simonetta AB: Methotrexate-induced toxic leukoencephalopathy. Pharmacotherapy 2002;22(9):1183–1187. 45. Allen JC, Rosen G, Mehta BM, Horten B: Leukoencephalopathy following high-dose iv methotrexate chemotherapy with leucovorin rescue. Cancer Treat Rep 1980;64(12):1261–1273. 46. Fernandez CV, Esau R, Hamilton D, et al: Intrathecal vincristine: an analysis of reasons for recurrent fatal chemotherapeutic error with recommendations for prevention. J Pediatr Hematol Oncol 1998;20(6):587–590. 47. Riva L, Conter V, Rizzari C, et al: Successful treatment of intrathecal methotrexate overdose with folinic acid rescue: a case report. Acta Paediatr 1999;88(7):780–782. 48. Alcaraz A, Rey C, Concha A, Medina A: Intrathecal vincristine: fatal myeloencephalopathy despite cerebrospinal fluid perfusion. J Toxicol Clin Toxicol 2002;40(5):557–561. 49. Iqbal Y, Abdullah MF, Turner C, Al-Sudairy R: Intrathecal vincristine: long-term survivor of potentially fatal chemotherapeutic error. Ann Saudi Medicine 2002;22(1):108. 50. Dettmeyer R, Driever F, Becker A, et al: Fatal myeloencephalopathy due to accidental intrathecal vincristin administration: a report of two cases. Forensic Sci Int 2001;122(1):60–64.

CHAPTER 56

51. Holland JF, Scharlau C, Gailani S, et al: Vincristine treatment of advanced cancer: a cooperative study of 392 cases. Cancer Res 1973;33(6):1258–1264. 52. Choi JH, Oh JC, Kim KH, et al: Successful treatment of cisplatin overdose with plasma exchange. Yonsei Med J 2002;43(1): 128–132. 53. Legha SS: Vincristine neurotoxicity. Pathophysiology and management. Med Toxicol 1986;1(6):421–427. 54. Sandler SG, Tobin W, Henderson ES: Vincristine-induced neuropathy. A clinical study of fifty leukemic patients. Neurology 1969;19(4):367–374. 55. Katz BJ, Ward JH, Digre KB, et al: Persistent severe visual and electroretinographic abnormalities after intravenous cisplatin therapy. J Neuroophthalmol 2003;23(2):132–135. 56. Bleyer WA: New vistas for leucovorin in cancer chemotherapy. Cancer 1989;63(6 Suppl):995–1007. 57. Choie DD, Longnecker DS, del Campo AA: Acute and chronic cisplatin nephropathy in rats. Lab Invest 1981;44(5):397–402. 58. Erdlenbruch B, Pekrun A, Schiffmann H, et al: Topical topic: accidental cisplatin overdose in a child: reversal of acute renal failure with sodium thiosulfate. Med Pediatr Oncol 2002; 38(5):349–352. 59. Favier M, de Cazanove F, Saint-Martin F, Bressolle F: Preventing medication errors in antineoplastic therapy. Am J Hosp Pharm 1994;51(6):832–833. 60. American Society of Health-System Pharmacists (ASHP) Council on Professional Affairs: ASHP guidelines on preventing medication errors with antineoplastic agents. Am J Health Syst Pharm 2002;59(17):1648–1668. 61. Desai ZR, Van den Berg HW, Bridges JM, Shanks RG: Can severe vincristine neurotoxicity be prevented? Cancer Chemother Pharmacol 1982;8(2):211–214. 62. Grisold W, Drlicek M: Paraneoplastic neuropathy. Curr Opin Neurol 1999;12(5):617–625. 63. Pelgrims J, De Vos F, Van den Brande J, et al: Methylene blue in the treatment and prevention of ifosfamide-induced encephalopathy: report of 12 cases and a review of the literature. Br J Cancer 2000;82(2):291–294. 64. Gadgil SD, Damle SR, Advani SH, Vaidya AB: Effect of activated charcoal on the pharmacokinetics of high-dose methotrexate. Cancer Treat Rep 1982;66(5):1169–1171. 65. Al-Sarraf M, Fletcher W, Oishi N, et al: Cisplatin hydration with and without mannitol diuresis in refractory disseminated malignant melanoma: a Southwest Oncology Group study. Cancer Treat Rep 1982;66(1):31–35. 66. Vogl SE, Zaravinos T, Kaplan BH: Toxicity of cis-diamminedichloroplatinum II given in a two-hour outpatient regimen of diuresis and hydration. Cancer 1980;45(1):11–15. 67. Chu G, Mantin R, Shen YM, Baskett G, et al: Massive cisplatin overdose by accidental substitution for carboplatin. Toxicity and management. Cancer 1993;72(12):3707–3714. 68. Christensen ML, Rivera GK, Crom WR, et al: Effect of hydration on methotrexate plasma concentrations in children with acute lymphocytic leukemia. J Clin Oncol 1988;6(5):797–801. 69. Schuchter LM, Hensley ML, Meropol NJ, Winer EP: American Society of Clinical Oncology Chemotherapy and Radiotherapy Expert Panel. 2002 update of recommendations for the use of chemotherapy and radiotherapy protectants: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2002;20(12):2895–2903. 70. Boyle FM, Wheeler HR, Shenfield GM: Glutamate ameliorates experimental vincristine neuropathy. J Pharmacol Exp Ther 1996;279(1):410–415. 71. Jackson DV, Wells HB, Atkins JN, et al: Amelioration of vincristine neurotoxicity by glutamic acid. Am J Med 1988;84(6):1016–1022. 72. Kosmidis HV, Bouhoutsou DO, Varvoutsi MC, et al: Vincristine overdose: experience with 3 patients. Pediatr Hematol Oncol 1991;8(2):171–178. 73. Straw JA, Szapary D, Wynn WT: Pharmacokinetics of the diastereoisomers of leucovorin after intravenous and oral administration to normal subjects. Cancer Res 1984;44(7): 3114–3119. 74. Mehta BM, Glass JP, Shapir WR: Serum and cerebrospinal fluid distribution of 5-methyltetrahydrofolate after intravenous calcium leucovorin and intra-Ommaya methotrexate administration in


75. 76.

77. 78.

79. 80. 81.

82.

83. 84.

85.

86. 87.

88. 89. 90.

91. 92. 93. 94. 95. 96.

937

patients with meningeal carcinomatosis. Cancer Res 1983;43: 435–438. Jardine LF, Ingram LC, Bleyer WA: Intrathecal leucovorin after intrathecal methotrexate overdose. J Pediatr Hematol Oncol 1996;18(3):302–304. Windemann BC, Balis FM, Murphy RF, et al: CarboxypeptidaseG2, thymidine, and leucovorin rescue in cancer patients with methotrexate-induced renal dysfunction. J Clin Oncol 1997; 15(5):2125–2134. Korst AE, Eeltink CM, Vermorken JB, van der Vijgh WJ: Pharmacokinetics of amifostine and its metabolites in patients. Eur J Cancer 1997;33(9):1425–1429. Kemp G, Rose P, Lurain J, et al: Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatininduced toxicities: results of a randomized control trial in patients with advanced ovarian cancer. J Clin Oncol 1996;14(7): 2101–2112. Alberts DS, Bleyer WA: Future development of amifostine in cancer treatment. Semin Oncol 1996;23(4 Suppl 8):90–99. Markman M, Cleary S, Pfeifle CE, Howell SB: High-dose intracavitary cisplatin with intravenous thiosulfate. Low incidence of serious neurotoxicity. Cancer 1985;56(10):2364–2368. van Rijswijk RE, Hoekman K, Burger CW, et al: Experience with intraperitoneal cisplatin and etoposide and i.v. sodium thiosulphate protection in ovarian cancer patients with either pathologically complete response or minimal residual disease. Ann Oncol 1997;8(12):1235–1241. Hirosawa A, Niitani H, Hayashibara K, Tsuboi E: Effects of sodium thiosulfate in combination therapy of cis-dichlorodiammineplatinum and vindesine. Cancer Chemother Pharmacol 1989; 23(4):255–258. Pfeifle CE, Howell SB, Felthouse RD, et al: High-dose cisplatin with sodium thiosulfate protection. J Clin Oncol 1985;3(2):237–244. Hausheer FH, Kanter P, Cao S, et al: Modulation of platinuminduced toxicities and therapeutic index: mechanistic insights and first- and second-generation protecting agents. Semin Oncol 1998;25(5):584–599. Speyer JL, Green MD, Kramer E, et al: Protective effect of the bispiperazinedione ICRF-187 against doxorubicin-induced cardiac toxicity in women with advanced breast cancer. N Engl J Med 1988;319(12):745–752. Catino A, Crucitta E, Latorre A, et al: Amifostine as chemoprotectant in metastatic breast cancer patients treated with doxorubicin. Oncol Rep 2003;10(1):163–167. van Acker FA, van Acker SA, Kramer K, et al: 7-monohydroxyethylrutoside protects against chronic doxorubicin-induced cardiotoxicity when administered only once per week. Clin Cancer Res 2000;6(4):1337–1341. Masauzi N, Higa T, Nakagawa S, et al: Pharmacokinetic study of busulfan in an AML patient treated with regular hemodialysis. Ann Hematol 1998;77(6):293–294. Ullery LL, Gibbs JP, Ames GW, et al: Busulfan clearance in renal failure and hemodialysis. Bone Marrow Transplant 2000;25(2): 201–203. Carlson L, Goren MP, Bush DA, et al: Toxicity, pharmacokinetics, and in vitro hemodialysis clearance of ifosfamide and metabolites in an anephric pediatric patient with Wilms’ tumor. Cancer Chemother Pharmacol 1998;41(2):140–146. Relling MV, Stapleton FB, Ochs J, et al: Removal of methotrexate, leucovorin, and their metabolites by combined hemodialysis and hemoperfusion. Cancer 1988;62(5):884–888. Saland JM, Leavey PJ, Bash RO, et al: Effective removal of methotrexate by high-flux hemodialysis. Pediatr Nephrol 2002; 17(10):825–829. Wall SM, Johansen MJ, Molony DA, et al: Effective clearance of methotrexate using high-flux hemodialysis membranes. Am J Kidney Dis 1996;28(6):846–854. Winchester JF, Rahman A, Tilstone WJ, et al: Will hemoperfusion be useful for cancer chemotherapeutic drug removal? Clin Toxicol 1980;17(4):557–569. Curran CF: Acute doxorubicin overdoses. Ann Intern Med 1991;115(11):913–914. Hachimi-Idrissi S, Schots R, DeWolf D, et al: Reversible cardiopathy after accidental overdose of mitoxantrone. Pediatr Hematol Oncol 1993;10(1):35–40.

938


97. Brivet F, Pavlovitch JM, Gouyette A, et al: Inefficiency of early prophylactic hemodialysis in cisplatinum overdose. Cancer Chemother Pharmacol 1986;18(2):183–184. 98. Lagrange JL, Cassuto-Viguier E, Barbe V, et al: Cytotoxic effects of long-term circulating ultrafiltrable platinum species and limited efficacy of haemodialysis in clearing them. Eur J Cancer 1994; 30A(14):2057–2060. 99. Pike IM, Arbus MH: Cisplatin overdosage. J Clin Oncol 1992; 10(9):1503–1504.

B

Thalidomide MICHAEL W. SHANNON, MD, MPH

At a Glance… ■

■

■

100. Lotz JP, Chapiro J, Voinea A, et al: Overdosage of vinorelbine in a woman with metastatic non-small-cell lung carcinoma. Ann Oncol 1997;8(7):714–715. 101. Pierga JY, Beuzeboc P, Dorval T, et al: Favourable outcome after plasmapheresis for vincristine overdose. Lancet 1992;340(8812):185.

Thalidomide has many useful clinical properties, possessing sedative-hypnotic, antibiotic, anti-inflammatory, anti-angiogenesis, and immunomodulatory effects. It consequently has a wide range of potential clinical uses. Thalidomide is also a very potent teratogen, capable of producing birth defects after a single dose. The limb deformity phocomelia is the best characterized of thalidomide’s effects. Adverse effects of thalidomide when taken therapeutically include somnolence, rash (including Stevens-Johnson syndrome), peripheral neuropathy, and hepatotoxicity.

Thalidomide is one of the most notorious drugs ever created. The agent was used around the world for approximately 5 years before its role as a potent teratogen was recognized. Banned after producing a generation of children with severe birth defects, the drug began making a surprise comeback in the 1980s. In 1998, thalidomide was approved by the Food and Drug Administration (FDA) for use in erythema nodosum leprosum. Since that time, the drug’s list of clinical indications has proliferated as its broad range of pharmacologic actions are exploited to treat leprosy, multiple myeloma, leprosy, and many other disorders.

HISTORY Thalidomide was first released in Germany as the drug Contergan in 1956 and in England in 1958 as Distaval. Originally developed to be an antibiotic, it was found to have a useful sedative effect. It was approved as a sedative-hypnotic, safer than barbiturates and other central nervous system (CNS) depressants of its era. Its liquid form was often given to crying children, earning it the title “West Germany’s baby sitter.”1 Proving to be effective in hyperemesis gravidarum, it became a popular

drug for the nausea of pregnancy, with the added benefit of offering women a full night’s sleep. Having an excellent safety profile, its use rapidly grew; it quickly became the third largest selling drug in Europe; at its peak it was sold in 48 countries.2 In North America, it was used briefly in Canada as the drug Kevadon; for a brief period Kevadon was distributed illegally in the United States. However, when a new drug application to market Kevadon in the United States was filed with the FDA in 1960, the drug’s approval was deferred by Dr. Frances O. Kelsey because reports of thalidomide-associated peripheral neuropathy had begun to appear and because animal safety data seemed inadequate. As the FDA continued to seek more data, in November 1961 thalidomide’s role in causing phocomelia (“seal limb”) in the offspring of women who used the drug during pregnancy was reported almost simultaneously by Drs. Lenz in West Germany and McBride in Australia. The drug was promptly removed from the market. By 1962, phocomelia, amelia, and other birth defects in more than 12,000 children in 46 countries were attributed to thalidomide; at least 17 cases of phocomelia occurred in the United States.3 While phocomelia, an obvious and debilitating birth defect, became synonymous with thalidomide, cardiac defects and other anomalies were also found in the progeny of pregnant women who used thalidomide.4 Birth defects were associated with ingestion of as little as a single dose. After its worldwide withdrawal in 1961, the drug was shunned for only a few years. In 1965 its efficacy in the treatment of erythema nodosum leprosum (ENL) was discovered. After years of growing scientific interest, and drug research and development, in July 1998 the FDA approved thalidomide for the treatment of ENL, a debilitating condition associated with lepromatous leprosy. Soon thereafter it was shown to be valuable as a treatment for aphthous ulcers, leading to its approval for this indication in 2001. Once clinical and experimental data indicated that thalidomide was also a potent angiogenesis inhibitor, its clinical role expanded even

CHAPTER 56

BOX 56-1

POTENTIAL CLINICAL USES FOR THALIDOMIDE

Dermatologic

Digestive/Gastrointestinal

Prurigo nodularis Pyoderma gangrenosum Actinic prurigo Erythema multiforme Uremic pruritis Bullous pemphigoid Cicatricial pemphigoid Toxic epidermal necrolysis

Recurrent aphthous ulcers Ulcerative colitis Oncologic

Langerhans’ cell histiocytosis Multiple myeloma Lymphoma Prostate cancer Renal cell carcinoma

Autoimmune

Chronic graft-versus-host disease Lupus erythematosus Rheumatoid arthritis Cold hemagglutination disease Ankylosing spondylitis

Infectious

Postherpetic neuralgia

Erythema nodosum leprosum HIV-associated wasting syndrome Tuberculosis-associated weight loss HIV–associated proctitis HIV-associated Microsporidium diarrhea Hepatitis

Other

Vascular

Sarcoidosis Behçet’s disease

Diabetic retinopathy Macular degeneration

Neurologic

HIV, human immunodeficiency virus

more. Thalidomide is now used for a broad range of conditions (Box 56-1).

PHARMACOLOGY Thalidomide is a glutamic acid derivative. Its structure is shown in Figure 56-1. The agent is available in 50-, 100-, and 200-mg capsules. For most of its clinical uses, thalidomide is prescribed in a dose of 3 to 6 mg/kg/day, taken in one to four divided doses. Customary doses are 200 to 800 mg daily. Absorption of thalidomide from the gut is slow but extensive; a 200-mg dose produces a peak concentration of 1 to 2 mg/L at 3 to 4 hours.5 Distribution characteristics include plasma protein binding of approximately 60% and an apparent volume of distribution (Vd) of approximately 1 L/kg.5,6 Thalidomide is primarily biotransformed through spontaneous, nonenzymatic hydrolytic cleavage.5 The drug also undergoes metabolism by the cytochrome P-450 isoenzyme CYP2C19. Multiple metabolites have been identified; certain drug effects (e.g., antiangio-

K

N

K

K NH

J

J J

J

O

K

O

O O FIGURE 56-1 Thalidomide structure.


939

genesis activity) are attributed to its metabolites rather than to the parent drug. The drug’s elimination half-life is approximately 6 hours. Thalidomide metabolites are eliminated in urine and feces within 48 hours of a dose; there is little excretion of unchanged drug. Drug pharmacokinetics are not altered by repeat dosing. Thalidomide possesses no significant drug interactions. Having a broad range of clinical effects, thalidomide has unclear cellular mechanisms of action. However, on a macroscopic level, the drug appears to have four primary actions: (1) immunomodulatory, (2) anti-inflammatory,7-9 (3) antiangiogenesis, and (4) hypnosedative. Thalidomide is an immunostimulant, producing an increase in total lymphocyte count and CD8+ T cells. It also increases interferon-γ production2 while significantly lowering levels of circulating tumor necrosis factor-α (TNF-α, also referred to as cachectin). For many conditions, its efficacy is based on this action. For example, ENL is associated with high circulating levels of TNF-α; thalidomide’s efficacy correlates with falling TNF-α concentrations. Recurrent aphthous ulcers and Behçet’s disease, other conditions for which thalidomide is useful, are also associated with elevated circulating TNF-α.10,11 Sedative effects of the drug appear to have a mechanism different from barbiturates; rather than enhancing γaminobutyric acid (GABA)-mediated neurotransmission, thalidomide appears to activate sleep centers in the forebrain.5 Recent data also suggest that thalidomide is an inhibitor of nitric oxide synthase.12 Although thalidomide is FDA approved only for the treatment of recurrent aphthous ulcers and erythema nodosum leprosum, the range of disorders for which it has been used, with reported clinical benefit, is extensive (see Fig. 56B-1). It has been used successfully to treat infectious conditions such as HIV-associated wasting syndrome and tuberculosis-associated weight loss. It has also been used to treat chronic graft-versus-host disease. However, its most rapidly expanding use has been as a chemotherapeutic agent for select cancers, including multiple myeloma,13-16 prostate cancer, myelofibrosis, renal cell carcinoma, lymphoma, Kaposi’s sarcoma, and thyroid cancer.17 It has also been used to treat a number of autoimmune or idiopatic disorders, including ankylosing spondylitis, sarcoidosis,18 and inflammatory bowel disease.19,20

TOXICITY The mechanisms of thalidomide toxicity are equally unclear. By whatever mechanisms, the drug is associated with a very broad range of adverse effects (Box 56-2). These toxicities are found in those taking the drug chronically; acute single overdose of thalidomide appears to produce only mild sedation; ingestions of as much as 14 g have led to minimal toxicity.5 The adverse effects associated with chronic thalidomide use include somnolence, rash, fatigue, constipation, abdominal pain, Stevens-Johnson syndrome, elevated liver enzymes, and peripheral edema.8 Endocrine effects are also multiple and include hyperprolactinemia (with

940

BOX 56-2


ADVERSE CLINICAL EFFECTS ASSOCIATED WITH THALIDOMIDE

Neurobehavioral

Dermatologic

Dizziness Increased appetite Mood changes Peripheral neuropathy Sedation or drowsiness

Brittle fingernails Exfoliative dermatitis Face/limb edema Pruritus Red palms Stevens-Johnson syndrome

Digestive/Gastrointestinal

Elevated hepatic transaminases Constipation Nausea

Hematologic

Endocrinologic/Reproductive

Cardiovascular

Neutropenia Thrombocytopenic purpura

Antithyroid effect Allergic vasculitis Decreased libido Deep venous thrombosis Galactorrhea Thromboembolism Hyperprolactinemia Hypoglycemia Increased adrenocorticotropic hormone Menstrual abnormalities

accompanying galactorrhea), an antithyroid effect,21 and amenorrhea.22,23 Peripheral neuropathy has been a recognized adverse effect of thalidomide since it was first released. The neuropathy characteristically affects sensory rather than motor neurons and lower more than upper extremities.24 Victims often complain of distal lower extremity painful paresthesias. The neuropathy seems to be dose related, although dose-unrelated occurrences have also been reported.25 At-risk groups are females rather than males and the elderly. The neuropathy is partially reversible and can be either an axonal length–dependent neuropathy or a ganglionopathy.26 Other clinical toxicities include sinus bradycardia, particularly in those taking other medications that decrease heart rate,27 deep venous thrombosis, pulmonary embolus, and other thromboembolic events.28,29 As many as 30% of subjects must cease thalidomide use due to unacceptable adverse effects.30

TERATOGENICITY Thalidomide is a powerful teratogen, producing effects when taken during much of pregnancy, particularly days 34 to 50 after the final period. The main categories of thalidomide embryopathy include limb deformity, craniofacial defects (microtia or anotia, eye defects, choanal atresia), cardiac disturbances (ductus arteriosus, conotrocal defects, septal defects), intestinal disorders (duodenal atresia, anal atresia, pyloric stenosis), genitourinary tract abnormalities (ectopic kidney, vaginal duplication, renal/testicular agenesis), and lung abnormalities. Limb deformities such as phocomelia occurred

when women took any amount of thalidomide during the 20th to the 36th day of pregnancy. Most birth defects, including phocomelia, have been attributed to the drug’s antiangiogenesis effects. Thalidomide does not produce second-generation birth defects.31 When it approved thalidomide, the FDA and drug manufacturer instituted severe controls over the drug. To minimize the risk for birth defects, the FDA has mandated that physicians prescribing thalidomide be registered in the System for Thalidomide Education and Prescribing Safety (STEPS) program. Patients taking the drug must receive drug education and acknowledge that they received this education. Women must agree in writing to have no intercourse or to use two methods of birth control should they engage in intercourse. Women must also undergo periodic pregnancy tests.

MANAGEMENT Acute overdose of thalidomide should be treated with initial stabilization and supportive care. Sedation can be anticipated. Activated charcoal adsorbs thalidomide and is a potentially valuable intervention, particularly if administered within 1 to 2 hours of ingestion. There are no specific laboratory data that would be useful in the diagnosis and management of thalidomide toxicity. An electrocardiogram and an arterial blood gas or pulse oximetry with end-tidal CO2 monitoring can be useful adjuncts in management. Other tests (e.g., toxic screen testing) may be useful to rule out coingestions. There is no known method of enhancing the elimination of thalidomide; elimination enhancement should not be necessary since patients quickly recover without sequelae. A pregnancy test should be considered in women of childbearing age since thalidomide ingestion during pregnancy has grave implications that may require pregnancy counseling. Patients with acute overdose who are asymptomatic or who have only transient lethargy can be safely discharged from the emergency department with close follow-up. REFERENCES 1. McFadyen RE: Thalidomide in America: a brush with tragedy. Clio Med 1976;11:79–93. 2. Bernstein JR: Thalidomide. Clin Toxicol Rev 1999;21(5):1–3. 3. Taussig HB: Thalidomide and phocomelia. Pediatrics 1962; 30:654–659. 4. Taussig HB: The evils of camouflage as illustrated by thalidomide. N Engl J Med 1963;269:92–94. 5. Teo SK, Colburn WA, Tracewell WG, et al: Clinical pharmacokinetics of thalidomide. Clin Pharmacokinet 2004;43:311–327. 6. Eriksson T, Bjorkman S, Hoglund P: Clinical pharmacology of thalidomide. Eur J Clin Pharmacol 2001;57(5):365–376. 7. Nasca MR, Micali G, Cheigh NH, et al: Dermatologic and nondermatologic uses of thalidomide. Ann Pharmacother 2003;37(9): 1307–1320. 8. Laffitte D, Revuz J: Thalidomide, an old drug with new clinical applications. Exp Opin Drug Saf 2004;3:47–56. 9. Matthews SJ, McCoy C: Thalidomide: a review of approved and investigational uses. Clin Ther 2003;25(2):342–395. 10. Jacobson JM, Greenspan JS, Spritzler J, et al: Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. N Engl J Med 1997;336:1487–1493.

CHAPTER 56

11. Sayarlioglu M, Kotan MC, Topcu N, et al: Treatment of recurrent perforating intestinal ulcers with thalidomide in Behcet’s disease. Ann Pharmacother 2004;38(5):808–811. 12. Shimazawa R, Sano H, Tanatani A, et al: Thalidomide as a nitric oxide synthase inhibitor and its structural development. Chem Pharm Bull (Tokyo) 2004;52:498–499. 13. Kyle R, Rajkumar S: Multiple myeloma. N Engl J Med 2004;351: 1860–1873. 14. Ghobrial I, Rajkumar S: Management of thalidomide toxicity. J Supportive Oncol 2003;1:194–205. 15. Ribas C, Colleoni G: Advances in the treatment of multiple myeloma: the role of thalidomide. Leuk Lymphoma 2003;44:291–298. 16. Singhal S,Mehta J, Desikan R, et al: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999;341(21):1565–1571. 17. Joglekar S, Levin M: The promise of thalidomide: evolving indications. Drugs Today (Barc), 2004;40(3):197–204. 18. Baughman RP, Judson MA, Teirstein AS, et al: Thalidomide for chronic sarcoidosis. Chest 2002;122(1):227–232. 19. Bariol C, Meagher AP, Vickers CR, et al: Early studies on the safety and efficacy of thalidomide for symptomatic inflammatory bowel disease. J Gastroenterol Hepatol 2002;17(2):135–139. 20. Bousvaros A, Mueller B: Thalidomide in gastrointestinal disorders. Drugs 2001;61(6):777–787. 21. deSavary N, Lee R, Vaidya B: Severe hypothyroidism after thalidomide treatment. J R Soc Med 2004;97:422.


941

22. Dharia S, Steinkampf M, Cater C: Thalidomide-induced amenorrhea: case report and literature review. Fertil Steril 2004; 82:460–462. 23. Frances C, El Khoury S, Gompel A, et al: Transient secondary amenorrhea in women treated by thalidomide. Eur J Dermatol 2002;12(1):63–65. 24. Jones G: Thalidomide: 35 years on and still deforming. Lancet 1994;343:1041. 25. Chaudhry V, Cornblath DR, Corse A, et al: Thalidomide-induced neuropathy. Neurology 2002;59(12):1872–1875. 26. Isoardo G, Bergui M, Durelli L, et al: Thalidomide neuropathy: clinical, electrophysiological and neuroradiological features. Acta Neurol Scand 2004;109:188–193. 27. Kaur A, Yu SS, Lee AJ, Chiao TB: Thalidomide-induced sinus bradycardia. Ann Pharmacother 2003;37:1040–1043. 28. Bennett CL, Schumock GT, Desai AA, et al: Thalidomideassociated deep vein thrombosis and pulmonary embolism. Am J Med 2002;113(7):603–606. 29. Bowcock SJ, Rassam SM, Ward SM, et al: Thromboembolism in patients on thalidomide for myeloma. Hematology 2002;7(1): 51–53. 30. Gordon JN, Goggin PM: Thalidomide and its derivatives: emerging from the wilderness. Postgrad Med J 2003;79(929): 127–132. 31. Smithells D: Does thalidomide cause second generation birth defects? Drug Saf 1998;19(5):339–341.

57

Transplant Agents and Other Immunosuppressives SHARITA E. WARFIELD, MD, MS ■ MATTHEW W. HEDGE, MD

At a Glance… ■

■ ■

■

Transplant agents and other immunosuppressives are being used increasingly as the prevalence of solid organ and cell transplant recipients increases. All transplant agents have important drug–drug or drug–food interactions, requiring careful dosing and close monitoring. Tacrolimus and cyclosporine, the most common transplant agents, are metabolized by CYP3A3. Their metabolism can be significantly slowed in the presence of CYP3A inhibitors, leading to elevated concentrations and resulting toxicity. The major toxicity resulting from tacrolimus and cyclosporine overdose is renal injury.

Transplantation of vital organs such as the kidney, liver, pancreas, heart, and bone marrow is efficiently used as a form of treatment for end-stage organ disease. It is the role of the body’s immune system to discriminate between self and nonself cells in the body and destroy the nonself cells. When an organ transplant is introduced to the body, it is recognized as foreign. It is this response that leads to transplants being rejected. Historically, immunosuppressive agents have been used to ensure the success of organ transplantation. However, the use of these agents was not without consequence. Older agents used in single and multiple drug protocols had many undesirable effects. The discovery and refinement of current conventional immunosuppressive agents, which function in a nonspecific manner to suppress the immune system, has helped revolutionize the field of transplantation. Until recently, these agents provided the mainstay of clinical immunosuppression with antiproliferative activity. They included antimetabolites, alkylating agents, and irradiation. The current belief is that T lymphocytes are primarily responsible for graft rejection. The introduction of agents that specifically act on T lymphocytes (cyclosporine, tacrolimus [FK506], and azathioprine) dramatically changed the outcome after transplantation. The use of immunosuppressive agents extends beyond organ graft protection. Many newer agents have shown efficacy in the treatment of dermatologic disorders including seborrheic dermatitis, cutaneous lupus erythematous, vulvar lichen sclerosus, and vitiligo.1-4 Some older agents have shown efficacy in the treatment of the vasculitides, rheumatoid arthritis, and multiple sclerosis.5,6 In general, overdose of transplant agents is rare. However, increasing indications for the newer agents coupled with the occasional dosing errors with

the older agents have sparked an interest in better understanding the toxicity and adverse effects of these drugs.

TACROLIMUS (FK506) Pharmacology Tacrolimus (FK506) is a macrolide immunosuppressant derived from Streptomyces tsukubaensis. It has been used in liver, heart, kidney, and other experimental forms of transplantation. It is similar to cyclosporine in its mode of action, efficacy, and toxicity profile. The exact mechanism by which tacrolimus produces immunosuppression remains unknown. It is proposed that tacrolimus inhibits T-lymphocyte activation by binding to an intracellular protein, FKBP-12. A complex is formed between tacrolimus and FKBP-12, calcium, calmodulin, and calcineurin. This complex inhibits the phosphatase activity of calcineurin. The inhibition of calcineurin is believed to prevent the dephosphorylation and translocation of nuclear factor of activated T cells (NF-AT), which is the cellular component thought to initiate gene transcription for the formation of lymphokines such as interleukin-2 (IL-2) and interferon-γ. Tacrolimus also inhibits the transcription for genes that encode IL-3, IL4, IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor–α (TNF-α), all of which are involved in the early stages of T-cell activation. In addition, it inhibits the release of preformed mediators from skin mast cells and basophils, as well as potentiating the effects of corticosteroids.

Pharmacokinetics The pharmacokinetic profile of tacrolimus has been studied extensively in adults and children. Bioavailability after oral administration averages 17% to 22%. The presence of food, particularly a high-fat meal, decreases the rate and extent of tacrolimus absorption. Peak whole-blood levels are achieved within 1.5 to 3 hours after oral dosing.7,8 Tacrolimus is highly protein bound and also binds to erythrocytes and lymphocytes. The volume of distribution in adults is 1.4 to 1.9 L/kg; in children, it is 2.6 L/kg. Tacrolimus is primarily metabolized in the liver via cytochrome P-450 isoenzymes CYP3A4 and CYP3A5. The metabolites are eliminated in the bile at a rate of 0.04 to 0.08 L/kg/hr in adults and 0.14 L/kg/hr in children. The elimination of tacrolimus is not affected by renal or mild hepatic dysfunction; however, in patients with severe hepatic dysfunction or hepatitis C, the clearance rate is prolonged.7-11 943

944


Tacrolimus is available in the United States and Canada in three formulations: oral, parenteral, and a topical ointment. Dosage varies and is based on body weight. Typically for adults, teenagers, or children, the oral dose will be 0.1 to 0.3 mg/kg/day. The parenteral dose is 0.01 to 0.05 mg/kg/day. DRUG INTERACTIONS The metabolism of tacrolimus by CYP3A increases the risk of drug interactions when it is used with drugs that are also metabolized via the cytochrome P-450 enzyme system. A variety of drug classes cause increased tacrolimus concentrations, including antifungal agents, corticosteroids, calcium channel blockers, macrolide antibiotics, and gastrointestinal (GI) prokinetic agents. Other substances such as cyclosporine, metronidazole, cimetidine, and grapefruit juice may lead to decreased tacrolimus concentrations. Nephrotoxicity has been reported in patients taking tacrolimus; the concomitant use of other nephrotoxins such as amphotericin, aminoglycosides, cisplatin, or nonsteroidal anti-inflammatory agents (NSAIDs) may place the patient at increased risk for this adverse effect.7,8

Toxicology CLINICAL MANIFESTATIONS Data are limited on cases of overdoses with tacrolimus. However, chronic overdose is known to cause nephrotoxicity. This usually is manifested early in therapy as an increase in serum creatinine and a decrease in urine output. Dosage adjustment or discontinuation of therapy will usually reverse the nephrotoxic effect. Neurotoxicity, which appears more commonly in patients with elevated tacrolimus concentrations or hepatic dysfunction, has also been reported. In severe cases, it may manifest as seizures, delirium, or coma. Some individuals may have a genetic predisposition to developing tacrolimus-induced neurotoxicity.6 ADVERSE EFFECTS The most common adverse effects associated with tacrolimus are listed in Box 57-1. Type 1 diabetes mellitus develops in approximately 20% of patients taking tacrolimus. It appears to be more common in African Americans, in patients receiving high-dose corticosteroids, and in patients with elevated tacrolimus levels.7,8

Management Supportive care is the mainstay of therapy. A single dose of charcoal should be given after an acute overdose to help decrease absorption. Benzodiazepines can be used to treat agitation and seizures if they develop. Currently, no robust data support the use of multiple-dose activated charcoal or hemodialysis as treatment for tacrolimus overdose.

BOX 57-1

MOST COMMON ADVERSE EFFECTS ASSOCIATED WITH TACROLIMUS

CNS

Pulmonary

Tremor Confusion Headache Hallucinations Dizziness Asthenia Insomnia Agitation Seizures

Pleural effusion Edema Atelectasis

Metabolic

Dermatologic

Hyperkalemia Hypomagnesemia Hyperglycemia Hypertension

Rash Pruritus Alopecia

GI

Nausea Diarrhea Pain Constipation

AZATHIOPRINE Pharmacology Azathioprine was originally approved by the Food and Drug Administration (FDA) in 1968 for use as an adjunct immunosuppressant agent. It was often used in combination with corticosteroids for solid organ transplantation. In recent years, azathioprine use has markedly declined and has been replaced by mycophenolate. Azathioprine is a pro-drug that is converted in the body to 6-mercaptopurine (6-MP). 6-MP is a purine analog that acts as an antimetabolite immunosuppressive agent inhibiting T-cell proliferation by interfering with the synthesis of nucleotides. Azathioprine is also used to treat Crohn’s disease, lupus nephritis, rheumatoid arthritis, psoriasis, myasthenia gravis, and other autoimmune diseases.

Pharmacokinetics Orally, azathioprine is well absorbed. Azathioprine is rapidly eliminated from the blood and converted in the liver by xanthine oxidase to 6-MP, which is then metabolized to 6-thiourate and several other metabolites. These metabolites are excreted in the urine; no azathioprine or 6-MP can be detected in the urine after 8 hours. The plasma half-life of azathioprine is less than 15 minutes, and the half-life of 6-MP is 1 to 3 hours. Azathioprine is 30% protein bound and only partially dialyzable. The drug is available in two forms: an oral 50 mg tablet and an injectable solution of 100 mg/20 mL vial. The intravenous and oral doses are equivalent. Intramuscular injection is not advised. The initial recommended dose is 3 to 5 mg/kg once a day, and the maintenance dose is reduced to 1 to 2 mg/kg once a day. Dose reduction is necessary in patients with impaired renal function.

CHAPTER 57

Transplant Agents and Other Immunosuppressives

DRUG INTERACTIONS The use of azathioprine with drugs including cotrimoxazole, carbamazepine, and ganciclovir affects leukocyte production and thus may induce hematologic toxicity in patients. The use of angiotensin-converting enzyme (ACE) inhibitors in patients taking azathioprine has been reported to cause anemia and severe leukopenia.12 Severe leukopenia can develop particularly in renal transplant patients. Allopurinol inhibits xanthine oxidase, the enzyme responsible for the inactivation of 6-MP to 6thiouric acid and other metabolites. The use of azathioprine and allopurinol in combination causes 6-MP to accumulate and places the patient at risk for marked immunosuppressive effects from azathioprine. Therefore, the dose of azathioprine should be reduced by 50% when used with allopurinol.13 Prolonged use of azathioprine with corticosteroids may cause muscle wasting. Azathioprine also is known to impair fertility by reducing sperm counts in males. When azathioprine is used with tubocurarine, it decreases the effect of tubocurarine and other nondepolarizing neuromuscular blocking agents.12

BOX 57-2

945

MOST COMMON ADVERSE EFFECTS ASSOCIATED WITH AZATHIOPRINE

Hematologic

Dermatologic

Leukopenia Pancytopenia Macrocytic anemia

Rash Alopecia Skin cancer Jaundice Bruising

GI

↓ Appetite Nausea Vomiting Diarrhea Pancreatitis

Systemic

Fatigue Fever Serum Sickness

Renal

Interstitial nephritis

Management Toxicology CLINICAL MANIFESTATIONS The principal and potentially serious toxic effects of azathioprine are hematologic and gastrointestinal. There also is an increased risk of secondary infection and cancer. Large overdoses of azathioprine may acutely cause abdominal pain, nausea, vomiting, and diarrhea. In general, patients undergoing azathioprine therapy experience nausea and vomiting for the first few months. Vomiting and abdominal pain may also be associated with hypersensitivity pancreatitis that rarely develops in these patients. Hepatotoxicity, manifested by elevated serum transaminases, alkaline phosphatase, and bilirubin, also is known to occur. Discontinuation of azathioprine therapy usually reverses the hepatotoxic effects. A rare but life-threatening hepatic veno-occlusive disease associated with chronic use of azathioprine has been reported.12 Periodic measurements of serum transaminases, alkaline phosphatase, and bilirubin are indicated to detect hepatotoxicity early. Leukopenia and thrombocytopenia are dose dependent but may occur with chronic therapy. Dose reduction or temporary withdrawal will reverse these toxicities. In addition, macrocytic anemia and bleeding are known to occur with azathioprine therapy. A single case has been reported of a renal transplant patient who ingested a large dose (7500 mg) of azathioprine. The immediate toxic reactions were nausea, vomiting, and diarrhea, followed by mild leukopenia and mild abnormalities in liver function. The white blood cell count, serum glutamic oxaloacetic transaminase (SGOT), and bilirubin returned to normal 6 days after the overdose.14 ADVERSE EFFECTS The most common adverse effects associated with azathioprine are listed in Box 57-2.

Overdose with azathioprine is rare; therefore, data regarding management in overdose are lacking. Supportive care seems to be the mainstay of treatment for GI manifestations. Protection from falls or injury seems prudent to avoid bruising or bleeding. Alanine transaminase (ALT), aspartate transaminase (AST), bilirubin, and alkaline phosphatase should be monitored. Hemodialysis may serve as an adjunct to supportive care with large ingestions, since it has been shown to remove up to 45% of azathioprine.12 No data support the use of multiple-dose activated charcoal for azathioprine overdose. Single-dose activated charcoal may prove useful but may be complicated by the GI manifestations that preclude its successful administration.

CYCLOSPORINE Cyclosporine is an 11–amino acid cyclic polypeptide produced by Beauveria nivea and Tolypocladium inflatum Gams. The amino acids at the 1, 2, 3, and 11 positions form an active site; experimental modifications of the drug have resulted in decreased immunosuppressive activity. Cyclosporine was introduced in the early 1980s and brought with it significant improvements to the field of organ transplantation. It has improved both initial and long-term allograft survival. The use of cyclosporine has also decreased the initial length of stay and the rate of readmission after transplantation. Cyclosporine is used in solid organ transplantation of heart, liver, and kidney as well as for treatment of rheumatoid arthritis and psoriasis. Minimal change, focal segmental, and immunoglobulin A (IgA) nephropathy may also be treated with cyclosporine.15 It has shown benefit in the initial treatment of type 1 diabetes mellitus. There have been reports of significant decreases in the patient’s insulin requirement if cyclosporine therapy is initiated within the first 2 months.15

946


Pharmacology Cyclosporine reversibly inhibits the proliferation of immunocompetent lymphocytes in G0 and G1 phases of the cell cycle, specifically, the T-cell lines. This inhibition of immune activity is accomplished by cyclosporine forming a complex with cyclophilin that binds to and inhibits the activity of the phosphatase, calcineurin. This in turn inhibits the production of the lymphokine, IL-2. IL-2 is a growth factor for the immune system and stimulates the replication of activated immunocompetent lymphocytes. This inhibition is greater in T-helper cells than in T-suppresser cells. The immunosuppressant activity of cyclosporine is largely due to the parent compound, because its metabolites have little pharmacologic activity.

Pharmacokinetics Two forms of cyclosporine are currently available: Neoral, a microemulsion formulation, and Sandimmune, the conventional formulation. Neoral has significantly better bioavailability and less variability in absorption, both intra- and interindividual. It allows for more consistent dosing. The interindividual oral biovariability can still be quite significant, between 20% and 50% of the area under the curve. This great variability in absorption necessitates frequent drug monitoring to establish and maintain a stable dosing regime. Both forms of cyclosporine are highly lipid soluble, with absorption significantly affected by diet; high-fat meals increase absorption. Cyclosporine has a large volume of distribution, between 3 and 5 L/kg, and is up to 90% protein bound. Cyclosporine is metabolized by the cytochrome P-450 system, specifically CYP3A4, with 94% of metabolites excreted in the bile. A small portion, 6%, is excreted by the kidney, and 0.1% is excreted unchanged. Because excretion mainly is via the bile, there is a potential for enterohepatic recirculation. Cyclosporine has approximately 25 metabolites, none with significant immunosuppressive activity. SPECIAL POPULATIONS The pediatric population is notably different from the adult population in the metabolism and excretion of cyclosporine. Clearance has been reported to be enhanced significantly in the pediatric population—up to 40% greater.15 This difference in clearance may be related to differences in body composition and an apparent decrease in the volume of distribution (Vd) in children. Cyclosporine is classified by the FDA as pregnancy class C but has been used during pregnancy. Placental transfer is estimated to be between 37% and 64%. There is little evidence that cyclosporine adversely affects fetal outcome. Although there does seem to be an increased rate of prematurity and a trend toward fetal malformation and low birth weight, only prematurity reached statistical significance in one meta-analysis.16 Cyclosporine clearance is decreased in the geriatric population. It is unclear whether this decrease relates to a decrease in hepatic function or a change in Vd or lipid

transport.15 Cyclosporine clearance has also been found to be decreased in patients with decreased levels of lowdensity lipoproteins. This most likely represents a decrease in the ability to transport the drug to the liver for metabolism and excretion. Since there is minimal renal excretion of cyclosporine, patients with poor but stable renal function do not require dose adjustment. Greater than 90% of cyclosporine is metabolized in the liver, particularly the cytochrome P-450 system, and then excreted in the bile. A patient with significantly decreased hepatic function requires changes in the dosing regime. DRUG INTERACTIONS Owing to the extensive number of drugs that are metabolized via the cytochrome P-450 system, the potential interactions are numerous. Many commonly prescribed therapeutics are metabolized at CYP3A, increasing the risk of potential drug–drug interactions. The macrolides, azole antifungals (e.g., fluconazole), antiretroviral protease inhibitors, and many calcium channel blockers are also known inhibitors of CYP3A. These drugs have the potential to elevate a patient’s cyclosporine level either through competition for the active site as a competitive inhibitor or through inhibition of the cytochrome via a secondary allosteric site as a noncompetitive inhibitor.17 Carbamazepine, a substrate of CYP3A, potentially acts as a competitive inhibitor. Many anticonvulsants such as carbamazepine, phenobarbital, phenytoin, and the glucocorticoids also interact with this cytochrome as inducers, increasing the amount of the enzyme and potentially leading to decreased cyclosporine levels and ineffective immunosuppression. Aminoglycosides, antineoplastics, antifungals such as amphotericin B, NSAIDs, and colchicines are known to cause renal dysfunction; concomitant use with cyclosporine may increase this risk.

Toxicology Generally, acute toxicity from an oral ingestion is minimal. However, neonates and patients who receive unintentional parenteral overdoses are of concern, for they can develop significant toxicity. Parenteral overdose produces significant morbidity although the number of reported cases is limited. Reported effects, mainly in premature neonates, include worsening renal failure, metabolic acidosis, cyanosis, coma, hyponatremia, and hyperbilirubinemia.18 There is also a case report of cerebral edema with uncal herniation due to an intravenous cyclosporine overdose.19 When cyclosporine is used with other drugs that cause nephrotoxicity, synergistic effects could lead to rejection of an allograft. The pattern of nephrotoxicity has been broken down into three classes, all defined by a decrease in glomerular filtration rate (GFR) of 25%. The three classes are defined by the time course as acute (onset within the first 7 days of initiation of treatment), subacute (onset within 7 to 60 days of initiation of treatment), and chronic (onset >30 days after initiation of treatment). Increased serum creatinine, reduced glomerular filtration, and

CHAPTER 57

Transplant Agents and Other Immunosuppressives

decreased renal plasma flow rates are believed to be secondary to alterations in intrarenal hemodynamic function. Cyclosporine is thought to cause increases in Ca2+ influx in response to vasoconstrictors, particularly in the afferent arteriole. Cyclosporine also increases levels of thromboxane A2. Thromboxane A2 increases vascular tone in the renal arterioles and myocyte proliferation in the intima of the vessel wall. Alternatively, an alteration in the ratio of thromboxane A2 to prostacyclin could cause this effect, since thromboxane A2 is a vasoconstrictor and prostacyclin is a vasodilator. Many patients taking cyclosporine report neurologic side effects. The complaints consist mainly of paresthesias and numbness, although visual disturbances and coma have been reported. Many symptoms improve upon discontinuation of cyclosporine; however, they often recur upon rechallenge. GI disturbances including nausea and vomiting have been reported. Dysfunction of the biliary tree has been observed, with patients developing cholestasis, cholelithiasis, and hyperbilirubinemia. Multiple endocrine effects have been noted with cyclosporine use, particularly hyperglycemia. The hyperglycemia is not associated with ketosis, and there is no change in the amount of secreted insulin or in the number of insulin receptors. Hyperglycemia is thought to be related to impaired glycogen synthesis with resulting accumulation of substrate.

Management Decontamination of the GI tract with activated charcoal is suggested following acute toxic ingestion, particularly since cyclosporine has limited oral bioavailability. Some case reports suggest that multiple-dose activated charcoal decreases the half-life of cyclosporine although it is unclear whether these reported declines in serum levels represent redistribution to the tissues or elimination of the drug.20,21 In the setting of parenteral overdose, various therapies have been attempted, some being more effective and having a better rationale than others. Plasmapheresis was used in an adult who developed hyperbilirubinemia after a 30 mg/kg unintentional intravenous overdose.22 Although this therapy would help eliminate drug that was either free or bound to serum proteins, most of the circulating cyclosporine is bound to red blood cells (up to 50%) and 10% is bound to lymphocytes. Consequently, there appears to be little theoretic benefit to this intervention. Exchange transfusion has been used to treat neonatal cyclosporine overdose. In one case report, it produced a 30% reduction in cyclosporine level. In another case report, exchange transfusion was unsuccessful in changing the clinical outcome, and the patient died.18 The timing of the transfusion in relation to the overdose was unclear. At autopsy, there was significant tissue accumulation of cyclosporine, suggesting sufficient time had elapsed for redistribution to the tissues to occur. LABORATORY MONITORING Several methods are used to measure serum cyclosporine concentration. High-performance liquid chromatography

947

(HPLC) and radioimmunoassay techniques are the most common; these tests have variable sensitivity for the detection of cyclosporine metabolites. Little evidence suggests that measuring acute serum cyclosporine concentrations is helpful in management, particularly since peak levels can be delayed by up to 4 hours. The value in serial cyclosporine levels is more to determine when to resume immunosuppression than to aid in acute management. Serum blood urea nitrogen (BUN), creatinine, transaminases, and bilirubin should be monitored in patients with underlying renal or hepatic dysfunction. ELIMINATION Cyclosporine is not effectively removed by hemodialysis or hemoperfusion. It is not known whether charcoal, either in single or multiple doses, is effective in enhancing elimination although multiple-dose activated charcoal has been suggested as an effective means of elimination enhancement. It has also been suggested that CYP3A inducers might be useful therapeutic adjuncts, but little evidence supports its efficacy.

MYCOPHENOLATE MOFETIL Mycophenolate mofetil is a prodrug that is rapidly metabolized to the active metabolite mycophenolic acid (MPA). MPA is a reversible, noncompetitive inhibitor of inosine monophosphate dehydrogenase, an essential enzyme in the production of purines. B and T lymphocytes have a greater reliance on the de novo pathway of purine synthesis, while other cell lines can use scavenger pathways to meet their metabolic needs. MPA is thus cytostatic in respect to lymphocytes.

Pharmacokinetics Mycophenolate mofetil is rapidly absorbed and converted to MPA. MPA has a large Vd—3.6 to 4 L/kg—and is up to 97% protein bound. MPA is then metabolized to the phenolic glucuronide (MPAG) form. MPAG is largely excreted by the kidney; 93% is eliminated either by glomerular filtration or secretion from the renal tubule. The remaining MPAG is eliminated in the GI tract via biliary excretion, or it is excreted unchanged. MPAG that has been secreted in the bile and eliminated into the GI tract undergoes enterohepatic recirculation. The absorption, metabolism, and area under the curve for children are similar to those of adults. Pharmacokinetics have not been studied in the geriatric population. Because mycophenolate mofetil requires metabolic activation, patients with significantly impaired hepatic function have lower levels of the active form of the drug and less immunosuppressive activity. Renal elimination is required for the excretion of the inactivated metabolite, and patients with impaired renal function have a prolonged exposure to the active form of the drug. Patients with significantly decreased renal excretion have similar peak drug levels but a decreased

948


rate of excretion, leading to an enlarged area under the curve compared with that of patients with normal renal function. Although mycophenolate mofetil has been shown to be teratogenic in animal experiments, it is classified as pregnancy class C.23 DRUG INTERACTIONS Only a few drug–drug interactions have been studied with this agent. Antacids with magnesium and aluminum hydroxides decrease the amount of MPA absorbed. Cholestyramine lowers the area under the curve by interrupting the enterohepatic recirculation, leading to increased drug excretion. MPA decreases the amount of hormone absorbed from oral contraceptives, but what effect that has on suppression of ovulation is unknown. MPAG is excreted through glomerular filtration and tubular secretion; drugs that block this secretion such as probenecid will increase the area under the curve. Alterations in gut flora have the potential to alter the enterohepatic circulation and change the absorption and excretion characteristics of the drug, with less hydrolysis of MPAG, leaving less MPA for reabsorption. There are no reported significant drug interactions with cyclosporine, acyclovir, or ganciclovir. In patients with renal dysfunction, trimethoprim-sulfamethoxazole may compete with MPAG in the renal tubule for secretion into the tubular lumen.

Toxicology Toxic manifestations of MPA are exaggerated therapeutic effects, consisting primarily of neutropenia. Adverse effects that have been noted include an increased incidence of GI disturbance, GI bleeding, herpesvirus infection, and neutropenia. Determination of drug levels is made either by enzyme-mediated immunofluorescence or HPLC.

Management There are currently no case reports of acute MPA overdose in humans. Rats have been able to tolerate up to 4 g/kg and monkeys up to 1 g/kg; typical adult dosing is 2 to 4 g/day. Since many of therapeutic effects are dose dependent, the toxic manifestations would most likely be exaggerated clinical responses. As for any overdose, supportive care is essential, with protection of the airway and evaluation of other toxic coingestants. Activated charcoal as a single dose may be useful in decreasing absorption of the drug. Evaluating serum drug concentration probably has more utility in determining when to restart MPA than in acute management. Secondary to the large Vd and protein binding of the drug, it is unlikely that either hemodialysis or hemoperfusion would be of significant benefit in enhancing elimination. There is significant enterohepatic recirculation, and animal studies suggest that cholestyramine can interrupt this circulation and

possibly enhance elimination. There is also a theoretic rationale for the use of multiple-dose activated charcoal to interrupt enterohepatic recirculation. REFERENCES 1. Braza TJ, DiCarlo JB, Soon SL, McCall CO: Tacrolimus 0.1% ointment for seborrhoeic dermatitis: an open-label pilot study. Br J Dermatol 2003;148:1242–1244. 2. Walker SL, Kirby B, Chalmers RJ: The effects of topical tacrolimus on severe recalcitrant chronic discoid lupus erythematous. Br J Dermatol 2002;147:405–406. 3. Assmann T, Becker-Wegerich P, Grewe M, et al: Tacrolimus ointment for the treatment of vulvar lichen sclerosus. J Am Acad Dermatol 2003;48:935–937. 4. Travis LB, Weinberg JM, Silverberg NB: Successful treatment of vitiligo with 0.1% tacrolimus ointment. Arch Dermatol 2003;139:571–574. 5. Boumpas DT, Kritikos HD, Daskalakis NG: Perspective on future therapy of vasculitis. Curr Rheumatol Rep 2000;2:423–429. 6. Yamauchi A, Ieiri I, Kataoka Y, et al: Neurotoxicity induced by tacrolimus after liver transplantation: relation to genetic polymorphisms of the ABCB1 (MDR1) gene. Transplantation 2002;74:817–821. 7. Prograf product information. Fujisawa, May 2002. Available at www.fujisawa.com/medinfo/pi/pi_page_pg.htm. Accessed January 6, 2005. 8. Tacrolimus. In Burnham TH (ed): Drug Facts and Comparisons. St. Louis, Facts and Comparisons, 2003, pp 1568c–1570a. 9. Spencer CM, Goa KL, Gillis JC: Tacrolimus: an update of its pharmacology and clinical efficacy in the management of organ transplantation. Drugs 1997;54:925–975. 10. Macphee IAM, Fredericks S, Tai T, et al: Tacrolimus pharmacogenetics: polymorphisms associated with expression of cytochrome P4503A5 and P-glycoprotein correlate with dose requirement. Transplantation 2002;74:1486–1489. 11. Wallemacq PE, Verbeeck RK: Comparative clinical pharmacokinetics of tacrolimus in pediatric and adult patients. Clin Pharmacokinet 2001;49:283–295. 12. Imuran product insert. September 2003 Available at webarchive.org/web/20030901170715/pharmacynetworkgroup. com/imuran-side-effects.htm. Accessed January 6, 2005. 13. Chan GL, Canafax DM, Johnson CA: The therapeutic use of azathioprine in renal transplantation. Pharmacotherapy 1987; 7(5):165–177. 14. Schusziarra V, Ziekursch V, Schlamp R, et al: Pharmacokinetics of azathioprine under hemodialysis. Int J Clin Pharmacol Biopharm 1976;14:298–302. 15. Kahan BD, Oates JA, Wood AJ: Cyclosporine. N Engl J Med 1989;321:1725–1738. 16. Bar Oz B, Hackman R, Einarson T, Koren G: Pregnancy outcome after cyclosporine therapy during pregnancy: a meta-analysis. Transplantation 2001;71:1051–1055. 17. Ngheim DD: Role of pharmacologic enhancement of P-450 in cyclosporine overdose. Transplantation 2002;74:1355–1356. 18. Arellano F: Acute cyclosporine overdose: a review of present clinical experience. Drug Saf 1991;6:266–276. 19. De Perrot M, Spiliopoulos A, Cottini S, et al: Massive cerebral edema after IV cyclosporine overdose. Transplantation 2000; 70:1259–1260. 20. Honcharik N, Anthone S: Activated charcoal in acute cyclosporine overdose. Lancet 1985;1:1051. 21. Qureshi ST, Smolinske S: Cyclosporin pharmokinetics with multidose charcoal after a ten-fold dosing error. J Toxicol Clin Toxicol 2003;41:747. 22. Kokado Y, Takahara S, Ishibashi M, Sonoda T: An acute overdose of cyclosporine. Transplantation 1989;47:1096–1097. 23. Tendron A, Gouyon JB, Decramer S: In utero exposure to immunosuppressive drugs: experimental and clinical studies. Pediatr Nephrol 2002;17:121–130.

S E C T I O N

E

CARDIOVASCULAR, HEMATOLOGIC, AND ENDOCRINE AGENTS

58

Digitalis FRÉDÉRIC LAPOSTOLLE, MD, DMC ■ STEPHEN W. BORRON, MD, MS

At a Glance… ■ ■ ■ ■ ■

■

Digitalis glycosides (digoxin and digitoxin) are drugs with small therapeutic indices. Digoxin is eliminated primarily via the kidneys, digitoxin by hepatic metabolism. Symptoms of toxicity may be vague, particularly in the elderly, and may involve multiple organ systems. Patients presenting with hyperkalemia, underlying cardiac disease, and advanced age have a poor prognosis. Digitalis Fab fragments may be lifesaving and should be administered early in case of serious poisoning or in the presence of poor prognostic factors. Cardiac conduction abnormalities, gastrointestinal disturbances, and both hypokalemia and hyperkalemia associated with digitalis toxicity are rapidly corrected by the administration of Fab fragments, obviating the need for other therapy.

Digitalis was introduced into clinical medicine by William Withering in 1785, after his investigation of a home remedy used by herbalists in the English countryside.1,2 He reported therapeutic efficacy and toxicity of leaves of Digitalis purpurea, commonly named foxglove. He recommended that digitalis “be continued until it acts either on the kidneys, the stomach, the pulse, or the bowel . . . let it be stopped upon the first appearance of any of these effects and I will maintain that the patient will not suffer from its exhibition, nor the practitioner be disappointed in any reasonable effects.” Thereafter, cardiac glycosides, including digoxin, digitoxin, and ouabain, were extracted from plants and largely prescribed. Nowadays, indications for cardiac glycosides are restricted to the treatment of heart failure with or without associated supraventricular arrhythmia. Due to a narrow therapeutic index (40% to 60% of the lethal dose is required to achieve the maximal therapeutic effect), digitalis toxicity remains frequent in patients with chronic heart diseases.3 Less frequently,

digitalis toxicity results from acute overdose in suicide attempts. Digitalis poisoning treatment strategy has been dramatically modified since 1976, with the introduction of digoxin-specific Fab fragments by Smith and colleagues.4

SCOPE OF PROBLEM Digitalis intoxication was once considered the most common adverse drug reaction in U.S. medical practice. Studies from the 1960s and 1970s showed that as many as 15% of all patients in medical admissions were taking digitalis, and 20% to 30% of these patients would have signs of toxicity.5 Prescribing habits and the incidence of toxicity have begun to change because of (1) better appreciation of digitalis pharmacodynamics and drug interactions, (2) more appropriate maintenance dosage, (3) easy and rapid availability of serum digoxin determinations, and (4) expanded drug therapy for congestive heart failure, eliminating the need to push digitalis to higher, more potentially toxic concentrations. Nevertheless, the number of patients receiving maintenance digitalis therapy remains high, and the numerous common untoward effects still demand attention and understanding. Recently, toxicity associated with chronic digoxin treatment has been reported in 6% to 23% of patients, especially in the elderly.3,6 The mortality rate of poisoned patients is poorly documented in cases of chronic intoxications but reaches 25% in cases of acute overdose.7 Neither pacing nor antidotal treatment has significantly reduced this mortality rate.7,8

PHARMACOLOGY The preparations of cardiac glycosides now used in clinical practice were initially derived from the leaves of plants from the species D. purpurea. Other plants that contain cardiac glycosides (e.g., strophanthus, red squill, 949

950


Digoxin (Polar) (12-Hydroxydigitoxin)

Digitoxin (Nonpolar)

Metabolized 55% – 75% Absorbed

90% – 100% Absorbed

6.8% Recycled

26% Recycled

3% Stool daily

30% Urine daily

= 33% of total body stores excreted per day – 30% as digoxin, 3% as metabolites

2% Stool daily

16% Urine daily

= 15 – 20% of total body stores excreted per day – 2% as digitoxin, 18% as metabolites (92% inactive, 8% active)

FIGURE 58-1 Digoxin and digitoxin pharmacokinetics, showing average values for absorption, excretion, enterohepatic circulation, and half-life. (From Doherty JE: Digitalis glycosides: pharmacokinetics and their clinical implications. Ann Intern Med 1973;79:229.)

TABLE 58-1 Digoxin and Digitoxin Main Phamacologic Characteristics

Absorption

Volume of distribution Protein binding Half-life Clearance

DIGOXIN

DIGITOXIN

55%–75% for tablets 90%–100% for liquid or encapsulated liquid 5.6 L/kg 25% 33–34 hr Renal

90%–100%

0.56 L/kg 95% 6–7 days Hepatic

and derivatives) have occasionally led to unsuspected cardiac complications. Recently, accidental contamination of dietary supplements by Digitalis lanata has been reported.9 Several preparations of digitalis are available. However, because of their ease of oral administration and duration of action, only two preparations are used in clinical practice today: digoxin and digitoxin. Their main pharmacologic characteristics are reported in Figure 58-1 and Table 58-1. Digoxin and digitoxin are both passively absorbed from the small intestine. Detailed pharmacodynamic studies have shown that drug action depends on tissue concentration, which is relatively constant in relation to serum concentrations, and that the major depot in humans is skeletal muscle.10,11 These findings lead to two conclusions: (1) the constant relationship of myocardial digoxin concentration to serum concentration supports measuring serum concentrations to monitor patients’ compliance

and toxicity, and (2) dosage requirements and the likelihood of toxicity can be anticipated on the basis of muscle mass and not overall body weight. Digoxin and digitoxin are eliminated differently (see Fig. 58-1). Digoxin is excreted primarily via the renal route, whereas digitoxin is eliminated primarily via metabolic inactivation. Because enterohepatic circulation has a role in the metabolism of both drugs, biliary production affects digitalis elimination. Bioavailability of the drug may vary with different manufacturing processes and malabsorption syndromes and because of inactivation of gut flora, which can be altered by antibiotics.12 Furthermore, digoxin is one of the breakdown products of digitoxin metabolism (about 8%) (Figs. 58-1 and 58-2).

Basic Mechanism Digitalis acts at the subcellular level by altering the sodium/potassium-adenosine triphosphatase (Na+/K+ATPase) transport system (Fig. 58-3). The effect is an intracellular gain of Na+ and loss of K+ and a corresponding extracellular gain in K+. Through interaction with Na+ and Ca2+ membrane transporters, an associated intracellular gain of Ca2+ is observed. In short, the net effect is a decreased intracellular K+ concentration and an increased Na+ and Ca2+ concentration. The increased Ca2+ augments myofibril interaction in cardiac muscle and leads to positive inotropic action responsible for digitalis’s usefulness in clinical practice.13 In an intact heart, the effects of digitalis can be separated into mechanical and electrophysiologic actions, with toxicity related to its excessive therapeutic effects and the status of the patient at the time of drug administration.

CHAPTER 58

Cardioactive

Cardioinactive -2H

Dihydrodigitoxin

+2H

Digitoxin (nonpolar, 3 sugar)

12–b

Hydroxylation 8%

Digitalis

951

Cardioinactive (+0)

-2H Digoxin (polar, 3 sugar) +2H

Digitoxigenin bis-digitoxiside (2 sugar)

Digoxigenin bis-digitoxiside (2 sugar)

Digitoxigenin mono-digitoxiside (1 sugar)

Digoxigenin mono-digitoxiside (1 sugar)

Digitoxigenin (0 sugar)

Digoxigenin (0 sugar)

Dihydrodigoxin

Dihydrodigoxigenin

Presence of sugar (digitoxose) Epidigoxigenin inhibits metabolic enzymatic degradation. After all sugar portions of molecules are Conjugation Conjugation removed, the “genin” is rapidly products products converted to cardioinactive compounds. FIGURE 58-2 Metabolic pathways of digoxin and digitoxin. Note that digoxin is part of the metabolic pathway of digitoxin. (From Doherty JE: Digitalis glycosides: pharmacokinetics and their clinical implications. Ann Intern Med 1973;79:229.) Epidigitoxigenin

K; Na;

K; Na-K-ATPase

Na;

FIGURE 58-3 Cellular interactions between Na+/K+ATPase pump and digoxin. Digitalis alters the Na+/K+ATPase transport system. The net effect is an intracellular loss of K+ and gain of Na+ and Ca2+. The increased Ca2+ augments myofibril interaction in cardiac muscle and leads to positive inotropic action.

Ca2;

Cell Na;/ Ca2; transporters

Ca2;

Na;

Normal Therapeutic Effects on Intact Heart (Summary of Actions) DIGITALIS INOTROPIC EFFECT A major therapeutic use for digitalis is for its inotropic effect. Digitalis augments the force of myocardial contraction by increasing the velocity of shortening and the velocity of developed tension of cardiac muscle.13 Therefore, there is less encroachment on compensatory mechanisms, allowing greater cardiac reserve. In patients with heart failure, digitalis causes a decrease in end-diastolic pressure and volume, increasing cardiac

output and stroke work. The usefulness of digoxin for congestive heart failure in patients in sinus rhythm has been the subject of some controversy. However, most conclude that digoxin is a weak inotropic agent.14,15 The Digitalis Investigators’ Group trial and the study by Krum and colleagues demonstrated the usefulness of digoxin in congestive heart failure.16,17 More precisely, in 1997, The Digitalis Investigators’ Group trial17 showed that although, in comparison with placebo, digitalis treatment did not reduce the mortality rate, it did reduce the rate of hospitalization, including hospitalization for worsening heart disease. In a nonfailing heart, the effects

952


of digitalis are more controversial. Positive inotropic action may occur, but it is not manifested by a measurable change in cardiac output or by a decrease in left ventricular filling pressure.18 DIGITALIS CHRONOTROPIC EFFECT The negative chronotropic effect of digitalis is primarily central, mediated through an increase in vagal tone associated with decreased sympathetic activity. Thus, effects of digitalis may vary, depending on the interaction of drug concentration and autonomic tone. Digitalis decreases the refractory period of both atrial and ventricular cells and tends to increase action potential amplitude and Vmax. This improves conduction within the muscle, as reflected in a shortened QT interval. The same mechanism accounts for the increased atrial rate in atrial flutter or atrial flutter-fibrillation.13 Digitalis decreases the rate of sinoatrial (SA) node depolarization. Digitalis increases the refractory period of the atrioventricular (AV) node and the bundle of His. It prolongs phase 3 of the action potential, accounting for decreased ventricular response in atrial fibrillation. Some AV nodal effects are independent of vagal tone and affect phase 0, thus decreasing conduction velocity.1 Most if not all effects of digitalis on the Purkinje system and ventricular muscle are direct effects and do not depend on autonomic interaction.13 Digitalis causes significant effects on myocardial automaticity (ability of tissue to undergo spontaneous depolarization) and excitability (ability of tissue to respond to a given stimulus). Inhibition of the Na+ pump leads to an influx of Na+ into the cell (see Fig. 58-3). This Na+ influx increases phase 4 depolarization in all cardiac tissue except the SA node and leads to the appearance of new or latent pacemakers, thus increasing automaticity. This influx also lowers the resting membrane potential threshold, thus increasing excitability.19 Na+ influx also causes delayed afterpotentials (oscillations in transmembrane potentials that follow full repolarizations of the membrane), and this effect provides a logical basis for understanding digitalisinduced arrhythmias.1,13

Digitalis Toxicity The toxic effects that occur when blood concentrations exceed the therapeutic range are almost uniformly a consequence of excessive normal physiologic responses. They can occur in any condition that increases the amount of digitalis in the body or modifies the cardiac sensitivity to digitalis. Drug interactions and other factors, such as electrolyte abnormalities, renal or hepatic failure, ischemia, or inflammation, predispose to digitalis toxicity. INTERACTION WITH OTHER DRUGS The importance of drug interactions in the development of digitalis toxicity was not truly appreciated until reliable assays of digoxin concentrations became widespread. Such interactions are important to consider, because introducing or discontinuing these drugs without changing the digoxin dose may lead to a digitoxic state. The most common interactions are listed in Table 58-2. By far, the most important and dangerous drug interactions with digoxin are caused by the antiarrhythmics. Quinidine20 causes an increase in serum digoxin in up to 90% of patients. The magnitude of the increase varies but is often twofold. The serum digoxin concentration begins to increase with the onset of quinidine therapy, and the concentration remains elevated as long as both drugs are continued. The adverse effects of elevated digoxin concentrations caused by quinidine are similar to those experienced with an overdose of digoxin. There is no evidence that other antiarrhythmics similar to quinidine in their action (type I) interact with digoxin.21-23 Procainamide, disopyramide, lidocaine, mexiletine, and flecainide do not increase serum digoxin concentrations. Another major antiarrhythmic drug that interacts with digoxin is amiodarone.24 Digoxin concentrations increased by 25% to 70% within 24 hours after adding amiodarone. The effect is mediated via a decrease in renal and nonrenal clearance. The result is more frequently bradyarrhythmias or heart block rather than tachyarrhythmias.

TABLE 58-2 Agents Affecting Digitalis Pharmacology ALTERATION

AGENTS

Decreased absorption

Antacids, antibiotics (neomycin, sulfasalazine, p-aminosalicylic acid), bran, cholestyramine, cytotoxic, kaolin-pectin Antibiotics inhibiting gut flora (erythromycin and tetracycline), anticholinergics

Increased absorption (less of a problem when the capsule form is used)12 Inhibited protein binding Increased renal excretion Decreased extra renal clearance Decreased volume of distribution Increased serum digitalis concentration

Clofibrate, phenobarbital, phenylbutazone, prazosin, warfarin Hydralazine, levodopa, nitroprusside Diatiazem, quinidine, verapamil Quinidine Amiodarone, aspirin, bepridil, diltiazem, flecainide, ibuprofen, indomethacin, nefidipine, nicardipine, nosoldipine, nitrendipine, propafenone

From Mooradian AD: Digitalis: an update of clinical pharmacokinetics, therapeutic monitoring techniques and treatment recommendations. Clin Pharmacokinet 1988;15(3):165–179.

CHAPTER 58

The interaction between Ca2+ channel–blocking drugs and digoxin varies greatly.20-22 The dihydropyridines (nifedipine, amlodipine, isradipine, nicardipine) have minimal or no effect, and diltiazem has such a small effect that toxicity is unlikely. On the other hand, verapamil increases serum digoxin concentrations as much as 70% by altering renal and extrarenal clearance, which can lead to lethal cardiac toxicity.21,25 Other antiarrhythmics, such as sotalol, aprindine, ajmaline, and moricizine, do not affect digoxin concentrations.21,22 Potentially toxic interaction may also occur with potassium-sparing diuretics (such as spironolactone), which inhibit tubular secretion of digoxin; with antihypertensive agents, which can significantly alter renal reperfusion and glomerular filtration rate; and with antiinflammatory drugs, especially indomethacin, in neonates or patients with renal dysfunction. Some antiadrenergic agents, such as clonidine, methyldopa, reserpine, and β blockers, in combination with digitalis, may lead to severe bradyarrhythmias, especially in patients with SA node disease.21,22 Reports have shown toxicity in patients with myocarditis when cyclosporine is added to digoxin in patients who have heart failure.26 Aside from the drug interactions discussed earlier, renal dysfunction leading to decreased renal excretion of digitalis is the major factor leading to the increased total of digitalis throughout the body. Neither dialysis nor cardiopulmonary bypass causes much body loss of digitalis. ALTERING SENSITIVITY TO DIGITALIS Toxicity from digitalis is not limited to situations that increase total body concentration of the drug but can develop with any condition that modifies the cardiac sensitivity to digitalis. These include myocardial infarction or ischemia, myocarditis, cardiomyopathy, amyloidosis, and other trauma, including surgery. A healthy heart tolerates large amounts of digitalis, whereas diseased myocardium appears to develop arrhythmias at lower serum concentrations.27 The myocardial disease leads to local areas of altered electrophysiology, which in turn can cause variation in digitalis uptake by cardiac tissue. The concentration differences and local ischemia lead to variation of cellular recovery times and set the stage, once again, for reentry phenomena. Intrinsic cardiac disease alone may produce similar rhythm disturbances, several of which are common in acute myocardial infarction. These rhythm disturbances have no specific distinguishing feature. However, digitalis toxicity can be implicated in most instances when withdrawal of the drug is followed by resolution of the arrhythmia. This increased sensitivity does not preclude careful use of digitalis when clinically indicated.28 ALTERING METABOLISM Metabolic factors are important in myocardial sensitivity to digitalis.22,29 Electrolyte abnormalities, especially hypokalemia and hypocalcemia, are well known, but aberrations of magnesium are important to consider. Other metabolic abnormalities, including acidosis,

BOX 58-1

Digitalis

953

FACTORS PREDISPOSING TO DIGITALIS INTOXICATION

Patient-related Factors

Electrolyte Abnormalities

Old age Severe heart disease Myocardial infarction Myocarditis Recent cardiac surgery Cor pulmonale Renal failure Hemodialysis Hypothyroidism Anoxia Amyloidosis

Hypokalemia Hypernatremia Hypercalcemia Hypomagnesemia Alkalosis Drugs

Diuretics Steroids Reserpine Catecholamines Quinidine Verapamil Amiodarone Cyclosporine

alkalosis, hypoxemia, and hyperthermia, may alter digitalis’s effect but are probably not independent risk factors. Diseases of other organ systems, especially chronic lung disease and hypothyroidism, predispose patients to digitalis toxicity. Acute cerebrovascular events may lead to toxicity by large sympathetic discharge, which may lower the arrhythmia threshold. Boxes 58-1 and 58-2 contain a more complete list.

CLINICAL PRESENTATION Pathophysiology Digitalis toxicity represents the result of the interactions of the drug on the transmembrane potentials and ionic current flows of the cardiac cells (direct effects) and those effects related to the autonomic nervous system (indirect). These interactions have various results depending on which cells are affected; they are expressed as abnormalities of atrial, AV nodal, or ventricular pathology. The mechanism of digitalis cardiotoxic rhythms may result from depression of conduction or alteration of impulse formation, with increased heterogeneity of refractory periods.

Manifestations CARDIAC Cardiac manifestations are frequent and dangerous presentations of digitalis toxicity.7,29 A healthy heart rarely has any signs of toxicity unless the ingested quantity is high. Therefore, accidental overdoses, especially in children, rarely present any cardiac findings but may show AV conduction disturbances. On the other hand, a diseased heart is prone to lethal arrhythmias. No arrhythmias are pathognomonic of digitalis toxicity because similar rhythms may represent underlying disease. A change in the rhythm, especially decreased pulse rate, may be the most important clue. Never-

954

BOX 58-2


DIGOXIN PHARMACOKINETIC INTERACTIONS

BOX 58-3

RHYTHM AND CONDUCTION DISTURBANCES IN DIGITALIS INTOXICATION

Bioavailability Decreased

Excitant

Cathartics Antacids Cholesterol-binding agents Malabsorption syndromes Bowel edema Eubacterium lentum Gastric hyperacidity

Atrial premature beats Atrial tachycardia Atrial flutter (rare) Atrial fibrillation (rare) Junctional premature beats Accelerated junctional rhythms Ventricular premature beats, bigeminy and multiformed Ventricular tachycardia Bidirectional tachycardia Ventricular fibrillation

Increased

Lanoxicaps or elixir Antibiotics (E. lentum) Omeprazole Distribution Decreased

Renal failure Hyperkalemia Aging Hypothyroidism Amiodarone Increased

Hypokalemia Hyperthyroidism Pregnancy Physical activity

Suppressant

Sinus bradycardia Sinoatrial block Type I second-degree AV block (Wenckebach) Bundle branch block Complete AV block Type II second-degree AV block (?) Combination Excitant and Suppressant

Atrial tachycardia with AV block Sinus bradycardia with junctional tachycardia Wenckebach with junctional premature beats Regularization of ventricular rhythm with atrial fibrillation AV, atrioventricular.

Elimination Decreased

Renal failure Excessive diuretics Aging Indomethacin Cyclosporine Spironolactone Verapamil Quinidine Propafenone Increased

Diarrhea Vasodilators From Lewis RP: Clinical use of serum digoxin concentrations. Am J Cardiol 1992;69:97G.

theless, toxicity should be suspected in any patient receiving the medication and exhibiting evidence of depressed conduction, alteration of impulse formation (automaticity), or both. Depressed conduction is related to slowing of SA and AV nodal conduction and prolonged nodal refractoriness from high vagal tone, but at high concentrations, digitalis may directly prolong AV nodal refractoriness. Thus, blocks of all types may be observed30 (Box 58-3). SA nodal block is relatively common since impulseforming alterations from digitalis toxicity are often manifested as suppression of atrial pacemakers,

primarily the SA node. SA nodal block may range from sinus pauses to the SA nodal Wenckebach phenomenon or to total SA nodal exit block. The resultant arrhythmia is frequently sinus bradycardia, which may be quite severe, especially in elderly patients and in those with SA node disease (Fig. 58-4). First-degree AV block (i.e., with prolonged PR interval), from digitalis is indistinguishable from other causes (Fig. 58-5). Second-degree AV block, with intermittent dropped beats, may be Mobitz type I (Wenckebach) or Mobitz type II (see Fig. 58-5). The resultant heart rhythm may be complicated by accelerated junctional escape beats. Third-degree block, or complete AV dissociation, is usually associated with a narrow QRS escape focus at adequate rates, and hemodynamic alterations are rare in the absence of other cardiac abnormalities (Fig. 58-6). Alterations of impulse formation may be divided into those that suppress higher pacemakers or those that excite lower pacemakers. Suppression of higher pacemakers is limited primarily to direct effect on the sinus node. Excitation is due to increased frequency of discharge of junctional or ventricular pacemakers, taking the form of accelerated junctional or accelerated ventricular tachycardias. The combination of suppressant and excitant effects should be considered digitalis toxicity until proven otherwise (Fig. 58-7). However, as

CHAPTER 58

Digitalis

955

FIGURE 58-4 The electrocardiogram of an 82-year-old woman recently begun on digitalis shows sinus rhythm with sinus arrest and atrioventricular dissociation with slow atrial escape and faster junctional escape rhythm.

the number of older patients with intrinsic cardiac disease increases, these arrhythmias are not specific for digitalis toxicity. Digitalis toxicity results in an exacerbation of the drug’s normal effects on refractory periods of the conduction system and myocardial cells. Increased heterogeneity of the refractory periods allows for the development of reentry phenomena, which are the probable mechanisms for the development of tachyarrhythmias. Myriad extrasystoles may be seen, such as premature ventricular contractions (PVCs) (see Fig. 58-7), ventricular parasystole, or ventricular or bidirectional tachycardia. The PVCs may be multiformed, bigeminal, paired, or in couplets. Before more current therapy, ventricular tachycardia related to digitalis toxicity carried a 50% mortality rate. Bidirectional tachycardia was almost always fatal. Conduction and rhythm disturbances can be seen in combination, resulting in various electrocardiographic presentations. The rhythms are usually manifested by an increased sinus rate with block or second-degree AV block with accelerated lower pacer. Examples are atrial fibrillation with slow ventricular response rate resulting in irregular bradycardia, or Wenckebach block with accelerated junctional escape beats (Fig. 58-8). Even

though nonspecific, digitalis toxicity should always be considered when this type of arrhythmia is encountered. NONCARDIAC Digitalis intoxication induces noncardiac as well as cardiac clinical effects.3,31,32 Gastrointestinal manifestations are present in both acute and chronic intoxication. Anorexia, nausea, and vomiting are common. These symptoms often occur early and may be the presenting complaint. In patients on chronic digitalis treatment, onset of these symptoms has to be considered a possible overdose symptom. Other gastrointestinal complaints are less common. Neurologic and visual manifestations are also frequent and range from headache and fatigue and weakness, to depression, confusion, disorientation, aphasia, delirium, and hallucinations. The visual disturbances of blurring and alteration in color are less common. A more complete list and incidence can be found in Table 58-3. In this study, vigorous attempts were made to establish digitalis as the cause of these symptoms.31 Digitalis intoxication should always be considered in patients, particularly in the elderly, who are receiving digitalis therapy and present with vague gastrointestinal complaints, malaise, or altered mental status.6,32

956


FIGURE 58-5 An 82-year-old man was referred for slow pulse. An electrocardiogram (ECG) 1 day before the present ECG showed 2:1 heart block. The patient was taking digoxin, 0.25 mg/day. Strips show first-degree atrioventricular (AV) block and 5:4 AV nodal block with a narrow QRS complex.

LABORATORY DERANGEMENTS As previously mentioned, the mechanism of cellular digitalis toxicity directly induces hyperkalemia, which is significantly correlated with digitalis poisoning severity and mortality. Mortality rates are greater in patients with serum potassium greater than 4.5 mEq/L, approaching 35% in patients with serum potassium greater than 5 mEq/L, and 100% in patients with concentrations greater than 6.4 mEq/L.33 A recent retrospective review has confirmed the importance of hyperkalemia as a poor prognostic indicator in digitalis poisoning.34

DIAGNOSIS Acute overdose may result from accidental or suicidal overdose in patients, whether or not previously treated

by digitalis.7,35,36 In such cases, the main challenge is early detection of digitalis toxicity. Recognition of chronic digitalis toxicity requires a high index of suspicion among patients manifesting any of the cardiac or noncardiac symptoms mentioned earlier. In both cases, definitive diagnosis is via serum digitalis determinations.

Digitalis Concentrations The concentration of digitalis in the serum is the net result of whole body absorption, distribution, and excretion. Measurement of serum concentrations is currently the cornerstone of digitalis poisoning diagnosis. The range of therapeutic concentration is 0.5 to 2.0 ng/mL for digoxin and 10 to 30 ng/mL for digitoxin. Due to the lack of specificity of digitalis poisoning symptoms, serum concentrations must be liberally obtained

CHAPTER 58

I

II

III

R

L

F

V1

V2

V3

V4

V5

in chronically treated patients who experience gastrointestinal symptoms, malaise, or any change from baseline rhythm disturbances. However, serum concentrations are not always diagnostic; major problems remain in diagnosing toxicity. Assays of different digitalis preparations often overlap, and accurate interpretation of results is possible only if the exact preparation is known. False-positive elevations may occur for several reasons. For example, spironolactone and hyperbilirubinemia interfere with the test. Far more frequent is a falsepositive assay result in patients with chronic renal failure. This elevation is thought to be caused by an endogenous circulating digoxin-like substance, which has been reported in more than 60% of patients with chronic renal insufficiency.37 Clinical correlations of therapeutic and toxic concentrations all have been made at steady-state concentrations. These concentrations are reached 6 to 8 hours after administration, and any measurements made before this time may give values two to three times greater than at steady-state concentrations. Digoxin undergoes bimodal elimination; thus, measurements made in the first few hours of administration (α elimination phase) do not correspond with toxicity. As the

Digitalis

957

FIGURE 58-6 Electrocardiogram (ECG) of a 79-year-old woman admitted with shortness of breath and weight loss. She was receiving maintenance digoxin therapy. The ECG shows atrioventricular (AV) dissociation secondary to a high-grade AV block with a narrow QRS complex.

V6

α elimination phase begins, concentrations more closely approach steady-state concentrations and correspond better with toxicity. Defining a toxic digitalis concentration is difficult because serum concentrations of patients with and without clinical toxicity overlap considerably. Figure 58-9 demonstrates this problem in an older study, but a more complete list is found in the review by Smith.38 Multiple factors, previously detailed, predispose patients to toxicity at concentrations well below 2 ng/mL, usually considered the upper limit of normal. Hypokalemia is the most important of these. Hypoxia caused by chronic pulmonary disease or advanced forms of heart disease is also important. Factors enhancing digitalis sensitivity are listed in Boxes 58-1 and 58-2.22 In summary, serum concentrations should be used as a guide to appropriate therapeutic doses and as an indication of toxicity. Serum concentrations also may verify drug compliance and aid dose regulation in patients with changing renal function, those who have undergone cardiac surgery, or those with severe congestive heart failure. It must be emphasized that toxicity cannot be diagnosed from serum concentrations alone. Special consideration must be given to those patients with underlying problems. In general, an

958


FIGURE 58-7 A, Admission electrocardiogram of an 89-year-old with a digoxin level of 2.4 ng/mL. B, One day later.

A

B

increased serum digitalis concentration indicates digitalis toxicity in patients chronically treated with digitalis who are manifesting cardiac or noncardiac symptoms.

THERAPY OF DIGITALIS INTOXICATION Successful therapy of digitalis intoxication depends not only on early recognition but also on early and, at times, aggressive management. Physicians must maintain a high index of suspicion about digitalis intoxication if they are to make this diagnosis, especially in patients with predisposing factors, such as old age, renal disease, chronic lung disease, or quinidine use. Most of these patients suffer from chronic overdose, rather than severe suicidal or accidental acute ingestion. In unusual circumstances, such as involuntary plant poisoning or poisoning through herbal supplements, the diagnosis may be particularly elusive.9,32,39-42 It should be remembered that gastrointestinal manifestations, such as anorexia, nausea, or vomiting, are often the first clinical signs in these rare poisonings. In these circumstances, electrocardiographic manifestations and hyperkalemia should strongly increase the suspicion of digitalis poisoning, calling for measurement of serum digitalis concentrations. When digitalis poisoning is diagnosed, precocious treatment, including antidotal therapy, should be considered.

Conventional Therapy GASTROINTESTINAL DECONTAMINATION A single dose of activated charcoal should be used in patients with acute poisoning if the patient has ingested a potentially toxic dose of digitalis and if charcoal can be administered during the first 2 hours following ingestion.43 Neither repeated charcoal administration in acute poisoning nor single-dose charcoal administration in patients with chronic overdose has been demonstrated to be of value.44

FIGURE 58-8 This rhythm strip shows atrial tachycardia with block. There is an atrial rate of approximately 150 beats/min with a 3:1 block.

TABLE 58-3 Noncardiac Symptoms of Digitalis Toxicity DEFINITE POSSIBLE NO INTOXICATION INTOXICATION INTOXICATION (%) (%) (%) Vomiting Anorexia Dizziness Fatigue Visual disturbances Syncope Abdominal pain Diarrhea Headache Delirium

48 34 14 14 9

30 27 19 16 5

27 18 23 11 7

6 6 2 0 0

3 4 2 2 1

2 0 2 0 0

Modified from Mahdyoon H, Battilana G, Rosman H, et al: The evolving pattern of digoxin intoxication: observations at a large urban hospital from 1980 to 1988. Am Heart J 1990;120:1189

CHAPTER 58

6 Serum digoxin concentration (ng/mL)

959

fragments corrects hyperkalemia,35 so that administration of calcium for hyperkalemia should probably be reserved (if ever used) for those situations in which digitalis Fab fragments are not available.

7

5

4

3

2

Digitalis

mean=3.0

mean=1.8

1

TREATING BRADYCARDIA OR OTHER BRADYARRHYTHMIAS Severe bradycardia and bradyarrhythmias are often related to increased vagal tone. Treatment is crucial, because bradyarrhythmias increase the risk for lifethreatening ventricular arrhythmias. Atropine is the treatment of first choice. A trial of 0.5 mg atropine may be given intravenously and repeated up to a total dose of 2.0 mg. Large cumulative doses of atropine may lead to anticholinergic encephalopathy. Adrenergic agonists, such as isoproterenol, should be avoided, because the risk for precipitating more severe arrhythmias is high due to their dromotropic effects.

0 Not toxic Toxic FIGURE 58-9 Results of 100 serum digoxin radioimmunoassay measurements. Sixteen patients were believed to be clinically toxic; their mean serum level was 3.0 ng/mL. Seven patients thought to be nontoxic also had serum levels of more than 3.0 ng/mL. Overlap of normal toxic values does occur; therefore, judgment must be used when evaluating results. (From Doherty JE: Digitalis glycosides: pharmacokinetics and their clinical implications. Ann Intern Med 1973;79:229.)

EXTRACORPOREAL REMOVAL TECHNIQUES There are no data to support the use of any extracorporeal removal techniques in acute or chronic digitalis poisoning. CORRECTION OF ELECTROLYTE DISORDERS Correction of hypokalemia and dehydration are important in cases of chronic toxicity. However, the pathophysiologic mechanism of hypokalemia should be kept in mind, and care should be taken to avoid secondary hyperkalemia. It is generally recommended that calcium be avoided in the treatment of hyperkalemia in digitalis poisoning, due to concerns that intracellular calcium concentrations are already elevated and that administration of further calcium may lead to life-threatening dysrhythmias. This notion has been called into question by Kuhn, who cites a study by Nola and colleagues in dogs, which demonstrated that calcium could safely be administered in digitalis toxicity, so long as the serum calcium did not exceed 20 mg/dL.44 A more recent paper by Hack and colleagues45 demonstrated that calcium can be safely administered in a pig model of acute digitalis intoxication. Caution should be exercised, however, in overinterpretation of these studies, which involved acute contemporaneous digitalis and calcium administration, rather than administration of calcium in a model with extant digitalis intoxication (with sufficient time to observe poisoning of the Na/K-ATPase pump). More importantly, it should also be remembered that antidotal treatment with Fab

TREATING ECTOPY One half to three fourths of patients developing highgrade ventricular tachyarrhythmias from digitalis toxicity will die. Early, aggressive therapy is essential in these situations. The following agents should be considered: Cardiac pacing. Cardiac pacing can be used to treat bradycardia and bradyarrhythmias and to prevent ventricular arrhythmias.7,8 But pacing is not immediately available everywhere and is associated with life-threatening ventricular arrhythmias and with other nonfatal complications, such as infection. As a rule, it should be performed only if treatment by Fab fragments is not rapidly available. A recent article by Chen and colleagues suggests that pacing can be safely performed in patients with chronic digitalis poisoning. The authors caution against its use in digitalis intentional overdose.46 Magnesium. The use of intravenous magnesium sulfate in digitalis toxicity has theoretical indications, especially if the magnesium concentration is low. Magnesium may be considered even when the magnesium concentration is normal or high if, as is often the case, the potassium concentration is elevated.47 Magnesium potentiates Na/K-ATPase activity without affecting binding of proteins. Hypermagnesemia and related side effects may occur, particularly in patients with renal dysfunction. It is unlikely to appear, however, with an initial bolus of 10 to 20 mmol. Magnesium sulfate generally is packaged as 1.5 to 3 g of magnesium sulfate in 10 or 20 mL. Intravenous use for a cardiac emergency is 3 g diluted to 100 mL and given over 10 minutes. This is often repeated once, followed by maintenance intravenous drips, while monitoring the magnesium and potassium concentrations. Other antiarrhythmic drugs, such as lidocaine and phenytoin, quinidine, procainamide, disopyramide, calcium channel blockers, and β blockers, have been previously used. Efficacy was poor and

960


the risk for side effects high. Nowadays, antidotal treatment is the first-line treatment for digitalis poisoning. Cardioversion. Direct current countershock should be the last resort in life-threatening arrhythmias, and if used, the lowest effective energy level for cardioversion is suggested. Even at low energy levels, the highest mortality rates for direct current cardioversion occur in digitalis toxicity. It should be performed only if treatment by Fab fragments is not rapidly available.

in acute and chronic poisonings in adults and in children. The fragments (molecular weight 50,000 Daltons) neutralize digoxin and digitoxin toxicity by reversing tissue binding of digitalis. Bound digitalis reaches high concentrations in the plasma, but the relatively small molecular size allows glomerular filtration and rapid excretion. Two methods of antidotal treatment with Fab fragments have been proposed,48 equimolar neutralization in patients with life-threatening poisoning and semiequimolar neutralization in patients with less severe intoxication and/or poor prognostic risk factors, although the latter has not been subjected to clinical trial. In effect, survival of patients who experience cardiac arrest due to digitalis poisoning is very poor. Smolarz and colleagues first suggested “prophylactic” neutralization to prevent secondary ventricular lifethreatening arrhythmias.49 Woolf and colleagues recommended the same strategy in poisoned children.50 Taboulet and colleagues recently suggested the following approach. Once again, it should be emphasized that “semimolar neutralization” has not been subjected to controlled clinical trials, although it has been routinely employed in France for several years.48 In patients with life-threatening intoxication, immediate equimolar neutralization:

ANTIDOTAL THERAPY The most immediate decision for the physician treating suspected digitalis overdose concerns the need for antidotal therapy. Digitalis in massive doses may be lethal after suicidal or accidental overdoses, which are not uncommon. Resultant ventricular arrhythmias are responsible for a high mortality rate, reaching 25% in recent studies.4,35,36 The end result is asystole and finally a complete loss of any cardiac electric activity. The best method for treating very high concentrations of digitalis poisoning is the use of digoxinspecific polyclonal antibody fragments (Fab). The first report of their use appeared in 1976 (Fig. 58-10).4 Efficacy and safety have since been clearly demonstrated

A

B

C I

II

III

IV

V

VI

V1

V2

V3

V4

V5

V6

D

FIGURE 58-10 Sequential electrocardiograms recorded before, during, and after treatment with digoxin-specific Fab fragments. A, In the tracing recorded immediately before the start of Fab infusion, serum potassium level is 8.7 mEq/L; the escape interval when pacer stimulus is reduced below threshold is 4.60 seconds. B, In the tracing recorded 15 minutes after the start of Fab infusion, serum potassium level is 8.0 mEq/L; the escape interval is 3.96 seconds. C, In the tracing recorded 30 minutes after the start of Fab infusion, the escape interval is 2.76 seconds. D, In the tracing recorded 2 hours after the start of Fab infusion, the serum potassium level is 7.4 mEq/L; a sinus mechanism is present at a rate of 75 beats/min, with first-degree atrioventricular block (P-R interval of 0.24 second). (From Smith TW, Haber E, Yeatman L, Butler VP Jr: Reversal of advance digoxin intoxication with Fab fragments of digoxin-specific antibodies. N Engl J Med 1976;294:797.)

CHAPTER 58

1. Asystole 2. Ventricular arrhythmia (fibrillation or tachycardia) 3. Bradycardia: heart rate less than 40 beats/min (after atropine venous infusion) 4. Serum potassium greater than 5.0 mmol/L In patients with severe intoxication and/or bad prognostic risk factors, semimolar neutralization: 1. Patients older than 55 years 2. Patients with cardiac disease 3. Bradycardia: heart rate less than 60 beats/min (after intravenous atropine) 4. Second- or third-degree SA or AV blocks 5. Serum potassium greater than 4.5 mmol/L Antidotal treatment is efficacious in the treatment of digitalis-induced cardiac as well as noncardiac disturbances. Hyperkalemia is best treated by Fab fragments. All others symptoms, including gastrointestinal symptoms, disappear after Fab fragment infusion. The dose of Fab fragments to administer is determined by calculating digitalis body load.7,8 Digitalis body load may be estimated, based on supposed ingested digitalis amount (in acute poisoning) or by measured digitalis blood concentrations. When these data are not available, in cases of acute toxicity, empirical dosing recommendations are that 20 vials (760 mg) of Digibind (GloxoSmithkline, Research Triangle Park, NC) is adequate to treat most life-threatening ingestions in both adults and children. However, in children it is important to monitor for volume overload. The physician may consider administering 10 vials, observing the patient’s response, and following with an additional 10 vials if clinically indicated. In cases of chronic intoxication, for adults, six vials (228 mg) usually is adequate to reverse most cases of toxicity. This dose can be used in patients who are in acute distress or for whom a serum digoxin or digitoxin concentration is not available. In infants and small children (weighing less than or equal to 20 kg), a single vial usually should suffice. Total digitalis body load is calculated in Box 58-4. The rate of Fab fragment administration is determined on the basis of the presence of life-threatening toxicity: the fragments are given over a few minutes in cases of ventricular disturbances and over 1 hour in cases of prophylactic indications. Resolution of digitalis poisoning symptoms after Fab fragment infusion is rapid. Reversal, including correction of serum potassium concentration, has been obtained in 75% of the patients within 1 hour.35 Vital signs, electrocardiogram, and serum potassium monitoring during Fab fragment infusion are means of assessing treatment efficacy and safety. It is important to understand that serum digitalis concentrations measured by routine methods rise dramatically after administration of digitalis Fab fragments. Free digitalis concentrations may be measured to distinguish bound from unbound fractions, but such measurements are technically more difficult to perform and generally less available. Prior history of allergy after Fab fragment administration is the sole contraindication to Fab fragment

BOX 58-4

Digitalis

961

CALCULATION OF DIGITALIS FAB FRAGMENT DOSAGE

Calculation of digitalis body load based on ingested digitalis amount: Digoxin body load (mg) = 0.8 × suspected ingested amount (mg) Digitoxin body load (mg) = 1 × suspected ingested amount (mg) NB: 0.8 and 1 are digoxin and digitoxin bioavailability. In case of elixirs and gel tablets, the value is 0.95. Calculation of digitalis body load based on serum digitalis concentration: Digoxin body load (mg) = [digoxin serm concentration (ng/mL)] × 5.6 (L/kg) × weight (kg)/1000 Digitoxin body load (mg) = [Digitoxin serum concentration (ng/mL)] × 0.56 (L/kg) × weight (kg)/1000 NB: 5.6 and 0.56 (L/kg) are digoxin and digitoxin’s respective volumes of distribution NB: Digoxin serum concentration (nmol/L) × 0.781 = digoxin serum concentration (ng/mL or μg/L) Digitoxin serum concentration (nmol/L) × 0.765 = digoxin serum concentration (ng/mL or μg/L) Thus, the dose of Fab fragments to administer is determined as follows: One vial of 40 mg of Fab fragments (Digibind) neutralizes 0.6 mg of digitalis (digoxin or digitoxin). One vial of 80 mg of Fab fragments (Digidot) neutralizes 1 mg of digitalis (digoxin or digitoxin). To obtain equimolar neutralization, dose of Fab fragments to administer equals the total body load of digitalis: 1.7 vials of Digibind or 1 vial of Digidot for 1 mg of digitalis body load.

administration. Adverse effects associated with Fab fragment administration are rare and minor. The adverse effects potentially observed are (1) exacerbation of congestive heart failure, resistant to digoxin administration; (2) allergy; and (3) “overshoot” hypokalemia. Allergic reactions are reported in less than 1% of cases.35

SUMMARY Digitalis intoxication is a common problem in medicine today. Toxicity is manifested by many systemic symptoms, the most important of which, clinically, are cardiac arrhythmias. Virtually every known arrhythmia has been reported to be caused by digitalis excess. Finally, the most important aid in the successful treatment of digitalis intoxication is prevention through patient education. Patients’ awareness of potential problems enables them to recognize problems early. Patient education is especially important in view of the length of digitalis use. When prevention fails, in patients with chronic treatment experimenting digitalis toxicity and in patients with acute poisoning, early diagnosis is crucial is in order to rapidly undertake appropriate treatment measures. Antidotal treatment using Fab fragments is the firstline treatment. Fab fragments can be used to obtain equimolar neutralization in patients with life-threatening symptoms in order to prevent life-threatening symptom complications.

962


REFERENCES 1. Schwartz A: Is the cell membrane Na+, K+-ATPase enzyme system the pharmacological receptor for digitalis? Circ Res 1976; 39(1):1–7. 2. Silverman ME: William Withering and an account of the foxglove. Clin Cardiol 1989;12(7):415–418. 3. Ordog GJ, Benaron S, Bhasin V, et al: Serum digoxin levels and mortality in 5,100 patients. Ann Emerg Med 1987;16(1):32–39. 4. Smith TW, Haber E, Yeatman L, Butler VP Jr: Reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific antibodies. N Engl J Med 1976;294(15):797–800. 5. Beller GA, Smith TW, Abelmann WH, Haber E, Hood WB Jr: Digitalis intoxication. A prospective clinical study with serum level correlations. N Engl J Med 1971;284(18):989–997. 6. Borron SW, Bismuth C, Muszynski J: Advances in the management of digoxin toxicity in the older patient. Drugs Aging 1997; 10(1):18–33. 7. Taboulet P, Baud FJ, Bismuth C, Vicaut E: Acute digitalis intoxication—is pacing still appropriate? J Toxicol Clin Toxicol 1993;31(2):261–273. 8. Bismuth C, Motte G, Conso F, Chauvin M, Gaultier M: Acute digoxin intoxication treated by intracardiac pacemaker: experience in sixty-eight patients. Clin Toxicol 1977;10:443–456. 9. Slifman NR, Obermeyer WR, Aloi BK, et al: Contamination of botanical dietary supplements by Digitalis lanata. N Engl J Med 1998;339(12):806–811. 10. Doherty JE: Digitalis glycosides. Pharmacokinetics and their clinical implications. Ann Intern Med 1973;79(2):229–238. 11. Doherty JE, de Soyza N, Kane JJ, et al: Clinical pharmacokinetics of digitalis glycosides. Prog Cardiovasc Dis 1978;21(2):141–158. 12. Lindenbaum J, Rund DG, Butler VP Jr, et al: Inactivation of digoxin by the gut flora: reversal by antibiotic therapy. N Engl J Med 1981;305(14):789–794. 13. Smith TW: Digitalis. Mechanisms of action and clinical use. N Engl J Med 1988;318(6):358–365. 14. Arnold SB, Byrd RC, Meister W, et al: Long-term digitalis therapy improves left ventricular function in heart failure. N Engl J Med 1980;303(25):1443–1448. 15. Mulrow CD, Feussner JR, Velez R: Reevaluation of digitalis efficacy. New light on an old leaf. Ann Intern Med 1984;101(1):113–117. 16. Krum H, Bigger JT Jr, Goldsmith RL, Packer M: Effect of long-term digoxin therapy on autonomic function in patients with chronic heart failure. J Am Coll Cardiol 1995;25(2):289–294. 17. Digitalis Investigation Group: The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336(8):525–533. 18. Braunwald E: Effects of digitalis on the normal and the failing heart. J Am Coll Cardiol 1985;5(5 Suppl A):51A–59A. 19. Rosen MR: Cellular electrophysiology of digitalis toxicity. J Am Coll Cardiol 1985;5(5 Suppl A):22A–34A. 20. Bigger JT Jr: The quinidine-digoxin interaction: what do we know about it? N Engl J Med 1979;301(14):779–781. 21. Marcus FI: Pharmacokinetic interactions between digoxin and other drugs. J Am Coll Cardiol 1985;5(5 Suppl A):82A–90A. 22. Pentel PR, Salerno DM: Cardiac drug toxicity: digitalis glycosides and calcium-channel and beta-blocking agents. Med J Aust 1990;152(2):88–94. 23. Leahey EB Jr, Reiffel JA, Giardina EG, Bigger JT Jr: The effect of quinidine and other oral antiarrhythmic drugs on serum digoxin. A prospective study. Ann Intern Med 1980;92(5):605–608. 24. Nademanee K, Kannan R, Hendrickson J, et al: Amiodaronedigoxin interaction: clinical significance, time course of development, potential pharmacokinetic mechanisms and therapeutic implications. J Am Coll Cardiol 1984;4(1):111–116. 25. Klein HO, Lang R, Di Segni E, Kaplinsky E: Verapamil-digoxin interaction. N Engl J Med 1980;303(3):160. 26. Robieux I, Dorian P, Klein J, et al: The effects of cardiac transplantation and cyclosporine therapy on digoxin pharmacokinetics. J Clin Pharmacol 1992;32(4):338–343.

27. Iesaka Y, Aonuma K, Gosselin AJ, et al: Susceptibility of infarcted canine hearts to digitalis-toxic ventricular tachycardia. J Am Coll Cardiol 1983;2(1):45–51. 28. Muller JE, Turi ZG, Stone PH, et al. Digoxin therapy and mortality after myocardial infarction. Experience in the MILIS Study. N Engl J Med 1986;314(5):265–271. 29. Marchlinski FE, Hook BG, Callans DJ: Which cardiac disturbances should be treated with digoxin immune Fab (ovine) antibody? Am J Emerg Med 1991;9(2 Suppl 1):24–34. 30. Da Costa D, Brady WJ, Edhouse J: Bradycardias and atrioventricular conduction block. BMJ 2002;324(7336):535–538. 31. Mahdyoon H, Battilana G, Rosman H, et al: The evolving pattern of digoxin intoxication: observations at a large urban hospital from 1980 to 1988. Am Heart J 1990;120(5):1189–1194. 32. Brunner G, Zweiker R, Krejs GJ: A toxicological surprise. Lancet 2000;356(9239):1406. 33. Gaultier M, Welti JJ, Bismuth C, et al: [Severe digitalis intoxication. Prognostic factors. Value and limitations of electrosystolic pacemaking (apropos of 133 cases).] Ann Med Interne (Paris) 1976;127(10):761–766. 34. Pap C, Zacher G, Karteszi M [Prognosis in acute digitalis poisoning.] Orv Hetil 2005;146(11):507–513. 35. Antman EM, Wenger TL, Butler VP Jr, et al: Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. Final report of a multicenter study. Circulation 1990;81(6):1744–1752. 36. Hickey AR, Wenger TL, Carpenter VP, et al: Digoxin Immune Fab therapy in the management of digitalis intoxication: safety and efficacy results of an observational surveillance study. J Am Coll Cardiol 1991;17(3):590–598. 37. Graves SW, Brown B, Valdes R Jr: An endogenous digoxin-like substance in patients with renal impairment. Ann Intern Med 1983;99(5):604–608. 38. Smith TW: Pharmacokinetics, bioavailability and serum levels of cardiac glycosides. J Am Coll Cardiol 1985;5(5 Suppl A):43A–50A. 39. Gowda RM, Cohen RA, Khan IA: Toad venom poisoning: resemblance to digoxin toxicity and therapeutic implications. Heart 2003;89(4):e14. 40. Kwan T, Paiusco AD, Kohl L: Digitalis toxicity caused by toad venom. Chest 1992;102(3):949–950. 41. Newman LS, Feinberg MW, LeWine HE: Clinical problem-solving. A bitter tale. N Engl J Med 2004;351(6):594–599. 42. Wamboldt FS, Jefferson JW, Wamboldt MZ: Digitalis intoxication misdiagnosed as depression by primary care physicians. Am J Psychiatry 1986;143(2):219–221. 43. Chyka PA, Seger D, Krenzelok EP, Vale JA: Position paper: Singledose activated charcoal. Clin Toxicol (Phila) 2005;43(2):61–87. 44. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists: Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. J Toxicol Clin Toxicol 1999;37(6):731–751. 45. Hack JB, Woody JH, Lewis DE, et al: The effect of calcium chloride in treating hyperkalemia due to acute digoxin toxicity in a porcine model. J Toxicol Clin Toxicol 2004;42(4):337–342. 46. Chen JY, Liu PY, Chen JH, et al: Safety of transvenous temporary cardiac pacing in patients with accidental digoxin overdose and symptomatic bradycardia. Cardiology 2004;102(3):152–155. 47. Reisdorff EJ, Clark MR, Walters BL: Acute digitalis poisoning: the role of intravenous magnesium sulfate. J Emerg Med 1986;4(6): 463–469. 48. Taboulet P, Baud FJ, Bismuth C: Clinical features and management of digitalis poisoning—rationale for immunotherapy. J Toxicol Clin Toxicol 1993;31(2):247–260. 49. Smolarz A, Roesch E, Lenz E, et al: Digoxin specific antibody (Fab) fragments in 34 cases of severe digitalis intoxication. J Toxicol Clin Toxicol 1985;23(4–6):327–340. 50. Woolf AD, Wenger T, Smith TW, Lovejoy FH Jr: The use of digoxinspecific Fab fragments for severe digitalis intoxication in children. N Engl J Med 1992;326(26):1739–1744.

59

Calcium Channel Antagonists STEVEN D. SALHANICK, MD

At a Glance… ■

■

■ ■

■ ■ ■ ■

Calcium channel antagonist overdose can cause severe and prolonged toxicity resulting in a high degree of morbidity and mortality. Calcium channel antagonists are structurally diverse and vary greatly with regard to central versus peripheral cardiovascular effects. Toxicity is primarily an extension of therapeutic effects. Many xenobiotics interact with calcium channel antagonists, particularly those that are oxidized by the cytochrome P-450 system including grapefruit juice and digoxin. Care should be exercised when prescribing calcium channel antagonists in association with other xenobiotics. Early aggressive decontamination is warranted given the severity of toxicity. Virtually all forms of supportive care have been successful. Antidotes include calcium salts, but their effectiveness is debated. A promising recent development is high-dose insulin therapy, which is thought to be effective owing to correction of insulin deficiency and to its effects on myocardial energy metabolism.

Cytosolic calcium increase due to influx of calcium from the extracellular matrix has important physiologic consequences in both cardiac and vascular smooth muscle. As early as the 1960s, the negative chronotropic, inotropic, and vasodilatory effects of drugs that blocked calcium influx through cell membrane calcium channels was recognized, leading to the development of these pharmaceuticals as antiarrhythmic and antihypertensive agents.1 Subsequently, a wide variety of indications for calcium channel antagonists has been realized, including tocolysis and cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Given the prevalence of hypertensive disease, as well as the variety of indications that have been found for antagonists of calcium channels, these drugs are widely prescribed. Furthermore, given the lethal nature of these drugs in overdose, they are a frequent cause of morbidity and mortality.2 Consequently, clinicians caring for patients exposed to overdose or potential overdose of calcium channel antagonists need to be familiar with the management of such patients.

STRUCTURE Calcium channel antagonists are a structurally diverse group of drugs (Fig. 59-1). They are organized on the basis of structure and pharmacologic activity into five classes.

Phenylalkylamines Verapamil is the prototypical phenylalkylamine. Verapamil depresses sinoatrial and atrioventricular

conduction, decreases myocardial contractility, and decreases peripheral vascular resistance. Verapamil is widely prescribed for the treatment of hypertension and is frequently used to control supraventricular tachyarrhythmias. It is often prescribed in extended-release form. Verapamil undergoes N-demethylation by CYP3A3 to norverapamil, which has approximately 20% of the activity of the parent compound.

Benzothiazepines Diltiazem is the prototypical benzothiazepine. Diltiazem is notable for its depressive effects on cardiac chronotropy and contractility. Diltiazem relaxes peripheral vascular smooth muscle to a lesser extent than do other calcium channel antagonists. It is metabolized to desacetyldiltiazem, which has 25% to 50% of the pharmacologic activity of the parent drug. Diltiazem is frequently sold as a sustained-release preparation.

Dihydropyridines Nifedipine is the prototypical dihydropyridine. Dihydropyridines are the largest group of calcium channel antagonists in clinical use. Dihydropyridines are notable for their predominant effect on vascular smooth muscle. They generally have little effect on cardiac inotropy or chronotropy. They uniformly decrease peripheral vascular resistance and coronary artery blood flow. Because of its high lipid solubility, nimodipine is indicated for the prevention of cerebral artery vasospasm following aneurysmal subarachnoid hemorrhage. Nisoldipine is marketed as an antihypertensive agent.3 It is notable for low bioavailability and marked peripheral vascular selectivity. Amlodipine, felodipine, and isradipine are remarkable for delayed time to peak plasma level and delayed onset of action. Dihydropyridines frequently cause reflex tachycardia owing to their peripheral vascular selectivity.

Diarylaminopropylethers Bepridil is the prototypical diarylaminopropylether. It reduces blood pressure and heart rate in patients with stable angina. An adverse side effect profile including rate-related QTc prolongation and torsades de pointes limits its use to refractory cases of angina.4,5

Tertraline Derivatives Mibefradil is the prototypical tertraline derivative. Mibefradil is unique in that it has effects on the T-type as well as the L-type calcium channel, which is the site of action of other calcium channel antagonists.6,7 T-type channels are thought to be involved in the control of 963


Phenylalkylamines

Benzothiazepines

OCH3

CH3

H3C

J J

CH

OCH3 CH3 CH2CH2 N

C

CH2CH2CH2

CN

OH3C

H S

H

N

OCOCH3

OCH3

CH3O

K

964

O CH2CH2N(CH3)2 Verapamil

Diltiazem Dihydropyridines

CH2OCH2CH2NH2 H3C

N

H N

H3C

CH3

H

COOC2H5

Cl Amlodipine

K

H3C

COCH3 CH3 H N

COOCH3

N

CH3

COOCH CH3

N H

H3C

CH3

NO2

Felodipine

O

H

CH3 C OCH2CH2NCH2

COOCH2CH3 CO Cl H3C

COOCH3

CH3 O

J

COOH3C Cl

N

O

K

O

K

H3C

N

H

J

J

H

Nicardipine

CH3

N

COOCH2CH2OCH3

(H3C)2HCOOC

Isradipine

NO2 COOCH2CHCH3CH3

COOCH3

H N

CH3

J

H3C

NO2

NO2COCH3CH3

K

H

O

Nifedipine

Nimodipine

Nisoldipine

Diarylaminopropylethers

Tetralene Derivatives

K

O

CH2

N

J J CHJ

NJCJ CJCJOJCH2 H 2 H H2

CH3

O

O

CH3

F

N

N N H

Bepridil

Mibefradil

FIGURE 59-1 Chemical structures of the major calcium channel antagonists by class. (From Salhanick SD, Shannon MW: Management of calcium channel antagonist overdose. Drug Saf 2003;26[2]:65–79.)

supraventricular arrhythmias. They have been identified in cardiac pacemaker cells but are rare in myocytes.6,8,9 They are involved in growth regulation of fibrosis and hypertrophy following myocardial infarction, and animal data suggest that mibefradil has beneficial effects on cardiac remodeling following myocardial infarction.10-12 Mibefradil also binds at the verapamil binding site, but it has effects similar to those of dihydropyridines, affecting

vascular smooth muscle without exhibiting negative inotropic effect.7,13 Mibefradil also acts at coronary vascular smooth muscle to increase coronary blood flow.13 Mibefradil has high oral bioavailability and a long serum half-life (17 to 25 hours); it does not produce precipitous hemodynamic changes.7 It is metabolized by the cytochrome P-450 (CYP) 3A4 and 2D6 isoenzymes. Consequently, it interacts with many other drugs

CHAPTER 59

including several cardiovascular agents. Because of the large number of potential and actual drug interactions, mibefradil was voluntarily removed from the market in the United States in 1998, despite its desirable profile.14

PHARMACOLOGY Calcium flux across cell membranes provides electrical signaling in cells and coupling of these signals to changes in cytosolic calcium.15 Given the multitude of functions of cytosolic calcium, transmembrane calcium channels are of tremendous physiologic importance. Several types of calcium channel have been described. They are primarily distinguished as low voltage activated or high voltage activated. Low-voltage-activated channels are poorly understood and found primarily in cells exhibiting repetitive electrical change. They are involved in pacemaker activity of cells, including the inflow of calcium into cardiac pacemaker cells during the first phase of depolarization.16 High-voltage-activated channels respond to relatively larger changes in the transmembrane potential. They function to couple electrical signals with increases in intracellular calcium. Five types of high-voltage channels have been described; classification is based on pharmacologic properties. The first described were the L-type channels classified on the basis of their sensitivity to dihydropyridines. Later, N-type channels were described in nervous tissue based on sensitivity to ω-conotoxin, a peptide isolated from the venom of the cone snail.17 The

Calcium Channel Antagonists

P-type channels of cerebellar Purkinje neurons, Q-type channels, and aforementioned T-type channels have all been subsequently identified. Molecular structures of the different types of calcium channels have been identified and correlate well with the pharmacologic classification (Fig. 59-2). All calcium channels (low and high voltage) share the α1 subunit that contains the calcium pore and voltage sensors. The α1 subunit contains four homologous domains, each with six transmembrane subunits that come together to form a pore in the cell membrane. There are six known α1 subunits among the various types of channels. Other protein subunits include at least four β subunits and α2, γ, and δ subunits.18,19 The β subunits are nonlinked cytoplasmic proteins that affect ionic gradients, rates of activation and inactivation, and dihydropyridine binding affinity of the L-type channels.20 The α2 and δ subunits are linked to one another and affect the rate of channel activation as well as increasing the ionic gradient across the channel. The function of the γ subunit may be to amplify the actions of the β subunit.20 Because of the complex nature of the L-type calcium channel, multiple receptor sites exist for the structurally diverse calcium channel antagonists.21 The calcium channel antagonists currently available act on the L-type channels of cardiac and vascular smooth muscle cells. While L-type channels exist in skeletal muscle, the current classes of calcium channel antagonists have not shown an effect on skeletal muscle. The intracellular release of relatively large amounts of calcium from mitochondrial and sarcolemmal stores in

a1 Subunit

a1 Subunit I

II

965

III

IV

III

II

IV

H2N HOOC I a2d Subunit

b Subunit

H2N

HOOC

NH3

g Subunit

COOH

NH2 H2N

COOH

HOOC FIGURE 59-2 Molecular structure of the L-type calcium channel. (From Salhanick SD, Shannon MW: Management of calcium channel antagonist overdose. Drug Saf 2003;26[2]:65–79.)

966


skeletal muscle is less dependent on a transmembrane calcium increase as a signaling mechanism.22 L-type channels are also found in nervous tissue, but their function there is not well understood.23 Antagonism of susceptible L-type channels results primarily in effects on the heart and peripheral vascular smooth muscle. Cardiac effects include negative inotropy due to a decrease in available calcium to facilitate excitation-contraction coupling in the myocardial cells as well as negative chronotropy due to blockade of L-type channels in pacemaker cells in the sinoatrial and atrioventricular nodes. Relaxation of vascular smooth muscle results in decreased afterload, decreased systemic blood pressure, and increased coronary vascular dilatation. The effect is primarily on arterial smooth muscle and thus does not affect venous capacitance and preload. The selectivity of the various calcium channel antagonists for cardiac versus peripheral vascular effects has long been recognized. The mechanism of this selectivity is not entirely clear. Charged drugs (e.g., verapamil) appear to block calcium channels preferentially in the open state, whereas nonpolar drugs block the channel in both open and closed states. This has been invoked to explain the selectivity of verapamil and other charged compounds for rhythmically depolarizing cardiac cells and why the effects may be more pronounced on pacemaker cells, which have a relatively depolarized diastolic membrane potential.24 Additionally, as stated above, there is a degree of variability in the molecular structures of the α1 subunit and the other subunits.18,19 Consequently, calcium channel antagonists act at the particular L-type channel with the α1 subunit that has the greatest affinity for the particular drug.21

rapid. Several have been formulated as extended-release preparations. Time to peak plasma concentration with extended-release preparations is 3 to 7 hours. Several conditions as well as xenobiotics may affect the pharmacokinetics of the calcium channel antagonists. CYP3A3/4 isoenzymes and CYP1A2 isoenzyme are involved in phase one metabolism of all calcium channel antagonists.25 Diltiazem and verapamil inhibit P glycoprotein–mediated drug transportation in the gut and peripheral tissues.25 Consequently, interactions with other xenobiotics are extensive (Table 59-2). Certain examples are notable. Verapamil and diltiazem both decrease digoxin clearance and reduce its distribution to peripheral tissues. Cyclosporin and carbamazepine bioavailability are also increased.26 Lithium toxicity has been reported during verapamil therapy, but the mechanism is not known.27 Cimetidine increases diltiazem, felodipine, nicardipine, nifedipine, and nisoldipine bioavailability as a result of interactions with CYP3A3/4.26 Importantly, grapefruit juice contains spiro ortho esters that are powerful inhibitors of the intestinal CYP3A enzymes, leading to increased bioavailability of felodipine, nifedipine, and verapamil.25,28 Given the extensive hepatic metabolism of calcium channel antagonists, it is not surprising that disease states of the liver affect the pharmacokinetics of calcium channel antagonists. Verapamil has an increased half-life with both concomitant hepatic disease and reductions in hepatic blood flow.29,30 Furthermore, nifedipine clearance is linearly related to hepatic blood flow in animals.31

PHARMACOKINETICS

Acute Toxicity

TOXICOLOGY

Acute effects following calcium channel antagonist overdose are both exaggerations of the therapeutic effects due to action at the therapeutically targeted Ltype channels of the vascular system as well as other pathophysiologic effects due to cross-reactivity with lower affinity L-type channels in other tissues.

The pharmacokinetics of calcium channel antagonists is summarized in Table 59-1. The calcium channel antagonists are rapidly and nearly completely absorbed from the gastrointestinal tract but have extensive first pass metabolism. Times to peak serum levels are typically

TABLE 59-1 Pharmacokinetics of Calcium Channel Blockers ABSORPTION (%) Verapamil Diltiazem Nifedipine Amlodipine Felodipine Isradipine Nicardipine Mibefradil Nimodipine Nisoldipine Nitrendipine Bepridil

>90 >90 >90 100 – – – >90 – – >80 100

BIOAVAILABILITY (%) 10–22 30–60 65–70 60-65 10–25 15–20 15–43 70–90 6.6 8.4 10–30 60

VOLUME OF DISTRIBUTION (L/kg) 4.7 5.3 0.8–1.4 21.4 9.7 69–161 L – 369 0.94 2.3 6.6 8.0

PROTEIN BINDING (%) 90 80–90 90 >95 >99 >95 98 799 – – 98 >99

TERMINAL HALF-LIFE (hr) 3–7 4 5 35 10.2 8 5 17–25 1–2 4 12 33–48

Adapted from Pearigen PD, Benowitz NL: Poisoning due to calcium antagonists: experience with verapamil, diltiazem and nifedipine. Drug Saf 1991;6:418.

CHAPTER 59


967

TABLE 59-2 Drug Interactions Involving Calcium Channel Blockers DRUG

INTERACTING DRUG

EFFECT

PROBABLE MECHANISM

COMMENT

Verapamil Bepridil (other calcium channel blockers possible, but less likely)

β blockers

Heart block, cardiac failure, asystole (after IV verapamil)

Additive depression of AV conduction, myocardial contractility

Primarily seen with verapamil; use with caution in patients taking β blockers

Digitalis

Aggravates heart block; asystole

Additive depression of cardiac conduction

Verapamil Diltiazem

Propranolol

Inhibition of first pass metabolism

Verapamil Diltiazem Bepridil (possibly)

Digoxin

Reduced oral clearance with increased levels of propranolol Reduced digoxin clearance, increased digoxin levels

Avoid use of calcium channel blockers in patients with digitalis toxicity Propranolol dose may need to be reduced

Verapamil Diltiazem

Cyclosporine

Increased cyclosporine levels

Uncertain

Verapamil

Quinidine

Hypotension (after IV verapamil)

Additive α-adrenergic blockade

Verapamil

Prazosin

Verapamil

Halothane

Increased prazosin levels; greater hypotensive effect Bradycardia Hypotension

Verapamil Diltiazem

Disopyramide Flecainide

Cardiac failure

Reduced clearance; additive α-blocking effect Additive depression of sinus node function and myocardial contractility Additive depression of myocardial contractility

Bepridil

Ventricular arrhythmias Torsades de pointes

Additive prolongation of QT interval

Verapamil Diltiazem

Quinidine Disopyramide Procainamide Sotalol Amiodarone Flecainide

Sinus arrest Heart block

All calcium channel blockers

Oral hypoglycemic agents

Hyperglycemia

Additive depression of sinus node function and AV nodal conduction Inhibition of insulin release usually stimulated by sulfonylurea drugs

All calcium channel blockers

Cimetidine

Verapamil

Rifampin Sulfinpyrazone

Increased oral bioavailability of calcium channel blockers Reduced oral bioavailability of verapamil

The pharmacokinetics is affected by the overdose state. All calcium channel antagonists undergo some degree of first pass metabolism. Several reports describe increased drug half-lives following overdose of verapamil, nifedipine, and diltiazem.32-35 The mechanism is thought to be saturation of the microsomal CYP system enzymes. Sustainedrelease products may have delayed absorption that results in altered pharmacokinetics. Case reports describing overdose of sustained-release preparations describe a delay in symptoms by as long as 15 to 24 hours.36-38

Inhibition of metabolism and renal excretion of digoxin

Inhibition of metabolism; reduced presystemic metabolism Accelerated metabolism; increased presystemic metabolism

Reduce digoxin dose after starting verapamil or diltiazem; monitor serum digoxin concentration Reduce cyclosporine dose after starting verapamil or diltiazem; monitor cyclosporine level Use IV verapamil cautiously in patients taking quinidine or other drugs with α-blocking activity Use combination cautiously; may need to decrease prazosin dose Avoid coadministration

Avoid use if possible, particularly in patients with impaired myocardial function Avoid coadministration

Use combination with extreme caution May need to increase oral hypoglycemic doses or use insulin to maintain glucose control; beware of hypoglycemia when calcium channel blockers are discontinued Reduce calcium channel blocker dose by 30% to 40% Increase verapamil dose; use alternative calcium channel blocker with less presystemic metabolism

In overdose, cardiac versus vascular selectivity is decreased but not abolished.39,40 Vasodilatation, particularly associated with agents preferentially affecting vascular smooth muscle, results in decreased systemic vascular resistance, hypotension, and shock. The patient may appear warm and well perfused owing to a lack of vasomotor tone. Negative inotropic and chronotropic effects lead to decreased cardiac output contributing to the shock state. Cardiac ejection fractions as low as 10% have been reported in poisoned patients.40,41 Depression

968


of myocardial conduction may cause depression of the sinus rate and any degree of atrioventricular block. Increased ventricular rate has been reported following overdose as a result of increased conduction across the accessory pathway in Wolff-Parkinson-White syndrome.42 Mortality is high and is preceded by worsening shock and acidosis, culminating in cardiac arrest. Effects not directly attributable to antagonism of L-type channels of the cardiovascular system are frequently noted. Some are due to effects on calcium channels in other tissues, while others may be attributable to the shock state. Pulmonary edema not consistent with the degree of myocardial depression has been reported following overdose with verapamil and amlodipine.43-49 Precapillary vasodilatation resulting in increase in transcapillary pressure is thought to be the mechanism.50-52 Other proposed mechanisms include change in endothelial permeability due to a direct effect of calcium antagonism, prostaglandin effects, and effects secondary to the sympathetic discharge associated with toxicity.53-56 Delirium, agitation, seizures, and depressed level of consciousness have been described with calcium channel antagonist overdose.57-59 Bowel infarction and ileus have been reported; however, they may be due entirely to the shock state.41,60-64 Hyperglycemia has been well documented with calcium channel antagonist toxicity.43,65,66 Calcium influx into pancreatic islet cells via L-type channels stimulates insulin release. Nonselective blockade following calcium channel antagonist overdose with resulting hypoinsulinemia is the cause of hyperglycemia.65,67,68 The decrease in insulin production produces ketoacidosis in addition to the lactic acidosis due to shock.69

Chronic Toxicity Calcium channel antagonists are essentially free of chronic toxicity.

Adverse Effects Prolongation of the QT interval, first-degree atrioventricular block, transient elevation of transaminases, and near syncope are reported. Most calcium channel antagonists are excreted in breast milk.70 Levels in breast milk may approach plasma levels; however, there are no reports of neonatal toxicity.70 Inhibition of sperm acrosomal activity resulting in reversible infertility in males taking calcium channel antagonists therapeutically has been reported.71

DIAGNOSIS Diagnosis of calcium channel antagonist overdose includes the patient’s history. If the patient is not cooperative, medication lists should be reviewed to determine if the patient has had access to calcium channel antagonists. Prehospital care providers may have seen medication containers or prescriptions. If the patient’s pharmacy can be identified, the pharmacist

may provide information. Family members should be questioned regarding medications available to the patient. Many reports of calcium channel antagonist toxicity describe co-ingestants with additive or synergistic effects. Consequently, a careful search for co-ingestants via history and laboratory analysis should be conducted as well. The physical examination may be notable for a warm, peripherally dilated patient who is hypotensive and bradycardic. Serum levels of calcium channel antagonists are rarely available to the clinician treating the overdosed patient. An elevated serum glucose level may be present and support the diagnosis. The presence of ketoacidosis should be determined, since it also supports the diagnosis. An electrocardiogram should be obtained to diagnose the presence of bradyarrhythmia that may be amenable to therapy. In cases of severe shock, invasive hemodynamic monitoring may confirm the decreased systemic resistance and provide evidence of response to therapy. The differential diagnosis includes anything that may cause peripheral vasodilatation or bradyarrhythmia including myocardial infarction, insult to the cardiac conduction system, and ingestion of other vasoactive xenobiotic (e.g., β-adrenergic antagonists, clinidine, guanfacine, and digoxin).

MANAGEMENT Supportive Measures Initial supportive care should be aggressive owing to the high mortality associated with calcium channel antagonist overdose and the potential for rapid progression of symptoms. Large-bore intravenous access must be obtained. Continuous cardiac monitoring should be initiated. Airway and ventilatory support should be provided early because of the difficulties associated with intubation in the profoundly hypotensive patient. No clear consensus exists regarding the optimal regimen for supportive care of the patient. Nearly every form of cardiovascular support has been tried, all with some reported success. Intravenous fluid therapy is typically initiated early following calcium channel antagonist overdose. Care should be exercised, however, given the aforementioned propensity of patients to develop pulmonary edema. Furthermore, these patients are not necessarily volume depleted; consequently, administration of large volumes of fluid should be avoided in favor of early administration of pharmacologic support or an antidote to avoid the complications of fluid overload. The choice of pharmacologic supportive agents is best guided by the hemodynamic picture, since no single agent is clearly more beneficial than the others. Adrenergic agents such as dopamine, norepinephrine, or epinephrine should be initiated in the setting of significant toxicity. The choice of agent should be determined by the clinician’s comfort with the agent administered and the clinical picture, with α-adrenergic agents administered to treat peripheral toxicity and

CHAPTER 59

β-adrenergic agents administered to treat cardiac manifestations of toxicity. Atropine may be given to treat bradycardia likely to be responsive. Obtaining adequate hemodynamic data may require invasive hemodynamic monitoring, including the placement of arterial lines, central venous catheters, or pulmonary artery catheters. Amrinone deserves special mention in the treatment of calcium channel antagonist toxicity. Amrinone inhibits phosphodiesterase III (found in cardiac and vascular tissues), resulting in decreased cyclic adenosine monophosphate (cAMP) breakdown. The increase in cAMP results in greater phosphorylation of L-type calcium channels, which increases their permeability to calcium ions. Amrinone does not increase myocardial oxygen demand as the catecholamines do. Data supporting the use of amrinone are limited, however. Amrinone has been shown to reverse myocardial depression in rats and dogs with verapamil toxicity.72-74 Human case reports describing beneficial effect of amrinone also have been published.75,76 Caution should be exercised, since amrinone can induce relaxation of vascular smooth muscle, potentially worsening the peripheral effects of calcium channel antagonists. Phosphodiesterase inhibitors thus have attractive properties for use in the management of calcium channel antagonist toxicity. Mechanical inotropic supportive measures may be necessary if pharmacologic measures fail. Transvenous pacing has been reported in several cases with varying results.59,77-84 Balloon pump and bypass have been successful therapies.41,69,81,83,85 Given the limited data, these therapies should be reserved for cases in which pharmacologic measures have failed.


969

protect from aspiration should be strongly considered. If whole-bowel irrigation is not feasible, multiple doses of activated charcoal may be considered although evidence of the clinical value of this intervention is lacking.

Laboratory Monitoring As mentioned above, levels of calcium channel antagonists are generally not available in time to be useful. Several laboratory studies may be helpful, however. Serum electrolytes should be monitored to prevent arrhythmogenic abnormalities that may occur during therapy. Serum calcium concentrations are imperative when therapy with calcium salts is performed. Arterial blood gasses may be used to monitor acidosis. Serum digoxin concentrations should be obtained in anticipation of administration of calcium salts. Calcium channel blocker overdose has no effect on total or ionized serum calcium concentrations.

Antidotes Several antidotes have been used for the treatment of calcium channel antagonist toxicity.

Decontamination

4-AMINOPYRIDINE 4-Aminopyridine is a potassium channel antagonist that causes an increase in intracellular calcium concentration by increasing calcium inflow across the L-type channel and an increase in calcium release from intracellular stores in the sarcoplasmic reticulum.88 4-Aminopyridine has improves hemodynamic parameters in cats and dogs.89,90 Human use has been reported, but safety and efficacy remain in question.91

Following performance of initial supportive measures (airway control, intravenous access), appropriate decontamination measures should be instituted. Activated charcoal is generally the best option, since it likely will absorb the greatest amount of ingested drug, is less invasive, and has fewer complications than gastric emptying procedures. Emesis induction should not be attempted given the risk for rapid deterioration in hemodynamic status, the difficulty of airway control and other therapeutic measures, and risk of aspiration in the patient with uncontrollable emesis. Gastric lavage with a No. 36 to 40 French tube (24 to 28 for children) should be considered with caution. Lavage should be considered only after life-threatening ingestions within 1 hour of the ingestion. Importantly, gastric lavage may cause vagal stimulation, leading to death in patients with heart block or other bradyarrhythmias. Patients with a bradyarrhythmia should not undergo lavage. Wholebowel irrigation with polyethylene glycol solution is recommended following overdose of sustained-release preparations.86-88 Many calcium channel antagonists are formulated as sustained-release preparations, and these are frequently implicated in toxicity.2 Whole-bowel irrigation should not be performed when the patient has ileus. Furthermore, nursing care is made more difficult when the unstable patient is producing a large amount of liquid stool. Vomiting is a risk, and airway control to

CALCIUM SALTS Calcium salts are frequently employed in the management of calcium channel antagonist overdose.38,92 Calcium salts are a reasonable first agent, since they are readily available and easily administered. Reports of this use of calcium salts date to the mid-1970s, and thus calcium is the first antidote reported in the English literature.93 The use of calcium salts is controversial, however. Animal data generally have been positive. Rats and rabbits given 5 to 15 mg/kg/min calcium chloride or gluconate with concurrent administration of nifedipine showed increased survival time, blood pressure, stroke volume, and cardiac output over controls; however, conduction disturbances were not affected.94 Furthermore, serum calcium concentrations correlated with increases in blood pressure and cardiac output following calcium chloride administration to verapamil-poisoned dogs.95 Human case reports show conflicting results. Several authors report minimal or no response to the administration of calcium salts to treat severe calcium channel antagonist toxicity.48,66,96-98 Proponents of the use of calcium argue that most of the reports of failed therapy are due to underdosing and that high doses of calcium are effective as antidote and without adverse effects.45 Several recommendations have been published for the administration of calcium salts. Calcium chloride has

970


been administered in bolus doses of 1 g every 15 to 20 minutes for a total of four doses or more aggressively as 1 g every 2 to 3 minutes until clinical effect is achieved.45 Continuous infusion of 0.2 to 0.4 mg/kg/hr calcium chloride (0.6 to 1.2 mg/kg/hr calcium gluconate) has been recommended.40,99 Buckley and colleagues reported giving 30 g calcium chloride over 12 hours resulting in a plasma calcium level of 23.8 mg/dL with hemodynamic improvement and no adverse clinical effects.45 Lam and colleagues advocate titrating calcium infusion to maintain a serum calcium level of 8 mg/dL.100 Howarth and associates recommend continuous infusion titrated to improvement in hemodynamic parameters.48 Initial bolus administration of calcium salts followed by measurement of serum calcium at a minimum of every 12 hours is reasonable practice. Serum calcium levels should be maintained in the normal range because of the lack of evidence for efficacy of above-normal concentrations. Other modes of therapy should be added if calcium therapy does not rapidly improve hemodynamic parameters. Several precautions should be taken during calcium therapy. Careful maintenance of intravenous sites is essential to prevent tissue damage due to extravasation of calcium chloride. Continuous cardiac monitoring and at least daily electrocardiograms should be performed to prevent arrythmias.100 Calcium should not be administered if there is an elevated digoxin level or if the clinician has reason to believe that digoxin ingestion may have occurred, because of the concern for resulting lifethreatening arrythmias.101-103 The effect of administering exogenous calcium to patients with therapeutic digoxin serum concentrations and calcium channel antagonist toxicity is unknown. It is prudent to obtain the digoxin concentration before initiation of calcium therapy and to withhold calcium therapy if a measurable digoxin concentration is present, because of the potential for concurrent overdose of digoxin, the unclear interaction between calcium and therapeutic digoxin concentrations, and the availability of other therapies. INSULIN Insulin as an antidote for calcium channel antagonist poisoning is based on several observations.104 Hyperglycemia in calcium channel antagonist toxicity is due to blockade of pancreatic L-type channels that results in decreased insulin production.66 Furthermore, calcium channel antagonist toxicity results in decrease in uptake of insulin or free fatty acids by the myocardium as well as a shift from oxidation of fatty acids to carbohydrates for the production of energy.69 Insulin increases cellular uptake of glucose and lactate and improves hemodynamic parameters in verapamil-poisoned dogs.104 Furthermore, measurement of the myocardial respiratory quotient and the ratio of myocardial oxygen delivery to myocardial work indicates that insulin therapy of verapamil-poisoned dogs causes an increase in energy efficiency of myocardial metabolism.104 Insulin improves survival in critically ill patients owing to a variety of causes regardless of degree of hyperglycemia or insulin resistance.105

Human data support the use of insulin as an antidote for calcium channel antagonist toxicity. Yuan and associates reported on three patients with verapamil toxicity and one with amlodipine and atenolol toxicity refractory to calcium salts, fluids, and vasopressors. Patients received bolus doses of 10 to 20 IU of regular insulin followed by a continuous insulin infusion of 0.1 to 1.0 IU/kg/hr. All patients showed improvement in hemodynamic parameters temporally associated with insulin administration.69 Serum verapamil concentrations obtained from two of these patients were markedly elevated, yet all patients survived without sequelae.69 Boyer and Shannon reported on two patients who failed to respond to calcium or glucagon and aggressive supportive care, yet responded rapidly to insulin administration at 0.5 IU/kg/hr.106 Supplemental glucose was required for only one of the patients. Insulin therapy with supplemental glucose as needed should therefore be initiated early in the treatment of calcium channel antagonist toxicity. The preferred regimen at the author’s institution for insulin therapy is as follows. Adult patients with serum glucose levels greater than 200 mg/dL receive one ampule (50 mL of 50% solution) of D-glucose (0.25 g/kg D-glucose for children). A serum potassium concentration of less than 2.5 mEq/dL is treated with 40 mEq orally or 20 mEq of potassium intravenously. A bolus dose of insulin, 1.0 U/kg, is given followed by an infusion at 0.5 to 1.0 IU/kg/hr titrated to clinical response. Therapeutic targets include a systolic blood pressure greater than 100 mm Hg and a sinus rhythm of greater than 50 beats per minute. Capillary glucose is checked every 20 minutes for 1 hour and then hourly thereafter. Serum potassium is checked hourly. Fluid therapy is halfnormal saline with 10% dextrose at an infusion rate equal to 80% of maintenance. Insulin infusion is weaned as toxicity resolves. k Hyperinsulinemia, euglycemia (HIE) is the term applied to the use of insulin as an antidote given the large doses of insulin administered. GLUCAGON Glucagon has been recommended as an antidote for calcium channel antagonist therapy in prior editions of this and in other standard texts. Glucagon has a specific receptor on the surface of the myocyte.107 Binding results in the stimulation of adenyl cyclase via G proteins followed by increased intracellular cyclic AMP, phosphorylation of L-type calcium channels, and influx of calcium.108 In addition, the C-terminal portion of glucagon is cleaved to miniglucagon, which releases calcium from the sarcoplasmic reticulum.109 Miniglucagon increases inotropy in embryonic chick ventricular myocytes. In vitro administration of both glucagon and miniglucagon produced a synergistic positive inotropic effect, thought to be due to effects on the L-type channel and the sarcoplasmic reticulum.109 Multiple studies show increased inotropy, chronotropy, and dromotropy following glucagon administration to animals poisoned by calcium channel antagonists.110-114 Human case reports are less conclusive, since they are confounded by multiple treatment regimens and uncontrolled conditions. The majority, however, describe

CHAPTER 59


971

Patient presents with calcium channel antagonist overdose

Clinical evidence of toxicity (hypotension, bradycardia)

Yes

No

Sustained release preparation

Single dose activated charcoal Observe in monitored setting > 12 hours (>24 If sustained release preparation)

No

Yes

Consider single dose activated charcoal

Whole bowel irrigation or multiple dose activated charcoal*

Initiate therapy**: Bolus calcium (Digoxin toxicity ruled out) Atropine (for bradycardias likely to be responsive) Insulin/Glucose Calcium infusion Phosphodiesterase inhibitors Glucagon Adrenergic agents Pacing Balloon pump Extracorporeal bypass *Efficacy not proven but potential benefits exceed risks in most circumstances **Therapy may need to be started prior to decontamination if patient is unstable

FIGURE 59-3 Algorithmic approach to the management of the patient with calcium channel antagonist toxicity.

beneficial effects on hemodynamic parameters following glucagon administration.76,115,116 The effects of glucagon begin within 1 to 3 minutes, peak at 5 to 7 minutes, and decline by 15 minutes.117 Doses between 0.5 and 14 mg intravenously have been reported, but typical dosing is 1 to 10 mg as an intravenous bolus followed by infusions of 3 to 6 mg/hr.115,116,118 The maintenance dose is determined by the initial effective dose, with the initial dose required to obtain response given as continuous infusion over 1 hour. The initial recommended pediatric dose is 50 to 150 μg/kg.119 Adverse effects of glucagon include nausea, vomiting, flushing, hyperglycemia, smooth muscle relaxation, and intestinal ileus.

Elimination No methods are known to enhance the elimination or metabolism of calcium channel antagonists. The high degree of protein binding and volumes of distribution generally larger than 1 L/kg make dialysis unlikely to be beneficial, and no benefit has ever been reported.

Significant enterohepatic circulation has not been demonstrated. Furthermore, gut dialysis with multipledose charcoal is not known to occur.

Disposition Given the severity of calcium channel antagonist toxicity and the potential for delayed toxicity, patients with a history of ingestion should be observed in a monitored setting for a minimum of 12 hours. If there is a question whether a sustained-release preparation is involved, the period of observation should be extended to 24 hours. Patients exhibiting signs of toxicity should be treated in an intensive care unit. Following resolution of toxicity, a careful search should be conducted for sequelae of prolonged hypotension including bowel infarction, stroke, and subendocardial myocardial infarction and those issues treated accordingly. An algorithmic approach to the care of the patient suffering calcium channel antagonist toxicity is shown in Figure 59-3. As always, psychiatric evaluation is prudent following intentional ingestion. The causes of therapeutic mis-

972


adventure should be investigated as well. Finally, a nonjudgmental evaluation of home safety should occur in cases of pediatric ingestion. REFERENCES 1. Kerins DM, Robertson RM, Robertson D: Drugs used for the treatment of myocardial ischemia. In Limbard LE, Hardman JG, Gilman AG (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New York, McGraw-Hill, 2001, p 853. 2. Litovitz TL, Klein-Schwartz W, Rodgers GC Jr, et al: 2001 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2002; 20:391–452. 3. Godfraind T, Salomone S, Dessy C, et al: Selectivity scale of calcium antagonists in the human cardiovascular system based on in vitro studies. J Cardiovasc Pharmacol 1992;20(Suppl 5): S34–S41. 4. Zusman RM, Higgins J, Christensen D, Boucher CA: Bepridil improves left ventricular performance in patients with angina pectoris. J Cardiovasc Pharmacol 1993;22:474–480. 5. Hollingshead LM, Faulds D, Fitton A: Bepridil: a review of its pharmacological properties and therapeutic use in stable angina pectoris. Drugs 1992;44:835–857. 6. Mishra SK, Hermsmeyer K: Selective inhibition of T-type Ca2+ channels by Ro 40-5967. Circ Res 1994;75:144–148. 7. Fang LM, Osterrieder W: Potential-dependent inhibition of cardiac Ca2+ inward currents by Ro 40-5967 and verapamil: relation to negative inotropy. Eur J Pharmacol 1991;196:205–207. 8. Bean BP: Classes of calcium channels in vertebrate cells. Ann Rev Physiol 1989;51:367–384. 9. Tseng GN, Boyden PA: Multiple types of Ca2+ currents in single canine Purkinje cells. Circ Res 1989;65:1735–1750. 10. Sandmann S, Bohle RM, Dreyer T, Unger T: The T-type calcium channel blocker mibefradil reduced interstitial and perivascular fibrosis and improved hemodynamic parameters in myocardial infarction-induced cardiac failure in rats. Virchows Archiv 2000;436:147–157. 11. Sandmann S, Claas R, Cleutjens JP, et al: Calcium channel blockade limits cardiac remodeling and improves cardiac function in myocardial infarction-induced heart failure in rats. J Cardiovasc Pharmacol 2001;37:64–77. 12. Sandmann S, Spitznagel H, Chung O, et al: Effects of the calcium channel antagonist mibefradil on haemodynamic and morphological parameters in myocardial infarction-induced cardiac failure in rats (comment). Cardiovasc Res 1998;39:339–350. 13. Osterrieder W, Holck M: In vitro pharmacologic profile of Ro 405967 a novel Ca2+ channel blocker with potent vasodilator but weak inotropic action. J Cardiovasc Pharmacol 1989;13:754–759. 14. Glasser SP: The relevance of T-type calcium antagonists: a profile of mibefradil. J Clin Pharmacol 1998;38:659–669. 15. Hille B: Ionic channels in excitable membranes. Current problems and biophysical approaches. Biophys J 1978;22:283–294. 16. Perez-Reyes E, Lee JH, Cribbs LL: Molecular characterization of a neuronal low-voltage-activated T-type calcium channel (comment). Nature 1998;391(6670):896–900. 17. Plummer MR, Logothetis DE, Hess P: Elementary properties and pharmacological sensitivities of calcium channels in mammalian peripheral neurons. Neuron 1989;2:1453–1463. 18. Mitterdorfer J, Grabner M, Kraus RL, et al: Molecular basis of drug interaction with L-type Ca2+ channels. J Bioenerg Biomembr 1998;30:319–334. 19. Catterall WA: Molecular properties of sodium and calcium channels. J Bioenerg Biomembr 1996;28:219–230. 20. Clusin WT, Anderson ME: Calcium channel blockers: current controversies and basic mechanisms of action. Adv Pharmacol 1999;46:253–296. 21. Welling A, Ludwig A, Zimmer S, et al: Alternatively spliced IS6 segments of the alpha 1C gene determine the tissue-specific dihydropyridine sensitivity of cardiac and vascular smooth muscle L-type Ca2+ channels. Circ Res 1997;81:526–532. 22. Braunwald E: Mechanism of action of calcium-channel-blocking agents. N Engl J Med 1982;307:1618–1627.

23. Siesjo BK: Calcium-mediated processes in neuronal degeneration. Ann N Y Acad Sci 1994;747:140–161. 24. Bers DM, Perez-Reyes E: Ca channels in cardiac myocytes: structure and function in Ca influx and intracellular Ca release. Cardiovasc Res 1999;42:339–360. 25. Abernethy DR, Schwartz JB: Calcium-antagonist drugs. N Engl J Med 1999;341:1447–1457. 26. Shah S, Shah AN, Shaw LM: Calcium channel blockers: an overview. In Kwon T, Shaw LM, Rosano TG, et al (eds): The Clinical Toxicology Laboratory Contemporary Practice of Poisoning Evaluation. Washington, DC, AACC Press, 2001, pp 291–:328. 27. Price WA, Giannini AJ: Neurotoxicity caused by lithium-verapamil synergism. J Clin Pharmacol 1986;26:717–719. 28. Rouhi AM: Citrus chemistry boosts drugs. Chem Eng News 2003;81:38–39. 29. Somogyi A, Albrecht M, Kliems G, et al: Pharmacokinetics, bioavailability and ECG response of verapamil in patients with liver cirrhosis. Br J Clin Pharmacol 1981;12:51–60. 30. Woodcock BG, Rietbrock N: Verapamil bioavailability and dosage in liver disease. Br J Clin Pharmacol 1982;13:240–241. 31. McAllister RG Jr, Hamann SR, Blouin RA: Pharmacokinetics of calcium-entry blockers. Am J Cardiol 1985;55:30B–40B. 32. Buckley CD, Aronson JK: Prolonged half-life of verapamil in a case of overdose: implications for therapy. Br J Clin Pharmacol 1995;39:680–683. 33. Ferner RE, Monkman S, Riley J, et al: Pharmacokinetics and toxic effects of nifedipine in massive overdose. Hum Exp Toxicol 1990;9:309–311. 34. Ferner RE, Odemuyiwa O, Field AB, et al: Pharmacokinetics and toxic effects of diltiazem in massive overdose. Hum Toxicol 1989;8:497–499. 35. Roberts D, Honcharik N, Sitar DS, Tenenbein M: Diltiazem overdose: pharmacokinetics of diltiazem and its metabolites and effect of multiple dose charcoal therapy. J Toxicol Clin Toxicol 1991;29:45–52. 36. Spiller HA, Meyers A, Ziemba T, Riley M: Delayed onset of cardiac arrhythmias from sustained-release verapamil. Ann Emerg Med 1991;20:201–203. 37. Tom PA, Morrow CT, Kelen GD: Delayed hypotension after overdose of sustained release verapamil. J Emerg Med 1994; 12:621–625. 38. Ramoska EA, Spiller HA, Winter M, Borys D: A one-year evaluation of calcium channel blocker overdoses: toxicity and treatment. Ann Emerg Med 1993;22:196–200. 39. Proano L, Chiang WK, Wang RY: Calcium channel blocker overdose. Am J Emerg Med 1995;13:444–450. 40. Pearigen PD, Benowitz NL: Poisoning due to calcium antagonists: experience with verapamil, diltiazem and nifedipine. Drug Saf 1991;6:408–430. 41. Salhanick SD, Wax PM: Treatment of atenolol overdose in a patient with renal failure using serial hemodialysis and hemoperfusion and associated echocardiographic findings. Vet Hum Toxicol 2000;42:224–225. 42. McGovern B, Garan H, Ruskin JN: Precipitation of cardiac arrest by verapamil in patients with Wolff-Parkinson-White syndrome. Ann Intern Med 1986;104:791–794. 43. Brass BJ, Winchester-Penny S, Lipper BL: Massive verapamil overdose complicated by noncardiogenic pulmonary edema. Am J Emerg Med 1996;14:459–461. 44. Stanek EJ, Nelson CE, DeNofrio D: Amlodipine overdose (comment). Ann Pharmacother 1997;31:853–856. 45. Buckley NA, Whyte IM, Dawson AH: Overdose with calcium channel blockers (comment). BMJ 1994;308(6944):1639. 46. Gelbke HP, Schlicht HJ, Schmidt G: Fatal poisoning with verapamil. Arch Toxicol 1977;37:89–94. 47. Herrington DM, Insley BM, Weinmann GG: Nifedipine overdose. Am J Med 1986;81:344–346. 48. Howarth DM, Dawson AH, Smith AJ, et al: Calcium channel blocking drug overdose: an Australian series. Hum Exp Toxicol 1994;13:161–166. 49. Leesar MA, Martyn R, Talley JD, Frumin H: Noncardiogenic pulmonary edema complicating massive verapamil overdose. Chest 1994;105:606–607.

CHAPTER 59

50. Humbert VH Jr, Munn NJ, Hawkins RF: Noncardiogenic pulmonary edema complicating massive diltiazem overdose. Chest 1991;99:258–259. 51. Gustafsson D: Microvascular mechanisms involved in calcium antagonist edema formation. J Cardiovasc Pharmacol 1987; 10(Suppl 1):S121–S131. 52. Low RI, Takeda P, Mason DT, DeMaria AN: The effects of calcium channel blocking agents on cardiovascular function. Am J Cardiol 1982;49:547–553. 53. Green K, Cheeks L, Hull DS: Effects of calcium channel blockers on rabbit corneal endothelial function. Curr Eye Res 1994;13:401–408. 54. Payne DK, Fuseler JW, Owens MW: Modulation of endothelial cell permeability by lung carcinoma cells: a potential mechanism of malignant pleural effusion formation. Inflammation 1994;18: 407–417. 55. Fedorak RN, Empey LR, Walker K: Verapamil alters eicosanoid synthesis and accelerates healing during experimental colitis in rats. Gastroenterology 1992;102(4 pt 1):1229–1235. 56. Simon RP: Neurogenic pulmonary edema. Neurol Clin 1993; 11:309–323. 57. Malcolm N, Callegari P, Goldberg J, et al: Massive diltiazem overdosage: clinical and pharmacokinetic observations. Drug Intell Clin Pharm 1986;20:888. 58. Wells TG, Graham CJ, Moss MM, Kearns GL: Nifedipine poisoning in a child. Pediatrics 1990;86:91–94. 59. Horowitz BZ, Rhee KJ: Massive verapamil ingestion: a report of two cases and a review of the literature. Am J Emerg Med 1989;7:624–631. 60. Fauville JP, Hantson P, Honore P, et al: Severe diltiazem poisoning with intestinal pseudo-obstruction: case report and toxicological data. J Toxicol Clin Toxicol 1995;33:273–277. 61. Goglin WK, Elliott BM, Deppe SA: Nifedipine-induced hypotension and mesenteric ischemia. South Med J 1989;82:274–275. 62. Gutierrez H, Jorgensen M: Colonic ischemia after verapamil overdose. Ann Intern Med 1996;124:535. 63. Sporer KA, Manning JJ: Massive ingestion of sustained-release verapamil with a concretion and bowel infarction. Ann Emerg Med 1993;22:603–605. 64. Wax PM: Intestinal infarction due to nifedipine overdose. J Toxicol Clin Toxicol 1995;33:725–728. 65. Devis G, Somers G, Van Obberghen E, Malaisse WJ: Calcium antagonists and islet function. 1. Inhibition of insulin release by verapamil. Diabetes 1975;24:247–251. 66. Enyeart JJ, Price WA, Hoffman DA, Woods L: Profound hyperglycemia and metabolic acidosis after verapamil overdose. J Am Coll Cardiol 1983;2:1228–1231. 67. Lebrun P, Malaisse WJ, Herchuelz A: Nutrient-induced intracellular calcium movement in rat pancreatic B cell. Am J Physiol 1982;243:E196–E205. 68. Malaisse WJ: Role of calcium in insulin secretion. Isr J Med Sci 1972;8:244–251. 69. Yuan TH, Kerns WP II, Tomaszewski CA, Ford MD, et al: Insulinglucose as adjunctive therapy for severe calcium channel antagonist poisoning. J Toxicol Clin Toxicol 1999;37:463–474. 70. Briggs GG, Freeman RK, Yaffe SJ: Drugs in Pregnancy and Lactation, 5th ed. Baltimore, Williams & Wilkins, 1998. 71. Benoff S, Cooper GW, Hurley I, et al: The effect of calcium ion channel blockers on sperm fertilization potential. Fertil Steril 1994;62:606–617. 72. Tuncok Y, Apaydin S, Gidener S, et al: The effects of amrinone and glucagon on verapamil-induced myocardial depression in a rat isolated heart model. Gen Pharmacol 1997;28:773–776. 73. Alousi AA, Canter JM, Fort DJ: The beneficial effect of amrinone on acute drug-induced heart failure in the anaesthetised dog. Cardiovasc Res 1985;19:483–494. 74. Makela VH, Kapur PA: Amrinone and verapamil-propranolol induced cardiac depression during isoflurane anesthesia in dogs. Anesthesiology 1987;66:792–797. 75. Goenen M, Col J, Compere A, Bonte J: Treatment of severe verapamil poisoning with combined amrinone-isoproterenol therapy. Am J Cardiol 1986;58:1142–1143. 76. Wolf LR, Spadafora MP, Otten EJ: Use of amrinone and glucagon in a case of calcium channel blocker overdose. Ann Emerg Med 1993;22:1225–1228.


973

77. Ramoska EA, Spiller HA, Myers A: Calcium channel blocker toxicity. Ann Emerg Med 1990;19:649–653. 78. Snover SW, Bocchino V: Massive diltiazem overdose. Ann Emerg Med 1986;15:1221–1224. 79. Watling SM, Crain JL, Edwards TD, Stiller RA: Verapamil overdose: case report and review of the literature. Ann Pharmacother 1992;26:1373–1378. 80. Hofer CA, Smith JK, Tenholder MF: Verapamil intoxication: a literature review of overdoses and discussion of therapeutic options. Am J Med 1993;95:431–438. 81. Hendren WG, Schieber RS, Garrettson LK: Extracorporeal bypass for the treatment of verapamil poisoning. Ann Emerg Med 1989;18:984–987. 82. Ishikawa T, Imamura T, Koiwaya Y, Tanaka K: Atrioventricular dissociation and sinus arrest induced by oral diltiazem. N Engl J Med 1983;309:1124–1125. 83. Frierson J, Bailly D, Shultz T, Sund S, Dimas A, et al: Refractory cardiogenic shock and complete heart block after unsuspected verapamil-SR and atenolol overdose. Clin Cardiol 1991;14:933–935. 84. Orr GM, Bodansky HJ, Dymond DS, Taylor M: Fatal verapamil overdose. Lancet 1982;2(8309):1218–1219. 85. Holzer M, Sterz F, Schoerkhuber W, et al: Successful resuscitation of a verapamil-intoxicated patient with percutaneous cardiopulmonary bypass. Crit Care Med 1999;27:2818–2823. 86. Tenenbein M, Cohen S, Sitar DS: Whole bowel irrigation as a decontamination procedure after acute drug overdose. Arch Intern Med 1987;147:905–907. 87. Tenenbein M: Whole bowel irrigation and activated charcoal. Ann Emerg Med 1989;18:707–708. 88. Kirshenbaum LA, Mathews SC, Sitar DS, Tenenbein M: Wholebowel irrigation versus activated charcoal in sorbitol for the ingestion of modified-release pharmaceuticals. Clin Pharmacol Ther 1989;46:264–271. 89. Agoston S, Maestrone E, van Hezik EJ, et al: Effective treatment of verapamil intoxication with 4-aminopyridine in the cat. J Clin Invest 1984;73:1291–1296. 90. Gay R, Algeo S, Lee R, et al: Treatment of verapamil toxicity in intact dogs. J Clin Invest 1986;77:1805–1811. 91. ter Wee PM, Kremer Hovinga TK, Uges DR, van der Geest S: 4Aminopyridine and haemodialysis in the treatment of verapamil intoxication. Hum Toxicol 1985;4:327–329. 92. Belson MG, Gorman SE, Sullivan K, Geller RJ: Calcium channel blocker ingestions in children (comment). Am J Emerg Med 2000;18:581–586. 93. Perkins CM: Serious verapamil poisoning: treatment with intravenous calcium gluconate. BMJ 1978;2(6145):1127. 94. Strubelt O, Diederich KW: Experimental investigations on the antidotal treatment of nifedipine overdosage. J Toxicol Clin Toxicol 1986;24:135–149. 95. Hariman RJ, Mangiardi LM, McAllister RG Jr, et al: Reversal of the cardiovascular effects of verapamil by calcium and sodium: differences between electrophysiologic and hemodynamic responses. Circulation 1979;59:797–804. 96. Crump BJ, Holt DW, Vale JA: Lack of response to intravenous calcium in severe verapamil poisoning. Lancet 1982;2(8304): 939–940. 97. MacDonald D, Alguire PC: Case report: fatal overdose with sustained-release verapamil. Am J Med Sci 1992;303:115–117. 98. Haddad LM: Resuscitation after nifedipine overdose exclusively with intravenous calcium chloride. Am J Emerg Med 1996;14: 602–603. 99. Kenny J: Treating overdose with calcium channel blockers (comment). BMJ 1994;308(6935):992–993. 100. Lam YM, Tse HF, Lau CP: Continuous calcium chloride infusion for massive nifedipine overdose. Chest 2001;119:1280–1282. 101. Gold H, et al: The effects of ouabain on the heart in the presence of hypercalcemia. Am Heart J 1927;3:45–50. 102. Nola GT, Pope S, Harrison DC: Assessment of the synergistic relationship between serum calcium and digitalis. Am Heart J 1970;79:499–507. 103. Smith PK, et al: Calcium and digitalis synergism: the toxicity of calcium salts injected intravenously into digitalized animals. Arch Intern Med 1939;64:322–328.

974


104. Kline JA, Leonova E, Raymond RM: Beneficial myocardial metabolic effects of insulin during verapamil toxicity in the anesthetized canine. Crit Care Med 1995;23:1251–1263. 105. van den Berghe G, Wouters P, Weekers F, et al: Intensive insulin therapy in the critically ill patients (comment). N Engl J Med 2001;345:1359–1367. 106. Boyer EW, Shannon M: Treatment of calcium-channel-blocker intoxication with insulin infusion. N Engl J Med 2001;344: 1721–1722. 107. Levey GS, Fletcher MA, Klein I, et al: Characterization of 125Iglucagon binding in a solubilized preparation of cat myocardial adenylate cyclase: further evidence for a dissociable receptor site. J Biol Chem 1974;249:2665–2673. 108. Mery PF, Fischmeister R: Glucagon stimulates the cardiac Ca2+ current by activation of adenylyl cyclase and inhibition of phosphodiesterase. Nature 1990;345(6271):158–161. 109. Sauvadet A, Rohn T, Pecker F, Pavoine C: Synergistic actions of glucagon and miniglucagon on Ca2+ mobilization in cardiac cells. Circ Res 1996;78:102–109. 110. Stone CK, Thomas SH, Koury SI, Low RB: Glucagon and phenylephrine combination vs glucagon alone in experimental verapamil overdose (comment). Acad Emerg Med 1996;3:120–125. 111. Stone CK, May WA, Carroll R: Treatment of verapamil overdose with glucagon in dogs. Ann Emerg Med 1995;25:369–374.

112. Zaritsky AL, Horowitz M, Chernow B: Glucagon antagonism of calcium channel blocker-induced myocardial dysfunction. Crit Care Med 1988;16:246–251. 113. Sabatier J, Pouyet T, Shelvey G, Cavero I: Antagonistic effects of epinephrine, glucagon and methylatropine but not calcium chloride against atrio-ventricular conduction disturbances produced by high doses of diltiazem, in conscious dogs. Fundam Clin Pharmacol 1991;5:93–106. 114. Jolly SR, Kipnis JN, Lucchesi BR: Cardiovascular depression by verapamil: reversal by glucagon and interactions with propranolol. Pharmacology 1987;35:249–255. 115. Doyon S, Roberts JR: The use of glucagon in a case of calcium channel blocker overdose. Ann Emerg Med 1993;22:1229–1233. 116. Walter FG, Frye G, Mullen JT, et al: Amelioration of nifedipine poisoning associated with glucagon therapy. Ann Emerg Med 1993;22:1234–1237. 117. Parmley WW, Glick G, Sonnenblick EH: Cardiovascular effects of glucagon in man. N Engl J Med 1968;279:12–17. 118. Love JN, Sachdeva DK, Bessman ES, et al: A potential role for glucagon in the treatment of drug-induced symptomatic bradycardia. Chest 1998;114:323–326. 119. DeRoos F: Calcium channel blockers. In Goldfrank LR, Howland MA, Flomenbaum NE, et al (eds): Goldfrank’s Toxicologic Emergencies. New York, McGraw-Hill, 2002, p 768.

60

b-Adrenergic Antagonists STEVEN B. BIRD, MD


The classic presentation of overdose is bradycardia, hypotension, hypoglycemia, and decreased mental status. Some agents may produce tachycardia and hypertension. Glucagon is the treatment of choice for bradycardia and hypotension. Combined pharmacologic therapy is often needed in moderateto-severe poisoning. Invasive measures such as transvenous pacing, intra-aortic balloon counterpulsion, and cardiopulmonary bypass should be considered if pharmacotherapy is ineffective.

INTRODUCTION AND RELEVANT HISTORY Since the first use of β-adrenergic antagonists (“β blockers”) for angina and hypertension in the early 1960s, the clinical indications for their use and number of prescriptions filled per year have increased dramatically. Currently, β-adrenergic antagonists are indicated for cardiac dysrhythmias, angina pectoris, hypertension, idiopathic hypertrophic subaortic stenosis, after myocardial infarction, for management of stable congestive heart failure, aortic dissection, thyroid storm, essential tremors, glaucoma, migraine prophylaxis, anxiety states, withdrawal states, and pheochromocytoma.1,2

EPIDEMIOLOGY Not unexpectedly, increased use of these agents has led to increased incidence of toxicity. Frishman and colleagues3 published the first review of β-adrenergic toxicity in 1979. The American Association of Poison Control Centers (AAPCC) reported a nearly sixfold increase in β-adrenergic exposures from 1984 to 2002, and an increase in mortality from 6 to 39 during the same time period.4,5 It has been estimated that by the year 2030, more than 20% of the U.S. population will be aged 65 years or older6 and that the number of people with congestive heart failure will increase to nearly 6 million.7 One may expect with an aging population, combined with everincreasing indications for β-adrenergic antagonists, that the number of poisonings (as well as the severity of the poisonings) will continue to increase. Therefore, an understanding of the pharmacology, toxicology, and clinical presentation of patients after β-adrenergic antagonist poisoning is essential.

PHARMACOLOGY β Blockers are generally classified on the basis of their cardioselectivity or the type of β-adrenergic receptor that is antagonized. These agents may also be classified according to the degree to which they possess partial agonist properties and also their membrane stabilization and antidysrhythmic effects (Table 60-1). As with many pharmaceutical agents, receptor selectivity is largely lost upon overdose. A thorough understanding of β-adrenergic receptor antagonist toxicity requires a brief review of these receptors. The distinction between α and β receptors was elucidated and published in 1948 by Ahlquist.8 Binding of epinephrine and norepinephrine to β receptors results in the phosphorylation of a G-protein complex on the cytoplasmic side of the cell membrane. Conformational changes in the G protein allow adenylate cyclase to catalyze the formation of cyclic adenosine monophosphate (cAMP) in the cytoplasm. In the myocyte, cAMP stimulates various protein kinases that phosphorylate calcium channels, thereby resulting in calcium entry into the cell and calcium-dependent calcium release from the sarcoplasmic reticulum. This calcium is responsible for the excitation-contraction coupling of myocytes.9 Nonspecific phosphodiesterases then hydrolyze cAMP and prevent further downstream effects.10 Further characterization of the β1 and β2 receptors was published in 1967 by Lands and associates.11 It was not until 1989 that a third β-adrenergic receptor was characterized,12 although this β3 receptor is primarily located on adipose cells and has no significant cardiovascular effects. A fourth type of β receptor that is responsible for partial agonist activity, termed the cardiac putative b4 adrenoreceptor, has been proposed.13 β1-Adrenergic specific receptors are found primarily in the myocardium, kidneys, and eyes, and they demonstrate roughly equal binding affinities for epinephrine and norepinephrine.11 β1-Receptor stimulation leads to increases in myocardial contractile force (inotropy) and rate (chronotropy) as a result of increased sinoatrial node firing as well as action potential conduction velocity.14 β1-Receptor activation also increases renin secretion by the kidney and aqueous humor production in the anterior chamber of the eye. β2 Receptors are found predominantly in vascular smooth and skeletal muscle, the pancreas, the liver, and adipose tissue. Agonism of β2 receptors leads to relaxation of smooth muscle in the lungs, blood vessels, uterus, and intestines. Metabolic effects of β2-receptor stimulation include lipolysis, glycogenolysis, and increased insulin secretion (Table 60-2). 975

β1 β1 β1 β1 β1, β1, β1 β1, β1 β1, β1, β1, β1, β1, β1,

NAME

Acebutolol Atenolol Betaxolol Bisoprolol Carteolol Carvedilol Esmolol Labetalol Metoprolol Nadolol Penbutolol Pindolol Propranolol Sotalol Timolol

β2 β2 β2 β2 β2 β2

β2

β2 β2, α1

ADRENERGIC RECEPTOR ANTAGONISM Yes No No No No Yes No Yes No No Yes Yes No No No

PARTIAL AGONIST

XTABLE 60-1 Classification of b Blockers

Yes No Yes No No No No No No No No Yes Yes No No

MEMBRANE STABILIZATION Moderate Low Low Low Low High Low Low Moderate-high Low High Moderate High Low Low

LIPID SOLUBILITY 40 50 90 80 85 25–35 N/A 30–40 40–50 30–50 100 99 30 90–100 75

ORAL BIOAVAILABILITY (%) 25 15 50 30–50 23–30 95 55 50 12 30 90–98 40–60 90 0 10

PROTEIN BINDING (%)

2.3 0.7 6.0 2.7–3.1 4.0 1.6 3.4 10 5.5 2.1 >30 2.0 3.6 0.2 1.5

VD (L/kg)

Renal Renal Hepatic Hepatic Renal Hepatic Esterase Hepatic Hepatic Renal Hepatic Renal Hepatic Renal Renal

ELIMINATION

3–6 6–9 14–22 9–12 6 6–10 0.15 3–6 3–4 14–24 20 3–12 3–5 5–12 4

HALF-LIFE (hr)

976 CARDIOVASCULAR, HEMATOLOGIC, AND ENDOCRINE AGENTS

CHAPTER 60

β-Adrenergic Antagonists

977

TABLE 60-2 b-Receptor Effects β1-RECEPTOR EFFECTS

β2-RECEPTOR EFFECTS

ORGAN

EFFECT

ORGAN/SYSTEM

EFFECT

Eye Kidney Heart

Increased aqueous humor production Increase renin production Increased inotropy and chronotropy

Lung Vascular system

Bronchial dilation Arteriole dilation Increased insulin secretion Increased lipolysis Increased glycogenolysis Increased lactic acid production Intracellular potassium shift

Metabolic system Other

PATHOPHYSIOLOGY The antagonism of β receptors and subsequent derangements in catecholamine physiologic effects cannot account for all the observed toxicity following β-receptor antagonist overdose. That is, if β-receptor antagonism alone were responsible for the observed clinical effects, then β-receptor agonism should provide adequate means to overcome the receptor blockade. However, experimental evidence and clinical experience suggest other mechanisms are at work. For instance, in isolated rat hearts depleted of catecholamines, the addition of β blockers produces toxicity. Additionally, in a canine model of acute β-blocker toxicity, Kerns and associates demonstrated no improvement in survival with the addition of high-dose epinephrine.15

concentration of propranolol in the central nervous system (CNS) may exceed that seen in plasma by as much as 20fold.23 Acebutolol, carteolol, penbutolol, pindolol, and timolol uniquely possess partial β-adrenergic agonist properties (also known as intrinsic sympathomimetic activity, or ISA), leading to a normal heart rate or even tachycardia. Therefore, bradycardia should not be viewed as invariably present after β-blocker poisoning. The decreased cAMP formation following β-blocker administration also leads to inhibition of sodium and calcium influx currents during phase 0 of the cardiac action potential, thereby classifying β blockers as Vaughn Williams class II antidysrhythmics.24 This effect is termed membrane stabilization.

Special Populations

PHARMACOKINETICS β Blockers are generally rapidly absorbed after ingestion, with peak effects occurring after 1 to 4 hours.16 Sustained-release formulations, however, produce prolonged absorption. It is prudent to keep in mind that pharmacokinetics may be altered greatly in the setting of overdose.17 The volume of distribution for β blockers varies widely: only atenolol and sotalol have volumes of distribution of less than one (see Table 60-1). Half-lives of these agents are generally brief (approximately 6 hours) but vary from a low of 10 minutes for esmolol, to 24 hours for nadolol. Low cardiac output states, hepatic dysfunction, and inducers of hepatic enzymes may alter the duration of action for those β blockers, which are metabolized by the liver. Similarly, renal dysfunction and low cardiac output may increase the duration of action for agents that are excreted unchanged in the urine (see Table 60-1). After acute oral overdose of immediate-release preparations, signs of toxicity usually begin within 30 minutes and peak by 2 hours. Toxicity after ingestion of sustained-release preparations or sotalol may be delayed until 20 hours after ingestion.18-21 Toxicity after β-blocker overdose may persist as long as several days.22 The lipid solubility of β blockers can significantly influence the degree of clinical toxicity observed after overdose owing to penetration of the blood-brain barrier. The agents with the highest degree of lipophilicity include metoprolol, penbutolol, propranolol, and carvedilol. The

Clinical effects observed with β-blocker toxicity may differ according to the age of the patient. Symptomatic hypoglycemia may be more common in children than in adults. The baseline cardiovascular disease present in many elderly patients may make overdoses or unintentional poisonings more severe in this age group.

Drug Interactions Drugs that induce hepatic mixed-function oxygenases may increase metabolism of betaxolol, bisoprolol, carvedilol, labetalol, metoprolol, penbutolol, and propranolol. Notable examples include phenytoin, phenobarbital, isoniazid, and rifampin. Other drugs (e.g., erythromycin, clarithromycin, cimetidine) may inhibit hepatic metabolism of these agents and therefore produce toxicity at unexpected doses. The other β blockers listed in Table 60-1 (except esmolol) undergo primarily renal elimination and can therefore be affected by agents that decrease renal clearance (e.g., nonsteroidal anti-inflammatory drugs). It is unknown whether the new cyclooxygenase II inhibitors sufficiently perturb β-blocker elimination. Owing to their significant effects on myocardial physiology, the principal drugs that interact with β blockers are other antihypertensive and antidysrhythmic agents. In both therapeutic doses and overdoses, the combination of a β blocker and a calcium channel blocker may lead to hypotension, bradycardia, and death.25-27 Combination treatment with peripheral

978


vasodilators such as hydralazine may lead to significant hypotension as a result of β-blocker inhibition of the usual reflex tachycardia. Administration of exogenous catecholamines, or the presence of any drug that leads to release or accumulation of catecholamines (e.g., cocaine, amphetamines, monoamine oxidase inhibitors), may lead to “unopposed α-adrenergic” stimulation and resultant hypertension, cardiac ischemia, or stroke.28-30

TABLE 60-3 Adverse Effects of b-Adrenergic Antagonists SYSTEM

EFFECTS

Cardiovascular

Hypotension Hypertension (partial agonists) Bradycardia, atrioventricular block, asystole Tachycardia (partial agonists) Prolonged PR interval Prolonged QT interval (sotalol) Prolonged QRS complex (membranestabilizing agents) Ventricular dysrhythmias (membranestabilizing agents, sotalol) Decreased level of consciousness Seizures Depression Insomnia Bronchospasm Respiratory depression Esophageal spasm Mesenteric ischemia Hypoglycemia Renal failure

TOXICOLOGY Clinical Manifestations Cardiac conduction abnormalities are common. Firstdegree atrioventricular (AV) block, intraventricular conduction abnormalities, high-grade AV block, nonspecific ST segment and T wave changes, QT prolongation, and asystole have all been recorded. Varying degrees of ventricular depolarization and repolarization abnormalities may occur, particularly with membrane stabilization agents and sotalol.31-33 Most patients with overdose present with hypotension and bradycardia.21 Ingestion of agents with ISA, however, may lead to tachycardia and hypertension.34,35 Sotalol is particularly toxic, with frequent reporting of ventricular tachycardia, torsades de pointes, and ventricular fibrillation19,36 owing to its effect on action potential duration and subsequent QT prolongation.37,38 CNS depression, ranging from drowsiness to coma, is a relatively common effect of β-blocker toxicity32 and generally reflects the severity of the poisoning.17,20 CNS toxicity may occur in the absence of bradycardia, hypotension, or hypoglycemia,21 particularly with the lipid-soluble agents.3,39,40 CNS depression also is exacerbated by β blocker–associated cerebral hypoperfusion, acidemia, and hypoxia.32 While bronchospasm has been traditionally been a concern following therapeutic use or overdose of β blockers, it remains an unusual complication of βblocker toxicity. When it does occur, bronchospasm is more likely to occur in patients with preexisting pulmonary disease. More common is respiratory depression, usually due to CNS toxicity.41 Central cyanosis may be present. Peripheral cyanosis due to antagonism of vascular β2 receptors with the accompanying “unopposed α1” effects may be evident21,32,42 and has led to mesenteric ischemia.43 Frank hypoglycemia is infrequently seen with βblocker toxicity, but normal serum glucose in the setting of significant β-blocker poisoning may in fact be relative hypoglycemia. Hypoglycemia is more common in children, persons with diabetes, and patients with uremia. The typical tachycardia seen during hypoglycemia may be diminished after β-blocker ingestion although other symptoms of hypoglycemia are relatively unchanged. Hyperkalemia is variably present and may be a clue to β-blocker poisoning. Renal effects after β-blocker poisoning are unusual, although oliguric renal failure has been reported rarely.44

CNS (lipid-soluble and membranestabilizing agents) Respiratory Gastrointestinal Metabolic Other

The adverse effects observed after therapeutic doses of β blockers are listed in Table 60-3. Chronic therapeutic use of β blockers leads to an increase in adrenergic receptor expression and a resultant increase in catecholamine sensitivity upon withdrawal of β blockers. This may in part explain the degree to which high doses of β blockers are tolerated, so long as the dose is increased slowly, and why acute ingestion of a similar dose may produce toxicity in patients not accustomed to β-blocker use.45

DIAGNOSIS Laboratory Testing β Blockers are not detected by current enzyme immunoassays. Routine serum or urine β-blocker concentrations are not available. Additionally, owing to interindividual variations in metabolism and protein binding and variations in dosing, determination of serum concentrations in the acute setting generally are not helpful22 but can be used as a confirmatory test when overdose is suspected.

Other Diagnostic Testing All patients with confirmed or suspected β-blocker overdose or symptoms consistent with β-blocker toxicity should be placed on continuous cardiac monitoring and have a 12-lead electrocardiogram (ECG) interpreted. Frequent recording of vital signs should be routine. Symptomatic patients should have determination of electrolytes, blood urea nitrogen (BUN), creatinine, glucose, and complete blood count. Determination of serum drug concentrations as indicated (e.g., digoxin)

CHAPTER 60

should be performed. For patients with abnormal vital signs, a chest radiograph and arterial blood gas measurement should be assessed.

Differential Diagnosis Other causes of cardiovascular collapse with hypotension and bradycardia (except with the possibility of tachycardia after poisoning with β blockers that possess partial agonist activity) include shock of anaphylactic, cardiogenic (including pulmonary embolism), septic, and hypovolemic etiologies. Additionally, other toxicologic sources must be considered, particularly poisoning with calcium channel blockers, organophosphorus or carbamate agents, antidysrhythmics, centrally acting antihypertensives, cardiac glycosides, cyanide, hydrogen sulfide, narcotics, chloroquine, sedative-hypnotics, and tricyclic antidepressants. β-Blocker poisoning should be suspected in any patient with hypotension, bradycardia, and seizures. Differentiation between β-blocker and calcium channel blocker toxicity may be aided by measurement of the serum glucose: hypoglycemia may be present with β-blocker poisoning, whereas hyperglycemia is often seen after poisoning by calcium channel blockers. The presence of hyperkalemia may also be a clue to β-blocker toxicity.

MANAGEMENT Supportive Measures When possible, historical data regarding the time of ingestion, agents involved, quantity ingested, other medications, and a medical history should be obtained. One should also pay particular attention to the vital signs and examination of the cardiopulmonary and neurologic systems As for any patient, priority should be given to establishment of adequate airway, breathing, and circulation. In at least two animal studies, the primary determinant of β-blocker toxicity and death was respiratory arrest.46,47 Therefore, early establishment of adequate ventilation is essential. All patients should have continuous cardiac monitoring, continuous pulse oximetry, an ECG, and frequent assessment of vital signs. Determination of the complete blood count, bedside finger-stick glucose, serum electrolytes, BUN, and serum creatinine should be performed. A chest radiograph and arterial blood gas measurement should be obtained in all symptomatic patients. If the diagnosis is uncertain, a comprehensive toxicology screen may be of benefit.

Decontamination Gastrointestinal decontamination with activated charcoal 1 g/kg (maximum, 50 to 60 g) should be done as soon as possible after initiation of supportive care. The use of syrup of ipecac to induce emesis cannot be advocated because of the risk of vomiting and aspiration,


979

particularly if respiratory or CNS depression follow. At least one author has suggested that prophylactic atropine may be beneficial to inhibit vagally mediated bradycardia during endotracheal or gastric intubation.24 In an effort to decrease any enterohepatic circulation, repeated doses of activated charcoal are recommended for symptomatic patients. Additionally, in patients poisoned with sustained-release formulations, placement of a nasogastric or orogastric tube and whole-bowel irrigation with a polyethylene glycol solution (20 to 30 mL/kg/hr in adults and 10 to 20 mL/kg/hr in children) should be considered.

Laboratory Monitoring Continuous cardiac monitoring and frequent ECGs are indicated for all patients. Serial determinations of serum potassium and glucose also are prudent, as is the determination of serum magnesium, particularly for agents known to cause torsades de pointes.

Antidotes GLUCAGON Glucagon is the most consistently effective agent for β-blocker poisoning in both laboratory studies and in humans21,32 and is the therapeutic drug of choice. Glucagon is a pancreatic polypeptide whose inotropic and chronotropic effects were first discovered in 1960.30 Glucagon is thought to activate adenylate cyclase independently of the β-adrenergic receptor, thereby increasing cAMP synthesis with the resultant increase in myocardial heart rate and contractility.48-54 It increases mean arterial pressure, cardiac index, and contractility without altering the left ventricular end-diastolic pressure.55-57 Glucagon is more effective in reversing hypotension than either epinephrine or isoproterenol.32 However, therapy with several agents simultaneously may be required. Glucagon has a half-life of roughly 20 minutes. After an initial IV bolus dose of 5 to 10 mg for adults (50 to 150 μg/kg in children), a continuous infusion of 1 to 5 mg/hr (10 to 50 μg/kg/hr in children) should be used, if effective. Continuous IV infusion of glucagon is preferred to intermittent bolus dosing owing to the more sustained increase in blood pressure observed after the former.58 Clinical effects begin in as few as 1 to 3 minutes, with peak effects seen at 5 to 7 minutes.48 It is recommended that glucagon be reconstituted in normal saline or 5% dextrose, because the diluent provided by the manufacturer contains 2 mg of phenol per 1 mg of glucagon, which may be toxic in doses of 25 mg or more.59,60 Nausea and vomiting (occurring in nearly one third of patients) are the most common side effects after glucagon therapy.61,62 Hyperglycemia may occur and is the basis for administration of glucagon for hypoglycemia; however, the stimulation of pancreatic insulin secretion by glucagon may also lead to hypoglycemia. As a result of insulin-mediated intracellular ion shifts, hypokalemia may occur. Rare but more significant

980


adverse effects after glucagon therapy include StevensJohnson syndrome, erythema multiforme minor, and acute allergic reaction.63 The few contraindications to glucagon therapy that exist are the presence of insulinoma, pheochromocytoma, or glucagon hypersensitivity.30 Because of limited hospital pharmacy stocking of glucagon, additional sources should be sought soon after initiation of continuous IV therapy.64,65 CALCIUM Presumably owing to the derangements in calciummediated myocardial contraction and vascular tone, IV calcium is variably effective in reducing hypotension.66-69 Calcium chloride 1 to 2 g intravenously every 5 to 10 minutes as necessary is commonly used, but it must be administered cautiously because of its highly irritating effects. One must give serious consideration to delivery via central venous access. Calcium gluconate may also be used but contains only one third the calcium of calcium chloride on a gram-for-gram basis. Hypercalcemia may be a theoretical concern. However, severely poisoned patients who receive several doses of calcium chloride should be intubated, thereby mitigating concerns about hypercalcemia-induced CNS and respiratory depression.70 CATECHOLAMINE AGENTS Because β blockers bind to the adrenergic receptors in a competitive fashion, one might expect that β agonists and vasopressors alone would reverse toxicity. Unfortunately, therapeutic response to these agents alone is limited and variable. Doses of catecholamines needed to achieve a significant response may be four or more times greater than doses generally used.20,21,71 The prodysrhythmic potential of these agents when used in high doses, particularly isoproterenol, mitigates some of the enthusiasm for their use. Nevertheless, catecholamines remain a vital part of the multitherapy strategy for severely poisoned patients. PHOSPHODIESTERASE INHIBITORS Inamrinone (formerly named amrinone) may produce an increase in contractility independently of the β receptor by inhibiting phosphodiesterase and thus slowing the breakdown of cAMP. Inamrinone increased inotropy in a canine model of β-blocker poisoning,72 but was of no additional benefit (and may have been detrimental) when added to glucagon therapy.73 The recommended dose of inamrinone for congestive heart failure is a 0.75 mg/kg IV bolus over 2 to 3 minutes, followed by a continuous infusion of 5 to 10 μg/kg/min. If needed, a repeat bolus dose may be given 30 minutes after the initiation of therapy. ATROPINE Although frequently ineffective, patients with bradycardia and hypotension warrant a trial of atropine therapy and may receive modest benefit.

TREATMENT OF SEIZURES Seizures that are not responsive to glucose should be managed with benzodiazepines, barbiturates, and possibly phenytoin.

Treatment of Bronchospasm Bronchospasm may be induced by β-blocker toxicity, particularly in patients with a history of reactive airway disease. Treatment should proceed much as for other nontoxicologic causes of asthma, including inhaled β2 agonists and anticholinergic agents and subcutaneous epinephrine as needed.

Nonpharmacologic Therapies External or transvenous cardiac pacing should be considered after failure of pharmacotherapy alone.74,75 However, electrical capture is not always possible after severe poisoning, and while the heart rate may respond to pacing, a consistent increase in blood pressure is not always achieved.21,76 Transvenous cardiac pacing may be most useful in treating refractory torsades de pointes due to sotalol poisoning.19,36 Other invasive measures that have been used with varying degrees of success in severe poisoning include intra-aortic balloon counterpulsion, cardiopulmonary bypass, and extracorporeal membrane oxygenation.18,76,77

Sotalol Intoxication The unique pharmacology and pharmacokinetics of sotalol warrant special attention. Patients may have significant tachycardia and hypertension due to sotalol toxicity. If no end-organ dysfunction is present, however, close monitoring in the hospital setting may be all that is required. If end-organ toxicity exists, then short-acting agents such as nitroprusside and esmolol should be used. As mentioned above, ventricular dysrhythmias, QT prolongation, and subsequent torsades de pointes may be more frequent with sotalol poisoning. Treatment of sotalol-induced ventricular tachydysrhythmias includes magnesium, lidocaine, phenytoin, and “overdrive” pacing with either transvenous electrical pacing or isoproterenol.78-81

Elimination Although the use of charcoal hemoperfusion after βblocker poisoning has been reported,74 the pharmacokinetic properties of most β blockers would appear to limit the usefulness of extracorporeal elimination. Owing to their low degree of protein binding and low volumes of distribution, atenolol and sotalol would be expected to be most responsive to extracorporeal elimination.20,82

Disposition All symptomatic patients after β-adrenergic antagonist ingestion or overdose, and patients with a history of

CHAPTER 60

sotalol ingestion should be admitted to the hospital. Patients with significant signs or symptoms of toxicity (including but not limited to altered mental status, bradycardia, hypotension, and dysrhythmias) should be managed in an intensive care unit. While no prospective studies exist, patients who do not ingest a sustainedrelease formulation and who remain asymptomatic with a normal ECG and normal vital signs should be observed for at least 6 hours. Ingestion of a sustained-release formulation necessitates admission or observation for at least 24 hours. From 30% to 40% of β-adrenergic receptor antagonist overdose patients remain asymptomatic.83 However, other authors have reported a mortality rate as high as 26%.84 In one review of the literature, 75% of deaths due to propranolol occurred at home.83 Therefore, it would appear that if a patient arrives in the emergency department alive and appropriate treatment is initiated early, the prognosis is good. Attempts at prolonged resuscitation after β-blocker overdose are warranted, since survival without neurologic sequelae has been reported.85 REFERENCES 1. Hoffman BB: Catecholamines, sympathomimetic drugs, and adrenergic receptor antagonists. In Hardman JG, Limbird LE (eds): Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 215–268. 2. Packer M, Coats AJ, Fowler MB, et al: Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651. 3. Frishman W, Silverman R, Strom J, et al: Clinical pharmacology of the new beta-adrenergic blocking drugs. 4. Adverse effects: choosing a beta-adrenoreceptor blocker. Am Heart J 1979;98:256. 4. Litovitz T, Veltri JC: 1984 annual report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med 1985;3:423–450. 5. Watson WA, Litovitz TL, Rodgers GC Jr, et al: 2002 annual report of the American Association of Poison Control Centers toxic exposure surveillance system. Am J Emerg Med 2003;21:353. 6. U.S. Census Bureau: Statistical Abstract of the United States: 2001, 121st ed. Washington, DC, U.S. Department of Commerce, 2001. 7. Field JL: Beyond four walls: research summary for clinicians and administrators on CHF management. In Cardiology Preeminence Round Table, Advisory Board. Washington, DC, 1994. 8. Alquist R: Study of adrenotropic receptors. Am J Physiol 1948;153:586. 9. Colucci WS, Wright RF, Braunwald E: New positive inotropic agents in the treatment of congestive heart failure: mechanisms of action and recent clinical developments. N Engl J Med 1986;314:290. 10. Insel PA: Seminars in medicine of the Beth Israel Hospital, Boston: adrenergic receptors—evolving concepts and clinical implications. N Engl J Med 1996;334:580. 11. Lands AM, Arnold A, McAuliff JP, et al: Differentiation of receptor systems activated by sympathomimetic amines. Nature 1967; 214(88):597. 12. Emorine LJ, Marullo S, Briend-Sutren MM, et al: Molecular characterization of the human beta 3-adrenergic receptor. Science 1989;245(4922):1118. 13. Kaumann AJ, Molenaar P: Modulation of human cardiac function through 4 beta-adrenoceptor populations. Naunyn Schmiedebergs Arch Pharmacol 1997;355:667. 14. Cirillo LA: Commonly used emergency cardiac medications. In Aghababian RV (ed): Emergency Management of Cardiovascular Disease. Boston, Butterworth-Heinemann, 1994, p 371. 15. Kerns W II, Schroeder D, Williams C, et al: Insulin improves survival in a canine model of acute beta-blocker toxicity. Ann Emerg Med 1997;29:748.


981

16. Hoffman B: Adrenoreceptor-blocking drugs. In Katzung B (ed): Basic and Clinical Pharmacology, 6th ed. Norwalk, CT, Appleton & Lange, 1995, p 137. 17. Jackson CD, Fishbein L: A toxicological review of beta-adrenergic blockers. Fundam Appl Toxicol 1986;6:395. 18. Love JN, Litovitz TL, Howell JM, Clancy C: Characterization of fatal beta blocker ingestion: a review of the American Association of Poison Control Centers data from 1985 to 1995. J Toxicol Clin Toxicol 1997;35:353. 19. Neuvonen PJ, Elonen E, Vuorenmaa T, Laakso M: Prolonged Q-T interval and severe tachyarrhythmias, common features of sotalol intoxication. Eur J Clin Pharmacol 1981;20:85. 20. Heath A: Beta-adrenoceptor blocker toxicity: clinical features and therapy. Am J Emerg Med 1984;2:518. 21. Weinstein RS: Recognition and management of poisoning with beta-adrenergic blocking agents. Ann Emerg Med 1984;13:1123. 22. Frishman W, Jacob H, Eisenberg E, Ribner H: Clinical pharmacology of the new beta-adrenergic blocking drugs. 8. Selfpoisoning with beta-adrenoceptor blocking agents: recognition and management. Am Heart J 1979;98:798. 23. Cruickshank J: The clinical importance of cardioselectivity and lipophilicity in β-blockers. Am Heart J 1980;100:160. 24. Linden CH: Beta-blocker poisoning. In Harwood-Nuss A (ed): The Clinical Practice of Emergency Medicine, 3rd ed. Philadelphia, Lippincott Williams & Wilkins, 2001, p 1439. 25. Benaim ME: Asystole after verapamil. BMJ 1972;2(806):169. 26. Wayne VS, Harper RW, Laufer E, et al: Adverse interaction between beta-adrenergic blocking drugs and verapamil—report of three cases. Aust N Z J Med 1982;12:285. 27. Opie LH, White DA: Adverse interaction between nifedipine and beta-blockade. BMJ 1980;281(6253):1462. 28. Billman GE: The effect of adrenergic receptor antagonists on cocaine-induced ventricular fibrillation: alpha but not beta adrenergic receptor antagonists prevent malignant arrhythmias independent of heart rate. J Pharmacol Exp Ther 1994;269:409. 29. Tseng CC, Derlet RW, Albertson TE: Acute cocaine toxicity: the effect of agents in non-seizure-induced death. Pharmacol Biochem Behav 1993;46:61. 30. Wolf LR: Beta-adrenergic blocker toxicity. In Haddad LM, Shannon MW, Wionshester JF (eds): Clinical Management of Poisoning and Drug Overdose, 3rd ed. Philadelphia, WB Saunders, 1998, p 1031. 31. Frishman WH: Beta-adrenergic receptor blockers: adverse effects and drug interactions. Hypertension 1988;11(3 pt 2):II21. 32. Critchley JA, Ungar A: The management of acute poisoning due to beta-adrenoceptor antagonists. Med Toxicol Adverse Drug Exp 1989;4:32. 33. Gwinup GR: Propranolol toxicity presenting with early repolarization, ST segment elevation, and peaked T waves on the ECG. Ann Emerg Med 1988;17:171. 34. Love JN: Acebutolol overdose resulting in fatalities. J Emerg Med 2000;18:341. 35. Thorpe P: Prindolol in hypertension. Med J Aust 1971;1:1242. 36. Totterman KJ, Turto H, Pellinen T: Overdrive pacing as treatment of sotalol-induced ventricular tachyarrhythmias (torsade de pointes). Acta Med Scand Suppl 1982;668:28. 37. Baliga BG: Beta-blocker poisoning: prolongation of Q-T interval and inversion of T wave. J Indian Med Assoc 1985;83:165. 38. Beattie JM: Sotalol induced torsade de pointes. Scott Med J 1984;29:240. 39. Koella WP: CNS-related (side-)effects of beta-blockers with special reference to mechanisms of action. Eur J Clin Pharmacol 1985;28(Suppl):55. 40. Buiumsohn A, Eisenberg ES, Jacob H, et al: Seizures and intraventricular conduction defect in propranolol poisoning: a report of two cases. Ann Intern Med 1979;91:860. 41. Weinstein RS, Cole S, Knaster HB, Dahlbert T: Beta blocker overdose with propranolol and with atenolol. Ann Emerg Med 1985;14:161. 42. Lund-Johansen P: The hemodynamic effects of adrenergic blocking agents. Cleve Clin J Med 1992;59:193. 43. Pettei MJ, Levy J, Abramson S: Nonocclusive mesenteric ischemia associated with propranolol overdose: implications regarding splanchnic circulation. J Pediatr Gastroenterol Nutr 1990;10:544.

982


44. Snook CP, Sigvaldason K, Kristinsson J: Severe atenolol and diltiazem overdose. J Toxicol Clin Toxicol 2000;38:661. 45. Lifshitz M, Zucker N, Zalzstein E: Acute dilated cardiomyopathy and central nervous system toxicity following propranolol intoxication. Pediatr Emerg Care 1999;15:262. 46. Langemeijer J, de Wildt D, de Groot G, Sangster B: Respiratory arrest as main determinant of toxicity due to overdose with different beta-blockers in rats. Acta Pharmacol Toxicol (Copenh) 1985;57:352. 47. Toet AE, te Biesebeek JD, Vleeming W, et al: Reduced survival after isoprenaline/dopamine in d,l-propranolol intoxicated rats. Hum Exp Toxicol 1996;15:120. 48. Parmley WW, Glick G, Sonnenblick EH: Cardiovascular effects of glucagon in man. N Engl J Med 1968;279:12. 49. Murad F: Effect of glucagon on heart. N Engl J Med 1968;279:434. 50. Jolly SR, Kipnis JN, Lucchesi BR: Cardiovascular depression by verapamil: reversal by glucagon and interactions with propranolol. Pharmacology 1987;35:249. 51. Levey GS, Epstein SE: Activation of adenyl cyclase by glucagon in cat and human heart. Circ Res 1969;24:151. 52. Kosinski EJ, Malindzak GS Jr: Glucagon and isoproterenol in reversing propranolol toxicity. Arch Intern Med 1973;132:840. 53. Robson RH: Glucagon for beta-blocker poisoning. Lancet 1980;1(8182):1357. 54. Peterson CD, Leeder JS, Sterner S: Glucagon therapy for betablocker overdose. Drug Intell Clin Pharm 1984;18:394. 55. Abel FL: Action of glucagon on canine left ventricular performance and coronary hemodynamics. Circ Shock 1983; 11:45. 56. Manchester JH, Parmley WW, Matloff JM, et al: Effects of glucagon on myocardial oxygen consumption and coronary blood flow in man and in dog. Circulation 1970;41:579. 57. Diamond G, Forrester J, Danzig R, et al: Acute myocardial infarction in man. Comparative hemodynamic effects of norepinephrine and glucagon. Am J Cardiol 1971;27:612. 58. Illingworth RN: Glucagon for beta-blocker poisoning. Practitioner 1979;223(1337):683. 59. Brancato DJ: Recognizing potential toxicity of phenol. Vet Hum Toxicol 1982;24:29. 60. Cronholm LS, Fishel CW: Bordetella pertussis-induced alteration of the normal hyperglycemic response of mice to 3’,5’-adenosine phosphate. J Bacteriol 1968;95:1993. 61. Vander Ark CR, Reynolds EW Jr: Clinical evaluation of glucagon by continuous infusion in the treatment of low cardiac output states. Am Heart J 1970;79:481. 62. Williams JF, Childress RH, Chip JN: Hemodynamic effects of glucagon in patients with heart disease. Circulation 1969;39:38. 63. Zavras GM, Papadaki PJ, Kounis NG, Dimopoulos JA: Glucagoninduced severe anaphylactic reaction. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 1990;152:110. 64. Love JN, Tandy TK: Beta-adrenoceptor antagonist toxicity: a survey of glucagon availability. Ann Emerg Med 1993;22:267. 65. Smith RC, Wilkinson J, Hull RL: Glucagon for propranolol overdose. JAMA 1985;254:2412. 66. Henry M, Kay MM, Viccellio P: Cardiogenic shock associated with calcium-channel and beta blockers: reversal with intravenous calcium chloride. Am J Emerg Med 1985;3:334.

67. Pertoldi F, D’Orlando L, Mercante WP: Electromechanical dissociation 48 hours after atenolol overdose: usefulness of calcium chloride. Ann Emerg Med 1998;31:777. 68. Brimacombe JR, Scully M, Swainston R: Propranolol overdose—a dramatic response to calcium chloride. Med J Aust 1991;155:267. 69. Brimacombe J: Use of calcium chloride for propranolol overdose. Anaesthesia 1992;47:907. 70. Pearigen PD: Calcium channel blocker poisoning. In Haddad JJ, Shannon MW, Winchester JF (eds): Clinical Management of Poisoning and Drug Overdose. Philadelphia, WB Saunders, 1998, p 1020. 71. Avery GJ II, Spotnitz HM, Rose EA, et al: Pharmacologic antagonism of beta-adrenergic blockade in dogs. 1. Hemodynamic effects of isoproterenol, dopamine, and epinephrine in acute propranolol administration. J Thorac Cardiovasc Surg 1979; 77:267. 72. Alousi AA, Canter JM, Fort DJ: The beneficial effect of amrinone on acute drug-induced heart failure in the anaesthetised dog. Cardiovasc Res 1985;19:483. 73. Love JN, Leasure JA, Mundt DJ: A comparison of combined amrinone and glucagon therapy to glucagon alone for cardiovascular depression associated with propranolol toxicity in a canine model. Am J Emerg Med 1993;11:360. 74. Anthony T, Jastremski M, Elliott W, et al: Charcoal hemoperfusion for the treatment of a combined diltiazem and metoprolol overdose. Ann Emerg Med 1986;15:1344. 75. Saitz R, Williams BW, Farber HW: Atenolol-induced cardiovascular collapse treated with hemodialysis. Crit Care Med 1991;19:116. 76. McVey FK, Corke CF: Extracorporeal circulation in the management of massive propranolol overdose. Anaesthesia 1991;46:744. 77. Lane AS, Woodward AC, Goldman MR: Massive propranolol overdose poorly responsive to pharmacologic therapy: use of the intra-aortic balloon pump. Ann Emerg Med 1987;16:1381. 78. Adlerfliegel F, Leeman M, Demaeyer P, et al: Sotalol posoning associated with asystole. Intensive Care Med 1993;19:57. 79. Arstall M, Mii J, Lehman R, Horowitz JD: Sotalol-induced torsades de pointes: management with magnesium infusion. Postgrad Med 1992;68:289. 80. Perrot D, Bui-Xuan B, Lang J, et al: A case of sotalol poisoning with fatal outcome. J Toxicol Clin Toxicol 1988;26:389. 81. Kenyon CJ, Aldinger GE, Joshipura P: Successful resuscitation using external cardiac pacing in beta-adrenergic antagonistinduced bradyasystolic arrest. Ann Emerg Med 1988;17:711. 82. Singh S, Lazin A, Cohen A, et al: Sotalol-induced torsades de pointes successfully treated with hemodialysis after therapy of conventional therapy. Am Heart J 1991;2:601. 83. Taboulet P, Cariou A, Berdeaux A, Bismuth C: Pathophysiology and management of self-poisoning with beta-blockers. J Toxicol Clin Toxicol 1993;31:531. 84. Langemeijer JJ, de Wildt DJ, de Groot G, Sangster B: Intoxication with beta-sympathicolytics. Neth J Med 1992;40:308. 85. Alderfliegel F, Leeman M, Demaeyer P, Kahn RJ: Sotalol poisoning associated with asystole. Intensive Care Med 1993;19:57.

61

Nitroprusside, ACE Inhibitors, and Other Cardiovascular Agents WILLIAM H. RICHARDSON, MD ■ DAVID P. BETTEN, MD ■ SARALYN R. WILLIAMS, MD ■ RICHARD F. CLARK, MD

■ ■

■

■

■ ■ ■

■

Early cyanide poisoning from nitroprusside may manifest with central nervous system effects and tachyphylaxis. Thiocyanate poisoning, in contrast to cyanide poisoning, occurs most frequently in the setting of renal insufficiency and does not cause a metabolic acidosis. Supportive care including intravenous fluids and inotropic agents are the mainstay of treatment in hydralazine and minoxidil poisoning. Nonspecific T-wave and ST-segment ECG abnormalities are commonly described in overdose and with therapeutic use of hydralazine and minoxidil. Nitrates/nitrites are contraindicated in the setting of sildenafil use even in the setting of acute coronary syndrome. The presence of angioedema is classically described with ACE inhibitors but can also occur with angiotensin receptor blockers. The use of alpha-1 antagonists may result in symptomatic hypotension in the absence of tachycardia due to isolated effects on the alpha-1 adrenergic receptor. In diuretic abuse and overdose, care should be directed toward identification and correction of fluid and electrolyte abnormalities.

NITROPRUSSIDE Sodium nitroprusside (SNP) is a potent vasodilator widely used due to its rapid onset of action, short halflife, and ease of titration. It is approved for reduction of blood pressure in hypertensive emergencies and for controlled hypotension during surgical procedures to reduce the risk for hemorrhage.1 The first human use of nitroprusside was reported in 1928,2 but its regular use in humans was not established until 1955 when a short-term infusion was used to treat severe hypertension.3 Approval for clinical use in the United States occurred in 1974 after a lyophilized preparation became available. In 1991 the Food and Drug Administration (FDA) approved new labeling for SNP to highlight the risk for cyanide toxicity associated with prolonged infusion at rates that exceed 2 μg/kg/min.1

Structure Each SNP molecule is composed of an iron center that is complexed with five cyanide molecules and one nitrosyl group. Cyanide comprises about 44% of the molecular weight of the compound. After infusion, the compound undergoes degradation and the cyanide molecules and the nitric oxide are released. Nitric oxide acts as an endothelium-relaxing factor that results in the desired vasodilatory effects of SNP (Fig. 61-1).4

SNP is soluble in water but is unstable when exposed to sunlight. Photodegradation may result in release of up to 40% of the cyanide into solution and reduced efficacy of the vasodilatory effect. Exposure to laboratory flourescent light does not result in the same degree of photodegradation.5 Even after mild to moderate photodegradation, SNP remains biologically active and is able to reduce blood pressure.6 Nitroprusside solutions that are protected from the sunlight are quite stable. Prevention of this photochemical reaction involves covering the infusion bag with aluminum foil or other opaque material to minimize the exposure to ultraviolet light.

Pharmacokinetics and Pathophysiology Nitroprusside is a nonselective vasodilator of both arteriolar and capacitance vasculature. Regional distribution of blood flow is not affected, and there is preservation of flow to all organs as long as hypotension is avoided. Renal blood flow is maintained, and pulmonary vasoconstriction due to hypoxia is reduced.4 After infusion of SNP solution, spontaneous dissociation of the compound occurs. The breakdown of the molecule is triggered by contact between nitroprusside and sulfhydryl groups that are found along vessel walls.7 Nitric oxide is released and is the active mediator of vasodilatory effects. Nitric oxide activates soluble guanylate cyclase resulting in increased intracellular concentrations of cyclic guanosine monophosphate (cGMP). Increased cGMP induces protein phosphorylation that reduces calcium influx into the cell. With less calcium movement, the smooth muscles are less likely to contract, resulting in relaxation. Vasodilation occurs with the reduced tone of the smooth muscles of blood vessels.8 Along with the release of nitric oxide, cyanide molecules are liberated into tissues or serum and can later be absorbed into erythrocytes.6 Cyanogenesis most likely occurs in the extracellular space9 rather than in the erythrocytes as previously thought.10,11 Cyanide is cleared via transulfuration within the liver. The primary sulfur donor is thiosulfate, which is the rate-limiting step. Healthy adults usually have adequate thiosulfate to clear the cyanide released from about 50 mg of SNP.12 Poor nutrition, recent surgery, and diuretic medications are considered risk factors for reduced thiosulfate stores. 2-

NO

NC

J J

At a Glance…

CN

Fe

NC

CN

CN

Nitroprusside FIGURE 61-1 Nitroprusside.

983

984


Children, and especially neonates, can have lower thiosulfate stores and may be more susceptible to elevated levels of cyanide.12 Cyanide acts as a nucleophilic acceptor for the transfer of sulfur from thiosulfate. Once thiocyanate is formed, the reaction is irreversible. The mechanism by which thiocyanate is formed is not entirely clear. Kinetic studies would suggest that cyanide detoxification occurs in a volume of distribution that is similar to the blood volume. A commonly accepted enzyme in the detoxification of cyanide is rhodanese; however, rhodanese may be restricted to the mitochondria in various tissues, including liver, kidney, and skeletal muscle. Thiosulfate may not be able to penetrate into the inner mitochondrial membrane. One theory suggests that sulfurtransferases including rhodanese may actually form sulfane sulfur that complexes with albumin. The sulfane–sulfur albumin complex reacts with cyanide to form thiosulfate.13 In contrast to this theory, an experiment in bloodless rats demonstrated that available thiosulfate reduces cyanide in the absence of blood proteins.14 Because thiocyanate is produced from thiosulfate, there is no further degradation of the thiocyanate. It is eliminated from the body primarily through renal excretion. The half-life of thiocyanate in an adult with normal renal function is about 2.7 days. The half-life in patients with renal insufficiency may be prolonged to 9 days.7 The elimination constants for thiocyanate were inversely proportional to the renal creatinine clearances when measured in patients with renal failure.15 In the first few minutes after infusion, SNP is found primarily in the serum compartment with minimal amounts in blood cells. The volume of distribution is the same as the extracellular space. The nonenzymatic breakdown of SNP occurs in minutes with the release of cyanide molecules and nitric oxide.7 The rapid breakdown of SNP correlates with the short half-life and clinical effect. Onset of action is within 30 seconds of the infusion, with peak hypotensive effects within 2 minutes. The effect on blood pressure dissipates within 3 minutes after discontinuation of the infusion.

Toxicology The amount of SNP that results in cyanide toxicity is variable, depending on the rate infused, amount infused, and thiocyanate stores of the individual. Cyanide clearance is a first order process when adequate thiosulfate is available; however, since thiocyanate stores are limited, the kinetics of detoxification are saturable. There is also interindividual variation in the ability to transulfurate the cyanide molecule into thiocyanate.16 In the average adult patient, erythrocyte cyanide levels rise rapidly when the infusion of SNP exceeds 1 to 2 μg/kg/min. Red blood cell cyanide levels from SNP tend to be higher than symptom equivalent levels from direct cyanide poisoning. There is a higher erythrocyte–plasma cyanide ratio during SNP-induced cyanogenesis.17,18 Those individuals with less reserves or low thiosulfate stores will accumulate the cyanide more quickly and may manifest signs and symptoms at lower doses.

As cyanide accumulates during an SNP infusion, it distributes into tissues and plasma and will concentrate in erythrocytes. Cyanide binds and inhibits a number of enzymes in the body. The metalloenzyme most sensitive to the binding of cyanide is probably cytochrome aa3, the last enzyme in the cytochrome system of oxidative phosphorylation. Cyanide has an affinity for the ferric iron that composes cytochrome aa3. As a result of cyanide binding, electron transport via the cytochromes is halted, causing cessation of oxidative phosphorylation. Adenosine triphosphate (ATP) can no longer be produced by this route. Electrons are not able to associate with oxygen as the final electron acceptor, so oxygen consumption diminishes as well. As cells shift to anaerobic metabolism, accumulation of lactate occurs, and a lactate-dependent acidosis develops.19 Cyanide inhibits other enzymes, including xanthine oxidase, succinate dehydrogenase, and Schiff base intermediates. The central nervous system (CNS) appears to be the most sensitive organ to the cytotoxicity of cyanide.19 Cyanide also inhibits glutamate decarboxylase, resulting in reduced production of γ-aminobutyric acid. This may cause an increased risk for convulsions.20 Thiocyanate toxicity rarely occurs during SNP infusion in the setting of normal renal function since it is cleared primarily through renal elimination. When thiocyanate was used as an antihypertensive in the early 1900s, cases of toxicity were described. Older literature reports mild toxicity characterized by abdominal pain, vomiting, tinnitus, weakness, and agitation. These early symptoms may progress to more profound CNS effects, including encephalopathy, delusions, lethargy, coma, and, rarely, death.21-23 The pathophysiology of CNS effects is not delineated. Thiocyanate does not affect the function of metalloenzymes such as cytochrome oxidases. Oxygen utilization is also not affected. As a result, thiocyanate toxicity does not result in a metabolic acidosis. When thiocyanate was used as an oral antihypertensive, cases of hypothyroidism were reported. The mechanism proposed for this observation was that thiocyanate interfered with thyroidal uptake of iodine.

Diagnosis In the setting of SNP infusions, close monitoring of patients for clinical evidence of cyanide toxicity must occur. The organ systems usually first affected are the ones most sensitive to histotoxic anoxia: the central nervous and cardiovascular systems. Early cyanide-induced CNS effects include agitation and restlessness. As cyanide poisoning progresses, encephalopathy may develop and may be misinterpreted as worsening hypertensive encephalopathy. This can progress to coma, and convulsions may occur. Cerebral death may occur simultaneously with terminal cardiovascular effects. The initial cardiovascular effects are tachycardia and worsening hypertension. Tachyphylaxis to SNP develops and may not be recognized initially as a manifestation of cyanide toxicity. Late findings include hypotension,

CHAPTER 61

Nitroprusside, ACE Inhibitors, and Other Cardiovascular Agents

shock, and bradydysrhythmias. Tachypnea may be seen early in the poisoning and can be followed by apnea. Since cyanide reduces oxygen utilization by the tissues, the mixed venous oxygen content will rise with a decline in the arteriovenous oxygen difference provided cardiac output has not dimished. Elevated venous oxygen concentrations may result in reddish skin coloration; however, cyanosis has also been reported in the setting of cyanide poisonings due to low cardiac output and intrapulmonary shunting.24 Due to disruption of oxidative phosphorylation and inability to produce ATP, an anion-gap metabolic acidosis ensues. A worsening metabolic acidosis is a sensitive marker for the presence of cyanide poisoning, although it is not specific for cyanide. Absence of a metabolic acidosis would infer that despite the body burden of cyanide from SNP, the cyanide is being effectively detoxified and is exerting minimal effects on the capacity of oxidative phosphorylation to manufacture ATP. Blood cyanide levels are usually not available in an expedient manner to assist in the diagnosis of cyanide poisoning. Plasma cyanide concentrations are a better reflection of tissue cyanide levels because cyanide in the plasma is in equilibrium with tissue levels25; however, erythrocyte cyanide levels are more commonly measured. In the setting of SNP infusion, cyanide accumulates in erythrocytes, so the red blood cell to plasma cyanide concentrations will be higher than after acute poisoning from inorganic cyanide.18,26 Thiocyanate levels do not correlate with the degree of cyanide poisoning.27 Likewise, an elevated thiocyanate level does not infer that the patient has high levels of cyanide. Thiocyanate levels correlate only with thiocyanate toxicity. Toxicity does not occur until thiocyanate levels have exceeded 100 mg/L. Thiocyanate levels will increase when thiosulfate is concurrently infused with the SNP.28

Management If cyanide toxicity is suspected in a patient receiving an SNP infusion, the infusion must be discontinued while the patient is administered maximal oxygen therapy. Patients with evidence of severe poisoning may require induction of methemoglobinemia with intravenous infusion of sodium nitrite. The dose may need to be adjusted to accommodate a patient with anemia. Sodium thiosulfate should be administered to provide substrate for the production of thiocyanate. In those patients who may not tolerate a reduction in oxygen carrying capacity from methemoglobinemia, sodium thiosulfate should be administered alone. In an animal model, simultaneous infusion of thiosulfate during SNP infusion provided protection against cyanide toxicity.29 Recommendations have included the mixing of thiosulfate into the SNP solution at a 10 to 1 ratio. This would require 1 g of thiosulfate for each 100 mg of SNP.25 The coadministration of thiosulfate with SNP reduces the rise in cyanide concentrations in circulation.7,17 Hydroxycobalamin is another treatment for cyanide poisoning since it binds to cyanide to form cyanocobal-

985

amin, a nontoxic compound. Hydroxycobalamin has been used to prevent accumulation of cyanide after SNP administration. Concurrent infusion of hydroxycobalamin resulted in lower erythrocyte and plasma cyanide levels in patients receiving SNP compared with controls who received a similar rate of nitroprusside infusion.30 One animal model compared infusion of thiosulfate to infusion of hydroxycobalamin during administration of SNP and measured the red blood cell and plasma cyanide levels. Thiosulfate appeared to be more effective in lowering cyanide levels; however, the amount of hydroxycobalamin that could be infused was a limiting factor, so smaller doses were used.31 Side effects from the use of hydroxycobalamin may include a transient reddish discoloration of the skin and mucous membranes. Anaphylaxis has rarely been reported. The use of hydroxycobalamin may be limited by availability and cost of the product.32 Thiocyanate toxicity due to accumulation of thiocyanate from renal failure may be easily removed with hemodialysis. Rapid decline in levels correlates with improvement in the CNS effects.33

NITRATES As a class, organic nitrates are commonly used for treatment of ischemic heart disease. Their effect of dilating coronary arteries and improving coronary blood flow in addition to reducing myocardial oxygen demand led to their use as a cornerstone of therapy in patients with ischemic heart disease. Nitroglycerin was first synthesized in 1846 by Sobrero and was developed 1 year later into a formulation for sublingual administration. In the 1850s, amyl nitrite was found to relieve angina when given inhalationally; however, its clinical effects had a short duration.34 In the 1870s, Murrell described the successful use of 1% nitroglycerin solutions in three patients who had symptoms consistent with angina pectoris. The patients would administer the solution orally via drops on a scheduled basis and if the symptoms occurred. Murrell also described the side effect of a severe headache that was associated with the administration of nitroglycerin, both from his patient’s experiences and his own selfadministration.35 Subsequent use of nitrates became widespread as a treatment modality for angina pectoris.

Pharmacokinetics and Pharmacology Nitroglycerin is a polyol ester of nitric acid and is known as glyceryl trinitrate. Organic nitrates of low molecular weight such as nitroglycerin tend to be volatile oily liquids. Organic nitrates such as isosorbide dinitrate are high-molecular-weight esters and are found in solid form. Organic nitrates are biotransformed in the liver via reductive hydrolysis. The reduction of nitrates results in the formation of water-soluble metabolites that have less vasodilatory activity than the parent compound. Nitro-

986


glycerin given sublingually reaches peak concentrations within 4 minutes after administration. The half-life of the parent compound is about 1 to 3 minutes. The dinitrate metabolites have a half-life of 40 minutes and have 10 times less potency as vasodilators.34 Isosorbide dinitrate also undergoes denitration after reacting with glutathione. The parent compound has a half-life of about 45 minutes but the metabolites have half-lives of 3 to 6 hours. Isosorbide-5-mononitrate has a longer half-life than the dinitrate formulation and has increased bioavailability since it does not undergo first pass metabolism.34 Organic nitrates release nitric oxide via denitration when exposed to vascular smooth muscle. The release of nitric oxide stimulates soluble guanylate cyclase, causing increased cGMP. Increased cGMP activates cGMPdependent protein kinase, culminating in dephosphorylation of the myosin light chain and subsequent vascular smooth muscle relaxation vasodilation.36 The mechanism for release of nitric oxide is not well elucidated. Nitroglycerin requires a three-electron reduction to release nitric oxide from its third carbon. This release occurs when nitroglycerin is exposed to mammalian vascular smooth muscle. Initial theories suggested that cellular thiols were needed to accomplish this biotransformation. Nonenzymatic release of nitric oxide may occur in the presence of large concentrations of thiol-containing compounds such as cysteine; however, the most abundant source of thiols, glutathione, does not release nitric oxide from nitroglycerin via this nonenzymatic process. Additional evidence in an experiment with bovine coronary smooth muscle cells suggests that nitroglycerin releases nitric oxide via an enzymatic process that is attached to cellular surface membrane. Glutathione may be required for this reaction as a cofactor, rather than a substrate.37,38 Nitroglycerin is also processed via enzymatic pathways that utilize glutathione S-transferases. Instead of releasing nitric oxide, this reaction releases inorganic nitrite (NO2–).38 The inorganic nitrite is not vasoactive unless at very high concentrations; however, it may oxidize ferrous iron in hemoglobin to ferric iron, resulting in methemoglobinemia. Tolerance to the antianginal effects may occur with continued use of organic nitrates. It is not a uniform phenomenon, since some individuals may develop only partial tolerance. The mechanisms of tolerance are not well understood and may be multifactorial. Tolerance may involve the reduced efficiency of the vascular wall to biotransform nitrates to nitric oxide. In addition, there has been a link between nitroglycerin tolerance and superoxide production from the endothelium. The superoxide may react with the nitric oxide to produce peroxynitrite. Peroxynitrite has a shorter half-life than nitric oxide and is less effective in activating guanylate cyclase.39 Removal of endothelium of the aorta in animal models markedly reduces the development of tolerance to nitroglycerin. The role of endothelium in promoting tolerance has been confirmed in another animal model and was associated with the activation of nitric oxide synthase and protein kinase C as well as the production of superoxide and peroxynitrite free radicals.40

Toxicology Since organic nitrates affect all smooth muscle beds, their effects extend beyond the coronary arteries. Low concentrations of nitroglycerin may result in venodilation that precedes the arteriodilation. Higher doses result in venous pooling and may reduce arteriolar resistance. A resulting decrease in systolic and diastolic blood pressure may result in dizziness, weakness, and postural hypotension. Syncope has even been described from the transgingival absorption of nitroglycerin paste that was inadvertantly used as toothpaste.41 Dilation of meningeal vessels is thought to result in the commonly reported side effect of headache. Although rare, induction of methemoglobin has been reported in the setting of organic nitrate use. Nitrite is formed from the breakdown of the nitroglycerin and acts as the oxidizer of ferrous iron to the ferric state. One case of methemoglobinemia was reported after an oral overdose of nitroglycerin tablets, although the methemoglobin level was only 7% with a hemoglobin of 14 g/dL.42 Intravenous nitroglycerin has been reported to result in methemoglobinemia, but the dose required is not clear. Higher infusions of nitroglycerin may be more likely to produce higher levels of methemoglobin than lower infusion rates.43 Cerebral vessel vasodilation from nitroglycerin infusion has been associated with a rise in intracranial pressure. Intracranial hypertension from therapeutic doses of nitroglycerin has been associated with oculomotor palsies, headache, vomiting, and coma. Reversal of these abnormalities occurred upon discontinuation of the nitroglycerin.44,45 Most preparations of nitroglycerin include propylene glycol as a diluent. Toxicity may occur in patients who accumulate propylene glycol. Since a large portion of propylene glycol is excreted by the kidneys, patients with renal insufficiency may be at greater risk for diminished clearance. Manifestations of toxicity may include hyperosmolality from the propylene glycol and a metabolic acidosis from its metabolism to lactate. Coma, stupor, and dysconjugate eye movements may occur. Hemolysis with subsequent hemoglobinuria has also been reported.46 Another potential interaction with nitroglycerin infusion is an interference with the efficacy of heparin infusion. Col and colleagues noticed a resistance to anticoagulation with heparin when nitroglycerin was concomitantly infused, and they performed in vitro and in vivo studies that supported their observation. These investigators found that the propylene glycol diluent alone could reduce the activated partial thromboplastin time (aPTT) prolongation induced by heparin. Infusion of nitroglycerin prepared with propylene glycol reduced the aPTT even more dramatically than just the propylene glycol.47 Another study suggested that patients on nitroglycerin infusions require more heparin to maintain their anticoagulation. In addition, two patients in this study were administered nitroglycerin infusion prepared without propylene glycol. Heparin resistance still occurred comparably with those patients who received the standard nitroglycerin preparation with propylene


glycol.48 In another study in patients with acute coronary syndromes, only nitroglycerin infusions that exceeded 350 μg/min had an effect on the aPTT and heparin requirements.49 The mechanism of this potential drug interaction is not clear. Drug interactions with medications that inhibit the cGMP phosphodiesterase-5 enzyme such as sildenafil may occur. In the presence of these inhibitors, nitrates cause a profound increase in cGMP. As a result, increased vasodilatory effects and hypotension results. Nitrates should be used with great caution in patients who have used sildenafil or one of its analogs in the previous 24 hours.50

Diagnosis The diagnosis of nitroglycerin-induced hypotension requires the association of abnormal vital signs with a recent exposure. Medications that are orally administered may have longer half-lives as opposed to the intravenous formulations of organic nitrates. The diagnosis of methemoglobinemia is suggested by the presence of cyanosis and reduced pulse oximetry in the setting of a relatively normal partial pressure of oxygen on arterial blood gas. Methemoglobin levels are measured using co-oximeter readings on heparinized blood samples. Levels that exceed 1.5 g/dL may induce cyanosis; however, levels below this threshold may still impact the oxygen-carrying capacity of critically ill patients, particularly if they are anemic. During a rapid nitroglycerin infusion, the presence of a persistant metabolic acidosis that may also be associated with hyperosmolality would suggest propylene glycol toxicity. A patient with significant renal insufficiency may be at high risk for propylene glycol toxicity due to diminished renal elimination. Many other medications that utilize propylene glycol, such as lorazepam, phenytoin, diazepam, and intravenous formulations of sulfamethoxazole and trimethoprim, may be associated with formation of a lactate-dependent acidosis.51

Management Cardiovascular effects and side effects from organic nitrates will resolve with discontinuation of the infusion. Hypotension may require fluid boluses of crystalloid or additional inotropic support given the clinical scenario. Methemoglobinemia that is symptomatic may be treated with the infusion of a 1% methylene blue solution. The infusion rate is usually a 1- to 2-mg/kg bolus with a repeat dose if no response occurs in 30 minutes. If the patient has underlying glucose 6-phosphate dehydrogenase deficiency, then the administration of methylene blue will not be efficacious and could potentially be deleterious. These patients may benefit from a transfusion of packed red blood cells to provide additional oxygen-carrying capacity. If a patient develops a severe metabolic acidosis from the accumulation of propylene glycol, hemodialysis will effectively remove the diluent. Reduction in the

987

half-life of propylene glycol has been reported with hemodialysis.46

HYDRALAZINE Hydralazine was introduced to the United States in the 1950s as an oral antihypertensive medication and has subsequently been approved for intramuscular and intravenous administration. Although labeled a class C medication during pregnancy, it is commonly used to treat hypertensive crisis in late gestation. Hydralazine is seldom the primary treatment for chronic hypertension because of tachyphylaxis and sympathetic discharge effects. Despite its use as an oral treatment agent for hypertension, reports of acute severe poisoning with hydralazine are rare. The American Association of Poison Control Centers (AAPCC) reported 212 exposures to the Toxic Exposure Surveillance System (TESS) in 2002. No deaths were reported of the 103 hydralazine exposures subsequently treated in a health care facility.52

Structure 1-Hydrazinophthalazine, or hydralazine (Apresoline, [Ciba Pharmaceuticals Summit, NJ]), has a hydrazine moiety in the 1-position of the hydrazine ring that is believed to produce the vasodilatory effects of the drug.53 The structure of hydralazine is shown in Figure 61-2.

Pharmacology and Pharmacokinetics Hydralazine directly relaxes arteriolar smooth muscle through its effects on cGMP. Venous smooth muscle is not affected. Hydralazine-induced vasodilation frequently stimulates an increase in heart rate and myocardial contractility. This sympathetic surge is primarily a baroreceptor-mediated reflex, but hydralazine may directly stimulate the release of norepinephrine from sympathetic neurons.54 Absorption of hydralazine from the gastrointestinal tract is rapid, with peak plasma levels occurring between 30 and 120 minutes. The volume of distribution (Vd) is 1.6 L/kg with approximately 90% protein binding. Hydralazine is primarily metabolized by N-acetylation in the liver. With therapeutic dosing, the half-life is approximately 1 hour, although the duration of clinical effects usually lasts longer. The rate of elimination is dependent on genetically established N-acetyl-transferase activity. Approximately 50% of patients in the United States are fast acetylators. Fast acetylators produce an inactive metabolite more rapidly; therefore, slow H2N

J

CHAPTER 61

HNJ

N

N

Hydralazine FIGURE 61-2 Hydralazine.


Toxicology Common side effects related to therapeutic use of hydralazine include tachycardia, hypotension, palpitations, headache, flushing, nausea, and dizziness. Many of these side effects may be minimized by administering a βadrenergic receptor blocker and diuretic in conjunction with hydralazine. Chest pain and myocardial injury may occur with hydralazine administration, especially in patients with significant coronary artery disease or angina. Electrocardiogram (ECG) abnormalities, including reversible ST-segment depression, have been reported in a young female intentionally overdosing on hydralazine.55 Caution should be used when considering hydralazine use in elderly patients and those with coronary artery disease. A coronary artery blood flow steal phenomenon, increased myocardial oxygen demand from greater sympathetic output, and lack of epicardial coronary artery vasodilation may precipitate myocardial ischemia. The second type of hydralazine-related side effects appears to be immunologically mediated through production of autoantibodies. The exact mechanism of this reaction is uncertain. Most commonly described is a drug-induced lupus-like syndrome manifesting as fever, myalgias, arthralgias, and rash. This reaction usually resolves after discontinuation of the medication but may require corticosteroids for refractory symptoms. Less commonly reported are pleuritis, pericarditis, vasculitis, hemolytic anemia, and nephritis. Patients can also rarely develop a pyridoxine-responsive polyneuropathy from hydrazone formation when hydralazine binds to pyridoxine.56

Diagnosis and Management Treatment of hydralazine poisoning is primarily supportive. Because no antidote exists, care should be directed toward improving hemodynamic status. Intravenous fluids are the initial management for hypotension. Additional vasopressor support with direct-acting αadrenergic receptor agonists such as norepinephrine and phenylephrine should be considered for refractory hypotension. Administration of inotropic agents should be cautiously titrated because hydralazine-induced sympathetic discharge may already contribute to tachycardia. For recent oral ingestions where the airway is stable, consideration may be given to the administration of a single dose of activated charcoal. No additional gastrointestinal decontamination is indicated. Due to the rarity of overdose and lack of significant morbidity, few data exist regarding the benefit of enhanced elimination. Presently, there is no indication for hemodialysis or other methods of enhanced elimination in the management of hydralazine toxicity. Cardiac telemetry for symptomatic patients is warranted until supportive care measures are no longer required,

and clinical recovery has occurred. ECG and complete cardiac evaluation for myocardial injury may be necessary in the setting of chest pain from hypotensioninduced cardiac ischemia in certain patient populations.

MINOXIDIL The hypotensive effects of minoxidil were discovered in 1965, and the oral tablet formulation became available as Loniten (Pharmacia and Upjohn, Peapack, NJ) in October 1979.57 It is primarily used to treat hypertension refractory to multiple other regimens. In 1988, a 2% Rogaine (Pharmacia and Upjohn, Peapack, NJ) formulation (topical minoxidil preparation) became available by prescription to enhance hair growth in male-pattern baldness. Hypertrichosis with minoxidil therapy was first described in 1980.58 In November 1997, the FDA approved the over-the-counter (OTC) sale of 5% Rogaine Extra Strength for Men. This topical formulation contains minoxidil 50 mg/mL in excipients of 30% ethanol vol/vol, 50% propylene glycol vol/vol, and purified water.57 Minoxidil overdose is uncommon today, and this is likely a reflection of its diminished use in the treatment of hypertension. However, the topical minoxidil preparations are frequently purchased OTC and provide an easy source of exposure for pediatric and intentional ingestions.57,59,60

Structure 6-Amino-1,2-dihydro-1-hydroxy-2imino-4-piperidinopyrimidine, or minoxidil, must be metabolized to minoxidil N-O sulfate by hepatic sulfotransferase to manifest vasodilatory properties.61 The parent compound is not active, and the active metabolite produced from sulfate conjugation may explain the prolonged effects of the drug. The structure of minoxidil is shown in Figure 61-3.

Pharmacology and Pharmacokinetics Minoxidil is rapidly and completely absorbed from the gastrointestinal tract, with peak plasma concentrations within 1 hour postingestion. The Vd is 2.8 to 3.3 L/kg, minimal plasma protein binding occurs, and the drug does not cross the blood-brain barrier. The large Vd is hypothesized to reflect an accumulation of the active drug in the vascular smooth muscle.62 While the half-life of minoxidil is 3 to 4 hours, the duration of action is

N

J

acetylators may have a greater or longer antihypertensive effect. Slow acetylators are also more likely to develop a hydralazine-induced lupus erythematosus–like syndrome and antinuclear antibodies.

N H2N

N+

J

988

O-

Minoxidil FIGURE 61-3 Minoxidil.

NH2

CHAPTER 61


typically 24 hours and may extend to 3 days. The pharmacokinetics of minoxidil N-O sulfate are less clear but may explain the longer duration of action. The primary route of elimination is hepatic glucuronide conjugation at the N-oxide position in the pyrimidine ring. The production of the active metabolite, minoxidil N-O sulfate, is a minor pathway. Twenty percent of the drug is excreted unchanged in the urine. Although minoxidil and its glucuronidation products are hemodialzyable, this does not reverse clinical effects from tissue sequestration of the active metabolite in the vascular smooth muscle. Minoxidil sulfate activates ATP-sensitive potassium channels, enhancing channel opening and subsequent potassium efflux. This causes hyperpolarization and subsequent vascular smooth muscle relaxation.63 While arteriolar vasodilation causes decreased peripheral vascular resistance and blood pressure, there is little effect on capacitance vessels. Hypertrichosis is also probably a consequence of potassium channel augmentation. A baroreceptor-mediated sympathetic response can sometimes occur even with therapeutic dosing of minoxidil.64 Sympathomimetic medications should be avoided due to excess cardiac stimulation with reflex tachycardia and baroreceptor activation from minoxidil therapy. Although renin and aldosterone secretion are increased during minoxidil therapy, it is thought that fluid retention occurs primarily from increased proximal renal tubular reabsorption secondary to reduced renal perfusion. Some side effects of minoxidil therapy, specifically fluid retention and reflex tachycardia, can be minimized by administering a diuretic and β-receptor antagonist in conjunction.

Toxicology Typical adult therapeutic dosing is 10 to 40 mg orally once a day up to a maximum of 100 mg per day. Pediatric dosing is 0.25 to 1.0 mg/kg to a maximum of 50 mg per day. The manufacturer package insert states it is difficult to establish an exact minoxidil serum toxic level due to patient variation, but levels above 2000 ng/mL are likely representative of an overdosage.65 An average adult consumption of 30 mg orally would produce a serum minoxidil level of 40 ng/mL 3 hours postingestion59; however, a 2-year-old was reported to consume 100 mg of minoxidil and developed significant tachycardia with a 3hour postingestion serum minoxidil level of 150 ng/mL.66 The highest reported serum minoxidil concentration was 3140 ng/mL in a 20-year-old woman who developed tachycardia, labile hypotension, ST-segment depression, and T-wave inversion after an unknown quantity of minoxidil was ingested in a suicide attempt. She was stabilized with intravenous fluids and supportive care and eventually discharged from the hospital.67 Common pharmacologic side effects related to therapeutic administration of minoxidil include tachycardia, hypotension, and hypertrichosis. Because heart rate, myocardial contractility, and myocardial oxygen consumption are increased, chest pain and myocardial injury may develop in patients with significant coronary

989

artery disease or angina. Worsening left ventricular systolic and diastolic dysfunction can develop in patients with congestive heart failure and pulmonary hypertension. While ECG abnormalities such as flattened and inverted T waves are commonly reported in therapeutic dosing or overdose of minoxidil from potassium channel activation,67 myocardial infarction has also been reported.60 In addition to sodium and fluid retention, pericardial effusions and pericarditis have been reported with minoxidil use, primarily in hemodialysis patients.68 Other rarely described complications include rashes, thrombocytopenia, nausea, headache, gynecomastia, polymenorrhea, and breast tenderness. Increased hair growth occurs on the scalp, face, back, arms, and legs. There are no reports of hypertrichosis occurring from a single ingestion or overdose.

Diagnosis and Management Cardiac and hemodynamic monitoring is warranted in the symptomatic patient. Additional cardiac evaluation and serial ECGs may be indicated if chest pain or other symptoms of cardiac ischemia develop. A serum radioimmunoassay is available through the manufacturer, but serum concentrations generally do not correlate with therapeutic response and are often delayed and unlikely to assist in management. Treatment of minoxidil poisoning is primarily supportive. No antidote exists, and a single dose of activated charcoal is only indicated in recent ingestions when airway reflexes are intact. Intravenous fluids are the initial management for hypotension. Additional vasopressor support with norepinephrine and phenylephrine should be considered for refractory hypotension. Cautious administration of inotropic support is necessary to avoid excessive tachycardia and cardiac stimulation. Although intravenous fluids should be used judiciously in the setting of hypotension, congestive heart failure in patients with reduced left ventricular function can develop. Enhanced elimination is not indicated. Cardiac telemetry and hemodynamic monitoring is necessary in these cases until clinical recovery has occurred. Serial ECGs and evaluation of cardiac markers for myocardial injury may be necessary in the setting of hypotension-induced cardiac ischemia, especially in the elderly or patients with coronary artery disease ingesting minoxidil. T wave changes from minoxidil-induced potassium channel activation usually resolve once the metabolites are eliminated.

SILDENAFIL Sildenafil (Viagra [Pfizer, New York, NY]) is the first oral drug approved by the FDA, in March 1998, for the treatment of male erectile dysfunction.69 This condition affects more than 30 million men in the United States alone. While the development of this agent has significantly improved the lifestyle of many patients, concerns for medication interaction and drug abuse have arisen. Over 6 million outpatient prescriptions were

990


written during its initial marketing phase from March to November 1998, and it is estimated that sildenafil has been prescribed to over 10 million men worldwide.70 Excessive consumer demand has created a black market, and sildenafil or similar agents are now commonly available over the Internet, in adult sex shops, and on the street due to its increasing use as a recreational drug.

Structure and Mechanism of Action Sildenafil is a selective inhibitor of phosphodiesterase type 5 (PDE5), which is responsible for degradation of the second messenger cGMP. Normally, sexual stimulation enhances release of nitric oxide, activating guanylate cyclase with conversion of GTP to cGMP. cGMP acts as a smooth muscle relaxant and increases arterial blood flow in the penis to enhance tumescence. Although sildenafil is not a direct smooth muscle relaxer, it inhibits the breakdown of cGMP, culminating in prolonged blood flow to the corpora cavernosa and ultimately sustained penile erection. Because nitric oxide is essential to initiate this cascade, sexual stimulation is necessary and sildenafil acts more as a facilitator of tumescence rather than as a direct vasodilatory agent.71 The structure of sildenafil is shown in Figure 61-4.

Pharmacology and Pharmacokinetics Sildenafil is rapidly absorbed after oral administration, with peak effects in 60 minutes. There is only 40% bioavailability of this agent due to extensive first pass metabolism. The volume of distribution is approximately 1.5 L/kg in the average adult, with 96% protein binding. Metabolism is primarily via the hepatic P-450 CYP3A4 pathway to N-desmethyl sildenafil, an active metabolite responsible for up to 20% of the pharmacologic effect.50 The majority of side effects from sildenafil are a result of CYP3A4 inhibition by cimetidine, macrolide antibiotics, antifungals, and protease inhibitors. The elimination half-life of sildenafil and its active metabolite is about 4 hours. While 13% of the drug is renally excreted and 80% fecally eliminated, significantly prolonged increased sildenafil concentrations can occur in the setting of severe renal dysfunction, hepatic insufficiency, and cytochrome P-450 inhibitors.

Toxicology The average therapeutic dose of sildenafil is 25 to 100 mg, with a maximum of one dose per day. Lower

K

K

O

S

K

O

O

HN N

N N

O Sildenafil

FIGURE 61-4 Sildenafil.

N N

dosing is advocated for patients older than 65 years and in those with renal or hepatic impairment. Although many side effects of sildenafil may be attributed to its inhibitory effect on other PDEs, the high selectivity it has for PDE5 may explain the low morbidity reported in overdose. There are few reports of serious side effects from isolated ingestion of sildenafil. One case reported a 42-year-old woman who developed weakness, flushing, headache, dizziness, tremor, and palpitations after ingestion of almost 2 g of sildenafil. While nasogastric tube irrigation and activated charcoal lavage occurred early after this ingestion, all symptoms rapidly resolved, and the patient was discharged in 12 hours.72 However, another case of presumed sildenafil ingestion leading to death reported a postmortem blood sildenafil concentration of 6.27 μg/mL by high-pressure liquid chromatography/mass spectroscopy. Although this concentration was four times higher than previously reported therapeutic levels, the patient had extensive baseline medical problems, including severe cardiomyopathy.70 While there is significant controversy regarding the interpretation of FDA postmarketing data, 1473 major adverse events, including 522 deaths, were reported within 13 months of sildenafil availability.73,74 In summarizing TESS data, despite inherent underreporting and reporting bias, it seems that most pediatric exposures to sildenafil are well tolerated, whereas older men with preexisting cardiovascular disease and potential drug-drug interactions are more likely to experience adverse side effects.71 The most recognized drug interaction involving sildenafil use is with the administration of nitrates or nitrites. Sildenafil synergistically potentiates the hypotensive effects of medications that promote vasodilatory mechanisms via nitric oxide pathways. This may also be seen when amyl or butyl nitrite are recreationally inhaled while using sildenafil. Due to excessive morbidity and mortality associated with combined use of sildenafil with nitrates or nitrites in men with cardiovascular disease, sildenafil is contraindicated in patients requiring those medications. In addition, nitrates are contraindicated up to 24 hours after the last sildenafil use should angina or myocardial infarction occur in this time frame.50 Other antihypertensives should also be used cautiously in this setting because sildenafil is known to produce small decreases in systolic and diastolic blood pressure. Common drug interactions include inhibitors of P-450 CYP3A4, such as cimetidine, ketoconazole, itraconazole, erythromycin, and clarithromycin. Starting doses of sildenafil should be no greater than 25 mg when patients are prescribed these other medications. The antiretroviral protease inhibitors also inhibit first pass metabolism of sildenafil, thus increasing its serum halflife and delaying peak concentrations. The most common side effects reported in clinical trials of therapeutic sildenafil use were headache, flushing, dyspepsia, and nasal congestion.69,75 Many of these effects, like dyspepsia due to lower esophageal sphincter relaxation, can be explained as a consequence of PDE5 inhibition. Because sildenafil is also a weak inhibitor of PDE6 in the retina, visual disturbances


Diagnosis and Management In the setting of isolated sildenafil overdose, supportive care including intravenous fluids, cardiac monitoring, and direct-acting α agonists for refractory hypotension are indicated. Obtaining serum concentration results via the manufacturer are not likely to assist in clinical management of overdose. Although few gastrointestinal decontamination data exist, a single dose of activated charcoal is appropriate in the setting of recent ingestion and adequate airway protection. The American College of Cardiology and the American Heart Association have several management recommendations for sildenafil-induced hypotension due to nitrate interaction. Discontinuing nitrate use, Tredelenberg positioning, intravenous fluid resuscitation, direct-acting α-agonist vasopressors, and intra-aortic balloon pump have all been advocated depending on the severity of hypotension.50 In the setting of acute coronary syndrome in a patient using sildenafil, recommendations include avoiding nitrates if sildenafil has been used in the past 24 hours. Administering other non-nitrate antianginal agents like β-receptor antagonists is more appropriate under those circumstances. Otherwise, standard therapy for acute coronary syndrome is indicated.

ACE INHIBITORS With the introduction of captopril in 1981, angiotensinconverting enzyme (ACE) inhibitors have gained widespread popularity due to their proven effectiveness in the treatment of hypertension and congestive heart failure.79 Those populations that appear to derive benefit are diabetics and patients with recent myocardial infarctions.80,81 With increasing use and various clinical indications, the

991

potential for increased frequency of both intentional and unintentional poisonings exists. Despite their widespread use, however, the number of reported cases of toxicity related to overdose with ACE inhibitors remains relatively small. As a class, the ACE inhibitors have proven to be relatively safe with a high therapeutic index and infrequently reported poor outcomes secondary to overdose.

Pharmacology and Pharmacokinetics There are currently 11 available ACE inhibitors approved for use by the FDA, including captopril, benazepril, enalapril, enaliprilat, fosinopril, lisinopril, moexipril, perinodpril, quinapril, ramipril, and trandolapril. While all contain a similar 2-methyl propanolol-L-proline moiety, the pharmacokinetic profiles differ considerably based on variations in this common core structure (Fig. 61-5).82 ACE inhibitors are generally well absorbed, reaching peak serum concentrations in the first 1 to 4 hours. The level of protein binding is low (25% to 60%), with the exception of benazepril (98%).83 Drug half-lives of these agents range from 2 to 12 hours. With the exception of lisinopril and captopril, ACE inhibitors are administered as prodrugs with good bioavailability. In the liver, each of the prodrugs are converted to active metabolites following the cleavage of an ester moiety. These active metabolites may demonstrate effects for several days due to slow dissociation from the ACE. With the exception of fosinopril, which is eliminated both renally and hepatically, ACE inhibitors are cleared predominantly via the kidneys. Dosage adjustments should be considered in those with impaired renal function.83 The effectiveness of ACE inhibitors lies in their ability to directly bind to the active site of the ACE and inhibit the production of angiotensin II (see Fig. 61-6). In the lung and vascular endothelium, ACE is responsible for converting inactive angiotensin I to the highly active compound angiotensin II. Angiotensin II is a potent vasoconstrictor having direct effects on vascular smooth muscle. In addition, angiotensin II stimulates aldosterone release that acts at the distal and collecting tubules of the kidney by increasing sodium retention while excreting potassium and hydrogen ions. By inhibiting the production of angiotensin II, ACE inhibitors are able to decrease peripheral vascular resistance, lower sodium and water retention, and decrease blood pressure. Other effects of ACE inhibitors include inhibiting bradykinin inactivation. Kininase II is responsible for the inactivation of bradykinin and is identical in structure to ACE. By inhibiting kininase II, ACE inhibitors allow bradykinin to accumulate, leading to a further decrease

CH3

O

K

including blurred vision, light perception abnormalities, and color perception distortions can also develop with therapeutic dosing. Higher doses of sildenafil can increase the frequency of visual disturbances, but these symptoms are usually transient, lasting less than a few hours. Although rarely reported, myocardial infarction has occurred in close temporal proximity to sildenafil usage,76 although this is likely a result of a transient decrease in blood pressure culminating in decreased coronary blood flow. These effects can be more significant in the setting of concomitant nitrate use. While a decrease in systemic vascular resistance may develop, sildenafil use is not thought to directly cause tachycardia.69 Effective treatment of erectile dysfunction might intuitively increase the risk for priapism, but no cases of priapism were reported in the initial clinical trials.69 More recently, a patient with sickle cell trait was reported to develop priapism while using sildenafil.77 Another case of priapism, successfully treated with aspiration and intracorporal injection of α-receptor agonists, was described in a 28-year-old man taking a 100-mg dose of sildenafil-citrate for prior penile traumainduced mild erectile dysfunction.78

J

CHAPTER 61

HSJCH2JCHJCJN Captopril FIGURE 61-5 Captopril.

COO-

992


in blood pressure through direct vasodilation and stimulation of prostaglandin biosynthesis.84 This accumulation of bradykinin also contributes to side effects of cough and angioedema commonly described with therapeutic ACE inhibitor usage.85 The renin-angiotensin system plays a vital role in regulating perfusion to the kidney in states of reduced renal flow. In the setting of bilateral renal artery stenosis, the ability of angiotensin II to maintain adequate post–glomerular efferent arteriolar tone by way of its vasoconstrictive properties ensures adequate glomerular perfusion. By inhibiting the production of angiotensin II, ACE inhibitors are capable of decreasing glomerular perfusion leading to prerenal azotemia. While bilateral renal artery stenosis may primarily cause a small percentage of hypertension, acute renal decompensation following the administration of an ACE inhibitor should raise suspicion for this particular etiology.86

Toxicity Hypotension is the most pronounced toxic effect of ACE inhibitor action. A “first dose phenomenon” similar to that described with α1-antagonists following initiation of treatment can result in lightheadedness, dizziness, and syncope. One study described a systolic blood pressure decrease of greater than 50 mm Hg in 10% of healthy volunteers after initiation of captopril therapy.87 Hypotension can be most pronounced in therapeutic and excessive dosing in patients with fluid depletion, renovascular disease, and congestive heart failure. Tachycardia is rarely reported in ACE inhibitor toxicity, and more frequently a relative bradycardia develops. Noncardiovascular effects in overdose include drowsiness, lethargy, and confusion. Renal and electrolyte abnormalities may occur as a result of renal insufficiency related to profound hypotension.88 In addition, decreased production of aldosterone may cause worsening hyperkalemia and hyponatremia. Hyperkalemia is more commonly seen in individuals with prior renal impairment or those taking potassium supplements or potassium-sparing diuretics such as spironolactone.89 The presence of oliguria and electrolyte abnormalities are generally short lived and improve with discontinuation of the inciting agent. Cases of ACE inhibitor overdose are frequently complicated by the presence of co-ingestants that may contribute to the clinical presentation.90 Death as a result of isolated ingestion of ACE inhibitors is exceedingly rare.91,92 Interestingly, children seem to be particularly resistant to the effects of ACE inhibitors, remaining asymptomatic in most cases despite large accidental ingestions.93 Angioedema is a frequently reported side effect of ACE inhibitor therapy with the potential for significant morbidity and mortality. The overall incidence is estimated to be approximately 0.1% to 0.2%. African Americans have a 4.5 times greater risk of ACE inhibitor–induced angioedema compared with those of European descent.94,95 Angioedema occurs as a result of increased perfusion in the capillary beds located in subcutaneous tissue and dermis with leakage of fluid into

the interstitium. With fluid accumulation comes swelling, most prominently in the periorbital, perioral, and oropharyngeal tissue, that can rapidly progress to airway obstruction. The mechanism behind angioedema in the setting of ACE inhibitor administration is thought to involve increased levels of bradykinin, substance P, and other inflammatory intermediates such as histamines, prostaglandin D, and leukotrienes.85 The onset of angioedema resulting from ACE inhibitor therapy is classically described to occur in two thirds of patients within the first week of therapy, with the remaining one third developing this potentially lifethreatening side effect weeks to years after initiation of the drug.96 ACE inhibitors should not be prescribed to patients who have a history of hereditary or acquired angioedema.97 Accumulation of bradykinin is felt to also be responsible for the persistent and often debilitating cough described in 5% to 10% of patients taking ACE inhibitors.

Management Initial management of ACE inhibitor poisoning should focus on aggressive supportive care with cardiac monitoring and ensuring adequate urine output. Hypotension is often responsive to intravenous fluid administration alone. Vasopressors have been used with success in cases of refractory hypotension.98 The presence of hyperkalemia should prompt urgent potassium-lowering intervention. Activated charcoal should be administered after recent ingestions in compliant and awake patients. Orogastric lavage, with its inherent risks, should not be routinely recommended due to the relatively low rates of morbidity and mortality associated with ACE inhibitors and the effectiveness of supportive care alone. Reports of asymptomatic patients following large ingestions of ACE inhibitors are relatively common.89,99 A study by Spiller and colleagues evaluated 48 children with ingestions not greater than adult therapeutic dosages of captopril and enalapril and found no adverse outcomes with close home monitoring and telephone follow-up.100 Maximum hemodynamic effects following ingestion should occur within the first 1 to 6 hours, depending on the particular ACE inhibitor ingested.101 Individuals manifesting hypotension at the time of evaluation should be monitored closely for at least 24 hours given the prolonged effects of many of these agents and their active metabolites. Other treatment options that have found limited yet sometimes dramatic effects in reversing hypotension seen with ACE inhibitor overdose include naloxone and angiotensin II administration. Naloxone is felt to work through inhibition of the naturally occurring endorphins that can inhibit angiotensin II activity. Success has been demonstrated in both animal models and in limited case reports.102,103 Angiotensin II administration has been effective in treating refractory hypotension from ACE inhibitor poisoning, but its lack of availability makes this intervention an unlikely treatment option.104 Particular ACE inhibitors such as captopril, enalapril, and lisinopril may be amenable to dialysis; however, it would be rarely

CHAPTER 61


993

FIGURE 61-6 Sites of action of ACE inhibitors in the metabolism of angiotensin II and bradykinin and the site of action of the angiotensin II receptor antagonists.

Ace Inhibitors Angiotensin

Angiotensin I Inactive metabolites

Angiotensin II receptor antagonist

Angiotensin converting enzyme Angiotensin II

Bradykinin

Vasodilation

Angioedema and cough

Vasoconstriction

Aldosterone secretion

PVR

Na+ and H2O retention Increased blood pressure

necessary given the effectiveness of other treatment options and the lack of clinical symptoms in most cases. Figure 61-6 shows the sites of action of ACE inhibitors in the metabolism of angiotensin II and bradykinin.

ANGIOTENSIN II RECEPTOR ANTAGONISTS Currently, seven angiotensin II receptor antagonists are available in the United States: losartan, valsartan, irbesartan, telmisartan, olmesartan, candesartan, and eprosartan. This new class of antihypertensive agent was introduced in 1995 and has gained popularity due to its outstanding side effect profile and effectiveness in treating hypertension and heart failure.105,106 These drugs are rapidly absorbed in the gastrointestinal tract and reach peak serum levels in 1 to 4 hours. Protein binding is greater than 90%, while bioavailability is generally low (less than 50%). Many of these drugs have active metabolites with effects lasting longer than their parent drug half-life, ranging from 6 to 24 hours. As a class, the angiotensin receptor antagonists and their metabolites are eliminated predominantly through biliary and fecal excretion and to a lesser degree by the kidneys. The angiotensin II receptor antagonists are similar to ACE inhibitors in their ability to reduce the effects of angiotensin II. Rather than decreasing the production of angiotensin II through inhibition of the ACE, angiotensin receptor blockers competitively antagonize angiotensin II at the type I angiotensin receptors. These receptors are located in the adrenal gland and peripheral vasculature. Inhibition results in a loss of the vasoconstrictive properties and aldosterone-promoting effects of angiotensin II. Type II angiotensin receptors are not affected by angiotensin II receptor antagonists. In contrast to stimulation of type I angiotension receptors, stimulation of uninhibited type II antiotension receptors by angiotensin II results in a vasodilatory response, further contributing to blood pressure reduction.107

This high specificity that angiotensin II antagonists have for the renin-angiotensin system is felt to be responsible for their favorable side effect profile. Angiotensin receptor antagonists block the effects of angiotensin II; however, they do not interfere with the metabolism of bradykinins. Due to a lack of bradykinin accumulation, cough, a side effect frequently reported with ACE inhibitors, is less likely to occur.108 Decreased accumulation of bradykinin would also be expected to decrease the incidence of angioedema; however, numerous cases of angioedema in the setting of angiotensin receptor antagonists have been reported.109,110 This challenges the previously held belief that bradykinin excess is responsible for angioedema. While the incidence of angioedema in patients taking angiotensin receptor antagonists is lower than that seen with ACE inhibitors, the use of these agents in patients with previous angioedema should be undertaken with caution. Patients with previous episodes of angioedema related to ACE inhibitors have had similar reactions when later given an angiotensin receptor antagonist.109,110 In individuals with severe renal artery stenosis or diffuse intrarenal vascular sclerosis, angiotensin receptor antagonists should be avoided because they can cause deleterious effects to renal function similar to that seen with ACE inhibitors.111 In addition, given their effect on aldosterone production, hyperkalemia can occur in individuals with normal renal function. Recent case reports have also noted a relationship between angiotensin receptor blockers and pancreatitis.112,113 Similar to ACE inhibitors, angiotensin receptor antagonists should be avoided in pregnancy because of teratogenic potential.114 There are no published reports of overdose involving this relatively new class of antihypertensive medication. Given the mechanism of action, hypotension and reflexive tachycardia would be anticipated to occur. Treatment with activated charcoal in individuals with recent ingestions is appropriate. Hypotension should be addressed with aggressive administration of intravenous fluid as well as vasopressors in cases of persistent hypotension.

994


a1-ADRENERGIC ANTAGONISTS With the introduction of prazosin in the early 1970s, the selective α1-adrenergic antagonists have gained acceptance as effective agents in the treatment of essential hypertension. Their ability to improve urinary retention in men with benign prostatic hypertrophy has more recently increased their popularity.115 Despite their increased use, overdose with these quinazoline-derived α1-receptor antagonists, including prazosin, doxazosin, and terazosin, is infrequently reported. Only 1555 cases of exposure were reported to the AAPCC’s TESS in 2002, with major effects requiring hospitalization reported in only 26 patients.52 The structure of prazosin is shown in Figure 61-7. The α1-antagonist nonspecific predecessors, such as phentolamine and phenoxybenzamine, inhibit both α1 and α2 receptors and continue to be used in limited circumstances. These nonspecific antagonists are attractive agents for the treatment of high catecholamine states such as pheochromocytomas, extravasation of vasopressors, and MAO inhibitor toxicity. Given their limited in-hospital administration, toxicity with these drugs is exceedingly rare.

Pharmacology and Pharmacokinetics Located on the smooth muscle of arterioles and veins in the peripheral circulation, α1 receptors respond to circulating catecholamines with vascular constriction leading to increased vascular tone and a resultant increase in blood pressure. Alpha-1 antagonists competitively inhibit these postsynaptically located adrenergic receptors. Unlike α2 receptors, which are located both in the periphery and centrally, α1 receptors appear to be present solely in the peripheral vascular system. α2 Receptors lie presynaptically and inhibit the release of norepinephrine when stimulated. In a similar fashion, stimulation of central α2 receptors will cause a decrease in sympathetic outflow. Phentolamine, capable of causing peripheral vasodilation via α1-antagonistic effects, acts antagonistically at α2 receptors as well producing an increase in sympathetic tone and a resultant tachycardia. The selectivity that agents such as prazosin, doxazosin, and terazosin have for the α1 receptor site is evident in the fact that tachycardia rarely occurs. In addition, α1antagonists have demonstrated the ability to depress sinus node sensitivity, further inhibiting a reflexive tachycardic response from the heart.116 However, like many agents in the setting of overdose, the selectivity that α1-antagonists have for particular receptors may be lost.117 The α1-adrenergic antagonists are rapidly absorbed with peak plasma levels reached in the first 1 to 3 hours. NH2

O

K

N

JN

O

NJ

Prazosin FIGURE 61-7 Prazosin.

O

N O

Bioavailability ranges from 43% to 69% with prazosin and doxazosin to greater than 90% with terazosin.118,119 Prazosin is highly metabolized in the liver, with its demethylated metabolite possessing a slower rate of excretion and the ability to cause prolonged hypotension.119 The half-life of prazosin is 3 hours, but in the setting of congestive heart failure may be prolonged up to 6 to 7 hours.120 The duration of action following therapeutic doses of prazosin is typically 7 to 10 hours due to active metabolites and tissue binding. Doxasozin and terazosin both possess half-lives of 9 to 12 hours allowing for once daily dosage and the potential for prolonged symptoms following overdose when compared to prazosin.

Toxicology Not surprisingly, hypotension is the most commonly seen side effect in therapeutic dosing as well as with overdose. Postural hypotension can be seen following treatment initiation, an increase in dose, or with the addition of other antihypertensive medications. Frequently referred to as the “first dose phenomenon,” lightheadedness, dizziness, palpitations, diaphoresis, and syncope may occur within 30 to 90 minutes of the initial dose. This symptomatic hypotension is felt to be secondary to selective antagonism of α1 receptors, causing peripheral vasodilation without a compensatory sympathetic response. To avoid this effect and potential complications, current recommendations include administration of medication prior to sleeping, low starting doses, and slow upward titration of the dose.121 Transient hypotension responsive to intravenous fluid is the most common presentation of symptomatic α1antagonist overdose.122-125 One elderly man who ingested 120 mg of prazosin had a prolonged course of hypotension, CNS depression, and respiratory failure secondary to pulmonary edema requiring vasopressor support and mechanical ventilation for 48 hours prior to recovery.123 Hypotension was accompanied by tachycardia in a 19-year-old male who ingested approximately 10 times the maximum therapeutic dose of prazosin, with symptoms resolving after several hours of observation and hydration.122 While tachycardia in overdose has been described, hypotension will more frequently be present with normocardia or mild bradycardia, consistent with isolated α1 receptor antagonism.123-125 Priapism has been reported with both therapeutic administration and overdose and is likely related to the sympatholytic effects from α1-adrenergic blockade. By inhibiting α1 receptors, a parasympathetically mediated erection can occur while inhibiting ejaculation and detumescence.126 Other symptoms described in overdose include headache, vertigo, paresthesias, and weakness.123 In one small series of patients with chronic renal insufficiency taking prazosin, neuropsychiatric effects were reported and felt to be secondary to poor drug clearance. These symptoms included delusions of grandeur, visual hallucinations, confusion, as well as electroencephalography findings consistent with metabolic encephalopathy. These symptoms resolved within 2 months of medication cessation.127


DIURETICS Diuretics make up the most commonly prescribed class of medications in the United States. One study found that 28% of individuals older than 70 years were taking diuretics at the time of hospital admission.128 Despite their widespread use, the frequency of intentional or accidental overdose remains relatively small. With overdose and therapeutic use, potential complications related to volume depletion and electrolyte abnormalities may occur. Those most susceptible appear to be the elderly and the malnourished, and patients with renal failure. Intentional overuse of diuretics has also been described in individuals with anorexia and bulimia, with up to one third of bulimic patients reporting diuretic abuse in an attempt to decrease body weight.129 Diuretics used for the treatment of hypertension can be divided into three major classes: thiazide diuretics, loop diuretics, and potassium-sparing diuretics.

THIAZIDE DIURETICS The thiazides were the first class of diuretics to be introduced in the 1950s when chlorothiazide was noted to be effective in decreasing blood pressure by reducing extracellular fluid volume and sodium in hypertensive patients. Other commonly used thiazide diuretics today include metolazone, chlorothalidone, indapamide, and hydrochlorothiazide. Thiazides act on the proximal

KO

K

Supportive care and observation following overdose with α-adrenergic agents should include blood pressure and urine output monitoring to ensure adequate perfusion of vital organs. Aggressive intravenous hydration should be administered to hypotensive patients. Placement of a symptomatic patient in a supine or Trendelenburg position may be effective in correcting mild hypotension. The administration of a single dose of activated charcoal in a timely fashion is appropriate in patients with preserved mental status. Given the benign nature of most overdoses of α1-antagonists, the risks associated with orogastric lavage in nearly all cases outweigh the potential benefit. If vasopressor support is required, direct-acting α agents such as norepinephrine and vasopressin would be preferred over nonspecific α- and β-agonists such as epinephrine. Stimulation of vascular β2 receptors by epinephrine could theoretically lead to worsened hypotension and tachycardia given the isolated α1 receptor blockade. Drug levels can be obtained; however, it is unlikely that these levels would be useful in the acute management of overdose.123,125 The occurrence of priapism warrants emergent urology consultation and the need for possible surgical intervention. Hemodialysis has not been reported after α1-antagonist overdose and would likely be of little benefit given the high rate of protein binding and large volume of distribution.

O

HN

S

O

K

Management

S

995

NH2

K

CHAPTER 61

O

N H

Cl

Hydrochlorothiazide FIGURE 61-8 Hydrochlorothiazide.

portion of the distal tubule and the distal portion of the ascending loops of Henle by inhibiting the sodium/ chloride symporter. The result is a decrease in renal sodium absorption and increase of sodium excretion into the urine. With less sodium uptake, the distal tubule is exposed to high sodium concentrations resulting in potassium excretion via the Na+/K+ pump. The structure of hydrochlorothiazide is shown in Figure 61-8. The most serious effects of thiazide diuretics at therapeutic dosing, chronic overuse, and intentional overdose are related to fluid and electrolyte imbalance. With the loss of large amounts of sodium comes a decreased uptake of free water from distal tubules, leading to the potential for volume depletion and hypotension. Symptomatic dehydration appears most commonly in the elderly, who possess limited physiologic reserve.128 Other evidence of decreased end-organ perfusion secondary to volume depletion includes cerebrovascular incidents and renal failure, often when used in conjunction with an ACE inhibitor or nonsteroidal anti-inflammatory drugs.130-132 The presence of hyponatremia (less than 135 mmol/L) has been seen in one fifth of elderly patients taking thiazide diuretics.133 The level of hypokalemia that may be induced appears to be dose dependent and more significant with thiazide diuretics when compared with loop diuretics.134 In addition to hyponatremia and hypokalemia, other electrolyte abnormalities such as hypochloremia, hypomagnesemia, hypercalcemia, hyperuricemia, and metabolic alkalosis can be seen. Thiazide-induced hypokalemia, while often mild at therapeutic dosing, becomes more concerning with diuretic abuse and in the setting of concomitant use of other potassium-wasting agents. The presence of significant hypokalemia and the potential for cardiac dysrhythmias warrants aggressive electrolyte replacement. The presence of hypokalemia in the setting of digoxin use is especially problematic because hypokalemia appears to enhance the effects of digoxin on the myocardium and predisposes the heart to additional dysrhythmias. Other symptoms, including nausea, vomiting, diarrhea, anorexia, and abdominal pain, have been described with thiazide diuretic overdose. CNS depression ranging from mild transient lethargy to coma has been reported in the setting of overdose and after therapeutic administration. CNS depressant effects have also occurred in the absence of significant hypotension, suggesting a direct-acting CNS depressant effect. Grand mal seizures have been reported with the use of high-dose thiazide-type diuretics in the pediatric and adult population.135,136 Other effects associated with thiazide use include pancreatitis,

996


Cl

K K

O

JNH

H2NJSJ O

O H2CJ

K

CJOH

O

Furosemide FIGURE 61-9 Furosemide.

cholecystitis, erectile dysfunction, thrombocytopenia, and hemolytic anemia.130,137-140

LOOP DIURETICS Four loop diuretics are currently approved for use in the United States: furosemide, bumetanide, ethacrynic acid, and torsemide. Their effectiveness lies in their ability to inhibit the Na+-K+-Cl- symporter found on the thick ascending limb of the loop of Henle, resulting in loss of sodium, chloride, and potassium ions in the urine. Loop diuretics also act as direct vasodilators that can reduce left ventricular filling pressures via increased systemic venous capacitance.141 The structure of furosemide is shown in Figure 61-9. Toxicity related to loop diuretic abuse in many ways is similar to that observed with thiazide diuretics, with the potential for developing hyponatremia, hypokalemia, hypocalcemia, hypomagnesemia, and fluid depletion. In addition to the potential risk for cardiac dysrhythmias, hypokalemia in the setting of furosemide overuse has led to significant muscular weakness and rhabdomyolysis. Hyponatremia can also be severe, resulting in seizures, lethargy, and coma. Rapid correction of hyponatremia following furosemide abuse resulted in central pontine myelinolysis in one report.142 Symptoms such as tetany and peripheral sensory and motor dysfunction resulting from loop diuretic abuse improve rapidly following electrolyte correction.136,143 The use of loop diuretics has also been associated with auditory nerve damage. This dose-dependent phenomenon is reported with furosemide and bumetadine use but is more frequently described with the use of ethacrynic acid. The intravenous administration of high doses of loop diuretics concomitantly with other potentially ototoxic drugs such as aminoglycosides is associated with the highest risks of ototoxicity.144,145 With discontinuation of treatment, hearing loss and tinnitus frequently improve.

POTASSIUM-SPARING DIURETICS While relatively weak in diuretic activity, potassiumsparing diuretics such as triamterene and amiloride are frequently administered in combination with loop and thiazide diuretics to decrease the amount of potassium excreted into the urine. These agents, in addition to spironolactone and eplerenone, act on the distal renal tubule to decrease sodium reabsorption and limit

excretion of potassium. While reports of toxicity related to overdose are exceedingly rare with potassium-sparing diuretics, the development of life-threatening hyperkalemia can occur with therapeutic dosing, frequently in patients with renal insufficiency or with coadministration of other potassium-elevating medications. One report found that 8.6% of patients treated with spironolactone developed hyperkalemia.146 The coadministration of a potassium-sparing diuretic with a loop or thiazide diuretic often obviates the need for supplemental potassium administration.147 Two cases of life-threatening hyperkalemia were reported in individuals who were taking potassium-containing salt substitutes while concurrently taking spironolactone.148 In overdose of these agents, gastrointestinal irritation and central nervous depression have also been reported. Spironolactone has other unique side effects related to its steroid structure, including development of gynecomastia, impotence, hirsutism, and menstrual irregularities. Use of triamterene is unique in its association with interstitial nephritis and nephrolithiasis.149

Management Treatment of diuretic toxicity is supportive with close monitoring and correction of electrolyte abnormalities and hypovolemia. The administration of activated charcoal should take place shortly after drug ingestion in order to limit absorption. Aggressive fluid administration is indicated in cases of diuretic-induced hypotension and shock. The possibility of co-ingestion with potassium supplements must be considered. Large potassium tablets may be visible on radiography, and although poorly adsorbed by activated charcoal, whole bowel irrigation may be an appropriate intervention to decrease absorption. An initial ECG should be performed in patients with diuretic overdose followed by continuous cardiac monitoring when electrolyte abnormalities are suspected. Significant hyperkalemia in the presence of ECG abnormalities should be corrected with insulin and dextrose, calcium, sodium bicarbonate, and cationexchange resins. REFERENCES 1. Food and Drug Administration: New labeling for sodium nitroprusside emphasizes the risk of cyanide toxicity. JAMA 1991;265:847. 2. Johnson CC: Mechanisms of actions and toxicity of nitroprusside. Proc Soc Exp Biol Med 1928;26:102–103. 3. Page IH, Corcoran AC, Dustan HP, Koppanyi T: Cardiovascular actions of sodium nitroprusside in animals and hypertensive patients. Circulation 1955;11:188–198. 4. Friederich JA, Butterworth JF: Sodium nitroprusside: twenty years and counting. Anesth Analg 1995;81:152–162. 5. Frank MJ, Johnson JB, Rubin SH: Spectrophotometric determination of sodium nitroprusside and its photodegradation products. J Pharm Sci 1976;65:44–48. 6. Arnold WP, Longnecker DE, Epstein RM: Photodegradation of sodium nitroprusside: biologic activity and cyanide release. Anesthesiology 1984;61:254–260. 7. Schulz V: Clinical pharmacokinetics of nitroprusside, cyanide, thiosulphate, and thiocyanate. Clin Pharmacokinet 1984;9:239–241. 8. Moncada S, Palmer RMJ, Higgs EA: Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991;43: 109–142.

CHAPTER 61


9. Kreye VAW, Reske SN: Possible site of the in vivo disposition of sodium nitroprusside in the rat. Naunyn Schmiedebergs Arch Pharmacol 1982;320:260–265. 10. Smith PR, Kruszyma H: Nitrprusside produced cyanide poisoning via a reaction with hemoglobin. J Pharmacol Exp Ther 1974;191:557–563. 11. Vesey CJ, Krapez JR, Cole PV: The effects of sodium nitroprusside and cyanide on haemoglobin function. J Pharm Pharmacol 1980;32:256–261. 12. Ivankovich AD, Braverman M, Stephens TS, et al: Sodium thiosulfate disposition in humans. Relation to sodium nitroprusside toxicity. Anesthesiology 1983;58:11–17. 13. Way JL: Cyanide intoxication and its mechanism of antagonism. Ann Rev Pharmacol Toxicol 1984;24:451–481. 14. Piantadose CA, Sylvia AL: Cerebral cytochrome a,a3 inhibition by cyanide in bloodless rats. Toxicology 1984;33:67–79. 15. Schulz V, Bonn R, Kindler J: Kinetics of elimination of thiocyanate in seven healthy subjects and in eight subjects with renal failure. Klin Wochenscher 1979;57:243–247. 16. Vesey CJ, Wilson J: Red cell cyanide. J Pharm Pharmacol 1978; 30:20–26. 17. Schulz V, Gross R, Patsch T, et al: Cyanide toxicity of sodium nitroprusside in therapeutic use with and without sodium thiosulfate. Klin Wochenschr 1982;60:1393–1400. 18. Vesey CJ, Cole PV: Blood cyanide and thiocyanate concentrations produced by long-term therapy with sodium nitroprusside. Br J Anaesth 1985;57:148–155. 19. Way JL, Sylvester D, Morgan RL, et al: Recent perspectives on the toxicodynamic basis of cyanide antagonism. Fundam Appl Toxicol 1984;4(Suppl):231–239. 20. Turský T, Sˇ ajter V: The influence of potassium cyanide poisoning on the γ-aminobutyric acid level in the rat brain. J Neurochem 1962;9:519–523. 21. Domalski CA, Kolk LC, Hines EA: Delirious reactions secondary to thiocyanate therapy of hypertension. Proc Mayo Clin 1953;28:272–280. 22. Garvin CF: The fatal toxic manifestations of the thiocyanates. JAMA 1939;112:1125. 23. Wald MH, Lindberg HA, Barker MH: The toxic manifestations of the thiocyanates. JAMA 1939;112:1120–1124. 24. Peters CG, Mundy JVB, Rayner PR: Acute cyanide poisoning. Anaesthesia 1982;37:582–586. 25. Curry SC, Arnold-Capell P: Nitroprusside, nitroglycerin, and angiotensin-coverting enzyme inhibitors. Crit Care Clin 1991;7: 555–581. 26. Vesey CJ, Simpson PJ, Adams L, Cole PV: Metabolism of sodium nitroprusside and cyanide in the dog. Br J Anaesth 1979;51:89–97. 27. Vesey CJ, Cole PV, Simpson PJ: Cyanide and thiocyanate concentrations following sodium nitroprusside infusion in man. Br J Anaesth 1976;48:651–660. 28. Cole PV, Vesey CJ: Sodium thiosulfate decreases blood cyanide concentrations after the infusion of sodium nitroprusside. Br J Anaesth 1987;59:531–535. 29. Michenfelder JD, Tinker JH: Cyanide toxicity and thiosulfate protection during chronic administration of sodium nitroprusside in the dog. Anesthesiology 1977;47:441–448. 30. Cottrell JE, Casthely P, Brodie JD, et al: Prevention of nitroprusside-induced cyanide toxicity with hydroxocobalamin. N Engl J Med 1978;298:809–811. 31. Krapez JR, Vesey CJ, Adams L, Cole PV: Effects of cyanide antidotes used with sodium nitroprusside infusions: sodium thiosulphate and hydroxocobalamin given prophylactically to dogs. Br J Anaesth 1981;53:793–804. 32. Zerbe NF, Wagner BKJ: Use of vitamin B12 in the treatment and prevention of nitroprusside-induced cyanide toxicity. Crit Care Med 1993;21:465–467. 33. Pahl MV, Vaziri ND: In-vivo and in-vitro hemodialysis studies of thiocyanate. J Toxicol Clin Toxicol 1982–1983;19:965–974. 34. Kerins DM, Robertson RM, Robertson D: Drugs used for the treatment of myocardial ischemia. In Hardman JG, Limbird LE, Gilman AG (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001. 35. Murrell W: Nitro-glycerine as a remedy for angina pectoris. Lancet 1879;1:234–236, 284–288.

997

36. Murad F: Cyclic guanosine monophosphate as a mediator of vasodilation. J Clin Invest 1986;78:1–5. 37. Chung SH, Fung HL: Identification of subcellular site for nitroglycerin metabolism to nitric oxide in bovine coronary smooth muscle cells. J Pharmacol Exp Ther 1990;253(2):614–619. 38. Harrison DG, Bates JN: The nitrovasodilators. New ideas about old drugs. Circulation 1993;87:1461–1467. 39. Münzel T, Sayegh H, Freeman BA, et al: Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance. J Clin Invest 1995;95:187–194. 40. Abou-Mohamed G, Johnson JA, Jin L: Roles of superoxide, peroxynitrite, and protein kinase C in the development of tolerance to nitroglycerin. J Pharmacol Exp Ther 2004;308(1):289–299. 41. O’Keefe JH, Kwong EM, Tangredi RG: Transgingival nitrate syncope. N Engl J Med 1986;315:1030. 42. Marshall JB, Ecklund RE: Methemoglobinemia from overdose of nitroglycerin. JAMA 1980;244:330. 43. Kaplan KJ, Taber M, Teagarden JR, et al: Association of methemoglobinemia and intravenous nitroglycerin administration. Am J Cardiol 1985;55:181–183. 44. Alexander J, Kaplan K, Davidson R, et al: Intravenous nitroglycerin-induced abducens nerve palsy. Am Heart J 1983;106: 1159–1160. 45. Ohar JM, Fowler AA, Selhorst JB, et al: Intravenous nitroglycerininduced intracranial hypertension. Crit Care Med 1985;13: 867–868. 46. Demey HE, Daelemans RA, Verpooten GA, et al: Propylene glycolinduced side effects during the intravenous nitroglycerin therapy. Intensive Care Med 1988;14:221–226. 47. Col J, Col-Debeys C, Lavenne-Pardonge E, et al: Propylene glycolinduced heparin resistance during nitroglycerin infusion. Am Heart J 1985;110:171–173. 48. Habbab MA, Haft J: Heparin resistance induced by intravenous nitroglycerin: a word of caution when both drugs are used concomitantly. Arch Intern Med 1987;147:857–860. 49. Becker RC, Corrao JM, Bovill EG, et al: Intravenous nitroglycerininduced heparin resistance: a qualitative antithrombin III abnormality. Am Heart J 1991;121(6 Pt 1):1849–1850. 50. Cheitlin MD, Hutter AM, Brindis RG, et al: Use of silfenafil (Viagra) in patients with cardiovascular disease. ACC/AHA Expert Consensus Document. Circulation 1999;99:168–177. 51. Kelner MJ, Bailey DN: Propylene glycol as a cause of lactic acidosis. J Anal Toxicol 1985;9:40–42. 52. Watson WA, Litovitz TL, Rodgers GC, et al: 2002 annual report of the American association of poison control centers toxic exposure surveillance system. Am J Emerg Med 2003;21(5):353–421. 53. Reece PA: Hydralazine and related compounds: chemistry, metabolism, and mode of action. Med Res Rev 1981;1:73–96. 54. Azuma J, Sawamura A, Harada H, et al: Mechanism of direct cardiostimulating actions of hydralazine. Eur J Pharmacol 1987;135:137–144. 55. Smith BA, Ferguson DB: Acute hydralazine overdose: marked ECG abnormalities in a young adult. Ann Emerg Med 1992;21(3):326–330. 56. Raskin NH, Fishman RA: Pyridoxine-deficiency neuropathy due to hydralazine. N Engl J Med 1965;273(22):1182–1185. 57. Farrell SE, Epstein SK: Overdose of Rogaine® Extra Strength for Men topical minoxidil preparation. J Toxicol Clin Toxicol 1999;37(6):781–783. 58. Zappacosta AR: Reversal of baldness in patient receiving minoxidil for hypertension. N Engl J Med 1980;303:1480–1481. 59. McCormick MA, Forman MH, Manoguerra AS: Severe toxicity from ingestion of a topical minoxidil preparation. Am J Emerg Med 1989;7:419–421. 60. MacMillan AR, Warshawski FJ, Steinberg RA: Minoxidil overdose. Chest 1993;103:1290–1291. 61. McCall JM, Aiken JW, Chidester CG, et al: Pyrimidine and triazine 3-oxide sulfates: a new family of vasodilators. J Med Chem 1983;26:1791–1793. 62. Gottlieg TB, Thomas RC, Chidsey CA: Pharmacokinetic studies of minoxidil. Clin Pharmacol Ther 1972;13:436–441. 63. Leblanc N, Wilde DW, Keef KD, Hume JR: Electrophysiologic mechanisms of minoxidil sulfate-induced vasodilation of rabbit portal vein. Circ Res 1989;65:1102–1111.

998


64. Allon MA, Hall WD, Macon EJ: Prolonged hypotension after initial minoxidil dose. Arch Intern Med 1986;146:2075–2076. 65. Manufacturer’s information, Upjohn Company, Kalamazoo, MI. 66. Isles C, MacKay A, Barton PJM, Mitchell I: Accidental overdosage of minoxidil in a child. Lancet 1981;1:97. 67. Poff SW, Rose SR: Minoxidil overdose with ECG changes: case report and review. J Emerg Med 1992;10:53–57. 68. Krehlik JM, Hindson DA, Crowley JJ, Knight LL: Minoxidilassociated pericarditis and fatal cardiac tamponade. West J Med 1985;143:527–529. 69. Goldstein H, Lue TF, Padma-Nathan H, et al: Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med 1998;338: 1397–1404. 70. Tracqui A, Miras A, Tabib A, et al: Fatal overdosage with sildenafil citrate (Viagra®): first report and review of the literature. Hum Exp Toxicol 2002;21(11):623–629. 71. Krenzelok EP: Sildenafil: clinical toxicology profile. J Toxicol Clin Toxicol 2000;38(6):645–651. 72. Hung DZ, Yang DY: Sildenafil overdose in a female patient. J Toxicol Clin Toxicol 2001;39(4):423–424. 73. Kloner RA, Zusman RM: Cardiovascular effects of sildenafil citrate and recommendations for its use. Am J Cardiol 1999;84:11N–17N. 74. Azarbal B, Mirocha J, Shah PK, et al: Adverse cardiovascular events associated with the use of Viagra. J Am Coll Cardiol 2000;35(Suppl 1):553A–554A. 75. Morales A, Gingell C, Collins M, et al: Clinical safety of oral sildenafil citrate (Viagra) in the treatment of erectile dysfunction. Int J Impot Res 1998;10:69–74. 76. Muniz AE, Holstege CP: Acute myocardial infarction associated with sildenafil (Viagra) ingestion. Am J Emerg Med 2000;18(3): 353–355. 77. Kassim AA, Fabry ME, Nagel RL: Acute priapism associated with the use of sildenafil in a patient with sickle cell trait. Blood 2000;95:1878–1879. 78. Sur RL, Cane CJ: Sildenafil-citrate associated priapism. Urology 2000;55(6):950. 79. Swedberg K, Held P, Kjekshus L, et al: Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1992;327:685–691. 80. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993;329(20):1456–1462. 81. Michaels AD, Maynard C, Every NR, Barron HV: Early use of ACE inhibitors in the treatment of acute myocardial infarction in the United States: experience from the National Registry of Myocardial Infarction. Am J Cardiol 1999;84(10):1176–1181. 82. Gavras H, Gavras I: Angiotensin-converting enzyme inhibitors. Properties and side effects. Hypertension 1988;11(3 Pt 2):37–41. 83. Song JC, White CM: Clinical pharmacokinetics and selective pharmacodynamics of new angiotensin converting enzyme inhibitors: an update. Clin Pharmacokinet 2002;41(3):207–224. 84. Gainer JV, Morrow JD, Loveland A, et al: Effect of bradykininreceptor blockade on the response to angiotensin-convertingenzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med 1998;339(18):1285–1292. 85. Israili ZH, Hall WD: Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology. Ann Intern Med 1992;117(3):234–242. 86. Parker SC, Hannah A, Brooks M, et al: Renal artery stenosis: a disease worth pursuing. Med J Aust 2001;175(3):149–153. 87. Hodsman GP, Isles CG, Murray GD, et al: Factor related to first dose hypotensive effect of captopril: prediction and treatment. BMJ 1983;286(6368):832–834. 88. Verughese A, Taylor AA, Nelson EB: Consequnces of angiotensinconverting enzyme inhibitor overdose. Am J Hypertens 1989;2(5 Pt 1):355–357. 89. Lau CP: Attempted suicide with enalapril. N Engl J Med 1986;315(8):197. 90. Lip GY, Ferner RE: Poisoning with anti-hypertensive drugs: angiotensin converting enzyme inhibitors. J Hum Hypertens 1995;9(9):711–715.

91. Park H, Purnell GV, Mirchandani HG: Suicide by captopril overdose. Clin Toxicol 1990;28(3):379–382. 92. Everson GW: Angiotensin converting enzyme inhibitor overdoses: a multicenter study. Vet Hum Toxicol 1990;32(4):352. 93. Spiller HA, Udicious TM, Muir S: Angiotensin converting enzyme inhibitor ingestion in children. Clin Toxicol 1989;27(6):435–353. 94. Brown NJ, Ray WA Snowden M, Griffin MR: Black Americans have an increased rate of angiotensin converting enzyme inhibitassociated angioedema. Clin Pharmacol Ther 1996;60(1):8–13. 95. Gibbs CR, Lip GYH, Beevers DG: Angioedema due to ACE inhibitors: increased risk in patients of African origin. Br J Clin Pharmacol 1991;48(6):861–865. 96. Chin HL , Buchan DA: Severe angioedema after long-term use of an angiotensin-converting enzyme inhibitor. Ann Intern Med 1990;112(4):312–313. 97. Orfan N, Patterson R, Dykewicz MS: Severe angioedema related to ACE inhibitors in patients with a history of idiopathic angioedema. JAMA 1990;264(10):1287–1289. 98. Augenstein WL, Kulig KW, Rumack BH: Captopril overdose resulting in hypotension. JAMA 1988;259:3302–3305. 99. Lechleitner P, Dzien A, Haring C, Glossmann H: Uneventful selfpoisoning with a very high dose of captopril. Toxicology 1990;64(3):325–329. 100. Spiller HA, Udicious TM, Muir S: Angiotensin converting enzyme inhibitor ingestion in children. Clin Toxicol 1989;27:345–353. 101. Olin BR: Drug Facts and Comparisons. St. Louis, Facts and Comparisons, 2000. 102. Geh SL, Nott MW, Majewski H, et al: Effect of captopril on blood pressure responses to enkephalins in chloralose-anaesthetized rats. Arch Int Pharmacodyn Ther 1986;279(2):282–290. 103. Varon J, Duncan SR: Naloxone reversal of hypotension due to captopril overdose. Ann Emerg Med 1991;10:1125–1127. 104. Trilli LE, Johnson KA: Lisinopril overdose and management with intravenous angiotensin II. Ann Pharmacother 1994;28(10): 1165–1168. 105. Mazzolai L, Burnier M: Comparative safety and tolerability of angiotensin II receptor antagonists. Drug Saf 1999;21(1):23–33. 106. Pitt B, Segal R, Martinez FA, et al: Randomized trail of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet 1997;349(9054): 747–752. 107. Sosa-Canache B, Cierco M, Gutierrez CI, et al: Role of bradykinins and nitric oxide in the AT2 receptor-medicated hypotension. J Hum Hypertens 2000;14(Suppl 1):40–46. 108. Lacourciere U, Brunner HR, Irwing R, et al: Effects of modulators of the rennin-angiotensin-aldosterone system on cough. J Hypertens 1994;12(12):1387–1393. 109. van Rijnsoever EW, Kwee-Zuiderwiju WJM, Feenstra J: Angioneurotic edema attributed to use of losartan. Arch Intern Med 1998;158(18):2063–2065. 110. Warner KK, Visconti JA, Tschampel MM: Angiotensin II receptor blockers in patients with ACE inhibitor-induced angioedema. Ann Pharmacother 2000;34(4):526–528. 111. Mimran A, Ribstein J, DuCailar G: Comparison of the acute renal effect of losartan and captopril in atheromatous renovascular disease. Am J Hypertens 1998;11:47A. 112. Birck R, Keim V, Fiedler F, et al: Pancreatitis after losartan. Lancet 1998;351(9110):1178. 113. Bosch X: Losartan-induced acute pancreatitis. Ann Intern Med 1997;127(11):1043–1044. 114. Barr M Jr: Teratogen update: angiotensin-converting enzyme inhibitors. Teratology 1994;50(6):399–409. 115. Cooper KL, McKeirnan JM, Kaplan SA: Alpha-adrenoceptor antagonists in the treatment of benign prostatic hyperplasia. Drugs 1999;57(1):9–17. 116. Sasso EH, O’Connor DT: Prazosin depression of baroreflex function in hypertensive man. Eur J Clin Pharmacol 1982;22(1):7–14. 117. Bateman DN, Hobbs DC, Twomey TM, et al: Prazosin, pharmacokinetics and concentration effect. Eur J Clin Pharmacol 1979;16(3):177–181. 118. Sonders RC: Pharmacokinetics of terazosin. Am J Med 1986; 80(5B):20–24. 119. Piotrovskii VK, Veiko NN, Ryabokon OS, et al: Identification of a prazosin metabolite and some preliminary data on its kinetics in hypertensive patients. Eur J Clin Pharmacol 1984;27(3):275–280.

CHAPTER 61


120. Baugham RA Jr, Arnold S, Benet LZ, et al: Altered prazosin pharmacokinetics in congestive heart failure. Eur J Clin Pharmacol 1980;17:425. 121. Hasford J, Bussmann WD, Delius W, et al: First dose hypotension with enalapril and prazosin in congestive heart failure. Int J Cardiol 1991;31(3):287–293. 122. McClean WJ: Prazosin overdose. Med J Aust 1976;1(16):592. 123. Lenz K, Druml W. Kleinberger G, et al: Acute intoxication with prazosin: case report. Hum Toxicol 1985;4(1):53–56. 124. Gokel Y, Dokur M, Paydas S: Doxazosin overdosage. Am J Emerg Med 2000;18(5):638–639. 125. Rygnestad TK, Dale O: Self-poisoning with prazosin. Acta Med Scand 1983;213(2):157–158. 126. Robbins DN, Crawford ED, Lackner LH: Priapism secondary to prazosin overdose. J Urol 1983;130(5):975. 127. Chin DK, Ho AK, Tse CY: Neuropsychiatric complications related to use of prazosin in patients with renal failure. BMJ 1986;293(6558):1347. 128. Baglin A, Boulard JC, Hanslick T, Prinseau J: Metabolic adverse reactions to diuretics. Clinical relevance to elderly. Drug Saf 1995;12(3):161–171. 129. Mitchell JE, Hatsukami D, Eckert ED, Pyle RL: Characteristics of 275 patients with bulimia. Am J Psychiatry 1985;142(4):482–485. 130. Garratty G, Houston M, Petz LD, Webb M: Acute immune intravascular hemolysis due to hydrochlorthiazide. Am J Clin Pathol 1981;76(1):73–78. 131. Rubinstein I: Fatal thrombosis of left internal carotid artery following diuretic abuse. Ann Emerg Med 1985;14(3):275. 132. O’Doherty NJ: Thiazide and cerebral ischemia. Lancet 1965;2(7425):1297. 133. Sunderam SG, Mankikar GD: Hyponatremia in the elderly. Age Ageing 1983;12(1):77–80. 134. Morgan DB, Davidson C: Hypokalemia and diuretics: an analysis of publications. BMJ 1980;280(6218):905–908. 135. Srivastava RN, Travis LB, Dodge WF, Kaye M: Prolonged coma and visual loss; unusual reaction to chlorthiazide. J Pediatr 1969;74(1):126–128. 136. Brucato A, Bonati M, Gaspari F, et al: Tetany and rhabdomyolysis due to surreptitious furosemide—importance of magnesium supplementation. Clin Toxicol 1993;31(2):341–344.

999

137. Vila JM, Blum L, Dosik H: Thiazide-induced immune hemolytic anemia. JAMA 1976;236(15):1723–1724. 138. Eckhauser ML, Dokler MA, Imbenbo AL: Diuretic-associated pancreatitis: a collective review and illustrative cases. Am J Gastroenterol 1987;82(9):865–870. 139. Grimm RH Jr, Grandtis GA, Prineas RJ, et al: Long-term effects on sexual function of five antihypertensive drugs and nutritional hygienic treatment in hypertensive men and women. Treatment of Mild Hypertension Study (TOMHS). Hypertension 1997;29 (1 Pt 1):8–14. 140. Eisner EV, Crowell EB: Hydrochlorothiazide-dependent thrombocytopenia due to IgM antibody. JAMA 1971;215(3):480–482. 141. Dormans TP, van Meyel JJM, Gerlag PGG, et al: Diuretic efficacy of high dose furosemide in severe heart failure: bolus injection versus continuous infusion. J Am Coll Cardiol 1996;28(2): 376–382. 142. Copeland PM: Diuretic abuse and central pontine myelinolysis. Psychother Psychosom 1989;52(1–3):101–105. 143. Kaufmann H, Elijovich F, Yahr MD: An unusual cause of tetany: surreptitious use of furosemide. Mt Sinai J Med 1984;51(5): 625–628. 144. Whitworth C, Morris C, Scott V, Rybak LP: Dose-response relationships for furosemide ototoxicity in rat. Hear Res 1993;71(1–2):202–207. 145. Bates DE, Beaumont SJ, Baylis BW: Ototoxicity induced by gentamicin and furosemide. Ann Pharacother 36(3):446–451. 146. Greenblatt DJ, Koch-Weser J: Adverse reactions to spironolactone. A report from the Boston Collaborative Drug Surveillance Program. JAMA 1973;225(1):40–43. 147. Hollenberg NK, Mickiewicz CW: Postmarketing surveillance in 70,898 patients treated with a triamterene/hydrochlorothiazide combination (Maxzide). Am J Cardiol 1989;63:37B–41B. 148. Yap V, Patel A, Thomsen J: Hyperkalemia with cardiac arrhythmia. Induction by salt substitutes, spironolactone and azotemia. JAMA 1976;236:2275–2276. 149. Carr MC, Prien EL, Babayan RK: Triamterene nephrolithiasis: renewed attention is warranted. J Urol 1990;144(6):1339–1340.

62

Clonidine and Related Imidazoline Derivatives JAMES F. WILEY II, MD, MPH

At a Glance… ■ ■ ■ ■ ■ ■

Clonidine and related imidazolines act at central and peripheral α2-adrenergic receptors and at imidazoline receptors. In overdose, imidazolines produce central nervous system depression, bradycardia, hypotension, and respiratory depression. As little as 0.1 mg or 1 clonidine tablet may cause major poisoning effects in young children. Pediatric clonidine exposure is increasing and reflects greater use of this drug for behavioral problems in children. Management of clonidine poisoning should focus on respiratory support and maintenance of hemodynamic stability. No antidote exists for clonidine toxicity, although reports of clinical improvement after naloxone or yohimbine administration have been described.

INTRODUCTION AND RELEVANT HISTORY Clonidine and related drugs, including apraclonidine, brimonidine, dexmedetomidine, guanabenz, guanfacine, methyldopa, naphazoline, oxymetazoline, tetrahydrozoline, tizanidine, and xylometazoline, share similar toxicity. Clonidine, guanabenz, guanfacine, and methyldopa have been used primarily as antihypertensive medications, although new indications have been developed for clonidine and guanfacine. Tetrahydrozoline, oxymetazoline, naphazoline, and xylometazoline are over-the-counter topical vasoconstrictors. Apraclonidine and brimonidine are prescribed for ocular hypertension and open-angle glaucoma. Tizanidine is a new muscle relaxant used for the spasticity associated with cerebral and spinal disorders. Dexmedetomidine is a new imidazole used for intravenous sedation and analgesia.1 Most examples of severe toxicity attributable to this class of drugs have occurred with clonidine. Clonidine was initially developed as a topical nasal decongestant in 1962. Subsequently, it was found to be a potent antihypertensive agent with sympatholytic effects not attributable to ganglionic blocking.2 Clonidine is synergistic in antihypertensive effect with diuretics and has been employed as a second or third agent in the treatment of essential hypertension. The advent of converting enzyme inhibitors has decreased the use of clonidine as an antihypertensive agent. Alternative off-label indications in adults include anesthetic premedication, induction of spinal anesthesia, ultrashort opiate detoxification, alcohol withdrawal, smoking cessation, and alleviation of postmenopausal hot flashes.3-8 In children, treatment of attention-deficit hyperactivity disorder (ADHD) accounts for the greatest off-label use.9 Refractory conduct disorder, Tourette’s syndrome, and

diagnosis of growth hormone deficiency make up other potential uses in children.10,11 Guanfacine has been evaluated for the treatment of children with both ADHD and Tourette’s syndrome12 and has been shown to induce growth hormone secretion without the concomitant hypotension or sedation common with clonidine.13

EPIDEMIOLOGY Clonidine exposure occurs in about 1 in 1000 poisonings and is notable for serious signs and symptoms after many ingestions.14-16 In 2004, there were 5802 clonidine and 1579 tetrahydrozoline exposures reported to U.S. poison centers. Major toxicity and death occurred in only 3.6% and 0.2% of clonidine exposures and in 0.1% and 0% of tetrahydrozoline exposures, respectively.17 Moderate toxicity, however, was observed in 22.8% of all clonidine exposures. Total clonidine exposures in children younger than 19 years have almost doubled in recent years.14 Many pediatric exposures involve the child’s own medication or that of another child in the household. This pattern contrasts with the previously reported situation of young toddlers ingesting a grandparent’s clonidine.16,18 Exposure to over-the-counter nose drops and eye drops is an another important cause of imidazoline poisoning but tends to be uneventful.19 Guanabenz, guanfacine, and methyldopa are rarely prescribed or ingested and appear to cause similar but lesser effects than clonidine.20-22

STRUCTURE AND STRUCTURE–ACTIVITY RELATIONSHIPS Clonidine and some related imidazolines are depicted in Figure 62-1.

PHARMACOLOGY Clonidine, guanabenz, guanfacine, oxymetazoline, tetrahydrozoline, naphazoline, xylometazoline, tizanidine, and dexmedetomidine are related imidazolines with central and peripheral α2-adrenergic agonist effects. In addition, some of the central antihypertensive effects may be attributable to binding of specific imidazoline receptors. As sympathomimetic agents, imidazolines have little to no β-adrenergic effect and have peripheral vasoconstrictive properties similar to specific α1-adrenergic agonists. However, imidazolines differ markedly from most sympathomimetics in their central inhibition of sympathetic outflow.23 Developed as an analog of 3,4-dihydroxyphenlyalanine (DOPA), methyldopa is chemically 1001

HN Tizanidine

J J

CH3

N

J

unrelated to the imidazolines but stimulates α2adrenergic receptors centrally through its metabolite, α-methyl norepinephrine.24 The imidazolines produce effects by a complex interaction with central α2-adrenergic receptors, peripheral α2-adrenergic receptors, and central imidazoline receptors. The α2-adrenergic receptors have subtypes A, B, and C, which are structurally distinct and have varying affinity for α2-adrenergic receptor agonists and antagonists. α2A-Adrenergic receptors are found predominantly in the brainstem, whereas α2B-adrenergic receptors are found on vascular smooth muscle cells.25 Central α2Aadrenergic receptors have a higher affinity for agonists (e.g., clonidine) than do peripheral α2B-adrenergic receptors.25 Binding at each of these receptors reduces the intracellular activity of adenyl cyclase through a pertussin toxin-sensitive G protein.26 Elucidation of the receptor-binding properties for the drugs under discussion have involved radioligand studies using [3H]clonidine. Clonidine strongly binds to central α2Aadrenergic receptors located in the brainstem (nucleus tractus solitarii). This binding has an inhibitory effect on norepinephrine release centrally, resulting in decreased sympathetic outflow.27-29 Therapeutically, this action causes reduced blood pressure, bradycardia, and sedation. The hypotensive changes are not seen in quadriplegic patients who receive clonidine.26 Clonidine also inhibits acetylcholine release. Clinically, this effect is manifest as dry mouth in therapeutic doses. In the hypothalamus, clonidine stimulates the release of growth hormone and has varying effects on sympathetic tone and blood pressure. In the spinal cord, clonidine decreases sympathetic tone and blood pressure and has analgesic properties that are similar to those of narcotic medications.26,30 The similarity in effects found upon stimulation of central α2-adrenergic receptors and opiate receptors has prompted much investigation into a possible molecular link between these sites. Clinical evidence supporting such a link includes the use of clonidine for ultrashort opiate detoxification,4,5 the successful use of clonidine for spinal analgesia,30 the likeness of toxicity found after overdose with narcotics and clonidine, the reversal of clonidine toxicity with naloxone in some patients,16 and the decreased density of central α2-adrenergic receptors in heroin addicts.31 Both opiate and central α2-adrenergic receptors act through G proteins. The possibility of “cross-talk” between these receptors through the Gprotein complex has been raised, although initial studies in a neuroblastoma-glioma cell line were not supportive.32

JN

HCl

J

Clonidine Brimonidine Dexmedetomidine FIGURE 62-1 Structure of clonidine and some other imidazolines.

N

HN

J

N H

N

Cl

OH

(H3C)3C

J

N J

J

J J

J

H3C

J

N

H N

H N

J

J

J J

J JN J JS

CH3 CH3

J

Cl N

N J

J

J

J

J

J

Br

H N

H N

J

J

Cl


....

1002

CH3

N H

Oxymetazoline

Other proposed mechanisms for α2-agonist inhibitory effects, such as hyperpolarization of neuronal cells by activation of potassium channels, inhibition of N-type voltage-gated calcium channels, and increased Na+/H+ exchange, may hold the answer regarding the relationship between imidazolines and opiates.24 Improved understanding concerning the relationship of central α2adrenergic and opiate receptors must await further study. Specific imidazoline (I) receptors of multiple types exist and have been identified in a variety of tissues and animal species. Current nomenclature delineates I1 and I2 receptors, with a further breakdown of I2 receptors into I2a (amiloride-sensitive) and I2b (amiloride-insensitive) receptors.33 These receptors do not act through G proteins.34 Clonidine has strong affinity at I1 receptors, which are located in the ventrolateral medulla in humans. Binding at these sites leads to decrease in blood pressure independent of central α2-adrenergic effects.35 An endogenous substance with imidazoline receptor affinity called clonidine-displacing substance has also been discovered, but its physiologic role has yet to be elucidated. Guanabenz is an agonist at I2 imidazoline receptors, which are strongly linked to monoamine oxidase A and B expression, but the mechanism of action and function of I2 receptors is uncertain and requires further study.36 Peripheral imidazoline effects are varied, relate to agonist effects at α2B-adrenergic receptors, and are usually overshadowed by central α2A-adrenergic receptor effects. Agonist activity at peripheral α2B-adrenergic receptors located on vascular smooth muscle cells causes vasoconstriction. Effects at these receptors typically require a higher serum concentration of agonist, as occurs after overdose and intravenous administration of agonist.25 Thus, intravenous administration of clonidine and supratherapeutic levels of clonidine are associated with hypertension and pallor in some patients. Stimulation of presynaptic peripheral α2-adrenergic receptors, however, reduces vasomotor tone in other blood vessel sites and inhibits renin release, which would lead to synergism with central effects.35 The net effect is a reduction of blood pressure and sympathetic outflow in both hypertensive and normotensive patients who receive clonidine. By reducing sympathetic outflow, imidazolines lower arterial pressure through reduction in both cardiac output and peripheral vascular resistance. Reduced cardiac output is from a decrease in heart rate and myocardial contractility.

CHAPTER 62

Clonidine and Related Imidazoline Derivatives

PATHOPHYSIOLOGY In overdose, the sympatholytic effects of imidazolines predominate. The organs most commonly affected are the brain and the heart. Decreased norepinephrine release in the central nervous system (CNS) causes lethargy, coma, miosis, hypotonia, respiratory depression, apnea, and hypothermia.14-18 Cardiac consequences of imidazoline toxicity include bradycardia (sinus or firstdegree atrioventricular [AV] block) and hypotension related to central α2-adrenergic and imidazoline receptor stimulation.14-18 Peripheral α2-adrenergic effects may cause vasoconstriction with hypertension. Rarely, malignant hypertension and seizures occur, particularly in patients with renal insufficiency who ingest large doses of clonidine.37 Children are particularly sensitive to the toxic effects of the imidazolines. As little as 0.1 mg of clonidine and 2.5 mL (1⁄2 teaspoon) of 0.05% tetrahydrozoline eye drops have caused significant toxicity.14,38,39

PHARMACOKINETICS Rapid absorption follows oral clonidine administration, with drug bioavailability of 75% to 96% after a single dose.40 Bioavailability falls with chronic administration to 65%.41 Maximal hypotensive effect coincides with peak plasma concentration 1 to 3 hours after ingestion. Therapeutic clonidine levels range from 0.5 to 2 ng/mL, with a close relationship between plasma concentration and clinical effects.23 Clonidine is 20% to 40% protein bound and has a volume of distribution of 2.9 to 5.3 L/kg.40 Clonidine undergoes hepatic metabolism to inactive compounds, but about half of a single oral dose is excreted unchanged in the urine. The elimination half-life is 12 to 16 hours and is prolonged in patients with renal insufficiency, often necessitating decreased dosing.41 In preoperative patients, clonidine may be given sublingually or rectally, with pharmacokinetics similar to oral administration.43,44 Clonidine patch formulations range from 2.5 to 7.5 mg of drug within a timed matrix delivery system. These systems provide a constant rate of transdermal clonidine administration over 7 days. Maximum plasma concentration occurs 2 to 3 days after application and peaks at 0.1 to 0.5 ng/mL. Elimination half-life ranges from 26 to 55 hours while the patch is applied. Drug

1003

delivery varies by application site, with highest absorption from the left arm and lowest from the thigh.45 Twenty to 75% of residual clonidine may remain in the patch after 7 days of use.46 Pharmacokinetic comparisons of certain imidazolines are shown in Table 62-1. α-Clonidine, brimonidine, naphazoline, tetrahydrozoline, oxymetazoline, and xylometazoline are approved and intended only for topical use; pharmacokinetic data based on ingestion are not available for these agents.

Special Populations PEDIATRIC Despite the frequent use of imidazolines (clonidine and guanfacine) in children, no controlled pharmacokinetic data exist. HEPATIC AND RENAL IMPAIRMENT Hepatic disease necessitates careful monitoring and possible dose reduction in patients receiving dexmedetomidine and guanabenz. Patients with renal disease should have a proportionate reduction in clonidine dose. Methyldopa is contraindicated in patients with active hepatic disease and in those who have experienced liver disorders attributable to prior methyldopa administration.47 PREGNANCY AND LACTATION Methyldopa and guanfacine have category B designation for use in pregnancy. However, a great deal of human experience with methyldopa suggests that the chance of fetal harm is very low and that the benefit of controlling hypertension in pregnancy using methyldopa far outweighs potential teratogenic risks. No human reproductive data exist for guanfacine. Clonidine, guanabenz, and dexmedetomidine all have category C designation in pregnancy, with some evidence of adverse fetal effects in animals. Clonidine is also excreted in breast milk; its safety for use while breast-feeding is unknown.47

Pharmacologic Agents Table 62-2 lists the most common imidazoline formulations available.

TABLE 62-1 Pharmacokinetics of Clonidine, Guanfacine, and Guanabenz DRUG

BIOAVAILABILITY (%)

Tmax (hr)

t1/2 (hr)

Vd (L/kg)

Clonidine Clonidine patch Guanfacine67,68 Guanabenz69 Dexmedetomidine Tizanidine

75–96 25–80* 95–100 75 100 20–40

1–3 40–80 1–3 2–5 0.1 1–2

12–16 26–55 17–24 7–14 2–3 2–4

3–5 3–5 4–6 7–17 1.3 8–16

*Twenty percent to 75% of drug remains in the patch after 7 days.26 Tmax, maximum plasma concentration; t1/2, half-life of drug; Vd, volume of distribution.

PROTEIN BINDING (%) 20–40 20–40 20–30 90 94 30

ELIMINATION Renal Renal Renal Hepatic Hepatic Hepatic

1004


TABLE 62-2 Imidazoline Formulations DRUG

FORM

DOSE/CONCENTRATION

BRAND NAME

Clonidine

Tablet

0.25 mg 0.1, 0.2, or 0.3 mg 0.1, 0.2, or 0.3 mg with 15 mg chlorthalidone 2.5 (3 cm2) 5.0 (7 cm2) 7.5 mg (10 cm2) 100 μg/mL, 500 μg/mL 1, 2 mg 4, 8 mg 125, 250, 500 mg 250 mg/5 mL 50 mg/mL 100 μg/mL 0.15%, 0.2%, 0.5% 0.1%

Dixarit Catapres Combipres

Patch

Guanfacine Guanabenz Methyldopa Dexmedetomidine Briminodine Naphazoline Tetrahydrozoline Tizanidine Oxymetazoline Xylometazoline

Intravenous Tablet Tablet Tablet Oral solution IV solution IV solution Topical ophthalmic Topical ophthalmic Topical nasal and ophthalmic Tablet Topical nasal and ophthalmic Topical nasal

0.05%, 0.1% 2, 4 mg 0.01%, 0.025%, 0.05% 0.05%, 0.1%

Drug Interactions Significant drug interactions are rare with imidazolines. They may combine with other antihypertensive medications (e.g., α1-adrenergic, β-adrenergic, and calcium channel antagonists) to produce hypotension or bradycardia. All forms of imidazolines may cause malignant hypertension in patients taking monoamine oxidase inhibitors. Methyldopa may alter lithium levels and has decreased bioavailability when ingested with iron formulations.47 Three sudden deaths were reported in children taking the combination of clonidine and methylphenidate for ADHD. Circumstances in each case led the U.S. Food and Drug Administration to conclude that both clonidine and methylphenidate have potential cardiotoxicity, but there was no convincing evidence for a lethal drug interaction involving these two medications.48,49 Cyclic antidepressants potentially interfere with the antihypertensive effect of clonidine. Clonidine may potentiate CNS depression when combined with ethanol, barbiturates, or other sedativehypnotic medications. Klonopin (clonazepam) and clonidine sound alike and may be inadvertently substituted for each other and result in accidental toxicity.

TOXICOLOGY Clinical Manifestations Clinical findings of clonidine and other imidazoline poisonings appear soon after ingestion. In one series of clonidine poisoning in children, 75% of patients had signs of toxicity within 1 hour of ingestion, and no patient had any new findings occur more than 4 hours

Catapres-TTS 1 Catapres-TTS 2 Catapres-TTS 3 Duraclon Tenex Generic Generic Precedex Alphagan-P Naphcon Forte, Vasocon, and others Tyzine, Visine, and others Sirdalud, Ternelin, Zanaflex Dristan, Afrin, Neosynephrine, Visine LR, and others Otrivin

after poisoning.16 Topical imidazoline exposure by unintentional oral ingestion or nasal administration in infants and young children can cause lethargy and coma within 1 hour.50 One case report describes the intentional poisoning with clonidine eye drops for criminal purposes resulting in prolonged coma, respiratory depression, and hemodynamic instability.51 The potential for rapid decompensation in patients who ingest imidazolines makes close observation of these patients imperative. About 60% of clonidine exposures reported to poison control centers are symptomatic.14 The relative frequency of clinical findings in symptomatic children and adults who ingest clonidine are shown in Table 62-3. Lethargy and coma typically accompany serious clonidine toxicity and occur soon after ingestion. Miosis, hyporeflexia, and hypotonia are common associated findings, particularly in children. This constellation of neurologic findings closely mimics opiate toxicity. Frequently, children with clonidine intoxication and coma have transient responsiveness to a painful stimulus, such as intravenous line placement or phlebotomy, but quickly revert back to profound CNS depression. Irritability, dilated pupils, and the presence of extensor plantar responses (i.e., positive Babinski’s sign) occur less frequently in children and are rarely seen in adults. Bradycardia and hypotension follow clonidine ingestion in a significant number of children and adults. Sinus bradycardia is the most common rhythm in these patients, with first-degree AV block seen occasionally. Although complete AV block and supraventricular tachycardia complicated clonidine ingestion in a 22-yearold woman with systemic lupus erythematosus and renal insufficiency,52 second-degree block or complete AV dissociation should prompt the consideration of toxicity

CHAPTER 62

Clonidine and Related Imidazoline Derivatives

1005

TABLE 62-3 Clinical Findings in Children and Adults after Clonidine Poisoning FINDING

CHILDREN, HOSPITAL BASED* ( procainamide > quinidine. Extracorporeal drug removal may be of some use for procainamide and N-acetylprocainamide but is of minimal benefit for other IA antiarrhythmics. Peak plasma levels for therapeutic doses occur at 1 to 3 hours but may be delayed in overdose. Symptomatic patients should be admitted for cardiac monitoring.

The class IA antiarrhythmics include quinidine, procainamide, and disopyramide. Although dissimilar in structure (Fig. 63-1), all three drugs suppress cardiac dysrhythmias via the same mechanisms and produce adverse effects typical of the group. In the past, these drugs were widely used for the control of both atrial and ventricular arrhythmias, but because of the high incidence of adverse effects with therapeutic use and overdose, newer, safer agents have largely replaced them.

Quinidine

CH2KCH

Disopyramide

H N

HO H

CH3O

CONH2

CH(CH3)2

J

N

CCH2CH2N CH(CH3)2

N Procainamide

H2N

CONHCH2CH2N(CH2CH3)2 . HCl

FIGURE 63-1 Although dissimilar in structure, all class IA antiarrhythmic agents share therapeutic and toxic effects.

Quinidine and its optical isomer quinine are extracted from the South American cinchona tree. Centuries ago, it was noted that patients with both malaria and atrial fibrillation, when treated with cinchona for malaria, were sometimes also cured of their arrhythmia. Jean-Baptiste de Senac, of Paris, recorded using cinchona in the treatment of atrial fibrillation in 1749. In 1936, Mautz demonstrated procaine to be effective in decreasing ventricular irritability, but this compound was rapidly metabolized and was too neurotoxic to be of clinical value. Procainamide, a congener of procaine, was introduced in 1955. Disopyramide was introduced in 1978.1

PHARMACOKINETICS Quinidine is well absorbed after ingestion, with a bioavailability of between 70% and 80%. Quinidine sulfate levels peak at 1.5 hours. The gluconate, sulfate, and polygalacturonate salts are sustained-release preparations, and blood levels of these may not peak until 4 hours after ingestion. Peak levels may be significantly prolonged in overdose.2,3 Quinidine is 75% to 95% protein bound and is metabolized by the liver via hydroxylation, with a half-life of approximately 6 hours.4 Quinidine has two metabolites with antiarrhythmic properties: 2′-quinidinone and 3-hydroxyquinidine. Its apparent volume of distribution is 3 L/kg. Approximately 20% of quinidine is excreted unchanged in the urine.2 Oral procainamide is absorbed well from the small intestine; levels peak 1 to 2 hours after ingestion. After intravenous administration, the drug distributes to the tissue within 30 minutes. Procainamide diffuses well into tissue and has a volume of distribution of 2 L/kg. Protein binding is approximately 15% to 20%.5 Procainamide is hydrolyzed by the liver into several active metabolites, the most significant being 1,4,2,-N-acetylprocainamide (NAPA).6 Procainamide has a half-life of 3 hours, and NAPA of 6 hours. Fifty percent of procainamide is excreted in the urine unchanged.7 Disopyramide is well absorbed orally, with peak levels occurring 2 to 3 hours after ingestion.8 Protein binding is 30%, and the volume of distribution is 0.8 L/kg. Disopyramide is partially metabolized by the liver, with 55% being excreted unchanged in the urine. The halflife of disopyramide is approximately 8 hours.9

PATHOPHYSIOLOGY A summary of reported adverse effects of these agents is found in Table 63-1. 1009

1010


TABLE 63-1 Noncardiac Effects of Class IA Antiarrhythmics

Recovery is usually complete within 5 days of removal of the drug.17

SYSTEM

EFFECTS

Metabolic Effects

Central nervous

Giddiness, depression, hallucinations* Blurred vision, sedation† Pleural fibrosis*, pneumonitis‡ Nausea, vomiting, diarrhea Hepatitis*,‡ Urinary retention Myopathy with muscle weakness* Rashes Lichen planus‡ IgG-mediated agranulocytosis,*,‡ thrombocytopenia*,‡ IgM-mediated hemolysis (most often in patients with G6PD)‡ SLE*,‡ Hypoglycemia†

Symptomatic hypoglycemia has been reported to occur after therapeutic doses of disopyramide. Goldberg and colleagues demonstrated hypoglycemia with administration of disopyramide. Hypoglycemia could be reproduced on readministration of the drug.18 Quinidine and disopyramide, like the sulfonylureas, have the ability to block potassium efflux from pancreatic β-cells, thus leading to increased insulin secretion resulting in hyperinsulinemia (Fig. 63-2).19 Hyperinsulinemia is well documented with use of quinine, a stereoisomer of quinidine, and with disopyramide, but its occurrence in the presence of other class IA antiarrhythmics has not been clearly documented.18,20,21

Pulmonary Gastrointestinal Genitourinary Muscloskeletal Skin Hematologic

Rheumatologic Other *Primarily procainamide † Primarily disopyramide ‡ Primarily quinidine

Anticholinergic Effects Many symptoms associated with class IA antiarrhythmics are related to the anticholinergic activity of these compounds. Disopyramide is the most anticholinergic, followed by procainamide and then quinidine. Confusion, hallucinations, tachycardia, decreased gastrointestinal motility, urinary retention, and dry mucous membranes all may occur with their use.3 Because some patients may suffer from cinchonism, the clinical presentation may be a confusing combination of the two syndromes.

Cardiac Effects The class IA antiarrhythmics, although structurally dissimilar, produce similar effects on the heart. These agents cause numerous cardiac arrhythmias, including heart block, atrial tachycardia, premature ventricular contractions, torsades de pointes, ventricular tachycardia, and ventricular fibrillation.3,10,22 The drug actions responsible for these arrhythmias are sodium channel blockade, potassium efflux blockade, and inhibition of the sodium/potassium–adenosine triphosphatase (Na+/K+-ATPase) pump. Other drug effects may play a role in the development of arrhythmia, but these are not as well described. Dysrhythmias can occur at therapeutic as well as toxic serum concentrations of these drugs. The cardiac effects of quinidine are the most studied, but all

Immune System Effects Hypersensitivity reactions most commonly occur with quinidine but may also occur with procainamide and disopyramide. Hypersensitivity may be manifested as fever, rash, thrombocytopenia, neutropenia, agranulocytosis, hepatitis, hemolytic anemia, or lymphadenopathy.3,10-12 These reactions frequently are unrelated to dose. Procainamide is the most common cause of druginduced lupus. Antinuclear antibodies occur in 50% to 75% of patients treated with procainamide, and 20% to 30% of those patients develop components of druginduced lupus.7 Patients suffer from arthralgias, myalgias, malar rash, fever, pleuritis, pleural effusion, and pericarditis. Renal involvement is rare.13 The mechanism responsible for the development of druginduced lupus remains under investigation. Metabolic products of procainamide have been found to inhibit the covalent binding of C4 to C2 in the complement cascade, which is thought to decrease the clearance of immune complexes.14,15 Thrombocytopenia has been reported to occur with therapeutic use of quinidine and procainamide.16,17 Druginduced thrombocytopenia is an immune-mediated reaction. The sensitizing drug induces antiplatelet antibodies, which cause the rapid destruction of platelets.

IAs, Sulfonylureas block

Ca2; (3) (2)

Glucose Metabolism Amino acids

K;

(1)

cAMP + ADP

[ATP] [ADP]

Ca2; Channel block

[Ca2;] + Calmodulin (4)

Phosphorylation of kinases

I (5)

Insulin FIGURE 63-2 The presence of glucose or amino acids triggers the conversion of ATP to cAMP.1 Cyclic AMP is needed to open calcium channels in the beta cell. Calcium ions then enter the cell3 and bind with calmodulin to activate kinases such as myosin–light chain kinase or protein kinase C4 to stimulate the release of insulin5. The initial depolarization of the beta cell triggers potassium efflux.2 The IA antiarrhythmics are thought to block the potassium efflux out of beta cells in the pancreas. This would prolong “depolarization“ of the cell and increase secretion of insulin. (Adapted from Gerich JE: Oral hypoglycemic agents. New Engl J Med 1989;321:1231–1245.)

CHAPTER 63

Class IA Antiarrhythmics: Quinidine, Procainamide, and Disopyramide

agents in this class act in a similar manner. Procainamide has less cardiotoxicity than quinidine and disopyramide at therapeutic doses.3

Effects on Ion Channels In a normal Purkinje cell, the rapid influx of sodium ions in phase 0 causes the interior of the cell to become more positive (Fig. 63-3 and 63-4). Phase 1 is associated with slow leakage of potassium out of the cell, causing a decrease in positive charge within the cell, which brings the cell slightly closer to its resting potential. During phase 2, voltage-dependent calcium channels open, allowing calcium ions to enter. This calcium influx, which sustains the positive charge within the cell, is reflected as the plateau of phase 2. The slow leak of potassium from the cell during phase 2 balances the inward flow of calcium, and the net result is little change

Na+ fast channel closes, transient outward K+ current begins

1 Ca2; in through

Millivolt

2 slow channels Na+ in through fast channels

Delayed rectifier K+ current (out)

0

3 Inwardly rectifying K+ current

4

4

Na+ in through slow channels

Na+ in through slow channels

Time (hr) FIGURE 63-3 Ion flow during Purkinje cell action potential.

in the membrane potential. In phase 3, however, further leakage of potassium out of the cell (potassium efflux) repolarizes the cell. In phase 4, the charge within the cell has returned to its resting potential and sodium begins to enter into the cell. This moves the cell membrane potential toward threshold again, and the next action potential can occur. Late phase 4 and phase 0 represent depolarization of the cardiac cell, whereas phases 1, 2, and 3 represent repolarization. Phases 0 to 3 correspond to systole, and phase 4 corresponds to diastole. Similar processes occur in other cardiac cells; however, each type of cardiac tissue has different concentrations of each kind of ion channel and thus has slightly varied patterns of depolarization and repolarization.

Sodium Channel Blockade The IA antiarrhythmic agents can produce widening of the QRS, ventricular tachycardia, and decreased inotropy by blocking fast sodium channels in cardiac cells. Electrical conductance is dependent on the rapid influx of sodium through fast sodium channels. In terms of the action potential, this slows the rate of rise of phase 0 (Vmax). Because phase 0 of the action potential corresponds to the QRS complex on the electrocardiogram (ECG), any toxin that slows the influx of sodium ions through the fast channels produces a widened QRS complex (Figs. 63-4 and 63-5). The class IA antiarrhythmics’ ability to block Na+ channels is dose dependent and is clinically significant only with high drug levels.22,23 At toxic serum concentrations, QRS widening, bundle branch block, and sinoatrial or atrioventricular block may be present. The sodium channel blockade caused by class IA antiarrhythmics increases as the heart rate increases. Normally, as the heart rate increases, both action potential duration and effective refractory period shorten.24 Studies using these agents have shown that the

1

1

0

Millivolt

Millivolt

2 0 3 4

1011

2 3

4

Time (hr) FIGURE 63-4 Normal Purkinje cell action potential and corresponding electrocardiographic pattern.

4

4

Time (hr) FIGURE 63-5 When sodium channels are blocked, the rate of rise of phase 0 (Vmax) is decreased. This corresponds to a widening of the QRS complex.


action potential duration and effective refractory period have a greater relative increase at higher heart rates.24-27 Thus, they exhibit time-dependent suppression of excitability, and this effect is more pronounced at higher heart rates. This effect may be explained by the tendency of these drugs to bind to sodium channels in their open state. When heart rates are higher, there are more open sodium channels, and therefore more channels susceptible to blockade.28 It may then be theorized that patients experiencing ventricular tachycardia secondary to procainamide and quinidine (and possibly disopyramide) toxicity may not respond favorably to overdrive pacing.24

Potassium Channel Blockade Repolarization in the heart is largely due to efflux of potassium out of the cells. When potassium channels are blocked, as with the class IA antiarrhythmics, repolarization is prolonged. Prolongation of repolarization is reflected by prolonged QT on the ECG. Blockade of the delayed rectifier current, IKr, is most often associated with drug-induced prolonged QT29-31 (Fig. 63-6). With potassium efflux blockade, prolonged QT, premature ventricular contractions, and torsades de pointes can be seen. Development of torsades de pointes is most likely dependent on both repolarization abnormalities and triggered activity. When repolarization is disorganized, the possibility of reentrant circuits is increased, and reentrant circuits are responsible for torsades de pointes.28-30,32-37 Afterdepolarization means electric oscillations of the conductive cell membrane that occur late in phase 2, throughout phase 3, or early in phase 4 of the action potential. This activity appears to occur primarily in Purkinje cells or deep subendocardial regions of the ventricular wall.38 Afterdepolarization that occurs in phase 2 or 3 is known as early afterdepolarization. Early afterdepolarizations might be caused by calcium (L-type) current or sodium currents29,33,39 or might be due to

EAD

1

Purkinje cell

K;

K; IAs K;

K; K;

Na;/K; ATPase

adrenergic effects.40-42 Afterdepolarization occurring in early phase 4 is termed delayed afterdepolarization.39 Early afterdepolarization–triggered activity tends to result in torsades de pointes. Delayed afterdepolarization activity tends to be more closely associated with premature ventricular contractions.26,43 The IA antiarrhythmics are capable of producing both. Not all afterdepolarizations lead to dysrhythmias. Because they occur during the relative refractory period of cellular repolarization, some of these membrane oscillations do not cause the cell to fire again. If the cell has sufficiently repolarized, some afterdepolarizations are capable of reaching threshold and causing abnormal firing and dysrhythmias. Action potentials produced by afterdepolarizations that reach threshold are called triggered activity (Fig. 63-7). Triggered activity is partly responsible for the tachyarrhythmias that occur at therapeutic levels of the IA antiarrhythmics.28,29,36,43 The development of torsades de pointes also revolves around heterogeneity of repolarization in the ventricles. If the triggered activity reaches area of muscle that is sufficiently repolarized, the impulse will be transmitted. As a result of different areas of cardiac muscle being in differing stages of repolarization, some areas will be refractory to depolarization from the triggered activity. The area of functional block creates the possibility for reentry, and reentrant circuits will propagate the arrhythmia.28,29,32,37,39,44,45 Quinidine’s potassium efflux blockade predominates at lower heart rates.46,47 This phenomenon is called reverse use dependence, meaning the duration of repolarization is greater at slower heart rates.28,48,49 Therefore, early afterdepolarization is more likely at slower heart rates.33,49 As the heart rate increases, quinidine’s blockade of Na+ channels is greater. Blockade of the movement of these positive ions into the interior of the cell keeps the blockade of potassium efflux counterbalanced.27 The inside of the cell remains relatively more negative, making early afterdepolarization activity less likely and decreasing the risk of development of torsades de pointes.46 Some patients may be at greater risk of developing torsades de pointes than others owing to a genetic

K; K;

IAs

0

K; K;

K;

Millivolt

1012

2 3 4

Na;/Ca2;

FIGURE 63-6 IA antiarrhythmics and other toxins may block the efflux of K+ from the cardiac cell, driving the charge on the interior of the cell membrane in a less negative direction, toward threshold. This change in charge leads to early afterdepolarization (EAD) formation.

Time (hr) FIGURE 63-7 Blockade of potassium efflux out of the cells leads to membrane oscillations or afterdepolarizations. If they attain threshold voltage, “triggered activity” will occur.

CHAPTER 63


predisposition of arrhythmia. Inherited defects of ion channels resulting in prolonged QT have variable penetrance, and not every carrier will manifest changes on a baseline ECG; however, this patient population may be at increased risk when exposed to agents that block potassium channels. This concept is termed repolarization reserve.30,50,51,52

Purkinje cell

Na+/K+-ATPase Blockade

Ca2; Na; 2

K;

Na;

Ca2; Ca2;

Na;

Na;/K; ATPase

Ca2;

DAD Ca2;

Na;/Ca2;

3 Na; 3 Na; FIGURE 63-9 Delayed afterdepolarizations resulting in premature ventricular contraction (PVC).

1 “Triggered activity”

0 Milivolt

The premature ventricular contractions observed in overdose may be caused by inhibition of the Na+/K+ATPase pump in cardiac cells. The Na+/K+-ATPase pump functions to repolarize the cell after contraction by transporting intracellular Na+ ions out of the cell in exchange for K+ ions transported into the cell. Class IA agents, in a fashion similar to digoxin, inhibit the Na+/K+-ATPase pump, resulting in intracellular Na+ accumulation.53 The intracellular Na+ is exchanged for extracellular Ca2+ by the Na+/Ca2+ pump, causing an increase in intracellular Ca2+ (Fig. 63-8). Normally, the sarcoplasmic reticulum takes up cytoplasmic Ca2+ and stores it; however, excessive intracellular Ca2+ is thought to overload the sequestration mechanism of the sarcoplasmic reticulum. The increased intracellular Ca2+ then activates the Na+/Ca2+ pump, which stimulates the exchange of intracellular Ca2+ for extracellular Na+. This creates an inward current of Na+ ions and results in delayed afterdepolarizations33,39,43 (Fig. 63-9). These delayed afterdepolarizations can result in triggered activity, usually manifested by premature ventricular contractions. Afterdepolarizations reach threshold more frequently as the heart rate accelerates. Dzimiri and Almotrefi demonstrated increasing inhibition of the Na+/K+-ATPase pump with decreasing serum potassium levels,53 which may explain the exacerbation of arrhythmias caused by class IA antiarrhythmics by hypokalemia. Low serum potassium levels further inhibit the Na+/K+-ATPase pump, worsening intracellular Ca2+ overload and resulting in an increased frequency of delayed afterdepolarization with resultant arrhythmia

Ca2;

Ca2; Ca2; Ca2; Ca2;

1013

2 3 Na+

4

PVC

Time (h) FIGURE 63-10 If the inhibition of the Na+/K+-ATPase pump leads to Ca2+ overload of the cell, the sarcoplasmic reticulum is unable to compensate by sequestration and the internal charge begins to increase, leading to delayed afterdepolarization (DAD) formation.

(Fig. 63-10). Conditions associated with exacerbation of this process include digitalis toxicity, hypernatremia, hypokalemia, and catecholamine excess.53

TOXICOLOGY Ca2;

Purkinje cell Ca2;

Ca2; Na;

S.R. 2 K; Na;/K; ATPase

Ca2; Na;

Ca2;

Na;/Ca2;

3 Na; 3 Na; + + FIGURE 63-8 Inhibition of the Na /K -ATPase pump leads to an increase in intracellular Na+. This, in turn, leads to an exchange of Na+ for Ca2+ via the Na+/Ca2+ pump. The excess intracellular Ca2+ is sequestered in the sarcoplasmic reticulum (SR).

Significant ingestion of these drugs produces primarily neurologic and cardiovascular consequences.10,54 Ingestion of more than 1 g of quinidine by an adult has been reported to produce symptoms. As little as 7 g of procainamide or 1.5 g of disopyramide is potentially toxic. In assessing the severity of a toxic ingestion, it is important to remember that the reported history of the amount of a drug ingested is very unreliable and individual responses to these drugs vary greatly. Underlying cardiac disease may make some patients symptomatic at lower than expected doses.

Central Nervous System Toxicity Toxicity from class IA antiarrhythmics may cause mydriasis and blurred vision. A patient’s mental status

1014


may range from lethargy and confusion to coma. Convulsions independent of hypotension secondary to quinidine have been reported.54 Summers et al reported on a 69-year-old man who developed confusion and hallucinations while receiving quinidine during hospitalization for myocardial infarction.55 The patient’s mental status cleared after the administration of physostigmine, leading the investigators to conclude that mental status changes were due to anticholinergic toxicity.

Cardiovascular System Toxicity The cardiotoxic effects of this class of drugs are the most threatening. Although tachycardia may be present early in serious poisoning, bradycardia secondary to conduction delays and blocks is most common. Other arrhythmias reported in overdose include atrial tachyarrhythmias, ventricular tachycardia, and fibrillation.54 Risk factors for developing torsades de pointes include female sex, hypokalemia, bradycardia, long QT syndrome, and hypomagnesemia.30,33,37 Hypotension and shock associated with class IA antiarrhythmics are primarily related to depressive actions on the heart rather than to direct effects on the peripheral vasculature.56,57 Disopyramide exhibits the greatest negative inotropic effect of the three and has been reported to cause congestive heart failure with therapeutic use.3,58 Quinidine syncope, which occurs at therapeutic and subtherapeutic levels, was initially thought to be caused by hypotension secondary to the vasodilatory effect of this drug. Ventricular tachyarrhythmias were ultimately determined to be responsible. Fifty percent of patients who develop torsades de pointes do so within the first 5 days of therapy; the remainder of the cases occurs weeks to years later, often after a dosage change.59 Disopyramide and procainamide, although less frequently than quinidine, have also been reported to cause fatal arrhythmias in the therapeutic range.60-63 The arrhythmias usually are nonsustained but occasionally have been fatal. Sudden death while on quinidine therapy has been estimated at 0.5%.10 Both polymorphic ventricular tachycardia and torsades de pointes have been reported. Both rhythms can produce a rotating axis on an electrocardiogram but respond differently to various therapeutic interventions.64 Torsades de pointes may be distinguished from polymorphic ventricular tachycardia by the following criteria: The initial complex follows a pause or sudden rate deceleration, which produces a long preceding RR interval. The initiating complex also has an accentuated U wave and occurs in the setting of a prolonged QT (Fig. 63-11).27,29,32,33,37,39,42-44,65,66

There have been efforts to determine who is at risk for arrhythmia based on ECG interpretation. A QT interval greater than 500 ms37,39 or prolongation of the QT interval by greater than 50%54 indicates greater risk for developing torsades de pointes. Not only does a long QT appear to have some prognostic value, but also QT dispersion may have some utility in stratifying high-risk patients who have quinidine-induced repolarization abnormalities. Several methods exist to measure QT dispersion, but in general it is calculated by measuring all QT segments, finding the shortest QT interval, and subtracting it from the longest QT segment. A value greater than 100 appears to predict arrhythmia.37,39,63,65

Gastrointestinal System Toxicity Dry mouth is a frequent complaint of patients exposed to class IA antiarrhythmics. Nausea, vomiting, and diarrhea also are common, although decreased bowel sounds, constipation, and ileus may occur secondary to the anticholinergic effects of these drugs.

Cinchonism First described in association with quinine, the complex of symptoms called cinchonism may occur in chronic overuse or acute overdose of quinidine, although it is more common with quinine. This syndrome is characterized by abdominal pain, diarrhea, nausea, vomiting, hearing loss, tinnitus, visual disturbances, encephalopathy, coma, and seizures.10 Symptoms typically resolve after removal of the causative agent.

Genitourinary System Toxicity Urinary retention and anuria have been reported. They are thought to be associated with the anticholinergic effects of these drugs.

Immune System Toxicity Thrombocytopenic purpura, angioedema, exfoliative dermatitis, livedo reticularis, and photodermatitis have all been reported. Urticaria, flushing, pruritus, bullous reactions, lichen planus, psoriasis, erythroderma, and erythema multiforme have been seen.67 Drug-induced lupus erythematosus is reported most frequently with procainamide, but is seen with other IA antiarrhythmics.

Musculoskeletal System Toxicity Myositis, muscle weakness, and myopathy have been associated with therapeutic use. One patient has been FIGURE 63-11 Rhythm strip of a patient with torsades de pointes suffering from chronic procainamide toxicity. Procainamide level was 27.5 μg/mL, and NAPA level was 62.4 μg/mL.

CHAPTER 63


described with diaphragmatic paralysis while taking 750 mg of procainamide twice daily.68

BOX 63-1

Pregnancy

β-Blockers

The class IA antiarrhythmic agents clearly cross the placenta. No evidence shows that they are teratogenic. Disopyramide has been associated with premature uterine contractions, which resolved on discontinuance of the drug.69

DRUG INTERACTIONS A particular form of cytochrome P-450 inhibition has been described with quinidine use. Debrisoquin, an antihypertensive agent used in Europe, is metabolized by the cytochrome P-450 isozyme CYP2D6 (debrisoquin hydroxylase). A number of other drugs are metabolized by the same isozyme. Ten percent of the Western population is genetically deficient in this enzyme and metabolizes debrisoquin slowly. Quinidine, although not metabolized by this isozyme, binds to CYP2D6, interfering with its function. Commonly prescribed medications metabolized by this pathway, when taken with quinidine, are metabolized more slowly, causing higher than expected serum concentrations.70 Drugs metabolized by CYP2D6 and potentially affected by quinidine are listed in Box 63-1.

Quinidine and Digitalis Quinidine is thought to decrease the volume of distribution of some cardiac glycosides. This seems particularly true in the presence of digoxin. When these drugs are given concomitantly, the usual digoxin dose should be reduced by 50%.71

LABORATORY STUDIES Serum quinidine levels of 1 to 4 μg/mL are considered therapeutic. Toxic symptoms are expected at levels greater than 5 μg/mL. Combined serum levels of both procainamide and its active metabolite, NAPA, must be measured for evaluation of procainamide toxicity. A combined level greater than 30 μg/mL is potentially cardiotoxic. Combined levels greater than 60 μg/mL are likely to cause lethargy and hypotension. Disopyramide levels greater than 5 μg/mL are considered toxic.

TREATMENT General Management Treatment of an overdose of a class IA antiarrhythmic should include early and aggressive management of the airway. The possibility of rapid decline in mental status and the onset of cardiac arrhythmias place these patients at very high risk of aspiration and pulmonary compromise. Once the airway is controlled, gastrointestinal

1015

DRUG METABOLIZED BY CYP2D6

Timolol Propranolol Metoprolol Propafenone Tricyclic Antidepressants

Nortriptyline Amitriptyline Desipramine Imipramine Clomipramine Neuroleptics

Thioridazine Fluphenazine Perphenazine Trifluperidol MAO Inhibitors

Amiflamine Methoxyphenamine Antiarrhythmics

Flecainide Encainide Other

Codeine Dextromethorphan Phenformin Methamphetamine

decontamination with oral activated charcoal may be considered. Repeat doses of charcoal are of minimal clinical benefit and may be harmful to patients with decreased gastrointestinal motility. Admission to an intensive care setting for cardiac monitoring is appropriate for all symptomatic patients. Seizures secondary to use of class IA antiarrhythmics respond readily to administration of benzodiazepines. Loading with other anticonvulsants is not indicated unless the seizures are recurrent or prolonged. Phenobarbital, 15 mg/kg intravenously, should be used for persistent seizure activity. Higher doses may occasionally be required and can be associated with respiratory depression. Monitoring of creatine phosphokinase levels for evidence of rhabdomyolysis should be carried out for any patient “found down” (obtunded) for an unknown period.

Cardiac Toxicity Class IA antiarrhythmics’ strong cardiac sodium channel blocker activity is responsible for the intraventricular conduction delays in overdose.55 Wide complex rhythms may respond to intravenous administration of a sodium bicarbonate bolus.72,73 The exact mechanism of action of

1016


sodium bicarbonate in the treatment of ventricular tachycardia secondary to Na_ blockade may be related to either the physical displacement of the drug from the Na_ channel by increased serum Na_ concentration72 or decreased binding to the channel by increasing the serum pH.73,74 Bradycardia unresponsive to atropine may require transcutaneous or transvenous pacing.54 Hypotension should initially be treated with IV fluids. Patients with a history of cardiac dysfunction should be closely monitored for signs of fluid overload and may need placement of a Swan-Ganz catheter for continued evaluation of fluid status. Both epinephrine and dopamine are effective in treating associated hypotension.75,76 Torsades de pointes is usually preceded by a relatively slow heart rate and a prolonged QT interval.1,3 Antiarrhythmics routinely used for ventricular tachycardia are often ineffective in its treatment. Patients presenting with torsades de pointes of any origin should be given 2 g of intravenous magnesium sulfate followed by a 1- to 2-g/hr infusion.64,77 Although the exact mechanism by which magnesium sulfate terminates torsades de pointes is not understood, research suggests it suppresses early afterdepolarization activity by shortening the plateau phase of cardiac depolarization.3 Hypokalemia also should be corrected. If these measures are ineffective, transvenous overdrive pacing may convert torsades de pointes.59,78-81 Isoproterenol may be considered but must be used with caution in patients with underlying cardiac disease.

2. 3. 4. 5. 6. 7. 8. 9.

10. 11.

12. 13. 14.

Extracorporeal Drug Removal Hemodialysis and hemoperfusion have been reported82-84 but are generally considered ineffective in the treatment of acute quinidine poisoning because of this drug’s large volume of distribution and extensive protein binding.2 The half-life of disopyramide is significantly reduced in patients undergoing hemodialysis, and this should be considered in patients not responding to supportive therapy.85 Hemodialysis doubles the clearance of procainamide and provides a fourfold increase in elimination of NAPA, the active metabolite of procainamide.86 Braden and associates demonstrated that hemoperfusion is superior to hemodialysis in the clearance of procainamide and NAPA.87 Domoto et al showed that continuous arteriovenous hemofiltration provides even higher clearance than episodic hemoperfusion.88 Dialysis equipment now capable of high flow rates may provide drug clearance that is equal if not superior to that of both hemofiltration and continuous arteriovenous hemofiltration. Extracorporeal membrane oxygenation (ECMO) has been reported in a 16-month-old child. The ECMO course lasted 11 days with the toddler surviving neurologically intact.89 Although ECMO is a consideration, the logistics make its use difficult and rare.

15. 16.

17. 18. 19. 20. 21. 22. 23. 24.

25.

REFERENCES 1. Bigger JT Jr, Hoffman B: Antiarrhythmic drugs, in Gilman AG, Roll TW, Nies AS, et al (eds): Goodman and Gilman’s The Pharma-

26.

cological Basis of Therapeutics. New York, Pergamon Press, 1990, pp 848–850. Ochs HR, Greenblatt DJ, Woo E: Clinical pharmacokinetics of quinidine. Clin Pharmacokinet 1980;5:50–168. Kim SY, Benowitz NL: Poisoning due to class IA antiarrhythmic drugs: quinidine, procainamide and disopyramide. Drug Saf 1990;5:393–420. Palmer KH, Martin B, Baggett B, Wall ME: The metabolic fate of orally administered quinidine gluconate in humans. Biochem Pharmacol 1969;18:8145–8160. Karlsson E: Clinical pharmacokinetics of procainamide. Clin Pharmacokinet 1978;3:97–107. Giardina EG, Dreyfuss J, Bigger JT Jr, et al: Metabolism of procainamide in normal and cardiac subjects. Clin Pharmacol Ther 1976;19:339–351. Galeazzi RL, Sheiner LB, Lockwood T, Benet LZ: The renal elimination of procainamide. Clin Pharmacol Ther 1976;19:55–62. Bryson SM, Whiting B, Lawrence JR: Disopyramide serum and pharmacologic effect kinetics applied to the assessment of bioavailability. Br J Clin Pharmacol 1978;6:409–419. Hinderling PH, Garrett ER: Pharmacodynamics of the antiarrhythmic disopyramide in healthy humans: correlation of the kinetics of the drug and its effects. J Pharmacokinet Biopharmaceutics 1976;4:231–242. Tiliakos N, Waites TF: Multiform quinidine toxicity. South Med J 74:1981;1267–1268. Cohen IS, Jick H, Cohen SI: Adverse reactions to quinidine in hospitalized patients: findings based on data from the Boston Collaborative Drug Surveillance Program. Prog Cardiovasc Dis 1977;20:151–163. Danielly J, DeJong R, Radke-Mitchell LC, Uprichard AC: Procainamide-associated blood dyscrasias [see comment]. Am J Cardiol 1994;74:1179–1180. Heyman MR, Flores RH, Edelman BB, Carliner NH: Procainamide-induced lupus anticoagulant. South Med J 1988;81: 934–936. Yung RL, Quddus J, Chrisp CE, et al: Mechanism of drug-induced lupus. 1. Cloned Th2 cells modified with DNA methylation inhibitors in vitro cause autoimmunity in vivo. J Immunol 1995; 154:3025–3035. Yung RL, Richardson BC: Drug-induced lupus. Rheum Dis Clini North Am 1994;20:61–86. Chong BH, Berndt MC, Koutts J, Castaldi PA: Quinidine-induced thrombocytopenia and leukopenia: demonstration and characterization of distinct antiplatelet and antileukocyte antibodies. Blood 1983;62:1218–1223. Landrum EM, Siegert EA, Hanlon JT, Currie MS: Prolonged thrombocytopenia associated with procainamide in an elderly patient. Ann Pharmacother 1994;28:1172–1176. Goldberg IJ, Brown LK, Rayfield EJ: Disopyramide (Norpace)induced hypoglycemia. Am J Med 1980;69:463–466. Horie M, Mizuno N, Tsuji K, et al: Disopyramide and its metabolite enhance insulin release from clonal pancreatic beta-cells by blocking K(ATP) channels. Cardiovasc Drug Ther 2001;15:31–39. Croxson MS, Shaw DW, Henley PG, Gabriel HD: Disopyramideinduced hypoglycaemia and increased serum insulin. N Z Med J 1987;100:407–408. Strathman I, Schubert EN, Cohen A, Nitzberg DM: Hypoglycemia in patients receiving disopyramide phosphate. Drug Intell Clin Pharm 1983;17:635–638. Hoffman BF, Rosen MR, Wit AL: Electrophysiology and pharmacology of cardiac arrhythmias. 7. Cardiac effects of quinidine and procaine amide. B. Am Heart J 1975;90:117–122. Ribeiro C, Longo A: Procainamide and disopyramide. Eur Heart J 1987;8:11–19. Lee RJ, Liem LB, Cohen TJ, Franz MR: Relation between repolarization and refractoriness in the human ventricle: cycle length dependence and effect of procainamide. J Am Coll Cardiol 1992;19:614–618. Kirchhof PF, Fabritz CL, Franz MR: Postrepolarization refractoriness versus conduction slowing caused by class I antiarrhythmic drugs: antiarrhythmic and proarrhythmic effects. Circulation 1998;97:2567–2574. The Sicilian gambit: a new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic

CHAPTER 63

27. 28. 29. 30. 31. 32. 33. 34. 35.

36. 37.

38.

39.

40. 41. 42.

43. 44. 45. 46. 47. 48.

49. 50.


mechanisms. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology [see comment]. Circulation 1991;84:1831–1851. Wyse KR, Bursill JA, Campbell TJ: Differential effects of antiarrhythmic agents on post-pause repolarization in cardiac Purkinje fibres. Clin Exp Pharmacol Physiol 1996;23:825–829. Grace AA, Camm AJ: Quinidine. N Engl J Med 1998;338:35–45. Roden DM: Acquired long QT syndromes and the risk of proarrhythmia [see comment]. J Cardiovasc Electrophysiol 2000;11:938–940. Roden DM: Drug-induced prolongation of the QT interval. N Engl J Med 2004;350:1013-–1022. Shieh CC, Coghlan M, Sullivan JP, Gopalakrishnan M: Potassium channels: molecular defects, diseases, and therapeutic opportunities. Pharmacol Rev 2000;52:557–594. el-Sherif N, Turitto G: Torsade de pointes. In Zipes DP, Jalife J (eds): Cardiac Electrophysiology. Philadelphia, WB Saunders, 2000, pp 662–673. Lazzara R: Antiarrhythmic drugs and torsade de pointes. Eur Heart J 1993;14:88–92. Woosley RL, Roden DM: Pharmacologic causes of arrhythmogenic actions of antiarrhythmic drugs. Am J Cardiol 1987;59:19E–25E. De Ponti F, Poluzzi E, Montanaro N: Organising evidence on QT prolongation and occurrence of torsades de pointes with nonantiarrhythmic drugs: a call for consensus. Eur J Clin Pharmacol 2001;57:185–209. Mathis AS, Gandhi AJ: Serum quinidine concentrations and effect on QT dispersion and interval. Ann Pharmacother 2002;36: 1156–1161. Al-Khatib SM, LaPointe NM, Kramer JM, Califf RM: What clinicians should know about the QT interval [see comment]. [Erratum in JAMA 2003;290(10):1318]. JAMA 2003;289: 2120–2127. Sicouri S, Antzelevitch C: Drug-induced afterdepolarizations and triggered activity occur in a discrete subpopulation of ventricular muscle cells (M cells) in the canine heart: quinidine and digitalis. J Cardiovasc Electrophysiol 1993;4:48–58. Anderson ME, Al-Khatib SM, Roden DM, Califf RM: Duke Clinical Research Institute/American Heart Journal Expert Meeting on Repolarization C—Cardiac repolarization: current knowledge, critical gaps, and new approaches to drug development and patient management. Am Heart J 2002;144:769–781. Martins JB: How do I prolong QT? Let me count the ways [comment]. J Cardiovasc Electrophysiol 2001;12:15–16. Darbar D, Fromm MF, Dellorto S, Roden DM: Sympathetic activation enhances QT prolongation by quinidine [see comment]. J Cardiovasc Electrophysiol 2001;12:9–14. Miyamoto S, Zhu B, Teramatsu T, et al: QT-prolonging class I drug, disopyramide, does not aggravate but suppresses adrenalineinduced arrhythmias: comparison with cibenzoline and pilsicainide. Eur J Pharmacol 2000;400:263–269. Binah O, Rosen MR: Mechanisms of ventricular arrhythmias. Circulation 1992;85:I25–31. Habbab MA, el-Sherif N: Drug-induced torsades de pointes: role of early afterdepolarizations and dispersion of repolarization. Am J Med 1990;89:241–246. Roden DM, Anderson ME: The pause that refreshes, or does it? Mechanisms in torsades de pointes. Heart (British Cardiac Society) 2000;84:235–237. Salata JJ, Wasserstrom JA: Effects of quinidine on action potentials and ionic currents in isolated canine ventricular myocytes. Circ Res 1988;62:324–337. Sosunov EA, Anyukhovsky EP, Rosen MR: Effects of quinidine on repolarization in canine epicardium, midmyocardium, and endocardium: 1. In vitro study. Circulation 1997;96:4011–4018. Anyukhovsky EP, Sosunov EA, Feinmark SJ, Rosen MR: Effects of quinidine on repolarization in canine epicardium, midmyocardium, and endocardium: 2. In vivo study. Circulation 1997;96:4019–4026. Yao JA, Trybulski EJ, Tseng GN: Quinidine preferentially blocks the slow delayed rectifier potassium channel in the rested state. J Pharmacol Exp Ther 1996;279:856–864. Roden DM: Taking the “idio” out of “idiosyncratic”: predicting torsades de pointes. Pacing Clin Electrophysiol 1998;21: 1029–1034.

1017

51. Donger C, Denjoy I, Berthet M, et al: KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome. Circulation 96:2778–2781, 1997. 52. Priori SG, Barhanin J, Hauer RN, et al: Genetic and molecular basis of cardiac arrhythmias: impact on clinical management.1 and 2. Circulation 1999;99:518–528. 53. Dzimiri N, Almotrefi AA: Interaction between potassium concentration and inhibition of myocardial Na+/K+-ATPase by two class 1A antiarrhythmic drugs: quinidine and procainamide. Arch Int Pharmacodyn Ther 1991;314:34–43. 54. Kerr F, Kenoyer G, Bilitch M: Quinidine overdose: neurological and cardiovascular toxicity in a normal person. Br Heart J 1971;33:629-631. 55. Summers WK, Allen RE, Pitts FN Jr: Does physostigmine reverse quinidine delirium? West J Med 1981;135:411–414. 56. Grant AO, Starmer CF, Strauss HC: Antiarrhythmic drug action: blockade of the inward sodium current. Circ Res 1984;55:427–439. 57. Li GR, Ferrier GR: Effects of quinidine on arrhythmias and conduction in an isolated tissue model of ischemia and reperfusion. J Cardiovasc Pharmacol 1991;17:239–248. 58. Podrid PJ, Schoeneberger A, Lown B: Congestive heart failure caused by oral disopyramide. N Engl J Med 1980;302:614–617. 59. Jackman WM, Friday KJ, Anderson JL, et al: The long QT syndromes: a critical review, new clinical observations and a unifying hypothesis. Prog Cardiovasc Dis 1988;31:115–172. 60. Riccioni N, Castiglioni M, Bartolomei C: Disopyramide-induced QT prolongation and ventricular tachyarrhythmias. Am Heart J 1983;105:870–871. 61. Olshansky B, Martins J, Hunt S: N-acetyl procainamide causing torsades de pointes. Am J Cardiol 1982;50:1439–1441. 62. Strasberg B, Sclarovsky S, Erdberg A, et al: Procainamide-induced polymorphous ventricular tachycardia. Am J Cardiol 1981;47: 1309–1314. 63. Hohnloser SH, Klingenheben T, Singh BN: Amiodaroneassociated proarrhythmic effects: a review with special reference to torsade de pointes tachycardia [see comment]. Ann Intern Med 1994;121:529–535. 64. Tzivoni D, Banai S, Schuger C, et al: Treatment of torsade de pointes with magnesium sulfate. Circulation 1988;77:392–397. 65. Malik M, Batchvarov VN: Measurement, interpretation and clinical potential of QT dispersion. J Am Coll Cardiol 2000;36:1749–1766. 66. Waldo AL, Wit AL: Mechanisms of cardiac arrhythmias. Lancet 1993;341:1189–1193. 67. Sun D, Reiner D, Frishman W, et al: Adverse dermatologic reactions from antiarrhythmic drug therapy. J Clin Pharmacol 1994;34:953–966. 68. Javaheri S, Logemann TN, Corser BC, et al: Diaphragmatic paralysis. Am J Med 1989;86:623–624. 69. Leonard RF, Braun TE, Levy AM: Initiation of uterine contractions by disopyramide during pregnancy. N Engl J Med 1978;299:84–85. 70. Caporaso NE, Shaw GL: Clinical implications of the competitive inhibition of the debrisoquin-metabolizing isozyme by quinidine. Arch Intern Med 1991;151:1985–1992. 71. Thatcher SK, Lemberg L: Digitalis-quinidine interaction. Heart Lung 1980;9:352–357. 72. Ranger S, Sheldon R, Fermini B, Nattel S: Modulation of flecainide’s cardiac sodium channel blocking actions by extracellular sodium: a possible cellular mechanism for the action of sodium salts in flecainide cardiotoxicity. J Pharmacol Exp Ther 1993;264:1160–1167. 73. Wasserman R, Brodsky L, Kathe J, et al: The effect of molar sodium lactate in quinidine intoxication. Am J Cardiol 1959;4:294. 74. Bellet S, Hamdan G, Somlyo A, et al: The reversal of cardiotoxic effects of quinidine by molar sodium lactate: an experimental study. Am J Med Sci 1959;237:177–189. 75. Nolan MT, Prichard JS: Non-fatal overdose with disopyramide. Irish Med J 1984;77:209. 76. Villalba-Pimentel L, Epstein LM, Sellers EM, et al: Survival after massive procainamide ingestion. Am J Cardiol 1973;32:727–730. 77. Vukmir RB: Torsades de pointes: a review. Am J Emerg Med 1991;9:250–255. 78. el-Sherif N, Bekheit SS, Henkin R: Quinidine-induced long QTU interval and torsade de pointes: role of bradycardiadependent early afterdepolarizations. J Am Coll Cardiol 1989; 14:252–257.

1018


79. Bauman JL, Bauernfeind RA, Hoff JV, et al: Torsade de pointes due to quinidine: observations in 31 patients. Am Heart J 1984; 107:425–430. 80. Kaseda S, Gilmour RF Jr, Zipes DP: Depressant effect of magnesium on early afterdepolarizations and triggered activity induced by cesium, quinidine, and 4-aminopyridine in canine cardiac Purkinje fibers. Am Heart J 1989;118:458–466. 81. Swiryn S, Kim SS: Quinidine-induced syncope. Arch Intern Med 1983;143:314–316. 82. Shub C, Gau G, Sidell P, Brennan L: The management of acute quinidine intoxication. Chest 1978;73:173–178. 83. Woie L, Oyri A: Quinidine intoxication treated with hemodialysis. Acta Med Scand 1974;195:237–239. 84. Reinmold E, Reynolds W, et al: Use of hemodialysis in the treaaatment of quinidine poisoning. Pediatrics 1973;52:95–99.

85. Horn J, M H: Disopyramide dialysability (letter). Lancet 1978;2:214. 86. Aitchison JD, Campbell RW, Higham PD: Time dependent variability of QT dispersion after acute myocardial infarction and its relation to ventricular fibrillation: a prospective study. Heart (British Cardiac Society) 2000;84:504–508. 87. Braden GL, Fitzgibbons JP, Germain MJ, Ledewitz HM: Hemoperfusion for treatment of N-acetylprocainamide intoxication. Ann Intern Med 1986;105:64–65. 88. Domoto DT, Brown WW, Bruggensmith P: Removal of toxic levels of N-acetylprocainamide with continuous arteriovenous hemofiltration or continuous arteriovenous hemodiafiltration. Ann Intern Med 1987;106:550–552. 89. Tecklenburg F, Thomas N, Webb S, et al: Pediatric ECMO for severe quinidine cardotoxicity. Pediatr Emerg Care 1997;13:111–113.

64

Diabetic Control Agents MICHAEL J. BURNS, MD ■ MICHAEL LEVINE, MD

At a Glance… ■

■

■

■

■

■

Overdose of hypoglycemic agents (e.g., insulin, sulfonylureas, and meglitinides) is likely to produce hypoglycemia, whereas overdose of antihyperglycemic agents (e.g., α-glucosidase inhibitors, biguanides, and thiazolidinediones) is unlikely to result in hypoglycemia. Biguanide-associated lactic acidosis is associated with a high mortality rate and should be suspected in any critically ill patient taking metformin. Biguanide-associated lactic acidosis occurs most commonly in patients with renal, hepatic, or cardiac dysfunction or alcohol abuse. After treating hypoglycemia due to sulfonylurea ingestion with dextrose, octreotide should be given to prevent rebound hypoglycemia. All patients with intentional sulfonylurea overdoses, sulfonylurea exposures in children, and sulfonylurea ingestions associated with symptomatic hypoglycemia should be admitted for a 12- to 24-hour period of observation. Patients with inadvertent insulin reactions can usually be safely discharged after several hours of emergency department observation, whereas patients with intentional insulin overdose should be admitted for inpatient observation.

INTRODUCTION AND RELEVANT HISTORY In recent years, the incidence of diabetes mellitus, especially type 2 diabetes, has dramatically increased in the United States and other Western countries. Currently, about 125 million people worldwide and 20 million Americans live with diabetes.1-4 In patients with type 2 or non–insulin-dependent diabetes mellitus (NIDDM) (also known as adult-onset diabetes), insulin resistance is the primary abnormality, which often necessitates treatment with an oral hypoglycemic agent to achieve euglycemia. In patients with type 1 or insulindependent diabetes (IDDM), impaired insulin secretion is the primary abnormality, which necessitates treatment with exogenous insulin to maintain euglycemia. Agents used to treat diabetes can be divided into two general categories: hypoglycemic agents (e.g., insulin, sulfonylureas, and meglitinides) and antihyperglycemic agents (e.g., biguanides, α-glucosidase inhibitors, and thiazolidinediones or glitazones).2 Although these agents may be used alone, they are often used in combination to treat patients with both types of diabetes mellitus (see Chapter 16). Insulin was first used to treat a patient with diabetes mellitus in 1921.3 Since that time, it has been the mainstay of treatment for type 1 diabetes patients and is some-

times part of the treatment regimen for those with type 2 diabetes. In 1942, it was observed that certain sulfonamides were associated with hypoglycemia in animals.2 Subsequently, a number of first-generation sulfonylurea compounds (i.e., tolbutamide, acetohexamide, tolazamide, and chlorpropamide) were created and marketed specifically for their hypoglycemic effect. In the 1950s, tolbutamide was the first sulfonylurea to be widely used for patients with type 2 diabetes.2 In the 1980s, the secondgeneration agents (i.e., glyburide, gliclazide, glipizide, and glimepiride) became commercially available. These agents are significantly more potent than the firstgeneration agents. Currently, chlorpropamide, glyburide, and glipizide account for most prescriptions of oral hypoglycemic agents. The biguanides, phenformin and buformin, became available for use as antihyperglycemic agents in the late 1950s.2 Phenformin was subsequently withdrawn from the market in the United States and Europe in 1977 because of an association with lactic acidosis; it is still available in other areas of the world.5 Metformin, another biguanide less frequently associated with lactic acidosis, became available for use in Europe in 1970 and the United States in 1995. Several other, novel classes of diabetes control agents were introduced in the late 1990s. In 1996, a new type of antihyperglycemic agent, referred to as an a-glucosidase inhibitor, became available for clinical use in the United States. Acarbose and miglitol are two agents in this class. In 1997, troglitazone was the first of the thiazolidinediones introduced to the U.S. market.6 Although troglitazone was removed from the U.S. market in 2000 because of its ability to cause a rare, idiosyncratic hepatocellular injury,7 other drugs in the glitazone class (i.e., rosiglitazone and pioglitazone) have become available and are frequently used. The meglitinides, repaglinide and nateglinide, are in the latest class of antihyperglycemic agents to obtain approval for clinical use in the United States. Repaglinide became available for use in 1997, and nateglinide became available in 2000. Common diabetes control agents that are currently available for clinical use are listed in Table 64-1.

EPIDEMIOLOGY Toxicity from diabetes control agents may be dose related, occurring after unintentional or intentional overdose, or idiosyncratic, occurring as unanticipated adverse effects during therapeutic administration. For the hypoglycemic agents, toxicity manifests largely as hypoglycemia or an overextension of the pharmacologic effects. Although 1019

1020


TABLE 64-1 Oral Hypoglycemic and Antihyperglycemic Agents DURATION OF ACTION (hr)*

CLASS

GENERIC NAME

TRADE NAME

α-Glucosidase inhibitors Biguanides Meglitinides

Acarbose Miglitol Metformin Nateglinide Repaglinide Acetohexamide Chlorpropamide Tolazamide Tolbutamide Glyburide Glipizide Glimepiride

Precose Glyset Glucophage Starlix Prandin Dymelor Diabinese Tolinase Orinase Micronase, Glynase, Diaβeta Glucotrol, Glucotrol XL Amaryl

2 2 1.5–4.9 2–4 1–3 12–18 24–72 16–24 6–12 18–24 16–24 24

Pioglitazone Rosiglitazone

Actos Avandia

16–24 12–24

Sulfonylureas (first generation) Sulfonylureas (second generation) Sulfonylureas (third generation) Thiazoldinediones

*The pharmacokinetic data are based on therapeutic dosing and may change after agent overdose. Adapted from Davis SN, Granner DK: Insulin, oral hypoglycemic agents, and the pharmacology of the endocrine pancreas. In Hardman JG, Limbrid LE, Gilman AG (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 1679–1714; Banting FG, Best CH, Collip JB, et al: Pancreatic extracts in the treatment of diabetes mellitus. Can Med Assoc J 1922;12:141–146; and Gerich JE: Oral hypoglycemic agents. N Engl J Med 1989;321:1123–1145.

agents from the antihyperglycemic class do not produce hypoglycemia when used alone, they can potentiate the hypoglycemic effect of the hypoglycemic agents when dosed with them. The toxic effects occur commonly but are infrequently reported to U.S. poison control centers. Infrequent reporting of toxicity is likely due to the familiarity of most clinicians with the toxicity from these agents and its treatment. Most exposures are unintentional (78%) and occur in adults (68%), whereas most deaths follow acute exposure with suicidal intent.8 In 2003, 12,736 diabetes control agent exposures were reported to U.S. poison centers, of which 4019 (32%) were due to sulfonylureas, 3811 (30%) to biguanides, 2914 (23%) to insulin, and 1586 (12%) to thiazolidinediones. The remainder of the exposures were uncharacterized.8 Major toxicity and death occurred in 2.5% and 0.2% of all diabetes control agent exposures, respectively.8

STRUCTURE AND CLASSIFICATION Sulfonylureas The sulfonylureas are classified into two main groups: the first-generation agents include chlorpropamide, tolbutamide, acetohexamide, and tolazamide; the secondgeneration agents include glyburide (or glibenclamide), glipizide, and glimepiride. Glimepiride has sometimes been referred to as a third-generation agent. Additional agents available outside the United States include gliclazide and gliquidone. The sulfonylureas are parasubstituted arylsulfonamides derived from sulfonic acid and urea. Sulfonylureas are closely related in structure to the sulfonamide antibiotics and thiazide diuretics. Differing side-chain substitutions on the para position of the benzene ring (R) and nitrogen on the urea moiety

(R1) result in varying potency and duration of action2 (Fig. 64-1). Second-generation agents are 100 to 150 times more potent than the first-generation agents owing to dif-fering binding affinity at the sulfonylurea receptor.2 Comparative characteristics of selected sulfonylureas are found in Table 64-2.

Biguanides The biguanides contain two guanidine molecules linked together with the elimination of an amino group. Metformin is N-1,1-dimethylbiguanide hydrochloride and is the only biguanide currently available in the United States (see Fig. 64-1). Phenformin and buformin are still available in other countries.

a-Glucosidase Inhibitors The α-glucosidase inhibitors are a relatively new class of drug used to treat diabetes. Acarbose, the first drug in this class approved for use in the United States, is a large, complex oligosaccharide derived from the microorganism Actinoplanes utahensis (see Fig. 64-1). Miglitol, which is considered a second-generation glucosidase inhibitor, has subsequently been approved. Meglitol is a small monosaccharide derivative that resembles glucose. Voglibose is currently pending U.S. Food and Drug Administration approval but is available in other countries.

Thiazolidinediones Two thiazolidinedione derivatives are available for clinical use in the United States: rosiglitazone and pioglitazone9 (see Fig. 64-1). The thiazolidinediones are structurally unrelated to other diabetes control agents. These drugs are also available in a combination with other agents, such as metformin.

CHAPTER 64

Diabetic Control Agents

1021

General Structure of Oral Sulfonylureas

J H

N

J

K K O

K

O

O

JSJN

R

R1

H

(Label)

J

J

J

K

H

KO

CH3

N

OK N

OH

H

OK Glimepiride

O

K

N

NH2

NJHNJH

H Metformin

Phenformin OH

HO O

O

JOH JOH J JOH HN

Acarbose

HO

OH

HO

OH

O

O OH OH HO OH

O

HCl

H

K

K

K

N

J

H

NH2

HO

O

K

N H

Pioglitazone

J

N

J

N

O

S

N

C4H4O4

NJH NJH

H3C

S N

K

J

OK N H

O

Rosiglitazone H3C

NH

Glipizide S

N

N

J

N

CH3

N

O

O SK NH O K NH

Chlorpropamide O O

J K J K K

N

NH

K

J J

O

O Tolbutamide

OK

H

J

CH3

C

K

K K

HN

O

JSJNJCJNJCH2CH2CH3

Cl

OKSKO

H

J

O

CH3

OH

HO N

Meglitol

OH

OH

J

J

J J J

J

S S A Chain Gly-Ile-Val-Glu-Gln-Cys-Cys-Ala-Ser-Val-Cys-Ser-Leu-Tyr-Gln-Leu-Glu-Asn-Tyr-Cys-Asn 5 10 15 21 S S

J

S S B Chain Phe-Val-Asn-Gln-His-Leu-Cys-Gly-Ser-His-Leu-Val-Glu-Ala-Leu-Tye-Leu-Val-Cys-Gly-Glu-Arg-Gly-Phe-Phe-Tyr-Thr-Pro-Lys-Ala 5 10 15 20 25 30 Insulin O CH3

CJOH

N H

O

Nateglinide

K

H O

OH

K

O

K

C

H N

K

H3C

O

N

Repaglinide

FIGURE 64-1 Selected structures for diabetes control agents.

Meglitinides

Insulin

The meglitinides are a novel class of insulin secretagogues that are structurally distinct from the sulfonylureas (see Fig. 64-1). They include repaglinide, which is a benzoic acid derivative, and nateglinide, which is a D-phenylalanine derivative.2

Insulin is an endogenous protein hormone consisting of two polypeptide chains (A and B chains) connected by two intersubunit disulfide bonds (see Fig. 64-1 and Chapter 16). The β cells of the pancreatic islets synthesize insulin initially as the polypeptide precursor,

1022


TABLE 64-2 Properties of Selected Sulfonylureas DURATION OF HYPOGLYCEMIC ACTION (hr)

THERAPEUTIC DAILY DOSE RANGE (mg)

RELATIVE POTENCY


First-Generation Agents Acetohexamide Chlorpropamide Tolbutamide Tolazamide

2.5 6 1 5

1–2 24–48 3–28 4–7

12–18 24–72 6–10 16–24

250–1500 100–500 500–3000 0.1–1000

Second-Generation Agents Glipizide Glyburide

100 150

1–5 1.5–3

16–24 18–24

2.5–40 6 1.25–20 7

Third-Generation Agents Glimepiride

150

2–8

12–24

1–4 1

DRUG

FREQUENCY OF HYPOGLYCEMIA (%)

4 9 3 4

Adapted from Davis SN, Granner DK: Insulin, oral hypoglycemic agents, and the pharmacology of the endocrine pancreas. In Hardman JG, Limbrid LE, Gilman AG (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 1679–1714; Gerich JE: Oral hypoglycemic agents. N Engl J Med 1989;321:1123–1145; and Baselt RC: Disposition of Toxic Drugs and Chemicals in Man, 7th ed. Foster City, CA, Biomedical Publications, 2004.

preproinsulin.2 In the rough endoplasmic reticulum, a portion of preproinsulin is cleaved to form proinsulin. Subsequent proteolytic cleavage of proinsulin in the Golgi apparatus forms insulin and a connecting segment or C peptide. Insulin is stored in secretory granules (along with equimolar amounts of the inert C peptide) in β cells until release into the circulation. Insulins may be classified according to their species of origin as porcine, bovine, or human and by their duration of action as short-, intermediate-, and long-acting (or regular, Lente, and Ultralente).2,10-12 Since 1921, insulin derived from beef or pork pancreas has been used therapeutically. During the past decade, however, human insulin has become the standard form of therapy. Human insulin is either derived enzymatically from pork insulin or produced from Escherichia coli using recombinant deoxyribonucleic acid techniques.2 More recently, insulin analogs have also become commercially available.13 Insulin is prepared as an injectable solution for subcutaneous or intravenous administration. Doses and concentrations of insulin are expressed in units (U). Short-acting and rapid-acting insulins available for use include the readily soluble, regular (crystalline zinc insulin) formulation or the analogs lispro and aspart.2 Intermediate-acting insulins include NPH (neutral protamine Hagedorn, an isophane suspension) and Lente (zinc suspension) formulations. Long-acting insulin preparations include Ultralente (extended insulin zinc suspension), protamine zinc suspension, and the analog glargine. The types of insulin and their pharmacokinetic properties are listed in Table 64-3.

PHARMACOLOGY AND PATHOPHYSIOLOGY Sulfonylureas The major mechanism of action of the sulfonylureas is to stimulate endogenous insulin secretion by pancreatic

β cells. The sulfonylureas bind to a specific sulfonylurea receptor type 1 (SUR1) of adenosine triphosphate (ATP)–sensitive potassium channels (KATP). These potassium channels are located on the plasma membrane of β cells. Sulfonylurea binding to the receptor results in closure of the ATP-sensitive potassium channel, membrane depolarization, opening of voltage-sensitive calcium channels, and subsequent exocytic release of insulin. Second-generation agents have higher binding affinity and are, thus, more potent in their clinical effects. Other minor effects of sulfonylureas include reduced hepatic gluconeogenesis and clearance of insulin, suppressed glucagon and somatostatin secretion, and enhanced peripheral tissue sensitivity to insulin (stimulate synthesis of glucose transporters).2 The extrapancreatic effects of sulfonylureas are not likely clinically significant in vivo.2,14,15

Biguanides The biguanides reduce fasting blood glucose levels and insulin concentrations by suppressing basal hepatic gluconeogenesis and improving peripheral tissue (i.e., fat, muscle) insulin sensitivity, thus enhancing peripheral insulin-mediated glucose uptake.2 The biguanides potentiate insulin and are only effective in the presence of this hormone. Specifically, the biguanides increase the binding of insulin to its receptors, increase tyrosine kinase activity, and promote the synthesis and translocation of glucose transporters to the cell surface. The biguanides may also decrease blood glucose levels by impairing glucose absorption from the small intestine.16 The biguanides are not insulin secretagogues and do not cause hypoglycemia, even at large doses.2 The biguanides also do not alter secretion of glucagon, cortisol, or somatostatin. Biguanides reduce blood triglycerides and free fatty acids. The pathophysiology of lactic acidosis from biguanides is largely due to inhibition of gluconeogenesis.17-22 At supratherapeutic levels, biguanides inhibit pyruvate

CHAPTER 64


1023

TABLE 64-3 Properties of Insulin Preparations Currently Available* TYPE OF INSULIN

BRAND NAME

TIME TO ONSET (hr)

TIME TO PEAK EFFECT (hr)

Rapid Regular (soluble crystalline zinc) Lispro Aspart

Novolin R Humalog NovoLog

0.5–1 0.25 0.17–0.33

1.5–4 0.5–1.5 1–3

DURATION OF ACTION (hr)

5–8 2–5 3–5

Intermediate NPH (isophane insulin suspension) Insulin zinc suspension

Novolin N

1–1.5

4–12

24

Lente

1–2

6–12

18–24

Slow Extended insulin zinc suspension Glarginine

Ultralente Lantus

4–8 2–5

16–18 5–24

20–36 18–24

*The pharmacokinetic data listed are for therapeutic doses with subcutaneous administration; times will vary with route of administration (intravenous versus subcutaneous administration and dose (therapeutic versus excessive doses). NPH, neutral protamine Hagedorn. Adapted from Davis SN, Granner DK: Insulin, oral hypoglycemic agents, and the pharmacology of the endocrine pancreas. In Hardman JG, Limbrid LE, Gilman AG (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 1679–1714; Hirsch IB: Drug therapy: insulin analogues. N Engl J Med 2005;352:174–183; Baselt RC: Disposition of Toxic Drugs and Chemicals in Man, 7th ed. Foster City, CA, Biomedical Publications, 2004; and Insulin preparations: drug information. UpToDate. Version 13.2. Accessed July 2, 2005.

carboxylase, the enzyme responsible for converting pyruvate to oxaloacetate (first step of gluconeogenesis). Elevations of pyruvate subsequently lead to lactate accumulation. Any condition that leads to elevated blood concentrations of biguanides (i.e., biguanide overdose, impaired excretion from hepatic and renal dysfunction) may precipitate lactate accumulation. Any medical condition that impairs lactate clearance (i.e., hepatic, renal, and cardiac dysfunction) will also lead to lactate accumulation and increase the risk for lactic acidosis. In addition, ethanol facilitates the accumulation of lactate; ethanol inhibits gluconeogenesis itself, and its metabolism results in an accumulation of reduced nicotinamide adenine dinucleotide (NADH), which inhibits conversion of lactate to pyruvate. Biguanide-induced lactic acidosis is primarily type B, or that which occurs in the absence of tissue hypoxia or hypoperfusion, and results from impaired clearance of lactate. Type A lactic acidosis, or that which occurs in the presence of hypoxia or hypoperfusion, is from the increased production of lactate. Type A lactic acidosis may also be operative in the lactic acidosis induced by biguanides. Respiratory, cardiac, and renal dysfunction or polydrug overdoses that produce seizures, hypoxia, or tissue hypoperfusion lead to lactic acid accumulation. In addition, phenformin, unlike metformin, has the added ability to inhibit cellular oxidative phosphorylation directly and increase the tissue generation of lactate.20,22,23

α-Glucosidase Inhibitors α-Glucosidase inhibitors have a unique mechanism of action, in that they are the only class of drug that is not directly designed to combat a specific pathophysiologic defect of type 2 diabetes.6 Rather, these agents competitively inhibit the activity of α-glucosidase, a brushborder enzyme responsible for breaking down disac-

charides (e.g., sucrose, maltose) and polysaccharides (e.g., starch) into monosaccharide. Therefore, the αglucosidase inhibitors delay intestinal glucose absorption and diminish postprandial glucose elevations.24 Acarbose also competitively inhibits the action of pancreatic αamylase. These drugs are not insulin secretagogues and do not result in hypoglycemia.

Thiazolidinediones The thiazolidinediones improve insulin sensitivity (largely in adipose tissue) and result in a reduction of fasting plasma glucose, insulin, and free fatty acids. These agents regulate gene expression and are associated with a delay of 4 to 12 weeks from initiation of dosing to therapeutic effects. The thiazolidinediones are selective agonists for the nuclear hormone receptor known as peroxisome-proliferation–activated receptor-g (PPARγ).2 After binding, there is activation of transcription of a variety of genes that regulate lipid and carbohydrate metabolism.6,25 Thus, similar to biguanides and αglucosidase inhibitors, the thiazolidinediones do not stimulate the pancreatic β cells to secrete more insulin.

Meglitinides Similar to sulfonylureas, meglitinides are insulin secretagogues that directly stimulate first-phase insulin release in pancreatic β cells. Although the meglitinides bind to a different receptor than the sulfonylureas, their mechanism of action is identical; their binding results in closure of KATP channels, membrane depolarization, opening of voltage-sensitive calcium channels, and subsequent exocytic release of insulin.2,26 Unlike the sulfonylureas, however, the meglitinides do not stimulate insulin secretion in the absence of glucose. In addition, these agents (particularly nateglinide) induce a more rapid but less sustained secretion of

1024


insulin than sulfonylureas.6 Although the magnitude of the glucose-lowering effects of repaglinide is similar to that of the sulfonylureas, it is associated with a significantly reduced risk for delayed hypoglycemia owing to a shorter duration of action.10 As compared with repaglinide, nateglinide has a higher binding affinity and quicker offset kinetics at the KATP channel. Thus, nateglinide has the more rapid onset and offset of insulinotropic effects of the two meglitinides.

Insulin Insulin stimulates the uptake, utilization, and storage of glucose, amino acids, and fatty acids by peripheral tissues2 (see Chapter 16). As an anabolic hormone, insulin impairs the catabolism of glycogen, proteins, and fats in all tissues. Insulin release by the pancreas is primarily regulated by and inversely correlated to blood glucose concentrations. Once released into the systemic circulation, insulin binds to specific membrane-bound receptors in peripheral tissues, which are ligandactivated protein kinases. Insulin binding stimulates tyrosine kinase activity, receptor autophosphorylation, and a cascade of phosphorylation and dephosphorylation reactions intracellularly, which serve to activate other intracellular signaling molecules.2 The downstream effects of insulin binding are multiple. One such effect is the translocation of glucose transport proteins to the cell surface and subsequent enhanced glucose uptake by peripheral tissues (e.g., skeletal muscle and adipose tissue). In addition to stimulating the uptake of glucose by peripheral tissues, insulin also impairs hepatic gluconeogenesis and glycogenolysis. Insulin further promotes hypoglycemia by inhibiting protein degradation and lipolysis. The usual substrates for hepatic gluconeogenesis (e.g., alanine, glutamine, pyruvate, glycerol, nonesterified fatty acids) are reduced in the presence of insulin. In addition to its effects on carbohydrate, protein, and lipid metabolism, insulin promotes cellular uptake of potassium and magnesium.

PHARMACOKINETICS Sulfonylureas The sulfonylureas are available for oral administration only. These drugs are well absorbed from the gastrointestinal (GI) tract, with bioavailabilities greater than 80%.27 Food and hyperglycemia reduce absorption. Once absorbed, all sulfonylureas are extensively (90% to 99%) bound to plasma proteins (predominantly albumin) and have small volumes of distribution (about 0.2 L/kg).2,27 With the exception of acetohexamide, all sulfonylureas are metabolized in the liver to inactive or less active metabolites; metabolites and small amounts of unchanged drug are eliminated in the urine. Acetohexamide is metabolized to hydroxyhexamide, which is more active and more slowly eliminated than the parent drug. Up to 20% of chlorpropamide is excreted unchanged in the urine.2

With therapeutic dosing, the hypoglycemic effects of these agents begin within 1 to 2 hours of oral dosing and peak by 4 to 6 hours; the first-generation agents may have a more delayed time to peak effect. Relative potencies, elimination half-lives, duration of hypoglycemic action, and therapeutic dose range are found in Table 64-2. With therapeutic dosing, the first-generation agents have variable elimination half-lives and a long duration of hypoglycemic action (12 to 24 hours), whereas the second-generation agents have short elimination halflives and a long duration of hypoglycemic action (12 to 24 hours).2,27 After overdose, the duration of hypoglycemic action may last days.11

Biguanides After oral administration, metformin has a bioavailability of 30% to 60%; significant concentrations (27%) of unabsorbed drug are recovered from feces.27 Peak plasma concentrations of metformin occur within 1 to 3 hours of a therapeutic dose. The antihyperglycemic effects of metformin begin in 1 hour and last about 12 hours after standard oral dosing. Metformin is not bound to plasma proteins, has a volume of distribution of 3.7 L/kg, and is largely excreted unchanged in the urine (50%) by both glomerular filtration and tubular secretion. At therapeutic doses, the plasma elimination half-life is estimated at 1.5 to 4.9 hours in subjects with normal renal function.28 Geriatric patients or those with renal impairment have prolonged elimination half-lives. The recommended daily oral doses for normal adult patients range from 500 to 2500 mg, either as a single dose of the extended-release preparation or twice daily with the normal-release preparation. Metformin can be used either as a single agent or in combination with a sulfonylurea or insulin in the management of diabetes.

α-Glucosidase Inhibitors Less than 2% of acarbose is absorbed from the GI tract, and more than 50% is excreted unchanged in the feces. Acarbose is metabolized in the GI tract by intestinal bacteria and digestive enzymes. Acarbose is mostly absorbed (34% of a dose) as metabolites of the parent drug. Elimination half-life of acarbose activity is normally about 2 hours in adults. Thus, bioaccumulation of the drug does not occur with dosing three times a day. Unlike acarbose, which has minimal absorption from the small intestine, miglitol is well absorbed from the small intestine. Both of these drugs have a small volume of distribution, and little to no protein binding at therapeutic doses. Miglitol is excreted unchanged by the kidney. The recommended oral dose for adult patients ranges from 25 to 100 mg three times daily, just before each meal.2

Thiazolidinediones Rosiglitazone and pioglitazone are rapidly absorbed (peak blood concentrations within 1 to 2 hours), with a bioavailability of 99% and 50%, respectively. These drugs

CHAPTER 64

are highly protein bound (99%) and have similar small volumes of distribution (0.2 to 1.0 L/kg) and elimination half-lives (2.7 to 7 hours). Both drugs are extensively metabolized by the liver cytochrome P-450 system. Pioglitazone is metabolized by CYP2C8 to metabolites with pharmacologic activity similar to and elimination half-lives longer than the parent drug. Rosiglitazone is metabolized by CYP3A4 to very weakly active compounds. No clinically significant drug interactions have been described with the thiazolidinediones.9,29 Although both thiazolidinediones are absorbed within 2 hours of oral administration, maximal clinical effect is not observed for 6 to 12 weeks. Pioglitazone is dosed from 15 to 45 mg once daily in adults, whereas rosiglitazone is administered as 4 to 8 mg daily in one or two divided doses.

Meglitinides The meglitinides are rapidly absorbed from the GI tract, with peak blood concentrations observed within 0.5 to 1 hour of an oral therapeutic dose. The onset and duration of clinical effects are rapid, occurring within 1 and 4 hours, respectively. Bioavailability is about 60% for both agents. These drugs are highly protein bound (more than 98%) and have small volumes of distribution (0.4 L/kg). In addition, both drugs are metabolized by CYP3A4 to inactive metabolites.2 Elimination half-lives are only 1 to 2 hours.26 Drugs that enhance or inhibit CYP3A4 enzyme may decrease or increase the clinical effects of these drugs, respectively.2,30 Small amounts of each drug are excreted by the kidney unchanged (10% to 16%).2 The recommended adult dose is 60 to 120 mg for nateglinide or 0.5 to 4 mg for repaglinide, three times daily, each dose administered within 10 minutes of a meal.


patients with diabetic autonomic neuropathy or in those who are receiving β-blocker therapy. Glucose is the principal energy substrate for the brain. The brain does not produce glucose and can only store a few minutes’ supply. Therefore, the brain is extremely sensitive to hypoglycemia. Concentrations of circulating glucose below 3 mmol/L (54 mg/dL) impair cerebral function, whereas more severe and prolonged hypoglycemia can cause convulsions, permanent neurologic damage, or death.32 The onset of hypoglycemia after acute sulfonylurea overdose occurs after a variable time interval; the latency is dependent on the size of the ingestion, the particular agent involved, and individual host factors (i.e., age, comorbid illness [hepatic or renal disease], presence of insulin resistance). It usually occurs within 6 to 8 hours of ingestion but may be delayed for 16 to 18 hours.33,34 In one study of sulfonylurea ingestion in children, 50% and 96% of patients developed hypoglycemia within 2 and 8 hours, respectively.34 A single tablet is sufficient to produce symptomatic hypoglycemia in children.33,34 The duration of hypoglycemia is dose related and ranges from several hours to several days. In one case, hypoglycemia lasted for 27 days after intentional chlorpropamide overdose.11 The signs and symptoms of sulfonylurea-induced hypoglycemia are identical to those associated with hypoglycemia from other causes. Signs and symptoms are manifestations of neuroglycopenia or are the consequence of the autonomic response to hypoglycemia (Box 64-1). Long-lasting or permanent neurologic dysfunction may occur if hypoglycemia is severe or prolonged before treatment.

BOX 64-1

SIGNS AND SYMPTOMS OF HYPOGLYCEMIA

Central Nervous System Effects (Neuroglycopenia)

TOXICOLOGY: CLINICAL MANIFESTATIONS AFTER OVERDOSE Sulfonylureas The principal effect of overdose of any of the sulfonylurea agents, whether in a diabetic or nondiabetic individual, is hypoglycemia. Although hypoglycemia has been defined in absolute terms as a plasma glucose concentration of less than 2.78 mmol/L (50 mg/dL),31 it is perhaps more usefully defined in functional terms as a depressed concentration of blood or plasma glucose producing evidence of a physiologic counter-regulatory hormone response or evidence of neurologic dysfunction (neuroglycopenia). As the plasma glucose concentration decreases to about 4 mmol/L (72 mg/dL), there is an increase in the secretion of counter-regulatory hormones (e.g., glucagon, epinephrine, growth hormone, and cortisol) and activation of the autonomic nervous system. If the plasma glucose concentration reaches 3.2 mmol/L (58 mg/dL), this increase in autonomic activity is normally of a sufficient magnitude to result in symptoms. This response may be modified in

1025

Lethargy to coma Dizziness Slurred speech, blurred vision, ataxia Irritability, anxiety, agitated delirium Headache Confusion, cognitive dysfunction, memory loss Seizures (single or multiple; focal or generalized) Focal neurologic deficits Hallucinations, altered personality Generalized weakness Paresthesias Autonomic and Other Effects

Diaphoresis Tachycardia, palpitations, tachyarrhythmias Syncope Hypertension Hunger Nausea, vomiting Tremor Piloerection Tachypnea Peripheral vasoconstriction, pallor Hypothermia

1026


Biguanides

Insulin

Acute biguanide overdose is usually well tolerated. GI effects occur most commonly and include nausea, vomiting, anorexia, hematemesis, metallic taste, abdominal pain, and diarrhea.35-37 Although hypoglycemia virtually never occurs in association with therapeutic doses of biguanides, it has rarely been described after overdose with these agents.38 Biguanide-induced lactic acidosis is the most serious complication of biguanide treatment. It is most commonly associated with therapeutic dosing of biguanides (see “Adverse Effects”) but has also been described after acute, large, intentional overdose in adults.39-46 Lactic acidosis has not been described after accidental ingestion of 1 or 2 tablets of metformin in children.47 Patients with biguanideassociated lactic acidosis typically present with relatively nonspecific symptoms, such as vomiting, somnolence, agitation, nausea, epigastric pain, anorexia, hyperpnea, lethargy, diarrhea, and thirst.22 Coma, hypothermia, seizures, and cardiovascular collapse may rapidly ensue.

Insulin overdose manifests primarily as hypoglycemia (see Box 64-1). Other effects include various metabolic abnormalities, such as hypokalemia, hypomagnesemia, hypophosphatemia, and hypocalcemia. Cardiac effects are uncommon but include tachyarrhythmias (i.e., atrial fibrillation, premature atrial and ventricular contractions, and ventricular tachycardia), bradyarrhythmias (i.e., sinus bradycardia, heart block), repolarization abnormalities on the electrocardiogram (i.e., T-wave flattening, ST-T changes, and QTc prolongation), angina and myocardial infarction, congestive heart failure, and hypertension. Hypothermia may occur with prolonged hypoglycemia. As for sulfonylureas, prolonged hypoglycemia may be associated with prolonged or permanent neurologic deficits.50 Insulin-induced hypoglycemia occurs very commonly as an unintentional adverse effect (see “Adverse Effects”) but may also occur as an intentional overdose (selfpoisoning with suicidal intent, poisoning of others with homicidal intent, or as part of Munchausen syndrome or Munchausen syndrome by proxy). Although intentional insulin overdose is uncommon, it likely occurs more frequently than is recognized or reported. In 2003, 2914 insulin exposures were reported to U.S. poison control centers, of which 493 (17%) were categorized as intentional.8 The time of onset and duration of hypoglycemia that occur with insulin overdose depend on the type and dose of insulin preparation used, the blood glucose of the patient, the caloric intake of the patient just before and after the overdose, and the presence of insulin antibodies (insulin resistance) in the patient. The onset of hypoglycemia may be delayed after overdose with extended-release preparations (e.g., NPH and Lente).51 The duration of hypoglycemia may be prolonged and last for days after massive subcutaneous overdose of insulin.52

α-Glucosidase Inhibitors Overdose of the α-glucosidase inhibitors has not been reported in the literature. Signs and symptoms of overdose would be expected to include nausea, abdominal bloating and pain, flatulence, and diarrhea. Because these agents do not stimulate endogenous insulin release, they should not produce hypoglycemia with overdose.

Thiazolidinediones There are no published data describing the effects of overdose with the thiazolidinediones. Supratherapeutic doses of these agents ingested over a week have not been associated with acute toxicity.3 Because this class of drugs does not stimulate insulin secretion, hypoglycemia is not expected to occur with overdose.

Meglitinides As insulin secretagogues, meglitinides are expected to produce hypoglycemia after overdose. Unlike the sulfonylureas, however, these agents have a very short duration of action. Thus, the hypoglycemic effect should not be delayed in onset or prolonged in effect. Limited clinical overdose experience with meglitinides, however, precludes confident clinical predictions at this time. Nakayama and colleagues reported a case of a 30-yearold nondiabetic woman who presented to the emergency department 1 hour after ingesting 3420 mg of nateglinide in a suicide attempt.48 Her initial blood glucose was 2 mmol/L (36 mg/dL) 1 hour after ingestion, which was treated with 50 mL of 50% dextrose. Four hours after ingestion, rebound hypoglycemia occurred, which necessitated further dextrose administration. The patient remained hypoglycemic for 6 hours after nateglinide ingestion. Surreptitious doses of repaglinide have been associated with severe hypoglycemia in an 18-year-old man.49

ADVERSE EFFECTS Sulfonylureas Sulfonylureas are generally well tolerated; adverse effects occur in 2% to 4% of patients, with less than 2% of patients discontinuing therapy because of side effects.15,53 As for sulfonylurea overdose, the most common and severe complication of sulfonylurea therapeutic dosing is hypoglycemia. Hypoglycemia is simply an extension of the therapeutic objective and effects of these agents. Hypoglycemia occurs in 2% to 4% of patients; severe hypoglycemia requiring patient hospitalization occurs in 0.4 cases per 10,000 patient-years of treatment.53,54 Clinically significant hypoglycemic reactions occur more commonly with agents that have a longer duration of action2 (see Table 64-2). Risk factors for sulfonylureainduced hypoglycemia include an age older than 60 years, impaired renal and hepatic function, poor nutrition, and multidrug therapy.55,56 The use of other diabetes control agents may result in inadvertent hypoglycemia from syn-

CHAPTER 64

ergistic effects (pharmacodynamic interaction). Alternatively, hypoglycemia may occur with the coadministration of drugs that interfere with sulfonylurea protein binding, metabolism, or excretion (pharmacokinetic interaction). The concurrent use of sulfonylureas with the histamine-2 (H2) receptor antagonists cimetidine and ranitidine, or with the antifungal azole derivatives ketoconazole and fluconazole, is associated with increased incidence of hypoglycemia.29 In addition, the antibiotics doxycycline, ciprofloxacin, and gatifloxacin have been associated with increased incidence of hypoglycemia in patients taking sulfonylureas.57-59 Furthermore, clofibrate, dicumarol, sulfonamides, sulfamethoxazole, angiotensinconverting enzyme inhibitors, nonsteroidal anti-inflammatory drugs (e.g., phenylbutazone, salicylates), β blockers, and ethanol may potentiate the hypoglycemic activity of these agents.2,29,60 Other adverse effects of sulfonylureas include hematologic (e.g., hemolytic anemia, bone marrow aplasia) and dermatologic (e.g., rashes, pruritus, erythema nodosum, erythema multiforme, and exfoliative dermatitis) complications. These effects are rare hypersensitivity reactions and usually occur during the first 6 weeks of therapy. Their incidence is less than 0.1% with all agents. GI side effects include nausea, vomiting, cholestatic jaundice, and liver function test abnormalities; they occur with a frequency of 1% to 3%. Weight gain is common in patients who achieve improved glycemic control and is probably the result of reduced caloric loss associated with the diminution in glycosuria.9,61 Chlorpropamide, unique among the sulfonylureas, has been associated with a disulfiram-type reaction. Some sulfonylureas (e.g., chlorpropamide, glyburide, and glipizide) may produce hyponatremia by inducing increased renal sensitivity to antidiuretic hormone (syndrome of inappropriate antidiuretic hormone, or SIADH).2,9,53 The sulfonylureas may be associated with an increased risk for cardiovascular mortality, but the data supporting this theory are conflicting.2,62 In addition, some sulfonylureas can precipitate acute porphyria in susceptible individuals.9

Biguanides When used at therapeutic doses, the most common side effects associated with metformin are GI and include anorexia, nausea, abdominal discomfort, and diarrhea. These symptoms occur in up to 20% of patients shortly after initiating therapy with metformin, but only rarely persist.2 Nonetheless, about 10% of patients cannot tolerate the drug at any dose.9 A metallic taste can also be observed in about 3% of patients taking metformin.63 The most serious adverse effect of metformin is lactic acidosis, which occurs in 0.06 cases per 1000 patientyears.17 The incidence is significantly less with metformin therapy than with phenformin. Lactic acidosis is defined as a metabolic acidosis due to an accumulation of lactic acid in the blood in excess of 5 mmol/L with an accompanying blood pH of less than 7.35.18,19 Biguanideassociated lactic acidosis is initially a type B lactic acidosis (not associated with tissue hypoxia or hypoperfusion).

BOX 64-2 • • • • • • • • •


1027

CONTRAINDICATIONS TO BIGUANIDE THERAPY

Renal impairment (plasma creatinine > 1.5 mg/dL [132 μmol/L] for men, > 1.4 mg/dL [124 μmol/L] for women) Cardiac or respiratory failure of sufficient magnitude to cause central hypoxia or reduced peripheral perfusion History of lactic acidosis Acute or chronic metabolic acidosis Severe infection that could lead to decreased tissue perfusion Liver dysfunction (demonstrated by abnormal liver function tests) Alcohol abuse with binge drinking sufficient to cause acute hepatotoxicity Use of iodinated radiographic contrast material (within 48 hours) Pregnancy

Adapted from Bailey CJ, Turner RC: Metformin. N Engl J Med 1996;334:574–579.

Type A lactic acidosis, however, is often superimposed on type B lactic acidosis in patients who are critically ill. Biguanide-associated lactic acidosis has a mortality rate of 12% to 50%.22 When this complication occurs at therapeutic doses, it usually is in the context of having been prescribed in patients for whom the drug was initially contraindicated (Box 64-2). It appears that a critical blood level of biguanide, as yet undefined, is required to produce the metabolic abnormalities that lead to lactic acidosis.64 The listed contraindications, especially impaired renal function, are likely to result in impaired elimination and excessive blood levels of metformin, thus increasing the likelihood of the critical blood level and accumulation of lactic acid (see “Pharmacology and Pathophysiology”). As already stated, significant lactic acidosis may also occur after metformin overdose in the absence of established risk factors.39,40 In patients with metformin-associated lactic acidosis, there are frequently additional factors that increase blood lactate concentrations, such as major illness causing tissue hypoperfusion or liver disease.28,65 Thus, an elevated plasma lactate concentration in someone who regularly takes metformin may primarily represent an underlying systemic process (e.g., septic shock) and not a direct complication of metformin therapy.28 Iodinated contrast materials may create a predisposition to metformin-induced lactic acidosis. Current consensus recommendations are to withhold metformin for 24 to 48 hours before a planned procedure that necessitates administration of iodinated contrast. The metformin should not be reinstituted until at least 48 hours after the iodinated contrast administration.66 Finally, treatment with metformin should be withheld if plasma lactate levels exceed 3 mmol/L (more than 3 mEq/L).2

a-Glucosidase Inhibitors Adverse effects associated with the α-glucosidase inhibitors are primarily GI and include dose-related increases in flatulence, abdominal discomfort and bloating, and diarrhea.2 Adverse effects tend to diminish with continued use.67 Thus, side effects can be minimized by

1028


starting with low doses and titrating the dose upward at 4- to 8-week intervals.2 Although approved for monotherapy, this class of drug rarely is used alone owing to its mild efficacy. More frequently, the α-glucosidase inhibitors are used in combination with sulfonylureas or insulin. This class of drugs is associated with dosedependent hepatotoxicity (elevations of hepatic transaminases).68 Hepatic transaminase elevations are usually asymptomatic and reversible with drug cessation.

Thiazolidinediones The thiazolidinediones are relatively well tolerated. Side effects, when they occur, include anemia, edema, headache, myalgia, and weight gain. On average, the thiazolidinediones cause an increase of 2 to 3 pounds for every 1% decrease in glycosylated hemoglobin value.25 Thus, these agents should be given cautiously, if at all, to patients with advanced heart failure or anemia. In Europe, the presence of congestive heart failure is considered a contraindication to the use of thiazolidinediones.9 Idiosyncratic hepatotoxicity has rarely been associated with pioglitazone or rosiglitazone therapy.69,70 The presence of hepatic dysfunction is considered a contraindication to treatment with thiazolidinediones. Hypoglycemia does not occur with thiazolidinedione monotherapy but has been described during combination therapy with sulfonylureas or insulin.

Meglitinides The most common adverse effects from meglitinides include GI symptoms, weight gain, and hypoglycemia. Repaglinide has an incidence of adverse reactions similar to that observed with sulfonylureas, whereas nateglinide appears to be better tolerated.2,6,26,30 Nateglinide appears to have a hypoglycemic effect that is more mild.30

Insulin The primary adverse reaction from insulin is hypoglycemia.2 Hypoglycemia may occur from an increase in insulin dose, change in insulin preparation, decreased food intake, increased exercise, or impaired insulin clearance (in those with renal dysfunction). The time of onset of hypoglycemia and time to peak hypoglycemic effect after therapeutic doses of insulin have been established and are listed in Table 64-3. The duration of hypoglycemia is less than that observed with insulin overdoses. Hypokalemia, hypomagnesemia, and hypophosphatemia may also occur as adverse effects of insulin, particularly if insulin is administered at high therapeutic doses.

DIAGNOSIS The diagnosis of acute toxicity from diabetes control agents often occurs in the setting of symptomatic hypoglycemia and a positive history of exposure. Hypoglycemia should be considered in every patient who

TABLE 64-4 Dosing of Dextrose AGE

DEXTROSE

Adults

0.5–1.0 g/kg or 1–2 mL/kg D-50 (50% dextrose) 2–4 mL/kg D-25 5–10 mL/kg D-10

Children Infants/newborns

presents after a seizure or with an alteration in mental status. The diagnosis should be rapidly excluded or confirmed on the basis of a bedside test for blood glucose concentration. When this cannot be done rapidly, or when the result is equivocal, an intravenous bolus of 50% dextrose (0.5 to 1 g/kg or 1 to 2 mL/kg D-50-W; Table 64-4) should be administered empirically. The diagnosis of hypoglycemia typically requires symptoms and a positive response to supplemental dextrose. A lack of response, however, does not exclude the diagnosis because prolonged, severe hypoglycemia can result in permanent neurology deficits that will not respond to correction of hypoglycemia. If a diagnosis of hypoglycemia is made, a patient history may help to establish whether toxicity from a diabetes control agent (e.g., sulfonylurea, meglitinides, insulin) is the likely cause. If the history does not suggest the diagnosis, other drug-associated and medical causes of hypoglycemia should be considered and addressed (Box 64-3). Specific drug levels are rarely necessary to make the diagnosis. When no explanation for hypoglycemia is initially apparent, however, measurements of serum insulin, C peptide, proinsulin, and sulfonylurea concentrations and a urine screen for sulfonylureas may be helpful to establish a diagnosis, particularly in the setting of accidental, surreptitious, or felonious poisoning. Standard blood and urine toxic screens should be performed to rule out the presence of other drugs associated with hypoglycemia (e.g., ethanol, salicylate). Because therapeutic doses of sulfonylureas can produce hypoglycemia, the qualitative presence of this class of agents in blood or urine of patients not regularly prescribed these drugs is sufficient to confirm the diagnosis. In the presence of exogenous insulin injection, C peptide and proinsulin levels are low. In the presence of sulfonylurea or meglitinide toxicity (insulin secretagogues) or an insulinoma, the proinsulin, insulin, and C-peptide levels should be elevated. Insulinomas can be differentiated from ingestion of insulin secretagogues by the presence of very high proinsulin levels in patients with insulinomas, with an increased ratio of proinsulin to insulin.71 The diagnosis of biguanide-induced lactic acidosis should be suspected in any patient receiving therapeutic or taking excessive doses of biguanides who becomes ill. Laboratory analysis in these patients should include measurements of blood glucose, blood urea nitrogen, creatinine, electrolytes, and lactate and urinalysis. The diagnosis is confirmed by documentation of an aniongap metabolic acidosis and an elevated serum lactate level (more than 5 mmol/L). For patients with an elevated

CHAPTER 64

BOX 64-3

CAUSES OF HYPOGLYCEMIA

Gastrointestinal

Diarrhea (especially in children) Pancreatitis Postgastrectomy Short gut syndrome Hepatic

Alcoholism Cirrhosis Fulminant hepatic failure Reye’s syndrome Metabolic/Endocrine

Adrenal insufficiency Beckwith-Wiedemann syndrome Carnitine deficiency Fructose intolerance Galactose intolerance Glucagon deficiency Glycogen storage diseases Growth hormone deficiency Hyperinsulinemia (neonates of diabetic mothers) Hypothyroidism Panhypopituitarism (Sheehan’s syndrome) Miscellaneous

Acquired immunodeficiency syndrome (AIDS) Autoimmune disorders Pregnancy Oncologic

Insulinoma Extrapancreatic/mesenchymal neoplasm


1029

TREATMENT Overview Treatment of diabetes control agent poisoning is largely directed at evaluating for and treating hypoglycemia. Although patients with significant central nervous system or respiratory depression may sometimes need airway protection, breathing assistance, and cardiovascular support, correction of hypoglycemia may be sufficient to normalize neurologic or cardiopulmonary function. In addition to fingerstick glucose determination and dextrose administration as necessary, supplemental oxygen, continuous pulse oximetry, and parenteral thiamine and naloxone should be considered in patients with altered mental status or seizures. All symptomatic patients should have an intravenous line established and continuous cardiac monitoring performed. Frequent neurologic evaluation and vital sign and fingerstick determinations should be performed in the initial several hours of evaluation. Fluid and electrolyte abnormalities should be corrected as necessary. Therapy (e.g., antidotal treatment, enhanced elimination) that is unique to each class of agents is discussed below. After initial patient stabilization, GI decontamination is recommended for patients who present after acute oral overdose of most diabetes control agents. Singledose administration of activated charcoal (1 g/kg orally or by nasogastric tube) is the preferred method of GI decontamination. Orogastric lavage is not routinely recommended because the risk for death after acute diabetes control agent overdose is very low. If performed, gastric lavage should be followed by the administration of activated charcoal.

Systemic Illness

Burns Hyperthermia Severe renal or cardiac dysfunction Sepsis Starvation (or anorexia nervosa) Toxin

Ackee fruit (hypoglycin A) β-Adrenergic blockers (especially propranolol) Disopyramide Ethanol (especially in children) Insulin Meglitinides Mushrooms Opioids Pentamidine Quinine/quinidine Salicylates Sulfonylurea Sulfonamides Valproic acid

anion gap or blood lactate level, an arterial blood gas should be performed. The hallmark of biguanideassociated lactic acidosis is severe acidosis without evidence of hypotension or hypoxia.

Sulfonylurea Poisoning Treatment with dextrose should be reserved for patients with symptomatic hypoglycemia and withheld from patients with low blood glucose values in the absence of symptoms. The administration of dextrose to an asymptomatic patient with numeric hypoglycemia may necessitate further treatment with dextrose and force a prolonged period of observation. Even in the absence of sulfonylurea exposure, exogenous dextrose administration can stimulate further insulin secretion, particularly when associated with transient hyperglycemia (overshoot). Rebound euglycemia or hypoglycemia often occurs and requires further treatment with dextrose. This pattern of cyclical hypoglycemia often results in a longer period of observation that would not have been necessary if dextrose had not been administered initially. Treatment with oral dextrose may be sufficient for patients with mild hypoglycemia, whereas those with significant symptoms should receive an intravenous bolus of concentrated dextrose (see Table 64-4). It is advisable to give no more dextrose than is necessary to achieve euglycemia; overshoot may precipitate rebound hypoglycemia. Frequent fingerstick blood glucose determinations help to guide initial and continued dextrose supplementation. Once euglycemia is achieved, patients

1030


should be given a meal if oral intake is feasible and not contraindicated. A continuous infusion of 10% to 20% dextrose in water (D-10 to D-20) may be necessary to maintain euglycemia in patients with an intentional sulfonylurea overdose. If concentrations of 20% dextrose or greater are used, the infusion should be given through a central venous catheter to avoid damage to peripheral veins. If oral dextrose is not an option (owing to patient altered mental status) and intravenous dextrose cannot be administered because of difficulty with intravenous access, glucagon can be administered to produce a temporary elevation in blood glucose. Glucagon is particularly helpful in the preadmission setting. Glucagon is administered by intramuscular or subcutaneous injection (1 mg for adults and children greater than 20 kg; 0.5 mg for children less than 20 kg). Glucagon increases blood glucose by promoting glycogenolysis and gluconeogenesis. It is usually effective only when adequate glycogen stores exist. Glucagon stimulates insulin release and, thus, needs to be followed by the parenteral administration of glucose.72 Glucagon is only a bridging therapy before successful intravenous access and dextrose administration. Glucagon administration may be associated with nausea and vomiting. In the setting of sulfonylurea toxicity, a profound rebound or recurrent hypoglycemia often occurs within 30 minutes of initial dextrose administration.73 Although dextrose is the recommended initial treatment for all episodes of symptomatic hypoglycemia, a number of additional drugs can be used as adjuncts in the management of sulfonylurea-induced hypoglycemia. The antihypertensive diazoxide effectively inhibits insulin secretion from the pancreatic β cells and has been used successfully in the management of refractory sulfonylurea-induced hypoglycemia.74 Specifically, diazoxide may bind at the sulfonylurea binding site to prevent membrane depolarization and insulin release. Diazoxide is given by slow intravenous infusion over 30 minutes (3 mg/kg in adults; 1 to 3 mg/kg in children); the dose may be repeated every 4 hours. Diazoxide is complicated by orthostatic hypotension, tachycardia, and sodium and water retention. Octreotide, a long-acting synthetic analog of somatostatin, is a potent inhibitor of insulin, glucagon, and growth hormone secretion. It has been reported to effectively inhibit excessive insulin secretion and significantly reduce dextrose requirements after sulfonylurea overdose. With octreotide treatment, insulin levels are reduced to baseline values, and there are fewer episodes of rebound hypoglycemia.73-79 It appears that octreotide is superior to diazoxide for reducing the subsequent amount of glucose needed after the initial dextrose treatment.73,74 The use of dextrose followed by octreotide should be considered first-line therapy in patients with sulfonylurea-induced hypoglycemia. Octreotide should be dosed in all individuals with a single episode of symptomatic hypoglycemia; it is not necessary to wait for recurrent hypoglycemia. Octreotide can be given by subcutaneous or intravenous injection (1 to 2 μg/kg in children and 50 to 100 μg in adults).76 The dose can be

repeated in 6 to 12 hours, if clinically necessary. No significant side effects occur with octreotide therapy. Activated charcoal has been demonstrated to bind effectively to chlorpropamide, tolbutamide, tolazamide, glibenclamide, and glipizide in vitro,80 and to tolbutamide, chlorpropamide, and glipizide in vivo.81-83 Although there has not previously been a study demonstrating clinical benefit from the administration of activated charcoal to patients who overdose on sulfonylureas, its administration is recommended in the overdose setting. The role of whole bowel irrigation is unknown after ingestion of sustained-release agents (e.g., Glucotrol XL) from this class. Most cases of sulfonylurea overdoses are adequately managed with dextrose supplementation, and attempts at enhanced elimination are not indicated. Alkalinization of the urine has been demonstrated to enhance the excretion of chlorpropamide (a weak acid, pKa 4.8), reducing its elimination half-life from 50 to 13 hours.81 However, in their position statement on urinary alkalinization, the American Academy of Clinical Toxicology and the European Association of Poison Centers and Clinical Toxicologists state “as the administration of dextrose alone is effective treatment in the majority of patients with chlorpropamide poisoning, which is now rare, urine alkalinization is only likely to be employed very occasionally.84 Urinary alkalinization is not expected to enhance urinary excretion of other sulfonylureas. Charcoal hemoperfusion was demonstrated to enhance elimination of chlorpropamide after overdose by a man with chronic renal failure.85 In general, the use of extracorporeal methods to enhance removal of sulfonylureas is not recommended; most agents are metabolized in the liver. Repeat-dose activated charcoal is ineffective in enhancing elimination of chlorpropamide, and therefore is not recommended.86 The use of multidose activated charcoal has not been investigated for other sulfonylureas.

Metformin Poisoning The treatment of biguanide toxicity is supportive. Initial management should focus on stabilization of the airway, breathing, and circulation. Adequate and early volume expansion is essential and may improve lactic acidosis. Hypoglycemia, although rarely present or profound, should be corrected with intravenous dextrose administration. The administration of intravenous bicarbonate to those with biguanide-induced lactic acidosis is controversial. Sodium bicarbonate may be detrimental by resulting in paradoxical acidification of cerebrospinal and intracellular fluid; increased hemoglobin affinity for oxygen, leading to impaired oxygen delivery to the tissues; hypernatremia and volume overload; severe hypokalemia and hypocalcemia; and increased cellular membrane permeability to biguanides, resulting in further increases in cellular lactate production.87,88 Sodium bicarbonate therapy is not recommended because it has not been associated with clinical benefit in patients with biguanide-induced or other forms of lactic acidosis.88-91

CHAPTER 64

Hemodialysis with a bicarbonate dialysate has been reported to dramatically increase the survival rate of patients with metformin-induced lactic acidosis. Lalau and associates reported on five patients with severe metformin-induced lactic acidosis, whose clinical status and metabolic abnormalities rapidly responded to bicarbonate hemodialysis despite incomplete removal of metformin as determined by serum sampling. All patients had acute renal failure, and three were in cardiovascular collapse at the time of presentation.92 In addition, Teale and colleagues reported on two patients with intentional metformin overdose with cardiovascular collapse, who were successfully managed with continuous venovenous hemodiafiltration.39 Hemodialysis is recommended as first-line treatment in patients with severe biguanide-induced lactic acidosis.

α-Glucosidase Inhibitor and Thiazolidinedione Poisoning The initial management of toxicity associated with α-glucosidase inhibitors and thiazolidinediones is supportive. Adequate volume expansion should be commenced early, if indicated. Hypoglycemia, which should only occur when these agents are ingested in combination with insulin secretagogues, should be treated with intravenous dextrose administration. In addition to standard laboratory analysis in poisoned patients, liver function tests should be obtained in patients who overdose on α-glucosidase inhibitors.

Meglitinide Poisoning Treatment is aimed at correcting symptomatic hypoglycemia with administration of intravenous dextrose as necessary. The risk for and duration of hypoglycemia should last only a few hours after ingestion of meglitinides. Thus, a 4-hour period of observation is sufficient for patients who ingest meglitinides, even for those who required initial treatment with dextrose for symptomatic hypoglycemia.

Insulin Toxicity The mainstay of treatment for insulin toxicity is the administration of supplemental dextrose for symptomatic hypoglycemia and correction of coexisting metabolic abnormalities (e.g., hypokalemia) as necessary. As for sulfonylurea toxicity, patients with mild hypoglycemia may be given an oral, rapidly acting dextrose formulation followed by a small meal. Patients who develop significant symptomatic hypoglycemia should receive an intravenous bolus of concentrated dextrose (see Table 64-4) followed by a continuous infusion of 10% or 20% dextrose. As for sulfonylurea overdose, overzealous administration of dextrose may precipitate rebound hyperinsulinemia (for patients without type 1 diabetes). Thus, the dextrose infusion should be titrated to just maintain euglycemia. Oral overdose of insulin will not produce clinical effects because of rapid breakdown in the stomach.


1031

Prolonged hypoglycemia (lasting days) has occurred in patients who have intentionally injected large subcutaneous overdoses of insulin.93 Although surgical excision of skin and subcutaneous tissue insulin depots has been described for such patients, the clinical utility of this approach is unknown and cannot be recommended.94,95,96

DISPOSITION Because of the potential for prolonged hypoglycemic effects, all patients who develop symptomatic hypoglycemia from sulfonylureas require admission for ongoing blood glucose monitoring and therapy with intravenous dextrose and octreotide, as necessary. The onset of hypoglycemia after sulfonylurea overdose may be delayed for up to 18 hours; therefore, all patients with deliberate overdose and all children with suspected ingestion must be admitted for up to 24 hours. A hospitalized patient is ready for medical discharge when euglycemia has been maintained for a period of 8 to 12 hours after the last dose of octreotide and supplemental parenteral dextrose. Appropriate psychiatric evaluation in cases of deliberate self-overdose should take place before final discharge. When the overdose was inadvertent, appropriate educational intervention should occur before discharge. Evidence of lactic acidosis associated with biguanide therapy or after biguanide overdose mandates hospital admission. Lactic acidosis is unlikely to develop in individuals with normal renal function after relatively small ingestions of metformin, but because a dose– response relationship has not been well characterized, all patients with metformin overdose should be observed for at least 6 hours. If there is no evidence of acidosis or hypoglycemia, and the patient remains asymptomatic at that time, then the patient may be discharged after appropriate psychiatric evaluation and educational intervention. For patients who ingest excessive doses of the thiazolidinediones, α-glucosidase inhibitors, or meglitinides, a 4- to 6-hour observation period is appropriate. The observation period may need to be extended if hypoglycemia occurs. The duration of hospital observation necessary after insulin toxicity depends on the quantity and type of insulin injected, patient intent, and duration of symptomatic hypoglycemia. Patients who experience an unintentional hypoglycemic episode associated with therapeutic dosing (an insulin reaction) typically require only several hours emergency department observation. These patients can be safely discharged provided they have eaten a small meal, do not develop recurrent hypoglycemia during their period of observation, are at their baseline mental and health status at the time of discharge, are reliable or are discharged with reliable caretakers, and have been observed in the emergency department beyond the time of expected peak effects from the injected insulin preparation (see Table 64-3). Patients who have intentionally overdosed on insulin

1032


should be admitted for inpatient observation (24 hours) because of the possibility for delayed and prolonged hypoglycemia. Most of these patients are symptomatic within 12 hours of overdose.93 Patients who require dextrose infusion after intentional insulin overdose should be observed for recurrent hypoglycemia for 8 to 12 hours after the dextrose infusion has been stopped. Intensive care unit admission is required for patients with significant and persistent central nervous system or cardiovascular abnormalities or those requiring large supplemental dextrose infusions to maintain euglycemia.

ACKEE FRUIT Ackee (Blighia sapida), the national fruit of Jamaica, was originally imported to the Caribbean from West Africa in the 18th century (see Chapter 24). The ackee tree is a tall, evergreen, fruit-producing tree and is found in various parts of the world, including the Caribbean, the Antilles, Central America, and parts of Florida.97 The fruit is yellow and opens while still attached to the tree to reveal three glassy black seeds surrounded by a thick, oily, yellow aril. The ackee fruit was first associated with Jamaican vomiting sickness (also called toxic hypoglycemic syndrome) in 1875. Risk factors associated with the development of Jamaican vomiting sickness are threefold: (1) consumption of raw or unripe ackee fruit; (2) consumption of ackee that is forcibly opened; and (3) consumption of water in which unripe ackee was cooked.98 The unripe ackee fruit contains hypoglycin A, which is a watersoluble liver toxin that causes profound hypoglycemia by interfering with certain cofactors and enzymes necessary for hepatic gluconeogenesis.99 Hypoglycin A, or cyclopropylaminoproprionic acid, interferes with carnitineacyl CoA transferase and β oxidation of long-chain fatty acids.100 Accumulations of serum carboxylic acids results in metabolic acidosis and leads to Jamaican vomiting sickness. Jamaican vomiting sickness is characterized by the onset of epigastric pain, which begins a few hours after eating the fruit. Shortly thereafter, there is a sudden onset of profuse vomiting and hypoglycemia. Seizures, coma, and metabolic acidosis are common, as is death.97 Death typically occurs by 12 hours after ingestion. The hypoglycemia is profound, often with blood sugars as low as 3 mg/dL.97 The fruit is illegal in the United States, but nonetheless, there have been at least two reported cases in the United States in the 1990s. The first known case of Jamaican vomiting sickness occurred in Ohio, in a Jamaican female, after the consumption of canned Ackee.101 The only other known case in the United States was a 27-year-old Jamaican man, residing in Connecticut, who presented with 2 months of jaundice, intermittent diarrhea, pruritus, right upper quadrant pain, and markedly elevated bilirubins.102 This patient with cholestatic jaundice had resolution of his symptoms after he ceased consumption of the ackee fruit. Treatment for poisoning from the ackee fruit is supportive, with correction of hypoglycemia, dehydration,

acidosis, and metabolic abnormalities provided as necessary.

REFERENCES 1. Winer N, Sowers JR: Epidemiology of diabetes. J Clin Pharmacol 2004;44:397–405. 2. Davis SN, Granner DK: Insulin, oral hypoglycemic agents, and the pharmacology of the endocrine pancreas. In Hardman JG, Limbrid LE, Gilman AG (eds): Goodman & Gilman’s the Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 1679–1714. 3. Banting FG, Best CH, Collip JB, et al: Pancreatic extracts in the treatment of diabetes mellitus. Can Med Assoc J 1922;12:141–146. 4. Amos AF, McCarty DJ, Zimmet P: The rising global burden of diabetes and its complications: estimates and projections to the year 2010. Diabet Med 1997;14(Suppl 5):S1–S85. 5. Williams RH, Palmer JP: Farewell to phenformin for treating diabetes mellitus. Ann Intern Med 1975;83:567–568. 6. Inzucchi SE: Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 2002;287:360–372. 7. Murphy EJ, Davern TJ, Shakil AO, et al: Troglitazone-induced fulminant hepatic failure: Acute Liver Failure Study Group. Dig Dis Sci 2000;45:549–553. 8. Watson WA, Litovitz TL, Klein-Schwartz W, et al: 2003 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2004;22: 335–404. 9. Krentz AJ, Bailey CJ: Oral antidiabetic agents: current role in type 2 diabetes mellitus. Drugs 2005;65:385–411. 10. Hirsch IB: Insulin analogues. N Engl J Med 2005;352:174–183. 11. Ciechanowski K, Borowiak KS, Potocka BA, et al: Chlorpropamide toxicity with survival despite 27-day hypoglycemia. J Toxicol Clin Toxicol 1999;37:869–871. 12. Rosenfeld L: Insulin: discovery and controversy. Clin Chem 2002; 48:2270–2288. 13. Hirsch IB: Drug therapy: insulin analogues. N Engl J Med 2005; 352:174–183. 14. Beck-Nielsen H, Hother-Nielsen O, Pedersen O: Mechanism of action of sulfonylureas with special reference to the extrapancreatic effect: an overview. Diabet Med 1988;5:613–620. 15. Gerich JE: Oral hypoglycemic agents. N Engl J Med 1989;321: 1123–1145. 16. Czyzyk A, Tawecki J, Sadowski J, et al: Effect of biguanides on intestinal absorption of glucose. Diabetes 1968;17:492–498. 17. Wilholm BE, Myrhed M: Metformin-associated lactic acidosis in Sweden 1977–1991. Eur J Clin Pharmacol 1993;44:589–591. 18. Arieff AI: Pathogenesis of lactic acidosis. Diabetes Metab Rev 1989;5:637–649. 19. Luft FC: Lactic acidosis update for critical care clinicians. J Am Soc Nephrol 2001;12:S15–S19. 20. Misbin RI: Phenformin-associated lactic acidosis: pathogenesis and treatment. Ann Intern Med 1984;87:591–595. 21. Lalau JD, Race JM: Lactic acidosis in metformin therapy. Drugs 1999;58(Suppl 1):55–60. 22. Luft D, Schmulling RM, Eggstein M: Lactic acidosis in biguanidetreated diabetics: a review of 330 cases. Diabetologia 1978;14:75–87. 23. Bernier GM, Miller M, Sporingate CS: Lactic acid and phenformin hydrochloride. JAMA 1963;184:43–46. 24. Lebovitz HE: Alpha glucosidase inhibitors. Endocrinol Metab Clin North Am 1997;539–551. 25. Yki-Jarvinen HY: Thiazolidinediones. N Engl J Med 2004;351: 1106–1118. 26. Landgraf R: Meglitinide analogues in the treatment of type 2 diabetes mellitus. Drugs Aging 2000;17:411–425. 27. Baselt RC: Disposition of Toxic Drugs and Chemicals in Man, 7th ed. Foster City, CA, Biomedical Publications, 2004. 28. Bailey CJ, Turner RC: Metformin. N Engl J Med 1996;334:57–579. 29. Scheen A: Drug interactions of clinical importance with antihyperglycaemic agents: an update. Drug Safety 2005;28:601–631. 30. Mikko N, Backman JT, Neuvonen M, et al: Rifampin decreases the plasma concentration and effects of repaglinide. Clin Pharmacol Ther 2000;68:495–500.

CHAPTER 64

31. Field LB: Hypoglycemia: Definition, clinical presentations, classification, and laboratory tests. Endocrin Metabol Clin North Am 1989;18:27–43. 32. Gerich JE: Control of glycaemia. Ballieres Clin Endocrinol Metabol 1993;7:551–586. 33. Quadrani DA, Spiller HA, Widder P: Five year retrospective evaluation of sulfonylurea ingestion in children. J Toxicol Clin Toxicol 1996;34:267–270. 34. Spiller HA, Villalobos D, Krenzelok EP, et al: Prospective multicenter study of sulfonylurea ingestion in children. J Pediatr 1997; 131:141–146. 35. Dobson HL: Attempted suicide with phenformin. Diabetes 1965;14:811–812. 36. Pashley NRT, Felix RH: Phenformin overdose. BMJ 1972;1: 112–113. 37. Spiller HA: Management of antidiabetic medications in overdose. Drug Safety 1998;19:411–424. 38. Bingle JP, Storey GW, Winter JM: Fatal self-poisoning with phenformin. BMJ 1970;3:752. 39. Teale KFH, Devine A, Stewart H, Harper NJH: The management of metformin overdose. Anaesthesia 1998;53:691–701. 40. Lacher M, Hermanns-Clausen M, Haeffner K, et al: Severe metformin intoxication with lactic acidosis in an adolescent. Eur J Pediatr 2005;164:362–365. 41. Bismuth C, Gaultier M, Conso F, et al: Acidose lactique induite par l’ingestion excessive de metformine. Nouv Presse Med 1976;5: 261–263. 42. McLelland J: Recovery from metformin overdose. Diabet Med 1985;2:410–411. 43. Assan A, Heuelin C, Ganeval D, et al: Metformin-induced lactic acidosis in the presence of acute renal failure. Diabetologia 1977;13:211–217. 44. Barrueto F, Meggs WH, Barchman JM: Clearance of metformin by hemofiltration in overdose. J Toxicol Clin Toxicol 2002;40:177–180. 45. Larcan A, Lambert H, Ginsbourger F: Acute intoxication by phenformine hyperlactatemia reversible with extra-renal purification. Vet Hum Toxicol 1979;21(Suppl):19–22. 46. Brady WJ, Carter CT: Metformin overdose. Am J Emerg Med 1997;15:107–108. 47. Spiller HA, Weber JA, Winter ML, et al: Multicenter case series of pediatric metformin ingestion. Ann Pharmacother 2000;34: 1385–1388. 48. Nakayama S, Hirose T, Watada H, et al: Hypoglycemia following a nateglinide overdose in a suicide attempt. Diabetes Care 2005;28:227–228. 49. Hirshberg B, Skarulis MC, Pucino F, et al: Repaglinide-induced factitious hypoglycemia. J Clin Endocrinol Metab 2001;86: 475–477. 50. Cooper AJ: Attempted suicide using insulin by a non diabetic: a case study demonstrating the acute and chronic consequences of profound hypoglycemia. Can J Psychiatry 1994;39:103–107. 51. Stapczynski JS, Haskell RJ: Duration of hypoglycemia and need for intravenous glucose following intentional overdoses of insulin. Ann Emerg Med 1984;13:505–511. 52. Roberge R, Martin TG, Delbridge TR: Intentional massive insulin overdose: recognition and management. Ann Emerg Med 1993;22:228–234. 53. Paice BJ, Paterson KR, Lawson DH: Undesired effects of sulphonylurea drugs. Adverse Drug React Acute Poisoning Rev 1985;4:23–26. 54. DeFronzo RA: Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 2000;133:73–74. 55. Veitch PC, Clifton-Bligh RJ: Long-acting sulfonylureas-long acting hypoglycaemia. Med J Aust 2004;180:84–85. 56. Harrower ADB: Comparative tolerability of sulfonylureas in diabetes mellitus. Drug Safety 2000;22:313–320. 57. Odeh M, Oliven A: Doxycycline-induced hypoglycaemia. J Clin Pharmacol 2000;40:1173–1174. 58. Roberge RJ, Kaplan R, Frank R, et al: Glyburide-ciprofloxacin interaction with resistant hypoglycemia. Ann Emerg Med 2000;36:160–163. 59. Menzies DJ, Dorsainvil PA, Cunha BA, et al: Severe and persistent hypoglycemia due to gatifloxacin interaction with oral hypoglycemic agents. Am J Med 2002;113:232–234.


1033

60. Kubacka RT, Antal EJ, Juhl RP, et al: Effects of aspirin and ibuprofen on the pharmacokinetics and pharmacodynamics of glyburide in healthy subjects. Ann Pharmacother 1996;30:20–26. 61. Welle S, Nair KS, Lockwood D: Effect of sulfonylurea and insulin on energy expenditure in type II diabetes mellitus. J Clin Endocrinol Metab 1988;6:593–597. 62. Aronow WS: Oral sulfonylureas and CV mortality. Geriatrics 2004;59:45–49. 63. Slagle M: Medication update. South Med J 2002;95:50–55. 64. Gan SC, Barr J, Arieff AI, Pear RG: Biguanide-associated lactic acidosis: case report and review of the literature. Arch Intern Med 1992;152:2333–2336. 65. Stades AME, Heikens JT, Erkelens DW, et al: Metformin and lactic acidosis: cause or coincidence? A review of the case reports. J Intern Med 2004;255:179–187. 66. Nisbet J, Sturtevant JM, Prins JB: Metformin and serious adverse effects. Med J Aust 2004;180:53–54. 67. Martin AE, Montgomery PA: Acarbose: an alpha-glucosidase inhibitor. Am J Health Syst Pharm 1996;53:2277–2290. 68. Carrasosa M, Pascual F, Aresti S. Acarbose-induced acute severe hepatotoxicity. Lancet 1997;349:698–699. 69. Al-Salaman J, Arjomand H, Kemp D, et al: Hepatocellular injury in a patient receiving rosiglitazone: a case report. Ann Intern Med 2000;132:121–124. 70. Maeda K: Hepatocellular injury in a patient receiving pioglitazone. Ann Intern Med 2001;135:306. 71. Hampton SM, Beyzavi K, Teale D, et al: A direct assay for proinsulin and its application in hypoglycemia. Clin Endocrinol 1988;29:9–16. 72. Thoma ME, Glauser J, Genuth S: Persistent hypoglycemia and hyperinsulinemia: caution in using glucagon. Am J Emerg Med 1996;14:99–101. 73. Boyle PJ, Justice K, Krentz AJ: Octreotide reverses hyperinsulinemia and prevents hypoglycemia induced by sulfonylurea overdoses. J Clin Endocrinol Metab 1993;76:752–756. 74. Palatnick W, Meatherall RC, Tenenbein M: Clinical spectrum of sulfonylurea overdose and experience with diazoxide. Arch Intern Med 1991;151:1859–1862. 75. Crawford BA, Perera C: Octreotide treatment for sulfonylureainduced hypoglycemia. Med J Aust 2004;180:540–541. 76. McLaughlin SA, Crandall CS, McKinney PE: Octreotide: an antidote for sulfonylurea-induced hypoglycemia. Ann Emerg Med 2000;36:133–138. 77. Carr R, Zed PJ: Octreotide for sulfonylurea-induced hypoglycemia following overdose. Ann Pharmacother 2002;36:1727–1732. 78. Green RS, Palatnick W: Effectiveness of octreotide in a case of refractory sulfonylurea-induced hypoglycemia. J Emerg Med 2003;25:283–287. 79. Krentz AJ, Boyle PJ, Justice KM, et al: Successful treatment of severe refractory sulfonylurea-induced hypoglycemia with octreotide. Diabetes Care 1993;16:184–186. 80. Kannisto H, Neuvonen PJ: Adsorption of sulfonylureas onto activated charcoal. J Pharmacol Sci 1984;73:253–256. 81. Neuvonen PJ, Karhainen S: Effects of charcoal, sodium bicarbonate, and ammonia chloride on chlorpropamide kinetics. Clin Pharmacol Ther 1983;33:386–393. 82. Neuvonen PJ, Kannisto H, Hirvisalo EL: Effect of activated charcoal on absorption of tolbutamide and valproate in man. Eur J Clin Pharmacol 1983;24:243–246. 83. Kivisto KT, Neuvonen PJ: The effect of cholestyramine and activated charcoal on glipizide absorption. Br J Clin Pharmacol 1990;30:733–736. 84. Proudfoot AT, Krenzelok EP, Vale JA: Position paper on urine alkalinization. J Toxicol Clin Toxicol 2004;42:1–26. 85. Ludwig SM, McKenzie J, Faiman C: Chlorpropamide overdose in renal failure: Management with charcoal hemoperfusion. Am J Kidney Dis 1987;10:457–460. 86. American Academy of Clinical Toxicology; European Association of Poison Centres and Clinical Toxicologists: Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. J Toxicol Clin Toxicol 1999;37:731–751. 87. Arieff AJ: Indications for use of bicarbonate in patients with metabolic acidosis. Br J Anaesth 1991;67:165–177.

1034


88. Forsythe SM, Schmidt GA: Sodium bicarbonate for the treatment of lactic acidosis. Chest 2000;117:260–267. 89. Fulop M, Hoberman HD: Phenformin-associated metabolic acidosis. Diabetes 1976;25:292–296. 90. Cooper JD, Walley KR, Wiggs BR, Russell JA: Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis. Ann Intern Med 1990;112:492–498. 91. Ryder RE: The danger of high dose sodium bicarbonate in biguanide-induced lactic acidosis: the theory, the practice and alternative therapies. Br J Clin Pract 1987;41:730–737. 92. Lalau JD, Westeel PF, Debussche X, et al: Bicarbonate hemodialysis: an adequate treatment for lactic acidosis in diabetics treated by metformin. Intensive Care Med 1987;13:383–387. 93. Arem R, Zoghbi W: Insulin overdose in eight patients: insulin pharmacokinetics and review of the literature. Medicine 1985;64:323–332. 94. Tofade TS, Liles EA: Intentional overdose with insulin glargine and insulin aspart. Pharmacotherapy 2004;24:1412–1418.

95 McIntyre AS, Woolf VJ, Burnham WR: Local excision of subcutaneous fat in the management of insulin overdose. Br J Surg 1986;73:538. 96 Campbell IW, Ratcliffe JG: Suicidal insulin overdose managed by excision of insulin injection site. BMJ 1982;285:408–409. 97. Toxic hypoglycemic syndrome—Jamaica, 1989–1991. MMWR Morb Mortal Wkly Rep 1992;41:53–55. 98. Ashcroft MT: Some noninfective diseases endemic in the West Indies. Trop Geogr Med 1978;30:5–21. 99. Feng PC, Patrick SJ: Studies of the action of hypoglycin-A, an hypoglycemic substance. Br J Pharmacol 1958;13:125–130. 100. Addae JR, Melvill GN: A re-examination of the mechanism of ackee induced vomiting sickness. West Ind Med J 1988;37:6–8. 101. McTague JA, Forney R: Jamaican vomiting sickness in Toledo, Ohio. Ann Emerg Med 1994;23:1116–1118. 102. Larson J, Vender R, Camuto P: Cholestatic jaundice due to ackee fruit poisoning. Am J Gastroenterol 1994;89:1577–1578.

65

Theophylline and Caffeine MICHAEL W. SHANNON, MD, MPH


■ ■ ■ ■

■

Methylxanthines are purine derivatives structurally related to adenosine. Methylxanthines have a narrow therapeutic index. Adverse effects can appear even at therapeutic doses and serum concentrations. Manifestations of theophylline intoxication vary according to mechanism of overdose (acute, chronic, or acute on therapeutic). The major life-threatening events of theophylline intoxication are seizures and cardiac arrhythmias. Metabolic consequences include hypokalemia, hyperglycemia, and metabolic acidosis. Management strategies for theophylline intoxication include supportive care, administration of multiple-dose activated charcoal, and, in severe cases, hemodialysis. Hemodialysis is preferred over hemoperfusion in the treatment of severe theophylline intoxication, because it is safer, more available, and equally effective.

Theophylline, caffeine, and theobromine are the major members of a group of pharmacologic agents known as methylxanthines. These drugs continue to have a ubiquitous position in society: Caffeine is used around the world for the pleasure that its mild stimulation provides. For almost a century, theophylline has been used for the treatment of respiratory ailments. Although theophylline use has fallen dramatically in recent years, it enjoys continued use as a therapeutic agent.

THEOPHYLLINE Theophylline is used to treat various illnesses. At one time, it was the primary therapy for asthma, considered valuable both for treatment of acute exacerbations and for long-term prophylactic therapy.1 Over the past two decades, β-adrenergic agonists have largely replaced theophylline for this indication, having a more favorable profile of safety and efficacy. However, theophylline is still used as a primary agent in areas where β-adrenergic agonists are less available and for individuals who have asthma that is resistant to β-adrenergic agonist and corticosteroid therapy.2 Moreover, data that suggest that theophylline has anti-inflammatory properties have led to a slight increase in its use.3,4 Besides asthma, theophylline is used for other syndromes of airway obstruction including chronic obstructive pulmonary disease in adults and bronchiolitis in infants, although there remains controversy about its efficacy in these diseases.5-8 Theophylline is prescribed for neonates, particularly premature neonates, who have apnea and bradycardia.9,10 Recent data suggest benefit in cardiac resuscitation, in

renal protection after exposure to nephrotoxic agents, and in the treatment of acute mountain sickness.11-14 Individuals develop theophylline intoxication by two general mechanisms. First, its general availability makes theophylline an agent that can be ingested by curious toddlers or suicidal adolescents or adults, producing acute intoxication. Second, because of its highly variable pharmacokinetics and narrow therapeutic index, theophylline is often responsible for unintentional chronic intoxication. By either mechanism, theophylline poisoning leads to a host of clinical and metabolic complications that often result in disastrous consequences, including death. A thorough understanding of theophylline intoxication, including rational and effective treatment algorithms (Box 65-1), is therefore necessary for management of this overdose.

BOX 65-1

TREATMENT ALGORITHM FOR ACUTE THEOPHYLLINE INTOXICATION

Supportive Care

Airway control, respiratory support, and vascular access as needed; cardiorespiratory monitoring Treatment of Life-Threatening Events

Seizures Give benzodiazepines. Add barbiturates if necessary. Avoid phenytoin. Paralyze if necessary. Provide electroencephalogram monitoring. Cardiac arrhythmias Supraventricular—administer adenosine. Consider β blocker or calcium channel blocker. Ventricular—treat specific rhythm disturbance according to advanced cardiac life support protocols. Laboratory Assessment

Electrolytes, arterial blood gas Serum theophylline concentration (obtain serial measures until plateau is documented) Electrocardiogram Gastrointestinal Decontamination

Administer activated charcoal. No established role for gastric emptying, e.g., ipecac or lavage. No role for cathartic administration. Correction of Metabolic Disturbances

Hyperglycemia does not require treatment. Hypokalemia should not be treated unless severe. Metabolic acidosis is typically modest and requires no treatment. Elimination Enhancement

Administer activated charcoal every 2–4 hours. Consider hemodialysis for severe cases. Hemoperfusion is also efficacious. 1035


N

J

J

OK N CH3

N

Caffeine

NH2

NJ

J

J

CH3

N

N

J

N

J

N

N

J

J

OK N CH3

N

J

J

N

CH3

J

K

O

H

J

Theophylline

H3C

J

N

K

J

OK N CH3

J

J

N

N

CH3

O

H

J

K

O

H3C

J

1036

Ribose

Theobromine Adenosine FIGURE 65-1 Theophylline and related compounds.

Structure and Structural Relationships As illustrated in Figure 65-1, the methylxanthines are purines that are structurally related to the nucleotides adenine and guanine. Theophylline is 1,3-dimethylxanthine. It is closely related to caffeine (1,3,7-trimethylxanthine) and theobromine (3,7-dimethylxanthine). Caffeine is found in high concentration in coffee and certain teas. Theobromine is primarily found in cocoa. A related drug, pentoxifylline, is prescribed for treatment of peripheral vascular disease. Adenosine, which is an adenine-ribose nucleoside, is closely related to theophylline in structure and appears to have an important role in theophylline’s pharmacologic actions and toxic effects. Theophylline products are available as solutions, tablets, and sustained-release capsules. Because of its poor solubility in water, theophylline has an intravenous form, aminophylline, which is about 80% theophylline by weight.15

Pharmacology PHARMACOKINETICS In its oral form, theophylline is most commonly prescribed as a sustained-release capsule. Sustainedrelease theophylline is designed to provide stable serum concentrations by having a gastrointestinal (GI) absorption rate that approximates that of drug elimination. These agents are not completely absorbed until 6 to 8 hours after ingestion. Overdoses of sustained-release theophylline can be associated with 15- to 24-hour delays to peak absorption. There is no significant presystemic clearance (first-pass effect) of the drug. Once absorbed, theophylline is distributed throughout the body with a relatively small volume of distribution (average, 0.45 L/kg, with a range of 0.3 to 0.7 L/kg).15 Young infants and elderly people tend to have larger volumes of distribution. Plasma protein binding is 40% to 65%. The therapeutic serum concentration of theophylline is generally considered to be 10 to 20 μg/mL, although lower serum concentrations can produce the desired therapeutic effect. As a general rule, 1 mg/kg of administered theophylline raises serum theophylline concentration by 2 μg/mL. Theophylline freely crosses the placenta and enters breast milk.15 The metabolism of theophylline occurs through its biotransformation by the cytochrome P-450 system. The specific isoenzymes of this superfamily responsible for theophylline metabolism are CYP1A2, CYP2E1, and CYP3A3. The primary metabolic step is N-demethylation by the enzyme CYP1A2, producing the pharmacologically active agent 3-methylxanthine. The secondary metabolic pathway is hydroxylation, forming inactive 1,3dimethyluric acid. Neonates also have the ability to metabolize theophylline by its methylation, producing caffeine. Moreover, neonates excrete about 50% of theophylline in urine unchanged (versus only 10% in children and adults).15 The rate of theophylline metabolism is variable; age is a very important influence (Table 65-1), with neonates

TABLE 65-1 Theophylline Elimination Patterns by Age POPULATION

AGE

Neonates and Infants Premature neonates Premature neonates Term infants Term infants

1 wk 41 d 18 wk 34 wk

Children and Adolescents Adults Asthmatic nonsmokers Healthy nonsmokers Healthy elderly nonsmokers Healthy elderly nonsmokers NA, not available.

HALF-LIFE (hr)

CLEARANCE (mL/kg/min)

30 20 6.9 3.7

0.29 0.64 0.80 2.0

4–15 yr

3.0

1.55

31 yr 22–35 yr 67 yr >70 yr

9.4 8.1 7.4 9.8

0.65 0.86 0.59 NA

CHAPTER 65

and elderly people eliminating the drug relatively slowly.16 Theophylline clearance is maximal between the ages of 1 and 9 years; it decreases by about 50% in adults.15 The reason for such age-dependent elimination rates is unclear but may be related to the relative activity of cytochrome P-450 enzymes. Theophylline also exhibits Michaelis-Menten (saturable) kinetics. As a result, across a narrow range, increments in dose are associated with corresponding increments in serum theophylline concentration. At high doses, however, increments lead to disproportionate elevations in serum concentration.17 Conversely, with severe theophylline intoxication, initial drug elimination rates are extremely slow, following zero order (dose-dependent) kinetics. With decreasing serum theophylline concentration, first order (dose-independent) kinetics eventually appear, leading to abrupt increases in elimination rate. These kinetics are often responsible for inadvertent theophylline intoxication, for example, if a clinician mistakenly assumes that a 50% increase in dose will always result in a 50% increase in serum theophylline concentration. DRUG–DRUG INTERACTIONS Theophylline is a drug whose metabolism is highly subject to alteration by concomitant drug use. A growing list of drugs, when prescribed with theophylline, can result in either increased or decreased clearance. Chronic theophylline intoxication is often a result of unrecognized drug interactions. The drugs that have been associated with increased theophylline clearance are relatively few; all are known to be inducers of cytochrome P-450 enzymes. Such agents include phenobarbital, phenytoin, carbamazepine, and tobacco smoke. Patients who are taking these drugs often have difficulty maintaining therapeutic serum theophylline concentrations, requiring inordinately high doses because of their high drug clearance rate. If these patients discontinue their medications or quit smoking because they feel unwell, theophylline elimination rates can quickly revert to normal. For example, theophylline clearance falls by about 40% within 1 week of abstinence from cigarette smoking.15 Passive smoking also appears to increase theophylline clearance.18 The list of agents that decrease theophylline clearance is extensive (Box 65-2). It is also notable that among drug classes, one member may inhibit clearance while others do not; for example, cimetidine, a histamine-2 (H2) antagonist, is a potent inhibitor of theophylline metabolism. However, the H2 antagonists ranitidine and famotidine do not appear to have this action. Other common drugs that diminish theophylline clearance include the macrolide antibiotics (e.g., erythromycin or clarithromycin) and the quinolone antibiotics (e.g., ciprofloxacin or norfloxacin). The erythromycin– theophylline interaction has been characterized as appearing between days 3 and 7 of their concomitant use, with serum theophylline concentrations rising by an average of 30% to 35% if dosing adjustments are not made.

BOX 65-2

Theophylline and Caffeine

1037

DRUGS COMMONLY REPORTED TO REDUCE THEOPHYLLINE METABOLISM

Allopurinol Cimetidine Ciprofloxacin Clarithromycin Diltiazem Disulfiram Enoxacin Erythromycin Fluvoxamine Interferon (recombinant α) Methotrexate Mexiletine Nifedipine Norfloxacin Ofloxacin Roxithromycin Tacrine Thiabendazole Troleandomycin Verapamil Adapted from American Academy of Pediatrics Committee on Drugs: Precautions concerning the use of theophylline. Pediatrics 1992;89:781; and Hendeles L, Jenkins J, Temple R: Revised FDA labeling guidelines for theophylline oral dosage forms. Pharmacotherapy 1995;15:409.

DRUG–DISEASE INTERACTIONS Several medical conditions have significant impact on theophylline pharmacokinetics. In young children, febrile illness can markedly reduce theophylline elimination; it is recommended that the dose of theophylline be reduced by half in children who are febrile for more than 24 hours.10 Influenza and respiratory syncytial virus have also been reported as infectious agents that can reduce theophylline elimination.10 Cardiac disease, particularly congestive heart failure, can reduce theophylline clearance by as much as 50%, presumably through hepatic congestion and secondary alterations in pharmacokinetic profile.15 Primary hepatic disease can also reduce theophylline clearance by as much as 50%. Both cystic fibrosis and hyperthyroidism have been associated with increased theophylline clearance, resulting in larger dosing requirements. Renal disease has no important effect on theophylline pharmacokinetics. PHARMACOLOGIC ACTIONS Methylxanthines have a number of pharmacologic actions that give them therapeutic value. They relax smooth muscles, including those of the bronchi, esophagus, and gastroesophageal sphincter. They are central nervous system (CNS) stimulants that can reduce fatigue and improve concentration. Physiologic dependence may occur with this action: Acute abstinence from caffeine is associated with malaise, headaches, emotional lability, and depression. Other CNS actions include stimulation of the CNS respiratory center, producing

1038


tachycardia. Cardiovascular effects include reduced peripheral vascular resistance with increased cardiac chronotropy and inotropy. Improved muscle function can enhance racing performance and improve pulmonary dynamics. Evidence indicates that theophylline is a potent inhibitor of renal erythropoietin production.19 Methylxanthines are also diuretics. MECHANISM OF ACTION Four major hypotheses have been advanced to explain theophylline’s pharmacologic effects. First is the theory that theophylline acts as an inhibitor of phosphodiesterase, the enzyme that breaks down intracellular cyclic adenosine monophosphate (cAMP). According to current theories, cAMP is created by the membrane-bound enzyme adenylate cyclase in response to a number of receptor-linked stimuli. cAMP effects a number of actions, including regulation of gated potassium channels. These actions are terminated when cAMP is metabolized by phosphodiesterase. Theophylline was once thought to be a potent inhibitor of phosphodiesterase. However, data now suggest that phosphodiesterase inhibition is negligible at therapeutic serum concentrations of theophylline, indicating that this mechanism alone cannot account for its actions.20,21 The extent of phosphodiesterase inhibition has not been studied in victims of theophylline intoxication. A second theory proposed for theophylline’s actions is that of secondary sympathetic nervous system stimulation. In therapeutic doses, theophylline produces marked increases in the level of circulating catecholamines, particularly epinephrine and norepinephrine.22-25 Theophylline’s actions of bronchodilation, cardiac and respiratory stimulation, and even metabolic changes such as depression in serum potassium may result from augmented plasma catecholamine activity. In a canine model of theophylline poisoning, hypokalemia, increased oxygen consumption, metabolic acidosis, and cardiac disturbances have been directly related to plasma catecholamine activity.22,23 The third potential mechanism of theophylline’s action is competitive antagonism of adenosine receptors. Adenosine, which is a bronchoconstrictor, anticonvulsant, and regulator of cardiac rhythm, interacts closely with theophylline through its competition for adenosine receptors.19,26 The structural similarity between these chemicals and their opposite physiologic functions supports this theory of adenosine receptor antagonism. Finally, theophylline’s actions may result directly from changes in intracellular calcium transport. For example, caffeine has been shown to inhibit the uptake and storage of calcium by the sarcoplasmic reticulum of striated muscle, thereby producing increased strength in skeletal muscle. In animal models, administration of a calcium channel blocker appears to protect against theophylline-induced toxicity and death.6

Clinical Toxicity Having a narrow therapeutic index, theophylline is associated with a high rate of adverse effects. For example, as

many as 15% of patients complain of adverse effects when their serum theophylline concentration is in the therapeutic range. Once serum theophylline concentrations exceed the therapeutic range (>20 μg/mL), the prevalence of adverse effects exceeds 65% to 70%.27 More than 90% of patients with serum theophylline concentrations greater than 30 μg/mL demonstrate signs of toxicity.15 It is also notable that theophylline intoxication has a high rate of iatrogenic origin; Schiff and colleagues found that in 68% of patients hospitalized with theophylline intoxication, inpatient or emergency department drug administration was responsible or contributed to toxicity.28 CLINICAL MANIFESTATIONS The signs and symptoms of theophylline intoxication can be placed into five categories: GI, musculoskeletal, cardiovascular, neurologic, and metabolic.15,29-31 Gastrointestinal The GI tract seems most sensitive to theophylline’s toxicity. The most common complaints associated with theophylline use are abdominal pain, heartburn, and vomiting.32 In some cases, hemorrhagic gastritis can occur. These effects result from GI actions that include increased production of gastric acid and pepsin as well as relaxation of the lower esophageal sphincter. With moderate to severe theophylline intoxication, vomiting can be difficult to control despite antiemetic therapy.33 Musculoskeletal Victims of theophylline intoxication often complain of generalized muscle aches. With moderate toxicity, muscular hypertonicity with frank myoclonus may develop. Coarse tremor has also been reported as a manifestation of toxicity.32 These effects have been attributed to the potassium disturbances that accompany theophylline intoxication or disturbances in intracellular calcium transport. Elevations in serum creatine phosphokinase levels have been reported with severe intoxication. Cardiovascular Theophylline has several cardiovascular effects, some of which can be life threatening. Even when serum theophylline concentrations are in the therapeutic range, sinus tachycardia is often present. Greater toxicity has effects on vascular tone and cardiac rhythm. Peripheral vasodilation is invariable with significant theophylline intoxication. This results in a widened pulse pressure and a fall in systemic vascular resistance.34 Hypotension is generally present rather than hypertension.22,23 The mechanism of vascular disturbances is thought to be vascular β-adrenergic receptor stimulation, produced by circulating plasma catecholamines. Theophylline is arrhythmogenic.35 Myocardial irritability appears with mild to moderate theophylline intoxication; electrocardiograms most often reveal ventricular premature beats. These are usually of no consequence. However, more severe myocardial irritability occurs with serious intoxication, producing bigeminy

CHAPTER 65

and other potentially unstable rhythms. These dysrhythmias may be a prelude to life-threatening cardiac arrhythmias such as ventricular tachycardia. Although sinus tachycardia is one of the most common of manifestations of toxicity, appearing in as many as 82% of cases,32 rhythm disturbances are a sign of severe theophylline intoxication and the most common cause of theophylline-induced fatalities. Sinus tachycardia can quickly progress to life-threatening rhythms, which can be either ventricular or supraventricular in origin.36 Supraventricular disturbances reported after theophylline intoxication include supraventricular tachycardia, atrial fibrillation, atrial flutter, and multifocal atrial tachycardia.37 Many of these rhythms, such as multifocal atrial tachycardia, are characteristic of theophylline intoxication.38 Supraventricular tachyarrhythmias result in increased myocardial oxygen demand, compromised cardiac output, shock, metabolic acidosis, and myocardial ischemia or infarction. Life-threatening arrhythmias of ventricular origin consist of ventricular tachycardia and ventricular fibrillation. The mechanism of cardiac rhythm disturbances is unclear. They may be secondary to elevated plasma catecholamine activity. Other data now suggest that the mechanism of rhythm disturbances is theophylline inhibition of cardiac adenosine receptors. Neurologic Neurologic manifestations of theophylline intoxication appear at relatively low serum concentration; users of theophylline may complain of anxiety and insomnia. In children, theophylline may produce behavioral disturbances (e.g., agitation and motor restlessness) that interfere with school function.39,40 Although results of clinical investigations have been mixed, most data have failed to demonstrate a consistent effect on learning, although some children are likely to have a detrimental neurobehavioral response to the medication.41,42 With moderate theophylline intoxication, more striking signs of neurologic disturbance appear. An early sign of intoxication is tachypnea, representing stimulation of CNS respiratory centers and often resulting in respiratory alkalosis. Worsening clinical toxicity is attended by anxiety, agitation, and delirium or hallucinosis.32 The single most serious neurologic consequence of theophylline intoxication is the appearance of seizures. Theophylline-induced seizures can present in many patterns. These seizures are usually generalized, although focal seizures have been described.43 In young infants, seizures may be subtle, consisting of generalized hypertonicity, posturing, eye deviation, and lip smacking without a clonic component. Theophylline-induced seizures can be single or repeated. They can appear without warning, although irritability, vomiting, and headache may be premonitory signs.10 Seizures may occur at serum theophylline concentrations less than 20 μg/mL.10 Once they appear, seizures can be extremely difficult to treat, being resistant to standard anticonvulsant therapy. Seizures due to theophylline use often predict a poor outcome; earlier case series reported a mortality rate of 50% to 100% among those who developed


1039

seizures.44,45 Numerous case reports and case series have reported disabling, permanent neurologic sequelae in those who develop theophylline-induced seizures.10,46-51 Neurologic and neurobehavioral complications can include amnesia, personality changes, quadriplegia, and intractable seizure disorder. In young infants, associated intracerebral hemorrhage has been reported.47 Neurologic sequelae are more common after long-term theophylline overmedication rather than acute single overdose. The mechanism of theophylline-induced seizures is not completely understood and is likely multifactorial. However, in one series, as many as 34% of children and 12% of adults developed abnormalities on electroencephalogram while taking the medication.46 Theophyllineinduced seizures have been linked to dysfunction of GABAergic inhibitory neurons and depressed serum pyridoxal levels52; in an animal model, pyridoxine, which promotes γ-aminobutyric acid (GABA) synthesis, was found to ameliorate theophylline-induced seizures.6,53 Theophylline’s relationship to CNS adenosine receptors has received considerable attention in recent years. The CNS has a dense population of adenosine receptors. These modulate the activity of various populations of neurons (e.g., cholinergic and glutaminergic). In vitro and in vivo studies have proved the importance of endogenous adenosine in regulating neuronal depolarization. For example, adenosine antagonists lead to marked alterations in seizure pattern after experimental administration of proconvulsant agents, producing uninterrupted electric discharge. Studies with radiolabeled theophylline have also shown it can displace adenosine from its receptor sites. In an animal model of theophylline-induced seizures, Shannon and Maher demonstrated that direct CNS administration of adenosine could forestall theophylline-induced seizures.54 In addition to its direct neuroexcitatory effects, theophylline has marked effects on cerebral vascular tone, an action that is also related to adenosine activity.55 Adenosine is a potent stimulator of cerebral vasodilation; marked increases in CNS adenosine activity occur in response to cerebral ischemia, representing another cerebroprotective effect. Theophylline antagonizes this action, producing sustained cerebrovasoconstriction, which compromises CNS delivery of oxygen and nutrients as well as removal of toxic metabolic wastes. Metabolic Metabolic complications of theophylline intoxication are many.56,57 Even in therapeutic doses, theophylline can produce depressions in serum potassium and elevations in blood glucose levels. With more severe intoxication, profound hypokalemia can result. Serum potassium concentrations as low as 1.7 mEq/L have been reported after theophylline poisoning.34,58 The mechanism of theophylline-induced hypokalemia is well defined. Although early theories attributed it to potassium losses as a result of vomiting or diuresis, these are unlikely to be the cause.59 For example, Amitai and Lovejoy demonstrated that the hypokalemia often precedes vomiting.60 The current belief is that hypokalemia results from increased intracellular transport of potassium ion,

1040


produced by amplification of sodium-potassium adenosine triphosphatase (Na+/K+-ATPase) or opening of calcium-linked potassium channels. This effect occurs secondary to catecholamine-induced β2-adrenergic stimulation.59,61-63 As a result, total-body potassium is preserved. Theophylline-induced hypokalemia promptly reverses as serum theophylline concentration declines, without potassium supplementation. The clinical consequences of theophylline-induced hypokalemia are unclear. Although hypokalemia has been implicated in the genesis of theophylline-induced cardiac arrhythmias, this is only speculative and is not supported by available data. Blood glucose elevations also appear to be a result of circulating plasma catecholamines. Serum blood glucose can rise to levels greater than 400 mg/dL; theophylline intoxication can mimic diabetic ketoacidosis.34,64 Metabolic acidosis with depression of serum bicarbonate levels is usually modest but can be severe, resulting in a high anion gap. Serum bicarbonate concentrations as low as 5 mEq/L have been reported after serum theophylline poisoning. Acidosis appears to result from the combination of increased lactate production and lipolysis with increased free fatty acid circulation.65 Other metabolic disturbances associated with theophylline intoxication include hypercalcemia, which has been reported in as many as 15% of patients.66 Hypomagnesemia, hypophosphatemia, and respiratory alkalosis have also been reported.56,58 Theophylline has not been proved to have significant human genotoxicity or fetotoxicity, although such effects have been observed in experimental models.6,15,67 However, it is listed as a pregnancy category C drug by the U.S. Food and Drug Administration.

Acute vs. Chronic Intoxication The clinical course of patients with theophylline poisoning is highly variable and often unpredictable. The reasons for such wide variations in reaction to a drug whose toxic manifestations are so clearly recognized have been an enigma that continues to challenge clinicians who must provide immediate and appropriate care to theophyllinepoisoned patients in order to prevent disastrous outcomes. During the past 20 years, a series of important modulators of theophylline poisoning have been identified. Early descriptions of the clinical course of theophylline intoxication suggested that serum theophylline concentrations were highly predictive of outcome. For example, in a study of 28 children with acute theophylline intoxication, Gaudreault and colleagues demonstrated that life-threatening toxicity did not appear with serum theophylline concentrations less than 70 μg/mL and that the lower the serum theophylline concentration, the less likely the risk for major toxicity.68 Bertino, Aitken, and others subsequently published case series indicating that serum theophylline concentration was not always predictive of clinical course and that patients with relatively low serum theophylline concentrations often had fatal outcomes.46,69-71 In 1985, Olson and colleagues were the first to clearly demonstrate that the clinical course of patients with

theophylline intoxication was largely influenced by the mechanism of their poisoning.72 This study found that victims of acute theophylline intoxication, although they were more likely to have metabolic consequences such as hypokalemia and hyperglycemia, seemed to tolerate elevated serum theophylline concentrations better than those with chronic overmedication. Those in the latter category had a lower incidence of metabolic disturbances but were more likely to have life-threatening seizures or cardiac disturbances. Moreover, these lifethreatening events occurred at lower serum theophylline concentrations than in those with acute intoxication who developed life-threatening events.72 Subsequent studies have attempted to clarify differences in outcome as influenced by method of intoxication.6 Consequently, three types of patients with theophylline intoxication have been identified: those with acute overdose, those with chronic overmedication, and those with acute-on-therapeutic intoxication. According to current definitions, the victim of acute theophylline overdose is one who has not been taking or receiving theophylline but is then exposed to a single dose exceeding 10 mg/kg. A patient who suffers an acute toxic overdose and who has been taking theophylline for only 1 or 2 days, not having reached steady-state concentrations (which require 4 to 5 half-lives), is also considered a victim of acute overdose. Common causes of acute overdose include ingestion by children, attempted suicide by young adults, and inadvertent administration of an excess dose by clinicians (physician, nurse, or pharmacist). Tenfold errors in drug administration are a common cause of acute intoxication in children. The findings of Gaudreault and colleagues have been borne out by larger, subsequent clinical investigations: Patients with acute theophylline overdose generally exhibit signs of minor toxicity at serum theophylline concentrations of 20 to 40 μg/mL, moderate toxicity with concentrations of 40 to 80 μg/mL, and severe toxicity with concentrations of greater than 70 to 80 μg/mL. In the absence of prompt, aggressive care, serum theophylline concentrations of greater than 100 μg/mL are often fatal (although survival with only supportive care has been reported with serum theophylline concentrations of 203 and 300 μg/mL.73,74 Victims of chronic theophylline overmedication differ from those with acute poisoning in several respects. First, epidemiologically, these patients are more likely to be very young (i.e., neonates) or elderly. They invariably have preexisting cardiorespiratory disease, which is the reason they are taking the medication. Unintentional overmedication can result from a number of causes, most commonly inappropriate dosing by the patient or health care provider (Table 65-2). Those with chronic overmedication have a substantially higher risk for major toxicity than those with acute intoxication (49% versus 10% in one study37). This higher incidence occurs despite lower serum theophylline concentrations in those with chronic overmedication.75 The most distinctive feature of chronic theophylline overmedication is the complete loss of predictive value provided by serum theophylline concentration. Victims

CHAPTER 65

TABLE 65-2 Common Causes of Chronic Theophylline Overmedication CAUSE Increased dosing by patient or parent Physician dosing error Drug interaction Cardiac disease Viral illness Hepatic disease Unknown

PERCENTAGE OF CASES 31 14 7 10 3 1 35

Adapted from Shannon M, Lovejoy F: The influence of age vs. peak serum concentration of life-threatening events after chronic theophylline intoxication. Arch Intern Med 1990;150:2045.

of chronic overmedication may have seizures, arrhythmias, and fatalities at serum theophylline concentrations as low as 20 to 30 μg/mL.49 Conversely, patients may survive serum concentrations as high as 100 μg/mL. Olson and coworkers suggested that among those with chronic overmedication, serum theophylline concentrations have some predictive value; however, others have not found this. Studies now indicate that age rather than peak serum theophylline concentration is most predictive of major toxicity after chronic theophylline overmedication; proportional increases in the risk of a lifethreatening event occur with advancing age.37,76 In the pediatric age group, the opposite is true; the younger the patient, the greater the risk for major toxicity.75,76 Age is not a risk factor in the development of major toxicity for those with acute theophylline overdose. Acute-on-therapeutic theophylline intoxication acts in an intermediate fashion, with metabolic disturbances and clinical consequences occurring in a pattern that lies between the other two populations.37,75,77 Differences between those with acute versus chronic theophylline intoxication are also evident in patients’ metabolic profile. For example, in those with acute intoxication, 85% to 95% develop hypokalemia, in contrast to 25% to 32% of those with chronic overmedication.72,77 Serum glucose level is typically higher and serum bicarbonate level lower in those with acute theophylline overdose.

Diagnosis of Theophylline Poisoning The diagnosis of theophylline poisoning is made in various ways. With acute overdose, patients, friends, or caretakers offer a history of recent use. In those with chronic overmedication, the diagnosis may be more elusive, with vague and nonspecific presenting complaints. Complaints of nausea, vomiting, and diarrhea may be erroneously diagnosed as gastroenteritis. In elderly patients, the presenting complaint is often respiratory decompensation; in such cases, the development of chronic theophylline overmedication has likely resulted from improper self-medication (i.e., taking extra doses). In many cases of theophylline


1041

intoxication, seizures may be the presenting feature. Various presenting signs require a high index of suspicion as well as a detailed review of medications that the patient is taking. Because increasing numbers of drugs are being found to inhibit cytochrome P-450 activity, close attention should be paid to those patients taking theophylline in combination with another drug. In those who receive inadvertent intravenous theophylline overdoses, representing either acute or acuteon-therapeutic poisoning, the error is often discovered when the clinical status deteriorates and tachycardia, agitation, or frank seizures appear. Serum theophylline concentrations are readily measured. However, theophylline may not be a part of a general toxic screen, and thus the test must be specifically requested. Because serum theophylline concentrations may be of limited value in patients with chronic theophylline overmedication, it is essential that a thorough clinical assessment be performed. After an acute toxic ingestion, theophylline concentrations should be measured every 2 to 4 hours until a plateau is documented because of the risk for delayed peak absorption after ingestion of sustained-release theophylline preparations.15,77,78 Ancillary laboratory tests that are important in the treatment of patients with theophylline intoxication include an electrocardiogram; chest radiograph; measurement of arterial blood gas, serum electrolytes, calcium, and blood sugar; and occasionally liver function tests. Because seizures may be associated with a cerebrovascular accident, cranial tomography should be considered for those who develop convulsions.

Management of Theophylline Poisoning SUPPORTIVE MEASURES General management principles are key in the care of patients with theophylline poisoning. For those with respiratory compromise, cardiac disturbances, or seizures, initial interventions must include airway control, assisted ventilation, and vascular access. Patients who present with respiratory failure as a result of exacerbation of their pulmonary disease or seizure require immediate endotracheal intubation. Hypotension may reflect theophylline-induced vasodilation, dehydration, or myocardial infarction. In such cases, based on clinical assessment and, ideally, central venous pressure monitoring, modest fluid boluses should be administered. If vasopressor therapy is needed, there are theoretic advantages to using phenylephrine, a potent peripheral vasoconstrictor. However, more conventional vasopressors, including dopamine, dobutamine, and norepinephrine, are also effective for blood pressure support. Cardiac arrhythmias also require immediate intervention and can be treated according to advanced cardiac life support algorithms. Isolated ventricular premature beats without hemodynamic compromise require no treatment. More significant signs of myocardial irritability should be treated with appropriate doses of lidocaine. Although the proconvulsant actions of lidocaine pose


theoretic risks, no evidence shows that lidocaine is detrimental when used in appropriate doses. Supraventricular arrhythmias can be treated with agents including β blockers, verapamil, or adenosine. Propranolol has been shown to reverse peripheral vasodilation, hypotension, tachycardia, hypokalemia, and hypercalcemia after theophylline poisoning.34,63,66,79 It may, however, produce bronchoconstriction in susceptible individuals. Esmolol, a very short-acting β1-specific antagonist, has been used successfully for reversal of tachycardia.80,81 The calcium channel blocker verapamil, although effective in the treatment of supraventricular tachycardia, carries the risk for exacerbating hypotension.82 The intimate relationship between theophylline and adenosine justifies the use of adenosine (Adenocard) as first-line treatment for theophylline-induced tachyarrhythmias. Supraventricular tachycardia is very responsive to adenosine therapy. If the basis of theophyllineinduced tachyarrhythmias is cardiac adenosine receptor antagonism, exogenous adenosine can be considered an “antidote” in reversing this effect. The dose of adenosine is 6 to 20 mg for adults and 0.1 mg/kg for children. Adenosine is effective only if delivered into the central circulation by rapid bolus. Having an elimination halflife of about 10 seconds, adenosine may not produce sustained control of arrhythmias. Like propranolol, adenosine has been associated with the occurrence of bronchoconstriction. Seizures are an ominous occurrence with theophylline intoxication because they are often multiple, are highly resistant to anticonvulsant therapy, and are associated with permanent neurologic disability. This recognition has led some physicians to recommend prophylactic anticonvulsant therapy to those patients who present with severe theophylline intoxication.15 In many victims, however, particularly those with chronic theophylline overmedication (who have the greatest likelihood of seizures), high-risk patients are difficult to identify, making it unclear who should receive preventive anticonvulsant therapy. Certainly, once they appear, seizures should be treated aggressively. The initial anticonvulsant should be a benzodiazepine (e.g., diazepam or lorazepam). Benzodiazepines are considered agents of choice because the benzodiazepine receptor is linked to GABAergic neurons. Large doses of benzodiazepines may be necessary to control seizures. The second anticonvulsant choice is a barbiturate such as phenobarbital.83 Like the benzodiazepines, barbiturates have actions at the GABA receptor; they are effective at terminating theophylline-induced seizures. Barbiturates do, however, have two disadvantages. First, they have a delayed onset of action. Also, being CNS depressants, they may produce severe respiratory depression if administered in conjunction with benzodiazepines. Phenytoin is relatively contraindicated in the treatment of theophylline-induced seizures, based on both empirical observation that it is ineffective in terminating theophylline-induced seizures and animal data that suggest that phenytoin increases the risk for theophyllineinduced seizures.83 If anticonvulsants are ineffective in terminating seizures, skeletal muscle paralysis may be

necessary to prevent the complications of prolonged tonic–clonic activity. However, with theophylline intoxication, paralysis carries the risk for masking continued seizure activity. Because experimental data suggest that continued electric discharge and resulting metabolic disturbances are pivotal in theophylline-induced neurologic injury, every effort should be made to provide electroencephalographic monitoring. GI disturbances, although generally not considered life threatening, have a critical role in the management of theophylline intoxication because they prevent both successful GI decontamination and elimination enhancement with multiple-dose activated charcoal. Therefore, a treatment priority is control of vomiting. Vast clinical experience indicates that conventional interventions, including antiemetic suppositories and low-dose metoclopramide, are ineffective therapies. Phenothiazines are also disappointing as antiemetics; they also may precipitate seizures because of their ability to lower seizure threshold. Several agents are effective in control of theophyllineinduced emesis. Parenteral H2 antagonists, particularly ranitidine, control gastric acid secretion and reduce the mucosal irritation that contributes to vomiting84 (Fig. 65-2). Metoclopramide is an effective antiemetic if given in adequate doses. For control of theophyllineinduced vomiting, the recommended dose is 0.1 to 1 mg/kg; lower doses are unlikely to be effective. Because metoclopramide doses of this magnitude have been associated with the development of acute dystonic

Pt. #1

100 80 60

Pt. #2

t1/ —3.7 hr

t1/ —2.4 hr

2

2

40 Theophylline (μg/mL)

1042

20 Vomiting

10 8 6 4 Droperidol

2

Ranitidine

Activated charcoal

1 0

4

8

12 16 20 24 28 32 0

4

8

12 16

Hours FIGURE 65-2 Serum theophylline concentrations and frequency of vomiting in two patients before and during treatment with ranitidine, droperidol, and repetitive activated charcoal. t1/2, elimination half-life of theophylline. (From Amitai Y, Yeung AC, Moye J, Lovejoy FH: Repetitive oral activated charcoal and control of emesis in severe theophylline toxicity. Ann Intern Med 1986;105:386.)

CHAPTER 65

reaction, diphenhydramine should be made readily available or administered prophylactically. Ondansetron, a nonsedating antiemetic that acts as an inhibitor of CNS serotonergic neurons, has also been successfully used to control theophylline-induced vomiting.85 Another agent that may be effective is droperidol.84 Aggressive GI decontamination is important because sustained-release theophylline tablets can coalesce, forming bezoars.86 Activated charcoal should be administered as soon as possible. Whole bowel irrigation has been advocated for the treatment of sustainedrelease theophylline ingestion; however, whole bowel irrigation fluids may promote theophylline desorption from activated charcoal. One study has suggested that whole bowel irrigation offers no additional benefit over activated charcoal.87 If confirmed by additional studies, these data would support omission of whole bowel irrigation as an adjunct to use of activated charcoal after theophylline ingestion. Metabolic disturbances generally do not require aggressive management. Insulin therapy is not recommended for hyperglycemia because blood glucose elevations are transient and inconsequential.34 Significant metabolic acidosis should be treated with administration of sodium bicarbonate. The most significant metabolic abnormality is hypokalemia, which can be profound. Because total-body potassium is unchanged, exogenous potassium theoretically is not needed. However, because hypokalemia may be a risk factor for cardiac disturbances, it is appropriate to treat severe depressions of serum potassium concentration. Potassium supplementation should be provided cautiously and with close monitoring of serum potassium values to prevent iatrogenic hyperkalemia. D’Angio and Sabatelli described a patient with theophylline intoxication who was treated with aggressive potassium replacement. As the patient’s serum theophylline concentration fell, however, serum potassium level rose, resulting in a hyperkalemic cardiac disturbance.88 ELIMINATION ENHANCEMENT Having a favorable pharmacokinetic profile, theophylline can be removed by a number of methods; because of its life-threatening toxicity, the drug should be removed as quickly as possible once the need has been determined.89 Multiple-dose activated charcoal is very effective at enhancing the elimination of theophylline from the body, even if toxic doses have been administered intravenously.84,90 Theophylline has the unusual property of diffusibility across the gut mucosa, such that if activated charcoal is present in the GI lumen, theophylline adsorbs to charcoal and is eliminated in the stool. This action is referred to as GI dialysis or enterocapillary exsorption (see Chapter 2). Animal models and case reports have demonstrated the efficiency with which repeat oral charcoal doses can eliminate theophylline that has been administered intravenously. Theophylline clearance rates as high as 100 mL/min, corresponding to serum elimination half-lives as low as 1 to 2 hours, have been reported with use of multiple-


1043

dose activated charcoal.15,78,91 Because it is so effective yet noninvasive, multiple-dose activated charcoal is the cornerstone of elimination enhancement procedures in patients with theophylline intoxication.92 For treatment of theophylline intoxication, activated charcoal should be administered in a dose of 1 g/kg (maximum 50 g) every 4 hours. If vomited, the dose should be repeated. Alternative administration strategies include 20 g every 2 hours or continuous nasogastric infusion of activated charcoal.93,94 Aggressive antiemetic therapy is usually necessary to permit retention of charcoal. Continuous assessment of bowel motility is important because of the risk for intestinal pseudoobstruction, which has been associated with use of multiple-dose activated charcoal in theophylline intoxication.95 Repeat doses of charcoal can be safely administered to young infants.96 In 1979, Russo demonstrated that theophylline could be rapidly removed from the body by hemoperfusion.91 Theophylline clearance rates that were four to six times greater than endogenous clearance could be produced by hemoperfusion, making this procedure extremely valuable in treating theophylline intoxication.48 With hemoperfusion, theophylline extraction ratios as high as 0.75, corresponding to elimination half-lives of 1 to 2 hours, were initially reported. Three hours of hemoperfusion removed more than 65% of a theophylline dose in early experiences.97 In contrast, hemodialysis, an alternative to hemoperfusion, could only double theophylline clearance rates.78 Hemoperfusion has become widely considered to be the definitive treatment for theophylline intoxication. However, because newer high-flux hemodialysis machines are capable of increasing theophylline clearance rates greater than 300 mL/min, comparable to the rates achieved with hemoperfusion,78 hemodialysis is now considered an option equal to charcoal hemoperfusion for serious theophylline intoxication. The criteria for hemodialysis (or hemoperfusion; HD/HP) after theophylline intoxication are controversial. Park and colleagues proposed the criterion of peak serum theophylline concentration greater than 60 μg/mL or a concentration of greater than 30 μg/mL in patients older than 60 years.50 Olson and coworkers have recommended hemoperfusion in those with acute intoxication and serum theophylline concentrations of greater than 100 μg/mL and in those with chronic overmedication and peak concentrations greater than 40 to 60 μg/mL.72 Greenberg and associates recommended that hemoperfusion be performed only in those with intractable hypotension, ventricular ectopy, or resistant seizures.82 Notably, all investigators have emphasized that a criterion for HD/HP is the appearance of seizures or arrhythmias, suggesting that HD/HP is also effective in reducing morbidity and mortality once major toxicity is manifested. However, data now suggest that most patients who received HD/HP after they had a seizure or cardiac arrhythmia continued to have these lifethreatening events. In contrast, as few as 5% of patients who receive HD/HP before major toxicity eventually develop a life-threatening event.37 Therefore, HD/HP is

1044

BOX 65-3


RECOMMENDATIONS FOR ELIMINATION ENHANCEMENT AFTER THEOPHYLLINE INTOXICATION

Acute Intoxication

1. Multiple-dose activated charcoal for all patients 2. HD/HP for patients with peak serum [theo] > 80–100 μg/mL* 3. HD/HP for patients with peak serum [theo] > 60–80 μg/mL and intractable vomiting 4. HD/HP for those with seizures or cardiac arrhythmias and serum [theo] > 100 μg/mL Chronic Overmedication

1. Multiple-dose activated charcoal for all patients 2. HD/HP for all patients younger than 6 mo or older than 65 yr with serum [theo] > 30–40 μg/mL *Exchange transfusion may be used as an alternative therapy for neonates. HD/HP, hemodialysis or hemoperfusion.

best considered a preventive intervention rather than a procedure that offers great benefit after major toxicity has developed. Based on the growing data that have analyzed major toxicity and its predictors as a function of method of intoxication, the following recommendations are rational (Box 65-3): For all patients with theophylline intoxication (serum theophylline concentration > 20 to 30 μg/mL), treatment should be initiated with multipledose oral charcoal. For those with acute theophylline intoxication, HD/HP should be performed in patients with a serum theophylline concentration of greater than 80 to 100 μg/mL. If uncontrolled vomiting prevents successful charcoal administration, HD/HP should be performed in all those with serum theophylline concentrations that exceed 60 to 80 μg/mL. The decision to perform HD/HP after chronic theophylline intoxication is more difficult for several reasons. First, the patients at greatest risk for seizures and cardiac arrhythmias cannot be identified on the basis of peak serum theophylline concentration. Second, these victims are usually very young or very old, ages at which HD/HP is technically more difficult. Finally, patients with chronic theophylline intoxication often have seizures and cardiac arrhythmias as their presenting manifestations, making the value of HD/HP less clear. Nonetheless, because of the evidence that high-risk patients are those at extremes of age, hemodialysis should be considered in all patients with a serum theophylline concentration of greater than 30 μg/mL, particularly those younger than 6 months or older than 65 years. HD/HP is technically difficult to perform in neonates, although it has been proved successful.98 Consequently, alternative methods of extracorporeal drug removal have been evaluated. Among these, exchange transfusion is the procedure with the greatest promise. Although an early case report found no benefit of exchange transfusion in infants with severe acute

theophylline intoxication,74 two recent case reports have demonstrated that significant amounts of theophylline can be removed with exchange transfusion, making this therapy a viable option in acutely poisoned neonates.99,100 Plasmapheresis has also been successfully used in the treatment of theophylline intoxication, reducing elimination half-life to 1.7 hours.101,102

CAFFEINE Caffeine is a plant alkaloid found in a wide variety of foods and beverages. Coffee, tea, and chocolate have the largest natural concentrations of caffeine. Caffeine is also added to carbonated beverages and a large number of over-the-counter medications including weight control aids, “alertness” tablets, pain relievers, diuretics, and cold remedies (Table 65-3). Finally, caffeine is prescribed for the treatment of apnea-bradycardia in newborns and as adjunctive therapy for cerebrovascular (migraine) headache.

Clinical Pharmacology Found in the most popular beverages in the world (coffee and soft drinks), caffeine is a widely consumed drug. Significant increases in caffeine use among children and adolescents has been observed in recent years and has been attributed to increased rates of hypertension, insomnia, chronic headache, motor tics, irritability, learning difficulties, and other adverse health effects.103-107 Caffeine can be administered by a number of routes, including oral, intravenous, subcutaneous, and rectal.

TABLE 65-3 Average Caffeine Content of Beverages, Foods, and Pharmaceuticals DOSE RANGE (mg) Beverages Coffee (5 oz) Brewed Instant Decaffeinated Tea (5 oz) Brewed Instant Iced (12-oz glass) Carbonated beverages, 12 oz Chocolate milk Food Dark chocolate, 1 oz Nonprescription Pharmaceuticals Weight control aids Alertness agents Analgesics Diuretics Cold remedies

40–200 30–150 1–5 20–100 25–50 65–80 25–200 2–10 5–30 100–200 100–200 30–65 100–200 15–30

CHAPTER 65

After ingestion, it is well absorbed, with an absorption pattern relatively unaffected by the presence of food. Peak plasma concentrations are achieved 30 to 60 hours after ingestion.108 Absorption after rectal and subcutaneous administration is equally rapid. It has an apparent volume of distribution of 1 L/kg. As with theophylline, caffeine metabolism occurs through biotransformation in the cytochrome P-450 system. The primary metabolic pathway for caffeine is its demethylation. 1-Demethylation produces theobromine (3,7dimethylxanthine), a pharmacologically active methylxanthine found widely in chocolate. 7-Demethylation of caffeine produces theophylline; as a result, caffeine ingestion produces measurable serum theophylline concentrations. The elimination half-life of caffeine is variable and highly age dependent; the average half-life in a nonsmoking adult is 3 to 6 hours. In contrast, premature neonates can have elimination half-lives that range from 1.5 to 6 days.108 Agents associated with induction of cytochrome P-450 enzymes (e.g., smoking) produce shorter half-lives. About 5% of caffeine is excreted unchanged in the urine. Significant amounts of caffeine are excreted into breast milk. Caffeine has a number of pharmacologic actions. Its most important property, mild CNS stimulation, is the basis for the worldwide enjoyment of caffeinated beverages, particularly coffee. This CNS stimulation is associated with increased alertness and concentration as well as mood elevation. In excessive doses, undesirable effects, including hyperactivity (particularly in children), anxiety, and insomnia, appear.41 Caffeine has become extremely valuable therapy in the treatment of the neonatal apnea-bradycardia syndrome. Newborns with this syndrome have recurrent hypoventilation, often accompanied by bradycardia. Both theophylline and caffeine are effective in treating this syndrome; stimulation of central respiratory centers by methylxanthines results in decreased apnea, increased minute ventilation, normalization of breathing pattern, increased ventilatory response to carbon dioxide, and reduction in both the need for and duration of mechanical ventilation. Another beneficial effect in newborns is increased cardiac output.109 Caffeine offers the advantages of excellent absorption after ingestion and a longer elimination half-life; these provide more sustained serum concentrations and more predictable pharmacokinetics. The therapeutic serum concentration of caffeine is 8 to 20 μg/mL. Caffeine is also a cardiotonic agent, producing positive inotropy and chronotropy. However, it does not consistently produce significant increases in pulse or blood pressure.110,111 In susceptible individuals, caffeine occasionally leads to the development of premature ventricular contractions, which are usually of no clinical consequence. Important vascular effects of caffeine include cerebral vasoconstriction and renal vasculature relaxation. Because cerebral vasodilation often contributes to the pathophysiology of headache, constriction of cerebral blood vessels by caffeine can be therapeutic. Enhanced renal blood flow is associated with a modest diuretic effect.


1045

Caffeine has two important GI effects: smooth muscle relaxation and stimulation of gastric secretion. Smooth muscle relaxation is most pronounced at the lower esophageal sphincter, where gastroesophageal reflux can result from caffeine use. In concert with increased secretion of both gastric acid and digestive enzymes, reflux can result in esophagitis (heartburn). These GI effects are also noted after ingestion of decaffeinated coffee, suggesting they are mediated by alkaloids other than caffeine. Metabolic effects of caffeine include increased fatty acid oxidation and glycogenolysis. According to one study, typical doses of caffeine, unlike theophylline, do not usually produce marked increases in circulating plasma catecholamines.112 However, catecholamine elevations have been reported in victims of caffeine intoxication.113 Caffeine exhibits all the properties of an addictive drug (tolerance, dependence, and an abstinence syndrome on immediate withdrawal). Tolerance to all its pharmacologic effects develops after repeated use.

Clinical Toxicology Undesirable effects of caffeine can appear after ingestion of as little as 50 mg; at these doses, anxiety, GI upset, and insomnia may occur. More significant toxicity appears after ingestion of 15 to 30 mg/kg. At this range, moderate toxicity is marked by vomiting, myoclonus, and myocardial irritability. Vomiting may be severe; frank hematemesis may occur.114 Fatal oral doses of caffeine have ranged from 5 to 50 g, with a mean of 10 g; the lethal dose is estimated to be 100 to 200 mg/kg.115 Clinical toxicity correlates with serum caffeine concentrations. Several cups of coffee yield a serum caffeine level of 5 to 10 μg/mL. Agitation and myoclonus occur at levels of 15 to 30 μg/mL; cardiac arrhythmias and seizures develop at 50 to 100 μg/mL. Fatalities have been associated with serum caffeine concentrations as low as 80 μg/mL to as high as 1560 μg/mL,116 although concentrations as high as 200 μg/mL have been associated with survival. Deaths have also been reported from the use of coffee enemas as a naturopathic therapy.117 Many of the consequences of caffeine poisoning are identical to those of theophylline, although they are associated with comparably higher serum caffeine concentrations. Seizures can appear without warning and are often repeated. Opisthotonos, decerebrate posturing, and generalized muscular hypertonicity are also common.118 Cardiac arrhythmias can be supraventricular or ventricular (ventricular tachycardia or fibrillation). Other manifestations of severe intoxication are rhabdomyolysis with resultant acute renal failure and pulmonary edema.119 Rhabdomyolysis has been attributed to increased muscular activity. Pulmonary edema is a frequent occurrence with severe poisoning and is thought to result, in part, from pulmonary vasculature dilation.108,118 Victims of caffeine intoxication develop the metabolic disturbances of hyperglycemia, hypokalemia, leukocytosis, ketosis, and metabolic acidosis. Chronic caffeine intoxication (caffeinism) is manifested by irritability, insomnia, anxiety, emotional lability, and

1046


chronic abdominal pain. Cardiovascular disease, myocardial irritability, and fibrocystic disease of the breast all have been associated with long-term caffeine consumption.112,120,121 However, for all these diseases, the association with caffeine has been controversial and inconsistent in clinical investigations. Caffeine is both mutagenic and teratogenic in laboratory animal species.108 A study of women suggested that more than 600 mg of caffeine daily could result in an increased incidence of spontaneous abortion and premature birth.108 A causal link between caffeine use and birth defects remains tenuous122; however, the Food and Drug Administration has advised pregnant women to avoid or limit caffeine intake. Caffeine has now been proved to produce a physiologic abstinence syndrome (withdrawal). Although it has been well recognized that abrupt termination of caffeine consumption could produce insomnia, malaise, and headache, little scientific investigation has addressed these phenomena. Silverman123 and Strain124 and their colleagues have shown that withdrawal from caffeine can produce an increase in depressive symptoms, anxiety, fatigue, headache, and decreased performance. Abstinence was also associated with a marked increase in the use of medications (e.g., headache relievers).

Management In patients with an acute caffeine overdose, initial attention should be directed to airway, breathing, and circulation. The sudden appearance of airway compromise and hypoxia as a result of seizures, cardiac disturbances, or pulmonary edema should be anticipated, particularly in patients who ingest more than 30 to 50 mg/kg of caffeine. Management of seizures and cardiac disturbances parallels their treatment in patients with theophylline intoxication. Therefore, seizures are preferably treated with a benzodiazepine (e.g., diazepam) or phenobarbital. There is no evidence that phenytoin is ineffective or harmful in the treatment of caffeine-induced seizures; however, because all methylxanthines are presumed to have similar mechanism of toxicity, phenytoin’s lack of efficacy in theophylline-induced seizures argues against its use. Cardiac disturbances should be treated according to standard management strategies. Adenosine, verapamil, and β-blocking agents all are effective treatments for supraventricular arrhythmias.114,125 Ventricular arrhythmias should be treated initially with intravenous lidocaine. GI decontamination measures should include administration of activated charcoal with a cathartic. Vomiting is likely in those with significant ingestion. Although this provides gastric evacuation, it thwarts efforts at activated charcoal administration. Aggressive antiemetic therapy should therefore be provided. Antiemetic therapy should include the administration of H2 antagonists, which reduce gastric hypersecretion. Other beneficial agents include metoclopramide, 0.1 to 1.0 mg/kg intravenously, and ondansetron, 0.6 mg/kg intravenously.

Laboratory evaluation should include electrolytes, blood glucose, creatine phosphokinase, arterial blood gas, and an electrocardiogram. Hypokalemia should be treated with modest potassium supplementation (because total-body potassium is preserved). Insulin is not recommended for treatment of hyperglycemia, although it has been suggested by others.126 Enhanced elimination is the final component of managing caffeine poisoning. A number of measures have been shown to be effective, including multiple-dose activated charcoal, peritoneal dialysis,114,119 and HD/HP.118,127 Although a proportion of caffeine is excreted from the urine unchanged, forced diuresis has no role in management. Diuresis should be provided only if patients have clinical evidence of severe rhabdomyolysis. Multiple-dose activated charcoal has not been clearly shown to enhance caffeine elimination but does eliminate any theophylline that is generated; it is therefore considered an integral component of treatment. Use of several antiemetic agents may be necessary to end vomiting. Peritoneal dialysis has been used but is unlikely to be more helpful than multiple-dose activated charcoal. Hemodialysis is the procedure that provides greatest efficacy with the lowest complication rate. Indications for hemodialysis are not clearly established but should include a serum caffeine concentration of greater than 100 μg/mL and life-threatening seizures or cardiac arrhythmias, regardless of serum caffeine concentration. Because it is both invasive and unlikely to be more effective than hemodialysis, hemoperfusion has little to no role in the management of caffeine intoxication. REFERENCES 1. Szefler SJ, Bender BG, Jusko WJ, et al: Evolving role of theophylline for treatment of chronic childhood asthma. J Pediatr 1995;127:176–185. 2. Yurdakul A, Taci N, Eren A, Sipit T: Comparative efficacy of oncedaily therapy with inhaled corticosteroid, leukotriene antagonist or sustained-release theophylline in patients with mild persistent asthma. Respir Med 2003;97:1313–1319. 3. Epstein PE: Hemlock or healer? The mercurial reputation of theophylline. Ann Intern Med 1993;119:1216–1217. 4. McFadden ER: Methylxanthines in the treatment of asthma: the rise, the fall, and the possible rise again. Ann Intern Med 1991;115:323–324. 5. Barr R, Rowe B, Camargo C: Methylxanthines for exacerbations of chronic obstructive pulmonary disease: meta-analysis of randomized trials. BMJ 2003;327:643. 6. Shibata M, Wachi M, Kagawa M, et al: Acute and subacute toxicities of theophylline are directly reflected by its plasma concentration in dogs. Methods Find Exp Clin Pharmacol 2000;22:173–178. 7. Murciano D, Auclair M-H, Pariente R, Aubier M: A randomized, controlled trial of theophylline in patients with severe chronic obstructive pulmonary disease. N Engl J Med 1989;320: 1521–1525. 8. Drazen JM, Gerard C: Reversing the irreversible. N Engl J Med 1989;320:1555–1556. 9. Henderson-Smart D, Steer P: Methylxanthine treatment for apnea in preterm infants. Cochrane Database Syst Rev 2001;3: CD000140. 10. American Academy of Pediatrics Committee on Drugs: Precautions concerning the use of theophylline. Pediatrics 1992; 89:781–782.

CHAPTER 65

11. Thomas N, Carcillo J: Theophylline for acute renal vasoconstriction associated with tacrolimus: a new indication for an old therapeutic agent? Pediatr Crit Care Med 2003;4:392–393. 12. Kapoor A, Kumar S, Gulati S, et al: The role of theophylline in contrast-induced nephropathy: a case-control study. Nephrol Dial Transplant 2002;17:1936–1941. 13. Huber W, Ilgmann K, Page M, et al: Effect of theophylline on contrast material-nephropathy in patients with chronic renal insufficiency: controlled, randomized, double-blinded study. Radiology 2002;223:772–779. 14. Fischer R, Lang SM, Steiner U, et al: Theophylline improves acute mountain sickness. Eur Respir J 2000;15:123–127. 15. Hendeles L, Jenkins J, Temple R: Revised FDA labeling guidelines for theophylline oral dosage forms. Pharmacotherapy 1995;15: 409–427. 16. Lowry JA, Jarrett RV, Wassermann G, et al: Theophylline toxicokinetics in premature newborns. Arch Pediatr Adolesc Med 2001;155:934–939. 17. Weinberger M, Ginchansky E: Dose-dependent kinets of theophylline disposition in asthmatic children. J Pediatr 1977;91: 820–824. 18. Mayo P: Effect of passive smoking on theophylline clearance in children. Ther Drug Monit 2001;23:503–505. 19. Bakris GL, Sauter ER, Hussey JL, et al: Effects of theophylline on erythropoietin production in normal subjects and in patients with erythrocytosis after renal transplantation. N Engl J Med 1990;323:86–90. 20. Fredholm BB: On the mechanism of action of theophylline and caffeine. Acta Med Scand 1985;217:149–153. 21. Polson JB, Krzanowski JJ, Goldman AL, Szentivanyi A: Inhibition of human pulmonary phosphodiesterase activity by therapeutic levels of theophylline. Clin Exp Pharm Physiol 1978;5:535–539. 22. Curry SC, Vance MV, Requa R, Armstead R: The effects of toxic concentrations of theophylline on oxygen consumption, ventricular work, acid base balance and plasma catecholamine levels in the dog. Ann Emerg Med 1985;14:554–561. 23. Curry SC, Vance MV, Requa R, Armstead R: Cardiovascular effects of toxic concentrations of theophylline in the dog. Ann Emerg Med 1985;14:547–553. 24. Higbee MD, Kumar M, Galant SP: Stimulation of endogenous catecholamine release by theophylline: a proposed additional mechanism of action for theophylline effects. J Allergy Clin Immunol 1982;70:377–382. 25. Vestal RE, Eiriksson CE, Musser B, et al: Effect of intravenous aminophylline on plasm plasma levels of catecholamines and related cardiovascular and metabolic responses in man. Circulation 1983;67:162–171. 26. Feoktistov I, Biaggioni I: Role of adenosine in asthma. Drug Dev Res 1996;39:333–336. 27. Visitsunthorn N, Udomittipong K, Punnakan L: Theophylline toxicity in Thai children. Asian Pac J Allergy Immunol 2001;19: 177–182. 28. Schiff GD, Hegde HK, LaCloche L, Hryhorczuk DO: Inpatient theophylline toxicity: preventable factors. Ann Intern Med 1991;114:748–753. 29. Paloucek FP, Rodvold KA: Evaluation of theophylline overdoses and toxicities. Ann Emerg Med 1988;17:135–144. 30. Shannon MW, Lovejoy FH, Woolf A: Prediction of serum theophylline concentration after acute theophylline intoxication [abstract]. Ann Emerg Med 1990;19:627. 31. Stavric B: Methylxanthines: toxicity to humans. Food Chem Toxicol 1988;26:541–565. 32. Baker MD: Theophylline toxicity in children. J Pediatr 1986; 109:538–542. 33. Amitai Y, Lovejoy FH: Characteristics of vomiting associated with acute sustained release theophylline poisoning: implications for management with oral activated charcoal. Clin Toxicol 1987; 25:539–554. 34. Biberstein MP, Ziegler MG, Ward DM: Use of beta-blockade and hemoperfusion for acute theophylline poisoning. West J Med 1984;141:485–490. 35. Lin CK, Chuand IN, Cheng KK, Chiang BN: Arrhythmogenic effects of theophylline in human atrial tissue. Int J Cardiol 1987;17:289–297.


1047

36. Sessler CN, Cohen MD: Cardiac arrhythmias during theophylline toxicity: a prospective continuous electrocardiographic study. Chest 1990;98:672–678. 37. Shannon M: Predictors of major toxicity after theophylline overdose. Ann Intern Med 1993;119:1161–1167. 38. Bittar G, Friedman HS: The arrhythmogenicity of theophylline: a multivariate analysis of clinical determinants. Chest 1991;99: 1415–1420. 39. Rachelefsky GS, Wo J, Adelson J, et al: Behavior abnormalities and poor school performance due to oral theophylline use. Pediatrics 1986;78:1133–1138. 40. Rappaport L, Coffman H, Guare R, et al: Effects of theophylline on behavior and learning in children with asthma. Am J Dis Child 1989;143:368–372. 41. Stein M, Krasowski M, Leventhal BL, et al: Behavioral and cognitive effects of methylxanthines: a meta-analysis of theophylline and caffeine. Arch Pediatr Adolesc Med 1996;150:284–288. 42. Schlieper A, Alcock D, Beaudry P, et al: Effect of therapeutic plasma concentrations of theophylline on behavior, cognitive processing and affect in children with asthma. J Pediatr 1991;118:449–455. 43. Nakada T, Keww IL, Lerner AM, Remler MP: Theophyllineinduced seizures: clinical and pathophysiologic aspects. West J Med 1983;138:371–374. 44. Zwillich CW, Sutton FD, Neff TA, et al: Theophylline-induced seizures in adults. Ann Intern Med 1975;82:784–787. 45. Phung ND: Theophylline toxicity in ambulatory elderly patients. Immunol Allergy Practice 1986;8:17–20. 46. Richards W, Church JA, Brent DK: Theophylline-associated seizures in children. Ann Allergy 1985;54:276–279. 47. Woody RC, Laney M: A second case of infantile intracranial hemorrhage and severe neurological sequelae following theophylline overdose. Dev Med Child Neurol 1986;28:120–121. 48. Sahney S, Abarzua J, Sessums L: Hemoperfusion in theophylline neurotoxicity. Pediatrics 1983;71:615–619. 49. Bahls F, Ma KK, Bird TD: Theophylline-associated seizures with “therapeutic” or low toxic serum concentrations: risk factors for serious outcome in adults. Neurology 1991;41:1309–1312. 50. Park GD, Spector R, Roberts RJ, et al: Use of hemoperfusion for treatment of theophylline intoxication. Am J Med 1983;74:961–966. 51. Parish RA, Haulman NJ, Burns RM: Interaction of theophylline with erythromycin base in a patient with seizure activity. Pediatrics 1983;72:828–830. 52. Seto T, Inada H, Kobayashi N, et al: Depression of serum pyridoxal levels in theophylline-related seizures. Brain Dev 2000;32:295–300. 53. Glenn GM, Krober MS, Kelly P, et al: Pyridoxine as therapy in theophylline-induced seizures. Vet Human Toxicol 1995;37:342–344. 54. Shannon M, Maher T: Anticonvulsant effects of intracerebroventricular Adenocard in theophylline-induced seizures. Ann Emerg Med 1995;26:65–68. 55. Pinard E, Riche D, Puiroud S, Seylaz J: Theophylline reduces cerebral hyperaemia and enhances brain damage induced by seizures. Brain Res 1990;511:303–309. 56. Hall KW, Dobson KE, Dalton JG, et al: Metabolic abnormalities associated with intentional theophylline overdose. Am J Emerg Med Ann Intern Med 1984;101:457–462. 57. Sawyer WT, Caravati EM, Ellison MJ, Krueger KA: Hypokalemia, hyperglycemia, and acidosis after intentional theophylline overdose. Am J Emerg Med 1985;3:408–411. 58. Robertson NJ: Fatal overdose from a sustained-release theophylline preparation. Ann Emerg Med 1985;14:154–158. 59. Buckley BM, Braithwaite RA, Vale JA: Theophylline poisoning. Lancet 1983;2:618. 60. Amitai Y, Lovejoy FH: Hypokalemia in acute theophylline poisoning. Am J Emerg Med 1988;6:214–218. 61. Clausen T, Flatman JA: Beta-2 adrenoceptors mediate the stimulating effect of adrenaline on active electrogenic Na-Ktransport in rat soleus muscle. Br J Pharmacol 1980;68:749–755. 62. Clausen T: Adrenergic control of Na-K-homeostasis. Acta Med Scand 1983;672(Suppl):111–115. 63. Kearney TE, Manoguerra AS, Curtis GP, Ziegler MG: Theophylline toxicity and the beta-adrenergic system. Ann Intern Med 1985;102:766–769.

1048


64. Polak M, Rolon MA, Chouchana A, Czernichow P: Theophylline intoxication mimicking diabetic ketoacidosis in a child. Diabetes Metab 1999;25:513–515. 65. Ryan T, Coughlan G, Mc Ging P, Phelan D: Ketosis, a complication of theophylline toxicity. J Int Med 1989;226:277–278. 66. McPherson ML, Prince SR, Atamer ER, et al: Theophyllineinduced hypercalcemia. Ann Intern Med 1986;105:52–54. 67. Neff RD, Leviton A: Maternal theophylline consumption and the risk of stillbirth. Chest 1990;97:1266–1267. 68. Gaudreault P, Wason S, Lovejoy F: Acute pediatric theophylline overdose: a summary of 28 cases. J Pediatr 1983;102:474–476. 69. Aitken ML, Martin TR: Life-threatening theophylline toxicity is not predictable by serum levels. Chest 1987;91:10–14. 70. Bertino JS, Walker JW: Reassessment of theophylline toxicityserum concentrations, clinical course, and treatment. Arch Intern Med 1987;147:757–760. 71. Covelli HD, Knodel AR, Heppner BT: Predisposing factors to apparent theophylline-induced seizures. Ann Allergy 1985;54: 411–415. 72. Olson KR, Benowitz NL, Woo OF, Pond SM: Theophylline overdose: acute single ingestion versus chronic repeated overmedication. Am J Emerg Med 1985;3:386–394. 73. Dean LS, Brown JW: Massive theophylline overdose: survival without hemoperfusion. JAMA 1982;248:1742. 74. Wells DH, Ferlauto JJ: Survival after massive aminophylline overdose in a premature infant. Pediatrics 1979;64:252–253. 75. Shannon M, Lovejoy F: Effect of acute versus chronic intoxication on clinical features of theophylline poisoning in children. J Pediatr 1992;121:125–130. 76. Shannon M, Lovejoy F: The influence of age vs. peak serum concentration of life-threatening events after chronic theophylline intoxication. Arch Intern Med 1990;150:2045–2048. 77. Shannon M, Lovejoy F: Hypokalemia after theophylline intoxication: the effects of acute vs. chronic poisoning. Arch Intern Med 1989;149:2725–2729. 78. Heath A, Knudsen K: Role of extracorporeal drug removal in acute theophylline poisoning: a review. Med Toxicol 1987;2:294–308. 79. Amin DN, Henry JA: Propranolol administration in theophylline overdose. Lancet 1985;1:520–521. 80. Gaar GG, Banner W, Laddu AR: The effects of esmolol on the hemodynamics of acute theophylline toxicity. Ann Emerg Med 1987;16:1334–1339. 81. Seneff M, Scott J, Friedman B, Smith M: Acute theophylline toxicity and the use of esmolol to reverse cardiovascular instability. Ann Emerg Med 1990;19:671–673. 82. Greenberg A, Piraino BH, Kroboth PD, Weiss J: Severe theophylline toxicity—role of conservative measures, antiarrhythmic agents and charcoal hemoperfusion. Am J Med 1984;76:854–860. 83. Blake KV, Massey KL, Hendeles L, et al: Relative efficacy of phenytoin and phenobarbital for the prevention of theophyllineinduced seizures in mice. Ann Emerg Med 1988;17:1024–1028. 84. Amitai Y, Yeung AC, Moye J, Lovejoy FH: Repetitive oral activated charcoal and control of emesis in severe theophylline toxicity. Ann Intern Med 1986;105:386–387. 85. Roberts JR, Carney S, Boyle SM, Lee D: Ondansetron quells drugresistant emesis in theophylline poisoning. Am J Emerg Med 1993;11:609–611. 86. Bernstein G, Jehle D, Bernaski E, Braen GR: Failure of gastric emptying and charcoal administration in fatal sustained-release theophylline overdose: pharmacobezoar formation. Ann Emerg Med 1992;21:1388–1390. 87. Burkhart KK, Metcalf S, Shurnas E, et al: Exchange transfusion and multidose activated charcoal following vancomycin overdose. Clin Toxicol 1992;30:285–294. 88. D’Angio R, Sabatelli F: Management considerations in treating metabolic abnormalities associated with theophylline overdose. Arch Intern Med 1987;147:1837–1838. 89. Borkan S: Extracorporeal therapies for acute intoxications. Crit Care Clin 2002;18:393–420. 90. Kulig KW, Bar-Or D, Rumack BH: Intravenous theophylline poisoning and multiple-dose charcoal in an animal model. Ann Emerg Med 1987;16:842–846. 91. Russo ME: Management of theophylline intoxication with charcoal-column hemoperfusion. N Engl J Med 1979;300:24–26.

92. Anonymous: Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. J Toxicol Clin Toxicol 1999;37:731–751. 93. Ohning BL, Reed MD, Blumer JL: Continuous nasogastric administration of activated charcoal for the treatment of theophylline intoxication. Pediatr Pharmacol 1986;5:241–245. 94. Park GD, Radomski L, Goldberg MJ, et al: Effect of size and frequency of oral doses of charcoal on theophylline clearance. Clin Pharmacol Ther 1983;34:664–666. 95. Longdon P, Henderson A: Intestinal pseudo-obstruction following the use of enteral charcoal and sorbitol and mechanical ventilation with papaveretum sedation for theophylline poisoning. Drug Safety 1992;7:74–77. 96. Shannon M, Amitai Y, Lovejoy FH: Multiple-dose activated charcoal for theophylline poisoning in young infants. Pediatrics 1987;80:368–370. 97. Goldberg MJ, Park GD, Berlinger WG: Treatment of theophylline intoxication. J Allergy Clin Immunol 1986;78:811–817. 98. Gitomer J, Khan A, Ferris M: Treatment of severe theophylline toxicity with hemodialysis in a preterm neonate. Pediatr Nephrol 2001;16:784–786. 99. Osborn HH, Henry G, Wax P, et al: Theophylline toxicity in a premature neonate-elimination kinetics of exchange transfusion. Clin Toxicol 1993;31:639–644. 100. Shannon M, Wernovsky B, Morris C: Exchange transfusion in the treatment of severe theophylline poisoning. Pediatrics 1992;89: 145–147. 101. Laussen P, Shann F, Butt W, Tibballs J: Use of plasmapheresis in acute theophylline toxicity. Crit Care Med 1991;19:288–290. 102. Gaudreault P, Guay J: Theophylline poisoning—pharmacological considerations and clinical management. Med Toxicol 1986;1: 169–191. 103. Nawrot P, Jordan S, Eastwood J, et al: Effects of caffeine on human health. Food Addit Contam 2003;20:1–30. 104. Pollak C, Bright D: Caffeine consumption and weekly sleep patterns in US seventh-, eighth-, and ninth-graders. Pediatrics 2003;111:42–46. 105. Hering-Hanit R, Gadoth N: Caffeine-induced headache in children and adolescents. Cephalalgia 2003;23:332–335. 106. Savoca M, Evans CD, Wilson ME, et al: The association of caffeinated beverages with blood pressure in adolescents. Arch Pediatr Adolesc Med 2004:158:473–477. 107. Davis R, Osorio I: Childhood caffeine tic syndrome. Pediatrics 1998;101:E4. 108. Dalvi R: Acute and chronic toxicity of caffeine: a review. Vet Hum Toxicol 1986;28:144–150. 109. Walther FJ, Erickson R, Sims M: Cardiovascular effects of caffeine therapy in preterm infants. Am J Dis Child 1990;144:1164–1166. 110. Lovallo W, Wilson MF, Vincent AS, et al: Blood pressure response to caffeine shows incomplete tolerance after short-term regular consumption. Hypertension 2004;43:760–765. 111. Myers M: Effects of caffeine on blood pressure. Arch Intern Med 1988;148:1189. 112. Chelsky L, Cutter JE, Griffith K, et al: Caffeine and ventricular arrhythmias—an electrophysiological approach. JAMA 1990; 264:2236–2240. 113. Benowitz N, Osterloh J, Goldschlager N: Massive catecholamine release from caffeine poisoning. JAMA 1982;248:1097–1098. 114. Walsh I, Wassermann GS, Mestad P, Lanman RC: Near fatal caffeine intoxication treated with perineal dialysis. Pediatr Emerg Care 1987;3:244–246. 115. Holmgren P, Norden-Pettersson L, Ahlner J: Caffeine fatalities— four case reports. Forensic Sci Int 2004;139:71–73. 116. Mrvos R, Reilly PE, Dean BS, Krenzelok EP: Massive caffeine ingestion resulting in death. Vet Hum Toxicol 1989;31:571–573. 117. Eisele J: Deaths related to coffee enemas. JAMA 1980;244: 1608–1609. 118. Dietrich AM, Mortensen M: Presentation and management of an acute caffeine overdose. Pediatr Emerg Care 1990;6:296–298. 119. Wrenn K, Oschner I: Rhabdomyolysis induced by a caffeine overdose. Ann Emerg Med 1989;18:94–97. 120. Lubin F, Ron E, Wax P, et al: A case-control study of caffeine and methylxanthines in benign breast disease. JAMA 1985;253: 2388–2392.

CHAPTER 65

121. Minton J: Caffeine and benign breast disease. JAMA 1985;254: 2408–2409. 122. Signorello L, McLaughlin J: Maternal caffeine consumption and spontaneous abortion: a review of the epidemiologic evidence. Epidemiology 2004;15:229–239. 123. Silverman K, Evans SM, Strain EC, Griffiths RR: Withdrawal syndrome after the double-blind cessation of caffeine consumption. N Engl J Med 1992;327:1109–1114. 124. Strain E, Mumford GK, Silverman K, Griffiths RR: Caffeine dependence syndrome: evidence from case histories and experimental evaluations. JAMA 1994;272:1043–1048.


1049

125. Price K, Fligner D: Treatment of caffeine toxicity with esmolol. Ann Emerg Med 1990;19:44–46. 126. Sullivan J: Caffeine poisoning in an infant. J Pediatr 1977;90: 1022–1023. 127. Holstege C, Hunter Y, Baer AB, et al: Massive caffeine overdose requiring vasopressin infusion and hemodialysis. J Toxicol Clin Toxicol 2003;41:1003–1007.

66

Anticoagulants MELISA W. LAI, MD ■ MICHELE BURNS EWALD, MD

At a Glance… ■

■ ■

There are two main anticoagulant medication mechanisms of action: (1) platelet aggregation inhibition, involving the glycoprotein IIb/IIIa receptor inhibitors eptifibatide and abciximab and the cyclooxygenase inhibitor aspirin; and (2) disruption of the coagulation cascade, involving the vitamin K inhibitors warfarin and superwarfarins, antithrombin III acceleration through factors II and X, the heparins, and fondaparinux, and direct thrombin (factor II) inhibition through leech-derived anticoagulants (hirudins) and ximelagatran. Even in overdose situations, anticoagulants rarely precipitate life-threatening hemorrhage. Treatment should be based on clinical assessment supported by the results of bleeding time studies (partial thromboplastin time, prothrombin time, International Normalized Ratio, hematocrit concentration, and platelet concentration).

Exposure Surveillance System (TESS) data from 2000 to 2004 show that the number of rodenticide anticoagulant exposures in the United States stayed constant at about 17,000 per year; the number of anticoagulant overdoses from medical therapeutic use increased each year during the same time period, from 2871 overdoses in 2000 to 4786 in 2004 (Table 66-1). Anticoagulation medications targeted toward various components of the coagulation cascade and platelet aggregation systems continue to be developed, and new trials to prove efficacy in vaso-occlusive events continue to be held. As such, the scope of the material in this chapter is constantly evolving, and specific product information data sheets should be referred to when encountering new anticoagulant therapies.

REVIEW OF COAGULATION Anticoagulation has become a fundamental basis of medical therapy for patients with cardiovascular and thromboembolic disease. Medications that disrupt or block platelet aggregation and fibrin cross-linkage are now the standard of care in management and prevention of vaso-occlusive events. The results of multiple studies on the treatment of acute coronary syndrome, deep vein thrombosis (DVT), and pulmonary embolism have led to the development, introduction, and implementation of new anticoagulant and antiplatelet medications as well as their dosing protocols. This increase in the number of available agents, in conjunction with the widespread use of anticoagulants, may explain the changing profile of anticoagulant overdose and exposure. Although anticoagulants have also had long-standing use as rodenticides, Toxic

Understanding the mechanism of coagulation is key to understanding the mechanism of action of various anticoagulants and therapies for overdose. The two components of the coagulation pathway are the platelet system and the coagulation cascade.

The Platelet System Platelet coagulation is mediated by both vascular wall adhesion through von Willebrand factor (vWF) and platelet aggregation through glycoprotein IIb/IIIa (gpIIb/IIIa) receptors. Vascular injury exposes collagen and releases tissue factor. Circulating inactive platelets adhere to the site of injury by binding either directly to collagen or indirectly through vWF, and then are “activated” by locally generated thrombin. Soluble

TABLE 66-1 Anticoagulant Exposures and Overdoses in the United States Therapeutic Anticoagulant Overdoses Glycoprotein IIb/IIIa inhibitor overdoses Other antiplatelet/anticoagulant overdoses Herparin overdosesNot reported Warfarin overdoses

2000 Not reported Not reported 138 2139 TOTAL

Anticoagulant-type Rodenticide Exposures Rodenticide exposures (warfarin-type) Rodenticide exposures (long-acting, superwarfarin) TOTAL

Total Anticoagulant Overdoses/Exposures

2001 3 993 149 2304

2002 9 1298 164 2684

2003 11 1490 176 2718

2004 14 1842 198 2732

2277

3449

4155

4395

4786

1181 16,006

492 16,423

462 17,100

341 16,481

337 16,054

17,187

16,915

17,562

16,822

16,391

19,464

20,364

21,717

21,217

21,177

Compiled from Annual Reports of the American Association of Poison Control Centers Toxic Exposure Surveillance System, 2000–2002.

1051

1052


ADP

TxA2

TxA2 ADP Endothelial Cell

Rolling

Subendothelium (vWF, collagen) Activated Platelet

Tissue factor (TF)

Adhesion, spreading

Aggregation, thrombus formation

Unactivated platelet

von Willenbrand Factor (vWF)

FIGURE 66-1 Platelet adhesion and aggregation to injured vascular wall. Platelets bind directly to collagen or to von Willebrand factor (vWF) and are “activated” by locally generated thrombin. Adenosine diphosphate (ADP) and thromboxane A2 (TxA2) are released by active platelets to recruit further platelets. Activated platelets bind to each other through fibrinogen linkages to gpIIb/IIIa receptors upregulated to platelet membrane surface.

factors such as adenosine diphosphate (ADP) and thromboxane A2 (TxA2) are released by activated platelets to recruit nonadherent platelets. Platelets then aggregate by adhering to each other through fibrinogen linkages. Fibrinogen molecules bind to the gpIIb/IIIa receptor, the most abundant platelet surface protein. The gpIIb/IIIa receptors can undergo up-regulation to effectively double in number on the surface of activated platelets (Fig. 66-1).

The Coagulation Cascade The coagulation cascade is a chain of events that starts with dormant enzymes (proteases) called coagulation factors and ends with the activation of the protein thrombin. Thrombin is needed for platelet activation and to cleave fibrinogen into fibrin for cross-linkage (Fig. 66-2). By having this chain of activations rather than one single activation, modifications made early in the cascade can quickly be amplified, leading to timely changes in thrombin production. Coagulation factor nomenclature uses Roman numerals; many also have eponyms or “given” labels (Table 66-2). An inactive factor will be written as simply the Roman numeral, whereas an activated factor has a small Roman alphabet letter “a” appended to it (e.g., inactive factor VII, when activated is written as factor VIIa). Although most coagulation factors are made by the liver, factor XIII is derived from platelets and factor VIII from endothelial cells. Factors II (prothrombin), VII (Stable), IX (Christmas), and X (Stuart) and anticoagulant proteins C and protein S are dependent on γ-carboxylase, a vitamin K–dependent liver enzyme.

Intrinsic and Extrinsic Pathways The coagulation cascade is triggered by either factors intrinsic to circulating blood (leading down the intrinsic pathway) or tissue-based factors extrinsic to blood (leading down the extrinsic pathway). The intrinsic system is activated when high-molecular-weight kininogens (precursors of bradykinin) and the enzyme

kallikrein activate factor XII in the presence of collagen exposed from an injury. Its major factors are XII, XI, IX, and VIII. Factor VIII, normally complexed to vWF, is activated upon dissociation. Factor X is not activated until both activated factors VIIIa and IXa are in the presence of calcium and platelet phospholipids (PLs). This pathway is measured by the partial thromboplastin time (PTT). The extrinsic pathway is initiated when thromboplastin (i.e., tissue factor [TF]), a lipid-rich protein released on tissue injury, directly activates factor VII, which in turn triggers IX with subsequent activation of factor X. This pathway is measured by the prothrombin time (PT). After convergence of the cascade at factor X, active factor Xa complexes with factor Va and Ca2+ in the presence of PLs to create the factor Va + Xa + calcium + PL complex that cleaves prothrombin (II) to thrombin (IIa).

Control of the Coagulation Cascade There are two “brakes” that control the coagulation cascade: the thrombolytic system and coagulation factor inhibition. In the thrombolytic system, the inactive precursor protein plasminogen is cleaved into the serum protease plasmin after coming into contact with thrombin. Plasmin then cleaves fibrin to break up the clot and, in doing so, creates fibrin degradation products that inhibit further thrombin formation. Coagulation factor inhibitors include antithrombin III (ATIII), protein C, and protein S. Protease inhibitor ATIII physically blocks the action of coagulation factors in the coagulation cascade (thrombin, IX, X, XI, and XII). This blockade is accelerated up to 2000 times by heparin. Protein C is activated by thrombin to cleave factor Va into its inactive form, preventing the factor Va + Xa + calcium + PL complex from cleaving prothrombin to thrombin. Protein S is a necessary cofactor of protein C.

Vitamin K and Coagulation Vitamin K is discussed in detail elsewhere in this text. Because of its important role in coagulation and the

CHAPTER 66

K

K

CH3

O

O

XIIa

Vitamin K3 (menadione)

IX

vWf::VIII

TF::VIIa

IXa

CH2

)

Vitamin K2 (menaquinone)

CH2

H CKC

K

CH3

Vitamin K1 (phytonadione) FIGURE 66-3 Structure of vitamin K subtypes. All subtypes have a recognizable two-ring basic structure.

Xa Ca2+ PL V IIa (thrombin)

I (fibrinogen)

Ia (fibrin) XIIIa

XIII

Stable fibrin (cross-linked) FIGURE 66-2 The coagulation cascade. HMWK, high-molecularweight kininogens (bradykinin precursors); PL, platelet phospholipids; PT, prothrombin time; PTT, partial thromboplastin time; TF, tissue factor (thromboplastin); vWF, von Willebrand factor.

mechanism of action for some anticoagulants, it is reviewed here. Vitamin K is a lipid-soluble vitamin found and manufactured in a synthetic and two natural forms. Natural vitamin K1 (phytonadione, phylloquinone) is synthesized TABLE 66-2 Coagulation Factors and Their Eponymous Names

VIII IX X XI XII XIII

)

CH2 H CKC H CH2 n

O

II (prothrombin)

I II III IV V VI VII

CH3

VII

VIIIa Ca2+ PL X

FACTOR*

CH3

O

TF

XIa

K

XI

1053

O

O

K

XII

Extrinsic (measure PT) Vessel injury

K

Intrinsic (measure PTT) exposed collagen HMWK+kallikrein

Anticoagulants

EPONYM/”TRIVIAL” NAME Fibrinogen Prothrombin Tissue factor Calcium Proaccelerin, labile† Accelerin Stable, proconvertin, serum prothrombin conversion accelerator (SPCA) Antihemophiliac factor A Christmas, antihemophiliac factor B Stuart-Power factor Plasma thromboplastin antecedent (PTA) Hageman factor Fibrin stabilizing factor (FSF)

*Activated factors append a letter “a” to the Roman numeral (e.g., inactive factor VII becomes activated factor VIIa). † Note that Labile is the eponym for factor V, while “factor V Leiden” refers to the gene defect in factor V resulting in diminished anticoagulation and consequent hypercoagulable state. Adapted from King MW: Blood coagulation. Retrieved July 12, 2004, from http://web.indstate.edu/theme/mwking/blood-coagulation.html.

by plants and algae. Natural vitamin K2 (menaquinone) is produced by bacteria. Vitamin K3 (menadione) is synthetic and converted to active K2 in vivo. All vitamin K subtypes are two-ring structures with variable carbon side chains (Fig. 66-3). Vitamin K is required for γ-carboxylation of glutamate residues to activate factors II, VII, IX, and X. Vitamin K produces γ-carboxylase (γ-carboxyglutamate), which chelates Ca2+, allowing binding of vitamin K–dependent clotting factors to phospholipid membranes during activation of the coagulation cascade. Reduction or absence of vitamin K leaves factors II, VII, IX, and X in their inactive states, halting the coagulation cascade. With an estimated plasma half-life of 1.7 hours,1 vitamin K1 depletion resulting in clinically significant change within the coagulation cascade is not expected for at least 24 hours; that is, five half-lives of vitamin K plus five half-lives of the vitamin K–dependent clotting factor with the shortest half-life (t1/2[factor VII] = 6 hours2): = 5(t1/2[vitamin K]) + 5(t1/2[factor VII])

ANTICOAGULANTS BY MECHANISMS OF ACTION Vitamin K Inhibition Warfarins and superwarfarins (4-hydroxycoumarins and inandiones) disrupt the vitamin K cycle by primarily inhibiting vitamin K 2,3-epoxide reductase and, to a lesser degree, vitamin K quinone reductase (Fig. 66-4). These drugs prevent the regeneration of active vitamin K1 (quinol) with subsequent depletion of vitamin K–dependent coagulation factors (II, VII, IX and X) and disruption of the coagulation cascade. WARFARIN Background Warfarin was developed after the discovery of the agent responsible for a hemorrhagic bovine disorder in which cows that ingested spoiled sweet clover silage would develop internal bleeding associated with plasma

1054


5

NAD(P)H-dependent quinone reductase Active Vitamin K1 quinone reductase

Vitamin K1 (phytonadione) Quinone form

Vitamin K1 (phytonadione) Quinol form

1

Carboxylase/ epoxidase Inactive Vitamin K1 2,3-epoxide

Inactive Factors II, VII, IX, X Proteins C and S

2

3

g-Carboxylation of glutamic acid residues Active Factors IIa, VIIa, IXa, Xa Proteins C and S

4 Vitamin K1 2,3-epoxide reductase FIGURE 66-4 The vitamin K cycle. Inactive vitamin K–dependent prozymogens are coagulation factors II, VII, IX, and X and proteins C and S. (1) Vitamin K1 (quinone form) is reduced by vitamin K1 quinone reductase to its active (quinol) form. (2) Quinol (hydroquinone, vitamin KH2) exists in hepatic microsomes. (3) Carboxylase-epoxidase (coupled) enzyme simultaneously catalyzes γ-carboxylation coagulation factors to active form and converts quinol to the inactive vitamin K1 2,3-epoxide. (4) Vitamin K1 2-3-epoxide → recycled via epoxide reductase to quinone. (5) Alternatively, NAD(P)H-dependent quinone reductase is not affected by warfarins → vitamin K administered exogenously may still be reduced and counter anticoagulation. (Adapted from Burkhart K: Anticoagulant rodenticides. In Ford MD, Delaney KA, Ling LJ, Erickson T [eds]: Clinical Toxicology. Philadelphia, WB Saunders, 2001, p 849.)

prothrombin reduction.3 From this clover, the natural bishydroxywarfarin (dicoumarol) was eventually derived in 1939; later, the Wisconsin Alumni Research Foundation synthesized and named the pharmaceutical agent warfarin, which became commercially available in 1955.3 In 2002, warfarin was the 64th-most frequently prescribed drug based on the number of prescriptions written.4 Usage and Indications Warfarin is a racemic mixture of R- and S-enantiomers. The S-enantiomer is five times more potent than the R orientation at producing hypoprothrombinemia (decreased prothrombin slows the coagulation cascade) in rats5 and 1.8 times more potent in humans.6 The Senantiomer is also eliminated more slowly than the Renantiomer in rats, but is more rapidly eliminated in humans.7 This difference in enantiomer potency and rate of elimination makes warfarin an appealing rodenticide. As a therapeutic anticoagulant in humans, warfarin is used for treatment of pulmonary embolism and DVT, to prevent atrial thrombus formation in atrial fibrillation, and for patients with severe peripheral vascular disease and arterial stenoses. Pharmacokinetics Warfarin’s only route of administration is oral, and it is almost completely absorbed from the gastrointestinal tract.4 Maximum plasma concentrations are reached within 20 minutes to 4 hours after ingestion.4,8 Wafarin is highly protein bound (99%), but only the free fraction of the drug is active.4 Warfarin’s half-life is 36 to 42 hours,9 and its duration of action after a single dose is 2 to 5 days8; it takes about 6 days to reach a steady state. Inhibition of vitamin K regeneration is almost immediate, but effects are delayed until existing stores of vitamin K are depleted and active coagulation factors re-

moved from circulation. Because of the rapid turnover of vitamin K, warfarin’s effects are dependent on factor half-life, and PT prolongation is not seen until factors are reduced to 25% of their normal values. For example, factor VII, which is depleted most rapidly, has a half-life of 5 hours; hence, it takes at least 15 hours until PT prolongation is evident. Metabolism Warfarin is metabolized in the liver through the cytochrome P-450 system. The R-enantiomer is primarily metabolized by isoenzymes CYP1A2 and CYP3A410 and excreted in the kidney. The S-enantiomer is metabolized more rapidly by CYP2C910 and secreted into bile. Elimination half-life is 24 to 36 hours. Drugs that inhibit the P-450 system, and subsequently prolong warfarin’s action, include erythromycin, metronidazole, thyroxine, isoniazid, and trimethoprim-sulfamethoxazole. Substances that enhance the P-450 system to induce warfarin’s metabolism, thus decreasing its effectiveness, include barbiturates, penicillin, carbamazepine, charbroiled foods, and tobacco smoke. Dosage and Therapeutic Monitoring Warfarin is dosed once daily orally and titrated to an appropriate international normalized ratio (INR) for different conditions. Warfarin use is monitored by measuring PT and calculating the INR. The INR “normalizes” variations in PT measurement due to different sensitivities of reagents used by different laboratories. Most clinicians opt for a goal INR of 2.0 to 2.5 in patients with atrial fibrillation; an INR of 2.5 to 3.0 for patients being treated for venous thromboses; and an INR as elevated as 2.5 to 3.5 in patients with mechanical prosthetic heart valves.9 The optimal children’s dose has been calculated to be 0.07 μ [weight in kg] + 0.54 mg,11

CHAPTER 66

Warfarin in Pregnancy Warfarin is a pregnancy category X drug (adverse effects reported, contraindicated in pregnancy) and is a teratogen that leads to a particular constellation of congenital defects after ingestion during the first trimester, particularly between weeks 6 and 9 of gestation. About one third of infants exposed to warfarin during this time period develop fetal warfarin syndrome (FWS; also known as warfarin embryopathy or fetal Coumarin syndrome).13 Infants with FWS display a range of physical and central nervous system anomalies, including nasal hypoplasia, stippling of uncalcified epiphyses (particularly of the axial skeleton), mild hypoplasia of nails and shortened fingers, low birth weight, and varying degrees of mental retardation. Patients who are breast-feeding may use warfarin for anticoagulation therapy. An inactive form of warfarin is excreted into breast milk,8 but several researchers have confirmed that active warfarin is not detectable in human milk, and there is no evidence of detectable warfarin levels, altered coagulation, or other adverse events in infants exposed to breast milk from mothers taking warfarin.14,15 Overdose In therapeutic overmedication, warfarin should be held and indications for vitamin K administration should be reviewed in consultation with those monitoring therapeutic dosing. Patients with an abnormally elevated INR or intentional warfarin overdose should be admitted to a hospital and placed on bed rest to minimize the risk for trauma with subsequent internal or intracranial bleeding. Often, depending on a patient’s INR, withholding warfarin administration for several days is sufficient to bring an INR down to therapeutic levels. Vitamin K is indicated for those with a significantly elevated INR that does not decrease when warfarin is withheld or when there is evidence of hepatic synthetic dysfunction (e.g., a significant increase in liver transaminase concentrations or in the INR). Fresh frozen plasma is indicated for those with active bleeding. In the absence of recent changes in dosing regimen, clinicians should investigate reasons for an increased INR, such as the use of other medications that may inhibit the cytochrome P-450 system, infection, or misuse or mislabeling. In acute overdose of warfarin, treating practitioners should determine the nature of the ingestion: unintentional (accidental) or intentional. In most accidental single ingestions, the amount of warfarin ingested is highly unlikely to result in a clinically apparent coagulopathy, and most patients may be monitored safely at home with appropriate caveats to avoid contact sports and situations increasing the likelihood of traumatic injury for several days. Intentional ingestions present the dilemma that a patient may ingest further warfarin when not being monitored. Repetitive

1055

ingestions can lead to a clinically significant coagulopathy. These patients should be dispositioned after consultation with a poison control center (the American Association of Poison Control Centers national poison control center hotline is 1-800-222-1222; www.aapcc.org) and appropriate psychiatric services. Nonbleeding Complications Warfarin use has been implicated in the rare development of nonhemorrhagic skin lesions ranging from simple ecchymosis and purpura to urticaria, purple toes, and skin necrosis.16 Warfarin skin necrosis usually appears over fatty tissues (breasts, buttocks, thighs) 3 to 6 days after warfarin therapy initiation; patients with protein C, protein S, and antithrombin III deficiency appear to be at greater risk for development of this condition.17 Warfarin should be discontinued in patients who acquire skin necrosis, and alternative anticoagulation should be started to prevent postcapillary thrombosis. Purple toe syndrome is thought to be caused by anticoagulant-induced bleeding into atherosclerotic plaques releasing cholesterol crystal emboli.18 Changing anticoagulation agents is thus unlikely to prevent or reverse progression. SUPERWARFARINS Background The superwarfarins, 4-hydroxycoumarins and inandiones, were developed in response to genetic resistance to warfarin in rats.19-21 They are primarily used as rodenticides and have no role in human medical therapeutic anticoagulation. In fact, warfarin ingestions were deemed “clinically insignificant” until 1976 when the superwarfarins were developed for use as rodenticides. The 4-hydroxycoumarins in use today are difenacoum, brodifacoum (D-Con), bromadiolone, and coumatetralyl. Inandiones include chlorophacinone, diphacinone, and pindone. Both the hydroxycoumarins and inandiones have a two-ring base structure similar to warfarin (Figs. 66-5 and 66-6). Both groups function just as warfarin does, by inhibiting vitamin K 2,3-epoxidase. Toxicokinetics Superwarfarins are highly lipid soluble and are mostly concentrated in the liver. On a mole-for-mole basis, they are 100 times more potent than warfarin.22 In overdose, their elimination half-life is weeks to months,22 up to 60 times longer than warfarin’s half-life of 35 hours. They also have a considerably longer duration of action: a rat that dies after a single superwarfarin ingestion would require 21 days of warfarin before meeting the same fate. C

O

K

K

whereas nomograms have been developed to guide initial dosage in adults based on clinical situation and target INR.12

Anticoagulants

O

FIGURE 66-5 Warfarin.


O

O

O

K

1056

K

K

R1

O

R2

4-Hydroxycoumarin Inandione FIGURE 66-6 Structures of 4-hydroxycoumarin (left) and indanedione (right). Note the two-ring base structure, similar to that of warfarin in Figure 66-3.

Ingestion Superwarfarin ingestions illustrate the toxicologist’s adage that “it is only the dose which makes a thing a poison” (Aureolus Paracelsus, 1493–1541). Given that repetitive dosing is necessary to achieve therapeutic anticoagulation with warfarin alone, it stands to reason that small single acute ingestions (e.g., a mouthful) are unlikely to produce a clinically significant coagulopathy: a 10-kg child would need to ingest 3000 mg/kg of a 0.005% warfarin-based rodenticide for coagulopathy to develop.23 Management of superwarfarin ingestion should be based on amount ingested as related to circumstance of ingestion. Most cases of superwarfarin exposure are either intentional ingestions by adults or unintentional ingestions by children (including ingestion of rat feces from poisoned rodents24). Case reports have also described warfarin and superwarfarins as agents of ingestion for Munchausen syndrome and Munchausen syndrome by proxy.25-31 Regardless of amount of superwarfarin ingested, clinically significant anticoagulation in a patient not already taking an anticoagulant agent is not anticipated for about 24 hours, that is, until there is both the depletion of existing vitamin K stores and subsequent loss of vitamin K–dependent clotting factor regeneration (factors II, VII, IX, and X). Table 66-3 lists half-lives of vitamin K and vitamin K–dependent clotting factors.32 Patients who have ingested superwarfarins intentionally should undergo routine decontamination and have their PT and INR monitored 24 and 48 hours after ingestion. In the acute phase, PT and INR should be reassessed every 6 hours if prolongation is observed.

TABLE 66-3 Half-Lives of Vitamin K and Its Dependent Clotting Factors* VITAMIN/FACTOR Vitamin K1 Factor II Factor VII Factor IX Factor X

There are no means of enhanced elimination of superwarfarins, and multidose activated charcoal has not shown any clear benefit.33 In asymptomatic patients, vitamin K1 (phytonadione) may be administered orally at an initial dose of 5 to 15 mg/day, although an ideal dose has not been established. Bruno and colleagues reported that weight-based dosing of 7 mg/kg over 24 hours divided every 6 hours was needed to treat brodifacouminduced coagulopathy from 344 g of rodenticide containing 0.005% brodifacoum (17.2 mg brodifacoum).34 Administration of vitamin K1,100 to 125 mg/day for several months, has been reported in cases of severe overdose without ill effect; hence, oral dosing of up to 40 to 50 mg three times daily should be considered in those with clinically significant coagulopathy. Historical recommendations for management of symptomatic patients using parenteral administration of vitamin K1 are changing35 (Table 66-4). Although intravenous (IV) administration of vitamin K1 may reverse anticoagulation more quickly than oral administration,36 IV administration remains controversial because it has been associated with anaphylactoid reactions.37-39 Lubetsky and associates reported that oral administration of vitamin K1 is as safe and efficacious in reversal of excessive anticoagulation as when administered intravenously,40 making the argument for IV administration of vitamin K1 a less appealing alternative. With unintentional single ingestions, PT prolongation is unlikely, owing to the relatively small doses ingested. In Thacker’s 14-year case series of children ingesting superwarfarins (1986 to 2000), PT and INR prolongation was seen in less than 0.5% of 11,751 exposures, and only 11 patients developed hemorrhage, all of minimal clinical significance (epistaxis [3], hemarthrosis [2], heme-positive stool [2], vomiting [2], minor bleeding not specified [1]).41 A prospective study of pediatric superwarfarin poisoning by Smolinske and colleagues showed that PT value prolongation was not seen until 48 hours after suspected ingestion and that clinically significant ingestion was apparent in only 2 of 110 patients.42 Children who ingest a small dose of a warfarin-based rodenticide (0.01%–0.005% strength) do not need to

TABLE 66-4 American College of Chest Physicians’ Recommended Dosing of Subcutaneous Vitamin K1 for Reversal of Warfarin/Superwarfarin-induced Coagulopathy in 1995

HALF-LIFE (t1/2) 1.7 hr 50–80 hr 6 hr 24 hr 25–60 hr

*Disruption of the clotting cascade following warfarin or superwarfarin ingestion is expected when vitamin K is depleted and its dependent clotting factors cease regeneration32 From Makris M, Watson HG: The management of coumarin-induced over anticoagulation. Br J Haematol 2001;114(2):271–280.

INR

BLEEDING

Any 20

Serious None None None None

DOSE OF VITAMIN K1 ADMINISTERED INTRAVENOUSLY OR SUBCUTANEOUSLY* 10 mg None 0.5–1 mg 3–5 mg 10 mg

*Intravenous or subcutaneous administration is in addition to oral vitamin K1 administration. Single oral route of administration of vitamin K1 has since proven equally effective.

CHAPTER 66

Intentional

• Notify closest Poison Control Center (PCC): 1-800-222-1222 • Observe at home • Diet rich in vitamin K

1–2 hours

• Check PT/INR on presentation then if INR < 6, once daily if INR > 6, every 6–8 ° • Administer oral vitamin K1 10–150 mg/day until INR < 2 • Discuss with PCC • Psychiatry consultation Yes

Stable?

No

After 1–2 days Decontamination with AC

Petechiae, gingival bleeding, epistaxis…?

Already on anticoagulation therapy?

No

Refer to ED

Signs of active hemorrhage?

Check PT/INR

Yes • Check PT/INR on presentation and then every 6 hours • Administer fresh frozen plasma • Administer oral vitamin K1 10–150 mg/day • Consider IV vitamin K1 administration (slow push with anaphylactoid precautions—see text) • Discuss with PCC

No

Yes

Yes No

1057

Unintentional

Superwarfarin ingestion

Refer to ED

Time of ingestion

Anticoagulants

INR > 2

No

INR < 2

Routine follow-up

Symptomatic? (e.g., petechiae) Yes

• Admit • Check PT/INR once daily • Administer oral vitamin K1 5–15 mg daily • discharge when INR < 2 • Psychiatry/social work consultation

FIGURE 66-7 Proposed general guideline for management of superwarfarin ingestion. Clinicians should take care to assess whether the ingestion is intentional or unintentional. Intentional ingestions are generally by adults; unintentional ingestions are generally by children. Unintentional ingestions are usually small (fewer than two are three mouthfuls) and are unlikely to cause clinically significant anticoagulation. The local poison control center should always be contacted, and the superwarfarin product should be reviewed for concentration of active ingredient and other possible toxins. Patients who have ingested intentionally may present hours to days after their ingestion, usually to a local emergency department (ED) secondary to symptoms such as ecchymosis development or petechiae. Active bleeding (e.g., melena, expanding hematoma, bright red blood from rectum, oozing wounds) requires immediate reversal with fresh frozen plasma (FFP). Lubetsky and colleagues concluded in 2003 that oral administration of vitamin K is as effective as IV administration for warfarin anticoagulation reversal,40 but patients unable to take vitamin K orally may require it intravenously. Note that IV administration of vitamin K remains controversial, with several reports of anaphylactoid reactions upon administration. In the event of anaphylaxis, IV vitamin K should be discontinued immediately and epinephrine administered in conjunction with antihistamines and steroids. Oral vitamin K may be continued unless a similar reaction is observed. AC, activated charcoal; INR, International Normalized Ratio; PT, prothrombin time. (Courtesy of M. W. Lai, MD, and M. W. Shannon, MD, MPH, Massachusetts/Rhode Island Poison Control Center [M. Burns Ewald, MD, Director], Boston.)

present to an emergency department.43 However, patients and parents should be advised to watch for signs of bleeding diatheses; asymptomatic patients can be observed at home if the history is certain that the ingestion was unintentional. If any symptoms develop, the child should have a routine medical screening examination and PT and INR drawn. Increases in PT and INR should be followed weekly until a downward trend is seen. Oral

vitamin K1, 5 to 10 mg, or a diet rich in vitamin K– containing vegetables can be encouraged in the interim. A proposed guideline for superwarfarin ingestion management is shown in Figure 66-7. Clinicians should take care to assess whether the ingestion is intentional or unintentional. Intentional ingestions are generally by adults; unintentional ingestions are generally by children.

1058


Antithrombin III Acceleration through Factor II and Factor X Inhibition Antithrombin III blocks coagulation factors II, IX, X, XI, and XII. Heparins bind to thrombin (factor IIa) and factor Xa to accelerate the anticoagulant effect of ATIII up to 2000 times. UNFRACTIONATED HEPARIN Unfractionated heparin (UFH) is a naturally occurring, negatively charged mucopolysaccharide (glycosaminoglycan) primarily synthesized and secreted by mast cells. Deriving its name from its particular abundance in liver, heparin was discovered by a medical student who, in studying ether-soluble procoagulants, stumbled on this water-soluble anticoagulant instead. Heparin is manufactured through extraction from bovine lung tissue and porcine intestines. Because UFH has varying polysaccharide side-chain lengths, its molecular weight ranges from 3000 to 30,000 daltons.44 UFH accelerates ATIII protease inhibition of thrombin by binding to thrombin (factor IIa) and factor Xa. When ATIII complexes to heparin that is bound to factors IIa and Xa, the complex causes conformational changes in these factors and inactivates them. UFH is only administered parenterally (intravenously or subcutaneously). Dosing is weight based, and depending on the reason for administration, patients may receive 50 to 80 U/kg IV boluses followed by continuous infusions of 12 to 18 U/kg/hour or subcutaneous injections ranging from 7500 U (for DVT prophylaxis) to 20,000 U (for DVT treatment). UFH is an easily titratable medication because of its short halflife of 1 to 2.5 hours and short duration of action of 1 to 3 hours. Therapeutic monitoring is through the PTT.45 The goal PTT for most vaso-occlusive events as well as thrombosis prophylaxis when heparin is used as a single agent is 60 to 80 seconds. Heparin is a pregnancy category C drug and the anticoagulant of choice during pregnancy; its negative charge and large size prevent its passage across the placenta. Overdose Because UFH is predominantly administered in the acute care setting, overdose is most often iatrogenic and may reflect transcription errors of the physician’s or other health care provider’s orders. Initial treatment is discontinuation of the heparin infusion. For patients with active bleeding requiring quick reversal, protamine sulfate (derived from salmon sperm and testes) should be administered. Protamine forms ionic bonds with heparin, preventing its attachment to factors II and Xa, with neutralization of heparin’s effects within 5 minutes of administration.46 Protamine should be dosed as follows: ■ 1 mg protamine per 100 U heparin ■ Administer up to 50 mg intravenously over 10 minutes (more rapid administration may result in hypotension or anaphylactoid reaction).47,48 ■ Half the dose of protamine for each half-life of heparin (about 90 minutes) that has passed since initial administration.

Watch for “rebound” hemorrhage: the half-life of protamine is shorter than that of heparin. Patients previously given protamine for heparin reversal, such as after cardiac bypass surgery, are at risk for becoming sensitized to protamine. Insulin-dependent diabetic patients face a similar risk because protamine is also used to extend the absorption rate of some insulin preparations. (e.g., neutral protamine Hagedorn [NPH] insulin). Antibodies to protamine that develop from NPH insulin administration or from prior heparin reversal with protamine predispose patients to anaphylactoid reactions from future heparin anticoagulation reversal with protamine.49-53 There are no published reports of concurrent NPH insulin use interfering with heparin therapeutic goals. ■

Nonbleeding Complications Patients who experience a drop in platelet count after initiation of heparin therapy may have heparin-induced thrombocytopenia (HIT). There are two forms of HIT. HIT I is characterized by a mild and transient drop in platelet count occurring within 2 days of heparin administration and is usually asymptomatic, resolving spontaneously.54 HIT II (heparin-induced thrombocytopenia and thrombosis, or HITT) is more serious, leading to vascular thromboses and their complications. HIT II appears to be immunologically mediated, with 0.5% to 3% of patients given UFH developing HIT II after first developing heparin-induced antibodies.55,56 The frequency of HIT II appears to be less in patients administered UFH subcutaneously compared with intravenously.57 Patients who develop HIT II should be taken off heparin immediately and should not have heparin in any form readministered. Clinicians may consider testing patients who develop HIT I for heparininduced antibodies before administering heparin products in the future. LOW-MOLECULAR-WEIGHT HEPARINS Low-molecular-weight heparins (LMWHs) are the fractionated active pentasaccharide segment of heparin. Commonly used LMWHs in the United States include enoxaparin (Lovenox), dalteparin (Fragmin), and ardeparin (Normiflo). Average molecular weights run from 4000 to 6000 Daltons. Because binding to factor IIa requires the heparin molecule to have at least 18 saccharide units, LMWHs display targeted factor Xa activity rather than the factor IIa and Xa binding seen with unfractionated heparin. LMWHs have fixed weight-based dosing and are generally administered either once or twice daily, depending on their reason for administration. Pharmacokinetics LMWHs have a higher bioavailability than unfractionated heparin owing to a lower affinity for and decreased binding to endothelium, macrophages, and heparin-binding proteins. Their plasma half-life is 4 to 6 hours, with hepatic metabolism and renal elimination. Patients receiving LMWH therapy do not routinely undergo therapeutic monitoring. Relative effectiveness

CHAPTER 66

Anticoagulants

1059

and concentration of LMWHs can be determined from serum anti–factor Xa concentrations, as measured in IU/mL, if needed. Because of its fixed-dosing regimen, overdoses of LMWHs are infrequent. Because of its renal elimination, patients with renal insufficiency may experience more potentiated effects if weight-based dosing does not take renal function into account. If a patient does suffer an overdose and has active bleeding, protamine should be administered using the same guidelines as for overdose of unfractionated heparin. Since 1 mg of available LMWHs equals approximately 100 anti-Xa units, 1 mg of protamine should be given for every 1 mg of LMWH for Xa neutralization. Protamine does not completely neutralize the anti-Xa activity of LMWH. This is likely due to decreased binding of protamine to LMWHs.58

not routinely undergo therapeutic monitoring. Plasma concentration of the drug can be quantified by serum anti–factor Xa activity when the anti–factor Xa assay is calibrated with fondaparinux. Hence, fondaparinux activity is expressed as milligrams of fondaparinux calibrator. The anti-Xa activity of the drug is enhanced by increasing drug concentration, reaching maximum values in about 3 hours.59 No specific reversal agent has been developed yet for fondaparinux. Because of its small volume of distribution, however, this anti–factor Xa drug is amenable to hemodialysis. Further direct factor Xa inhibitors are being developed, including idraparinux, a “depo” fondaparinux requiring only onceweekly administration.61

DIRECT FACTOR XA INHIBITORS (FONDAPARINUX) Similar to LMWHs, selective factor Xa inhibitors catalyze Xa inactivation by ATIII without inhibiting thrombin. These medications are essentially heparin derivatives, displaying similar structural features as UFH and LMWHs (Fig. 66-8). Fondaparinux (Arixtra) selectively binds ATIII and potentiates ATIII’s neutralization of factor Xa by a factor of 300.59 Currently, only fondaparinux has been approved for therapeutic anticoagulation in humans by targeting this stage in the coagulation cascade. Representative of this emerging anticoagulant class, fondaparinux demonstrates 100% bioavailability and is 94% bound to ATIII. Peak plasma levels are seen in 2 hours. The volume of distribution (Vd) is 100 mL/kg. At least half of the drug is excreted unchanged in urine, and its elimination half-life is 17 to 21 hours. Fondaparinux is administered once daily by either IV or subcutaneous routes at a fixed non–weight-based dose. Presently, fondaparinux is approved for DVT prophylaxis, particularly after lower extremity surgery. Oncedaily subcutaneous injection without monitoring has been shown to be as safe as adjusted-dose IV heparin for treatment of pulmonary embolus.60 Administration in patients who weigh less than 50 kg is contraindicated because of doubling of the incidence of major bleeding.59 Patients receiving fondaparinux therapy do

LEECH-DERIVED ANTICOAGULANTS (HIRUDINS)

H

COO– –O3SOCH2 H H H O O OH

O

OSO3– OSO3– O

COO– O

OH OH O O HO OH HNSO3–

O–

OH

HNSO3– OSO3– O OSO3–

O

HNSO3–

O COO– OH

OSO3– O O

OSO3–

OH OMe HNSO3–

FIGURE 66-8 Top, Representative repeat unit of unfractionated heparin and low-molecular-weight heparin (LMWH). LMWH contains five repeating units. Bottom, fondaparinux.

Direct Thrombin Inhibition Background Leech-derived anticoagulants are small molecules that directly inhibit thrombin (factor IIa). Halting the coagulation cascade at this stage prevents fibrinogen cleavage into fibrin, which is necessary for cross-linkage and subsequent clot formation. Hirudin is the actual 65–amino acid anticoagulant protein found in leech salivary glands. Recombinant DNA hirudins such as desirudin (Revasc) and lepirudin (Refludan) have been developed, as well as hirudin analogs such as bivalirudin (Angiomax). Hirudins are primarily used as heparin substitutes for patients unable to tolerate heparins because of HIT. To date, no published studies have indicated that hirudin use for acute coronary syndrome offers long-term advantage over heparin, but hirudins have been shown to be more effective in preventing postoperative DVT when compared with UFH.62 Hirudins can be administered by either intravenous or subcutaneous routes. Recombinant hirudins are pregnancy category B drugs. Animal studies have not shown teratogenic effects, but hirudins can cross the placental barrier in rats; it is unknown whether hirudins cross the human placenta.63 Effectiveness of hirudin anticoagulation may be assessed through measuring the PTT. Although overdose is rare, hemodiafiltration has been successfully used to manage a 30-fold overdose of lepirudin without bleeding complications.64 XIMELAGATRAN AND MELAGATRAN Melagatran is a direct thrombin inhibitor with a low molecular weight (429 Daltons). It has poor oral absorption (3% to 7% alone, 1% with food), but its prodrug, ximelagatran (Exanta), possesses better absorptive properties. Rapid hydrolysis and reduction of ximelagatran to melagatran increases melagatran’s oral bioavailability to 25%. At present, melagatran and ximelagatran are primarily being used for DVT prevention and anticoagulation for patients with atrial fibrillation. Early studies suggest that it is “superior” to warfarin for prevention of DVTs while maintaining a similar hemorrhagic complication profile,65 as well as the advantage of fixed dosing.

1060


Melagatran and ximelagatran reach peak plasma levels in 2 hours and are 0% to 15% protein bound. Their Vd is 200 mL/kg, and they are renally excreted with an elimination half-life of 3.5 hours. Fixed dosing of melagatran, 2 to 3 mg subcutaneously, is followed by oral doses of ximelagatran at either 24 mg twice daily or 36 mg twice daily, depending on the reason for administration. Dose adjustments are made empirically for patients with renal insufficiency. Although there is no monitoring for therapeutic levels of these direct thrombin inhibitors, the PTT may be tested in patients with renal impairment in order to titrate to an appropriate fixed dose. Overdose There is no specific melagatran or ximelagatran antagonist in the event of an overdose. Patients with active hemorrhage should be administered fresh frozen plasma for replacement of coagulation proteins or prothrombin concentrate. Although there have been no reports of hemodialysis to remove the drug, its small molecular weight and volume of distribution suggest that it could be effectively hemodialyzed.

Inhibition of Platelet Aggregation (Antiplatelet Anticoagulation Therapies) GLYCOPROTEIN IIB/IIIA INHIBITION The gpIIb/IIIa receptor is the most prevalent cell surface protein on platelets. Activation of platelets from their exposure to thrombin at the site of endothelial injury up-regulates gpIIb/IIIa receptors, doubling or even tripling their number. Fibrin cleaved from fibrinogen in the coagulation cascade cross-links to itself as well as between platelets by adhering to the gpIIb/IIIa receptor. Inhibition of the gpIIb/IIIa receptor arrests platelet aggregation through these fibrin connections.

Since their development in the mid-1990s, there are now multiple gpIIb/IIIa inhibitors in use, primarily for the treatment of acute coronary syndromes. Multiple studies have shown the effectiveness of gpIIb/IIIa antagonists in reducing the incidence of death or myocardial infarction in patients who undergo percutaneous coronary intervention (PCI, or cardiac catheterization) for unstable angina (UA) or non–ST elevation myocardial infarction (NSTEMI).66 Table 66-5 compares the three gpIIb/IIIa inhibitors used in the United States today.67-71 Others are xemilofiban, sibrafiban, orbofiban, and lamifiban. When used concomitantly with heparin, gpIIb/IIIa inhibitors should lower the PTT goal (to a range of either 50–70 or 40–60 seconds). In overdose, the gpIIb/ IIIa infusion should be discontinued, and platelets should be administered for active bleeding or a platelet count of less than 20 × 109/L. ADENOSINE DIPHOSPHATE–INDUCED PLATELET AGGREGATION INHIBITION Platelet activation leads to release of ADP, a soluble factor that induces further platelet aggregation through their recruitment and activation. Drugs in the thienopyridine class (ticlopidine [Ticlid] and clopidogrel [Plavix]) are platelet aggregation inhibitors that work by irreversibly inhibiting ADPinduced platelet aggregation. They selectively and noncompetitively inhibit the binding of ADP to its platelet receptor (P2 receptors) by irreversibly modifying the receptor. Doing so halts the ADP-mediated activation of the gpIIb/IIIa complex necessary for platelet linkage.72-74 The thienopyridine derivatives have similar chemical structures (clopidogrel adds a carboxymethyl side group). Both are metabolized by CYP1A to active metabolites that have not yet been isolated.74 They affect

TABLE 66-5 Comparison of Properties of Three Major gpIIb/IIIa Inhibitors* EPTIFIBATIDE67

TIROFIBAN68

ABCIXIMAB69

Trade name Manufactured by/from

Integrelin Solution-based peptide synthesis

Aggrastat Nonpeptide

Complete platelet inhibition

1–2 hr

Return to platelet function after d/c of infusion Elimination half-life

30 min

Unclear; inhibition as early as 5 min 3–8 hr

ReoPro Chimeric (human-murine) monoclonal antibody Fab fragment Within 2 hr

1–2.5 hr

1.5–3 hr

Molecular weight Vd Excretion

832 185 mL/kg Renal 50%

495.1 22–42 L Renal 65%

Dose adjustment in renal failure? Provides benefit in PCI? Hemodialyzable?

Yes

Yes

Phase 1 < 10 min Phase 2 ~ 30 min 47455.4 Unknown Renal and protein catabolism70 No

Clear benefit Yes

Benefit Yes

No change N/A

48 hr

*Drugs used in the United States in 2003. gpIIb/IIIa, glycoprotein IIb/IIIa71; PCI, percutaneous coronary intervention (coronary artery catheterization).

CHAPTER 66

only P2 receptors and do not inhibit ADP-induced changes in platelet shape. Thienopyridines are being used as alternative antiplatelet agents in acute coronary syndromes. A single dose of 375 mg of clopidogrel achieves maximal platelet aggregation inhibition of 40% to 50% 2 to 6 hours after ingestion.74 The same level of platelet inhibition is achieved in 3 to 7 days when clopidogrel is dosed at 75 mg once daily. Peak response is expected 5 days after the initial dose, and a return to baseline platelet function comes 5 days after discontinuation. Ninety-four percent to 98% protein bound, thienopyridines undergo about 50% to 60% renal excretion and 30% to 50% excretion in bile.75,76 Table 66-6 summarizes the pharmacokinetic parameters of clopidogrel and ticlopidine. Thienopyridine use in patients undergoing PCI has become increasingly popular. This drug class has become an effective alternative antiplatelet medication for aspirin-intolerant patients with atherosclerotic cardiac disease. However, the one exception for thienopyridine use in patients suffering an acute coronary event is when a patient is likely to undergo a coronary artery bypass graft. The delay in recovery of platelet function may complicate intraoperative and postoperative care. There is no therapeutic monitoring for thienopyridine use. However, routine quantitative platelet analysis (e.g., through a complete blood count) is indicated for patients taking thienopyridines because they can cause neutropenia and thrombocytopenia. The platelet function analyzer (PFA 100, Dade Behring, Illinois) may be used to assess platelet aggregation, although the gold standard for this measurement is optical aggregometry. Overdose of thienopyridines remains a rare occurrence compared with other anticoagulant overdoses. Ingestion of up to 6000 mg clopidogrel has been reported.77 Animal studies have reported dyspnea, seizures, gastrointestinal bleeding, and ultimately death after single acute ingestions of 500 mg/kg ticlopidine in mice and 2000 mg/kg clopidogrel in rats.78 Although no thienopyridine antiplatelet reversal agent has yet been developed, DDAVP (desmopressin) administration may temporarily improve primary hemostasis by stimulating release of vWF factor from storage in endothelial cells and platelets.74 Patients who overdose with clopidogrel or ticlopidine should undergo routine decontamination with activated charcoal and receive supportive measures.

TABLE 66-6 Pharmacokinetics of the Thienopyridines* CLOPIDOGREL Trade name Oral bioavailability Metabolism Clearance Elimination half-life

Plavix 50% CYP1A Linear 8 hr

Protein bound

94%–98%

*Available in 2004.

TICLOPIDINE Ticlid 80% CYP1A Nonlinear 12.6 hr after single dose 4–5 days with repeated dosing 98%

Anticoagulants

1061

Because thienopyridines irreversibly change the ADP platelet receptor, return of platelet function is dependent on new platelet formation; platelet transfusion may be indicated for patients with active hemorrhage. ASPIRIN Acetylsalicylic acid (aspirin) has become a routine and ubiquitous agent in the treatment and prevention of unstable angina and myocardial infarction. Aspirin acetylates and irreversibly inhibits platelet cyclooxygenase to inhibit thromboxane production and hence interfere with platelet aggregation. A single 81-mg dose of aspirin or as little as 10 mg taken daily for 1 week will impair platelet function for the lifetime of a cohort of affected platelets. Overdose Hematologic complications of aspirin overdose are rarely seen, probably because the more active issues of metabolic derangement and subsequent central nervous system depression from salicylate toxicity must first be addressed. PT prolongation is fairly common, whereas disseminated intravascular coagulation, thrombocytopenia, and acute hemorrhage from aspirin overdose are uncommon.79 Management of aspirin toxicity is addressed in greater depth elsewhere in this text (see Chapter 48). BOTANICALS WITH ANTICOAGULANT PROPERTIES Several botanicals have been demonstrated to show anticoagulant synergy with existing synthetic agents as well as when used as single agents. Garlic has been shown to inhibit platelet aggregation, and patients with previously stable INRs on warfarin have had elevated INRs after adding garlic to their diets.80,81 Ginger may inhibit platelet aggregation, but ingestion of up to 40 g of cooked ginger does not seem to affect platelet function. Gingko may also affect platelet aggregation and has been implicated in increased bleeding complications in patients taking anticoagulants.82 It has been suggested that ginseng can possibly inhibiting platelet aggregation; however, a decreasing INR was noted in one case report, and animal studies show no effect of ginseng on INR.83 SNAKE VENOM Almost all snakes of the Crotalidae, Viperidae, and Crotalinae families have heparin-like substances that can lead to coagulopathy.84 Elapidae bites rarely lead to hematologic disturbances; exceptions include Naja nigricollis, Ophiophagus hannah (king cobra), and the Naja atra (Chinese cobra).85,86 All patients with snake envenomations should have PT, PTT, INR, and fibrin split products monitored for development of coagulopathies. Detailed management of snake envenomations is discussed in elsewhere in this text (See Chapters 21A and 21B).

SUMMARY Anticoagulant medications play an important role in the treatment and prevention of thromboembolic and

1062


Intrinsic exposed collagen HMWK+kallikrein

XII

Extrinsic Vessel injury

XIIa Warfarin XI

TF

XIa

IX

IXa

VIIa

VII

VIIIa Xa inhibitors X

Heparins

Xa Antithrombin III

II (prothrombin)

IIa (thrombin)

I (fibrinogen)

Ximelagatran

Ia (fibrin) XIIIa

Inhibition Activation

XIII

Stable fibrin (cross-linked)

FIGURE 66-9 Summary of anticoagulant targets in the coagulation cascade. HMWK, high-molecular-weight kininogens.

cardiovascular disease (Fig. 66-9). Even in overdose, they rarely precipitate life-threatening hemorrhage. In overdose, treatment should be based on clinical assessment of the patient, consideration of the nature of the overdose (unintentional versus intentional), and evaluation of bleeding time studies, hematocrit, and platelet concentration. Reversal agents, if available, should be administered for active exsanguination. In supratherapeutic administration of anticoagulants, most patients still need to maintain a certain degree of anticoagulation. In these cases, expectant management should be coordinated in conjunction with clinicians familiar with a patient’s therapeutic monitoring trends. All overdoses of anticoagulants merit consultation with a poison control center. REFERENCES 1. Park BK, Scott AK, Wilson AC, Haynes BP, Breckenridge AM: Plasma disposition of vitamin K1 in relation to anticoagulant poisoning. Br J Pharmacol 1984;18:655–662. 2. Makris M, Watson HG: The management of coumarin-induced over-anticoagulation. Br J Haematol 2001;114(2):271–280. 3. Top 200 most prescribed drugs 2002. In Nissen D (ed): Mosby’s Drug Consult. Retrieved July 12, 2004, from http://www.mosbys drugconsult.com/DrugConsult/Top_200/. 4. Wittkowsky AK: Warfarin and other coumarin derivatives: pharmacokinetics, pharmacodynamics, and drug interactions. Semin Vasc Med 2003;3(3):221–230. 5. Breckenridge A: Oral anticoagulant drugs: pharmacokinetic aspects. Semin Hematol 1978;15(1):19–26.

6. Choonara IA, Haynes BP, Cholerton S, Breckenridge AM, Park BK: Enantiomers of warfarin and vitamin K1 metabolism. Br J Clin Pharmacol 1986;22(6):729–732. 7. Breckenridge A: Oral anticoagulant drugs: pharmacokinetic aspects. Semin Hematol 1978;15(1):19–26. 8. Luer J, Patterson LE: Warfarin (drug evaluation). In Klasco RK (ed): DRUGDEX System. Greenwood Village, CO, Thomson MICROMEDEX, 2004. 9. Hirsh J, Dalen JE, Anderson DR, et al: Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Sixth ACCP Consensus Conference on Antithrombotic Therapy. Chest 2001;119(1):8S–21S. 10. Kaminsky LS, Zhang Z: Human P450 metabolism of warfarin. Pharmacol Ther 1997;73(1):67–74. 11. Tait RC, Ladusans EJ, El-Metaal M, Patel RG, Will AM: Oral anticoagulation in paediatric patients: dose requirements and complications. Arch Dis Child 1996;74(3):228–231. 12. Schulman S: Care of patients receiving long-term anticoagulant therapy. N Engl J Med 2003;349(7):675–683. 13. Jones KL: Smith’s Recognisable Patterns of Human Malformation, 5th ed. Philadelphia, WB Saunders, 1997, pp 568–569. 14. Clark SL, Poerter TF, West FG: Coumarin derivatives and breastfeeding. Obstet Gynecol 2000;96(6 Pt 1):938–940. 15. Orme ML, Lewis PJ, de Swiet M, et al: May mothers given warfarin breast-feed their infants? BMJ 1977;1(6076):1564–1565. 16. Chan YC, Valenti D, Mansfield AO, Stansby G: Warfarin induced skin necrosis. Br J Surg 2000;87(3):266–272. 17. Yang Y, Algazy KM: Warfarin-induced skin necrosis in a patient with a mutation of the prothrombin gene. N Engl J Med 1999;340(9):735. 18. Raj K, Collins B, Rangarajan S: Purple toe syndrome following anticoagulant therapy. Br J Haematol 2001;114(4):740. 19. Kruse JA, Carlson RW: Fatal rodenticide poisoning with brodifacoum. Ann Emerg Med 1992;21(3):331–336. 20. Chua JD, Friedenberg WR: Superwarfarin poisoning. Arch Intern Med 1998;158(17):1929–1932. 21. Breckenridge A: Oral anticoagulant drugs: pharmacokinetic aspects. Semin Hematol 1978;15(1):19–26. 22. Kruse JA, Carlson RW: Fatal rodenticide poisoning with brodifacoum. Ann Emerg Med 1992;21(3):331–336. 23. Parsons BJ, Day LM, Ozanne-Smith J, Dobbin M: Rodenticide poisoning among children. Aust N Z J Public Health 1996;20(5): 488–492. 24. Watts RG, Castleberry RP, Sadowski JA: Accidental poisoning with a superwarfarin compound (brodifacoum) in a child. Pediatrics 1990;86(6):883–887. 25. White ST, Voter K, Perry J: Surreptitious warfarin ingestion. Child Abuse Neglect 1985;93(3):349–352. 26. Lazarus A, Kozinn WP: Munchausen’s syndrome with hematuria and sepsis: an unusual case. Int J Psychiatry Med 1991;21(1):113–116. 27. Souid AK, Korins K, Keith D, Dubansky S, Sadowitz PD: Unexplained menorrhagia and hematuria: a case report of Munchausen’s syndrome by proxy. Pediatr Hematol Oncol 1993;10(3):245–248. 28. Babcock J, Harman K, Pedersen A, Murphy M, Alving B: Rodenticide-induced coagulopathy in a young child: a case of Munchausen syndrome by proxy. Am J Pediatr Hematol Oncol 1993;15(1):126–130. 29. Stanziale SF, Christopher JC, Fisher RB: Brodifacoum rodenticide ingestion in a patient with shigellosis. South Med J 1997;90(8): 833–835. 30. Zahner J, Schneider W: Munchausen syndrome in hematology: case reports of three variants and review of the literature. Ann Hematol 1994;68(6):303–306. 31. Ayass M, Bussing R, Mehta P: Munchausen syndrome presenting as hemophilia: a convenient and economical “steal” of disease and treatment. Pediatr Hematol Oncol 1993;10(3):241–244. 32. Makris M, Watson HG: The management of coumarin-induced over-anticoagulation. Br J Haematol 2001;114(2):271–280. 33. Donovan JW: Brodifacoum therapy with activated charcoal: effect on elimination kinetics. Vet Hum Toxicol 1990;32:50. 34. Bruno GR, Howland MA, McMeeking A, Hoffman RS: Long-acting anticoagulant overdose: brodifacoum kinetics and optimal vitamin K dosing. Ann Emerg Med 2000;36(3):262–267.

CHAPTER 66

35. Becker RC, Ansell J: Antithrombotic therapy: an abbreviated reference for clinicians. Arch Intern Med 1995;155(2):149–161. 36. Watson HG, Baglin T, Laidlaw SL, Makris M, Preston FE: A comparison of the efficacy and rate of response to oral and intravenous vitamin K in reversal of over-anticoagulation with warfarin. Br J Haematol 2001;115(1):145–149. 37. de la Rubia J, Grau E, Montserrat I, Zuazu I, Paya A: Anaphylactic shock and vitamin K1. Ann Intern Med 1989;110(11):943. 38. O’Reilly RA, Kearns P: Intravenous vitamin K1 injections: dangerous prophylaxis. Arch Intern Med 1995;155(19):2127–2128. 39. Wjasow C, McNamara R: Anaphylaxis after low dose vitamin K. J Emerg Med 2003;24(2):169–172. 40. Lubetsky A, Yonath H, Olchovsky D, et al: Comparison of oral vs intravenous phytonadione (vitamin K1) in patients with excessive anticoagulation: a prospective randomized controlled study. Arch Intern Med 2003;163(20):2469–2473. 41. Thacker JL: Long-acting anticoagulant rodenticides. Minnesota Poison Control System, Hennepin County Medical Center. Retrieved December 13, 2003, from http://www.mnpoison.org/index.asp. 42. Smolinske SC, Scherger DL, Kearns PS, et al: Superwarfarin poisoning in children: a prospective study. Pediatrics 1989;84(3): 490–494. 43. Shaw S, Anderson J: Warfarin rodenticide poisoning treatment in children. Centre for Clinical Effectiveness, Institute for Public Health and Health Services Research Southern Health Care Network, Monash University, Evidence Centre Report, 1999. 44. Weitz JI: Low-molecular-weight heparins. N Engl J Med 1997;337(10):688–698. 45. Bates SM, Ginsberg JS: Treatment of deep-vein thrombosis. N Engl J Med 2004;351(3):268–277. 46. Protamine sulfate (drug evaluation). In Klasko RK (ed): DRUGDEX System. Greenwood Village, CO, Thomson MICROMEDEX, 1996. 47. Wakefield TW, Hantler CB, Wrobleski SK, Crider BA, Stanley JC: Effects of differing rates of protamine reversal of heparin anticoagulation. Surgery 1996;119(2):123–128. 48. Horrow JC. Protamine: a review of its toxicity. Anesth Analg 1985;64(3):348–361. 49. Ellerhorst JA, Comstock JP, Nell LJ: Protamine antibody production in diabetic subjects treated with NPH insulin. Am J Med Sci 1990;299(5):298–301. 50. Weiss ME, Chatham F, Kagey-Sobotka A, Adkinson NF Jr: Serial immunological investigations in a patient what had a lifethreatening reaction to intravenous protamine. Clin Exp Allergy 1990;20(6):713–720. 51. Hakala T, Suojaranta-Ylinen R: Fatal anaphylactic reaction to protamine after femoropopliteal by-pass surgery. Ann Chir Gynaecol 2000;89(2):150–152. 52. Porsche R, Brenner ZR: Allergy to protamine sulfate. Heart Lung 1990;28(6):418–428. 53. Kim R: Anaphylaxis to protamine masquerading as an insulin allergy. Del Med J 1993;65(1):17–23. 54. Fabris F, Luzzatto G, Stefani PM, et al: Heparin-induced thrombocytopenia. Haematologica 2000;85(1):72–81. 55. Chong BH, Chong JH: Heparin-induced thrombocytopenia. Exp Rev Cardiovasc Ther 2004;2(4):547–559. 56. Mattioli AV, Bonetti L, Sternieri S, Mattioli G: Heparin-induced thrombocytopenia in patients treated with unfractionated heparin: prevalence of thrombosis in a 1 year follow-up. Ital Heart J 2000;1(1):39–42. 57. Girolami B, Prandoni P, Stefani PM, et al: The incidence of heparin-induced thrombocytopenia in hospitalized medical patients treated with subcutaneous unfractionated heparin: a prospective cohort study. Blood 2003;101(8):2955–2959. 58. Sugiyama T, Itoh M, Ohtawa M, Natsuga T: Study on neutralization of low molecular weight heperin by protaminesulfate and its neutralization characteristics. Thromb Res 1992;68:119–129. 59. Arixtra prescribing information 2003. Retrieved December 14, 2003, from http://www.sanofi synthelabous.com/products/pi_ arixtra/pi_arixtra.html. 60. The Matisse Investigators: Subcutaneous fondaparinux versus IV unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 2003;349(18):1695–1702.

Anticoagulants

1063

61. Drouet L: New and future antithrombotic agents in thromboembolic venous disease [French]. Rev Prat 2003;53(1):58–61. 62. Eriksson BI, Ekman S, Kabelo P, et al: Prevention of deep-vein thrombosis after total hip replacement: direct thrombin inhibition with recombinant hirudin, CGP 39393. Lancet 1996;347(9002): 635–639. 63. Refludan product information 2003. 64. Bauersachs RM, Lindhoff-Last E, Ehrly AM, et al: Treatment of hirudin overdosage in a patient with chronic renal failure. Thromb Haemost 1999;81(2):323–324. 65. Francis CW, Berkowitz SD, Comp PC, et al: Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med 2003;349(18):1703–1712. 66. Braunwald E: Application of current guidelines to the management of unstable angina and non-ST-elevation myocardial infarction. Circulation 2003;108(Suppl III):28–37. 67. Kaufman M: Eptifibatide (drug evaluation). In Klasco RK (ed): DRUGDEX System. Greenwood Village, CO, Thomson MICROMEDEX, 2004. 68. Heath J, Bunch C: Tirofiban (drug evaluation). In Klasco RK (ed): DRUGDEX System. Greenwood Village, CO, Thomson MICROMEDEX, 2004. 69. Brueggman J: Abciximab (drug evaluation). In Klasco RK (ed): DRUGDEX System. Greenwood Village, CO, Thomson MICROMEDEX, 2004. 70. Abciximab. Retrieved July 21, 2004, from http://www.drugs.com/ MMX/Abciximab.html. 71. Hurlbut KM: Glycoprotein IIb-IIIa receptor antagonists. POISINDEX Managements, Healthcare Series, Vol. 118. Greenwood Village, CO, Thomson MICROMEDEX, 2003. 72. Clopidogrel (Plavix) product information, 5 July 2002. 73. Ticlopidine (Ticlid) product information, March 2001. 74. Kam PCA, Nethery CM: The thienopyridine derivatives (platelet adenosine diphosphate receptor antagonists), pharmacology and clinical developments. Anaesthesia 2003;58(1):28–35. 75. Brunch C: Clopidogrel (drug evaluation). In Klasco RK (ed): DRUGDEX System. Greenwood Village, CO, Thomson MICROMEDEX, 2004. 76. Falcao A, Hunter M, Raasch R: Ticlopidine (drug evaluation). In Klasco RK (ed): DRUGDEX System. Greenwood Village, CO, Thomson MICROMEDEX, 2004. 77. Clopidogrel (drug evaluation). In Klasko RK (ed): DRUGDEX System. Greenwood Village, CO, Thomson MICROMEDEX, 2004. 78. Hurlbut KM, Waksman J, Kulig K: Ticlopidine and related agents. POISINDEX Managements, Healthcare Series, Vol. 118. Greenwood Village, CO, Thomson MICROMEDEX, 2003. 79. Hurlbut KM, Fish S, Kulg K, et al: Salicylates. POISINDEX Managements, Healthcare Series, Vol. 118. Greenwood Village, CO, Thomson MICROMEDEX, 2003. 80. Spoerke DG, Hulko KM, Rumack BH, and the POISINDEX Editorial Staff: Plants: allium species. In Klasco RK (ed): POISINDEX System. POISINDEX Managements, Healthcare Series, Vol. 118. Greenwood Village, CO, Thomson MICROMEDEX, 2003. 81. Luer J, Patterson LE, for the DRUGDEX Editorial Staff. DRUGDEX Drug evaluations. Warfarin. Drug-Drug interactions. Ginger. 82. Luer J, Patterson LE, and the DRUGDEX Editorial Staff: DRUGDEX drug evaluations. Warfarin. Drug–drug interactions. Gingko. 83. Luer J, Patterson LE, and the DRUGDEX Editorial Staff: DRUGDEX drug evaluations. Warfarin. Drug–drug interactions. Ginseng. 84. Editorial staff: African snakes: Viperidae. In Klasko RK (ed): POISINDEX System. POISINDEX Managements, Healthcare Series, Vol. 118. Greenwood Village, CO, Thomson MICROMEDEX, 2004. 85. Editorial staff: African snakes: Elapidae. In Klasko RK (ed): POISINDEX System. POISINDEX Managements, Healthcare Series, Vol. 118. Greenwood Village, CO, Thomson MICROMEDEX, 2004. 86. Editorial staff: Asian snakes: Elapidae. In Klasko RK (ed): POISINDEX System. POISINDEX Managements, Healthcare Series, Vol. 118. Greenwood Village, CO, Thomson MICROMEDEX, 2004.

1064


SUGGESTED READING Brass LF: 2000. The molecular basis for platelet activation. In Hoffman R, Benz EJ Jr, Shattil SJ, et al (eds): Hematology: Basic Principles and Practice, 3rd ed. New York, Elsevier Science, 2000, pp 1753–1770. Davis WE, Monet DM: Thrombolytic agents and anticoagulants. In Haddad LM, Shannon MW, Winchester JF (eds): Clinical Management of Poisoning and Drug Overdose, 3rd ed. Philadelphia, WB Saunders, 1988.

Quader MA, Stump LS, Sumpio BE: Low molecular weight heparins: current use and indications. J Am Coll Surg 1998;187(6):641–658. Retrieved December 11, 2003, from http://www.facs.org/jacs/ articles/sumpio.html. Su M, Hoffman RS: Anticoagulants. In Goldfrank LR, Flomenbaum NE, Lewin NA, et al (eds): Goldfrank’s Toxicologic Emergencies, 7th ed. New York, McGraw-Hill Professional, 2002, pp 631–654.

67

Thyroid Agent Toxicity LUKE YIP, MD

At a Glance… ■

■

■ ■

■

■

■

Toxicity from thyroid preparations may result in a hyperadrenergic state with primary effects on the cardiovascular and central nervous systems. Although acute thyroid hormone overdose has been associated with moderate thyrotoxicosis and thyroid storm, most patients develop only mild signs and symptoms and do not require hospitalization. There does not appear to be a reported pediatric death due to acute thyroid hormone toxicity in the literature. Accidental acute ingestions of less than 5 mg of thyroxine may be managed at home and do not require emergent medical assessment and gastrointestinal decontamination. Patients with signs of thyroid hormone toxicity should be admitted to the hospital for close observation and expectant treatment. Treatments for exogenous thyroid storm include supportive care, hydration, antipyretics, β-adrenergic antagonists, iodinecontaining contrast agents, corticosteroids, and gastrointestinal decontamination, as necessary. Iodide, propylthiouracil, and methimazole have minimal efficacy in the management of exogenous thyroid hormone toxicity.

Thyroid hormones are essential in normal growth and development, in many metabolic processes, and in the treatment of thyroid disorders. The clinical uses of thyroid hormones include replacement therapy for hypothyroidism, suppressive therapy to abolish thyroidstimulating hormone (TSH) secretion in patients with differentiated thyroid carcinoma after total thyroidectomy or with diffuse and nodular nontoxic goiter. However, thyroid hormones are also abused by patients with thyrotoxicosis factitia, a syndrome due to surreptitious excess thyroid hormone ingestion because of psychopathologic disorders.1-6 Acute thyroid hormone overdose has been associated with either few signs and symptoms that do not require hospitalization,7-11 a mild to moderate thyrotoxicosis (e.g., flushing, tachycardia, fever, diarrhea, irritability, and insomnia),12-15 or a thyroid storm.16-18 Most cases follow a generally benign clinical course.7-11 The incidence of life-threatening reactions that require treatment has been low,2,12,14-16,19-22 and morbidity5,18,23-28 and mortality26,29,30 have rarely been reported after an acute single or repeated thyroid hormone overdose. Adverse reactions or toxicity during therapeutic use may occur.23,31-34

EPIDEMIOLOGY Thyroid hormone–containing tablets are commonly prescribed drugs. Despite the fact that large numbers of

thyroid hormone-containing drugs are prescribed each year in the United States to an estimated 4% of the adult population, only a small proportion of patients suffer accidental or intentional poisoning.14,35 In 2004, there were 10,647 thyroid preparation exposures reported to U.S. poison centers, of which 89% were unintentional.35 Moderate to major toxicity occurred in 445 (4.2%) and death occurred in 3 (0.3%) exposures. Deaths could generally be attributed to the effects of co-ingestants and not to the thyroid preparations themselves.

THYROID HORMONE PHYSIOLOGY AND PHARMACOLOGY The mature thyroid gland contains follicles composed of thyroid follicular cells that surround secreted colloid, a proteinaceous fluid that contains large amounts of thyroglobulin, the glycoprotein precursor of thyroid hormones. The basolateral surface of the thyroid follicular cells is apposed to the bloodstream, and an apical surface faces the follicular lumen. Dietary iodine is reduced to iodide and is absorbed in the small intestine. Thyroid follicular cells actively transport plasma iodide into their cytoplasm, and it is oxidized to iodine before binding to tyrosyl residues present in the thyroglobulin molecules. Iodination of the tyrosyl residues within thyroglobulin, a process called organification of the iodine, is catalyzed by thyroid peroxidase. If one iodine atom replaces a hydrogen atom, then monoiodotyrosine is formed; if two iodine atoms are joined in the tyrosyl ring, diiodotyrosine is the resultant product. Monoiodotyrosine and diiodotyrosine then undergo oxidative condensation to yield various iodothyronines. These include 3,5,3′,5′-tetraiodothyronine (thyroxine, T4) and 3,5,3′-triiodothyronine (triiodothyronine, T3) (Fig. 67-1). Iodine makes up 66% of T4 and 58% of T3 by weight. Thyroid hormone secretion from the thyroid gland is regulated by the hypothalamic-pituitary-thyroid axis, which begins in the supraoptic nucleus cells of the hypothalamus. These cells secrete thyrotropin-releasing hormone (TRH), a tripeptide, and it is carried through the pituitary portal circulation to the anterior pituitary gland. TRH stimulates the pituitary gland to secrete TSH into the general circulation, which binds to its receptor on the basolateral surface of the follicular cells, resulting in thyroglobulin reabsorption from the follicular lumen and proteolysis within the cell to yield T4 and T3 for secretion into the bloodstream. T4 and T3 are reversibly bound to plasma proteins synthesized by the liver. Transthyretin (TTR) has a low affinity and rapid dissociation constant and has a greater role in delivering iodothyronines to various tissues. In 1065


I HO

J

J J O

J

I

J I

J J

J

NH2

J

1066

CH2JCHJCOOH

3„, 5, 3-Triiodothyronine (T3)

3„

HO

J

J J

J

5„

I

O

I

J J

3

J

5

I

J

NH2

J

I

CH2JCHJCOOH

3, 5, 3„, 5„-Thyroxine (Tetraiodothyronine, T4) FIGURE 67-1 Chemical structure of thyroxine (T4) and triiodothyronine (T3).

contrast, thyroxine-binding globulin (TBG), with its relatively high binding affinity and slower dissociation constant, serves as a stable hormone reservoir in the circulation. Albumin has low binding affinity and may act similarly to TTR to provide tissue delivery of the hormone. Circulating T4 is almost entirely bound (99.97%) to these plasma proteins and is predominantly bound to T4binding globulin (75% to 80%). TTR binds 15% to 20% and albumin binds 5% to 10%. In contrast, plasma T3 is bound to a lesser extent. Target tissue responses are related principally if not exclusively to these free fractions of circulating T4 and T3. After thyroid hormones overdoses, there is little change in TBG concentration, and free hormone levels increase directly or even disproportionately with the total serum thyroid hormone concentrations. T3 is metabolically more active than T4 and is generated by removal of either iodine atom from the outer ring (at 3′ or 5′ position) of the T4 molecule. Peripheral deiodination contributes 80% to 85% of the daily T3 production and most total daily T3 production

results from extrathyroidal deiodination in such tissues as the liver and kidneys. The principal actions of thyroid hormones in target tissues are initiated by the binding to specific nuclear receptors, T3 receptors, which were first identified as cellular homologs of the avian erythroblastosis virus oncogene (c-erbA). These receptors have properties of (1) binding T3 with high affinity; (2) binding specific oligonucleotide sequences, called T3 regulatory elements, which are present in the regulatory regions of thyroid hormone-responsive genes; and (3) binding one another to form dimers; an important aspect of T3 action. Within hours of thyroid hormone administration, T3 binding to these receptors stimulates transcription of certain messenger RNAs that are then translated into proteins (e.g., β-myosin heavy chain in myocardium), which are ultimately responsible for effecting thyroid hormone actions in various tissues. Those actions include increases in metabolic rate, body temperature, heart rate, and myocardial contractility.

PHARMACOKINETICS Dosing The commercially available thyroid preparations and their approximate equivalent dosages are provided in Table 67-1. Recommended therapeutic T4 and T3 dosing is listed in Table 67-2.

Absorption The average T4 bioavailability is 80% after an oral therapeutic dose, and the time to maximal absorption is 2 hours. The serum T4 level reaches its peak 4 hours after ingestion of 3 mg T4.36 Gastrointestinal diseases such as sprue, diabetic diarrhea, short bowel syndrome, and ileal-jejunal bypass surgery may reduce absorption.

TABLE 67-1 Thyroid Preparations* APPROXIMATE EQUIVALENT DOSE

AVAILABLE ORAL DOSES†

3,3,5′-triiodo-L-thyronine sodium T3 (synthetic) 3,5,3′,5’-tetraiodothyronine, T4 (thyroxine sodium)

25 μg

5, 25, and 100 μg

100 μg

25 to 300 μg

T4:T3 sodium salts in ratio of 4:1 Desiccated pork thyroid with T4 and T3 in approximate ratio of 4:1 38 μg T4 and 9 μg T3 per grain

50/12.5 μg

12.5/3.1 to 150/37.5 μg

60–65 mg (1 grain)

1

GENERIC NAME

BRAND NAME

SUBSTRATE

Liothyronine sodium

Cytomel

Levothyroxine sodium

Liotrix

Synthroid Levoxyl Levothyroid Eltroxin Thyrolar

Thyroid extract

Armour Thyroid

Thyroglobulin

⁄4 to 5 grains (15 to 300 mg)

65 mg

*Only the preparations available in the United States are listed. Preparations other than the ones mentioned in this table may be available in other countries. † Levothyroxine and liothyronine (Triostat, 10 μg/mL, 1 mL vial) are also available commercially as parenteral preparations.

CHAPTER 67

Thyroid Agent Toxicity

1067

TABLE 67-2 Therapeutic T4 and T3 Dose ORAL T4 DAILY DOSE

ORAL T3 DAILY DOSE

INTRAVENOUS T3 DOSE

ADULT

100–200 μg

5–20 μg every 8–12 hr

PEDIATRIC

25 μg; increase gradually to 3–5 μg/kg/day

10 μg every 8 hr; may increase to 20 μg every 8 hr 0.2 μg/kg/dose (up to 10 μg) every 8 hr; may be increased to 0.4 μg/kg/dose (up to 20μg) every 8 hr

Cholestyramine, calcium carbonate, sucralfate, aluminum hydroxide, ferrous sulfate, soybean formula, lovastatin, and dietary fiber supplements may also impair T4 absorption from the gastrointestinal (GI) tract. The maximum effects of T4 are apparent 1 to 3 weeks after initiating oral therapy, and the effects persist for the same amount of time after discontinuing the drug. T3 is 95% absorbed from the GI tract after an oral therapeutic dose, and the serum T3 level begins to rise at 1.5 to 2.5 hours.37 The serum T3 level peaks 2 hours after ingestion of 6 grains (360 mg) of desiccated thyroid and 4 hours after ingestion of 75 μg T3.36

Distribution T4 has a 10-L volume of distribution (Vd) and is distributed into most body tissues and fluids, with highest concentrations in the liver and kidneys. T3 has a volume distribution of 38 L. T4 and T3 are primarily bound to thyroxine-binding globulin and to a lesser extent to thyroxine-binding prealbumin and albumin. T4 is more extensively and tightly bound than T3. It is estimated that 0.04% of T4 and 0.5% of T3 are unbound (free) hormone, which is available to elicit a physiologic effect.

Elimination Endogenously secreted T4 (35%) is enzymatically monodeiodinated by type I 5′-monodeiodinase to T3 in the peripheral tissues (e.g., liver and kidney) and accounts for 80% of total daily T3 production. T4 is also enzymatically monodeiodinated to reverse T3 (rT3). In the liver, T4 may undergo glucuronidation and sulfation, which is eliminated in bile; some is hydrolyzed in the intestine and reabsorbed, and the remainder is hydrolyzed in the colon and eliminated unchanged in the feces. After an oral 3-mg T4 dose, a significant increase in serum T3 level is evident at 4 hours, and peak level is achieved between 2 and 4 days.36 The elimination half-life of T4 is 6 to 7 days. Drugs that increase nondeiodinative T4 clearance include rifampin, carbamazepine, and phenytoin. Selenium deficiency and amiodarone may block T4 conversion to T3. One metabolic pathway for T3 and rT3 is peripheral monodeiodination. The half-life of T3 is 1 to 2 days. The maximum effects of T3 are apparent within 24 to 72 hours after initiating oral therapy, and the effects persist

0.1–0.4 μg/kg/dose (up to 20 μg) every 8–12 hr

for up to 72 hours after discontinuing the drug. Urinary T3 elimination increases linearly with the rise in urine flow rate and is doubled or tripled when urine flow rate is increased by fivefold to eightfold during acute hydration.38

TOXICOKINETICS Adult In a thyroidectomized patient who had ingested an estimated 2000 μg T4, the serum concentrations of most thyroid hormones reached a peak on the second day.39 The serum T3 level peaked 1 day later and did not exceed the upper limit of the reference range. The serum T4 and rT3 levels returned to the reference range 13 to 17 days after ingestion. The serum TSH level was rapidly suppressed and reached nadir on the 6th day after ingestion. The serum T4 half-life and metabolic clearance rate were 10.4 days and 0.64 L/day, respectively. An acute single oral ingestion of a large amount of T4 does not induce a proportional increase in the serum T3 level in an athyreotic person. The serum T4 metabolic clearance rate is decreased, and the serum T4 half-life is prolonged. This is consistent with D1 deiodinase activity in the thyroid being one of the major determinants in the metabolic clearance of serum T4. Two hours after an acute oral T4 overdose, the serum T4, free T4, and free T3 levels were 2.27, 7.17, and 2.85 times the upper limit of the reference range, respectively.40 Two hours after an acute oral triiodothyronine overdose, the serum total T4 and T3 levels were 1.83 and 25 times the upper limit of the reference range, whereas the T3 resin uptake (T3RU) remained in the reference range.19

Pediatric Two previously healthy female pediatric patients were hospitalized, treated with ipecac, gastric lavage, propranolol, prednisone, cholestyramine, and propylthiouracil (PTU) after inadvertent ingestion of 2500 μg T4. The patients remained asymptomatic throughout their hospital course.41 Serial serum T4, T3, rT3, and thyroglobulin levels were obtained during the 20 days after ingestion. Serum T4 concentrations were elevated 2 hours after ingestion and returned to the reference range after 13 days. The serum

1068


TSH levels reached their nadir 14 hours after ingestion and remained low until the fourth day, after which they rose gradually. However, the TSH levels remained below their initial values at 20 days after ingestion. The serum T3 concentrations peaked 11 hours after ingestion and decreased to reference values after 3 days. Both T3 production and degradation constants were significantly increased. The serum rT3 concentration peaked on the second day after ingestion and decreased to reference values on the fourth day. Both rT3 production and degradation constants were below reference values. The T3/rT3 ratio decreased from a reference value of 3 to 1 and then increased after 13 days to as high as 8. The serum thyroglobulin concentration continuously decreased, with a half-life of 1 to 5 days, and began rising after 2 to 13 days. The toxicokinetics data from 15 previously healthy patients aged 12 to 49 months who were treated with GI decontamination within 6 hours of the overdose showed elevation in serum T4 concentration as early as 1 to 2 hours after ingestion.8 In 71% of patients, peak serum T4 level was reached within 12 hours, whereas the serum T3 concentration did not peak until after 24 hours after ingestion. The mean elimination half-life of T4 was 2.8 ± 0.4 days (range, 1.5–4.5 days), and the mean elimination half-life of T3 was 6 ± 1.7 days (range, 2.2–12.3 days), which is five times longer than that observed in physiologic conditions. Also, in physiologic conditions, the elimination half-life of T3 is shorter than that of T4. The toxicokinetics data from a 13-year-old boy who was treated with activated charcoal, propranolol, and dexamethasone showed his serum T4 level began to decline 48 to 72 hours after ingestion, whereas the serum T3 level began to decline 24 to 36 hours after ingestion.22 The calculated total T4 and T3 half-lives were 5.7 and 5.3 days, respectively. The serum TSH concentration was undetectable 19 hours after ingestion and remained suppressed for 10 days after the overdose. Administration of two additional doses of charcoal, 4 hours apart on the second day after ingestion, did not significantly change the T4 or T3 half-life. The patient’s free T4 and TSH returned to the normal range 2 weeks later. Serum T4 levels may be elevated as early as 30 minutes after an acute overdose21; T3 and rT3 levels may be elevated after 1.5 hours,42 and serum TSH level may be undetectable after 19 hours.22

DRUG INTERACTIONS In patients with endogenous thyrotoxicosis, there is a significant increase in serum free T4 and T3 levels after intravenous heparin (5000–30,000 U) administration.43 This effect may be due to a hormonal shift from the cellular to the intravascular compartment when both cellular and intravascular hormonal binding sites are blocked by heparin. However, the metabolic significance of this is unknown. Certain drugs may interfere with the GI absorption of T4, including sucralfate, cholestyramine resin, iron and calcium supplements, and aluminum hydroxide.44 In addition, certain drugs that induce

cytochrome P-450 enzymes may enhance biliary excretion of T4 (e.g., phenytoin, carbamazepine, and rifampin) and necessitate increased oral T4 dosing.

THYROID HORMONE TOXICOLOGY Thyroid hormones regulate normal growth and development and act to maintain normal metabolic homeostasis. Some of the principal effects of thyroid hormones are to stimulate metabolic activity and oxygen consumption of numerous peripheral tissues (e.g., heart, skeletal muscle, liver, kidney) and to enhance the effects of other hormones (e.g., catecholamines). Thyrotoxicosis is the state produced by an excess of thyroid hormone. Although thyrotoxicosis occurs largely as a result of hyperthyroidism, or an overactive thyroid gland, the condition may also occur from ingestion of excess thyroid hormone. Toxicity from excessive exposure to thyroid preparations manifests as an exaggeration of the physiologic effects of thyroid hormone and results in a hyperadrenergic state with primary effects on the GI, cardiovascular, and central nervous systems. Thyroid hormone intoxication may occur after accidental or intentional and acute or chronic exposure. Acute thyroid hormone overdose occurs most commonly in children and is generally benign; major morbidity or mortality occurs very rarely in this setting.9,11,26,29,30 Chronic exposure to excessive doses of thyroid hormone is more commonly associated with more severe illness and may present with thyroid storm. Mortality, however, is still rare with chronic overdose. Accidental chronic overexposure occurs from medication error (by physician, pharmacists, nurses, or patients) or from continued administration with therapeutic intent in patients with decreased thyroid hormone dose requirements. Intentional chronic overingestion of thyroid hormone is often referred to as factitious thyrotoxicosis.45 Individuals with factitious thyrotoxicosis are often health care workers who ingest the hormone for weight reduction. “Hamburger thyrotoxicosis” is an unusual cause of exogenous thyrotoxicosis that follows the ingestion of ground beef contaminated with thyroid tissue.46 Cooking the contaminated beef does not inactivate iodothyronines. Although inclusion of the thyroid gland in meat product preparations is now banned in the United States, this entity should still be considered in the differential diagnosis of thyrotoxicosis presenting with elevated serum T3 and T4, especially in a cluster pattern. Acute toxicity from thyroid hormone may also occur during the initial stages of thyroid hormone replacement therapy in those with hypothyroidism (see “Adverse Effects”).

CLINICAL MANIFESTATIONS Acute Overdose The temporal relation between acute overdose and the onset of signs and symptoms is delayed by hours to days.

CHAPTER 67

The latency is longer (3 to 7 days) after ingestion of T4 because of the time it takes for peripheral conversion to T3, the bioactive hormone. Clinical signs and symptoms after acute T3 ingestion or desiccated thyroid (both T3 and T4 present) may occur within a few hours but usually appear after 2 to 3 days. Adult patients primarily present with cardiovascular and central nervous system manifestations.14,15,18,40 Vomiting may be evident as soon as 2 hours after ingestion, tachycardia may be noted after 2 to 6 hours, and fever has been reported after 6 hours.15,19,40 However, cardiovascular signs and symptoms usually do not become apparent until 16 hours to 4 days after ingestion, and neurologic manifestations may not occur until 2 to 6 days after ingestion. Cardiovascular effects include tachycardia, shortness of breath, palpitations, vasodilation, systolic hypertension, and increased cardiac contractility. Hypotension, congestive heart failure, tachyarrhythmias, and cardiovascular collapse may occur.17 Common tachyarrhythmias include sinus tachycardia, atrial fibrillation, paroxysmal atrial tachycardia, and atrial flutter.17 Electrocardiographic changes are nonspecific. Common neurologic effects are the result of sympathetic nervous system overactivity and include anxiety, agitation, restlessness, diaphoresis, hyperthermia, tachypnea, mydriasis, hyperactive bowel sounds, vomiting, diarrhea, and tremor.17,18 Other neurologic manifestations may include a lack of energy, confusion, acute psychosis, mutism, combativeness, slurred or unintelligible speech, hyperreflexia, seizures, and coma.17,18 Other effects have included acute abdominal pain, peptic ulcer disease, muscle weakness and pain, malaise, weight loss, and delayed onset laminar desquamation of palms and soles and alopecia areata.17 Laboratory abnormalities include leukocytosis, hyperglycemia, hepatic aminotransferase abnormalities, and elevations of blood urea nitrogen, creatinine, and creatine phosphokinase (rhabdomyolysis). Fluid and electrolyte disturbances may include hypokalemic alkalosis and sodium and water retention.17 Acute thyroid hormone overdoses are well tolerated by children; there are no reported deaths due to acute toxicity in the literature. In one retrospective review of 92 children (ages 6 years or younger) with acute T4 ingestion, no significant symptoms developed in those who ingested doses up to 3.75 mg T4 with GI decontamination and 2.0 mg T4 without GI decontamination.11 In this study, clinical effects occurred in 8.7% and included irritability, hyperactivity, increased appetite, vomiting, diarrhea, fever, flushing, and rash. In this study, researchers concluded that ingestion of less than 5.0 mg T4 equivalent of thyroid hormone is not associated with significant toxicity. Other toxic effects reported in children include supraventricular tachycardia, extrasystoles, hypertension, diaphoresis, abdominal pain, lethargy, extremity jerking, and seizures.7-9,12,20-22,24,42,47-54 Although children usually tolerate relatively large doses of thyroid hormone without major toxicity, significant toxicity may rarely occur. For instance, Kulig and colleagues reported on a 30-month-old boy who had two grand mal seizures 7 days after acute ingestion of an


1069

estimated 18 mg of T4.24 GI decontamination was performed with 3.5 hours of ingestion. There is not consistently a close correlation between the severity and type of symptoms and the ingested amount or serum T4 levels shortly after ingestion. Tenenbein and colleagues reported an overdose of 30 mg of T4 in a child with no significant toxicity.10 The time course of signs and symptoms of toxicity is similar for both children and adults.

Chronic Overdose As for acute overdose, signs and symptoms of chronic overdose primarily affect the cardiovascular and sympathetic and central nervous systems. Clinical effects may begin within a few days of the first dose.6,26,30 Unlike those following acute overdose, cardiovascular and neurologic effects tend to be more severe. For instance, there is a greater incidence of unstable arrhythmias (e.g., atrial and ventricular fibrillation), left ventricular heart failure, and serious neurologic effects (e.g., stupor, coma, aphasia, hemiparesis, and seizures).5,26,28 When death occurs, it usually results from a lethal ventricular arrhythmia (e.g., ventricular fibrillation).26,30 Other clinical effects noted with chronic excessive exposure include insomnia, heat intolerance, asthenia, sialorrhea, arthromyalgia, diarrhea, weight loss, fatigability, dyspnea on exertion, anxiousness, apprehension, hostility, restlessness, anorexia, jitteriness, depression, heat intolerance, warm moist palms, and generalized muscle weakness.2,5,28 The natural history of signs and symptoms of chronic toxicity is illustrated in one series of six adult patients (ages 46–74 years) who were erroneously administered between 70 and 1200 mg of T4 for 2 to 12 days.26 All patients developed tachycardia, fever, nervousness, insomnia, heat intolerance, asthenia, arthromyalgia, and diarrhea within 3 days of ingesting the first T4 dose. Severe neurologic signs and symptoms occurred in all patients between day 7 and 10 after ingestion; coma developed in five patients, stupor in one patient, and aphasia with hemiparesis occurred in one patient. Left ventricular failure, atrial fibrillation, and ventricular fibrillation developed between days 8 and 11 in five patients. One patient developed diffuse ST-T wave changes on electrocardiogram on day 29. Intense laminar desquamation of the palms and soles developed between days 17 and 37 in five patients. One patient died; the other patients recovered completely.

ADVERSE EVENTS The adverse drug effects associated with chronic thyroid hormone therapy include sinus tachycardia, nonsinus supraventricular tachycardias (e.g., atrial flutter and fibrillation), premature atrial contractions, coronary artery spasm, acute myocardial infarction, left ventricular hypertrophy, cardiac failure, reduced bone density and mass, thyroid storm, coma, and death.23,31-34 Tachycardia is often out of proportion to fever. Adverse effects may also occur during acute exposure to thyroid hormones

1070


with therapeutic intent. Initiation of thyroid hormone replacement therapy in hypothyroid patients has been rarely associated with arrhythmias and death.44 Thus, in patients older than 60 years and in those with known cardiac disease, thyroid hormone replacement is initiated at a lower daily dose of levothyroxine (e.g., 12.5 to 25 μg/day) and increased slowly to avoid cardiac adverse effects. Idiosyncratic or allergic reactions may occur with animal-derived products such as desiccated thyroid and thyroglobulin.

DIAGNOSIS There are no essential tests recommended after thyroid hormone exposure. However, serum T4, T3, and thyroglobulin levels may have some diagnostic and prognostic value. Elevated serum T4 and T3 levels help to confirm excessive ingestion of thyroid preparations. In children, a serum T4 concentration greater than 75 μg/dL within 7 hours after ingestion may be predictive of who will develop toxicity (e.g., fever, tachycardia, and agitation) 12 to 48 hours after ingestion.8 Despite this study, measurements of serum T4 and T3 do not always correlate with the severity of illness and need for therapy, particularly in those with chronic thyroid preparation overdose. With acute thyroid hormone overdose, the initial serum TSH may not be suppressed until pituitary thyrotrophs respond to thyroid hormone excess and circulating TSH is metabolically cleared. The serum T4/T3 ratio and thyroglobulin concentration may be helpful in distinguishing those patients with thyrotoxicosis factitia from those with endogenous causes of thyrotoxicosis.55 The serum T4/T3 ratio in patients taking exogenous, excessive doses of T4 is higher than in patients with endogenous thyrotoxicosis, in whom there is a marked T3 secretion. In patients with thyrotoxicosis from Graves’ disease, the mean T4/T3 ratio is 28 (range, 11–57), whereas patients with thyrotoxicosis factitia have a mean ratio of 70 (range, 48–114). Ordinarily, small amounts of thyroglobulin are released into the serum during normal T4 release from the thyroid gland. Thus, patients with thyrotoxicosis factitia have either low or undetectable serum thyroglobulin levels,3 as compared with those with endogenous thyrotoxicosis, in which thyroglobulin levels are normal or increased. Endogenous hyperthyroidism due to Graves’ disease or nodular thyroid disease can also be differentiated from thyroid hormone overdose by measuring thyroidal uptake of iodine-123 or technetium99m. The uptake is increased in hyperthyroidism due to Graves’ disease or nodular thyroid disease, whereas it is suppressed with overdose. However, it should be understood that the uptake is also suppressed in hyperthyroidism associated with thyroiditis, metastatic thyroid cancer, and struma ovarii. The dynamic pattern of a patient’s serial thyroid function tests may provide evidence for diagnosis of exogenous T3 ingestion.6 The serum T3 concentration

will most likely far exceed that observed in endogenous causes of hyperthyroidism. The rapid fall in serum T3 concentration indicates that T3 toxicosis is a transient event rather than a sustained physiologic process. The serum T4/T3 ratio will be expected to consistently be less than 20, which is less than that observed in conditions of endogenous hyperthyroidism associated with T3 toxicosis. This ratio reflects the extreme elevation of serum T3 concentration and the decreased T4 concentration with T3 suppression of TSH. An increased serum T4/T3 ratio may be observed in thyrotoxic states other than ingestion of excess amounts of T4. Patients receiving amiodarone therapy have elevated T4/T3 ratios (mean, 57; range, 27–120), and it has been associated with increased serum thyroglobulin concentration (mean, 118 ng/dL; range, 17–460 ng/dL).56 In addition to thyroid function testing, routine laboratory analysis in patients who have taken excessive doses of thyroid hormones should include a complete blood count and measurement of serum electrolyte, blood urea nitrogen, creatinine, glucose, creatine phosphokinase (CPK), calcium concentrations, and pregnancy testing in women of childbearing age. Serum acetaminophen and salicylate concentrations should be performed in all intentional overdose patients. In patients with chest pain or cardiovascular toxicity, an electrocardiogram should be performed, and laboratory evaluation should include serial measurements of serum CPK and troponin concentrations. Other studies that may be helpful include head computed tomography, lumbar puncture, and toxicology studies of blood and urine.

Differential Diagnosis The sympathomimetic effects of thyroid hormone overdose may present similarly to many other toxicologic and nontoxicologic entities (Box 67-1). Other toxic etiologies to consider include anticholinergic, neurolepticmalignant, serotonin, and sedative-hypnotic withdrawal syndromes; and poisoning by hallucinogens, lithium, monoamine oxidase inhibitors, strychnine, sympathomimetics (e.g., cocaine, amphetamines, methylxanthines, cough and cold preparations, decongestants), salicylates, dinitrophenol and pentachlorophenol, and nicotine. Occasionally, thyrotoxicosis may be associated with ingestion of amiodarone, lithium, and excessive doses of iodine. Nontoxicologic conditions that should be considered in the differential diagnosis include endogenous thyrotoxicosis, traumatic head injury, intracranial hemorrhage, heatstroke, systemic infection, pheochromocytoma, hypoglycemia, malignant hyperthermia, and lethal catatonia. As mentioned, specific thyroid function laboratory testing helps differentiate endogenous thyrotoxicosis from exogenous thyrotoxicosis (overdose). In addition, the relatively short duration of symptoms and the absence of exophthalmos, pretibial myxedema, onycholysis of fingernails, thyroid bruit, and goiter are helpful in ruling out endogenous hyperthyroidism.

CHAPTER 67

BOX 67-1

DIFFERENTIAL DIAGNOSIS OF THYROID HORMONE OVERDOSE

Hyperthyroidism • Endogenous hyperthyroidism due to Graves’ disease, multinodular goiter, solitary functioning adenoma, thyroiditis • Hyperthyroidism associated with drug use such as thyroid hormone preparations, amiodarone, iodide-containing compounds, interferon, lithium Acute disorders associated with sympathetic nervous system activation: infection, heatstroke, hemorrhage, trauma, pheochromocytoma, conditions associated with severe pain, and drug withdrawal states Toxic drug ingestion • Amphetamine, cocaine, methylxanthines, and other sympathomimetic agents • Cyclic antidepressants and monoamine oxidase inhibitors • Salicylates • Dinitrophenol and pentachlorophenol • Nicotine overdose • Central hallucinogens • Lithium and other psychotropic agents • Toxic syndromes (e.g., neuroleptic malignant syndrome and serotonin syndrome)

MANAGEMENT Overview The treatment plan of patients who have ingested thyroid hormone is dependent on the intent of the exposure (suicidal or accidental), estimated dose ingested, time since ingestion, associated ingestion of other compounds, toxic effects present on presentation, and the patient’s age, comorbid conditions, and reliability (when considering outpatient treatment). As noted already, healthy adults and children may tolerate even relatively large doses of thyroid hormone without serious consequences.7,8,11,12,52,57,58 On the other hand, lifethreatening toxicity can occur in elderly patients or those with underlying cardiac disease.44,58-60 Indications for inpatient observation and treatment include (1) signs and symptoms of toxicity; (2) elderly age or the presence of underlying cardiopulmonary disease; (3) ingestion of more than 100 μg/kg of T4 or 30 μg/kg of T3; (4) serum T4 concentrations greater than 75 μg/dL and/or T3 levels greater than 350 ng/dL; and (5) unreliable patients or caretakers. Patients with mild to moderate signs of toxicity can be admitted to a monitored floor bed, whereas those patients manifesting significant cardiovascular or neurologic signs and symptoms should be managed in an intensive care unit. Emergent medical assessment and GI decontamination are not recommended for every patient exposed to thyroid hormones. Most cases of accidental ingestion can be managed with home observation and telephone follow-up by health care professionals for a period of 7 days. Gastrointestinal decontamination is unnecessary


1071

for children younger than 12 years who accidentally ingest an estimated 2 mg or less of T4 and may not be necessary for ingestions up to 5 mg.9,11 These patients may be observed at home pending the onset of symptoms. Although the absence of initial symptoms does not preclude the possibility for delayed significant toxicity (e.g., seizures),24 prophylactic treatment with antithyroid agents (e.g., propranolol, PTU, and corticosteroids) is not recommended in the absence of toxic effects.7-11 Patients who have ingested thyroid hormone with suicidal intent should be emergently assessed in a hospital, receive GI decontamination, and be observed for signs and symptoms of thyroid hormone toxicity or coingestants. After GI decontamination and an emergency department observation period of several hours, it may be acceptable to transfer an otherwise healthy, asymptomatic patient who ingested thyroid hormone with suicidal intent to an inpatient psychiatric facility. This is provided that the receiving facility is knowledgeable of the delayed toxic effects that can occur from thyroid hormone, can monitor for these effects, and will transfer the patient back to an acute care facility should these effects occur. Otherwise, it is more prudent to admit these patients to the hospital for close observation for a period of 3 to 5 days.

Decontamination GI decontamination is recommended after intentional or accidental thyroid hormone overdose (greater than 5 mg T4 equivalent), provided it can be initiated within a few hours of ingestion. Although it has not been well studied, single-dose administration of activated charcoal (1 g/kg orally or by nasogastric tube) is the preferred method of gastrointestinal decontamination. The bile acid sequestrant, cholestyramine, is an acceptable alternative agent for GI decontamination. Clinical studies have shown that cholestyramine significantly interferes with T4 absorption from the GI tract and interrupts T4 and T3 enterohepatic circulation.61,62 One in vitro study showed that 50 mg of cholestyramine resin is capable of irreversibly binding 3 mg of T4.61 The typical cholestyramine dose is 50 to 150 mg/kg/dose (adult, 3–9 g), and this dose can be repeated every 6 to 8 hours. Neither cathartic nor whole bowel irrigation has been formally studied as a decontamination method after thyroid hormone overdose.

Supportive Care Supportive measures should include treatment of hyperthermia; correction and maintenance of fluid, electrolyte, and acid–base balance; and monitoring of cardiac rhythm and respiratory status. Intravenous fluid should be administered such that urine output is at least 1 to 2 mL/kg/hr. Hyperthermia should be managed using standard measures. Case reports suggest that dantrolene may be effective adjunct therapy for endogenous thyrotoxicosis,63-65 but its efficacy remains to

1072


be established in exogenous thyroid hormone toxicity. Dantrolene inhibits the effects of high circulating T4 levels on calcium flux across the sarcoplasmic reticulum.63 Hypertension requiring medical treatment is rare and, if clinically indicated, should be managed as a hypertensive emergency.

Specific Treatment Measures Specific treatment measures for exogenous thyroid storm include the administration of β-adrenergic antagonists to suppress the signs and symptoms and administration of agents that block conversion of T4 to T3 (active hormone) and block the release of thyroid hormone from the thyroid gland. β-ADRENERGIC ANTAGONISTS Agents in this class (e.g., propranolol and esmolol) rapidly reduce catecholamine-dependent signs and symptoms, such as tachycardia, supraventricular tachyarrhythmias, hypertension, tremor, palpitation, tension, and psychomotor agitation.14,15,20,21,28,34,47,49,54 Propranolol, and possibly other β blockers, also partially inhibit the conversion of T4 to T3.66 The typical oral propranolol dose is 0.2 to 0.5 mg/kg/dose (adult, 10–40 mg) every 4–6 hours; the dose should be adjusted according to the response, and large doses (240–280 mg/day) may be required in severely toxic patients. The intravenous propranolol dose is 0.1 mg/kg (adult, 2–10 mg) over 10 minutes and may be repeated up to three times as clinically indicated. An esmolol infusion can be initiated by administering 0.5 mg/kg over 1 minute, then 50 μg/kg/min for 4 minutes; if the response is inadequate, rebolus with 0.5 mg/kg and then 50 to 200 μg/kg/min for up to 48 hours. CALCIUM CHANNEL ANTAGONISTS Diltiazem appears to be an effective alternative therapy in controlling thyrotoxic symptoms in patients in whom β-blocker therapy may be contraindicated.67,68 The oral diltiazem dose is 1 to 3 mg/kg/dose (adult, 60–180 mg) every 6 to 8 hours. Diltiazem may be administered intravenously as a bolus injection (0.25 mg/kg), typically 20 mg intravenously given initially followed by 5 to 10 mg/hr. IODINATED RADIOCONTRAST AGENTS Oral iodinated radiocontrast agents (e.g., sodium ipodate and iopanoic acid) are potent inhibitors of peripheral T4 bioconversion to T3 and appear to be effective adjunct treatment for patients with either exogenous8,42,47,69 or endogenous thyrotoxicosis.70-73 After administration of these contrast agents, there is marked prolongation in serum T4 half-life, with a concurrent sharp increase in serum rT3 level and a marked decrease in serum T3 level.42,47,69 Although not important for exogenous thyroid hormone overdose, these agents also release large amounts of iodide with their

metabolism, which subsequently blocks the release of T4 and T3 from the thyroid. The typical sodium ipodate and iopanoic acid dose for adults is 3 g and that for children is 150 mg/kg/dose, and may be repeated for recurrence of symptoms. Sodium ipodate, 250 mg/kg/dose every 3 days for 18 days followed by 500 mg/kg/dose every 3 days for 21 days, has been successfully used to treat a patient with moderately severe neonatal Graves’ disease.71 CORTICOSTEROIDS The major effect of corticosteroids, particularly dexamethasone (2 mg every 6 hours for four doses), is to alter peripheral T4 metabolism such that conversion from T4 to T3 is diminished and to rT3 is enhanced.74-76 In those with endogenous thyroid storm, relative adrenal insufficiency is often present, and corticosteroid administration (hydrocortisone at 200 to 400 mg daily) is important as part of treatment to reduce mortality. The presence of relative adrenal insufficiency in exogenous thyroid storm is unclear. PROPYLTHIOURACIL AND METHIMAZOLE The antithyroid thionamide drugs PTU and methimazole (MMI) inhibit the synthesis of both T4 and T3. These agents interrupt thyroid peroxidase–catalyzed inorganic iodide oxidation and thyroidal T4 secretion.66,77 PTU and MMI have limited to no efficacy in the management of exogenous thyroid hormone toxicity (see below for toxicity from these agents). IODIDE Iodide acutely inhibits thyroid hormone biosynthesis and release, and, like the thionamides, has no proven clinical utility in the treatment of exogenous thyroid hormone exposure.

Enhancement of Elimination Multiple doses of activated charcoal have been used and case reports suggest it does not appreciably alter serum thyroid hormone levels or improve clinical outcome.8,22 However, multiple doses of cholestyramine may be an effective means of decreasing the body’s exogenous hormone load by binding GI tract T4 and disrupting enterohepatic recirculation. Cholestyramine has been used successfully to treat iatrogenic thyrotoxicosis (Fig. 67-2).61,62 Hemodialysis is ineffective because of the high protein binding and limited renal excretion of thyroid hormones. Exchange transfusion,40,48 plasmapheresis,26,40,78 and hemoperfusion26 have been used in the management of acute and nonacute thyroid hormone poisoning, but conclusive studies are lacking. Observations suggest that these extracorporeal techniques do not remove significant amount of thyroid hormones relative to the total ingestion and that their efficacy decreases with time.

Serum total T4 nmol/L

CHAPTER 67

200

Serum free T4 pmol/L

100 75

50

Serum total T3 nmol/L

25

3.5

2.5

Serum TSH mU/L

1.5 0.9 0.5 0.1 0

2

4 Days

6

8

FIGURE 67-2 The use of the bile acid sequestrant cholestyramine to lower serum thyroid hormones in iatrogenic hyperthyroidism. Two patients with iatrogenic hyperthyroidism were administered 4 g of cholestyramine four times a day. The alterations in serum total T4, free T4, total T3, and thyroidstimulating hormone (TSH) levels in the two subjects (●—●; ▲—▲) and one control (■—■) (n = 3, values = mean ± SE) are shown. The normal serum values are as follows: total T4, 51 to 142 nmol/L; free T4, 10 to 36 pmol; total T3, 1.2 to 3.4 nmol/L; and TSH, 0.4 values for T4 and T3 and the lower normal range values for TSH. (From Shakir KMM, Michaels RD, Hays JH, et al: The use of bile acid sequestrants to lower serum thyroid hormones in iatrogenic hyperthyroidism. Ann Intern Med 1993;118:113.)

TOXICOLOGY OF THYROID ANTAGONISTS Thyroid antagonists are drugs that interfere with one or more steps in iodine metabolism, thyroid hormone synthesis, or hormone release by the thyroid gland. Drugs that prevent the secretion of thyroid hormones include iodides and lithium. The toxicity of iodine (see Chapter 96) and lithium (see Chapter 30) are discussed elsewhere. Amiodarone may produce both hyperthyroidism and hypothyroidism; its toxicity is discussed in Chapter 63. The toxicity of the thionamides, PTU and MMI (Tapazol), is discussed here. Another thionamide available in Great Britain, carbimazole (Neo-Mercazole), is converted to MMI after absorption.


1073

PTU and MMI inhibit organification of iodide and the coupling of iodotyrosines for hormonally active iodothyronines. PTU also partially inhibits the peripheral deiodination of T4 to T3. Both agents are readily absorbed from the GI tract within an hour, and inhibition of thyroid iodine organification begins within 20 to 30 minutes.44 The Vd for PTU is about 0.3 L/kg, and 75% is protein bound. The Vd for MMI is 0.6 L/kg, and protein binding is minimal. The plasma elimination halflives of PTU and MMI are 1 to 2 hours and 4 to 6 hours, respectively. Intrathyroidal accumulation of drug occurs. Both PTU and MMI cross the placental barrier and appear in human breast milk. There is a paucity of information regarding acute PTU or MMI overdose. Acute ingestion of an estimated 5 to 13 g of PTU in a 12-year-old patient did not result in any clinically significant effects.82 A low incidence of adverse effects (3% to 7%) has been associated with therapeutic use of both PTU and MMI.16,44,79-85 Most toxic reactions to thionamides occur with a few weeks or months of beginning therapy. Adverse drug events associated with PTU use include skin rash (purpuric or urticarial), granulocytopenia, eosinophilia, lupus-like syndrome, acute hepatitis, cholestatic hepatotoxicity, hepatic necrosis, liver failure, and death. Diagnostic laboratory studies may reveal complete blood count and liver function test abnormalities, hepatocellular necrosis around the central veins with moderate to severe lymphocytes and neutrophils infiltration in the portal areas and lobules on liver biopsy, positive migration inhibition factor test to PTU, and PTU-induced peripheral lymphocyte transformation.81,85,86 PTU may traverse the placenta and cause neonatal hepatitis and lymphocyte sensitization.86 Management of PTU toxicity includes immediate discontinuation of the drug, supportive care, steroid therapy, and, in cases of fulminant liver failure, orthotopic liver transplantation.16,80,81,87,88 Adverse drug events associated with MMI use include agranulocytosis, pancytopenia, plasmocytosis, serum sickness, acute include hepatitis, cholestatic jaundice, granulomatous hepatitis, hepatocellular necrosis, and death.79,89-94 Diagnostic laboratory studies may reveal abnormalities in the complete blood count, liver function tests, liver biopsy, and bone marrow biopsy.89,90,92 Management of MMI toxicity includes immediate discontinuation of the drug, supportive care, and, in cases of severe bone marrow toxicity, reverse isolation, antibiotics, dexamethasone, and granulocyte colonystimulating factor therapy.89,92 Agranulocytosis from both agents has an overall incidence of about 1 in 500 patients. Like other adverse effects, agranulocytosis occurs with greatest incidence in the first few weeks of treatment. Agranulocytosis is usually heralded by fever and a sore throat. This adverse drug effect is reversible upon discontinuation of the offending thionamide. The treatment of thionamide overdose is entirely supportive. Previously euthyroid patients who ingest these agents are not expected to become hypothyroid, as because these agents have a relatively short duration of action ( 1000/mm3), severe diffuse myalgias, and dermatologic changes resembling scleroderma. Termed the eosinophilia-myalgia syndrome (EMS), this disease had other features that included pulmonary disturbances (dyspnea, cough, pulmonary infiltrates, and pulmonary hypertension, which occurred in about 60%), peripheral neuropathy, alopecia, edema, coronary artery spasm, and cardiac arrhythmias.48,62 The illness bore a striking resemblance to the unexplained “toxic oil” epidemic that occurred in Spain in 1981.48,63 When it was found that all cases of EMS could be traced to Ltryptophan synthesized by a single manufacturer, analysis revealed that owing to changes in the manufacturing method, the tryptophan was contaminated with an impurity, 1,1′-ethylidenebis [L-tryptophan].48 There is still controversy about whether the true cause of EMS was discovered. Nonetheless, after the FDA’s ban of tryptophan-containing products, the disease quickly and almost completely disappeared. This important mass poisoning has been extensively reviewed by others.62,64-69 Adverse effects have also occurred with the simultaneous use of tryptophan and antidepressants of the

CHAPTER 68

monoamine oxidase (MAO) inhibitor or serotonin reuptake inhibitor classes. In the case of MAO inhibitors, tryptophan was once recommended as adjunctive therapy for those who had a poor response to MAO therapy.70 However, after this combination began being used more consistently, reports began to describe hypertensive crises, myoclonus, and delirium after their combined use.71 This syndrome, now referred to as a serotoninergic syndrome (see Chapter 10A), appears to result from excess stimulation of central nervous system serotonin receptors and can include other features such as myoclonus, hyperreflexia, diaphoresis, priapism, and tremor. At its extreme, the serotoninergic syndrome can produce seizures, coma, and death. In addition to MAO inhibitors, the newer serotonin reuptake inhibitors (e.g., fluoxetine, paroxetine, and sertraline) have the potential to produce this syndrome after ingestion of tryptophan, although there has not been a sudden increase in reports of these cases. Tryptophan has been reintroduced to the market as an amino acid supplement following a great deal of diligence in improving its manufacturing. Thus far, there have been no new cases of EMS, nor a rise in the incidence of so-called serotoninergic syndrome since it has become more readily available.

Herbal, Traditional, and Alternative Medicines

1087

and stomach for corrosive injury, and anticipation of air emboli. Diluting agents should not be administered because of their potential to enhance oxygen liberation.

Other Therapies The promotion of tonics, extracts, and elixirs has a consistent ability to entice consumers. Their list is constantly changing. In rare circumstances, these alternative medicines prove to have therapeutic value. In most cases, they have no beneficial action but also no toxicity. These agents can occasionally be highly toxic, however. For example, laetrile was promoted in the early 1980s as an alternative treatment for cancer. Prepared from crushed apricot pits, this agent contained high concentrations of amygdalin, a cyanogenic alkaloid. Although it was not proved to have therapeutic value, laetrile did result in cases of cyanide intoxication after overdose.75 Other therapies, including ingestion of shark cartilage, boiled urchin, and algae, continue to be promoted without clear, scientifically proven benefit. REFERENCES

CALCIUM SUPPLEMENTS Use of calcium supplements has increased considerably during the past decade as the diminishing calcium intake of Americans is documented and the relationship between deficient calcium intake and osteoporosis, particularly in women, is recognized. Some calcium supplements that are derived from bone meal are reported to contain lead.

Hyperoxygenation Therapy Hyperoxygen therapy is being increasingly promoted as a health aid. It has become particularly popular as an alternative treatment for AIDS. Acting in a fashion similar to white blood cells in their destruction of microbial agents, ingestion of oxygen-liberating agents is thought to augment host defense mechanisms. Hydrogen peroxide is the most common agent used for hyperoxygenation therapy. Hydrogen peroxide used for this purpose is generally sold in a 25% to 50% concentration, in contrast to the 3% to 5% concentration of household hydrogen peroxide. The user is directed to ingest several drops daily. Because the agent is refrigerated, the potential for inadvertent ingestion is increased.72 Toxicity from hyperoxygen therapy has been reported after ingestion of excess amounts. The two major consequences of this ingestion are corrosive injury of the GI tract and excess liberation of oxygen, resulting in the formation of gas emboli. One milliliter of a concentrated hydrogen peroxide solution can liberate about 115 mL of oxygen; ingestion of 2 ounces of 35% hydrogen peroxide could release 6.9 L of oxygen in the stomach.72,73 Several researchers have described life-threatening or fatal gas emboli after ingestion of concentrated hydrogen peroxide.72-74 Treatment of concentrated hydrogen peroxide therapy includes supportive care, assessment of the esophagus

1. Verhoef M, Sutherland L, Brkich L: Use of alternative medicine by patients attending a gastroenterology clinic. Can Med Assoc J 1990;142:121. 2. Eisenberg D, Kessler R, Foster C, et al: Unconventional medicine in the United States: prevalence, cost, and patterns of use. N Engl J Med 1993;328:246. 3. Spigelblatt L, Laine-Ammara G, Pless I, et al: The use of alternative medicine by children. Pediatrics 1994;94:811. 4. Pearl W, Leo P, Tsang WO: Use of Chinese therapies among Chinese patients seeking emergency department care. Ann Emerg Med 1995;26:735. 5. Sampson W, London W: Analysis of homeopathic treatment of childhood diarrhea. Pediatrics 1995;96:961. 6. Weizman Z, Alkrinawi S, Goldfarb D, et al: Efficacy of herbal tea preparation in infantile colic. J Pediatr 1993;122:650. 7. Kleijnen J, Knipschild P, ter Riet G: Clinical trials of homeopathy. BMJ 1991;302:316. 8. Jacobs J, Jimenez L, Gloyd S, et al: Treatment of acute childhood diarrhea with homeopathic medicine. A randomized clinical trial in Nicaragua. Pediatrics 1994;93:719. 9. Delbanco T: Bitter herbs; mainstream, magic and menace. Ann Intern Med 1994;121:803. 10. Reports C: Herbal roulette. Consumer Reports 1995;(Nov):698–705. 11. Pereira C, Nishioka S: Poisoning by the use of Datura leaves in a homemade toothpaste. Clin Toxicol 1994;32:329. 12. Woolf G, Petrovic L, Rojter S, et al: Acute hepatitis associated with the Chinese herbal product Jin Bu Huan. Ann Intern Med 1994;121:729. 13. Bakhiet A, Adam S: Therapeutic utility, constituents and toxicity of some medicinal plants: A review. Vet Hum Toxicol 1995;37:255. 14. Ody P: The Complete Medicinal Herbal. London, Dorling Kindersley, 1993. 15. Vuksan V, Sievenpiper J, Koo V, et al: American ginseng (Panax quinquefolium L) reduces postprandial glycemia in nondiabetic subjects and subjects with type 2 diabetes mellitus. Arch Intern Med 2000;160:1009. 16. Tauchert M: Efficacy and safety of crataegus extract WS 1442 in comparison with placebo in patients with chronic stable New York Heart Association class-III heart failure. Am Heart J 2002;143:910. 17. Chan T, Chan J, Tomlinson B, et al: Poisoning by Chinese herbal medicines in Hong Kong: a hospital-based study. Vet Hum Toxicol 1994;36:546. 18. Chan T, Critchley J: The spectrum of poisonings in Hong Kong: An overview. Vet Hum Toxicol 1994;36:135.

1088

CAMS, NUTRITIONALS, AND PERFORMANCE ENHANCERS

19. Southern California Evidence-Based Practice Center R: Evidence Report/Technology Assessment Number 76 Task Order Number Nine. Rockville, Md: Agency for Healthcare Research and Quality, 2003. 20. Lee T, Lam T: Allergic contact dermatitis to Yunnan Paiyao. Contact Dermatitis 1987;17:59. 21. Saxe T: Toxicity of medicinal herbal preparations. Am Fam Physician 1987;35:135. 22. Ridker P: Toxic effects of herbal teas. Arch Environmental Health 1987;42:133. 23. Katz M, Saibil F: Herbal hepatitis: Subacute hepatic necrosis secondary to chaparral leaf. J Clin Gastroenterol 1990;12:203. 24. Mostefa-Kara N, Pauwels A, Pines E, et al: Fatal hepatitis after herbal tea. Lancet 1992;340:674. 25. Gordon D, Rosenthal G, Hart J, et al: Chaparral ingestion—the broadening spectrum of liver injury caused by herbal medications. JAMA 1995;273:489. 26. Centers for Disease Control and Prevention (CDC): Chaparralinduced toxic hepatitis—California and Texas. MMWR Morb Mortal Wkly Rep 1992;41:812. 27. Perharic L, Shaw D, Leon C, et al: Possible liver damage with the use of Chinese herbal medicine for skin disease. Vet Hum Toxicol 1995;563:563. 28. Chan TY: Anticholinergic poisoning due to Chinese herbal medicines. Vet Hum Toxicol 1995;37:156. 29. Coremans P, Lambrecht G, Schepens P, et al: Anticholinergic intoxication with commercially available thorn apple tea. Clin Toxicol 1994;32:589. 30. Eddleston M, Rajapakse S, Rajakanthan: Anti-digoxin Fab fragments in cardiotoxicity induced by ingestion of yellow oleander: a randomised controlled trial. Lancet 2000;355:967. 31. Segelman A, Segelman F, Karliner J, et al: Sassafras and herb tea— potential health hazards. JAMA 1976;236:477. 32. Ridker P, Ohkuma S, McDermott W, et al: Hepatic venocclusive disease associated with the consumption of pyrrolizidinecontaining dietary supplements. Gastroenterology 1985;88:1050. 33. Huxtable R, Luthhyy J, Zweifel U: Toxicity of comfrey-pepsin preparations. N Engl J Med 1986;315:1095. 34. Huxtable R: Herbal teas and toxins: novel aspects of pyrrolizidine poisoning in the United States. Perspect Biol Med 1980;24:1. 35. Roulet M, Laurini R, Rivier L, et al: Hepatic veno-occlusive disease in newborn infant of a woman drinking herbal tea. J Pediatr 1988;112:433. 36. Vanherweghem J, Depierreux M, Tielemans C, et al: Rapidly progressive interstitial renal fibrosis in young women. Association with slimming regimen including Chinese herbs. Lancet 1993;174:174. 37. Vanhaelen M, Vanhaelen-Fastre R, But P, et al: Identification of aristolochic acid in Chinese herbs. Lancet 1994;343:174. 38. Schmeiser H, Pool B, Wiessler M: Identification and mutagenicity of metabolites of aristolochic acid formed by rat liver. Carcinogenesis (Lond) 1986;7:59. 39. Nortier JL, Martinez MC, Schmeiser HH, et al: Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J Med 2000;342:1686. 40. Huang K: The Pharmacology of Chinese Herbs. Boca Raton, FL, CRC Press, 1993, p 388. 41. Bisset N: Arrow poisons in China. Part II. Aconiturn—botany, chemistry, and pharmacology. J Ethnopharmacol 1981;4:247. 42. Chan T, Tomlinson B, Critchley J, et al: Herb-induced aconitine poisoning presenting as tetraplegia. Vet Hum Toxicol 1994;36:133. 43. Fatovich D: Aconite: a lethal Chinese herb. Ann Intern Med 1992;21:309. 44. Tai Y-T, But P-H, Young K, et al: Cardiotoxicity after accidental herb-induced aconite poisoning. Lancet 1992;340:1254. 45. Perron A, Patterson J, Yanofsky N: Kombucha “mushroom” hepatotoxicity. Ann Emerg Med 1995;26:660. 46. Centers for Disease Control and Prevention (CDC): Unexplained severe illness possibly associated with consumption of kombucha tea—Iowa. MMWR Morb Mortal Wkly Rep 1995;44:892.

47. Lin T-J, Lu C-C, Chen K-W, et al: Outbreak of obstructive ventilatory impairment associated with consumption of sauopus androgynus vegetable. Clin Toxicol 1996;34:1. 48. Spyker D, Love L, Brooks S: An outbreak of pulmonary poisoning. Clin Toxicol 1996;34:15. 49. Centers for Disease Control and Prevention (CDC): Jin Bu Huan toxicity in children—Colorado. MMWR Morb Mortal Wkly Rep 1993;42:633. 50. Nelson L, Shih R, Hoffman R: Aplastic anemia induced by an adulterated herbal medication. Clin Toxicol 1995;33:467. 51. Espinoza E, Mann M-J, Bleasdell B: Arsenic and mercury in traditional Chinese herbal balls. N Engl J Med 1995;333:803. 52. Chan T, Lee K, Chan A, et al: Poisoning due to Chinese proprietary medicines. Hum Exp Toxicol 1995;14:434. 53. Pachter L: Culture and clinical care—folk illness beliefs and behaviors and their implications for health care delivery. JAMA 1994;271:690. 54. Pachter L, Cloutier M, Bernstein B: Ethnomedical (folk) remedies for childhood asthma in a maintained Puerto Rican community. Arch Pediatr Adolesc Med 1995;149:982. 55. Risser A, Mazur L: Use of folk remedies in a Hispanic population. Arch Pediatr Adolesc Med 1995;149:978. 56. McElvaine M, Harder E, Johnson L, et al: Lead poisoning from the use of Indian folk medicines. JAMA 1990;264:2212. 57. Kulshrestha M: Lead poisoning diagnosed by abdominal x-rays. Clin Toxicol 1996;34:107. 58. Spoerke D: Toxicity of homeopathic products. Vet Hum Toxicol 1989;31:259. 59. Ames B: A role for supplements in optimizing health: the metabolic tune-up. Arch Biochem Biophys 2004;423:227. 60. Philen R, Ortiz D, Auerbach S, et al: Survey of advertising for nutritional supplements in health and body building magazines. JAMA 1992;268:1008. 61. Dyer J: Gamma-hydroxybutyrate—a health-food product producing coma and seizurelike activity. Am J Emerg Med 1991;9:321. 62. Swygert L, Maes E, Sewell L, et al: Eosinophilia-myalgia syndrome—results of national surveillance. JAMA 1990;264:1698. 63. Hertzman P, Falk H, Kilbourne E, et al: The eosinophilia-myalgia syndrome: the Los Alamos Conference. J Rheumatol 1991;18:867. 64. Hertzman P, Blevins W, Mayer J, et al: Association of the eosinophilia-myalgia syndrome with the ingestion of tryptophan. N Engl J Med 1990;322:868. 65. Belongia E, Hedberg C, Gleich G, et al: An investigation of the cause of the eosinophilia-myalgia syndrome associated with tryptophan use. N Engl J Med 1990;323:357. 66. Kamb M, Murphy J, Jones J, et al: Eosinophilia-myalgia syndrome in L-tryptophan-exposed patients. JAMA 1992;267:77. 67. Centers for Disease Control and Prevention (CDC): Analysis of Ltryptophan for etiology of eosinophilia-myalgia syndrome. MMWR Morb Mortal Wkly Rep 1990;39:789. 68. Centers for Disease Control and Prevention (CDC): Eosinophiliamyalgia syndrome: follow-up survey of patients—New York. MMWR Morb Mortal Wkly Rep 1991;40:401. 69. Slutsker L, Hoesly F, Miller L, et al: Eosinophillia-myalgia syndrome associated with exposure to tryptophan from a single manufacturer. JAMA 1990;264:1213. 70. Pope H, Jonas J, Hudson J, et al: Toxic reactions to the combination of monoamine oxidase inhibitors and tryptophan. Am J Psychiatr 1985;142:491. 71. Blackwell B: Monoamine oxidase inhibitor interactions with other drugs. J Clin Psychopharmacol 1991;11:55. 72. Luu T, Kelley M, Strauch J, et al: Portal vein gas embolism from hydrogen peroxide ingestion. Am J Emerg Med 1992;21:1391. 73. Giberson T, Kern J, Pettigrew D, et al: Near-fatal hydrogen peroxide ingestion. Ann Emerg Med 1989;18:778. 74. Rackoff W, Merton D: Gas embolism after ingestion of hydrogen peroxide. Pediatrics 1990;85:593. 75. Hall A, Linden C, Kulig K, et al: Cyanide poisoning from Laetrile ingestion: Role of nitrite therapy. Pediatrics 1986;78:269.

69

The Vitamins ALLISON A. MULLER, BS, PHARMD ■ FRED M. HENRETIG, MD

At a Glance… ■

■

■

The most crucial specific intervention for vitamin A poisoning is immediate discontinuation of vitamin A; this measure alone suffices in most cases. Prompt withdrawal of vitamin D supplements and implementation of a diet low in calcium and vitamin D are sufficient therapy for mild to moderate cases of vitamin D poisoning. It probably is prudent to caution against the use of high-dose vitamin C therapy for patients with known nephrolithiasis, G6PD deficiency, iron overload conditions, pregnancy, and perhaps for women taking oral contraceptives.

INTRODUCTION AND RELEVANT HISTORY The vitamins are a defined group of essential organic micronutrients that are required in the human diet for optimal nutrition and to prevent specific deficiency syndromes.1,2 This requirement is due to either a complete inability to synthesize these nutrients de novo or an inadequate rate of synthesis to maintain optimal health. Medical uses for the vitamins include the prevention or treatment of deficiency states and the treatment of rare vitamin-responsive inborn errors of metabolism. A less accepted current usage of vitamins has been routine high-dose consumption by healthy adults. This practice has gained popularity with the lay public and some health care workers in an effort to enhance appearance, longevity, or athletic performance or to prevent or ameliorate nondeficiency-specific disease states. The clinically significant vitamin exposures occur most often under these circumstances of intentional chronic overdose. The water-soluble vitamins typically are excreted renally when ingested in excess, although very large doses taken chronically have resulted in adverse effects. The fat-soluble vitamins are stored in tissues, and excessive consumption is thus more likely to result in toxicity. Accidental overdose of pediatric multivitamin preparations by children also occurs frequently, although this is rarely a cause for significant concern aside from co-ingested iron in combination products. Serious iron toxicity is rare even in this context. Occasionally, vitamins are chosen as an intentional acute overdose agent. An unfortunately not uncommon scenario is the acute overdose by a young pregnant woman of her prescribed prenatal vitamin and mineral supplement. In this context, with a typical elemental iron content of 62.5 mg per tablet, serious iron poisoning may occur, although toxicity related to

co-ingested vitamins is again rarely of significance (see also Chapter 72). The medical use of vitamins can be traced to the 1753 discovery by British naval surgeon James Lind of the protection from scurvy afforded to sailors by the addition of fresh citrus fruits to their diets during long voyages.1 Ascorbic acid (vitamin C) was, of course, subsequently identified as the antiscorbutic factor and became the first of the 13 named vitamins. Vitamins are currently classified as water soluble (nine vitamins: ascorbate, thiamine, riboflavin, niacin, pyridoxine, biotin, pantothenic acid, folate, and cyanocobalamin) or fat soluble (four vitamins: A, D, E, and K). Several of the vitamins exist in nature or in vivo as different but closely related chemical compounds or precursors and are referred to as vitamers. Many vitamins require processing in vivo to become biologically active. The water-soluble vitamins or their derivatives function primarily as coenzymes for apoenzymes. An example is pyridoxine (when converted to pyridoxal phosphate) as coenzyme to the glutamic acid decarboxylase apoenzyme, forming a holoenzyme that synthesizes γ-aminobutyric acid from glutamic acid. The fat-soluble vitamins A and D interact with specific intracellular receptors and have hormonal or prohormonal effects.2 Amounts of vitamins necessary daily to protect normal, healthy persons from vitamin deficiency states range from micrograms to milligrams and are designated the minimum daily requirements (MDRs). Currently in the United States, recommendations on daily intake are expressed as reference daily intakes (RDIs) for vitamins and minerals (Table 69-1). These replace the U.S. recommended daily allowance (RDA) and are based on average RDI values for the U.S. population over the age of 4 years.2,3 Megadose usage typically involves selfadministration of doses 20 to 660 times these recom-

TABLE 69-1 Reference Daily Intakes (RDIs)3 VITAMIN

RDI

A C D E B6 B12 Thiamine Riboflavin Niacin Folic acid

5000 IU 60 mg 400 IU 30 IU 2 mg 6 μg 1.5 mg 1.7 mg 20 mg 0.4 mg

IU, international units.

1089

1090


mended amounts. In the United States, efforts to regulate vitamin usage have had a complex and politically charged history. Currently, the U.S. Food and Drug Administration (FDA) has the authority to regulate the labeling of vitamin and mineral supplements. Currently, the FDA does not regulate the nutrient content of vitamin supplements, except those intended for use by children less than 12 years of age and by pregnant or lactating women, despite the well-recognized hazards of megadose vitamin usage.2 A number of vitamin-responsive metabolic disorders have been described, involving at least eight of the nine water-soluble vitamins and vitamin D.1,4,5 Classic examples include pyridoxine-dependent infantile convulsions, pernicious anemia, and vitamin D–sensitive rickets. Pyridoxine dependency was first described in the early 1950s,1 and the same era witnessed the observation that the dementia associated with pellagra (niacin deficiency) was similar in some ways to that of schizophrenia.4,5 Early studies in the psychiatric literature suggested beneficial results in treating schizophrenia with massive doses of niacin, prompting further extension of this concept to other vitamins and to other illnesses.4,6 Pauling’s 1970 monograph Vitamin C and the Common Cold7 helped popularize the use of megadoses of vitamins for prevention and treatment of a number of illnesses ranging from viral infections to cancer. The increased interest in personal fitness and preventive health of the 1970s provided fertile ground for the expansion of this concept of vitamin megadosing. By the 1980s, more than 70% of Americans believed that vitamins could prevent fatigue, and 21% believed that diseases such as cancer and arthritis were caused by vitamin deficiency.4,8 A 1987 survey found that half of adult Americans took occasional vitamin supplements, and more than 20% took vitamins daily.9 The popularity of vitamin supplements is a reflection of broad media coverage of studies detailing the roles of vitamins in preventing and treating cancer, cardiovascular disease, ocular disorders, respiratory disorders, and osteoporosis.10-12 Nutritional authorities caution that insufficient scientific evidence exists to support the megadosing of dietary antioxidants to prevent chronic illnesses such as cardiovascular disease or cancer.13 It has been recommended that all adults take one multivitamin daily, since most people do not obtain a sufficient amount of all vitamins from dietary consumption alone.14

FAT-SOLUBLE VITAMINS In general, toxic effects of vitamins are most often related to overdosing of the fat-soluble vitamins and have been observed particularly with excessive ingestion of vitamins A and D (Table 69-2). Adverse effects ascribed to vitamins E and K have been uncommon and noted primarily with parenteral use. In view of the prominent place afforded to vitamin A toxicity in reported medical literature, this vitamin is reviewed in some detail relative to the other vitamins covered in this chapter.

Vitamin A INTRODUCTION AND RELEVANT HISTORY Vitamin A has a long and fascinating history. As early as 1500 BC, night blindness that could be remedied by the topical application of roasted liver was described in Egypt, and Hippocrates later recommended the ingestion of cow liver as a cure.15 In 1865, ophthalmia brasiliana, an eye disorder of poorly nourished slaves, was described. Further linkage of keratomalacia to nutritional deficiency was provided in the 1880s with descriptions of night blindness among Russian Orthodox Catholics who fasted during Lent and particularly with the description of corneal sloughing in breast-fed infants of fasting mothers.15 Perhaps the oldest and largest recorded experience with vitamin toxicity is associated with both acute and chronic exposure to excess vitamin A. The 19th-century Arctic explorer Elisha Kane described a syndrome of severe headache, vomiting, drowsiness, and irritability occurring a few hours after the ingestion of polar bear liver.16 This syndrome is recognized today as being quite likely due to acute hypervitaminosis A–induced pseudotumor cerebri. Modern authors continue to describe similar phenomena, for example, the 1984 report of a 25-year-old Sri Lankan woman who developed pseudotumor and markedly elevated serum vitamin A levels 1 week after consuming a meal of shark liver (see Toxicology).17 STRUCTURE The vitamin A family consists of several related compounds, with their respective stereoisomers, which exhibit the vitamin’s biologic effects. Retinol, also referred to as vitamin A1, is the alcohol form, which is found primarily as an ester in the liver of many animals and saltwater fish (Fig. 69-1). Retinal, which is the vitamin A aldehyde, functions as the chromophore of the retina when it combines with the protein opsin to form rhodopsin. βCarotene, or provitamin A, is a dimer of retinal that occurs in many pigmented plants. Retinoic acid, the carboxylic acid of retinol, is believed to be the relevant vitamer at the cellular level for most functions of vitamin A other than in the visual cycle. Vitamin A is classically quantified by bioassay in rats, although purified preparations may also be determined spectrophotometrically.15 The “retinol equivalent” is equal to 1 μg of all-trans-retinol (3.3 IU) or 6 μg of dietary β-carotene (10 IU). PHARMACOLOGY AND PATHOPHYSIOLOGY Vitamin A is believed to act through hormone-like activity on intracellular receptors, in addition to the wellunderstood specific effect of one of its vitamers, retinal, as the chromophore in the visual light-sensing cells. Vitamin A is essential in the visual cycle, in the maintenance of the functional and structural integrity of epithelium in mucus-secreting or keratinizing tissues, in bone growth, and in reproduction and embryologic development. It has an important role in enhancing immune function and reducing sequelae of some

CHAPTER 69

The Vitamins

1091

TABLE 69-2 Vitamin Toxicity Overview VITAMIN

TOXIC DOSE

PRINCIPAL TOXIC EFFECTS

A

Acute: 75,000–100,000 IU (P) >1 million IU (A) Chronic: 18,000 IU/day (P) 20,000–50,000 IU/day (A)

Initial: CNS; increased ICP with headache, irritability, lethargy, ophthalmoplegia, papilledema Later: hair loss, peeling skin, hepatomegaly CNS: increased ICP, pseudotumor cerebri Mucocutaneous: dry, scaly, peeling skin; hair loss, brittle nails; cheilitis, stomatitis, gingivitis Hepatic: early–hepatomegaly, anorexia, vomiting, +/– abnormal LFTs; late–hepatic fibrosis, ascites, cirrhosis, esophageal varices Skeletal: bone pain, cortical hyperostoses; premature epiphyseal closure (P) Reproductive: teratogenic effects on face, ears; occasional CNS, cardiac (less so than with isotretinoin) Metabolic: hypercalcemia Renal: hypercalciuria, nephrocalcinosis CV: metastatic calcifications in heart, vessels CV: infantile hypercalcemia, supravalvular aortic stenosis syndrome

D

Teratogenic: >10,000 IU/day 1600–2000 IU/day (P) 60,000 IU/day (A)

E

Teratogenic: (?) 2000–4000 IU/day Probably variable, with idiosyncratic hypersensitivity (?) 400–3000 IU/day

K

(?) (Occurs with therapeutic IV dose)

Pyridoxine Niacin

117–500 mg/day 3.0–4.5 mg/day

Thiamine

Acute: (?) (rare, occurs with therapeutic IV dose) Chronic: 5 mg/day (?), probably > 4 g/day

C

CNS: headache, weakness GI: nausea, cramps, diarrhea Heme: increased effect of anticogulants Anaphylactoid reaction Heme: hemolysis, jaundice in newborns (especially with G6PD deficiency) Peripheral sensory neuropathy Cutaneous: flushing, pruritus GI: cholestatic jaundice, hepatitis Heme: thrombocytopenia CV: atrial fibrillation Misc: gout, myopathy Anaphylactic reaction Misc: headache, irritability, tachycardia GI: nausea, cramping, diarrhea Renal: nephrolithiasis (especially in predisposed patients) Heme: hemolysis with G6PD deficiency Misc: rebound scurvy after withdrawal

A, adult; CNS, central nervous system; CV, cardiovascular; GI, gastrointestinal; G6PD, glucose-6-phosphate dehydrogenase; Heme, hematologic; ICP, intracranial pressure; LFTs, liver function tests; Misc, miscellaneous; P, pediatric.

infections (e.g., measles in young children18) and may play a significant role in anticarcinogenesis. Several synthetic analogs of vitamin A have been developed as pharmaceutical agents for dermatologic applications. In the visual system, both rods and cones utilize 11-cisretinal as the chromophore. In the photoreceptor cells of the rods, especially sensitive to low-intensity light, this vitamer combines with the membrane protein opsin to form rhodopsin, which is the light-absorbing holoreceptor. The cones, which are the color-sensitive photoreceptor cells, are of three types, each having a separate protein that when combined with 11-cis-retinal responds optimally to red, green, or blue wavelengths of light. The visual cycle involves an interaction of the photon-activated rhodopsin with a G protein and interconversions of 11-cisretinal to several stereoisomers.19 The basal mucus-secreting cells of many epithelia depend on vitamin A for normal structure and mucus secretion. These influences appear to be mediated primarily by retinoic acid, via changes in nuclear

transcription. Retinoic acid receptors have been described that belong to a receptor “superfamily” that includes receptors for calcitriol as well as thyroid and steroid hormones.15 Possible anticarcinogenic effects of vitamin A have been attributed to its ability to induce differentiation of malignant cells and to function in the synthesis of cellsurface glycoproteins and glycolipids that may play an important role in cell adherence and communication. Splenic lymphocyte proliferation and killer cell cytotoxic activity is impaired in vitamin A deficiency. Therefore, differentiation of these immune cells may play a role in the vitamin’s beneficial effect on immunity and resistance to infection.20 The primary food sources for vitamin A are liver, dairy products, egg yolk, and fish (providing retinol or retinol esters) and yellow and green vegetables (providing β-carotene).15 In the average American diet, about 50% of the vitamin intake comes from animal-based products and 50% from vegetable sources. Absorption and

1092


Vitamin A

Vitamin D3

J J J J J J J J J

J J J J J J J J JJ

21

22 20

24 23

18 11 9

12 8

b-Carotene

13

17

14

26 25 27

16 15

7 6

J J J J J

J J J J

19

CH2OH

4 3

5 2

CH2

10

K

1

HO Retinol

Cholecalciferol Vitamin E

Vitamin K

O

K

O R

J

K

CH3

CH2[CH2JCH2JCHJCH2]3H

OH

O

A

COOH N

N

NH2

O OKCJCKCJCJCJCH2OH

N

N N

Ascorbic acid

S

CH2CH2OH

OH OH

J

CH2OH CH2OH

Thiamine

J

OH

Niacin

J

Pyridoxine

OH

B FIGURE 69-1 Fat-soluble (A) and water-soluble (B) vitamins reported to have toxic effects in humans.

utilization of the vitamin is complex and varies with the source. Most animal-derived vitamin A is consumed in the form of retinol esters, typically retinyl palmitate, and when vitamin A is ingested in usual dietary amounts, absorption is virtually complete. These esters are hydrolyzed in the intestinal lumen and brush border and then taken up by the intestinal cells bound to a cellular retinol-binding protein (CRBP). There they are reesterified and incorporated into chylomicrons for transport to the liver, where they are stored. Hepatic vitamin A storage capacity is considerable (average content of retinyl esters is 100 to 300 μg/g), with reserves sufficient to withstand several months of a vitamin A–free diet before the plasma concentration decreases markedly or deficiency symptoms appear. The liver normally releases vitamin A after hydrolysis to retinol, 95% of which is bound to an α1-globulin, the retinolbinding protein (RBP). When the liver becomes saturated with vitamin A as a result of excessive ingestion or hepatic disease or both, retinyl esters may appear in the blood, eventually accounting for as much as 65% of the total circulating retinoids. Circulating retinol is carried to cells of various target organs, where it is taken up by a membrane-bound protein very similar to CRBP, re-esterified, then hydrolyzed and delivered to the appropriate intracellular sites by a cytosolic CRBP. The

fate of ingested carotenoids is slightly different.15,21 Only about one third of the carotene content of a meal is absorbed. Some β-carotene is cleaved in the intestinal mucosa and esterified and transported to the liver via the lymphatics, while some is absorbed intact. When carotenoids are present in large amounts in the diet, they may cause an elevated blood carotene level (normal range, 50 to 200 μg/dL), associated with a benign and reversible yellowish (or “golden suntan”) discoloration of the skin (but not the sclera, as occurs in jaundice). In most cases, excessive consumption of carotene does not lead to hypervitaminosis A, presumably because only limited conversion to retinol occurs. However, this occasionally occurs, as it did in a 20-year-old Japanese woman whose diet consisted mainly of pumpkin for 2 years. She subsequently developed vitamin A poisoning with hepatotoxicity, confirmed via liver needle biopsy.22 In addition to hepatic storage and tissue uptake, some retinol is glucuronidated. Other water-soluble metabolites are also excreted, with no retinol normally found unchanged in the urine.15 SPECIAL POPULATIONS In adults, vitamin A deficiency is usually related to chronic illnesses associated with fat malabsorption such as inflammatory bowel disease, biliary or pancreatic

CHAPTER 69

insufficiency, and cirrhosis. Children suffering from general malnutrition are especially susceptible, and it is believed that vitamin A deficiency is responsible for more than 250,000 cases per year worldwide of irreversible pediatric blindness, in addition to greatly enhanced mortality from infectious diseases, especially measles.15,18 Features characteristic of vitamin A deficiency include night blindness and keratomalacia progressing to permanent blindness, keratinization and drying of the skin with follicular hyperkeratosis, increased incidence of respiratory infections, urinary calculi due to associated changes in the urinary tract epithelium, diarrhea, and occasional impairment of hearing, taste, and smell.15 TOXICOLOGY With excessive vitamin A intake, hepatic storage capacity is exceeded, and the previously noted normal pattern of almost all circulating vitamin A existing as retinol bound to RBP is altered, with an increasing proportion of plasma retinoids being present as retinyl esters loosely associated with lipoproteins. Clinical case reports of vitamin A toxicity typically involve normal or only slight elevation of retinol (normal range, 30 to 70 μg/dL), with markedly elevated retinyl esters (normal, 40%) to eliminate CO to negligible levels. Many experts recommend HBO or administration of oxygen at 2 to 3 atmospheres pressure absolute (ATA) in a hyperbaric chamber. Although HBO is reasonably safe, it is considerably more expensive and less convenient than administration of oxygen at ambient pressure (“normobaric” oxygen, or NBO), particularly if transfer to another facility is required. In experimental animal models of severe CO poisoning, HBO therapy decreases brain injury by a variety of mechanisms, including improved mitochondrial oxidative metabolism, inhibition of leukocyte adherence to injured vasculature, and reduced lipid peroxidation. In this setting, HBO has a paradoxical, and beneficial, antioxidant effect.23,28,61-63 However, although treatment with HBO eliminated hippocampal cell death in a mouse model of CO poisoning, there was no difference in learning and memory testing.64 At least seven case series and nonrandomized clinical trials of HBO for CO poisoning have been published.65-71 Few of these studies assessed outcomes by objective measures, and none were blinded. All reported a benefit from HBO over standard NBO therapy. five randomized clinical trials studying the effect of HBO on neuropsychological outcomes have been published and are listed in Table 87-6. Three of these trials reported a

Yes

Yes Yes

All

Yes

Yes No

No No

No LOC Noncomatose All

No

No

No LOC

BLINDED?

NEUROPSYCHOLOGICAL TESTS?

3

3–6

1 1

1

NO. OF TREATMENTS

3

54

14 Unk.

10

35 (46) 201 (31)

639

59 (68)

7 (22) 42 (15)

58 (34)

76

87

30 276

170

NO. NBO PATIENTS

NO. (%) NBO PATIENTS WITH POOR OUTCOME*

*Some authors did not report the number of patients lost to follow-up by treatment group, making totals approximate. LOC, loss of consciousness; NBO, normobaric oxygen; Unk., unknown.

Raphael, 198941 Thom, 199543 Mathieu, 199645 Scheinkestel, 199942 Weaver, 200235 Total*

STUDY

PATIENTS INCLUDED

LOST TO FOLLOWUP (%)

682

76

104

30 299

173

NO. HBO PATIENTS

182 (27)

19 (25)

82 (79)

0 (0) 26 (9)

55 (32)

NO. (%) HBO PATIENTS WITH POOR OUTCOME*

No (trend toward harm) Yes

Yes Yes

No

HBO BENEFIT REPORTED

21.0

N/A (harm: 1 in 9.1) 2.9

4.5 15.4

50.0

NO. NEEDED TO TREAT TO BENEfiT ONE PATIENT

TABLE 87-6 Randomized Trials of Neuropsychological Outcomes in Carbon Monoxide Poisoning Treated with HBO versus Normobaric Oxygen

CHAPTER 87 Carbon Monoxide Poisoning 1303

1304

ENVIRONMENTAL, INDUSTRIAL, AND HOUSEHOLD PRODUCT TOXICOLOGY

benefit to HBO, and two showed NBO to be equally efficacious. These trials have differed greatly in entry criteria, blinding, time from poisoning to experimental therapy, and outcome measures studied. Only two were double-blinded, employed sham “hyperbaric” therapy in the NBO arm, and measured outcomes by objective neuropsychological testing.42,43 These studies produced conflicting results; one study found a strong advantage to HBO, whereas the other showed no benefit and a nonsignificant trend toward harm. A fifth randomized trial used a nonclinical end point, which makes interpretation of results and extrapolation to clinical practice virtually impossible.54 Methodologic differences between studies and missing data make formal metaanalysis of these trials impossible. A crude summary of the results suggests that HBO provides an advantage over NBO that is nearly statistically significant (P = 0.056; Chisquared, 1 degree of freedom), but clinically very modest; only 1 of every 21 patients receiving HBO appeared to benefit from the therapy. If HBO does prevent neurologic injury, it must do so by a mechanism other than enhancing CO elimination from the blood. In all trials for which the data are reported, COHb had declined to negligible levels in almost all patients by the time HBO therapy could be initiated, and COHb levels did not correlate with neurologic outcome or response to therapy. From animal studies, HBO appears to displace CO from mitochondrial cytochromes, has antioxidant effects that minimize ischemic-reperfusion injury, and prevents cellular apoptosis. Although expensive and inconvenient, HBO therapy is reasonably safe; chamber-related complications occur in 0 to 8% of patients.35,43,72 Complications include middle ear or sinus barotrauma (most common), seizures (1%), pneumothorax, gas embolism, and intolerable claustrophobia. HBO therapy is not available in most American hospitals. Transport to a center that can deliver HBO may contribute greatly to expense, inconvenience, and treatment delay. Unfortunately, no single or combination of factors has been shown to reliably predict which CO poisoning patients will develop DNS. Most CO-poisoned patients recover completely with NBO alone, and therefore would not benefit from or need HBO therapy. In addition, no trial of HBO therapy has included children. Although outcomes are generally worse in elderly people, regardless of treatment, it is unclear whether the benefits of HBO are any greater in this group. Despite the lack of reliably identifying patients with CO poisoning at high risk for developing DNS, criteria have been proposed to use as indications for HBO in patients with CO poisoning73,74 (Box 87-1). These indications have not been prospectively evaluated and validated, but their presence should provoke strong consideration for HBO treatment. Almost all experts recommend HBO therapy for pregnant women with significant CO poisoning, regardless of stage of pregnancy or severity of clinical signs and symptoms. A landmark study in pregnant ewes showed that COHb levels in the fetus rise more slowly than in the mother, ultimately reaching a level 98% higher than the

BOX 87-1

INDICATIONS AND CONSIDERATIONS FOR HYPERBARIC OXYGEN TREATMENT IN CARBON MONOXIDE POISONING

Accepted Indications

Altered mental status History of loss of consciousness or syncope Coma Seizures Focal neurologic deficits Pregnancy with evidence of fetal distress Considerations

Metabolic acidosis Cardiac end-organ effects (severe arrhythmia, ischemia, or infarction) Extremes of age COHb level > 25%–40% Abnormal neuropsychometric testing Persistent neurologic symptoms after 4–6 hr of high-flow normobaric oxygen Pregnancy with COHb level > 15%–20% COHb, carboxyhemoglobin. Adapted from references 73, 74, and 85.

maternal level.75 When CO exposure was discontinued, CO was eliminated from the fetus at about half the maternal rate. However, these results cannot be extrapolated directly to humans. Sheep hemoglobin A has a lower affinity for CO than human hemoglobin A, whereas sheep fetal hemoglobin has a much higher affinity for CO than human fetal hemoglobin.76 During human poisoning, the peak fetal COHb percentage should be within 1% to 4% of maternal peak levels.36,76 CO poisoning interferes with oxygen delivery to the fetus, but because the normal fetus is profoundly hypoxic and acidotic by postnatal standards, it unclear at what threshold this would lead to injury. Although unclear, pregnant patients likely need longer treatment with oxygen because of the slower elimination of CO across the placenta, particularly when the CO exposure occurred over several hours or more.75 It is known that severe maternal CO poisoning can cause intrauterine fetal demise, limb and vertebral anomalies, cranial deformities, brain injury, transient hepatomegaly, and congestive heart failure in the newborn.77-79 It is unclear, however, whether mild to moderate maternal CO poisoning can produce adverse fetal outcomes. Three case series have examined pregnancy outcomes in CO-poisoned women.77-79 In all cases, women with minor CO poisoning (no loss of consciousness and normal mental status) delivered healthy babies, despite not receiving HBO. Animal studies suggest that a single CO exposure can lead to intrauterine hypoxia, fetal brain injury, and increased rates of fetal death.80-82 It is unclear from these studies, however, whether exposures that lead to adverse fetal

CHAPTER 87

outcome can occur in the absence of significant maternal poisoning. The efficacy of NBO or HBO for preventing adverse fetal outcomes for pregnant patients with CO poisoning has not been determined. To date, pregnant women have been excluded from all published trials of HBO in CO poisoning. HBO is generally considered safe for the fetus and has been used safely in pregnant women with CO poisoning.83 The results in these patients were similar to those of the pregnant women treated without HBO. When the mothers had normal mentation, the fetuses universally did well, whereas maternal coma or loss of consciousness carried a poor prognosis despite HBO. Patients who develop cardiac arrest as a result of CO poisoning have very poor outcomes. In one series of such patients, none (0 of 18) survived to hospital discharge despite aggressive therapy, including HBO.84 A reasonable algorithm for managing CO-poisoned patients is presented in Figure 87-1. This management strategy is in keeping with a recent position statement of the Undersea and Hyperbaric Medical Society and the consensus report of a panel of CO-poisoning experts.73,85 Unresolved issues include which subgroups of CO poisoned patients are most likely to benefit from HBO, the optimum HBO treatment pressure and number of sessions, the necessary intensity of NBO therapy in patients not receiving HBO, and the “window of opportunity” after which brain injury is irreversible even with therapy.73 In addition to oxygen therapy, several novel neuroprotective strategies have been evaluated in a mouse model of CO poisoning. Glutamate antagonists (riluzole), caspase-inhibitors (disulfiram), nitric oxide synthase inhibitors (N-nitro-L-arginine methyl ester, or L-NAME), adenosine agonists (2-chloro-N 6-cylopentyladenosine, or CCPA), and adenosine deaminase inhibitors (erythro-9-2-hydroxy-3-nonyl-adenine, or EHNA), have all been shown to prevent hippocampal damage and learning and memory defects in mice.86-88 HBO did not prevent neurologic injury in the same model.64 Although riluzole and disulfiram have been found to be safe and effective treatment for other human diseases, neither has been tested in human victims of CO poisoning.

Elimination DISPOSITION Victims of CO poisoning can be released from the hospital after 4 to 6 hours of oxygen therapy (whether NBO or a combination of HBO) if they are neurologically normal, have no more than mild symptoms, and have no unmet medical or psychiatric needs. NBO may be discontinued before 4 hours for patients with mild CO poisoning whose symptoms have resolved and who have COHb levels below 5%.89 Patients who do not recover fully after initial therapy should receive further high-flow oxygen treatment and consideration for HBO referral and treatment. Patients with moderate to severe CO poisoning should be considered for HBO treatment upon arrival and subsequently admitted to the hospital, preferably to an intensive care unit.

Carbon Monoxide Poisoning

1305

Signs/symptoms of CO poisoning

Oxygen 100% by non-rebreather mask

Measure CO level in: • Patient (venous COHb level) • Another exposed family member • Environmental air (by EMS/fire dept)

CO poisoning unlikely. Work up for alternate causes.

No

CO level elevated?

Yes

Syncope, persistent altered mental status, seizure, hypotension or ataxia?

No Pregnant?

Yes Yes

Yes

HBO readily available?

No

Yes

Fetal distress?

No: Either acceptable

Single HBO treatment

4–6 hours mask O2

Abnormalities persist?

Symptoms persist?

Yes Repeat HBO (up to 3 sessions)

Yes: Either acceptable

No Discharge to safe environment

FIGURE 87-1 Suggested management algorithm for carbon monoxide poisoning.

Upon hospital discharge, patients should be warned of the possibility of delayed neuropsychological complications and provided with instructions about what to do if these occur. All patients diagnosed with CO poisoning who are discharged from the emergency department after NBO treatment should also have mandatory medical follow-up within 1 to 2 weeks so that repeat neurologic evaluation can be conducted. Most

1306


patients return to normal within 3 to 12 months.13,21 Because of the increased risk of cardiovascular mortality, patients who suffer myocardial infarction due to CO poisoning should have long-term follow-up and cardiac risk assessment performed.56 REFERENCES 1. U.S. Department of Health and Human Services (USDHHS), Centers for Disease Control and Prevention (CDC), National Center for Health Statistics (NCHS), Compressed Mortality File (CMF) compiled from CMF 1999–2002, Series 20, No. 2H 2004 on CDC WONDER On-line Database. Available at http://wonder.gov/ mort SQL.htm, accessed January 13, 2005. 2. Mott JA, Wolfe MI, Alverson CJ, et al: National vehicle emissions policies and practices and declining US carbon monoxide-related mortality. JAMA 2002;288:988–995. 3. Johnson EJ, Moran JC, Paine SC, et al: Abatement of toxic levels of CO in Seattle rinks. Am J Public Health 1975;65:1087–1090. 4. Cobb N, Etzel RA: Unintentional carbon monoxide-related deaths in the United States, 1979 through 1988. JAMA 1991;266:659–663. 5. Chisholm CD, Reilly J, Berejan B: Carboxyhemoglobin levels in patients with headache. Ann Emerg Med 1987;16(4):170. 6. Heckerling PS; Occult carbon monoxide poisoning: a cause of winter headache. Am J Emerg Med 1987;5:201–204. 7. Heckerling PS, Leikin JB, Maturen A: Occult carbon monoxide poisoning: validation of a prediction model. Am J Med 1988;84: 251–256. 8. Heckerling PS, Leikin JB, Maturen A, Perkins JT: Predictors of occult carbon monoxide poisoning in patients with headache and dizziness. Ann Intern Med 1987;107:174–176. 9. Turnbull TL, Hart RG, Strange GR, et al: Emergency department screening for unsuspected carbon monoxide exposure. Ann Emerg Med 1988;17:478–484. 10. Dolan MC, Haltom TL, Barrows GH, et al: Carboxyhemoglobin levels in patients with flu-like symptoms. Ann Emerg Med 1987;16:782–786. 11. Heckerling PS, Leikin JB, Maturen A, et al: Screening hospital admissions from the emergency department of occult carbon monoxide poisoning. Am J Emerg Med 1990;8:301–304. 12. Lavonas EJ, Kerns WP, Tomaszewski CA, et al: Epidemic carbon monoxide poisoning despite a CO alarm law: Mecklenburg County, NC, December, 2002. MMWR Morb Mortal Wkly Rep 2004;53: 189–192. 13. Piantadosi CA: Diagnosis and treatment of carbon monoxide poisoning. Respir Care Clin North Am 1999;5:183–202. 14. Okeda R, Funata N, Takano T, et al: The pathogenesis of carbon monoxide encephalopathy in the acute phase: physiological and morphological correlation. Acta Neuropathol 1981;54:1–10. 15. Goldbaum LR, Orellano T, Dergal E: Studies on the relationship between carboxyhemoglobin concentration and toxicity. Aviat Space Environ Med 1977;48:969–970. 16. Coburn RF: The carbon monoxide body stores. Ann N Y Acad Sci 1970;174:11–22. 17. Coburn RF, Mayers LB: Myoglobin oxygen tension determines from measurements of carboxyhemoglobin in skeletal muscle. Am J Physiol 1971;220:66–74. 18. Brown SD, Piantadosi CA: In vivo binding of carbon monoxide to cytochrome C oxidase in rat brain. J Appl Physiol 1990;69:604. 19. Hardy KR, Thom SR: Pathophysiology and treatment of carbon monoxide poisoning. J Toxicol Clin Toxicol 1994;32:613–629. 20. Zhang J, Piantadosi CA: Mitochondrial oxidative stress after carbon monoxide hypoxia in the rat brain. J Clin Invest 1992;90:1193–1199. 21. Thom SR, Ohnishi TS, Ischiropoulos H: Nitric oxide release by platelets inhibits neutrophil B2 integrin function following acute carbon monoxide poisoning. Toxicol Appl Pharmacol 1994;128: 105–110. 22. Verma A, Hirsch DJ, Glatt CE, et al: Carbon monoxide: a putative neural messenger. Science 1993;259:381–384. 23. Thom SR, Fisher D, Xu YA, et al: Role of nitric oxide-derived oxidants in vascular injury from carbon monoxide in the rat. Am J Physiol 1999;276(3 Pt 2):H984–H992. 24. Thom SR: Carbon monoxide-mediated brain lipid peroxidation in the rat. J Appl Physiol 1990;68:997–1003.

25. Choi HS: Delayed neurological sequelae in carbon monoxide intoxication. Arch Neurol 1982;40:433–435. 26. Ginsberg MD, Myers RE, McDonaugh BF: Experimental carbon monoxide encephalopathy in the primate. II. Clinical aspects, neuropathology and physiologic correlation. Arch Neurol 1974;30:209–216. 27. Thom SR: Dehydrogenase conversion to oxidase and lipid peroxidation in brain after carbon monoxide poisoning. J Appl Physiol 1992;73:1584–1589. 28. Thom SR, fisher D, Xu YA, et al: Adaptive responses and apoptosis in endothelial cells exposed to carbon monoxide. Proc Natl Acad Sci U S A 2000;97:1305–1310. 29. Pace N, Stajman E, Walker EL: Acceleration of carbon monoxide elimination in man by high pressure oxygen. Science 1950;111: 652–654. 30. Peterson JE, Stewart RD: Absorption and elimination of carbon monoxide by inactive young men. Arch Environ Health 1970;21:165–171. 31. Jay GD, McKindley DS: Alterations in pharmacokinetics of carboxyhemoglobin produced by oxygen under pressure. Undersea Hyperb Med 1997;24:165–173. 32. Langehennig PK, Seeler RA, Berman E: Paint removers and carboxyhemoglobin. N Engl J Med 1976;295:1137. 33. Leiken JB, Kaufman D, Lipscomb JW, et al: Methylene chloride report of 5 exposures and 2 deaths. Am J Emerg Med 1990; 8:534–537. 34. Ratney RS, Wegman DH, Elkins HB: In vivo conversion of methylene chloride to carbon monoxide. Arch Environ Health 1974;28:223–236. 35. Weaver LK, Hopkins RO, Chan KJ, et al: Hyperbaric oxygen for acute carbon monoxide poisoning. N Engl J Med 2002;347: 1057–1067. 36. Tikuisis P: Modeling the uptake and elimination of carbon monoxide. In Penney DG (ed): Carbon Monoxide. Boca Raton, FL, CRC Press, 1996, pp 45–67. 37. Longo LD: Carbon monoxide effects on oxygenation of the fetus in utero. Science 1976;194:523–525. 38. Hill EP, Hill JR, Power GG, et al: Carbon monoxide exchanges between the human fetus and mother: a mathematical model. Am J Physiol 1977;232:H311–H323. 39. Barret L, Danel V, Faure J: Carbon monoxide poisoning: a diagnosis frequently overlooked. Clin Toxicol 1985;23:309–313. 40. Parkinson RB, Hopkins RO, Cleavinger HB, et al: White matter hyperintensities and neuropsychological outcome following carbon monoxide poisoning. Neurology 2002;58:1525–1532. 41. Raphael J-C, Elkharrat D, Jars-Guincestre M-C, et al: Trial of normobaric and hyperbaric oxygen for acute carbon monoxide intoxication. Lancet 1989;414–419. 42. Scheinkestel CD, Bailey M, Myles PS, et al: Hyperbaric or normobaric oxygen for acute carbon monoxide poisoning: a randomised controlled clinical trial. Med J Aust 1999;170:203–210. 43. Thom SR, Taber RL, Mendiguren II, et al: Delayed neuropsychologic sequelae after carbon monoxide poisoning: prevention by treatment with hyperbaric oxygen. Ann Emerg Med 1995; 25:474–480. 44. Deschamps D, Geraud C, Julien H, et al: Memory one month after acute carbon monoxide intoxication: a prospective study. Occup Environ Med 2003;60:212–216. 45. Mathieu D, Wattel F, Mathieu-Nolf M, et al: Randomized prospective study comparing the effect of HBO versus 12 hours of NBO in non comatose CO poisoned patients. Undersea Hyperbar Med 1996;23(Suppl):7–8. 46. Weaver LK, Howe S, Hopkins R, Chan KJ: Carboxyhemoglobin half-life in carbon monoxide-poisoned patients treated with 100% oxygen at atmospheric pressure. Chest 2000;117:801–808. 47. Touger M, Gallagher EJ, Tyrell J: Relationship between venous and arterial carboxyhemoglobin levels in patients with suspected carbon monoxide poisoning. Ann Emerg Med 1995;25:481–483. 48. Buckley RG, Aks SE, Eshom JL, et al: The pulse oximetry gap in carbon monoxide intoxication. Ann Emerg Med 1994;24:252–255. 49. Moureu H, Chovin P, Truffer L, Lebbe J: Nouvelle micromethode pour la determination rapide et precise de l’oxycarbonemie par absorption selective dans l’infrarouge [New micromethod for the rapid and precise determination of blood carbon monoxide by

CHAPTER 87

50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66.

67. 68. 69. 70. 71.

selective absorption in the infrared spectrum (French)]. Arch Mal Prof 1957;18:116–124. Widdop B: Analysis of carbon monoxide. Ann Clin Biochem 2002; 39:378–391. Otten EJ, Rosenberg JM, Tasset JT: An evaluation of carboxyhemoglobin spot tests. Ann Emerg Med 1985;14:850–852. Cunnington AJ, Hormbrey P: Breath analysis to detect recent exposure to carbon monoxide. Postgrad Med J 2002;78:233–237. Kurt TL, Anderson RJ, Reed WG: Rapid estimation of carboxyhemoglobin by breath sampling in an emergency setting. Vet Hum Toxicol 1990;32:227–229. Ducasse JL, Celsis P, Marc-Vergnes JP: Non-comatose patients with acute carbon monoxide poisoning: hyperbaric or normobaric oxygenation? Undersea Hyperbar Med 1995;22:9–15. Myers RAM, Britten JS: Are arterial blood gases of value in treatment decisions fro carbon monoxide poisoning? Crit Care Med 1989;17:139–142. Henry CR, Satran D, Lindgren B, et al: Myocardial injury and longterm mortality following moderate to severe carbon monoxide poisoning. JAMA 2006;295:398–402. Messier LD, Myers RAM: A neuropsychological screening battery for emergency assessment of carbon-monoxide-poisoned patients. J Clin Psychol 1991;47:675–684. Silver DA, Cross M, Fox B, Paxton RM: Computed tomography of the brain in acute carbon monoxide poisoning. Clin Radiol 1996;51:480–483. Sawada Y, Takahashi M, Ohashi N, et al: Computerised tomography as an indication of long-term outcome after acute carbon monoxide poisoning. Lancet 1980;1:783–784. Parkinson RB, Hopkins RO, Cleavinger HB, et al: White matter hyperintensities and neuropsychological outcome following carbon monoxide poisoning. Neurology 2002;58:1525–1532. Brown SD, Piantodosi CA: Recovery of energy metabolism in rat brain after carbon monoxide hypoxia. J Clin Invest 1991;89: 666–672. Thom SR: Antagonism of carbon monoxide-mediated brain lipid peroxidation by hyperbaric oxygen. Toxicol Appl Pharmacol 1990; 105:340–344. Thom SR: Functional inhibition of leukocyte B2 integrins by hyperbaric oxygen in carbon monoxide-mediated brain injury in rats. Toxicol Appl Pharmacol 1993;123:248–256. Gilmer B, Kilkenny J, Tomaszewski C, Watts JA: Hyperbaric oxygen does not prevent neurologic sequelae after carbon monoxide poisoning. Acad Emerg Med 2002;9:1–8. Ely EW, Moorehead B, Haponik EF: Warehouse workers’ headache: emergency evaluation and management of 30 patients with carbon monoxide poisoning. Am J Med 1995;98:145–155. Gorman DF, Clayton D, Gilligan JE, Webb RK: A longitudinal study of 100 consecutive admissions for carbon monoxide poisoning to the Royal Adelaide Hospital. Undersea Hyperb Med 1992;20:311–316. Goulon M, Barios A, Rapin M: Carbon monoxide poisoning and acute anoxia due to breathing coal gas and hydrocarbons. J Hyperbar Med 1986;1:23–41. Mathieu D, Nolf M, Durocher A: Acute carbon monoxide poisoning: risk of late sequelae and treatment by hyperbaric oxygen. J Toxicol Clin Toxicol 1985;23:315–324. Myers RAM, Snyder SK, Emhoff TA: Subacute sequelae of carbon monoxide poisoning. Ann Emerg Med 1985;14:1167. Roche L, Bertoye A, Vincent P: Comparison de deux groupes de vignt intoxications oxycarbonees traitees par oxygenennormobare et hyperbare [French]. Lyon Med 1968;220:1483–1499. Wilms SJ, Turner F, Kerr J: Carbon monoxide or smoke inhalations treated with oxygen (hyperbaric vs normobaric): 118 reviewed. Undersea Biomed Res 1985;S56.

Carbon Monoxide Poisoning

1307

72. Scheinkestel CD, Bailey M, Myles PS, et al: Hyperbaric or normobaric oxygen for acute carbon monoxide poisoning: a randomized controlled clinical trial. Undersea Hyperb Med 2000;27:163–164. 73. Hampson NB, Mathieu D, Piantadosi CA, et al: Carbon monoxide poisoning: interpretation of randomized clinical trials and unresolved treatment issues. Undersea Hyperb Med 2001; 28:157–164. 74. Kao LW, Nanagas KA: Carbon monoxide poisoning. Emerg Med Clin North Am 2004;22:985–1018. 75. Longo LD, Hill EP: Carbon monoxide uptake in fetal and maternal sheep. Am J Physiol 1977;232:H324–H330. 76. Longo LD: Carbon monoxide poisoning in the pregnant mother and fetus and its exchange across the placenta. Ann N Y Acad Sci 1970;174:313–341. 77. Caravati EM, Adams CJ, Joyce SM, Schafer NC: Fetal toxicity associated with maternal carbon monoxide poisoning. Ann Emerg Med 1988;17:714–717. 78. Koren G, Sharav T, Pastuszak A, Garrettson LK, et al: A multicenter, prospective study of fetal outcome following accidental carbon monoxide poisoning in pregnancy. Reprod Toxicol 1991;5:397–403. 79. Norman CA, Halton DM: Is carbon monoxide a workplace teratogen? A review and evaluation of the literature. Ann Occup Hyg 1990;34:335–347. 80. Ginsberg MD, Myers RE: Fetal brain damage following maternal carbon monoxide intoxication: an experimental study. Acta Obstet Gynecol Scand 1974;53:309–317. 81. Ginsberg MD, Myers RE: Fetal brain injury after maternal carbon monoxide intoxication: clinical and neuropathologic aspects. Neurology 1976;26:15–23. 82. Singh J: Early behavioral alterations in mice following prenatal carbon monoxide exposure. Neurotoxicology 1986;7:475–482. 83. Elkharrat D, Raphael JC, Korach JM, et al: Acute carbon monoxide intoxication and hyperbaric oxygen in pregnancy. Intens Care Med 1991;17:289–292. 84. Hampson NB, Zmaeff JL: Outcome of patients experiencing cardiac arrest with carbon monoxide poisoning treated with hyperbaric oxygen. Ann Emerg Med 2001;28:36–41. 85. Thom SR, Weaver LK: Carbon monoxide poisoning. In Feldmeier JJ (ed): Hyperbaric Oxygen 2003 Indications and Results: The Hyperbaric Oxygen Therapy Committee Report. Kensington, MD: Undersea and Hyperbaric Medical Society, 2003, pp 11–17. 86. Tomaszewski C, Gilmer B, Watts JA: The neuroprotective effects of dimethyl sulfoxide on memory following acute carbon monoxide poisoning in mice. Ann Emerg Med 2000;36:S69. 87. Gilmer B, Thompson C, Tomaszewski C, Watts JA: The protective effects of experimental neurodepressors on learning and memory following carbon monoxide poisoning. J Toxicol Clin Toxicol 1999; 37:606. 88. Thompson C, Gilmer B, Tomaszewski C, Watts JA: The neuroprotective effects of glutamate antagonism on memory following acute carbon monoxide poisoning. J Toxicol Clin Toxicol 1999;37:608. 89. Ilano AL, Raffin TA: Management of carbon monoxide poisoning. Chest 1990;7:165–169. 90. Vagts SA: Non-fire Carbon Monoxide Deaths Associated with the Use of Consumer Products: 1999 and 2000 Annual Estimates. Bethesda, MD, U.S. Consumer Products Safety Commission, 2003. 91. Burney RE, Wu SC, Nemiroff MJ: Mass carbon monoxide poisoning: clinical effects and results of treatment in 184 victims. Ann Emerg Med 1982;11:399.

88

Cyanide and Related Compounds—Sodium Azide ALAN H. HALL, MD

At a Glance… ■ ■ ■ ■

■

■ ■

■ ■

■

Severe acute cyanide poisoning can be seen in a wide variety of settings, including enclosed-space fire smoke inhalation. Cyanide is a credible toxic terrorism threat agent. Whole-blood cyanide levels require several hours or longer to obtain. Emergent suspicion of the diagnosis and the decision to administer specific antidotes must be made on clinical and screening laboratory grounds. Elevated plasma lactate levels are a specific and sensitive indicator of the presence of significant cyanide poisoning in both smoke inhalation and pure cyanide poisoning cases. Several specific cyanide antidotes are available throughout the world. In the United States, only the cyanide antidote kit containing amyl nitrite for inhalation administration and sodium nitrite/ sodium thiosulfate for intravenous administration is available as of June 2006. Amyl nitrite inhalation is an effective first-aid measure, especially in cases of hydrogen cyanide gas exposure. Growing evidence indicates that hydroxocobalamin may be the cyanide antidote of choice because of its efficacy and superior safety and adverse effects profile. The nitrite and thiosulfate antidote kit is not efficacious for sodium azide poisoning; hydroxocobalamin may be of theoretical benefit based on limited in vitro data.

INTRODUCTION AND RELEVANT HISTORY Cyanide poisoning may be encountered in a wide variety of settings. Cyanide salts and hydrocyanic acid are used in common industrial processes such as electroplating, jewelry and metal cleaning, precious metal extraction, laboratory assays, and photographic processes.1-4 Hydrogen cyanide is a chemical intermediate for the manufacture of synthetic fibers, plastics, and nitriles.5 Criminal tampering by replacement of the ingredients in over-the-counter capsules with cyanide salts has resulted in a number of deaths.6,7 Victims of enclosed-space firesmoke inhalation may have both cyanide and carbon monoxide poisoning.8,9 Cyanide and carbon monoxide are synergistic toxicants10 (see Chapters 86 and 87). Nontraumatic deaths in aircraft accidents may be due to inhalation of carbon monoxide and cyanide combustion products.11 A number of compounds can liberate cyanide on spontaneous or thermal decomposition or by chemical reaction with acids (e.g., cyanogen, cyanogen bromide, cyanogen iodide, cyanogen chloride, calcium cyanide).1 Cyanogen halides and hydrogen cyanide are potential

chemical warfare agents.12 At low concentrations, however, cyanogen halides are primarily lacrimating and pulmonary irritant agents.3 Cyanogenic compounds (laetrile, amygdalin from plant sources, nitrile compounds such as acetonitrile or propionitrile) can release cyanide during metabolism, chemical reaction in the gut, or bacterial degradation after ingestion.3,13-17 Acute cyanide poisoning from apricot or peach kernels is unusual because the pits are usually swallowed whole and simply pass through the gastrointestinal tract; rare cases have been reported.18 Severe or fatal cyanide poisoning with symptom onset delay of several hours has followed accidental acetonitrile ingestion from glue-on artificial nail–removing compounds.19,20 Acrylonitrile is a special case. After inhalation or dermal exposure, it both undergoes hepatic metabolism releasing cyanide and is itself hepatotoxic. Whole blood cyanide levels as high as 4.3 μg/mL have been found in patients with acrylonitrile poisoning.17 In addition to supportive care and cyanide antidotes, treatment with N-acetylcysteine in a manner similar to that for acetaminophen poisoning has been recommended to prevent hepatotoxicity17 (see Chapter 47). Sodium nitroprusside releases cyanide during metabolism, which can result in elevated whole blood cyanide levels, and, occasionally, clinical cyanide poisoning.21-24 Coadministration of sodium thiosulfate or hydroxocobalamin can prevent cyanide toxicity, especially in patients receiving sodium nitroprusside infusions at rates greater than 2 μg/kg/minute24,25 (see Chapter 61). The frequent lack of correlation between blood cyanide levels and cyanide poisoning symptoms during nitroprusside administration suggests that the decision of whether to administer antidote therapy must be made on clinical grounds (e.g., presence of lactic acidosis or signs and symptoms consistent with cyanide poisoning). Clinical symptoms in this setting may, however, be due to thiocyanate accumulation.26 Chronic exposure to low levels of cyanide has been postulated to cause retrobulbar optic atrophy (in heavy smokers) and ataxic peripheral neuropathy (tropical ataxic neuropathy), as well as konzo (spastic upper motor neuron paraparesis) in people who consume large amounts of improperly prepared cassava, which contains the cyanogenic glycosides linamarin and lotaustralin in both roots and leaves.27,28 Development of these neuropathies seems to require both chronic lowlevel cyanide exposure and either a deficiency of the endogenous cyanide-detoxifying enzyme rhodanese or protein-calorie malnutrition with dietary sulfur deficiency. A condition resembling acute cyanide poisoning treatable with hydroxocobalamin has resulted from acute ingestion of improperly prepared cassava.29 1309

1310


Mild disorders of vitamin B12 and folate levels and some subclinical thyroid function abnormalities were noted in one group of workers with chronic cyanide salt exposure.2 Thyroid enlargement (goiter) and altered iodine-131 uptake have also been described in workers chronically exposed to cyanide3 and in populations eating an iodinedeficient monotonous cassava diet.30

EPIDEMIOLOGY Despite widespread cyanide and cyanogenic compound use, serious acute cyanide poisoning is rare. Of a total of 2,267,979 human poison exposures reported to the American Association of Poison Control Centers Toxic Exposure Surveillance System (TESS) during 2001, only 303 involved cyanide poisoning; of these, 17 were in children younger than 6 years of age, 17 were in patients 6 to 19 years of age, and 263 were in patients older than 19 years of age (the remainder were in patients of unknown age).31 Of the 295 cases in which the reason for exposure was known, 237 were unintentional exposures, 37 were intentional exposures, and 21 were classified as other. A total of 199 (65%) of these patients were treated in a health care facility.31 Of cyanide antidotes available in the United States, amyl nitrite was not listed in the 2001 TESS database, sodium nitrite administration was recorded in 27 instances, and sodium thiosulfate administration was recorded in 57 instances. Of the 303 cyanide exposures, clinical outcome was known in only 194 (64%).31 In 64 cases (21%), no signs or symptoms of cyanide poisoning developed; 116 patients (38%) became symptomatic, and 7 (2.3%) developed major symptoms (life-threatening signs or symptoms; significant residual disability or disfigurement).31 Fourteen TESS-reported patients (4.6%) died of cyanide poisoning during 2001.31 Some details of these 14 fatal cyanide poisonings were available.31 One involved combined carbon monoxide and cyanide poisoning from smoke inhalation (carboxyhemoglobin level, 35%; whole blood cyanide level, 40 μg/mL). Of the 13 “pure” fatal cyanide poisoning cases, all were adults.31 Ingestion of the involved cyanide compound was intentional in 12, and 1 case was classified as unintentional misuse. In three of these cases, whole blood cyanide levels were more than 20 μg/mL, 66 μg/mL, and 26.7 μg/mL; times after ingestion were not specified. An adult man who worked in a jewelry shop drank from an already-open bottle of soda and rapidly developed fatal cardiac arrest. The soda was subsequently found to have a pH of 7 and a cyanide concentration of 100 mg/L.31 An elderly retired chemist accidentally ingested a swallow of sodium cyanide–copper cyanide etching solution. He was apparently successfully resuscitated from the initial severe cyanide poisoning, but subsequently developed fatal liver, renal, and pancreatic

damage, suggesting that copper poisoning contributed to the fatal outcome.31

PHARMACOLOGY Pathophysiology Cyanide produces histotoxic hypoxia by binding with the ferric iron (Fe3+) of mitochondrial cytochrome oxidase, thus disrupting the normal functioning of the electron transport chain and the ability of cells to utilize O2 in oxidative phosphorylation.1 The result is a shift to anaerobic metabolism, a substantial decrease in adenosine triphosphate synthesis, depletion of cellular energy stores, and greatly increased lactic acid production, which causes an elevated anion-gap metabolic acidosis. Numerous iron- or copper-containing enzymes are inhibited by cyanide, but cytochrome oxidase inhibition is the major intracellular toxic mechanism in cyanide poisoning.3 The tissue hypoxia of cyanide poisoning has several causes. Those tissues most dependent on oxidative phosphorylation—heart and brain—are the most severely and rapidly affected. Central inhibition of the respiratory centers leads to hypoventilation, which in turn produces hypoxic hypoxia. Myocardial depression with decreased cardiac output produces stagnation hypoxia. Until the stage of respiratory depression or arrest, the blood is relatively normally oxygenated. However, the tissues are unable to extract and utilize this O2, which leads to a greater than normal amount of O2 in venous blood and an increased venous O2 percent saturation. Cyanide binding to cytochrome oxidase is a reversible process. The endogenous enzyme, rhodanese, is a natural defense against cyanide exposure. This enzyme complexes cyanide with sulfane sulfur, forming much less toxic thiocyanate. The body’s sulfur pool is small, however, and the availability of sulfane sulfur constitutes the rate-limiting factor in natural cyanide detoxification. In the absence of an exogenous source of sulfur, rhodanese activity is too slow to prevent serious toxicity or death in significant cyanide poisoning. The central nervous system is a primary target organ in cyanide poisoning.32,33 The mechanism by which cyanide exposure causes neurotoxicity is not completely understood. An increase in intraneuronal calcium levels and lipid peroxidation, perhaps initiated by cyanideinduced decreased adenosine triphosphate levels, which impairs sodium and calcium extrusion processes, might be a mechanism of nerve injury.34 Cyanide-induced apoptosis is mediated by cytochome-c release from mitochondria.35 Generation of reactive oxygen species (ROS) also plays an important role in cyanide-induced apoptosis in cortical neurons.33

Pharmacokinetics TOXICOKINETICS The toxicokinetics of cyanide are not well understood. Available data are either from animal experiments or

CHAPTER 88

Cyanide and Related Compounds—Sodium Azide

anecdotal human case reports. In dog plasma in vitro, cyanide is about 60% protein bound.36 In vivo, whole blood cyanide levels may be four or more times greater than serum levels because of the concentration of cyanide in erythrocytes.1 The volume of distribution (Vd) of cyanide in dogs is 0.498 L/kg.37 A similar Vd of 0.41 L/kg was estimated in a single case of human potassium cyanide poisoning.38 In this same case, estimates of other toxicokinetic parameters were area under the curve (AUC) 48 μg/mL/hr, clearance 163 mL/min, initial phase half-life (t1/2α) 20 to 30 minutes, and terminal-phase elimination half-life (t1/2β) 19 hours.38 The last value is consistent with findings in dogs showing only minimal excretion within the first 3 hours after oral administration, despite absorption of about 95%.36 In victims of human cyanide poisoning from smoke inhalation, blood cyanide half-life was about 60 minutes.9

1311

TOXICOLOGY

The clinical presentation depends on the route, dose, and time elapsed since exposure. Patients with inhalation exposure to high concentrations may experience sudden loss of consciousness after only a few breaths.3,44 Combined inhalation and dermal or pure dermal exposure to a gas containing 19% hydrogen cyanide caused severe acute cyanide poisoning in two workers with whole blood cyanide levels of 5.3 and 6.75 μg/mL, respectively.45 Patients who ingest potentially fatal amounts of cyanide salts may not develop lifethreatening symptoms for up to 0.5 to 1 hour after exposure.38 Delayed onset of symptoms (after 1 to 12 or more hours) may follow exposure to cyanogens such as laetrile, amygdalin, and nitrile compounds.6,15,19,20 In patients who do not experience sudden collapse, the initial signs and symptoms can resemble those of anxiety or hyperventilation.1 Early signs include central nervous system stimulation (giddiness, headache, anxiety), tachycardia, hyperpnea, mild hypertension, and palpitations.6 Late signs are nausea, vomiting, tachycardia or bradycardia, hypotension, seizures (rare), coma, apnea, dilated pupils, and a variety of cardiac effects, including erratic supraventricular or ventricular arrhythmias, atrioventricular blocks, ischemic changes on electrocardiography, and asystole.1 Noncardiogenic pulmonary edema may rarely occur, even after ingestion of cyanide salts.39 Of 21 acute cyanide poisoning victims, the following effects were noted: loss of consciousness (N = 15), metabolic acidosis (N = 14), cardiopulmonary failure (N = 9), anoxic encephalopathy (N = 6), and diabetes insipidus or conditions mimicking this condition (N = 1–3), which may be an ominous sign.16 The smell of “bitter almonds” (often described as “musty”) may be appreciated in some cases, but the ability to detect this odor is genetically determined, and many people cannot do so.1 Cyanosis is a late sign usually only noted at the stage of apnea and circulatory collapse.1 Dermal exposure to cyanide can result in systemic cyanide poisoning due to serious burns from molten cyanide salts, immersion in vats of cyanide salt solutions (with the potential for ingestion and vapor inhalation as well as dermal exposure), or total-body contamination with cyanide salts in confined spaces. Severe acute cyanide poisoning can rarely result from dermal exposure to hydrogen cyanide gas.45

Clinical Manifestations

Diagnosis

The natural history of severe acute cyanide poisoning is a rapid progression (faster with inhalation than ingestion) to coma, shock, respiratory failure, and death.1 Less severely poisoned patients administered only intensive supportive care have survived,6,39 whereas patients also administered specific antidotes have survived with whole blood cyanide levels as high as 40 μg/mL.40 Most patients who recover from acute cyanide poisoning do not have permanent sequelae, although rare cases of parkinsonianlike states with bilaterally symmetric lesions in the basal ganglia (putamen or globus pallidus) or memory deficits and personality changes have been reported.16,41-43

The initial physical examination focuses on the vital signs and the respiratory, cardiovascular, and central nervous systems. Continuous vital signs and electrocardiographic monitoring should be done. Whole blood cyanide levels are available, but generally take hours to obtain and cannot be used to guide emergent diagnosis or therapy.1 They can, however, document the diagnosis and response to treatment.

TOXICODYNAMICS In a single patient not treated with specific antidotes, the average urinary cyanide excretion over nearly 40 hours was 0.64 mg/hr after a probable ingestion of between 117 and 511 mg of potassium cyanide.6 In this same patient, the mean whole blood cyanide level 1 hour after ingestion was 8.2 μg/mL. This level increased to a mean of 19.7 μg/mL at 3 hours and to 23.4 μg/mL at 9 hours after ingestion. Despite intensive supportive treatment, this patient died about 40 hours after ingestion. In contrast, in a patient who survived ingestion of 1 g of potassium cyanide after treatment with sodium nitrite and sodium thiosulfate, the highest whole blood cyanide level was 15.68 μg/mL at 1.75 hours after ingestion; this level decreased to 0.82 μg/mL at 5 hours after ingestion.38 In another patient who survived cyanide poisoning secondary to dermal and inhalation exposure to propionitrile, treatment with hydroxocobalamin– sodium thiosulfate was associated with a decrease in the whole blood cyanide level from 5.71 μg/mL at 2 hours after exposure to 0.93 μg/mL 30 minutes later.13 Specific cyanide antidote administration is associated with more rapid decreases in whole blood cyanide levels than is seen in patients not administered antidotes.1

LABORATORY TESTING Plasma lactate, serum electrolytes, and arterial blood gases should be monitored as frequently as necessary to

1312


guide fluid, electrolyte, sodium bicarbonate, and respiratory therapy. Pulse oximetry may be unreliable in cases of smoke inhalation with combined carbon monoxide and cyanide poisoning and after administration of methemoglobin-inducing cyanide antidotes. Based on anecdotal case reports and animal experiments, certain screening laboratory values may help suggest the diagnosis when no history is available.1 Cyanide produces lactic acidosis, which can be confirmed by plasma lactate measurements.15,46 Normal plasma lactate levels are 1.0 mEq/L (mmol/L) or less. Lactic acidosis is present when serum lactate levels are more than 2.0 mEq/L (mmol/L). In combined poisoning with carbon monoxide and cyanide from smoke inhalation, plasma lactate levels may be the best marker of the presence and severity of a cyanide poisoning component.9 Plasma lactate levels of 10 mEq/L (mmol/L) or greater in smoke inhalation victims without severe burns or levels of 8 mEq/L (mmol/L) or greater in patients with “pure” cyanide exposure are sensitive and specific indicators of cyanide poisoning.47,48 If the patient is still breathing or is receiving assisted ventilation, the arterial partial pressure of O2 may be relatively normal. Cyanide inhibits the extraction of O2 from the blood at the tissue level. Thus, more O2 than normal is present in the venous blood; this may be reflected by an increased (>40 mm Hg) peripheral venous partial pressure of O2, an increased measured peripheral venous O2 percent saturation (>70%), or a narrowing of the normal difference between the measured arterial O2 percent saturation and the measured central venous or pulmonary artery O2 percent saturation (the normal central venous O2 percent saturation is about 70%).1,16 However, a mixed venous O2 percent saturation less than 90% does not, in itself, exclude acute cyanide poisoning.15 OTHER DIAGNOSTIC TESTING If pulmonary edema develops, a chest radiograph should be obtained periodically. A smoke inhalation clinical scoring system (scale from 1 to 10) based on the following clinical findings has been proposed: hoarseness (1 point); stridor (1 point); carbonaceous sputum (1 point); soot in the airways (1 point); singed nasal hairs (1 point); facial burns (1 point); abnormal chest auscultation findings (1 point); mental status change (1 point); and abnormal findings on chest radiography (2 points). In one case series, this clinical scoring system was predictive of a fatal outcome after smoke inhalation exposure from enclosed-space fires; it was also the strongest predictor of measured carboxyhemoglobin and whole blood cyanide levels.49 DIFFERENTIAL DIAGNOSIS Other cytochrome oxidase inhibitors such as hydrogen sulfide and sodium azide may produce clinical and laboratory findings similar to those seen in cyanide poisoning (see Chapter 91 and later discussion in this chapter on Sodium Azide). Although sodium nitrite might

have some efficacy in the treatment of hydrogen sulfide poisoning, it is ineffective for treating sodium azide poisoning.50

MANAGEMENT Supportive Measures Cyanide-exposed patients with only restlessness, anxiety, or hyperventilation do not require antidote therapy. Such patients should be administered supplemental O2 and undergo a few hours of clinical monitoring. Antidotes should be administered only if more serious symptoms develop. Rescuers must not enter areas with high airborne concentrations of cyanide without a self-contained breathing apparatus or air-supplied respirators. Mouthto-mouth breathing should be avoided if at all possible, and care must be taken by rescuers not to inhale the victim’s exhaled breath. Appropriate prehospital care consists of airway management, including endotracheal intubation if required, administration of 100% supplemental O2 by tight-fitting mask or endotracheal tube, placement of at least one large-bore intravenous line, administration of sodium bicarbonate if shock (with presumed metabolic acidosis) is present, decontamination of exposed skin or eyes, administration of standard antiarrhythmic or anticonvulsant medications if necessary, and administration of amyl nitrite by inhalation. Amyl nitrite pearls may be broken in gauze and held close to the nose and mouth of patients who are spontaneously breathing. Alternatively, they may be placed into the lip of the facemask or inside the resuscitation bag in patients with apnea or hypoventilation. Amyl nitrite should be inhaled for 30 seconds of each minute, and a used pearl should be replaced with a fresh one every 3 to 4 minutes. Amyl nitrite and supplemental O2 administration alone have been efficacious in treating hydrogen cyanide–poisoned patients in one occupational exposure setting.51 Supportive measures alone may sometimes prove to be satisfactory,39,44 although patients administered specific antidotes together with supportive therapy have survived with higher whole blood cyanide levels, awakened sooner from coma, and had more rapid resolution of acidosis.6,38,39 Standard antiarrhythmic and anticonvulsant medications are appropriate for the treatment of cyanideinduced arrhythmias and seizures. Atropine or vasopressors may be required if symptomatic bradycardia or hypotension unresponsive to less aggressive measures are present. Normobaric O2 is synergistic with cyanide antidotes. Although not proved, hyperbaric oxygen (HBO) may be efficacious in patients not responsive to supportive and antidotal therapy, and some severely cyanide-poisoned patients treated with HBO have survived.14,46 Smoke inhalation victims with serious known carbon monoxide poisoning and suspected cyanide toxicity may be treated with HBO when available.8

CHAPTER 88


Decontamination Exposed skin and eyes should be copiously flushed with water or normal saline. Contaminated clothing should be removed and isolated in impervious containers. Inducing emesis is contraindicated because of the potential for rapid progression to coma or seizures. Gastric aspiration might be beneficial within about 30 minutes after ingestion of cyanide salts. Although older references question the efficacy of activated charcoal administration, a single dose of about 1 g of activated charcoal per kilogram of body weight may be administered to patients who have ingested cyanide salts and related compounds.

Antidotes In the United States and some other countries, specific therapy consists of the administration of the antidotes found in the cyanide antidote kit. Once intravenous access has been established, amyl nitrite inhalation should be discontinued and sodium nitrite administered intravenously. The usual adult dose is 300 mg (one 10-mL ampoule of 3% solution). The pediatric dose for the average child is 0.12 to 0.33 mL/kg administered over absolutely no less than 5 minutes intravenously. Sodium nitrite is a potent vasodilator, and rapid administration may cause significant hypotension, which can be avoided by initial slow administration, either (1) by slow intravenous push over absolutely no less than 5 minutes, or (2) by diluting the dose in 50 to 100 mL of 5% dextrose in water, initially beginning with a slow infusion rate, and then increasing to the most rapid rate possible without causing hypotension. Frequent blood pressure monitoring should be done during sodium nitrite administration. Another potentially serious, although rare, adverse effect of sodium nitrite administration is induction of excessive methemoglobin levels. Induction of some level of methemoglobinemia has long been thought to be the mechanism of action of sodium nitrite because methemoglobin has a greater affinity for cyanide than cytochrome oxidase. This hypothesis has been questioned. Excessive methemoglobin induction occurs most often in patients given excessive amounts of sodium nitrite, but it is rarely seen with therapeutic doses. Methemoglobin levels should be monitored, especially when multiple doses of sodium nitrite are required. Inducing levels greater than 30% to 40% must be avoided. The determinant of when “enough” sodium nitrite has been infused is the patient’s clinical response. Sodium nitrite is followed by intravenous administration of sodium thiosulfate, in an adult dose of 12.5 g (one 50-mL ampoule of a 25% solution). The average pediatric dose is 1.65 mL/kg. No cases of significant adverse effects from sodium thiosulfate administration have been reported in humans, despite more than 50 years of clinical use of the drug. A continuous infusion of 1 g of sodium thiosulfate per hour for 24 hours was considered efficacious in one case of potassium cyanide ingestion poisoning.52

1313

In cases of smoke inhalation with known carbon monoxide and suspected cyanide poisoning, sodium thiosulfate and 100% supplemental O2 can be administered initially if hydroxocobalamin is not available. Sodium nitrite administration should be withheld until the patient is at pressure in an HBO chamber, where dissolved plasma O2 can adequately compensate for induced methemoglobinemia.8 When HBO was not immediately available for treatment of smoke inhalation patients, sodium nitrite was administered successfully without significant complications.53 Second doses of sodium nitrite and sodium thiosulfate at one half the initial amounts may be administered 30 minutes after the first doses if clinical response is inadequate. With exposure to certain nitrile compounds, continued metabolic release of cyanide may cause prolonged poisoning requiring multiple antidote doses. If producing a satisfactory clinical response, sodium thiosulfate alone could be used in such cases because its inherent toxicity is low. Alternate antidotes in clinical use in other parts of the world such as hydroxocobalamin (Cyanokit), dicobalt– ethylenediaminetetra-acetic acid (Kelocyanor), and 4dimethylaminophenol (4-DMAP) are not available in the United States as of June 2006. A growing body of evidence, primarily from patients with combined carbon monoxide and cyanide poisoning from enclosed-space fire smoke inhalation, but also from patients with aliphatic nitrile or cyanide salt poisoning, indicates that hydroxocobalamin may be the cyanide antidote of choice.47,54,55 Hydroxocobalamin is more rapidly acting than sodium thiosulfate, does not produce methemoglobinemia, which can impair oxygen transport as do 4-DMAP and the nitrites, does not cause hypotension as does sodium nitrite, and has a much better adverse effect and safety profile than do the nitrites, 4-DMAP and Kelocyanor.47,54 It has been shown to be safe and effective for decreasing low whole blood cyanide levels in volunteer heavy smokers and is an effective and safe cyanide antidote in a variety of experimental animal species.56,57 The only noted side effect in patients treated with hydroxocobalamin has been transient reddish-brown discoloration of the urine, sclera, mucous membranes, and skin from the color of the medication itself.47,54 Hydrocobalamin can be combined with sodium thiosulfate in more severe poisoning cases because there is an antidotal synergy.47,54,57 Because of its intense reddish-brown color and peak light absorption at 352 and 525 nm, hydroxocobalamin can interfere with automated colorimetric clinical chemistry measurements of aspartate aminotransferase, total bilirubin, creatinine, magnesium, and serum iron.58

Elimination Hemodialysis cannot be considered standard treatment for cyanide poisoning, but it has been efficaciously used as supportive therapy in a patient who developed renal failure secondary to rhabdomyolysis in the course of severe cyanide poisoning.16 One patient with severe acute

1314


cyanide poisoning treated with supportive measures, antidotes, and charcoal hemoperfusion has also been reported.4 This patient was improving after antidotal and supportive therapy at the time that hemoperfusion was begun. Hemoperfusion has no place in the treatment of acute cyanide poisoning.

Disposition Asymptomatic patients with apparent minimal exposure should be observed in a controlled setting for 4 to 6 hours. If exposure was to a nitrile compound, the onset of symptoms may be delayed for 12 hours or longer; in this situation, a longer period of observation and monitoring is necessary. Patients who have serious symptoms (coma, seizures, shock, metabolic acidosis, cardiac arrhythmias, ischemic electrocardiographic changes, or hypoventilation) and all those administered antidotes should be admitted to an intensive care unit for clinical monitoring until all symptoms have resolved, or for a minimum period of 24 hours. Outpatient follow-up at intervals for a period of weeks should be arranged to screen for the possible development of rare delayed central nervous system effects. Given the acute shortage of suitable organ donors, brain-dead poisoning victims should not be excluded as donors, if: (1) clinical and laboratory evidence shows true brain death (not central nervous system depression or lack of central nervous system activity due to the continued presence of the poison); (2) the poison itself has not irretrievably damaged or destroyed the organ under consideration for transplantation; and (3) the organ being considered for transplantation is not a reservoir, such that the transplanted organ itself might secondarily poison the transplant recipient. Organs have been successfully transplanted from brain-dead acute cyanide poisoning victims without causing secondary cyanide poisoning.59,60

SODIUM AZIDE Sodium azide is a white to colorless crystalline solid that is highly soluble in water and is used as a preservative in aqueous laboratory reagents and biologic fluids and in automobile airbags as a gas generator.61 It has also been investigated for use as an herbicide, insecticide, nematocide, fungicide, and bacteriocide and is used in the manufacturing of rubber, latex, wine, and Japanese beer, and as a chemical intermediate in lead azide production.61 Its use in automotive airbags has not resulted in sodium azide poisoning, but it has rarely caused relatively minor chemical burns by producing nitrogen gas and sodium oxide; the latter reacts with water to form corrosive sodium hydroxide.61 Sodium azide poisoning has most often occurred as a result of accidental or suicidal ingestion of colorless, odorless, tasteless laboratory solutions, which can be mistaken for water or normal saline, and has occurred in health care settings or laboratories.61–63 Suicidal cases have generally been seen in individuals with access to the

chemical in laboratories because otherwise it has limited availability.63,64 One patient died after mistakenly ingesting 1 g of sodium azide obtained from a hospital but intended to be added as a preservative to a container for his 24hour urine specimen.65 The 2001 American Association of Poison Control Centers TESS31 does not have a specific listing for sodium azide. A recent systematic review covering the period of 1927 to 1999 found that a total of 38 publications constituted the knowledge base of sodium azide human health effects.61 Of these, 32 publications were case reports, 5 were occupational studies, and 1 paper was an experimental study of the use of sodium azide as a potential antihypertensive agent (since abandoned because of significant side effects).61,64 There were a total of 185 exposed people, with 116 from the experimental study.61 Adults were involved in 183 cases and children in 2 cases. Of the 69 acute poisoning cases, 43 followed ingestion (26 survivors; 17 fatalities), 12 followed inhalation from occupational exposure (all 12 patients survived), 9 were exposed by the intravenous route from sodium azide contamination of hemodialysis apparatus (all 9 survived), and 5 patients had dermal exposure (4 survivors; 1 fatality).61 The dermal exposure fatality involved exposure to a metal azide during an explosion causing 45% total-body surface area burns.61 The hemodialysis patients exposed by the intravenous route developed hypotension, blurred vision, headache, nausea, vomiting, syncope, and cramping when ultrafilters used for preparation of dialysis fluid were pretreated with a preservative consisting of 0.25% sodium azide and 25% glycerin and not flushed.66 Ingestion is the most common route of exposure in serious poisoning cases.61 Fatality is usually associated with doses greater than 700 mg (or 10–13 mg/kg), whereas nonfatal poisoning has been seen with doses ranging from 0.3 to 150 mg (or 0.004–2 mg/kg).61 In a series of four fatal and six nonfatal sodium azide poisoning cases, the lowest dose in survivors was 5 to 10 mg, and the highest dose was 80 mg.67 The lowest fatal doses were 0.7 g in women and 1.2 to 2 g in men.67 Sodium azide is rapidly absorbed from the gastrointestinal and respiratory tracts (as hydroazoic acid vapor).61 Its extent of dermal absorption is unclear, but a single fatal case from a warehouse accident has been reported.61 Sodium azide is metabolized by the liver and excreted by the kidneys, but human absorption, distribution, metabolism, and excretion kinetics data are not available,61 except for a half-life of about 2.5 hours calculated in a single fatal case.68 Hypotension is the most common clinical effect, and the time between exposure and the onset of hypotension is somewhat predictive of survival.61 When hypotension occurs within minutes to 1 hour after exposure, it is a physiologic response, and the clinical course is most often benign. When the hypotension is delayed in onset more than 1 hour, it “. . . constitutes an ominous sign for death.”61 Other common clinical effects are nausea, vomiting, diarrhea, headache, dizziness, temporary vision loss, pal-

CHAPTER 88


pitations, dyspnea, temporary loss of consciousness, and depressed sensorium.61 Markedly depressed sensorium, seizures, coma, hypothermia, cardiac dysrhythmias, chest pain, tachypnea, cyanosis, noncardiogenic pulmonary edema, acute respiratory distress syndrome (ARDS), metabolic acidosis, oliguria, and cardiorespiratory arrest are seen in severe poisoning cases.61,62,65,68 The hypotensive effects are due to dilation of peripheral blood vessels, but it is unclear whether this effect is caused by the parent compound or its metabolism to nitric oxide.61 Sodium azide does inhibit heme-containing enzymes such as catalase, peroxidase, and cytochrome oxidase,61,69,70 but its lethality may be due instead to enhanced excitatory nervous transmission in the central nervous system, caused by the parent compound itself or by metabolically released nitric oxide.61,71 One case of cardiomyopathy presenting as an acute myocardial infarction was reported in a previously healthy 29-year-old female student who mistakenly ingested 700 mL of a buffering solution containing 0.1% sodium azide.72 Nausea, weakness, and confusion occurred initially and prompted overnight observation in a hospital. These effects had resolved by the following morning, and she was discharged, only to develop exertional dyspnea over the following 24 hours and severe precordial chest pain radiating to the left arm 3 days after ingestion. Electrocardiogram and creatine kinase elevations indicated possible myocardial infarction. Cardiac catheterization and chest x-ray were consistent with cardiomyopathy. Over several hours, the patient developed episodes of ventricular tachycardia and refractory hypotension and died in asystolic arrest. At autopsy, histology of the left ventricle revealed cardiomyopathy but no monocellular infiltrates to suggest an inflammatory etiology.72 Chest pain for 6 months after survival of acute sodium azide poisoning has been reported in one patient who ingested 80 mg.67 Sodium azide levels in blood are not readily available, and diagnosis and treatment decisions must be based on clinical grounds. Postmortem blood concentrations have ranged from 7.4 to 8.3 mg/L in one acutely fatal suicidal case to between 40 and 262 mg/L in other reported cases.64 Interestingly, cyanide has been detected in the postmortem blood in three sodium azide fatalities (0.38 mg/L, 1.6 mg/L, and 9 mg/L), but it is not clear whether the cyanide production took place in vivo or in the postmortem remains.64 Severe hypotension may be unresponsive to volume expansion and vasopressors.61 Phenobarbital had a protective effect against sodium azide poisoning in mice and rats, whereas diazepam and phenytoin did not.71 Phenobarbital should thus be considered for patients with seizures after sodium azide exposure not responsive to other anticonvulsants. There is no specific antidote for sodium azide poisoning in current clinical use61,72 and only symptomatic and supportive treatment can be given.63 The U.S. cyanide antidote kit containing amyl nitrite, sodium nitrite, and sodium thiosulfate has not been efficacious in human poisoning cases or in animal experiments.61,67,71,73

1315

Kelocyanor (dicobalt EDTA) and sodium thiosulfate alone have been ineffective for prevention of sodium azide poisoning in experimental animals.71 Hydroxocobalamin has not been administered to sodium azide–poisoned humans. An in vitro study in isolated rat mitochondria found that when hydroxocobalamin was added to sodium azide–inhibited mitochondria, cytochrome-c oxidase was less inhibited than when sodium azide was added alone.74 This gives a potential theoretical mechanism of action for hydrocobalamin in the treatment of sodium azide poisoning, and further studies should be pursued. When it is available, hydroxocobalamin could be administered to patients with life-threatening sodium azide poisoning because of its highly favorable safety profile. It is notably efficacious for reversing the severe hypotension seen in acute cyanide poisoning, and severe hypotension unresponsive to usual treatments is a hallmark of sodium azide poisoning. REFERENCES 1. Hall AH, Rumack BH: Clinical toxicology of cyanide. Ann Emerg Med 1986;15:1067. 2. Blanc P, Hogan M, Mallin K, et al: Cyanide intoxication among silver-reclaiming workers. JAMA 1985;253:367. 3. Hartung R: Cyanides and nitriles. In Clayton GD, Clayton FE (eds): Patty’s Industrial Hygiene and Toxicology, Vol. 11, 4th ed. New York, John Wiley, 1994, p 3119. 4. Krieg A, Saxena K: Cyanide poisoning from metal cleaning solutions. Ann Emerg Med 1987;16:582. 5. Hathaway GJ, Proctor NH, Hughes JP: Hydrogen cyanide. In Proctor and Hughes’ Chemical Hazards of the Workplace, 4th ed. New York, Van Nostrand Reinhold, 1996, p 346. 6. Hall AH, Rumack BH, Schaffer MI, Linden CH: Clinical toxicology of cyanide: North American clinical experiences. In Ballantyne B, Marrs TC (eds): Clinical and Experimental Toxicology of Cyanides. Bristol, UK, John Wright, 1987, p 312. 7. Anonymous: Cyanide poisoning associated with over-the-counter medication—Washington State. MMWR Morb Mortal Wkly Rep 1991;40:161. 8. Hart GB, Strauss MB, Lennon PA, Whitcraft DD: Treatment of smoke inhalation by hyperbaric oxygen. J Emerg Med 1985;3:211. 9. Baud FJ, Barriot P, Toffis V, et al: Elevated blood cyanide concentrations in victims of smoke inhalation. N Engl J Med 1991;325:1761. 10. Norris JC, Moore SJ, Hume AS: Synergistic lethality induced by the combination of carbon monoxide and cyanide. Toxicology 1986;40:121. 11. Mayes RW: The toxicological examination of the British Air Tours Boeing 737 accident at Manchester in 1985. J Forensic Sci 1991;36:179. 12. Barr SJ: Chemical warfare agents. Top Emerg Med 1985;7:62. 13. Bismuth C, Baud FJ, Djeghout H, et al: Cyanide poisoning from propionitrile exposure. J Emerg Med 1987;5:191. 14. Scolnik B, Hamel D, Woolf AD: Successful treatment of lifethreatening propionitrile exposure with sodium nitrite/sodium thiosulfate followed by hyperbaric oxygen. J Occup Med 1993; 35:577. 15. Yeh MM, Becker CE, Arieff AI: Is measurement of venous oxygen saturation useful in the diagnosis of cyanide poisoning? Am J Med 1992;93:582. 16. Yen D, Tsai J, Wang L-M, et al: The clinical experience of acute cyanide poisoning. Am J Emerg Med 1995;13:524. 17. Peden NR, Taha A, McSorley PD, et al: Industrial exposure to hydrogen cyanide: implications for treatment. BMJ 1986;293:538. 18. Suchard JR, Wallace WL, Gerkin RD: Acute cyanide poisoning caused by apricot kernel ingestion. Ann Emerg Med 1998;32:724. 19. Kurt TH, Day LC, Reed WG: Cyanide poisoning from glue-on nail remover. Am J Emerg Med 1991;9:201.

1316


20. Michaelis HC, Clemens C, Kijewski H, et al: Acetonitrile concentrations and cyanide levels in a case of suicidal oral acetonitrile ingestion. J Toxicol Clin Toxicol 1991;29:447. 21. Schulz V, Gross R, Pasch T, et al: Cyanide toxicity of sodium nitroprusside in therapeutic use with and without sodium thiosulfate. Klin Wochenschr 1982;60:1393. 22. Linakis JG, Lacouture PG, Woolf A: Monitoring cyanide and thiocyanate concentrations during infusion of sodium nitroprusside in children. Pediatr Cardiol 1991;12:214. 23. Vesey CJ, Cole PV, Linnell JC, Wilson J: Some metabolic effects of sodium nitroprusside in man. BMJ 1974;2:140. 24. Cottrell JE, Casthely P, Brodie JD, et al: Prevention of nitroprusside-induced cyanide toxicity with hydroxocobalamin. N Engl J Med 1978;298:809. 25. Vesey CJ, Cole PV: Blood cyanide and thiocyanate concentrations produced by long-term therapy with sodium nitroprusside. Br J Anaesthiol 1985;57:148. 26. Osuntokun BO: Chronic cyanide intoxication of dietary origin and a degenerative neuropathy in Nigerians. Acta Hortic 1994;375:311. 27. Tylleskar T, Howlett WP, Rwiza HT, et al: Konzo: a distinct disease entity with selective upper motor neuron damage. J Neurol Neurosurg Psychiatr 1993;56:638. 28. Ngudi DD, Kuo YH, Lambein F: Cassava cyanogens and free amino acids in raw and cooked cassava leaves. Food Chem Toxicol 2003;41:1193. 29. Espinoza OB, Perez M, Ramirez MS: Bitter cassava poisoning in eight children: a case report. Vet Hum Toxicol 1992;34:65. 30. Delange F, Ekpechi LO, Rosling H: Cassava cyanogenesis and iodine deficiency disorders. Acta Hortic 1994;375:289. 31. Litovitz TL, Klein-Schwartz W, Rodgers GC, et al: 2001 annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2002;20:391. 32. Shou Y, Gunasekar PG, Borowitz JL, et al: Cyanide-induced apoptosis involves oxidative-stress-activated NF-kappaB in cortical neurons. Toxicol Appl Pharmacol 2000;164:196. 33. Bi QN, Sun PW, Gunasekar PG, Isom GE: Involvement of CA2+/calmodulin-dependent protein kinase II in cyanide-induced cytotoxicity in cultured cerebellar granular cells [abstract]. Toxicologist 1996;30:186. 34. Shou Y, Li L, Prabhakaran K, et al: p38 Mitogen activated protein kinase regulates BAX translocation in cyanide-induced apoptosis. Toxicol Sci 2003;75:99. 35. Christel D, Eyer P, Hegemann M, et al: Pharmacokinetics of cyanide poisoning in dogs, and the effects of 4-dimethylaminophenol or thiosulfate. Arch Toxicol 1977;38:177. 36. Sylvester DM, Hayton WL, Morgan RL, Way JL: Effects of thiosulfate on cyanide pharmacokinetics in dogs. Toxicol Appl Pharmacol 1983;69:265. 37. Hall AH, Doutre WH, Ludden T, et al: Nitrite/thiosulfate treated acute cyanide poisoning: estimated kinetics after antidote. Clin Toxicol 1987;25:121. 38. Graham DL, Laman D, Theodore J, Robin ED: Acute cyanide poisoning complicated by lactic acidosis and pulmonary edema. Arch Intern Med 1977;137:1051. 39. Feihl F, Domenighetti G, Perret C: Intoxication massive au cyanure avec evolution favorable. Schweiz Med Wschr 1982;112:1280. 40. Jouglard J, Fagot G, Deguigne B, Arlaud J-A: L’intoxication cyanhydrique aigue et son traitement d’urgence. Mars Med 1971;9:571. 41. Rosenberg NL, Myes JA, Martin MRW: Cyanide-induced parkinsonism: clinical, MRI, and 6-fluorodopa PET studies. Neurology 1989;39:142. 42. Feldman JM, Feldman MD: Sequelae of attempted suicide by cyanide ingestion: a case report. Int J Psychiatr Med 1990;20:173. 43. Steffens W, Leng G, Bayer KB: Nitrile poisonings: cyanide formation, clinical course and treatment [abstract]. J Toxicol Clin Toxicol 2003;41:410. 44. Steffens W, Leng G, Pelster M: Percutaneous hydrocyanic acid poisoning [abstract]. J Toxicol Clin Toxicol 2003;41:483. 45. Goodhart GL: Patient treated with antidote kit and hyperbaric oxygen survives cyanide poisoning. South Med J 1994;87:814. 46. Megarbane B, Delahaye A, Goldgran-Toledano D, et al: Antidotal treatment of cyanide poisoning. J Chin Med Assoc 2003;66:193. 47. Baud FJ, Borron SW, Megarbane B, et al: Value of lactic acidosis in the assessment of the severity of acute cyanide poisoning. Crit Care Med 2002;30:2044.

48. Shusterman D, Alexeef G, Hargis C, et al: Predictors of carbon monoxide and hydrogen cyanide exposure in smoke inhalation patients. Clin Toxicol 1996;34:61. 49. Hall AH, Rumack BH: Hydrogen sulfide poisoning: an antidotal role for sodium nitrite? Vet Human Toxicol 1997;39:152. 50. Wurzburg H: Treatment of cyanide poisoning in an industrial setting. Vet Hum Toxicol 1996;38:44. 51. Heintz B, Bock TA, Kierdorf H, Sieberth HG: Cyanid Intoxikation: Behandlung mit Hyperoxigenation und Natriumthiosulfat. Dtsch Med Wochenschr 1990;115:1100. 52. Kirk MA, Gerace R, Kulig KW: Cyanide and methemoglobin kinetics in smoke inhalation victims treated with the cyanide antidote kit. Ann Emerg Med 1993;22:9. 53. Megarbane B, Baud F: Cyanide poisoning: diagnosis and antidote choice in an emergency situation [abstract]. J Toxicol Clin Toxicol 2003;41:438. 54. Santiago I: [Gas poisoning]. An Sist Sanit Navar 2003;26(Suppl 1):173. 55. Suchard JR, Wallace KL, Gerkin RD: Acute cyanide toxicity caused by apricot kernal ingestion. Ann Emerg Med 1998;32:724. 56. Forsyth JC, Mueller PD, Becker CE, et al: Hydroxocobalamin as a cyanide antidote: safety, efficacy and pharmacokinetics in heavily smoking normal volunteers. J Toxicol Clin Toxicol 1993;31:277. 57. Hall AH, Rumack BH: Hydroxycobalamin as a cyanide antidote. J Emerg Med 1987;5:115. 58. Curry SC, Connor DA, Rashke RA: Effect of the cyanide antidote hydroxocobalamin on commonly ordered serum chemistry studies. Ann Emerg Med 1994;24:65. 59. Swanson-Bierman B, Krenzelok EP, Snyder JW, et al: Successful donation and transplantation of multiple organs from a victim of cyanide poisoning. Clin Toxicol 1993;31:95. 60. Hantson P, Mahieu P, Hassoun A, Otte J-B: Outcome following organ removal from poisoned donors in brain death status: a report of 12 cases and review of the literature. Clin Toxicol 1995;33:709. 61. Chang S, Lamm SH: Human health effects of sodium azide exposure: a literature review and analysis. Int J Toxicol 2003;22:175. 62. Singh N, Singh CP, Brar CK: Sodium azide: a rare poisoning. J Assoc Physicians India 1994;42:755. 63. Wollenek G: Akute vergiftungen durch natriumazid. Wein Klin Wochenschr 1989;101:314. 64. Marquet P, Clément S, Lotfi H, et al: Analytical findings in a suicide involving sodium azide. J Anal Toxicol 1996;20:134. 65. Herbold M, Schmitt G, Aderjan R, Pedal I: Tödliche natriumazidvergiftung im krankenhaus: eine vermeidbarer zwischenfall. Arch Kriminol 1995;196:143. 66. Arduino MJ: CDC investigations of noninfectious outbreaks of adverse events in hemodialysis facilities, 1979–1999. Semin Dial 2000;13:86. 67. Chiba M, Ohmichi M, Inaba Y: [Sodium azide: a review of biological effects ad case reports] [Japanese]. Nippon Eiseigaku Zasshi 1999;53:572. 68. Senda T, Nishio K, Hori Y, et al: [A fatal case of fatal acute sodium azide poisoning] [Japanese]. Chudoku Kenkyu 2001;14:339. 69. Bennett MC, Mlady GW, Kwon Y-H, Rose GM: Chronic in vivo sodium azide infusion induces selective and stable inhibition of cytochrome c oxidase. J Neurochem 1996;66:2606. 70. Bennett CM, Mlady GW, Fleshner M, Rose GM: Synergy between chronic corticosterone and sodium azide treatments in producing a spatial learning deficit and inhibiting cytochrome oxidase activity. Proc Natl Acad Sci U S A 1996;93:1330. 71. Smith RP, Louis CA, Kruszyna R, Kruszyna H: Acute neurotoxicity of sodium azide and nitric oxide. Fundam Appl Toxicol 1991;17:120. 72. Judge KW, Ward NE: Fatal azide-induced cardiomyopathy presenting as acute myocardial infarction. Am J Cardiol 1989;64:830. 73. Klein-Schwartz W, Gorman RL, Oderda G, et al: Three fatal sodium azide poisonings. Med Toxicol Adverse Drug Exp 1989;4:219. 74. Vieira Lopes LC, Campello AP: Effect of hydroxocobalamin on the inhibition of cytochrome c oxidase by cyanide. I. In intact mitochondria. Res Comm Chem Pathol Pharmacol 1975;12:521.

89

Isocyanates and Related Compounds JASON VENA, MD ■ CHARLES MCKAY, MD


■ ■

■

The isocyanates are widely used precursors to polyurethane products, as well as carbamate insecticides. Methyl isocyanate was released at the worst industrial disaster in history on December 2 and 3, 1984, at Bhopal, India. Isocyanates are chemical compounds consisting of R–N=C=O groups, which react with compounds containing reactive hydrogen atoms to form polymers. Toxicity of the isocyanates varies inversely with molecular weight, related to volatility and vapor pressure. The most common occupational illness associated with the isocyanates is diisocyanate asthma, which has a distinct mechanism of toxicity as compared with atopic asthma. Management of isocyanate exposure is supportive; asthmatic symptoms should be managed as for atopic asthma.

The isocyanates are a diverse group of molecules that contain one or more R−N=C=O moieties, used most commonly in the synthesis of polyurethane plastics, foams, paints, and coatings, as well as in the production and degradation of carbamate insecticides. Regarding the latter, the isocyanates are known for the worst industrial disaster in history, in which thousands died in Bhopal, India in 1984 (discussed later). Demand for polyurethanes, and thus their isocyanate precursors, is strong. Worldwide production of polyurethanes had been estimated at 2.2 to 3.4 million tons (2 to 3 million tonnes) in 2001; an automobile may contain 110 pounds (50 kg) of polyurethane and a residence 440 to 660 pounds (200–300 kg).1 Because of their commercial ubiquity, clinically relevant toxicity, and historical infamy, the isocyanates merit awareness by the medical toxicologist. This chapter discusses four isocyanates of commercial importance: methyl isocyanate (MIC), methylene diphenyl diisocyanate (MDI), toluene-2,4 and 2,6 diisocyanate (TDI, or 2,4-TDI or 2,6-TDI), and hexamethylene diisocyanate (HDI).

PHYSICOCHEMICAL PROPERTIES MIC (CAS 624-83-9) is most commonly associated with production and degradation of carbamate insecticides. At ambient conditions, it is a colorless liquid with a pungent odor and a high vapor pressure (348 mm Hg). Its odor threshold of 2.1 parts per million (ppm) is two orders of magnitude greater than its recommended exposure limits (see “Regulations”). Water solubility is 10% at 59° F (15° C). MIC reacts violently with water in an exothermic reaction producing polymeric MIC gas (perhaps creating trimers of MIC under the conditions

seen at Bhopal2). Flammability is high, with a flash point of 19° F (−7° C). Pyrolysis results in decomposition to hydrogen cyanide and carbon dioxide. Environmental degradation of MIC is prolonged in air, with an atmospheric half-life estimated at 3 months; water degradation is shorter, at a half-life of about 2 days.3 MDI (CAS101-68-8), TDI (CAS 584-84-9 and 91-08-7), and HDI (CAS 822-06-0) are known as diisocyanates, that is, molecules containing two isocyanate moieties. Their use is predominantly in the formation of polymers, namely polyurethane plastics and foams, by means of reaction with alcohols (polyols). At ambient conditions, MDI and 2,4-TDI are white-yellow solids, whereas 2,6-TDI and HDI are clear to pale yellow liquids. The vapor pressures of the diisocyanates (0.000005–0.5 mm Hg) are low. Water solubilities are low to insoluble. Flammabilities are low, with flash points above 200° F (93° C). The diisocyanates are less reactive with water than MIC, and under conditions of controlled water addition, they have the desirable effect of producing foams.4 In addition, the less toxic MDI has replaced TDI in many settings. Environmental degradation is more rapid than with MIC, with the diisocyanates having atmospheric half-lives of hours to 2 days, as well as “rapid” water degradation.3 Table 89-1 provides a comparison of these agents.

SOURCES OF EXPOSURE MIC is both a crop pesticide reagent and an ingredient, as well as a degradation product of the pesticide metamsodium. Air concentrations of MIC were found to be up to 2.5 ppb in the 72 hours following ground injection of metam-sodium for field fumigation in California.3 Cigarettes may contain four micrograms of MIC each, and workers who are in an environment at the threshold value for an 8-hour workday may be exposed to 460 μg daily.3 On the night of December 2 and 3, 1984, the introduction of water into two MIC storage tanks at the Union Carbide plant in Bhopal (capital of Madhya Pradesh, India, population 900,000) overwhelmed multiple safety systems and released about 27 tons of MIC into the environment within 1 to 2 hours, resulting in a mean estimated air concentration 1350 times the U.S. Occupational Safety and Health Administration (OSHA) limit (see “Regulations”). The diisocyanates (MDI, TDI, HDI) are used in countless global industries, including adhesives, painting and varnishing, wire coating, vehicle building, mining, upholstery, plastics, rubber, insulation, and textiles.4 The major group of workers potentially exposed are those in the foam and rubber industry, who use the isocyanate monomers during manufacturing. 1317

1318


TABLE 89-1 Comparison of Common Isocyantes VAPOR PRESSURE (mm Hg) AT 77° F/25° C

ODOR THRESHOLD (ppm)

CONVERSION (ppm TO mg/m3)*

COMPOUND

STRUCTURE

MOL. WT. (g/mol)

Methyl isocyanate Hexamethylene diisocyanate Toluene diisocyanate (shown as 2,4-TDI)

CH3N=C=O OCN(C6H12)NCO

57.05 168.22

348 0.03

2.1 0.001

1 ppm = 2.3 mg/m3 1 ppm = 6.9 mg/m3

174.15

0.05

0.17

1 ppm = 7.12 mg/m3

250.25

5 × 10–6

0.4

1 ppm = 10.2 mg/m3

NCO H3C

Methylene diphenyl diisocyanate

NCO

[OCN(C6H6)]2-CH2

*mg/m3 = ppm × mol. wt./24.45, under conditions of 1 atmosphere and 25° C.

TOXICITY Mechanisms of isocyanate toxicity are incompletely understood. Much of the literature regarding the cellular and molecular toxicity of MIC followed from the acute, high-dose exposure in Bhopal. Most of the literature available concerning the diisocyanates focuses on the occupational asthma phenomenon (see “Clinical Manifestations”), a predominantly chronic, low-dose exposure. MIC toxicity, despite the horrible disaster of 1984, remains enigmatic for several reasons. Although the Bhopal incident released mostly MIC (probably in trimerized form), it is likely that decomposition products such as hydrogen cyanide, nitrogen oxides, carbon monoxide, and other molecules (including reagents, etc.) played a role in the toxicity experienced by the Bhopal victims.5 Descriptions of “relief of symptoms” when sodium thiosulfate was administered to 30 Bhopal victims 2 months after the event prompted Indian authorities to recommend widespread thiosulfate treatment, although ultimately this was not carried out. Details of the reported response to delayed thiosulfate administration in these 30 victims are not known, and conclusions about efficacy cannot be drawn. A two-part study conducted on rats by Jeevaratnam and Sriramachari6,7 examined the histopathologic manifestations of pulmonary MIC toxicity both by inhalational (232, 465, and 930 ppm) and subcutaneous (164.3, 328.6, and 657.2 mg/kg) routes. In the acute phase, concentration- and dose-dependent necrotizing bronchitis and pulmonary edema were seen by inhalation, whereas subcutaneous administration resulted in vascular endothelial damage and pulmonary edema, apparently leaving normal bronchial epithelium.6 The subacute and chronic phase (10 weeks) demonstrates a convergence of the inhalational and subcutaneous group tissue findings, both manifesting a diffuse interstitial pulmonary fibrosis.6 A burst of research activity in the immediate postBhopal era regarding the systemic toxicity of MIC

appears to have been short-lived, but quite interesting. Jeevaratnam and Sriramachari8 examined the nonpulmonary viscera of rats exposed to both inhalational and subcutaneous MIC and found vascular congestion, focal hepatocellular necrosis, and tubular rupture and degeneration in the kidney. Other authors have investigated in animal and in vitro models the inhibition of cardiac Na+/K+-ATPase in rabbits,9 binding to erythrocyte membrane sulfhydryl groups in rats,10 and changes in free amino acids in the brain and plasma of mice.11 These data are not directly applicable to occupational exposures of much lower concentrations, particularly given the propensity of isocyanates to react with surface water and proteins, decreasing their absorption. Issues of carcinogenicity and reproductive effects of MIC are unclear. The Agency for Toxic Substances and Disease Registry (ATSDR) of the Centers for Disease Control and Prevention (CDC) reports that MIC is not classified in terms of carcinogenicity, nor for reproductive effects, but makes mention of some of the observations at Bhopal, which included an apparent increase in stillbirths and spontaneous abortions.12 Dhara and Dhara2 cited a few epidemiologic, animal, and cytogenetic studies from the Bhopal experience that yielded no definitive conclusions for humans but do suggest the need for further observation. The mechanisms of diisocyanate toxicity (see “Clinical Manifestations”) are likewise incompletely understood. Asthma induced by the diisocyanates differs mechanistically, yet less so clinically, from atopic asthma. This form of occupational asthma is of great concern because sensitization to subsequent lower exposure levels has been demonstrated. Diisocyanate asthma, in contrast to atopic asthma, appears to lack a consistent immunoglobulin E (IgE)–associated mechanism. The prevalence of diisocyanate-specific IgE in symptomatic patients has been reported to be less than 20%; furthermore, these antibodies have been found in asymptomatic patients, indicating a weak association with the disease state.4,13 Regarding the airway inflammatory

CHAPTER 89

response, it appears that diisocyanate-induced asthma results in an increased neutrophil influx with increased interleukin-8 (IL-8) production, as compared with atopic asthma, which demonstrates relatively more eosinophils.13 The cellular immune response differs as well. Diisocyanate-induced asthma seems to invoke more of a helper T-cell subset 1 (TH1) response (with a subsequent neutrophil, IL-8, and interferon-γ [IFN-γ] response), as compared with atopic asthma, which has a predominantly TH2-mediated response.14 Transmigration of these inflammatory and immune cells across endothelial and epithelial basement membranes is, in part, mediated by enzymes known as matrix metalloproteinases (MMPs). In a recent murine model by Lee and colleagues,15 in which bronchioalveolar lavage (BAL) fluid is examined after nebulized TDI exposure, MMP inhibitors are shown to blunt the migration of leukocytes and decrease the expression of adhesion molecules, interleukins, and tumor necrosis factor-α that are initiated after TDI exposure. Extrapulmonary sensitization (e.g., skin sensitization resulting in pulmonary effects) may also play a role in diisocyanate-induced asthma. As for immune recognition, the diisocyanates appear to haptenize with native protein in order to initiate a cellular response; in most models, albumin has been the carrier protein used. Wisnewski and coworkers16 examined HDI-exposed volunteers, through inhalational (20–30 parts per billion [ppb]) and skin (0.1% v/v) routes, and found that keratin 18 and keratin 10, both type I (acidic) keratins of the respiratory epithelium and skin, respectively, were conjugated to HDI and might play a role in antigen presentation. Genetics also appear to play a role; allelic variations of glutathione S-transferase appear to alter susceptibility to isocyanate hypersensitivity.17 Carcinogenesis and reproductive issues regarding the diisocyanates are also being investigated, but current knowledge regarding these in humans is limited. Bolognesi and colleagues18 provide a review of the evidence regarding TDI and MDI carcinogenesis and conclude that, although some short-term animal studies have shown gene mutations and chromosomal damage, the few epidemiologic studies produced have not been able to demonstrate that TDI and MDI are occupational carcinogens. As with MIC, the potential role of metabolic intermediates and adducts is undergoing continued study.

CLINICAL MANIFESTATIONS The toxicity of the isocyanates will vary by the specific substance (e.g., MIC versus TDI), dose, route, and chronicity of the exposure. In humans, the predominant effects of the isocyanates are mucosal and respiratory, both upper and lower, consistent with an intermediate water solubility (see Chapter 9), and in some cases, dermal. A distinction should be made between the chronic effects of an acute exposure and the chronic effects of a chronic exposure, as provided by the examples of Bhopal and diisocyanate asthma, respectively (discussed subsequently).

Isocyanates and Related Compounds

1319

Acute Exposure Despite the confounders and limitations described, the largest acute human MIC exposure was the Bhopal incident. More than 200,000 people were exposed to MIC at this tragic event.19 The immediate (1 week) death toll has been estimated at 2500, thought to be due predominantly to acute pulmonary edema.20 Early autopsy results revealed severe necrotizing lesions of the upper and lower respiratory tract as well as pulmonary edema. In survivors, respiratory symptoms were described as rhinorrhea, throat irritation, cough with frothy expectoration, and dyspnea. Chest films obtained 2.5 to 3 months after exposure in 903 subjects revealed only 65 that were thought to be associated with acute gas exposure,2 although the immediate radiographic appearance in these patients is unknown. Ocular toxicity in the acute phase included symptoms of severe burning and photophobia associated with chemosis and corneal ulceration; only a few cases of iritis were seen, and blindness was not known to have occurred.2 Chronic effects of acute exposure to MIC resulted (and continue to result by some accounts) in much morbidity and mortality. The death toll is recently said to be greater than 6000, and the number of victims with chronic health effects greater than 50,000.5 Later pulmonary deaths may have been related to secondary infections,20 as well as interstitial fibrosis and other structural changes,2 consistent with findings from an animal model7 (see “Toxicity”). Beckett21 stratified 454 adults by distance from the incident site and found forced midexpiratory flow rate (FEF25–75) reductions that correlate with distance from the incident, concluding that small airways obstruction may be attributed to gas exposure. Chronic ocular issues may include chronic conjunctivitis and corneal opacities.22 Chronic neurologic effects are reported, but these are not well defined, and associations may be stronger with a mass casualty event than with the chemical itself.2 Reproductive and pediatric effects of MIC are discussed later. Acute diisocyanate toxicity is predominantly pulmonary and may be subdivided into four entities: chemical bronchitis, hypersensitivity pneumonitis, asthma, and acute nonspecific airways disease.4 Chemical bronchitis is typically associated with an acute, higher-level exposure, resulting in marked upper respiratory and ocular irritation symptoms as well as cough, chest pain, and tightness; transitory or permanent changes in pulmonary function tests may be seen.4 High-level exposures would be expected to produce symptoms as seen with MIC, including pulmonary edema and death. Hypersensitivity pneumonitis is a rare presentation; in one series by Baur,23 16 patients were diagnosed clinically from 1780 isocyanate workers based on their symptoms of repeated episodes of fever, dyspnea, and malaise after a latency period of several hours after isocyanate exposure. Of those selected, 14 agreed to participate in the study, yielding the confirmatory findings of decreased diffusion capacity (10 patients), reticulonodular pattern on chest film (9 patients), and the presence of serum IgG to TDIalbumin (10 patients). Five patients underwent lung biopsy, revealing lymphohistiocytic infiltrates in all.

1320


Diisocyanate asthma is the most common manifestation of diisocyanate-associated pulmonary disease, with the initial description in 1951 by Fuchs and Valade.4 Asthma associated with the diisocyanates may be subdivided into immediate, late-onset, and dual-onset forms. An interesting case series by Zammit-Tabona and colleagues24 provides insight into these presentations. In their series, 11 foundry workers with exposure to MDI and symptoms consistent with asthma were subjected to a single inhalational MDI challenge at a concentration less than 0.02 ppm for 60 minutes. Seven patients, two of whom were atopic, developed asthmatic reactions as measured by spirometry (>20% fall in forced expiratory volume in 1 second [FEV1]). One patient was discounted owing to response to formaldehyde challenge. The remaining six had late-onset reactions, with onset an average of 5 hours after the exposure; two of these patients also had immediate-onset reactions (before the end of the challenge). Four of the six patients also developed recurrent nocturnal asthmatic symptoms, away from any known exposure, for a period of 3 to 7 days after the single-dose challenge.

Chronic Exposure Chronic MIC exposure and resulting effects are not well defined in the literature. In regard to chronic pulmonary diisocyanate exposure, the clinical effects may be divided into isocyanate-associated asthma and chronic nonspecific airways disease.4 Diisocyanate asthma may be diagnosed after several years of potential exposure; whether this phenomenon is due to the chronicity of the exposure and disease latency or to a delay in diagnosis25 is unknown. Diisocyanate asthma may develop within months after exposure4; however, newer employees may have had exposures during previous jobs, confounding the time course.26 Loss of sensitization after removal from exposure is a possibility in diisocyanate asthma. Mapp and colleagues27 found that in a group of TDI-sensitized patients, provocation after increasing intervals of time following TDI exposure indicates a reversible increase in airway responsiveness. In a recent 30-year follow-up of workers at a single TDI factory unit, Ott and colleagues26 reported an initial decline in FEV1 within the first 2 years of reporting symptoms, but no acceleration of decline in lung function thereafter. These two studies seem to be in contrast to the findings of Padoan and associates,28 in which 87 subjects with TDI-induced asthma were followed for 11 years. In this group, airway reactivity to methacholine challenge persisted even after 10 years of nonexposure, and the presenting FEV1 and provocative dose were among the factors predictive of subsequent reactivity and decline in pulmonary function. All these considerations highlight the importance of early recognition of respiratory symptoms and removal of employees from further isocyanate exposure. Case reports exist for diisocyanate-associated skin lesions in chronically exposed workers. Larsen and colleagues29 reported on 10 nurses in an outpatient orthopedic clinic who worked with diisocyanate-

containing casting material. Patch testing to five types of diisocyanates yielded one patient with a “doubtful” reaction toward two types. Their conclusion that the diisocyanates are predominantly irritants rather than sensitizers stands in contrast to other animal studies and case reports identifying positive patch testing or IgE antibodies to isocyanates after dermal exposure. Any potential carcinogenic risk after chronic diisocyanate exposure in humans is only theoretical at this time and is based on very heavy (e.g., 6 mg/m3) chronic inhalation exposures in animal models.18,30

PRENATAL AND PEDIATRIC ISSUES The reproductive effects of the isocyanates in humans are largely undefined, but some evidence for adverse effects exists at massive exposure doses. In the case of the Bhopal disaster, Dhara and Dhara2 reported on a study indicating that a higher rate of miscarriages occurred in the affected area, as well as higher perinatal and neonatal mortality rates. In a recent letter,19 Ranjan and associates discussed their findings of a selective growth retardation in boys exposed in utero or as young children to the Bhopal disaster versus matched controls. Reproductive toxicity data regarding the diisocyanates are also limited, but reassuring. One study found a no observed adverse effect level (NOAEL) of about 0.3 ppm MDI in pregnant Wistar rats with regard to maternal and developmental toxicity.31 Other studies showed NOAELs in the range of 0.1 to 0.3 ppm TDI in CD rats in regard to reproductive toxicity.32,33

ASSESSMENT Diagnosis of isocyanate-associated disease is best defined in the occupational setting, particularly for diisocyanateinduced asthma. Important historical components include a suspected exposure and symptoms of airway hyperreactivity, including cough, wheezing, and shortness of breath; these may be delayed by several hours after each exposure and therefore may present as nocturnal asthma in day-shift workers. Fever and respiratory symptoms in exposed workers would suggest hypersensitivity pneumonitis. A full medical, occupational, and social history should be elicited, including personal and family history of pulmonary disease, potential sources of previous isocyanate exposure (and perhaps sensitization), and smoking status. Pulmonary function testing begins with sequential peak expiratory flow measurements both during and away from a potential exposure. Inhalational challenge testing may be indicated and is divided into nonspecific bronchial hyperresponsiveness (NSBH) and specific bronchoprovocation testing (SBPT).34 NSBH is performed by challenging the patient with a known airway reactant such as methacholine or histamine, whereas SBPT involves the use of the suspect diisocyanate itself. Generally, a 20% decrease in FEV1 during either test supports a diagnosis of reactive airways4,28; however, the SBPT is considered

CHAPTER 89

the gold standard.34 Nonspecific testing is often performed in lieu of SBPT because of the lack of availability of such tests at many centers. Many organizations have published guidelines on the diagnosis of occupational asthma, including that of the diisocyanates, and are included in a review by Bernstein and Jolly.34 Laboratory evaluation for diisocyanate-associated asthma is not well-defined, although currently an area of research interest (see “Toxicity”). Other ancillary tests that may be useful include chest radiography, bronchoalveolar lavage, and biopsy, particularly in cases of suspected hypersensitivity pneumonitis.23

MANAGEMENT Treatment of isocyanate-associated disease, regardless of the specific moiety or the acuity, requires removal of the patient from the source of exposure, followed by surface decontamination as needed (see Chapter 2). Management of the patient’s airway and breathing takes precedence over further care. Co-inhalations should always be suspected, especially in the setting of fire (e.g., carbon monoxide, cyanide gas). Management in the disaster setting is addressed in Chapter 103. In cases of diisocyanate-associated asthma, acute treatment should follow that of standard principles for the atopic asthmatic. Removal of the worker from any further isocyanate exposure is required because the safe concentration for reexposure of sensitized individuals has not been defined.

PREVENTION It is uncertain at what levels and duration of exposure diisocyanate-associated pulmonary disease develops.4 Although there are mandated exposure guidelines (see “Regulations”), some authors believe these to be too lenient. Baur35 advises that although occupational exposure limits for the various diisocyanates in most Western countries are placed at about 10 ppb, a more appropriate “health-based” level based on current research would be 2.5 to 5 ppb. Environmental monitoring is an important component of exposure prevention. There are several methods for detecting the presence of isocyanates, including colorimetry (wet and dry) and chromatography (thin layer, gas, and high-performance liquid).4 Each regulatory or advisory body, as discussed next, adopts an explicit method for standardizing detection of the environmental burden.

REGULATIONS AND EXPOSURE ADVISORIES In the United States, multiple agencies, both governmental and private, dispense recommended worker exposure limits in multiple formats. In general, it is helpful to categorize these into “regulatory” (enforceable) and

Isocyanates and Related Compounds

1321

TABLE 89-2 Regulatory and Advisory Limits for Representative Isocyanates

MIC MDI TDI HDI

OSHA PEL (ppb)

NIOSH REL (ppb)

20 (TWA) 20 (C) 20 (C) None

20 (TWA) 5 (C) None 5 (TWA)

NIOSH ACGIH AIHA IDLH (ppb) TLV (ppb) ERPG (ppb) 3000 7500 2500 N/A

20 5 5 N/A

25–5000 N/A N/A N/A

ACGIH, American Conference of Government and Industrial Hygienists; AIHA, American Industrial Hygiene Association; C, ceiling limit; ERPG, emergency response planning guidelines; HDI, hexamethylene diisocyanate; IDLH, immediate danger to life or health; MDI, methylene diphenyl diisocyanate; MIC, methyl isocyanate; N/A, not available; NIOSH, National Institute of Occupational Safety and Health; OSHA, Occupational Safety and Health Association; PEL, permissible exposure limit; ppb, parts per billion; REL, recommended exposure limit; TDI, toluene-2,4 and 2,6 diisocyanate; TLV, threshold limit value; TWA, threshold weighted average.

“advisory” types. OSHA provides regulatory values. The National Institute of Occupational Safety and Health (NIOSH), also a federal program, provides advisory limits. Private programs such as the American Conference of Government and Industrial Hygienists (ACGIH) and the American Industrial Hygiene Association (AIHA) also provide advisory limits. The AIHA guidelines are for emergency exposures only. These are summarized in Table 89-2 for MIC, MDI, TDI, and HDI.36,37 There are also regulations at the state level, superseded at all times by federal regulation. Other nations have their own regulations. Refer to Chapter 82 for definitions and further details on regulatory agencies and promulgations. REFERENCES 1. Bakke JV (ed): Isocyanates: Risk assessment and preventive measures. Meeting of the Nordic Supervisory Authorities in Copenhagen, April 27, 2000. Norwegian Labor Inspection Authority. Available at: http://www.arbeidstilsynet.no. 2. Dhara VR, Dhara R: The Union Carbide disaster in Bhopal: A review of health effects. Arch Environ Health 2002;57(5):391–404. 3. Ontario Ministry of the Environment, Standards Development Branch. Information Draft on the Development of Air Standards, December 2002. Available at: http://www.ene.gov.on.ca. 4. Sullivan JB, Krieger GR: Clinical Environmental Health and Exposures, 2nd ed. Philadelphia, Lippincott Williams & Wilkins, 2001, pp 994–998. 5. Dhara VR, Gassert TH: The Bhopal syndrome: persistent questions about acute toxicity and management of gas victims. Int J Occup Environ Health 2002;8:380–386. 6. Jeevaratnam K, Sriramachari S: Comparative toxicity of methyl isocyanate and its hydrolytic derivatives in rats. I. Pulmonary histopathology in the acute phase. Arch Toxicol 1994;69(1):39–44. 7. Sriramachari S, Jeevaratnam K: Comparative toxicity of methyl isocyanate and its hydrolytic derivatives in rats. II. Pulmonary histopathology in the subacute and chronic phases. Arch Toxicol 1994;69(1):45–51. 8. Jeevaratnam K, Sriramachari S: Acute histopathological changes induced by methyl isocyanate in lungs, liver, kidneys and spleen of rats [abstract]. Indian J Med Res 1994;99:231–235. 9. Jeevaratnam K: Effect of methyl isocyanate on rabbit cardiac Na+, K+ ATPase. Arch Toxicol 1995;69(10):694–697. 10. Bhattacharya BK, Sharma SK, Jaiswal DK: Binding of [1-14C] methyl isocyanate to erythrocyte membrane proteins. J Appl Toxicol 1996;16(2):137–138.

1322


11. Gupta M, Prabha V: Changes in brain and plasma amino acids of mice intoxicated with methyl isocyanate. J Appl Toxicol 1996; 16(6):469–473. 12. Retrieved February 13, 2004, from http://www.atsdr.cdc.gov/ MHMI/mmg182.html. 13. Liu Q, Wisnewski AV: Recent developments in diisocyanate asthma. Ann Allergy Asthma Immunol 2003;90(Suppl):35–41. 14. Wisnewski A, Herrick CA, Liu Q, et al: Human γ/δ T-cell proliferation and IFN-γ production induced by hexamethylene diisocyanate. J Allergy Clin Immunol 2003;112:538–546. 15. Lee KS, Jin SM, Kim HJ, Lee YC: Matrix metalloproteinase inhibitor regulates inflammatory cell migration by reducing ICAM-1 and VCAM-1 expression in a murine model of toluene diisocyanateinduced asthma. J Allergy Clin Immunol 2003;111(6):1278–1284. 16. Wisnewski AV, Srivastava R, Herrick C, et al: Identification of human lung and skin proteins conjugated with hexamethylene diisocyanate in vitro and in vivo. Am J Respir Crit Care Med 2000;162:2330–2336. 17. Frew AJ: Advances in environmental and occupational disorders. J Allergy Clin Immunol 2003;111:S824–S828. 18. Bolognesi C, Baur X, Marczynski B, et al: Carcinogenic risk of toluene diisocyanate and 4,4′-methylenediphenyl diisocyanate: epidemiological and experimental evidence. Crit Rev Toxicol 2001;31(6):737–772. 19. Ranjan N, Saranji S, Padmanabhan V, et al: Methyl isocyanate exposure and growth patterns of adolescents in Bhopal [letter]. JAMA 2003;290(14):1856–1857. 20. Environmental Protection Agency: Air toxics. Available at http://www.epa.gov. Updated May 30, 2003. 21. Beckett WS: Persistent respiratory effects in survivors of the Bhopal disaster. Thorax 1998;53(Suppl 2):S43–S46. 22. Raizada JK, Dwivedi PC: Chronic ocular lesions in Bhopal gas tragedy [abstract]. Indian J Ophthalmol 1987;35(5–6):453–454. 23. Baur X: Hypersensitivity pneumonitis (extrinsic allergic alveolitis) induced by isocyanates. J Allergy Clin Immunol 1995;95(5 Part 1): 1004–1010. 24. Zammit-Tabona M, Sherkin M, Kijek K, et al: Asthma caused by diphenylmethane diisocyanate in foundry workers. Clinical, bronchial provocation, and immunologic studies. Am Rev Respir Dis 1983;128:226–230.

25. Mapp CE, Boschetto P, Dal Vecchio L, et al: Occupational asthma due to isocyanates. Eur Respir J 1988;1(3):273–279. 26. Ott MG, Klees JE, Poche SL, et al: Respiratory health surveillance in a toluene di-isocyanate production unit, 1967–1997: clinical observations and lung function analyses. Occup Environ Med 2000;57(1):43–52. 27. Mapp CE, Polato R, Maestrelli P, et al: Time course of the increase in airway responsiveness associated with late asthmatic reactions to toluene diisocyanate in sensitized subjects. J Allergy Clin Immunol 1985;75(5):568–572. 28. Padoan M, Pozzato V, Simoni M, et al: Long-term follow-up of toluene diisocyanate-induced asthma. Eur Respir J 2003; 21:637–640. 29. Larsen TH, Gregersen P, Jemec GB: Skin irritation and exposure to diisocyanates in orthopedic nurses working with soft casts. Am J Contact Dermat 2001;12(4):211–214. 30. U.S. National Library of Medicine: Integrated risk information system (IRIS). Available at: http://toxnet.nlm.nih.gov. Updated on December 16, 2002. 31. Gamer AO, Hellwig J, Doe JE, Tyl RW: Prenatal toxicity of inhaled polymeric methylenediphenyl diisocyanate (MDI) aerosols in pregnant Wistar rats [abstract]. Toxicol Sci 2000;54(2):431–440. 32. Tyl RW, Neeper-Bradley TL, Fisher LC, et al: Two-generation reproductive toxicity study of inhaled toluene diisocyanate vapor in CD rats. Toxicol Sci 1999;52(2):258–268. 33. Tyl RW, Fisher LC, Dodd DE, et al: Developmental toxicity evaluation of inhaled toluene diisocyanate vapor in CD rats. Toxicol Sci 1999;52(2):248–257. 34. Bernstein DI, Jolly A: Current diagnostic methods for diisocyanate induced occupational asthma. Am J Ind Med 1999;36:459–468. 35. Baur X: Are we closer to developing threshold limit values for allergens in the workplace? Ann Allergy Asthma Immunol 2003;90(Suppl):11–18. 36. National Institute for Occupational Safety and Health: Pocket Guide to Chemical Hazards. Available at: http://www.cdc.gov. 37. Olson KR, ed: Poisoning and Drug Overdose, 3rd ed. Stamford, CT, Appleton & Lange, 1999.

90

Hydrofluoric Acid and Other Fluorides ANTHONY J. SCALZO, MD ■ CAROLYN M. BLUME-ODOM, RN, BSN


■ ■

Hydrofluoric acid is highly toxic by the dermal, inhalation, ocular, and oral routes. Symptoms and tissue effects may be delayed. HF exposure can induce systemic toxicity related to electrolyte abnormalities. Hypocalcemia Hypomagnesemia Hyperkalemia Treatment is directed at rapid and complete deactivation of absorbed fluoride ion. Treatment options vary by site of exposure. Dermal: initial water irrigation and use of calcium gluconate via various routes Topical calcium gluconate gel Subcutaneous intralesional calcium infiltration Regional intravenous calcium infusion—Bier block technique Intra-arterial calcium infusion Ocular: water/normal saline irrigation, 1% calcium gluconate drops Inhalation: fresh air and nebulized 2.5% calcium gluconate Ingestion: cautious lavage with calcium gluconate, support for systemic complications

cleaning products. The majority of exposures in the home setting involve the distal extremities, primarily the hands and fingers. A case of hydrofluoric acid burns to the hand has been reported after ignition of a compressed air duster containing 1,1-difluoroethane, which decomposes to HF at high temperatures.2 Other products of concern to the lay public are wire wheel cleaners, which contain ammonium bifluoride in a concentration of 15.9%. As little as 2 mL of this type of product has proved fatal in toddlers when ingested.3

STRUCTURE-ACTIVITY RELATIONSHIPS Hydrofluoric acid is a colorless, corrosive liquid or gas, which fumes at concentrations greater than 40% to 48%,4 boils at 19.5°C, and has an odor threshold in air of 0.5 to 3 ppm.5 The vapor pressure of HF gas over a concentrated solution (70% HF at 80°F) is relatively high at 150 mm Hg and thus resembles acetone and other volatile liquids.6 HF is miscible in water and in solution has virtually no odor as opposed to in gaseous form, where it has a strong, irritating odor. HF is manufactured from calcium fluoride (fluorospar), which is reacted with sulfuric acid to form HF gas7: CaF2 + H2SO4 ↔ 2 HF + CaSO4

INTRODUCTION AND EPIDEMIOLOGY Hydrofluoric acid (HF) is an aqueous solution of the inorganic acid of elemental fluorine. HF will dissolve anything that has glass or silica content as well as various metals, rubber, leather, and most organic materials including human tissue. In the industrial setting, HF is used to etch and frost glass, clean metal parts before electroplating, and etch silicon wafers in electronic semiconductor materials. HF is used in the petroleum industry to manufacture high-octane gasoline and in various metal processes, including pickling stainless steel, producing aluminum and uranium, and cleaning and removing rust from iron, copper, and brass. The majority of inhalation exposures and those involving high concentrations are nearly exclusive to industry. Industrial exposures, though less frequent than home exposures, normally account for the majority of severe exposures accompanied by long-term morbidity and mortality. An 11-year investigation by the U.S. Occupational Safety and Health Administration (OSHA) of nine deaths attributed to HF indicated that unsafe work practices were contributing factors in all nine.1 In the home setting, HF exposures can occur when rust removers are used with inadequate dermal protection. Consumer HF-containing products are most commonly rust removers and aluminum and chrome

where CaF2 = fluorospar and H2SO4 = sulfuric acid. The gas is then cooled to be stored as anhydrous HF liquid, which by definition refers to concentrations greater than 99%. Most injuries from HF do not involve anhydrous HF but varying concentrations of >20% used in diverse industry applications or household products with lower concentrations. HF and additional free fluoride ions are also generated when ammonium bifluoride dissociates in aqueous solution: NH4HF2 → HF + F– + NH4+

where NH4HF2 = ammonium bifluoride.

PHARMACOLOGY AND TOXICOLOGY Pathophysiology Concentrated solutions of HF are strong proton (H+) donors that can cause coagulative necrosis similarly to other strong inorganic acids (e.g., HCl), while dilute solutions of HF are weak acids. HF is referred to as a binary hydride, and it has the highest bond dissociation energy, so it requires more energy to dissociate compared with other halogen group series acids (i.e., HF > hydrochloric acid [HCl] > hydrobromic acid [HBr] or > hydriodic acid [HI]). The reverse is true with regard to 1323

1324


strength of acidity (ability to donate a proton, or H+). HF has a dissociation constant (Kd) of 3.53 × 10–4, which is 1000 times less dissociated than HCl. It has a pKa of 3.8.8 Cellular damage from the proton donated by HF causes initial tissue injury by dehydration and corrosion. It is the fluoride ion, however, that is responsible for the majority of tissue damage from HF. Fluoride ion has a permeability coefficient similar to that of water (P = 1.4 × 10–4 cm/sec).4,9 HF in the systemic circulation may dissociate to H+ and free fluoride ions, which may cause severe acidosis as well as systemic fluorosis.8,10 The presence of free fluoride ions results in a number of pathophysiologic effects. Fluoride ions are intensely electronegative and attract several cellular and systemic cations such as calcium and magnesium. In this process, biologically active calcium and magnesium are depleted at a rapid rate. Specifically, the binding of calcium may exceed the rate at which calcium can be mobilized from bone, and this process may lead to severe systemic hypocalcemia.11 Fluoride ion exposure also results in low ionized calcium.12,13 In general, low ionized or low total calcium may be associated with significant neurologic effects including tetany and seizures as well as cardiovascular instability and other effects.14-16 Although the systemic depletion of calcium may be severe, in most cases of HF poisoning, clinical evidence of hypocalcemia such as tetany, Chvostek’s sign, and Trousseau’s sign may be absent.17 Some authors have described patients with leg cramping.18 Because of the rapid onset of hypocalcemia, early replacement of calcium is crucial in significant exposures and should not await laboratory confirmation. The electrocardiogram at the bedside may also offer clues, since hypocalcemia is a well-known cause of prolonged QTc interval. One author described recurrent ventricular tachycardia in association with QT prolongation after an adult was exposed to 30% HF over 44% body surface area (BSA) and survived.19 The hypomagnesemia seen with HF poisoning may also cause prolonged QT and atypical ventricular tachycardia.20 According to the World Health Organization (WHO) guidelines, increased likelihood of significant hypocalcemia may be suspected if the patient has a dermal burn of 1% BSA from HF concentrations of 50% or greater, any dermal burn of 5% BSA regardless of the concentration of HF, inhalation of HF vapors from solutions of greater than or equal to 60%, or even small ingestions of HF solutions including more dilute household products.21,22 In clinical practice, however, there are often exceptions to these guidelines. Additionally, free fluoride ions inhibit many membrane and intracellular enzymes including those of the Krebs cycle and importantly the Na+/K+-ATPase pump8,23 as well as enzymes that are magnesium or manganese dependent.24 Inhibition of Krebs cycle enzymes may result in cellular energy failure, which contributes to cell death. Fluorides react with trace amounts of aluminum (Al3–) to form AlF4-– complexes that have been shown to activate G proteins in cell membranes, which may alter cell-signaling processes and lead to inflammation.25 Fluoride ions also stimulate phospholipase A2, which may liberate arachidonic acid, the precursor for various

inflammatory eicosanoids.25 On a more emergent level, fluoride reportedly stimulates adenylate cyclase,26 which in the myocardium results in increased cyclic adenosine monophosphate (AMP) and may increase the possibility of arrhythmias.20 Direct myocardial tissue injury is also possible from high myocardial fluoride levels in cases of fatal systemic fluorosis from serious dermal burns.10 Changes in potassium flux across membrane channels have been implicated in fluoride poisoning and are the subject of recent research on the use of amiodarone for its potassium channel blocking effects.27 The Na+/K+ATPase system is responsible for pumping sodium ions out of the cell and potassium ions into the cell to maintain normal extracellular levels of each cation. When poisoned by fluoride ions, this pump will result in excess extracellular potassium, which exacerbates the hyperkalemic state. The resultant hyperkalemia is likely a contributory factor in enhancing myocardial irritability. The effects of hypocalcemia and dysfunction of the Na+/K+-ATPase system on potassium flux may not be immediate. Delayed ventricular fibrillation, frequently described in severe dermal exposure, ingestions, and inhalation exposures to concentrated HF may be due to late-onset hyperkalemia.23 Others report this arrhythmia in the absence of hyperkalemia.13,19 The mechanism of acute fluoride-induced sudden cardiac death from ventricular arrhythmias has been attributed to profound hypocalcemia, but in canine studies this lethal effect appears to be more temporally due to the elevation in serum potassium.23 A large fraction of the increase in extracellular potassium may derive from transfer across the erythrocyte membrane of red blood cells in circulation that are exposed to the fluoride ion.28 In vitro studies show that while fluoride ion decreases extracellular calcium, it increases intracellular calcium, which is believed to trigger calcium-dependent K+ channels that allow for enhanced K+ efflux and resultant hyperkalemia.29 Moreover, in dogs this fluoride-induced hyperkalemia cannot be prevented by glucose, insulin, or bicarbonate.23 From a pathophysiologic standpoint, the treatment of fluoride-induced hyperkalemia may depend on removal of fluoride as well as potassium. This is problematic at best. To some extent, the treatment of HF-induced hypocalcemia with intravenous (IV) calcium should help correct some effects of hyperkalemia. Although sodium bicarbonate administration may lower extracellular potassium and correct the acidosis of systemic HF poisoning, it also may lower ionized calcium.30 Maintaining normal to supranormal extracellular calcium levels may diminish the likelihood of ventricular arrhythmias (ventricular fibrillation, or VF) in severe HF exposure.8 In one report, a 33-year-old man developed severe hypocalcemia (0.78 mmol/L ionized calcium), metabolic acidosis (pH 7.04), and several episodes of VF after ingesting HF. As much as 4 g of IV calcium chloride including 1 g/hr infusion were administered, yet the patient still had five episodes of VF. An ultrahigh dose of calcium at 200 mL/hr (20 g/hr calcium chloride) was subsequently infused and achieved an ionized calcium level of 4.34 mmol/L; no further VF was observed.8

CHAPTER 90

The delayed pain characteristic of HF dermal exposures can be attributed to some of these pathophysiologic effects on potassium flux across the membrane but likely is more complex. Some authors have attributed pain as secondary to the precipitation of calcium fluoride and magnesium fluoride in deep tissues as well as hyperkalemia, which leads to neural stimulation.31,32 We question, however, the notion of attributing pain (nociceptive stimulus) to tissue deposition of insoluble calcium and magnesium salts of fluoride. The effective correction of pain due to fluoride toxicity employs calcium and possibly magnesium to complex with free fluoride ions. This process generates insoluble calcium fluoride or magnesium fluoride, yet is the very therapy that alleviates pain. The authors believe that the neural stimulation theory from enhanced K+ flux and in some cases extracellular hyperkalemia is more plausible. The stimulation of unmyelinated free nerve endings (C fibers) and later, slower conducting myelinated A-δ fibers in damaged tissue likely occurs after HF exposure. Fluoride-induced calcium deficiency at the cellular membrane allows enhanced outward K+ flux through Ca2+-dependent K+ channels.29,33 Extracellular hyperkalemia at the cell membrane surface may not always translate to abnormal serum potassium even in severe or fatal human HF poisoning,22,34,35 but it may occur and be life threatening.18,23 Hyperkalemia is associated with peripheral neural depolarization as well as depolarization in muscle and excitable cardiac tissue.36-38 Mild to moderate hyperkalemia shifts the resting potential toward depolarization and there is an increase in conduction velocity in human atrial cells, whereas severe hyperkalemia may lead to a reduction in conduction velocity.36 This discussion of potassium in no way diminishes the consequences of severe systemic hypocalcemia or hypomagnesemia seen in serious HF exposures. Hypocalcemia, especially in combination with hypomagnesemia, is a major contributing factor in myocardial irritability in many cases. Enhanced potassium flux at the cellular level is probably insufficient explanation for the mechanism of pain. The molecular mechanism of pain, especially in damaged or inflamed tissue, is complex, and sodium channels, voltage-gated potassium channels (Kv), and a host of neuropeptides and excitatory amino acids are involved.39 Protons (H+) and lower tissue pH may stimulate a subpopulation of C fibers and contribute to pain.40 Substance P (an 11–amino acid peptide), released from vesicles in sensory nerve fibers, also may contribute to pain.41 Hyperkalemia may signal increases in calcitonin gene–related peptide (CGRP), a known nociceptive neuropeptide, as evidenced by in vitro release of CGRP by potassium chloride.42 High extracellular potassium appears to enhance the release of glutamate in the central nervous system.43,44 Glutamate receptors are localized in the peripheral nervous system on nociceptive, afferent, unmyelinated C-fiber type nerves.45 Studies in animal models of pain have shown that peripheral glutamate is involved in nociceptive transmission under normal conditions and with

Hydrofluoric Acid and Other Fluorides

1325

inflammation.46 Thus, inflamed and injured tissue having suffered the initial burn effects of the H+ ions and subsequently the effects of fluoride ions will likely have exposed free unmyelinated nerve endings that will signal the pain sensation.47 In summary, fluoride ion results in alterations of potassium flux with extracellular hyperkalemia, as well as hypocalcemia and hypomagnesemia, all of which contribute to altered membrane excitability of peripheral sensory nerves as well as cardiac tissue. These ion derangements, especially hyperkalemia, may herald the release of nociceptive peptides such as CGRP and glutamate, all of which play a role in the generation of pain. More research is needed at the molecular biologic level to further clarify these constructs.

Toxic Pathology and Clinical Effects HF and related products may cause dermal, ocular, pulmonary, gastrointestinal (GI), and systemic injury. Unique exposure routes, however, include a case of intradermal injection of 5 mL of 7% HF in a suicide attempt with severe local and systemic effects including hypocalcemia,48 and fulminant colitis following selfadministration of an HF enema.49 Nevertheless, most HFrelated injuries that the emergency or occupational physician encounters are from dermal exposures with resultant injury largely dependent on the concentration of HF and extent of exposure. Oral and inhalation exposures, however, should be considered potentially fatal irrespective of HF concentration. Industrial exposures may involve exposure to anhydrous HF and varying concentrations below that to approximately 20% HF. Household products usually contain HF in lower concentrations but may also cause injury from misuse or failure to use protective equipment. Household products used as rust removers and aluminum wheel cleaners for automobiles usually contain 6% to 12% and less than 20% HF.50 Consumers may use these products without wearing gloves or protective garments, and the lack of immediate pain or irritation often is deceiving. Vinyl or rubber gloves are superior to latex, since HF attacks latex. Additionally, since moist skin appears to be more permeable to HF, a glove with a pinhole leak may allow HF to contact skin and the occlusive, moisture-retaining effect of the glove may enhance absorption.6,51 Other forms of fluoride that dissociate to HF upon contact with water include ammonium bifluoride found in automobile alloy wheel cleaners. Exposures, both dermal and inhalational, to ammonium bifluoride–containing products has resulted in deaths and serious morbidity including marked hypocalcemia, hypomagnesemia, and ventricular fibrillation in several pediatric patients.3,13,52 Additional forms of fluoride that are significant for human health include sodium fluoride as found in fluoridated water supplies or dental products. Sodium fluoride tablets, which generally contain 0.25 to 1 mg of fluoride ion, have caused fluoride poisoning in children.53,54 As opposed to HF in household and automobile cleaners, the fluoride contained in toothpaste usually is not consumed in quantities sufficient to cause

1326


toxicity with common daily use. Dental preparations containing fluoride include toothpaste and gels as well as mouthwashes, topical fluoride gels, and dental rinses that may induce minimal toxicity in accidental overdoses. The forms of fluoride found in these products usually release only small amounts of free fluoride anion, thus reducing the risk of acute toxicity. Nevertheless, cases of fluoride poisoning have occurred with ingestion of fluoride rinses as well as large ingestions of toothpaste (4.5 to 9 ounces with 0.15% fluoride ion w/v) in small children.55 Some consider approximately 5 mg/kg of F− ion from dental products as “toxic,” with nausea, vomiting, diarrhea, and abdominal cramping likely to occur at this dose,53 whereas others believe the toxic range is 5 to 10 mg/kg.56 The estimated lethal dose of fluoride is in excess of 30 mg/kg.57 In a series of 87 children, those who ingested up to 8.4 mg/kg from dental products had mild, self-limited primarily GI symptoms.58 A 15-kg toddler who ingests a full 4.6-ounce tube of children’s fruit-flavored toothpaste, however, could be at risk for significant toxicity. This exposure can be calculated as follows: A 4.6-ounce tube of a popular children’s flavored toothpaste contains 2.4% sodium fluoride and has 0.15% w/v of fluoride ion. 4.6 ounces × 29.57 mL/oz = 136.02 mL in the tube. 136.02 mL × 0.15 g/100 mL (0.15% w/v fluoride) = 204.03 mg of fluoride. 204.03 mg fluoride in a 15-kg child = 13.6 mg/kg. Serious poisoning due to fluoride-containing dental products has been reported. GI hemorrhage, hypocalcemia, hypomagnesemia, ventricular tachycardia, and ventricular fibrillation have been reported in a 43-yearold following an ingestion of up to 25 ounces of a topical fluoride gel containing 1.23% fluoride.59 Death occurred following ingestion of 200 mg (16 mg/kg) of fluoride in a 3-year-old boy.60 Subgingival irrigation of deep periodontal pockets with a 2% stannous fluoride (SnF2) solution resulted in extensively erythematous mucosa of half of the hard palate and necrosis of the soft tissue close to the palatal aspect of two molars.61 Excessive fluoridation has also been associated with skeletal fluorosis.5 The American Academy of Pediatrics Committee on Nutrition and Fluoridation recommends that the optimal daily dose of fluoride effective in preventing dental caries is 0.05 to 0.07 mg/kg/day.62 Dental fluorosis, characterized by mottled teeth, has occurred with excessive fluoridation. There is evidence that levels of fluorosis have increased in part owing to widespread use of fluoridated water in food processing and dentifrices containing sodium fluoride used in combination with ingestion of fluoridated water.5 DERMAL TOXICITY When in contact with skin, HF dissociates into hydrogen ions and free fluoride ions. There may be a latent period before a clinically evident burn is apparent, dependent on the concentration of the acid and the length of time it is in contact with the skin.63-65 Other mineral acids are

rapidly neutralized, whereas the process of tissue destruction may continue for days with HF.66 Fluoride ions penetrate tissues deeply, causing tissue damage and the potential for systemic toxicity depending on the HF acid concentration. In general, exposure to HF solutions of greater than 50% concentration results in immediate pain and tissue destruction.4,21,67 The skin appears blanched, and within 1 to 2 hours the dermal lines are obliterated by edema.65 Even a small cutaneous exposure to greater than 50% HF can be rapidly fatal.17,68 Two cases of delayed death at 7 days and at 15 days resulting from multiple organ system failure have been reported following significant dermal burns from 70% HF.69,70 Dermal contact with concentrations of 20% to 50% HF usually result in a burn that develops within a few hours.31 In fact, concentrations greater than 20% HF have a potential for serious toxicity regardless of the degree of surface area involved.71 Contact with solutions of less than 20% HF concentration results in dermal injury that usually develops with a latent period of about 24 hours.72 Hand and finger involvement is common in household product exposures73-76 as well as industrial-strength solutions of HF.4,77 The clinical presentation of exposure to strong HF solutions of greater than 20% begins with pain at the site that is characteristically intense77 and often described by patients as “burning,” “deep,” “throbbing,” or “exquisite.”64 Local erythema and edema may or may not be present initially, but later a pale, blanched appearance of the skin is apparent in more severe burns from concentrated HF (e.g., >50%).24,65,77 Extensive bullae and maceration of tissue may be seen.74 Gray areas may develop and progress to frank necrosis and deep ulceration within 6 to 24 hours.24 Since subungual tissue is lacking in stratum corneum, it is particularly susceptible to the penetration of fluoride ions, and exposure may result in a gray, black, or bluish discoloration of the nails.21,78 This is of clinical importance, since the nail bed is generally inaccessible to administration of topical calcium therapy. Tissue fluoride may be extremely high at the site of the burn, but such burns also result in elevated serum fluoride levels. In a fatal industrial exposure to 70% HF over 9% BSA, the burn site had 303 μg of fluoride per gram of dry tissue (normal, 0.2 to 0.8 μg/g) and serum fluoride was measured at 4.17 μg/mL (normal, 0.01 to 0.04 μg/mL).10 In another case, a serum fluoride level of 21.3 μg/mL (normal, 0 to 0.5 μg/mL) was reported in a child who survived an 11% BSA burn from a combination product consisting of 8% hydrofluoric acid and 23% hydrochloric acid.20 Urinary fluoride (toxic, >10 mg/L) is also used to document exposures.13,79 Secondary contamination attendants to the victims of HF exposure has been reported in two emergency department (ED) personnel who developed respiratory and skin irritation from patients who had not been decontaminated prior to arrival.80 In another case, all three members of an operating room team developed marked conjunctival and nasal irritation from presumably unbound fluoride present in tissue that they were débriding on the fifth day postinjury.69

CHAPTER 90

OCULAR TOXICITY Ocular toxicity with concentrated HF solutions may be immediate or delayed.67 Denuded corneal and conjunctival epithelium, corneal stromal edema, and conjunctival ischemia may be seen.81 Severe eyelid edema and conjunctival chemosis with decreased visual acuity has also been described in a worker sprayed with aerosolized and solid particles of HF.82 Even vapors of HF can cause ocular damage.83,84 Anhydrous HF may result in immediate damage and globe perforation necessitating enucleation.85 Lid deformities, uveitis, and glaucoma have also been described.4 Delayed effects may be seen, as evidenced by a 25-yearold sprayed in the eye with HF who was treated in an ER and released, only to return 5 days later with a foreign body sensation in his affected eye. Examination revealed a corneal erosion measuring 4 × 5 mm accompanied by marked conjunctival injection, chemosis, and subconjunctival hemorrhages.82 In a 3-year-old child, initial symptoms of pain and redness resolved with irrigation alone after she had sprayed her eyes with a wire wheel cleaner containing an unknown percentage of phosphoric acid and hydrofluoric acid. Pain, however, returned in 4 days. She sustained bilateral corneal opacities, which were treated with topical antibiotics and corticosteroids under the care of an ophthalmologist. Her ocular examination was normal at 30 days postexposure.86 INHALATION TOXICITY Upon inhalation, HF has resulted in local pulmonary as well as systemic effects. Acute lethal inhalation exposures in humans have resulted in congestion, edema, or necrosis in the liver, kidneys, and spleen, as noted on autopsy.87 The American Conference of Governmental Industrial Hygienists’ (ACGIH) threshold limit value (TLV) and the OSHA permissible exposure limit (PEL) have both been set at 3 ppm or 2.6 mg/m3.88 Since TLV is a ceiling threshold level and PEL is a time-weighted average over 8 hours, these standards are not very useful to the emergency physician confronted with a worker who has been exposed in a factory accident to HF at 100 or 150 ppm for a short time. Thus, some researchers have sought to define a short-term exposure limit (STEL) at which brief (≤10 minutes) exposures at higher levels might produce irritation but not serious or irreversible effects on the respiratory tract. In one such study, rats were used to derive an STEL for humans of 130 ppm for a 10 minute or less exposure.88 Potroom workers in the aluminum smelting industry are at increased risk for inhalation of HF89 and particulate fluoride salts,90 which have caused inflammatory responses in the upper and lower respiratory tracts of healthy individuals at HF levels of less than 5 mg/m3.25 In a volunteer study, 20 individuals exposed to HF at levels varying from 0.2 mg/m3 to 5.2 mg/m3 had elevated levels of plasma fluoride that correlated with increasing concentrations of HF. The authors also found that exposures above 2.5 mg/m3 were associated with pronounced upper respiratory tract symptoms and with increased neutrophils and tumor necrosis factor–α


1327

(TNF-α) in nasal fluid.25 In some cases, HF inhalation may result in pulmonary edema and severe lung injury1 or death,91 whereas others report an adult respiratory distress syndrome (ARDS)–like syndrome necessitating prolonged intubation but with normal pulmonary function at outcome.92 Postmortem examination of tissue in fatal inhalation cases has revealed bronchi obstructed with mucus and blood and severely ulcerated, necrotizing tracheobronchitis with pseudomembrane formation.91 The sudden onset of asthma in an adult with no previous history has been reported immediately following an inhalation exposure to an 8% to 9% HF rust remover.93 Chemical pneumonitis has been reported in a previously healthy 26-year-old woman who used three 10-ounce applications of an 8% HF-containing rust remover in an attempt to remove a stain in a bathtub. On presentation, she had shortness of breath, orthopnea, fever, nonproductive cough, severe right shoulder pain, and auscultated wheezes and crackles over her right thorax. A chest radiograph revealed a right lower lobe infiltrate. Over the ensuing 3 to 4 days, her respiratory status deteriorated and she was intubated, requiring a fraction of inspired oxygen (FIO2) of 1.0 and positive end-expiratory pressure (PEEP) of 10 cm H2O to maintain oxygen saturation above 70%. All cultures for bacteria, viruses, fungi, and mycobacteria were negative.94 Respiratory symptoms may be persistent for months to years following inhalation of HF.91 While changes in respiratory function have been described with large exposures as mentioned above, there also appears to be an association between low-level HF exposure and a decline in chronic lung function as measured by forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1).25,89 INGESTION TOXICITY The toxicity of HF in oral ingestions is generally severe and rapid, with death occurring in less than 1 hour in some cases.4,22 This route of exposure is not uncommon, as reported by one regional poison center over a 2-year period. The authors found 1172 HF exposures 99 of which were human cases of ingestion.34 All these ingestions involved products which contained 6% to 8% HF. Hypocalcemia was found in 4 of 29 cases in which calcium was measured, and all four of these patients were adults who intentionally drank 3 oz or more in a suicide attempt. Two of these patients died. GI symptoms after HF ingestion include throat pain, nausea, vomiting, gastric pain, and hematemesis.8,34,35 Endoscopic studies show esophageal erythema and edema35 as well as superficial ulcerations in the stomach in treated cases.8 Systemic symptoms are also likely with HF ingestion and may be life threatening. A survivor of two swallows of an 8% HF-containing rust remover developed severe hypocalcemia and received 1100 mg of calcium gluconate in the first few hours. Despite calcium replacement, the patient became hypotensive (BP 62/40, HR 140) and developed ventricular fibrillation for which she was defibrillated as many as 30 times35; she ultimately survived neurologically intact.

1328


Ingestion of ammonium bifluoride (NH4HF2) resulting in death in two children has been reported3,52 and survival in two others.13 In one case, a 3-year-old girl ingested an unknown quantity of a wheel cleaner containing NH4HF2, which had been placed in a drinking cup. Within 20 minutes of ingestion she was obtunded, flaccid, and with circumoral cyanosis. She was intubated and treated with multiple doses of IV and nebulized calcium gluconate, but within 30 minutes of arrival she suffered bradyasystolic arrest. Curiously, the QTc interval remained normal until the time of the arrest. She could not be resuscitated, and postmortem examination revealed severe pulmonary hemorrhage as well as hemorrhagic necrosis of the pharynx, esophagus, and stomach.52 Both of two survivors of significant NH4HF2 ingestion displayed significant hypocalcemia (one, 4.2 mg/dL, and the other, 2.6 mg/dL; normal, 9 to 11 mg/dL) and one displayed severe hypomagnesemia (0.3 mg/dL; normal, 1.5 to 2.1 mg/dL). An electrocardiogram (ECG) available in the first case revealed a slightly prolonged QTc (0.48 seconds) that prompted treatment with IV calcium. One patient developed delayed ventricular fibrillation at approximately 3.5 hours and the second at an estimated 6 to 7 hours postingestion.13 Urinary fluoride levels confirmed the exposure in both cases (77 and 110 mg/L; toxic, >10 mg/L).

DIAGNOSIS Laboratory and Other Diagnostic Testing Diagnosis of acute fluoride toxicity is based on clinical presentation and history of exposure. The onset of systemic toxicity may be rapid and abrupt; hence, treatment is best initiated prior to definitive knowledge of the electrolyte status of the patient. Frequent monitoring of calcium, magnesium, potassium, and phosphorus as well as arterial blood gas (ABG) levels is essential during evaluation and treatment of HF exposure. Hypocalcemia, hypomagnesemia, hyperkalemia, and acidosis are suggestive of HF toxicity. Renal and hepatic functions are important parameters to monitor, since toxicity to these organs may accompany systemic fluorosis.85 Continuous cardiac monitoring and hourly serum calcium concentrations are essential during parenteral (i.e., subcutaneous, intravenous, or intra-arterial) calcium supplementation to guard against the risk of hypercalcemia associated with the inexact nature of dosing with calcium salts.20 Serum and urinary fluoride levels may be used as indicators of severity of exposure, since neutralized fluoride is eliminated primarily by the renal system. Fluoride levels are not very useful in the management of acute overdose, and normal or reference values vary in the literature. For serum, the generally accepted “normal” range is 0.01 to 0.04 μg/mL; some use an upper reference limit of no more than 2 μmol/L. The normal range for urine fluoride varies from 0.2 to 3.2 mg/L (toxic, >10 mg/L).

Differential Diagnosis Phosphoric acid may be present in products used for etching metals and creating semiconductor products. It may also burn the skin but does not have the delayed effects characteristic of HF. If the patient has severe pain in the extremities or other areas of the skin without noticeable redness early following exposure to unknown chemicals, HF toxicity should be considered.

MANAGEMENT Regardless of the route of HF exposure, initial management is aimed at thorough decontamination to reduce the absorption of fluoride. This is followed by attempts at rapid and complete deactivation and neutralization of absorbed fluoride ion to prevent or minimize tissue damage and systemic toxicity.

Dermal Exposure First aid for dermal exposure to HF is immediate removal of contaminated clothing, taking extreme caution to protect attending personnel from cross-contamination, and irrigation of the exposed site with copious amounts of water for a minimum of 15 to 20 minutes. Decontamination is followed by careful débridement of vesicles and bullae to allow topical neutralization efforts to be optimally effective.4 A wide variety of treatment options have been devised to treat tissue hypocalcemia by deactivating free fluoride ions at the site of injury, thereby promoting formation of a nontoxic, insoluble calcium salt. Selection of a treatment modality is based on the history of the exposure and clinical status of the patient (Fig. 90-1). Initial topical neutralization should include massage of a 2.5% to 5% calcium gluconate gel into the burn site.64,75,85,95 An extemporaneous preparation of calcium gluconate gel 2.5% to 5% is formulated by adding 3.5 to 7 g of calcium gluconate powder to a 5-ounce tube of water-soluble surgical lubricant (e.g., K-Y Jelly).4,21 Alternatively, the gel may be formulated by adding 10 1-g calcium carbonate tablets (e.g., Tums antacid tablets), which have been crushed into a fine powder, to 20 mL of water-soluble surgical lubricant to create a slurry.95 The calcium carbonate will not be fully dissolved. Some authors advocate formulating the gel with dimethyl sulfoxide (DMSO), since it is thought to enhance the absorption of calcium into underlying tissues20,96; however, safety and efficacy of DMSO use have not been established.66 Calcium chloride should not be used as a substitute for either the gluconate or the carbonate forms of calcium in topical applications owing to its potential for cellular toxicity and tissue irritation.95 To facilitate application to the hands and digits, it is recommended to place 10 mL of the prepared gel inside a sterile surgical glove that is a half-size too large and insert the patient’s hand into the glove.4,75,95 Bending the fingers intermittently ensures optimal contact between the gel and the treatment area and facilitates main-

CHAPTER 90


1329

HF burn

Immediate water irrigation for 15–20 minutes

Calcium gluconate 2.5% gel (Use when affected area is limited to recent exposures ( 20%)

FIGURE 90-1 Dermal treatment of hydrofluoric acid burns.

tenance of joint mobility. If the patient obtains pain relief within 1 hour, liberal use of the gel can be continued for 3 to 4 days at 4- to 6-hour intervals85 or whenever pain recurs.21 It is hypothesized that topical treatment with calcium pulls fluoride ions back across the skin by a diffusion gradient.95 This rationale suggests that topical administration of calcium is more efficacious in recent exposures (24 hours) or when the skin shows evidence of altered integrity such as a toughened outer coagulum and blisters that may limit the access of subcutaneous tissues to administered calcium.95 When pain persists beyond 45 to 60 minutes of topical calcium neutralization7,65,66 or if severe burns from solutions greater than 20% HF are present on initial consultation,21,78,85,97 subcutaneous intralesional administration of calcium gluconate should be considered. Tissue destruction and associated pain may be minimized by subcutaneous intralesional administration of calcium gluconate, as introduced in 1932 by Freehagen and Wellmann,98 with proven efficacy by Jones99 in 1939. A standard protocol in use, first described by Dibbell78 in 1970, involves multiple subcutaneous intralesional injections of 10% calcium gluconate beneath the affected area by means of a 30-gauge needle to deliver a maximum volume of 0.5 mL/cm2 of tissue, extending 5 mm beyond the injured site.4,65,72,78,100 Each injection of

0.5 mL of 10% calcium gluconate solution delivers 4.2 mg of elemental calcium, which has been estimated to neutralize 0.025 mL of 20% HF.101 A plastic surgeon or hand specialist should be consulted prior to attempting tissue infiltration. Subcutaneous injections into the tissues of the fingers must not be circumferential nor should they exceed 0.5 mL per affected digit owing to the possibility of the injection itself producing vascular impairment or of local compartment syndrome in already edematous tissue,65 If local pain recurs, repeat injections21,78 may be warranted, with extension of the treated site beyond the recommended 5 mm.72,97 When tissues of the face are infiltrated, it is advised that a 5% calcium gluconate injection be used to reduce the risk of tissue irritation, potential scarring, and keloid formation.4,85 Administering large volumes of subcutaneous calcium gluconate in single or repeated injections should be avoided because it may result in hypercalcemia, decreased tissue perfusion, local compartment syndrome, and ischemia-induced necrosis.7,20,63 Calcium chloride should never be substituted for calcium gluconate in subcutaneous injections owing to the risk of tissue necrosis related to its hypertonicity.4,11,21 Velvart102 recommends that subcutaneous calcium injections not be attempted when necrosis is apparent on presentation in favor of a more definitive treatment modality. The main disadvantage of subcutaneous infiltration is obvious discomfort to the patient. Since the end point of therapy is cessation of pain, the use of anesthesia has been discouraged during the infiltration procedure21,65,78 although parenteral morphine is often required. Local calcium infiltration may require removal

1330


of fingernails to gain access to contaminated subungual structures that are easily penetrated by HF because of the lack of corneum stratum. In some instances, “burr holes” into the fingernails may be sufficient to deliver adequate calcium to underlying tissues.7 Fingernail removal is a disfiguring process that requires up to several months for regrowth, causing extended disability in occupations requiring the use of the hands and fingers. An alternative to fingernail removal is trimming the nail plate back to its attachment at the nailbed4 or injecting the nail bed via a lateral or volar route through the fat pad,75 which is accomplished under digital nerve block. Instead of local injection and fingernail removal, one can infuse calcium locally. The decision to advance to more definitive modes of calcium delivery is warranted when fingernail removal is being considered or when there is lack of response to topical or subcutaneous injection. Regional IV calcium infusion is a therapeutic option proposed for treatment of HF burns of the upper extremity to promote analgesia while minimizing tissue destruction.103-107 Success has been reported with HF injuries to the lower extremity.108 Calcium gluconate, 10 mL of a 10% solution in 30 to 40 mL of normal saline, is injected intravenously into the affected limb by means of the Bier block technique. Ischemia of the limb is maintained with a tourniquet for 20 to 25 minutes to allow calcium to accumulate in tissues at the site of injury.106 Some clinicians utilize a second tourniquet proximal to the first to prevent inadvertent systemic calcium administration. In the event of failure of regional IV calcium infusion, a second infusion should be attempted.103,107 Patients should have continuous cardiac monitoring and frequent serum calcium level measurements during Bier block–IV calcium infusion. Some authors advise regional IV calcium infusion as a viable alternative to subcutaneous intralesional infiltration owing to the discomfort imposed on the patient during infiltration without anesthesia and the need for fingernail removal in some instances.106,107 Adverse effects reported with regional IV calcium infusion have been limited to minor complaints of warmth and burning during the calcium infusion and discomfort during maintenance of tourniquet inflation.106 Transient forearm fasciculation for up to 1 hour has been reported in one case.106 An additional yet more invasive means of fluoride ion deactivation is delivery of calcium by an intra-arterial infusion method. This treatment modality is indicated for severe exposures to HF of greater than 20% concentration, late presentations (>24 hours) unresponsive to other therapies, extensive burn areas where available tissue space is limited for subcutaneous infiltration of calcium.77 Aschinger and colleagues109 introduced the procedure, specified for injuries to the distal extremities, in 1979, with modifications by Velvart102 in 1983 and Vance77 in 1986. The technique for intra-arterial infusion involves the percutaneous insertion of a long catheter into the radial, ulnar, or brachial artery, as determined by the site of injury. The origin of vascular supply to the injured area is identified by digital subtraction

arteriography. A pressure transducer and monitor are used to confirm the position of the catheter; once the catheter is optimally in place, a dilute solution of calcium salts (10 mL of 10% calcium gluconate in 40 to 50 mL 5% dextrose) is infused over a 4-hour period by means of a pump apparatus. Treatments are repeated at 4-hour intervals until the patient remains pain free for a 4-hour period. Continuous cardiac monitoring, vital signs, and calcium levels are closely observed during intra-arterial calcium infusion. Lin and colleagues110 recommend modifying the above procedure by continuously infusing calcium over a 12-hour period using an ambulatory infusion pump. This modification offers the patient additional comfort and mobility during the treatment period while maintaining excellent clinical efficacy. Intra-arterial calcium infusion enables the delivery of large volumes of calcium to the injured site without impairment of surrounding structures or induction of local tissue toxicity.77,102 Some toxicologists and vascular hand surgeons with extensive experience in the use of intra-arterial calcium infusion may consider this technique earlier in the course of management, while taking necessary precautions including continuous arterial waveform monitoring. This technique is most appropriate when it is advantageous to administer large amounts of calcium to the burn site in the case of extensive burns from highly concentrated HF accompanied by a considerable risk of hypocalcemia and systemic toxicity. A single 10-mL intra-arterial infusion of 10% calcium gluconate delivers 84 mg (4.7 mEq) of elemental calcium to tissues injured by HF.77 The infusion is painless to the patient and avoids the need for fingernail removal. Case reports have demonstrated proven efficacy for pain relief up to 24 hours after the injury with intraarterial infusion.102 When intra-arterial infusion is employed early in the course of treatment, initial tissue débridement should be conservative, since rejuvenation of avital tissue has been noted.102 Despite its advantages, intra-arterial infusion has significant drawbacks in that it requires hospitalization, specialized equipment, and coordination by a vascular surgeon experienced in the technique.77 Complications include local arterial spasm, arteritis, and soft tissue loss.77 Siegel and Heard105 reported nerve palsies, carpal tunnel syndrome, and persistent increased sensitivity to cold and paresthesias from their experience in treating 38 extremities in 28 patients.

Ocular Exposure The speed with which irrigation is instituted is the most important factor in preventing damage from ocular exposure to HF. An immediate single irrigation with tap water or isotonic NaCl for 15 to 20 minutes is the best initial first aid and should be instituted immediately at the scene. Multiple or prolonged irrigations are discouraged on the basis of studies in rabbit eyes which indicate that multiple irrigations can increase the rate of corneal ulceration from 6% to 40%.81 Although the pH of the burn surface may rapidly return to normal after initial irrigation, deeper tissues may remain at con-

CHAPTER 90

siderable risk for serious injury. Some clinicians recommend that once the patient is in the ED, an additional 5 to 10 minutes of irrigation with a 1% calcium gluconate solution should be instituted to ensure that adequate decontamination has been achieved and that remaining fluoride ion on the surface of the eye is neutralized.21,85 Calcium gluconate 1% drops should be instilled every 2 to 3 hours for up to 2 to 3 days,82,84,85 accompanied by conventional use of cycloplegics and antimicrobial agents when necessary. Efficacy of this treatment has been demonstrated in several cases involving HF concentrations of up to 49%.84 The use of corticosteroid agents is proposed by some clinicians to lessen fibroblast formation in the cornea.85,111 Systemic analgesic agents are helpful in controlling the pain associated with ocular exposure to HF. An ophthalmology consultation and examination are highly advisable for all patients with ocular exposure to HF. It is not feasible to extrapolate treatment for dermal HF burns to the eye.81,86 Many irrigants that have been suggested as immediate first aid in dermal exposures (e.g., Hyamine 0.2% and Zephiran 0.05%) can induce additional toxicity to the eye.81 Other irrigant solutions have been proposed for the treatment of ocular exposure to HF. Hatai86 suggested the use of milk or lactated Ringer’s solution as appropriate eye irrigants, since both have physiologic compatibility with the eye and both have a divalent calcium ion. Further research is needed to evaluate their efficacy. Water, isotonic sodium chloride (NaCl), and isotonic magnesium chloride (MgCl2) when available are the best irrigating solutions for HF exposures to the eye in an experimental rabbit model.81

Inhalation Exposure Inhalation exposure to HF is most common in industrial settings. Multiple organ systems are at risk, since HF fumes at concentrations greater than 40% to 48%. Rapid removal from the contaminated environment is key to reducing morbidity and mortality. Rescue personnel should wear self-contained breathing apparatus (SCBA) and containment suits to prevent exposure. To patients in respiratory distress, 100% humidified oxygen should be administered immediately, followed by administration of a 2.5% to 3% calcium gluconate solution in normal saline with 100% oxygen via nebulization.7,85 HF inhalation is accompanied by a significant risk for immediate or delayed-onset pulmonary edema, especially with prolonged exposure or exposure to high concentrations. If there is evidence of pulmonary edema, the patient should be placed on intermittent positive pressure breathing (IPPB) with PEEP and calcium should be delivered per nebulization.85 In a reported case, 5% calcium gluconate per IPPB was employed utilizing a nebulizer after an inhalation exposure to 100% HF. Chest films and computed tomographic (CT) scan were normal at 21 days postexposure when the patient was discharged.92 Patients exposed to HF by inhalation may require intubation and mechanical ventilation, especially when exposed to concentrations exceeding 60%.6 Inhaled HF


1331

is rapidly introduced into the liver and kidneys via the blood stream and is accompanied by a high risk for systemic toxicity.85 It is essential to maintain an adequate airway and closely monitor serum calcium, magnesium, and potassium levels; arterial blood gases (ABGs); and O2 saturation. Continuous observation for 24 to 48 hours after inhalation exposure to HF in a health care facility is suggested. Some clinicians recommend the early use of corticosteroids to prevent noncardiogenic pulmonary edema and to control the inflammatory response.85,98 Since there is not complete agreement about this recommendation, the use of steroids as a standard regimen remains controversial.

Oral Exposure Oral exposure to HF results in rapid systemic absorption even with dilute solutions and is associated with a high risk for systemic toxicity. Simple dilution with a demulcent will not arrest the progression of tissue damage or the development of systemic toxicity when HF preparations are ingested. Induced emesis is contraindicated, as is neutralization with oral sodium bicarbonate.21 Recommended first aid is oral administration of 1 to 2 cupfuls of milk or water. Milk is preferred owing to the presence of calcium ions,35 though milk of magnesia may be given for its available magnesium ions and its demulcent effect on oral and gastric mucosa. To the authors’ knowledge, there are no reports of benefit from activated charcoal in the management of oral exposures to HF. Treatment in the ED may include cautious nasogastric lavage with a small-bore nasogastric tube to remove residual HF if this can be performed within 60 to 90 minutes of ingestion and perforation has not occurred.4,21 It has been advocated to add 10% calcium gluconate to the lavage fluid to help bind fluoride present in the GI tract.4,13 Lavage with 20 mL of calcium chloride in 1000 mL of normal saline has been initiated after ingestion of 10% HF.8 Chan and Duggin8 contend that it does not matter which form of calcium is used for lavage so long as enough calcium is provided to bind available fluoride. In a rare case of a self-administered concentrated HF enema, calcium carbonate enemas were given to bind intraluminal fluoride ion.49 A gastroenterology/surgery consultation and examination are highly advisable for all patients with significant or symptomatic oral exposure to HF.

Systemic Toxicity: Flouride-induced Electrolyte and Cardiac Abnormalities Systemic toxicity should be anticipated with any ingestion or inhalation of HF and with any dermal exposure involving a large surface area or a high concentration of HF. Continuous cardiac monitoring, hourly electrolyte values, and frequent ABG determinations are essential during the acute phase of systemic toxicity. IV access is essential for the supplementation of depleted electrolytes and sodium bicarbonate.

1332


HYPOCALCEMIA Hypocalcemia has been associated with a prolonged QTc interval and ventricular fibrillation. In adults, a slow IV, prophylactic infusion of 20 mL of 10% calcium gluconate is recommended when systemic toxicity is anticipated.85 Continuous cardiac monitoring is indicated, since too rapid calcium administration may induce cardiac arrhythmias, most notably bradycardia. Prior to calcium administration, a serum calcium level should be drawn but the initial prophylactic infusion should not be delayed pending results. Calcium should be infused until the level reaches the upper limit of normal in an effort to prevent ventricular fibrillation related to hypocalcemia in myocardial tissue.20,21,24 Some clinicians propose the substitution of chloride salt for calcium gluconate, since it provides increased amounts of calcium ion. Calcium chloride however, has a potential for irritation and is best delivered by a central line. In addition, calcium chloride is acidifying and so should not be used when acidosis coincides with hypocalcemia. It is important to note that attempts to increase extracellular calcium through supplementation may exacerbate potassium efflux, so treatment of hypocalcemia may confound hyperkalemia in the setting of systemic fluorosis.23 HYPERKALEMIA Hyperkalemia may precipitate the development of peaked T waves and cardiac arrhythmias. Aggressive measures such as hemodialysis may be required to achieve normalization of potassium levels.23,35 Although there are recent reports of the use of cation exchange resins (e.g., Kayexalate) for hyperkalemia,112 no one has reported such use to treat the hyperkalemia of HF exposure. Considering the time delay in rise of extracellular potassium, this may be an intervention to consider in advance of the anticipated hyperkalemia seen in significant HF exposures. HYPOMAGNESEMIA Hypomagnesemia is associated with QT prolongation and ventricular arrhythmias. Correction of hypomagnesemia is achieved with IV magnesium sulfate. ACIDOSIS Sodium bicarbonate may be used to correct acidosis. Inducing a slight metabolic alkalosis with sodium bicarbonate is indicated to enhance the excretion of fluoride ions in the urine.31 ALTERNATE FORMS OF FLUORIDE AND RELATED TOXICITY With exposures to oral forms of fluoride including toothpastes, oral rinses, dentifrices, and oral supplements, it is important to establish the type and the amount of the fluoride salt present in the product as well as the amount ingested. Table 90-1 gives a partial listing of fluoride salts and the amount of elemental fluoride in each. When ingested amounts of elemental fluoride exceed 5 to 8 mg/kg,58 provision of calcium in the form of milk

TABLE 90-1 Elemental Fluoride Amounts in Common Fluoride Salts SALTS OR PRODUCT

ELEMENTAL FLUORIDE

Sodium fluoride (NaF), 2.2 mg Stannous fluoride (SnF2), 4.1 mg Sodium monofluorophosphate (MFP) 7.6 mg Fluoride toothpaste

1 mg 1 mg 1 mg

Oral nutritional supplements

Maximum of 1 mg per gram of toothpaste The maximum allowable amount of elemental fluoride in a tube of toothpaste is 260 mg 0.25 to 1.0 mg per tablet or milliliter of product

and dairy products or calcium-containing antacid tablets will bind fluoride in the stomach. Fluoride salts dissociate in the acidic environment of the stomach to form HF acid, which causes GI irritation. When large amounts of fluoride salts are ingested, there is a risk of systemic fluoride toxicity, but this is rarely the case in accidental ingestion. REFERENCES 1. Blodgett DW, Suruda AJ, Crouch BI: Fatal unintentional occupational poisonings by hydrofluoric acid in the U.S. Am J Ind Med 2001;40:215–220. 2. Foster KN, Jones L, Caruso DM: Hydrofluoric acid burn resulting from ignition of gas from a compressed air duster. J Burn Care Rehabil 2003;24:234–237. 3. Klasner AE, Scalzo AJ, Blume CM, Johnson P: Ammonium bifluoride causes another pediatric death (letter). Ann Emerg Med 1998;31:525. 4. Caravati EM: Acute hydrofluoric acid exposure. Am J Emerg Med 1988;6:143–150. 5. Agency for Toxic Substance and Disease Registry: Toxicologic Profiles for Fluorides. U.S. Department of Health and Human Services, 2002. 6. Mayer L, Guelich J: Hydrogen fluoride inhalation and burns. Arch Environ Health 1963;7:445–447. 7. MacKinnon MA: Hydrofluoric acid burns. Dermatol Clin 1988;6:67–74. 8. Chan BSH, Duggin GG: Survival after a massive hydrofluoric acid ingestion. J Toxicol Clin Toxicol 1997;35:307–309. 9. Gutknecht J, Walter A: Hydrofluoric and nitric acid transport through lipid bilayer membranes. Biochem Biophys Acta 1981;644:153–156. 10. Mayer TG, Gross PL: Fatal systemic fluorosis due to hydrofluoric acid burns. Ann Emerg Med 1985;14:149–153. 11. Greco RJ, Hartford CE, Haith LR Jr, Patton ML: Hydrofluoric acid–induced hypocalcemia. J Trauma 1988;28:1593–1596. 12. Mullet T, Zoeller T, Bingham H, et al: Fatal hydrofluoric acid cutaneous exposure with refractory ventricular fibrillation. J Burn Care Rehabil 1987;8:216–219. 13. Klasner AE, Scalzo AJ, Blume CM, et al: Marked hypocalcemia and ventricular fibrillation in two pediatric patients exposed to a fluoride-containing wheel cleaner. Ann Emerg Med 1996;28: 713–718. 14. Lynch RE: Ionized calcium: pediatric perspective. Pediatr Clin North Am 1990;37:373–389. 15. Jankowski S, Vincent SL: Calcium administration for cardiovascular support in critically ill patients: when is it indicated? J Intensive Care Med 1995;10:91–100.

CHAPTER 90

16. Riggs JE: Neurologic manifestations of fluid and electrolyte disturbances. Neurol Clin 1989;7:509–523. 17. Dowbak G, Rose K, Rohrich RJ: A biochemical and histologic rationale for the treatment of hydrofluoric acid burns with calcium gluconate. J Burn Care Rehabil 1994;15:323–327. 18. Yu-Jang S, Li-Hua L, Wai-Mau C, Kuo-Song C: Survival after a massive hydrofluoric acid ingestion with ECG changes (letter). Am J Emerg Med 2001;19:458–460. 19. Yamaura K, Kao B, Iimori E, et al: Recurrent ventricular tachyarrhythmias associated with QT prolongation following hydrofluoric acid burns. J Toxicol Clin Toxicol 1997;35:311–313. 20. Bordelon BM, Saffle JR, Morris SE: Systemic fluoride toxicity in a child with hydrofluoric acid burns: case report. J Trauma 1993;34: 437–443,. 21. Upfal M, Doyle C: Medical management of hydrofluoric acid exposure. J Occup Med 1990;32:726–731. 22. Manoguerra AS, Neuman TS: Fatal poisoning from acute hydrofluoric acid ingestion. Am J Emerg Med 1986,4:362–363. 23. McIvor ME, Cummings CE, Mower MM, et al: Sudden cardiac death from acute fluoride intoxication: the role of potassium. Ann Emerg Med 1987;16:77–81. 24. Kirkpatrick JJR, Enion DS, Burd DAR: Hydrofluoric acid burns: a review. Burns 1995;21:483–493. 25. Lund K, Ekstrand J, Boe J, et al: Exposure to hydrogen fluoride: an experimental study in humans of concentrations of fluoride in plasma, symptoms, and lung function. Occup Environ Med 1997;54:32–37. 26. McIvor ME: Acute fluoride toxicity: pathophysiology and management. Drug Saf 1990;5:79–85. 27. Su M, Chu J, Howland MA, et al: Amiodarone attenuates fluorideinduced hyperkalemia in vitro. Acad Emerg Med 2003;10: 105–109. 28. Danowski TS: The transfer of potassium across the human red blood cell membrane. J Biol Chem 1941;139:693–705. 29. Cummings CC, McIvor ME: Fluoride-induced hyperkalemia: the role of Ca2+-dependent K+ channels. Am J Emerg Med 1988;6:1–3. 30. Cooper DJ, Walley KR, Wiggs BR, Russell JA: Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis: a prospective, controlled clinical trial. Ann Intern Med 1990;112:492–498. 31. Bertolini JC: Hydrofluoric acid: a review of toxicity. J Emerg Med 1992;10:163–168. 32. Bracken WM, Cuppage F, McLaury RL, et al: Comparative effectiveness of topical treatments for hydrofluoric acid burns. J Occup Med 1985;27:733–739. 33. Gofa A, Davidson RM: NaF potentiates a K(+)-selective ion channel in G292 osteoblastic cells. J Membr Biol 1996;149:211–219. 34. Kao W, Dart RC, Kuffner E, Bogdan G: Ingestion of lowconcentration hydrofluoric acid: an insidious and potentially fatal poisoning. Ann Emerg Med 1999;34:35–41. 35. Stremski ES, Grande GA, Ling LJ: Survival following hydrofluoric acid ingestion. Ann Emerg Med 1992;21:1396–1399. 36. Nygren A, Giles WR: Mathematical simulation of slowing of cardiac conduction velocity by elevated extracellular. Ann Biomed Eng 2000;28:951–957. 37. Bradberry SM, Vale JA: Disturbances of potassium homeostasis in poisoning. J Toxicol Clin Toxicol 1995;33:295–310. 38. Seneviratne KN, Peiris OA, Weerasuriya A: Effects of hyperkalaemia on the excitability of peripheral nerve. J Neurol Neurosurg Psychiatry 1972;35:149–155. 39. Rasband MN, Park EW, Vanderah TW, et al: Distinct potassium channels on pain-sensing neurons. Proc Natl Acad Sci U S A 2001;98:13373–13378. 40. Steen KH, Reeh PW, Anton F, Handwerker HO: Protons selectively induce lasting excitation and sensitization to mechanical stimulation of nociceptors in rat skin, in vitro. J Neurosci 1992;12:86–95. 41. Onuoha GN, Alpar EK: Levels of vasodilators (SP, CGRP) and vasoconstrictor (NPY) peptides in early human burns. Eur J Clin Invest 2001;31:253–257. 42. Hoogerwerf WA, Zou L, Shenoy M, et al: The proteinase-activated receptor 2 is involved in nociception. Neuroscience 2001;21: 9036–9042.


1333

43. Wu A, Fujikawa DG: Effects of AMPA-receptor and voltagesensitive sodium channel blockade on high potassium-induced glutamate release and neuronal death in vivo. Brain Res 2002;946:119–129. 44. Katayama Y, Becker DP, Tamura T, Hovda DA: Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury. J Neurosurg 1990;73:889–900. 45. Carlton SM, Zhou S, Coggeshall RE: Evidence for the interaction of glutamate and NK1 receptors in the periphery. Brain Res 1998;790:160–169. 46. Carlton SM: Peripheral excitatory amino acids. Curr Opin Pharmacol 2001;1:52–56. 47. Messlinger K: What is a nociceptor? Anaesthesist 1997;46:142–153. 48. Gallerani M, Bettoli V, Peron L, Manfredini R: Systemic and topical effects of intradermal hydrofluoric acid. Am J Emerg Med 1998;16:521–522. 49. Cappell MS, Simon T: Fulminant acute colitis following a selfadministered hydrofluoric acid enema. Am J Gastroenterol 1993;88:122–126. 50. Perry HE: Pediatric poisonings from household products: hydrofluoric acid and methacrylic acid. Curr Opin Pediatr 2001;13:157–161. 51. Kunkel DB: Hydrofluoric acid: a toxin on the rise. Emerg Med 1988(Feb 15):237–242. 52. Mullins ME, Warden CR, Barnum DW: Pediatric death and fluoride-containing wheel cleaner (letter). Ann Emerg Med 1998;31:524–525. 53. Mallatt ME, Smith CE: Acute fluoride ingestion: recognition and management. J Indiana Dent Assoc 1996;75:23–24, 26. 54. Monsour PA, Kruger BJ, Petrie AF, McNee JL: Acute fluoride poisoning after ingestion of sodium fluoride tablets. Med J Aust 1984;141:503-–505. 55. Shulman JD, Wells LM: Acute fluoride toxicity from ingesting home-use dental products in children, birth to 6 years of age. J Public Health Dent 1997;57:150–158. 56. Spoerke DG, Bennett DL, Gullekson DJ: Toxicity related to acute low dose sodium fluoride ingestions. J Fam Pract 1980;10:139–140. 57. Whitford GM: Fluoride in dental products: safety considerations. J Dent Res 1987;66:1056–1060. 58. Augenstein WL, Spoerke DG, Kulig KW, et al: Fluoride ingestion in children: a review of 87 cases. Pediatrics 1991;88:907–912. 59. Fisher K, Picciotti M, Henretig F, et al: Fluoride (Fl) toxicity from a topical dental care product (TDCP) (abstract). Vet Human Toxicol 1991;33:365. 60. Eichler HG, Lenz K, Fuhrmann M, Hruby K: Accidental ingestion of NaF tablets by children: report of a poison control center and one case. Int J Clin Pharmacol Ther Toxicol 1982;20:334–338. 61. Sjostrom S, Kalfas S: Tissue necrosis after subgingival irrigation with fluoride solution. J Clin Periodontol 1999;26:257–260. 62. AAP Committee on Nutrition: Fluoride supplementation. Pediatrics 1986;77:758–761. 63. Dale RH: Treatment of hydrofluoric acid burns. BMJ 1952;1:728–732. 64. Browne TD: The treatment of hydrofluoric acid burns. J Soc Occup Med 1974;24:80–89. 65. Edelman P: Hydrofluoric acid burns. Occup Med 1986;1:89–103. 66. Anderson WJ, Anderson JR: Hydrofluoric acid burns of the hand: mechanism of injury and treatment. J Hand Surg [Am] 1988; 13:52–57. 67. Bosse GM, Matyunas NJ: Delayed toxidromes. J Emerg Med 1999;17:679–690. 68. Tepperman PB: Fatality due to acute systemic fluoride poisoning following a hydrofluoric acid skin burn. J Occup Med 1980;22: 691–692. 69. Gubbay AD, Fitzpatrick RI: Dermal hydrofluoric acid burns resulting in death. Aust N Z J Surg 1997;67:304–306. 70. Muriale L, Lee E, Genovese J, Trend S: Fatality due to acute fluoride poisoning following dermal contact with hydrofluoric acid in a palynology laboratory. Ann Occup Hyg 1996;40:705–710. 71. Rao RB, Hoffman, RS: Caustics and batteries. In Goldfrank’s Toxicologic Emergencies, 7th ed. New York, McGraw-Hill, 2002, Chapter 87. 72. Matsuno K: The treatment of hydrofluoric acid burns. Occup Med 1996;46:313–317. 73. Mangion SM, Buelke SH, Braitberg G: Hydrofluoric acid burn from a household rust remover. Med J Aust 2001;175:270–271.

1334


74. Asvesti C, Guadagni F, Anastasiadis G, et al: Hydrofluoric acid burns. Cutis 1997;59:306–308. 75. Roberts JR, Merigian KS: Acute hydrofluoric acid exposure (letter). Am J Emerg Med 1989;7:125–126. 76. El Saadi MS, Hall AH, Hall PK, et al: Hydrofluoric acid dermal exposure. Vet Hum Toxicol 1989;31:243–247. 77. Vance MV, Curry SC, Kunkel DB, et al: Digital hydrofluoric acid burns: treatment with intra-arterial calcium infusion. Ann Emerg Med 1986;15:890–896. 78. Dibbell DG, Iverson RE, Jones W, et al: Hydrofluoric acid burns of the hand. J Bone Joint Surg [Am] 1970;52:931–936. 79. Kono K, Yoshida Y, Watanabe M, et al: Urine, serum and hair monitoring of hydrofluoric acid workers. Int Arch Occup Environ Health 1993;65(1 Suppl):S95–S98. 80. Horton DK, Berkowitz Z, Kaye WE: Secondary contamination of ED personnel from hazardous materials events, 1995–2001. Am J Emerg Med 2003;21:199–204. 81. McCulley JP, Whiting DW, Petitt MG, Lauber SE: Hydrofluoric acid burns of the eye. J Occup Med 1983;25:447–450. 82. Rubinfeld RS, Silbert DI, Arentsen JJ, Laibson PR: Ocular hydrofluoric acid burns. Am J Ophthalmol 1992;114:420–423. 83. Rose L: Further evaluation of hydrofluoric acid burns of the eye. J Occup Med 1984;26:483–486. 84. Bentur Y, Tannenbaum S, Yaffe Y, Halpert M: The role of calcium gluconate in the treatment of hydrofluoric acid eye burn. Ann Emerg Med 1993;22:1488–1490. 85. Trevino MA, Herrmann GH, Sprout WL: Treatment of severe hydrofluoric acid exposure. J Occup Med 1983;25:861–863. 86. Hatai JK, Weber JN, Doizaki K: Hydrofluoric acid burns of the eye: report of possible delayed toxicity. J Toxicol Cutaneous Ocul Toxicol 1986;5:179–184. 87. Meldrum M: Toxicology of hydrogen fluoride in relation to major accident hazards. Regul Toxicol Pharmacol 1999;30:110–116. 88. Dalbey W, Dunn B, Bannister R, et al: Acute effects of 10-minute exposure to hydrogen fluoride in rats and derivation of a shortterm limit for humans. Regul Toxicol Pharmacol 1998;27:207–216. 89. Radon K, Nowak D, Heinrich-Ramm R, Swzadkowski D: Respiratory health and fluoride exposure in different parts of the modern primary aluminum industry. Int Arch Occup Environ Health 1999;72:297–303. 90. Healy J, Bradley SD, Northage C, Scobbie E: Inhalation exposure in secondary aluminum smelting. Ann Occup Hyg 2001;45:217–225. 91. Braun J, Stob H, Zober A: Intoxication following the inhalation of hydrogen fluoride. Arch Toxicol 1984;56:50–54. 92. Kono K, Watanabe T, Dote T, et al: Successful treatments of lung injury and skin burn due to hydrofluoric acid exposure. Int Arch Occup Environ Health 2000;73(Suppl):S93–S97. 93. Franzblau A, Sahakian N: Asthma following household exposure to hydrofluoric acid. Am J Ind Med 2003;44:321–324.

94. Bennion JR, Franzblau A: Chemical pneumonitis following household exposure to hydrofluoric acid. Am J Ind Med 1997; 31:474–478. 95. Chick LR, Borah G: Calcium carbonate gel therapy for hydrofluoric acid burns of the hand. Plast Reconstr Surg 1990;86:935–940. 96. Zachary LS, Reus W, Gottlieb J, et al: Treatment of experimental hydrofluoric acid burns. J Burn Care Rehabil 1986;7:35–39. 97. Iverson RE, Laub DR, Madison MS: Hydrofluoric acid burns. Plast Reconstr Surg 1971;48:107–112. 98. Freehagen K, Wellman M: Atzwirkungen des Fluorwasserstoffs und Gegenmittel. Angew Chem 1932;45:537–538. 99. Jones AT: The treatment of hydrofluoric acid burns. J Ind Hyg Toxicol.1939;21:205–212. 100. Blunt CP: Treatment of hydrofluoric acid skin burns by injection with calcium gluconate. Ind Med Surg 1964;33:869–871. 101. Carney SA, Hall M, Lawrence JC, Ricketts CR: Rationale of the treatment of hydrofluoric acid burns. Br J Ind Med 1974;31: 317–321. 102. Velvart J: Arterial perfusion for hydrofluoric acid burns. Hum Toxicol 1983;2:233–238. 103. Henry JA, Hla KK: Intravenous regional calcium gluconate perfusion for hydrofluoric acid burns. J Toxicol Clin Toxicol 1992;30:203–207. 104. Wilkes GJ: Intravenous calcium gluconate for hydrofluoric acid burns of the digits. Emerg Med 1983;5:155–158. 105. Siegel DC, Heard JM: Intra-arterial calcium infusion for hydrofluoric acid burns. Aviat Space Environ Med 1992;63:206–211. 106. Graudins A, Burns MJ, Aaron CK: Regional intravenous infusion of calcium gluconate for hydrofluoric acid burns of the upper extremity. Ann Emerg Med 1997;30:604–607. 107. Ryan JM, McCarthy GM, Plunkett PK: Regional intravenous calcium—an effective method of treating hydrofluoric acid burns to limb peripheries. J Accid Emerg Med 1997;14:401–404. 108. Ryan JM, McCarthy GM, Plunkett PK: Regional intravenous infusion of calcium for hydrofluoric acid burns of the upper extremity (letter). Ann Emerg Med 1998;31:526. 109. Achinger R, Kohnlein HE, Jacobitz K: A new treatment method of hydrofluoric acid burns of the extremities. Chir Forum Exp Klin Forsch 1979;229–231. 110. Lin TM, Tsai CC, Lin SD, Lai CS: Continuous intra-arterial infusion therapy in hydrofluoric acid burns. J Occup Environ Med 2000;42:892–897. 111. Vaughn D, Asbury T: General Ophthalmology. Los Altos, CA, Lange, 1983, p 39. 112. Kim HJ, Han SW: Therapeutic approach to hyperkalemia. Nephron 2002;92(Suppl 1):33–40.

91

Hydrogen Sulfide TEE L. GUIDOTTI, MD, MPH

At a Glance… ■

■

■

■

■ ■ ■

Severe acute hydrogen sulfide poisoning can be seen in a variety of settings but is most commonly observed in the oil and gas industry. High concentrations of hydrogen sulfide may cause “knockdown,” a sudden loss of consciousness, which may be accompanied by apnea. Unprotected rescuers are at high risk of death. Self-contained breathing apparatus should always be worn during rescue attempts. In addition to altered consciousness, hydrogen sulfide sometimes causes pulmonary edema and keratoconjunctivitis (“gas eye”). Laboratory studies are rarely available for confirmation; therefore, the diagnosis is based on history and clinical grounds. Supportive care, with attention to the airway, is critical. Sodium nitrite, a component of the Taylor cyanide kit, is a useful antidote for hydrogen sulfide but only if given promptly. Hyperbaric oxygen may also be effective in severe cases.

Hydrogen sulfide (H2S) has been recognized as an occupational hazard since the time of Ramazzini in the 18th century. H2S is among the most common causes of fatal gas inhalation exposures in the workplace and is mostly a problem today in the oil and gas industry, in swine confinement facilities, and in manure collection systems. H2S is generated in municipal sewers and sewage treatment plants, pulp and paper operations (in Kraft and especially sulfite mill technologies), construction zones in wetlands (such as marshes), asphalt roofing, and pelt processing (in which soaking in sulfide solution loosens hair for removal), and may be a hazard in confined spaces in which organic material, such as fish or offal, has decayed or in which inorganic sulfides may be reduced.1-6 H2S may be both an occupational and a potential community environmental health risk in areas with geothermal activity and hot springs, such as Rotorua, New Zealand.7 H2S is the principal hazard in the “sour gas industry,” that part of the natural gas industry extracting sulfurcontaining natural gas. Organic sulfur is reduced to hydrogen sulfide during the prolonged degradation process of organic material underground that forms natural gas and petroleum. Sour gas is distributed in oil and gas fields worldwide but is concentrated in western Canada, Texas and the Gulf Coast, Michigan, the Middle East (including Saudi Arabia and Abu Dhabi), central Asia (including Kazakhstan, Iran, and Pakistan), and Russia. Most sour gas falls between 2% and 35% H2S, but some wells in the Canadian province of Alberta exceed 98%.8-12

MECHANISM OF ACTION The primary toxicity of H2S is conventionally assumed to result from inhibition of cytochrome-c oxidase and possibly other heme-containing macromolecules by aqueous sulfide.13,14 H2S is classified as a cellular asphyxiant, together with carbon monoxide, cyanide, and azide. H2S interacts with a number of enzymes and other macromolecules, including hemoglobin and myoglobin. The effect of H2S in disrupting cytochrome-c oxidase activity is the same as oxygen deprivation or asphyxiation except that it may act more quickly. This is thought to be the primary mechanism of action of the characteristic reversible neurotoxicity associated with H2S, the sudden loss of consciousness called “knockdown.”6 The mechanism of action of H2S is often attributed to inhibition of cytochrome-c oxidase and therefore to a mechanism identical to that of cyanide.15 However, there are clearly other mechanisms.16 One lethal end point of H2S exposure is respiratory paralysis, a dose-dependent reduction in ventilatory drive resulting in apnea, which follows an initial hyperpnea.17 Infusion of the sulfide ion alone into the circulation mimics the systemic effects of H2S inhalation. The apneic response to H2S is not enhanced by intra-arterial injection of sulfide into the carotid artery, which delivers blood directly to the brain, compared with intravenous injection into the femoral artery, in which mixing occurs in the general circulation. The apneic response can also be blocked by paralysis of the vagal nerve by lidocaine or by infusion of sodium bicarbonate solution, in the absence of acidosis. These findings strongly suggest that a peripheral receptor in the lung is responsible for the apneic response.18 Hydrogen sulfide may also be a neuromodulator, and so toxic exposure may involve direct functional effects as well as cell toxicity.16,19,20 Pulmonary edema and mucosal irritation, particular of the eye, are nonspecific irritant effects of hydrogen sulfide, reflecting its chemical reactivity.21

TOXICOKINETICS H2S is poorly soluble in water. Exposure occurs exclusively by the inhalation route, and to date all described toxicity incidents have involved exposure in the gaseous phase. H2S is inhaled and enters the circulation directly across the alveolar-capillary barrier. Once absorbed, H2S dissociates in part into hydrosulfide ion, HS−, then is spontaneously transformed into sulfide [S2-] and then sulfate [SO42-]. Some H2S remains as free H2S in blood, and this fraction appears to interact with metalloproteins, disulfide-containing proteins, and thio-S-methyl1335

1336


transferase, forming methyl sulfides. The sulfide ion binds to heme compounds and is itself metabolized by oxidation to sulfate. Sulfate is then excreted by the kidney or lost in intermediary metabolism. Little is known of the toxicokinetics of H2S and sulfide.22

CLINICAL PRESENTATION

TABLE 91-1 Health Effects of Hydrogen Sulfide at Various Exposure Levels CONCENTRATION (ppm) 0.01–0.3 1–5

Pathophysiology It has been known for many years that H2S has potent neurotoxic properties. Respiratory paralysis may occur if exposure is prolonged, presumably as a direct consequence of sulfide toxicity inhibiting brainstem respiratory nuclei. However, the studies cited on apnea,16,18 supported by studies suggesting a chemoreceptor response,20 suggest that there are other pathways that affect central activity. Animal studies of the toxicity of H2S are often difficult to interpret. Exposure to H2S is known to increase levels of taurine in cerebrospinal fluid, for example, but it is not clear whether this is a toxic effect or a protective effect because taurine may act on neurons to reduce the neurotoxicity of some agents.23 Likewise, H2S is known to increase serum glucose levels in postpartum rats, but an aggravating effect on diabetes has not been suggested in the literature on human toxicity.24 Chronic low-level exposure to H2S is associated with abnormal proliferation and ramification of Purkinje cells in the cerebellum of rats, but there is no comparable human exposure outcome with which to compare these observations.24 In healthy, fit human volunteers, exposure to H2S as low as 5 ppm during exercise (30 minutes) is associated with an early shift from aerobic to anaerobic metabolism, as indicated by increasing blood lactate levels, but without symptoms.25 This observation precipitated a review of occupational exposure levels in the United Kingdom.26 In the past, there was a controversy over whether sulfhemoglobin occurs after high-level H2S exposure, but the weight of evidence is that it does not.14

Manifestations ACUTE TOXICITY Acute central neurotoxicity, pulmonary edema, and the mucosal effects are the characteristic features of acute toxicity of H2S. Odor perception, olfactory paralysis, and keratoconjunctivitis are the characteristic effects of H2S at lower concentrations.3,5,6,9,11,21 In addition to the effect of olfactory paralysis, which is an effect at higher exposure levels (>100 ppm), olfactory fatigue occurs at lower, ambient levels, so that the person exposed may not be as aware of the odor because of habituation, even though there is no toxic effect on olfaction. See Table 91-1 for health effects of hydrogen sulfide at various exposure levels. H2S-induced acute central toxicity leading to reversible unconsciousness is sudden and is colloquially called a “knockdown.”6 Knockdowns can be acutely fatal as a consequence of respiratory paralysis and cellular anoxia. Very high concentrations (500–1000 ppm) are associated with a knockdown. This is an abrupt loss of

10 15 20 20–50

100 150–200 250–500 500

1000

EFFECTS Odor threshold (highly variable) Moderate offensive odor, may be associated with nausea, tearing of the eyes, headaches, or loss of sleep with prolonged exposure; healthy young male subjects experience no decline in maximal physical work capacity. 8-hour occupational exposure limit in Alberta, OSHA PEL 15-minute occupational exposure limit in Alberta Ceiling occupational exposure limit evacuation level in Alberta; odor very strong Keratoconjunctivitis (eye irritation) and lung irritation. Possible eye damage after several days of exposure; may cause digestive upset and loss of appetite Eye and lung irritation; olfactory paralysis, odor disappears Sense of smell paralyzed; severe eye and lung irritation Pulmonary edema may occur, especially if prolonged Serious damage to eyes within 30 minutes; severe lung irritation; unconsciousness and death within 4 to 8 hours; amnesia for period of exposure; knockdown Breathing may stop within one or two breaths; immediate collapse

OSHA, Occupational Safety and Health Administration; PEL, permissible exposure limit. From Guidotti TL: Hydrogen sulfide. Occup Med 1996;46(5):367–371.

consciousness and collapse, described by those who witness it as appearing much like turning off the switch on a mechanical doll. A knockdown may be fatal if exposure is prolonged. If exposure is transient, as usually happens in the oil patch, recovery may be equally rapid and apparently complete.9,27 Some veteran oilfield workers have returned to what they were doing without reporting the event and without treatment, considering the experience all in a day’s work. Central effects observed after a knockdown might represent primary toxicity of H2S, secondary effects from low-level cellular anoxia, or the sequelae of acute brain injury. The long-term central effects of a knockdown in any given case may represent an episode of toxic anoxia, or even a secondary traumatic injury. In at least one case, focal cortical necrosis was documented following a knockdown in which the patient never recovered consciousness. H2S is irritating to mucous membranes, although this feature of H2S exposure may have been overly emphasized in the literature.26 H2S penetrates deeply into the respiratory tract because its solubility is relatively low, rendering it capable of causing alveolar injury leading to acute pulmonary edema.

CHAPTER 91

The irritant effect is also seen in the upper airway; experimental studies suggest that the olfactory mucosa do not recover as fast as the bronchial epithelium. Recently, this pattern of toxicity was demonstrated to be attributable to selective toxicity of olfactory mucosa in the nasal passages.28 Human subjects exposed to transient high levels of H2S have been reported to show deficits on standardized tests of smell and taste years later, suggesting that the effect may be a permanent sequela under some circumstances.29 Pulmonary edema is also a well-recognized acute effect of H2S toxicity, especially when exposure is prolonged. Older studies suggest that 20% of cases of H2S toxicity reaching the emergency department showed evidence of pulmonary edema.9 Experimental studies have shown that although H2S at high concentrations produces a marked alveolitis and profuse edema, it is only moderately cytotoxic for pulmonary cells and does not seem to disrupt the basement membrane of the alveolar endothelium. Thus, the ultimate prognosis for recovery and remodeling may be good if the patient can be supported through the acute episode.9,30,31 Acute inhalation of H2S may be fatal, depending on the concentration and duration of exposure and the duration of anoxia. In one series of 152 cases from China, an overall mortality rate of 5% was reported.30,32 It is not clear whether hydrogen sulfide exposure is associated with chronic respiratory sequelae. Exposure in the short term does not appear to be associated with reduced lung function or increased airways reactivity.33,34 However, other studies have suggested that a reduction in residual volume is a subclinical effect.35 Crosssectional studies of sewer workers, who are exposed to hydrogen sulfide, suggest that after accounting for smoking, lung function is significantly reduced and may show an accelerated rate of decline among age groups.31 A single case report has suggested interstitial fibrosis, but this has not been observed in other studies or case series.36 Prolonged anoxia, which might be due in these incidents to respiratory paralysis, pulmonary edema, or asphyxia in a confined space, results in a severe metabolic acidosis that further complicates resuscitation. Overwhelming exposure may be associated at autopsy with skin and organ discoloration, pulmonary edema, and renal tubular necrosis.5,6 Most standards for the protection of occupational and community populations are based on prevention of keratoconjunctivitis (eye irritation) and respiratory tract irritation. The slope of the exposure–response relationships for these conditions is not as steep as it is for central nervous system effects.37 “Gas eye,” or keratoconjunctivitis, is a superficial inflammation of the cornea and conjunctiva that is often recurrent in workers in sour gas plant who are exposed for prolonged periods to relatively low concentrations. A peculiar feature of this effect is that it can be associated with reversible chromatic distortion and visual changes. It has been suggested that the corneal epithelium develops a fine punctate stain and becomes edematous, and that small vesicles form that act as a diffraction grating. This results in a colored halo surrounding the object. This effect is sometimes accompanied by blepharo-

Hydrogen Sulfide

1337

spasm, tearing, and photophobia. In the viscous rayon industry, this problem is encountered with carbon disulfide exposure.5,21,37 There are few data on teratogenicity, mutagenicity, or carcinogenicity for H2S, largely because it is so toxic. In animal studies, H2S appeared unlikely to cause reproductive toxicity after exposures that are plausible in occupational and workplace situations.38,39 Exposure to 75 ppm is reported to prolong delivery time of gravid rat dams at the time of parturition, and rat pups exposed at the same level in utero or neonatally showed only minor delays in ear and hair development.38 Exposure to lower levels, although still toxic in human context, has been shown to elevate circulating glucose in maternal rats, with secondary metabolic effects in the offspring.24 H2S appears to enhance the mutagenicity of peroxide but is not genotoxic alone.40 Evidence for cancer in human populations is weak. Studies of residents of Rotorua, which is a largely Maori community and cultural center, have observed an excess of cancers of the sinus overall (which may be confounded by wood dust exposure in Rotorua’s extensive native craft industry) and of lung cancer in Maori women, which was not completely explained by higher smoking rates but which was accompanied by a statistically significant deficit among Maori men.41

Laboratory Features The management of H2S toxicity does not depend on laboratory confirmation or monitoring sulfide levels.42-50 Sulfide measurements can be made on postmortem brain tissue, but this is currently a research tool that has not been validated for forensic use in humans.51 Blood sulfide levels are not diagnostic of H2S toxicity, must be performed within 2 hours of exposure, but are seldom available, are subject to many limitations, and are not available on an emergency basis.5 Urinary thiosulfate levels show promise as a biologic exposure indicator in the monitoring of occupational exposure but are profoundly influenced by diet and have not been validated for human toxicity.5 The partial pressure of oxygen in arterial blood may be normal in H2S toxicity, unless there is pulmonary edema or another reason for respiratory compromise. Metabolic acidosis and a low arteriovenous oxygen difference may indicate anoxia at the cellular level and may correlate with severity of toxicity, but this has not been documented. The chest film may show evidence of noncardiogenic pulmonary edema.5

TREATMENT Treatment of transient exposures, and of knockdowns in which the worker has regained consciousness, is not specific.52 Removal from exposure is critical, of course. Unlike cyanide intoxication, there is no evidence that H2S intoxication would confer a risk on the rescuer during mouth-to-mouth resuscitation.5 Patients should be observed for pulmonary edema overnight, and metabolic acidosis should be treated.13 Because workers may encounter H2S while performing

1338


hazardous tasks, incidental injuries may require treatment.53 Overwhelming exposures and prolonged knockdowns may require aggressive treatment, but the circumstances in which these exposures occur often lead to delays in transport and treatment. Combined treatment with hyperbaric oxygen and nitrite has emerged as the treatment of choice, but the literature remains anecdotal, reflecting experience acquired one case at a time.2,14,44,54-60 Increased oxygen tension may overcome some of the physiologic disadvantages of nitrite treatment. Empirically, nitrite treatment alone has been used successfully in managing acute cases, but its mechanism of action remains uncertain. Nitrite treatment is based on the observation that H2S resembles cyanide in that both bind reversibly to cytochromes, although there appear to be differences at a biochemical level.13 The theory is that methemoglobin generated by nitrite would displace the sulfide, as it does cyanide, and regenerate the active cytochrome oxidase.58 Although methemoglobin is more effective in binding sulfide than oxyhemoglobin, the complex between sulfide and methemoglobin does not last long enough to make much difference. The sulfide disappears quickly from the circulation under conditions of good oxygenation anyway. The evidence suggests that nitrite can only be effective within the first few minutes after exposure and may actually slow sulfide removal thereafter. There are also reasons to believe that the methemoglobin hypothesis is insufficient to explain the action of nitrite even in the first few minutes. A further practical problem with this approach is that it may add to the anoxic burden that already may exist from the cytochrome poisoning, respiratory paralysis due to central toxicity, and ventilation-perfusion mismatch associated with pulmonary edema. It may also induce hypotension and further complicate the anoxia with hypoperfusion. Administration of nitrites is usually begun with inhalation of amyl nitrite perles (for 30 seconds out of every minute) followed by sodium nitrite intravenously, in the same dosages as for cyanide poisoning. The literature suggests infusion of 300 mg of fluid containing 10 mL of 3% NaNO2 over 4 minutes, titrating the drop in blood pressure to maintain systolic pressure above 80 mm Hg (10.6 kPa).13,55-58 In children, the recommended intravenous treatment dose would be as for cyanide intoxication (see Chapter 88). Because of the potential for inducing hypotension in a child, however, such treatment should only be considered in cases in which the cause is indisputably hydrogen sulfide exposure and the patient is not already recovering. Because hydrogen sulfide is primarily an occupational exposure, occasional episodes of toxicity may occur in adolescents30 but would be extremely rare in children. Treatment with oxygen and supportive care alone has been recommended in order to avoid further complicating the toxic effects with iatrogenic anoxia and nitrite toxicity. However, confirmation that oxygen therapy alone works is limited to anecdotal reports and experimental studies with H2S-exposed mice did not show increased survival with oxygen alone.

Hyperbaric oxygen therapy is an attractive and logical option for treating H2S intoxication, and anecdotal evidence suggests that it may be effective.59 The utility of oxygen is probably related to the oxygenation of marginally anoxic tissues and the displacement of sulfide from binding sites on cytochrome-c oxidase, but this has not been worked out. By the nature of such poisoning incidents, it is difficult to perform clinical trials and to compare therapies. A series of three treatments at 2.5 atmospheres for 90 minutes each has been recommended.60 Given the low morbidity of hyperbaric oxygen treatment in skilled hands,61 it is a prudent intervention if facilities are available.62,63 Outcomes are not guaranteed, and neurologic sequelae may still occur following treatment.46 Decontamination is not required for the protection of health providers and bystanders. However, the foul odor of hydrogen sulfide may complicate management and cause anxiety among other patients. Removal of clothing and simple skin washing with soap and water should remove the odor from the patient. Airing outdoors should greatly reduce the odor from clothing. Many antidotes to H2S intoxication have been proposed, but few have shown efficacy. Ascorbate has been proposed to reverse methemoglobinemia, but because this is not the problem in sulfide toxicity, this intervention, although benign, is unlikely to be useful.63 Sodium thiosulfate has been proposed as a treatment for H2S intoxication on analogy to its role in cyanide toxicity, but its efficacy has not been demonstrated, and the rationale is in question. Sulfide is oxidized and excreted sufficiently rapidly by the body that clearance is not the problem. Thiosulfate is a metabolite of sulfide and not a substrate for enzymatic oxidation, which destroys the toxic moiety, in the case of cyanide intoxication.5,13 There is evidence that the respiratory paralysis observed in some fatal knockdowns is associated with monoamine oxidase inhibition.64 This inhibition is reversed by dithiothreitol (DTT), which also displaces sulfide from brain tissue in vitro after exposure in animals.65 DTT has also been found to be protective if given to animals as pretreatment before exposure. These observations have led to efforts to use this agent and other thiol compounds as specific antidotes. In practice, however, these approaches have been disappointing. Pretreatment with several agents is associated with increased survival in animals: pyruvate,66 α-ketocarboxylic acids,67 bicarbonate,18 and glucose (unpublished observation). To date, these pretreatments have not led to successful therapeutic or prophylactic interventions.

DISPOSITION Patients presenting to the emergency department after significant acute hydrogen sulfide exposure should be admitted or observed for several hours in most cases, owing to the substantial risk of development for pulmonary edema. The prognosis for recovery after exposure to hydrogen sulfide is an area of controversy. The evidence is strong for neurologic sequelae following knockdown, in the context of acute high exposure, but weak for effects associated with chronic, low-level exposure.

CHAPTER 91

Chronic Sequelae of Acute Exposure Chronic central nervous system effects after repeated or prolonged knockdowns have not been adequately studied. The available evidence strongly suggests that knockdowns are sometimes, if not usually, associated with chronic neurologic sequelae.4,32,37,42-46 However, case series describing these effects may be confounded by effects of head trauma during falls, anoxia from apnea, or seizure activity. Extrapyramidal symptoms resembling Parkinson’s diseases may appear during recovery from an H2S-induced coma.46-48 Experimental studies on mice do suggest a cumulative effect in reducing brain cytochrome-c oxidase activity. Experimental studies also help to localize the effects of H2S in the brain and appear to suggest anoxia as the mechanism. The available animal evidence points to injury to the cerebral cortex, cerebellum, and possibly brainstem and spinal cord at concentrations approaching those humans might encounter. The lesions are similar to those seen in oxygen deficiency and in poisoning by other cytochrome oxidase inhibitors.17,42,47

Chronic Effects of Lower-Level Exposure Although there is sufficient evidence to conclude that a chronic toxicity syndrome exists as a sequela of knockdown, the evidence to date is weak for the conclusion that a chronic toxicity syndrome exists as a result of longterm, low-level exposure. Ecological studies of residents of Rotorua suggest some excess morbidity in both the central and peripheral nervous systems, but the pattern is not consistent, being strongest for mononeuritis. There was an elevated risk for cardiovascular disease but a reduced frequency of stroke and evidence for an elevated prevalence of high blood pressure. Other potential confounders include mercury (which was not measured) and other sulfides (not reported).41 Kilburn and colleagues have published data48 suggesting neurobehavioral effects observed in populations exposed to low levels of H2S, including single exposures below 1.0 or 0.5 ppm. The subjects consisted primarily of litigants, involved in a lawsuit for compensation for damages arising out of their exposure. The studies describe a pattern of poor recall, delayed reaction time, unilateral (not bilateral) changes in visual performance, and abnormal balance (requiring special technology to detect). The group has described similarly nonspecific patterns for other potential hazards. In these studies to date, the effects of litigation, posttraumatic stress, anticipation of compensation, and test bias cannot easily be ruled out. Neurobehavioral testing is also easily confounded by effects of learning, practice, motivation, sleep, education, distraction, depressed mood, and stress. The wide range of “normal” performance on these tests renders them rather insensitive and nonspecific in identifying neurotoxic outcomes, limitations freely acknowledged in the neurobehavioral literature. This literature is therefore difficult to interpret. The Medical Diagnostic Review, a population-based prevalence survey and clinical screening conducted in

Hydrogen Sulfide

1339

southern Alberta in the mid-1980s, found no evidence of an excess in prevalence of neurologic signs and findings, both soft and hard, in populations living downwind of sour gas facilities.49 Animal studies show no evidence of behavioral change after exposures of less than 80 ppm, a concentration that is effectively much higher in rats than humans because upper airway clearance is less in the rat.50 Other properties of H2S have been difficult to assess because mucosal irritation and cellular anoxia dominate the clinical picture. Secondary effects may be overlooked in the more obvious acute toxicity profile of H2S. Respiratory, cardiac, eye, and host defense disorders emerge as the most likely secondary effects to be associated with H2S, but the evidence remains inconclusive.11,37

PREVENTION H2S is heavier than air. Workers entering a depression or confined space in which the gas has collected are likely to be at highest risk, although potentially lethal exposures can and do take place in the open air. Personal protection required is the self-contained breathing apparatus (SCBA).68 In the past, tympanic membrane defects (perforated eardrums) excluded workers from certification for SCBA gear, on the grounds that H2S could bypass the SCBA; this is not supported by the evidence and no longer recommended.69 H2S is very odorous, with a low olfactory threshold, from less than 0.01 to 0.3 ppm. By 1 to 5 ppm, the odor is very offensive, like rotten eggs. However, the gas has poor warning properties at high exposure levels. As with most strong odors, workers may become accustomed to them in the short term, a phenomenon known as olfactory fatigue. There is also a specific mechanism known as olfactory paralysis that results in loss of the ability to perceive the odor, owing to neurotoxicity affecting the olfactory bulb and fibers. In relatively high concentrations (about 100 ppm), H2S paralyzes the olfactory mechanism, preventing perception of any smell. This removes the primary warning sign of H2S exposure and the principal warning to, say, oilfield workers caught in a plume.5,6,14,27,69,70 As in most such incidents, casualties usually occur in twos or more, as would-be rescuers rush to save their coworkers and in their haste neglect to protect themselves with an SCBA. Intensive training and ready availability of personal protective equipment are required to prevent such situations.68 Although there have been no documented cases of serious, irreversible injury or death in the public attributed to Alberta’s sour gas industry, there have been a number of occupational fatalities arising from H2S exposure in Alberta.12 As a consequence, the oil and gas industry, the Alberta Government, and representatives of local residents and public agencies have developed an elaborate network of stakeholder organizations and public consultation mechanisms, which have been a model for other jurisdictions. Other locations where H2S is a prominent hazard include Texas, Louisiana, and Iran. When a well blowout releases substantial quantities of sour gas, the usual management strategy is to ignite the gas, so that combustion converts the H2S to less toxic

1340


sulfur dioxide, notwithstanding the recognized irritant effects of this agent. This protects the community and nearby workers and allows crews to get closer to cap or shut down the well. The OSHA Permissible Exposure Limit and the NIOSH Recommended Exposure Limit for H2S are both 10 ppm, 8-hour time-weighted average. OSHA also has a short-term standard of 15 ppm. Alberta has adopted the same set of standards as occupational exposure levels and in addition has a ceiling of 20 ppm and an evacuation standard for the general population of 5 ppm.6,71 Studies on normal volunteers during exercise suggest that 5 ppm of H2S is easily tolerated and results in minimal detectable physiologic change.25 In the absence of definitive studies of community residents or low-level exposure of workers, this is the best evidence available that current occupational exposure standards are probably adequate, bearing in mind that timeweighted averages are generally of less significance than peak exposures for this agent for neurotoxicity but may be more suitable for irritant effects.

The encroachment of communities on industrial sites and oil and gas fields that were once relatively isolated, together with economic incentives to site wells and facilities where deposits exist in urban locations, has resulted in many conflicts in land use and regulatory requirements for emergency planning to protect residents and create setbacks, or buffer zones, between gas facilities and populated areas. The Alberta Energy and Utilities Board and its predecessor agencies have been particularly proactive in emergency planning based on projected concentrations generated by computer models in the event of an uncontrolled release. Because of the nature of incidents involving H2S, emergency response usually involves high levels in uncontrolled situations requiring rescue. Table 91-2 summarizes acute exposure levels proposed for both emergency planning and response purposes. The exposure–response curve for lethality is extremely steep for hydrogen sulfide.6,72 Among inhaled toxic substances, H2S gives little margin of safety. One can visualize an encounter with concentrations of H2S

TABLE 91-2 Guidelines for Emergency Planning and Response GUIDELINE

CONCENTRATION (ppm)

Emergency response planning guidelines (ERPGs)

Note: Concentrations are modeled for planning purposes.

ERPG-1

0.1

ERPG-2

30

ERPG-3

100

Acute exposure guideline levels (AEGLs)

AEGL 1

AEGL 2

AEGL 3

Note: In actual uncontrolled incidents, it may not be possible to measure exposure.

10 min 30 min 60 min 4 hr 8 hr 10 min 30 min 60 min 4 hr 8 hr 10 min 30 min 60 min 4 hr 8 hr

0.75 0.60 0.51 0.36 0.33 41 32 27 20 17 76 59 50 37 31

INTERPRETATION Source: American Industrial Hygiene Association, 2004. ERPGs are intended to guide land use and resource planners and to determine appropriate emergency response contingencies for communities near facilities. They assume exposure of the general population, including more susceptible individuals. Exposure for up 1 hour without experiencing ”other than mild transient adverse health effects or perceiving a clearly defined objectionable odor.” Exposure for up to 1 hour without developing “irreversible or other serious health effects or symptoms that could impair an individual’s ability to take protective action.” Maximum airborne concentration “below which it is believed nearly all individuals could be exposed for up to one hour without experiencing or developing lifethreatening health effects.” Source: U.S. Environmental Protection Agency, Office of Pollution Prevention and Toxics, 2002. Intended to be guidelines in context of emergency response only: oncein-a-lifetime, short-term exposure to airborne chemicals that are acutely toxic. (Note: the significant figures in which AEGLs are given far exceed the accuracy of exposure assessment in most real uncontrolled incidents.) “Concentrations above which predicted that general population, including susceptible individuals, could experience notable discomfort, irritation or certain asymptomatic non-sensory effects that are not disabling and that are transient and reversible.” “Concentrations above which predicted that general population, including susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape.” “Concentrations above which predicted that general population, including susceptible individuals, could experience life-threatening health effects or death.”

CHAPTER 91

above 500 ppm as being much like hitting a wall, with the degree of damage having much more to do with concentration, analogous to the speed with which one hits the wall, than with the duration of contact with the wall. Concentration is much more important than duration of exposure. Fatal exposures to hydrogen sulfide in humans, for example, may in theory take place at 150 ppm for 6 hours (concentration-time product = 0.252) or 650 ppm for 8.5 minutes (0.005). This means that, for H2S, higher concentrations are much more toxic, even with proportionally shorter exposure levels. This also appears to be true for experimental pulmonary edema induced in the rat. Many current models for risk assessment use a concentration-time constant for lethality of the general form Cn × t, where n ranges from 1.43 to more than 4.36; the empirical evidence favors the higher exponents. Occupational exposure levels based on time-weighted averages do not take this into account.6,72 Sour gas, the accepted term in the oil patch for natural gas containing H2S, contains more than natural gas and hydrogen sulfide. The process stream contains variable amounts of methyl mercaptans (CH3SH, [CH3]2S, and [CH3]2S2), carbonyl sulfide (COS) and carbon disulfide (CS2), and some trace metals. Mercaptans are also added to natural gas as a safety measure to ensure detection of leaks. Production also involves exposure to a variety of production chemicals incidental to gas exposure.8,73 Flaring introduces numerous other products of incomplete combustion and has become a particularly controversial issue in Alberta in recent years. A major study of downwind exposure to emissions from gas facilities and effects on animals is under way, and findings are expected to be available in the near future. REFERENCES 1. Kangas J, Jäppinen P, Savoilainen H: Exposure to hydrogen sulphide, mercaptans and sulfphur dioxide in the pulp industry. Am Ind Hyg Assoc J 1984;45:787–790. 2. Hoidal CR, Hall AH, Robinson MD, et al: Hydrogen sulphide poisoning from toxic inhalations of roofing asphalt. Ann Emerg Med 1986;15:826–830. 3. Osbern LN, Crapo RO: Dung lung: a report of toxic exposure to liquid manure. Ann Intern Med 1981;95:312–314. 4. Parra O, Mon E, Gallego M, Morera J: Inhalation of hydrogen sulphide: a case of subacute manifestations and long term sequelae. Br J Indust Med 1991;48:286–287. 5. Milby HT, Baselt RC: Hydrogen sulfide poisoning: clarification of some controversial issues. Am J Indust Med 1999;35:192–195. 6. Guidotti TL: Hydrogen sulfide. Occup Med 1996;46(5):367–371. 7. Bates MN, Garrett N, Graham B, Read D: Air pollution and mortality in the Rotorua geothermal area. Aust N Z J Public Health 1997;21(6):581–586. 8. Hoffman H, Guidotti TL: Natural gas. In Greenberg MI, Hamiton RJ, Phillips SD (eds): Occupational, Industrial and Environmental Toxicology. Philadelphia, Mosby, 1997, pp 359–366. 9. Burnett WW, King EG, Grace M, Hall WF: Hydrogen sulfide poisoning: review of 5 years’ experience. Can Med Assoc J 1977; 117:1277–1280. 10. Alberta Environment Sour-Gas Processing-Plant Applications: A Guide to Content. Calgary: Energy Resources Conservation Board, Guide G-26, 1981. 11. Arnold IMF, Dufresne RM, Alleyne BC, Stuart PJW: Health implications of occupational exposures to hydrogen sulfide. J Occup Med 1985;27:373–376.

Hydrogen Sulfide

1341

12. Evans H: Occupational hygiene at an Alberta (Canada) natural gas processing plant. Ann Occup Hyg 1989;47:221–224. 13. Smith L, Kruszyna H, Smith RP: The effect of methemoglobin on the inhibition of cytochrome c oxidase by cyanide, sulphide or azide. Biochem Pharmacol 1977;26:2247–2250. 14. Smith RP, Gosselin RE: Hydrogen sulphide poisoning. J Occup Med 1979;21:93–97. 15. Roth SH, Skrajny B, Bennington R, Brookes: Neurotoxicity of hydrogen sulphide may result from inhibition of respiratory enzymes. Proc West Pharmacol Soc 1997;40:41–43. 16. Geer JJ, Reiffenstein R, Almeida AF, Carter JE: Sulfide-induced perturbations of the neuronal mechanisms controlling breathing in rats. J Appl Physiol 1995;78(2):433–440. 17. Haggard HW, Henderson Y: The influence of hydrogen sulphide upon respiration. Am J Physiol 1922;61:289–296. 18. Almeida AF, Guidotti TL: Differential sensitivity of lung and brain to sulfide exposure: a peripheral mechanism for apnea. Toxicol Sci 1999;50:287–293. 19. Boehning D, Snyder SH: Novel neural modulators. Annu Rev Neurosci 2003;26:105–131. 20. Klentz RD, Fedde MR: Hydrogen sulfide: effects on avian respiratory control and intrapulmonary CO2 receptors. Respir Physiol 1978;32(3):55–67. 21. Tansy MF, Kendall FM, Fantasia J, et al: Acute and subchronic toxicity studies of rats exposed to vapors of methyl mercaptan and other reduced-sulphur compounds. J Toxicol Environ Health 1981;8:71–88. 22. Haggard HW: The toxicology of hydrogen sulphide. J Indust Hyg 1925;7:113–121. 23. Hayden LJ, Goeden H, Roth SH: Exposure to low levels of hydrogen sulfide elevates circulating glucose in maternal rats. J Toxicol Environ Health 1990;31:45–52. 24. Roth SH, Skrajny B, Reiffenstein RJ: Alteration of the morphology and neurochemistry of the developing mammalian nervous system by hydrogen sulphide. Clin Exp Pharmacol Physiol 1995;22(5):79–80. 25. Bhambhani Y, Burnham R, Snydmiller G, MacLean I: Effects of 10ppm hydrogen sulfide inhalation in exercising men and women. Cardiovascular, metabolic, and biochemical responses. J Occup Environ Med 1997;39(2):22–29. 26. Costigan MG: Hydrogen sulfide: UK occupational exposure limits. Occup Environ Med 2003;60(12):918–928. 27. WHO International Programme on Chemical Safety. Environmental Health Criteria 19: Hydrogen Sulphide. Geneva, World Health Organization, 1983. 28. Brenneman KA, James RA, Gross EA, Dorman DC: Olfactory neuron loss in adult male CD rates following subchronic inhalation exposure to hydrogen sulfide. Toxicol Pathol 2000;28(2):26–33. 29. Hirsh AR, Zavala G: Long term effects on the olfactory system of exposure to hydrogen sulfide. Occup Environ Med 1999;56:284–287. 30. Nikkanen HE, Burns MM: Severe hydrogen sulphide exposure in a working adolescent. Pediatrics 2004;113(4):927–929. 31. Richardson DB: Respiratory effects of chronic hydrogen sulphide exposure. Am J Ind Med 1995;28:99–108. 32. Wang DX. A review of 152 cases of acute poisoning of hydrogen sulfide [in Chinese]. Chin J Prev Med 1989;23:330–332. 33. Bhambhani Y, Burnham R, Snydmiller G, et al: Effects of 10-ppm hydrogen sulfide inhalation on pulmonary function in health men and women. J Occup Environ Med 1996;38(10):1012–1017. 34. Jäppinen P, Vikka V, Marttila O, Haatela T: Exposure to hydrogen sulphide and respiratory function. Br J Ind Med 1990;47:824–828. 35. Buick JB, Lowry RC, Magee TRA: Is a reduction in residual volume a sub-clinical manifestation of hydrogen sulfide intoxication? Am J Ind Med 2000;37:296–299. 36. Duong TX, Saruda AJ, Maier LA: Interstitial fibrosis following hydrogen sulfide exposure. Am J Ind Med 2001;40(2):221–224. 37. Guidotti TL: Occupational exposure to hydrogen sulfide in the sour gas industry: some unresolved issues. Int Arch Occup Environ Health 1994;66:153–160. 38. Hayden LJ, Goeden H, Roth SH: Growth and development in the rat during sub-chronic exposure to low levels of hydrogen sulfide. Toxicol Ind Health 1990;6(3–4):389–401. 39. Dorman DC, Brenneman KA, Struve MF, et al: Fertility and developmental neurotoxicity effects of inhaled hydrogen sulfide in Sprague-Dawley rates. Neurotoxicol Teratol 2000;22:71–84.

1342


40. Berglin EH, Carlsson J: Effect of hydrogen sulfide on the mutagenicity of hydrogen peroxide in Salmonella typhimurium strain TA102. Mutat Res 1986;175(1):5–9. 41. Bates MN, Garrett N, Graham B, Read D: Cancer incidence, morbidity and geothermal air pollution in Rotorua, New Zealand. Int J Epidemiol 1998;20(3):339–408. 42. Kilburn K: Case report: profound neurobehavioural deficits in an oil field worker overcome by hydrogen sulfide. Am J Med Sci 1993;306:301–305. 43. Snyder JW, Safir EF, Summerville GP, Middleberg RA: Occupational fatality and persistent neurological sequelae after mass exposure to hydrogen sulfide. Am J Emerg Med 1995; 13:199–203. 44. Tvedt B, Edland A, Skyberg K, Forberg O: Delayed neuropsychiatric sequelae after acute hydrogen sulfide poisoning: affection of motor function, memory, vision, and hearing. Acta Neurol Scand 1991;84:348–351. 45. Tanaka S, Fujimoto S, Tamagaki Y, et al: Bronchial injury and pulmonary edema caused by hydrogen sulphide poisoning. Am J Emerg Med 1999;17(4):427–429. 46. Schneider JS, Tobe EH, Mozley PD Jr, et al: Persistent cognitive and motor deficits following acute hydrogen sulphide poisoning. Occup Med (Lond) 1998;48(4):255–260. 47. Inoue N. Extrapyramidal syndrome induced by chemical substances [in Japanese]. Nippon Rinsho 1993;51(11):2924–2928. 48. Kilburn KH: Exposure to reduced sulphur gases impairs neurobehavioral function. South Med J 1997;90(10):997–1006. 49. Spitzer WO, for the McGill Inter-University Research Group: The Southwestern Alberta Medical Diagnostic Review: Summary. Montreal, June 1986. 50. Struve MF, Brisbois JN, James RA, et al: Neurotoxicological effects associated with short-term exposure of Sprague-Dawley rats to hydrogen sulphide. Neurotoxicol 2001;22(3):375–385. 51. Smith RP, Kruszyna R, Kruszyna H: Management of acute sulfide poisoning: effects of thiosulfate, oxygen, and nitrite. Arch Environ Health 1976;31:166–169. 52. Goodwin LR, Francom D, Dieken FP, et al: Determination of sulphide in brain tissue by gas dialysis/ion chromatography: postmortem studies and two case reports. J Anal Toxicol 1989;13(2): 105–109. 53. Gabbay DS, De Roos F, Perrone J: Twenty-foot fall averts fatality from massive hydrogen sulphide exposure. J Emerg Med 2001;20(2):141–144. 54. Stine RJ, Slosberg B, Beacham BE: Hydrogen sulfide intoxication: a case report and discussion of treatment. Ann Intern Med 1976;85:756–758. 55. Vannatta JB: Hydrogen sulfide poisoning: report of four cases and brief review of the literature. J Okla State Med Assoc 1982; 75:29–32.

56. Mack RB: World enough and time: hydrogen sulfide poisoning. N C Med J 1987;48:33–34. 57. Ravizza AG, Carugo D, Cerchiari EL, et al: The treatment of hydrogen sulfide intoxication: oxygen versus nitrites. Vet Human Toxicol 1982;24:241–242. 58. Beck JF, Bradbury CM, Conors AJ, Donini JC: Nitrite as antidote for acute hydrogen sulfide intoxication? Am Ind Hyg Assoc J 1981;42:805–809. 59. Smilkstein MJ, Bronstein AC, Pickett HM, Rumack BH: Hyperbaric oxygen therapy for severe hydrogen sulphide poisoning. J Emerg Med 1985;3:27–30. 60. Whitcraft DD III, Bailey TD, Hart GB: Hydrogen sulfide poisoning treated with hyperbaric oxygen. J Emerg Med 1985;3:23–25. 61. Gorman DF: Problems and pitfalls in the use of hyperbaric oxygen for the treatment of poisoned patients. Med Toxicol Adverse Drug Exp 1989;4:393–399. 62. Peters JW: Hydrogen sulfide poisoning in a hospital setting. J Am Med Assn 1981;246:1558–1589. 63. Demaret D, Fialaire J: Les intoxications par l’hydrogène sulfuré dans une raffinerie de gaz naturel. J Eur Toxicol 1974;1:32–36. 64. Warenycia MW, Smith KA, Blashko CS, et al: Monoamine oxidase inhibition as a sequel of hydrogen sulfide intoxication: increase in brain catecholamine and 5-hydroxytryptamine levels. Arch Toxicol 1989;63:131–136. 65. Warenycia MW, Goodwin LR, Francom DM, et al: Dithiothreitol liberates non-acid labile sulfide from brain tissue of H2S-poisoned animals. Arch Toxicol 1990;64(8):650–655. 66. Dulaney M Jr, Hume AS: Pyruvic acid protects against the lethality of sulfide. Res Commun Chem Pathol Pharmacol 1988;59:133. 67. Hume AS, Dulaney MD: The effectiveness of various ketocarboxylic acids in preventing sulfide-induced lethality. Toxicologist 1988;8:28. 68. Mattarano DA, Merinar T: Respiratory protection on offshore drilling rigs. Appl Occup Environ Hyg 1999;14:141–148. 69. Ronk R, White MK: Hydrogen sulphide and the probabilities of “inhalation” through a tympanic membrane defect. J Occup Med 1985;27(5):337–340. 70. Turner RM, Fairhurst S: Toxicology of substances in relation to major hazards: hydrogen sulphide. London, HMSO, 1990, pp 1–14. 71. Provincial Advisory Committee on Public Safety and Sour Gas: Public Safety and Sour Gas: Findings and Recommendations— Final Report. Calgary, Alberta, Energy and Utilities Board, 2000. 72. Prior MG, Sharma AK, Yong S, Lopez A: Concentration-time interactions in hydrogen sulphide toxicity in rats. Can J Vet Res 1988;52:375–379. 73. Cottle MKW, Guidotti TL: Process chemicals in the oil and gas industry: potential occupational hazards. Toxicol Ind Health 1989;6:41–56.

92

Petroleum Distillates and Plant Hydrocarbons WILLIAM J. LEWANDER, MD ■ ALFRED ALEGUAS, JR., RPH, BSPharm, PHARMD


Patients should be evaluated for pulmonary, gastrointestinal, and CNS toxicity. Management is primarily symptomatic and supportive. Radiographic findings do not always correlate with clinical presentation. All symptomatic or suicidal patients should be admitted. Patients who remain asymptomatic for 6 hours with normal radiographic findings may be considered for discharge.

ingestions generally involve larger volumes along with a greater likelihood of co-ingested toxins. The most common route of exposure is by ingestion, but inhalation, cutaneous, and intravenous exposures have been reported. Nearly one quarter require treatment in a health care facility. The most commonly ingested products in this group in order of frequency are (1) gasoline, (2) lubricating oil, (3) mineral spirits, (4) lighter fluid or naphtha, (5) lamp oil, and (6) kerosene.1

PATHOPHYSIOLOGY Hydrocarbons are a group of organic compounds composed primarily of hydrogen and carbon. Common hydrocarbons are derived either directly from plants (e.g., pine oil) or from petroleum distillates. Although often mixtures, petroleum distillates are of three basic types: aliphatic, halogenated, and aromatic hydrocarbons. Aromatic and halogenated hydrocarbons are discussed in other chapters. Petroleum distillates are produced from the fractional distillation of crude petroleum and contain various amounts of aliphatic (straight chain) and aromatic (cyclic) hydrocarbons. Those classified predominantly as aliphatic hydrocarbons are discussed here. Some examples are kerosene, gasoline, mineral spirits, naphtha, mineral seal oil, diesel oil, and fuel oil (see Table 73-1). Turpentine is a hydrocarbon made from pine oil.

EPIDEMIOLOGY Hydrocarbon exposures are frequent and account for an inordinate number of health care visits and hospital admissions. The American Association of Poison Control Centers reported 59,132 hydrocarbon exposures in 2002.1 Twenty-two percent of exposed individuals required treatment in a health care facility, and nearly 22% of these patients were considered to have suffered exposures of moderate or major severity. Nearly half of all exposures occur in children younger than 6 years of age, and the vast majority of exposures are unintentional. Nevertheless, intentional exposures are not uncommon and frequently have greater potential for toxicity. Fifteen deaths were reported as a result of hydrocarbon exposure in 2002.1 Petroleum distillates continue to be the most commonly reported cause of hydrocarbon poisoning, accounting for more than 39,000 exposures. Unmarked, poorly stored containers and an attractive aroma or color may account for the high percentage of exposures among young children. In adults, poisoning is most often by intentional ingestion, occupational exposure, or inadvertant aspiration when siphoning fuels. Adult

Petroleum distillates are potent solvents, capable of destroying lipid-containing cell membranes. The toxicity of petroleum distillates is mainly a result of their potential to cause a fulminant and sometimes fatal pneumonitis when aspirated. Central nervous system (CNS), gastrointestinal (GI), hepatic, renal, cardiovascular, and hematologic toxicity may also occur. Cutaneous toxicity may occur with prolonged dermal exposure. After oral ingestion, pulmonary toxicity occurs from aspiration rather than by GI absorption. Aspiration may occur when the hydrocarbon is initially ingested or during vomiting. Although vomiting often precedes and results in aspiration, lack of vomiting does not preclude the possibility that aspiration has occurred. The potential for aspiration is determined by the physical properties of viscosity, surface tension, and volatility. The risk of aspiration involving any particular petroleum distillate increases with low viscosity, low surface tension, and high volatility.2 However, the single most important property determining aspiration potential is viscosity, the tendency to resist flow. Low viscosity allows penetration further into the distal airways. Viscosity is measured in Saybolt seconds universal (SSU). Substances with an SSU value greater than 100 have a low aspiration potential (e.g., mineral and fuel oil), whereas those with an SSU value of less than 45 have a high potential for aspiration (e.g., gasoline, kerosene, mineral seal oil). Low surface tension may allow the petroleum distillate to spread from the upper GI tract to the trachea, and high volatility (i.e., tendency of a liquid to become a gas) increases the likelihood of pulmonary absorption and risk of CNS depression that can blunt the gag reflex. When aspirated, petroleum distillates dissolve surfactant, resulting in alveolar collapse, ventilation-perfusion mismatch, and subsequent hypoxemia.2-4 Bronchospasm and direct capillary damage lead to a chemical pneumonitis and hemorrhagic bronchitis and alveolitis that peak in intensity at about 3 days.5 A late process of alveolar proliferation and thickening may occur, peaking at about 10 days.5 Upper airway injury may occur and includes hyperemia, mucosal irritation, and inflammation 1343

1344


of the oropharynx. A case of epiglottitis has been reported after gasoline ingestion.6 Systemic toxicity is uncommon after ingestion or aspiration but may develop if a petroleum distillate contains toxic additives, if it is a vehicle for more toxic substances, or if a massive ingestion has occurred. The specific toxin involved determines whether cardiovascular, renal, hepatic, or hematologic toxicity ensues.7 Petroleum distillate inhalation abuse (e.g., gasoline sniffing) does not produce a chemical pneumonitis but instead leads to complex CNS toxicity caused by the combined effects of its many constituents (e.g., aromatic hydrocarbons, naphthenes, and tetraethyl lead).8,9

Plant Hydrocarbons (Terpenes) Terpenes are aliphatic or cyclic hydrocarbons and include turpentine, pine oil, and camphor. Pine oil, a component of many household cleaners, is a product of pine trees and is composed primarily of terpene alcohols. It is normally present in cleaners in concentrations of 20% to 35% and occasionally as high as 60% in products such as Pine Sol. Turpentine is a distillate from pine trees and is commonly used as a solvent for paints and varnishes. Camphor is discussed in Chapter 99. Pine oil is well absorbed from the GI tract and is metabolized by the epoxide pathway and excreted in the urine.10 The volume of distribution is thought to be quite large, with the highest concentrations found in the brain, lungs, and kidneys. Turpentine is also readily absorbed through the GI tract and lungs11 and distributed throughout the body. The highest concentrations are found in the liver, spleen, kidneys, and brain.12 The details of turpentine metabolism remain unclear. Elimination of turpentine and its metabolites is primarily by the kidneys. Because of the terpenes’ lower volatility and higher viscosity, the risk of aspiration is somewhat less than with the more volatile or less viscous hydrocarbons. In addition to the aspiration risk, pine oil and turpentine produce more CNS and GI symptoms than do the aliphatic hydrocarbons. Ingestions of turpentine exceeding 2 mL/kg are potentially toxic.11 Although adults have survived pine oil ingestions of up to 500 g,13 the commonly cited lethal dose is 60 to 120 g. In children, the minimum lethal dose is probably 14 g.10

CLINICAL PRESENTATION The initial signs and symptoms following petroleum distillate ingestion usually involve three main organ systems: pulmonary, GI, and CNS. The majority of children who present to health care facilities after a petroleum distillate exposure remain asymptomatic. Patients who aspirate generally demonstrate initial symptoms (e.g., coughing, gasping, and choking) within 30 minutes; these reach peak intensity between 24 and 48 hours after exposure.14 During the first 24 hours, tachypnea with grunting respirations, nasal flaring, retractions, and

cyanosis may develop or may be delayed as long as 2 days.4 The characteristic odor of the petroleum distillate may be apparent on the breath. Although auscultation may reveal rales, rhonchi, and wheezing, lower airway involvement cannot be predicted by initially normal findings on examination. Hemoptysis and pulmonary edema may be observed in severe cases. Laboratory evaluation (e.g., arterial blood gases, pulse oximetry) may reveal hypoxemia (from ventilation-perfusion mismatching) and early hypocarbia. This may progress to hypercarbia and acidosis. As many as 75% of hospitalized patients demonstrate chest film abnormalities. These abnormalities occur within 2 hours in up to 88% of patients and in 98% by 12 hours.7,15,16 Common early changes include unilateral and bilateral basilar infiltrates, punctate perihilar densities, and localized areas of atelectasis.15-18 Pneumatoceles are infrequent but when they occur are delayed in onset (e.g., 3 to 15 days) and resolution (e.g., 15 days to 21 months).19 Pleural effusion, pneumothorax, pneumomediastinum, pneumopericardium, and subcutaneous emphysema may develop.15,17,20,21 Symptoms correlate poorly with radiographic findings, and both may be delayed in onset.7,22 It is best to treat patients rather than rely on the absence of or delayed resolution of radiographic findings. Although fever and leukocytosis may be noted in as many as 15% to 20% of victims during the first 48 hours, their persistence suggests bacterial superinfection.14 GI symptoms are common and include local irritation of the oropharynx, nausea, vomiting, and abdominal pain. Vomiting appears to increase the likelihood of aspiration.17,23 CNS toxicity may occur in the presence of aspiration-induced hypoxemia, large ingestions, or toxic additives (e.g., aromatic hydrocarbons). Symptoms range from lethargy (91%) or somnolence (5%) to coma (3%) and seizures (1%).7,24 Cardiovascular toxicity is uncommon, but both fatal dysrhythmias and myocardial dysfunction have been reported.25 Dysrhythmias and sudden death after siphoning gasoline may be attributed to hypoxia or absorption after aspiration resulting in myocardial sensitization to endogenous catecholamines.7,22 A 19-monthold girl developed severe, reversible myocardial dysfunction after ingesting paint thinner.24 Isolated case reports of acute renal tubular necrosis,26,27 supraglottitis,28 severe burns after prolonged immersion in gasoline,29 and hemoglobinuria secondary to intravascular hemolysis have been reported.28,30 One case report associated turpentine ingestion with hemorrhagic cystitis.31 Both inhalation abuse and parenteral administration of petroleum distillates have been reported to cause toxicity. CNS manifestations of inhalation abuse include confusion, dizziness, agitation, incoordination, and coma.7,8,32,33 Inhalation of leaded gasoline has also been associated with the development of organic lead poisoning.8,9,32,33 Parenteral administration has resulted in thrombophlebitis, cellulitis, and necrotizing myositis with compartment syndrome. Systemic toxicity includes seizures, hemorrhagic pneumonitis, pulmonary edema, and febrile reactions.34-36

CHAPTER 92

Systemic toxicity of pine oil and turpentine ingestion primarily consists of GI irritation and CNS depression. Signs and symptoms include nausea, vomiting, diarrhea, weakness, somnolence, or agitation. Severe cases may present as stupor or coma; seizures are uncommon.37 When systemic toxicity occurs, it usually develops within 2 to 3 hours of the exposure. GI and CNS symptoms generally resolve within 12 hours in moderately severe exposures. Dysuria and hematuria thought to be secondary to hemorrhagic cystitis have been reported in a turpentine ingestion 12 to 72 hours after exposure.31

DIAGNOSTIC EVALUATION All symptomatic patients should receive a medical evaluation. A thorough history should include product identification, approximate amount, concentration, time of ingestion, and symptoms before presentation. The physical examination should focus on the vital signs and mental status, and the pulmonary and GI systems. If significant aspiration has occurred, respiratory symptoms should develop within 6 hours and reach peak intensity 24 to 48 hours after exposure.14 Pulse oximetry should be performed and a chest film obtained. Laboratory evaluation for symptomatic patients and for those who have ingested concomitant toxins may include arterial blood gas determination; complete blood count; determinations of electrolytes, glucose, blood urea nitrogen, and creatinine; urinalysis; and liver function tests. A directed toxic screen may help confirm the presence of toxic additives or other concomitant ingestions. Patients without symptoms for 6 hours after exposure remain asymptomatic.14 The distinctive odors of pine oil and turpentine and a thorough history and physical examination are the keys to diagnosis. The examination should focus on the pulmonary, GI, and central nervous systems. No specific laboratory tests help determine severity.11 If aspiration is suspected, an arterial blood gas determination and appropriately timed chest radiograph should be obtained.

MANAGEMENT Clinical and radiographic assessment of a patient’s respiratory status determines initial management. Patients who remain asymptomatic with normal findings on chest films (obtained 4 or more hours after exposure) may be discharged after 6 hours of observation. Patients who are symptomatic, who have abnormal findings on chest films, or who have suicidal intent should be hospitalized. Gastric decontamination is not recommended for petroleum distillate ingestions because absorption and systemic toxicity are minimal, and spontaneous or induced vomiting increases the risk of aspiration and pneumonitis.38-40 Patients who have ingested toxic additives or other toxins with systemic toxicity should be considered for gastric decontamination. This decision is complex, often must be individualized, and should be made after con-

Petroleum Distillates and Plant Hydrocarbons

1345

sultation with the regional poison center. The incidence of aspiration pneumonitis may be increased by either gastric lavage or ipecac-induced emesis. Either method is acceptable in an awake, alert patient.16,38 When GI decontamination is indicated in patients with altered mental status, the airway should first be protected by endotracheal intubation. Activated charcoal is indicated only if an adsorbable toxic additive or concomitant ingestion has occurred. Clothing that has been contaminated should be carefully removed, and contaminated skin washed with soap and water.7 Patients with respiratory symptoms should be given oxygen, placed on cardiopulmonary and pulse oximetry monitors, and have intravenous access established. An arterial blood gas determination and chest film should be obtained. Findings on chest films do not always correlate with the clinical status of the patient. The need for intubation should be based on the clinical assessment of respiratory distress. Continuous positive airway pressure may be necessary to maintain oxygenation, and bronchospasm should be treated with noncardioselective bronchodilators because of potential myocardial sensitization to catecholamines.41 Supportive care of serious petroleum distillate pneumonitis includes careful monitoring of fluid and electrolyte balance, continuous pulse oximetry, and serial chest films. Complete blood counts with differential and sputum Gram staining and cultures help identify bacterial superinfection. The regional poison center should be consulted. Fever and leukocytosis secondary to chemical pneumonitis are commonly noted during the first 24 to 48 hours, and prophylactic antibiotics should not be instituted.39,42,43 Treatment with antibiotics should be provided only to patients with documented bacterial pneumonia (e.g., Gram staining or culture of sputum or tracheal aspirate) or worsening of chest film findings, chest pain, leukocytosis, and fever after the first 40 hours.7,22 Several animal and clinical investigations have failed to demonstrate any benefit from corticosteroid treatment. Two animal studies indicate they may be harmful42-45; therefore, corticosteroids should not be administered. Several reports document the efficacy of both extracorporeal membrane oxygenation and highfrequency jet ventilation as alternative therapies when conventional treatment for respiratory failure is unsuccessful.46-49 Most patients with petroleum distillate poisoning recover fully with supportive care. The majority have no significant sequelae despite the report of minor pulmonary function abnormalities in as many as 82% of asymptomatic survivors of aspiration pneumonitis.20 Long-term follow-up with pulmonary testing should be considered. When indicated, psychiatric consultation should be obtained and poison prevention education given before discharge. With plant hydrocarbons, the time and amount of ingestion, evidence of aspiration, and patient’s level of consciousness largely determine treatment. A fully alert patient who is seen within 2 hours of ingesting greater than 2 mL/kg of turpentine should be considered for GI decontamination. Although not clearly defined

1346


for pine oil, lavage is generally recommended for ingestions of greater than 5 mL in adults.50 Airway protection is recommended for all but the alert patients because of the risk of aspiration. Activated charcoal is not useful, and the apparent large volume of distribution of terpenes precludes the use of hemodialysis or hemoperfusion.

Disposition Medical disposition is based on clinical toxicity and time since ingestion. Patients who are either asymptomatic or who have only mild GI or CNS symptoms after 6 hours are unlikely to develop serious complications. All patients with evidence of significant toxicity (i.e., pulmonary or CNS) should be admitted for symptomatic and supportive care. REFERENCES 1. Watson WA, Litovitz TL, Rodgers GC, et al: 2002 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2003;21:353. 2. Gerarde HW: Toxicologic studies on hydrocarbons. 9. The aspiration hazard and toxicity of hydrocarbons and hydrocarbon mixtures. Arch Environ Health 1963;6:329. 3. Giammona ST: Effects of furniture polish on pulmonary surfactant. Am J Dis Child 1967;13:658. 4. Truemper E, DeLaRocha SR, Atkinson SD: Clinical characteristics, pathophysiology, and management of hydrocarbon ingestion: case report and review of the literature. Pediatr Emerg Care 1987;3:187. 5. Gross P, McNerney JM, Babyak MA: Kerosene pneumonitis: an experimental study with small doses. Am Rev Respir Dis 1963;88:656. 6. Grufferman S, Walker FW: Supraglottitis following gasoline ingestion. Ann Emerg Med 1982;11:368. 7. Ellenhorn MJ, Barceloux DG: Medical Toxicology, Diagnosis, and Treatment of Human Poisoning. New York, Elsevier, 1988, p 940. 8. Fortenberry JD: Gasoline sniffing. Am J Med 1985;79:740. 9. Edminster SC, Bayer MJ: Recreational gasoline sniffing: acute gasoline intoxication and latent organolead poisoning. J Emerg Med 1985;3:365. 10. Jill RM, Barer J, Leighton Hill L, et al: An investigation of recurrent pine oil poisoning in an infant by the use of gaschromatographic mass spectrometric methods. J Pediatr 1975; 87:115. 11. McGuigan MA: Turpentine. Clin Toxicol Rev 1985;8:1. 12. Sperling F: In vivo and in vitro toxicology of turpentines. Clin Toxicol 1969;2:21. 13. Koppel C, Tenczer J, Tennesmarm U, et al: Acute poisoning with pine oil: metabolism of monoterpenes. Arch Toxicol 1981;49:73. 14. Anas N, Narnasonthia V, Ginsburg CM: Criteria for hospitalizing children who have ingested products containing hydrocarbons. JAMA 1981;246:840. 15. Eade NR, Taussig LM, Marks MI: Hydrocarbon pneumonitis. Pediatrics 1974;54:351. 16. Beamon RF, Siegel CJ, Landers G, et al: Hydrocarbon ingestion in children: a six year retrospective study. JACEP 1976;5:771. 17. Foley JC, Dreyer NB, Soule AB Jr, et al: Kerosene poisoning in young children. Radiology 1954;62:817. 18. Ervin ME: Petroleum distillates and turpentine. In Haddad LM, Winchester JF (eds): Clinical Management of Poisoning and Drug Overdose. Philadelphia, WB Saunders, 1983, p 771. 19. Bergeson PS, Hates SW, Lustgarten MD, et al: Pneumatoceles following hydrocarbon ingestion. Am J Dis Child 1975;129:49.

20. Gurwitz D, Kattan M, Levison H, et al: Pulmonary function abnormalities in asymptomatic children after hydrocarbon pneumonitis. Pediatrics 1970;62:789. 21. Brunner S, Rovsing H, Wulf H: Roentgenographic changes in the lungs of children with kerosene poisoning. Am Rev Respir Dis 1964;89:250. 22. Klein BL, Simon JE: Hydrocarbon poisonings. Pediatr Clin North Am 1986;33:411. 23. Bratton L, Haddow JE: Ingestion of charcoal lighter fluid. J Pediatr 1974;87:633. 24. Myocardial dysfunction after hydrocarbon ingestion (abstract). Crit Care Med 1994;22:3. 25. Bass M: Death from sniffing gasoline (letter). N Engl J Med 1978;299:203. 26. Barrientos A, Ortuno MT, Morales JM, et al: Acute renal failure after use of diesel fuel as shampoo. Arch Intern Med 1977;137:1217. 27. Crisp AJ, Bhalla AK, Hoffbrand BI: Acute tubular necrosis after exposure to diesel oil. BMJ 1979;2:177. 28. Crisp AJ, Bhalla AK, Hoffbrand BI: Acute tubular necrosis after exposure to diesel oil. BMJ 1979;2:177. 29. Walsh WA, Scarpa FJ, Brown RS, et al: Gasoline immersion burn case report. N Engl J Med 1974;291:830. 30. Stockman JA: More on hydrocarbon-induced hemolysis. J Pediatr 1977;90:848. 31. Klein FA, Hackler RH: Hemorrhagic cystitis associated with turpentine ingestion. Urology 1980;16:187. 32. Poklis A, Burkett CD: Gasoline sniffing: a review. Clin Toxicol 1977;11:35. 33. Chessare JD, Wodarcyk K: Gasoline sniffing and lead poisoning in a child. Am Fam Physician 1988;38:181. 34. Wason S, Greiner PT: Intravenous hydrocarbon abuse. Am J Emerg Med 1986;4:543. 35. Neeld EM, Limacher MC: Chemical pneumonitis after the intravenous injection of hydrocarbons. Radiology 1978;129:36. 36. Tennenbein M: Hydrocarbon ingestion. Curr Probl Pediatr 1986;16:221. 37. Jacobziner H, Raybin HW: Turpentine poisoning. Arch Pediatr 1961;78:357. 38. Press E, Adams WC, Chittenden RF, et al: Report of the subcommittee on accidental poisoning: co-operative kerosene poisoning study. Pediatrics 1962;29:648. 39. Litovitz T, Green AE: Health implications of petroleum distillate ingestion. Occup Med 1988;3:555. 40. Cachia EA, Fenech FF: Kerosene poisoning in children. Arch Dis Child 1964;39:502. 41. James FW, Kaplan S, Benzing G: Cardiac complications following hydrocarbon ingestion. Am J Dis Child 1971;121:431. 42. Steele RW, Conklin RH, Mark HM: Corticosteroids and antibotics for the treatment of fulminant hydrocarbon aspiration. JAMA 1972;219:1424. 43. Brown J, Burke B, Dajani AS: Experimental kerosene pneumonia: evaluation of some therapeutic regimens. J Pediatr 1974;84:396. 44. Zieserl E: Hydrocarbon ingestion and poisoning. Compr Ther 1979;5:35. 45. Marks MI, Chicoine L, Legere G, et al: Adrenocorticosteroid treatment of hydrocarbon pneumonia in children: a cooperative study. J Pediatr 1972;81:366. 46. Scazo AJ, Weber TR, et al: Extracorporeal membrane oxyenation for hydrocarbon aspiration. Am J Dis Child 1990;144:867. 47. Weber TR, Tracey TF, et al: Prolonged extracorporeal support for nonneonatal respiratory failure. J Pediatr Surg 1992;27:1100. 48. Bysani GK, Rucoba RJ, et al: Treatment of hydrocarbon pneumonitis. Chest 1994;106:300. 49. Lee LK, Shannon M: The use of high frequency oscillatory ventilation in hydrocarbon pneumonitis. Int J Med Toxicol 2003;6(2):10. 50. Brook MP, McCarron MM, Mueller JA: Pine oil cleaner ingestion. Ann Emerg Med 1989;18:391.

93

Chlorinated Hydrocarbons ROBERT B. PALMER, PHD ■ SCOTT D. PHILLIPS, MD

At a Glance… ■

■

■

■ ■ ■

■ ■ ■

Chlorinated hydrocarbons generally share three acute health effects: dermatitis, narcosis, and the ability to induce cardiac arrhythmias. One of these compounds, carbon tetrachloride, was banned in the United States because of its propensity for hepatotoxicity and carcinogenesis. Trichloroethylene and tetrachloroethylene (perchloroethylene) continue to be employed as industrial solvents and the latter as a dry cleaning agent. Most of these compounds are highly volatile but generally not flammable—some have been used for fire extinguishing. CNS toxicity is prominent and may result from accidental exposure or intentional abuse. Seizures and coma are possible. Cardiac toxicity has been attributed to membrane stabilization and “sensitization” to catecholamines, although other mechanisms may play a role. Sudden sniffing deaths may occur. Carbon tetrachloride may cause hepatic necrosis. Other chlorinated hydrocarbons may cause fatty liver. Defatting of the skin may lead to chronic irritant dermatitis. Removal from exposure and supportive care is indicated in the treatment of disease caused by chlorinated hydrocarbons.

Compounds of only carbon, hydrogen, and chlorine are collectively known as chlorinated hydrocarbons. These compounds are used for a variety of industrial and medical purposes, including degreasing solvents in manufacture and topical anesthetics. Chlorinated hydrocarbons are not naturally occurring. Human exposures to these compounds are typically either the result of solvent abuse or occupational or environmental in nature. Although the specific toxicity profiles for the individual chlorinated hydrocarbons vary, essentially all these compounds share three fundamental acute effects: dermatitis, narcosis, and the potential to induce cardiac dysrhythmias. Literally hundreds of compounds are classifiable as chlorinated hydrocarbons, but the most commonly encountered are chlorinated derivatives of methane, ethane, and ethylene (Table 93-1). These compounds are the focus of this chapter. Trichloromethane (chloroform) was first used as a veterinary anesthetic in 1847; its first reported use in human surgery came later that same year.1,2 Chloroform was the anesthetic agent of choice for nearly a century until the post–World War II era when compounds less toxic to the heart and liver were developed. Chloroform has also gained notoriety as an anesthetic agent used for murder or to incapacitate people for nefarious purposes.3 More recent medical applications of chloroform include topical use in herpes labialis, where it was shown to decrease time to scab formation when

compared with control.4 Warmed (40° C) chloroform has also been used to liquefy cholesterol gallstones.4 Other medical applications for chlorinated hydrocarbons include the use of small oral doses of carbon tetrachloride as an antihelminthic agent to treat hookworm infection in the 1920s. Despite its efficacy, use of carbon tetrachloride for this purpose was associated with hepatic necrosis, renal injury, and gastrointestinal hemorrhage, especially in alcoholics and malnourished children. Because of this, carbon tetrachloride was replaced with tetrachloroethylene for the management of both hookworm and pinworm. Tens of thousands of cases were treated with tetrachloroethylene, and only mild adverse effects, such as giddiness and lightheadedness, were reported. Chloroform, as part of “Hermann’s mixture” (chloroform, eucalyptus oil, and castor oil), was also employed in the management of hookworm infestation.5 In addition to its former use as an antihelminthic agent, carbon tetrachloride saw widespread industrial use as a degreasing solvent, dry cleaning agent, grain fumigant, and as fire extinguisher component.6 However, as a result of its potential toxicity, household use of carbon tetrachloride was banned in 1970, and its use as a grain fumigant was discontinued in the United States in 1985.6 The principal contemporary use of carbon tetrachloride is as an intermediate in the synthesis of chlorofluorocarbon refrigerants.7 The two-carbon (ethane and ethene) chlorinated derivatives have been used extensively as degreasing solvents, in the preparation of many insecticidal fumigants, and in dry cleaning. Trichloroethylene is also used in the textile industry for removing basting threads and as a swelling agent for dying polyester as well as a diluent for paints and varnishes. Trichloroethylene has also seen use as an inhaled anesthetic and is known to have poor muscle relaxant but excellent analgesic properties.4,6 In the past, trichloroethylene was used in the extraction of olive oil; however, the use of this solvent in the food industry was eliminated in 1975.8 Tetrachloroethylene is still used in American veterinary medicine as an antihelminthic and is available in capsules ranging from 0.2 to 5.0 mL and marketed by Parke Davis as NemaWorm. The antihelminthic activity of tetrachloroethylene is reportedly due to the ability of the compound to interfere with the release of lysosomal enzymes in the gut of nematodes. This results in paralysis of the parasitic worms, breaking their adhesion to the intestinal wall.9

PHYSICOCHEMICAL PROPERTIES The chlorinated hydrocarbons discussed in this chapter are small aliphatic (acyclic open chain) organic com1347

MW: 153.8 g/mol Density:1.594 g/mL Vapor pressure: 12 kPa CAS: 56–23–5

Cl ⎥ Cl ⎯ C ⎯ C1 ⎥ Cl

Tetrachloromethane (carbon tetrachloride)

MW: 119.4 g/mol Density: 1.492 g/mL Vapor pressure: 21 kPa CAS: 67-66-3

H ⎥ Cl ⎯ C ⎯ Cl ⎥ Cl

Trichloromethane (chloroform)


Odor threshold > 10 ppm

Heavy colorless volatile nonflammable liquid a sweet ether-like odor

Odor threshold 85 ppm

Heavy colorless volatile nonflammable liquid with a sweet taste and odor

Odor threshold variable from 25–150 ppm

Colorless volatile nonflammable liquid with a sweet ether-like odor

Dichloromethane (methylene chloride; DCM)

H ⎥ Cl ⎯ C ⎯ Cl ⎥ H

PHYSICAL DESCRIPTION

COMPOUND

TLV (TWA): 5 ppm PEL (TWA): 10 ppm PEL (STEL-C): 25 ppm IDLH: 200 ppm

TLV (TWA): 10 ppm PEL (STEL-C): 50 ppm IDLH: 500 ppm

TLV (TWA): 50 ppm PEL (TWA): 25 ppm PEL (STEL): 125 ppm IDLH: 2300 ppm

EXPOSURE GUIDELINES

TABLE 93-1 Commonly Encountered Chlorinated Hydrocarbons

Trichloromethyl radical Phosgene Hydrochloric acid

Chloromethanol Hydrochloric acid Phosgene Carbon dioxide Diglutathionyl dithiocarbonate

Carbon monoxide Carbon dioxide Formaldehyde Formic acid

METABOLITES

Irritant Burns with high concentrations CNS depression with high concentrations Hepatorenal toxicity


Irritant Burns with high concentrations CNS depression with high concentrations

POTENTIAL TOXICITIES

CNS Skin Heart Liver Kidney


CNS Skin Heart

TARGET ORGANS

2B

2B

2B

IARC CLASS

1348 ENVIRONMENTAL, INDUSTRIAL, AND HOUSEHOLD PRODUCT TOXICOLOGY

C=C

H

Cl

C=C

Cl

Cl

Clear colorless volatile nonflammable liquid a sweet ether-like odor that will rapidly sink to the bottom when mixed with water

Odor threshold 50–100 ppm

TLV (TWA): 25 ppm TLV (STEK): 100 ppm PEL (TWA): 100 ppm PEL (STEL-C): 200 ppm IDLH: 150 ppm

TLV (TWA): 50 ppm TLV (STEL): 100 ppm PEL (TWA): 100 ppm PEL (STEL-C): 200 ppm IDLH: 1000 ppm

TLV (TWA): 350 ppm TLV (STEL): 450 ppm PEL (TWA): 350 ppm IDLH: 700 ppm

EXPOSURE GUIDELINES

Trichloroethanol (TCE) Trichloroacetic acid (TCA) Dichloroacetic acid Trichloroacetic acid

Trichloroethanol Trichloroacetic acid Chloroform Chloroacetic acid Dichloroacetic acid

Trichloroethanol Trichloroacetic acid

METABOLITES

Irritant Burns with high concentrations CNS depression with high concentrations Noncardiogenic pulmonary edema Hepatorenal toxicity


Irritant Burns with high concentrations CNS depression with high concentrations

POTENTIAL TOXICITIES

CNS Skin Heart Lung Liver Kidney


CNS Skin Heart

TARGET ORGANS

2A

2A

3

IARC CLASS

CAS, chemical abstract service; IARC, International Agency for Research on Cancer; IDLH, immediate danger to life and health; MW, molecular weight; PEL, permissible exposure limit; STEL, short-term exposure limit; TLV, threshold limit value, TWA: time-weighted average.

MW: 165.8 g/mol Density: 1.623 g/mL Vapor pressure: 1.9 kPa CAS: 127-18-4

Cl

Cl

Tetrachloroethene (tetrachloroethylene; perchloroethylene; PCE)


Cl

Cl

Trichloroethene (trichloroethylene; TCE)

MW: 133.4 g/mol Density: 1.338 g/mL Vapor pressure: 13 kPa CA: 71-55-6 Clear colorless volatile nonflammable liquid a pleasant sweet ether-like odor May be dyed blue

Colorless watery volatile nonflammable liquid a pleasant sweet ether-like odor

1,1,1-Trichloroethane (methylchloroform; TCA)

Cl H ⎥ ⎥ Cl ⎯ C ⎯ C — H ⎥ ⎥ Cl H

PHYSICAL DESCRIPTION

COMPOUND

TABLE 93-1 Commonly Encountered Chlorinated Hydrocarbons (Cont’d)

CHAPTER 93 Chlorinated Hydrocarbons 1349

1350


pounds. They are typically clear colorless liquids, although trichloroethylene may be dyed blue. As is typical of halogenated organic solvents, the chlorinated hydrocarbons are poorly miscible in water but highly miscible with other less polar organics such as diethyl ether. They are most often quite volatile, a property that led to their use as inhaled anesthetic agents, and have a characteristic sweet chloroform-like odor, which most patients did not find objectionable. Inhalation of high concentrations of chlorinated hydrocarbons is irritating to the mucosa. Although workers generally cannot detect concentrations of chlorinated hydrocarbons at the recommended workplace standard levels, they are typically able to smell these compounds at airborne concentrations at the immediate danger to life and health (IDLH) level. In general, vapor pressure decreases and boiling point increases with increasing molecular weight. Therefore, in progressing from chloromethane (a gas), to dichloromethane, to chloroform, and ultimately to carbon tetrachloride, volatility steadily decreases. Despite their volatility (i.e., ease of going from liquid to vapor), the chlorinated hydrocarbons are generally not flammable. The exceptions to this rule are 1,2-dichloroethane and 1,2-dichloroethylene, which are flammable. Interestingly, although trichloroethane liquid is not flammable and no flashpoint has been defined using traditional methods, the vapor of this compound will burn. However, it takes an enormous amount of energy to ignite trichloroethane, and once ignited, the compound will not sustain combustion. In the presence of an open flame, chlorinated hydrocarbons such as methylene chloride decompose without burning and can be converted to phosgene and hydrogen chloride. Many of the chlorinated hydrocarbon solvents of industrial importance are photolabile. For example, chloroform is subject to photochemical decomposition to phosgene and hydrogen chloride. Chemical stabilizers such as small amounts of ethanol, triethylamine, or epichlorohydrin are often added to prevent degradation of the solvent in the presence of light.10 The number of chlorine atoms that can be added to a chlorinated hydrocarbon is determined by the number of hydrogen atoms on the unsubstituted hydrocarbon (i.e., the chlorine atoms replace only the hydrogen atoms of the hydrocarbon). The simplest chlorinated hydrocarbons are the chloromethanes. This series of compounds is created by progressively adding one to four chlorine atoms to methane (CH4). The chloromethane series includes, in order of fewest to greatest number of chlorines, chloromethane, dichloromethane (methylene chloride), trichloromethane (chloroform), and tetrachloromethane (carbon tetrachloride) (see Table 93-1). The chloroethane series is based on substitution of ethane (CH3CH3) with chlorine. These compounds contain two carbon atoms connected by a single bond. The carbon skeleton of the chloroethylenes, although also composed of two carbons, is based on ethylene (ethene; CH2CH2), in which the two carbon atoms are joined with a double bond. Therefore, the chloroethane derivatives contain one to six chlorine atoms, whereas

Cl

Cl

H

H

Cl

CKC

C KC H

H

Cl

cistransFIGURE 93-1 Chemical structures of cis- and trans- isomers of 1,2-dichloroethylene.

the chloroethylenes bear a maximum of four chlorine atoms. Chlorinated derivatives of three (propane), four (butane), and five (pentane) carbon chains also exist but are less commonly encountered and will therefore not be discussed further. Various isomers (compounds with the same molecular formula but different arrangements of atoms) can be formed from the chloroethanes and chloroethylenes when two or more chlorine atoms are present on the molecule. Isomerism is not possible in the chloromethane series because there is only a single carbon atom. The chloroethane isomers may have the chlorine atoms distributed on one or both carbon atoms in any combination. This is also true in the chloroethylene series, in which up to four chlorine atoms may be added. Notably, within the chloroethylenes, an additional form of isomerism, “geometric” or “cis-/trans-” isomerism, is also possible because of the double bond prohibiting rotation about the carbon–carbon bond. This lack of available rotation results in the molecule having defined, noninterchangeable sides. In the 1,2-dichloroethylenes, both chlorines may be on the same side of the double bond (cis-) or on opposite sides of the double bond (trans-) (Fig. 93-1). Isomerism can result in differences in biologic activity. When examined in inhalation studies in rats, the trans-1,2-dichloroethylene isomer is twice as potent as an anesthetic than the cis-1,2-dichloroethylene isomer.11 These two isomers cannot interconvert without breaking the carbon–carbon double bond. Further, subchronic dosing studies in animals indicate that 1,1dichloroethane is about five times less injurious than 1,2dichloroethane.12 Geometric isomerism is not possible in the chloroethanes because there is free rotation around the carbon–carbon single bond.

EXPOSURE Historically, significant exposures to chlorinated hydrocarbons occurred as a result of medicinal applications (e.g., as inhaled anesthetics and antihelminthic agents). However, this route of exposure has been largely mitigated by bans on the use of these agents as anesthetics, surgical disinfectants, and food extraction solvents. Currently, most exposures are the result of industrial contact from activities requiring large volumes of degreasing solvents (e.g., aircraft manufacture), in the manufacture and use of large volumes of paints and varnishes, or from work in the dry cleaning industry. Extensive industrial use of the chlorinated hydrocarbons has resulted in the release of these compounds into the environment where they may leach into ground water.

CHAPTER 93

Most chlorinated hydrocarbon exposures generally fall into one of three broad categories: (1) very large acute exposure as a result of solvent abuse, (2) chronic higher concentration occupational exposure, and (3) chronic low-level exposure as a result of contamination of ground water supplies or other environmental sources.

TOXICOKINETICS Absorption Absorption of chlorinated hydrocarbons after ingestion is variable but can be significant. The one-carbon chloromethane compounds tend to be well-absorbed after ingestion. Absorption is increased further with physical exertion in the case of methylene chloride and with alcohol consumption after both inhalation and ingestion of carbon tetrachloride.13,14 Serious toxicity from chlorinated hydrocarbon ingestion is typically the result of large volume deliberate (i.e., suicidal) ingestions. Ingestion of these compounds as a result of low-level drinking water contamination does not cause acute toxic effects. Inhalation is the primary route of exposure to the chlorinated hydrocarbons both occupationally and as a result of abuse. Because of their volatility, the chlorinated hydrocarbons are easily inhaled, and because of their lipophilicity, they are typically well absorbed. In fact, about 70% of an inhaled dose of methylene chloride is absorbed.15 As a general rule, absorption through intact skin is inefficient, although transdermal penetration through damaged skin may be more efficient. Most chlorinated hydrocarbons are not transdermally absorbed to levels of clinical significance unless contact is prolonged and an impermeable barrier prevents evaporation. The most significant exception to this rule is carbon tetrachloride, for which amounts capable of causing adverse health effects may be absorbed through the skin.16 Gastrointestinal effects, as well as liver damage and kidney failure, have been reported in individuals using a topically applied lotion containing carbon tetrachloride.16 Chloroform and methylene chloride are also percutaneously absorbed to a somewhat greater extent than other chlorinated hydrocarbons, but to a lesser degree than is seen with carbon tetrachloride. Percutaneous absorption can also be increased by trapping the liquid against the skin with clothing or gloves. Tetrachloroethylene is absorbed through the skin only to a very limited degree. Although a single dermal exposure to a chlorinated hydrocarbon may not represent a toxicologic hazard, repeated dermal exposures to certain substances may become significant.17 This is illustrated by the observation that application of dichloroethane to the skin of guinea pigs causes blood levels of trichloroethylene to increase.18

Distribution After absorption, chlorinated hydrocarbons are rapidly distributed to body tissues. As a result of their lipophilic

Chlorinated Hydrocarbons

1351

character, large concentrations tend to be deposited in the fat, brain, and blood.17 It is also notable that the lipophilic character of chlorinated hydrocarbon compounds such as chloroform and trichloroethylene allows some crossing of the placenta and potential exposure of the fetus.17 Placental crossing is also known to occur with chloroform and dichloroethane exposure.4,17 As expected from the partitioning of the chlorinated hydrocarbons into lipophilic tissues, their volumes of distribution are relatively large, ranging from about 2.6 L/kg for chloroform to about 10 L/kg for trichloroethylene.19,20

Metabolism and Elimination The chlorinated hydrocarbons are eliminated from the body through two fundamental routes: exhaled air and hepatic metabolism. That portion eliminated from the lungs is largely as unchanged parent compound, although some is first metabolically converted to carbon dioxide. The extent of biotransformation is variable by compound and exposure dose. Species dependence also exists in the clearance of chlorinated hydrocarbons because some animals have more active metabolic pathways than others, which makes interspecies comparisons problematic.21 For example, scaling of metabolic parameters for tetrachloroethylene determined in mice overestimates human metabolism.22 The main metabolic routes are oxidative transformation through the cytochrome P-450 systems and subsequent conjugation (Fig. 93-2). The P-450 enzymes involved exist primarily in the liver and kidneys, although they are also present to a lesser extent in the lungs and gastrointestinal tract. The initial oxidative transformation creates a reactive intermediate that is then conjugated with a polar moiety such as glutathione or glucuronic acid in order to create a more watersoluble compound that can be eliminated from the body. The kinetics of these enzymatic transformations is not always linear in humans.22 Other enzyme systems may also be involved with the biotransformation of chlorinated hydrocarbons. For example, ethanol changes the metabolism of trichloroethylene, suggesting that alcohol dehydrogenase may also be involved in its elimination.20 The influences of aliphatic alcohols on the effects of chlorinated hydrocarbons containing a carbon–carbon double bond have been studied. It appears that the alcohols may influence the hepatotoxicity of some chlorinated hydrocarbons.23 A secondary metabolic pathway also exists for methylene chloride and involves a glutathione transferase– dependent pathway, which produces carbon dioxide, formaldehyde, and formic acid.24,25 The initial metabolic activation is the proposed source of toxicity for many of the chlorinated hydrocarbons (see Fig. 93-2). Hepatic P-450 enzymes oxidatively convert the chlorinated hydrocarbon to free radicals. These reactive radicals may then combine with molecular oxygen to form peroxy radicals, or they may react with endogenous lipids to form lipid radicals. By their very nature, free radicals are highly unstable and react essentially as soon as they are created. Therefore, the toxic effects of these


Cl

Chloral

Chloral hydrate

Cl Trichloroacetic acid

CJC

H

Cl

H

J J

J J

Cl OH

O

ClJCJCl +CO2

ClJCJCJH

Cl Chloroform

Glucuronyl transferase

CJC

O

O O

Glyoxalic acid

O

J J

Cl

J J

K

K

Oxalic acid

O

H

Cl

H

OH

K

O

HO

K

K

O

J

ClJCJCJOH

2,2,2-Trichloroethanol

CJC

O

Alcohol dehydrogenase

Glyoxalyl chloride

OH

Cl

OH

J J

K

Cl

K

O

ClJCJCJH

-H2O

H

Chloral hydrate dehydrogenase

Cl OH

+H2O

J J

K

O

J J

J J

Cl

ClJCJCJH OH

Cl

HO

K

Dichloroacetic acid

H

Formic acid

CO2

J J

Dichloroacetyl chloride

J J

O

O

H

Trichloroethylene glycol

Cl

CJC

Cl

Trichloroethylene oxide

CO+

HJCJCJOH

Cl

OH OH

K

Trichloroethylene

ClJCJCJCl

O

J

NADPH/O2

H

pathway

H

Cl

J

Cl

Cl

J

P450

CKC

J

Cl

Cl

Minor

K

ClJCJCJH Epoxide hydrolase

O

H

Cl

J J

J J

Cl

J J

1352

OH OH

ClJCJCJH HO

Trichloroethanol-glucuronide (Urochloralic acid) FIGURE 93-2 An abbreviated metabolic scheme for trichloroethylene.

reactive metabolites typically occur at or near their site of production. Additional significant clinical effects may result from the individual toxicities of the metabolites. For example, about 25% to 34% of an absorbed dose of methylene chloride is metabolically converted to carbon monoxide.15 This biotransformation takes place primarily in the liver but also occurs to a lesser extent in the kidneys and lungs and is mediated by the 2E1 isozyme of the cytochrome P-450 system.26,27 This pathway is also saturable in the presence of high substrate (methylene chloride) concentrations.25 Carbon monoxide and carboxyhemoglobin may be formed for several hours after cessation of exposure.25,28 The two-carbon compounds, 1,1,1-trichloroethane, trichloroethylene, and tetrachloroethylene, undergo biotransformation to form trichloroacetic acid and trichloroethanol, which are excreted in the urine in both free and conjugated forms.29-31 In addition,

both trichloroacetic acid and dichloroacetic acid, which may be hepatotoxic, are produced.32 As a general rule, there is relatively little bioaccumulation of the chlorinated hydrocarbons in adipose tissues unless chronic high-concentration exposure has been maintained. Trichloroethylene’s elimination follows a two-compartment model, with the first elimination half-life being about 0.5 to 3 hours and the second about 22 to 30 hours.33,34 However, it is known that adipose tissues can act as a reservoir for trichloroethylene deposition.35 The extent of significant adipose deposition seems to correlate well with long-term high-concentration occupational exposure; however, ongoing exposure could not be excluded. One report describes an individual with exhaled trichloroethylene breath concentrations of 135 ng/L (1.8 mg/day) 4 years after the last exposure to the compound following a 20-year

CHAPTER 93

occupational exposure.36 The elimination half-life of the chlorinated hydrocarbons may also vary by route of administration. A half-life of 72 hours is observed after inhalation of tetrachloroethylene, whereas the half-life is about doubled (144 hours) when the compound is ingested.19,30 The extended elimination profile seen with tetrachloroethylene actually affects the minority of the inhaled dose. With acute exposure to most chlorinated hydrocarbons, a large portion of the dose is excreted as unchanged parent compound in the air expired from the lungs.37,38 In the case of methylene chloride, the saturability of the enzymatic conversion to carbon monoxide has a dramatic effect on the elimination of the compound. A dose-dependent elimination of methylene chloride is observed, with low-dose exposures being principally eliminated through the lungs as carbon monoxide while a greater proportion of unchanged parent methylene chloride is exhaled in the setting of larger exposures.39

EFFECTS ON BODY SYSTEMS Central Nervous Chlorinated hydrocarbons exert dose-dependent effects on the central nervous system (CNS), where the dose is a function of both the duration of exposure and the concentration of the substance. The effects of these compounds are not mediated by interaction with any specific CNS receptor. Rather, the mechanism of toxicity appears to be alteration of neurotransmission as a result of direct effect to nerve cell membranes by the chlorinated hydrocarbons,40,41 which may be temporary or permanent.42 In animal models, low-dose exposures to chlorinated hydrocarbons produce minimal histologic evidence of damage to nerve cells.43 In high-dose exposure, the histologic results are equivocal.43 No specific pathologic changes in the CNS are seen as a result of death from chlorinated hydrocarbon exposure. Rather, alterations in the CNS observed at autopsy are typically the result of underlying disease.44 Acute high-level exposures can be encountered in cases of solvent abusers or with large accidental releases of chlorinated hydrocarbon solvents in a workplace. Chronic high-level exposure is really only germane in the circumstance of long-term solvent inhalation abuse. Chronic low-level exposure is typically the result of routine occupational encounters with solvents in the course of normal work procedures. Chronic very-lowconcentration exposures, as would be seen from drinking ground water contaminated with small amounts of chlorinated hydrocarbon solvents, are not expected to have any effects on the CNS. Acute high-level exposure typically causes CNS depression, dizziness, narcosis, nausea, vomiting, seizures, coma, and possibly death from respiratory failure. Because there is no discrete receptor and no requirement for metabolic activation of the chlorinated hydrocarbon to exert effects on the CNS, onset of effects is rapid.


1353

Likewise, because effects are not the result of a covalent drug-receptor interaction, recovery from intoxication is typically rapid and, except when very high doses are abused chronically or significant hypoxic insult is incurred, recovery is usually fairly prompt and complete. Most deaths associated with acute high doses are caused by either narcosis and apnea or cardiac arrest, which is discussed in greater detail under Cardiovascular. Chronic high-dose exposure to chlorinated hydrocarbons, most frequently as a result of long-term solvent abuse, may have substantial effects on the CNS. The primary pathologic change to the CNS from solvent abuse is degeneration of the white matter (leukoencephalopathy).45 Other CNS changes observed at autopsy in the brains of toluene abusers include substantial atrophy and mottling of the white matter, as well as myelin and oligodendrocyte loss with relative axonal preservation.45 These conditions are characterized for toluene, not chlorinated hydrocarbon, abuse, and it is known from animal studies that some differences in specific neurologic effects may exist between the individual solvents.46 However, a pathologic picture similar to that seen with toluene abuse may occur in cases of chronic chlorinated hydrocarbon abuse. Metabolites may also contribute to CNS effects, especially in the case of metabolically produced carbon monoxide from significant methylene chloride exposure.47 Chronic exposure to chlorinated hydrocarbons at lower levels is most frequently associated with occupational settings. The CNS depression and narcosis seen with acute high-dose exposure is generally not seen with chronic low-dose exposures. The occurrence of solventinduced encephalopathy from low-dose exposure is a matter of some debate. Several epidemiologic studies have looked for cognitive dysfunction in workers exposed to individual and mixtures of solvents with batteries of psychometric tests.48-50 However, these studies are often difficult to interpret because of confounders such as simultaneous exposure to multiple chemicals, including alcohol use, and have not consistently and definitively shown any predictable CNS dysfunction with this exposure paradigm.

Cardiovascular The effects of chlorinated hydrocarbons on the cardiovascular system are visible on heart rate, contractility, and conduction. In general, the effects on all three of these parameters are dose-dependent depressive clinical effects. These depressant effects are likely at least twofold in etiology. First, the chlorinated hydrocarbons exert solvent-like effects that alter the fluidity of myocardial cell membranes, causing direct myocardial depression of contractility.51,52 Second, because of their lipophilic character, the chlorinated hydrocarbons readily cross the blood-brain barrier and disrupt the neuronal control of both heart rate and contractility. In fact, trichloroethylene (TCE) was once used as an inhaled agent for human anesthesia but was abandoned because of its cardiac depressant effects, which caused excessive bradycardia and hypotension.52

1354


The effects of chlorinated hydrocarbons on cardiac conduction are slightly more complex but can be considered to fall into two basic categories: depression and sensitization. The depressant effects are the result of the solvents acting to stabilize the myocardial cell membranes to depolarization.53 This increased membrane stability blocks conduction impulse transmission resulting in an increased risk for dysrhythmias. In vitro evidence also suggests that some depressant activity appears to be the result of the ability of the chlorinated hydrocarbons to attenuate calcium dynamics in cardiac myocytes during excitation-contraction coupling.54 The potency of the tested compounds to inhibit calcium dynamics in the cardiac myocytes expressed as IC50 correlated strongly (r = 0.9829) with compound lipophilicity expressed as octanol:water partition coefficient.54 Sudden death in humans following large exposure to chlorinated hydrocarbons has been reported numerous times and is often referred to as “sensitization.” Often, those afflicted by sudden death are solvent abusers, although death following occupational exposures to some solvents has occurred.55,56 The strong link between solvent abuse and sudden death was the genesis of the descriptive term sudden sniffing death, which is sometimes used to refer to this condition. Postmortem examination of people who died under such circumstances is often without adequate anatomic abnormality to alternatively explain death. The demise is sudden and often without apparent neurologic involvement such as seizures, so it seems likely that the cause of death is a dysrhythmiaassociated sudden cardiac arrest. As such, the concept of “myocardial sensitization” has been offered as an explanation. The actual pathophysiology of myocardial sensitization is poorly understood. The general theory is that the myocardium becomes more responsive to the effects of systemic catecholamines, including endogenously released epinephrine, and that any excess catecholamine exposure causes irritability of the myocardium, resulting in dysrhythmias. Hypoxia may be an alternative explanation. Perhaps the most widely cited study of myocardial sensitization from halogenated hydrocarbon inhalation was reported in 1971 by Reinhardt and colleagues.57 Due to the frequency with which it is cited in other works, this study deserves a brief discussion. In this investigation, the potential of 13 compounds to produce dysrhythmias in a dog model was examined. Nine of the test compounds were fluorocarbon derivatives (Freon), seven of which were also chlorinated; two compounds (isobutane and propane) were simple hydrocarbons; one was an aliphatic ether (dimethyl ether); and the last was vinyl chloride. Two exposure circumstances were used and designated “standard exposure” (test compound inhaled over 10 minutes) and “short-term exposure” (high concentration of test compound inhaled for 30 seconds accompanied by a stimulus to frighten the animal in order to stimulate endogenous epinephrine release). In the standard exposure experiment, the animals were equipped with continuous electrocardiographic monitors and received an intravenous injection of epinephrine (0.008 mg/kg over 9 seconds) followed by

the desired dose of test compound through mask inhalation. Midway through a 10-minute inhalation of test compound, a “challenge injection” of epinephrine was given, and the electrocardiogram was observed for the development of alterations in cardiac rhythm. The short-term exposure experiments were conducted in a similar fashion, except a high concentration of test compound was inhaled by the animal for only 30 seconds, and an external stimulus was applied to frighten the animal. The external stimulus used was a loud recording of noises such as sirens, gongs, and jet takeoffs. The authors examined the electrocardiographic data for the presence of marked responses, which they defined as development of a dysrhythmia considered to pose a serious threat or ending in cardiac arrest. In the standard exposure group, marked responses were seen only with higher concentrations of test compound, although not every animal who received the higher-dose test compound developed a marked response. The total number of dogs used in each phase of the experiment ranged from 6 to 13. Of the 367 dog exposures studied in the standard exposure experiments, 111 cases of marked response were reported, of which 14 were ventricular fibrillation and cardiac arrest. Alternatively stated, a cardiac arrest rate of only 3.8% was observed. In the short-term study, 66 dog exposures provided 9 marked responses, none of which were ventricular fibrillation or cardiac arrest. Notably, two animals manifested a bigeminal rhythm with areas of the electrocardiogram suggestive of multiple ventricular beats. The authors further indicated that the potential activity of a given compound depended at least partly on the specific halogen atoms present in the test compound. Those compounds that contained chlorine atoms produced the greatest degree of effect, whereas those halogenated only with fluorine were less effective. No brominated or iodinated compounds were studied. The nonhalogenated compounds produced a marked response rate similar to that seen with the halogenated compounds. The authors suggested that smaller doses of epinephrine were required to induce life-threatening dysrhythmias or cardiac arrest following exposure to the test compounds. Other investigators have indicated that the concentrations of epinephrine required to cause cardiac dysrhythmias with exposure to inhaled chlorinated hydrocarbons are within the physiologic range.58 However, even with the significantly higher doses of epinephrine used in Reinhardt’s dog study, none of the animals in the short-term exposure group suffered cardiac arrest. The cardiotoxicity associated with inhaled chlorinated hydrocarbons appears to be exacerbated in the setting of hypoxia and hypercarbia.57,59 A lack of protective effect against development of cardiac dysrhythmias because of tolerance with long-term use has been suggested as support for the theory of myocardial sensitization. Although the principle of myocardial sensitization has been proposed in human cases of sudden death from solvent abuse, definitive data are lacking. Several other factors may be either responsible or at least contributory to sudden death in chlorinated hydro-

CHAPTER 93

ClJC

Liver Chlorinated hydrocarbons, especially carbon tetrachloride and chloroform, are known to cause centrilobular hepatic necrosis and hepatomegaly.17 The destruction of liver cells, which may progress to involve the entire hepatic lobule, requires the metabolic activation of the chlorinated hydrocarbon (Fig. 93-3). The metabolically produced radicals are highly reactive, so the site of toxic effect is the liver because this is the site of radical production. The two most significant effects of free radical production are steatosis and carcinogenesis. Free radicals bind components of hepatocytes, resulting in inhibition of lipoprotein secretion.17,43 This causes an accumulation of fatty tissues in the liver, resulting in steatosis. When radicals react with DNA, the resulting adducts may be carcinogenic. Although other chlorinated hydrocarbons do not cause hepatic necrosis, many induce fatty changes in the liver. Even though the fatty changes are typically

Cl

●

O2

H

J J

J J

J J

ClJCJCl

Cl

P450

ClJC JOO

Cl

Cl

Cl

Carbon tetrachloride

Trichloromethyl radical

Trichloromethyl peroxy radical

●

+

H

H

C KC

CKC

Lipid

Lipid

●

Lipid radical

+

O2

J J

Cl

ClJC

H

●

OO C KC

Cl Lipid

J J

Cl

ClJCJH Cl

Lipid peroxy radical

H +

CKC

1355

listed cases, a brain trichloroethylene concentration of 2.5 mg/100 g was detected 33 days after death demonstrating the significant partitioning of the solvent into the CNS.55

carbon exposures. For example, chronic solvent abuse is associated with the development of cardiomyopathy, which is a known substrate for dysrhythmias. This may explain the lack of tolerance to cardiac dysrhythmias in people with a long-standing history of solvent abuse. Hypoxia and hypercarbia also put patients at greater risk for potentially lethal cardiac dysrhythmias; and hypoxia, anoxia, and suffocation all result from excessive oxygen displacement or positioning following loss of consciousness when chlorinated solvents are inhaled in large quantities. Finally, depression of sinus node impulse generation can be induced, leading to profound bradycardia with subsequent ventricular escape rhythms. In short, sudden death associated with inhalation of high concentrations of chlorinated hydrocarbon solvents, especially solvent abuse, is probably multifactorial, and myocardial sensitization to endogenous catecholamines is likely not the sole etiology. When victims of sudden sniffing death are examined at autopsy, both gross and microscopic examinations are frequently normal. This has been demonstrated not only in animals but also in human cases.57,60 Two papers have also examined the postmortem tissue concentrations of trichloroethylene in cases of human death following acute occupational exposure.55,56 In one of the

Cl


+

●

H Lipid

H C KC

Lipid radical

Lipid

H

H CKC

●

Lipid Lipid radical FIGURE 93-3 Metabolic activation of carbon tetrachloride to form free radical species.

OOH C KC Lipid

Lipid hydroperoxide

●

1356


reversible, it is a matter of some discussion as to whether or not the fatty changes are a prelude to hepatocyte death. The significance of the damage and ultimate prognosis for recovery are based on several factors. Among these factors are the magnitudes of exposure, underlying liver health, and presence or absence of other hepatotoxins. It is also important to realize that the extent of CNS involvement is not necessarily predictive of liver or kidney injury.

Kidney Renal damage may also be associated with exposure to some of the chlorinated hydrocarbons. Reported toxic effects of chlorinated hydrocarbon poisoning on the kidney include azotemia, oliguria, anuria, ketonuria, acute tubular necrosis, and renal failure.61,62 Granular casts and red blood cells have also been seen in the urine after chloroform exposure.37 Although inadequate to explain all cases of renal injury that have been reported after exposure to chlorinated hydrocarbons, at least part of the mechanism of injury in the kidney is likely the same as in the liver: production of reactive free radical and other reactive metabolites in the kidney by P450–mediated oxidation.63 It has been suggested that occupational exposure to chlorinated solvents is linked to glomerulonephritis, but this association has not been clearly defined.61,62 Renal failure has been reported after dermal exposure to carbon tetrachloride.16

Dermal Because chlorinated hydrocarbon solvents are very hydrophobic, they tend to dissolve the lipids in the epidermis. This defatting of the skin surface often leads to a chronic irritant dermatitis. Most chlorinated hydrocarbon solvents are mild irritants. However, repeated or prolonged dermal contact may produce inflammation or burns. Trapping of solvents such as chloroform and methylene chloride under jewelry like rings and watches results in an almost immediate burning sensation on the contacted skin. Skin exposed to chlorinated hydrocarbon solvents may become hyperkeratotic, scaly, or thickened, and painful cracks or fissures may also be present.14 Tetrachloroethylene (perchloroethylene) is a much stronger irritant than the other chlorinated hydrocarbon solvents, and even brief contact with this compound can result in blistering and burns.14 Beyond simply the discomfort associated with solventcaused dermatitis, the violation of the integrity of the skin as a barrier may also have significant clinical consequences. Dermal absorption of chlorinated hydrocarbon solvents alone is generally insufficient to cause systemic illness. However, when the skin is no longer intact, absorption of solvents may be greater, potentially leading to systemic effects. Dermal absorption of some important chlorinated hydrocarbon compounds may be clinically significant through the contribution of this route of exposure to the total-body burden of the compounds. In addition, although the chlorinated hydrocarbons are not themselves allergenic, it is possible that destruction of

the skin by these solvents may make the skin more permeable to sensitizing agents with which the exposed individual may be working. Effects of chlorinated hydrocarbon exposure on the skin may also be systemic. Development of local scleroderma on the volar surfaces of the forearms and dorsal surfaces of the ankles in a 26-year-old woman with a history of working with tetrachloroethylene was reported, although this patient also worked with other solvents and this association remains elusive.64 Exposure to trichloroethylene is associated with a unique toxicity known as “degreaser’s flush.” This condition is manifested by flushing of the face after ingestion of ethanol in people with chronic exposure to trichloroethylene vapor. The flushing is a result of vasodilation of the superficial blood vessels on the face. The exact mechanism of this effect is unclear, but it may be due to the direct effects of the trichloroethylene metabolites chloral hydrate and trichloroacetic acid on the vasculature. The time course of degreaser’s flush is predictable. Typically, red blotches develop on the nose and malar eminences within about 30 minutes after the individual ingests alcohol. The blotches increase in size and then become confluent, resulting in a generalized flushing of the face and neck, which peaks within about an hour. The flushing then gradually diminishes to disappearance over the course of the subsequent hour. In daily drinkers of alcohol, degreaser’s flush is generally not observed until after about 3 weeks of daily exposure to trichloroethylene vapor. Notably, once established, the flushing reaction may occur with ethanol ingestion as much as 3 weeks after the last trichloroethylene vapor exposure.

Ocular Like the skin, damage to the eye as a result of ocular chlorinated hydrocarbon exposure is largely due to delipification. Most often, the result of ocular exposure is mild chemical conjunctivitis, although direct application of high-concentration liquid chlorinated solvents may cause pain or burning with corneal dulling.14 Diplopia, visual blurring, and blindness have also been reported with contact with bulk chlorinated hydrocarbon solvents.14 Punctate staining of the epithelium may be seen with fluorescent examination. Unless serious chemical burns result, the damage is generally reversible. Both carbon tetrachloride and tetrachloroethylene have been implicated in development of optic neuritis, although this is not universally supported in the literature.42 Blepharospasm has been reported after exposure to high concentrations of chloroform vapor.6 However, most cases of exposure to airborne chlorinated hydrocarbons do not result in persistent ocular damage even when the solvent concentrations are quite high. Systemically absorbed chlorinated hydrocarbons do not typically cause ocular toxicity. However, development of blue-gray corneal opacities was observed in a dog model after systemic, but not intraocular, administration

CHAPTER 93

of dichloroethane.17 No reports of similar systemically mediated ocular effects in humans exist.

Pulmonary Exposure of the lungs to chlorinated hydrocarbons must be divided into two distinct situations: aspiration and inhalation. The effects on the lungs from these two different routes of exposure are quite different. With aspiration of liquid solvent, potentially severe chemical pneumonitis is the primary concern. This is largely due to the solubility of lung surfactant in the chlorinated hydrocarbon solvent leading to profound inflammation of the lung. In contrast, inhalation of solvent vapor does not typically cause this sort of injury, although massive inhalation has caused pulmonary hemorrhage.14,65 Even though respiratory arrest may be seen with large inhalation exposures to chlorinated hydrocarbons, the mechanism is typically CNS depression (solvent narcosis) rather than direct damage to the lung. Because of the volatility of the chlorinated hydrocarbon solvents, the lungs represent a major exposure pathway. Although metabolism by P-450 enzymes in the Clara cells may produce some reactive metabolites, the lungs are not a principal target organ for chlorinated hydrocarbon toxicity.66 Pulmonary irritation is possible, and is expected with high-concentration exposures. Very large pulmonary exposures to some compounds, including methylene chloride, may produce chemical pneumonitis or noncardiogenic pulmonary edema.14,67,68

Teratogenicity and Carcinogenicity The association of reproductive effects, including teratogenicity, and carcinogenicity with exposure to the chlorinated hydrocarbon compounds is a topic that is hotly debated. Vinyl chloride, which is not discussed in this chapter, is an International Association for Research on Cancer (IARC) class 1 compound, and knowledge of this association fuels concern about the cancer-causing potential of other chlorinated hydrocarbons. Conflicting data between studies, as well as significant species dependence in observed effects, make evaluation and comparison of much of the data difficult. Interpretation of the human epidemiologic data is further hindered by the presence of confounders such as simultaneous significant exposure to other potentially toxic compounds, poor quality of exposure measurements, and recall bias. Perhaps the simplest case is that for 1,1,1-trichloroethane. Data suggest no teratogenic effects in laboratory animals or humans; further, carcinogenicity of this compound has not been demonstrated in humans. Animal data suggest that tetrachloroethylene is fetotoxic, and both tetrachloroethylene and trichloroethylene have been reported to cause developmental abnormalities in animals.69,70 However, these observations do not seem to translate to human epidemiologic investigations. No adverse effects on reproduction have been shown in humans after exposure to tetrachloroethylene. Although trichloroethylene exposure is a suggested culprit in human cases of birth defects and


1357

increased rates of spontaneous abortion, inadequate data regarding the amounts of other compounds to which the mothers were exposed is missing, making establishment of a link impossible.69,70 Although associations between exposure to tetrachloroethylene and development of malignancy (leukemia as well as liver, esophageal, and urinary tract tumors) and also between trichloroethylene and other cancers (non-Hodgkin’s lymphoma, hepatic and renal cancers) have been alleged, the epidemiologic data are not sufficient to establish a definitive connection.71,72 Impurities in the chlorinated hydrocarbon solvents may significantly influence evaluation of cancer-causing potential. One study reported development of pulmonary tumors in mice exposed to trichloroethylene; however, the trichloroethylene used in the experiments may have been contaminated with trace amounts of the stabilizer epichlorohydrin, a known carcinogen.73 Tetrachloroethylene and trichloroethylene are both classified as IARC 2A compounds, whereas 1,1,1-trichloroethane is IARC class 3 based on animal studies. Concerns about possible adverse health effects have resulted in published efforts describing methods to limit occupational exposure to chlorinated hydrocarbon solvents and influence both technologic innovation and legislation on industrial metal degreasing.74 The case of association is modestly stronger for adverse reproductive effects and carcinogenicity with exposure to the one-carbon chlorinated derivatives. Although methylene chloride and chloroform have not been shown to be teratogenic in some animal models, chloroform is highly embryotoxic and causes changes in sperm morphology in animals.14,75 Chloroform readily crosses the placenta.76 Two cases of eclamptic toxemia were reported in pregnant women who worked in a laboratory where chloroform was used, although the association was circumstantial.77 The situation for carbon tetrachloride is similar. This compound also crosses the placenta and has been detected in cord blood in exposed humans.69,76 Carbon tetrachloride has been reported to be both fetotoxic and teratogenic in rats.78 Other investigators have not observed teratogenic effects in rats or rabbits.69 At carbon tetrachloride doses of 0.1 and 0.01 of the LD50 given to mice on days 1, 6, and 11 of gestation, no evidence of teratogenicity or fetotoxicity was observed.79 Carcinogenicity of other compounds may be enhanced by exposure to carbon tetrachloride.80 Methylene chloride, chloroform, and carbon tetrachloride are all classified as IARC class 2B. Except for vinyl chloride, the data in animals suggest an association with development of cancer; data in humans are inadequate to establish causality.

DIAGNOSIS Although patients presenting with acute chlorinated hydrocarbon toxicity may be quite ill, the signs and symptoms are nonspecific. Further, specific laboratory assays for the detection of chlorinated hydrocarbons are not routinely available in most hospital laboratories but

1358


are from certain reference laboratories. Therefore, to diagnose chlorinated hydrocarbon toxicity, it is necessary to obtain a history of exposure. In cases of acute occupational exposure, container labels or material safety data sheets may be available. Additional helpful information, such as air monitoring results, may be available from local emergency medical services personnel or fire department hazardous materials teams who responded to the incident. Cases of chronic exposure in which no immediate life threats exist may be more challenging to reconcile. Such incidents require careful physical examination along with a detailed history and differential diagnosis. Although it is most often essentially impossible to determine exact dose, especially in chronic exposure circumstances, some topics that should be addressed include the conditions of use, temperature, ventilation systems and other workplace controls in place, use of personal protective equipment, and whether the agent is aerosolized or used as bulk solvent. In the evaluation of less critical patients presenting with possible chronic toxicity, the history must include not only workplace exposure but also potential household and hobby sources such as home improvement, automotive repair, art, and cleaning activities. In general, chlorinated hydrocarbons are CNS depressants, although this diminished level of consciousness may be preceded by an initial brief period of CNS excitation. The exact effects on the CNS and the time course of onset are largely dose dependent. Dose is determined by duration of exposure, concentration of the solvent, and minute ventilation volume. Individual susceptibility may also play a role in the development of specific signs and symptoms. Large inhalation exposures are typically manifested by headache, fatigue, lethargy, nausea, and abdominal discomfort. Continued exposure may result in a progression to ataxia, stupor, coma, and death. Higher concentration exposures are generally associated with more rapid onset of more significant signs and symptoms. In some rare cases, coma and death may occur within minutes. Fortunately, with removal from the source of exposure, recovery is typically rapid provided the victim has not suffered serious trauma or hypoxic insult. Because of its prolonged elimination time, recovery may be somewhat slower after exposure to high concentrations of tetrachloroethylene. Clinical presentation after ingestion of chlorinated hydrocarbon solvents is analogous to that seen with inhalation. However, the CNS depression may be delayed in onset with ingestion as a result of the time lag required for systemic absorption. In cases of large ingestions of trichloroethylene or tetrachloroethylene, onset of neurologic signs and symptoms may be delayed for several hours. As previously stated, trichloroethylene is eliminated very slowly. Therefore, prolonged coma may result after significant ingestions. Furthermore, it is possible that cardiac dysrhythmias may develop hours after ingestion of trichloroethylene when CNS depression is present or after significant methylene chloride exposure as a result of carbon monoxide production. One other special case that must be kept in mind is the potential for metabolic production of carbon monoxide

from significant exposures to dichloromethane. Although recovery may be slightly slower than with inhalation, recovery from chlorinated hydrocarbon poisoning as a result of ingestion is typically complete within about 24 hours in the absence of secondary effects such as aspiration, hypoxia, or carbon monoxide production.

MANAGEMENT The initial approach to the medical management of acute chlorinated hydrocarbon toxicity is appropriate supportive care. As toxic exposure to this class of compounds is associated with substantial CNS and respiratory depression, as well as the possibility of oropharyngeal edema due to chemical burns, early and aggressive airway management is paramount. In these situations, as well as in cases of large ingestions, protection of the airway with endotracheal intubation is appropriate. Pulse oximetry and cardiac monitoring should be initiated and intravenous access obtained with crystalloid fluids. Baseline laboratory evaluation of acid–base status, electrolytes, and renal and hepatic function is appropriate. Chest radiography to assess endotracheal tube placement or the possibility of aspiration is indicated if clinically appropriate. Interestingly, some chlorinated hydrocarbons are radiopaque, which may assist in locating significant depots. In cases of significant methylene chloride exposure, absorption may be prolonged; therefore, serial carboxyhemoglobin determinations are appropriate until a definitive downward trend is demonstrated. Chlorinated hydrocarbon toxicity frequently causes profound diarrhea, which may exacerbate electrolyte imbalances. As such, fluid intake and output should be monitored closely as significant volumes of fluid and associated electrolytes may need to be replaced. There is no specific antidotal therapy for chlorinated hydrocarbon intoxication. As such, treatment is symptomatic and supportive using standard basic and advanced life support interventions. Dysrhythmias resulting from chlorinated hydrocarbon toxicity should be managed according to standard advanced cardiac life support protocols. Many sources recommend that clinicians avoid the use of catecholamines such as epinephrine during the course of resuscitation of chlorinated hydrocarbon–induced cardiac arrest because of the possibility of myocardial sensitization to endogenous catecholamines. However, because myocardial sensitization has not been definitively shown to be the principal mechanism for sudden death associated with chlorinated hydrocarbon exposure and because administration of catecholamines such as epinephrine and dopamine is a standard resuscitative measure, complete avoidance of these therapies may be unwise.

Decontamination and Prevention of Absorption External decontamination after exposure to chlorinated hydrocarbons is necessary to limit continued absorption by the victim as well as to protect the rescuers. Largely as

CHAPTER 93

a result of the volatility of these compounds, simple decontamination techniques are quite effective. Removal of clothing followed by washing with copious amounts of water is the management of choice. Addition of soap to the decontamination rinse may assist in increasing the solubility of the chlorinated hydrocarbon compounds in the decontamination water. As with most liquid chemicals, the possibility of enhancement of absorption through vasodilation as a result of using scrubbing brushes or hot decontamination water exists with chlorinated hydrocarbon solvents. However, these compounds are sufficiently volatile and their percutaneous absorption generally low enough that this concern is largely theoretical. Special attention should be given to the decontamination of open wounds and mucous membranes. Gastric decontamination after ingestion of chlorinated hydrocarbons should be undertaken on a carefully considered case-by-case basis. Induction of emesis is contraindicated because these compounds are commonly associated with CNS depression. Gastric aspiration may be considered in cases of large carbon tetrachloride or chloroform ingestion presenting shortly after ingestion in an attempt to limit the risk for hepatic damage. Administration of a single dose of activated charcoal may be considered, especially in cases of polysubstance ingestion. However, the clinician should remain mindful that the efficacy of activated charcoal has not been proved in cases of chlorinated hydrocarbon ingestion and that the potential for CNS depression, emesis, and aspiration exists. There are no specific antidotes for toxic exposure to chlorinated hydrocarbons. N-acetylcysteine (NAC) is beneficial in preventing damage due to acetaminophen intoxication as well as in cases of fulminant hepatic failure.81,82 There are several proposed mechanisms of action for the hepatoprotective effects of NAC, including acting as both a glutathione precursor and a glutathione surrogate. Based on this theory, case reports have suggested using NAC to assist in minimizing hepatic damage as a result of acute carbon tetrachloride exposure.83 Additional case reports suggest benefit from hyperbaric oxygen therapy in cases of methylene chloride or carbon tetrachloride poisoning.28,38 Enhancement of elimination from the gastrointestinal tract using methods such as whole-bowel irrigation is not appropriate for toxic ingestions of chlorinated hydrocarbons. Because chlorinated hydrocarbons are eliminated largely through the lungs, hyperventilation may be beneficial. A case report of tetrachloroethylene poisoning suggested some benefit in accelerated clearance with hyperventilation.30 Because of the large volumes of distribution, clearance of the chlorinated hydrocarbons using hemodialysis is generally ineffective. However, in cases of chlorinated hydrocarbon–induced renal failure, hemodialysis may be necessary and should be continued until renal function normalizes.

Disposition In cases of toxicity after inhalation of chlorinated hydrocarbons, cessation of symptoms and complete


1359

recovery are expected shortly after termination of the exposure. Typically, if the patient is asymptomatic, discharge is appropriate as soon as any alterations in mental status clear. The oral pathway may require a longer observation period. Depending on the circumstances of the exposure, discussion of safety practices at the worksite or referral for psychiatric evaluation may be warranted. Patients with persistent CNS depression, cardiac dysrhythmias, or pulmonary involvement should be admitted until the clinical picture resolves. Further, in the event of a significant exposure, admission, with serial clinical and laboratory evaluations, is recommended. Renal and hepatic injury typically resolves with generalized supportive care and returns to baseline within days to weeks. REFERENCES 1. Beattie C: History and principles of anesthesiology. In Hardman JG, Limbird LE, Gilman AG (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New York, McGraw-Hill, 2001. 2. Dilger JP: Basic pharmacology of inhalational anesthetic agents. In Bowdle TA, Horita A, Kharasch EDe (eds): The Pharmacologic Basis of Anesthesiology: Basic Science and Practical Applications. New York, Churchill-Livingstone, 1994. 3. Nashelsky MB, Dix JD, Adelstein EH: Homicide facilitated by inhalation of chloroform. J Forensic Sci 1995;40:134–138. 4. Reynolds JEF: Martindale: The Extra Pharmacopoeia, 28th ed. London, The Pharmaceutical Press, 1982. 5. Dykes MH: Halogenated hydrocarbon ingestion. Int Anesthesiol Clin 1970;8:357–368. 6. Hathaway GJ, Proctor NH, Hughes JP, et al: Chemical Hazards of the Workplace, 4th ed. New York, Van Nostrand Reinhold, 1996. 7. Lewis RA: Lewis’ Dictionary of Toxicology. Boca Raton, FL, Lewis, 1998. 8. American Conference of Industrial Hygienists: Documentation of the Threshold Limit Values and Biological Exposure Indices, 6th ed. Cincinnati, Author, 1996. 9. Hazardous Substances Data Bank, National Library of Medicine. Englewood, CO, Micromedex, 2000. 10. International Programme on Chemical Safety: Environmental Health Criteria 163—Chloroform. Geneva, World Health Organization, 1994. 11. Smyth HF: Hygiene standards for daily inhalation. The Donald E. Cummings Memorial Lecture. Am Ind Hyg Q 1956;17:129–185. 12. Hoffman HT, Birnstiel H, Jobst P: On the inhalation toxicity of 1,1and 1,2-dichloroethane. Arch Toxicol 1971;27 :248–265. 13. New PS, Lubash GD, Scherr L: Acute renal failure associated with carbon tetrachloride intoxication. JAMA 1962;181:903–906. 14. Harbison RM: Hamilton and Hardy’s Industrial Toxicology, 5th ed. St. Louis, Mosby, 1998. 15. DiVincenzo GD, Kaplan CJ: Uptake, metabolism, and elimination of methylene chloride vapor by humans. Toxicol Appl Pharmacol 1981;59:130–140. 16. Perez AJ, Courel M, Sobrado J, Gonzalez L: Acute renal failure after topical application of carbon tetrachloride. Lancet 1987; 1:515–516. 17. Barceloux DG: Halogenated solvents, trichloroethylene and methylene chloride. In Sullivan JB, Krieger GR (eds): Clinical Environmental Health and Toxic Exposures. Philadelphia, Lippincott Williams & Wilkins, 2001. 18. Jakobson I, Wahlberg JE, Holmberg B, Johansson G: Uptake via the blood and elimination of 10 organic solvents following epicutaneous exposure of anesthetized guinea pigs. Toxicol Appl Pharmacol 1982;63:181–187. 19. Baselt RC: Disposition of toxic drugs and chemicals in man, 6th ed. Foster City, CA, Chemical Toxicology Institute, Biomedical Publications, 2002. 20. Koppel C, Lanz HJ, Ibe K: Acute trichloroethylene poisoning with additional ingestion of ethanol: concentrations of trichloro-

1360

21.

22. 23. 24. 25. 26. 27. 28. 29. 30. 31.

32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48.


ethylene and its metabolites during hyperventilation therapy. Intensive Care Med 1988;14:74–76. Reitz RH, Gargas ML, Mendrala AL, Schumann AM: In vivo and in vitro studies of perchloroethylene metabolism for physiologically based pharmacokinetic modeling in rats, mice, and humans. Toxicol Appl Pharmacol 1996;136:289–306. Ward RC, Travis CC, Hetrick DM, et al: Pharmacokinetics of tetrachloroethylene. Toxicol Appl Pharmacol 1988;93:108–117. Cornish HH, Barth ML, Ling B: Influence of aliphatic alcohols on the hepatic response to halogenated olefins. Environ Health Perspect 1977;21:149–152. Gargas ML, Clewell HJ 3rd, Andersen ME: Metabolism of inhaled dihalomethanes in vivo: differentiation of kinetic constants for two independent pathways. Toxicol Appl Pharmacol 1986;82:211–223. Mahmud M, Kales SN: Methylene chloride poisoning in a cabinet worker. Environ Health Perspect 1999;107:769–772. Kim NY, Park SW, Suh JK: Two fatal cases of dichloromethane or chloroform poisoning. J Forensic Sci 1996;41:527–529. Guengerich FP, Kim DH, Iwasaki M: Role of human cytochrome P-450 IIE1 in the oxidation of many low molecular weight cancer suspects. Chem Res Toxicol 1991;4:168–179. Rioux JP, Myers RA: Hyperbaric oxygen for methylene chloride poisoning: report on two cases. Ann Emerg Med 1989;18:691–695. Barceloux DG, Rosenberg J: Trichloroethylene toxicity. J Toxicol Clin Toxicol 1990;28:479–504. Koppel C, Arndt I, Arendt U, Koeppe P: Acute tetrachloroethylene poisoning: blood elimination kinetics during hyperventilation therapy. J Toxicol Clin Toxicol 1985;23:103–115. Lash LH, Qian W, Putt DA, et al: Renal and hepatic toxicity of trichloroethylene and its glutathione-derived metabolites in rats and mice: sex-, species-, and tissue-dependent differences. J Pharmacol Exp Ther 2001;297:155–164. Lash LH, Parker JC: Hepatic and renal toxicities associated with perchloroethylene. Pharmacol Rev 2001;53:177–208. Mycroft FJ, Fan A: Trichloroethylene (TCE). Hazard Rev 1985;2:1–4. Kostrzewski P, Jakubowski M, Kolacinski Z: Kinetics of trichloroethylene elimination from venous blood after acute inhalation poisoning. J Toxicol Clin Toxicol 1993;31:353–363. Perbellini L, Olivato D, Zedde A, Miglioranzi R: Acute trichloroethylene poisoning by ingestion: clinical and pharmacokinetic aspects. Intensive Care Med 1991;17:234–235. Kohlmuller D, Kochen W: Exhalation air analyzed in long-term postexposure investigations of acetonitrile and trichloroethylene exposures in two subjects. Clin Chem 1994;40:1462–1464. Schroeder HG: Acute and delayed chloroform poisoning. Br J Anaeseth 1965;37:972–975. Burkhart KK, Hall AH, Gerace R, Rumack BH: Hyperbaric oxygen treatment for carbon tetrachloride poisoning. Drug Saf 1991;6:332–338. U.S. Department of Health and Human Services: ATSDR case studies in environmental medicine: methylene chloride toxicity. Atlanta, Agency for Toxic Substances and Disease Registry, 1990. Bass M: Sudden sniffing death. JAMA 1970;212:2075–2079. England A, Jones RM: Inhaled anaesthetic agents: from ether to halothane. Br J Hosp Med 1992;47:699–702. Onofrj M, Thomas A, Paci C, et al: Optic neuritis with residual tunnel vision in perchloroethylene toxicity. Eur Neurol 1999;41:51–53. Kalf GF, Post GB, Snyder R: Recent advances in the toxicology of benzene, the glycol ethers and carbon tetrachloride. Annu Rev Pharmacol Toxicol 1987;27:399–427. Cohen MM: Central nervous system in carbon tetrachloride intoxication. Neurology 1957;7:238–244. Kornfeld M, Moser AB, Moser HW, et al: Solvent vapor abuse leukoencephalopathy: comparison to adrenoleukodystrophy. J Neuropathol Exp Neurol 1994;53:389–398. Rebert CS, Matteucci MJ, Pryor GT: Acute effects of inhaled dichloromethane on the EEG and sensory-evoked potentials of Fischer-344 rats. Pharmacol Biochem Behav 1989;34:619–629. Barrowcliff DF, Knell AJ: Cerebral damage due to endogenous chronic carbon monoxide poisoning caused by exposure to methylene chloride. J Soc Occup Med 1979;29:12–14. Edling C, Ekberg K, Ahlborg G Jr, et al: Long-term follow up of workers exposed to solvents. Br J Ind Med 1990;47:75–82.

49. Gregersen P: Neurotoxic effects of organic solvents in exposed workers: two controlled follow-up studies after 5.5 and 10.6 years. Am J Ind Med 1988;14:681–701. 50. Rasmussen K, Jeppesen HJ, Sabroe S: Solvent-induced chronic toxic encephalopathy. Am J Ind Med 1993;23:779–792. 51. Herd PA, Lipsky M, Martin HF: Cardiovascular effects of 1,1,1trichloroethane. Arch Environ Health 1974;28:227–233. 52. Zakhari S: Cardiovascular toxicology of halogenated hydrocarbons and other solvents. In Acosta D (ed): Cardiovascular Toxicology. New York, Raven, 1992. 53. Henry J, Cassidy S: Membrane stabilizing activity: a major cause of fatal poisoning. 1986;1:1414–1417. 54. Hoffmann P, Heinroth K, Richards D, et al: Depression of calcium dynamics in cardiac myocytes—a common mechanism of halogenated hydrocarbon anesthetics and solvents. J Mol Cell Cardiol 1994;26:579–589. 55. Ford ES, Rhodes S, McDiarmid M, et al: Deaths from acute exposure to trichloroethylene. J Occup Environ Med 1995;37: 749–754. 56. Coopman VA, Cordonnier JA, De Letter EA, Piette MH: Tissue distribution of trichloroethylene in a case of accidental acute intoxication by inhalation. Forensic Sci Int 2003;134:115–119. 57. Reinhardt CF, Azar A, Maxfield ME, et al: Cardiac arrhythmias and aerosol “sniffing.” Arch Environ Health 1971;22:265–279. 58. Shepherd RT: Mechanism of sudden death associated with volatile substance abuse. Hum Toxicol 1989;8:287–291. 59. Ramsey JD, Flanagan RJ: The role of the laboratory in the investigation of solvent abuse. Hum Toxicol 1982;1:299–311. 60. Alha A, Korte T, Tenhu M: Solvent sniffing death. Z Rechtsmed 1973;72:299–305. 61. Bell GM, Gordon ACH, Lee P: Proliferating glomerulonephritis and exposure to organic solvents. Nephron 1985;40:161. 62. Harrington JM, Whitby H, Gray CN: Renal disease and occupational exposure to organic solvents: a case referent approach. Br J Ind Med 1989;46:643. 63. Boogaard PJ, Caubo ME: Increased albumin excretion in industrial workers due to shift work rather than to prolonged exposure to low concentrations of chlorinated hydrocarbons. Occup Environ Med 1994;51:638–641. 64. Czirjak L, Pocs E, Szegedi G: Localized scleroderma after exposure to organic solvents. Dermatology 1994;189:399–401. 65. Patel R, Janakiraman N, Johnson R, Elman JB: Pulmonary edema and coma from perchloroethylene. JAMA 1973;223:1510. 66. Nichols WK, Covington MO, Seiders CD, et al: Bioactivation of halogenated hydrocarbons by rabbit pulmonary cells. Pharmacol Toxicol 1992;71:335–339. 67. Garriott J, Petty CS: Death from inhalant abuse: toxicological and pathological evaluation of 34 cases. Clin Toxicol 1980;16:305–315. 68. Trense E, Zimmermann H: Fatal inhalation poisoning with chronically acting tetrachloroethylene vapors. Zentralbl Arbeitsmed 1969;19:131–137. 69. Barlow SM, Sullivan FM: Reproductive hazards of industrial chemicals: an evaluation of animal and human data. London, Academic Press, 1982. 70. Schardein JL: Chemically induced birth defects, 3rd ed. New York, Marcel-Dekker, 2000. 71. Chang YM, Tai CF, Yang SC, et al: A cohort mortality study of workers exposed to chlorinated organic solvents in Taiwan. Ann Epidemiol 2003;13:652–660. 72. Raaschou-Nielsen O, Hansen J, McLaughlin JK, et al: Cancer risk among workers at Danish companies using trichloroethylene: a cohort study. Am J Epidemiol 2003;158:1182–1192. 73. U.S. Department of Health and Human Services: ATSDR toxicological profile for trichloroethylene. Atlanta, Agency for Toxic Substances and Disease Registry, 1992. 74. von Grote J, Hurlimann C, Scheringer M, Hungerbuhler K: Reduction of occupational exposure to perchloroethylene and trichloroethylene in metal degreasing over the last 30 years: influences of technology innovation and legislation. J Expo Anal Environ Epidemiol 2003;13:325–340. 75. Clayton GD, Clayton FE: Patty’s Industrial Hygiene and Toxicology, 4th ed. New York, John Wiley & Sons, 1994. 76. Dowty BJ, Laseter JL, Storer J: The transplacental migration and accumulation in blood of volatile organic constituents. Pediatr Res 1976;10:696–701.

CHAPTER 93

77. Tylleskar-Jensen J: Chloroform—a cause of pregnancy toxemia? Nord Med 1967;77:841–842. 78. Registry of Toxic Effects of Chemical Substances: NIOSH. Englewood, CO, Micromedex, 1999. 79. Hamlin GP, Kholkute SD, Dukelow WR: Toxicology of maternally ingested carbon tetrachloride (CCl4) on embryonal and fetal development and in vitro fertilization in mice. Zool Sci 1993;10:111–116. 80. Takizawa S, Watanabe H, Naito Y, Inoue S: Preparative action of carbon tetrachloride in liver tumorigenesis by a single application of N-butylnitrosourea in male ICR/JCL strain mice. Gann 1975;66:603–614.


1361

81. Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH: Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose: analysis of the national multicenter study (1976 to 1985). N Engl J Med 1988;319:1557–1562. 82. Harrison PM, Wendon JA, Gimson AE, et al: Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure. N Engl J Med 1991;324:1852–1857. 83. Valles EG, de Castro CR, Castro JA: N-acetyl cysteine is an early but also a late preventive agent against carbon tetrachloride-induced liver necrosis. Toxicol Lett 1994;71:87–95.

94

Benzene and Related Aromatic Hydrocarbons DANA B. MIRKIN, MD

At a Glance… ■

■

■

■ ■

■

Being highly lipophilic, all can produce narcosis if inhaled in high concentration, with CNS depressant effects that compare with those of general anesthetics The major aromatic compounds of toxicologic importance are toluene, benzene, styrene, ethylbenzene, trimethylbenzene, and xylene. The toxicity of the aromatic hydrocarbons is variable. Some, such as benzene, are highly toxic, affecting the CNS, bone marrow, and other vital organs. Many of the aromatic compounds are metabolized by cytochrome P450 isozymes. Metabolites of aromatic compounds are excreted in urine, making biological monitoring for occupational exposures relatively simple. In contrast, analysis of aromatics and their metabolites in blood is difficult. Treatment of severe exposure is supportive and includes the provision of fresh air or oxygen. There is probably little role for gastrointestinal decontamination since aromatics are not well adsorbed by activated charcoal.

Aromatic hydrocarbons are benzene derivatives; they constitute more than 50% of the different chemicals in common use.1,2 Aromatic solvents are found widely in many diverse occupations and products, in degreasing operations, lacquers manufacturing, printing, electronics and rubber (especially tire) manufacturing, paints, resins, pharmaceuticals, and glues and adhesives. They are liquids that typically exhibit high vapor pressures and low boiling points that rise with increasing molecular weight. This group of compounds has chemical structures of unsaturated cyclic compounds with the benzene ring as its basis. Benzene is the simplest homolog within the group. Aromatic hydrocarbons are divided into the benzene group (one ring), the naphthalene group (two rings), and the anthracene group (three rings). Polycyclic aromatic hydrocarbons (polynuclear aromatic hydrocarbons) have multifused benzene rings.3 This chapter reviews only the aromatic hydrocarbons in the benzene (single-ring) group, specifically benzene and its common derivatives, styrene, toluene, and xylene. These four compounds have historically been used as solvents, antiknock agents in motor fuel, and process intermediates and feedstock for chemical synthesis. Although originally derived from coal tar, the main source of aromatic organic compounds today is petroleum. The term aromatic originally stemmed from the pleasant odor characteristic of the earlier recognized compounds in the group; these substances were used in perfumes and flavorings. However, some aromatic hydrocarbons are odorless.

Aromatic solvents are characterized by nonpolarity and high lipid solubility. Structurally, their molecules are flat, with reactive electron clouds above and below the ring. The aromatic solvents have historically been found as mixtures in occupational settings, such as combinations of toluene, benzene, styrene, ethylbenzene, trimethylbenzene, and xylene. Exposure to aromatic solvents occurs through contact with vapor or liquid with absorption through inhalation or the skin. Acute inhalational exposure to high airborne concentrations can produce dizziness, syncope, confusion, euphoria, respiratory irritation, and in some instances, coma through direct neurotoxicity (solvent narcosis). Inhalational exposure to high airborne concentrations may also sensitize the myocardium to catecholamines, both endogenous and exogenous, leading to potentially dangerous dysrhythmias, once dubbed “sudden sniffing death syndrome.” Their individual toxicity correlates with physical chemical properties, inherent toxicity, and clinical pharmacokinetics, including metabolite production. Some aromatics, such as benzene and styrene, have metabolites that are their primary toxins.

BENZENE Benzene, CAS registry 71-43-2, also referred to as annulene, benzeen (Dutch), benzen (Polish), benzol, benzole, benzolo (Italian), bicarburet of hydrogen, coal naphtha, cyclohexatriene, fenzen (Czech), phene, phenyl hydride, pyrobenzol, pyrobenzole, and Polystream, is a clear, colorless to yellow liquid. Its odor threshold is 1.54 to 4.68 ppm, with a taste threshold in water of 0.5 to 4.5 mg/L. The molecular weight is 78.11.4,5 Benzene in mixtures deviates from Raoult’s law. Its vapor concentration is frequently higher than would be expected based on the concentration of benzene found in a solvent or hydrocarbon mixture. This is especially true of mixtures of hydrocarbons or solvents containing more than 5% benzene, from which substantial exposures to benzene vapors might occur during routine use.6 Benzene, a highly flammable liquid, was first discovered in 1825 by Michael Faraday, who isolated it from a liquid condensed from compressed oil gas.7 The heating of coal in a “by-product coke oven” resulted in the extraction of benzene, a significant by-product that, because of its low cost, excellent solvent properties, and rapid rate of evaporation, was used to make solutions of rubber or inks. Benzene was also involved in the chemical synthesis of dyes or halobenzene derivatives and other chemicals.8 In the 19th century, benzene was a common household degreasing agent and used in the dry-cleaning industry until its flammability, rather than its toxicity, led to its replacement by chlorinated 1363

1364


hydrocarbon solvents. Benzene was one of the first cancer chemotherapeutic agents recommended for the treatment of leukemia. The rationale for this astonishing treatment was that leukopenia occurred in some cases of benzene poisoning. However, “benzene therapy” was short-lived because of the complex action of the substance on the blood and the ensuing toxicity.9 Today, benzene is a widely used chemical with an annual production ranging from 10 to 30 billion pounds.10,11 Recently, the mandatory decrease of lead alkyls in gasoline has led to an increase in the aromatic hydrocarbon content of gasoline to maintain high octane levels and antiknock properties. In the United States, gasoline typically contains less than 2% benzene by volume, but in other countries, benzene concentrations can be as high as 5%.11 Human exposure to benzene takes place in factories, refineries, and other industrial settings. Although only a relatively small number of individuals are occupationally exposed to benzene, the general population is exposed to benzene contained in gasoline, automobile exhaust, and diesel fuel. Benzene is present in cigarette smoke, and smoking is the main source of benzene exposure for many people.7 It is found naturally in the environment at low concentrations.12 For example, a hen’s egg contains 35 to 133 μg of benzene. Many other foods (haddock fillet, red beans, blue cheese, cheddar cheese, pineapple, roasted filberts, potato tubers, cooked chicken, tomatoes, strawberries, black currants, roasted peanuts, soybean milk, codfish) also contain benzene in minute quantities. However, the exposure to benzene through normal dietary intake is not considered to be significant for the general population. Intakes per day from other exposures include smoking (1800 μg), passive smoke (50 μg), filling a gas tank (10 μg), driving or riding in a car (40 μg), and breathing outdoor air (120 μg).10,13 In 1897, Santesson, a professor of pharmacology at the University of Stockholm, first reported the deaths from aplastic anemia of four female industrial workers who used a benzene-based rubber cement in the course of their work in a tire factory. Subsequently, Selling at Johns Hopkins (1910) substantiated his suspicion that benzene was the cause of aplastic anemia among workers in a canning factory, inducing leukopenia and marrow aplasia in rabbits by injecting them with benzene (subcutaneously, 1 mL/kg daily). Weiskotten (1920) at Syracuse University College of Medicine administered benzene by inhalation to rabbits (240 ppm) and produced similar results. Confirmed by subsequent studies, the direct relationship between benzene exposure and aplastic anemia was established.14 Acceptance of the cause-and-effect association between benzene exposure and leukemia was, however, slower in gaining acceptance after initial case reports by LeNoir and Claude in 1897 and Delore and Borgomano in 19287 because few cases of leukemia were observed compared with reports of aplastic anemia associated with benzene exposure during that period. Nevertheless, Vigliani (1938) described benzene toxicity and classified it into four groups: (1) typical aplastic anemia, (2) atypical aplastic anemia with the bone marrow appearing

to be quite active in the formation of undifferentiated cells, (3) atypical aplastic anemia in which the marrow appeared to be either “hyperplastic” or “metaplastic,” and (4) aleukemic leukemia.14 A cottage industry in shoemaking existed in Turkey, with families making shoes in their poorly ventilated homes. A petroleum-based solvent was used as a base for the glue until 1955 to 1960, when a change was made to a benzene-based glue. Professor M. Aksoy of the Department of Hematology at the University of Istanbul recognized an unusual number of cases of aplastic anemia and leukemia among his clinic patients. Aware of Vigliani’s work, he studied the shoemakers of Istanbul, a cohort that numbered 28,500, and initially described 217 cases of bone marrow depression and 26 cases of leukemia (1971). He detected several cases of “preleukemia” and subsequently reported that of 51 cases of pancytopenia, 13 developed leukemia (1972).14 U.S. agencies, such as the Occupational Safety and Health Administration (OSHA) and the National Institute of Occupational Safety and Health (NIOSH) conducted further studies that established benzene as a leukemogen; those agencies and others attempted to determine acceptable levels of workplace exposure.15 A scientific consensus group (International Agency for Research on Cancer, IARC) concluded in 1982 that benzene was etiologically related to the development of acute nonlymphocytic leukemia based on epidemiologic studies.16 Later, a retrospective study was conducted on a welldefined cohort of workers in Ohio who were engaged in the manufacture of a rubberized material termed Pliofilm, in which benzene was used as a solvent for the rubber. The study showed elevated risks for leukemia associated with benzene exposure and argued that the risk was cumulative with prolonged exposure.14 Despite criticism of the Pliofilm study, subsequent analyses have supported the role of benzene as a leukemogen, and the argument has since revolved around estimates of risk. An opportunity to use a larger cohort of benzeneexposed workers, which might be a better source of data for relating dose to leukemogenesis, arose in China where Dr. S-N. Yin of the Institute of Health of the Chinese Academy of Medical Sciences studied more than 500,000 workers demonstrating yet again the associations between benzene exposure and aplastic anemia and leukemia. Although the average benzene exposure concentration of the entire exposed cohort was determined to be 5.6 ppm, ranges of exposure among subcohorts of workers developing aplastic anemia and leukemia were found to be much higher, 29 to 361 ppm over varying periods of time. A joint effort on the part of Dr. Yin’s group and the U.S. National Cancer Institute (NCI) involving almost 75,000 exposed workers and 36,000 controls demonstrated significantly elevated levels of acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and aplastic anemia associated with benzene exposure at levels below 10 ppm. However, the accuracy of exposure measurements and estimates in the Chinese cohorts

CHAPTER 94

have since been questioned, and exposure levels may have been much higher than originally reported.17 The controversy regarding a “safe” level for occupational exposure continues. The benzene ring is not a structure that readily binds covalently to glutathione, proteins, DNA, and RNA. It requires metabolic activation to a more reactive structure beginning with conversion to an epoxide (i.e., benzene oxide). Benzene oxide, in equilibrium with its oxepin form, is further metabolized to hydroquinone and catechol, which can then be readily converted to a benzoquinone (ortho- or para-), the ultimate toxic metabolite of benzene. Another potentially toxic metabolite, muconaldehyde, may arise from opening of the benzene oxide ring.9,15 The mechanisms by which benzene produces bone marrow damage involve several targets of benzene metabolites. These include inhibition of spindle formation, which impairs mitosis; inhibition of the synthesis of interleukin-1, an essential factor in normal bone marrow function; covalent binding to proteins and DNA, forming adducts; inhibition of DNA polymerase contributing to irreversible changes in DNA; and chromosome damage, observed in MDS. Although the impact of these and other possible effects may have differential significance in the development of benzene toxicity, all appear to occur in the course of the development of benzene-induced hemopathies.8 Upon inhalation of benzene vapors, respiratory uptake varies from 47% to 80%; dermal absorption from liquid ranges from 0.05% to 0.2%. Absorption data for oral exposure are not available for humans; however, in animals, absorption rates following oral ingestion of benzene have been found to be 90% to 100%.11 Benzene is distributed throughout the body after absorption into the blood. Because it is lipophilic, a high distribution to fatty tissue is expected. Benzene crosses the human placenta and is present in the cord blood in amounts equal to or greater than that in maternal blood.4 After inhalational exposure, most benzene is excreted unchanged in exhaled air. Absorbed benzene is rapidly detected in all organs. Its excretion involves a biphasic urinary excretion of conjugated derivatives (sulfates and glucuronides) with a half-life of 0.7 hours. The half-life of benzene in lipid tissues is about 24 hours. Metabolism of benzene occurs primarily in the liver, although metabolism in bone marrow is also believed to play an important role in myelotoxicity. After rapid absorption from the lungs, benzene undergoes both phase I and II biotransformation in the liver. The primary phase I biotransformation of benzene involves cytochrome P-450 2E1-catalyzed (CYP2E1) conversion initially to phenol and subsequently to hydroquinone and catechol.18 The opening of the benzene ring, to eventually form muconic acid, appears to include a number of intermediates that arise from muconaldehyde.19 The many urinary metabolites of benzene include sulfate and glucuronic acid conjugates of the hydroxylated ring metabolites, several glutathione derivatives,

Benzene and Related Aromatic Hydrocarbons

1365

and muconic acid. At least one residue of a DNA adduct (7-phenylguanine) has been reported.19 Factors that alter the metabolism of benzene have the potential to influence its hematopoietic toxicity and carcinogenicity. Current research centers on the identification of risk factors for susceptibility to benzene toxicity, and there is evidence that metabolic susceptibility and genetic predisposition may play a major role. Metabolism and disposition are among the most important determinants of benzene toxicity. This variability results from intrinsic differences in the activities of xenobiotic metabolizing enzymes (so-called genetic polymorphisms). Variable factors in sensitivity include (1) hepatic CYP2E1, a major enzyme of the cytochrome P-450 family involved in benzene oxidation; (2) conjugating enzymes such as glutathione transferases; and (3) comparative activity of myeloperoxidase and myeloreductase (NQO1) in bone marrow. Benzene toxicity is thought to be exerted through oxidation metabolites formed in the liver primarily through pathways mediated by the cytochrome P-450 family of enzymes; benzene oxide may be sufficiently stable to reach the bone marrow. Interindividual variations in benzene metabolism are related to CYP2E1 expression, possibly owing to polymorphism of the CYP2E1 gene. CYP2E1 is found in both the liver and bone marrow. Another enzyme found to metabolize benzene is CYP1B1.20 An important protective mechanism against oxidative stress is the detoxification of lipid peroxidation products by glutathione S-transferase-theta (GSTT1) and -mu (GSTM1). Phase II metabolizing enzymes such as GSTT1 show genetic polymorphisms that correlate with GSTT1 activity. Studies have demonstrated an increased risk for myelodysplastic syndromes in individuals with a GSTT1 gene defect or absence. 20 Hydroxylated metabolites of benzene are activated to toxic and genotoxic species in the bone marrow through oxidation by myeloperoxidase (MPO). NAD(P)H:quinone oxidoreductase (NQO1) is an enzyme capable of reducing the oxidized quinone metabolites and thereby potentially reducing their toxicities. A polymorphism in NQO1, a C609T substitution, has been identified, and individuals homozygous for this change (T/T) have no detectable NQO1. A higher frequency of an inactivating polymorphism in NQO1 has been reported in a cohort of patients with myeloid leukemias, especially those with an abnormality of chromosome 5 or 7, a chromosomal aberration associated with benzene exposure. It has been postulated that homozygotes (who display a complete loss of enzyme activity), as well as heterozygotes (who are at risk for loss of the remaining wild-type allele in their hematopoietic stem cells), may be particularly vulnerable to leukemogenic changes induced by carcinogens such as benzene.15,19,20 Limited gender comparisons suggest that males metabolize benzene at a higher rate then females, who retain benzene longer, owing to their higher body-fat content. There is little evidence, however, that women and offspring are more susceptible to clastogenic or leukemogenic actions of benzene.

1366


It remains unknown whether benzene affects reproductive function in humans.21 A study of benzeneexposed female dental surgeons failed to show an adverse effect on fertility, whereas another study of aircraft maintenance workers exposed to solvents and fuel showed some adverse effects on sperm function, including a decline in sperm motility, but the finding could not be attributed solely to benzene exposure.20 It has been demonstrated that pretreatment of rats with ethanol, a CYP2E1 inducer, enhances metabolism of benzene and potentiates its acute myelotoxicity. Pretreatment of male B6C3F1 mice with acetone, another CYP2E1 inducer, increases benzene oxidation about five times. Pretreatment with diethyldithiocarbamate, a CYP2E1 inhibitor, completely abolishes benzene oxidation. Pretreatment of mice with inducers of metabolism such as 3-methylcholanthrene and β-naphthoflavone increased both benzene metabolism and benzene toxicity. Toluene inhibits benzene metabolism.22 Workers exposed to a combination of benzene and toluene produced significantly lower urinary phenol (a biomarker for benzene exposure) than those exposed to either benzene or toluene alone; toluene has also been shown to lower the toxicity of benzene in animals. It should be noted that Aroclor 1254, a polychlorinated biphenyl (PCB) used as a coolant in electrical transformers, is also known to alter the toxicity and metabolism of benzene.11 It is unclear what role phenobarbital plays; one author claims a negligible effect, whereas another states it alters the toxicity and metabolism of benzene.11,15 Benzene readily enters the central nervous system (CNS) and may cause immediate effects including headache, nausea, dizziness, confusion, convulsions, and coma leading to death.21,23 It has even been used as a general anesthetic. CNS responses to airborne levels are generally as follows: 2.5 ppm, no effect regardless of duration; 50 to 150 ppm, headache and lassitude; 500 ppm, sleepiness after 3 to 4 hours; 3000 ppm, sleep within 30 minutes, then progressive stupor; 7000 ppm, stupor within 30 minutes. Oral ingestion of 9 to 12 g of benzene causes staggering gait, vomiting, delirium, tachycardia, hypotension, coma, and occasionally death.23 Severe inhalation may lead to noncardiogenic pulmonary edema. Ventricular arrhythmias may result from increased sensitivity of the myocardium to catecholamines. Benzene can cause chemical burns to the skin with prolonged contact or massive topical exposure.21 Evidence of benzene poisoning may appear in a few weeks or only after many years of exposure, or it may not be discovered until the onset of infection from bone marrow suppression, long after exposure has ceased. Benzene produces a continuum of effects on the bone marrow ranging from reversible abnormalities to AML. These effects appear to be dose dependent. Chronic exposure to benzene results in bone marrow depression and tissue damage, with effects ranging from decreases in selective blood elements (leukocytes, lymphocytes, or platelets) to aplastic anemia (decreases in all cell types). Pancytopenia, aplastic anemia, AML, and their variants

may occur.21 Findings are variable, especially in early examination of blood. The most common abnormality is a decrease in total white blood cell count, which may be accompanied by a relative lymphocytosis and a macrocytic, normochromic, or slightly hyperchromic anemia and thrombocytopenia. The bone marrow may reveal nonspecific changes initially. Depression of bone marrow function occurs after months or years of relatively low-level exposure. Myelotoxicity may initially manifest as stimulation of all three bone marrow elements, which is soon followed by progressive anemia and thrombocytopenia. As the disease progresses, the bone marrow may become aplastic or hyperplastic in a manner that does not always correlate with the peripheral blood picture. In the early stages, bone marrow depression is reversible; continued exposure, however, has led to fatal aplastic anemia.23 After benzene exposure, decreases in circulating blood cells may also be observed in the presence of a dysplastic marrow characterized by abnormal architecture, chromosomal damage in many cells, and inadequate hematopoiesis leading to MDS, a preleukemic state that usually proceeds to AML. MDS is now believed to be a result of benzene exposure. There is interest centering on the possibility that environmental benzene exposure in the general public (such as exposure to vehicle exhaust emissions) may be associated with a rise in the occurrence of non-Hodgkin’s lymphoma (NHL).20 Causality is also suspected for chronic myelogenous leukemia and chronic lymphocytic leukemia.21 Benzene was formerly suspected of causing multiple myeloma, but subsequent studies have failed to confirm an association. In fact, the weight of the evidence, at present, leans against an association between benzene and multiple myeloma. There have been unproven associations between benzene exposure and acute lymphoblastic leukemia, myelofibrosis, and lymphomas. The diagnosis of benzene poisoning is based on a history of exposure and typical clinical findings. With chronic hematologic toxicity, erythrocyte, leukocyte, and thrombocyte counts may first increase and then decrease before the onset of aplastic anemia. Such a pattern may signal a history of benzene exposure. Biomarkers of exposure to benzene have been developed and carefully evaluated. Concentrations of the parent compound in exhaled breath parallel blood concentrations. This is confounded by smoking, which also causes elevations of benzene in exhaled breath. Urine benzene is quite specific and correlates well with concentrations between 32 and 800 μg/m3, but it is easily confounded by smoking. Moreover, measurements at these levels are at the limit of detection, rendering them unreliable.24 Urinary excretion of a variety of benzene metabolites (i.e., phenol, catechol, hydroquinone, 1,2,4-trihydroxybenzene, S-phenylmercapturic acid, and t,t-muconic acid) have shown correlation with benzene exposure in occupational settings. Phenol, catechol, and hydroquinone analyses are neither sensitive nor specific because relatively high levels are found in nonexposed

CHAPTER 94

individuals. Similarly, t,t-muconic acid is not specific because it is a metabolite of sorbic acid, a common food additive. Nevertheless, urinary phenols have been useful for respiratory exposure greater than 5 ppm (16 mg/m3). Testing for urinary phenol is required by OSHA in workers exposed to benzene in an emergency involving an unexpected significant release of benzene. Below this concentration, there is too much interference from food and medication and results are unreliable. S-phenylmercapturic acid (SPMA), an end product of the conjugation of benzene oxide and glutathione (GSH), is a suitable urinary biomarker of low-level benzene exposure (0.01 ppm) because of its specificity and relatively long half-life (9 hours). It is very specific for benzene. Adducts to hemoglobin and cysteine groups of proteins have been demonstrated in rodents, but not in humans. DNA damage manifested by chromosome abnormalities has been detected in benzene-exposed workers, although such measures have not yet found widespread acceptance as biomarkers of effect. Blood benzene is useful for determining exposure to concentrations exceeding 0.25 ppm but is also confounded by smoking. The specimen must be collected at or immediately after exposure because the half-life of benzene in the blood has been reported to be as brief as 30 to 60 minutes.24 Potential etiologies for aplastic anemia include idiopathic, inborn (Fanconi’s anemia), dose-related reactions (e.g., antineoplastic agents, benzene, chloramphenicol, inorganics, irradiation); idiosyncratic reactions (e.g., acetazolamide, arsenicals, barbiturates, chloramphenicol, gold, insecticides, phenothiazines, phenylbutazone, pyrimethamine, solvents, sulfa drugs, thiouracils); viral infections (e.g., hepatitis); pregnancy; and rheumatoid arthritis. Many medications can cause aplastic anemia. For a summary of clinical management, refer to Box 94-1. A spot urine phenol measurement of all exposed, including the victim, rescuers, and health care personnel, may serve as a useful indicator of high-level exposure to benzene. It is not immediately clinically useful because it may take days for the result to be reported, and it does not alter immediate therapy. Nevertheless, measurement should be made to ensure appropriate follow-up of those exposed. Acute high-level exposure to benzene may lead to hematotoxicity at a later date; thus, it is important to identify exposed individuals so that their blood indices can be followed to ensure appropriate diagnosis and treatment. This is mandated for occupational exposures by OSHA. OSHA (29CFR1910.1028) requires that after an emergency (unexpected) exposure to benzene, a urine phenol should be collected at the end of the work shift. The specimen’s specific gravity must be corrected to 1.024 for proper adjustment of the phenol level. Levels of 75 mg/L or higher require complete blood counts with differentials every month for 3 months. A spot urine level higher than 20 mg/L suggests excessive occupational exposure, although the test is nonspecific and can be confounded by the presence of other aromatic com-

Benzene and Related Aromatic Hydrocarbons

BOX 94-1

1367

TREATMENT PROTOCOL FOR ACUTE EXPOSURE TO AROMATIC HYDROCARBONS

1. Avoid unprotected contact with liquid and vapor via appropriate skin and respiratory protection. 2. Decontaminate victim by removal from exposure, removal and disposal of contaminated clothing, and copious irrigation of contaminated eyes and skin. 3. Monitor O2 and intravenous line. 4. Do not induce emesis; gastric lavage if recent (within 30 minutes) ingestion. 5. Protect airway from aspiration. 6. Provide supportive care to maintain airway, oxygenation, ventilation, and circulation. 7. Treat coma, seizures, arrythmias, and other complications if they occur. 8. Avoid sympathomimetics (e.g., epinephrine), if possible, to prevent potentially fatal tachyarrythmias. Tachyarrhythmias may require treatment with β blockers (esmolol, metoprolol, or propranolol). 9. Perform chest roentgenogram, liver profile, urinalysis, serum electrolytes, blood urea nitrogen, creatinine, electrocardiogram, and complete blood counts with differential as necessary. 10. Do specific lab analyses as required, e.g., OSHA requires a urine phenol analysis for benzene exposure to determine the need to monitor for delayed hematotoxicity. 11. Monitor for 12–24 hours if exposure is substantial. OSHA, Occupational Safety and Health Administration.

pounds both in the workplace and in the diet of those exposed. Over-the-counter cough and sore throat lozenges can cause an elevated urine phenol. Benzene can also be measured in expired air for up to 2 days after exposure.21 A baseline complete blood count with differential should be obtained along with the urine phenol. Other laboratory tests, including liver function studies, electrolytes, chest x-ray, and blood gases, may be ordered based on clinical findings. There is no antidote. Benzene overexposure requires prolonged (months to years) follow-up of hematologic parameters beyond the acute phase to monitor for changes in blood cell counts and differentials that may require hematology consultation and treatment (e.g., transfusion). OSHA (29CFR1910.1028) requires that baseline and annual testing be made available to workers occupationally exposed to benzene. Workers are offered medical exams consisting of a medical and occupational history and complete blood count with differential. Abnormal findings trigger medical evaluations, which may lead to removal from exposure and evaluation by a hematologist or other appropriate specialist. Urine S-phenylmercapturic acid measurement at the end of the work shift is a sensitive and specific marker of exposure to low levels of benzene and can be used to detect overexposure. The American Conference of Governmental Industrial Hygienists (ACGIH) has established a biologic exposure index (BEI) of 25 μg/g creatinine.

1368


Recovery from acute benzene exposure depends on severity of symptoms. Symptoms may persist for 2 to 3 weeks. Chronic effects of benzene intoxication may arise and persist long after an acute exposure occurs. Benzene is a leukemogen; leukemia can occur before or after aplastic anemia. Individual response to either acute or chronic benzene exposure is variable.

STYRENE Styrene, also known as cinnamene, phenylethylene, and vinyl benzene, is a high-production-volume chemical, with more than 10 billion pounds produced annually in the United States.25 Styrene is a colorless to slightly yellow, oily liquid that spontaneously polymerizes unless inhibited. It is liquid at room temperature and highly flammable.26,27 At low concentrations, it has a sweet odor; at concentrations above 100 ppm, it’s odor is objectionable. Styrene has a low vapor pressure and is soluble in organic solvents, but only slightly soluble in water.27 Although styrene was discovered in 1831, it did not become commercially important until 1942, when it was used in the synthesis of unsaturated polyesters and reinforced plastics. Currently, styrene is widely used to make plastics and resins for surface coatings. It is also used as a chemical intermediate. Styrene-containing polymers are used to make tires, boat hulls, shower stalls, bath tubs, dental restorative plastics, and many other plastic products. Styrene can be synthesized but is also found naturally in storax, a gum derived from styracaceous trees. Primary exposures to styrene occur during its manufacture and polymerization, particularly in situations in which open polymerization processes are used, for example, in boat building or shower-stall manufacturing. Styrene is present in tobacco smoke and has been detected in ambient urban air samples. Styrene is naturally present in foods such as strawberries, beef, and spices, and is naturally produced in the processing of foods such as wine and cheese. Styrene is permitted as a direct food additive in small quantities under the Food and Drug Act, and as an indirect food additive that migrates from packaging materials into food. It undergoes rapid biodegradation; styrene levels in surface water and groundwater are generally very low (10%).10,12 Dermal exposure may result in mild to moderate irritation, whereas ocular exposure can cause moderate irritation with superficial damage to the corneal epithelium at concentrations of 5.25% sodium hypochlorite or greater.28,30 If chlorine bleach is mixed with certain other household cleaning products, toxicity may result from inhalation of gaseous by-products. For example, if chlorine bleach is mixed with a strong acid, chlorine gas evolves. If chlorine bleach is mixed with ammonia, chloramine gas evolves. Both gases can be very irritating to the nasal and oral mucosa, respiratory tract, and ocular surfaces. When chlorine gas comes in contact with moist tissue, it is transformed to hydrochloric acid and nascent oxygen. When chloramine gas contacts moist tissue, it is transformed into hydrochloric acid, gaseous ammonia, and nascent oxygen. The oxygen radicals generated are strong oxidizing agents that, along with the acids and ammonia, can cause corrosive effects and cellular injury.31,32 Very little experimental data exist regarding the toxicity of the powdered all-fabric oxygen bleaches and oxygen stain fighters. The bleaching system in these products is commonly sodium percarbonate or sodium perborate, with stabilization and alkalinity contributed by sodium carbonate. A review of several manufacturers’ material safety data sheets reveals that sodium percarbonate and sodium perborate powders are generally classified as mild to moderate mucosal, dermal, and respiratory irritants, and as moderate to severe eye irritants. On contact with moisture, sodium percarbonate breaks down into hydrogen peroxide and sodium carbonate, whereas sodium perborate breaks down into hydrogen peroxide and sodium borate. The concentration of these by-products in the traditional all-fabric bleaches is generally of a level that may cause mucosal irritation on ingestion, although borates could cause systemic toxicity. (Borates are discussed in Chapter 99.) However, some of these all-fabric bleaches contain more than 70% sodium

Soaps, Detergents, and Bleaches

1449

carbonate, which has been reported to be corrosive in solutions of 15% or more.16 The concentration of byproducts from the oxygen stain removers could theoretically be high enough to cause corrosive injury, but as of yet, this effect has not been reported. It would likely depend on the quantity of moisture available in the exposed area. In addition, some of these products contain up to 5% sodium metasilicate, which may be corrosive in solutions of 0.5% or more.13,15 Further research and experience in this area are needed.

Manifestations CHLORINE BLEACH Ingestion of small amounts of household chlorine bleach is generally associated with nausea, vomiting, abdominal pain, diarrhea, and coughing.26,27,33,34 Less common symptoms include dyspnea, drooling, temporary dysphagia, skin burns, and oral burns.27 Most investigations in the literature show no evidence of esophageal injury, but a minority show self-limiting erythema and exudates, still without mucosal ulceration. If corrosive injury is present, symptoms may include vomiting, drooling, chest or throat pain, and dysphagia. Progression to stricture has been reported, but is very rare, as are fatalities. Such outcomes are generally due to large intentional ingestions or to co-ingestants.12,26-28,35,36 Large ingestions of chlorine bleach have also been shown to lead to hyperchloremic acidosis and hypernatremia. The conversion in the stomach of sodium hypochlorite to hypochlorous acid and chlorine contributes to the hyperchloremic acidosis, whereas fluid loss and sodium overload (from the sodium salt of hypochlorite) contribute to the hypernatremia.34,37 Aspiration of bleach or bleach-containing vomitus can rarely lead to respiratory complications such as airway edema and pneumonitis manifested as wheezing, tachypnea, stridor, and retractions. These symptoms may be present without concomitant esophageal injury. It is speculated that respiratory epithelium may be more sensitive to household bleach than pharyngeal and esophageal mucosa.12,28 This is similar to the inhalation of powdered laundry detergents discussed previously. Ocular exposure to chlorine bleach can be associated with a burning sensation, tearing, erythema, injection, photophobia, and blepharospasm. If thorough irrigation is performed immediately, sequelae are limited to superficial loss of corneal epithelium, slight corneal epithelial haze, and conjunctival edema, all of which subside within 48 hours. If the bleach is left on the eye for a longer period time, tissue necrosis may spread through the entire thickness of the corneal epithelium, possibly leading to irreversible damage and infection.30 Dermal exposure to chlorine bleach may infrequently cause irritation, erythema, and pruritus. Allergic contact dermatitis has been rarely reported.26,38 CHLORINE BLEACH MIXED WITH OTHER PRODUCTS Exposure to chlorine or chloramine gas can cause irritation and cellular injury to the moist surfaces of the

1450


nasal passages, oral and respiratory mucosa, and eyes. The extent of injury depends on the concentration of gas, duration of exposure, and preexisting cardiopulmonary disease. With home exposure, it is very difficult to determine the amount or concentration of gas in the immediate area. Acute mild exposures to chlorine or chloramine gas are generally limited to the upper respiratory tract and may manifest as coughing, dyspnea, stridor, hoarseness, and sore throat. Other common symptoms include chest pain, dizziness, vomiting, ocular irritation, and nasal irritation. Severe exposure can progress to tracheobronchitis, pneumonitis, pulmonary edema, pneumomediastinum, and, ultimately, respiratory failure.31,39 This is rare in the household setting, but may occur as a result of continued exposure long after initiation of respiratory and ocular irritation. Residual interstitial infiltrates, dyspnea on exertion, and reduced vital capacity have been reported after prolonged exposure.40 Death occurs very rarely and may be more common in individuals with previous respiratory illness or dysfunction.39 OXYGEN BLEACHES Ingestion of the powdered all-fabric oxygen bleaches and oxygen stain removers may result in nausea, vomiting, and diarrhea. Because these products are powders, mucosal contact time may be prolonged, which could result in epithelial damage to the mouth and esophagus.2 Ocular exposure to these products can produce moderate irritation and erythema with the possibility of severe irreversible eye damage with prolonged contact.41,42 The granular nature of the products may also contribute to abrasive injury. Dermal exposure to the dry product may be mildly irritating, with exposure to the wet product possibly producing mild to moderate irritation, erythema, and dryness. Allergic contact dermatitis has not been reported. Inhalation of dust from the products may cause mild respiratory irritation with associated coughing and dyspnea.41,42

Management INGESTION Management of chlorine bleach ingestion is dependent on the properties of the specific product and on the individual’s symptoms. Ingestion of regular household bleach (4% to 6% sodium hypochlorite) can initially be managed at home by dilution with milk or water. If an animal is exposed, water should be used because other fluids may cause further GI irritation. Oral fluid intake should be limited to 4 oz for children and 8 oz for adults, so as not to distend the stomach. GI decontamination by any means is unnecessary, with spontaneous vomiting often occurring nonetheless. If vomiting or diarrhea is excessive, fluid and electrolytes should be replaced and monitored as necessary, possibly in a health care facility. Observation should continue at home for the next 8 hours for symptoms of esophageal damage or of aspiration. Symptoms such as drooling, dysphagia, chest or throat pain, and vomiting warrant emergency department investigation for corrosive injury. Symptoms

such as wheezing, tachypnea, stridor, and retractions warrant a chest x-ray and respiratory supportive care. Animals exposed to chlorine may not have the ability to display symptoms of corrosive injury nor vocalize their discomfort. Therefore, all ingestions of chlorine bleach in animals should be evaluated by a veterinarian for corrosive esophageal injury. Ingestion of “ultra” or “advanced” bleach may require more diligent monitoring owing to the higher concentrations of sodium hypochlorite and sodium hydroxide, as well as the possibility of increased contact time with mucosal surfaces because of increased product viscosity. However, management still begins in the home and follows the same steps described previously. All ingestions of a large amount of chlorine bleach (>5 mL/kg), regardless of whether they are regular or ultra preparations, should be managed in a health care facility because of the possibility of systemic effects and a greater chance of local tissue injury. Management should include supportive care, investigation for corrosive injury, and 4 to 6 hours of monitoring of arterial blood gases, serum pH, and serum electrolytes, with appropriate treatment. Despite the uncertainty over the true toxicity of powdered oxygen bleach products, it is suggested that ingestions be managed similarly to those of chlorine bleach, as described previously, with diligent monitoring for symptoms of esophageal injury. OCULAR EXPOSURE Eye exposures to regular household bleach should be managed by immediately irrigating the eye on-site with lukewarm water or saline continuously for 15 minutes. If irrigation cannot be performed immediately or if irritation persists immediately after irrigation, emergency department care is warranted, including a slit-lamp examination with fluorescein dye. Eye exposure is to an ultra or advanced chlorine bleach or powdered oxygen bleach–stain remover should be irrigated for 20 minutes on-site, followed by an emergency department evaluation for corneal injury. If exposure to chlorine or chloramine gas causes significant ocular irritation, eye irrigation should be performed for 20 minutes, followed by slit-lamp examination if irritation persists for 1 to 2 hours after exposure. DERMAL EXPOSURE Management of dermal exposure to any of the bleaches should begin with irrigation of the exposed area for 5 to 10 minutes with lukewarm water. Exposed clothing should be removed to prevent further contamination. Occlusive creams or ointments should be avoided in the early stages. If skin becomes blistered or broken, or begins bleeding or oozing, the care of a physician should be sought. The rare case of contact dermatitis to chlorine bleach is best referred to a dermatologist. INHALATION Inhalation of chlorine or chloramine gas can often be managed on-site or at home with fresh air, cool oral liquids, and inhaled steam. Most patients with exposure

CHAPTER 102

to chlorine or chloramine gas will have resolution of symptoms within 6 hours of exposure. If symptoms worsen at any time or persist for longer than 6 hours, emergency supportive care is warranted.39 Patients with preexisting respiratory conditions may be more sensitive to exposure, but can still be monitored at home if symptoms are mild and air exchange is not compromised.31 Anecdotal evidence has suggested that nebulized sodium bicarbonate may be an effective adjunct for chlorine gas exposure. Prospective, randomized, controlled trials have not been carried out. A nonrandomized, nonblinded investigation of its use in chloramine gas exposure did not find a significant difference compared with oxygen alone.32 Inhalation of powdered oxygen bleach can be managed with fresh air and cool oral fluids. If symptoms persist for more than 6 hours after inhalation, emergency supportive care should be sought. REFERENCES 1. Watson WA, Litovitz TL, Klein-Schwartz W, et al: 2003 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2004;22(5): 335–404. 2. Temple AR, Spoerke DG: Household Cleaning Products and Their Accidental Exposure. New York, Soap and Detergent Association, 1989. 3. The Soap and Detergent Association. Available at: http://sdahq. org (accessed June 2004). 4. Litke DW: Review of phosphorus control measures in the United States and their effects on water quality. U.S. Geological Survey National Water-Quality Assessment Program: Water Resources Investigations Report 99-4007. Denver, CO, U.S. Geological Survey, 1999. 5. Peters G, Johnson GQ, Golembiewski A: Safe use of detergent enzymes in the workplace. Applied Occup Environ Hygiene 2001;16(3):389–396. 6. Mofenson HC, Greensher J: The Nontoxic Ingestion. Pediatr Clin North Am 1970;17(3):583–590. 7. DiCarlo MA: Scientific reviews. Household products: a review. Vet Human Toxicol 2003;45(2):256–261. 8. Mack RB: Decant the wine, prune back your long-term hopes: cationic detergent poisoning. N C Med J 1987;48(11):593–595. 9. Kanerva L, Jolanki R, Estlander T: Occupational allergic contact dermatitis from benzalkonium chloride. Contact Derm 2000;42:357–358. 10. McGuigan MA: Bleach, soaps, detergents, and other corrosives. In Haddad LM, Shannon MW, Winchester JF (eds): Clinical Management of Poisoning and Drug Overdose, 3rd ed. Philadelphia, WB Saunders, 1998, pp 830–835. 11. Riordan M, Rylance G, Berry K: Poisoning in Children 4: Household products, plants, and mushrooms. Arch Dis Child 2002;87(5):403–406. 12. Bates N: Acute poisoning: bleaches, disinfectants and detergents. Emerg Nurse 2001;8(10):14–19. 13. Gosselin RE, Smith RP, Hodge HC, Braddock JE: Clinical Toxicology of Commercial Products, 5th ed. Baltimore, Williams & Wilkins, 1984. 14. Gloxhuber C: Toxicological properties of surfactants. Arch Toxicol 1974;32:245–270. 15. Krenzelok EP, Clinton JE: Caustic esophageal and gastric erosion without evidence of oral burns following detergent ingestion. J Am Coll Emerg Phys 1979;8(5):194–196. 16. Klasco RK (ed): POISINDEX System, Vol. 121. Thomson MICROMEDEX, Greenwood Village, CO (expires September 2004).

Soaps, Detergents, and Bleaches

1451

17. Kynaston JA, Patrick MK, Shepherd RW, et al: The hazards of automatic-dishwasher detergent. Med J Aust 1989;151:5–7. 18. Winter ML, Ellis MD: Automatic dishwashing detergents: their pH, ingredients, and a retrospective look. Vet Hum Toxicol 1986; 28(6):536–538. 19. Schweigert MK, Mackenzie DP, Sarlo K: Occupational asthma and allergy associated with the use of enzymes in the detergent industry: a review of the epidemiology, toxicology, and methods of prevention. Clin Exp Allergy 2000;30:1511–1518. 20. Vincent JC, Sheikh A: Phosphate poisoning by ingestion of clothes washing liquid and fabric conditioner. Anaesthesia 1998;53: 1004–1006. 21. Wheeler DS, Bonny AE, Ruddy RM, Jacobs BR: Late-onset respiratory distress after inhalation of laundry detergent. Pediatr Pulm 2003;35:323–325. 22. Einhorn A, Horton L, Altieri M, et al: Serious respiratory consequences of detergent ingestions in children. Pediatrics 1989;84(3):472–474. 23. Krenzelok EP: Liquid automatic dishwashing detergents: a profile of toxicity. Ann Emerg Med 1989;18(1):60–62. 24. van Berkel M, de Wolff FA: Survival after acute benzalkonium chloride poisoning. Hum Toxicol 1988;7:191–193. 25. Purohit A, Kopferschmitt-Kubler MC, Moreau C, et al: Quaternary ammonium compounds and occupational asthma. Int Arch Occup Environ Health 2000;73:423–427. 26. Racioppi R, Daskaleros PA, Besbelli N, et al: Household bleaches based on sodium hypochlorite: review of Acute Toxicology and Poison Center Experience. Food Chem Toxicol 1994;32(9): 845–861. 27. Harley EH, Collins MD: Liquid household bleach ingestion in children: a retrospective review. Laryngoscope 1997;107:122–125. 28. Babl FE, Kharsch S, Woolf A: Airway edema following household bleach ingestion. Am J Emerg Med 1998;16:514–516. 29. Code of Federal Regulations. 16 CFR 1700.14(a)(5). 30. Ingram TA: Response of the human eye to accidental exposure to sodium hypochlorite. J Endodon 1990;16(5):235–238. 31. Mrvos R, Dean BS, Krenzelok EP: Home exposures to chlorine/ chloramine gas: review of 216 cases. South Med J 1993;86(6): 654–657. 32. Pascuzzi TA, Storrow AB: Mass casualties from acute inhalation of chloramine gas. Milit Med 1998;163(2):102–104. 33. Jakobsson SW, Rajs J, Jonsson JA, Persson H: Poisoning with sodium hypochlorite solution: report of a fatal case. Supplemented with an Experimental and Clinico-Epidemiological Study. Am J Forensic Med Pathol 1991;12(4):320–327. 34. Ward MJ, Routledge PA: Hypernaetremia and hyperchloraemic acidosis after bleach ingestion. Hum Toxicol 1988;7:37–38. 35. Kiristioglu I, Gurpinar A, Kilic N, et al: Is it necessary to perform an endoscopy after the ingestion of liquid household bleach in children? Acta Paediatr 1999;88:233–236. 36. French RJ, Tabb HG, Rutledge LJ: Esophageal stenosis produced by ingestion of bleach: report of two cases. South Med J 1970;63(10):1140–1144. 37. Ross M, Spiller H: Fatal ingestion of sodium hypochlorite bleach with associated hypernatremia and hyperchloremic metabolic acidosis. Vet Hum Toxicol 1999;41(2):82–86. 38. Eun HC, Lee AY, Lee YS: Sodium hypochlorite dermatitis. Contact Derm 1984;11(1):45. 39. Krenzelok E: Chlorine/chloramines. J Toxicol Clin Toxicol 1995; 33(4):355–356. 40. Reisz GR, Gammon RS: Toxic pneumonitis from mixing household cleaners. Chest 1986;89(1):49–52. 41. U.S. Environmental Protection Agency: Sodium carbonate peroxyhydrate fact sheet (128860), 2002. Available at: http://www. epa.gov. 42. National Institutes of Health, National Library of Medicine Specialized Information Services: Household Products Database. Available at: http://householdproducts.nlm.nih.gov (accessed June 2004).

S E C T I O N

J

DISASTERS AND TERRORISM

103

Principles of Emergency Management and Management of Hazardous Materials Incidents JAMES CISEK, MD, MPH

At a Glance… ■

■

■

■ ■

■

■

Disaster preparedness and management should be based on an “all-hazards approach,” leading to comprehensive, risk-based, and integrated responses. Immediate disaster response is local. Communities must plan an initial response to all disasters based on available resources. Regional and national response must not be relied on primarily, but disaster management plans should readily integrate components at all levels as they come into play, emphasizing partnership and flexibility. The disaster life cycle is composed of four elements: (1) mitigation (long-term efforts to prevent or reduce the probability of disasters or lessen the consequences of a disaster), (2) preparedness (establishment of authorities and responsibilities for emergency actions and collection of resources to support them), (3) response (prompt critical actions to save lives and property), and (4) recovery (restoration of vital infrastructure, assessment of damage, and timely restoration of economic activity and rebuilding of the community). Hazardous materials releases may be unintentional or intentional. Chemical terrorism has occurred and will likely reoccur. Although most hazardous materials releases result in few or no casualties, disastrous exceptions, such as the releases of methyl isocyanate in Bhopal, of radionuclides in Chernobyl, of hydrogen sulfide and natural gas in Gaoqiao, and of deadly explosive materials in Neyshabur, remind us of their terrifying potential for human tragedy. Although the all-hazards approach provides a base for response to chemical disasters, additional expertise and elements will be required, including hazard identification, exposure assessment, decontamination, and prehospital and hospital management, including the appropriate use of antidotes, which may be needed in large quantity. The approach to hazardous materials emergencies is multidisciplinary, requiring consultation and cooperation from all involved specialists.

PRINCIPLES OF EMERGENCY MANAGEMENT This chapter begins with a generalized discussion of disaster management and then focuses on management aspects of a unique disaster involving hazardous materials. All disasters are unexpected events, require a rapid response to save life and property, generate more need than available resources can manage, and require unusual procedures for resolution. Disasters may be natural (e.g., infections, drought, hurricanes, floods, severe winter storms, earthquakes, wildfires), human made (e.g., industrial, transportation, power outage), or national security threats (attack, terrorism). It is important to remember that early disaster declaration by an appropriate local, state, or federal official is an essential step that allows authorities to suspend regulations, allows the expenditure of funds for purchasing and hiring of elements for disaster control, grants authority to order evacuations, puts extensive liability protections into place, and creates the expectation that the government is primarily responsible for controlling the impact of the event. In 1979, The Federal Emergency Management Agency (FEMA) coined the term comprehensive emergency management (CEM) to reflect a change in orientation from preparedness for a single hazard toward an “allhazards” approach to potential disasters that threaten life and property.1 CEM strives to minimize the impact caused by an emergency in a locality. FEMA stresses the importance of disaster planning being integrated, comprehensive, risk based, and all-hazard in approach. The similarities among all types of disasters suggest strongly that many of the same management strategies will apply to all such emergencies. It is critical to remember that all disasters are initially a local event, so that all disaster management must begin at the local

1453

1454


level. Effective disaster management requires a close partnership between all aspects of government (local, county, state, regional, federal) and the private sector. FEMA developed the Integrated Emergency Management System (IEMS) so as to integrate these critical partnerships into an all-hazards approach to emergency management. The IEMS as defined by FEMA focuses on four specific goals: 1. Promotion of a full federal, state, local, and tribal government partnership with emphasis on flexibility for achieving common goals 2. Emphasizing emergency management measures with known proven effectiveness 3. Achieving more complete integration of emergency management planning into policy-making and operational systems 4. Building on established emergency management plans, systems, and capabilities to enhance their applicability to the full spectrum of possible hazards

RE C

FEMA has defined a four-phase disaster life cycle for CEM that involves mitigation, preparedness, response, and recovery. These four phases appear in a circular association such that activities in one phase overlap those of the previous (Fig. 103-1). Mitigation involves long-term efforts to prevent or reduce the probability of disasters or lessen the consequences of a disaster once it has occurred. Examples of mitigation activities include the issuance of flood insurance, flood hazard mapping with the prohibition of home building or the removal of homes within a flood plane, improved building safety for earthquakes or tornados, the opening of shelters in emergencies, and the relocation to temporary housing in the aftermath of a disaster. Although mitigation can improve community safety, it does not eliminate susceptibility for all hazards. Disasters evolve rapidly and are too complex for effective extemporization. Localities must be prepared for disasters that cannot be mitigated away. Emergency management

RY VE O

MITIGA TI O N

1. Mitigation PR

RE

SPONSE

EPAREDNESS

DISASTER FIGURE 103-1 The disaster cycle.

2. Preparedness 3. Response 4. Recovery

mandates that preparedness actions be taken before an emergency has occurred. Preparedness establishes the authorities and responsibilities for emergency actions and collects the resources to support them. Preparedness mandates that jurisdictions have a plan for response, trained personnel to respond, and necessary structural and equipment resources with which to respond. FEMA states that preparedness planning covers three objectives: 1. Maintaining existing emergency management capability in readiness 2. Preventing emergency management capabilities from themselves falling victim to emergencies 3. Augmenting the jurisdiction’s emergency management capability The preparedness process begins with a comprehensive community hazard assessment done in collaboration with community, state, and federal personnel. This assessment begins with the accurate identification of community hazards and their potential consequences and then compares and prioritizes these risks. This is the approach required of all jurisdictions and agencies that intend to be compliant with the National Fire Protection Association’s Standard on Disaster/ Emergency Management and Business Continuity Programs.2 It then proceeds through a capability analysis that evaluates personnel and equipment needs, and moves to the development of an operations plan. The most important aspect of preparedness is the creation of an all-hazards emergency operations plan (EOP). Training and exercises are clearly defined in the EOP. Training allows personnel to become familiar with their assigned responsibilities and to acquire the skills necessary to perform those tasks. Exercising allows for the testing of plans and the evaluation of skills acquired by response personnel. In addition, the EOP assists in the rapid response that is required for effective disaster relief. Response activities that are time sensitive are clearly defined so as to be performed most efficiently. The EOP includes a listing by position and organization of what kinds of tasks are to be performed. When more than one organization performs a task, one should be given primary responsibility, and the others should be given a supporting role. The EOP must be attentive to relevant local and state laws, federal regulations, and mutual aid agreements. Finally, the EOP provides an adaptable emergency management minimum set of procedures that can be relied on when responding to an unknown disaster. Hazard-specific appendices provide additional critical information relevant to a particular hazard (e.g., hazardous materials, hurricane). Response is the third phase of emergency management and covers the period during and immediately after a disaster. The response phase of a disaster begins with a need for prompt critical actions to save lives and property. In addition, procedures must be initiated to stabilize the situation so that the locality can reorganize. Critical actions include emergency notification of emergency management personnel, warning and evacu-

CHAPTER 103

Principles of Emergency Management and Management of Hazardous Materials Incidents

ating or sheltering the population, keeping the population informed, rescuing individuals, providing medical treatment, maintaining the rule of law, assessing damage, addressing mitigation issues that arise from response activities, and requesting help from outside the jurisdiction. Recovery is the fourth and final phase of the emergency management cycle. It continues until all systems return to normal operation. Short-term recovery begins to restore vital utilities (e.g., power, water, sanitation, communications), transportation infrastructure, the removal of debris, and the assessment of damage. Once some stability is achieved, the jurisdiction can begin recovery efforts for the long term, restoring economic activity and rebuilding community facilities and family housing with attention to long-term mitigation needs. Recovery should incorporate mitigation as demonstrated by a town relocating portions of its flood-prone community and transforming the area into a park.

MANAGEMENT OF HAZARDOUS MATERIALS INCIDENTS Epidemiology Exposure to hazardous materials is unfortunately as much a fact of modern life as are such things as vehicular crashes and infectious diseases. The term hazardous material is used here to mean any substance that can be harmful to humans, animals, or the environment when released in any uncontrolled manner. This chapter focuses on the management principles applicable to acute exposure to hazardous materials, including largescale incidents. It does not address the issues surrounding chronic lower-level exposure or terrorism-related events. It must be clearly understood that planning and responding to a hazardous materials incident has many similarities to those needed in a terrorism-related event. An attack on the United States might focus on the release of a toxic chemical from a fixed facility or during transportation. Prehospital providers must think about the potential for terrorism in their response to all hazardous materials events. The potential for a secondary device (e.g., explosive) with potential harm to first responders is a consideration at all hazardous materials events. Terrorism and weapons of mass destruction are discussed in other chapters of this book. One need not live near a chemical manufacturing plant, heavy industry, or a chemical dump site to be at risk for exposure to hazardous materials. A source of potential exposure is the nearest road, railroad track, or waterway. In 2002, the U.S. Department of Transportation reported 15,399 hazardous materials incidents, with 515 that were considered serious.3 During 2002, the Chemical Transportation Emergency Center (CHEMTREC) logged more than 121,809 telephone calls for hazardous materials emergency assistance.4 Most of these voluntary calls were informational: Medical emergencies represented only 18% of the calls. According to the Occupational Safety and Health Administration (OSHA), more than 575,000 chemicals

1455

are used in the workplace. More than 1.5 billion tons of hazardous cargo is shipped nationwide each year by air, rail, sea, and land. These include flammable liquids, pressurized gases, explosives, poisons, and radioactive material. The U.S. Department of Transportation indicates that about 800,000 shipments of hazardous materials are transported each day.5 In regard to bulk rail shipments, the industry uses roughly 200,000 rail tank cars. A subset of these cars moves more than 275,000 shipments of chlorine, anhydrous ammonia, propane gas, and gasoline every year. The motor carrier industry dedicates more than 400,000 large trucks to the transportation of hazardous materials. A subset of this fleet participates in about 18 million shipments of gasoline and 125,000 shipments of explosives a year. In 1990, the Agency for Toxic Substances and Disease Registry began an active, state-based Hazardous Substances Emergency Events Surveillance (HSEES) system to define the public health implications of the release of hazardous substances. The HSEES system collected data from 16 states in 2001.6 This most recent information indicates that 75% of the events occurred at fixed facilities, with equipment failure (38%) and operator error (30%) being the most common factors associated with the release. Of the transportation events, 85% occurred during ground transport (e.g., truck, van), and 10% involved transport by rail. Fewer events involved water, air, pipeline, or other transportation modes. Most events involved the release of one substance (91%), whereas two substances were released in 4%. Air releases were involved in 42% of cases, followed by spill releases (40%), fires (4%), and threatened releases and explosions (0.8%). Ammonia, sulfur dioxide, and carbon monoxide were the substances most commonly released. Human victims were involved in 8% of the releases. Of the events with victims, 62% involved only one victim, and 79% involved one or two victims. Multiple-casualty events were uncommon. Of the total victims, 89% were injured in fixed-facility events. Employees (51%) were the population group most often injured, followed by the general public (21%), students (8%), and responders (13%). The substances released most often were not the most likely to result in victims. As an example, chlorine was released in only 1.2% of the events, but 19% of the chlorine releases resulted in injury. The most commonly reported injuries in fixed-facility events were respiratory irritation (31%), headache (12%), eye irritation (11%), and gastrointestinal problems (10%). Transportation-related events were associated with a greater incidence of trauma (32%) than fixed facilities (2%) were. In total, 1% of all victims died.

Hazardous Materials Events of Greatest Magnitude Hazardous materials incidents occur with great frequency, and keeping up with the details of releases from across the United States can be very challenging. Previous hazardous materials events must be studied so that history does not repeat itself and for the development of better prevention strategies. The U.S.

1456


Chemical Safety Board is an excellent resource to facilitate the dissemination of objective information regarding larger-scale incidents. The U.S. Chemical Safety Board is an independent federal agency whose mission is to prevent industrial chemical accidents and save lives.7 This is accomplished by investigating chemical incidents and hazards, determining fundamental causes of a release, and issuing safety recommendations to government agencies, industry, labor unions, trade associations, and other organizations. This organization determines the causes of accidents, but does not issue fines or penalties. The investigative staff includes chemical and mechanical engineers, industrial safety experts, and other specialists drawn from the private and public sectors. The board can be accessed at the website www.chemsafety.gov. Four world events involving the release of hazardous materials deserve brief overview. The events involving Bhopal, Chernobyl, Gaoqiao, and Neyshabur are discussed here. The release of sarin in Tokyo is discussed in Chapter 105A. BHOPAL The events in Bhopal, India, represent the largest modern hazardous materials incident outside of warfare and terrorism. On the night of December 3, 1984, a cloud of methyl isocyanate gas leaked from a storage tank at the Union Carbide plant in Bhopal, India. Methyl isocyanate is used in the manufacture of carbamate insecticides. As a liquid, it has a low boiling point and is heavier than air in its gaseous form. It has a strong odor and is irritating to the eyes, skin, and respiratory tract. It may be toxic both by inhalation and cutaneous exposure. At the time of the incident, no plans existed to alert the local population in the event of a disaster. Populationbased methods for protection and evacuation did not exist. The plant was located in a densely populated area, with poorly constructed housing adjacent to the plant. Knowledge of the hazardous materials being used and the products manufactured was lacking among the employees, and there were no standard operating practices and few engineering controls. About 50,000 lb of methyl isocyanate in liquid and vapor form was released into the atmosphere when a valve on a storage tank opened for about 2 hours. Light winds prevented rapid dispersal of the heavier-than-air cloud. The accident happened at night, when most of the residents were asleep. Because of the rapid onset of symptoms and the large numbers of people affected, local hospitals were rapidly overwhelmed. Many patients were treated in the hospital garden. Local citizens helped each other in the initial rescue attempt. No local medical authority on methyl isocyanate was immediately available. More than 200,000 people were exposed, and about 500 people in the surrounding area were killed before reaching medical treatment. The total death count was about 2500. One hospital alone treated 25,000 patients in the first 24 hours. Immediate respiratory problems consisted of severe coughing, dyspnea, pharyngitis, and pulmonary edema. Severe conjunctival irritation and corneal ulceration developed. Gastrointestinal symptoms

consisted of increased salivation, nausea, vomiting, abdominal pain, and defecation. Central nervous system symptoms were manifested by coma, seizures, dizziness, limb weakness, and tremors.8 Ninety-five percent of the dead and severely injured came from the neighborhood immediately adjacent to the plant. A crowded railway station situated 1 km from the plant had more than 100 dead: 200 people were unconscious, and 600 were lying about injured. Several studies of survivors were undertaken 3.5 months after the incident.9 Patients in these studies were categorized according to their distance from the plant on the night of the accident. Group 1 consisted of those 0.5 to 2 km from the plant, and group 2 was composed of those at least 8 km from the plant. Both groups were matched socioeconomically and demographically. All of the group 1 sample and 42% of group 2 had symptoms at the time of the incident. At the time of the study, 80% of group 1 and 28% of group 2 had continued respiratory complaints consisting of cough, with or without sputum production; breathlessness; and chest pain. Fifty-seven percent of group 1 had abnormal chest radiographs, 49% had documented restrictive defects, and 21% had obstructive defects. Smokers constituted 12%. It is unclear whether previous pulmonary disease was present or whether some patients had both restrictive and obstructive pulmonary disease. In a group of children categorized in the same manner, most symptoms occurred in the immediate area of the plant, although the more remote group was not without symptoms. Ninety-five percent of children from group 1 had immediate cough, and 74% experienced breathlessness.10 Three months later, 84% noted persistent cough, and 48% suffered from continued breathlessness. Abnormal radiographs were found in 66% of group 1 children, compared with 8.1% of group 2 children. Pulmonary testing was performed on children older than 7 years. Obstructive defects were found in 28 of 33 children. Persistent abdominal pain and anorexia were found in the group 1 children only. Group 1 children experienced persistent conjunctivitis, and 10% demonstrated visual abnormalities. No persistent eye abnormalities were found in group 2. Persistent neurobehavioral symptoms consisted of poor memory and weakness. Comprehensive psychological testing was not performed. Some children who later developed obvious psychic disturbances had been classified as dead at the time of the accident and had been initially placed in morgues. Others had witnessed the deaths of parents or siblings. A recent study found selective growth retardation in boys, but not girls, who were either exposed to the released gases as toddlers or born to exposed parents.11 It is theorized that methyl isocyanate is quickly degraded into trimethylamine, which in mice has been reported to produce selective growth retardation of male progeny mice. This is associated with a decrease in the serum testosterone in the mice. CHERNOBYL Late in the evening of April 25, 1986, the fourth reactor at Chernobyl was shut down for routine maintenance

CHAPTER 103


and testing. This electrical generating plant is located 130 km north of Kiev, near the current convergent borders of Ukraine, Belarus, and Russia. Inadequate safety precautions and operational errors during the testing resulted in a sudden increase in heat production, which ruptured part of the nuclear fuel. The watercooled, graphite-moderated reactor did not have a concrete containment vessel. By 1:30 AM (April 26), hot fuel particles, reacting with water, had caused a steam explosion. Within seconds, this was followed by a second explosion. The explosions totally destroyed the Unit 4 reactor core and roof of the building. By 5:00 AM, although more than 100 local firefighters succeeded in extinguishing conventional fires, a graphite moderator fire began and was not extinguished until May 6. This fire was responsible for the dispersion of radionuclides into the atmosphere. Seven months later, the remains of the destroyed reactor and building were enclosed in a concrete sarcophagus designed to provide some containment of the damaged nuclear fuel and to reduce further releases of radioactivity until a more permanent containment facility could be designed and implemented. Thankfully, only 3% to 5% of the total amount of radiation was released. Fifty thousand people were evacuated from the nearby town of Pripyat after a delayed public announcement a day and a half after the release began. It is estimated that a total of 135,000 persons were evacuated and permanently rehoused outside of the 30-km exclusion zone; in addition, 500,000 mothers and children from the surrounding area were reportedly sent to resorts along the Black Sea, and another 300,000 were sent to other locations. It was estimated that 30 to 60 km2 of topsoil and road surfaces would have to be removed to properly decontaminate the area.12-15 Firefighters and plant personnel suffered the highest radiation exposures and casualties. No members of the general public received sufficient radiation doses to induce acute radiation syndrome. Three deaths were immediately associated with the accident. Two hundred thirty-seven patients were admitted for acute radiation syndrome, of which 28 died. Bone marrow transplantation was performed in 13 patients, with death occurring in all but 2 of these patients. Fifty tons of radioactive dust was dispersed over 140,000 square miles of mainly Belarus, Ukraine, and a part of Russia. Seventy percent of the radiation was deposited over Belarus. The doses to individuals outside of this area were small and varied depending on whether rainfall occurred during the passage of the radioactive cloud. The plume moved predominately northward and then over Western Europe. The initial international detection came from Sweden, when radiation alarms went off 2 days after the accident. The accident was announced that evening by the Soviet Union. The isotopes of greatest concern were iodine-131 (131I) and cesium-137 (137Cs). The affected area was large because of the dispersion of small particles into the upper atmosphere and the duration of the release. Almost 5 million people were exposed to either internal or external radiation. The major routes of human exposure

1457

to radiation were from the ingestion of cow’s milk contaminated with 131I (resulting in internal exposure), contact with γ/β radiation from the radioactive cloud, and contact with 137Cs deposited on the ground (resulting in external exposure). Children who consumed fresh cow’s milk in May and June 1986 received the highest doses to the thyroid. Estimates of cancer increases were initially said to be “no more than 1000” and have risen in the past 10 years since the accident. Most of the pilots who helped to entomb the reactor are dead or have leukemia. More and more of the cleanup workers have required treatment for radiation-induced diseases. Thyroid cancer has increased a 100-fold in Belarus. The World Health Organization (WHO) predicts that one third of all the children from the area around Gomel who were between 0 and 4 years of age at the time of the accident will develop thyroid cancer during their lifetime—a total of 50,000 children in this group alone. The negative social and psychological consequences of this event have been profound. There was no identified increase in congenital anomalies, adverse pregnancy outcomes, or other radiation-induced disease in either the contaminated area or in Western Europe. The WHO established the International Program on the Health Effects of Chernobyl Accident to further define the long-term significance of this accident. GAOQIAO In December 2003, there occurred a release of natural gas and hydrogen sulfide at the Chuandongbei gas field in China. The gas field is run by the China National Petroleum Corporation. Although the exact cause of the release is unclear, it led to the evacuation of more than 41,000 people in a 25-km2 area. The mountainous terrain and muddy roads made it difficult for villagers to flee and hindered rescue work. At least 233 people died, and more than 10,000 people were treated for hydrogen sulfide toxicity. Thousands of animals died as the gas devastated villages and poisoned farms. NEYSHABUR In February 2004, 48 rail cars derailed and caught fire outside of Neyshabur, Iran. This community is an ancient city of 170,000 people in a farming region 400 miles east of the capital, Tehran. Firefighters had nearly put out the blaze when an explosion occurred about 5 hours after the derailment. The cars contained sulfur, gasoline, fertilizer, and cotton. The explosion killed 320 people and injured 460 others. Nearly 200 of the dead were rescue workers who were fighting the fires when the blast occurred. The blast was so powerful that Iranian seismologists recorded a quake of magnitude 3.6 at the time of the explosion, and the blast shattered windows 6 miles away.

Hazardous Materials Preparedness In planning for chemical, radiation, and biologic disasters, one must consider all the possibilities, from human error, to employee sabotage, to mentally ill workers, to

1458


terrorism. A specific hazardous materials appendix to the EOP must be developed. This hazardous materials appendix must be updated regularly, simple to follow, and cost effective; must provide for resources that are immediately available; and should minimize manpower needs. This appendix should contain detailed instructions to follow, including emergency response operations; a roster of emergency assistance phone numbers; a description of each service’s legal authority and responsibility during an emergency; a description of the structure and responsibility of the designated response organization; a section on resource laboratories for analysis of chemical and patient data; and a cleanup and disposal equipment resource section. Hazardous materials planning begins with the Emergency Response Commission, established in each state under the Superfund Amendments and Reauthorization Act of 1986 (SARA). This commission, appointed by the governor of the state, must coordinate with the Local Emergency Planning Committees (LEPCs) in their development of plans for emergency response to hazardous materials emergencies. It is the responsibility of the LEPC to develop plans to define and coordinate contaminated areas, to decontamination and triage on scene, to optimize resource and information management, and for the transportation to definitive medical care. This preplanning begins with developing a clear understanding of the potential toxic chemicals stored, transported, and used within a community. A community’s “right to know” is mandated by the Comprehensive Environmental Response, Compensation and Liability Act (CERCLA) amendments of 1986, otherwise known as SARA, Title III. Title III of SARA, the Emergency Planning and Community Right to Know Act, encourages state and local planning and provides planning groups with information concerning chemical releases and the potential chemical risks in their communities. A list of 402 extremely hazardous materials, published in the Federal Register (November 17, 1986), gave threshold planning quantities. If these materials are produced, used, or stored in quantities exceeding the thresholds, they become subject to the emergency planning requirements. Additionally, requirements were set for emergency notification whenever a release of hazardous material exceeded a reportable quantity. In addition to community notification, workers are protected by the OSHA Hazard Communication Standard, which states that “hazards of all chemicals produced or imported by chemical manufacturers or importers [must be] evaluated, and information concerning their hazards [must be] transmitted to affected employers and employees within the manufacturing sector. This transmittal of information is to be accomplished by means of comprehensive hazard communication programs, which are to include container labeling and other forms of warning, material safety data sheets (MSDS), and employee training” (29 CFR 1910.1200). Workers must know the hazards of the chemicals with which they work and methods to protect themselves in the event of an accident or incident. There should also be some training in first aid and decontamination procedures at the plant.

Ideally, a plant’s MSDS should be on file in the emergency department, and emergency physicians should be familiar with them. Additionally, patients should be transported from the plant to the department along with copies of the appropriate MSDS. Surveying the major pipelines in one’s area and knowing major road, rail, and water shipping routes in one’s community are critical. Prevention strategies should include consideration of restricted transportation routes and times of access to these venues. Little regulation exists to limit the routes and times of day that may be used for hazardous materials transportation. The District of Columbia and New York City have enacted bills to require shippers of certain hazardous materials to obtain a permit and conform to routes, times, and other safety conditions when traveling into or out of these cities. This was in response to recent terrorism concerns. Hazardous materials training of first responders is paramount.16 Rescuers must be trained in the use of protective equipment and in decontamination procedures to minimize contamination of citizens, medical personnel, vehicles, medical facilities, and the environment. Persons using a self-contained breathing apparatus (SCBA) must be properly fit tested, be trained in their use, and understand the limitations of the equipment. Specifically, the time limitations of the supply tank and the reserve tank must be understood so that egress from the contaminated area can be accomplished before loss of supply air. Local hazardous materials response units with special training and equipment exist in many communities. These units are responsible for evaluation and management of scene hazards and decontamination before transport. With multiple casualties, the real possibility exists that many patients will present to local hospitals while still contaminated. All medical facilities should have plans to identify contaminated patients, protect personnel and the hospital environment, and provide for decontamination with protective equipment.17,18 Sheltered off-site locations for treatment should be available if a hospital is overwhelmed or must be evacuated. Warning mechanisms and a plan for early evacuation will minimize injuries to hospital personnel. Planning for the treatment of persons exposed to chemicals involves all levels of the health care team, from firefighters to hazardous materials teams to emergency medical services personnel to hospital providers. It is important to establish a unified command approach such that the prehospital plan seamlessly interfaces with that of the hospital. It is essential to ensure that exposure is limited to the smallest number of people possible. Guidelines must be established for triage, decontamination, and medical management.19 Patients may require specialized care and early transportation to hospitals providing medical specialists in burn and trauma care, hyperbaric oxygen, and medical toxicology. Important resources may include an emergency physician, a medical toxicologist, a trauma surgeon, a pharmacologist, an industrial hygienist, an occupational medicine specialist, testing laboratories, and chemists. Plans must also include members from the mental health community,

CHAPTER 103


media relations, and security. Large amounts of antidotes specific to the potential exposures must be available at the scene and within the hospital. Plans should include sources of specialized equipment that may be needed for a given hazard. Planning must include the provision of equipment for air sampling, decontamination, handling of spills (e.g., absorbent materials, diking equipment), and protective equipment for rescuers. This equipment must be strategically located in the community, and its location must be known to all responders. An adequate supply of air tanks and SCBAs and equipment to refill tanks with adequatequality breathing air must be available. Planning must include concerns for the environment. Environmental liability resulting from critical life-saving actions has been a concern for first responders. Section 107 of CERCLA addresses this issue. Section 107(d)(1), often known as the “Good Samaritan” provision, states: “No person shall be liable under this subchapter for costs or damages as a result of actions taken or omitted in the course of rendering care, assistance, or advice in accordance with the National Contingency Plan (NCP) or at the direction of an on-scene coordinator appointed under such plan, with respect to an incident creating a danger to public health or welfare or the environment as a result of any releases of a hazardous substance or the threat thereof.” This does not preclude liability for costs or damages as a result of negligence. In addition, section 107(d)(2) provides that state and local governments are not liable under CERCLA “as a result of actions taken in response to an emergency created by the release or threatened release of a hazardous substance generated by or from a facility owned by another person.” In response to a hazardous materials event, prehospital providers should undertake any necessary emergency actions to save lives and protect the public and themselves. Once any imminent threats to human health are addressed, first responders should immediately take all reasonable efforts to contain the contamination and avoid or mitigate environmental consequences. The Environmental Protection Agency (EPA) will not pursue enforcement actions against state and local responders for the environmental consequences of necessary and appropriate emergency response actions. The EPA cannot prevent a private person from filing suit under CERCLA. However, first responders can use CERCLA’s Good Samaritan provision as a defense to such an action.

Hazardous Materials Response In general terms, the sequence of events in a disaster is as follows: An accident occurs. Knowledge of it is transmitted to appropriate agencies; these agencies respond and gather more data. They may activate additional resources. Fire and the hazardous materials team assume charge and direct law enforcement to control and secure the scene. The scope of the problem is defined. The necessary plans for the solution of the problem are activated, and followup and evaluation are accomplished. First and foremost is notification of appropriate agencies, that is, police, fire department, hazardous

1459

materials team, emergency medical system, local disaster coordinator, county and state officials, and federal agencies. It is beyond the scope of this chapter to indicate who must be notified in any given incident. This varies with the incident and with local and state regulations. Various local and state agencies may have jurisdiction over a particular kind of hazard. These interests may overlap, depending on the nature of the chemical, the location of a spill, and the various laws in a state. The fire chief and the hazardous materials team assume charge and usually have the police set up perimeters and evacuate the surrounding area, if necessary. If the hazardous materials release involves terrorism, the Federal Bureau of Investigation assumes charge of the scene. Crowd control and control of access to the site are also the responsibility of the police agency. A fire agency has responsibility to respond to the chemical or fire hazard and to initiate mitigation, extrication, decontamination, and first aid to casualties. An Emergency Medical Service (EMS) agency is responsible for medical decisions and treatment. Other agencies may have jurisdiction and authority or serve in an advisory capacity, such as the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the EPA, OSHA, FEMA, and the state health department. Local municipal authorities must know how to gain access to other sources of help, including state and federal agencies. At all times, it is critical for all responders to know who is in control. The agency that assumes control may change as more information concerning the exact nature of the hazard becomes available or during different phases of the entire operation, including cleanup.

Identification of the Release Identification of the hazardous material should be attempted before approach to the spill. Community preplanning should identify the specific sites that contain hazardous materials. One can read the placarding on the truck or train car from afar (Fig. 103-2). Be aware that placarding may be wrong 40% of the time, and manifest papers may be wrong 35% of the time. Binoculars are an invaluable aid. The bill of lading (cargo manifest) is located in the cab of a truck, but it may not be accessible without full protective gear. The diamond-shaped placard on the side of a tank or rail car with the Department of Transportation (DOT) number on it will identify the specific material, and the DOT Emergency Response Guidebook will provide the hazard class and general emergency information as well as evacuation distances.20 Some states also have numbered placards with emergency telephone numbers to call. These telephone numbers are a good first resource. Follow-up continues by contacting the shipper and confirming materials that are in the container or vehicle. The various symbols within the diamond-shaped placard should identify the general class of material being shipped. The absence of a placard should not lead one to believe that danger is absent. An empty tank car is considered to be one that

1460


FIGURE 103-2 Table of placards and applicable response guide pages. (From Office of Hazardous Materials Regulation: Emergency Response Guidebook. Washington, DC, Materials Transportation Bureau, U.S. Department of Transportation, 1980.)

Guide 15

Guide 55

Guide 59

Guide 11

Guide 19

Guide 38

Guide 26

Guide 26

Guide 46

Guide 47

Guide 52

Guide 63

Guide 46

Guide 46

Guide 16

Class Number A number 2 at the bottom of a placard without any name means that the material in the tank is a gas. Specific chemical group is at the center. Guide 41

Guide 20

CHAPTER 103


contains less than 300 gallons of material. One should treat a chemical spill and injuries from an unplacarded vehicle with the same caution. Identification of the shipper may be possible by reading the markings on the truck or train car from a distance. The shipper may be contacted to assist in chemical identification and provision of resources. On a train, the waybill can be found with the conductor. Call the nearest company trainmaster, relay the number of the car and the location, and get information and handling information from the tracking computer. The waybill contains a standard transportation code (STC) number that identifies the specific chemical. Chemicals whose numbers begin with 49 are classified as hazardous. The waybill contains specific chemical names and handling information. With train cars numbered from engine to caboose, one can thus learn what chemical the car contains. Packaging configuration can provide valuable information for hazard identification. There are three categories of packaging: stationary bulk storage containers at fixed facilities that come in a variety of sizes and shapes; bulk transport vehicles for truck and rail transportation; and labeled fiberboard boxes, drums, or cylinders for smaller quantities of hazardous materials. The shape and configuration of the container can often be a useful clue to the presence of hazardous materials. Rapid emergency information can be obtained by calling CHEMTREC at 800-424-9300 in an emergency situation and giving the name of the compound. In an emergency, CHEMTREC will connect emergency personnel with the manufacturer’s and/or shipper’s personnel, who can advise on emergency handling. CHEMTREC can then advise what sort of rescue gear may be needed and what decontamination, if any, is needed at the site. Injuries that involve human exposures and injuries will be referred to an appropriate poison control center. The Agency for Toxic Substances and Disease Registry can be accessed at any time by calling 404-498-0120. ATSDR can provide additional valuable information and also has physicians available to provide medical treatment recommendations.

EXPOSURE ASSESSMENT The assessment of exposure risks in the hazardous materials scene environment requires equipment and methods from the field of industrial hygiene. The industrial hygienist can perform qualitative and quantitative studies both on site and in the laboratory. Members of the hazardous materials team perform exposure assessments in the setting of an acute release of a toxic substance. Before discussing actual monitoring methods, however, it would be useful to define some terms and review some fundamental industrial hygiene concepts. First, any chemical can be handled safely if proper precautions are taken. In an uncontrolled chemical release, hazardous environments can be approached with proper personal protective equipment. In most major incidents and in some minor incidents, this

1461

includes full-body suits that are impermeable to the hazardous material, and a positive-pressure demand style of SCBA. Personnel wearing an SCBA must be fully trained in its use, limitations, and what to do if the equipment fails. These persons must be medically cleared for SCBA use before acceptance as part of an emergency response team. The SCBA must have been properly inspected, maintained, and cleaned at regular intervals. A full respirator program as required by OSHA (29 CFR 1910.134) must be in place. This includes periodic medical monitoring. Second, any chemical, no matter now nontoxic, can be hazardous if handled inappropriately. For example, a release of methane or nitrogen in an enclosed space can cause asphyxiation. Numerous reports have been published of attempted rescues in such “nontoxic” environments, in which the initial victim and the rescuers all died of simple asphyxiation. The identity of the specific agent is only one of a number of factors affecting the actual hazard. Other factors include the air concentration, potential for skin contact, duration of exposure, temperature of the material, and individual susceptibility of the exposed persons. Inhalation of air contaminants is the most frequent route of exposure for hazardous materials. Air contaminants may be found in a variety of forms, such as gases, vapors (the gaseous form of a substance that is primarily liquid or solid at room temperature), dusts (solid particles entrained in air), fumes (tiny solid particles often formed when a metal is heated, as in welding), mists (liquid particles entrained in air), and smoke (carbon or soot particles from incomplete combustion). Fumes, dusts, and smokes are measured in mass units of contaminant per volume unit of air (e.g., milligrams per cubic meter or parts per million). These two units can be easily interconverted if molecular weight, temperature, and altitude are known. Because fumes are minute solid particles, respirators designed specifically for protection against fumes will have no efficacy against vapors or gases, and vice versa. Once an air concentration is determined, several criteria exist for assessing the risk for exposure. The level that is immediately dangerous to life and health (IDLH) “represents a maximum concentration from which, in the event of respirator failure, one could escape within 30 minutes without experiencing any escape-impairing or irreversible health effects.” The IDLH level is used to determine the unquestionable need for a reliable positive-pressure demand SCBA. Standby personnel with full protective gear and a lifeline should be available when the IDLH level is exceeded. Specific IDLH values can be found in the National Institute for Occupational Safety and Health (NIOSH) Pocket Guide to Chemical Hazards.21 The most widely used criteria for assessing exposure levels are the threshold limit values (TLVs) for hundreds of common industrial chemicals, which are updated and published annually by the American Conference of Governmental Industrial Hygienists.22 They “represent conditions under which it is believed that nearly all

1462


workers may be repeatedly exposed day after day without adverse effect.” Most TLVs are established for 8-hour time-weighted average exposures (TWAs). In general, these values protect against the effects of a lifetime of chronic exposure. However, short-term exposure limits and ceiling limits for some substances are also included in the TLV list. TLVs are designed to protect a population of healthy workers and are not meant to be applied to a general community population that may include infants, elderly people, and infirm people. Thus, care should be exercised when clinical interpretations based on TLVs are made at a hazardous materials scene. In addition to TLVs, a set of legally enforceable workplace standards, known as permissible exposure limits (PELs), has been established. A common fallacy is the use of odor as a measure of exposure. Information about odor may sometimes be helpful in the qualitative identification of agents or as a crude guide to the exposure level. Odor thresholds for a wide variety of materials have been published. However, wide variations between reference sources and considerable individual variation in the ability to perceive specific odors may occur. For example, up to 40% of the population cannot detect the almond-like odor of cyanide. Some materials have excellent warning properties. For example, if the odor or irritation of ammonia is absent, one can be sure that there will be no toxic sequelae due to exposure to this agent. However, some materials, such as carbon monoxide, are odorless at lethal levels. Other agents, such as hydrogen sulfide, have a characteristic odor initially but induce olfactory fatigue. As a result, lethal exposures may result as exposed individuals perceive levels to be diminishing. Thus, quantitative assessments based on odor thresholds are quite unreliable and possibly dangerous. Air concentrations can be measured at specific locations, and computer models can sometimes be used to predict worst-case ambient concentrations at downwind locations. Environmental monitoring can be performed with direct reading instruments providing real-time measurements of levels, or it can be performed by taking air samples that can be analyzed subsequently. Direct reading instruments include photoionization detectors, portable gas chromatographs, portable infrared spectrophotometers, portable carbon monoxide detectors, flammable gas detectors, and oxygen detectors. A simple direct reading method for instantaneous levels is the colorimetric detector tube. In addition to monitoring the environment, it is important to provide medical surveillance for exposed victims and rescuers, both to assess potential health effects and to provide information about the exposure. Excellent documentation is essential because many of these incidents result in litigation. It is important to document subjective complaints and objective findings and assessments thoroughly and carefully. One should not document that symptoms are all due to a “toxic exposure” unless this is clearly the case. Describe actual clinical findings as they are manifest. The physician’s initial charting may be a deciding factor in determining

whether someone gets their deserved compensation. It may also determine whether abuses of the system occur, which cost public and private organizations large sums of money.

DIAGNOSTIC STUDIES The diagnostic studies for each patient will depend on the clinical presentation and the specific agents to which they have been exposed. Please refer to specific chapters in this textbook for the discussion of specific toxins.

FIELD DECONTAMINATION AND TRIAGE In the event that the chemical is unknown, the safest way to rescue any victim is for rescuers to enter the area in fully encapsulated suits (level A) with positive-pressure SCBA. The exact type of level A suit is determined by the nature of the chemical involved. Firefighters are trained in use of this gear, whereas many EMS rescue teams are not. Under medical guidance, the firefighters begin decontamination and rescue of casualties and begin first aid. The fire department is the most qualified to assess the potential for fires and explosions and to advise medical personnel of such. The smallest number of rescuers possible should enter the contaminated area. At least two should go in together, employing a buddy system, to ensure each other’s safety. A backup person with a similar level of protective gear should remain at the boundary to assist the rescuers in the event of an accident. Hyperthermia and dehydration can occur quickly in the fully encapsulated level A suites. Adequate hydration and close attention to rescuer vital signs are important. Standard principles of triage apply in a chemical disaster. The sequence for field decontamination is illustrated by the following example: A truck transporting a concentrated liquid chemical turns over on a highway, and the tank begins to leak. A large pool of chemical is rapidly filling a low section of roadway, and a hazy cloud begins to form over the pool. The driver and companion, who are both injured, begin to move away under their own power. They begin to cough and choke, and then they pass out. Several bystanders enter to help and are overcome and lose consciousness. In the meantime, all the victims have chemical on their clothing. Without going into specific details of particular chemicals, how might rescue be accomplished? The first responders must attempt to identify the chemical from the placard on the truck. Especially note the logo W, which means USE NO WATER. The chemical may ignite, explode, or produce toxic fumes with water. The responders should notify central dispatching for fire department, police, and EMS backup and indicate that specialized resources or expertise may be required for a hazardous materials incident. If the placard can be read, the dispatcher can call CHEMTREC for specific handling information. Police, fire department, or EMS personnel should have access to the DOT Emergency

CHAPTER 103


Response Guide: Emergency Handling of Hazardous Materials in Surface Transportation. Access to other guides, Poisindex, or a poison control center for further information should be available, if possible. A triage or medical station should be set up upwind from the site at a “safe” distance. Distances are listed in the DOT Emergency Response Guidebook. An area designated as contaminated or hot should be defined (Fig. 103-3). An intermediate or containment area should be established. Rescuers can continue decontamination and emergency treatment in this area. Cutaneous decontamination is not required for all patients exposed to a hazardous material. Exposure to an inhaled toxicant (e.g., carbon monoxide or arsine gas) poses little risk for skin injury, mucous membrane injury, or secondary contamination such that decontamination

1463

is not required. Many gases and vapors (e.g., isocyanates, chlorine) can cause skin and mucous membrane injury and necessitate formal decontamination. Any liquid or solid material must be removed promptly. If uncertainty exists, then prompt decontamination is mandatory. The nature of the hazard and the necessary protective equipment must be determined before first responders enter an area of chemical spill (e.g., equipment for extrication and diking, decontamination showers, oxygen, protective gear, and transportation vehicles). Rescuers should enter the contaminated area with full protective gear unless the hazard assessment indicates otherwise. If the details of the release are uncertain, level A protective gear is essential. Level A suites are composed of various materials, and proper suit selection is important.

FIGURE 103-3 Sequence for field detonation.

ZONE A Hot zone Contaminated area

Wind direction ± 20°

Containment Area Plastic sheeting tarps Children's wading pool Hose

Decon-Solutions Disposal bags and Clean blankets

Water

Hot li

ne

Containment Area Plastic sheeting tarps Children's wading pool First aid ± Triage Hose

ZONE B Warm zone Containment area

Additional showers Decontamination solutions Decontamination of equiment Removal of self-contaminated breathing apparatus Additional disposal drums and bags ZONE C Clean area Triage area Cold zone

Ambulance

Police car

Non A.L.S. vehicle

1464


Only a minimum of first aid, such as attention to the cervical spine and exsanguinating hemorrhage, should be attempted in a highly toxic environment. Do not intubate or establish intravenous access in a highly toxic environment. Move victims from the immediate area of the spill. Remove all clothing. In general, wash the entire body, including the hair, quickly with water. Exceptions to this rule include contaminants that are elemental metals, such as sodium, which react violently with water. All the wash water should be contained (if possible). This can be done in a number of ways. Children’s plastic wading pools or plastic sheeting may be used with an earthen dam or brick border to prevent used wash water from entering ground water. Three fire ladders may be laid sideways in a triangle and tarpaulins placed over them to form a pool. All waste water, hoses, tarpaulins, pools, and so on are left inside the “hot zone” for the environmental cleanup team (see Fig. 103-3). In the event of mass decontamination, the effluent water does not need to be contained and can be allowed to flow into the sewer or other location. The victims may then move into the warm zone for further decontamination. Rescuers then discard outer layers of gloves, boot covers, and suits and place these in disposal containers. SCBAs may need to be left on and are the last piece of equipment removed. In the containment area, more thorough washing should take place. This may be done in a similar manner by setting up a hose or some type of shower. If possible, all waste water must be contained so as not to spread contamination. More thorough attention to injuries and advanced airway management can be given in this warm zone. With very toxic materials, rescuers still will be hampered in their efforts by protective suits and SCBA. The victims are wrapped again in clean blankets as they move from zone B (containment area) to zone C (cold zone). Rescuers discard additional protective clothing, and the SCBA is removed last, on entering the cold zone. All contaminated equipment and clothing are placed in bags and drums for later decontamination or disposal. Here, more extensive triage can take place, and intravenous lines and other advanced life support treatment can take place. Note that all movement is upwind from the spill. Because one cannot be absolutely sure that decontamination is complete in the field, one should use a non–advanced life support vehicle if possible. Decontamination of an advanced life support vehicle is time consuming and costly, and availability is extremely limited. To have one out of service for decontamination imposes a hardship on the community. The selection of receiving hospitals must be based on the number of victims and the hospital’s ability to manage concomitant trauma, burns, contamination, and systemic toxicity. All equipment and gear in vehicles and in the emergency department should be protected from any contamination by layers of plastic and blankets, if possible. Decisions about evacuation are based on the identification of the chemical, information from the transporter or manufacturer, chemical characteristics,

explosive characteristics, danger of fire, means of safe evacuation, and weather conditions.

REGIONAL ASSESSMENT OF EXPOSURE A major hazardous spill may raise fears in the general population of possible long-term toxic effects. Patients and workers immediately exposed to the chemical hazard, as well as firefighters, EMS personnel, and police, may require ongoing medical surveillance. The long-term environmental impact also must be assessed. If a survey of the immediate area and patient population shows no significant hazard, then the public may be reassured. In the event a persistent hazard is determined to exist, local and national authorities may need to expand testing in concentric circles from the exposure site. The health care providers must be aware of the mass psychogenic component that is commonly present in perceived environmental exposures. Whether or not patients are suffering toxic effects, it is likely that they also will experience symptoms and signs of catecholamine release. Some individuals may have nonspecific symptoms, such as headaches, nausea, vomiting, hyperventilation, chest pain, and paresthesias.23

HOSPITAL MANAGEMENT Decontamination is always best performed before hospital arrival. A patient is never too unstable to have clothing removed and a brief decontamination performed in the field. Secondary decontamination procedures should be considered at the hospital after field decontamination. Initial decontamination will be required at the hospital for those patients not evaluated at the scene. The Tokyo sarin gas experience indicates that at least 80% of hospital patients will independently appear at a healthcare facility, without transport by first responders.24 Decontamination may occur inside the hospital in specially designed facilities equipped with a separate ventilation system that will provide adequate air flow. Air return from this room must never recirculate within the hospital and must be directly vented outside. Some specialized sites have floor drains leading to holding tanks that are easily accessed by hazardous waste contractors for toxicant removal. These holding tanks are expensive and should not preclude a hospital from participating in decontamination. An expenditure of large amounts of money is not necessary for the safe, efficient management of patients. Most hospitals decontaminate patients outside the emergency department. Portable curtains provide privacy, and warm water can be delivered outside in all weather. Portable decontamination stretchers allow for synchronous decontamination and resuscitation. Portable wading pools are an inexpensive means of containment of irrigation fluid for ambulatory patients. If a large-scale decontamination effort is needed, the effluent can be allowed to flow into the sewer.

CHAPTER 103


Contaminated patients must always be decontaminated before entry into the main emergency department. All hospital protocols must focus on efficient rapid patient processing. Hospitals must not rely on fire departments for decontamination because they will likely be deployed to the site of the release. Cutaneous surface swipes before and after dermal cleansing can provide valuable information on the extent of contamination and efficacy of removal. Portable radiation detectors guide the duration and intensity of decontamination. Assessing the adequacy of chemical decontamination is more difficult in that the laboratory analysis takes more time. The physician will often not know “how clean is clean?” and will be forced to terminate decontamination based on less objective criteria. Protection of hospital personnel is of primary importance.25 Most health care facilities are poorly prepared to handle contaminated casualties. The medical team must always be equipped with a level of protection consistent with the contamination of the victim. Patient care must never be initiated before the donning of appropriated protection. There is a great deal of controversy regarding what level of personal protective equipment is appropriate for hospital personnel. Recent consensus opinions for health care facility–based personnel recommend level C personal protective equipment with OSHA operations-level training curricula modified to the health care environment.26,27 Level C includes a nonencapsulating chemical-resistant suit and an air-purifying respirator. Hospitals may choose a powered air-purifying respirator (more expensive) because the work of breathing is much less with these devices, and fit testing is not required. An SCBA or airsupplied respirator is not required if the decontamination occurs outside of the hospital. Chemically resistant clothing and gloves are vital for the safe management of patients. Water irrigation, mild soap, and gentle washing are the initial approach for all toxicants except elemental metals (e.g., sodium, lithium). These metals explode on contact with water and should be removed by other methods before the application of water. Occasionally, detergents are required to remove viscous materials. The irrigation of contaminated wounds should take priority to lessen system absorption of toxicants. Care must be taken not to allow irrigation runoff to contaminate clean skin. A small number of dermal toxicants require special attention. Phenol is best removed with 200– to 400– molecular weight polyethylene glycol or isopropanol. Small amounts of water could increase dermal absorption of phenol. “Deluge” quantities of water are required when polyethylene glycol is not available. Limited data indicate that hexavalent chromium may be treated with topical ascorbic acid to allow reduction to the trivalent (less toxic) state. White phosphorus fumes or flames spontaneously on contact with air. Before débridement, the phosphorus should be covered with a moistened gauze. A Wood’s lamp allows visualization of phosphorus in tissues. Copper sulfate irrigation of wounds for phosphorus visualization can cause copper

1465

TABLE 103-1 Antidotes for Common Hazardous Materials Toxicants ANTIDOTE

TOXIN

Lilly cyanide antidote kit Methylene blue Atropine or pralidoxime

Cyanide Methemoglobin Organophosphates, carbamates, nerve agents Hydrofluoric acid Carbon monoxide, cyanide, hydrogen sulfide Cesium, thallium Heavy metals

Calcium Oxygen or hyperbaric oxygen Prussian blue (Radiogardase) Chelators (DTPA, BAL, DMSA)

toxicity and provides little benefit over a Wood’s lamp. Calcium gluconate is the antidote in hydrofluoric acid (HF) exposures (Table 103-1). HF is a weak acid but causes systemic and local toxicity through its strong affinity for calcium and magnesium ions. Severe exposure to concentrated HF is associated with rapid hemodynamic compromise. Intravenous calcium must be administered early in these cases to control arrhythmias and shock. Dilute HF ( 3 Gy) should emphasize treatment of radiation-induced neutropenia and the prevention of infection. Initial care is directed toward reduction of pathogen acquisition through reverse isolation, low-microbial-content food and water, selective use of gastrointestinal (GI) decontamination, and consideration of antibiotic prophylaxis for opportunistic bacterial, viral, or fungal infections. Established or suspected infection in the neutropenic 1467

1468


patient is managed in the same manner as for chemotherapy patients. Antibiotic prophylaxis should be considered in the severely neutropenic patient and in afebrile patients at the highest risk for infection. Second, high-level local radiation injury occasionally arises from touching lost or covertly placed industrial radiation sources. These incidents often involve significant radiation burns to either the hands or other localized anatomic regions. However, the appearance of these lesions is usually delayed in time as noted below. Acute local irradiation events may occur separately or coexist with the ARS. Deterministic thresholds exist as follows for certain ranges of localized skin radiation dose: 1. 3 Gy threshold for epilation, beginning 14 to 21 days postaccident. 2. 6 Gy for erythema, which may be observed transiently postaccident, and appears in permanent form 14 to 21 days thereafter. The pathophysiology for erythema involves arteriolar constriction with capillary dilation and local edema. 3. 10 to 15 Gy for dry desquamation of the skin secondary to irradiation of the germinal layer. Dry desquamation results from response of the germinal epidermal layer to radiation. There is diminished mitotic activity in cells of the basal and parabasal layers with thinning of the epidermis and desquamation of large macroscopic flakes of skin. 4. 20 to 50 Gy for wet desquamation (partial thickness injury) at least 2 to 3 weeks postexposure, depending on dose. In moist desquamation, microscopically, one finds intracellular edema, coalescence of vesicles forming macroscopic bulla, and a wet dermal surface, coated by fibrin. 5. For doses of more than 50 Gy to a localized area, overt radionecrosis and ulceration occurs secondary to endothelial cell damage and fibronoid necrosis of the arterioles and venules in the affected area. A cutaneous syndrome, arising from high-level whole body irradiation along with local injury, has also been described by various researchers.10,11 Third, accidents occur in either the industrial or government sector primarily involving inhalation or ingestion of radioactive material without overt systemic signs and symptoms. These accidents often involve medical misadministration of correctly prescribed radioisotopes or accidents involving nuclear medicine therapy or brachytherapy.

ACUTE RADIATION EXPOSURE The correct diagnosis of acute radiation injury may be made approximately 85% of the time by a traditional, well-designed medical history. However, physicians often do not include radiation injury in the differential diagnosis of the usual radiation prodromal symptoms of nausea, vomiting, and diarrhea. Analysis of the recent

history of radiation medicine shows many cases of delayed diagnosis. In a review of four recent major radiation accidents3 involving lost high-level gamma sources (Bangkok, Thailand [February, 2000]; Mit Halfa, Egypt [May, 2000]; Tammiku, Estonia [October, 1994]; Goiania, Brazil [September, 1987]12), the average time from beginning of the accident until definitive diagnosis averaged approximately 22 days. However, in the recent nuclear criticality accident in Tokaimura, Japan13 (September, 1999), awareness of the accident was essentially immediate because it occurred in an industrial environment with many witnesses. Therefore, radiation accidents are recognized in a dichotomous fashion: either soon postaccident (industrial or medical setting), or 2 to 4 weeks or more postaccident when the patient becomes ill due to neutropenia and sepsis (misplaced sources found or stolen by a member of the public). The clinical presentation of the externally irradiated patient will be much different in these two scenarios. In addition, the patient presenting primarily with internal contamination will have few signs and symptoms and will generally have a normal physical examination. In a terrorism event, radiation dose may be estimated early using rapid-sort, automated biodosimetry, employing such parameters such as the clinical history, the time to emesis (TE), and lymphocyte depletion kinetics.14-20 For TE of less than 2 hours, the effective whole body dose is at least 3 Gy. If TE is less than 1 hour, the whole body dose most probably exceeds 4 Gy. Lymphocyte depletion follows dose-dependent, first-order kinetics after highlevel gamma and criticality incidents. Patient radiation dose can be estimated very effectively from the medical history, serial lymphocyte counts, and TE, and subsequently confirmed with chromosome-aberration bioassay, the current U.S. and world gold standard. These data may be effectively analyzed using a computer tool developed at the Armed Forces Radiobiology Research Institute (Biodosimetry Assessment Tool [BAT]; http://www. afrri.usuhs.mil/). Input to BAT includes historical and clinical data, TE, and serial complete blood counts (CBCs), and the output provides a statistically weighted estimate of dose. It is possible therefore to determine the magnitude of the exposure within the first 12 to 18 hours postevent. The program is currently available free of charge for the personal computer (PC) laptop and will soon be available for the personal digital assistant (PDA).17 The medical management of patients with acute, moderate to severe radiation exposure (effective whole body dose greater than 3 Gy) should emphasize the rapid administration of colony-stimulating factors (CSF). All of these compounds decrease the duration of radiation-induced neutropenia and stimulate neutrophil recovery. For those patients developing febrile radiationinduced neutropenia, adherence to the current Infectious Diseases Society of America guidelines for highrisk neutropenia is recommended (IDSA; http://www. idsociety.org/).

CHAPTER 104

INDUSTRIAL TOXICOLOGY OF COMMON RADIOISOTOPES Following an accidental intake of radioactive material, dose, toxicity, and treatment methods are dependent on various factors such as the identity of the radionuclide and its physical and chemical characteristics (physical and biological half-life, particle size, chemical composition, solubility, etc.). In the inhalation pathway, particle characteristics (size, chemical composition, chemical solubility in body fluids) are important determinants of dose. The fate of inhaled particles is critically dependent on particle physicochemical properties and the size of aerosol particles determines the region of the respiratory tract where most will be deposited. Highly insoluble particles may remain in the lung for long periods of time, and a small fraction will be transported to the tracheobronchial lymph nodes by pulmonary macrophages. Insoluble particles may be swallowed and therefore excreted primarily in the feces. Treatment considerations for internal contamination of radioisotopes are very similar to traditional poison control measures and fall into several major categories21: 1. Reduce and/or inhibit absorption of the isotope in the GI tract. 2. Block uptake to the organ of interest. 3. Utilize isotopic dilution. 4. Alter the chemistry of the substance. 5. Displace the isotope from receptors. 6. Utilize traditional chelation techniques. The most common isotopes seen in the management of internal contamination will now be presented along with selected case histories. It is hoped that these case histories will give the reader some idea of the decisionmaking process involved in management of internal contamination cases.

CASE HISTORY: ESTIMATING THE MAXIMUM CREDIBLE INHALATION ACCIDENT Two scientists at a government facility accidentally break the integrity of a glovebox known to contain americium 241. Nasal swipes taken within 10 minutes postaccident read 10,000 dpm and 12,000 dpm alpha for the left and right nares, respectively. The presenting issue is to estimate the maximum credible accident. Mansfield22 has given a rough rule of thumb that the combined activity of both nasal swipes should approximate 5% of deep lung deposition, using the International Commission on Radiological Protection (ICRP) 30 lung model. Using this rule of thumb to estimate the magnitude of the incident, we have the total anterior nasal passage activity to be 22,000 dpm alpha = 9.9 nCi. The estimated lung deposition is therefore on the order of 200 nCi, or approximately 10 annual limits of intake (ALI; 1 ALI = 5 rem) for inhalation. Experience has

Medical Management of Radiation Incidents

1469

shown that this is generally a very conservative overestimate, but useful for initial estimates, pending the results of bioassay.23

MEDICAL CONSIDERATIONS FOR SELECTED RADIONUCLIDES23 Tritium (3H) Dose to total body water is the critical issue in the management of tritium accidents. The ICRP 67 model for tritium24 assumes two compartments for tritiated water, A and B, with age-dependent biologic half-lives ranging from 3 to 10 days for compartment A and 8 to 40 days for compartment B. In addition, organically bound tritium is treated in an age-dependent manner. For accident dosimetry purposes, tritium retention may be approximated by a single exponential with a half life of 10 days. For reference, the ALI for tritium is 80,000 μCi. Medical management of tritium intake is directed toward increasing body water turnover by increasing oral fluid intake, thereby diluting the tritium and increasing excretion by physiologic mechanisms. An increase in oral fluids of 3 to 4 L/day reduces the biologic half-life of tritium by a factor of 2 to 3 and therefore reduces whole body dose in the same proportion. CASE STUDIES: TRITIUM EXPOSURE Six male teens at a government dormitory facility break an exit sign, releasing approximately 10 Ci of tritium gas. The highest levels of tritium are found on the public telephone (157,000 dpm). Urine samples are taken from all six teens and sent for tritium bioassay. From liquid scintillation counting at a national laboratory, the highest urine value is found to be 6.5 μCi/L in a 17-yearold boy. Using the conservative rule of thumb from ICRP 65 that 1 μCi/L peak tritium concentration in urine corresponds to an integrated whole body dose of 10 mrem,21 the maximum estimated dose is approximately 65 mrem (0.65 mSv) whole body. Prior to receiving the urine bioassay results, all teens were instructed to increase oral hydration to 3 to 4 L/day. There were no adverse medical events from this tritium intake. Historically, tritium exposures have resulted in relatively low whole body dose, but Seelentag and Minder25 have reported cases of two fatalities possibly related to high-level tritium intake in an industrial environment over a period of years. From these cases, they concluded that there is possible evidence that two people died secondary to radiation-induced bone marrow suppression, although there was also prior exposure to strontium and radium.

Strontium Sr 90 is the predominant isotope of interest in this chemical series, and a comprehensive model for strontium

1470


retention, developed by Snyder and colleagues26 that indicates that 73% of material in the transfer compartment is eliminated with a 3-day half-life, 10% with a 44 day half-life, and 17% with a 4000-day half-life. All chemical forms except SrTiO3 are considered relatively soluble (class D in the ICRP 30 formalism). SrTiO3 is considered insoluble (class Y). In the ICRP 76 treatment27 of alkaline earth distribution, an agedependent biokinetic model is given, with transfer to soft tissue, cortical and trabecular bone volume and surface, two liver compartments, and the renal system. For most forms of strontium, except titanate, bone surface is the dose-limiting organ for both inhalation and ingestion. Because of the biologically significant rate of strontium transfer to the GI tract, it is also necessary to block intestinal absorption in those cases where intake is by inhalation. The following treatments are useful in the medical management of inhalation cases with strontium: 1. Intravenous (IV) calcium gluconate 2 g in 500 mL over 4 to 6 hours (competes for strontinum at bone binding sites). 2. Ammonium chloride (300 mg orally) to produce a moderate metabolic acidosis. 3. Barium sulfate 300 g orally as soon as possible postaccident to block intestinal absorption.

Iodine The thyroid is the critical organ after intake of radioactive iodine. Retention in the thyroid is described by a three-component exponential with half-lives of 0.24 days, 11 days, and 120 days. In the ICRP 67 model, agedependent elimination rate constants are given. In this model, uptake to the thyroid is 30%, with 70% of intake routed to prompt urinary excretion. The ICRP 67 model24 for adults has a half-life of 80 days for iodine in the thyroid and 12 days for iodine in the rest of the body. For accident dosimetry, the effective half-life of iodine may be taken to be approximately 12 days. Thyroid blocking in adults is accomplished by administering 130 mg potassium iodide (KI) orally as soon as possible postaccident and one tablet daily for 7 to 14 days. Another convenient way to administer stable iodide is five or six drops of saturated solution of KI (SSKI, 1 g/mL). In addition, potassium perchlorate (200 mg) may be used in patients with iodine sensitivity. The timing of iodine administration is as soon as possible postaccident, up to 6 hours. However, in a situation with continuing exposure, stable iodine may be 50% effective even 5 to 6 hours after exposure to radioiodine. CASE STUDY: RADIOIODINE ADMINISTRATION IN PREGNANCY23,28 A 26-year-old female nurse presents with clinical hyperthyroidism.23,28 During the laboratory analysis, a T4 level is found to be 19.5 μg/dL (normal 5 to 12.5 μg/dL). She is given 9.2 mCi iodine 131 (NaI) for thyroid ablation, and the patient’s hyperthyroid symptoms subside within

1 week. However, the patient is subsequently found to be 14 weeks pregnant at the time of iodine administration by ultrasound dating. The fetal self dose in this case is calculated to be 2.4 rad (0.024 Gy; dose conversion factor [DCF] = 0.068 mGy/MBq), but the fetal thyroid dose is calculated to be 88 Gy (DCF = 260 mGy/MBq). This is ablative to the fetal thyroid. The mother and fetus were followed throughout the remainder of the pregnancy by a specialist in fetalmaternal medicine. The pregnancy was clinically uneventful, with a normal delivery. At birth, the infant was found to be profoundly hypothyroid and in the 6th percentile for growth on standard growth charts. At 1 year of age, the baby also exhibited minor developmental delay on standard neurocognitive tests.

Cesium Following systemic uptake of cesium, the isotope is uniformly distributed in the body with distribution similar to potassium. Systemic retention for cesium is often represented by a two exponential retention function with retention half-lives of approximately 2 days and approximately 110 days. However, a range of retention half-lives has been noted.12 The most effective means for removing radioactive cesium is the oral administration of ferric ferrocyanate, commonly called Prussian blue (PB). Insoluble PB (ferric hexacyanoferrate, Fe4[Fe(CN)6]3) is an orally administered drug that enhances excretion of isotopes of cesium and thallium from the body by means of ion exchange. One gram orally three times daily for 2 to 3 weeks reduces the biological half-life of radiocesium to about one third the normal value. PB has a high affinity for cesium, whose metabolism follows an entero-enteric cycle. Orally administered PB traps cesium in the gut, interrupts its reabsorption from the GI tract, and thereby increases fecal excretion. Thus, the biologic half-life of cesium is significantly reduced after decorporation therapy with PB. CASE STUDY: CESIUM The most famous case12 involving cesium intake was the radiologic accident in Goiania, Brazil, in 1987. In September 1987, two men removed the rotating assembly of a cesium 137 teletherapy unit and breached the capsule containing 50.9 TBq (1375 Ci) of 137Cs. The source was in the form of soluble 137CsCl, which is highly dispersible in the environment. The teletherapy assembly was initially sold to a junkyard and the junkyard owner believed that it had mystical power since it glowed blue in the dark (Cherenkov radiation from the cesium beta decay). Samples of the material were given to many friends and relatives, resulting in widespread contamination to people and to the environment. Residual contamination levels near the initial breach of containment were on the order of 1.1 Gy/hr. Approximately 112,000 persons were monitored for radioactive contamination, of whom 249 were contaminated externally or internally. Four individuals died of

CHAPTER 104

the acute radiation syndrome, with whole body dose in the range 4 to 7 Gy. These included the 38-year-old wife of the junkyard owner (5.7 Gy), 18- and 22-year-old employees (4.5 and 5.3 Gy, respectively), and a 6-year-old niece of the junkyard owner (6.0 Gy). The latter case represented a situation of extreme internal contamination (1 × 109 Bq) by ingestion, since the young girl was playing with a piece of the source while eating a sandwich. Forty-six individuals, internally contaminated in this incident, were treated with PB in daily divided doses of 3 to 20 g. The use of PB reduced the average 137Cs biologic half-life from 110 to 115 days to about 40 days, with a consequent reduction in dose.

Uranium The two most common uranium isotopes seen in research and in industry are uranium 238 and 235. Acute toxicity is most closely related to chemical rather than radiologic properties, particularly with regard to the renal system. For uranium entering the transfer compartment, approximately 20% is transferred to mineral bone with a half-life of 20 days and 2.3% to bone with a halflife of 5000 days. In addition, 12% and 0.05% are transferred to the kidneys with half-lives of 6 and 1500 days, respectively. Systemic body retention of uranium is given by a five exponential retention function with halflives of 0.25, 6, 20, 1500, and 5000 days.19-31 Uranium has an overall effective half-life of 15 days, and 85% of retained uranium resides in bone. Kidney toxicity is the basis of occupational exposure limits. In acidic urine, the uranyl ion binds with renal tubular surface proteins, and some of the bound UO22+ is therefore retained in the kidney. The kidney is the first organ to show chemical damage in the form of nephritis and proteinuria. Oral doses or infusions of sodium bicarbonate have historically been the treatment of choice and should be dosed to keep the urine alkaline by frequent pH measurements. The non-toxic uranium carbonate complex is increased by three to four orders of magnitude in alkaline urine and promptly excreted.30,32 Annual occupational limits for uranium are based on levels estimated to induce renal damage. The threshold for transient renal injury is estimated to be 0.058 mg U/kg body weight or intake of 4.06 mg in a 70-kg individual. Likewise, the threshold for permanent renal damage is estimated to be 0.3 mg U/kg body weight, or 21 mg U in a 70-kg person. Permanent renal damage is shown by a permanent increase in blood urea nitrogen and creatinine, along with proteinuria and a decrease in glomerular filtration rate. From animal research, the 50% lethality level is estimated to be 1.63 mg/kg body weight, or 114 mg in a 70-kg person. A very useful Internet calculator for determining organ levels of uranium from either ingestion or inhalation is found through Martindale’s Online Center (http://www. martindalecenter.com/CalculatorsD_Rad.html). This very extensive calculator originated through the WISE Uranium Project in the Netherlands. Current research on decorporation therapy of uranium and the actinides has evaluated analogs to


1471

siderophores.30,31 Siderophores are agents produced by microorganisms to obtain Fe(III) from the environment. These compounds are good candidates for trial since actinide and uranium biokinetics are associated with Fe(III) transport and storage systems. The association rate constant for actinide-ligand and uranium-ligand binding is generally found to be much greater than that for diethylenetriamine-penta-acetic acid (DTPA) binding. Durbin and colleagues33,34 have considered a linear hydroxypyridinone derivative of deferoxamine: 3,4,3LIHOPO, or simply LIHOPO. LIHOPO is readily given by IV injection in a rat model with low toxicity and has been found to be an effective chelator for both actinides and for uranium. Consider a rat model where plutonium and americium particulates are inhaled. The summary of experiments below shows relative improvement ratios for decorporation therapy using LIHOPO compared with traditional methods using DTPA.23 1. Plutonium: LIHOPO/DTPA = a factor of 6.7 improvement for plutonium deposition in lungs. 2. Americium: LIHOPO/DTPA = a factor of 2.0 improvement for americium deposition in lungs. 3. Plutonium: LIHOPO/DTPA = a factor of 4.8 improvement for plutonium deposition in skeleton. In a plutonium wound model in rats, LIHOPO was found to be 2 to 40 times more effective than DTPA in chelation therapy, depending on the nature of the experiment and route of LIHOPO administration. In another series of experiments, small oral doses of LIHOPO mobilized more americium than plutonium from liver and bone. Furthermore, in rat experiments using injected uranium, LIHOPO was 3.6 times more effective in renal protection than NaHCO3 and 1.7 times more effective in decreasing dose to bone volume.32 These experiments appear to be quite promising for eventual human use. Durbin and colleagues33 have also recently presented experiments designed to identify the most effective multidentate 1,2-HOPO and Me-3,2-HOPO ligands for chelation of Pu(IV) in vivo. Nine HOPO ligands, when injected or given orally, were found to be superior to CaDTPA for reducing plutonium 238 retention in the mouse model. These tetradentate and hexadentate compounds are found to be highly effective, but moderately toxic, and deserve more intensive study prior to human studies. While these experiments to date appear quite promising, U.S. Food and Drug Administration (FDA) phase I human trials have not yet begun. Therefore, the compounds will not be available in the clinic for several years. A recent review article34 provides additional details of this preclinical research. Henge-Napoli and colleagues35,36 have evaluated the efficacy of ethane-1-hydroxy-1,1 bisphosphonate (EHBP, etidronate, Didronel [Proctor and Gamble, Mason, OH]) in experiments to obtain com pounds that will reduce the fixation of uranium in its main target organs of bone and kidney. Etidronate, a synthetic analog of pyrophosphate, is used in the treatment of moderate to severe Paget’s disease, heterotopic ossification, and hypercalcemia associated with malignant neoplasms. The

1472


work of Henge-Napoli and colleagues showed that one injection of EHBP (50 to 100 mol/kg), given acutely after uranium inhalation in animals, reduced uranium deposition in the renal system by a factor of five, and still a factor of two when given 30 minutes postexposure. This work is particularly important since Etidronate is currently approved by the FDA for reduction of bone resorption, is clinically accepted, and has a well-studied adverse reaction profile. Etidronate has pharmacologic actions that are similar to pyrophosphate, a salt of phosphoric acid, which occurs naturally in the body and acts to inhibit bone metabolism. In contrast to the endogenous compound, etidronate is resistant to enzymatic metabolism. The drug decreases both normal and abnormal bone resorption, thereby reducing bone turnover and slowing the remodeling of pagetic or heterotopic bone. In another series of animal experiments, Destombes and colleagues37 compared the carbonic anhydrase inhibitor acetazolamide (Diamox [Barr Pharmaceuticals, Pomona, NY]), with bicarbonate in the treatment of internal contamination with uranium. This work is quite important since acetazolamide is also currently approved by the FDA and could be adapted easily for use in cases of uranium contamination in a mass casualty terrorist incident. Carbonic anhydrase is an enzyme responsible for forming hydrogen and bicarbonate ions from carbon dioxide and water. By inhibiting this reaction, acetazolamide reduces the availability of these ions for active transport. Hydrogen ion concentrations in the renal tubule lumen are therefore reduced by acetazolamide, leading to an alkaline urine and an increased excretion of bicarbonate, sodium, potassium, and water. A reduction in plasma bicarbonate results in a metabolic acidosis, which rapidly reverses the diuretic effect. Acetazolamide is classically used for the prophylaxis and treatment of altitude sickness, and as an adjunct treatment for glaucoma and epilepsy. It has also long been approved by the FDA for use as a diuretic. Acetazolamide is rapidly absorbed from the GI tract, and peak serum concentrations for the tablets and extendedrelease capsules are achieved in 2 to 4 hours and 8 to 12 hours, respectively. For use in urinary alkalization, the adult dose is 5 mg/kg IV or as needed to maintain an alkaline diuresis. In their recent animal work, Destombes and colleagues37 noted that acetazolamide is three times more effective than bicarbonate in reducing the renal content of uranium, but has no effect on skeletal content. These experiments appear quite promising clinically and deserve to be extended.

Actinides Plutonium is the model element in this series. After plutonium enters the transfer compartment, approximately 45% translocates to the liver and 45% to bone. The retention time is assumed to be 20 years in the liver and 50 years in bone. The classical plutonium retention function is given by Durbin38 based on her data and that of earlier work by Langham.39 The Durbin model for

plutonium uses a five-component exponential with halflives of 1.2, 5.5, 42, 300, and 4000 days. The retention functions for other actinides are similar to that for plutonium. Trisodium calcium diethylenetriaminepentaacetate (Ca-DTPA) and Zn-DTPA chelation therapy are the treatment of choice for inhalation accidents involving actinides. Ca-DTPA is a calcium salt of DTPA, and Zn-DTPA is similar, except for the substitution of Zn for Ca. Ca-DTPA appears to be approximately 10 times more effective than Zn-DTPA for initial chelation of transuranics; therefore, Ca-DTPA should be used whenever larger body burdens of transuranics are involved. Approximately 24 hours after exposure, Zn-DTPA is, for all practical purposes, as effective as Ca-DTPA. This comparable efficacy, coupled with its lesser toxicity, makes Zn-DTPA the preferred agent for protracted therapy. The route of administration may be either slow IV push of the drug over a period of 3 to 4 minutes, IV infusion (1 g in 100 to 250 mL D5W, Ringer’s lactate, or normal saline), or inhalation in a nebulizer (1:1 dilution with water or saline). The Centers for Disease Control and Prevention (CDC) has included both Zn- and CaDTPA in the Strategic National Stockpile.

THE RADON ISSUE Radon (radon 222) is the sixth element in the radioactive decay chain of 238U, one of the major natural isotopes on earth. Radon gas poses an environmental risk because of its potential carcinogenic properties (increases in small cell and squamous cell carcinomas of the lung). This risk is not primarily due to radon’s chemical and radiologic characteristics (noble gas; physical half-life 3.825 days), but mostly to the short-lived, reactive alphaemitting progeny that occur after radon in the decay chain. Radon is formed in soil and rock from the radioactive decay of its parent, radium (radium 226, half-life 1622 years), and can easily diffuse from its source. Radon tends to accumulate in enclosed structures, including mines, buildings, and basements, as a combination of diffusion from the soil and flow from air pressure differentials. Most biologic damage in human lungs is caused by its alpha-emitting progeny, particularly polonium (polonium 218 and 210, half-lives 3.11 min and 138.4 days, respectively) and lead 214. The conventional radiologic units associated with radon dose are particularly confusing and derive from historical epidemiologic considerations of working populations in underground mines. Radon activity may be expressed in pCi/L (equal to 37 Bq/m3 in SI units) and one working level (WL) is equivalent to a radon concentration of 100 pCi/L at equilibrium and to approximately 200 pCi/L at 50% equilibrium, which is typical of many buildings. The working level is therefore a unit of radioactivity per liter of air or water. One working level month (WLM) is historically defined as a month of occupational exposure (170 hours) to one WL of airborne radon activity. One

CHAPTER 104

WLM equates to approximately 5 pCi/L-year under typical conditions of equilibrium and an assumption of 75% occupancy. In addition, one WLM (5 pCi/L-year) results in approximately 0.5 rad (0.5 cGy) of absorbed alpha dose to the lung. The current Environmental Protection Agency (EPA) voluntary indoor air action level is 4 pCi/L air, and most recent documents40-42 continue to use the correlation that 10,000 pCi/L of radon in water correlates to 1 pCi/ L in air (transfer coefficient of 10-4). In poorly ventilated residences, typical radon concentrations are in the range 0.5 to 1.5 pCi/L, somewhat dependent on weather, proximity to the basement substructures, and human use patterns. Typical residential exposures are about 0.2 WLM per year, equivalent to 1 pCi/L-year

PATIENT ASSESSMENT IN RADIATION TERRORISM EVENTS Victims of radiation terrorism events require prompt diagnosis and treatment of medical and surgical conditions as well as conditions related to radiation exposure. Hospital emergency personnel should triage victims using traditional medical and trauma criteria. Radiation dose can be estimated early postevent using rapid-sort, automated biodosimetry and clinical parameters such as the clinical history, TE,43,44 and lymphocyte depletion kinetics. Patient radiation dose can be estimated very effectively from the medical history, serial lymphocyte counts, and TE, and subsequently confirmed with chromosome-aberration bioassay, the current gold standard. These data are effectively analyzed using the Armed Forces Radiobiology Research Institute Biodosimetry Assessment Tool. The medical management of patients with acute, moderate to severe radiation exposure (effective whole body dose greater than 3 Gy) should emphasize the rapid administration of granulocyte colony stimulating factor (G-CSF).45 These compounds appear to decrease the duration of radiation-induced neutropenia and to stimulate neutrophil recovery in patients who have received myelotoxic insult. For those patients developing febrile radiation-induced neutropenia, adherence to the current Infectious Diseases Society of America guidelines for high-risk neutropenia is recommended (http://www.idsociety.org/).

CLINICAL MANIFESTATIONS OF HIGH-LEVEL EXTERNAL EXPOSURE Radiation damage results from the inherent sensitivity of certain cell types to radiation, with mitotically active cells most sensitive to acute effects. The inherent sensitivity of these cells results in a constellation of clinical syndromes (ARS) that occur within a predictable range of dose (greater than 2 Gy) after whole body irradiation delivered at a relatively high dose rate. The clinical components of ARS include hematopoietic, GI, and cerebrovascular syndromes and are reviewed elsewhere.14,43-45


1473

Symptoms of acute, high dose radiation are dependent on the absorbed dose and may appear within hours to days and follow a somewhat predictable course. Individuals suffering from a lethal dose of radiation may experience a compression of these phases over a period of hours, resulting in early death. Because of the rapid cell turnover of the lymphohematopoietic elements, these cells are among the most radiation-sensitive tissue in mammals. As such, irradiation of bone marrow stem and progenitor cells results in exponential death. The onset of cytopenia is variable and dose dependent. In particular, the duration of neutropenia may be prolonged, requiring prolonged administration of hematopoietic growth factors, blood product support, and antibiotics. The primary goal of medical therapy is to shift the survival curve to the right by about 2 Gy. Many casualties in a terrorist-initiated weapon event (IND) whose dose exceeds 6 to 8 Gy will also have significant blast and thermal injuries that will preclude survival when combined with their radiation insult The medical management of patients with acute, moderate to severe radiation exposure (effective whole body dose greater than 3 Gy) should emphasize early initiation of G-CSF, transfusion support as needed, antibiotic prophylaxis, and treatment of febrile neutropenia, which is discussed in more detail below. Additional supportive medications may include antiemetics, antidiarrheals, fluid and electrolytes replacement, and topical burn creams. In the case of coexisting trauma (combined injury), wound closure should be performed within 24 to 36 hours. In non-neutropenic patients, antibiotics should be directed toward the foci of infection and the most likely pathogens. For those who experience significant neutropenia (absolute neutrophil count [ANC] less than 500 cells/mm3), broad-spectrum prophylactic antimicrobials should be given during the potentially long duration of neutropenia. Prophylaxis should include a fluoroquinolone, an antiviral agent (if indicated), and an antifungal agent.43-45 These antimicrobials should be continued until either the patient experiences a neutropenic fever and requires alternate coverage or experiences neutrophil recovery (ANC greater than 500 cells/mm3). In patients who experience first fever, traditionally therapy is directed at gram-negative bacteria (in particular, Pseudomonas aeruginosa), because infections of this type may be rapidly lethal. Any focus of infection that develops during the neutropenic period will require a full course of therapy.

DELAYED EFFECTS OF RADIATION EXPOSURE It is common to distinguish late organ effects from the acute effects of radiation exposure. Deterministic effects typically show a sigmoid dose–response curve above an appropriate threshold, and the severity of the harm from radiation exposure increases with dose. Effects are nonneoplastic and are expressed in the exposed individual. In contrast, stochastic effects represent a probabilistic tissue response to radiation exposure. Stochastic effects

1474


are nonthreshold and expressed in the exposed population. Damage in reproductive cells may give rise to inheritable genetic mutations, while damage in somatic cells may increase the chance of neoplasia. Leukemias and bone cancers have a minimum latency time of 2 to 5 years, while solid tumors have a minimum latency time of approximately 10 years. For carcinomas of normal adult onset, current evidence suggests that the latency period may be greater than 10 years. From the adult atomic bomb data,46 there is statistically significant evidence for all radiation-induced leukemia (except chronic lymphocytic leukemia [CLL]), as well as for breast, thyroid, colon, stomach, lung, and ovarian carcinoma, and borderline or inconsistent results for radiation-induced carcinoma of the esophagus, liver, skin, bladder, and central nervous system (CNS), as well as multiple myeloma and lymphoma. Regarding non-neoplastic disease,46 there is strong evidence for radiation-induced cataracts, hyperparathyroidism, a decrease in the T cell–mediated and humoral immune response, and chromosomal aberrations in lymphocytes. The International Agency for Research on Cancer Study Group47 recently studied combined mortality data for 96,000 nuclear industry workers in the United States, Canada, and the United Kingdom. The exposure was primarily to low-level gamma radiation and the risk analysis was based on a constant linear relative risk model, excess relative risk (ERR) = 1 + b(dose). In this study, the ERR was found to be 2.2 per sievert for leukemia, with ERR for all other cancers, excluding leukemia, being essentially zero. Additional risk estimates for carcinoma from large epidemiologic studies have been published recently.48,49 The Biological Effects of Ionizing Radiation (BEIR) V50 excess cancer mortality estimates are widely quoted in the radiation medicine literature. Consider, for example, the hypothetical risk for a single occupational or terrorist exposure to 10 rem (0.1 Sv). Risk is traditionally expressed as lifetime risk per 100,000 exposed persons. Approximately 20,000 cancer deaths would occur in the absence of radiation exposure. For the hypothetical acute dose of 0.1 Sv, 770 excess cancers (660 nonleukemia and 110 leukemia) would be expected in the male cohort and 810 excess cancers (730 nonleukemia and 80 leukemia) expected in the female cohort. The risk model as a function of dose D is of the form: risk(D) = risk(0)[1 + f(D)g(age,sex,...)]

BEIR V also estimated the genetic effects of 1 rem (0.01 Sv) per generation. The autosomal-dominant natural incidence is approximately 10,000 cases per million. For an additional dose of 1 rem above natural background, one would expect an additional 5 to 20 cases in the first generation and 25 cases at genetic equilibrium. Most cases would be clinically mild in a 3:1 mild:severe ratio. The natural incidence of X-linked disease is estimated in BEIR V at 400 cases per million. For a dose of 1 rem we expect less than one additional case in the first generation and fewer than five cases at equilibrium. Regarding translocations/trisomies, the

natural incidence is approximately 600 translocations and 3800 trisomies per million. At 1 rem, we would expect fewer than an additional five translocations in the first generation and less than one additional trisomy. If we consider congenital abnormalities as an entire entity, the current incidence is approximately 20,000 to 30,000 per million. Given 1 rem whole body doseequivalent, it is expected that an additional 10 would occur in the first generation and 10 to 100 at equilibrium. In all of these calculations, BEIR V assumes a doubling dose of 100 rem (1 Sv). Risk analysis from radiation exposure is a complicated and controversial science.

PRENATAL AND PEDIATRIC ISSUES Differential cell sensitivity to radiation damage is simply expressed by the law of Bergonie and Tribondeau (1906)51 as follows: Cells are generally radiosensitive if they have a high mitotic rate, have a long mitotic future, and are of a primitive type. The developing embryo and fetus fit within these conditions. Pregnancy dating as taught in medical school is the gestational age calculated from beginning of the last menstrual period so that the average length of pregnancy is 280 days or 40 weeks (95% confidence interval [CI] 2 weeks), split into three trimesters. During the first 2 weeks following ovulation, successive developmental phases are fertilization of the ovum, formation of the free blastocyst, and implantation of the blastocyst into the uterus.52 Prior to comparing the effects of radiation on the fetus, it is interesting to compare risks that normally occur during pregnancy. For example, if the patient contracts maternal rubella in the first trimester, approximately 80% of cases will have a fetus with congenital infection. If infection occurs early in the second trimester, there is approximately a 54% incidence of congenital infection. By infection in the third trimester, approximately 25% of fetuses will be born with congenital syndrome. Additionally, if maternal alcohol consumption52 is considered, two to three drinks per day will cause a risk of approximately 10% incidence of fetal alcohol syndrome (FAS). Heavy maternal drinking in pregnancy (more than five drinks per day) will also cause approximately a 30% incidence of FAS. The issue of maternal smoking is particularly important in the incidence of fetal growth retardation, and many experts consider intrauterine growth retardation directly proportional to number of cigarettes smoked.52 Deterministic effects52-55 of radiation exposure to the embryo/fetus may be considered in stages. Preconception, generally no statistically significant effects are noted at low to moderate radiation doses. When the fetus receives a moderate dose in the preimplantation phase, generally an “all or none” effect is noted. If implantation succeeds, the pregnancy is often successful. At a threshold of 10 to 20 rad, transient growth retardation has been noted shortly after implantation. During the period of organogenesis (7 to 13 weeks’ gestation), the embryo is sensitive to the lethal, teratogenic, and growth-retarding effects of radiation because of the

CHAPTER 104

criticality of cellular activities and the high proportion of radiosensitive cells. Growth retardation, gross congenital malformations, microcephaly, and mental retardation are the predominant effects for a uterine dose of greater than 50 rad (0.5 Gy). For survivors of in utero exposure, important clinical sequelae are microcephaly, mental retardation, growth and development delay, and lower IQ and poorer school performance. The highest risk for mental retardation occurs during major neuronal migration in the 8- to 15-week period of time. There is no report of external irradiation inducing morphologic malformation in humans unless the individual also had growth retardation or a CNS anomaly. Generally, there exist specific windows of opportunity for radiation damage in certain organs during fetal development: Cataracts: 0 to 6 days (gestational) Exencephaly: 0 to 37 days Embryonic death: 4 to 11 days Anencephaly or microcephaly: 9 to 90 days Anophthalmia: 16 to 32 days Cleft palate: 20 to 37 days Skeletal dyscrasias: 25 to 85 days Growth retardation: 50+ days Occasionally the question arises regarding a clinical decision to terminate a pregnancy because of first trimester radiation exposure to the fetus. It is important in this regard to consider that the normal rate of first trimester preclinical loss is greater than 30%. For a fetal exposure of 0.1 Gy (10 rad), this risk is increased by less than 1%. A useful number to consider is that the lifetime risk for induction of childhood tumors is approximately 1 in 2000 per rad or 5% per sievert. Consider a case where a fetus received a 5-rad whole body dose in a nuclear medicine procedure where the mother was not known to be pregnant. At 5 rad, the maximal risk for childhood leukemia is 1 in 400. Conversely, the probability of not having a childhood cancer is greater than 99%. If the fetal absorbed dose is greater than 50 rad in the 7- to 13-week window, then there is a substantial risk for growth retardation and CNS damage. It is relatively unusual to have a fetal dose in the range of 25 to 50 rad during the organogenesis period of 7 to 13 weeks. However, if pregnancy termination is at issue for any fetal dose, it is important to have parental value input as well as scientific and clinical input from the physician of record. However, the ultimate decision belongs with the patient. Childhood irradiation problems are of particular concern for the primary care physician. From the atomic bomb data, the doubling dose for childhood abnormalities is at least 1.7 to 2.2 Sv (170 to 220 rem), but these data reflect both a high dose and a high dose rate. According to the BEIR V report, the minimal doubling dose in humans for chronic exposure is at least 4 Sv (400 rem) and greater than 20 rad for children. In cases of childhood irradiation therapy for CNS tumors, depression and somnolence have been noted clinically as well as late development of cognitive dysfunction. For a tumor dose of 40 to 65 Gy, at long-term follow-up, mental


1475

retardation was found in 17% of patients, although 89% functioned at a satisfactory level. Behavioral disorders were found in 39% of this cohort. Mental retardation was greatest in those irradiated at less than 3 years of age or if the tumor was in the thalamus or hypothalamus.54,55 Childhood acute lymphoblastic leukemia (ALL) is the most common childhood neoplasm. Current therapy can be expected to produce remission in greater than 95% of children, and 70% do not have a recurrence. At least 2000 new cases occur each year in children under the age of 15 years. However, treatment including radiation therapy can be potentially carcinogenic. Second neoplasms are relatively common, especially for children younger than 5 years or who have received cranial irradiation.56-58 The Children’s Cancer Study Group57 is an excellent retrospective cohort study of adverse effects from 9720 children exhibiting second neoplasms after ALL treatment. The median follow-up was 4.6 years (range 2 months to 16 years). The study results showed 43 second neoplasms, including 24 CNS neoplasms, 10 new leukemias and lymphomas, and 9 other neoplasms. These data represent a 7-fold excess of all cancers and a 22-fold increase of CNS neoplasms. All children with CNS tumors had undergone cranial irradiation with 18 to 24 Gy. Late deaths and survival after childhood cancer were recorded in the U.K. National Register of Childhood Tumours.57 In a retrospective cohort study, 9080 5-year survivors of childhood cancer were followed for variable periods of time. In this study, 781 deaths were recorded; 74% of these deaths were due to recurrent tumor with treatment-related effects in 15% of deaths, and a second primary tumor in 7% of cases. The important point for the primary care physician is that continued close medical monitoring of survivors of childhood cancer is very important. Childhood thyroid cancer near Chernobyl59 has been studied extensively after that accident. In the Gomel region of Belarus, north of Chernobyl, children are currently screened for thyroid cancer by physical examination, ultrasound imaging of the thyroid, and thyroid function tests. Prior to the accident, the thyroid cancer rate was 0.5 per million population. In the period 1991 to 1994, the corresponding rate was 96.4 per million. This represents almost a 200-fold increase. Intracranial tumors after radium treatment for skin hemangioma during infancy have been studied through the Swedish Cancer Registry.60 In this study, 11,805 infants treated with Ra 226 for hemangioma of the skin between 1930 and 1965 (402,958 person-years of risk) were followed through the Swedish Registry. In this relatively lose-dose study, 47 intracranial tumors developed in 46 people. The standard incidence ratio was 1.89 (95% CI 1.2 to 2.83), with a mean brain dose of 7 cGy.49 As can be seen, analysis of radiation risk is a rapidly changing and complicated issue, and current health physics references should be consulted for the latest information. In addition, Internet programs (e.g., National Institute for Occupational Safety and Health– Radio-Epidemiological Program, http://www.niosh-

1476


irep.com/irep_niosh/) are available to calculate the probability of causation of cancer development after either an acute or a chronic dose. Appendix C gives a hypothetical calculation for a nonradiation worker (secretary) who receives 0.5 Sv over the course of 6 months due to a lost source placed in her desk.

LABORATORY AND CLINICAL HISTORY Upon admission to the emergency department after a radiation incident, it is always appropriate to obtain a CBC with differential, either as a baseline level or as a beginning step for lymphocyte kinetic analysis. Other laboratory tests should be considered as appropriate to the presenting medical situation. The TE, measured from the irradiating event, decreases with increasing whole body dose. For TE of greater than 1 but less than 2 hours, the effective whole body dose is likely at least 3 Gy. If TE is less than 1 hour, the whole body dose likely exceeds 4 Gy. In a mass casualty incident, patients who experience emesis less than 4 hours postaccident should be triaged to professional medical care while those with emesis greater than 4 hours can be instructed to receive delayed medical attention, either with their private physician or with a peripheral center available to deal with minimally injured patients. Patients who experience radiationinduced emesis within 1 hour after a radiation incident will require extensive and prolonged medical intervention, and an ultimately fatal outcome will occur in many instances.

CASE STUDIES IN RADIATION MEDICINE Clinical Example: Historical Radiation Burns (U.S. Surgery Cases, 1949) The history of medicine is replete with examples of radiation burns,61 either from incorrect implementation of a proper radiation procedure, or of improper use of radiation therapy to treat benign conditions. Viewed in a historical context, many early workers experimenting with the medical use of radiation therapy suffered burns to the hands that eventually required excision and grafting. Of interest are early radiologists performing various prolonged fluoroscopic examinations and dentists experiencing radiation burns to the fingers from holding films in the mouths of patients during exposure. We will consider here only two cases, but many case reports are available describing the use of radiation therapy for treatment of acne, eczema, port-wine hemangiomas, plantar warts, epidermophytosis, and pruritus ani, among other benign conditions. Figure 104-1 illustrates atrophy and facial deformity following radium treatment of a hemangioma. Two operations eventually were required with excision and repair with a cross lip flap. Figure 104-2 presents a young female patient with multiple facial carcinomas throughout the nose and chin resulting from radium therapy for eczema. There was extreme involvement of the nose and chin with malignant loss of the nose. Repair (requiring four operations) was accomplished by complete excision and immediate free grafting with application of a prosthetic acrylic nose.

FIGURE 104-1 Atrophy and facial deformity following radium treatment of a hemangioma. Two operations eventually were required with excision and repair with a cross lip flap. (From Brown JB, McDowell F, Fryer MP: Surgical treatment of radiation burns. Surg Gynecol Obstet 1949;88:609–622. With permission of American College of Surgeons.)

CHAPTER 104


1477

FIGURE 104-2 A patient with multiple facial carcinomas near the nose and chin resulting from radium therapy for eczema. There was extensive involvement of the nose and chin with malignant loss of the nose. Plastic repair (requiring four operations) was accomplished by complete excision and immediate free grafting with application of a prosthetic acrylic nose. (From Brown JB, McDowell F, Fryer MP: Surgical treatment of radiation burns. Surg Gynecol Obstet 1949;88:609–622. With permission of American College of Surgeons.)

Residential Radiation Accident Case Study (Estonia, 1994) On October 21, 1994, an Estonian citizen, RIH, along with his two brothers, visit a radioactive waste facility to scavenge for scrap metal, overriding the electrical alarm system and cutting various padlocks.62 RIH climbs into one of the vaults to obtain salvageable metal and passes a large Cs-137 source to his brothers. At this time, none of the brothers realize that this metallic object is highly radioactive. During the theft, RIH injures his leg slightly when an aluminum drum falls against it. Shortly after entry into the repository, RIH begins to feel ill and goes home. Other occupants of the house are the man’s stepson (RT), the boy’s mother, and the boy’s greatgrandmother. The cesium source is initially placed in the man’s coat pocket that hangs in the hall. It eventually is placed in the kitchen drawer along with various tools. RIH is hospitalized soon thereafter with severe injury to his leg. During the intake medical history, he claims that he received the injury while working in the nearby forest and he is therefore treated for crush injury. On November 2, 1994, RIH dies and medical authorities have no suspicion of radiation exposure as the etiology of the medical condition. By November 9, 1994, it is clear that the stepson RT has come in contact with the source multiple times while living in the house and while working on his bicycle. Shortly thereafter, the 4-month-old pet dog dies. The dog had slept much of the time in the kitchen near the cesium source. RT is also eventually admitted to the hospital with severe hand burns, which physicians diagnose as radiation burns and the police are notified. A Russian medical delegation also arrives soon thereafter to provide medical and health physics consultation. After an extensive radiation dose reconstruction, the deceased father, RIH, is thought to have received

approximately 1830 Gy local dose to his thigh and approximately 4 Gy whole body. Clinically, RIH experienced many of the effects of the hematopoietic subset of ARS along with severe, extensive local injury to his thigh (dose rate estimated to be 2000 to 3000 Gy/hr) (see Figure 104-3 for cell responses to irradiation). He died on day 12 postaccident from neutropenic sepsis and in acute renal failure. An autopsy showed acute radiation necrosis of the right thigh and hip, along with hemorrhage and intestinal thinning of the GI wall. The cause of death was ARS with both hematopoietic and GI components, along with severe local radiation necrosis. The stepson, RT, is estimated to have received doses of 20 to 30 Gy to his left hand, 8 to 10 Gy to his right hand, and approximately 2.5 Gy whole body during various episodes of bicycle maintenance. Other family members received hand doses in the range 8 to 20 Gy and whole body doses in the range of 1 to 2.5 Gy. The cumulative dose was based on each individual’s recollection of the degree of occupancy of various locations in the house. In addition, spatial computer analysis, chromosome aberration analysis, and other specialized assays were employed.

U.S. Fatal Criticality Accidents (Neutron-Gamma Exposures) Two early criticality (weapons research) events occurred with a 6.2-kg plutonium sphere at Los Alamos National Laboratory.63-66 The first incident occurred on August 21, 1945, when a worker was preparing a critical assembly by stacking tungsten carbide bricks around the plutonium core as a reflector. He moved the final block over the assembly but, noting that this block would make the assembly supercritical, he withdrew it. The brick fell onto the center of the assembly, resulting in a super-prompt critical state of approximately 6 × E+15 fissions. The worker sustained an average whole body dose of

Lymphocytes

1478


Percent of normal 100

Low dose

50 0 Sublethal doses

Lethal doses

Granulocytes Reticulocytes Platelets

100

0 100

50

Erythrocytes

High dose

50

50 0 100

0 100 50 0 0

5 10 15 20 25 30 35 40 45 50 55 60

Days after exposure FIGURE 104-3 Hematopoietic response of various cell lines to an acute irradiation incident. The threshold is approximately 50 to 100 cGy.

approximately 5.1 Gy and a dose to the right hand of approximately 100 to 400 Gy. Within 36 hours postaccident, blisters were noted on the volar aspect of the right third finger, and within 24 hours thereafter, extensive erythema and eventual blistering was noted on both palmar and volar surfaces of the hand. By the third week, the right hand had progressed to a dry gangrene. Desquamation of the epidermis involved almost all of the skin of the dorsum of the forearm and hand. In addition, epilation was almost complete at the time of death. The patient died of sepsis 28 days postaccident. At autopsy, severe skin necrosis was observed as well overt dry gangrene. The cardiorespiratory system was significant for pericarditis, cardiac hypertrophy, pulmonary edema, and alveolar hemorrhage. The spleen was noted to have no germinal centers, and the mucosa of the large bowel was ulcerated, as was the buccal mucosa. The bone marrow was noted to be hypoplastic, and lymph nodes also showed significant lymphocyte depletion. A solitary ulcer was noted in the large colon, as was a right renal infarct. This case is an excellent example of the hematopoietic component of ARS with perhaps the beginning of the GI component. The second criticality accident occurred in 1946 during an approach to criticality demonstration at which several observers were present. The operator used a

screwdriver as a lever to lower a hemispherical beryllium shell reflector into place. While holding the top shell with his left thumb, the screwdriver slipped and caused a critical configuration. The fission yield in this accident was estimated at 3 × E+15 fissions. The operator received an estimated acute whole body dose of approximately 21 Gy, with a dose to the left hand of approximately 150 Gy and somewhat less to the right hand. Clinically, the patient complained of nausea in the hour prior to admission and vomited once in the first hour postaccident. On the fifth day post-accident there was a precipitous drop in his neutrophil count, and his condition began to decline rapidly. The patient rapidly lost weight, became mentally confused on day 7 postevent, became comatose, and died quietly on the ninth day in cardiovascular shock (GI and CNS syndrome). At the time of death, both hands showed extensive radiation damage. At autopsy, the cardiorespiratory system was remarkable for cardiac hemorrhage and myocardial edema, and the terminal bronchi showed features of aspiration pneumonia. In addition, most of the GI tract showed sloughing, most pronounced in the jejunum and ileum. Widespread hyaline changes were also noted in the renal tubular epithelium. The third major U.S. criticality accident occurred on December 30, 1958, during purification and concentration of plutonium. In the process, unexpected plutonium-rich solids were washed from two vessels into a single large vessel that contained layered, dilute aqueous and organic solutions. Accident analysis shows that the aqueous layer initially was slightly below delayed critical (approximately 203 mm thick, critical thickness 210 mm). When the stirrer was started, the central portion of the liquid system was thickened, changing system reactivity to super-prompt critical. The excursion yield was approximately 1.5 × E+17 fissions. Bubble generation was the negative feedback mechanism for terminating the neutron spike. The dose to the patient’s upper extremity was estimated to be 120 Gy ± 50%. The clinical course of this case has traditionally been divided into four separate phases of varying duration: Phase 1 (20 to 30 minutes postevent): immediate physical collapse and mental incapacitation, progressing eventually into semiconsciousness Phase 2 (90 minutes): signs and symptoms of cardiovascular shock accompanied by severe abdominal pain Phase 3 (28 hours): subjective minimal clinical improvement Phase 4 (2 hours): rapidly appearing irritability and mania, progressing to coma and death The clinical course was remarkable for continuing, profound hypotension, tachycardia, and intense dermal and conjunctival hyperemia. The patient died 35 hours postexposure of the cardiovascular-CNS syndrome. On autopsy, examination of the heart showed acute myocarditis, myocardial edema, cardiac hypertrophy, and a fibrinous pericarditis. Examination of the brain demonstrated cerebral edema, diffuse vasculitis, and

CHAPTER 104

cerebral hemorrhage. The GI system showed necrosis of the anterior gastric wall parietal cells, acute upper jejunal distention, mitotic suppression throughout the entire GI tract, and acute jejunal and ileal enteritis. The fourth fatal U.S. criticality accident occurred on July 24, 1964, at the United Nuclear Fuels Recovery Plant, Wood River Junction, Rhode Island. A chemical processing plant was designed to recover highly enriched uranium from scrap material left over from the production of fuel rods. The critical excursion occurred when nearly all of the uranium had been transferred, resulting in approximately 1.0 to 1.1 × E+17 fissions. The acute dose to the operator was estimated to be 100 Gy. Approximately 4 hours postaccident, the patient experienced transient difficulty in speaking, hypotension, and tachycardia. A portable chest x-ray 16 hours postadmission showed hilar congestion. On day 2, the patient became very disoriented, hypotensive, and anuric and died 49 hours postaccident in cardiovascular shock. At autopsy, examination of the heart, lungs, and abdominal cavity revealed acute pulmonary edema, bilateral hydrothorax, hydropericardium, abdominal ascites, acute pericarditis, interstitial myocarditis, and inflammation of the ascending aorta. Examination of the GI tract showed severe subserosal edema of the stomach and of the transverse and descending colon.

Industrial Radiography Accident at the Yanango Hydroelectric Power Plant (1999) Prior to hydrostatic testing of a pipe under repair at the Yanango hydroelectric power plant in the San Ramon District in Peru (300 km east of Lima, Peru), Ir 192 radiography was required to check welded repairs for defects. At 11:30 A.M. on February 20, 1999, an industrial radiographer and his assistant took their equipment to the area of a large, 2-m diameter pipe where repairs were underway. Their radiography equipment, a projection type camera designed to use a cable to drive a radiation source in and out through a guide tube, was reported to contain a 1.37 TBq (37 Ci) Ir 192 source. The welders had not yet completed their repairs, so the radiographer and his assistant left their locked camera (with the drive cable attached, but the guide tube not connected) in order to proceed with other tasks. They returned later that night to perform the radiography. On development of their x-ray films, the radiographer discovered that the film had not been exposed. He checked his radiography equipment around midnight and discovered that the iridium source was missing. A search was initiated, and at 1 A.M. on February 21 the radiographer recovered the source at the home of the welder. The welder reported he had found the source in the pipe, had picked it up with his right hand, and put it into the right rear pocket of his loose fitting denim trousers. The welder then took a minibus and arrived home after a 30-minute ride. He experienced slight nausea earlier that evening and also noted some discomfort in his right thigh. On arrival home, he asked his wife to check a painful area on the back of his right thigh and she noted


1479

the area was reddened. A local physician was consulted and gave a diagnosis of “insect bite” and was told to use hot compresses on the inflamed area. Once aware of the accident, the company promptly notified the national authority for radiation safety and regulation, the Instituto Peruano de Energia Nuclear (IPEN).67 IPEN personnel then notified the head of the radiotherapy department of the Instituto de Enfermedades Neoplasicas (INEN) in Lima, where arrangements had previously been made for treatment of persons with radiation injury. Subsequently, IPEN personnel gathered information about the incident and arranged medical examinations for all potentially exposed persons, including the welder’s three children (ages 10 and 7 years and 18 months), his wife, and his assistant. Arrangements were then made to facilitate transport of the welder and his family to INEN in Lima. The welder was admitted to the hospital on February 21, 1999, approximately 20 hours after the discovery of the accident. Extensive clinical and dosimetric details of this accident have been published elsewhere.68,69 Physical examination of the patient on admission revealed a 37-year-old, well-built Peruvian man weighing approximately 78 kg. A painful, erythematous area was noted on the right upper posterior thigh. Over the next few days, a very painful, bullous lesion surrounded by a large inflammatory halo developed, reaching 4 cm2 in size by day 3. The right hip, buttock, and thigh became quite swollen over several days, and a computed tomography scan performed on February 26 showed generalized, marked edema involving all muscle groups in the right posterior thigh as well as in subcutaneous tissue. Swelling in the area diminished several days later, but extension, denudation, and necrosis of the lesion progressed rapidly. By March 19, 1 month after the accident, the patient’s deteriorating health was evident. He had lost 7 kg in weight and was in intense pain with clinical pain control increasingly difficult, and his lesion now involved an area of more than 10 × 12 cm. The lesion at this time had dark, firm necrotic edges, was partially covered with a fibrin crust, and appeared superficially infected. The wound later progressed to approximately 2 cm in depth, with necrosis of underlying fat and involvement down to the semitendinosus and biceps femoralis muscles. Nerve involvement was suspected and subsequently diagnosed using nerve conduction studies. A team of experts, at the request of the IAEA, arrived on March 19 to consult with the Peruvian physicians regarding details of the accident, treatment protocols, lessons learned, and so forth. The team noted slightly depressed white blood cell counts indicating low-level whole body irradiation, estimated to be between 1 and 3 Gy. The team at this time discussed the potential need for a right hemipelvectomy. Also, in this time period, the source was calibrated and found to be somewhat less than the 1.37 TBq originally reported. Measurements indicated its activity was approximately 0.962 T.Bq (26 Ci). By the end of March, the thigh lesion had now extended to 20 × 15 cm, with a large area of central necrosis and a surrounding fibrotic rim. Electromy-

1480


ography at this time confirmed signs of denervation of the sciatic nerve. Histologic studies of the necrotic lesions revealed microscopic hemorrhages, extensive areas of coagulation necrosis, edema, severe inflammation, and destruction of vascular structures. In addition, walls of small and moderate-sized arteries showed a distinct postradiation necrotizing vasculitis. Subsequent surgical exploration and débridement of the area revealed that the lesion had extended to the femur and to the sciatic nerve. On August 16, the right hip was disarticulated and a left iliac colostomy was performed. The patient left the burn center on day 205 postaccident for transfer to a rehabilitation center. By late September, the radionecrosis and superficial infection was noted to extend to the perineum, including the anal sphincter and scrotum. In May 2000, the patient was transferred from Lima to an intensive care unit in a hospital near his home town. Because of severe psychological issues, close family contact proved to be of significant therapeutic value. At the last physical examination, the patient had some closure of the necrotic perineal area, with formation of granulation tissue and progressive fibrosis. The urethral fistula was still present and requires plastic reconstruction.

CONCLUSION In evaluation of the magnitude of a radiation event (either an industrial accident or terrorist event), it is important for the health physicist, physician, and radiobiologist to work closely together and to evaluate many variables, particularly the initial patient medical history and physical examination and the timing of prodromal signs and symptoms (nausea, vomiting, diarrhea, transient incapacitation, hypotension), and other signs and symptoms suggestive of high-level exposure. The diagnosing physician charged with medical care of patients following a radiation accident is therefore likely to see at least two distinct patient presentations: (1) a normal-appearing patient with few signs or symptoms, or perhaps offering symptoms of unexplained nausea and vomiting, or of unexplained skin lesions, or (2) a very ill patient with stigmata of the acute radiation syndrome and/or local radiation injury. The astute diagnostician must be aware of these different presentations.

APPENDIX A. A BRIEF INTRODUCTION TO RADIATION PHYSICS AND TO RADIOLOGICAL UNITS In order for the toxicologist or emergency medicine specialist to provide initial treatment and advice to the nuclear accident victim, it is necessary to consider only a few basic ideas from radiation physics. Radioactive materials are materials that emit ionizing radiation. They emit various types of energetic particles to reach a more stable quantum ground state. These radioisotopes are chemically and physically identical to their nonradioactive counterparts and behave metabolically in the human body only according to their chemical properties.

The fact that an isotope is radioactive does, however, determine the effective half-life in the body. As is well known in toxicology, the radioactive half-life is the time required for a radioactive substance to lose half of its radioactivity. Each radionuclide has a unique half-life. Half-lives range from extremely short fractions of a second to billions of years. A long half-life implies a low specific activity (activity per unit mass) and a short halflife implies a high specific activity. If TB is the biological half-life of the stable element as degraded via normal metabolic pathways and TR is the radioactive half-life, then the effective half-live T(eff) is the parallel combination: 1/T(eff) = 1/TB + 1/TR

From Equation 1, we can see, if the radioisotope is long-lived (TR >> TB), then the effective half-life is essentially the biologic or metabolic half-life TB. Conversely, if the isotope is short-lived (TB >> TR), the effective halflife is dominated by the radioactive half-life. Ionizing radiation refers to radiation (alpha, beta, photons, and neutrons) whose energy is sufficient to strip electrons from atoms or molecules. Essentially all types of radiation from the atomic nucleus are ionizing. Nonionizing radiation includes visible light, microwaves, radio waves, ultrasound, and so forth and are not included for consideration here. Alpha particles (energetic helium nuclei) generally do not pass through the keratinizing layer of skin and therefore are primarily of interest in situations involving inhalation or ingestion of radioactive material. Generally, alpha particles are emitted only from the very heavy nuclei. Beta particles (energetic electrons) have a greater range in air and in tissue. Beta particles therefore are of interest in estimation of skin dose and in situations involving internal deposition. Gamma rays are photons emitted from the nucleus that generally penetrate the skin, soft tissue, and bone. Gamma rays are involved in the vast majority of radiation accidents involving external irradiation. X-rays are relatively lower-energy photons arising from transitions between atomic energy levels and are occasionally involved in radiation accidents arising from improper use of industrial or medical equipment. Generally, most of the lighter radioisotopes emit both beta and gamma rays while the very heavy elements typically emit alpha particles along with relatively low energy photons. However, given the large number of isotopes, it is difficult to generalize, and many isotopes have a large number of emissions. Atomic nomenclature shows the abbreviation of the element and atomic number A (number of protons + neutrons) as shown: A

(element) or (element)-A

Examples are 60Co or Co 60 and 137Cs or Cs 137 (see Box 104-1). Radiation energies are typically measured in electron-volts (eV), kilo-electron volts (KeV) or millionelectron volts (MeV). For example, the main gamma ray of interest in Cs 137 is 661 KeV or 0.661 MeV. Co 60 emits

CHAPTER 104

BOX104-1

RADIOISOTOPES OFTEN INVOLVED IN VARIOUS COMMERCIAL SECTORS

The University “Seven”

The Industrial “Four”

H3 C 14 P 32 Co 60 I 125/I 131 Cf 252

Ir 192 Co 60 Cs 137 Sr 90 The Military “Three”

U 235 Pu 239 Am 241

two very penetrating gamma rays of energy, 1.17 MeV and 1.33 MeV. Ir 192 (iridium) is widely used throughout the world in industrial radiography, and this radioisotope is probably the most significant isotope involved in localized radiation injury. In the United States, over a million high-level Ir 192 sources exist, and a few are unaccounted for at any point in time. It is an interesting phenomenon that specific isotopes tend to be involved in radiation accidents in certain industries. For example, only seven isotopes tend to appear in most university accidents as noted above, generally four isotopes in most accidents in the industrial sector, and essentially three in the military environment. The above list is somewhat of a generalization and there is certainly crossover between sectors, but this short list probably accounts for 90% of accidents in their respective sectors. In radiation physics, “exposure” relates to the amount of ionization produced by x-rays or gamma rays in air under standard conditions. Exposure R is the quotient Q/m, where Q is the sum of the electrical charges on all the ions of one sign produced in air when electrons and positrons liberated by photons in a volume element of air whose mass is m, are completely stopped. The traditional unit of exposure is the roentgen (R) defined by 1 R = 2.58 × 104 C/kg. The SI unit of exposure is the C/kg. Dose refers to the absorption of radiation energy per unit mass of absorber (e.g., soft tissue, lung, bone, etc.). The conventional unit of radiation dose is the rad (1 rad = 100 ergs/g of absorbed energy). The SI unit of dose is the gray (Gy), equal to 100 rad, and also equal to 1 joule/kg. Dose may refer either to whole body dose, partial body dose, or to organ dose. Dose equivalent is dose multiplied by a factor to account for the varying effectiveness of various types of radiation. The traditional unit of dose equivalent is the rem, while the SI unit is the sievert (Sv), equal to 100 rem. Generally, it is not necessary to consider dose equivalent in the initial evaluation of the patient involved in a radiation accident. For soft tissue, it is quite acceptable medically to assume that 1 R is approximately numerically equal to 1 rad, which is approximately equal to 1 rem. This is not true for other organs such as bone or lung. However, such approximations are quite adequate in a mass casualty radiation event.


1481

Activity is the number of disintegrations or nuclear transformations per unit of time occurring in radioactive material. The conventional unit of activity is the curie (Ci; 1 Ci = 3.7 × 1010 disintegrations per second. The SI unit of activity is the becquerel (Bq) equal to one disintegration per second. Therefore 1 Ci = 3.7 × 1010 Bq. The activity per unit mass (specific activity, SA) is another useful quantity defined as Ci/g or Bq/kg. SA is defined by Ci/g = (1.3 × 108)/(half-life in days × atomic mass).

Example 1. Internal Dose from a Cardiac Scan A patient is given 20 mCi technetium-99m as part of a cardiac stress test performed in a university teaching hospital. First, express this activity in SI units. We therefore have 20 × E-3 Ci × 3.7 E+10 Bq/Ci = 740 MBq. What is the patient dose from this medical procedure? From the Radiation Internal Dose Information Center (RIDIC) and from CDC Dosimetry Services (http:// www.internaldosimetry.com/linkedpages/doseestimates. html), we have a DCF (dose per unit input; 1.3 E-2 mSv/ MBq for 99mTc). The effective dose equivalent is therefore 740 MBq × (1.3 E-2 mSv/MBq) = 9.6 mSv = 0.96 rad. Our patient has therefore received an effective dose of about 1 rad during the cardiac stress test. The key to effective and efficient internal dose calculations is proper determination of the DCF. Another very useful compilation of DCF data and health physics information in general is the Radiation Dose Assessment Resource, RADAR (http://www.ieo.it/radar/). Assume that 99mTc has an effective half-life of 6 hours. After one half-life (6 hours), there is 10 mCi remaining, after two half-lives (12 hours), there is 5 mCi remaining, and so forth.

Example 2. Regulatory Limits What are the current regulatory limits to the public and to occupational workers (Table 104-1)?

Example 3. Illustrations of Commonly Used Radioisotopes Give some illustrations of commonly used radioisotopes and their uses (Table 104-2).

TABLE 104-1 Regulatory Limits Members of the Public Occupational Limits Total effective dose equivalent Lens of the eye Single organ dose equivalent Skin dose equivalent Extremity dose equivalent

Limit 100 mrem 5 rem 15 rem 50 rem 50 rem 50 rem

1482


TABLE 104-2 Commonly Used Radioisotopes and Their Use NUCLIDE

HALF-LIFE

SpA (Ci/g)

EMITS

USE

H-3 Co-60 I-131 Cs-137 Ir-192 Ra-226 U-235 Pu-238 Pu-239 Pu-241 Am-241

12.3 yr 5.3 yr 8.05 days 30 yr 84 days 1620 yr 7 x 108 yr 87 yr 24,400 yr 13.2 yr 458 yr

9640 1130 1.23 x 105 87 9170 0.99 2.1 x 10-6 17.2 0.061 112 3.2

Beta Beta, gamma Beta, gamma Beta, gamma Beta, gamma Alpha, gamma Alpha, beta, gamma Alpha Alpha Beta Alpha, gamma

Luminous signs Medical therapy Medical therapy Medical therapy Industrial radiography Medical therapy Reactors/weapons Thermoelectric generation Reactors/Weapons Waste product Smoke detectors

SpA, specific activity.

Example 4. Typical Radiation Dose in Life Activities and in Common Medical Procedures Provide some illustrative dose estimates for common life and medical activities (approximate doses) (Table 104-3).

Example 5. Common Industrial Applications of Radioactive Materials Describe various common applications where radioactivity is used, and therefore where the possibility of an accident exists (not comprehensive). IONIZING RADIATION: MEDICAL, INDUSTRIAL, AND CONSUMER PRODUCT APPLICATIONS Radiography, analytical, and irradiation techniques (e.g., irradiation of food products) Instrument calibration techniques using unsealed radioactive sources Industrial gamma and x-ray industrial radiography (nondestructive testing) Medical diagnostic radiography

TABLE 104-3 Dose Estimates for Common Life and Medical Activities ACTIVITY

DOSE ESTIMATE

Natural background and manmade radiation (annual average dose equivalent, including radon) Diagnostic chest x-ray Flight from Los Angeles to Paris Barium enema Smoking 1.5 packs per day for 1 year

360 mrem

Heart catheterization Mild acute radiation syndrome LD50 for acute whole body irradiation Occupational limit for a radiation worker Limit of a member of the public

6–10 mrem 5 mrem 800 mrem 16,000 mrem = 16 rem 45,000 mrad = 45 rad = 0.45 Gy 200 rad = 2 Gy 450 rad = 4.5 Gy 5 rem = 0.05 Sv 0.1 rem = 0.001 Sv = 1 mSv

Industrial beta and neutron radiography; x-ray fluorescence gauges such as instrumentation to detect residential lead levels Photon switching gauges (level gauges) Medical therapy: radiation beam therapy and brachytherapy for cancer treatment High-level radiation sources for sterilization of food and medical products, food preservation, and crosslinking, curing, and grafting Radioisotope tracer techniques in research and the therapeutic use of radiopharmaceuticals Use of radioisotopes for self-luminous dials and devices Radioisotopes for enhancement of electrical discharge, static elimination, and commercial and residential smoke (approximately 0.9 μCi of 241Am in each residential smoke detector. Use of radioisotopes for nuclear batteries, such as those used in spacecraft and in remote areas of the earth for instrumentation

APPENDIX B. ASSETS AVAILABLE TO ASSIST IN THE MEDICAL MANAGEMENT OF RADIATION ACCIDENTS Two major U.S. organizations are available to assist the toxicologist in the initial medical management of the radiation victim. These are the Radiation Emergency Assistance Center/Training Site (REAC/TS; www.orau. gov/reacts/), a Department of Energy medical asset located in Oak Ridge, Tennessee, and the Armed Forces Radiobiology Research Institute (AFRRI) located in Bethesda, Maryland. Since its formation in 1976, REAC/TS has provided medical support and advice in the medical management of many radiation accidents. A 24-hour emergency response team is available through the U.S. Department of Energy 24-hour number in Oak Ridge, Tennessee (865-576-1005). The Center’s team of physicians, nurses, health physicists, radiobiologists, and emergency coordinators is prepared around the clock to provide medical and health physics assistance at the local, national, or international level.

CHAPTER 104

The AFRRI is a tri-service laboratory chartered in 1961 to conduct research in the field of radiobiology and related matters essential to the operational and medical support of the U.S. Department of Defense and the military services. The institute collaborates with other governmental facilities, academic institutions, and civilian laboratories in the United States and other countries. Its research findings have had broad military and civilian applications. The AFRRI Biodosimetry Team may be reached at 301-295-0484 and the Medical Radiobiology Advisory Team (MRAT) physician may be reached at 301-295-0530. In particular, the Biodosimetry Assessment Tool (BAT) is a comprehensive software application developed by the AFRRI for recording diagnostic information in suspected radiologic exposures. The application, for use on the Microsoft Windows operating system, is available at www.afrri.usuhs.mil. A companion program, the First-responder Radiological Assessment Triage (FRAT) software application, is a complementary product under development for use on hand-held PDAs. It is being designed as templates into which first responders record clinical signs and symptoms, lymphocyte counts, physical dosimetry, radioactivity, and location-relevant dose estimates. The FRAT and BAT applications compare collected data with known radiation dose response to provide triage and multiparameter dose assessment. The software allows the entry of exposure information based on multiple parameters (physical dosimetry, prodromal symptoms, hematology, radiation cytogenetics, etc.). Templates are available for recording exposure information based, for example, on physical dosimetry (e.g., personnel dosimeters) or contamination (e.g., radioactivity bioassay counting). An integrated, interactive human body map permits convenient documentation of the location of a personnel dosimeter, radiation-induced erythema, and radioactivity detected by an appropriate radiation detection device.


APPENDIX C. RADIATION RISK EXAMPLE A 25-year-old secretary, while on vacation, is notified that an old radium source was found in the back of a desk drawer in her office. The source is traced to a hospital decommissioned some 20 years ago. A time and motion health physics analysis indicates that she may have received, at most, 50 rem (0.5 Sv) over the course of 6 months. The risk analysis was performed using the SURVRAD software,70 which generally uses state of the art radiation epidemiology risk models. The SURVRAD computer output follows: Run date March 6, 2005 Title 25 year-old secretary with source in her desk Sex Female Race All races Type vital statistic Period-specific Life table used 1990 Truncate last plateau No Risk coefficients From Thompson et al (1994) and Preston et al (1994) Type lifetime risks: Incidence Leukemia Minimal latency (yr) 2 Plateau (yr) 40 Solid cancers Minimal latency (yr) 10 Plateau (yr) 100 Leukemia plateau Beginning (age) 27 End (age) 67 Solid cancer plateau Beginning (age) 35 End (age) 100 DRREF 2.0 Age at first exposure 25 Age at last exposure 25 Total dose equivalent (SV) 0.5000000

RADIATION-INDUCED CANCERS 5

1483

BASELINE CANCERS 5

MODEL

SITE

PER 10

90.0% CI

PER 10

PC (90.0% CI)

RR RR RR RR RR RR RR RR RR RR RR RR RR RR RR RR RR RR RR AR AR AR AR

Oral cavity Digestive Esophagus Stomach Colon Rectum Liver Pancreas Respiratory Lung Nonmelanoma Breast Uterus Ovary Bladder Kidney CNS Thyroid Nonleukemia Leukemia ALL AML CML

121 1653 107 144 683 151 0 195 2369 2526 42 4122 0 86 865 514 23 43 7195 157 40 48 52

(52, 280) (715, 3817) (46, 248) (62, 332) (295, 1577) (65, 349) (0, 0) (84, 450) (1025, 5470) (1094, 5833) (18, 98) (1785, 9518) (0, 0) (37, 199) (374, 1999) (223, 1189) (10, 54) (18, 100) (3116, 16617) (67, 362) (17, 93) (21, 112) (22, 120)

826 11073 245 937 5710 1095 190 1387 5779 5386 111 14569 53 1798 1352 828 483 492 47011 203 22 86 54

0.13 (0.05, 0.30) 0.13 (0.06, 0.30) 0.30 (0.09, 1.00) 0.13 (0.06, 0.31) 0.11 (0.05, 0.25) 0.12 (0.05, 0.28) 0.00 (0.00, 0.00) 0.12 (0.05, 0.29) 0.29 (0.12, 0.69) 0.32 (0.13, 0.76) 0.28 (0.07, 1.00) 0.22 (0.10, 0.51) 0.00 (0.00, 0.00) 0.05 (0.02, 0.11) 0.39 (0.15, 1.00) 0.38 (0.13, 1.00) 0.05 (0.02, 0.11) 0.08 (0.03, 0.19) 0.13 (0.06, 0.31) 0.44 (0.11, 1.00) 0.64 (0.00, 1.00) 0.36 (0.07, 1.00) 0.49 (0.04, 1.00)

1484


Probabilities of causation (PCs) represent the likelihood that either a cancer (for incidence) or cancer death (for mortality) is attributable to radiation exposure. PCs are based on the end of the plateau period for the last age at exposure. The probability of causation PC is defined as the (RR-1)/RR, where RR is the relative risk. As noted above, PC is only significant in this case for those cancers of hematopoietic origin (ALL, acute myeloid leukemia [AML], chronic myelogenous leukemia [CML]), although with large uncertainty. CLL is thought by most investigators not to be radiation-related.

REFERENCES 1. Gusev IA, Guskova AK, Mettler FA (eds): Medical Management of Radiation Accidents, 2nd ed. Boca Raton, FL, CRC Press, 2001. 2. Mettler FA, Upton AC: Medical Effects of Ionizing Radiation, 2nd ed. Philadelphia, WB Saunders, 1995. 3. Ricks RC, Berger ME, O’Hara FM Jr: The Medical Basis for Radiation-Accident Preparedness. The Clinical Care of Victims. Proceedings of the Fourth International REAC/TS Conference on the Medical Basis for Radiation-Accident Preparedness, Orlando, FL, March 2001. Pearl River, NY, Parthenon, 2002. 4. Fajardo LF, Berthrong M, Anderson RE: Radiation Pathology. New York, Oxford University Press, 2001. 5. Bevelacqua JJ: Basic Health Physics. Problems and Solutions. New York, Wiley Inter-Science, 1999. 6. Scleien B, Slaback LA, Birky BK (eds): Handbook of Health Physics and Radiological Health, 3rd ed. Baltimore, MD, Williams & Wilkins, 1998. 7. Shapiro J: Radiation Protection, 4th ed. Cambridge, MA, Harvard University Press, 2002. 8. Cember H: Introduction to Health Physics, 3rd ed. New York, McGraw-Hill, 1996. 9. Armed Forces Radiobiology Research Institute: Medical Management of Radiological Casualties. Military Medical Operations. Bethesda, MD, Armed Forces Radiobiology Research Institute, accessed November 21, 2006 at http://www.afrri.usuhs.mil. 10. Gottlober P, Krahn G, Peter RU: Cutaneous radiation syndrome: clinical features, diagnosis and therapy. Hautarzt 2000;51(8): 567–574. 11. Gottlober P, Steinert M, Weiss M, et al: The outcome of local radiation injuries: 14 years of follow-up after the Chernobyl accident. Radiat Res 2001;155(3):409–416. 12. International Atomic Energy Agency TECDOC-1009. Dosimetric and Medical Aspects of the Radiological Accident in Goiania in 1987. IAEA, Vienna, Austria, June 1998. 13. Tsujii H, Akashi M (eds): Proceedings of an International Symposium on the Criticality Accident in Tokaimura. Medical Effects of Radiation Emergency. Chiba, Japan, National Institute of Radiological Sciences, 2001. 14. Goans RE: Clinical care of the radiation accident patient: patient presentation, assessment, and initial diagnosis. In Ricks RC, Berger ME, O’Hara FM Jr (eds): The Medical Basis for Radiation-Accident Preparedness. The Clinical Care of Victims. Proceedings of the Fourth International REAC/TS Conference on the Medical Basis for Radiation-Accident Preparedness, Orlando, FL, March 2001. Pearl River, NY, Parthenon, 2002, pp 11–22. 15. Goans RE, Holloway EC, Berger ME, Ricks RC: Early dose assessment following severe radiation accidents. Health Phys 1996;72(4):513–518. 16. Goans RE, Holloway EC, Berger ME, et al: Early dose assessment in criticality accidents. Health Phys 2001;81(4):446–449. 17. Sine RC, Levine IH, Jackson WE, et al: Biodosimetry assessment tool: a post-exposure software application for management of radiation accidents. Milit Med 2001;166(12 Suppl):85–87. 18. Goans RE: Medical Lessons from US and International Radiation Accidents. Chapter 21. In Brodsky A, Johnson RH, Goans RE: Proceedings of the 2004 Health Physics Society Summer School. Madison, WI, Medical Physics Publishing, 2004, pp 373–393.

19. Brodsky A, Johnson RH, Goans RE, eds: Public Protection from Nuclear, Chemical, and Biological Terrorism. Health Physics Society 2004 Summer School. Medical Physics Publishing, 2004. 20. Koenig K, Goans RE, Hatchett RJ, et al: Medical treatment of radiological casualties: current concepts. Ann Emerg Med 2005; 45(6):643–652. 21. NCRP Report No. 65. Management of Persons Accidentally Contaminated with Radionuclides. Bethesda, MD, National Council on Radiation Protection and Measurements, 1980. 22. Mansfield WG: Nuclear Emergency and Radiological Decision Handbook. Livermore, CA, Lawrence Livermore National Laboratory, May 1997. 23. Goans RE: Update on the treatment of internal contamination. In Ricks RC, Berger ME, O’Hara FM Jr (eds): The Medical Basis for Radiation-Accident Preparedness. The Clinical Care of Victims. Proceedings of the Fourth International REAC/TS Conference on the Medical Basis for Radiation-Accident Preparedness, Orlando, FL, March 2001. Pearl River, NY, Parthenon, 2002. 24. ICRP Publication 67. Age-Dependent Doses to Members of the Public from Intake of Radionuclides: Parts 1,2. Atlanta, Elsevier, 1993. 25. Seelentag W: Two cases of tritium fatality. In Moghissi AA, Carter MW, eds. Tritium. Phoenix, AZ, Messenger Graphics, 1973. 26. Snyder WS, Cook MJ, Ford MR: Estimates of (MPC)w for occupational exposure to Sr90, Sr89, and Sr85. Health Phys 1964; 10(3):171–182. 27. ICRP Publication 76. Strontium Biokinetic Model. New York, Pergamon, 1995. 28. Rubery E, Smales E: Iodine Prophylaxis Following Nuclear Accidents, Proceedings of a WHO/CEC Workshop. Geneva, World Health Organization, July 1988. 29. Durbin PW: Metabolic models for uranium. In: Biokinetics and Analysis of Uranium in Man F1-F62. US Uranium Registry Report USUR-05 HEHF 47. Springfield, VA, National Technical Information Service, 1984, pp 121–137. 30. Fong FH Jr: Acute effects of internal exposure to depleted uranium. In: Proceedings of the Depleted Uranium Health and Safety Information Exchange Meeting, November 30–December 1, 1993. U.S. Department of Energy. Oak Ridge, TN, Oak Ridge Associated Universities, 1993, pp 9–14. 31. Wrenn ME, Lipzstein J, Bertelli L: Pharmacokinetic models relevant to toxicity and metabolism for uranium in humans and animals. Radiat Protect Dosimetry 1989;26:243–248. 32. West CM: Depleted uranium processing and use. In Proceedings of the Depleted Uranium Health and Safety Information Exchange Meeting, November 30–December 1, 1993. U.S. Department of Energy. Oak Ridge, TN, Oak Ridge Associated Universities, 1993, pp 2–8. 33. Durbin PW, Kullgren B, Ebbe SN, et al: Chelating agents for uranium(VI): 2. Efficacy and toxicity of tetradentate catecholate and hydroxypyridinonate ligands in mice. Health Phys 2000;78(5): 511–521. 34. Durbin PW, Kullgren B, Xu J, Raymond KN: Multidentate hydroxypyridinonate ligands for Pu(IV) chelation in vivo: comparative efficacy and toxicity in mouse of ligands containing 1,2-HOPO or Me-3,2-HOPO. Int J Radiat Biol 2000;76(2):199–214. 35. Henge-Napoli MH, Stradling GN, Taylor DM, eds: Decorporation of radionuclides from the human body. Radiat Protect Dosimetry 2000;87(1 Special issue). 36. Henge-Napoli MH, Ansoborlo E, Chazel V, et al: Efficacy of ethane1-hydroxl-1,2-bisphosphonate (EHBP) for the decorporation of uranium after intramuscular contamination in rats. Int J Radiat Biol 1999;75(11):1473–1477. 37. Destombes C, Laroche P, Cazoulat A, Gerasimo P: Reduction of renal uranium uptake by acetazolamide: the importance of urinary elimination of bicarbonate. Ann Pharm Fr 1999;57(5):397–400. 38. Durbin PW: Plutonium in man: a new look at old data. In Stover BJ, Lee WSS (eds): Radiobiology of Plutonium. Salt Lake City, UT, JW Press, 1972. 39. Langham WH, Bassett SH, Harris PS, Carter RE: Distribution and excretion of plutonium administered intravenously to man. Health Phys 1980;38(6):1031–1060. 40. Radon in Drinking Water: Risk Assessment by the National Academy of Sciences, 1998. Accessed November 21, 2006, at www.epa.gov.

CHAPTER 104

41. National Research Council Staff: Health Risks of Radon and Other Internally Deposited Alpha-Emitters: BEIR IV. Washington, DC, National Research Council, January 1988. 42. National Research BEIR VI Committee: Health Effects of Exposure to Radon: BEIR VI. National Research Council, Washington, DC, June 1999. 43. Goans RE, Wald N: Radiation accidents with multi-organ failure— selected historical experience in the United States. Radiationinduced multi-organ involvement and failure: a challenge for pathogenetic, diagnostic and therapeutic approaches and research. Advanced Research Workshop. BJR 2005;27(Suppl):41–46. 44. Goans RE, Waselenko JK: Medical management of radiological casualties. Proceedings of the NCRP 2004. Health Phys 2005;89: 505–512. 45. Waselenko JK, MacVittie TJ, Blakely WF, et al: Medical management of the acute radiation syndrome: recommendations of the Strategic National Stockpile Radiation Working Group. Ann Intern Med 2004;140:1037–1051. 46. Shigematsu I, Ito C, Kamade N, et al: In Hiroshima International Council for Medical Care of the Radiation-Exposed (ed): A-Bomb Radiation Effects Digest. Translated by Brian Harrison. Harwood Academic Publishers. Chuo University, Tokyo, Japan, 1995. Chur, Switzerland, Bunkodo Ltd/Harwood Academic Publishers. 47. IARC Study Group on Cancer Risk among Nuclear Industry Workers: Direct estimates of cancer mortality due to low doses of ionising radiation: an international study. Lancet 1994;344:1039–1043. 48. Ivanov VK, Gorski AI, Tsyb AF, et al: Solid cancer incidence among the Chernobyl emergency workers residing in Russia: estimation of radiation risks. Radiat Environ Biophys 2004 43:35–42. Epub 2004 Feb 5. 49. Sigurdson AJ, Doody MM, Rao RS, et al: Cancer incidence in the US radiologic technologists health study, 1983–1998. Cancer 2003;97(12):3080–3089. 50. Health Effects of Exposure to Low Levels of Ionizing Radiation: BEIR V. Washington, DC, National Research Council, December, 1990. 51. Casarett AP: Radiation Biology. Prentice-Hall. Prepared under the auspices of the Atomic Energy Commission, 1968. 52. Cunningham FG, MacDonald PC, Gant NF, et al: Williams Obstetrics, 19th ed. Norwalk, CT, Appleton & Lange, 1993. 53. Garcia-Algar O, Puig C, Vall O, et al: Effects of maternal smoking during pregnancy on newborn neurobehavior: neonatal nicotine withdrawal syndrome. Pediatrics 2004;113(3 Pt 1):623–624. 54. Kal HB, Struikmans H: Pregnancy and medical irradiation; summary and conclusions from the International Commission on Radiological Protection, Publication 84. Ned Tijdschr Geneeskd 2002;146(7):299–303.


1485

55. Harding LK, Thomson WH: Radiation and pregnancy. Q J Nucl Med 2000;44(4):317–324. 56. Radiation and your patient: a guide for medical practitioners. Ann ICRP 2001;31(4):5–31. 57. Robertson CM, Hawkins MM, Kingston JE: Late deaths and survival after childhood cancer: implications for cure. BMJ 1994;309(6948):162–166. 58. Neglia JP, Meadows AT, Robison LL, et al: Second neoplasms after acute lymphoblastic leukemia in childhood. N Engl J Med 1991;325(19):1330–1336. 59. Niedziela M, Korman E, Breborowicz D, et al: A prospective study of thyroid nodular disease in children and adolescents in western Poland from 1996 to 2000 and the incidence of thyroid carcinoma relative to iodine deficiency and the Chernobyl disaster. Pediatr Blood Cancer 2004;42(1):84–92. 60. Karlsson P, Holmberg E, Lundberg LM, et al: Intracranial tumors after radium treatment for skin hemangioma during infancy—a cohort and case-control study. Radiat Res 1997;148(2):161–167. 61. Brown JB, McDowell F, Fryer MP: Surgical treatment of radiation burns. Surg Gynecol Obstet 1949;88:609–622. 62. International Atomic Energy Agency (IAEA): The Radiological Accident in Tammiku, Estonia. Vienna, Austria, IAEA, 1994. 63. McLaughlin TP, Monahas SP, Pruvost NL, et al: A Review of Criticality Accidents 2000 Revision. LA-13638. Los Alamos, NM, Los Alamos National Laboratory, May 2000. 64. Hempelmann LH, Lisko L, Hoffman JG: The acute radiation syndrome: a study nine cases and a review of the problem. Ann Intern Med 1952;36(2):279–510. 65. Shipman TL, Lushbaugh LL, Peterson DF, et al: Acute radiation death resulting from an accidental nuclear critical excursion. J Occup Med 1961;March(Special Suppl):145–192. 66. Karas JS, Stanbury JB: Fatal radiation syndrome from an accidental nuclear excursion. N Engl J Med 1965;272(15):755–776. 67. Goans RE: Project Sapphire. Health Phys 1995;68(3):296–298. 68. Zaharia M, Goans RE, Berger ME, et al: Industrial radiography accident at the Yanango hydroelectric power plant. In Ricks RC, Berger ME, O’Hara FM Jr, eds: The Medical Basis for RadiationAccident Preparedness. The Clinical Care of Victims. Proceedings of the Fourth International REAC/TS Conference on the Medical Basis for Radiation-Accident Preparedness, Orlando, FL, March 2001. Pearl River, NY, Parthenon, 2002. 69. The Radiological Accident in Yanango. Vienna, Austria, International Atomic Energy Agency, 2000. 70. SURVRAD, V2.1. User’s Guide. Tulsa, OK, Viking Software Corporation, 1995.

105

Chemical Weapons

A

Nerve Agents EDWARD W. CETARUK, MD

At a Glance… ■

■ ■

■ ■

■

■

■ ■ ■

Nerve agents are highly toxic organophosphate compounds that inhibit the enzyme acetylcholinesterase as their mechanism of action. Their mechanism of action is identical to that of organophosphate pesticides, although they are more highly toxic. Historically, they have been manufactured and used by the military. However, more recently, they have been manufactured and used by nongovernmental terrorist groups as well. Nerve agents can be absorbed by multiple routes: inhalational, dermal, and ingestion. Patients present with a cholinergic syndrome that may include excessive salivation, lacrimation, incontinence of bowel and bladder, abdominal cramping, respiratory distress including wheezing and dyspnea, vomiting, miosis, muscular weakness, fasciculations, and paralysis, coma, and seizures. Antidotes for nerve agent poisoning include atropine (to block the effect of excess acetylcholine at muscarinic receptors), an oxime (to reactivate acetylcholinesterase), and a benzodiazepine (e.g., diazepam) for treatment of nerve agent–induced seizures. Early administration of antidotes and aggressive advanced life support measures can result in survival for even severely poisoned patients. Decontamination is extremely important in the treatment of nerve agent casualties. Nerve agents can be detected by a wide range of chemical detection equipment. Proper personal protection equipment is essential for those responding to a nerve agent release.

RELEVANT HISTORY Nerve agents are extremely toxic organophosphate compounds that were initially developed by the German chemist Gerhard Schrader, who synthesized tabun in 1937 (GA) while researching new insecticides. Tabun was followed by the development of sarin (GB) in 1938, soman (GD) in 1944, and then VX (developed by Ghosh in England) in 1952. Although stockpiled in great quantities during both World War I and World War II, nerve agents were not employed in warfare until the Iran-Iraq War during the 1980s. Many additional nerve agents have been developed since the G agents, including derivatives of the G and V agents, newer binary agents, and others not described in the open scientific

literature. However, resources are readily available that provide detailed information regarding the preparation of nerve agents, as well as other chemical weapons.1 The government of Iraq was responsible for the first large-scale use of nerve agents in warfare as well as against civilians. The Iraqi army use of tabun in a 1984 attack on Iranians near al-Basrah is the first documented use of a nerve agent in warfare. During the 1980s, Iraqi military forces also undertook an attempt to eradicate, relocate, and otherwise commit genocide against the Kurdish population of northern Iraq. The Kurds sought self rule for the ethnic region of Kurdistan, which encompasses geographic portions of northern Iraq, southeastern Turkey, and western Iran. During this war, they often allied themselves with the Iranians and were considered traitors and saboteurs by the Iraqi regime. al-Anfal was the name given to a series of eight military offensives, conducted in six geographic areas between February and September 1988. However, their first use of chemical weapons is reported to have occurred almost 1 year earlier, with the bombing of Sheikh Wasan and the Balisan Valley on April 16, 1987. Based on reports from survivors and medical care providers, both mustard and nerve agents were used. The operation was under the command of Saddam Hussein’s cousin, Ali Hassan al-Majid, also known as “Chemical Ali,” and officially began in February 1988 with conventional and chemical weapon attacks on 25 to 30 villages in the Jafati valley, including Sergalou, Bergalou, and Halabja, a town just a few miles from the Iranian border. The eighth and final Anfal operation was against the 300 to 400 Kurdish villages of Badinan, a 4000 square-mile area of the Zagros Mountains bounded to the east by the Greater Zab River and to the north by Turkey. The actual number of people killed during this genocide may never be known but has been estimated to be in the hundreds of thousands. To date, the most significant uses of nerve agents against civilians by a terrorist group have been by the Aum Shinrikyo cult of Japan. This cult, led by Chizuo Matsumoto, who later took the name Shoko Asahara (“Bright Light”) to attract followers, was well financed with assets estimated in the hundreds of millions of dollars. It subscribed to Asahara’s “doomsday” philosophy that included causing catastrophic anarchy in Japan so that he could take power in the aftermath. The Aum chemical weapons program was able to produce significant quantities of VX and sarin, and lesser amounts of other nerve agents, mustard agent, phosgene, and cyanide. Nerve agents were used in a number of 1487

1488


assassinations of cult “enemies,”2,3 as well as two largescale attacks.4-7 The first was in Matsumoto, Japan on June 27, 1994, when the cult released about 20 kg of sarin vapor from a specially equipped van in an effort to assassinate three district court judges hearing a civil suit brought against the cult. This attack killed seven people and sent several hundred more to local hospitals, with 58 being admitted for treatment. The Aum subsequently perpetrated another, larger-scale nerve agent attack in Tokyo on March 20, 1995. In this attack, about 159 ounces of sarin was released from eight nylonpolyethylene bags (three additional bags were recovered intact) that were punctured by Aum cult members between 7:46 AM and 8:01 AM on five of Tokyo’s main subway lines, causing 12 deaths. Ultimately, Tokyo hospitals and clinics saw 5510 patients: 17 critical, 37 severe, and 984 moderately ill. More than 70% of those presenting for treatment had no objective signs of nerve agent poisoning. Additional aspects of this event are addressed later under Management of Mass Casualties. All nerve agents are organic ester derivatives of phosphoric acid, with varied chemical functional groups replacing the hydroxyl radical group of the basic phosphate structure. All are volatile liquids at room temperature, colorless, tasteless, and odorless. However, several of the G agents have been reported to have a fruity or sweet smell.8 Their vapors are all heavier than air; hence, they tend to remain close to the ground, traveling downwind, downhill, and into geographic depressions. These physical characteristics make them ideal for controlled deployment and dissemination by either military forces or terrorists, although weather conditions can unpredictably disperse chemical agent releases, resulting in exposure to the terrorists who released the agent.6 The physiochemical properties affect their use as chemical weapons. Volatility and vapor pressure determine the likelihood that a chemical agent will be an inhalational threat. At room temperature, nerve agents exist as liquids and therefore must be aerosolized or evaporated to become inhalational threats. In traditional military munitions, nerve agents are disseminated by artillery shells or rockets using low-order bursting charges to disperse the agent on impact, or can be sprayed from aircraft. Binary and trinary nerve agents, whereby multiple separate chemical components combine during the flight of a projectile (e.g., partitioned 155-mm artillery shell, GB-2, M687) to deliver active agent on impact, have also been developed. In their attack on the Tokyo subway system, the Aum Shinrikyo simply allowed sarin that leaked from punctured nylonpolyethylene bags to evaporate. Because this dissemination method was relatively inefficient, affecting primarily nearby people, it caused only 12 fatalities out of potentially hundreds or thousands. Another important characteristic of nerve agents is persistence: the ability to remain present and active in the environment after dissemination. Although nerve agents with high volatility pose significant inhalation hazard, they soon evaporate and dissipate, limiting their persistency. Agents with low volatility and vapor pressure,

such as the V agents, do not readily evaporate and therefore do not pose an inhalational threat, but they are persistent. Ambient temperature directly correlates with an agent’s rate of evaporation and inversely correlates with its persistence. Generally speaking, sarin evaporates about as fast as water, cyclosarin about 20 times slower, and VX about 1500 times slower.1 Heavily splashed tabun, soman, or cyclosarin (GF) will persist for 1 or 2 days and V agents for weeks to months.1 As a result of their environmental persistence (creating a prolonged contact threat), the V agents have often been weaponized and deployed (e.g., land mines) to deny territory or the use of equipment to an enemy on the battlefield. Also, some of the G agents (e.g., soman) have been “thickened” to decrease their volatility and make them more persistent. Additional factors that affect an agent’s persistence in the environment include hydrolysis (all agents undergo spontaneous hydrolysis) and density (higher-density liquids and aerosols remain in the environment longer).

PATHOPHYSIOLOGY OF INJURY Nerve agents exert their primary toxicity at cholinergic synapses of the central and peripheral nervous systems and at neuromuscular junctions that use acetylcholine (ACh) as their neurotransmitter. It is released from presynaptic postganglionic parasympathetic nerve fibers (innervating exocrine glands and smooth muscle), somatic motor nerve endings (i.e., the neuromuscular junction), and both parasympathetic and sympathetic preganglionic nerve fibers, and at synapses within the central nervous system (CNS). Under normal physiologic conditions, ACh binds to specific receptors (AChRs) on the postsynaptic membrane of the cholinergic synapse. AChRs are divided into two major types: nicotinic (found at cholinergic synapses in the CNS, at parasympathetic and sympathetic autonomic ganglia, and at the neuromuscular junction) and muscarinic (found at cholinergic synapses in the CNS, at postganglionic parasympathetic nerve termini, and at the postganglionic sympathetic fibers that release acetylcholine rather than norepinephrine) of sweat glands. Binding of ACh to a nicotinic receptor results in opening of membrane sodium channels and depolarization of the postsynaptic neuron or skeletal muscle cell. Muscarinic AChRs modulate their effects through the G-protein secondary messenger system and are found on smooth muscle and exocrine glands and in the CNS. The enzyme acetylcholinesterase (AChE, E.C. 3.1.1.7) is located on the postsynaptic membrane of all cholinergic synapses and the neuromuscular junction where it terminates or regulates cholinergic activity by hydrolyzing ACh within the synapse. AChE is a serine esterase that contains an active site composed of neighboring esteratic and anionic active sites that cooperate to catalyze the hydrolysis of acetylcholine. The choline quaternary nitrogen of ACh forms an electrostatic bond with a glutamate amino acid residue in the anionic site, essentially positioning the acetyl moiety of ACh in the esteratic active site. The carbonyl carbon of ACh binds to

CHAPTER 105

the hydroxyl group of serine-203 residue of the enzyme’s esteratic site, forming an unstable tetrahedral enzymesubstrate intermediate (which is also stabilized by hydrogen bonding with other amino acid residue moieties within the esteratic site), which spontaneously collapses, releasing the choline moiety and leaving the acetyl group bound to the esteratic site. The acetyl–AChE bond is then quickly and spontaneously hydrolyzed by weakly nucleophilic H2O, releasing acetic acid and regenerating AChE to its active form. Hydrolysis of ACh decreases its concentration in the synapse and at postsynaptic AChRs, terminating cholinergic stimulation of the postsynaptic cell. Nerve agents are derivatives of phosphoric acid whose relative toxicity, as well as their toxicokinetics, is largely determined by the molecular substitutions on the organophosphate skeleton. Their primary mechanism of toxicity is the inhibition of AChE by acting as pseudosubstrates, occupying AChE’s esteratic active site and inhibiting its hydrolysis of ACh in the synapse. The nucleophilic hydroxyl group of serine-203 (activated by the adjacent imidazole nitrogen of histidine) attacks this electrophilic phosphorous atom of the nerve agent (activated by the presence of an adjacent alkyl moiety, also called a “leaving group”), forming a stable covalent bond and phosphorylating the AChE serine residue. In contrast to the relatively unstable tetrahedral ACh–AChE intermediate, the nerve agent–AChE intermediate is extremely slow to spontaneously hydrolyze. This results in noncompetitive inhibition of AChE, leading to increased synaptic concentrations of ACh and continual stimulation of the postsynaptic acetylcholine receptors, producing a clinical cholinergic toxidrome. Similar to the loss of acetylcholine’s choline moiety, nerve agents bonded to AChE undergo dealkylation to release a functional group in a process referred to as “aging.”9,10 However, unlike acetylcholine, the loss of this leaving group results in an irreversible nerve agent– AChE bond that permanently inactivates AChE. Amino acid mutation studies have shown that the configuration and type of amino acids within the catalytic gorge of AChE containing the anionic and esteratic active sites is thought to have significant impact on AChE’s interaction with each anticholinesterase compound, especially the alkyl functional (leaving) group.10–13 This may explain why this aging can occur within minutes for some nerve agents (e.g., soman) or over many hours for others (e.g., VX).9 In vitro studies have shown that soman irreversibly phosphonylates AChE within minutes (half-life of 2.2 ± 0.3 minutes).10 Once aged, AChE cannot be reactivated by spontaneous hydrolysis or by an oxime antidote (see later). Nerve agents inhibit a number of serine esterases, including acetylcholinesterase (red blood cell cholinesterase or true cholinesterase, E.C. 3.1.1.7), butyrocholinesterase (plasma cholinesterase or pseudocholinesterase, E.C. 3.1.1.8), carboxylesterase (EC 3.1.1.1), and neurotoxic esterase (NTE).14 Nerve agents are also thought to exert toxic effects by inhibiting other noncholinesterase targets.15,16 These include serine proteases, a large family of enzymes that also use a serine hydroxyl group in their

Chemical Weapons

1489

esteratic active site. These proteases are important in the formation, as well as breakdown, of many biologically active peptides (e.g., enkephalin, endorphin, substance P), that, in turn, modulate the activity of neurotransmitters. For example, substance P acts to modulate the nicotinic acetylcholine response. These noncholinesterase effects of anticholinesterase compounds may explain the clinical manifestations of nerve agent exposure not explained by acetylcholinesterase inhibition alone.16 Van Meter and colleagues showed that sarin could induce seizures in rabbits, even though their AChE had already been profoundly inhibited by a prior dose of sarin (administered with atropine to prevent seizures).17

CLINICAL PRESENTATION Nerve agents exert their toxic effects at peripheral muscarinic and nicotinic nerves by inhibiting acetylcholinesterase, resulting in excess acetylcholine at the postsynaptic acetylcholine receptors, and by multiple, and not completely understood, CNS effects (Table 105A-1). The clinical manifestations can be described in terms of organ systems, acetylcholine receptor distribution, routes of nerve agent exposure, and severity of exposure. The characteristic clinical toxicity of nerve agents is a cholinergic toxidrome, which is a direct result of excess acetylcholine binding to nicotinic and muscarinic acetylcholine receptors in the CNS, the autonomic nervous system, and the neuromuscular junction. Muscarinic manifestations of nerve agent poisoning include excess exocrine secretions and smooth muscle contraction. These effects are often summarized in the mnemonics SLUDGE or DUMBELS, which include salivation, lacrimation, urination, gastrointestinal distress, defecation or diarrhea, emesis, bronchoconstriction and bronchorrhea, and miosis. The most clinically significant of these are the respiratory effects, bronchorrhea and bronchoconstriction, and should be the initial focus of clinical assessment, treatment, and antidote administration. Nicotinic manifestations of nerve agent poisoning are primarily the result of excess acetylcholine at the neuromuscular junction causing skeletal muscle fasciculations, weakness, and eventually, paralysis. Paralysis of the skeletal muscles involved in respiration, including the diaphragm, adds to muscarinic-mediated respiratory distress and can rapidly lead to respiratory failure or apnea. Excessive acetylcholine at autonomic ganglia may cause increased heart rate and hypertension. However, these manifestations are not typically clinically significant in the overall picture of nerve agent poisoning. Diaphoresis is also seen as a result of excessive cholinergic tone at the autonomic ganglia of sweat glands (Table 105A-2). As mentioned previously, the respiratory system is the site of the most serious acute clinical manifestations of nerve agent poisoning. The direct effects of the nerve agent on the respiratory tract (bronchorrhea and bronchoconstriction), inhibition of the CNS medullary respiratory center, and paralysis of the diaphragm and

1490


TABLE 105A-1 General Properties of Nerve Agents

COMMON NAME

CHEMICAL NAME

Tabun (GA)

Ethyl N, N-dimethylphosphoroamidocyanidate (CAS 77-81-6) Isopropyl methyl phosphonofluoridate (CAS 107-44-8) O-cyclohexyl phosphonofluoridate (CAS 329-99-7) Pinacolyl methyl phosphonofluoridate (CAS 96-64-0) O-ethyl-S-(2-isopropylaminoethyl) methyl phosphonothiolate (CAS 50782-69-9)

Sarin (GB)

Cyclosarin (GF)

Soman (GD)

VX

LCt50 (RESPIRATORY AT REST)

LD50 (DERMAL)

VAPOR PRESSURE (mmHg)

VOLATILITY (mg/m3)

VAPOR DENSITY*

PERSISTENCY†

400 mg/min/m3

1–1.5 mg/ person

0.037 at 20º C

610 at 25º C

5.63

1–2 days

100 mg/min/m3

N/A

2.10 at 20º C

16,091 at 20º C

4.86

Hours

N/A

N/A

0.044 at 20º C

438 at 20º C

6.2

1–2 days

0.16 mg/min/m3

N/A

0.40 at 25º C

3900 at 25º C

6.33

1–2 days

100 mg/min/m3

10 mg/ person

0.0007 at 20º C

10.5 at 25º C

9.2

Days to weeks

*Air = 1.0. † Persistency is highly dependent on weather conditions. As ambient temperature decreases, persistency increases. Persistency durations given are for “heavily splashed liquid” under “average weather conditions.” N/A, not available. From U.S. Army Field Manual 3-9. Washington, DC, Department of the Army, 1990.

TABLE 105A-2 Signs and Symptoms Following Short-Term Nerve Agent Exposure SITE OF ACTION

SIGNS AND SYMPTOMS

Ciliary body Conjunctivae Nasal mucous membranes

Frontal headache, eye pain on focusing, blurred vision Hyperemia Rhinorrhea, hyperemia, but this may also be present after systemic absorption Following systemic absorption of liquid and prolonged vapor expossure Tightness in chest sometimes with prolonged wheezing, expiration suggestive of bronchoconstriction or increased secretion, dyspnea, slight pain in chest, increased bronchial secretion, cough, pulmonary edema, cyanosis Anorexia, nausea, vomiting, abdominal cramps, epigastric and substernal tightness (cardiospasm) with “heartburn” and eructation, diarrhea, tenesmus, involuntary defecation Increased sweating Increased salivation Increased lachrymation Bradycardia Slight miosis, sometimes unequal, later maximal miosis (pinpoint pupils); sometimes mydriasis is observed Frequent, involuntary microurination Easy fatigue, mild weakness, muscular twitching, fasciculation cramps, generalized weakness including muscles of respiration with dyspnea and cyanosis Pallor, occasional elevation of blood pressure Ataxia, generalized weakness, coma with absence of reflexes, Cheyne-Stokes respiration, convulsions, depression of respiratory and circulatory centers resulting in dyspnea and fall in blood pressure; emotional effects very often occur

Bronchial tree Gastrointestinal system Sweat glands Salivary glands Lachrymal glands Heart Pupils Bladder Striated muscle Sympathetic ganglia Central nervous system

From Grob D: Manifestations and treatment of nerve gas poisoning in man. US Armed Forces Med J 1956;7(6):781–789. Used with permission.

skeletal muscles associated with respiration18,19 combine to cause respiratory failure. Neurologic symptoms include seizures, coma, muscular weakness and paralysis, and delayed neuropsychiatric effects, including depression and anxiety. Gastrointestinal symptoms include vomiting, abdominal cramping, and diarrhea. Respiratory

failure is the ultimate cause of death after nerve agent poisoning. The severity (i.e., acuity and dose) and route of exposure are also significant factors in determining the clinical presentation of nerve agent poisoning. Nerve agents are well absorbed by all routes (e.g., inhalation,

CHAPTER 105

ingestion, and dermal route). Nerve agents absorbed through the inhalation route cause symptoms within seconds to minutes of exposure, whereas absorption by the dermal route may result in a delay in onset of symptoms because of the time required for the agent to be systemically absorbed. Victims of a vapor or aerosol nerve agent exposure may initially complain of eye pain exacerbated by accommodation, loss of dark adaptation, dim or blurred vision, conjunctival irritation, lacrimation, and miosis. These effects are thought to result both from direct exposure of the eye to the nerve agent vapor and CNS effects.20-22 Upper respiratory tract symptoms (e.g., rhinorrhea and nasal congestion) are followed by progressive respiratory complaints, including chest tightness, dyspnea, wheezing, shortness of breath, cough, and increased bronchial secretions. If the exposure is significant or prolonged, other signs of respiratory toxicity rapidly develop, including severe bronchoconstriction, wheezing, bronchorrhea, respiratory distress, and apnea. Inhalational exposure to nerve agents results in the most rapid onset of symptoms because of rapid absorption of nerve agent through the large surface area of the pulmonary bed. Studies have shown that a high percentage of inhaled nerve agent is retained in the lungs, and the systemically absorbed dose is a factor of minute ventilation and the nerve agent vapor concentration.23 Also, if the concentration of the inhaled nerve agent vapor is high, patients may not develop symptoms in a typical “respiratory route pattern,” with dyspnea, wheezing, and bronchorrhea, but may rapidly

Chemical Weapons

1491

lose consciousness, become apneic, and have seizures due to the rapid absorption of the agent into the CNS (Table 105A-3). Dermally absorbed nerve agent will initially cause localized symptoms at the site of exposure (e.g., fasciculations, diaphoresis). The rate of dermal absorption of nerve agent is dependent on the physical characteristics of the agent, environmental temperature, type, and condition of the skin exposed.24,25 Absorption increases on damaged skin and varies with anatomic location.26 As agent is systemically absorbed, victims develop other cholinergic symptoms, such as bronchorrhea and bronchoconstriction, gastrointestinal symptoms, muscle weakness, and seizures. Development of miosis is delayed3 and is often absent following dermal absorption. It is important to note that dermal exposure to nerve agents may result in latent or progressive intoxication, even after appropriate skin decontamination, owing to deposition of the nerve agents in the skin and delayed systemic absorption.24,25 Therefore, victims of dermal nerve agent exposure must be observed for a minimum of 18 hours after decontamination for the delayed development of toxicity. Sidell reported a case in which a 33-year-old man was splashed in the face and mouth with about 1 mL of a 25% (v/v) soman solution.27 He immediately rinsed his face and mouth with water and was asymptomatic until collapsing about 10 minutes after the exposure. He was immediately treated with atropine (4 mg intravenously, 8 mg intramuscularly) and 2-PAM (2 g intravenously over

TABLE 105A-3 Signs and Symptoms in Patients with Moderate to Severe Sarin Exposure PATIENTS SIGN OR SYMPTOM Eye

Chest

Gastrointestinal tract Neurologic

Ear, nose, and throat Psychological

Miosis Eye pain Blurred vision Dim vision Conjunctival injection Tearing Dyspnea Cough Chest oppression Wheezing Tachypnea Nausea Vomiting Diarrhea Headache Weakness Fasciculations Numbness of extremities Decrease of consciousness level Vertigo and dizziness Convulsion Running nose sneezing Agitation

NO. OF PATIENTS

PERCENTAGE (N = 111)

110 50 44 42 30 10 70 38 29 7 28 67 41 6 83 41 26 21 19 9 3 28 5 37

99.0 45.0 39.6 37.8 27.0 9.0 63.1 34.2 26.1 6.3 31.8* 60.4 36.9 5.4 74.8 36.9 23.4 18.9 17.1 8.1 2.7 25.2 9.0 33.3

*N = 88. From Okumura T, Takasu N, Ishimatsu S, et al: Report on 640 victims of the Tokyo subway sarin attack. Ann Emerg Med 1996;28(2):129–135. Used with permission.

1492


30 minutes). Endotracheal intubation was unsuccessful due to trismus. Signs and symptoms included miosis, coma, markedly injected conjunctiva, marked oral and nasal secretions, prominent muscular fasciculations, tachycardia, cyanosis, bronchoconstriction, and decreased respiratory rate and amplitude. He began to awaken after 30 minutes but continued to have fasciculations, tremor, nausea, vomiting, abdominal pain, and restlessness over the next 36 hours. Red blood cell cholinesterase activity was undetectable until 10 days after the exposure. Sidell also reported a case of a 52-year-old man with an inhalational exposure to sarin.27 Within minutes of noticing increased nasal and oral secretions and difficult breathing while wearing a protective gas mask (later determined to have been damaged), he developed seizures, respiratory distress, miosis, muscular fasciculations, cyanosis, wheezing, and copious secretions. His respirations were less labored, and cyanosis decreased within minutes of being treated with atropine (intravenously and intramuscularly), 2-PAM intravenously, and oxygen. He received a total of 14 mg of atropine, and 6 g of 2-PAM was administered over 1 hour. An electrocardiogram taken 1 hour after admission showed global ST-segment depression. Additional electrocardiograms obtained 18 and 42 hours after admission showed ST-segment elevation in leads I, aVL and V1–3 and ST-segment elevation in leads I, aVL, and V2–6. as well as T-wave inversion in leads I, II, aVL, and V2-6. No cardiac enzymes were obtained, and the patient’s electrocardiogram normalized within 4 months.27

PRENATAL AND PEDIATRIC ISSUES Because of the relatively indiscriminant nature of terrorist attacks on civilians, children will likely be among the victims. A report of the sarin attacks in Matsumoto, Japan in 1994 lists the victims’ ages as 3 to 86 years.28 Although information regarding pediatric nerve agent poisoning is minimal, the release of a nerve agent could disproportionately affect children by several mechanisms. If the agent were aerosolized, the higher minute ventilation of children could result in a larger relative inhalational dose compared with adults. Further, the breathing zone for the typical adult is 4 to 6 feet above the floor, compared with a child’s, which is much closer to the ground depending on the child’s height. Because nerve agent vapor (e.g., sarin) is likely to be at its highest concentration closer to the ground, children potentially face a greater inhalational exposure compared with adults. Also, preambulatory infants, toddlers, or young children will not be able to remove themselves from the scene of a chemical agent release. Even if they were able to walk, they may not know in which direction to escape. These factors may leave proportionately more children poisoned at a scene than adults. Pediatric victims of nerve agent poisoning may not present with the same pattern of clinical signs and symptoms typically seen in adults. Reports of pediatric organophosphate pesticide poisoning have noted that children are less likely to manifest muscarinic-mediated

glandular hypersecretion and may present with more marked signs of central toxicity such as coma.29 As is seen in other illnesses, pediatric patients often precipitously decompensate as their condition worsens, necessitating more careful assessment and closer monitoring of pediatric nerve agent victims compared with adults. The more permeable skin of infants and children would also increase absorption of nerve agents because of dermal exposure. Also, because their larger surfaceto–body mass ratio, children may absorb a larger relative dose of nerve agent than adults for a given exposure. Their relatively larger body surface area also increases the rate at which they will lose body heat when they undergo water decontamination. Skin decontamination with cold water, or in cold weather conditions, may result in hypothermia in children unless the decontamination water can be warmed or postdecontamination shower warming equipment is used (e.g., heating lamps, warm indoor environment). Because children have smaller bodies, they require smaller equipment (e.g., endotracheal tubes, needles and tubing, oxygen masks and ventilators). Additionally, the personal protective equipment (PPE) worn by first responders, which is essential for the safe response to a chemical terrorist event (e.g., level A), makes moving, working, and delivering care to victims much more difficult. These challenges are compounded when caring for small children, who present unique challenges of their own (e.g., obtaining intravenous access). Finally, the psychological impact that a terrorist attack will have on a child cannot be underestimated. The child will likely witness and experience events that are well beyond the child’s scope of understanding and may be forced to do so without the comfort of a parent (who may indeed be a victim). Therefore, as much as is possible, provisions should be made to move children to places of safety where they can be appropriately medically observed, but spared ongoing exposure to the traumatic exposure of a terrorist incident and its aftermath. Ideally and if possible, they should also be reunited with their parents, or other family members, as soon as possible after all medical concerns have been properly attended to. Adjustment of antidote dosing in children is also essential. In 2003, the U.S. Food and Drug Administration (FDA) approved a pediatric-dose atropine autoinjector. Although not yet widely available, it raises concerns regarding the use of adult-dose autoinjectors in children.30 However, published experience with children receiving supratherapeutic doses of nerve agent antidote has not reported cases of significant poisoning.30-32 Ideally antidotes should be administered in appropriate pediatric doses according to weight and severity of poisoning. The doses approved for use in children and adolescents with symptoms of nerve agent poisoning include 0.5 mg for children weighing between 15 and 40 lb, 1 mg for children weighing between 40 and 90 lb, and 2 mg doses for adults and children weighing more than 90 lb. These doses should be repeated and titrated according to clinical response (i.e., improvement and stabilization of respiratory function or control of seizures or other serious neurologic toxicity). A study of

CHAPTER 105

accidental atropine administration using atropine autoinjectors in 268 children found that many received higher than therapeutic doses, and in 20 children, the atropine was administered by an adult. However, only 8% experienced serious signs of atropinization, and no seizures of life-threatening cardiac arrhythmias were reported.31 The administration of an oxime antidote is indicated for pediatric nerve agent poisoning and should be done using established pediatric doses: 25 to 50 mg/kg intravenously or intramuscularly. Benzodiazepines are also indicated for severe nerve agent poisoning and should be administered in the appropriate pediatric doses according to the benzodiazepine used. Pediatric dosing for nerve agent antidotes is summarized in Table 105A-4. The initial assessment of any suspected nerve agent victim should include airway, breathing, and circulation. The initial assessment and triage of pediatric victims of nerve agent poisoning is also different from the approach used for adults. The clinical presentation of a child poisoned by nerve agent may differ from that of an adult. An effective response to a mass casualty incident (MCI) includes rapid assessment, triage, and treatment of victims. However, the typical parameters used for assessing adult victims of a nerve agent attack may not be appropriate for assessing the pediatric victims of the same attack. Although there is no replacement for sharp clinical acumen is assessing and treating any patient, adult or pediatric, the Pediatric Assessment Triangle (PAT) is a tool developed for the assessment of pediatric patients that uses only visual and auditory clues to develop a first impression of the severity of the child’s condition and to identify physiologic instability. It offers a quick (30–60 seconds) standardized approach to triage, resuscitation, treatment, and transport. The PAT includes assessment of appearance, work of breathing, and circulation to

Chemical Weapons

1493

the skin. Appearance is assessed by generally observing the child (e.g., alertness, age-appropriate speech and behavior). Work of breathing is assessed by listening for abnormal breath sounds (e.g., wheezing) and looking for signs of increased work of breathing (e.g., grunting, retractions). Skin circulation is assessed by looking for signs of poor skin perfusion (e.g., pallor, mottling, cyanosis). The combination of all three components of the PAT should determine a child’s degree of nerve agent poisoning and need for treatment. In addition, the JumpSTART system is an adaptation of the START (Simple Triage and Rapid Treatment) algorithm developed as a more appropriate system for assessing children.33 It should be considered another possible tool for the triage of children in a nerve agent mass casualty incident and is delineated in Figure 105A-1. Similar to children, elderly victims with impaired mobility may find it difficult to escape from the scene of a nerve agent release. Therefore, it is theoretically possible that they may have prolonged exposure at the incident scene. Also, elderly individuals with preexisting medical conditions, especially cardiac and pulmonary disease, may have lower tolerance of the clinical manifestations of nerve agent poisoning (e.g., respiratory distress, hypoxia) or to the adverse effects of antidotes (e.g., atropine). However, the overall approach to triage and treatment of elderly victims is the same as for adults. There are very few data regarding nerve agent poisoning in pregnancy. However, there were five pregnant women among the victims of the Tokyo sarin attack.4,5 All had signs and symptoms of mild exposure and were admitted for observation, but none required antidotal treatment. Although one victim reportedly underwent an elective abortion as a result of the exposure (F. R. Sidell, personal communication), followup questionnaires sent to victims 1 month and 1 year after the incident reported no fetal malformations.28

TABLE 105A-4 Pediatric Nerve Antidote Indications and Doses SYMPTOMS

TRIAGE LEVEL: DISPOSITION

ATROPINE*

PRALIDOXIME

BENZODIAZEPINES (E.G., DIAZEPAM, MIDAZOLAM)

Asymptomatic Miosis, mind rhinorrhea Miosis and any other symptom

Delayed: observe Delayed: admit or observe Immediate-moderate: admit

None None

None None

None None

0.05 mg/kg IV or IM Repeat as needed q5–10 min until respiratory status improves

25–50 mg/kg IV or IM (may repeat q1h) Adverse effects: Muscle rigidity Hypertension Laryngospasm Tachycardia

Immediate-severe: admit critical care status

0.05–0.1 mg/kg IV, IM, 25–50 mg/kg IV or IM per endotracheal tube as above No maximum Repeat q5–10 min as above

For any neurologic effect 30 days to 5 years: 0.05 to 0.3 mg/kg IV (maximum of 5 mg/dose) May repeat q15–30 min 5 years and older: 0.05 to 0.3 mg/kg IV (maximum of 10 mg/dose) May repeat q15–30 min See above

Apnea, convulsions, cardiopulmonary arrest

*Correct hypoxia before IV use due to increased risk for ventricular arrhythmias. From Walter Reed Army Medical Center.

1494


Able to walk?

Yes

Secondary triage*

Minor

*Evaluate infants first in secondary triage using the entire JumpStart algorithm

No No

Breathing?

Breathing Position upper airway

Immediate

APNEIC No

Palpable pulse?

Deceased

Yes Yes

5 rescue breaths

APNEIC Deceased

Breathing Immediate

45

Respiratory rate

Immediate

15–45

Palpable pulse?

No Immediate

Yes

cholinergic toxidrome), and on a situational basis, in which multiple patients present with similar or identical symptoms that, collectively, suggest a diagnosis of nerve agent poisoning.34 Regardless of how the diagnosis is determined, because of the extreme toxicity of nerve agents, victims must be evaluated as quickly as possible to determine their need for airway management (i.e., intubation) and the administration of antidotal therapy (e.g., atropine and oxime). Therefore, the clinical assessment of a nerve agent victim is based on the severity of their cholinergic toxidrome. Although useful retrospectively, the measurement of cholinesterase activity is not practical in the acute assessment of a nerve agent victim because of the delay in obtaining results. Further, in the case of an MCI, the initial assessment of victims must be accomplished in a rapid and efficient manner so as to triage victims for treatment. Victims of a vapor nerve agent exposure will likely present with ocular and upper respiratory symptoms as described previously. Miosis is the earliest sign of a vapor nerve agent exposure but may be absent or delayed in a dermal exposure. Patients with only miosis and upper respiratory tract symptoms can be observed without treatment. Patients with lower respiratory tract manifestations (e.g., wheezing, dyspnea), neurologic symptoms (e.g., seizures, weakness) or multiple-organ system involvement should receive antidotal therapy with atropine and an oxime (see Treatment section). The assessment of victims of dermal nerve agent exposure should also be based on the severity of their clinical cholinergic toxidrome. However, it is important to note that initial symptoms can be localized to the site of nerve agent exposure and that severe or fatal toxicity can develop up to 18 hours after exposure. All patients should be reassessed frequently for worsening, or resolution, of symptoms, the effectiveness of antidote administration, or the need for additional antidote.

“P” (inappropriate), posturing or “U” Immediate

AVPU “A”, “V” or “P” (appropriate)

Delayed FIGURE 105A-1 JumpStart algorithm. AVPU: alert, verbal, painful, unresponsive (referring to neurologic function). (From Romig LE: Pediatric triage: a system to JumpSTART your triage of young patients at MCIs. JEMS 2002;27(7):52–58, 60–63. Used with permission.)

Therefore, in the absence of any additional data regarding nerve agent poisoning and its treatment during pregnancy, all therapeutic interventions recommended for adults should be used in pregnant patients as well.

ASSESSMENT The diagnosis of nerve agent poisoning may be made on the basis of a single patient’s presentation (i.e., a

TREATMENT The most immediate concern in the treatment of acute nerve agent poisoning is to establish an airway and provide adequate ventilation and oxygenation, using advance life support techniques including intubation and ventilation with supplemental oxygen. Mouth-tomouth resuscitation is not recommended because of the high risk for rescuer contamination and poisoning. Note that oropharyngeal intubation may be difficult owing to trismus from muscular spasm and fasciculations or seizures.24,27 Succinylcholine should be used with extreme caution and at lower doses because its pharmacologic half-life and duration of paralysis may be markedly prolonged as a result of nerve agent inhibition of plasma cholinesterase.35 During the 1991 Persian Gulf War, military patients who had received pyridostigmine (a carbamate acetylcholinesterase inhibitor) as a nerve agent pretreatment and then underwent intubation using succinylcholine did not exhibit prolonged paralysis. However, they did have copious upper airway secretions requiring large amounts of atropine.36 These

CHAPTER 105

initial advanced life support measures should be accompanied by the earliest possible administration of nerve agent antidotes, including atropine, an oxime, and a benzodiazepine for the treatment of seizures. Initial ventilation may demonstrate marked airway resistance due to severe bronchoconstriction and bronchorrhea. Therefore, atropine should be administered as soon as possible by whatever route is available (e.g., intramuscular, intravenous, endotracheal) to reverse the respiratory effects of the nerve agent. Decontamination is a critical step in the care of nerve agent victims. Continued absorption of agent will significantly undermine the effectiveness of advanced life support measures and antidotes administered to victims of nerve agent poisoning. Therefore, treatment plans and protocols should provide for decontamination taking place as early as possible. The key to successful mass casualty decontamination is to use the fastest approach that will cause the least harm and do the most good for the most people. The choice of decontamination methods depends on the route and intensity of exposure and available resources. Briefly, victims with dermal exposure require thorough decontamination, including undressing and full-body water decontamination. Largevolume, low-pressure water is the preferred method of decontamination. Soap is also recommended but has not been found to offer significant benefit over timely and adequate water decontamination. Victims with only vapor exposure (i.e., no possible contact with liquid agent) to nerve agent can be adequately decontaminated by removing them from the exposure and undressing them. If the exposure occurred indoors, moving the patient into outdoor fresh air and undressing them should be sufficient. If nerve agent is released outdoors in sufficient quantity to create toxic ambient concentrations, upwind evacuation from the plume of agent is necessary, as is respiratory protection for rescuers and victims if possible. See the Management of Mass Casualties section for a more complete discussion of decontamination. Decontamination should begin with removal of the victim’s clothing. It is estimated that removal of all clothing will provide about 80% of all possible decontamination after vapor exposure to a nerve agent. In addition, nerve agents from aerosols or vapors can adsorb into victims’ clothing and then off-gas well after the victim has been removed from the site of exposure. Victims of the 1995 Tokyo subway sarin attack were transported from the scene of the attack without any form of decontamination. Prehospital first responders quickly became symptomatic until ambulances were ordered to keep all windows open to maximize ventilation during transport. Hospital-based care providers also became symptomatic after exposure to off-gassing victims who were brought into the hospital without decontamination.4,5 Atropine is a direct-acting competitive muscarinic receptor antagonist. It binds to muscarinic AChRs, preventing ACh from binding, thereby decreasing cholinergic tone at the postsynaptic cell or organ, including smooth muscle, exocrine glands, and muscarinic synapses within the CNS. Other potent antimuscarinic

Chemical Weapons

1495

compounds have also been investigated as potentially effective organophosphate antidotes.27,37,38 Atropine reverses muscarinic-mediated smooth muscle contraction and exocrine hypersecretion. This clinical effect is most important in the lungs, where excessive bronchorrhea and bronchoconstriction lead to hypoxemia, decreased ventilation, respiratory failure, and death. However, note that the respiratory failure is also the result of CNS nerve agent toxicity at the medullary respiratory center. Atropine does not bind to nicotinic receptors and therefore does not have any therapeutic effect at the neuromuscular junction or ganglia. Because the AChRs found at the neuromuscular junction are nicotinic, atropine does not reverse skeletal muscle paralysis. Atropine eye drops can be used to reverse nerve agent–induced miosis and paralysis of accommodation.39 Adverse effects of atropine are unlikely except if administered to a victim misdiagnosed with a cholinergic toxidrome (i.e., nerve agent or other organophosphate poisoning). These include increased heart rate, drying of secretions, mydriasis, loss of accommodation, and decreased sweating.32 The last of these adverse effects is the most significant and can lead to severe hyperthermia, especially in the setting of a warm environment or physical exertion.31,40 All patients who receive atropine should be monitored not only for therapeutic improvement but also for signs of anticholinergic effects. The recommended adult dose of atropine is 2 mg, which can be administered intravenously, intramuscularly, endotracheally, or by autoinjector (e.g., Mark I kit). The autoinjector is an effective means of administering atropine expeditiously because it can quickly deliver antidote through clothing (including PPE). Animal studies have shown that atropine administered by autoinjector was absorbed at a rate intermediate between intravenous administration and intramuscular administration with a conventional syringe.41,42 Atropine administration should be repeated in 2-mg doses every 5 to 10 minutes based on clinical response. The most critical indicator of antidotal response is pulmonary function (i.e., drying of bronchial secretions and decreased airway resistance). This can be assessed by the patient’s self-reported ease of breathing or by improved compliance if the patient is being artificially ventilated. There is no dose limit for the total amount of atropine administered, and end of therapy should be determined by clinical stabilization. Patients who require continued antidotal treatment after initial improvement should suspected of having continued dermal nerve agent absorption and undergo repeat decontamination. The early administration of antidotes is critical in the treatment of nerve agent poisoning. Antidotal therapy for nerve agent poisoning includes atropine, an oxime, and a benzodiazepine (each is discussed in detail later). The decision to administer an antidote is based on the severity of poisoning and route of exposure. Victims of an inhalational exposure that present with mild symptoms including miosis, eye pain, and rhinorrhea, but no other significant signs or symptoms, may be observed without the administration of antidote. Those with any complaints of respiratory distress, including

1496


shortness of breath, complaints of chest tightness, wheezing, or dyspnea, should be treated with a initial administration of 2 mg of atropine plus pralidoxime, 600 mg through intramuscular autoinjector or 500 to 1000 mg/hour through intravenous infusion. If respiratory symptoms are significant (e.g., dyspnea, wheezing, shortness of breath), or the victim has additional symptoms such as weakness or vomiting, the initial doses of atropine and pralidoxime should be doubled to 4 mg of atropine through intramuscular or intravenous injection, and 1200 mg of pralidoxime (i.e., two 600-mg intramuscular autoinjectors). Victims with severe manifestations of nerve agent poisoning, including severe respiratory distress or apnea, seizures or coma, or significant skeletal muscle weakness, should receive initial doses of atropine and pralidoxime of 6 mg and 1800 mg, respectively, as well as a benzodiazepine to treat or prevent seizures.

OXIME ANTIDOTES Oximes are the second important antidote in the treatment of nerve agent poisoning.43 Their primary role is to reactivate AChE after it has been phosphorylated by a nerve agent by removing the nerve agent from its active site. Oximes reactivate AChE by acting as potent nucleophiles that attack the phosphorous moiety of the nerve agent, cleaving the nerve agent–serine-203 bond and displacing the nerve agent from the enzyme active site as an oxime–phosphate complex.10 Because atropine effectively antagonizes the muscarinic effects of nerve agent poisoning, oximes are clinically most important because of their ability to reactivate AChE in nicotinic synapse, restoring neuromuscular function and reversing skeletal muscle paralysis. In the United States, 2-pralidoxime chloride (2-PAM, pyridine-2-aldoxime methochloride, Protopam) is the only oxime currently approved by the FDA for the treatment of organophosphate or nerve agent poisoning. However, other oximes, including obidoxime, pralidoxime iodide (2-PAM iodide), pralidoxime mesylate (P2S), pralidoxime methylsulfate, and trimedoxime (TMB4), are available in other countries. The differences in the oxime effectiveness are mainly due to the variation in aging rates that the nerve agent, the oxime, and the animal model, including human, used.44-47 The reactivation of AChE inhibited by VX, sarin, or GF is possible hours after the intoxication, whereas soman-inhibited AChE cannot be reactivated within minutes after intoxication because of its rapid aging of AChE. Pralidoxime can be administered by repeat intramuscular injection (e.g., autoinjector), as described earlier, to reach the traditional therapeutic level of 4 μg/mL.48,49 If pralidoxime is administered intravenously, a dosing regimen consists of an intravenous bolus of 500 to 1000 mg over 30 minutes, followed by an infusion of 500 mg/hour, appears to maintain a concentration of about 13 mg/L for a 70-kg person, which is above the previously reported minimum therapeutic level (4 μg/mL)48,49 and below the level at which adverse effects are seen

(14 μg/mL).50 The infusion should be continued until the patient’s muscle weakness has resolved. As a general rule, any victim that receives atropine should also receive an oxime antidote. Newer oximes under active development include the bisquaternary oxime Hagedorn agents (H oximes). HI-6 has been shown to as effective, or superior, to 2-PAM in the treatment of OP pesticide poisoning.47,51 HI-6 plus atropine has been reported to produce a protective ratio of 42 against VR (O-isobutyl S-[2-(diethylamino) ethyl]methylphosphonothioate, a structural isomer of VX, also known as Russian VX), whereas pralidoxime plus atropine under identical conditions produced a protective ratio of 6 (P. M. Lundy, personal communication). Interestingly, although comparable to other oximes as a reactivator of AChE in in vitro studies,46 HI6 has been shown to be a more effective antidote in studies in which AChE was permanently and irreversibly inhibited (aged).52,53 The newer bispyridinium oximes, including HI-6, have been found to have significant pharmacologic properties not associated with the reactivation of nerve agent–inhibited AChE.52-55 However, HI-6 and HLö-7 chloride salts are unstable over time in aqueous solution and must be stored as lyophilized powder, complicating their use in autoinjectors.56 Recent research has shown the HI-6 dimethanesulphonate salt (HI-6 DMS) to be stable in aqueous solution, as well as safe and effective against nerve agents, making it more attractive for use in autoinjectors.57 Overall, HI-6 has shown potential advantages over other oximes and may eventually emerge as the oxime of choice.55,58,59 Several countries, including Canada, Sweden, the former Yugoslav entities, and the Czech Republic, are investigating HI-6 as their oxime of choice for the treatment of nerve agent poisoning.

BENZODIAZEPINES Victims with severe nerve agent poisoning are likely to also have seizures. The addition of a benzodiazepine has been shown to improve survival from nerve agent poisoning and to decrease the development of permanent brain damage.60,61 Diazepam is available in an autoinjector and is issued (in addition to 3 Mark I autoinjectors) to U.S. military personnel as part of their nerve agent medical countermeasure kit. It is recommended that a benzodiazepine be administered for any seizure activity as well as for any moderate to severe manifestations of nerve agent poisoning (before the development of seizures). Although diazepam is most commonly recommended, other benzodiazepines should be considered if diazepam is not available, as might be the case in an MCI.

OTHER MEDICAL COUNTERMEASURES IN DEVELOPMENT Atropine, oximes, and benzodiazepines have been the mainstay of therapy for nerve agent poisoning for almost

CHAPTER 105

as long as nerve agents have been a threat. Additional therapeutic measures in development include other anticholinergic compounds such as biperiden, scopolamine, and trihexyphenidyl. The excitatory neurotransmitter glutamate and its stimulation of the N-methyl-D-aspartate (NMDA) receptors, has also been found to play a role in nerve agent–induced seizures. This work has lead to research in the development of NMDA receptor antagonists such as MK801 and gacyclidine (GK-11) that may find a place in nerve agent treatment in the future.59,62

MANAGEMENT OF MASS CASUALTIES Decontamination and patient management priorities at the scene of a terrorist attack using nerve agents include collection of victims at a point upwind of the chemical hazard, the establishment of a clean–dirty line between the contaminated (i.e., “hot”) and uncontaminated (i.e., “cold”) zones, and the administration of initial medical treatment if necessary (i.e., antidotes, advanced life support). Plans should include means to decontaminate both ambulatory and nonambulatory victims and provide a way for emergent medical treatment to be administered as soon as possible once the patient exits the “warm” decontamination zone (Fig. 105A-2). If adequate PPE is available for medical personnel, treatment may be started earlier (i.e., before or during decontamination). Basic principles of mass casualty decontamination include the following: (1) decontamination should take place as soon as possible—expect the ratio of unaffected to affected to be about 5:1; (2) disrobing is decontamination and should be the earliest step in the process; (3) high-volume, low-pressure water showers are the best mass decontamination method; and (4) after a known dermal exposure, first responders must be decontami-

Triaged nonambulatory patients Immediate patients

Hot zone

1497

nated as soon as possible.63 Terrorist attacks using nerve agents in cold weather present additional decontamination challenges. If ambient temperatures are above 18.3° C (65° F), all methods of decontamination can be done outdoors. As ambient fall below 18.3° C (65° F), heated enclosures should be made available for postdecontamination shelter. As ambient temperatures fall further, water decontamination should take place in a heated enclosure, and under extreme weather conditions (e.g., below 1.7° C [35° F]), dry decontamination methods are recommended (e.g., removal of all outer garments and dry blotting of the skin with absorbents) until victims can be transported to a heated facility for water decontamination. However, regardless of the ambient temperature, people who have been exposed to a known life-threatening level of chemical contamination should disrobe, undergo decontamination with copious amounts of high-volume, low-pressure water or an alternative decontamination method, and be sheltered as soon as possible.64 In 2003, the FDA approved a reactive skin decontamination lotion (RSDL) for use as a decontaminating liquid for dermal nerve agent exposure. It is an oximate-based skin decontaminant developed in Canada and currently in use worldwide.65 In the absence of a water-flushing or showering system, it represents a viable method of portable decontamination. Ideally, all victims would undergo adequate decontamination before leaving the incident scene. Historically, however, about 70% to 80% of victims of an MCI evacuate themselves and each other from the incident scene and then self-triage to nearby health care facilities. This creates the need for decontamination plans and equipment at the receiving health care facilities. This was the case during the 1995 Tokyo sarin attack, when there was no field decontamination of victims at the incident scene. Secondary contamination occurred at the receiving hospitals, with 23% of the Saint Luke’s hospital staff developing signs and symptoms of

Wind direction

Incident site

Ambulatory patient assembly area (secondary triage)

Chemical Weapons

C L O T H I N G R E M O V A L

Decontamination area

V A P O R

Ambulatory

H A Z A R D

Clear treatment area

Z O N E

Rapid treatment

Non-ambulatory

Warm zone

T R A N S P O R T

Cold zone

FIGURE 105A-2 The dual-corridor emergency decontamination system has two corridors for the triage, decontamination, and treatment of nerve agent victims. (From U.S. Army Soldier and Biological Chemical Command (SBCCOM): Guidelines for mass casualty decontamination during a terrorist chemical incident. Aberdeen, MD, Edgewood Chemical Biological Center, 2003.)

1498


sarin poisoning while treating the hundreds of victims, many of whom were contaminated, who presented to the hospital. Forty-six percent of those working in a poorly ventilated hospital chapel became symptomatic. However, only one nurse was admitted, and no one required antidotal treatment.4,5,34,66 An inhalational exposure is likely due to the use of a nerve agent aerosol or vapor, as in the Tokyo subway attacks of 1995. Victims exposed to nerve agent vapor adsorb the agent into their clothing and off-gas the agent after they have been removed from the exposure. The risks associated with off-gassing include continued inhalational exposure for the patient and medical care providers who will be in close proximity to the patient, especially indoors and in confined spaces (e.g., ambulances). This was seen after the Matsumoto and Tokyo sarin attacks, in which prehospital care providers became symptomatic from exposure to sarin off-gassing from victims transported to hospitals by ambulance. Hospital care providers also became symptomatic as a result of off-gassing from patients brought into the hospital without decontamination. The hospital response to a terrorist nerve agent attack should anticipate mass casualties arriving unannounced, contaminated, and in a disorganized fashion. Saint Luke’s Hospital’s first victim arrived on foot 30 minutes after the attack and was followed by about 500 more within the next 30 minutes. Among 640 victims who presented to Saint Luke’s Hospital on the day of the attack, 15% arrived by emergency vehicle (only 10% by ambulance), 48% by foot or private vehicle, and 25% by taxi. Radiodispatched taxis played a significant role in transporting victims from the scene and were also important in communicating information.4,5 Typically, because they are the most able to flee the incident scene and make their way to the hospital, most of the early presenters are less severely affected than those incapacitated at the scene. Ten percent of first responders developed acute signs and symptoms of nerve agent poisoning (some requiring treatment) primarily as the result of sarin vapor offgassing from the clothing of victims during ambulance transport to hospitals.4 In comparison, 35% of emergency responders developed signs of sarin toxicity while rescuing victims of the 1994 Matsumoto sarin attack, although most were thought to have been exposed as a result of entering the area of the sarin release without adequate respiratory protection.67

PRINCIPLES OF PREPAREDNESS It is a commonly accepted concept that all disasters are local. This is a very important reality that must be considered in all stages of disaster planning and preparedness. As much as outside assets (e.g., state, federal, nongovernmental) are mobilized as soon as any major MCI takes place, it is arguably unlikely that logistics will allow them to be involved in the initial emergency response at a significant level within 48 hours of the incident. Therefore, consumable supplies, medications, antidotes, personnel, and safe food and water should be

stockpiled in quantities to suffice for at least 3 days or more, depending on the community’s accessibility. An important step in preparing to respond to a nerve agent terrorist attack is to perform community risk assessments to identify potential targets, their degree of vulnerability to attack, and when an attack would be likely to occur. By determining the maximum number of potential victims for a “worst case scenario” attack, preparations can be made to respond. Advance planning should include identifying potential staging areas, victim collection points, sites for decontamination stations, and sites for victim and responder sheltering in extreme weather conditions for all sites (e.g., sports arenas, mass transit systems) that are deemed at high risk for a terrorist MCI based on a community vulnerability analysis. Additionally, alternatives for all sites mentioned should also be determined. Another essential step is to take inventory of any and all resources that are available in your community to respond to a terrorist attack. This assessment should include decontamination equipment, personnel, hospital beds, alternative health care facilities, ambulances, antidotes, ventilators, PPE, and additional items too numerous to list here. This should be followed be an estimation of what is needed to respond to an MCI in your community (based on a vulnerability assessment). In the event that a community’s maximal response capability could not adequately respond to a worst case scenario, emergency preparations should include planning to rapidly access, or even predeploy in the case of a scheduled event (e.g., large sporting event), outside assets to close the gap between likely emergency response needs and those locally available. Access to outside assets can be facilitated by the advanced establishment of interagency and interjurisdictional memoranda of understanding that delineate how and when assets are brought in to assist with a local MCI or major disaster. The difference between the two is the gap that additional planning and preparation can lessen. Emergency planners should avail themselves of the many published after-action reports and “lessons learned” developed after MCIs that have occurred as the result of both terrorist acts and natural events.4-7,66-71 One of the most important and critical assets for responding to an MCI is personnel. However, it is important to include in an emergency response plan the possibility, or likelihood, that responders at all levels may also be victims of the attack, degrading the ability for the emergency and medical communities to respond. Additionally, it has become an established fact that first responders, and even health care facilities, may be targeted with secondary devices or nerve agent releases. Further, the possibility of a mixed weapon or multiplelocation attacks should be considered in the allocation of resources once the incident has occurred. Although this chapter focuses on nerve agents, an “allhazards approach” should be used as the basis for developing a plan to respond to a terrorist nerve agent attack. By establishing robust plans and procedures for responding to any hazardous materials (Hazmat) event, additional measures (e.g., specific antidote availability,

CHAPTER 105

BOX 105A-1

NERVE AGENT–RELATED INTERNATIONAL CLASSIFICATION OF DISEASES CODES

ICD-9-CM

Toxic effect of organophosphate & carbamate Accidental poisoning by other specified gases and vapors Suicide and self-inflicted poisoning using other specified gases and vapors Assault by poisoning using other gases and vapors Injury due to terrorism involving chemical weapons Injury due to war operations by gases, fumes, and chemicals Death due to terrorism involving chemical weapons

989.3 E869.8 E952.8 E962.2 E979.7 E997.2 U01.7

ICD-10

Accidental poisoning by and exposure to other and unspecified chemicals and noxious substances Intentional self-poisoning (suicide) by and exposure to other gases and vapors Assault (homicide) by gases and vapors Assault (homicide) by other specified chemicals and noxious substances Assault (homicide) by unspecified chemical or noxious substance War operations involving chemical weapons and other forms of unconventional warfare

X49 X67 X88 X89 X90 Y36.7

medical training for the recognition and treatment of nerve agent poisoning) can be developed and added. Moreover, it is of paramount importance that any and all emergency plans be exercised regularly using realistic scenarios. See the International Classification of Diseases Codes in Box 105A-1. REFERENCES 1. Ledgard J: The Preparatory Manual of Chemical Warfare Agents. Columbus, OH, The Paranoid Publications Group, 2003. 2. Morimoto F, Shimazu T, Yoshioka T: Intoxication of VX in humans. Am J Emerg Med 1999;17(5):493–494. 3. Nozaki H, Aikawa N, Fujishima S, et al: A case of VX poisoning and the difference from sarin. Lancet 1995;346(8976):698–699. 4. Okumura T, Takasu N, Ishimatsu S, et al: Report on 640 victims of the Tokyo subway sarin attack. Ann Emerg Med 1996;28(2): 129–135. 5. Ohbu S, Yamashina A, Takasu N, et al: Sarin poisoning on Tokyo subway. South Med J 1997;90(6):587–593. 6. Tu A: Anatomy of Aum Shinrikyo’s organization and terrorist attacks with chemical and biological weapons. Arch Toxicol Kinetics Xenobiotic Metabolism 1999;7(3):45–82. 7. Tu A: The first mass chemical terrorism using sarin in Matsumoto, Japan. Arch Toxicol Kinet Xenobiot Metab2001;9(3):65–93. 8. Neitlich H: Effect of percutaneous GD on human subjects. Report No.: CRDL Technical Memorandum 2-21,DTIC AD471794. Fort Belvoir, VA, Defense Technical Information Center, 1965. 9. Berends F, Posthumus CH, vd SI, Deierkauf FA: The chemical basis of the “ageing process” of DFP-inhibited pseudocholinesterase. Biochim Biophys Acta 1959;34:567–568. 10. Fleisher JH, Harris LW: Dealkylation as a mechanism for aging of cholinesterase after poisoning with pinacolyl methylphosphonofluoridate. Biochem Pharmacol 1965;14(5):641–650. 11. Saxena A, Doctor BP, Maxwell DM, et al: The role of glutamate-199 in the aging of cholinesterase. Biochem Biophys Res Commun 1993;197(1):343–349.

Chemical Weapons

1499

12. Shafferman A, Ordentlich A, Barak D, et al: Aging of phosphylated human acetylcholinesterase: catalytic processes mediated by aromatic and polar residues of the active centre. Biochem J 1996;318(Pt. 3):833–840. 13. Sidell FR, Groff WA: The reactivatibility of cholinesterase inhibited by VX and sarin in man. Toxicol Appl Pharmacol 1974;27(2): 241–252. 14. Vranken MA, De Bisschop HC, Willems JL: “In vitro” inhibition of neurotoxic esterase by organophosphorus nerve agents. Arch Int Pharmacodyn Ther 1982;260(2):316–318. 15. Duysen EG, Li B, Xie W, Schopfer LM, et al: Evidence for nonacetylcholinesterase targets of organophosphorus nerve agent: supersensitivity of acetylcholinesterase knockout mouse to VX lethality. J Pharmacol Exp Ther 2001;299(2):528–535. 16. O’Neill JJ: Non-cholinesterase effects of anticholinesterases. Fundam Appl Toxicol 1981;1(2):154–160. 17. Van Meter WG, Karczmar AG, Fiscus RR: CNS effects of anticholinesterases in the presence of inhibited cholinesterases. Arch Int Pharmacodyn Ther 1978;231(2):249–260. 18. Rickett DL, Glenn JF, Beers ET: Central respiratory effects versus neuromuscular actions of nerve agents. Neurotoxicology 1986;7(1):225–236. 19. Wright PG: An analysis of the central and peripheral components of respiratory failure produced by anticholinesterase poisoning in the rabbit. J Physiol 1954;126(1):52–70. 20. Rengstorff RH: Accidental exposure to sarin: vision effects. Arch Toxicol 1985;56(3):201–203. 21. Rubin LS, Krop S, Goldberg MN: Effect of sarin on dark adaptation in man: mechanism of action. J Appl Physiol 1957; 11(3):445–449. 22. Rubin LS, Goldberg MN: Effect of sarin on dark adaptation in man: threshold changes. J Appl Physiol 1957;11(3):439–444. 23. Oberst FW, Koon WS, Christensen MK, et al: Retention of inhaled sarin vapor and its effect on red blood cell cholinesterase activity in man. Clin Pharmacol Ther 1968;9(4):421–427. 24. Blank IH, Griesemer RD, Gould E: The penetration of an anticholinesterase agent (sarin) into skin. I. Rate of penetration into excised human skin. J Invest Dermatol 1957;29(4):299–309. 25. Craig FN, Cummings EG, Sim VM: Environmental temperature and the percutaneous absorption of a cholinesterase inhibitor, VX. J Invest Dermatol 1977;68(6):357–361. 26. Duncan EJ, Brown A, Lundy P, et al: Site-specific percutaneous absorption of methyl salicylate and VX in domestic swine. J Appl Toxicol 2002;22(3):141–148. 27. Sidell F. Sarin and soman: observations on accidental exposures. Report No.: Edgewood Arsenal Technical Report 4747, DTIC AD769737. Fort Belvoir, VA, Defense Technical Information Center, 1973. 28. Morita H, Yanagisawa N, Nakajima T, et al: Sarin poisoning in Matsumoto, Japan. Lancet 1995;346(8970):290–293. 29. Rotenberg JS: Diagnosis and management of nerve agent exposure. Pediatr Ann 2003;32(4):242–250. 30. Aaron C: Safety of adult nerve agent autoinjectors in children. J Pediatr 2005;146(1):8–10. 31. Amitai Y, Almog S, Singer R, et al: Atropine poisoning in children during the Persian Gulf crisis. A national survey in Israel. JAMA 1992;268(5):630–632. 32. Kozer E, Mordel A, Haim SB, et al: Pediatric poisoning from trimedoxime (TMB4) and atropine automatic injectors. J Pediatr 2005;146(1):41–44. 33. Romig LE: Pediatric triage: a system to JumpSTART your triage of young patients at MCIs. JEMS 2002;27(7):52–58, 60–63. 34. Nozaki H, Hori S, Shinozawa Y, et al: Secondary exposure of medical staff to sarin vapor in the emergency room. Intensive Care Med 1995;21(1):1032–1035. 35. Selden BS, Curry SC: Prolonged succinylcholine-induced paralysis in organophosphate insecticide poisoning. Ann Emerg Med 1987;16(2):215–217. 36. Baker D, Rustick J: Anaesthesia for casualties of chemical warfare agents. In Anaesthesia and Perioperative Care of the Combat Casualty. Washington, DC, Office of the Surgeon General, U.S. Army Medical Center, 1995, p 850. 37. Sidell FR: Soman and sarin: clinical manifestations and treatment of accidental poisoning by organophosphates. Clin Toxicol 1974;7(1):1–17.

1500


38. Bird SB, Gaspari RJ, Lee WJ, Dickson EW: Diphenhydramine as a protective agent in a rat model of acute, lethal organophosphate poisoning. Acad Emerg Med 2002;9(12):1369–1372. 39. Nozaki H, Aikawa N, Shinozawa Y, et al: Sarin poisoning in Tokyo subway. Lancet 1995;345(8955):980–981. 40. Robinson S, Buckingham R, Pearcy M, et al: 1952 Field test of atropine. In The Physiological Effects of Atropine and Potential Atropine Substitutes. Fort Belvoir, VA, Defense Technical Information Service, 1953. 41. Sidell FR, Markis JE, Groff W, Kaminskis A: Enhancement of drug absorption after administration by an automatic injector. J Pharmacokinet Biopharm 1974;2(3):197–210. 42. Friedl KE, Hannan CJ Jr, Schadler PW, Jacob WH: Atropine absorption after intramuscular administration with 2-pralidoxime chloride by two automatic injector devices. J Pharm Sci 1989;78(9):728–731. 43. Grob D, Johns RJ: Use of oximes in the treatment of intoxication by anticholinesterase compounds in patients with myasthenia gravis. Am J Med 1958;24(4):512–518. 44. Dawson RM: Review of oximes available for treatment of nerve agent poisoning. J Appl Toxicol 1994;14(5):317–331. 45. Lundy PM, Hansen AS, Hand BT, Boulet CA: Comparison of several oximes against poisoning by soman, tabun and GF. Toxicology 1992;72(1):99–105. 46. Worek F, Kirchner T, Backer M, Szinicz L: Reactivation by various oximes of human erythrocyte acetylcholinesterase inhibited by different organophosphorus compounds. Arch Toxicol 1996; 70(8):497–503. 47. Worek F, Widmann R, Knopff O, Szinicz L: Reactivating potency of obidoxime, pralidoxime, HI 6 and HLo 7 in human erythrocyte acetylcholinesterase inhibited by highly toxic organophosphorus compounds. Arch Toxicol 1998;72(4):237–243. 48. Sidell FR, Groff WA: Intramuscular and intravenous administration of small doses of 2-pyridinium aldoxime methochloride to man. J Pharm Sci 1971;60(8):1224–1228. 49. Sundwall A: Minimum concentrations of N-methylpridinium -2-aldoxime methane sulphonate which reverse neuromuscular blockade. Biochim Pharmacol 1961;8:432–434. 50. Eyer P: The role of oximes in the management of organophosphorus pesticide poisoning. Toxicol Rev 2003;22(3):165–190. 51. Clement JG, Bailey DG, Madill HD, et al: The acetylcholinesterase oxime reactivator HI-6 in man: pharmacokinetics and tolerability in combination with atropine. Biopharm Drug Dispos 1995;16(5):415–425. 52. Kusic R, Jovanovic D, Randjelovic S, et al: HI-6 in man: efficacy of the oxime in poisoning by organophosphorus insecticides. Hum Exp Toxicol 1991;10(2):113–118. 53. Kassa J: Review of oximes in the antidotal treatment of poisoning by organophosphorus nerve agents. J Toxicol Clin Toxicol 2002;40(6):803–816. 54. van Helden HP, Busker RW, Melchers BP, Bruijnzeel PL: Pharmacological effects of oximes: how relevant are they? Arch Toxicol 1996;70(12):779–786.

B

55. Koplovitz I, Stewart JR: A comparison of the efficacy of HI6 and 2PAM against soman, tabun, sarin, and VX in the rabbit. Toxicol Lett 1994;70(3):269–279. 56. Eyer P, Hell W, Kawan A, Klehr H: Studies on the decomposition of the oxime HI 6 in aqueous solution. Arch Toxicol 1986;59(4):266–271. 57. Lundy PM, Hill I, Lecavalier P, et al: The pharmacokinetics and pharmacodynamics of two HI-6 salts in swine and efficacy in the treatment of GF and soman poisoning. Toxicology 2005;208(3): 399–409. 58. Kassa J, Cabal J, Bajgar J: The choice: HI-6, pralidoxime or obidoxime against nerve agents? ASA Newsletter 1997;97:4. 59. Aas P: Future considerations for the medical management of nerve-agent intoxication. Prehospital Disaster Med 2003;18(3): 208–216. 60. Rump S, Kowaczyk M: Management of convulsions in nerve agent acute poisoning: a Polish perspective. J Med Chem Def 2003;1:1–14. 61. Martin LJ, Doebler JA, Shih TM, Anthony A: Protective effect of diazepam pretreatment on soman-induced brain lesion formation. Brain Res 1985;325(1–2):287–289. 62. Lallement G, Clarencon D, Galonnier M, et al: Acute soman poisoning in primates neither pretreated nor receiving immediate therapy: value of gacyclidine (GK-11) in delayed medical support. Arch Toxicol 1999;73(2):115–122. 63. U.S. Army Soldier and Biological Chemical Command (SBCCOM): Guidelines for mass casualty decontamination during a terrorist chemical incident. Aberdeen, MD, Edgewood Chemical Biological Center, 2003. 64. U.S. Army Soldier and Biological Chemical Command (SBCCOM): Guidelines for cold weather mass decontamination during a terrorist chemical agent incident, revision 1. Aberdeen, MD, Edgewood Chemical Biological Center, 2003. 65. Sawyer TW, Parker D, Thomas N, et al: Efficacy of an oximatebased skin decontaminant against organophosphate nerve agents determined in vivo and in vitro. Toxicology 1991;67(3):267–277. 66. Okumura T, Suzuki K, Fukuda A, et al: The Tokyo subway sarin attack: disaster management. 2. Hospital response. Acad Emerg Med 1998;5(6):618–624. 67. Nakajima T, Sato S, Morita H, Yanagisawa N: Sarin poisoning of a rescue team in the Matsumoto sarin incident in Japan. Occup Environ Med 1997;54(10):697–701. 68. Yokoyama K, Yamada A, Mimura N: Clinical profiles of patients with sarin poisoning after the Tokyo subway attack. Am J Med 1996;100(5):586. 69. Okumura T, Suzuki K, Fukuda A, et al: The Tokyo subway sarin attack: disaster management. 1. Community emergency response. Acad Emerg Med 1998;5(6):613–617. 70. Matsui Y, Ohbu S, Yamashina A: Hospital deployment in mass sarin poisoning incident of the Tokyo subway system: an experience at St. Luke’s International Hospital, Tokyo. Jpn Hosp 1996;15:67–71. 71. Smithson AE: Stimson Center Report No. 35. Ataxia: The Chemical and Biological Terrorism Threat and the US Response. Washington, DC, The Henry L. Stimson Center, 2005.

Vesicants LAWRENCE STILWELL BETTS, MD, PHD ■ BRIAN CHRISTOPHER BETTS, MD


■

Sulfur mustard (or “mustard”) is the most significant member of the vesicant agents. It is the only vesicant with known use in combat. Skin lesions produced by contact with vesicant agents are nonspecific and, alone, are of little diagnostic value in identifying the etiology in early cases. History of the use of, or presence of, a vesicant agent, or prior cases with similar presentations, is of great value in approaching the differential diagnosis. The most important preventive measure to control exposure is avoidance of contact; the most important treatment measure to limit injury is prompt decontamination.

CHAPTER 105

■ ■ ■ ■ ■

Chemical Weapons

1501

Skin decontaminants available to the general public include a dilute hypochlorite solution (0.5%); military chemical agent decontaminants, such as the M291 kit, can be used as available. There is no specific antidote for mustard, and medical management of cases is based on treating signs and symptoms as they develop. Patient management ranges from very simple, for erythema or minor vesicles, to extremely complex, for immunosuppressed patients with multisystem derangements and extensive skin lesions. Disposition of casualties varies with intensity of exposure, delay and efficacy of decontamination, and severity of injuries. Repeated occupational exposures to mustard at levels that result in toxic effects are known to cause cancer of the upper airways.

RELEVANT HISTORY

use by Iraq was reported during the 1980s during in the Iran–Iraq conflict. Some of the Iranian casualties were evacuated and treated in Belgium, the country where mustard was first used in warfare in 1915 and in France. An excellent discussion and color image presentation of the clinical findings and medical management of these casualties is provided by Jan L. Willems.1 The images can also be found in the Textbook of Military Medicine.2 Lewisite, or dichloro-2-chlorovinylarsine, is an arsenical compound that produces toxic effects more rapidly than mustard. Lewisite has not been used in combat and has a low military threat potential. The widely known chelating agent, dimercaprol, or British Anti-Lewisite (BAL), was originally developed for use as an antidote for Lewisite. BAL currently finds therapeutic application in the treatment of some metal poisonings. Phosgene oxime (dichloroformoxime) is the only representative of the halogenated oxime group with military application. It is not a true vesicant. Although it causes irritation and corrosion, reaction to contact results in a solid, urticaria-like lesion that is not filled with fluid. The military includes it as a vesicant agent, and a

A vesicant is a chemical that produces vesicles or blisters at the site of contact. This class of “military chemical agents,” specifically sulfur mustard (also called H; HD; CAS No. 505-60-2; mustard gas, mustard), has been a major military threat agent since its introduction in combat in World War I. The vesicants constitute a hazard to exposed skin and mucous membranes in both the vapor and liquid states. Three groups of vesicants are considered useful for tactical military weapons as “chemical agents”: the mustard agents, the arsenicals, and the halogenated oximes. The main vesicant agents and their short-hand military designations are listed in Table 105B-1. Sulfur mustard (bis-[2-chloroethyl] sulfide) was first used as a weapon in World War I. Mustard was responsible for more battlefield casualties than caused by all of the other chemical agents. Mustard is the most important agent in the vesicant group and remains a current military threat today. Although chemical agents were not used on the battlefield in World War II, their TABLE 105B-1 Vesicant Groups* AGENT Mustard Agents bis-(2-chloroethyl) sulfide (Impure) (C4H8CL2S and contaminants bis-(2-chloroethyl) sulfide (distilled)† (C4H8CL2S) 60% bis-(2-chloroethyl) sulfide and 40% bis-(2-[2-chloroethylthio]-ethyl) ether mixture† mustard with Lewisite mixture nitrogen mustards: bis(2-chloroethyl)ethylamine (HN1) 2-Chloro-N-(2-chloroethyl)-Nethylethanamine (HN2) 2,2′,2′′ tri(chloroethyl)amine (HN3)

MILITARY SYMBOL

COMMON NAME

ONSET OF PAIN

TISSUE DAMAGE

H

Mustard; sulfur mustard; Yperite; ”lost“ Distilled mustard; sulfur mustard —

Delayed—hours

Immediate

Same

Same

Same

Same

HL HN1, HN2, and HN3

— Nitrogen mustard

Same Same

Same Same

HD HT

Organic Arsenical Agents dichloro-2-chlorovinylarsine (C2H2AsCl3) methyldichloroarsine phenyldichloroarsine ethyldichloroarsine

L

Lewisite

Immediate

Seconds to minutes

MD PD ED

— — —

Same Same Same

Same Same Same

Halogenated Oxime Agents dichloroformoxime (Cl2CNOH)

CX

Phosgene oxime

Immediate

Seconds

*Prototype agent in italics. † Lewisite, or agent ”T” (a vesicant chemically related to mustard), is added to decrease the freezing point and maintain the liquid form at lower ambient temperatures

1502


brief discussion is included in this chapter. Phosgene oxime has not been used in combat, and there is little information regarding its use and toxicity. Although it is considered to have a low military threat potential, its rapid penetration of protective garments and rapid onset of severe effects make it of military interest.2 Because of the amount of information available on the use and effects of mustard from World War I and the Iran–Iraq conflict, and the relative lack of information on Lewisite and phosgene oxime, this chapter discusses mustard as the prototype vesicant.

EXPOSURE SCENARIOS Mustard can contaminate environmental surfaces, including food and water supplies. During World War I, exposure to mustard resulted in a large number of casualties, but relatively few deaths. These findings underlie the reasons vesicants have military application. The potential for their use, with the accompanying fear of injury and need to avoid exposure, requires personnel to carry or wear protective equipment and to be fearful when touching anything, including food and water supplies. The need for precautions and the use of protective equipment restricts and impairs the ability to maneuver and fight. The resulting casualties decrease the strength of the fighting force, require medical assets, and further affect morale. It is easy to understand why the mere threat to use a chemical agent can be a powerful military tactic. The potential to use a vesicant against an unprotected and unknowing civilian population could be an even greater weapon in the hands of a terrorist. The volatility of a chemical agent and its persistence in the environment are inversely related: The more volatile agents have less persistence in the environment. They simply evaporate based on their vapor pressure. However, the vapor may still present a significant hazard! Temperature is the main environmental factor affecting persistence. Other environmental factors, such as terrain, wind, and rain, also affect dispersal and persistence. All these factors have been exploited in the past to obtain a

military advantage. At temperatures below 57° F (14° C), mustard is a solid, but still biologically active, chemical. It forms a persistent, oily liquid at higher temperatures that may be detected by its garlic- or onion-like (mustard) odor. In areas such as the Middle East, where summer temperatures often exceed 100° F (38° C), evaporation into the vapor state becomes significant. Such temperatures increase the risk for exposure to mustard vapor, but they simultaneously decrease its persistence.3 The finding of more casualties with eye and lung damage during the Iran–Iraq conflict than were observed in World War I has been attributed to the higher temperatures and increased volatilization in the hotter climate. Mustard vapor is also much denser than air and forms high vapor concentrations close to the ground or in low-lying areas. When an agent evaporates off the ground after dispersal, injuries may occur low on the body or in individuals in low-lying areas. To maintain mustard in the liquid state at lower temperatures, mustard has been mixed with other chemicals (including Lewisite) to decrease its freezing point. Chemical warfare material (CWM), composed of stockpiled agents (Table 105B-2) and “nonstockpiled” materials (such as buried items and contaminated objects from former production and storage), are currently being destroyed under federal statute and the Chemical Weapons Convention demilitarization program.4 Although extremely remote, there is a possibility of accidental release during storage, transportation, or destruction of the agent or its original container. Programs have been established to inform and educate adjacent communities regarding the potential risks and planned emergency response actions. In 2001, the Agency for Toxic Substances and Disease Registry released a draft toxicologic profile for “Mustard Gas” for review and comment. When officially released in 2003, the name of the profile was changed to “Sulfur Mustard.” This profile provides a comprehensive review of the environmental release and public exposure concerns.5 Nonmilitary “environmental” exposures have been reported in the literature.6,7 Often these reports involve adults or children finding undetonated shells. In some

TABLE 105B-2 Chemical Agents in the U.S. National Stockpile AGENT bis-(2-chloroethyl) sulfide bis(2-chloroethylthioethyl)ether dichloro-2-chlorovinylarsine ethyl N,N-dimethyl phosphoroamidiocyanidate isopropyl methylphosphonofluoridate O-ethyl-S-(2-diisopropylaminoethyl)-methyl phosphonothiolate

MILITARY SYMBOL/ NAME

CHEMICAL ABSTRACT SERVICE (CAS) NUMBER

H, HD; sulfur mustard HT L; Lewisite GA; Tabun

505-60-2 63918-89-8 541-25-3 77-81-6

GB; Sarin VX

107-44-8 50782-69-9

The Convention on the Prohibition of the Development, Production, Stockpiling, and Use of Chemical Weapons and Their Destruction, also known as the Chemical Weapons Convention (CWC), was signed by the United States on January 13, 1993, and ratified by Congress on April 25, 1997. The CWC mandates that nonstockpile chemical warfare materials (CWM) be destroyed by 2007. Extensions to this deadline can be obtained.4 From National Center for Environmental Health: Final Recommendations for Protecting the Health and Safety against Potential Adverse Effects of Long-Term Exposure to Low Doses of Agents: GA, BV, VX, Mustard Agent (H, HD, V), and Lewisite (L). Public Health Service, Centers for Disease Control and Prevention. Washington DC, U.S. Department of Health and Human Services, 1988.

CHAPTER 105

instances, the shells had remained under water or buried for many years before being found. The shells may leak or even detonate. Accidental exposures of this type still present possible patient scenarios that may be encountered by public service and medical personnel.

The relationship between the toxic effects caused by mustard and the mechanism of cellular tissue injury that causes them is not well understood.8 The liquid and vapor states of mustard pass rapidly through intact skin. As a potent alkylating agent, mustard reacts rapidly with structural and functional molecules of the cell, forming adducts. The altered molecules include nucleic acids, proteins, lipoproteins, and peptides, which affect various cell functions and lead to the observed injuries. Because of the rapid rate of these cellular reactions, mustard is quickly “fixed” after only a few minutes in a biologic milieu. Mustard is then no longer present as the “free,” reactive agent. Blister fluid, blood, or other body fluids do not present a continuing exposure hazard to the individual or the caregiver. It must be remembered that mustard may contaminate inanimate objects (such as clothing or equipment) and remain “free” and biologically available for many days! These objects can result in a source of continued or accidental exposure to the vesicant. As little as a 10-μg droplet of mustard on the skin can produce vesication. The LD50 from dermal contact to mustard is about 100 mg/kg. This is equivalent to about 7 g, or 5 to 8 mL, of the liquid agent for the average 70-kg person. When dispersed, this amount could cover about one fourth of the body surface with erythema or vesication.2 The LD50 for human oral exposure is estimated to be 0.7 mg/kg.9 Exposure levels for aerosols or vapors are often expressed in the inhalation and military literature as the product of the substance’s concentration (“C,” in mg/m3) and the duration of exposure (“t” in minutes)— the C · t (or Ct) value expressed as X mg · min/m3. It has been stated that equal Ct values cause equal toxic effects; that is: C × t = k (constant effect) in a relationship known as Haber’s rule.10 Note that in the practical application of Haber’s rule, caution must be used because departures from the rule are possible.11 Table 105B-3 provides Ct values for injuries by different routes of exposure to mustard in the aerosol or vapor states. Although it is unlikely that quantitative exposure data will be available to the treating physician during the early phases of treatment, military chemical agent detectors are becoming more widely distributed. When available, these provide valuable exposure information in the assessment, treatment, and demonstration of contamination and decontamination of patients.

MANIFESTATIONS Mustard is the only vesicant that does not cause immediate pain. The exposed individual is asymptomatic

1503

TABLE 105B-3 Mustard Ct Values for Aerosol or Vapor Exposure and Injuries CT VALUE (mg · min/m3) INJURY >10

PATHOPHYSIOLOGY OF INJURY

Chemical Weapons

Estimated 12–70 100–500 200–2000 ~1500

Eye damage (under laboratory conditions) Eye damage (under field conditions) Airway damage Threshold for skin damage in eye- and respiratory-protected individuals Estimated LCt50 through inhalation

From Sidell FR, Urbanetti JS, Smith WJ, Hurst CG: Vesicants. In Medical Aspects of Chemical and Biological Warfare. Textbook of Military Medicine. Washington, DC, Borden Institute, 1997; and U.S. Army Soldier and Biological Chemical Command (USASBCCOM): Distilled Mustard (HD) Material Safety Data Sheet. Aberdeen Proving Ground, MD, 1999.

until the effects become apparent after a period of delay—usually a few hours to 24 hours. Even in cases with severe (heavy) exposure, the onset of symptoms does not appear in the first hour. All body surfaces that come into contact with the liquid or vapor can be affected, but the eye is the most sensitive target organ, with effects ranging from mild conjunctivitis to severe eye damage. The warm, moist, and thin regions of the skin (such as the groin or axilla) are the most severely affected with erythema and vesicles, with the thicker sites (such as the palm or sole) being less affected. Respiratory tract injuries can range from mild irritation of the upper respiratory tract to severe bronchiolar damage with necrosis and hemorrhage of the mucosa and musculature. Acute, chronic, or delayed clinical effects can also be seen in the hematopoietic, gastrointestinal, and central nervous systems after severe exposures.12 At very high doses, the systemic effects on the blood-forming tissues can result in leukopenia, thrombocytopenia, and anemia. After mild to moderate exposures, death from systemic effects is not anticipated.13 Erythema is an early, mild presentation of skin injury and may be the extent of response to a light (small or mild) exposure. The effects are delayed and do not become apparent until an hour or more after exposure; they may be delayed up to a day or more. The skin reaction resembles sunburn that may be present with itching, burning, or stinging. Frequently, small vesicles form in a linear array that may later join together into larger vesicles. The appearance of vesicles follows the erythema, and they may take several days to fully develop. Data from the early studies of mustard reveal variations in skin sensitivity between individuals with apparently the same, as well as differing, amounts of skin pigmentation. Highly pigmented individuals appear to be more resistant to the acute dermal effects.14 The nonspecific skin lesions produced by mustard resemble those following contact with plants (Rhus family—poison ivy, oak, and sumac) or other contact irritants. Although difficult to differentiate from effects of typical exposures, suspicious circumstances and a corresponding history of exposure are invaluable in making the diagnosis of vesicant exposure. Often, the initial case or cases will not

1504


be attributed to a chemical vesicant agent. Melanoderma may develop after unroofing of the blisters, aiding in the physical diagnosis. The latency period for ocular effects is shorter than that for the skin. Ocular effects may appear after exposure to mustard concentrations barely perceptible by odor. These levels are below those that cause effects on the skin or in the respiratory tract.13 As the Ct increases (with direct contact of liquid mustard being the worst case), the effects progress to severe damage to the cornea and intraocular structures. Photophobia occurs with even minimal exposures, and it may persist for weeks. Mustard produces varying degrees of inflammation to the respiratory tract, depending on the Ct. Coughing and shortness of breath are common. The onset and severity of symptoms correspond to the degree of injury, but the injury may develop over a period of several days. Because of the rapid reaction with moist tissues, injury is often confined to the airways and adjacent tissue. Necrosis and sloughing of these tissues may occur. Death from pulmonary insufficiency, due to airway injury and infection, is seen in a small percentage of personnel who reach a medical facility. These deaths commonly occur several days or more after exposure.13 Mustard is classified as a known human carcinogen based on human data from manufacturing experience and combat casualties.15 The human evidence indicates a causal relationship with cancers of the respiratory tract and skin, and possibly leukemia.12

National Advisory Committee’s (NAC) acute exposure guideline levels (AEGLs)21,22 into Army policy, the AEGLs are used as guidance to protect individuals from the harmful effects of a single, short-term (8 hours or less) exposure to sulfur mustard. The three AEGL exposure levels have time durations ranging from 10 minutes to 8 hours. The effects at the three levels range from minor discomfort at the lowest concentration and exposure duration (AEGL-1) to potentially life threatening at the highest and longest exposure level (AEGL-3) (Table 105B4). The U.S. Army has also adopted an immediately dangerous to life or health (IDLH) level of 0.7 mg/m3 and a short-term exposure limit (STEL) of 0.003 mg/m3 for civilian and Department of Defense workers initially published as interim recommendations by the Centers for Disease Control and Prevention (CDC).23 On the other end of the exposure spectrum, the Agency for Toxic Substances and Disease Registry (ATSDR) has adopted “minimum risk levels” (MRL: a level below which daily human exposure is likely to be without appreciable risk of untoward non-cancer health effects over a specified duration of time). The following MRLs for sulfur mustard have been established for acute inhalation (1–14 days): 0.0007 mg/m3; intermediate duration inhalation (14–365 days): 0.00002 mg/m3; and acute oral (1–14 days): 0.0005 mg/kg/day and intermediate duration oral: 0.00007 mg/kg/day. Chronic MRLs have not been established.24

PRENATAL AND PEDIATRIC ISSUES

Decontamination involves the physical removal or chemical deactivation of the vesicant. Both fresh and sea water have been used for the mechanical removal and dissolution of solid or liquid vesicants. Although water (with or without soap) is not the ideal option, it may be the only available decontaminant, and it is a reasonable option.25 However, at least one military guidance document cautions against the use of water for removing known mustard agent contamination from the skin.26 Care should be taken to avoid spreading the agent during the decontamination process, and the use of absorbent powders (Fuller’s earth, talcum powder, flour) has been recommended to prevent this from occurring.27 A 0.5% hypochlorite solution (diluted household bleach in water [1:9]) has been used since World War I for decontaminating the skin. A freshly made (daily) solution of alkaline (pH = 10–11) hypochlorite is currently recommended by the U.S. military as the universal decontaminating solution for all liquid and solid agents on the skin.28 Either solution should be rinsed off the intact skin and hair within 4 minutes, taking care to avoid contact with wounds or the eyes.13 Poisindex recommends an alternate skin decontamination method of washing with water and a 2.5% sodium thiosulfate solution.29 The use of a hypochlorite solution is not recommended for abdominal wounds, open chest wounds, wounds exposing nervous tissue, or the eye. These sites should be rinsed liberally with appropriate irrigation fluid (normal saline, lactated Ringer’s solution). Vapor exposures are treated by simple removal from the

No specific information is available that directs exposure or treatment considerations different from those presented. From the clinical experience involving pediatric casualties during the Iran–Iraq conflict, the onset of symptoms in children was earlier and more severe than in adults.16 Mustard is known to be a mutagen and a carcinogen.

ASSESSMENT There is no specific laboratory test available for evaluating exposure to mustard. Analysis of a mustard metabolite, thiodiglycol, in the urine has been developed by the U.S. Army Medical Research Institute of Chemical Defense (USAMRICD) to verify that an exposure to mustard has occurred.17 Additional methods for analyzing other mustard metabolites as exposure indicators have been developed and are undergoing evaluation.18,19 The current U.S. Army “Standards and Guidelines as of March 2006” give a general population limit (GPL: maximum concentration for long-term exposure to sulfur mustard by the civilian general population) of 0.00002 milligrams per cubic meter of air (0.00002 mg/m3) and 0.0004 milligrams per cubic meter of air (0.0004 mg/m3) for civilian and Department of Defense personnel who work with sulfur mustard (WPLs).20 Incorporating the

TREATMENT

CHAPTER 105

Chemical Weapons

1505

TABLE 105B-4 National Research Council Acute Exposure Guideline Levels (AEGLs) of Sulfur Mustard (adopted by the U.S. Army [in parts per million of air [ppm] and milligrams per cubic meter of air [mg/m3]) AEGL-1 SINGLE, ACUTE EXPOSURE PERIOD IN MINUTES

10 30 60 240 480

AEGL-2

Conjunctival injection and minor General conjunctivitis with discomfort; no functional irritation, edema, photophobia, decrement in humans and eye irritation in humans

AEGL-3 Estimated lethal dose estimate in mice

ppm

mg/m3

ppm

mg/m3

ppm

mg/m3

0.6 0.02 0.01 0.003 0.001

0.40 0.13 0.067 0.017 0.008

0.09 0.03 0.02 0.004 0.002

0.60 0.20 0.10 0.025 0.013

0.59 0.41 0.32 0.08 0.04

3.9 2.7 2.1 0.53 0.27

All of the AEGL-1 and AEGL-2 levels, and the 240 minute and 480 minute AEGL-3 levels, are at or below the odor threshold for sulfur mustard. From National Research Council of The National Academies: Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 3. Washington, DC, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, 2003; National Advisory Council: Acute Exposure Guideline Levels (AEGLs) for Sulfur Mustard (Agent HD). Final Acute Exposure Guidance Levels (AEGLs). Washington, DC, National Advisory Committee on Exposure Guideline Levels for Hazardous Substances, 2001; and United States Army Center for Health Promotion and Preventive Medicine (USACHPPM): Chemical Agent Air Standards Status Table: Existing Standards and Guidelines as of March 2006. Environmental Medicine Program, 2006.

contaminated atmosphere.30 There are additional skin decontaminants used by the military (M291 resin kit), which may become more generally available with increased homeland defense capabilities. Sulfur mustard, in both the impure and pure forms (H and HD, respectively), has been a major military threat agent since its introduction in World War I. It is both a vapor and a liquid threat to all exposed skin and mucous membranes. The effects of mustard are delayed, appearing hours after exposure. This lack of early warning signs may result in a longer period of exposure before decontamination. There is no specific antidote for mustard, and management is based on symptomatic and supportive therapy for the lesions or systemic effects. (See also Chapters 2B, 9, and 15.) Immediate decontamination (within 2 minutes) prevents or maximizes the reduction of tissue damage. BAL (2, 3-dimercapto-1-propanol; dimercaprol) was developed as an antidote for Lewisite. BAL is currently used in medicine as a chelating agent for heavy metals. There is evidence that BAL in oil, given intramuscularly, will reduce the systemic effects of Lewisite. However, caution should be taken because there are toxic effects associated with the use of BAL. BAL skin ointment and BAL ophthalmic ointment decrease the severity of skin and eye lesions when applied immediately after early decontamination. However, neither of these formulations is currently manufactured. There is no antidote or specific treatment for phosgene oxime.

MANAGEMENT OF MASS CASUALTIES Actual measurements of air concentrations of the liquid or vapor will not likely be available in most casualty situations. Based on history and clinical findings, prompt decontamination followed by symptomatic care is

indicated. Topical decontamination is not effective once a chemical agent has been absorbed. For mustard, the greatest efficacy of this treatment is obtained if accomplished in less than 2 minutes after contact, but it may have some value even 15 minutes later.31 As discussed previously, a dilute 0.5% hypochlorite solution is used by the military as the preferred decontaminating solution for removing mustard from the skin. If this solution is not available, water (with or without soap) can be used. Care should be taken during decontamination not to force a superficial chemical agent into the skin, or create a wound from a high-pressure water stream. Highvolume, low-pressure water (with or without soap) should be used for decontaminating large numbers of exposed individuals. Further treatment for mustard exposure should be based on the clinical findings after decontamination.

PRINCIPLES OF PREPAREDNESS Prevention of contact and prompt decontamination are the paramount public health measures. Individual exposures are difficult to recognize, and a high index of suspicion must be maintained by public service and medical personnel to recognize cases and avoid selfcontamination. Butyl rubber provides a good barrier to mustard.28 The National Institute for Occupational Safety and Health (NIOSH), the U.S. Army Soldier Biological and Chemical Command (SBCCOM), and the National Institute for Standards and Technology (NIST) are working to develop appropriate standards and test procedures for all classes of respirators that will provide respiratory protection from chemical, biological, radiological, and nuclear (CBRN) agent inhalation hazards. Further information can be obtained at http://www.cdc.gov. Contact with mustard does not cause immediate pain and, therefore, does not provide a

1506


warning to decontaminate or use personal protective equipment (PPE). Contact with the other two groups of vesicants in either liquid or vapor state results in immediate irritation or pain and provides a warning to decontaminate immediately and don PPE. The immediate onset of irritation or pain may result in less severe lesions from these two groups. Topically applied barrier and other decontamination creams, as well as decontamination powders, have been recently developed. Distribution will initially be limited to military applications.

18.

19.

20.

REFERENCES 1. Willems JL: Clinical management of mustard gas casualties. Ann Med Milit Belg 1989;3S:1–61. 2. Sidell FR, Urbanetti JS, Smith WJ, Hurst CG: Vesicants. In Medical Aspects of Chemical and Biological Warfare. Textbook of Military Medicine. Washington, DC, Borden Institute, 1997. 3. Borak J, Sidell FR: Agents of chemical warfare: sulfur mustard. Ann Emerg Med 1992;21(3):303–308. 4. Committee on Review and Evaluation of the Army Non-Stockpile Chemical Materiel Disposal Program: Disposal of Neutralent Wastes Board on Army Science and Technology. Board on Army Science and Technology. National Research Council, 2001 5. Rosemond GA, Beblo DA, Amata R, authors and chemical managers: Toxicological Profile for Sulfur Mustard (formerly called Mustard Gas). Washington, DC, U.S. Department of Health and Human Services Public Health Service, Agency for Toxic Substances and Disease Registry (ATSDR), 2003. 6. Aasted A, Darre MD, Wulf HC: Mustard gas: clinical, toxicological, and mutagenic aspects based upon modern experience. Ann Plastic Surg 1987;19:330–333. 7. Ruhl CM, Park DJ, Danisa O, Morgan RP, et al: A serious skin sulfur mustard burn from artillery shell. J Emerg Med 1994;12(2):159–166. 8. Papirmeister B, Feister AJ, Robinson SI, Ford RD: Medical Defense Against Mustard Gas: Toxic Mechanisms and Pharmacological Implications. Baton Rouge, FL, CRC Press, 1991. 9. U.S. Army Soldier and Biological Chemical Command (USASBCCOM): Distilled Mustard (HD) Material Safety Data Sheet. Aberdeen Proving Ground, MD, 1999. 10. Rinehart WE, Hatch T: Concentration-time product (CT) as an expression of dose in sublethal exposures to phosgene. Ind Hyg J 1964;25:545–553. 11. Rozman KK, Doull J: The role of time as a quantifiable variable of toxicity and the experimental conditions when Haber’s c × t product can be observed: implications for therapeutics. J Pharmacol Exp Ther 2001;296(3):663–668. 12. Pechura CM, Rall DP (eds): Veterans at Risk: The Health Effects of Mustard Gas and Lewisite. Institute of Medicine. Washington, DC, National Academy Press, 1993. 13. Departments of the Army, the Navy, and the Air Force, and Commandant, Marine Corps: Treatment of Chemical Agent Casualties and Conventional Military Chemical Injuries FM 8-285. Chapter 4: Vesicants. Washington, DC, Author, 1995. 14. Marshall EK, Lynch V, Smith HW: On dichlorethylsulfide (mustard gas) II: variations in susceptibility of the skin to dichlorethylsulfide: J Pharmacol Exp Ther1919;12:291–301. 15. U.S. Department of Health and Human Services (USDHHS): Report on Carcinogens, 10th ed. Washington, DC, Public Health Service, National Toxicology Program, 2002. 16. Momeni AZ, Aminjavaheri M: Skin manifestations of mustard gas in a group of 14 children and teenagers: a clinical study. Int J Dermatol 1994;33(3):184–187. 17. U.S. Army, Headquarters: Assay Techniques for Detection of Exposure to Sulfur Mustard, Cholinesterase Inhibitors, Sarin, Soman,

21.

22.

23.

24.

25. 26. 27.

28.

29. 30.

31.

GF, and Cyanide. Technical Bulletin Medical 296. Washington, DC, Author, 1996. Black RM, Read RW: Improved methodology for the detection and quantization of urinary metabolites of sulphur mustard using gas chromatography-tandem mass spectrometry. J Chromatogr 1995;665:97–105. Black RM, Read RW: Application of liquid chromatographyatmospheric pressure chemical ionization mass spectrometry, and tandem mass spectrometry, to the analysis and identification of degradation products of chemical warfare agents. J Chromatogr 1997;759:79–92. United States Army Center for Health Promotion and Preventive Medicine (USACHPPM): Chemical Agent Air Standards Status Table: Existing Standards and Guidelines as of March 2006. Environmental Medicine Program, 2006, http://chppm-www. apgea.army.mil/chemicalagent/PDFFiles/CWA-AirTableMarch 2006.pdf, accessed October 25, 2006. National Advisory Council: Acute Exposure Guideline Levels (AEGLs) for Sulfur Mustard (Agent HD). Final Acute Exposure Guidance Levels (AEGLs). Washington, DC, National Advisory Committee on Exposure Guideline Levels for Hazardous Substances, 2001. National Research Council of the National Academies: Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol 3. Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Washington, DC, 2003, http://fermat.nap.edu/books/0309088836 /html/R1.html, accessed October 25, 2006. Department of Health and Human Services: Interim Recommendations for Airborne Exposure Limits for Chemical Warfare Agents H and HD (Sulfur Mustard). Centers for Disease Control and Prevention. Fed Reg 2004;69(86):24164–24168, http://a257.g.akamaitech.net/7/257/2422/14mar20010800/edo cket.access.gpo.gov/2004/pdf/04-9946.pdf, accessed October 25, 2006. Agency for Toxic Substances and Disease Registry (ATSDR): Minimal Risk Levels (MRLs) for Hazardous Substances. Atlanta, Author, 2005, http://www.atsdr.cdc.gov/mrllist 12 05.pdf, accessed October 25, 2006. Hurst CG: Decontamination. In Medical Aspects of Chemical and Biological Warfare. Textbook of Military Medicine. Washington, DC, Borden Institute, 1997. U.S. Army Center for Health Promotion and Preventive Medicine (USACHPPM). Chemical. In Medical NBC Battlebook; Technical Guide 244. Aberdeen Proving Ground, MD, Author, 2000. Departments of the Army, the Navy, and the Air Force: Vesicants (blister agents). In Part 3: Chemicals; NATO Handbook on the Medical Aspects of NBC Defensive Operations AMedP-6(B). U.S. Army Field Manual 8-9. Washington, DC, Author, 1996. U.S. Army Medical Research Institute of Chemical Defense (USAMRICD): Decontamination in Medical Management of Chemical Casualties Handbook, 3rd ed. Aberdeen Proving Ground, MD, Author, 1999. Coppock R, Hurlbut KM: Mustard gas. In POISINDEX® Information System. Thomson Micromedex Healthcare Series Volume 118. Greenwood Village, CO, 2003. Wartell MA, Kleinman MT, Huey BM, Duffy LM (eds): Decontamination. In Strategies to Protect the Health of Deployed U.S. Forces: Force Protection and Decontamination. Commission on Engineering and Technical Systems. National Research Council. Washington, DC, National Academy Press, 1999. National Center for Environmental Health: Final Recommendations for Protecting the Health and Safety against Potential Adverse Effects of Long-Term Exposure to Low Doses of Agents: GA, BV, VX, Mustard Agent (H, HD, Y), and Lewisite (L). Public Health Service. Centers for Disease Control. Washington, DC, U.S. Department of Health and Human Services, 1988.

CHAPTER 105

C

■

■ ■

■ ■

1507

Choking Agents LAWRENCE STILWELL BETTS, MD, PHD ■ BRIAN CHRISTOPHER BETTS, MD

At a Glance… ■

Chemical Weapons

Choking agents cause acute effects in the upper respiratory tract and lungs, including irritation, increased secretions, cough, dyspnea, chest tightness, and pulmonary edema. Termination of inhalation exposure by removal of the victim to fresh air (and with copious skin irrigation for liquid exposure), while maintaining the safety of the rescuer, is the initial and most important postexposure action. There is no specific, postexposure management for any of the choking agents. Depending on the severity of exposure, a period of observation is necessary to fully assess and treat potential lung damage and the delayed development of pulmonary edema. The development of several different chronic pulmonary sequelae is possible after acute exposure to agents in this class. After even a mildly significant acute event, follow-up pulmonary function testing may reveal persistent changes.

RELEVANT HISTORY In the classification of military chemical warfare agents, choking agents are often included in the larger category of “pulmonary” or “lung-damaging” agents. Smokes, as members of the choking agents, are among the oldest of the chemical agents. The use of smoke dates back to the time when humans first exploited this by-product of fire in warfare. Industrial process chemicals, namely, chlorine (military symbol: CL) and phosgene (CG), were

used in World War I as simple, but large-scale, chemical weapons. Their use was intended to demoralize the enemy by causing widespread effects from an unseen, and unnatural, opposing force. These two chemicals are representative of the class of chemical warfare agents that cause choking and damage in the upper airways and lungs. The continuum of dose-related toxic effects is similar for all of the choking agents with differences in each agent’s properties and potency. Chloropicrin (PS), diphosgene (DP), sulfur mustard (H, HD), and Lewisite (L) are also considered by the military as choking agents, but the latter two substances are primarily classified as vesicants. The choking agents also include chemicals that are used in conventional warfare, such as zinc-containing smoke (HC), as well as chemicals associated with industrial and agricultural processes. The United States does not consider nonlethal chemicals, such as riot control agents and herbicides, as “chemical warfare agents,” which are controlled under the 1925 Geneva Convention.1 Table 105C-1 provides data on selected choking agents and their sources. The riot control agents, such as tear gas and pepper spray, may cause choking and other temporary clinical features associated with the choking agents, but they are not discussed in this chapter. Specific chemicals that cause choking and that are internationally classified as “chemical weapons (CW),” or feedstock, are listed under the Convention on the Prohibition of the Development, Production, Stockpiling and Use of Chemical Weapons and on their Destruction (Chemical Weapons Convention, CWC),” which entered into force in 1997.2 This international treaty prohibits

TABLE 105C-1 Select Military Choking Agents CHEMICAL

CHEMICAL SYNONYM

CHEMICAL ABSTRACT SERVICE (CAS) NUMBER

MILITARY CHEMICAL INDUSTRIAL OR AGRICULTURAL AGENT SYMBOL PRODUCT USES OR BY-PRODUCT

Phosgene

Carbonyl chloride

75-44-5

CG

Chlorine

Molecular chlorine

7782-50-5

CL

Chloropicrin

Trichloronitromethane; 76-06-2 nitrochloroform Trichloromethylchloro 503-38-8 formate HC/HC smokes, TiCl4†, Mixture of chemicals; others 7550-45-0†

Diphosgene Military smoke*

PS DP HC; FM†

Perfluoroisobutylene PFIB

382-21-8

—

Oxides of nitrogen

Numerous

—

Nitrogen oxides; NOx

Synthesis of drugs, plastics, adhesives, dyes, pesticides Chemical synthesis; bleaching agent; water/waste disinfection Fumigant; pesticide; organic synthesis; dyes Limited chemical synthesis Visualization of air movement in ventilation assessments; chemical synthesis; pigments† Pyrolysis product of organofluoride polymers Combustion of fuels; welding and other high-temperature operations; fermentation

*Military ”HC“ smoke contains a mixture of chemicals that cause choking. The military also generates smoke through the partial combustion of fuel. † Titanium tetrachloride (TiCl4).

1508


the development, production, stockpiling, and use of chemical weapons. However, it does not prohibit production, processing, consumption, or trade of related chemicals that are verified for use in peaceful purposes. Chlorine was the first lethal choking agent used as a chemical weapon in modern warfare. Chlorine was released in Ypres, Belgium in 1915, but it is not controlled as a potential chemical weapon under the CWC. The use of chlorine as a weapon is now obsolete, but its industrial use is enormous. In addition to the chemicals that have been used, or have the potential to be used, as military weapons, perfluoroisobutylene (PFIB), or 1,1,3,3,3-pentafluoro-2-(trifluoromethyl)-1-propene—a thermal decomposition product of tetrafluoroethylene (Teflon) and other organofluoride polymers—is also a controlled chemical under the CWC. Table 105C-2 provides a list of specifically identified (“named”) chemicals that are controlled under the CWC. The “oxides of nitrogen (NOx)” comprise a group of compounds that are products of combustion and explosion generated from the discharge of munitions and propellants. These oxides are considered by the U.S. military as choking agents, but they are not used as chemical warfare agents. These compounds can also arise from sources unrelated to combat, including fires, internal combustion engine exhaust, food processing,

and biologic fermentation (see discussion of silo filler’s disease in Chapter 9). Military smokes are also considered choking agents because of their use in military applications. They are not directly used in chemical warfare, and like PFIB and the oxides of nitrogen, excessive exposure can damage the airways or lungs. The clinical features that follow exposure to any of these chemicals are similar—hence their collective grouping as “choking agents.” Most important, this class contains chemicals that are associated with the development of potentially fatal pulmonary edema. The onset of this pulmonary edema may be delayed for many hours and is “permeability related,” or noncardiogenic in origin.3

EXPOSURE SCENARIOS The historical use of trench warfare, with the massing of large numbers of troops in interconnected, low-lying positions, made the use, or even the potential for use, of a chemical that could cause choking and lung damage a tactic that could be exploited to military advantage. Denser-than-air gases could be released and follow the pathway created by the defensive earthen channels. With a wind favorable to the user, the opposing forces would be forced to abandon their positions or be required to

TABLE 105C-2 Named Chemicals and Chemical Abstract Service (CAS) Numbers Scheduled under the Chemical Weapons Convention (CWC) Schedule 1*

Schedule 2†

Schedule 3‡

Toxic chemicals: sarin (107-44-8); soman (99-64-0); tabun (77-81-6); VX (50782-69-9); sulfur mustards (various); Lewisites (various); nitrogen mustards (various); saxitoxin (50782-69-9); ricin (9009-86-3) and related congeners Precursors: methylphosphonyldifluoride (676-99-3); O-ethyl O-2-diisopropylaminoethyl methylphosphonite (57856-11-8); chlorosarin: o-isopropyl methylphosphonochloridate (1445-76-7); chlorosoman: o-pinacolyl methylphosphonochloridate (7040-57-5); and related congeners Toxic chemicals: amiton: O,O-diethyl S-[2(diethylamino)ethyl] phosphorothiolate (78-53-5); PFIB: 1,1,3,3,3pentafluoro-2-(trifluoromethyl)-1-propene (382-21-8); BZ: 3-quinuclidinyl benzilate (6581-06-2); and related congeners Precursors: methylphosphonyl dichloride(676-97-1); Dimethyl methylphosphonate (756-79-6); N,N-dialkyl (Me, Et, n-Pr or i-Pr) phosphoramidic dihalides (various); dialkyl (Me, Et, n-Pr or i-Pr) N,N-dialkyl (Me, Et, n-Pr or i-Pr)-phosphoramidates (various); arsenic trichloride (7784-34-1); 2,2-diphenyl-2-hydroxyacetic acid (76-93-7); quinuclidin-3-ol (1619-34-7); N,N-dialkyl (Me, Et, n-Pr or i-Pr) aminoethyl-2-chlorides (various); N,N-dialkyl (Me, Et, n-Pr or i-Pr) aminoethane-2-ols (various); N,N-dialkyl (Me, Et, n-Pr or i-Pr) aminoethane-2-thiols (various); thiodiglycol: bis(2-hydroxyethyl)sulfide (111-48-8); pinacolyl alcohol: 3,3-dimethylbutan-2-ol (464-07-3); and related congeners Toxic chemicals: phosgene (75-44-5); cyanogen chloride (506-77-4); hydrogen cyanide (74-90-8); chloropicrin (76-06-2); and related congeners Precursors: phosphorus oxychloride (10025-87-3); phosphorus trichloride (7719-12-2); phosphorus pentachloride (10026-13-8); trimethyl phosphate (121-45-9); triethyl phosphate (122-52-1); dimethyl phosphate (868-85-9); diethyl phosphate (762-04-9); sulfur monochloride (10025-67-9); sulfur dichloride (10545-99-0); thionyl chloride (7719-09-7); ethyldiethanolamine (139-87-7); methyldiethanolamine (105-59-9); triethanolamine (102-71-6); and related congeners

*Criteria considered for listing chemical in schedule 1: chemical has been developed, produced, stockpiled, or used as a chemical weapon; chemical has a high potential for use in prohibited activities due to similarities in structure and toxicity as chemicals listed in Schedule 1; chemical has significant lethality or incapacitating properties that could have application as a chemical weapon; chemical could be used as a precursor in the final stage of production of a Schedule 1 chemical; and chemical has little or no use for nonprohibited purposes. † Criteria considered for listing chemical in schedule 2: chemical poses a significant risk due to its lethality or incapacitating toxicity and other properties useful in chemical weapons; chemical may be used as a precursor in the final stages of making schedule 1 or 2 chemicals; chemical may be important in the production of schedule 1 or 2 chemicals; and chemicals is not produced in large quantities for purposes that are not prohibited. ‡ Criteria considered for listing chemical in schedule 3: chemical has been produced, stockpiled, or used as a chemical weapon; chemical poses a risk due to its lethality or incapacitating toxicity and other properties useful in chemical weapons; chemical may be important in the production of one or more chemicals listed in schedule 1 or schedule 2; and chemical may be produced in large commercial quantities for non-prohibited purposes Data from Organisation for the Prohibition of Chemical Weapons (OPCW): Convention on the Prohibition of the Development, Production, Stockpiling and Use of Chemical Weapons and on Their Destruction (Chemical Weapons Convention). The Hague, Netherlands, 1997. Available at http://www.opcw. org (updated 2003).

CHAPTER 105

don cumbersome protective equipment. However, even before the end of World War I, the volatile choking agents were replaced with the more persistent (and more controllable) vesicants in order to deny terrain and maneuverability, harass the opposition, cause casualties, consume resources, and create fear. Although no longer a military threat on the battlefield, chemicals that can cause choking and pulmonary damage are found in large quantities in industrial and agricultural settings. The sizeable amounts and widespread availability of this group of chemical agents create the potential for an occupational or environmental catastrophe—or an attractive weapon to a terrorist for release into an enclosed structure. These choking agents do not need to be synthesized by a terrorist; they only need to be commandeered! Concern for the use of these agents by terrorists caused the Centers for Disease Control and Prevention to issue an alert through the Health Alert Network on New Year’s Eve 2003.4 Phosgene replaced chlorine as a chemical weapon and accounted for 80% of all chemical fatalities during World War I.5 Although phosgene was stockpiled in munitions for use in World War II, it was not used and is no longer stockpiled by the U.S. military.6 Phosgene is extensively used as a feedstock in many chemical processes. It is also formed when chlorinated compounds are heated to decomposition. This can occur when a chlorinated compound—found in solvents, degreasers, and dry cleaning agents—contacts a high temperature source, such as a welding arc or flame. Plastic materials containing chlorinated compounds produce phosgene when they burn. Phosgene is considered a potential chemical weapon,7 and the potential for individual or mass exposure from weaponized military use, industrial accidents, or acts of terror still presents a significant risk. The physiologic effects caused by exposure to phosgene and their medical management are representative of the general class of “choking agents.” Military smokes, or “obscurants,” are used to conceal personnel and equipment. Exposure to obscurants may occur in training or combat situations, or the products or devices may be used by terrorists during an attack. HC smoke is produced from a reaction involving zinc oxide, hexachloroethane, and fine aluminum particles. HC smoke contains zinc chloride, as well as phosgene, carbon monoxide, and other chlorinated hydrocarbons. There are many other military obscurants, including chlorosulfonic acid (CSA); titanium tetrachloride (FM), and partially burned hydrocarbons. Although militarily useful in low concentrations, exposure to high or heavy concentrations of obscurants for extended periods can result in illness or death.5,8 Choking agents can be produced from nonmilitary processes or sources. PFIB results from the pyrolysis of materials containing organofluoride polymers, such as tetrafluoroethylene (Teflon). Modern military vehicles, aircraft, and vessels use significant amounts of these polymers. Fires in vehicles, aircrafts, ships, and structures present possible situations in which PFIB can be formed and inhaled. Oxides of nitrogen (NOx) are formed as products of combustion and of fermentation (see

Chemical Weapons

1509

Chapters 9 and 86). NOx may be produced with carbon monoxide during combustion of a fuel in air (air is about 78% nitrogen and about 21% oxygen). In individuals with exposure to exhaust gases from internal combustion engines using various fuels, the physiologic effects of NOx may be initially combined and masked with those caused by carbon monoxide.9,10 Silo filler’s disease is caused by the inhalation of nitrogen dioxide (one member of the family of NOx compounds), which is formed during fermentation of corn and other green plants.11

PATHOPHYSIOLOGY OF INJURY Choking agents can cause asphyxiation; irritation and damage to mucous membranes (affecting the airways, alveoli, or the tissues surrounding them); alteration of systemic processes; or an allergic response.12 The toxic effects caused by exposure to a specific inhaled chemical are due to many factors, including the properties of the chemical, the chemical concentration, and the duration of exposure—the latter two factors comprise the “Ct” product discussed in Chapter 105B. Additional factors are related to the health status of the exposed individual, as well as the individual’s level of activity during, and after, the exposure. Heavy activity during exposure results in deeper breathing and deeper penetration of the toxicant into the lungs. Heavy activity after exposure results in greater physiologic stress on the respiratory and circulatory systems—and perhaps a greater degree of tissue damage. The potential to cause delayed pulmonary edema through effects leading to membrane disruption at the alveolar–capillary bed is common to all the choking agents (see Chapters 8 and 9).

MANIFESTATIONS Choking agents cause acute clinical effects in the upper respiratory tract and lungs, including irritation, increased secretions, cough, dyspnea, chest tightness, and pulmonary edema. One of the most important clinical features of agents in this class is the potential to cause pulmonary edema after a clinically unremarkable latent period. The period of time before the onset of pulmonary edema is related to the severity of the exposure (Ct) and to the prognosis. The onset of signs and symptoms of pulmonary edema within 4 hours of exposure is a sensitive indicator of a poor prognosis. Without intensive medical support, there is a high risk for death in patients with this early finding.6 Acute exposure to choking agents may result in chronic bronchitis, emphysema, bronchiolitis obliterans, or reactive airway dysfunction syndrome (RADS) (see Chapters 8 and 9).

PRENATAL AND PEDIATRIC ISSUES Clinically significant exposure to choking agents can result in acute hypoxia in the mother and an associated lowered PO2 level available to the fetus. This may result in

1510


harm to the pregnancy or the fetus. Asthma, in any age group, may be nonspecifically initiated or exacerbated by exposure to the irritant effects of the choking agents.

ASSESSMENT A history of exposure is essential to make and confirm an early diagnosis during the latent period. A period of observation is necessary as the dose-dependent clinical effects resulting from pulmonary damage become apparent over time. The prognosis for patients developing early pulmonary edema, cyanosis, and hypotension is poor. Survival is greater in patients developing these findings 4 to 6 hours or longer after exposure, and in those with immediate, intensive medical care.6

TREATMENT The primary initial treatment consists of cessation of exposure. For inhalation exposure, moving the patient to fresh air and insuring an open airway and proper ventilation is essential, while taking precautions to prevent the rescuer or caregiver from also becoming a victim! For exposure to liquids, remove clothing and rinse liquid agents off the skin with copious soap or detergent and water irrigation. The eyes should be rinsed with running water or saline. Supplemental oxygen, intubation, suction, and mechanical ventilation are used as needed to treat respiratory distress. Based on the exposure history and clinical findings, a period of forced rest and observation is important in the medical management. The potential development of delayed, noncardiogenic pulmonary edema requires medical observation for a suitable period of time based on the severity of exposure and the clinical course. Treatment of pulmonary edema and other clinical findings, and the use of steroids and other therapeutic agents and modalities, are discussed elsewhere in this text. See Chapters 9, 86, 93, and 102. A short latent period is a harbinger of a more severe clinical course. Patients developing pulmonary edema within 12 hours of exposure will usually require intensive pulmonary care. Based on U.S. Army triage recommendations, patients with dyspnea and no objective signs should be observed closely and reevaluated hourly. Asymptomatic patients with known exposures should be observed and reevaluated every 2 hours. If these patients remain asymptomatic for 24 hours, they may be considered for discharge. Patients with doubtful exposures, and no symptoms after 12 hours of observation, can also be considered for discharge at that time.6 The chest radiograph is helpful in the assessment before discharge. If not available, Borak and Diller recommend an observation period of 24 hours for asymptomatic patients after suspected phosgene inhalation.3

MANAGEMENT OF MASS CASUALTIES The activity of patients under evaluation after inhalation of any of the choking agents should be controlled. Physical activity12 and emotional factors3 can influence the development and severity of clinical findings.

PRINCIPLES OF PREPAREDNESS The absence of early signs or symptoms involving mucous membrane irritation or respiratory distress, or a warning odor of a chemical, does not prove that an exposure was inconsequential. It is necessary to maintain vigilance for patients presenting with a reliable history of exposure to a choking agent, or with developing signs and symptoms consistent with such an exposure. REFERENCES 1. Sidell FR: Riot control agents. In Textbook of Military Medicine: Medical Aspects of Chemical and Biological Warfare. Washington, DC, Office of the Surgeon General, Department of the Army, 1997. 2. Organisation for the Prohibition of Chemical Weapons (OPCW). Convention on the Prohibition of the Development, Production, Stockpiling and Use of Chemical Weapons and on their Destruction (Chemical Weapons Convention). The Hague, NL, 1997 Available at http://www.opcw.org (updated 2003). 3. Borak J, Diller WF: Phosgene exposure: mechanisms of injury and treatment strategies. J Occup Environ Med 2001;43:110–119. 4. Centers for Disease Control and Prevention (CDC): Update on Public Health Precautions related to Orange Threat Level. 2. Public Health Information and Resources for a Possible Chemical Emergency. Distributed via Health Alert Network. CDCHAN00178-03-12-31-UPD-N. Atlanta, Author, December 31, 2003. 5. Departments of the Army, the Navy, and the Air Force: Lung damaging agents. In Part Three: Chemicals. NATO Handbook on the Medical Aspects of NBC Defensive Operations AMedP-6(B). U.S. Army Field Manual 8–9. Washington, DC, Author, 1996. 6. U.S. Army Medical Research Institute of Chemical Defense (USAMRICD): Pulmonary (Choking) Agents in Medical Management of Chemical Casualties Handbook, 3rd ed. Aberdeen Proving Ground, MD, Author, August 1999. 7. Sidell FR, Frantz D: Overview. Defense Against the Effects of Chemical and Biological Warfare Agents. In Textbook of Military Medicine: Medical Aspects of Chemical and Biological Warfare. Washington, DC, Office of the Surgeon General, Department of the Army, 1997. 8. Evans EH: Casualties following exposure to zinc chloride smoke. Lancet 1945;2:368–370. 9. Anderson DE: Problems created for ice arenas by engine exhaust. Am Ind Hyg Assoc J 1971;32:790–801. 10. Hedberg K, Hedberg CW, Iber C, et al: An outbreak of nitrogen dioxide-induced respiratory illness among ice hockey players: JAMA 1989;262:3014–3017. 11. Douglas WW, Hepper NGG, Colby TV: Silo-filler’s disease. Mayo Clin Proc 1989;64:291–304. 12. Urbanetti JS: Toxic inhalational injury. In Textbook of Military Medicine: Medical Aspects of Chemical and Biological Warfare. Washington, DC, Office of the Surgeon General, Department of the Army, 1997.

CHAPTER 105

D

ANDIS GRAUDINS, MBBS (HONS), PHD

■

Lacrimators are also known as irritant incapacitants, tear gas, and riot control or harassing agents.

■

Lacrimators are used primarily by law enforcement and military personnel for riot control. Lacrimators usually result in transient incapacitation with skin and mucosal membrane irritation. When used at high concentrations (i.e., enclosed, poorly ventilated spaces), lacrimators may produce significant respiratory and ocular effects. Following chronic, high concentration exposures, lacrimators may produce reactive airways dysfunction and dermatitis in sensitized individuals. Physical injury (i.e., cutaneous burns and trauma) may be sustained after exposure to exploding cartridges used to deploy lacrimators. Treatment is largely supportive; decontamination of the skin and mucosal surfaces is the mainstay of therapy. Medical staff should protect themselves with gloves, gowns, and eyewear and work in a well-ventilated environment to avoid secondary exposure to lacrimators from contaminated clothing.

■

■

■

■ ■

1511

Lacrimators

At a Glance…

■

Chemical Weapons

INTRODUCTION AND RELEVANT HISTORY Lacrimators, also known as irritant incapacitants, tear gas, and riot control or harassing agents, are aerosol-dispersed chemicals that produce near-immediate eye, skin, and upper respiratory tract irritation. Lacrimators have become widely accepted by law enforcement and military personnel as a method of controlling civilian crowds and criminal uprisings in correctional facilities. Virtually all police departments use tear gas as a nonlethal means of subduing suspected criminals. These agents are also advertised as nonlethal personal safety agents (in lieu of gun ownership). Ownership by civilians, however, is illegal in many countries. Large amounts of tear gas have been used worldwide. Tear gas has been used to suppress demonstrations and civil unrest in culturally diverse places, such as Chile, Panama, South Korea, and the Gaza strip and West Bank in Israel. The true incidence of complications associated with the use of these agents is unknown because of the difficulty in collecting epidemiologic information on victims of mass exposures to tear gas. Consequently, the overall safety of these agents has been questioned by the medical community.1,2 Although the modern use of irritant incapacitants is for riot control, historically these agents were used in warfare to incapacitate enemy forces. From antiquity to the Middle Ages, oxides of sulfur were combusted upwind

of enemies with the aim of enveloping them in a cloud of smoke. Arsenical smoke was used sporadically from the 15th to 17th centuries. In the 20th century, the Paris police were the first to use chemical agents in 1912. Grenades filled with ethylbromoacetate (EBA) were deployed against “lawless gangs.” EBA was also used in the early phases of World War I by French ex-police conscripts.3,4 Modern tear gas agents were first used in the United States during the crime waves of the 1920s to combat gangsters and as personal protection agents.5 Subsequently, many harassing agents have been developed. Dispersal systems have also been refined in the ensuing years to improve delivery of these agents. As many as 15 different irritants have been developed during the course of this century. Of these, only four lacrimator agents remain in common use worldwide: 1-chloracetophenone (CN, Mace); 2-chlorobenzylidene malonitrile (CS); dibenz-1,4-oxazepine (CR); and capsaicin (pepper spray, “pepper Mace”).4

CHLOROACETOPHENONE CN is the oldest of the currently used lacrimators. The name “Mace” originally described this agent alone.4 The eponym MACE was derived from a particular chemical formulation of CN: methylchloroform chloroacetophenone. CN is manufactured by chlorination of acetophenone with selenium oxychloride.4,5 Its chemical formula is C6H5COCH2Cl. Under normal atmospheric conditions, chloroacetophenone exists as a white solid or powder.4 It can be delivered as a smoke from thermal grenades or artillery shells or as a solid or liquid aerosol. CN is heat stable, breaking down only when exposed to temperatures greater than 300° C for 15 minutes or more.4 CN is poorly soluble in water, even when alkalinized; this characteristic predicts a moderate degree of environmental persistence and resistance to skin decontamination with soap and water.4,6 When used in large amounts, CN can persist in the environment for hours to days, depending on prevailing meteorologic conditions.4,7 Although less potent than CS, CN is the most toxic of the currently used lacrimators.3,4,6 The concentrationtime product (mg · min/m3) of CN that will incapacitate 50% of exposed individuals (ICt50) is about 10 times greater than that for CS, yet the concentration-time product that will be lethal to 50% of exposed individuals (LCt50) is about 6 times less than that for CS3,4,6 (Table 105D-1). At high concentrations, CN has produced permanent corneal epithelial damage, severe skin irritation with blistering, noncardiogenic pulmonary edema, and asphyxiation. At least five deaths have occurred from acute pulmonary injury or asphyxiation when CN grenades were used in enclosed spaces.3,4,6,8,9

1512


TABLE 105D-1 Riot Control Agents: Comparison of Potency and Toxicity

TC50 [eyes] (mg/m3) TC50 [airway] (mg/m3) ICt50 (mg · min/m3) LCt50 (mg · min/m3)

CN

CS

CR

0.3 0.4 20–40 7000–14,000

0.004 0.023 3–5 60,000

0.002 0.002 0.7 >100,000

TC50, the concentration in air (mg/m3) that will irritate the eyes of 50% of the population exposed; ICt50, the concentration time product (mg · min/m3) that incapacitates 50% of the population exposed; LCt50, the concentration time product (mg · min/m3) that is lethal to 50% of the population exposed. Modified from Beswick FW: Chemical agents used in riot control and warfare. Hum Toxicol 1983;2:247–256; Sidell FR: Riot control agents. In Sidell FR, Takafuji ET, Frank DR (eds): Textbook of Military Medicine. I. Warfare, Weaponry, and the Casualty: Medical Aspects of Chemical and Biological Warfare. Washington DC, Office of the Surgeon General, 1997, pp 307–324; and Blain PG: Tear gases and irritant incapacitants: 1-chloroacetophenone, 2-chlorobenzylidene malonitrile and dibenz[B,F]-1,4-oxazepine. Toxicol Rev 2003;22(2):103–110.

105D-1). CR is about 5 to 10 times more potent than CS and is effective at concentrations as low as 1 mg/m3.4,6 The lethal dose in humans is thought to be 2 times that of CS and more than 10 times that of CN.3,4,6 CR is more stable than CN or CS because of a lower water solubility and vapor pressure.6 CR is, thus, much more persistent in the environment than the other lacrimators.3,4,6 CR is commonly deployed as a liquid but can also be aerosolized. Because CR is usually delivered in solution, its effects tend to be localized to the skin and eyes. Pulmonary effects are rare owing to its low vapor pressure. Compared with other lacrimators, skin and eye effects are not as persistent following CR exposure. Based on animal studies, CR appears to be less toxic than CN or CS, but few data exist to support or refute these observations in humans.3

CAPSAICIN

CS was first produced in 1928 by Corson and Stoughton (hence the designation CS).4,6 Because it is more effective and less toxic than CN (see Table 105D-1), CS became the standard riot control agent used by military and law enforcement agencies in 1959.4 CS is still the riot control agent most commonly used worldwide today.4,6 Chemically, CS is a variant of an older, previously used irritant, bromobenzyl cyanide. It is a stable gas with a pepper-like odor.10 CS exists as a crystalline powder and is dispersed by aerosol blowers, hand-held devices, or bursting thermal grenades.4,7 The chemical formula of CS is CIC6H4CHCCH(CN)2.4,6 Vaporization of CS can be achieved by igniting a mixture of the powder with a fuel substance, producing clouds of white smoke containing CS vapor.10 When detonated in the open, a CS grenade can produce a cloud 6 to 9 M in diameter. The concentration of CS at the center of the cloud can range from 2000 to 5000 mg/m3, rapidly declining at the periphery.2 Detonation in an enclosed space, or multiple-grenadeburst detonation, has the potential for producing much higher concentrations. High-temperature dispersal (>700° C) of CS has been shown to release small amounts of hydrogen cyanide and hydrochloric acid as air contaminants.11 The clinical effects of this are unknown. CS is rapidly hydrolyzed in water and even more rapidly in aqueous alkaline solutions.6 Unlike CN, CS is readily inactivated in soap and water.4,6 The U.S. military has developed hydrophobic, microencapsulated formulations of CS (CS1 and CS2) that are resistant to water degradation.4 These formulations have not been used by civilian authorities because of their environmental persistence.

Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is the active ingredient largely responsible for the irritating and pungent effects of the fruits of the various species of Capsicum. These include the Mexican chile pepper and the Hungarian red pepper.12 The potent topical irritant effects of capsaicin have made its use as a personal protection and immobilizing device appealing for both law enforcement agencies and the civilian population. Repeated topical capsaicin application has been used for cutaneous counterirritant effects in chronic pain and inflammatory conditions. In 1993, more than 6 million “pepper gas” spray units were sold in the United States alone.13 When used as a harassing agent, capsaicin is used as a spray at close quarters. When used correctly, capsaicin can result in transient, severe skin and mucous membrane irritation, incapacitating an assailant rapidly. Improper use has resulted in significant morbidity in a small number of reported cases. News reports in the lay press have raised the issue of deaths in custody temporally related to the use of capsaicin sprays. Extensive testing by the Federal Bureau of Investigation in the 1980s found no evidence of toxic problems with capsaicin use.14 No firm scientific data currently substantiate any casual relationship between these deaths and capsaicin exposure. In these situations, victims are often in an agitated state requiring restraint, which may be implemented in a way that unintentionally produces postural asphyxia.14 Victims are often under the influence of alcohol and drugs of abuse, which may increase aggression, mask occult trauma, and delay recognition of medical problems. In the absence of any definite link between capsaicin exposure and sudden death, law enforcement agencies currently continue to use capsaicin as a harassing agent.

DIBENZOXAZEPINE

EXPOSURE SCENARIOS

CR was first synthesized in 1962.4 It is the most potent and least toxic lacrimator currently used4,6 (see Table

Riot control agents are generally dispersed as liquid or solid aerosols.4,6 The circumstances of an exposure (i.e.,

CHLORBENZYLIDENE MALONITRILE

CHAPTER 105

intended target and purpose) dictate the specific method of riot control agent delivery. Irritant smoke can be produced by combining the agent (CN or CS) with a pyrotechnic mixture containing chlorate and lactose. The igniter vaporizes the irritant, which then condenses into a cloud of solid or liquid particles 1 to 2 μm in diameter that can be easily inhaled.7 This method is best used in the control of large-scale riots. CS also exists as a micropulverized powder that can be dispersed by mechanical force, using a vehicle- or aircraft-mounted “smoke” generator, or from a hand-held tank using carbon dioxide as a propellant.7 This method does not require the use of a thermal agent to volatilize the irritant. Most lacrimators have low water solubility, which necessitates their dissolution in a hydrocarbon organic solvent when used in pressurized, hand-held, delivery devices.6 For instance, Mace is a 1% solution of CN in a solvent mixture containing kerosene, 1,1,1-trichloroethane, and Freon 113.6 The United Kingdom police personnel carry hand-held CS spray devices that contain 5% CS in a methyl isobutyl ketone solvent.6 Pepper spray devices contain tetrachloroethylene, Freon, or isopropyl alcohol as the hydrocarbon vehicle.6 These organic solvent mixtures are irritants themselves and will potentiate lacrimator toxicity.3,6 CN and CS can also be delivered by a thermal grenade or a cartridge fired from a gun. Grenades are often launched into confined spaces by law enforcement agencies to incapacitate criminals in siege situations. Thermal grenades may produce fires.7 There is a risk for mechanical trauma and burns to victims hit by projectiles or in close proximity to exploding grenades.15,16 In general, CS and CN used as a particulate smoke tend to affect the eyes and respiratory tract to a greater degree than the skin. Aerosols and liquid sprays are likely to produce more marked effects on the skin and eyes with less effect on the respiratory tract.

PATHOPHYSIOLOGY OF INJURY The mechanism of tissue injury from CN and CS is not fully elucidated but likely results from alkylation of key tissue enzymes and direct reactivity of their respective chloride moiety with mucosal tissue.6 Both CN and CS are SN2 alkylating agents and likely produce tissue toxicity after binding and inhibiting key sulfhydrylcontaining enzymes (e.g., lactic dehydrogenase and thioctic acid of the pyruvate decarboxylase complex).6 Alkylation of cellular proteins also increases the potential for mutagenesis.3 In addition, CS exposure has been shown to result in the production of bradykinin locally, which could produce tissue edema and inflammatory injury.3,17 Animal studies and postmortem human data have demonstrated intra-alveolar hemorrhage, pulmonary exudation of protein and polymorphonuclear cells, and tissue necrosis after exposure to high concentrations of CN.8,9 This is followed by suppressed phagocytic capability of immunocompetent cells. Increased susceptibility to infection is a potential consideration after large or repeated exposures to CN.18,19 The actual

Chemical Weapons

1513

risk for infection to humans after massive exposures to CN or other lacrimators is unknown. Additionally, little is known about the risk for chronic pulmonary toxicity, genotoxicity, or reproductive toxicologic effects associated with CN and CS exposure. When animals are given lethal doses of CS by parenteral injection, CS is metabolized to cyanide, as evidenced by elevated levels of blood thiocyanate within hours.6 Inhalation and cutaneous exposures, however, do not produce significant amounts of free cyanide in plasma because systemic absorption of CS by these routes is extremely small.3,6 Thus, victims of CS poisoning do not need treatment for cyanide toxicity.6 The mechanism of action of capsaicin on cutaneous nerve endings has been extensively studied. Application of capsaicin to the skin or mucous membranes results in widespread excitation of cutaneous C-fiber polymodal nociceptor afferent nerve terminals. Capsaicin achieves this by nonspecifically opening nerve fiber sodium, calcium, and potassium channels and releasing substance P from nerve endings.20 This produces an intense sensation of burning pain and marked hyperalgesia to skin heating and pressure. Symptoms may be exacerbated by the presence of sweat or the application of cold water. Hyperalgesia may persist for as long as 24 hours. Cutaneous vasodilation is also seen at the site of application and the surrounding skin through an axon flare reflex.20

MANIFESTATIONS All lacrimators produce near-immediate stinging and burning of the skin and mucosal surfaces, lacrimation, blepharospasm, salivation, and rhinorrhea.4,6,7,21 Inhalation produces a sensation of chest constriction with dyspnea, gagging, and burning of the respiratory tract.4,6,22 The dermal irritant effects of all agents are enhanced in the presence of moisture or sweat on the skin. Hot, humid weather can produce a similar augmentation of irritant effects.4,10 Sensitivity to tear gas is individual and age dependent.6 Children appear to be more susceptible to the toxic effects.6 In most instances, the effects of tear agents are transient and dissipate within 30 minutes of removal from the source of exposure.23 More prolonged effects may be seen with higher-concentration, enclosedspace exposures. In addition, ocular effects may be prolonged. Conjunctivitis and blurred vision may persist for as long as 24 hours after exposure.22 The eye is the most sensitive organ to tear gas agents.3,4,6 The threshold value for eye irritation is as low as 0.002 mg/m3 for CR3,4,6 (see Table 105D-1). An effective aerosol concentration of 5 mg/m3 results in severe burning of the eyes, with lacrimation, blepharospasm, and conjunctival injection. Ocular injuries include mild conjunctival irritation, corneal and periorbital edema, focal corneal epithelial injury, iridocyclitis, and necrotizing, coagulative keratoconjunctivitis.4,6,24 Permanent corneal damage has occurred from CN particles becoming embedded on the cornea, particularly after exposure to aerosolized particulates.25 Epithelial recovery of the

1514


cornea may take months, leaving permanent corneal opacities and visual loss.26 Direct spraying of CN, capsaicin, and similar agents onto the face from highpressure aerosols has the potential to produce barotrauma to the eyes. Cutaneous injury from tear agents is more likely to occur with aerosol or liquid spray exposures; prolonged, concentrated exposures; direct contact of an agent to skin or exposure through wet clothing; or exposure to skin that is thin, moist, abraded, or has preexisting disease.4,6 Skin effects include simple stinging and burning, erythema, vesication, and allergic dermatitis. For instance, CN exposure has resulted in cutaneous allergic reactions and dermatitis, skin burns, and bullous eruptions from prolonged exposure or direct spraying of CN onto the skin.27,28 Generalized papulovesicular rashes responding to treatment with systemic steroid therapy have also been reported.28 Despite initial enthusiasm for the use of CS as a less toxic alternative to CN, reports of significant toxicity of CS have appeared in the medical literature. Severe reactions to CS have resulted from its direct spraying onto cutaneous surfaces. Vesicular dermatitis with blistering, crusting, and marked facial swelling has developed from 12 hours to 3 days after either single or repeated exposures to CS.29 Allergic contact dermatitis has been documented in cases of recurrent exposure to CS, with allergy subsequently confirmed by patch testing.29 Skin discomfort may recur up to 48 hours after CR exposure when exposed skin contacts water.30,31 Cutaneous application of capsaicin over days to weeks can result in habituation to its irritant effects and hypalgesia of the skin.20 In contrast, severe dermatitis, labeled Hunan hand syndrome, may result after skin exposure to capsaicin. This is particularly common in people who handle chile peppers with bare hands, resulting in severe pain and erythema of exposed surfaces.32,33 Relief from symptoms may be difficult to achieve. Respiratory effects from lacrimators include nasal irritation, rhinorrhea, sneezing, mouth burning, sore throat, cough, chest tightness, and bronchorrhea. Effects typically resolve within 30 minutes for most exposures.4,6 Tidal volume and minute ventilation have been observed to decrease with experimental exposure to CS.34 The reasons for this are uncertain. Inhalation of capsaicin by asthmatic and nonasthmatic volunteers resulted in coughing and transient increases in airway resistance. This is postulated to be due to stimulation of airway sensory nerves. High-concentration, enclosed-space exposures to lacrimators have resulted in acute laryngotracheobronchitis, pulmonary edema, and death.6 Pulmonary edema is delayed in onset, occurring 6 to 8 hours after exposure.35 Death is extremely rare but has occurred from pulmonary edema 12 hours after exposure to CN.8,36 Severe respiratory distress and bronchopneumonia were identified in a 4-month-old infant after exposure to CS for 2 to 3 hours in an enclosed space.37,38 Respiratory symptoms may persist for days to weeks after exposure and include cough, dyspnea, hemoptysis, and wheezing.2,39 Reactive airways dysfunction has been described after exposure to CS and CR.6,40,41 Permanent lung damage is

unlikely to occur from lacrimator exposure; long-term effects typically resolve by 12 weeks after exposure.6 Respiratory symptoms and signs are uncommon after exposure to capsaicin; effects are likely related to direct exposure of the respiratory tract to capsaicin. Laryngeal edema, stridor, and pulmonary edema requiring endotracheal intubation were observed in an 11-year-old boy 4 hours after the intentional inhalation of several sprays of a capsaicin in a hydrofluorocarbon vehicle. His clinical condition improved over 24 hours.42 A 4-week-old infant accidentally sprayed in the face with a 5% capsaicin aerosol developed respiratory failure and pulmonary edema, requiring extracorporeal membrane oxygenation.42 It is difficult to ascertain the degree of influence that inhaled capsaicin had in the evolution of pulmonary injury in both cases. Exposure to high concentrations of hydrocarbon propellant may have also had a role in the development of lung injury.42 Nausea and vomiting may result from swallowing saliva that contains CS. Oral ingestion of CS has resulted in oropharyngeal irritation and pain, nausea, vomiting, abdominal cramping, and diarrhea.4,6,43 Increases in pulse and blood pressure often occur immediately after tear agent exposure. These cardiovascular responses are transient and are secondary to the anxiety and pain of exposure rather than the direct effects of tear agents.6 The risk for congenital anomalies, stillbirth, and spontaneous abortion was not increased in areas of heavy tear gas use in Londonderry during the late 1960s.44 However, cytotoxic and mutagenic activity has been observed in mammalian cells in culture exposed to CS.45 Animal studies have been unable to conclusively prove any carcinogenic or teratogenic effects after exposure to CR or CS tear gas.46

ASSESSMENT The diagnosis of tear agent exposure is based on a suggestive history and physical findings. The acute onset of irritant effects to the eyes, nose, and respiratory tract in one or more patients following an airborne chemical exposure suggests tear agent toxicity. Similar effects may occur after exposure to other irritant or corrosive gases (i.e., choking agents, ammonia), allergic reactions, and exacerbations of asthma or chronic obstructive disease. The history should include details of the exposure (time, duration, nature), associated trauma, treatment before arrival, and symptoms and past medical history of the victim. Of particular importance is whether the exposure occurred in an enclosed space or out in the open. The physical examination should focus on the patency of the airway and adequacy of respirations, vital signs, mental status, and ocular and skin findings. Patients with eye symptoms should have fluorescein and slit-lamp examination to determine the presence of corneal injury. Patients with respiratory symptoms must be reevaluated frequently. Although lacrimators may be identified by gas chromatography/mass spectrometry and other techniques,6 laboratory identification of lacrimators is not possible or necessary at most hospitals.

CHAPTER 105

TREATMENT Most victims exposed to lacrimators develop transient symptoms and signs of skin and mucosal irritation that usually subside within 15 to 30 minutes of removal from the source of the exposure.4,6 Thus, medical treatment is often unnecessary. Treatment of victims after more significant exposure is supportive. The first priorities of treatment are health care provider self-protection and patient decontamination to reduce ongoing irritation. Health care personnel should protect themselves with gloves, gowns, and eyewear. Victims should be treated in a well-ventilated area to prevent atmospheric accumulation of the tearing agent. Contaminated clothing should be removed and discarded in plastic bags. Exposed skin areas should be washed with copious amounts of warm water and soap. Attempted orotracheal intubation of patients exposed to CS has resulted in severe blepharospasm and lacrimation in anesthesiologists performing the procedure owing to oropharyngeal contamination with tear gas.47 This situation may result in difficulty or delay in airway control in a patient with otherwise normal airway anatomy. The eyes should be irrigated for at least 30 minutes with normal saline in symptomatic patients. This should be followed by ophthalmologic assessment for ocular injury, including fluorescein and slit-lamp examination for corneal ulceration and abrasion. Particulate matter should be removed carefully with a cotton swab. Treatment with topical antibiotics, cycloplegics, and oral analgesics should be provided as necessary. Persisting symptoms and signs require formal ophthalmologic follow-up. Skin erythema alone does not usually require any treatment and usually diminishes within 24 hours. Severely affected skin areas that are denuded and oozing may be treated with wet compresses containing avena (colloidal oatmeal) or aluminum acetate (Burow solution).4,6 Contact dermatitis due to CN or CS has responded to topical or systemic corticosteroid therapy and antipruritics.4,27,48 Immersion of the hands in vinegar has been successful in providing relief if applied within 30 minutes of exposure to capsaicin.49 Topical lidocaine gel has also been successful in relief of irritation.32 Prolonged immersion of hands in vegetable oil after exposure to chile slurry has also been found to provide better long-term relief from the pain of Hunan hand than bathing in cool tap water.50 Milk compresses and topical antacid suspensions have also been suggested as effective analgesics measures for the relief of capsaicin-induced dermal irritation.51,52 Respiratory symptoms due to CN or CS exposure are usually transient and should disappear within 15 to 30 minutes of removal from the exposure environment. Factors that may increase the risk for persisting pulmonary symptoms and development of pulmonary edema include prolonged exposure to CN or CS in an enclosed space, direct inhalation of capsaicin into the respiratory tract, or a history of asthma or other chronic lung disease. Humidified oxygen should be provided as necessary. Bronchospasm may respond to inhaled β-adrenergic agonists and oral or parenteral corticos-

Chemical Weapons

1515

teroids. Patients with persistent symptoms or signs of respiratory distress may be at risk for delayed pulmonary edema and require observation for 12 to 24 hours. Standard supportive measures and ventilatory support are indicated for pulmonary edema. Extracorporeal membrane oxygenation has been successfully used to support an infant with pulmonary edema after exposure to capsaicin aerosol.42 Because reactive airways dysfunction may be a long-term consequence of patients presenting with significant acute respiratory symptoms, pulmonary specialist follow-up may be necessary for severely affected patients. Finally, attention should also be paid to the potential for physical injury and burns to victims of harassing agents. Injury may be masked by the presence of alcohol or other drugs of abuse. Trauma may be due to the violent situations in which the individuals were involved or may be a direct consequence of ballistic trauma due to the projectiles used to propel harassing agents.

MANAGEMENT OF MASS CASUALTIES Similar to other airborne toxicants, tear gas release can create a multiple-casualty incident. The priorities in management of mass casualties from tear gas include immediate removal of all victims from the source of exposure, decontamination of symptomatic patients, and the provision of supportive care as indicated. Fortunately, less than 1% of exposed patients require medical care because of the mild and transient nature of their symptoms.6 In ideal situations, prehospital, hazardous material (Hazmat) personnel provide on-scene triage, initial patient assessment, decontamination, and symptomatic treatment. Hazmat personnel only transport patients with significant or persistent effects. In circumstances in which prehospital care does not occur and multiple victims present unannounced to the hospital, symptomatic care and patient decontamination (e.g., clothing removal, eye and skin irrigation) should be delivered in a predetermined, segregated area of the emergency department (see Chapter 103). Activation of a hospital’s internal disaster plan is unlikely necessary for multiple casualties from a tear gas incident but will depend on the number and experience of hospital personnel, the number of victims, and the severity of their illness.

PRINCIPLES OF PREPAREDNESS Preparation for casualties from tear gas exposure does not require any specialized equipment that would not already be present in most emergency departments (see Chapter 103). The presence of a decontamination area that is segregated from the rest of the emergency department and can treat multiple victims simultaneously is ideal. It is recommended that you be familiar with the treatment of chemical casualties and the principles of advanced Hazmat life support in order to optimize patient care.

1516


REFERENCES 1. Fraunfelder FT: Is CS gas dangerous? Current evidence suggests not but unanswered questions remain. BMJ 2000;320:458–459. 2. Hu H, Fine J, Epstein P, et al: Tear gas—harassing agent or toxic chemical weapon? JAMA 1989;262:660–663. 3. Beswick FW: Chemical agents used in riot control and warfare. Hum Toxicol 1983;2:247–256. 4. Sidell FR: Riot control agents. In Sidell FR, Takafuji ET, Frank DR (eds): Textbook of Military Medicine. I. Warfare, Weaponry, and the Casualty: Medical Aspects of Chemical and Biological Warfare. Washington DC, Office of the Surgeon General, 1997, pp 307–324. 5. Sanford JP: Medical aspects of riot control (harassing agents). Annu Rev Med 1976;27:421–429. 6. Blain PG: Tear gases and irritant incapacitants: 1-chloroacetophenone, 2-chlorobenzylidene malonitrile and dibenz[B,F]-1,4oxazepine. Toxicol Rev 2003;22(2):103–110. 7. Compton AF: Chloracetophenone (CN). In Compton AF (ed): Military Chemical and Biological Agents—Chemical and Toxicological Properties. Caldwell, NJ, Telford Press, 1987. 8. Stein AA, Kirwan WE: Chloroacetophenone (tear gas) poisoning: a clinicopathologic report. J Forensic Sci 1964;9:374–382. 9. Chapman AJ, White C: Death resulting from lacrimatory agents. J Forensic Sci 1978;23:527–530. 10. Danto BL: Medical problems and criteria regarding the use of tear gas by police. Am J Forensic Med Pathol 1987;8:317–322. 11. Kluchinsky TA Jr, Savage PB, Fitz R, Smith PA et al: Liberation of hydrogen cyanide and hydrogen chloride during high-temperature dispersion of CS riot control agent. AIHA J 2002;63:493–496. 12. Virus RM, Gebhart GF: Pharmacologic actions of capsaicin: apparent involvement of substance P and serotonin. Life Sci 1979;25:1273–1283. 13. Wily J, Balmier D, Farina P: Severe pulmonary injury in an infant after pepper gas self defence spray exposure [abstract]. J Toxicol Clin Toxicol 1995;33:519. 14. Krolikowski FJ: Oleo capsicum (O.C.): the need for careful evaluation. Am J Forensic Med Pathol 1994;15:267. 15. Zekri AM, King WW, Yeung R, Taylor WR: Acute mass burns caused by O-chlorobenzylidene malononitrile (CS) tear gas. Burns 1995;21:586–589. 16. Clarot F, Vaz E, Papin F, et al: Lethal head injury due to tear-gas cartridge gunshots. Forensic Sci Int 2003;137:45–51. 17. Cucinell SA, Swentzel KC, Biskup R, et al: Biochemical interactions and metabolic fate of riot control agents. Fed Proc 1971;30:86–91. 18. Kumar P, Flora SJ, Pant SC, et al: Toxicological evaluation of 1chloroacetophenone and dibenz[b,f]-1,4-oxazepine after repeated inhalation exposure in mice. J Appl Toxicol. 1994;14:411–416. 19. Kumar P, Vijayaraghavan R, Pant SC, et al: Effect of inhaled aerosol of 1-chloroacetophenone (CN) and Dibenz (b,f)-1,4 oxazepine (CR) on lung mechanics and pulmonary surfactants in rats. Hum Exp Toxicol. 1995;14:404–409. 20. Lynn B: Capsaicin: actions on nociceptive C-fibres and therapeutic potential. Pain 1990;41:61–69. 21. Tominack RL, Spyker DA: Capsicum and capsaicin—a review: case report of the use of hot peppers in child abuse. J Toxicol Clin Toxicol 1987;25:591–601. 22. Punte CL, Gutentag PJ, Owens EJ: Inhalation studies with chloracetophenone, diphenylaminochlorasine and pelargonic morpholide. Eleven human exposures. Am Ind Hyg Assoc J 1962;23:199–202. 23. Holland P, White RG: The cutaneous reactions produced by Ochlorobenzyl-idenemalononitrile and -chloroacetophenone when applied directly to the skin of human subjects. Br J Dermatol 1972;86:150–154. 24. Vesaluoma M, Muller L, Gallar J, et al: Effects of oleoresin capsicum pepper spray on human corneal morphology and sensitivity. Invest Ophthalmol Vis Sci 2000;41:2138–2147. 25. Gaskins JR, Hehir RM, McCaulley DF, Ligon EW Jr : Lacrimating agents (CS and CN) in rats and rabbits. Acute effects on mouth, eyes, and skin. Arch Environ Health 1972;24:449–454. 26. Liss G: Reaction to Mace. J Am Intraocul Implant Soc 1982;8:371.

27. Treudler R, Tebbe B, Blume-Peytavi U, et al: Occupational contact dermatitis due to 2-chloracetophenone tear gas. Br J Dermatol 1999;140:531–534. 28. Thorburn KM: Injuries after use of the lacrimatory agent chloroacetophenone in a confined space. Arch Environ Health 1982;37:182–186. 29. Ro YS, Lee CW: Tear gas dermatitis. Allergic contact sensitization due to CS. Int J Dermatol 1991;30:576–577. 30. Holland P: The cutaneous reactions produced by dibenzooxazepine (CR). Br J Dermatol 1974;90:657–659. 31. Ballantyne B, Gazzard MF, Swanston DW, Williams P: The comparative ophthalmic toxicology of 1-chloroacetophenone (CN) and dibenz(b.f)-1:4-oxazepine(CR). Arch Toxicol 1975;34:183–201. 32. Williams SR, Clark RF, Dunford JV: Contact dermatitis associated with capsaicin: Hunan hand syndrome. Ann Emerg Med 1995;25:713–715. 33. Weinberg RB: Hunan hand. N Engl J Med 1981;305:1020. 34. Cole TJ, Cotes JE, Johnson GR: Ventilation, cardiac frequency and pattern of breathing during exercise in men exposed to Ochlorbenzylidene malonitrile (CS) and ammonia gas in low concentrations. Q J Exp Physiol 1977;62:341–351. 35. Vaca FE, Myers JH, Langdorf M: Delayed pulmonary edema and bronchospasm after accidental lacrimator exposure. Am J Emerg Med 1996;14:402–405. 36. Thomas RJ, Smith PA, Rascona DA, et al. Acute pulmonary effects from o-chlorobenzylidenemalonitrile “tear gas”: a unique exposure outcome unmasked by strenuous exercise after a military training event. Mil Med 2002;167:136–139. 37. Park S, Giammona ST: Toxic effects of tear gas on an infant following prolonged exposure. Am J Dis Child 1972;123:245–246. 38. Fuller RW: Pharmacology of inhaled capsaicin in humans. Respir Med 1991;85(Suppl A):31–34. 39. Hill AR, Silverberg NB, Mayorga D, Baldwin HE: Medical hazards of the tear gas CS. A case of persistent, multisystem, hypersensitivity reaction and review of the literature. Medicine 2000; 79:234–240. 40. Hu H, Christiani D: Reactive airways dysfunction after exposure to tear gas. Lancet 1992;339:1535. 41. Roth VS, Franzblau A: RADS after exposure to a riot-control agent: a case report. J Occup Environ Med 1996;38:863–865. 42. Winograd HL: Acute croup in an older child: an unusual toxic origin. Clin Pediatr 1977;16:884–887. 43. Solomon I, Kochba I, Eizenkraft E, MaharshakN: Report of accidental CS ingestion among seven patients in central Israel and review of the current literature. Arch Toxicol 2003;77:601–604. 44. Himsworth H: Report of the enquiry into the medical and toxicological aspects of CS (orthochlorbenzylidene malonitrile). II. Enquiry into toxicological aspects of CS and its use for civil purposes. London, Her Majesty’s Stationary Office, 1971. 45. Ziegler-Skylakakis K, Summer KH, Andrae U: Mutagenicity and cytotoxicity of 2-chlorobenzylidene malonitrile (CS) and metabolites in V79 Chinese hamster cells. Arch Toxicol 1989;63:314–319. 46. Anonymous: NTP toxicology and carcinogenesis studies of 2chloroacetophenone (CAS No. 532-27-4) in F344/N rats and B6C3F1 mice (inhalation studies). Natl Toxicol Program Tech Rep Ser 1990;379:1–191. 47. Bhattacharya ST, Hayward AW: CS gas—implications for the anaesthetist. Anaesthesia 1993;48:896–897. 48. Parneix-Spake A, Theisen A, Roujeau JC, Revuz J: Severe cutaneous reactions to self-defense sprays. Arch Dermatol 1993;129:913. 49. Vogl TP: Treatment of Hunan hand. N Engl J Med 1982;306:178. 50. Jones LA, Tandberg D, Troutman WG: Household treatment for “Chile burns” of the hands. J Toxicol Clin Toxicol 1987;25:483–491. 51. Herman LM, Kindschu MW, Shallash AJ: Treatment of Mace dermatitis with topical antacid suspension. Am J Emerg Med 1998;16:613–614. 52. Anderson W: Relief of capsaicin contact dermatitis. Ann Emerg Med 1995;26:659–660.

CHAPTER 105

E

■

1517

Central Nervous System Disabling Agents JEFFREY R. SUCHARD, MD

At a Glance… ■

Chemical Weapons

3-Quinuclidinyl benzilate (BZ, QNB) or similar agents may disable by producing antimuscarinic effects, including visual impairment, ataxia, and delirium. Treatment consists of supportive care and the judicious use of restraints, sedation, and/or anticholinesterase agents (e.g., physostigmine) to reverse central antimuscarinic toxicity. Ultrapotent opioids (fentanyl derivatives) may be used as incapacitating agents, producing an opioid toxidrome with depressed mental status and respiratory drive. Treatment consists of airway management and opiate-receptor antagonists (e.g., naloxone).

RELEVANT HISTORY Central nervous system (CNS) disabling or incapacitating agents are nonlethal compounds intended to temporarily disrupt an enemy’s ability to fight. For over 2000 years, military planners have occasionally used chemical agents to alter the mental status of and temporarily incapacitate their enemy rather than cause death or permanent physical injury. In an era before aerosol dissemination of chemical agents was technically feasible, food or water contamination was the primary method used to disable the enemy; belladonna alkaloids were frequently used for this purpose. As early as 200 BCE, the Carthaginian officer Maharbal mixed wine with the antimuscarinic agent “mandragora” and then abandoned camp during a feigned retreat. Rebellious African forces discovered and drank the drugged wine and subsequently were easily taken prisoner or slaughtered when they fell into a stupor.1 According to the U.S. military, the ideal CNS disabling agent should be potent, effective, persistent, logistically feasible, predictable, treatable, unlikely to produce permanent injuries or death when used as intended (high therapeutic index), and affordable.2 From 1953 to 1973, the U.S. Army investigated many methods of incapacitation to find one suitable for standardization.1 Nonchemical agents, such as noise, high-intensity photostimulation, microwaves, and olfactory assault, generally proved impractical, potentially physically damaging, or too easy to thwart with routine respiratory protective measures. Although several types of chemical and biowarfare (CBW) agents (e.g., lacrimators, vomiting agents, staphylococcal enterotoxin B, mild exposures to nerve agents or vesicants) were considered for use as incapacitants by the U.S. military, the psychochemical agents—chemicals that disable by producing behavioral or direct CNS effects—were considered most suitable for study and investment. The psychochemical agents were classified into four general categories: stimulants, depressants, psychedelics,

and deliriants. The stimulants included amphetamines, cocaine, caffeine, nicotine, strychnine, and metrazole. None of the stimulants proved effective as airborne incapacitating agents. In addition, it was feared that stimulants could enhance performance rather than hinder it following low- to moderate-dose exposures. CNS depressant agents were either insufficiently potent or had a relatively narrow therapeutic index (TI; median lethal dose ÷ lowest median effective dose), with lethal doses in the range of 10 to 20 times the effective incapacitating dose. From 1959 to 1965, D-lysergic acid diethylamide (LSD) was the primary psychedelic agent studied by the U.S. military. LSD had an inhaled ID50 (the dose incapacitating 50% of those exposed) of only 5.6 μg/kg, but results were unpredictable, with exposed victims still occasionally capable of effective volitional activities. The deliriants, anticholinergic drugs with prominent CNS effects, were considered most suitable for use as military incapacitating agents. Of the deliriants, 3quinuclidinyl benzilate (U.S. military designation BZ) was considered the most ideal for use as a CNS disabling agent.1 BZ is stable when delivered by a thermal munition, environmentally persistent, and more potent than a variety of widely recognized anticholinergic agents (e.g., atropine and scopolamine).1 The U.S. military weaponized and stockpiled BZ as its only incapacitating agent in the 1960s. These stockpiles were subsequently destroyed. The drug, however, is still used in medical pharmacology research as a muscarinic receptor antagonist; it is designated QNB for such purposes. Modern use of CNS disabling agents in warfare has been reported, but the veracity of such reports is not clear. In 1995, during the Balkan wars, Serbian military forces allegedly used BZ against civilians, who reported hallucinations associated with attacks by artillery shells that emitted smoke. Although BZ exposure has not been completely excluded, the hallucinations could be ascribed to exhaustion and other physical and psychological stressors.3,4 In contrast, the modern use of nonlethal agents as weapons against terrorists is well documented. In October 2002, the Russian Federal Security Service used CNS disabling agents to end a standoff with terrorists in a Moscow theater. Chechen rebels held more than 800 hostages and threatened to detonate explosives unless their political demands were met. After a 3-day siege, “gas” was introduced into the theater’s ventilation system and quickly subdued both the terrorists and their hostages. More than 650 of the hostages were hospitalized, and 128 died; all but five apparently died of the effects of the “gas.”5 The identity of the agent used was not at first disclosed. Early reports suggested the use of BZ,6 but the clinical findings and time course of

1518


symptom onset were not consistent. Traces of halothane, however, were detected in two of the victims that were transported to Germany.7,8 Several days after the incident, the Russian Health Minister stated that the agent used was a derivative of fentanyl,7,9 which was not expected to cause fatalities Although expert opinion is not uniform, current consensus holds that the “knockout gas” was composed of an ultrapotent opioid aerosol (possibly carfentanil9 or remifentanil10) probably along with halothane. The relatively high case fatality rate could be due to multiple factors, including variability in dose, displacement of oxygen by rapid introduction of gas into the building, failure to adequately notify health care teams and supply them with antidotes, and poor physical condition of the hostages due to limited food and water and to immobility during their captivity. This use of an incapacitant by the Russian military as an antiterrorist agent has rejuvenated U.S. military interest in developing an effective nonlethal chemical weapon.9

EXPOSURE SCENARIOS Like most chemical and biological agents, CNS disabling agents would be most effective if disseminated as an aerosol, vapor, or gas. Incapacitating agents could be delivered outdoors as an aerosol from low-flying aircraft (e.g., crop dusters), vehicle-mounted or hand-held spray devices, or detonation of artillery, missiles, or bombs. If the agent is used outdoors, low-wind conditions would be preferable, to minimize rapid dissipation. The Moscow theater siege illustrates the prototypical exposure environment for effective delivery of CNS disabling agents: an enclosed space, which allows for near-simultaneous respiratory exposure to all building occupants (particularly if a ventilation system is available for agent delivery). An enclosed space allows for more accurate estimation of the appropriate dose of incapacitant to achieve rapid tranquilization of multiple persons while minimizing permanent harm. The Moscow siege also illustrates the grim reality that incapacitating agents can have unpredictable and lethal effects, even when conditions a priori are presumed to be ideal. Because the general tactical goals of war are to kill combatants and destroy material goods, conventional weapons or physically injurious chemical or biological agents would have more utility. CNS disabling agents, however, could be used in operations in which casualties were to be minimized or avoided, such as capture scenarios or when civilians are present. Terrorist use of CNS disabling agents seems less probable because conventional weapons or other chemical agents would be easier to procure and because the diminished likelihood of casualties would lessen the imperative to respond to threats.

PATHOPHYSIOLOGY OF INJURY The CNS disabling agents discussed do not possess unique pathophysiology. Like other anticholinergic agents, 3-

quinuclidinyl benzilate is a potent competitive antagonist of both peripheral and central muscarinic receptors (see Chapter 39). A detailed review of opiate pathophysiology is found in Chapter 33 and of LSD in Chapter 45. The features distinguishing the CNS disabling agents from other members of their respective classes relate mostly to potency and time course of effects.

MANIFESTATIONS BZ produces clinical effects similar to those of atropine, although it is more potent. The ID50 for BZ is 6.2 μg/kg (approximately 0.5 mg for adults), whereas the ID50 for atropine is 140 μg/kg (8 to 14 mg). Mild cognitive impairment is seen in 50% of individuals with BZ doses of approximately 2.5 μg/kg.1 BZ has a slower onset and longer duration of action than atropine does. The effects of BZ are barely measurable 1 hour after exposure to the ID50 dose. Central effects are seen after about 4 hours, peak at 8 to 10 hours, and then gradually subside over 24 to 72 hours. The duration of incapacitation from an ID50 dose is roughly 24 hours.1,2 Doubling the dose increases the rate of onset of effects and produces incapacitation within 1 hour of exposure but also prolongs recovery an additional 48 hours.1 In actual use, wide variation in dosing among exposed individuals is expected, with consequent variability in symptom onset and offset. It is estimated that the human ID50 is approximately 40-fold lower than the lethal dose (therapeutic index of 40).1 Although toxicity from BZ is most likely to occur after inhalation of vapor or liquid aerosol, symptoms may also result from intravenous or intramuscular injection or, to a small degree, from skin contact with liquid. Effects may be delayed up to 24 hours after dermal absorption. The clinical signs and symptoms of BZ exposure are the typical antimuscarinic effects. Peripheral signs include tachycardia, mydriasis, and dry skin and mucous membranes. Mild exposures cause drowsiness, lapses of attention, and difficulty in following complex instructions. Moderate exposures (≈ 4 μg/kg) cause somnolence or stupor, mumbling speech, ataxia, slowing of thought processes, and confusion. Higher exposures cause full delirium with staring, muttering, and hallucinations, with fluctuating lucid intervals.1 Bizarre behaviors are often seen among individuals with antimuscarinic delirium, including undressing, crawling or climbing motions, and plucking or picking at the air or garments (carphology or “woolgathering”). As mentioned above, depressant psychochemical agents were found by the U.S. military either to be insufficiently potent or to have relatively narrow therapeutic indices, where lethal doses exceeded incapacitating doses by factors of only 10 to 20. In actual use, when precise dose control is not possible, unintentional lethal dosing would not be unexpected. A recent review by Wax et al, however, illustrates that some ultrapotent fentanyl derivatives have very high therapeutic indices and might therefore be considered as potential CNS disabling

CHAPTER 105

agents when aerosolized.9 Morphine has a therapeutic index of 70. Fentanyl is roughly 300 times as potent as morphine and has a TI of 300, sufentanil is 4500 times as potent as morphine with a TI of 25,000, remifentanil is 220 times as potent as morphine with a TI of 33,000, and carfentanil is 10,000 times as potent as morphine with a TI of 10,600. Such figures, however, are usually based on animal data, often from a single animal species, and do not necessarily apply to humans.9 Even if such agents were found to have remarkable safety margins in controlled settings, the doses required to induce rapid unconsciousness could also cause significant respiratory depression or apnea. With appropriate supportive care, such doses might be safe. Hypoxic brain injury might result, however, if exposed persons do not rapidly receive assisted ventilation or antidotal therapy; this is the likely reason for the “gas” fatalities in the Moscow theater incident. The aerosolized doses necessary to incapacitate humans and rate of onset and duration of clinical effects has not yet been elucidated. The clinical manifestations following opioid aerosolization, however, are similar to those experienced by other routes (see Chapter 33). LSD is a difficult agent to disseminate and consequently is most likely to be used in a clandestine manner, such as food or water contamination.2 An early stage of nausea is commonly seen, followed in 45 to 60 minutes by CNS effects (anxiety, euphoria, delusions, kaleidoscopic imagery, etc) and peripheral signs of sympathetic stimulation (see Chapter 45).

ASSESSMENT The diagnosis of CNS disabling agent toxicity is based on a suggestive history coupled with toxidrome recognition on physical examination. Rapid identification of the chemical agents will not be possible by laboratory tests available at most hospitals. Diagnosis is further supported by the complete reversal of toxic effects following empiric antidotal therapy. Chemical warfare agent poisoning should be suspected when a group of patients have the acute onset of a similar constellation of signs or symptoms. Multiple casualties with altered mental status first require evaluation to rule out the more lethal chemical agents, such as nerve agents or cyanide. The presence of coma, miosis, and respiratory depression could occur with either nerve agents or opioids; the additional presence of seizures, fasciculations, and cholinergic findings suggests nerve agent toxicity. BZ will produce an anticholinergic toxidrome. Unintentional atropine overdose from nerve agent antidote autoinjectors may mimic BZ toxicity; multiple simultaneous atropine casualties may occur if a group believes it has been exposed to nerve agent, although clinical history should easily differentiate these exposures. Intoxication with LSD might be difficult to differentiate from intentional self-exposure to cannabinoids, but the treatment is similar and supportive for both. Anxiety reactions and malingering may mimic any potential CNS-disabling agent exposure, although peripheral signs of toxicity may be blunted or absent.

Chemical Weapons

1519

TREATMENT For most CNS disabling agent casualties, only symptomatic and supportive treatment will be necessary. Victims should be rapidly removed from the exposure environment, and airway support should be provided as necessary. To avoid hyperthermia with BZ intoxication, restrictive clothing should be removed, especially in hot environments. Psychomotor agitation may respond to verbal assurance in mildly affected individuals, while restraints, nonspecific sedation (e.g., with benzodiazepines), or antidotal physostigmine may be indicated for more seriously poisoned patients. Physostigmine, a reversible carbamate acetylcholinesterase inhibitor, has been used safely to reverse antimuscarinic toxicity from BZ exposure.1,2 Intravenous doses of 30 μg/kg (about 2 mg in 70- to 75-kg persons) are effective in reducing peripheral effects, but higher doses (at least 45 μg/kg) are often required to significantly reverse severe central cognitive effects. For unclear reasons, physostigmine appears to be ineffective if given during the first 4 to 6 hours after BZ exposure.1,2 Physostigmine is primarily indicated for the treatment of agitated delirium or to confirm diagnosis (see Chapter 39). Physostigmine has a short duration of action (20 minutes to 2 hours) and may require repeated dosing every 1 to 2 hours for recurrent agitation. Careful patient monitoring is necessary during physostigmine administration to avoid inducing excess cholinergic effects. Patients with suspected opioid agent toxicity may require emergent airway support and administration of an opiate-receptor antagonist (e.g., naloxone; see Chapter 33). Larger than usual doses of naloxone (up to 10 mg) may be needed to completely reverse the toxic effects from potent, synthetic, opioid agents. Data from animal studies suggest that repeated administration of naloxone may be necessary for a period of 2 to 24 hours following fentanyl derivative toxicity.9,11,12 The high lipophilicity of fentanyl derivatives allows for their redistribution from tissues to the CNS, making recrudescent opiate toxicity (e.g., CNS and respiratory depression) a real possibility. The treatment of LSD intoxication is entirely supportive. Because of the possibility of prolonged and recurrent clinical effects, patients exposed to BZ and high-potency opioid derivatives require a prolonged period of hospital observation (12 to 24 hours).

MANAGEMENT OF MASS CASUALTIES With mass casualties from BZ exposure, control and containment of delirious victims is the primary concern. These victims may be capable of injuring themselves or others, so dangerous objects (e.g., weapons, small items that may be swallowed) should be removed.2 Loose restraints or tethers are preferable to allowing victims to roam freely without supervision. Separation of affected individuals into small groups, rather than a single large group, may prevent a crowd control crisis induced by a few agitated victims.1 Intravenous physostigmine dosing

1520


to multiple victims may not be feasible under field conditions. Intramuscular (1 to 2 mg) or oral (2 to 5 mg) dosing every 1 to 2 hours titrated as needed may help maintain victim comfort and manageability.1,2 Physostigmine may be mixed into juice to mask its bitter taste for oral administration.1 Mass casualties from opioid toxicity can easily outstrip resources necessary to avoid complications from respiratory depression. Intramuscular or subcutaneous naloxone administration, as opposed to the intravenous route, should save time and minimize permanent injury or death when the number of victims greatly exceeds the number of rescuers.

PRINCIPLES OF PREPAREDNESS CNS disabling agents appear less likely to be used than conventional weapons or other chemical warfare agents. Therefore, in preparing for chemical weapons casualties, it would be prudent to concentrate more on the agents intended to inflict fatalities or permanent injuries. If used as intended, the CNS disabling agents should temporarily incapacitate, and the victims may require only monitoring and supportive therapy. Nevertheless, agents with lower therapeutic indices can cause fatalities, since precise control of the administered dose is not possible and individuals may have varying susceptibilities to toxic effects. If time and resources permit, preparations for chemical casualties should include stockpiling and training in the use of physostigmine and naloxone, the antidotes for CNS disabling agents. Airway management equipment would likely already be part of the armamentarium for chemical casualty preparedness.

REFERENCES 1. Ketchum JS, Sidell FR: Incapacitating Agents. In Sidell FR, Takafuji ET, Frank DR (eds): Medical Aspects of Chemical and Biological Warfare. Washington DC, Office of the Surgeon General, 1997, pp 287–305. 2. Chemical casualties: centrally acting incapacitants. J R Army Med Corps 2002;148(4):388–391. 3. Hay A: Surviving the impossible: the long march from Srebrenica—an investigation of the possible use of chemical warfare agents. Med Confl Surviv 1998;14(2):120–155. 4. Sharp D: Alleged chemical warfare in Bosnia conflict. Lancet 1998;351:1500. 5. Russia: officials raise hostage death toll. NTI Global Security Newswire. November 8, 2002. Available at http://www.nti.org/ d_newswire/issues/2002/11/8/7s.html, accessed October 27, 2006. 6. Lethal Moscow gas an opiate? CBSNEWS.com. October 29, 2002. Available at http://www.cbsnews.com/stories/2002/10/29/world/ main527298.shtml, accessed October 27, 2006. 7. Enserink M, Stone R: Toxicology: questions swirl over knockout gas used in hostage crisis. Science 2002;298(5596):1150–1151. 8. Schiermeier Q: Hostage deaths put gas weapons in spotlight. Nature 2002;420(6911):7. 9. Wax PM, Becker CE, Curry SC: Unexpected “gas” casualties in Moscow: a medical toxicology perspective. Ann Emerg Med 2003;41:700–705. 10. Chemical and Biological Weapons Nonproliferation Program: The Moscow Theater hostage crisis: incapacitants and chemical warfare. Available at http://cns.miis.edu/pubs/week/02110b. htm, accessed October 27, 2006. 11. Shaw ML, Carpenter JW, Leith DE: Complications with the use of carfentanil citrate and xylazine hydrochloride to immobilize domestic horses. J Am Vet Med Assoc 206:833, 1995. 12. Miller MW, Wild MA, Lance WR: Efficacy and safety of naltrexone hydrochloride for antagonizing carfentanil citrate immobilization in captive Rocky Mountain elk (Cervus elaphus nelsoni). J Wildlife Dis 32:234, 1996.

I N D E X

Note: Page number followed by the letter f refer to figures; those followed by letter t to tables, and the letter b to boxed material. A Abacavir, 890t–891t, 898, 898f ABC mnemonic, 1115 ABCDE mnemonic, 401, 405, 406t Abdomen, examination of, 23–24 Abortifacients, 350–351, 351b Abortificant, definition of, 1435b Absinthe oil, 1440t Absorbants, in gastrointestinal decontamination, 37–38 Absorbent powders, in vesicant decontamination, 1504 Absorption of dietary nutrients, 273 of drugs, 81–82, 81f, 82f definition of, 98 in elderly, 379 in neonate, 363, 365t in pregnancy, 348 interactions involving, 98, 98b, 98t routes of, 82–83 of thyroid hormones, 1066–1067 Abuse, drug. See Drug overdose; Illicit drug(s), abuse of; specific substance. ACE inhibitors. See Angiotensin-converting enzyme (ACE) inhibitors. Acephate, 1172t Acetaldehyde dehydrogenase, in ethanol metabolism, 590, 590f Acetaminophen, 825–831 ethanol interactions with, 592–593, 592t hepatotoxicity of, 230–231 in breast milk, 366t nephrotoxicity of, 263 pharmacokinetics of, 826, 827f pharmacology of, 825 Acetaminophen poisoning, 826–832 N-acetyl-parabenzoquinone-imine binding hypothesis in, 826 clinical manifestations of, 828 diagnosis of, 828–829, 829f fatalities due to, organ donation after, 127 in pregnancy, 351–352 liver failure due to, treatment of, 240 management of, 829–831 antidotes in, 14t, 830–831 decontamination in, 829 elimination in, 831 supportive measures in, 829 patient disposition in, 831–832 phases of, 828b quantitation and interventions for, 71t signs and tests for, 64t

Acetazolamide for uranium contamination, 1472 for vitamin A overdose, 1094 Acetic acid ocular injury due to, 307 uses and toxic effects of, 305t Acetic anhydride ocular injury due to, 307 uses and toxic effects of, 305t Acetone, for ocular adhesive injury, 311t, 312 Acetonitrile for removal of acrylic nails, 1430 toxicity of, 1430 Acetylcholine action of, 199 at neuromuscular junction, 200 chemical structure of, 465f structure of, 722f Acetylcholinesterase. See Cholinesterase. N-Acetylcysteine (NAC), 1168t for acetaminophen poisoning, 351, 830–831 dosage of, 830 for Amanita mushroom poisoning, 460 for drug-induced liver disease, 240 N-Acetyl-parabenzoquinoneimine (NAPQI) acetaminophen metabolism and, 592–593 binding hypothesis of, in acetaminophen poisoning, 826 Acetylsalicylic acid. See Aspirin. Acid(s). See also specific acid. chemical identification and structure of, 304 effect of, on gastrointestinal tract, 281 inorganic, 305–307, 306b mechanism of action of, 304 ocular injury due to, 304–307 clinical presentation of, 304–305 organic, 307 pK of, 81, 81f, 82f structure-activity relationships of, 1408–1409 uses and toxic effects of, 305t α1-Acid glycoprotein, for tricyclic antidepressant intoxication, 544 Acid-base homeostasis disorders of, 105–112 definitions of, 105–106 in salicylate poisoning, 839–840 in smoke inhalation victims, 1291 metabolic, 106–112. See also Metabolic acidosis; Metabolic alkalosis. mixed, 105–106, 113

Acid-base homeostasis (Cont’d) disorders of (Cont’d) respiratory, 105, 112–113, 112b, 113b simple, 105 fundamental concepts of, 105 Acidemia, vs. alkalemia, 105 Acidosis lactic, 107, 108t metabolic. See Metabolic acidosis. renal tubular, drug-related, 109–110, 109b respiratory, 112, 112b definition of, 105 Ackee fruit, hypoglycin in, 318, 485, 494 Acne, occupational, 1252t Aconite poisoning, 1083 cardiovascular disturbances due to, 164 Acrolein, 1380–1381 Acrylamide, neuropathy due to, 206t Acrylic nails, 1430 Acrylonitrile, 1309 ACTH (adrenocorticotropic hormone), 320, 321 Actinide isotopes, exposure to, 1472 Activated charcoal as absorbant, 37–38 for β-adrenergic blocker overdose, 979 for antipsychotic overdose, 715 for barbiturate overdose, 692 for benzodiazepine overdose, 682 for calcium channel blocker overdose, 969 for chlorinated hydrocarbon ingestion, 1359 for clonidine overdose, 1007 for cocaine overdose, 765 for colchicine overdose, 862 for cyanide poisoning, 1313 for cyclosporine overdose, 947 for dextromethorphan overdose, 778 for drug overdose, gastrointestinal complications of, 283 for gamma-hydroxybutyric acid overdose, 817 for hallucinogen overdose, 800 for herbicide poisoning, 1202 for methotrexate overdose, 933 for muscle relaxant overdose, 700 for mushroom poisoning, 455–456 for NSAID overdose, 873 for organochlorine insecticide poisoning, 1234 for phencyclidine overdose, 778 for phenobarbital overdose, 736 for salicylate poisoning, 844

1521

1522

INDEX

Activated charcoal (Cont’d) for selective serotonin reuptake inhibitor overdose, 556 for sulfonylurea overdose, 1030 for thalidomide overdose, 940 for theophylline overdose, 1043 for thyroid hormone overdose, 1071, 1072 for tricyclic antidepressant overdose, 543 for triptan overdose, 855 multiple-dose, 38 contraindications to, 45–46, 45b, 46b dosing of, 46, 46b efficacy of, 30b for barbiturate overdose, 692 for NSAID overdose, 874 indications for, 44–45, 45b, 46b postabsorptive elimination enhancement of, 44 single-dose, 39 substances not absorbed by, 29b Active transport, definition of, 81 Acute exposure guideline levels (AEGLs), National Advisory Committee, of sulfur mustard, 1504, 1505t Acute intermittent porphyria in children, 395, 395f drug safety in, 395–396, 395b vs. botulism, 524t Acute lung injury criteria for, 170 heroin overdose causing, 645, 649 management of, 651–652 Acute lymphoblastic leukemia, childhood, 1475 Acute radiation syndrome, 1467, 1468 Acute toxic encephalopathy, work-related, 1249t Acute tubular necrosis, 251, 252b, 252f agents associated with, 255–256, 255b Acyclovir, 894t–895t, 901, 901f Addiction therapy, for marijuana abuse, 752 Addison’s disease, treatment of, 326 Adefovir, 890t–891t, 899, 899f Adenoma, hepatic, in anabolic steroid users, 1104 Adenosine, 193 for theophylline intoxication, 1042 in ethanol tolerance and dependence, 599 structure of, 1036f Adenosine diphosphate, in platelet aggregation inhibition, 1060–1061, 1061t Adenosine monophosphate, in neurotransmission, 192–193 Adenosine receptors activation of, 194 classification of, 193–194 Adenosine triphosphate, 193 depletion of, in hepatic injury, 224b Adenosine triphosphate receptors, 194 ADH (antidiuretic hormone), 115, 319 drug-induced alterations in, 116b syndrome of inappropriate secretion of, 116 Adhesive(s) cyanoacrylate, ocular injury due to, 308 neonatal exposure to, 369–370 Adolescents, selective serotonin reuptake inhibitor therapy for, 552 Adrenal agents, 326t Adrenal cortex, 325–330 α-Adrenergic agonists. See also specific agent. cardiac disturbances due to, 148 direct-acting, 196b for hypotension, 715 β-Adrenergic agonists, direct-acting, 196b

α1-Adrenergic antagonists, 994–995, 994f. See also specific agent. β-Adrenergic antagonists, 975–981. See also specific agent. cardiac disturbances due to, 147, 147b treatment of, 148t classification of, 976t drug interactions with, 977–978 for alcohol withdrawal syndrome, 602 for thyroid hormone overdose, 1072 for ventricular arrhythmias, due to sedative intoxication, 668 history of, 975 intoxication with, 978–981 antidote for, 14t clinical manifestations of, 978, 978t diagnosis of, 978–979 differential diagnosis of, 979 epidemiology of, 975 in elderly, 380 management of antidotes in, 979–980 decontamination in, 979 supportive measures in, 979 pathophysiology of, 977 patient disposition and, 980–981 pharmacokinetics of, 977–978 pharmacology of, 975, 976t, 977t pulmonary toxicity due to, 186t α-Adrenergic receptors, types of, 195 β-Adrenergic receptors, 975 effects of, 977t types of, 195 Adrenocorticotropic hormone (ACTH), 320, 321 Adsorbents, elimination enhancement of 29, 29t, 30b Adult respiratory distress syndrome, 170 colchicine-induced, 861 Adverse drug reactions, in elderly, 377 Aerosols definition of, 170 fluorocarbon, cardiac disturbances due to, 146–147 Aflatoxins, 238f, 1243 carcinogenicity of, 237 Afterdepolarization, due to class IA antiarrhythmics, 1012, 1012f Age, of victim and offender, in criminal poisonings, 121 Agency for Toxic Substances and Disease Registry (ATSDR), 1264, 1504 Aggression, in anabolic steroid users, 1105 Agitation, anticholinergic-induced, treatment of, 729–730 Agonist(s). See also specific agonist. classification of, 92–93 definition of, 92 Agranulocytosis antipsychotic agents causing, 713 thionamide-induced, 323 Air contaminants in, 1262 inhalation of, 1461. See also Hazardous material incident(s). lead in, 1131 pollution of, 9, 9f Airway(s) compromise of, 170 management of. See also Endotracheal intubation. advanced, 15–18 Akathisia antipsychotics causing, 711 management of, 715

Alacramyn Fab2 fragment, for scorpion stings, 447 Albendazole, 912–913 Alcohol(s). See also specific alcohol, e.g., Ethanol. chemical structure of, 623t dependence on and withdrawal from, 598–602 gamma-hydroxybutyric acid in, 811–812 higher, 624–625 in common products and medications, 589t molecular mass of, 608t molecular weight of, 26b, 623t neonatal exposure to, 369, 370 signs and tests for, 63t toxic, removal of, 58 Alcohol addiction, pathophysiology of, 598 Alcohol Craving Scale scores, 812 Alcohol dehydrogenase, in ethanol metabolism, 589–590, 590f Alcoholic cerebellar degeneration, 595 Alcoholic dementia, 595 Alcoholic ketoacidosis, 107–108, 596, 596t Alcoholic withdrawal seizures, 599–600 Alimentary toxic aleukia, 1243 Alkalemia, vs. acidemia, 105 Alkali(s). See also specific alkali. ingestion of, gastrointestinal effects of, 281 mechanisms of action of, 302–303, 303f ocular injury due to, 302–304 structure-activity relationships of, 1408 uses and toxic effects of, 303t Alkali therapy, for methanol poisoning, 609 Alkaline diuresis, forced, for salicylate poisoning, 845 Alkalinization, urinary. See Urinary alkalinization. Alkaloids, 473, 475–476, 478b–480b. See also specific alkaloid, e.g., Theophylline. belladonna, 200 anticholinergic properties of, 723b diterpene ester, 476 ergot, 198 pulmonary toxicity due to, 187t nicotine, 482–483 toxicity of, 497–498 plant, gastrointestinal irritation due to, 477 pyrrolizidine, 476 hepatotoxicity of, 239b, 494, 1082 in herbal teas, 1082–1083, 1082t tropane, 483 xanthine-derived, 194 Alkalosis metabolic. See Metabolic alkalosis. respiratory, 112–113, 113b definition of, 105 Alkylating agents, pharmacologic parameters of, 929t Alkyltryptamines, 794–795, 795t, 798t Allamanda, 489f Allergic alveolitis, extrinsic, 173–174, 175t, 176 Allergic contact dermatitis occupational chemicals causing, 1245 plant-induced, 495 Allergy drug, 878. See also Hypersensitivity reactions. latex, in health care workers, 1246 Allopurinol, hepatitis due to, 235b Allyl chloride, neuropathy due to, 206t Almotriptan, pharmacokinetics of, 852t Alocasia, 489f Alopecia eyebrow and eyelid, systemic substances causing, 309b scalp, colchicine-induced, 862

INDEX

Alprazolam recommended dosage of, 672t structure of, 673f Alternative medicine, 1085–1087 homeopathy in, 1085–1086 hyperoxygenation therapy in, 1087 lead contamination in, 1132 nutritional supplements in, 1086–1087 tonics, extracts, and elixirs in, 1087 Aluminum, 1157–1158 occupational exposure to, 183 Aluminum phosphide, in rodenticides, 1218 Alveolar epithelial cells, 168–169 Alveolar macrophages, 169 Alveolus(i), diffuse damage to, 171 Amanita mushrooms, 455, 457–458, 458b, 459f, 461f maturation of, 459f poisoning with, 234 clinical presentation of, 459, 462–463 diagnosis of, 459–460, 459f, 463 management of, 460–461, 463 pathophysiology of, 458–459, 462 Amanita smithiana mushrooms, 468 Amantadine, 894t–895t, 904, 904f for neuroleptic malignant syndrome, 217 American Academy of Forensic Sciences (AAFS), 122 American Association of Poison Control Centers (AAPCC) data, on pulmonary toxicity, 167 American Conference of Governmental Industrial Hygienists (ACGIH), 1265 American ticks, 200 Americium isotope, accidental inhalation of, 1469 α-Amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptors, 202 γ-Aminobutyric acid. See Gamma-aminobutyric acid entries. Aminoglutethimide, mechanism of toxicity of, 328 Aminoglycosides nephrotoxicity of, 255 overdose of, 882 4-Aminopyridine, for calcium channel blocker intoxication, 969 Amitraz, in insecticides, 1188–1189, 1188f Amitriptyline cardiac disturbances due to, 148–149, 150f, 155f pharmacokinetic parameters of, 539t Ammonia, 303–304, 1399–1402 anhydrous, 1399 aqueous, 1399 elevated levels of, in ornithine transcarbamylase deficiency, 392, 392f exposure to clinical manifestations of, 1400–1401 epidemiology of, 1399 management of, 1401–1402 pathophysiology of, 1400, 1400t structure-activity relationships of, 1399 Ammonium bifluoride, ingestion of, 1327–1328 Ammonium chloride, for strontium inhalation accident, 1470 Ammonium hydroxide ocular injury due to, 303–304 uses and toxic effects of, 303t Amnestic shellfish poisoning, 516, 517 Amobarbital, 689t

Amodiaquine, hepatitis due to, 235b Amoxapine pharmacokinetic parameters of, 539t structure of, 538f Amoxicillin-clavulanic acid, hepatitis due to, 235b Amphetamines, 781–790, 782b. See also related compounds. complications associated with, 781b history of, 781–782 intoxication with, 784–790, 784f cardiovascular complications in, 143, 786 CNS complications in, 785–786 diagnosis of, 788 epidemiology of, 782–783 management of, 788, 789t–790t, 790 obstetric and prenatal complications in, 787–788 pathophysiology of, 783 pulmonary complications in, 786–787 systemic complications in, 787 neurologic effects of, 196 pharmacokinetics of, 783–784 pharmacology of, 783 social use of, 231 structure-activity relationships of, 783 tolerance to, 785 Amphotericin B, 884 toxic effects of, in neonate, 370–371 Ampicillin, for shigellosis, 532 Amprenavir, 892t–893t, 902, 903f Amrinone for calcium channel blocker intoxication, 969 in emergency care, 20t, 21 Amygdalin, 484–485 Amyl nitrite pearls, for cyanide poisoning, 1312 Anabolic steroids, 1101–1106 abuse of adverse effect(s) of, 1101, 1102t anabolic, 1103–1104 cardiovascular, 1105 erythropoiesis as, 1104 feminization as, 1104 hepatotoxicity as, 1104–1105 psychological, 1105–1106 reproductive, 1104 virilizing, 1104 common agents in, 1102–1106, 1103t diagnosis of, 1107 management of, 1108 pharmacology of, 1102 structure of, 1101–1102, 1102f Anabolic Steroids Control Act, 1101 Anamirta species, toxicity of, 484 Anaphylactic reactions to Crotalidae antivenom, 409–410, 413–417, 416t to hymenoptera stings, 163, 449 to jellyfish stings, 514 Anaphylaxis antibiotic-induced, 878–880, 879t clinical presentation of, 879 pathophysiology of, 879 treatment of, 879–880, 880f Anaplastic anemia, benzene-induced, 1364, 1367 Androctonus australis, 443, 443f Androgens anabolic effects of, 330, 331–332, 1103 biosynthesis of, 1103f Androstenedione abuse of diagnosis of, 1107

1523

Androstenedione (Cont’d) abuse of (Cont’d) management of, 1108 potential adverse effects of, 1102t structure and pharmacology of, 1106 Anemia anaplastic, benzene-induced, 1364, 1367 hemolytic antibiotic-induced, 881 Heinz body, 289 in acute and chronic poisoning, 298, 298b Anesthesia toxicity, inhaled in children with folate and vitamin B12 metabolic disorders, 394 malignant hyperthermia due to, 213 in children, 395 Anesthetics. See specific agent. Angel dust. See Phencyclidine (PCP). Angioedema, ACE inhibitors causing, 992 Angiotensin II receptor antagonists, 993 hepatotoxicity of, 236 pulmonary toxicity due to, 186t Angiotensin-converting enzyme (ACE) inhibitors, 991–993, 991f hepatotoxicity of, 236 nephrotoxicity of, 253 toxicity of, 992 management of, 992–993, 993f Animal products, occupational exposure to, disorders associated with, 175t Animal venom. See Envenomation. Anion gap elevated, metabolic acidosis with, 106–109, 106b causes of, 25b vs. ketoacidosis, 107–108 in ethylene glycol poisoning, 615 in methanol poisoning, 607, 608f normal, metabolic acidosis with, 109–110, 109b Anionic surfactants, ocular injury due to, 308 Anorectic agents, pulmonary toxicity due to, 187t ANS (autonomic nervous system), herbal teas affecting, 1082 Antagonists. See also specific antagonist. classification of, 92–93 definition of, 92 Anthozoa, 507 Antiandrogens, 332, 335 Antiarrhythmic agents. See also specific agent. class IA, 151, 152t, 153b, 1009–1016 drug interactions with, 1015, 1015b history of, 1009 intoxication with pathophysiology of, 1009–1013, 1010f–1013f treatment of, 1015–1016 noncardiac effects of, 1010t pharmacokinetics of, 1009 toxicology of, 1013–1015, 1014f class IB, 151, 152t, 153b class IC, 151, 152t, 153b pulmonary toxicity due to, 186t Anti-asthmatic agents, pulmonary toxicity due to, 186t Antibiotics, 877–883, 877b. See also specific agent. essential oils as, 1435–1436 for smoke inhalation victims, 1292 history of, 877 hypersensitivity reactions to, 877–881, 878t multisystem involvement in, 878–880, 880f organ-specific, 880–881

1524

INDEX

Antibiotics (Cont’d) nephrotoxicity of, 255, 255b, 264 pharmacologic parameters of, 929t prophylactic for corrosive injury, 1412 for Elapidae bites, 430 pulmonary toxicity due to, 186t toxic effects of, in neonate, 370 Anticholinergic(s), 721–732. See also specific agent. cardiac disturbances due to, 148–149, 149b, 150f classification of, 721–722 gastrointestinal disturbances due to, 283 history of, 721 intoxication with antidote for, 14t clinical manifestations of, 727–728, 727b death from, 728 diagnosis of, 728–729 differential diagnosis of, 729, 729b in elderly, 380 in special populations, 727 management of, 729–731 patient disposition and, 732 signs and symptoms of, 723t signs and tests for, 63t special considerations in, 731–732 vs. botulism, 524t pharmacokinetics of, 725, 725t pharmacology of, 724 structure of, 722f Anticholinergic syndrome agents producing, 722–724 central, 724 management of, 715 toxic and medical conditions confused with, 729b Anticholinergic toxins, 498 Anticholinesterases, for non-native Elapidae snakebites, 430–431 Anticoagulants, 1053–1062, 1062f. See also specific agent. exposures and overdoses of, 1051t for non-native Elapidae snakebites, 431 in rodenticides, 1220 leech-derived, 1059 mechanism of action of, 1053–1061 Anticonvulsant(s), 735–743. See also specific agent. for alcohol withdrawal syndrome, 602 for epilepsy, 735 pulmonary toxicity due to, 187t Anticonvulsant hypersensitivity syndrome, 690, 735 Antidepressants. See also specific agent. intoxication with in children with ornithine transcarbamylase deficiency, 392 in elderly, 380 tricyclic, 540–545. See also Tricyclic antidepressants. Antidiuretic hormone (ADH), 115, 319 drug-induced alterations in, 116b syndrome of inappropriate secretion of, 116 Antidotes development of, 28–29 emergency, 14t–15t for acetaminophen poisoning, 14t, 830–831 for β-adrenergic blocker poisoning, 979–980 for anticholinergic poisoning, 730–731 for arsenic poisoning, 14t, 1152–1153, 1153t

Antidotes (Cont’d) for arsine poisoning, 1155 for benzodiazepine poisonoing, 682 for calcium channel blocker poisoning, 14t, 969–971 for cardiovascular plant poisoning, 501 for clonidine poisoning, 1007 for colchicine poisoning, 863 for Crotalidae snakebites, 408–419, 409t, 410t. See also Antivenom therapy. for cyanide poisoning, 1313 for digitalis poisoning, 14t, 960–961, 960f, 961b for ethylene glycol poisoning, 616–619, 618b, 618t, 619t for gamma-hydroxybutyric acid poisoning, 817 for hazardous material toxins, 1465, 1465t for hepatotoxicity, 501 for hydrofluoric acid toxicity, 14t for iron poisoning, 14t, 1126–1127, 1126b for mercury poisoning, 14t for methanol poisoning, 14t for muscle relaxant intoxication, 700–701, 701t for nerve gas poisoning, 732, 1495–1496 in pediatric population, 1492–1493, 1493t for neurologic plant toxicity, 501 for organophosphate poisoning, 15t, 1178–1180 for overdose, in pregnant patient, 350, 350t for plant-induced multisystem organ failures, 501 for selective serotonin reuptake inhibitor poisoning, 557 for tricyclic antidepressant poisoning, 543–545 placental permeability of, 350t Antiestrogens, 330–331, 334, 335 Antifungals, 884. See also specific agent. toxic effects of, in neonate, 370–371 Antihelmintics, 911–917. See also specific agent. Antihistamines, 201, 721–732. See also Histamine entries; specific agents. anticholinergic properties of, 723b classification of, 722 for anaphylaxis, 880, 880f intoxication with clinical manifestations of, 728 death from, 728 diagnosis of, 728–729 in special populations, 727 management of, 729–731 patient disposition and, 732 special considerations in, 731–732 nonsedating, 726t, 731 pharmacokinetics of, 725, 726t pharmacology of, 724–725 sedating, 722, 726t structure of, 723f Antihyperglycemic agents, 317–318, 317t, 318t, 1020t. See also specific agent. adverse effects of, 1026–1028 history of, 1019 intoxication with, 1026, 1026b diagnosis of, 1028–1029 epidemiology of, 1019–1020 management of, 1030–1031 patient disposition and, 1031–1032 mechanism of action of, 317 pharmacokinetics of, 1024–1025 pharmacology of, 1022–1024 structure and classification of, 1020–1022, 1021f

Antihypertensive agents. See also specific agent. nephrotoxicity of, 253–254 sympatholytic, cardiac disturbances due to, 148, 149f Anti-inflammatory agents. See also specific agent. nonsteroidal. See Nonsteroidal antiinflammatory drugs (NSAIDs). pulmonary toxicity due to, 186t Antimetabolites, nephrotoxicity of, 255–256 Antimitotice, pharmacologic parameters of, 929t Antimony, 917, 1158 Antimuscarinic compounds, structure of, 721–722, 722f Antimuscarinic plants, 483 Antineoplastic agents. See Chemotherapeutic agents; specific agent. Antiparkinsonism agents, anticholinergic properties of, 723b Antiperspirants, 1432 Antiprogestin, 334 Antipsychotic agents, 703–717. See also specific agent. adverse effects of, 710–713 cardiac disturbances due to, 156, 707, 712 management of, 715 classification of, 704, 705t dosage of, 705t drug interactions with, 709 extrapyramidal side effects of, 707–708, 710–712 management of, 715–717 hematologic toxicity of, 713 history of, 703–704 intoxication with, 709–717 clinical manifestations of, 709–710 diagnosis of, 713, 714b differential diagnosis of, 713 epidemiology of, 703–704 in special populations, 708–709 management of, 714–717 pathophysiology of, 707–708 patient disposition and, 717 metabolic effects of, 712–713 neuroreceptor affinities for, 706t pharmacokinetics of, 708–709, 709t pharmacology of, 704–707 seizures due to, 707, 712 management of, 714–715 structure-activity relationships of, 704, 706f terminology associated with, 703 Antipyrine, in breast milk, 366t Antiretroviral agents, 890t–897t. See also specific agent. toxic effects of, in neonate, 371 Antischistosome agents, 915 Antiseptic properties, of iodine, 1389 Antiseptics, essential oils as, 1435 Antispasmodics. See also specific agent. anticholinergic properties of, 723b Antithrombin III inhibition, of factor II and factor X, 1058–1059 Antitoxin, equine, for botulism, 525 Antituberculous agents. See also specific agent. hepatotoxicity of, 233 Antivenom therapy for black widow spider bites, 434–435, 435t for Crotalidae snakebites administration of, 408–419, 410t characteristics of, 409t Crotalidae immune Fab (CroFab), 413–419 coagulopathies with, late-onset and persistent, 416t, 417–418 complications with, 413–417, 415t, 416t

INDEX

Antivenom therapy (Cont’d) for Crotalidae snakebites (Cont’d) contraindications to, 413 dosage of, 415t, 418 premarketing clinical trials for, 414b recurrent complications with, 415t redosage of, 419 studies of, 414t guidelines for use of, 410t median lethal dose (LD50) neutralizing units in, 409t Wyeth-Ayerst ACP, 409–413 complications of, 409–411 dosage of, 411 infusion guidelines for, 411–412, 412b route of administration of, 411 skin test for, 411 for Elapidae snakebites native, 425 non-native, 430 for hymenoptera stings, 450 for jellyfish stings, 514–515 for scoprion stings, 446–447 for sea snake bites, 515 Antiviral agents, 889, 890t–897t, 896–906. See also specific agent. Ants, 447–448 Aphenol, in clove oil, 1439 Apidae, 447. See also Hymenoptera stings. Apnea, clonidine-induced, 1005 Apneustic breathing, 24 Apoptosis, in hepatic injury, 224b Appendicitis, vs. botulism, 524t Appetite suppressants, cardiac complications of, 786 Areca catechu, toxicity of, 496 Areflexia, 205 Argyria, 1165 Aristolochia fangchi, 1083 Aromatherapy, definition of, 1435b Aromatic hydrocarbons, 1363–1375. See also Benzene; Hydrocarbons. exposure to, 1363 treatment protocol for, 1367b Arrhythmias, 134–139. See also specific arrhythmia. abnormal conduction impulse causing, 134, 135f alcohol-induced, 597 drug-induced recognition and management of, 140–164. See also under specific agent. tricyclic antidepressants in, 541 in poisoned patients, 135–136, 136f, 137f management of, 136–139, 137t mechanisms of, 134–135 toxic causes of, 24–25, 25b triggered rhythms causing, 134–135 Arrhythmogenesis, in poisoned patients, 135–136, 136f, 137f Arsenic, 6, 1147–1154 history of, 1147 in rodenticides, 1218 inorganic, 1148t, 1152t hepatotoxicity of, 235–236 organic, 1148t pentavalent, 1148–1149, 1149f pharmacokinetics of, 1149 sources of, 1147–1148, 1148b trivalent, 1149, 1149f uses of, 1148 Arsenic poisoning, 1149–1150 acute vs. chronic, 1149–1150, 1150t cardiac disturbances due to, 158t, 163

Arsenic poisoning (Cont’d) diagnosis of, 1151 differential diagnosis of, 1151–1152, 1152b gastrointestinal disturbances due to, 280 in children, 1149 management of antidotes in, 14t, 1152–1153, 1152t extracorporeal elimination in, 1153 supportive measures in, 1152 neuropathy due to, 205, 206t, 1150 patient disposition in, 1153–1154 Arsine, 1152t, 1154–1155 cardiac disturbances due to, 158t, 163 Arthritis, gouty, colchicine for, 860 Arthropods, venomous, 433–453. See also specific arthropod. beetles, 452 centipedes, 452–453, 453f hemiptera, 451–452 hymenoptera, 447–451 lepidoptera, 451, 451f, 452f millipedes, 453 scorpions, 440–447 spiders, 433–438 ticks, 452 Asbestos, exposure to, 182–183 Asbestosis, 182 Ascorbic acid. See Vitamin C. Asphyxia, in smoke inhalation victims, 1284t, 1286 signs and symptoms of, 1289 Asphyxiants chemical, 176 cardiac disturbances due to, 158t, 162–163 simple, 176 workplace gases as, 1246 Aspirin. See also Salicylate entries. anticoagulant properties of, 1061 gastrointestinal disturbances due to, 279 hepatitis due to, 235b hypersensitivity reactions to, 842 Reye’s syndrome and, 836 Asthma, 171–173 occupational, 171, 1248t classic form of, 171–172 irritant-induced, 171 sensitizer-induced, 171–173 high-molecular-weight agents and jobs associated with, 173t low-molecular-weight agents and jobs associated with, 172, 174t treatment of, 173 vs. acute inhalation syndromes, 181t Atazanavir, 894t–895t, 903, 903f Atherosclerosis ethanol consumption and, 597 work-related, 1251t Atractylis gummifera, hepatotoxicity of, 494–495 Atracurium, in rapid sequence intubation, 16t Atraxotoxin (funnel-web spider toxin), 200 Atrial fibrillation, alcohol-induced, 597 Atrial flutter, alcohol-induced, 597 Atrioventricular block drug-induced, 135, 136f in digitalis intoxication, 954, 956f Atropine for β-adrenergic blocker intoxication, 980 for bradycardia, 959 for cholinergic symptoms, 200 for muscarine mushroom poisoning, 465 for muscle relaxant intoxication, 700, 701t for nerve gas poisoning, 1178, 1491, 1495–1496 in pediatric population, 1492–1493, 1493t

1525

Atropine (Cont’d) for organophosphate poisoning, 1178 in pregnant patient, 358 in rapid sequence intubation, 16t intoxication with, antidote for, 14t structure of, 722f usage of, during pregnancy and lactation, 727 Australian funnel web spider, 437–438 Autism, thimerosal in vaccines and, 1279 Autoimmunity, drug-induced, 880 Automatic dishwashing detergent statistics of, 1444t, 1445t toxicity of, 1446–1447 management of, 1447–1448 Automobile emissions, lead in, 1131 Autonomic nervous system (ANS), herbal teas affecting, 1082 Autoreceptors, in neurotransmission, 192f, 193 Avermectines, 1189–1190, 1189f Axonopathy(ies), 205 Ayahuasca, hallucinogenic effects of, 499 Ayurvedic medicine, 1085 Azathioprine, 944–945 drug interactions with, 945 intoxication with, 945, 945b Azotemia, in acute renal failure, 250 B Baby powder, 1415–1416 inhalation of, 1416–1417 Bacillus cereus, food poisoning due to, 529–530 Baclofen intoxication with, 698 properties of, 696t withdrawal from, 699 Bag-mask-valve device, in opioid toxicity therapy, 650 BAL. See British antilewisite (BAL). Balsam azalea, 493f Barbiturates, 687–692, 687f. See also specific agent. abuse of, 689 classification of, 688t dependence on, 689–690 drug interactions with, 690–691, 691t for alcohol withdrawal syndrome, 602 history of, 687 in rapid sequence intubation, 16t, 17 mechanism of action of, 203 overdose of clinical presentation of, 691, 691f, 691t deaths from, 660, 660f management of, 691–692 pharmacology and pharmacokinetics of, 687–688, 688t signs and tests for, 63t therapeutic uses of, 688–689, 689t tolerance to, 689 Barium, 1158–1159 Barium carbonate, in rodenticides, 1219 Barium sulfate, for strontium inhalation accident, 1470 Base(s), pK of, 81, 81f Bath oils, 1428–1429 Batrachotoxin, 201 Battery(ies), impaction of, in gastrointestinal tract, 281 Beetle stings, 452 Behavioral sensitization, in amphetamine toxicity, 785 Belladonna alkaloids, 200 anticholinergic properties of, 723b Bentazon herbicides, 1206–1207, 1206f Benzalkonium chloride for hydrofluoric acid burns, 312 ingestion of, 1447

1526

INDEX

Benzene, 1363–1368 exposure to, 1363–1364, 1367–1368 bone marrow depression associated with, 1365, 1366 OSHA standards for, 1367 metabolism of, 1365 factors altering, 1365–1366 poisoning with diagnosis of, 1366 evidence of, 1366 management of, 1367, 1367b synonymous terms for, 1363 urinary excretion of, 1366–1367 Benzethonium chloride, for hydrofluoric acid burns, 312 Benzodiazepine(s). See also specific agent. absorptions rates of, 675–676, 675t classification of, 676t CNS effects of, 1518 drug interactions with, 678 duration of action of, 676 for alcohol withdrawal syndrome, 600–602, 601t for cocaine toxicity, in pregnant patients, 354 for hyperthermic syndromes, 216 for nerve gas poisoning, 1496 in pediatric population, 1493, 1493t for neuroleptic malignant syndrome, 216 for seizures alcoholic-related, 602 NSAID-induced, 873 strychnine-induced, 1217 theophylline-induced, 1042 history of, 671–673 in elderly, 677–678 in patients with hepatic and renal impairment, 678 in pregnancy, 678 in rapid sequence intubation, 16t, 17 metabolic pathway of, 675f pharmacokinetics of, 674–678, 675f, 675t, 676t pharmacology of, 673–674 recommended dosage of, 672t structure-activity relationships of, 673, 673f tolerance to, 677 Benzodiazepine poisoning, 679–680 acute, 680 adverse effects of, 679–680 CNS effects of, 1518 diagnosis of, 680–681 differential diagnosis of, 681 in children with maple syrup disease, 393 in elderly, 380 in pregnancy, 679–680 management of, 681–683, 1519 antidotes in, 14t, 682–683, 682f decontamination in, 682 supportive measures in, 681–682 manifestations of, 679 patient disposition in, 683 signs and tests for, 64t Benzothiazepine(s), structure of, 963, 964f Benztropine, for acute dystonia, 715 Benzydamine, toxic effects of, 871 Benzyl alcohol, 623t, 625 neonatal exposure to, 370 overdose of, 883 Bephenium hydroxynaphthoate, 917 Beryllium exposure to acute, 1159 long-term, 1160 occupational, 183 hepatotoxicity of, 236b

Beta-blockers, signs and tests for, 64t Betel nuts, toxicity of, 497 Bhopal, India, hazardous material incident in, 9, 1456 Bicarbonate–carbonic acid system, 105 Bicuculline, 204 Biguanides contraindications to, 1027b duration of action of, 318t history of, 1019 intoxication with, 1026 adverse effects of, 1027 management of, 1030–1031 mechanism of action of, 318 pharmacokinetics of, 1024 pharmacology of, 1022–1023 structure and classification of, 1020, 1021f Bile, secretion of, 272 Bile acid sequestrants, 336, 338 Bilirubin-albumin ratio, calculation of, 394 Binge drinkers, cardiac disturbances in, 146 Bioavailability, of drugs, 91 Biologic agents gastrotoxicity of, 277–279 nephrotoxicity of, 256 Biologic toxins, 399–431. See also specific animal bites and stings. epidemiology of, 399–401, 400t, 401t etiology of, 399 Biopsy, muscle, for malignant hyperthermia, 215 Biotransformation, of drugs, 84–86 in elderly, 379 in neonate, 364–365, 365t in pregnancy, 348 interactions involving, 99–101, 100t nonmicrosomal, 101–103 phase I metabolism in, 84–86, 85f, 85t phase II metabolism in, 86, 86f–87f subtypes and sites of, 84t Biphenyls, polychlorinated. See Polychlorinated biphenyls (PCBs). Bipyridyl herbicides, 1195–1200. See also specific compound. Bis-[2-chloroethyl] sulfide. See Sulfur mustard. Bismuth, 1160 Bisphosphonates, 324–325, 325t for steroid-induced osteoporosis, 325 toxicity of, 325 Bites centipede, 453, 453f sea snake, 513 snake. See Snakebite(s). spider, 163, 433–438. See also under specific spider. Bithionol, 917 Black foot disease, 1151 Black locust pods, 490f Black widow spider(s), 200 species of, 433 venomous bites of clinical presentation of, 434 pathophysiology of, 433–434 treatment of, 434–435, 435t Bleach(es), 1448–1451. See also specific agent, e.g., Chlorine. hair, 1426 ingestion of, 1408 management of, 1450 oxygen, 1450 sources of, 1448 toxicity of, 1448–1449 management of, 1450–1451 manifestations of, 1449–1450 Blepharospasm, chloroform–induced, 1356

Blister(s), coma, in barbiturate overdose, 691 Blister beetle, 452 Blood concentrations, toxicant, 56 Blood flow, fetal-placental, 348 Blood levels of lead health effects of lowest observed in adults, 1133t in children, 1138t in children, 1137t of toluene, 1372–1373 Blood studies, toxicologic, 27b Blood transfusion. See Transfusion. Blood urea nitrogen, in acute renal failure, 250, 255, 258 Blood-brain barrier, 83 Blue-ringed octopus, 509, 509f stings from, 513 BMAA (β-N-methylamino-L-alanine), 203 BOAA (β-N-oxalylamino-L-alanine), 202–203 Body paint, 1431–1432 Body stuffers/packers asymptomatic, management of, 652, 652b illicit drug smuggling by, 648, 762, 768 opiate toxicity in delayed and prolonged, 649 management of, 652 Body water. See Water, total-body. Bone marrow, effect of benzene on, 1365, 1366 Borate hepatotoxicity of, 235–236 poisoning with, 1431 Boric acid antiseptic effects of, 1417 intoxication with, 1417–1418 gastrointestinal disturbances due to, 281 management of, 1418–1419 patient disposition and, 1419, 1419t pharmacokinetics of, 1417 Boron, 1379–1380 Botanicals, anticoagulant properties of, 1061 Botulism, 521–526 bacteriology of, 521 differential diagnosis of, 524t food-borne clinical manifestations of, 522–523, 523t diagnosis of, 523 management of, 523, 525 restaurant-acquired, 522 iatrogenic, 521, 526 infant, 521, 525–526 intestinal, 521 pathophysiology of, 522 types of, 521–522 wound, 521, 526 Bowen’s disease, 1150 Bowman’s membrane, 301 Bradyarrhythmias cholinomimetics-induced, 150 digitalis-induced, treatment of, 959 management of, 137t, 139 work-related, 1251t Bradycardia carbamazepine-induced, 738 clonidine-induced, 1004–1005 digitalis-induced, treatment of, 959 Brain death, toxicologic testing in, 78 Brainstem auditory evoked potential, abnormal, toluene-induced, 1373 Breast milk clonidine in, 1003 neonatal toxic exposures through, 365, 365t, 366t salicylates in, 366t, 837 styrene in, 1368

INDEX

Breast-feeding antipsychotic use during, 708 as risk factor in infant botulism, 526 cocaine abuse and, 368 contraindications to, 367t Breath ethanol analyzer, 593–594 Breath odor, in toxin identification, 23 Brimonidine dosage of, 1004t structure of, 1002f British antilewisite (BAL), 1168t, 1501, 1505 for arsenic poisoning, 1152–1153 for lead poisoning in adults, 1135 in children, 1141 for mercury poisoning, 1116 Bromates, 1387–1388, 1388b in hair products, 1427 Bromethalin, in rodenticides, 1220 Bromide intoxication with, 1386–1387, 1386b diagnosis and management of, 1387 pharmacokinetics of, 1386 relevant history of, 1385–1386, 1385t Bromine, 1388–1389, 1389t Bromine compounds, 1385–1389. See also specific compound. Bromism, clinical manifestations of, 1386, 1386b Bromocriptine for MAO inhibitor overdose, 568 for neuroleptic malignant syndrome, 216, 716 L-dopa with, serotonin syndrome due to, 212, 573 Bromoderma, 1386 Bronchial pneumonia diquat-induced, 1196 in smoke inhalation victims, 1290 Bronchiolitis obliterans, in microwave popcorn workers, 184–185 Bronchiolitis obliterans fibrosa, 171 Bronchiolitis obliterans with organizing pneumonia, 171 therapeutic drug–induced, 188t Bronchoalveolar lavage, for lead poisoning, in pregnant patient, 357 Bronchodilators, inhaled or parenteral, for smoke inhalation victims, 1292 Bronchopulmonary injury, in smoke inhalation victims, signs and symptoms of, 1289–1290 Bronchoscopy, for smoke inhalation victim, 1292 Bronchospasm β-adrenergic blocker–induced, 978 management of, 980 therapeutic drug–induced, 188t Bronstead-Lowry expression, 81–82 Brown recluse spider species of, 435–436 venomous bites of, 436 treatment of, 436–437 Buckeye, 490f Buckthorn, hallucinogenic effects of, 499 Buckthorn toxin, 205 Bufotenin (bufotenine), 198, 794, 795t formulations and route of administration of, 797 structure of, 796f Bulimia nervosa, laxative abuse in, 284 Bullets, retained, lead absorption from, 1132 Bumblebees, 447 Buprenorphine, 636, 647 chemical structure of, 637f liver metabolism of, 642, 643f

Bupropion, 550 overdose of, 555 pharmacokinetics of, 551t Burns chemical. See also under specific agent. classification of, 1409, 1409t decontamination of, 34 esophageal, 1410 ocular. See also Ocular injury. acids causing, 304–307, 305t, 306b alkalis causing, 302–304, 303t solvents causing, 307 dermal hydrofluoric acid causing, 1326 treatment of, 1328–1330, 1329f iodine causing, 1389 esophageal, caustic ingestions causing, 1410 radiation, 1468, 1476 “Bush” tea, hepatotoxicity of, 497 Buspirone, serotonin syndrome due to, 212, 573 Busulfan, pharmacologic parameters of, 929t Butabarbital, 689t 1,4-Butanediol, 803–804, 807f, 808t Buthus occitanus, 444, 444f Buttercup, 490f γ-Butyrolactone, 803–804, 807f, 808t Byssinosis, 180t C Cadmium, 1160–1161 nephrotoxicity of, 268 occupational exposure to, 183–184 Caffeine, 1044–1046 cardiovascular effects of, 144–145, 145f clinical pharmacology of, 1044–1045 in beverages, foods, and pharmaceuticals, 1044t in breast milk, 366t overdose of, 1045–1046 in neonate, 371 management of, 1046 structure of, 1036f Caffeinism, 1045 Cage compounds, 1231. See also Organochlorine insecticides. Caladium, 491f Calcitonin, 325 for cholecalciferol poisoning, 1220 Calcium as food supplement, 1087 in emergency care, 20t, 21 Calcium carbonate, dimethyl sulfoxide with, for hydrofluoric acid burns, 1328 Calcium channel blockers, 963–972. See also specific agent. cardiac disturbances due to, 151, 152t, 153, 978, 978t drug interactions with, 967t for thyroid hormone overdose, 1072 gastrointestinal disturbances due to, 283 intoxication with, 966–972 acute, 966–968 chronic, 968 diagnosis of, 968 in elderly, 380 management of, 968–972, 971f antidotes in, 14t, 969–971 decontamination in, 969 elimination in, 971 supportive measures in, 968–969 patient disposition and, 971–972 pharmacokinetics of, 966, 966t pharmacology of, 965–966, 965f pulmonary toxicity due to, 186t structure of, 963–965, 964f

1527

Calcium chloride for β-adrenergic blocker intoxication, 980 for calcium channel blocker intoxication, 969–970 Calcium gluconate for fish poisoning, 518 for hydrofluoric acid burns, 312, 1328, 1331 intralesional injections of, 1329 for strontium inhalation accident, 1470 Calcium homeostasis, 324, 324f Calcium hydroxide ocular injury due to, 304 treatment of, 311–312, 311t uses and toxic effects of, 303t Calcium ions, in neurotransmission, 193 Calcium oxalate, plants containing, gastrointestinal irritation from, 477, 480, 496 Calcium oxalate crystalluria, in ethylene glycol poisoning, 615, 616f Calcium salts, for calcium channel blocker intoxication, 969–970 Callilepsis laureoa, hepatotoxicity of, 494–495 Calorie requirements daily, 117t in acute renal failure, 258 Camphor hepatotoxicity of, 239b history of, 1419 ingestion of, 1420–1421 neonatal exposure to, 370 pharmacokinetics of, 1420t pharmacology of, 1419–1420 Campylobacter jejuni, food poisoning due to, 533 Cancer. See also specific type. baseline, 1483 chemotherapy for, 927. See also Chemotherapeutic agents. gastrointestinal, 284 hepatic agents associated with, 237–238, 238f in anabolic steroids users, 1105 lung, work-related, 1248t–1249t radiation-induced, 1474, 1483 Cannabis sativa, 747. See also Marijuana. Capillary endothelial cells, 169 Caplan syndrome, 182 Capsaicin, 1512. See also Lacrimators. Capsicum peppers, toxicity of, 499–500 Carbamates, 1171–1172, 1173t cardiac disturbances due to, 149–151, 150b intoxication with, antidote for, 15t pharmacokinetics of, 1174 pharmacology of, 1174–1175 structure of, 1172, 1173f Carbamazepine intoxication with, 738 management of, hemodialysis or hemoperfusion in, 59 mechanism of action of, 194 pharmacokinetics of, 738 Carbamide peroxide, in teeth whitening products, 1430 Carbidopa, for neuroleptic malignant syndrome, 716 Carbon dioxide, in smoke, 1283, 1288 Carbon disulfide, 197 neuropathy due to, 206t Carbon monoxide, 1297 exposure to, biochemical events associated with, 1298–1299 in smoke, 1283, 1286 pharmacokinetics of, 1299 sources of, in fatal poisoning, 1297t

1528

INDEX

Carbon monoxide (Cont’d) structure-activity relationships of, 1297–1298 Carbon monoxide poisoning, 1297–1306. See also Smoke inhalation. cardiovascular disturbances due to, 158t, 162–163 clinical manifestations of acute effects in, 1299, 1299t, 1300t chronic effects in, 1299–1300 diagnosis of, 1300–1302, 1300t differential diagnosis of, 1302 epidemiology of, 1297, 1297t fatalities due to, 1297, 1297t organ donation after, 127–128, 128t in pregnancy, 355–356, 355f, 356b in special populations, 1299 management of, 1293, 1302–1306, 1305f decontamination in, 1302 hyperbaric oxygen therapy in, 1302, 1303t, 1304–1305, 1304t supportive measures in, 1302 neurotoxic effects of, 197 pathophysiology of, 1298–1299 patient disposition in, 1305–1306 quantitation and interventions for, 71t vs. botulism, 524t Carbon tetrachloride, 1347, 1348t absorption of, 1351 intoxication with, 234–235 liver necrosis due to, 229 metabolic activation of, 230f, 1355, 1355f placental permeability of, 1357 Carbonyl chloride, 1225–1226 Carboxyhemoglobin (COHb), 295t, 298 fetal, 1299 in carbon monoxide poisoning, 1298 diagnostic testing of, 1300–1301, 1300t in smoke inhalation injuries, 1285, 1286 elevation of, 1289 Carboxypeptidase, methotrexate toxicity limited with, 934 Carcinogen(s). See also specific carcinogen. hepatic, 237–238, 238f work-related, 1252t in herbal teas, 1082 in smoke, 1288 sulfur mustard as, 1504 Carcinogenicity, of chlorinated hydrocarbons, 1357 Cardiac arrhythmias. See Arrhythmias; specific arrhythmia. Cardiac conduction system abnormal, 134, 135f effect of β-adrenergic blockers on, 978 effect of cocaine on, 760 effect of tricyclic antidepressants on, 540, 541f Cardiac glycoside poisoning, 497 Cardiac pacing difficulties in, drug overdose and, 139, 140f for β-adrenergic blocker intoxication, 980 for bradycardia, 959 Cardiomyopathy amphetamine-induced, 786 antipsychotic agents associated with, 712 beer-drinkers’, 1162 cocaine-induced, 760 Keshan’s, 1164 Cardiotoxicity, chemotherapy-induced, 930–931 rescue agents limiting, 935 Cardiovascular toxicity amphetamine-induced, 143, 786 anabolic steroid–induced, 1105

Cardiovascular toxicity (Cont’d) arrhythmias associated with, 134–139. See also Arrhythmias. chemical asphyxiants associated with, 158t, 162–163 chlorinated hydrocarbon–induced, 1353–1355 class IA antiarrhythmic–induced, 1014, 1014f cocaine-induced, 141–143, 758–760 management of, 142, 142t, 765, 766t–767t, 767 colchicine-induced, 861 Crotalidae envenomation associated with, 405t heavy metals associated with, 158t, 163 herbal teas associated with, 1082 hypotension associated with, 133–134 industrial chemical–induced, 1246–1247 iron-induced, 1120 marijuana-induced, 750 natural products associated with, 163–164 opioid-induced, 644 plant-induced, 481–482 pulmonary edema associated with, 139–140 specific drugs associated with, 140–163 stings and bites associated with, 163 theophylline-induced, 143–144, 144f, 1038–1039 triptan-induced, 853–854 Cardioversion, for arrhythmias, 960 Carisoprodol properties of, 696t withdrawal from, 699 Carminative agent, definition of, 1435b Carrier oils, definition of, 1435b Cascara sagrada, hepatotoxicity of, 239b Castor beans, 486f Castor oil plant seeds, ingestion of, gastrointestinal effects of, 278 Cataracts, systemic substances causing, 309b Catecholaminergic system, 194–197, 196b Catecholamines. See also Dopamine, Epinephrine; Norepinephrine. drugs affecting neurotransmission of, 195 effects of, 194–195 for β-adrenergic blocker intoxication, 980 Catechol-O-methyl transferase, 561 Caterpillars, 451, 451f, 452f Catfish, 510 stings from, 513 venom of, 511–512 Catharsis, 39 Cationic surfactants, ocular injury due to, 308 Cefazolin, in breast milk, 366t Ceftriaxone poisoning, in children with Crigler-Najjar disease, 394, 394b Cell sensitivity, to radiation damage, 1474 Center for Study of Criminal Poisoning (CSCP), 122–123, 123f Centipedes, 452 bites from, 453, 453f Central hyperexcitation syndrome, 197 Central nervous system (CNS) Crotalidae envenomation affecting, 405t depression of. See Depression, CNS. effect of amphetamines on, 785–786 effect of chlorinated hydrocarbons on, 1353 effect of class IA antiarrhythmics on, 1013–1014 effect of cocaine on, 760–761 management of, 767–768 effect of hallucinogens on, 798–799 effect of herbal teas on, 1082

Central nervous system (CNS) (Cont’d) effect of lead poisoning on, 1134, 1138 effect of marijuana on, 749 effect of nerve gas on, 1488, 1490t, 1491t effect of NSAIDs on, 872 effect of opioids on, 642, 644, 649 effect of salicylates on, 840–841 pediatric, environmental toxicants and, 1272 Central nervous system (CNS) disabling agents exposure to, 1518 assessment of, 1519 manifestations of, 1518–1519 mass casualties following management of, 1519–1520 principles of preparedness in, 1520 pathophysiology of, 1518 treatment of, 1519 relevant history of, 1517–1518 Centruroides exilicauda, 440, 440f Centruroides sculpturatus, 440 envenomation of goat serum antivenom for, 446 grades of, 443, 444t Centruroides vitatus, 444, 444f Century plant, 486f Cephalosporins cross-reactivity of, 878 nephrotoxicity of, 255 Cerebellar degeneration, alcoholic, 595 Cerebral edema, salicylate-induced, 840 Cerebrospinal fluid levels, in lithium toxicity, 583 Cesium isotopes, exposure to, 1470–1471 Cestodes, 912 Chamomile, allergic reactions to, 1082 Chamomile oil, 1440t Chaparral leaf, hepatotoxicity of, 239b Charcoal, activated. See Activated charcoal. Charcoal hemoperfusion cartridges, 54 “Chasing the dragon,” 644 consequence of, 645 Cheese, tyramine in, 568, 569b Chelation therapy. See also specific chelator. for heavy metal poisoning, 1167–1168, 1168t for inhalation actinide accidents, 1472 for iron poisoning, 1126–1127 in pregnancy, 352–353 for lead poisoning in adults agents for, 1135 indications for, 1135–1136 in children indications for, 1141–1142 oral agents for, 1141 parenteral agents for, 1140–1141 in pregnancy, 357, 368 for mercury poisoning, 1116 Chemical(s) corrosive, 1407–1413, 1407t effect of, on gastrointestinal tract, 281 ingestion of clinical manifestations of, 1409–1410 diagnosis of, 1410–1411 in special populations, 1409 management of, 1411–1413 patient disposition and, 1413 ocular injuries due to, 302–307 acids as, 304–307, 305t, 306b alkalis as, 302–304, 303f, 303t solvents as, 307 structure-activity relationships of, 1408–1409

INDEX

Chemical(s) (Cont’d) dose response curve of, 1269, 1270f hepatotoxic, 225, 228t, 234–236 high-production-volume. See also Industrial toxicant(s). in commercial use, 1237 information sources for, 1254t, 1255 industrial, threshold limit values for, 1461–1462 occupational exposure to, disorders associated with, 175t uncontrolled release of, 1461. See also Hazardous material incident(s). Chemical antagonism, 92 Chemical asphyxiants, cardiac disturbances due to, 158t, 162–163, 176 Chemical burns classification of, 1409, 1409t decontamination of, 34 to esophagus, 1410 to eyes acids causing, 304–307, 305t, 306b alkalis causing, 302–304, 303t solvents causing, 315 Chemical irritant dermatitis, plant-induced, 495 Chemical spot tests, 66 Chemical warfare material. See also Chemical weapons. stockpiled, 1502, 1502t Chemical weapons, 1487–1520. See also specific agent for details. anticholinergics as, 732 choking agents as, 1507–1510 CNS disabling agents as, 1517–1520 lacrimators as, 1511–1515 nerve gases as, 1487–1499 vesicants as, 1500–1506 Chemical Weapons Convention (CWC) demilitarization program of, 1502 named chemicals and chemical abstract service number scheduled under, 1508, 1508t Chemoprotectants, limitation of drug toxicity with, 934–935 Chemotherapeutic agents, 927–936. See also specific agent. leukopenia due to, 298, 299b mechanism of action of, 927–928 nephrotoxicity of, 255–256, 255b, 267 overdose of, 927–928 diagnosis of, 932–933 management of, 933–935 enhanced elimination in, 935 rescue agents in, 934–935 manifestations of, 930–932 pharmacology of, 928, 929t, 930 pulmonary toxicity due to, 187t CHEMTREC, rapid emergency information from, 1461 Chenopodium oil, 1440t Chernobyl childhood thyroid cancer near, 1475 hazardous material incident in, 1456–1457 Chest pain amphetamine-induced, 786 cocaine-induced, 758 Cheyne-Stokes breathing, 24 Children. See also Neonates. acute intermittent porphyria in, drug safety and, 395–396, 395b, 395f acute lymphoblastic leukemia in, 1475 arsenic poisoning in, 1149 aspirin-related fatalities in, 836, 836f caustic ingestions in, 1409

Children (Cont’d) Crigler-Najjar disease in, ceftriaxone toxicity with, 393–394, 394b cyclosporine clearance in, 946 effects of radiation on, 1475 environmental toxins in, 1269–1273, 1269b assessing risk of, 1269–1270, 1270f, 1270t developmental pharmacology for, 1270–1271, 1271f governmental and nongovernmental approaches to, 1272–1273 physiologic susceptibilities of, 1271–1272, 1271f ethanol metabolism in, 591 fatty acid metabolic disorder in, valproate toxicity with, 390–391, 391f folate metabolic abnormality in, methotrexate toxicity with, 394, 394f glucose-6-phosphate dehydrogenase deficiency in, oxidant toxicity with, 393 hemodialysis and hemoperfusion in, 56 lead poisoning in, 1136–1142. See also Lead poisoning, in children. malignant hyperthermia in, inhaled anesthetic toxicity with, 394–395 maple syrup disease in, benzodiazepines toxicity with, 392–393, 393f nerve gas poisoning in, 1492–1494, 1493t, 1494f organochlorine insecticide toxicity in, 1232 ornithine transcarbamylase deficiency in, antidepressant toxicity with, 391–392, 392f poison prevention in, 383–389 active vs. passive strategies for, 383 educational programs in, 386–387 general strategies for, 384 physician’s responsibility in, 388–389 poison control centers and, 387–388, 388t product packaging changes in, 384–386, 385t specific strategies for, 384–388 sticker trials for, 386 salicylate pharmacokinetics in, 838 selective serotonin reuptake inhibitor therapy for, 552 thyroid cancer in, after Chernobyl, 1475 tricyclic antidepressant exposure in, 537–538 triptan use in, 853 vitamin A deficiency in, 1093 vitamin B12 metabolic abnormality in, methotrexate toxicity with, 394 warfarin-based rodenticide ingestion by, 1056–1057 China, Gaoqiao, hazardous material incident in, 1457 Chinaberry, 486f Chinese herbal medicine, 1078–1079 Chinese proprietary medicine, 1080, 1084 Chloracne, work-related, 1252t Chloral hydrate drug interactions with, 662, 663t history and structure of, 659, 659f intoxication with management of, 668 manifestations of, 662–663 pharmacokinetics of, 661–662, 662t toxic effects of, in neonate, 371 Chlorambucil, pharmacologic parameters of, 929t Chloramphenicol, overdose of, 883

1529

Chlorbenzylidene malonitrile, 1512. See also Lacrimators. Chlordiazepoxide for alcohol withdrawal syndrome, 600, 601t recommended dosage of, 672t Chlordimeform, in insecticides, 1188–1189, 1188f Chlorinated hydrocarbon insecticides. See Organochlorine insecticides. Chlorinated hydrocarbons, 1347–1359. See also Hydrocarbons, chlorinated; specific compound. Chlorine, 1391–1396 as choking agent, 1507, 1507t, 1508 chronic exposure to, 1395–1396 intoxication with, 1392–1393 case studies of, 1394–1395, 1394t diagnosis of, 1392 management of, 1393–1394 triage algorithm for, 1393f relevant history of, 1391 structure of, 1392, 1392f Chlorine bleach, toxicity of, 1449–1450 management of, 1450–1451 Chlormethiazole drug interactions with, 663t history and structure of, 660 intoxication with, 663 diagnosis of, 666 pharmacokinetics of, 662t Chlormezanone adverse effects of, 664 drug interactions with, 663t intoxication with, 663–664 pharmacokinetics of, 662t Chloroacetophenone, 1511. See also Lacrimators. Chloroethylnitrosoureas, nephrotoxicity of, 267 Chlorofluorocarbons chemical formulas of, 1378t history of, 1377 inhalation of clinical manifestations of, 1378 management of, 1378–1379 pathophysiology of, 1378 pharmacokinetics of, 1378 structure of, 1377–1378 Chloroform, 1347, 1348t, 1350 absorption of, 1351 exposure to, blepharospasm caused by, 1356 hepatotoxicity of, 236 Chlorophenoxy herbicides, 1200–1202, 1200f Chloropicrin, as choking agent, 1507, 1507t Chlorothiazide, in breast milk, 366t Chlorphenesin, properties of, 696t Chlorpheniramine, prophylactic, for nonnative Elapidae snakebites, 430 Chlorpromazine for neonatal opiate withdrawal, 368t for serotonin syndrome, 217 history of, 659 Chlorzoxazone intoxication with, 699 properties of, 696t Choking agents exposure to, 1508–1509 assessment of, 1510 manifestations of, 1509 pathophysiology of, 1509 prenatal and pediatric issues following, 1509–1510 treatment of, 1510 relevant history of, 1507–1508 select military, 1507t

1530

INDEX

Cholecalciferol, in rodenticides, 1219–1220 Cholecystokinin, in regulation of gastrointestinal function, 271 Cholera, 528–529 management of, 529 Cholestasis, without hepatitis, drug- or toxininduced, 237, 237b Cholestatic jaundice, in anabolic steroid users, 1104–1105 Cholestyramine for fecal excretion of organochlorine insecticides, 1234–1235 for thyroid hormone overdose, 1071, 1072, 1073f mechanism of toxicity of, 337 Choline acetyltransferase, in acetylcholine synthesis, 199 Cholinergic system, 199–201 Cholinesterase inhibition of by carbamates, 1174–1175 by organophosphates, 1175–1176, 1175t, 1489 pharmacology of, 1174 true, 199 Cholinomimetics, cardiac disturbances due to, 149–151, 150b Choreoathetosis/salivation syndrome, pyrethroid-induced, 1187 Chromatographic assays, 67–69, 70f, 71f Chromium, 1161–1162 Chronic fatigue syndrome, 1281. See also Idiopathic environmental intolerance. Chronic obstructive pulmonary disease, 177–178 definition of, 177 Cicutoxin, in water hemlock, 498 Cidofovir, 896t–897t, 905–906, 905f Cigarettes, clove, 1439 Ciguatera fish poisoning, 516 cardiovascular disturbances due to, 163–164 clinical manifestations of, 517 management of, 518 Ciguatoxin, 201 Cimetidine for acetaminophen poisoning, 831 for anaphylaxis, 880, 880f for methemoglobinemia, 294 usage of, during pregnancy and lactation, 727 Cinchonism, 1014 Cinnamon oil, 1436, 1440t Ciprofloxacin, for shigellosis, 532 Circulatory shock, management of, 133–134 Circulatory support, in emergency care, 18–21, 19b, 20t Cirrhosis drug- or toxin-induced, 237 Indian childhood, 1162 Cisplatin nephrotoxicity of, 267, 932 rescue agents limiting, 934–935 pharmacologic parameters of, 929t Citalopram overdose of, 554 pharmacokinetics of, 551t Clara cells, 169 Cleaners, household, corrosives in, 1407–1408, 1407t Clearance, of drugs, 90–91 Clinical toxicologists, roles of, 1259 Clinic-based education, in childhood poisoning prevention, 386–387

Clitocybe mushrooms, 464, 464f Clomipramine, pharmacokinetic parameters of, 539t Clonazepam overdose of, cardiac disturbances due to, 156, 156f recommended dosage of, 672t Clonidine, 1001–1007 adverse effects of, 1005–1006 cardiac disturbances due to, 148, 149f drug interactions with, 1004 for akathisia, 715 for neonatal opiate withdrawal, 368t history of, 1001 intoxication with clinical manifestations of, 1004–1005, 1005t diagnosis of, 1006 epidemiology of, 1001 management of, 1006–1007 pathophysiology of, 1003 patient disposition and, 1007 pharmacokinetics of, 1003, 1003t pharmacology of, 1001–1002 structure of, 1002f Clonidine patch, 1007 pharmacokinetics of, 1003t Clonidine withdrawal syndrome, 1006 Clopidogrel, 1060–1061, 1061t Clorazepate, recommended dosage of, 672t Clorgyline, 565 Clostridium botulinum, 200, 521. See also Botulism. Clostridium perfringens, food poisoning causing, 527–528 Clove cigarettes, 1439 Clove oil, 1439, 1441t Clubionid spider, 437 Clupeotoxin poisoning, 516 CNS. See Central nervous system (CNS). Coagulation, 1051–1053 intrinsic and extrinsic pathways of, 1052 platelet, 1051–1052, 1052f vitamin K and, 1052–1053, 1053f Coagulation cascade, 1052, 1053f, 1053t control of, 1052 Coagulation factors, 1053t antithrombin III inhibition of, 1058–1059 decreased production of, salicylate poisoning and, 841 half-lives of, 1056t Coagulopathy late-onset and persistent, CroFab antivenin causing, 416t, 417–419 warfarin/superwarfarin-induced, reversal of, vitamin K for, 1056, 1056t Coal worker’s pneumoconioses, 179, 182 Cobalt, 1162 occupational exposure to, 184 Cobra(s), 425, 427f Cobra bites, 426–428, 429t Cocaine, 6, 755–769 history of, 755 neurologic effects of, 196 pharmacokinetics of, 757–758 pharmacology of, 757 structure-activity relationships of, 756, 757f toxicity of, 758–769 clinical manifestations of, 758–763, 759t diagnosis of, 763–764 differential diagnosis of, 764–765 management of, 765, 766t–767t, 767–768 patient disposition and, 768–769 transport of, by body stuffers and packers, 762, 768. See also Body stuffers/packers.

Cocaine (Cont’d) use/abuse of cardiovascular complications in, 141–143, 758–760 management of, 142, 142t, 765, 766t–767t, 767 CNS complications in, 760–761 management of, 767–768 during pregnancy, 354–355, 762–763 endocrine complications in, 763 epidemiology of, 755–756 fatal, 756 organ donation after, 130 gastrointestinal complications in, 762 head and neck complications in, 762 hematologic complications in, 763 hepatic complications in, 231, 763 hyperthermias associated with, 761–762 pulmonary complications in, 761 management of, 768 renal failure associated with, 762 management of, 768 rhabdomyolysis associated with, 762 management of, 768 urologic complications in, 763 withdrawal from, in neonate, 367–368 Cocaine abstinence syndrome, phases of, 761 Cocaine washed out syndrome, 761 Cockroach powder ingestion, suicide by, 235 Codeine, 645 pharmacology of, 636 Coenzyme Q, for progressive spongiform leukoencephalopathy, 652 Cognitive functioning, effect of marijuana on, 749 COHb. See Carboxyhemoglobin (COHb). Colchicine, 476, 859–863 classification and structure of, 859, 859f drug interactions with, 860 history of, 859 pharmacokinetics of, 859–860 Colchicine poisoning clinical manifestations of, 860–862 diagnosis of, 862 effects of, 860 gastrointestinal effects of, 277–278 leukopenia due to, 298, 299b multisystem organ failure due to, 499 pathophysiology of, 860 phases of, 862t treatment of, 862–863 Colchicum autumnale, 859 Colesevelam, mechanism of toxicity of, 337 Colestipol, mechanism of toxicity of, 337 Colitis, Clostridium difficile, 277 Colognes, 1429 Colon cathartic, 283 structure and function of, 273–274 Color vision. See also Visual entries. styrene affecting, 1368 Coma barbiturate-induced, stages of, 691t benzodiazepine-induced, 682 chlorophenoxy-induced, 1201 clonidine-induced, 1004–1005 diquat-induced, 1196 isoniazid-induced, 922 paraquat-induced, 1197 tricyclic antidepressant–induced, 541 Coma blisters, in barbiturate overdose, 691 Combustion, smoldering vs. flaming, 1283 Committee on Environmental Health (COEH) statements, on pediatric environment health, 1273

INDEX

Common oleander, 493f Community education, in childhood poisoning prevention, 386 Compartment syndrome, Crotalidae snakebites causing, 412 Comprehensive Environmental Response, Compensation and Liability Act (CERCLA), Good Samaritan provision of, 1459 Conditioner, hair, 1428–1429 Cone shells, 509–510 Congestive heart failure, risk of, in anabolic steroid abusers, 1105 Coniine, in poison hemlock, 498 Connective tissue disease, silicosis associated with, 182 Consciousness assessment of, 24 definition of, 24 Constipation, toxic disorders presenting with, 282–284 Constriction band therapy, for Crotalidae snakebites, continual adjustment of, 407 Consumer Product Safety Commission (CPSC), 1262 Contact dermatitis antibiotic-induced, 881 lacrimator-induced, 1515 occupational chemicals causing, 1245, 1252t plant-induced, 495, 500 Contact urticaria, plant-induced, 495 Continuous arteriovenous hemofiltration, for paraquat poisoning, 1200 Continuous renal replacement therapy, for lithium toxicity, 585, 586t Continuous venovenous hemodiafiltration for lithium toxicity, 585, 585f, 586t for salicylate poisoning, 846 Continuous venovenous hemofiltration, 47–48, 47b, 47t, 48b for lithium toxicity, 585, 585f, 586t Contraceptive pills, estrogens in, 333 Controlled Substances Act (1970), 755 Convallaria majalis, 1081t, 1082 Cooling measures, for hyperthermic syndromes, 216 Co-oximetry, in methemoglobinemia diagnosis, 292, 293 Copper, 1162 hepatotoxicity of, 236 occupational exposure to, 184 Copper chromium arsenate, 1148 Coprine, chemical structure of, 465f Coprine-containing mushrooms, 458b, 465–466, 465f Coprinus mushrooms, 465, 465f Coral(s), 509 hydroid, 508–509 stings from, 512 management of, 514 Coral snake(s), 423 Coral snakebites clinical manifestations of, 424 diagnosis of, 424 pathophysiology of, 423–424 prognosis of, 425, 426f treatment of, 424–425 Coriaria species, toxicity of, 484 Cornea, anatomy and physiology of, 301, 302f Coronary atherosclerotic disease, ethanol consumption and, 597 Corrosives. See Chemical(s), corrosive; specific agent.

Corticosteroids. See also specific agent. for anaphylaxis, 879–880, 880f for baby powder inhalation, 1417 for chlorine exposure, 1394 for corrosive injury, 1412 for smoke inhalation victims, 1292 for thyroid hormone overdose, 1072 topical, neonatal exposure to, 370 Cortinarius mushrooms, 467–468, 468f Cosmetics, 1423–1433. See also specific cosmetic product. dermatitis caused by, 1423t history of, 1423–1425 product categories of, 1424t toxicology of, 1427–1429 Cough, therapeutic drug–induced, 188t Coumaphos, 1172t Covalent binding, in hepatic injury, 224b COX. See Cyclooxygenase (COX) entries. Coyotillo, hallucinogenic effects of, 499 Crack baby behavior, 763 Crack cocaine, 755. See also Cocaine. Crack dancing, 761 Crack eye, 762 Crack lung, 761 Crank. See Methamphetamines. Creatine abuse of, 1107 management of, 1107–1108 potential adverse effects of, 1102t structure and pharmacology of, 1106–1107, 1106f Creatinine clearance, reduced, salicylate poisoning causing, 841 Crigler-Najjar disease, in children, 393–394 drugs to avoid in, 394, 394t Criminal poisoning. See Forensic toxicology. Crotalidae envenomation of, 399–420. See also Snakebite(s). North American species of, 399, 400t Crotalidae immune Fab (CroFab) antivenin, 413–419 coagulopathies with, late-onset and persistent, 416t, 417–419 complications with, 413–417, 415t, 416t contraindications to, 413 dosage of, 415t, 418 premarketing clinical trials for, 414b redosage of, 419 studies of, 414t Crown-of-thorns starfish, 509 stings from, 513 venom of, 511 Crystal meth. See Methamphetamines. Crystalluria, calcium oxalate, in ethylene glycol poisoning, 615, 616f Cubozoa, 507 Cupboard spider, 433 Cushing’s syndrome, treatment of, 326, 330 Cyad tree fruit, hepatotoxicity of, 239b Cyanide, 6–7, 7f chronic exposure to, 1309–1310 in smoke, 1285, 1287 lethal blood level of, definition of, 1285 toxicodynamics of, 1311 toxicokinetics of, 1310–1311 Cyanide poisoning, 1309–1314 cardiac disturbances due to, 158t, 163 clinical manifestations of, 1311 diagnosis of, 1311–1312 differential diagnosis of, 1312 due to nitroprusside therapy, 983–985 epidemiology of, 1310

1531

Cyanide poisoning (Cont’d) fatalities due to, organ donation after, 128, 129t in smoke inhalation, 1286, 1287 management of antidotes in, 1313 decontamination in, 1313 elimination in, 1313–1314 hydroxycobalamin in, 985 in smoke inhalation victims, 1293 supportive measures in, 1312 neurologic effects of, 204 pathophysiology of, 1310 patient disposition in, 1314 Cyanoacrylates, ocular injury due to, 308 treatment of, 311t, 312 Cyanogenic plants, 484–485, 499 Cyanosis in methemoglobinemia, 292–293 work-related, 1249t Cyclobenzaprine intoxication with, 698–699 properties of, 696t Cyclooxygenase (COX), acetaminophen inhibition of, 825 Cyclooxygenase (COX) inhibitors, 865 nephrotoxicity of, 263 nonselective, 868t Cyclopeptide-containing mushrooms, 457–461, 458b overview of, 457–458 pathophysiology of, 458–459 toxic effects of clinical presentation of, 459 diagnosis of, 459–460, 459f management of, 460–461 Cyclophosphamide cardiotoxicity of, 930–931 pharmacologic parameters of, 929t Cyclosarin general properties of, 1490t history of, 1488 Cyclosporine, 945–947 drug interactions with, 914 intoxication with, 914–915 nephrotoxicity of, 264–266, 265f, 266f CYP1A2 isoenzyme, 100, 552 substrates, inhibitors, and inducers of, 85t, 100t CYP2C9 isoenzyme, 100 substrates, inhibitors, and inducers of, 85t, 100t CYP2C19 isoenzyme, 100–101, 539 substrates, inhibitors, and inducers of, 85t, 100t CYP2D6 isoenzyme, 101, 539, 552, 708–709 in dextromethorphan metabolism, 776 substrates, inhibitors, and inducers of, 85t, 100t CYP2E1 isoenzyme, 101 in benzene metabolism, 1366 in ethanol metabolism, 589–590, 590f substrates, inhibitors, and inducers of, 85t, 100t CYP3A4 isoenzyme, 101, 553 substrates, inhibitors, and inducers of, 85t, 100t CYP4A4 isoenzyme, 552 Cyproheptadine for akathisia, 715 for muscle relaxant intoxication, 701t for serotonin syndrome, 217, 574 Cyproterone acetate, hepatitis due to, 235b Cytochrome oxidase, inhibition of, formic acid causing, 309

1532

INDEX

Cytochrome P-450 system barbiturate interaction with, 690 changes in activity of, at various ages, 1271, 1271f chlorinated hydrocarbon metabolism involving, 1351–1352, 1352f class IA antiarrhythmic interaction with, 1015 drug interactions involving, 99–101, 100t drug metabolism involving, 84–86, 85f major isoenzymes in, 85t polymorphisms in, 93, 93t SSRI metabolism involving, 552 Cytochrome-b5 reductase deficiency of, in congenital methemoglobinemia, 292 in methemoglobin reduction, 291, 292f Cytotoxic plants, causing multiorgan failure, 481 D D2 receptor antagonism, antipsychotics and, 704–706, 706t Dancing mania, 10, 1280 Dantrolene for malignant hyperthermia, 218 for MAO inhibitor overdose, 568 for neuroleptic malignant syndrome, 216, 716 for serotonin syndrome, 218 hepatitis due to, 235b properties of, 696t Dapsone for brown recluse spider bites, 437 overdose of, 883–884 Date rape, gamma-hydroxybutyric acid–related, 804 Datura stramonium, 1081t, 1082 Daunorubicin cardiotoxicity of, 930 pharmacologic parameters of, 929t DDT (dichlorodiphenyltrichloroethane), 1231. See also Organochlorine insecticides. pathophysiology of, 1232 Deadly nightshade, 200 Death adder bites, 428, 429t Débridement of brown recluse spider bites, 437 of snakebite wounds, 412–413 Decongestants, cardiovascular complications of, 143 Decontamination, 31–41. See also specific product or procedure. controversy and consensus regarding, 31 decision analysis for, 40 dermal, 27–28, 28b, 28t, 31–34 for plant-related poisonings, 501 in mass casualty situations, 33–34, 33f–35f dual-corridor emergency, 1497, 1497f duration of, 33 extracorporeal principles of, 55 toxic substances amenable to, 57, 58t for flammable material exposures, 34 for fluoride exposures, 34 for hazardous material exposures in field, 1462–1464, 1463f in hospital, 1464–1465 for high-pressure injection injuries, 34, 36 for hymenoptera stings, 450 for nerve gas exposures, 1495, 1497–1498, 1497f for phenol exposures, 34 for radionuclide exposures, 34 for vesicant exposures, 1504–1505

Decontamination (Cont’d) for water-reactive material exposures, 34 gastrointestinal. See Gastrointestinal decontamination. in mass casualty situations management of, 1497–1498, 1497f personnel associated with, 33–34, 33f–35f principles of, 1497 in pregnant patient, 349–350 integrated approach to, 40, 41f methods of, 31 ocular, 31–34 for lacrimator exposures, 1515 for plant-related poisoning, 501 personnel associated with, 33–34 temperature for, 33 tetanus prophylaxis and, 36 Decontamination foam (EasyDECON 200), 32 Decontamination solutions, choice of, 32–33 Deferoxamine, 1168t adverse effects of, 1127 for iron poisoning, 1126–1127, 1126b in pregnancy, 352–353 Deferoxamine challenge test, 1126 Degreaser’s flush, trichloroethylene associated with, 1356 Dehydroepiandrosterone abuse of diagnosis of, 1107 management of, 1108 potential adverse effects of, 1102t structure and pharmacology of, 1106 Delavirdine, 892t–893t, 900, 900f Delirium anticholinergic-induced, 727 treatment of, 729–730 calcium channel blocker–induced, 968 tricyclic antidepressant–induced, 541 Delirium tremens, in alcohol withdrawal, 600 Dementia, alcoholic, 595 Demyelinating neuropathy, 205 Dendrocnide species, toxicity of, 500 Dental amalgams mercury-containing, 1113 release of mercury from, 1277–1279, 1278f Dental fluorosis, 1326 Dental products essential oils in, 1435–1436 sodium fluoride in, 1325–1326 Dentrifices, 1430–1431 Denture cleaners, 1430 Deodorants, 1432 Deoxyhemoglobin, 295t Department of Transportation (DOT) Emergency Response Guidebook, 1459, 1460f, 1463 Depilatories, 1432–1433 Depression CNS β-adrenergic blockers causing, 978 antipsychotics causing, 710 benzodiazepine intoxication causing, 680 phenobarbital causing, 736 thiazide-induced, 995 tricyclic antidepressant intoxication causing, 541 valproate intoxication causing, 739 epidemiology of, 549 in elderly, 377 Dermal. See also Skin entries. Dermal absorption of drugs, 83 of herbicides, 1198, 1201–1202, 1204 of nerve gases, 1491–1492

Dermal absorption (Cont’d) systemic toxicity after, toxins associated with, 28b Dermal burns hydrofluoric acid causing, 1326 treatment of, 1328–1330, 1329f iodine causing, 1389 Dermal decontamination, 27–28, 28b, 28t, 31–34. See also Decontamination. for plant-related poisonings, 501 in mass casualty situations, 33–34, 33f–35f Dermal exposure to bleaches, 1450 to soaps and detergents, 1448 Dermatitis chlorinated hydrocarbon–induced, 1356 contact antibiotic-induced, 880 occupational chemicals causing, 1245, 1252t cosmetic, ingredients causing, 1423t lacrimator-induced, 1515 plant-induced, 495–496 toxin-induced, 499–500 Dermatologic disorders, colchicine-induced, 862 DES (diethylstilbestrol), 334 in utero exposure to, 335 Descemet’s membrane, 301 Desipramine, pharmacokinetic parameters of, 539t Desmopressin, 319 Desoxycorticosterone, mechanism of toxicity of, 329 Detergent(s), 1443–1448 cationic, 1447 enzyme-containing, 1443–1444 ocular injury due to, 307–308 sources of, 1444 statistics for, 1444t synthetic, surfactants used in, 1443, 1446b toxicity of, 1444–1445 management of, 1447–1448 manifestations of, 1445–1446 Dexamethasone for hair straightener burns, 1428 for ocular mustard injury, 312 for thyroid hormone overdose, 1072 Dexmedetomidine dosage of, 1004t pharmacokinetics of, 1003t structure of, 1002f Dexrazoxane cardiotoxicity of, rescue agents limiting, 935 doxorubicin toxicity limited with, 935 Dextromethorphan, 648 intoxication with clinical effects of, 776–777 diagnosis of, 777 epidemiology of, 773 treatment of, 777–778 neuropharmacology of, 773–774 pharmacology of, 776 serotonin syndrome and, 573 structure of, 773f Dextrose dosage of, 1028t for insulin overdose, 1028t, 1031 for sulfonylurea overdose, 1028t, 1029–1030 Diabetes insipidus, nephrogenic, lithiuminduced, 581, 582 Diabetes mellitus agents for, 1019–1032. See also specific agent. antipsychotic-induced, 712 glucocorticoid-induced, 329–330

INDEX

Diabetic ketoacidosis, antipsychotic-induced, 712 Dialysis. See also Hemodialysis; Peritoneal dialysis. for acetaminophen poisoning, 831 for acute renal failure, 259 Diaphoresis, intoxication associated with, 23 Diarrhea, intoxicants causing, 277 Diarylaminopropylethers, structure of, 963, 964f Diazepam for acute dystonia, 715 for alcohol withdrawal syndrome, 601, 601t for camphor-induced seizures, 1421 for hyperthermic syndromes, 216 for neuroleptic malignant syndrome, 216, 717 for seizures, organophosphate-induced, 1177 for serotonin syndrome, 218 in breast milk, 366t recommended dosage of, 672t structure of, 673f Diazinon, 1172t Diazoxide, 318 for sulfonylurea overdose, 1030 Dibenzoxazepine, 1512. See also Lacrimators. Dichlorodiphenyltrichloroethane (DDT), 1231. See also Organochlorine insecticides. pathophysiology of, 1232 Dichloromethane. See Methylene chloride. 1,3-Dichloropropene, 1225 Diclofenac for ocular mustard injury, 312 toxic effects of, 870 Didanosine, 890t–891t, 898, 898f Dieffenbachia, 486f Dietary exposure, to bromides, 1 Dietary nutrients, absorption of, 273 Dietary supplements gamma-hydroxybutyric acid in, 804, 805f Internet resources on, 1441b Diethylcarbamazine, 914–915 Diethyldithiocarbamate, ethanol interactions with, 592 Diethylene glycol, 623t, 626, 626t N,N-Diethyl-m-toluamide in insecticides, 1191–1192, 1191f toxicity of, 1192 Diethylstilbestrol (DES), 334 in utero exposure to, 335 Diffuse alveolar damage, 171 Diffusion definition of, 81 facilitated processes in, 81 Diflunisal, toxic effects of, 870 Digestion, drugs inhibiting, 276, 276t Digitalis altering sensitivity to, 953 cardiac disturbances due to, 157, 158t, 159, 159f, 160f chronotropic effect of, 952 drug interactions with, 952–953, 952t, 1015 inotropic effect of, 951–952 intoxication with, 949, 952–953 cardiac symptoms of, 953–955, 954b, 957f, 958f clinical presentation of, 953–955 diagnosis of, 956–958, 959f factors predisposing to, 953b noncardiac symptoms of, 955, 958t

Digitalis (Cont’d) intoxication with (Cont’d) rhythm and conduction disturbances in, 954b, 955, 958f treatment of, 958–961 antidotal therapy in, 14t, 960–961, 960f, 961b dysrhythmia therapy in, 959 ectopy therapy in, 959–960 electrolyte disorder correction in, 959 gastrointestinal decontamination in, 958 pharmacology of, 949–953, 950f, 950t, 951f, 952t therapeutic and toxic concentrations of, 956–958, 959f therapeutic use for, 951–952 Digitalis body load, calculation of, 961b Digitoxin. See also Digitalis. pharmacokinetics of, 950f, 951f pharmacologic characteristics of, 950t Digoxin. See also Digitalis. in breast milk, 366t intoxication with gastrointestinal effects of, 281 quantitation and interventions for, 71t pharmacokinetics of, 950f, 951f pharmacologic characteristics of, 950t Dihydralazine, hepatitis due to, 235b Dihydropyridines, structure of, 963, 964f 2,6-Diisocyanate physicochemical properties of, 1317, 1318t sources of, 1317 toxicity of, 1318–1321. See also Isocyanates, intoxication with. Diltiazem for ocular mustard injury, 312 for thyroid hormone overdose, 1072 Dimercaprol, for lead poisoning, in adults, 1135 2,3-Dimercaptopropanol-sulfonic acid, 1168t for arsenic poisoning, 1153 2,3-Dimercaptosuccinic acid, 1168t for arsenic poisoning, 1153 for lead poisoning, in pregnant patient, 357 for mercury poisoning, 1116 Dimethyl sulfoxide, with calcium carbonate, for hydrofluoric acid burns, 1328 Dimethylnitrosamine, carcinogenicity of, 237–238 Diphenhydramine for acute dystonia, 715 for anaphylaxis, 880, 880f usage of, during pregnancy and lactation, 727 Diphenoxylate, 646 gastrointestinal disturbances due to, 283 Diphosgene, as choking agent, 1507, 1507t Diphoterine, for ocular injury irrigation, 311 Diphtheria, vs. botulism, 524t Diquat, 1195–1197, 1195f Disaster cycle. See also Emergency management. four-phase, FEMA defined, 1454–1455, 1454f sequence of events in, 1459 Dishwashing detergents statistics of, 1444t, 1445t toxicity of management of, 1447–1448 manifestations of, 1445–1447 Disopyramide cardiac disturbances due to, 151, 152t, 153b pharmacokinetics of, 1009

1533

Disseminated intravascular coagulation–like syndrome, Crotalidae snakebite causing, 402, 403t Dissociative agents, 773–778. See also Dextromethorphan; Ketamine; Phencyclidine (PCP). Distribution, 83 of drugs in elderly, 379 in neonate, 363–364, 365t in pregnancy, 348 interactions involving, 98–99 of thyroid hormones, 1067 volume of, estimation of, 83 Disulfiram ethanol interactions with, 592 hepatitis due to, 235b Disulfoton, 1172t Diterpene alkaloids, 476, 482 Dithiothreitol, in reversal of knockdowns, 1338 Di-tryptophan animal of acetaldehyde (DTAA), 7, 7f Diuresis for bromide poisoning, 1387 forced, for salicylate poisoning, 845 in renal failure, 254–255 Diuretics, 995–996, 995f, 996f for vitamin A overdose, 1094 nephrotoxicity of, 253 pulmonary toxicity due to, 187t toxicity of, management of, 996 DNA damage, in hepatic injury, 224b DNA synthesis, chemotherapeutic disruption of, 927–928 Dobutamine, in emergency care, 20, 20t Dogbane, 491f Domoic acid, in food poisoning, 203 L-Dopa, bromocriptine with, serotonin syndrome due to, 212 Dopamine for prerenal failure, 258 in emergency care, 20, 20t in neurotransmission, 194 synthesis of, 194 Dopamine agonists, 196 Dopamine antagonists, 196 Dopamine receptors blockade of, 196–197 subtypes of, 195 Dose-response curves, 91–92, 92f Dothiepin, pharmacokinetic parameters of, 539t Down-regulation, of drug receptor density, 93 Doxepin, pharmacokinetic parameters of, 539t Doxorubicin cardiotoxicity of, 930 rescue agents limiting, 935 pharmacologic parameters of, 929t Drug(s). See also named drug and drug group. adverse reactions of, in elderly, 377 bromide-containing, 1385t response of, genetic difference in, 93–94, 94t therapeutic administration of, pulmonary toxicity due to, 185, 186t–187t, 188t Drug Abuse Warning Network (DAWN), 13, 773 opioid overdose estimates by, 635 Drug action, targets of, 91–92, 92f Drug allergy, 878. See also Hypersensitivity reactions.

1534

INDEX

Drug disposition, 81–88. See also Absorption; Biotransformation; Distribution; Excretion. Drug interactions, 97–103 direct receptor effects in, 103 drugs commonly involved in, 97b epidemiology of, 97–98 indirect receptor effects in, 103 mechanisms of pharmacodynamic, 102 pharmacokinetic, 98–103, 98b, 98t, 100t primary, 97, 97b nutrients involved in, 102–103, 102b Drug overdose. See also under specific drug. activated charcoal for, gastrointestinal complications of, 283 cardiac pacing in, difficulties of, 139, 140f during pregnancy, neonatal toxic effects of, 365, 367–368 fatalities due to multiple organ procurement after, 127–130 organ donation after, 130 pulmonary toxicity due to, 187t screening for. See Toxicologic screens. serum quantitation of, 69–73 altered analytic, pharmacokinetic, and pharmacodynamic relationships in, 72–73, 72f availability and accuracy of, 71–72 rationale and use of, 69–71, 71t vs. poisoning, 13 Drug safety, in children with acute intermittent porphyria, 395–396, 395b Drug screening, drugs and toxins not detected by, 28b DTAA (di-tryptophan animal of acetaldehyde), 7, 7f Dual-corridor emergency decontamination, in mass casualty situations, 1497, 1497f DUMBELS mnemonic, 1489 Dusts, definition of, 170 Dysentery, Shigella causing, 532 Dysgeusia, 274 Dyskinesia, tardive antipsychotic agents causing, 711 management of, 716 Dyspnea amphetamine-induced, 786 cocaine-induced, 761 in paraquat poisoning, 1197 Dystonia, acute antipsychotics causing, 711 management of, 715 E Ear(s), examination of, 23 Ecstasy. See 3,4-Methylenedioxymethamphetamine (MDMA). Eczema, radiation therapy for, facial carcinomas following, 1476, 1477f Edema cerebral, salicylate-induced, 840 laryngeal, caustic ingestions causing, 1410 pulmonary. See Pulmonary edema. Edrophonium, for non-native Elapidae snakebites, 430 EDTA. See Ethylenediaminetetraacetic acid (EDTA). Educational programs, in childhood poisoning prevention clinic-based, 386–387 community-wide, 386

Efavirenz, 892t–893t, 900, 900f Effective dose, median (ED50), 92 Efficacy, of drug, 91 Elapidae bites of, 422–431. See also Snakebite(s), Elapidae. non-native, 425–431 North American, 423–425 Elderly adverse drug reactions in, 377 anatomic and physiologic changes in, 378–380, 378t anticholinergic intoxication in, 379b, 380 antipsychotic use in, 708 benzodiazepine sensitivity in, 677–678 cardiovascular drug intoxication in, 379b, 380 cyclosporine clearance in, 946 depression in, 377 ethanol metabolism in, 591 hypoglycemic drug intoxication in, 379b, 380 organochlorine insecticide toxicity in, 1233 pharmacodynamic features in, 378–379 pharmacokinetics in, 379 poisoning in evaluation of, 380 high-risk drugs associated with, 379–380, 379b prevention of, 381 treatment of, 380–381, 381t unintentional, 377 psychotherapeutic drug intoxication in, 379b, 380 salicylate intoxication in, 379–380, 379b, 838 selective serotonin reuptake inhibitor therapy in, 550 suicide among, 377–378 toxicologic issues in, 377–381 epidemiology of, 377–378 Electrocardiography, of tricyclic antidepressant intoxication, 541f, 542 Electroconvulsive therapy, for neuroleptic malignant syndrome, 217 Electrolyte(s) daily requirements of, 117t imbalance of, 115–116, 117t. See also specific disorder. digitalis-induced, correction of, 959 fluoride-induced, 1331 salicylate-induced, 840 Eletriptan, pharmacokinetics of, 852t Elimination. See Excretion. Elixirs, 1087 for childhood lead poisoning, 1140 Emergency antidotes, 14t–15t Emergency department episodes, related to gamma-hydroxybutyric acid, 804, 804f Emergency management assessment of toxicity in, 24 circulatory support in, 18–21, 19b, 20t clinical evaluation in, 21–27, 22t evidence of arrhythmia in, 24–25, 25b evidence of gastrointestinal disturbances in, 25–26, 26b evidence of metabolic acidosis in, 25, 25b evidence of osmolality disturbances in, 25, 26b evidence of seizures in, 26, 26b comprehensive, 1453–1454 decontamination procedures in, 27–30. See also Decontamination.

Emergency management (Cont’d) effective, 1454 history taking in, 21 laboratory evaluation in, 26–27, 27b of poison patients, 13, 14t–15t, 15–18 physical examination in, 21, 23–24 principles of, 1453–1455 Emesis caffeine-induced, 1045 management of, 1046 in gastrointestinal decontamination, 36 intoxicants causing, 277 theophylline-induced frequency of, 1042f management of, 1042 Emmenagogue agent, definition of, 1435b Emtricitabine, 890t–891t, 899, 899f Encephalopathy lead-induced, in children, 1138 toxic, work-related, 1249t Wernicke’s, 594–595 Endocrine system cocaine-induced toxicity of, 763 pediatric, environmental toxicants and, 1272 β-Endorphins, receptor selectivity of, 198 Endoscopy, in gastrointestinal decontamination, 37 Endotracheal intubation, 13, 15–18 age-specific tube sizes for, 16t clinical conditions necessitating, 15b complications of, 18 equipment for, 16, 16b in children, 18 of smoke inhalation victim, 1292 pharmacotherapy used in, 16t postintubation management of, 18 rapid sequence technique of, 18. See also Rapid sequence intubation. Enflurane, hepatitis due to, 235b Enfuvirtide, 894t–895t, 903–904, 904f Enteritis, Campylobacter causing, 533 Enterobiasis (oxyuriasis), poquil for, 916 Enterocapillary exsorption, for theophylline overdose, 1043 Envenomation marine, 507–515 clinical manifestations of, 512–513 diagnosis of, 513 epidemiology of, 507–511, 508f–512f, 511t, 512t management of, 513–515 pharmacology of, 511–512 relevant history of, 507, 508t nephrotoxicity of, 256 scorpion, 163, 440, 442–447. See also Scorpion stings. snake, 399–431. See also Snakebite(s). spider, 163, 433–438. See also under specific spider. Environmental endocrine disrupters, 1233 Environmental intolerance, idiopathic, 1275, 1280–1281 toxicogenic and psychogenic theories of, 1281 Environmental laws, 1261 Environmental Protection Agency (EPA), 1261–1262 Environmental Protection Agency (EPA) guidelines for maximum mercury exposure, 369 for reference dose or reference concentration, 1270

INDEX

Environmental toxicology. See also Air; Carcinogen(s); specific toxin. clinical considerations in, 1258–1259 federal agencies concerned with, 1261–1265 formal approach to, 1259–1260, 1259f history of, 1257–1258 nongovernmental organizations concerned with, 1265–1266 Environmental toxins clear-cut exposure to, 1258 neonatal exposure to, 368–369 nephrotoxicity of, 267–268 nonoccupational exposure to, limits in, 1261 occupational exposure to, limits in, 1260–1261 pediatric exposure to, 1269–1273, 1269b. See also Children, environmental toxins in. poorly defined exposure to, 1258–1259 situational factors associated with, 1258 toxicologic testing for, 78 Enzyme(s). See also specific enzyme. drug interactions involving, 99–101, 100t nonmicrosomal, 101–103 drug-metabolizing, 93, 93t. See also Biotransformation; Cytochrome P-450 system; specific isoenzyme. inhibition of, in hepatic injury, 224b pancreatic, 272 Eosinophilia antibiotic-induced, 881 pulmonary, therapeutic drug–induced, 188t Eosinophilia-myalgia syndrome, 7 Ephedrine, 781, 782f cardiovascular complications of, 143 hepatotoxicity of, 239b Epilepsy, anticonvulsants for, 735 Epinephrine for anaphylaxis, 879, 880f for Irukandji syndrome, 514 for jellyfish stings, 514 in emergency care, 20, 20t in neurotransmission, 194 prophylactic, for non-native Elapidae snakebites, 430 Epirubicin, cardiotoxicity of, 930 Eplerenone, mechanism of toxicity of, 329 Erasmus syndrome, 182 Ergot(s), cardiac disturbances due to, 158t, 161–162, 162f Ergot alkaloids, 198 pulmonary toxicity due to, 187t Ergotamine, cardiac disturbances due to, 161–162 Erythema multiforme, antibiotic-induced, 881 Erythema nodosum leprosum, thalidomide for, 938 Erythrocyte(s) disorders of, 289–299, 298b, 299b. See also specific disorder. hemolysis of, 289–291, 290b, 290f metabolism of, 289f oxidant stress of, 289, 289f Erythrocytic mean cell volume, elevation of, agents causing, 298, 298b Erythromycin, for Campylobacter enteritis, 533 Erythropoiesis, anabolic steroid–induced, 1104 Erythroxylum coca, 755. See also Cocaine. Esmolol, for thyroid hormone overdose, 1072 Esophageal burns, caustic ingestions causing, 1410 Esophageal stricture, caustic injury–induced, 1410

Esophagus disorders of, 274 function of, 272 Essence, definition of, 1435b Essential oils, 1435–1442. See also specific oil. definitions of, 1435b Internet resources on, 1441b therapeutic uses of, 1435–1436 toxicity of, 1436, 1440t–1441t management of, 1440 Estonia, residential radiation accident case study in, 1477, 1478f Estrogens, 332–334 biosynthesis of, 1103f in contraceptive pills, 333 medroxyprogesterone acetate with, 335 postmenopausal use of, 332–333 Ethanol, 589–602, 589t. See also Alcohol entries. blood concentration of, 590–591, 590t in non–alcohol-dependent population, 593t cardiovascular effects of, 146, 146f, 596–597 consumption of, cancers associated with, 284 drug interactions with, 592–593, 592t for ethylene glycol poisoning, 618–619, 619t dosage of, 619t gastrointestinal effect of, 279, 597 hypoglycemia due to, 318 illicit making of, lead exposure resulting from, 1132 in body paint and makeup, 1432 in breast milk, 366t in colognes and perfumes, 1429 intoxication with, 593–602 acute, 593–594, 593t chronic, 594–597 addiction, tolerance, dependency, and withdrawal in, 598–602 neuropsychiatric effects of, 594–595 other effects of, 595–597, 596f, 596t, 597f pathophysiology of, 598–599 signs and symptoms of, 593t metabolic pathway of, 605f metabolism of, 590–591, 591f in special populations, 591 neonatal exposure to, 370 pharmacokinetics of, 589–591, 590f, 590t, 591f withdrawal from, 599–602 gamma-hydroxybutyric acid in, 811–812 management of, 600–602, 601t pathophysiology of, 598–599 severity of, 598 symptoms of, 599–600 Ethchlorvynol drug interactions with, 663t, 664 intoxication with, 664 diagnosis of, 666 pharmacokinetics of, 662t, 664 structure of, 659f Ethers, glycol, 627–631, 628t ingestion of, 629t–630t Ethylene glycol, 611–612 lethal dose of, 612 metabolic pathway of, 605f physical properties of, 612t toxokinetics and toxicology of, 612–614, 613f, 613t Ethylene glycol poisoning, 611–621 clinical presentation of, 614, 614t diagnosis of, 614–616, 615t, 616f

1535

Ethylene glycol poisoning (Cont’d) fatalities due to, organ donation after, 129–130 management of, 616–620 algorithm for, 621f antidotes in, 616–619, 618b, 618t, 619t critical analysis of, 620–621, 621f hemodialysis in, 58, 619–620, 619b metabolic acidosis in, 108–109 pathogenesis of, 613f Ethylene oxide, neuropathy due to, 206t Ethylenediaminetetraacetic acid (EDTA), 1168t for calcium hydroxide burns, 311–312 for lead poisoning in adults, 1135 in children, 1141–1142 in pregnancy, 357 Etidronate, 325 for steroid-induced osteoporosis, 329 Etomidate, in rapid sequence intubation, 16t Etorphin, chemical structure of, 637f Eucalyptus oil, 1436–1437, 1441t Eugenol, in clove oil, 1439 Exchange transfusion. See Transfusion, exchange. Excitotoxicity, of neurons, 202 Excretion fecal, of organochlorine insecticides, 1234–1235 of drugs, 87–88, 88b in adult vs. neonate, 365t in breast milk, 366t in pregnancy, 348 interactions involving, 101–102 of herbicides, 1199–1200 of thyroid hormones, 1067 Exposure(s), occupational. See Occupational exposure(s). Extracorporeal decontamination, principles of, 55 Extremity(ies), examination of, 24 Eye(s) anatomy of, 301, 302f decontamination of, 31–34. See also Decontamination. for lacrimator exposures, 1515 for plant-related poisoning, 501 movement of, disturbance of, 24 physiology of, 301 toxic injury to. See Ocular injury. Eyebrows, alopecia of, systemic substances causing, 309b Eyelids, alopecia of, systemic substances causing, 309b F F(ab)2 immunoglobulin, for coral snakebites, 425 Fab fragments for colchicine overdose, 863 for coral snakebites, 425 for Crotalidae snakebites, 413–419 for digitalis poisoning, 157, 960–961, 960f, 961b for scorpion stings, 447 Fabric softeners, cationic surfactants in, 1447 Facial makeup, 1424t, 1431–1432 Factor II, antithrombin III inhibition of, 1058–1059 Factor Xa inhibitors, 1059, 1059f Fair Packaging and Label Act (1966), 1423 False nails, 1430 Famciclovir, 894t–895t, 902, 902f Fasciotomy for Crotalidae snakebites, 412 for Elapidae snakebites, 430

1536

INDEX

Fat maldistribution, nucleoside reversetranscriptase inhibitors causing, 898 Fatalities aspirin-related, in children, 836, 836f drug overdose–induced multiple organ procurement after, 127–130 organ donation after, 130 fire-related, 1284. See also Smoke inhalation. forensic investigations in, 1284–1285 occupational, U.S. Bureau of Labor Statistics on, 1237 Fat-soluble vitamins, 1089, 1090–1096, 1091t. See also specific vitamin. Fatty acid metabolism, 390–391, 391f disorders of, in children, valproate toxicity with, 391 Fatty liver, 228–229, 229b Fecal discoloration, agents causing, 277, 277t Fecal excretion, of organochlorine insecticides, 1234–1235 Federal Agencies, concerned with environmental toxicology, 1261–1265 Federal Caustic Poison Act (1927), 1407 Federal Emergency Management Agency (FEMA), 1453 four-phase disaster cycle defined by, 1454–1455, 1454f Federal Hazardous Labeling Act (1960), 384 Federal Hazardous Substances Act (1960), 1407 Felbamate intoxication with, 740 pharmacokinetics of, 740 Feminization, anabolic steroid–induced, 1104 Fenofibrate, mechanism of toxicity of, 338 Fenoprofen, toxic effects of, 871 Fentanyl, 645–646 chemical structure of, 640f in rapid sequence intubation, 16t, 17 therapeutic index of, 1519 toxic effects of, in neonate, 371 Ferritin, 1119 Ferrous salts, 1119, 1119t. See also Iron. Fetal alcohol syndrome, 1474 Fetus carboxyhemoglobin (COHb) levels in, 1299 development of, effects of maternal marijuana use on, 750 effects of radiation on, 1474–1475 exposure of to amphetamines, 787–788 to benzodiazepines, 679–680 to choking agents, 1509–1510 to cocaine, 762 to mercury, 1114, 1115 to salicylates, 837, 841 placental transfer of substances to, 348 Fever inhalational, 178–179, 180t–181t work-related, 1250t Fibric acid derivatives, 336, 338 Fibrosis, asbestos-induced, 182–183 Field decontamination, of hazardous material–contaminated patient, 1462–1464, 1463f Fipronil, 1190–1191, 1190f Fire fatalities due to, 1284. See also Smoke inhalation. forensic investigations in, 1284–1285 toxic products of, 1288

Fire ants, 447–448 stings of, 448, 449 First aid, for Crotalidae snakebites, 406–407, 407t ineffective or dangerous, 407–408 First responders, hazardous materials training for, 1458 Fish, tyramine in, 568, 569b Fixed oil, definition of, 1435b FK506. See Tacrolimus. Flaming combustion, vs. smoldering combustion, 1283 Flammable materials, cutaneous decontamination from, 34 Flashbacks, hallucinogen-induced, 799 Flatworms (flukes), 911–912 Flavonoids, in ginkgo, 483 Flora, gastrointestinal, altered, 276 Flubendazole, 913 Fludrocortisone, mechanism of toxicity of, 329 Fluid(s) body intracellular composition of, 113–114 redistribution of, cellular responses to, 114–115 regulation of, 113, 113f, 115 tonicity of, 113 daily requirements of, 117t Fluid balance assessment of, 116 daily, regulation of, 115–116, 116b management of, 115–116, 117t Fluid imbalance diuretic-induced, 995, 996 salicylate-induced, 840 Fluid spaces, intracellular and extracellular, movement of water between, 114 Fluid therapy for clonidine overdose, 1006 for colchicine overdose, 862 for hypotension, 133, 715 for jellyfish stings, 514 for lithium poisoning, 584 for malignant hyperthermia, 218 for salicylate poisoning, 843 for smoke inhalation, 1292 in emergency care, 19 Flukes (flatworms), 911–912 Flumazenil chemical structure of, 682f for benzodiazepine overdose, 682–683 for muscle relaxant intoxication, 701t for sedative intoxication, 667 Fluoride(s) adverse effects of, 325 alternate forms of, 1332, 1332t cardiac disturbances due to, 158t cutaneous decontamination from, 34 electrolyte abnormalities due to, 1331 gastrointestinal disturbances due to, 280 in dental products, 1325–1326, 1431 sulfuryl, 1227–1228 Fluoride ions, pathophysiologic effects of, in hydrofluoric acid, 1324 Fluoroacetate, in rodenticides, 1217 Fluorocarbons history of, 1377 inhalation of cardiac disturbances due to, 146–147 clinical manifestations of, 1378 management of, 1378–1379 pathophysiology of, 1378 pharmacokinetics of, 1378 structure of, 1377–1378

Fluoroquinolones, overdose of, 882 Fluorosis dental, 1326 skeletal, 1326 5-Fluorouracil cardiotoxicity of, 931 pharmacologic parameters of, 929t Fluoxetine overdose of, 554 pharmacokinetics of, 551t Flurazepam, recommended dosage of, 672t Flurbiprofen, toxic effects of, 871 Fluvoxamine overdose of, 554 pharmacokinetics of, 551t Folate metabolism, 394f abnormal, in children, methotrexate toxicity with, 394 Folk remedy(ies), 1084–1085, 1085t definition of, 1084 lead contamination in, 1132 childhood poisoning due to, 1137 Fomepizole for ethylene glycol poisoning, 616–618, 618b, 618t for methanol poisoning, 14t, 610 Food(s) lead in, 1132 MAO inhibitor interaction with, 568–569, 569b mercury-contaminated, ingestion of, 1114 styrene in, 1368 vitamin A–rich, 1091–1092 warfarin interaction with, 102b Food and Drug Administration (FDA), 1263 Food and Drug Administration (FDA) assignment, of drug categories for pregnancy, 347–348, 347t Food poisoning. See also Seafood poisoning. Bacillus cereus causing, 529–530 Campylobacter causing, 533 Clostridium botulinum causing, 521–526. See also Botulism. Clostridium perfringens causing, 527–528 domoic acid in, 203 illness caused by, 526 Salmonella causing, 530–532 Shigella causing, 532–533 Staphylococcus causing, 527 Vibrio cholerae causing, 528–529 Forensic toxicology, 119–131 analytical tests used in, historical development of, 120 arousal of suspicion in, 122 case examples of, 124–125 clinical issue(s) in, 126–131 criteria for organ and donor acceptability as, 126–127 specific substance fatalities as, 127–130 definition of, 119 historical development of, 119–120 homicidal poisoner’s characteristics in, 121–122 investigative issues in, 120–121 legal issues in, 123–124 organizations and resources for, 122–123, 123f trial strategies in, 124 victim in, sources of poison in, 121 Formamidines, 1188–1189, 1188f Formic acid ocular injury due to, 307 removal of, hemodialysis in, 57 uses and toxic effects of, 305t

INDEX

Formicidae, 447–448. See also Hymenoptera stings. Foscanet, 896t–897t, 905, 905f Fosphenytoin intravenous, vs. intravenous phenytoin, 737 pharmacokinetics of, 737 Four o’clocks, 491f Foxglove, 487f Fragrance preparations, 1424t, 1429 Free-basting, 756. See also Cocaine entries. Freon, 1377–1379 Frovatriptan, 850–851, 850f, 850t pharmacokinetics of, 852t Fuller’s earth, as absorbant, 38 Fume(s) definition of, 170 elemental mercury, exposure to, 1114 Fume fever syndrome, work-related, 1251t Fumigants, 1225–1228 Fungicides. See also specific compound. toxicity of, 229t Funnel-web spider toxin (atraxotoxin), 200 Furosemide, 996, 996f for prerenal failure, 258 for vitamin A overdose, 1094 G G protein–linked receptors, in neurotransmission, 192–193, 192f GABAergic system, 203–204. See also Gammaaminobutyric acid entries. Gabapentin, 204 intoxication with, 741 pharmacokinetics of, 740 Gallbladder diseases of, 275–276 structure and function of, 272–273 Gallium-desferrioxamine, for ocular mustard injury, 312 Gamma-aminobutyric acid, 538 effect of isoniazid on, 920 inborn error of metabolism of, 814 inhibition of activity of, insecticide-induced, 1232 Gamma-aminobutyric acid receptors, 194 benzodiazepine action at, 674, 677, 677f ethanol effects on, 598 types of, 203, 673–674 Gamma-butyrolactone, 803–804, 807f, 808t Gamma-hexachlorocyclohexane (lindane), 1231. See also Organochlorine insecticides. Gamma-hydroxybutyric acid, 803–818 analogs of, 806 as anesthetic, 811 as food supplement, 1086 clinical trials of, 812 distributors of, 806 dose-response effects of, in vivo and in vitro, 813t drug interactions with, 812 endogenous, 807, 809–810 production of, 815 exogenous, 810, 810f for alcohol dependence and withdrawal, 811–812 for narcolepsy, 811 history of, 803–804 overdose of, cardiovascular disturbances due to, 163 pharmacokinetics of, 810–812, 811t, 812t pharmacology of, 806–807, 809–810, 810f street names for, 806 structure of, 807f structure-activity relationships of, 806, 808t

Gamma-hydroxybutyric acid (Cont’d) use/abuse of acute overdose in, 816–817, 816b clinical manifestations of, 813–814, 813b, 813t diagnosis of, 814–816 qualitative and quantitative screening methods in, 815–816 specimen collection and storage in, 815 differential diagnosis of, 816 epidemiology of, 804–806, 804f, 805f management of antidotes in, 817 decontamination in, 817 supportive measures in, 816–817, 816b patient disposition in, 817–818 Gamma-hydroxybutyric acid withdrawal syndrome, 814 Ganciclovir, 894t–895t, 901, 901f Gaoqiao, China, hazardous material incident in, 1457 Gas(es). See also specific gas. combustible, 1283 definition of, 170 irritant, 176–177, 178t poison, in smoke inhalation injuries, 1285. See also Carbon monoxide poisoning; Smoke inhalation. volcanic, 9 water-soluble irritant, inhalation and toxicity of, 1245–1246 Gas chromatography, 69, 71f Gas chromatography analysis, of organochlorine insecticides, 1233–1234 “Gas eye,” hydrogen sulfide–induced, 1337 Gasping-baby syndrome, 7–8, 370 Gastric. See also Stomach. Gastric emptying, 36–37 drugs altering, 274–275 Gastric inhibitory peptide, in regulation of gastrointestinal function, 271 Gastric lavage for antipsychotic overdose, 715 for calcium channel blocker overdose, 969 for carbamazepine overdose, 738 for clonidine overdose, 1007 for iron poisoning, 1124–1125 for organochlorine insecticide poisoning, 1234 for salicylate poisoning, 844 for sedative overdose, 667 in decontamination, 37 Gastric perforation, salicylate poisoning causing, 841 Gastrin, in regulation of gastrointestinal function, 271 Gastritis, toxic disorders mimicking, 276–277, 277t Gastroenteritis plant-induced, 480–481 Salmonella causing, 530–532 toxic disorders mimicking, 276–277, 277t with hemorrhage, 278 Gastrointestinal decontamination absorbants in, 37–38 aggressive, for theophylline overdose, 1043 catharsis in, 39 decision analysis for, 40 emetics in, 36 endoscopy in, 37 for digitalis intoxication, 958 for neonatal poisoning, 372

1537

Gastrointestinal decontamination (Cont’d) for plant-related poisonings, 500 for thyroid hormone overdose, 1071 integrated approach to, 40, 41f laparotomy in, 37 lavage in, 37. See also Gastric lavage. toxin absorption in, 28, 29b, 29t elimination enhancement of, 29, 29t, 30b whole bowel irrigation in, 39. See also Whole bowel irrigation. Gastrointestinal tract altered flora of, 276 cancer of, 284 Crotalidae envenomation affecting, 405t drug absorption from, 98, 98b, 98t in pregnancy, 348 effect of arsenic on, 1150 effect of class IA antiarrhythmics on, 1014 effect of cocaine abuse on, 762 effect of colchicine on, 861 effect of herbal teas on, 1080–1081 effect of iron on, corrosive, 279–280, 1120 effect of nerve gas on, 1490, 1490t, 1491t effect of opioids on, 644 effect of poisoning on, 25–26, 274–282 treatment for, 284–285 effect of salicylates on, 279, 841 effect of theophylline on, 280–281, 1038 irritation of, plant-induced, 477, 480, 644 clinical manifestations of, 496–497 malabsorption by drug-induced, 276, 276t treatment of, 285 mechanical injury to, 284 pediatric, environmental toxicants and, 1272 structure, function, and regulation of, 271–274 toxin elimination from, 28, 29b, 29t. See also Gastrointestinal decontamination; specific procedure. Gell and Coombs classification, of immune reactions, 878, 878t Gels, teeth-cleaning, 1430 Gemfibrozil, 336 Gender relationships, in criminal poisonings, 121 Genetic mutations, in malignant hyperthermia, 214 Genetic variability, in drug response, 93–94, 94t Germander, hepatotoxicity of, 239b, 494 GH (growth hormone), 320 toxicity of, 320 Gingivitis, 274 Ginkgo tree, 483 Ginseng, toxicity of, 1083 Glasgow Coma Scale score, in heroin user, 651 Glomerular filtration rate, in acute renal failure, 255 Glucagon, 318 for β-adrenergic blocker intoxication, 979–980 for calcium channel blocker intoxication, 970–971 for hypoglycemia, 318–319, 319t for sulfonylurea overdose, 1030 in emergency care, 20t, 21 Glucocorticoid(s), 326–327, 326t adverse effects of, 329–330 mechanism of toxicity of, 327 Glucocorticoid antagonists adverse effects of, 330 mechanism of toxicity of, 328–329

1538

INDEX

Glucose for hypoglycemia, 318, 319t in GABA synthesis, 203 physiologic disturbances of. See also Hyperglycemia; Hypoglycemia. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, in children, oxidant toxicity with, 393 α-Glucosidase inhibitors intoxication with, 1026 adverse effects of, 1027–1028 management of, 1031 pharmacokinetics of, 1024 pharmacology of, 1023 structure and classification of, 1020, 1021f Glutamate(s), 202 Glutamate receptors, 202 Glutamic acid, in GABA synthesis, 203 Glutaminergic system, 202–203 Glutethimide drug interactions with, 663t, 664 intoxication with, 664–665 pharmacokinetics of, 662t, 664 structure of, 659f Glycine, 204 as neurotransmitter, 204 Glycoalkaloids, plants containing, gastroenteritis from, 481 Glycol(s), toxic removal of, 58 Glycol ethers, 627–631, 628t ingestion of, 629t–630t P-Glycoprotein, substrates, inhibitors, and inducers of, 88, 88b Glycoprotein IIB/IIIA inhibition, 1060, 1060t Glycopyrrolate, for muscarine mushroom poisoning, 465 Glycosides, 476–477, 478b cardiac, 497 cyanogenic, 484–485, 499 saponin, 485 Glycyrrhizic acid, in licorice root, 485 Glyphosate herbicides, 1202–1205, 1202f, 1204t surfactants in, 1203 Goat serum antivenom, for Centruroides sculpturatus envenomation, 446 Gold, 1162–1163 antidote for, 14t Golden orb weaver spider, 438 GoLYTELY. See Polyethylene glycol. Gonadal agents, 330–335, 335t Gonadotropin(s) suppression of, anabolic steroid–induced, 1104 treatment with, 320–321 Gonadotropin-releasing hormone (GRH), 319–320 Gouty arthritis, colchicine for, 860 Granulocyte colony-stimulating factor, for colchicine overdose, 863 Grayanotoxins, 476, 482 Gray-baby syndrome, chloramphenicolinduced, 1270 Greater celandine, hepatotoxicity of, 239b GRH (gonadotropin-releasing hormone), 319–320 Growth arrest, childhood lead poisoning causing, 1139 Growth hormone (GH), 320 toxicity of, 320 Guanabenz dosage of, 1004t pharmacokinetics of, 1003t Guanfacine dosage of, 1004t pharmacokinetics of, 1003t

Guanosine analogs, 894t–895t, 900–902 Guanosine monophosphate, in neurotransmission, 192–193 Guanosine triphosphate, in neurotransmission, 192 Guillain-Barré syndrome, vs. botulism, 523, 524t Gyromitra mushrooms, 463, 463f Gyromitrin chemical structure of, 463f mushrooms containing, 458b, 463–464, 463f H Haber’s rule, 1503 Hagedorn agents, for nerve gas poisoning, 1496 Hair, mercury accumulation in, 1115 Hair care products, 1424t, 1425–1427 Hair coloring preparations, 1424t, 1425–1426 Hair conditioner, 1428–1429 Hair lighteners, 1426 Hair loss. See Alopecia. Hair sprays, 1428 Hair straighteners, 1427–1428 Hair waving agents, 1426–1427 Halazepam, recommended dosage of, 672t Haldane effect, 1298 Half-life distribution, 88, 89f elimination, 88, 89f Hallucinations definition of, 793 in alcohol withdrawal, 599 plant-induced, 484, 498–499 with ketamine anesthesia, 775 Hallucinogen(s), 793–801. See also specific agent. cardiovascular effects of, 146 classification of, 794–796, 795t formulations and administration of, 797 history of, 793 intoxication with, 798–801 chromosomal abnormalities associated with, 799 diagnosis of, 800, 800b dose-response characteristics of, 799 “flashbacks” associated with, 799 management of, 800–801 morbidity and mortality due to, 799 patient disposition and, 801 physiologic disturbances associated with, 798 psychedelic effects of, 798–799 psychiatric disorders associated with, 799 natural, 794–795, 795t pharmacokinetics of, 797, 798t structure of, 796f structure-activity relationships of, 796–797 Hallucinogen persisting perceptual disorder, 799 Halogen(s), 1385–1396. See also specific compound, e.g., Bromide. Halogenated hydrocarbons. See also Hydrocarbons. neonatal exposure to, 368–369 Haloperidol, for phencyclidine intoxication, 777 Halothane, hepatotoxicity of, 232–233 Hand dishwashing detergent statistics of, 1444t, 1445t toxicity of, 1445–1446 management of, 1447–1448 Harassing agents, 1511. See also Lacrimators. Hard metal disease, 1162 Hard water, decreased soap effectiveness in, 1443

Harrison Narcotics Act (1914), 755 Hawaiian baby woodrose seeds, hallucinogenic effects of, 498 Hazardous material(s). See also Chemical(s); Chemical weapons; Industrial toxicant(s). antidotes for, 1465, 1465t classification of, 1239–1240, 1239b, 1240b, 1240f exposure to, 1455 release of, identification of, 1459, 1460f, 1461 Hazardous material incident(s). See also Mass casualty incident(s). diagnostic patient studies in, 1462 exposure in assessment of, 1461–1462 regional, 1464 field decontamination in, 1462–1464, 1463f hospital decontamination in, 1464–1465 identification of materials in, 1459, 1460f, 1461 in Bhopal, 1456 in Chernobyl, 1456–1457 in Gaoqiao, 1457 in Neyshabur, 1457 management of, 1455–1461 hospital, 1464–1465 of greatest magnitude, 1455–1457 preparedness for, 1457–1459 response to, 1459 triage following, 1462–1464, 1463f Hazardous materials training, of first responders, 1458 Hazardous Substances Emergency Events Surveillance (HSEES) system, 1455 HCG (human chorionic gonadotropin), 320–321 Head and neck, cocaine abuse affecting, 762 Headaches, withdrawal, following triptan overuse, 855 Heart. See also Cardiac; Cardio- entries. examination of, 23 toxic effects on, 133–164. See also Cardiovascular toxicity. Heart block drug-induced, 135, 136f in digitalis intoxication, 954, 955f Heavy metal(s), 1111–1116. See also specific metal. Heavy metal poisoning, 1157–1168. See also specific metal. antidotes for, 14t cardiac disturbances due to, 158t, 163 chelation therapy for, 1167–1168, 1168t gastrointestinal disturbances due to, 279–280 in neonate, 368–369 nephrotoxicity due to, 255b, 256 neuropathies due to, 205 Hedeoma pulegiodes, 1437 Heinz body, 289, 290 Heinz body hemolytic anemia, 289 Helminths, 911–912 Hemangioma, radiation therapy for, atrophy and facial deformity following, 1476, 1476f Hematologic system antipsychotic agents affecting, 713 cocaine abuse affecting, 763 colchicine intoxication affecting, 861 Crotalidae envenomation affecting, 405t herbal teas affecting, 1081–1082 NSAID overdose affecting, 872 salicylate intoxication affecting, 841

INDEX

Hematologic toxicants, in workplace, 1250t Hematopoietic system iron poisoning affecting, 1121 lead poisoning affecting, 1134 in children, 1139 Heme synthesis pathway, 395f Hemiptera stings, 452 Hemlock poison, 488f coniine in, 498 water, 489f cicutoxin in, 498 Hemlock water dropwort, 483–484 Hemodialysis, 54. See also Dialysis; Peritoneal dialysis. complications of, 56–57, 56b considerations for, 55–56 efficacy of, evaluation of, 57 for arsenic poisoning, 1153 for barbiturate poisoning, 692 for biguanide poisoning, 1031 for bromide poisoning, 1387 for busulfan poisoning, 935 for colchicine poisoning, 863 for cyclopeptide mushroom poisoning, 461 for ethylene glycol poisoning, 619–620, 619b for herbicide poisoning, 1202 for isoniazid poisoning, 924 for lithium poisoning, 584–585, 585f, 586t for methanol poisoning, 610 for phenobarbital poisoning, 736 for procainamide poisoning, 1015 for salicylate poisoning, 846–847 in pregnancy, 353, 354 for sedative poisoning, 668 for theophylline poisoning, 1043–1044, 1044b for thyroid hormone overdose, 1072 in pregnant patient, 350 in special populations, 56 risk and cost-benefit considerations in, 57 substances removed by, 58–59 Hemofiltration, continuous venovenous, 47–48, 47b, 47t, 48b Hemoglobin maternal and fetal, oxygen dissociation curve of, 355, 355f oxidation of, 289f Hemoglobin pigment, comparison of, 295t Hemolysis, 289–291, 290b, 290f Heinz body, 290 Hemolytic anemia antibiotic-induced, 881 Heinz body, 289 Hemoperfusion, 54 complications of, 56–57, 56b considerations for, 55–56 evaluation of, 57 for carbamazepine poisoning, 738 for cyclopeptide mushroom poisoning, 461 for methotrexate poisoning, 935 for muscle relaxant overdose, 700–701 for paraquat poisoning, 1199–1200 for phenobarbital poisoning, 736 for sedative overdose, 668 for sulfonylurea poisoning, 1030 for theophylline poisoning, 1043–1044, 1044b for tricyclic antidepressant overdose, 545 in pregnant patient, 350 in special populations, 56 risk and cost-benefit considerations in, 57 substances removed by, 58–59

Hemorrhage gastroenteritis with, 278 intracerebral, amphetamine-induced, 785 Hemosiderin, 1119 Henderson-Hasselbalch equation, 105 Henna, 1431 Heparin for non-native Elapidae snakebites, 431 low-molecular-weight, 1058–1059 unfractionated, 1058 Hepatic. See also Liver entries. Hepatic adenoma, in anabolic steroid users, 1105 Hepatic carcinogens, work-related, 1252t Hepatic disease benzodiazepine pharmacokinetics and, 678 drug- or toxin-induced general management of, 238–239 specific management of, 239–240 selective serotonin reuptake inhibitors and, 550, 552 Hepatic failure acute, 238–239 treatment of, 239, 240 antipsychotic-induced, 708 thionamide-induced, 323 valproate-induced, 739 Hepatic injury molecular mechanisms of, 224b toxin-induced, 223. See also Hepatotoxicity. diversity and classification of, 228, 229t Hepatic metabolism altered, antibiotic-induced, 881 of opioids, 642, 643f Hepatic tumors, drug- or toxin-induced, 237–238, 238f Hepatic zones, 223, 223f Hepatitis acute, 229–230, 229t, 230f cholestatic, drug- or toxin-induced, 237, 237b hepatocellular chemical-induced, 234–236 drug-induced, 230–234, 235b mushroom-induced, 234 herbal, 1081 mixed, drug- or toxin-induced, 236–237, 236b peliosis, in anabolic steroid users, 1105 Hepatocellular carcinoma, in anabolic steroid users, 1105 Hepatocytes, 223 Hepatomegaly, arsenic-induced, 1150 Hepatotoxic agents, 225, 226t–227t. See also specific agent. in workplace, 1252t Hepatotoxicity, 223–240 anabolic steroid–induced, 1104–1105 chemical-induced, 234–236 chlorinated hydrocarbon–induced, 1355–1356, 1355f cocaine-induced, 231, 763 drug-related, 230–234, 236–238, 787, 872, 900 diagnosis of, 225, 226t–227t, 228, 228b, 229t epidemiology of, 223–225 mechanisms of, 230–234 industrial chemical–induced, 1246 iron-induced, 232, 1120 management of, 238–240 mushroom-induced, 234 plant-induced, 238, 239b, 485, 494 salicylate-induced, 841

1539

Herb(s). See also specific herb. barbiturate interactions with, 690t contamination of, 1080, 1081t hepatotoxicity of, 238, 239b improper identification of, 1080 Internet resources on, 1441b nephrotoxicity of, 256 Herbal hepatitis, 1081 Herbal medicine, 1077–1084 adverse effects of, 1079–1080 Chinese, 1078–1079 patent (proprietary), 1084 clinical toxicity of, 1081t, 1083–1084 definition of, 1078 FDA regulation of, 1078 teas in, 1080–1083, 1082t terminology in, 1079 Herbicides, 1195–1207. See also specific compound. bentazon, 1206–1207, 1206f bipyridyl, 1195–1200 chemical classification of, 1195t chlorophenoxy, 1200–1202, 1200f effect of, on gastrointestinal tract, 279 glyphosate, 1202–1205, 1202f, 1204t toxicity of, 229t triazine, 1205 urea, 1205–1206, 1205f, 1206t Heroin, 644–645 chemical structure of, 637f overdose of, 645 acute lung injury due to, 645, 649 in pregnancy, 355 pharmacology of, 636 Hexacarbons, neuropathy due to, 206t γ-Hexachlorocyclohexane (lindane), 1231. See also Organochlorine insecticides. Hexachlorophene, neonatal exposure to, 369 Hexafluorine, for hydrofluoric acid burns, 312 Hexamethylene diisocyanate physicochemical properties of, 1317, 1318t sources of, 1317 toxicity of, 1318–1321. See also Isocyanates, intoxication with. High-density lipoprotein, in anabolic steroid abusers, 1105 High-molecular-weight sensitizing agents, associated with occupational asthma, 173t High-performance liquid chromatography, 69 High-pressure injection injuries, decontamination concerns regarding, 34, 36 Hippuric acid, as marker of toluene exposure, 1372–1373 Hirudins, 1059 Histamine, 201 Histamine metabolism, MAO inhibitors in, 567 Histamine receptor(s), 201, 724–725, 726t Histamine receptor blockers, 732 Histaminergic system, 201 Hobbies, lead exposure in, 1131–1132 Hobo spider, 437 Holly berries, toxicity of, 496 Homeopathy, 1085–1086 Homicidal poisoner, characteristics of, 121–122 Homicidal poisoning case registry reporting form, 123, 123f Honeybees, 447 Hospital admission for coral snakebites, 424–425 for Crotalidae snakebites, 408 recurrent, 417

1540

INDEX

Hospital decontamination, of hazardous material–contaminated patient, 1464–1465 Hospital response, to terrorist attack, 1498 Hot water immersion therapy, for sea urchins toxin, 514 Household products. See also specific product. age-related statistics for, 1444t corrosives in, 1407–1408, 1407t. See also Chemical(s), corrosive. hepatotoxic, 229t hydrofluoric acid–containing, 1323, 1325. See also Hydrofluoric acid, exposure to. outcome-related statistics for, 1445t 5-HT. See Serotonin. Huffer’s rash, 1372 Hugh’s classification, of ocular injury, 310, 310t Human chorionic gonadotropin (HCG), 320–321 Humidifier fever, 179 Huntington’s chorea, amphetamine exacerbation of, 785 Hycanthone, 915 Hydralazine hepatitis due to, 235b pharmacology and pharmacokinetics of, 987–988 toxicity of, diagnosis and management of, 988 Hydrazines, 920, 1380 Hydrocarbons. See also specific compound. aromatic, 1363–1375. See also Benzene. exposure to, 1363 treatment protocol for, 1367b cardiac disturbances due to, 146–147 chlorinated, 1347–1359 absorption of, 1351 prevention of, 1358–1359 carcinogenicity of, 1357 commonly encountered, 1348t–1349t distribution of, 1351 exposure to, 1350–1351 cardiovascular effects of, 1353–1355 CNS effects of, 1353 dermal effects of, 1356 hepatic effects of, 1355–1356, 1355f ocular effects of, 1356–1357 pulmonary effects of, 1357 renal effects of, 1356 metabolism and elimination of, 1351–1353, 1352f physicochemical properties of, 1347, 1350, 1350f poisoning with diagnosis of, 1357–1358 management of, 1358–1359 patient disposition and, 1359 teratogenicity of, 1357 toxicokinetics of, 1351–1353 from petroleum distillates, 1343. See also Petroleum distillates. halogenated, 1377–1379 neonatal exposure to, 368–369 inhaled, signs and tests for, 64t plant, 1344 poisoning with, management of, 1345–1346 polyaromatic, fires generating, 1288 Hydrochloride acid ocular injury due to, 306 uses and toxic effects of, 305t Hydrochlorothiazide, 995, 995f

Hydrocortisone for anaphylaxis, 879 for thyroid hormone overdose, 1072 prophylactic, for non-native Elapidae snakebites, 430 Hydrofluoric acid, 1323–1332 exposure to clinical effects of, 1325–1328 dermal burns in, 1326 treatment of, 1328–1330, 1329f diagnosis of, 1328 differential diagnosis of, 1328 home and industrial, 306b, 1323 inhalational, 1327 treatment of, 1331 management of, 1328–1332 antidotes in, 14t ocular burns in, 306–307, 1327 treatment of, 311t, 312, 1330–1331 oral, 1327–1328 treatment of, 1331 pathophysiology of, 1323–1325 structure-activity relationships of, 1323 systemic, 1331–1332 toxic effects of, 305t Hydrogen cyanide. See also Cyanide entries. in smoke, 1285, 1287 Hydrogen peroxide, in hair products, 1426, 1427 Hydrogen peroxide poisoning, gastrointestinal disturbances due to, 281 Hydrogen sulfide, 1335–1341 exposure to cardiovascular disturbances due to, 158t, 162 chronic sequelae of, 1339 clinical manifestations of, 1336–1337 emergency planning and response to, guidelines for, 1340t health effects of, 1336t laboratory features of, 1337 OSHA-permissible limits of, 1340 pathophysiology of, 1336 patient disposition with, 1338 prevention of, 1339–1341, 1340t treatment of, 1337–1338 lethality of, exposure-response curve for, 1340–1341 mechanism of action of, 1335 toxicokientics of, 1335–1336 Hydroid corals, 508–509 Hydroxocobalamin, for cyanide poisoning, 1313 γ-Hydroxybutyric acid. See Gammahydroxybutyric acid. 4-Hydroxybutyric aciduria, 814 Hydroxycobalamin, for cyanide poisoning, 985 4-Hydroxycoumarin, 1055, 1056f Hydroxymethylglutaryl-CoA inhibitors, 336–337, 338 hepatotoxicity of, 236 pulmonary toxicity of, 187t 5-Hydroxytryptamine (5-HT). See Serotonin. Hydroxyzine, for anaphylaxis, 880 Hydrozoa, 507 Hygiene products, 1424t, 1432 oral, 1424t, 1430–1431 Hymenoptera classification of, 447–448, 447f envenomation of pharmacokinetics of, 449 pharmacology of, 448–449

Hymenoptera stings cardiovascular disturbances due to, 163 clinical manifestations of, 449–450 diagnosis of, 450 epidemiology of, 448 in special populations, 449 management of, 450 nephrotoxicity of, 256 pathophysiology of, 448–449 patient disposition after, 450–451 prevention of, 448b Hyperamylasemia, 275 Hyperbaric oxygen therapy. See also Oxygen therapy. for brown recluse spider bites, 437 for carbon monoxide poisoning, 1302, 1303t, 1304–1305, 1304t in pregnant patient, 356, 356b for cyanide poisoning, 1312, 1313 for hydrogen sulfide poisoning, 1338 Hyperchloremic metabolic acidosis, 109 Hyperglycemia calcium channel blocker–induced, 968 protease inhibitor–induced, 902 Hyperglycemic agents, 318, 319, 319t Hyperkalemia, 117t hydrofluoric acid–induced, 1324, 1325 in hydrofluoric acid injury, 1332 NSAID-induced, 872 Hyperlipidemia, protease inhibitor–induced, 902 Hypermagnesemia, 1163 Hypernatremia, 117t Hyperoxygenation therapy, 1087 Hyperprolactinemia, cocaine-induced, 763 Hyperpyrexia, salicylate poisoning and, 841 management of, 844 Hypersensitivity pneumonitis, 173–174, 175t, 176, 180t work-related, 488, 1246, 1248t, 1251t Hypersensitivity reactions, 171–176. See also Anaphylactic reactions. quinidine-induced, 1010 to antibiotics, 877–881, 878t multisystem involvement in, 878–880, 879t, 880f organ-specific, 880–881 to irritant gases, 1246 to lamotrigine, 741 to salicylate products, 841 Hypersensitivity vasculitis, antibiotic-induced, 880, 881 Hypertension clonidine-induced, 1005 contraceptive pills causing, 333–334 glucocorticoid-induced, 330 scorpion stings causing, 446 Hypertensive reactions, with MAO inhibitors, foods implicated in, 568–569, 569b Hyperthermia cocaine-induced, 142–143, 761–762 management of, 767 intoxication associated with, 23 malignant. See Malignant hyperthermia. treatment of, 238 work-related, 1250t Hyperthyroidism, treatment of, 323 Hypnotics. See Sedative-hypnotics; specific agent. Hypocalcemia, in hydrofluoric acid injury, 1324–1325, 1332 Hypochlorite solutions for organophosphate decontamination, 1177 for vesicant decontamination, 1504

INDEX

Hypoglycemia β-adrenergic blocker–induced, 978 causes of, 1029b diabetic control agent–induced, 1026–1027 diagnosis of, 1028 management of, 1029–1031 disopyramide–induced, 1010 ethanol causing, 318 signs and symptoms of, 1025b sulfonylureas causing, 317 treatment of, 318–319, 319t vacor causing, 318 Hypoglycemic agents, 317–319, 317t, 318t, 1020t. See also specific agent. adverse effects of, 1026–1027, 1028 history of, 1019 intoxication with clinical manifestations of, 1025, 1025b, 1026 diagnosis of, 1028–1029, 1029b epidemiology of, 1019–1020 in elderly, 379b, 380 management of, 1029–1030, 1031 patient disposition and, 1031–1032 signs and tests for, 64t mechanism of action of, 317 pharmacokinetics of, 1024–1025 pharmacology of, 1022–1024 structure and classification of, 1020–1022, 1021f Hypoglycin, in ackee fruit, 318, 485, 494 Hypokalemia, 117t theophylline-induced, 1039–1040 management of, 1043 thiazide-induced, 995 Hypomagnesemia, in hydrofluoric acid injury, 1332 Hyponatremia, 117t treatment of, 320 vasopressin causing, 319 Hypotension ACE inhibitor–induced, 992 antihypertensive drug–induced, 148 calcium channel blockers–induced, 151 clonidine-induced, 1004–1005 deferoxamine-induced, 1127 intoxications associated with, 19b management of, 133–134, 715 mechanism of, 133 opiate overdose causing, 649 orthostatic, antipsychotics causing, 707, 710 refractory, tricyclic antidepressant intoxication causing, 541 sympathetic-inhibiting drug–induced, 147 theophylline-induced, 144 tricyclic antidepressant–induced, 156 Hypothalamic agents, 319–320 Hypothalamus-pituitary axis, 319 Hypothalamus-pituitary-adrenal axis, suppression of, 329 Hypothalamus-pituitary-gonadal axis, interruption of, anabolic steroid–induced, 1104 Hypothalamus-pituitary-thyroid axis, 321, 322f Hypothermia, intoxication associated with, 23 Hypovolemia, in poisoned patient, management of, 116, 118 Hypoxemia, definition of, 1289 Hyssop oil, 1441t I Iatrogenic botulism, 521, 526. See also Botulism. Ibogaine, hallucinogenic effects of, 498 Ibotenic acid, chemical structure of, 462f

Ibotenic acid–containing mushrooms, 458b, 461–463, 462f Ibuprofen, toxic effects of, 870, 870f Idarubicin, pharmacologic parameters of, 929t Idiopathic environmental intolerance, 1275, 1280–1281 toxicogenic and psychogenic theories of, 1281 Ifosfamide, pharmacologic parameters of, 929t Illicit drug(s) abuse of. See also under specific drug. fatalities due to, 636 organ donation after, 130 serotonin syndrome due to, 212 transport of, 648, 762, 768. See also Body stuffers/packers. Imidacloprid, in insecticides, 1191, 1191f Imidazoles, 884, 912–914. See also specific agent. Imidazolines, 1004t. See also specific agent. Imipramine, pharmacokinetic parameters of, 539t Immediately dangerous to life or health (IDLH) levels of hazardous materials, 1461 of sulfur mustard, 1504 Immune reactions, Gell and Coombs classification of, 878, 878t Immune system effect of antiarrhythmics on, 1010, 1014 effect of marijuana on, 750 in infants, environmental toxicants and, 1272 Immunoassays, 66, 69f Immunoglobulin(s), F(ab)2, for coral snakebites, 425 Immunoglobulin E (IgE)–independent reaction, 878 Immunosuppressives, 943–948. See also specific agent. nephrotoxicity of, 264–266, 265f, 266f Impila, hepatotoxicity of, 239b Impotence, cocaine-induced, 763 Impulse, abnormal, arrhythmias due to, 134 Inamrinone, for β-adrenergic blocker intoxication, 980 Inandione, 1055, 1056f India, Bhopal, hazardous material incident in, 1456 Indian childhood cirrhosis, 1162 Indinavir, 892t–893t, 903, 903f Indole-containing mushrooms, 458b, 466–467, 466f Indomethacin, toxic effects of, 871 Industrial emissions, lead in, 1131 Industrial poisoning, 1237–1255 chemical agents in, information sources for, 1254t, 1255 classification of hazardous materials in, 1239–1240, 1239b, 1240b, 1240f historical perspectives of, 1237–1238 inadequate physician training regarding, 1239 laboratory evaluation of, 1253, 1255 occupational fatalities due to, 1237 occupational history in, 1240–1245, 1241f assessing causation in, 1242–1243 current job and, 1240–1241 environment in, 1242 exposure characterization in, 1243–1244 exposure route in, 1244–1245 previous job and, 1242 routine survey in, 1240 workplace exposure levels and monitoring in, 1244

1541

Industrial poisoning (Cont’d) organ-specific, 1246–1247, 1248t–1253t, 1253 pathophysiology of, 1245–1246, 1247t recognition of occupational diseases in, 1238–1239 Industrial radiation accident, at Yanango hydroelectric power plant, 1479–1480 Industrial toxicant(s). See also Chemical(s); specific toxicant. contamination of, 1238 inhalation absorption of, 1246 latency of, 1238 nonoccupational conditions affecting response to, 1239 unavailable information regarding, 1238–1239 Industrial toxicology, of radioisotopes, 1469 Infant botulism, 521, 525–526. See also Botulism. Infant toxicologic screening, 78 Infertility, gonadotropin-releasing hormone for, 320 Ingestion, of herbicides, 1198, 1201, 1203–1204 Inhalants. See also specific inhalant. abuse of. See Solvents, abuse of. hydrocarbon, signs and tests for, 64t toxic, 176–185 Inhalation occupational, of organic and inorganic materials, 178–179, 180t–181t, 182 of fluorocarbons, cardiac disturbances due to, 146–147 of herbicides, 1196, 1202, 1204 of hydrofluoric acid, 1327 treatment for, 1331 of nerve gases, 1491 passive, of marijuana, 751 smoke, 1283–1293. See also Smoke inhalation. Inhalational fevers, 178–179, 180t–181t Innervation, of gastrointestinal tract, 271 Inocybe mushrooms, 464, 464f Inorganic acids, 305–307, 305t. See also specific acid. Insect stings, 447–453. See also specific insect sting. Insecticides. See also specific compound. arsenic-based, 1148t carbamate. See Carbamates. hepatotoxicity of, 236b ingestion of, in pregnancy, 357–358 organochlorine, 1231–1235. See also Organochlorine insecticides. organophosphate. See Organophosphates. toxicity of, 229t Insulin(s), 317, 317t currently available preparations of, properties of, 1023t for calcium channel blocker intoxication, 970 history of, 1019 intoxication with, 1026 adverse effects of, 1028 management of, 1031 pharmacology of, 1024 structure and classification of, 1021–1022, 1021f Intelligence quotient, childhood lead poisoning affecting, 1138–1139 Intensive care unit, admission to, 57 Intermediate syndrome, organophosphateinduced, 1180

1542

INDEX

International Classification of Diseases codes, nerve gas–related, 1499b Internet resources for chemical agents, 1254t for essential oils, herbs, and dietary supplements, 1441b Interstitial nephritis, acute, 256–257, 257b Interstitial pneumonitis, 171 Intestinal botulism, 521. See also Botulism. Intoxication. See Poisoning; under specific agent. Intracellular organelles, damage to, in hepatic injury, 224b Intracerebral hemorrhage, amphetamineinduced, 785 Intraocular pressure, increased, steroidinduced, 330 Intubation, endotracheal. See Endotracheal intubation. Investigative issues, in forensic toxicology, 120–121 Iodides, 1390 for thyroid hormone overdose, 1072 Iodine, 1389–1390 radioactive, therapeutic use of, 322–323 during pregnancy, 1470 Iodism, 1390, 1390b Iodophores, 1390–1391 Ipecac, 36 for NSAID overdose, 873 Ipratropium, structure of, 722f Iran, Neyshabur, hazardous material incident in, 1457 Iraq, use of chemical warfare in, 1487 Iris, 490f Iron dietary, 1119–1120 lethal dose of, 1122 minimum toxic dose of, 1122 occupational exposure to, 184 pharmacology and pharmacokinetics of, 1119–1120 plasma, 1120 preparations of, 1119, 1119t serum concentrations of, 1122–1123 Iron poisoning, 1121–1127 cardiovascular manifestations of, 158t, 163, 1120 clinical manifestations of, stages in, 1121–1122 diagnosis of, 1122–1123, 1124f differential diagnosis of, 1123–1124 gastrointestinal manifestations of, 279–280, 1120 hematopoietic manifestations of, 1121 hepatotoxicity due to, 232, 1120 in pregnancy, 352–353, 352f management of, 1124–1127, 1125f antidote in, 14t, 1126–1127, 1126b decontamination in, 1124–1126 elimination enhancement in, 1127 metabolic acidosis in, 1121 neurologic manifestations of, 1121 pathophysiology of, 1120–1121 patient disposition in, 1127 range of toxicity in, 1122 signs and tests for, 64t Iron sulfur elixir, for lead poisoning, in children, 1140 Irrigation for ocular injury duration of, 311 solutions in, 310–311 whole bowel. See Whole bowel irrigation. Irritant dermatitis occupational chemicals causing, 1245 plant-induced, 495

Irritant gases, water-soluble, inhalation and toxicity of, 1245–1246 Irritant incapacitants, 1511. See also Lacrimators. Irukandji syndrome, 512, 513 management of, 514 Ischemia, in hepatic injury, 224b Isocyanates, 1317–1321 exposure to prenatal and pediatric issues concerning, 1320 regulations and advisories concerning, 1321, 1321t sources of, 1317 intoxication with, 1318–1319 assessment of, 1320–1321 clinical manifestations of, 1319–1320 management of, 1321 prevention of, 1321 physicochemical properties of, 1317, 1318t Isoniazid, 919–924 drug interactions with, 920–921, 920t for tuberculosis, 919 in breast milk, 366t intoxication with acute, 922, 923f adverse events in, 921–922 diagnosis of, 922 management of, 922–924, 923b signs and tests for, 64t metabolic actions of, 921t pharmacology of, 919–921 structural relationships of, 919f with or without rifampicin, hepatotoxicity of, 233 Isopropyl alcohol, 623–624, 623t in shampoo, 1428 removal of, hemodialysis or hemoperfusion in, 58 Ivermectin, 915–916, 1189–1190, 1189f J Japan, use of chemical warfare in, 1487–1488 Jaundice after repeated exposure to halothane, 232–233 cholestatic, in anabolic steroid users, 1104–1105 Jellyfish, 507, 508, 509f stings from, 512 management of, 514–515 venom of, 511 Jequirity beans, 487f Jimson weed, 200, 487f Lantana, 487f Jin bu huan, 1084 hepatotoxicity of, 239b Job titles, associated with occupational asthma, 173t, 174t Jumping spider, 437 JumpSTART system algorithm, for nerve gas mass casualty incident, 1493, 1494f Juniper oil, 1441t Juvenile parkinsonism, methylenedioxymethamphetamine-induced, 785 K Karwinskia humboldtiana, 484 Kava, hepatotoxicity of, 239b Kepone shakes, 1233 Keratoconjunctivitis, hydrogen sulfide–induced, 1337 Keratocytes, stromal, 302 Kernicterus, risk of, in jaundice patient, 393–394

Keshan’s cardiomyopathy, 1164 Ketamine in rapid sequence intubation, 16t, 17 intoxication with clinical effects of, 775 diagnosis of, 775–776 epidemiology of, 773 treatment of, 777 neuropharmacology of, 773–774 pharmacology of, 775 structure of, 773f Ketoacidosis alcoholic, 107–108, 596, 596t diabetic, antipsychotic-induced, 712 Ketoconazole hepatitis due to, 235b mechanism of toxicity of, 328 Ketoprofen, toxic effects of, 871 Kidney(s). See Renal entries. toxic injury to. See Nephrotoxicity. “Killer” bees, 447 Knockdowns, hydrogen sulfide–induced, 1336 reversal of, 1338 Kombucha mushroom, toxicity of, 1084 Korsakoff’s psychosis, 595 Krait bites, 428, 429t Krazy Glue, ocular injury due to, 308 Krebs cycle, inhibition of, in hydrofluoric acid poisoning, 1324 Kussmaul breathing, 24 L Lacrimators, 1511–1515 comparison of potency and toxicity of, 1512t exposure to, 1512–1513 assessment of, 1514 manifestations of, 1513–1514 pathophysiology of, 1513 principles of preparedness in, 1515 treatment of, 1515 relevant history of, 1511 β-Lactam antibiotics cross-reactivity of, 878 overdose of, 881–882 Lactate acidosis, nucleoside reversetranscriptase inhibitors causing, 896–897 Lactation anticholinergic use during, 727 antihistamine use during, 727 antipsychotic use during, 708 lead toxicokinetics and, 1137–1138 selective serotonin reuptake inhibitor therapy during, 552 Lactic acidosis, 107, 108t Lacy tree philodendron, 492f Laetrile, 1087 Lamivudine, 890t–891t, 898, 898f Lamotrigine hepatitis due to, 235b intoxication with, 741 pharmacokinetics of, 741 Lantana, 487f Laparotomy, in gastrointestinal decontamination, 37 Laryngeal edema, caustic ingestions causing, 1410 Laryngotracheal injury, in smoke inhalation victims, signs and symptoms of, 1289 Latex allergy, in health care workers, 1246 Lathyrism, 484 Latrodectus spiders, 433–435, 435t

INDEX

Laundry detergent statistics of, 1444t, 1445t toxicity of, 1446 management of, 1447–1448 Lavage. See Bronchoalveolar lavage; Gastric lavage; Nasogastric lavage. Lavender oil, 1441t Laxatives abuse of chronic, 283–284 gastrointestinal effects of, 282 for gastrointestinal decontamination, 39 types of, 282b Lead, 1129–1142 history of, 1129 neonatal exposure to, 368 nephrotoxicity of, 267–268 prenatal exposure to, 356–357 source(s) of, 1130–1132, 1130f folk and alternative medicine as, 1132 food as, 1132 hair dyes as, 1425 hobbies as, 1131–1132 industrial and automotive emissions as, 1131 occupational, 1130, 1131b paint as, 1130–1131 retained bullets as, 1132 soil as, 1131 substance abuse as, 1132 water as, 1131 toxicokinetics of, 1132–1133 in children, 1137–1138 Lead lines, 1139 Lead poisoning antidote for, 14t cardiac disturbances due to, 158t, 163 epidemiology of, 1129–1132 population rates in, 1129–1130 gastrointestinal disturbances due to, 279 in adults, 1133–1136 assessment of, 1134–1135 clinical manifestations of, 1133–1134 treatment of, 1135–1136. See also Chelation therapy. in children, 1136–1142 clinical manifestations of, 1138–1139, 1138t, 1139f diagnosis of, 1139 epidemiology of, 1136–1137, 1137t history of, 1136 prevention of, 1142 treatment of, 1139–1142. See also Chelation therapy. in pregnancy, 356–357 mechanisms of, 1133, 1133t neuropathy due to, 205, 206t, 1139, 1139f LED (light-emitting diode), for methanolinduced retinal injury, 313 Legal issues, in forensic toxicology, 123–124 Leiurus quinquestriatus, 443, 443f Lemon grass oil, 1441t Lenten rose, 491f Lepidoptera stings, 451 Lethal dose, median (LD50), 92 antivenom, neutralizing units in, for Crotalidae snakebites, 409t of sulfur mustard, 1503 Leucovorin, methotrexate toxicity limited with, 934 Leukemia acute lymphoblastic, childhood, 1475 benzene-induced, 1364, 1366 Leukocytes, 298

Leukoencephalopathy, progressive spongiform heroin overdose causing, 645 treatment of, 652 Leukopenia, 298, 299b Leukotriene antagonists, pulmonary toxicity due to, 186t Levamisole, 913–914 Level of consciousness, assessment of, 24 Levetiracetam, 743 Levodopa for neuroleptic malignant syndrome, 716 serotonin syndrome and, 573 Levonorgestrel, implantable, 334 Levothyroxine, 322 mechanisms of toxicity of, 322–323 Lewisite, 1501 antidote for. See British antilewisite (BAL). Licorice root, 485 Lidocaine for tricyclic antidepressant poisoning, 155 for ventricular arrhythmias, 715 cocaine-induced, 765 in rapid sequence intubation, 16–17, 16t Ligand-gated ion channels, in neurotransmission, 192, 192f, 202 Light-emitting diode (LED), for methanolinduced retinal injury, 313 Lily of the valley, 487f Lindane (gamma-hexachlorocyclohexane), 1231. See also Organochlorine insecticides. Linezolid, 565 Lionfish, 510, 510f Lipid(s) intestinal absorption of, 273 metabolism of, 335–338 agents affecting, 336–337 Lipid peroxidation, in hepatic injury, 224b Lipid-lowering agents, 326t Lipstick, 1431 Liquids, teeth-cleaning, 1430 Lithium, 579–586 available preparations of, 580t drug interactions with, 580, 581t half-life of, 580 in breast milk, 366t nephrotoxicity of, 257, 266–267 neuroleptic malignant syndrome and, 208–209 pharmacokinetics of, 579–580, 581t pharmacology of, 579, 580t renal clearance of, 580 serotonin syndrome and, 212 SSRI inhibitor interaction with, 572, 572t therapeutic uses of, 579, 579t Lithium poisoning, 580–581, 581f acute-on-chronic, 580, 583 cardiac disturbances due to, 158t, 161, 582 clinical manifestations of, 581–582 diagnosis of, 582–583, 582t endocrine disturbances due to, 582 gastrointestinal disturbances due to, 280, 582 in elderly, 380 management of, 583–586 decontamination in, 584 disposition in, 585–586 elimination in, 584–585, 585f, 586t hemodialysis or hemoperfusion in, 58 supportive measures in, 583–584 patient history in, 582 quantitation and interventions for, 71t signs and tests for, 64t

1543

Liver. See also Hepatic; Hepato- entries. alterations to, in pregnancy, 348 effect of ethanol on, 279 fatty, 228–229, 229b inflammation of. See Hepatitis. Liver function tests, for acute hepatitis, 229t Liver transplantation for acute hepatic failure, 240 for cyclopeptide mushroom poisoning, 461 Lobelia, 492f Lobelia inflata, 1081t, 1082 Lofepramine, pharmacokinetic parameters of, 539t Lomotil, overdose of delayed toxicity associated with, 649 management of’, 649 Loop diuretics, 996, 996f. See also Diuretics. Loperamide, 646 gastrointestinal disturbances due to, 283 Lophophora williamsii, 796 Lopinavir, 892t–893t, 903, 903f Lorazepam for alcohol withdrawal syndrome, 601, 601t for camphor-induced seizures, 1421 for hypertension, in hallucinating patient, 800 for hyperthermic syndromes, 216 for neuroleptic malignant syndrome, 216, 717 for phencyclidine intoxication, 777 for seizures, 714 for serotonin syndrome, 218 recommended dosage of, 672t structure of, 673f Low-density lipoprotein, in anabolic steroid abusers, 1105 Low-density lipoprotein cholesterol, elevation of, steroid-induced, 330 Lowest observable adverse effect level (LOAEL), in nonoccupational environmental toxicology, 1261 Low-molecular-weight heparin, 1058–1059 Low-molecular-weight sensitizing agents, associated with occupational asthma, 174t Loxosceles spiders, 435–437 LSD. See Lysergic acid diethylamide (LSD). Lung(s). See also Pulmonary; Respiratory entries. acute injury to, 170 anatomy and physiology of, 168–169 auscultation of, 23 occupational diseases of, 184–185 particle deposition in, 169 work-related cancer of, 1248t–1249t Lye. See Sodium hydroxide. Lysergamides, 794, 795t Lysergic acid, chemical structure of, 485f Lysergic acid amide, hallucinogenic effects of, 484 Lysergic acid diethylamide (LSD) cardiovascular effects of, 146 CNS effects of, 1517, 1519 formulations and route of administration of, 797 mechanism of action of, 198 pharmacokinetics of, 798t structure of, 796f synthesis of, 794 time of onset and duration of action of, 798t use/abuse of epidemiology of, 794 false-positive urinary testing for, 800, 800b

1544

INDEX

M M2 protein blockers, 894t–895t, 904–905 Ma huang. See Ephedrine. Mace, 796 Macrolides, overdose of, 882 Magnesium, 1163 Magnesium citrate as cathartic, 38 for clonidine overdose, 1007 Magnesium hydroxide, for iron poisoning, 1125 Magnesium sulfate for barium carbonate poisoning, 1219 for digitalis poisoning, 959 for torsades de pointes, 1016 Makeup, facial, 1424t, 1431–1432 Malabsorption, gastrointestinal drug-induced, 276, 276t treatment of, 285 Malathion, 1172t Maleic anhydride ocular injury due to, 307 uses and toxic effects of, 305t Malignant hyperthermia clinical manifestations of, 214 diagnosis of, 215 differential diagnosis of, 215 history and epidemiology of, 213 in children, 394–395 inhaled anesthesia toxicity with, 395 management of, 218 pathophysiology of, 213–214 signs and symptoms of, 210t Malignant hyperthermia equivalent, 215 Malignant syndrome complications of, 215–216 management of, 218 Malnutrition, in chronic ethanol intoxication, 596 Mamba bites, 428–429 Manchineel tree, toxicity of, 499 Mandragora officinarum, 1081t, 1082 Manganese, 1163–1164 chronic poisoning with, 196–197 Manganese madness, 197, 1164 Mania, dancing, 10, 1280 Man-made vitreous fibers, exposure to, 182–183 Mannitol for ciguatera poisoning, 518 for prerenal failure, 258 for snakebite-induced compartment syndrome, 412 for vitamin A overdose, 1094 MAO inhibitors. See Monoamine oxidase (MAO) inhibitors. Maple syrup disease, in children, 392–393, 393f benzodiazepine toxicity with, 393 Maprotiline pharmacokinetic parameters of, 539t structure of, 538f Marijuana, 747–752 alcohol and other drugs combined with, 751 hallucinogenic effects of, 498 passive inhalation of, 751 pharmacokinetics of, 748–749 pharmacology of, 748 structure of, 747, 748f therapeutic use of, 747 tolerance to and dependence on, 750 use/abuse of, 749–750 diagnosis of, 751 epidemiology of, 747 management of, 751–752

Marijuana Tax Act (1937), 747 Marine life. See also specific species. envenomation by, 507–515, 508t ingestion of, poisoning by, 515–518, 516f Marsh marigold, 492f Mass casualty incident(s). See also Hazardous material incident(s). choking agent exposure causing, 1510 CNS disabling agent exposure causing management of, 1519–1520 principles of preparedness in, 1520 decontamination in, 33–34, 33–35f personnel associated with, 33–34 in Iraq, 1487 in Japan, 1487–1488 lacrimator exposure causing, 1515 nerve gas exposure causing management of, 1497–1498, 1497f principles of preparedness in, 1498–1499 vesicant exposure causing management of, 1505 principles of preparedness in, 1505–1506 Maternal toxicologic screening, 78 Mazzotti reaction, 914 MDA (3,4-methylenedioxyamphetamine), 782f, 785 MDMA. See 3,4-Methylenedioxymethamphetamine (MDMA). Meats, processed, tyramine in, 569, 569b Mebendazole, 912, 916–917 Mechanical ventilation, for drug-induced pulmonary edema, 140 Median effective dose (ED50), 92 Median lethal dose (LD50), 92 antivenom, neutralizing units in, for Crotalidae snakebites, 409t of sulfur mustard, 1503 Medical toxicology, as subspecialty, 10–11 Medications. See Drug entries; specific medication. Mediterranean glue thistle, hepatotoxicity of, 239b Medroxyprogesterone acetate, estrogen therapy with, 335 Mees’ lines, 1150 Mefenamic acid, toxic effects of, 871 Meglitinides duration of action of, 318t intoxication with, 1026 adverse effects of, 1028 management of, 1031 mechanism of action of, 318 pharmacokinetics of, 1025 pharmacology of, 1023–1024 structure and classification of, 1021, 1021f Melagatran, 1059–1060 Melaleuca alternifolia, 1438 Melphalan, pharmacologic parameters of, 929t Membrane-depressant agents, cardiac disturbances due to, 151, 153–154, 153b, 154f–155f treatment of, 154t Mental status, depressed, colchicine-induced, 861 Mentha piperit, 1438 Mentha pulegium, 1437 Meperidine, 646 MAO inhibitor interactions with, 572, 572t Mephobarbital, 689t Meprobamate drug interactions with, 663t, 665 history and structure of, 659f, 660 intoxication with, 665 diagnosis of, 666 pharmacokinetics of, 662t, 665

Mercury elemental intoxication with, 1113–1114. See also Mercury poisoning. pharmacology of, 1112 exposure to at Minamata Bay, 8, 8f clinical characteristics of, 1116t EPA’s guidelines for, 369 neonatal, 368–369 neuropathy due to, 205, 206t occupational, 184 inorganic intoxication with, 1114. See also Mercury poisoning. pharmacology of, 1112–1113 nephrotoxicity of, 268 organic intoxication with, 1114–1115. See also Mercury poisoning. pharmacology of, 1113 pharmacology of, 1112–1113 products containing, 1111–1112, 1112b, 1112f release of, from dental amalgams, 1277–1279, 1278f sources of, 1111 Mercury poisoning, 1278 antidote for, 14t cardiac disturbances due to, 158t, 163 clinical presentation of, 1113–1115 diagnosis of, 1115 elemental, 1113–1114 gastrointestinal disturbances due to, 280 inorganic, 1114 organic, 1114–1115 treatment of, 1115–1116 Mescal beans, 488f Mescaline, 795t, 796, 796f pharmacokinetics of, 798t time of onset and duration of effects of, 798t Metabolic acidosis, 106–110 assessment of, 25, 25b clinical features and consequences of, 110 elevated anion-gap, 106–109, 106b causes of, 25b, 109 vs. ketoacidosis, 107–108 hemodialysis for, 56 hyperchloremic, 109 in colchicine intoxication, 862 in ethylene glycol intoxication, 108–109 in iron poisoning, 1121 in methanol intoxication, 108 in paraldehyde intoxication, 109 in renal failure, 107 in salicylate intoxication, 108 in toluene intoxication, 109 isoniazid-induced, 922 normal anion-gap, 109–110, 109b treatment of, 110 Metabolic alkalosis causes of, 111, 111b clinical features of, 111 definition of, 105, 110 in poisoning and drug overdose, 111 treatment of, 111–112 Metabolism first pass, 82 of drugs. See Biotransformation. Metal chelators, 1167–1168, 1168t. See also Chelation therapy; specific chelator. Metal fume fever, 179, 180t, 1167, 1167b Metal pneumoconioses, 183–184 Metallothionein, 1167–1168 Metaxalone, properties of, 696t

INDEX

Metered-dose inhalers, pulmonary toxicity due to, 187t Metformin poisoning, 1030–1031 Methadone, 12–13 chemical structure of, 637f in breast milk, 366t Methamphetamines, 782–783, 782f neurotoxicity of, 785–786 pulmonary toxicity of, 787 Methanol, 605 lethal dose of, 605 metabolic pathway of, 605f neonatal exposure to, 370 pharmacology of, 605–606 Methanol poisoning, 605–610, 606f clinical manifestations of, 607 diagnosis of, 607–608, 608f, 608t fatalities due to, organ donation after, 129, 130t metabolic acidosis in, 108 neurotoxic effects of, 197 ocular injury due to, 309–310 management of, 313 quantitation and interventions for, 71t route of toxicity in, 605 treatment of, 313, 609–610, 609f algorithm for, 621f antidotes in, 14t hemodialysis or hemoperfusion in, 58 Methaqualone history and structure of, 659f intoxication with, 665 diagnosis of, 666–667 pharmacokinetics of, 662t Methemoglobin, 291, 295t Methemoglobin fraction, 294–295 Methemoglobinemia, 289, 291–295 diagnosis of, 292–293, 987 differential diagnosis of, 293 etiology of, 292 in neonate, 370 pathophysiology of, 291–292 smoke inhalation causing, 1288 treatment of failure to respond to, 295, 295b in asymptomatic patients, 293 in symptomatic patients, 293–295, 987 methylene blue in, 294, 1382, 1405 Methimazole for hyperthyroidism, 323 for thyroid hormone overdose, 1072 toxicity of, 1073 Methocarbamol, properties of, 696t Methohexital, 689t in rapid sequence intubation, 16t Methotrexate monitoring levels of, 933–934 nephrotoxicity of, 267, 932 neurotoxicity of, 931 pharmacology of, 928, 929t Methotrexate poisoning gastrointestinal effects of, 282 in children with folate and vitamin B12 metabolic disorders, 394 rescue agents limiting, 934 Methprylone, structure of, 659f Methyl bromide, 1226–1227 neuropathy due to, 206t Methyl chloroform, 1349t neonatal exposure to, 369–370 Methyl isocyanate physicochemical properties of, 1317, 1318t sources of, 1317 toxicity of, 1318–1321. See Isocyanates, intoxication with.

Methyl isothiocyanate, 1228 β-N-Methylamino-L-alanine (BMAA), 203 N-Methyl-D-aspartate receptors ethanol effects on, 598 for nerve gas–induced seizures, 1497 Methyldopa dosage of, 1004t hepatitis due to, 235b Methylene blue therapy for ifosfamide toxicity, 933 for methemoglobinemia, 294, 987, 1382, 1405 failure to respond to, 295, 295b Methylene chloride, 1348t absorption of, 1351 carbon monoxide poisoning due to, 1299 Methylene diphenyl diisocyanate physicochemical properties of, 1317, 1318t sources of, 1317 toxicity of, 1318–1321. See also Isocyanates, intoxication with. 3,4-Methylenedioxyamphetamine (MDA), 782f, 783, 785. See also Amphetamines. 3,4-Methylenedioxymethamphetamine (MDMA). See also Amphetamines. cardiovascular complications of, 143 fatal overdose of, organ donation after, 130 hepatotoxicity of, 231–232, 787 MAO inhibitor interactions with, 572, 572t neurological complications of, 785 pulmonary toxicity of, 786–787 structure of, 782f, 783 Methylprednisolone, for anaphylaxis, 880, 880f 4-Methylpyrazole, for gamma-hydroxybutyric acid overdose, 817 Methylxanthine(s), mechanism of action of, 194 Methylxanthine poisoning gastrointestinal effects of, 280–281 in neonate, 371 Methyprylon (methyprylone) intoxication with, 665 diagnosis of, 667 pharmacokinetics of, 662t, 665 Methysergide maleate, for serotonin syndrome, 574 Metrifonate, 915 Metronidazole, in breast milk, 366t Metyrapone, mechanism of toxicity of, 328 Mibefradil, structure of, 963–965, 964f Michaelis-Menten kinetics, 90 of theophylline, 1037 Microwave popcorn workers, bronchiolitis obliterans in, 184–185 Midazolam for seizures, organophosphate-induced, 1177 in rapid sequence intubation, 16t, 17 recommended dosage of, 672t Mifepristone, mechanism of toxicity of, 328–329 Migraine, triptans for, 849, 850t Military smokes (obscurants), exposure to, 1507t, 1509 Milk for caustic alkali ingestion, 1411–1412 for soap or detergent ingestions, 1447 Millipedes, 453 Minamata disease, 8, 8f Mineral oil, for ocular adhesive injury, 311t, 312

1545

Mineralocorticoid(s), 327 adverse effects of, 330 mechanism of toxicity of, 329 Mineralocorticoid antagonists, 327 adverse effects of, 330 mechanism of toxicity of, 329 Minoxidil, 988–989, 988f Minute ventilation, in infants, environmental toxicants and, 1272 Miosis, in opioid poisoning, 644, 649 Mirtazapine, 198, 538 for serotonin syndrome, 218 overdose of, 555 pharmacokinetics of, 551t parameters in, 539t Misoprostol overdose, gastrointestinal effects of, 282 Mist, definition of, 170 Mistletoe toxicity, 496 Mitigation phase, in emergency management, 1454, 1454f Mitotane, mechanism of toxicity of, 328 Mitoxantrone, pharmacologic parameters of, 929t Moclobemide, 565, 567 Mold, as source of systemic disease, 1279–1280 Molecular absorbent regenerating system, for cyclopeptide mushroom poisoning, 461 Molecular adsorbents recirculating system, 54–55 for water-soluble drug hepatotoxicity, 240 substances removed by, 59 Molecular weight, of toxicants, 55 Monkshood, 492f Monoamine oxidase (MAO) inhibitors, 561–574 cardiovascular complications of, 143 characteristics of, 564t classic, 563 food interactions with, 568–569, 569b for depression, 549 in neurotransmission, 195 intoxication of clinical manifestations of, 565–567, 566f diagnosis of, 567 treatment of, 567–568 isoenzymes of, 562, 563t pharmacology of, 563–565, 564f, 564t, 565b physiology of, 561–562, 562f representative reactions of, 562, 562f reversible, 563 selective serotonin reuptake inhibitors and, 198 serotonin syndrome and, 211, 212, 569–574 structure of, 563–564, 564f tricyclic antidepressant interaction with, 572–573 triptan interaction with, 853 Monomethylhydrazine, chemical structure of, 481f Morbidity and mortality associated with delirium tremens, 600 associated with hallucinogen toxicity, 799 associated with neuroleptic malignant syndrome, 210 in opioid abusers, 636 Morning glory hallucinogenic effects of, 498 serotonin receptors in, 198 Morphine chemical structure of, 640f pharmacology of, 636 receptor selectivity of, 198 therapeutic index of, 1519

1546

INDEX

Motor functions, effect of marijuana on, 749 Mouthwashes, 1430 toxicity of, 1431 Mucociliary escalator, 168 Mucositis, cinnamon-induced, 1436 Multiple chemical sensitivity. See Idiopathic environmental intolerance. Multiple system organ failure, salicylate poisoning causing, 841 Multiple-dose activated charcoal. See Activated charcoal, multiple-dose. Multisystem organ failure, 499–500 cytotoxic plants producing, 481 Multivitamin(s). See also Vitamin entries. supplementary, for alcohol withdrawal syndrome, 600 with iron, 1119, 1119t Munchausen syndrome by proxy, laxative abuse in, 284 Muscarine, chemical structure of, 465f Muscarine-containing mushrooms, 458b, 464–465, 464f Muscarinic receptors, 199–200 Muscimol, chemical structure of, 462f Muscimol-containing mushrooms, 458b, 461–463, 462f Muscle biopsy, for malignant hyperthermia, 215 Muscle relaxants, 695–701. See also specific agent. drug interactions with, 697 intoxication with, 697–701 acute, 698–699 diagnosis of, 699–700 differential diagnosis of, 700, 700b in children with malignant hyperthermia, 395 management of, 700–701, 701t patient disposition and, 701 pharmacokinetics of, 697 pharmacologic properties of, 696t structure of, 695 therapeutic use of, adverse effects of, 697–698 withdrawal from, 699 Musculoskeletal disorders class IA antiarrhythmic–induced, 1014–1015 colchicine-induced, 862 theophylline-induced, 1038 Mushroom worker’s lung, 470 Mushrooms, 455–471. See also specific species. anticholinergic properties of, 723b coprine-containing, 458b, 465–466, 465f cyclopeptide-containing, 457–461, 458b, 459f environmental and farming issues associated with, 487–488 gastrointestinal-irritant, 469–470 gyromitrin-containing, 458b, 463–464, 463f hallucinogenic properties of, 198, 794–795, 795t ibotenic acid–containing, 458b, 461–463, 462f indole-containing, 458b, 466–467, 466f ingestion of, syndromes associated with, 456t kombucha, toxicity of, 1084 muscarine-containing, 458b, 464–465, 464f muscimol-containing, 458b, 461–463, 462f orellanine-containing, 458b, 467–468, 468f spores of, 456, 457f toxic effects of, 234, 256, 279 management of, 455–457, 457b, 457f, 458b pitfalls in, 471b

Mustard agents, ocular injury due to, 308–309 treatment of, 311t, 312 Mustard gas. See Sulfur mustard. Myasthenia gravis, vs. botulism, 524t Mycophenolate mofetil, 947–948 Mycotoxins, 237. See also specific type. ingestion of, gastrointestinal effects of, 278–279 molds producing, 1280 Mydriasis, in opioid poisoning, 644 Myelodysplastic syndrome, benzene-induced, 1364, 1366 Myocardial infarction amphetamine-induced, 786 cocaine-induced, 142, 758 management of, 767 vs. botulism, 524t work-related, 1251t Myocardial membranes, depression of, druginduced, 135–136, 137f Myocarditis, antipsychotic agents associated with, 712 Myopathy nucleoside reverse-transcriptase inhibitors causing, 898 steroid-induced, 329 Myristica fragrans, 196, 796, 1081t, 1083, 1437 Myrrh oil, 1441t N NAC. See N-Acetylcysteine (NAC). NADH/NAD+ ratio, in chronic ethanol intoxication, 596, 596f NADPH methemoglobin reductase, 292 Nail care products, 1429–1430 Nail polish, 1429–1430 Nail polish remover, 1430 Na+/K+-ATPase pump, dysfunction of, in hydrofluoric acid poisoning, 1324 Nalmefene duration of action of, 199 for opioid-induced CNS symptoms, 652 Naloxonazin, chemical structure of, 640f Naloxone cardiac disturbances due to, 148 chemical structure of, 640f duration of action of, 199 for clonidine overdose, 1007 for heroin overdose, in pregnant patient, 355 for muscle relaxant intoxication, 701t for opioid overdose, 650–651 Naltrexone chemical structure of, 640f duration of action of, 199 α-Naphthyl-thiourea, in rodenticides, 1219 NAPQI. See N-Acetyl-parabenzoquinoneimine (NAPQI). Naproxen, toxic effects of, 871 Naratriptan, drug interactions with, 854t Narcolepsy, gamma-hydroxybutyric acid for, 811 Nasogastric lavage for hydrofluoric acid poisoning, 1331 for plant-related poisoning, 500 Nasogastric suction, continuous, for arsenic poisoning, 1153 National Advisory Committee (NAC) acute exposure guideline levels (AEGLs), of sulfur mustard, 1504, 1505t National Center for Environmental Health (NCEH), 1264–1265 National Electronic Surveillance System, 1262

National Fire Protection Association (NFPA) Committee, hazard signal system, 704, 1239, 1240b, 1240f National Institute for Environmental Health Services (NIEHS), 1273 National Institute of Environmental Health Sciences (NIEHS), 1265 National Institute of Occupational Safety and Health (NIOSH), 1263–1264 exposure levels immediately dangerous to life or health defined by, 1244 National stockpile, chemical agents in, 1502, 1502t Nausea. See also Emesis. intoxicants causing, 276–277 Nebulizers, pulmonary toxicity due to, 187t Nefazodone, 550 overdose of, 554–555 pharmacokinetics of, 551t serotonin syndrome due to, 212 Nelfinavir, 892t–893t, 903, 903f Nematocysts, 507–508, 508f Nematodes, 911 Neonates. See also Children. cocaine intoxication in, withdrawal from, 367–368 maternal drug abuse during pregnancy affecting, 762–763 toxic effects of, 365, 367–368 methemoglobinemia in, 370 opioid intoxication in, withdrawal from, 367, 368t pharmacokinetics in, 363–365 vs. adults, 365t potential toxicity of drugs in, 364t selective serotonin reuptake inhibitors intoxication in, withdrawal from, 368 toxic exposures in, 363–372 dermatologic, 369–370 environmental, 368–369 epidemiology of, 363 iatrogenic, 369–372 through breast milk, 365, 365t, 366t treatment of, 372 withdrawal syndromes in cocaine and, 367–368 opioids and, 367, 368t selective serotonin reuptake inhibitors and, 368 Neostigmine, for non-native Elapidae snakebites, 430–431 Nephritis, interstitial, acute, 256–257, 257b Nephropathy antibiotic-induced, 881 Chinese-herb, 1083 Nephrotoxicants, in workplace, 1251t Nephrotoxicity acute. See Renal failure, acute. bromide, 1388 chlorinated hydrocarbon–induced, 1356 chronic. See Renal failure, chronic. diquat-induced, 1196 drug-related, 253–257, 255b, 263–267, 264f–266f, 581, 872–873, 932 factors affecting, 252b environmental and occupational, 267–268 industrial chemical–induced, 1246 lead-induced, 1134 in childhood, 1139 of animal venom, 256 of biologic agents, 256 of heavy metals, 255b, 256 of herbs and plants, 256

INDEX

Nephrotoxicity (Cont’d) of iodinated radiocontrast agents, 257 of toluene, 1372 plant-induced, 256, 485 Nerve gas(es), 1487–1499 exposure to assessment of, 1494 clinical presentation of, 1489–1492 in pregnancy, 358 mass casualties following, management of, 1497–1498, 1497f moderate to severe, signs and symptoms of, 1491t prenatal and pediatric issues following, 1492–1494, 1493t, 1494f principles of preparedness for, 1498–1499, 1499b short-term, signs and symptoms of, 1490t treatment of, 1494–1497 antidotes in, 15t, 732, 1178–1179, 1495–1496 for pediatric population, 1492-1493, 1493t decontamination in, 1495 medical countermeasure in development in, 1496–1497 general properties of, 1490t organophosphate as, 1173, 1487. See also Organophosphates. relevant history of, 1487–1488 Nerve-gas–related International Classification of Diseases codes, 1499b Neuraminidase inhibitors, 894t–897t, 905–906 Neuroleptic(s), 703. See also Antipsychotic agents. Neuroleptic malignant syndrome, 197, 707–708, 711–712 clinical manifestations of, 209 complications of, 215–216 diagnosis of, 214–215 diagnostic criteria for, 209–210, 714t differential diagnosis of, 215 history and epidemiology of, 208–209 incidence of, 208 management of, 216–217, 716–717 pathophysiology of, 209 signs and symptoms of, 210t Neurologic symptoms. See also Autonomic nervous system (ANS); Central nervous system (CNS); Peripheral nervous system (PNS). in poisoned patient, 24 iron poisoning–induced, 1121 plant-induced, 483–484 Neuromuscular syndromes, 208–218. See also specific syndrome. Neuron(s), 191, 192f excitotoxicity of, 202 Neuropathy(ies) arsenic poisoning causing, 1150 delayed, organophosphate poisoning causing, 1180 demyelinating, 205 lead poisoning causing, in children, 1139, 1139f neurotoxins producing, 206t peripheral nucleoside reverse-transcriptase inhibitors causing, 897–898 thalidomide causing, 940 symmetric generalized, 204–205 toxic, characteristics of, 205b work-related, 1249t

Neuropsychiatric sequelae, chronic, organophosphate poisoning causing, 1180 Neuropsychiatric symptoms, in alcohol withdrawal, 599 Neuroreceptor affinities, for antipsychotic agents, 706t Neurotoxic agents, 191 cellular targets and, 191b neuropathy due to, 206t Neurotoxic shellfish poisoning, 516, 517 Neurotoxicity, 191–206 industrial chemical–induced, 1247, 1253 neurotransmitter systems and, 193–204 nicotine-induced, 497–498 of toluene, 1371 Neurotransmission definition of activity of, 191 presynaptic, 193 synaptic, 191–193, 192b, 192f neurotoxicity and, 191–204 Neurotransmitter system(s), 193–204 catecholaminergic, 194–197, 196b cholinergic, 199–201 GABAergic, 203–204 glutaminergic, 202–203 glycinergic, 204 histaminergic, 201 opioids as, 198–199 purinergic, 193–194 serotonergic, 197–198 Neutron-gamma exposures, U.S. fatal criticality radiation accidents following, 1477–1479 Nevirapine, 892t–893t, 900, 900f Neyshabur, Iran, hazardous material incident in, 1457 Niacin (nicotinic acid). See Vitamin B3. Nickel, 1164 occupational exposure to, 184 Niclosamide, 916 Nicotinamide-adenine dinucleotide phosphate, depletion of, in paraquat poisoning, 1197 Nicotine alkaloids, 482–483 toxicity of, 497–498 Nicotinic acid (niacin). See Vitamin B3. Nicotinic receptors, 199 Nifedipine, for hypertension, with scorpion stings, 446 Niridazole, 914 Nitrates hepatotoxicity of, 236b organic, 985–987 pharmacokinetics and pharmacology of, 985–986 toxicity of, 986–987 diagnosis and management of, 987 Nitric acid ocular injury due to, 306 uses and toxic effects of, 305t Nitric oxide as irritant, 177, 178t in neuron excitotoxicity, 202 in smoke, 1285 Nitrites hepatotoxicity of, 236b intoxication with, antidote for, 14t Nitroethane, 1430 Nitrofurantoin, overdose of, 883 Nitrogen mustard, ocular injury due to, 308 Nitrogen oxides, 1402–1405, 1402t as choking agents, 1507t, 1508 exposure to, 1509 clinical manifestations of, 1403–1404

1547

Nitrogen oxides (Cont’d) exposure to (Cont’d) management of, 1404–1405 nonoccupational, 1403 pathophysiology of, 1403, 1403t Nitroglycerin, 985 for serotonin syndrome, 218 release of nitric oxide from, 986 toxicity of, 986–987 diagnosis and management of, 987 Nitroprusside. See Sodium nitroprusside. N-methyl-D-aspartate (NMDA) receptors, 202, 204 ethanol effects on, 598 No observable adverse effect level (NOAEL) in isocyanate toxicity, 1320 in pediatric environmental toxicity, 1269 No observed adverse effect level/uncertainty factor (NOAEL/UF), in nonoccupational environmental toxicology, 1261 Nongovernmental organizations, concerned with environmental toxicology, 1265–1266 Non-nucleoside reverse-transcriptase inhibitors, 892t–893t, 899–900 adverse effects of, 899–900 Nonserum, serum sickness–like reactions, antibiotic-induced, 880 Nonsteroidal anti-inflammatory drugs (NSAIDs), 865–874. See also specific agent. acute interstitial nephritis due to, 257 cardiopulmonary toxicity of, 873 classification of, 865, 866b depressed renal function associated with, 101 drug interactions with, 869, 869t effect of, on gastrointestinal tract, 279 hematologic toxicity of, 872 hepatotoxicity of, 224–225, 233, 872 history of, 865 mechanism of action of, 865–866, 867f, 868f metabolic toxicity of, 872 nephrotoxicity of, 253, 257, 263–264, 264f, 872–873 neurologic toxicity of, 872 overdose of clinical effects of, 871–873 diagnosis of, 873 management of, 873–874 patient disposition and, 874 pharmacokinetics of, 868–869, 868t structure and structural relationships of, 865, 867f toxicology of, 869–871, 870f use of, in pregnancy, 869 Nontoxic ingestions, 22b Norbromide, in rodenticides, 1221 Norepinephrine in emergency care, 20, 20t in neurotransmission, 194 Normeperidine, neurotoxicity of, 199 Nortriptyline, pharmacokinetic parameters of, 539t Nose, examination of, 23 NSAIDs. See Nonsteroidal anti-inflammatory drugs (NSAIDs). Nucleoside reverse-transcriptase inhibitors, 889, 890t–891t, 896–899. See also specific agent. adverse effects of, 11 Nutmeg, 484, 796, 1437, 1441t hallucinogenic effects of, 498

1548

INDEX

Nutmeg (Cont’d) time of onset and duration of effects of, 798t toxicity of, 1083 Nutraceuticals, definition of, 1080 Nutrients absorption of, 273 drug interactions with, 102–103, 102b Nutritional status, influence of, on lead absorption, 1132 Nutritional supplementation, 1086–1087 for lead poisoning in children, 1140 in pregnant patient, 357 Nylon flock worker’s lung, 185, 1248t Nystagmus intoxication associated with, 24 systemic substances causing, 309b O Obidoxime, for organophosphate poisoning, 1178, 1179 Observation, of poisoned patients, 29–30 Obstetric toxicity, amphetamine-induced, 787–788 Occupational diseases. See also Industrial poisoning; specific disease. recognition of, 1238–1239 vs. common diseases, 1238 Occupational exposure(s). See also Industrial poisoning. to asbestos fibers, 182–183 to asphyxiants, 176 to environmental toxins, 1260–1261 to hazardous materials, classification of, 1239–1240, 1239b, 1240b, 1240f to inhalational organic and inorganic materials, 178–179, 180t–181t, 182 to irritant gases, 176–177, 178t to man-made vitreous fibers, 182–183 to metal dusts and fumes, 183–184 to plant and animal proteins, 173, 175t toxicologic testing of, 78 Occupational fatalities, in private industry, U.S. Bureau of Labor Statistics on, 1237 Occupational Safety and Health Act (1970), 1244 Occupational Safety and Health Administration (OSHA) benzene exposure standards of, 1367 lead exposure standards of, 1130 permissible exposure levels published by, 1244 Occupational sources, of lead, 1130, 1131b Occupational toxins, nephrotoxicity of, 267–268 O-cresol, as marker of toluene exposure, 1373 Octopus, 509, 509f stings from, 513 Octreotide for hormone disorders, 320 for hypoglycemia, 319, 319t for sulfonylurea overdose, 1030 Ocular decontamination, 31–34. See also Decontamination. for lacrimator exposures, 1515 for plant-related poisoning, 501 Ocular exposure, to herbicides, 1202, 1204 Ocular injury, 302–313 bleaches causing, 1450 chlorinated hydrocarbons causing, 1356–1357 corrosive chemicals causing, 302–307 acids as, 304–307, 305t, 306b alkalis as, 302–304, 303f, 303t solvents as, 307

Ocular injury (Cont’d) cyanoacrylates causing, 308 detergents causing, 307–308 examination of, 310 Hughes classification of, 310, 310t hydrofluoric acid causing, 306–307, 1327 treatment of, 311t, 312, 1330–1331 mechanisms of repair of, 302 mustard agents causing, 308–309 prognosis of, 310, 310t soaps and detergents causing, 1448 surfactants causing, 308 systemic agents causing, 309–310, 309b treatment of, 310–313 irrigation solutions in, 310–311 special agents in, 313, 313t special considerations in, 311–313, 311t Oils. See also specific oil. bath, 1428–1429 essential, 1435–1442 definitions of, 1435b Internet resources on, 1441b therapeutic uses of, 1435–1436 toxicity of, 1436, 1440t–1441t management of, 1440 Olanzapine, for serotonin syndrome, 574 Oleander common, 493f yellow, 488f fruit of, 489f Olfactory fatigue, hydrogen sulfide and, 1339 Oliguria, in acute renal failure, 250, 254 Ophthalmia neonatorum, 1165 Ophthalmic drops, toxic effects of, in neonate, 371–372 Opiate(s) cardiac disturbances due to, 158t, 161 definition of, 198, 635 excretion of, 642 intoxication with, 199 antidote for, 15t clinical manifestations of, 648–649 signs and tests for, 63t Opioid(s), 198–199, 635–653. See also specific agent. cramping and constipation with, 283 definition of, 198, 635 endogenous, 637 exogenous, 637 history of, 635 in rapid sequence intubation, 16t, 17 intoxication with, 199, 642, 644 antidote for, 15t clinical manifestations of, 648–650 diagnosis of, 650 epidemiology of, 635–636, 636f management of, 650–652 patient disposition and, 652–653 pulmonary manifestations of, 187t signs and tests for, 63t pharmacodynamics of, 637–638 pharmacokinetics of, 639–642, 643f pharmacology of, 636–637 synthetic, 637, 637f withdrawal from, 281 in neonate, 367, 368t Opioid antagonists, 652 Opioid receptors, 198–199, 638–639 activity of opiate/opioid on, 642t δ, 638, 639t, 640t κ, 638, 639t, 640t μ, 638, 639t, 640f, 640t molecular representation of, 642f regulation of cellular effectors by, 643f

Opium, 6, 635 tincture of, for neonatal opiate withdrawal, 368t Oral discoloration, 274, 274t Oral diseases, 274, 274t Oral hygiene products, 1424t, 1430–1431 Oral ingestion(s) nontoxic, 22b of hydrofluoric acid, 1327–1328 treatment for, 1331 Orellanine, chemical structure of, 467f Orellanine-containing mushrooms, 458b, 467–468, 468f Organ donation, after fatal poisoning, criteria for, 126–127 Organic acids, 305t, 307. See also specific acid. Organic dust toxic syndrome, 179, 181t work-related, 1251t Organic nitrates, 985–987 pharmacokinetics and pharmacology of, 985–986 toxicity of, 986–987 diagnosis and management of, 987 Organic solvents, nephrotoxicity of, 255b, 256 Organizations, for forensic toxicology, 122–123 Organochlorine insecticides, 1231–1235 intoxication with adverse effects of, 1233 clinical manifestations of, 1233 diagnosis of, 1233–1234 differential diagnosis of, 1234 epidemiology of, 1231 in special populations, 1232–1233 management of, 1234–1235 pathophysiology of, 1232 patient disposition and, 1235 pharmacokinetics of, 1232 relevant history of, 1231 structure of, 1231–1232 Organophosphates, 1171–1180, 1172t. See also Nerve gas(es); specific agent. history of, 1171–1172 intoxication with cardiac disturbances due to, 149–151, 150b chronic neuropsychiatric sequelae in, 1180 clinical presentation of, 1175t, 1176 delayed polyneuropathy in, 1180 diagnosis of, 1176–1177 fatalities due to, organ donation after, 129 in pregnancy, 357–358 intermediate syndrome in, 1180 management of, 1177–1180 antidotes in, 15t, 1178–1180 new therapies in, 1180 neuropathy due to, 206t delayed, 1180 pathophysiology of, 1174–1176 vs. botulism, 524t pharmacokinetics of, 1173–1174 structure of, 1172, 1173f WHO classification of, 1173 Ornithine transcarbamylase deficiency, in children, 391–392, 392f antidepressant toxicity with, 392 Orphenadrine intoxication with, 699 properties of, 696t Oseltamivir, 894t–895t, 905, 905f Osmolality, 114 calculation of, 25 disturbances in, 25, 26t urine, changes in, 250, 251f

INDEX

Osmolar gap, 26b in ethylene glycol poisoning, 615, 615t in methanol poisoning, 607, 608f Osmolarity, 114 Osteoporosis, steroid-induced, 329 Ototoxicity bromide, 1388 styrene, 1368–1369 Over-the-counter medications, cardiovascular complications of, 143 Over-the-counter sleep aids, anticholinergic properties of, 723b β-N-Oxalylamino-L-alanine (BOAA), 203 Oxamniquine, 915 Oxazepam for alcohol withdrawal syndrome, 601, 601t recommended dosage of, 672t Oxazolidinones, overdose of, 883 Oxcarbazepine, 743 Oxidant stress, 289, 289f agents producing, 290b in children with G6PD deficiency, 393 Oxidation, in biotransformation, 86, 86f–87f Oxides of nitrogen. See Nitrogen oxides. Oxime therapy for nerve gas poisoning, 1505 for organophosphate poisoning, 1179 in pregnant patient, 358 Oxygen dissociation curve, of maternal and fetal hemoglobin, 355, 355f Oxygen therapy before rapid sequence intubation, 16 for chlorine exposure, 1393 for hydrofluoric acid inhalations, 1331 for smoke inhalation victims, 1291 hyperbaric. See Hyperbaric oxygen therapy. supplemental for anaphylaxis, 879 for cyanide poisoning, 1312 Oxygen-carrying capacity, in methemoglobinemia, monitoring of, 294–295 Oxymetazoline dosage of, 1004t structure of, 1002f Oxytocin, 319 P Pacing. See Cardiac pacing. Paclitaxel, pharmacologic parameters of, 929t Pain chest. See Chest pain. of latrodectism, 434 Paint, lead-based, 1130–1131 childhood poisoning due to, 1136–1137 Palivizumab, 896t–897t, 906 Pancreas diseases of, 275, 275b effect of ethanol on, 279 structure and function of, 272 Pancreatitis intoxicants and, 275, 275b valproate-induced, 739 Pancuronium, in rapid sequence intubation, 16t, 17 Papaver somniferum, 635 Paper wasps, 447f Papilledema, systemic substances causing, 309b Paracetamol. See Acetaminophen entries. Paraldehyde poisoning, metabolic acidosis in, 109 Paralytic shellfish poisoning, 516, 517 Para-phenylenediamine, in hair products, 1425

Paraquat, 1197, 1197f toxicity of clinical features of, 1198–1199 management of, 1199–1200, 1199t mechanisms of, 1197 Parasympathetic activity, cardiac effects of, 135, 136f Parathion, 1172t Parathyroid gland, 324–325, 324f physiologic disturbances of, toxin-induced, 324–325, 324b, 325t Parathyroid hormone (PTH), 324 Paregoric, for neonatal opiate withdrawal, 368t Parenchymal lung disease, therapeutic drug–induced, 188t Parenteral absorption, of drugs, 82–83 Parkinsonism antipsychotic agents causing, 711 juvenile, methylenedioxymethamphetamine-induced, 785 management of, 715 Paromomycin, 917 Parotitis, toxic, 274 Paroxetine overdose of, 554 pharmacokinetics of, 551t Particulate material, deposition of, in lungs, 169 Paxillus involutus mushrooms, 469, 469f PCBs. See Polychlorinated biphenyls (PCBs). PCP. See Phencyclidine (PCP). PeaCe pill. See Phencyclidine (PCP). Pediatric Assessment Triangle (PAT), 1493 Pediatric Environment Health Specialty Units (PEHSUs), 1273 Pediatric environmental health, 1269–1273, 1269b. See also Children, environmental toxins in. Peliosis hepatitis, in anabolic steroid users, 1105 Penciclovir, 894t–895t, 901f, 902 D-Penicillamine, 1168t for arsenic poisoning, 1153 for lead poisoning, in children, 1141 Penicillin(s) action of, at GABA receptor, 204 for cyclopeptide mushroom poisoning, 460 overdose of, 881–882 Penicillin G, overdose of, 882 Pennyroyal, hepatotoxicity of, 497 Pennyroyal oil, 1437–1438, 1441t hepatotoxicity of, 239b Pentazocine, 647–648 Pentobarbital, 689t Peppermint oil, 1438–1439, 1441t Peptic ulcers, steroid-induced, 330 Peptides, gastric, 271 Peradeniya Organophosphorus Poisoning (POP) Scale, 1176 Perceptual disturbances, hallucinogen-induced acute, 798–799 recurring, 799 Perchloroethylene, hepatotoxicity of, 236 Perfluoroisobutylene, as choking agent, 1507t, 1508 Performance enhancers, 1101–1108. See also Anabolic steroids; Creatine; Dehydroepiandrosterone. Perfumes, 1429 Peripheral nervous system (PNS) lead poisoning affecting, 1134 toxicity specific to, 204–205, 205b Peritoneal dialysis, 48–49, 49b, 50b. See also Dialysis; Hemodialysis. for lithium poisoning, 584, 586t

1549

Personal care soap. See Soap(s). Personal protective equipment and training, for organophosphate decontamination, 1178 Pesticides. See Fungicides; Herbicides; Insecticides; Rodenticides. Petroleum distillates, 1343–1346. See also Hydrocarbons; specific agent. poisoning with clinical presentation of, 1344–1345 diagnostic evaluation of, 1345 epidemiology of, 1343 management of, 1345–1346 pathophysiology of, 1343–1344 patient disposition with, 1346 Peyote cactus, 488f hallucinogenic effects of, 498 P-glycoprotein, substrates, inhibitors, and inducers of, 88, 88b pH drug absorption influenced by, 81–82 renal elimination and, 102 Phallotoxins, in Amanita mushrooms, 457–458 Pharmacodynamics, 91–93, 92f in drug interactions, 103 in elderly, 378–379 of agonists and antagonists, 92–93 targets of drug action in, 91–92, 92f Pharmacogenomics, 93–94, 94t future directions of, 94 Pharmacokinetic antagonism, 92 Pharmacokinetics, 88–91, 88f–90f first order kinetics in, 89–90, 90f in drug interactions, 98–103, 98b, 98t, 100t in elderly, 379 Michaelis-Menten kinetics in, 90 neonatal, 363–365 vs. adult, 365t other models of, 89 two-compartment model of, 88–89, 89f zero order kinetics in, 90 Pharmacology, 81–94 drug disposition in, 81–88 genetic variability of response in, 93–94, 94t pharmacodynamics in, 91–93, 92f pharmacokinetics in, 88–91, 88f–90f Phenacetin, nephrotoxicity of, 263 Phencyclidine (PCP) intoxication with clinical effects of, 774 diagnosis of, 775 epidemiology of, 773 treatment of, 777–778 neuropharmacology of, 773–774 pharmacology of, 774 structure of, 773f Phenobarbital for camphor-induced seizures, 1421 for neonatal opiate withdrawal, 368t for seizures, 714 intoxication with, 736 quantitation and interventions for, 71t pharmacokinetics of, 735 Phenol cutaneous decontamination from, 34 ocular injury due to, 307 treatment of, 311t, 312 uses and toxic effects of, 305t Phenothiazides, cardiovascular effects of, 156 Phenylalkylamines, structure of, 963, 964f Phenylbutazone, toxic effects of, 871 Phenylcyclidine, cardiovascular effects of, 146 Phenylephrine, in emergency care, 20t, 21 Phenylethanolamine-N-methyltransferase, ethanol effects on, 599

1550

INDEX

Phenylethylamines, 795t, 796 Phenylpiperidines. See also specific agent. pharmacology of, 636–637 Phenylpropanolamine cardiovascular complications of, 143 toxicity of, 196 Phenytoin for tricyclic antidepressant intoxication, 544 hepatotoxicity of, 233–234 intoxication with, 736–737 management of, 737 intravenous administration of, 737 vs. intravenous fosphenytoin, 737 pharmacokinetics of, 736 prophylactic, with busulfan therapy, 933 Phocomelia, thalidomide-associated, 8, 8f, 938 Phorate, 1172t Phosdrin, 1172t Phosgene as choking agent, 1507, 1507t as irritant, 176–177, 178t exposure to, 1509 Phosgene oxime, 1501–1502 Phosphene, 1225–1226 Phosphodiesterase inhibitors, for βadrenergic blocker intoxication, 980 Phosphorus cardiac disturbances due to, 158t, 163 cutaneous decontamination from, 34 in rodenticides, 1218 suicide using, 235 Photodermatitis, plant-induced, 500 Photosensitivity, antibiotic-induced, 881 Physician’s responsibility, in childhood poisoning prevention, 388–389 Physostigmine for anticholinergic intoxication, 730–731 for anticholinergic syndrome, 715 for benzodiazepine poisoning, 1519 for gamma-hydroxybutyric acid overdose, 817 for muscle relaxant intoxication, 700, 701t for tricyclic antidepressant intoxication, 544–545 Phytophotodermatitis, plant-induced, 495–496 Picrotoxin, 204, 484 Pill-associated caustic injury, 1410 Pine oil, 1344, 1441t systemic toxicity of, 1345 Piperazine, 914 Piperidine antihistamines, nonsedating, 731–732 Piroxicam, toxic effects of, 871 Pituitary agents, 320 mechanisms of toxicity of, 320–321 pK, of acid or base, 81, 81f, 82f Placenta carbon monoxide transfer across, 355 drug transfer across, 348 lead transfer across, 356 solvent transfer across, 1357 Plant(s) anticholinergic properties of, 723b, 724 cardiovascular toxicity of, 481–482 cyanogenic, 484–485 hallucinogenic, 484, 498–499 hepatotoxic, 238, 239b, 485, 494–495, 497 nephrotoxic, 256, 485 neurotoxic, 483–484, 497–498 poisonous. See also Plant poisoning. types of, 474t–475t sodium channel–binding properties of, 482

Plant dermatitis, 495–496 Plant hydrocarbons (terpenes), 1344. See also Hydrocarbons. poisoning with, management of, 1345–1346 Plant poisoning, 473–502. See also specific plant. clinical manifestations of, 496–497 diagnosis of, 500 history of, 473 management of, 500–502 multisystem organ failure due to, 481 pathophysiology of, 477, 480–483 patient disposition and, 501–502 pharmacokinetics of, 478b–480b structure-activity relationships of, 473, 475–477 Plant products, occupational exposure to, disorders associated with, 175t Plasmapheresis for chemotherapy overdose, 935 for cyclopeptide mushroom poisoning, 461 for cyclosporine overdose, 947 Plastics, fires involving, 1288 Platelet(s), 299 coagulation of, 1051–1052, 1052f Platelet aggregation, inhibition of, 1060–1061, 1060t Pneumoconioses, 179, 182 metal, 183–184 work-related, 1248t–1249t Pneumonia, bronchial diquat-induced, 1196 in smoke inhalation victims, 1290 Pneumonitis chemical chlorinated hydrocarbon–induced, 1357 hydrofluoric acid–induced, 1327 hypersensitivity, 173–174, 175t, 176, 180t work-related, 488, 1246, 1248t, 1251t interstitial, 171 PNS. See Peripheral nervous system (PNS). Podophyllum poisoning gastrointestinal effects of, 278 multisystem organ failure due to, 499 Poinsettia, toxicity of, 499–500 Point-of-care testing, 66–67 Poison(s), 6–7. See also specific substance. associated with systemic toxicity, after dermal absorption, 28b biologic, 399–431. See also Snakebite(s). epidemiology of, 399–401, 400t, 401t etiology of, 399 decontamination method based on, 31–32 definitions of, 13, 124 disposition of, 81–88 nondrug, toxicologic testing for, 78 placental permeability of, 350t quantitation and interventions for, 71t radiopaque, 27b sources of, in victim, 121 Poison Control Centers, 10, 387–388, 388t Poison hemlock, 488f coniine in, 498 Poison ivy, 493f Poison Prevention Packaging Act (1970), 385, 1407–1408, 1423 products covered by, 385t Poison treatment paradigm, for Crotalidae snakebites, 405, 406b Poisoner(s), 5–6, 5f, 6f homicidal, characteristics of, 121–122 Poisoning cardiovascular, 133–164. See also Cardiovascular toxicity. childhood. See also under Children. etiology of, 383–384

Poisoning (Cont’d) childhood (Cont’d) prevention of, 383–389 unique metabolism and, 390–396 clinical evaluation of, 21–27, 22t arrhythmias in, 24–25, 25b assessment of toxicity in, 24 gastrointestinal disturbance in, 25–26 laboratory studies in, 26–27, 27b metabolic acidosis in, 25, 25b physical examination in, 21, 23–24, 23t seizures in, 26 definition of, 13 drug. See specific agent, e.g., Acetaminophen poisoning. food, 521–533. See also Food poisoning. forensic, 119–131. See also Forensic toxicology. gaseous. See specific gas, e.g., Carbon monoxide poisoning. gastrointestinal, 271–285 general approach to, 13–30 hematologic consequences of, 289–299 hepatic, 223–240. See also Hepatotoxicity. history of, 3–5, 13 in elderly. See under Elderly. in neonate. See under Neonates. in pregnant patient. See under Pregnancy. management of advanced airway, 15–19 circulatory support in, 18–21, 19b, 20t decontamination procedures in, 31–41. See also Decontamination; specific procedure. emergency, 13, 14t–15t, 15–18 manifestations of, 7–10 patient disposition with, 30 pulmonary, 167–189. See also Pulmonary toxicity. renal, 249–268. See also Nephrotoxicity; Renal failure. snake. See Snakebite(s). vs. drug overdose, 13 Poisoning prevention education, attributes of, 387b Poisoning prevention resources, 389, 389b Pokeweed, 492f toxicity of, 496 Poliomyelitis, vs. botulism, 524t Polish, nail, 1429–1430 Pollution, air, 9, 9f Polyacetylenes, 477 Polyaromatic hydrocarbons. See also Hydrocarbons. fires generating, 1288 Polychlorinated biphenyls (PCBs) hepatotoxicity of, 236b neonatal exposure to, 369 neuropathy due to, 206t Polyethylene glycol, 623t, 626–627 for iron poisoning, 1126 for lithium poisoning, 584 for phenol burns, 312 in whole bowel irrigation, 39 Polymer fume fever, 179, 180t, 1288 Polyvinyl chloride, fires involving, 1288 Pontiac fever, 179, 180t Popcorn worker’s lung, 1248t Poquil, 916–917 Porcine stress syndrome, 213 Porphyrias, 298 Portable decontamination systems, 33, 34f Portuguese man-of-war, 508, 509f Positive end-expiratory pressure, for smoke inhalation victims, 1292

INDEX

Potassium disorders of. See Hyperkalemia; Hypokalemia. restricted intake of, in acute renal failure, 258 Potassium channel blockade, class IA antiarrhythmics in, 1012–1013, 1012f Potassium hydroxide ocular injury due to, 304 uses and toxic effects of, 303t Potassium-sparing diuretics, 996. See also Diuretics. Potency, drug, 91 Powder(s) absorbent, for vesicant decontamination, 1504 baby, 1415–1417 teeth-cleaning, 1430 Pralidoxime for muscarinic symptoms, 200 for nerve gas poisoning, 1491–1492, 1496 in pediatric population, 1493t for organophosphate poisoning, 1178, 1179 in pregnant patient, 358 for sarin poisoning, 1492 Prazepam, recommended dosage of, 672t Praziquantel, 915 Prazosin, 994–995, 994f Precocious puberty, anabolic steroid–induced, 1103 Prednisolone for corrosive injury, 1412 for hypersensitivity pneumonitis, 176 for toxin-induced liver disease, 240 in breast milk, 366t Prednisone for baby powder inhalation, 1417 for cholecalciferol poisoning, 1220 for hair straightener burns, 1428 for vitamin A overdose, 1094 in breast milk, 366t Pregnancy, 347–358 acetaminophen poisoning in, 351–352 amphetamine use during, 788 anticholinergic use during, 727 antihistamine use during, 727 antipsychotic use during, 708 benzodiazepine use during, 678, 679–680 carbon monoxide poisoning in, 355–356, 355f, 356b class IA antiarrhythmic use during, 1015 cocaine use/abuse during, 354–355, 762–763 drug absorption in, 348 drug abuse in, toxic effects of, 365, 367–368 drug distribution in, 348 drug excretion in, 348 FDA drug category assignment for, 347–348, 347t heroin overdose in, 355 imidazoline use during, 1003 iron poisoning in, 352–353, 352f lead poisoning in, 356–357, 1137–1138 marijuana exposure during, 750 metabolism in, 348 NSAID use during, 869 organophosphate poisoning in, 357–358 physiologic changes during, 348, 349t poisoning in antidotes for, 350, 350t decontamination for, 349–350 enhanced elimination for, 350 supportive measures for, 348–349 radioiodine administration during, 1470 salicylate poisoning in, 353–354, 841 scorpion envenomation and, 443

Pregnancy (Cont’d) selective serotonin reuptake inhibitor therapy in, 552 thallium poisoning in, 1166 warfarin use during, 1055 Prehospital care for coral snakebites, 424 for Crotalidae snakebites, 406–407, 407t ineffective or dangerous, 407–408 for smoke inhalation victims, 1291–1292 Prenatal toxicity, amphetamine-induced, 787–788 Preparedness phase, in emergency management, 1454, 1454f Prerenal failure, 251–254, 253f treatment of, 257–258 urine composition in, 251t Pressurized paint, wounds inflicted by, decontamination of, 36 Priapism, cocaine-induced, 763 Primidone, 689t barbiturate interaction with, 690 Procainamide cardiac effects of, 1010–1011 intoxication with, hemodialysis for, 1015 pharmacokinetics of, 1009 Proctitis, 284 Prodrug(s), bioactivation of, CYP enzymes in, 86 Product packaging changes, in childhood poisoning prevention, 384–386, 385t Progestins, 331, 334 Progressive spongiform leukoencephalopathy heroin overdose causing, 645 treatment of, 652 Propofol, in rapid sequence intubation, 16t Propoxyphene, 647 Propranolol for akathisia, 715 for serotonin syndrome, 574 for thyroid hormone overdose, 1072 in breast milk, 366t Propylene glycol, 623t, 625 Propylthiouracil for hyperthyroidism, 323 for thyroid hormone overdose, 1072 toxicity of, 1073 Prostaglandins overdose of, gastrointestinal effects of, 282 synthesis of, NSAID-inhibition of, 865–866, 867f, 868f Prostata, hepatotoxicity of, 239b Protamine, for heparin overdose, 1057 Protease inhibitors, 892t–895t, 902–903 adverse effects of, 902–903 Protein binding, 55, 83–84 Prothrombin, decreased production of, salicylate poisoning and, 841 Protriptyline pharmacokinetic parameters of, 539t structure of, 538f Pruritus, opioid-induced, 652 Prussian blue as absorbant, 38 for cesium contamination, 1471 for thallium poisoning, 1166, 1216 Pseudo-anaphylactic reactions, 878 Psilocin, 794–795, 795t chemical structure of, 467f Psilocybe mushrooms, 466, 466f Psilocybin, 794–795, 795t cardiovascular effects of, 146 chemical structure of, 467f

1551

Psilocybin (Cont’d) pharmacokinetics of, 798t structure of, 796f time of onset and duration of effects of, 798t Psychiatric patients, caustic ingestions by, 1409 Psychological reactions, adverse, to marijuana, 749 Psychosis corticosteroid-induced, 330 in anabolic steroid users, 1105 Korsakoff’s, 595 Psychotropic agents fatal overdose of, multiple organ procurement after, 127–130 pulmonary toxicity due to, 187t PTH (parathyroid hormone), 324 Puberty, precocious, anabolic steroid– induced, 1104 Puffer fish, 516f tetrodotoxin in, 201 Puffer fish poisoning, 515–516 clinical manifestations of, 517 Pulmonary. See also Lung(s). Pulmonary absorption, of drugs, 83 Pulmonary edema amphetamine-induced, 787 calcium channel blocker–induced, 968 cocaine-induced, 761 drug-induced, 139–140, 188t hydrogen sulfide–induced, 1337 in smoke inhalation victims, 1290 salicylate-induced, 840 management of, 844 Pulmonary eosinophilia, therapeutic drug–induced, 188t Pulmonary function tests, for botulism, 523 Pulmonary infiltrates, with eosinophilia, antibiotic-induced, 881 Pulmonary system, Crotalidae envenomation affecting, 405t Pulmonary toxicity, 167–189 amphetamine-induced, 786–787 chlorinated hydrocarbon–induced, 1357 cocaine-induced, 761 management of, 768 definition of terms in, 170 hypersensitivity reaction in, 171–176. See also Hypersensitivity reactions. inhalant injury in, 176–185. See also specific agent. 3,4-methylenedioxymethamphetamine and, 786–787 scope of, 167–168 therapeutic medications causing, 185, 186t–187t, 188t work-related, 1248t Pulse oximetry in methemoglobinemia diagnosis, limitations of, 293 noninvasive, 1301 Pupil(s), pinpoint, intoxication associated with, 24 Pure Food and Drug Act (1906), 1263 Purinergic system, 193–194 Purines. See specific purine. Purkinje cells, action potential of, normal, 1011, 1011f Purple toe syndrome, 1055 Pus (woolly) caterpillar, 451, 451f, 452f Pyrantel pamoate, 916 Pyrazinamide, hepatitis due to, 235b Pyrethrins, 1186–1188, 1186f Pyrethroids intoxication with acute, 1187

1552

INDEX

Pyrethroids (Cont’d) intoxication with (Cont’d) chronic, 1187–1188 exposure routes in, 1186 treatment of, 1188 mechanism of action of, 1186 structure of, 1186f uses of, 1186 Pyrethrum, 1186–1188 Pyridoxal phosphate, in GABA synthesis, 203 Pyridoxal phosphate antagonist, 204 Pyridoxine. See Vitamin B6. Pyriminil, in rodenticides, 1219 Pyrolysis, 1283 Pyrrolizidine alkaloids, 476 hepatotoxicity of, 239b, 494, 1082 in herbal teas, 1082–1083, 1082t Pyrvinium pamoate, 916–917 Q QRS interval, prolonged, in tricyclic antidepressant poisoning, 540, 541f, 545 QT interval, prolonged drug-induced, 156–157, 156f, 157b in hydrofluoric acid poisoning, 1324 Quantal dose-effect curves, 92 Quinidine arrhythmogenic effect of, 136 cardiac disturbances due to, 151, 152t, 153b, 1010–1011 digitalis interaction with, 1015 pharmacokinetics of, 1009 Quinine poisoning, ocular injury due to, 310 management of, 313 R RACE acronym, 1283 Racial relationships, in criminal poisonings, 121 Rad, as radiation dose unit, 1481 Radiation, 1467–1484 accidents involving, 1468 at Chernobyl, 1456–1457 case studies of, 1476–1480, 1476f–1478f medical management of, 1482–1483 exposure to acute, 1468 clinical manifestations of, 1473 delayed effects of, 1473–1474 from cardiac scan, 1481 laboratory and clinical history of, 1476 prenatal and pediatric issues in, 1474–1476 regulatory limits in, 1481t risk of, case scenario in, 1483–1484 sources of, 1467–1468 ionizing, medical, industrial, and consumer product applications of, 1482 Radiation dose estimates for, in common life and medical activities, 1482t unit of, 1481 Radiation medicine, case studies in, 1476–1480, 1476f–1478f Radiation physics, introduction to, 1480–1482, 1481b, 1481t, 1482t Radiation terrorism events, patient assessment in, 1473 Radiation therapy for eczema, facial carcinomas following, 1476, 1477f for hemangioma, atrophy and facial deformity following, 1476, 1476f Radiation-induced cancers, 1483

Radiocontrast agents, iodinated for thyroid hormone overdose, 1072 nephrotoxicity of, 257 Radiography, abdominal, iron tablet detection by, 1123, 1124f Radioiodine, therapeutic use of, 322–323 during pregnancy, 1470 Radioisotopes. See also specific isotope. commonly used, 1482t cutaneous decontamination from, 34 industrial toxicology of, 1469 involved in commercial sectors, 1481b medical considerations for, 1469–1472 Radiopaque toxins, 27b Radon, 1472–1473 Rapid sequence intubation. See also Endotracheal intubation. bradycardia with, 17 for organophosphate poisoning, 1177 in emergency airway management, 13 pharmacotherapy used in, 16t technique of, 18 Rat poison, suicide by, 235 Rattlesnakes. See Snakebite(s), Crotalidae. Reactive airways dysfunction syndrome, 171 irritant-induced, 181t Reactive skin decontamination lotion, FDAapproved, for nerve gas exposures, 1497 Receptors. See also specific receptor. drug interactions involving, 103 in neurotransmission, 192–193, 192f Recovery phase, in emergency management, 1454f, 1455 Red baneberry, 489f Red squill, in rodenticides, 1220–1221 Red tides, 515 Reepithelialization, ocular, 302 Reference concentration (RfC), EPA guidelines for, 1270 Reference dose (RfD), EPA guidelines for, 1270 Relaxants, muscle, 695–701. See also Muscle relaxants. Rem, as dose equivalent unit, 1481 Rem unit, 1481 Renal disease antipsychotics and, 708 benzodiazepine pharmacokinetics and, 678 selective serotonin reuptake inhibitors and, 550, 552 Renal excretion, of drugs, 87–88, 88b in elderly, 379 in neonate, 365t in pregnancy, 348, 349t interactions involving, 101–102 Renal failure acute, 249–259 causes of, 249b classification of, 250, 250f convalescent phase of, 255 diuretic phase of, 254–255 historical perspectives on, 249–250 in bromide intoxication, 1388 initial phase of, 254 oliguric phase of, 254 parenchymal, 256–257, 257b pathophysiology of, 250–251, 251f, 251t prerenal, 251–254, 253f treatment of, 257–258 toxic, 251, 252b, 252f, 255–256, 255b. See also Acute tubular necrosis. treatment of, 257–259

Renal failure (Cont’d) chronic, 261–268 causes of, 261b clinical approach to, 262–263, 262f clinical presentation of, 261–262 drug-induced chemotherapeutic agents in, 267 immunosuppressives in, 264–266, 265f, 266f lithium in, 266–267 tacrolimus in, 266 therapeutic agents in, 263–264, 264f toxin-induced, environmental and occupational, 267–268 cocaine-induced, 762 management of, 768 colchicine-induced, 862 hemodialysis or hemoperfusion for, 56 metabolic acidosis in, 107 Renal tubular acidosis, drug-related, 109–110, 109b Reproduction, effects of lead poisoning on, 1134 Reproductive toxicants, in workplace female, 1252t male, 1253t Reproductive toxicology, industrial chemical–induced, 1253 Residential radiation accident case study, in Estonia, 1477, 1478f Resources, for forensic toxicology, 122–123 Respiration abnormal patterns of, 24 control of, 169–170 Respiratory acidosis, 112, 112b definition of, 105 Respiratory alkalosis, 112–113, 113b definition of, 105 Respiratory distress syndrome, adult, 170 colchicine-induced, 861 Respiratory drive, control of, 169–170 Respiratory system effect of clonidine on, 1005 effect of colchicine on, 861 effect of hydrofluoric acid on, 1327 effect of lacrimators on, 1515 effect of marijuana on, 749 effect of nerve gas on, 1489, 1490t, 1491 effect of opioids on, 199, 644 effect of sulfur mustard on, 1504 Response phase, in emergency management, 1454–1454, 1454f Restaurant-acquired botulism, 522. See also Botulism, food-borne. Retinal injury methanol-induced, 313 quinine-induced, 313 Retinol, 1090. See also Vitamin A. Reverse tolerance, in amphetamine toxicity, 785 Reye’s syndrome, aspirin and, 836 RfC (reference concentration), EPA guidelines for, 1270 RfD (reference dose), EPA guidelines for, 1270 Rhabdomyolysis anticholinergic-induced, 728 treatment of, 730 cocaine-induced, 762 treatment of, 768 in acute renal failure, 257 work-related, 1250t Rhamnaceae family, hallucinogenic effects of, 499 Rhubarb, 488f

INDEX

Ribavirin, 896t–897t, 906, 906f Ribosome-inactivating proteins, plants containing gastroenteritis from, 480–481 toxicity of, 496 Rifampicin, hepatotoxicity of, 233 Rimantadine, 894t–895t, 904f, 905 Ringer’s lactate for emergency care, 19 for ocular injury irrigation, 311 for prerenal failure, 258 Riot control, 1511. See also Lacrimators. Ritonavir, 892t–893t, 903, 903f Rizatriptan, pharmacokinetics of, 852t Rockfish, 510 Rocuronium, in rapid sequence intubation, 16t, 18 Rodenticides, 1213–1221. See also specific compound. hypoglycemia due to, 318 name, ingredient, and type of, 1214t–1216t neuropathy due to, 205, 206t toxicity of, 229t high, 1213, 1216–1219 low, 1220–1221 moderate, 1219–1220 Roentgen (R), definition of, 1481 Ronnel, 1172t Rosary peas, ingestion of, gastrointestinal effects of, 278 Rose oil, 1441t Rotonavir, 892t–893t, 903, 903f Roundworms, 911 Rove beetle, 452 Rubefacient agent, definition of, 1435b Rumack-Matthews nomogram, for acetaminophen poisoning therapy, 829f, 830 RYR1 gene mutation, in malignant hyperthermia, 214 S Sabah toxicity, 1084 Saddleback caterpillar, 451, 451f St. Anthony’s fire, 10, 1280 St. John’s wort, 565 serotonin syndrome and, 573 Salicylate(s), 835–847 absorption of, 836–837 common preparations of, 838, 838t distribution of, 837 dosage of, 836 history of, 835 hypersensitivity reactions to, 841 in breast milk, 366t, 837 in special populations, 838 metabolism and excretion of, 837–838 pharmacokinetics of, 836–838 structure of, 836f structure-activity relationships of, 836 Salicylate poisoning, 838–847 acid-base disturbances in, 839–840 clinical manifestations of, 838, 838b, 839t CNS abnormalities in, 840 diagnosis of, 841–843 differential diagnosis of, 843 epidemiology of, 835–836, 835f, 836f fetal, 841 fluid and electrolyte abnormalities in, 840 gastrointestinal abnormalities in, 279, 841 hematologic abnormalities in, 841 hepatic abnormalities in, 841 hyperpyrexia in, 841 in elderly, 379–380, 838 in pregnant patient, 353–354, 841

Salicylate poisoning (Cont’d) management of, 843–847 decontamination in, 844 elimination in, 844–845, 846b extracorporeal techniques in, 845–846 hemodialysis or hemoperfusion in, 58 supportive measures in, 843–844 metabolic derangement in, 108, 840–841 multiple system organ failure following, 841 patient disposition in, 846–847 pulmonary edema in, 840 quantitation and interventions for, 71t renal abnormalities in, 841 signs and tests for, 64t tinnitus in, 841 Saline solution, for ocular injury irrigation, 311 Salivary glands, function of, 271–272 Salivation, 274 Salmonellosis, 530–532 management of, 531–532 pathophysiology and clinical manifestations of, 531 Salvia divinorum, 794, 796 hallucinogenic effects of, 499 Salvinorin A, 795t, 796 Salvinorin C, 795t, 796 Sand corn, 493f Sandalwood oil, 1441t Saponins, 485 triterpene, gastrointestinal irritation due to, 477 Saquinavir, 894t–895t, 903, 903f Sarin general properties of, 1490t history of, 1487–1488 inhalational exposure to, 1492 Sassafras carcinogenic effect of, 1082 hepatotoxicity of, 494 Sassafras oil, 1441t Saturation gap, in methemoglobinemia, 293 Sauerkraut, tyramine in, 569, 569b Sauropus androgynus, 1081t, 1084 Saxitoxins, 516 toxic dose of, 515 Scalp hair loss, colchicine-induced, 862 Scombroid fish poisoning, 515 cardiovascular disturbances due to, 164 clinical manifestations of, 517 Scopolamine structure of, 722f transdermal, toxicity of, 722–723 Scopolamine eyedrops, toxicity of, 723–724 Scoring methods, of Crotalidae snakebites, 404b, 404t Scorpion(s), 440–447, 440f medically important species of, 441t morphology of, 440, 441f neurotoxin producing, 201 Scorpion fish, 510 Scorpion stings, 163, 440, 442–447 clinical manifestations of, 443–445, 444f, 444t diagnosis and differential diagnosis of, 445 epidemiology of, 440, 442 in special populations, 443 management of, 445–447 antidotes in, 446–447 patient disposition in, 447 supportive care in, 445–446 pathophysiology of, 442 prevention of, 442b Scorpion venom pharmacokinetics of, 442–443, 443f pharmacology of, 442

1553

Scotch broom, hallucinogenic effects of, 498–499 Scotomas, systemic substances causing, 309b Scyphozoa, 507 Sea anenome, 509 stings from, 512 Sea snails, 509–510 Sea snakes, 510–511, 512f bites from, 513 venomous, 512t Sea urchins, 509, 509f toxins of, 514 Sea wasps, 508, 509f Seafood poisoning, 515–518. See also Food poisoning. clinical manifestations of, 517 diagnosis of, 517–518 epidemiology of, 515–516, 516f management of, 518 structure-activity relationships of, 516 Secobarbital, 689t Secretin, in regulation of gastrointestinal function, 271 Sedative-hypnotics, 659–668. See also specific agent. adverse effects of, 661 cardiovascular complications of, 140–141 chemical structures of, 659, 659f for alcohol withdrawal syndrome, 602 history and usage of, 659–660 human deaths attributed to, 660, 661f human exposures to, 660, 660f intoxication with, 661 diagnosis of, 666–667 management of, 667–668 patient disposition and, 668 pharmacokinetics of, 661, 662t structure and structure-activity relationships of, 660–661 toxic effects of, in neonate, 371 Seizures β-adrenergic blocker–induced, 980 alcoholic-related, 599–600 management of, 602 amphetamine-induced, 785 anticholinergic-induced, 728 management of, 730 antipsychotic-induced, 707, 710, 712 management of, 714–715 camphor-induced, management of, 1421 class IA antiarrthythmic–induced, 1015 cocaine-induced, 760 during pregnancy, 354–355 management of, 768 management of, 26 methylxanthine-induced, 194 NSAID-induced, management of, 873 opioid-induced, management of, 651 organophospate-induced, management of, 1177 salicylate-induced, 840 management of, 844 theophylline-induced, 1039 management of, 1042 toxic causes of, 26b tricyclic antidepressant–induced, 541 vincristine-induced, 931 work-related, 1249t Selective serotonin reuptake inhibitors (SSRIs), 549–557 adverse effects of, 555–556, 555b drug interactions with, 552–553, 553t gastrointestinal effects of, 281 in children and adolescents, 552 in elderly, 550

1554

INDEX

Selective serotonin reuptake inhibitors (SSRIs) (Cont’d) in patients with renal and hepatic disease, 550, 552 in pregnant and lactating patients, 552 intoxication with, 553–554 clinical manifestations of, 554–555 diagnosis of, 556 differential diagnosis of, 556 fatalities due to, organ donation after, 127 management of, 556–557 MAO inhibitors and, 198 pharmacokinetics of, 550, 551t pharmacology of, 550, 550b serotonin syndrome and, 211–212, 572 structure-activity relationships of, 549 triptan interaction with, 853 withdrawal from, 556 in neonate, 368 Selegiline, serotonin syndrome and, 573 Selenium, 1164–1165 Sellick maneuver, 18 Senecio longilobus, hepatotoxicity of, 497 Sepsis, Yersinia enterocolitis, deferoxamineinduced, 1127 Serotonergic system, 197–198 Serotonin, 197 chemical structure of, 467f dopamine activity and, 209 excess of, in MAO inhibitor overdose, 568 malignant hyperthermia and, 214 metabolism of, MAO inhibitor in, 566, 566f reuptake of, inhibitors of. See Selective serotonin reuptake inhibitors (SSRIs). role of, in hallucinogen pharmacology, 796 Serotonin antagonism, antipsychotics and, 707 Serotonin receptors classes of, 851, 851t hallucinogen affinity for, 796–797 identification of, 197 partial agonist activity of, 197–198 stimulation of, 211 triptan activation of, 851 Serotonin syndrome, 143, 198, 210–213 agents causing, 571–573, 572t clinical manifestations of, 212, 570, 571t complications of, 215–216 diagnosis of, 212–213, 214–215, 570–571 differential diagnosis of, 215 epidemiology of, 210–211 management of, 217–218, 573–574, 651 pathophysiology of, 211–212, 570 relevant history of, 569–570 signs and symptoms of, 210t triptan with SSRIs and, 855 Sertraline overdose of, 554 pharmacokinetics of, 551t Serum quantitation, of overdosed drugs, 69–73 altered analytic, pharmacokinetic, and pharmacodynamic relationships in, 72–73, 72f availability and accuracy of, 71–72 rationale and use of, 69–71, 71t Serum sickness antibiotic-induced, 880 Crotalidae antivenom causing, 410–411 Sexual assaults, drug-facilitated, toxicologic testing for, 78 Shampoo, 1428–1429 Shellfish poisoning, 516 clinical manifestations of, 517

Shiga toxin, 532 Shigellosis, 532–533 Shock, circulatory, management of, 133–134 Short term exposure limit (STEL), of sulfur mustard, 1504 Sick-building syndrome, 1243, 1281. See also Idiopathic environmental intolerance. Sildenafil, 989–991, 990f mechanism of action of, 990 toxicity of, 990–991 diagnosis and management of, 991 Silibibin, for cyclopeptide mushroom poisoning, 460 Silicosis, 179, 182 Silver, 1165 Silverleaf nightshade, 488f Sinoventricular conduction, 138 Sinus tachycardia anticholinergic-induced, 728 antipsychotics causing, 710 marijuana-induced, 750 theophylline-induced, 1039 tricyclic antidepressant intoxication causing, 541 Sinusitis, chronic, cocaine-induced, 762 Skeletal fluorosis, 1326 Skin. See also Dermal entries. examination of, 23 pediatric, environmental toxicants and, 1271 Skin cancer, work-related, 1252t Skin disorders, work-related, 1252t Skin eruptions (rashes) antibiotic-induced, 880–881 arsenic-induced, 1150 lamotrigine-induced, 741 NNRTI-induced, 899–900 Skin necrosis, warfarin-induced, 1055 Skin tests, for Wyeth-Ayerst ACP, 411 Skullcap, hepatotoxicity of, 239b Sleep aids, over-the-counter, anticholinergic properties of, 723b SLUDGE mnemonic, 200, 1489 Small intestine diseases of, 275 structure and function of, 272 Smog, London, 9, 9f Smoke carcinogens in, 1288 composition of, 1283 definition of, 170 from synthetic materials, 1287 particulate fractions of, 1288 Smoke alarms, 1285 Smoke inhalation, 1283–1293. See also Carbon monoxide poisoning. clinical manifestations of, 1288–1290 diagnostic evaluation of, 1290–1291 epidemiology of, 1283–1285 management of, 1291–1293 pathophysiology of, 1286–1288 factors in, 1284t patient disposition in, 1293 toxicology of, 1288–1290 Smoldering combustion, vs. flaming combustion, 1283 Snails, sea, 509–510 Snake, sea, 510–511, 512f, 512t bites from, 513 Snake venom, anticoagulant properties of, 1061 Snakebite(s), 399–431 Crotalidae, 399–420 clinical manifestations of, 401–403, 402t, 403t

Snakebite(s) (Cont’d) Crotalidae (Cont’d) degree of envenomation in, 406t diagnosis of, 403–405, 404b differential diagnosis of, 403–404 epidemiology of, 399–401, 400t, 401t etiology of, 399, 400t fatal, 419t pathophysiology of, 401 prognosis of, 419–420, 419t scoring methods for, 404, 404b, 404t severity score of, 405t treatment of, 405–419 antidotes in, 408–419, 409t, 410t. See also Antivenom therapy. Crotalidae immune Fab (CroFab) in, 413–419, 414b, 415t, 416t débridement in, 412–413 fasciotomy in, 412 first aid and prehospital care in, 406–408, 407t hospital care in, 408 mannitol infusion in, 412–413 poison paradigm in, 405, 406b Wyeth-Ayerst ACP in, 409–413, 412b Elapidae native, 423–425 clinical manifestations of, 424 pathophysiology of, 423–424 prognosis of, 425, 426f treatment of, 424–425 non-native, 425–431 clinical manifestations and pathophysiology of, 425–429, 427b, 429t diagnosis of, 429–430 epidemiology of, 425 treatment of, 430–431 Snakebite severity score, 405t Snow on the mountain, 493f Soap(s), 1428–1429, 1443–1448 definition of, 1443 sources of, 1444 statistics for, 1444t toxicity of, 1444–1445 management of, 1447–1448 manifestations of, 1445–1446 Social wasps, 447 Society of Forensic Toxicologists (SOFT), 122 Sodium, disorders of, 117t. See also Hypernatremia; Hyponatremia. Sodium azide, 1314 intoxication with, 1314–1315 Sodium bicarbonate for barbiturate overdose, 692 for biguanide overdose, 1030 for intraventricular conduction delays, 1015–1016 for salicylate poisoning, 845 for selective serotonin reuptake inhibitor overdose, 557 for tricyclic antidepressant overdose, 155, 155f, 543–544, 544f for ventricular arrhythmias, 715 nebulized, for chlorine exposure, 1393–1394 Sodium carbonate, ocular injury due to, 307–308 Sodium channel blockade, class IA antiarrhythmics in, 1011–1012, 1011f Sodium channel toxins, 497 Sodium channel–binding properties, of plants, 482

INDEX

Sodium chloride ocular irrigation with, for hydrofluoric acid burns, 1330–1331 restriction of, in acute renal failure, 258 Sodium fluoride, in dental products, 1325–1326 Sodium hydrate. See Sodium hydroxide. Sodium hydroxide, 1407 exposure to, 1408 in depilatories, 1432–1433 ingestion of, 1408 ocular injury due to, 304 uses and toxic effects of, 303t Sodium ipodate, for thyroid hormone overdose, 1072 Sodium metasilicate, ocular injury due to, 307–308 Sodium monofluoroacetate, in rodenticides, 1217 Sodium nitrite, for cyanide poisoning, 1313 Sodium nitroprusside, 983–985, 1309 cyanide release by, 983–984 pharmacokinetics of, 983 structure of, 983, 983f toxicity of, 984 diagnosis of, 984–985 management of, 985 Sodium phosphate, ocular injury due to, 307–308 Sodium polystyrene sulfonate, for lithium poisoning, 584 Sodium silicate, ocular injury due to, 307–308 Sodium thiopental, 689t in rapid sequence intubation, 16t, 17 Sodium thiosulfate for bromate intoxication, 1388 for cyanide poisoning, 1313 for hydrogen sulfide poisoning, 1338 Sodium-potassium pump, inhibition of, by class IA antiarrhythmics, 1013, 1013f Soil, lead in, 1131 Solanine, toxicity of, 496 Solubility, of irritant gases, 177, 178t Solvents. See also specific solvents; classes of solvents. abuse of, cardiac disturbances due to, 146–147 aromatic, 1363–1375 chlorinated, 1347–1359 halogenated, 1377–1382 nephrotoxicity of, 255b, 256 volatile, abuse of, 1381–1382 Soman, general properties of, 1490t Soot, 1288 Sorbitol, as cathartic, 39 Sotalol, intoxication with, 980 Sour gas, in oil patches, 1341 Spectrometric assays, 66, 67t, 68t Speed. See Methamphetamines. Spider(s) neurotoxin producing, 200 venomous, 433–438 Latrodectus species as, 433–435, 435t Loxosceles species as, 435–437 other, 437–438 Spider bites, 163, 433–438. See also under specific spider. Spironolactone, mechanism of toxicity of, 329 Spongiform leukoencephalopathy, progressive heroin overdose causing, 645 treatment of, 652 Spontaneous chemical interconversion, of gamma hydroxybutyric acid, 815–816

Sprinkler systems, 1285 Squamous cell carcinoma, caustic injury–induced, 1410 Squaw mint (pennyroyal) oil, 1437–1438, 1441t hepatotoxicity of, 239b SSRIs. See Selective serotonin reuptake inhibitors (SSRIs). Stannosis, 1166 Staphylococcus, food poisoning due to, 527 Starfish crown-of-thorns, 509 stings from, 513 venom of, 511 Statins. See Hydroxymethylglutaryl-CoA inhibitors. Stavudine, 890t–891t, 899, 899f Steatosis, drug-induced, 229, 229b Stephania tetrandra, 1083 Steroids. See also specific agent. anabolic, 1101–1106. See also Anabolic steroids. for toxin-induced liver disease, 239–240 precursor, 1106 Stickers, warning, in childhood poisoning prevention, 386 Stimulants pulmonary toxicity due to, 187t signs and tests for, 64t Stinging nettles, toxicity of, 500 Stingrays, 510, 511f venomous, 511t, 513 Stings insect, 447–453. See also specific insect sting. marine life, 512–513 scorpion, 440, 442–446. See also Scorpion stings. Stomach. See also Gastric entries. diseases of, 274–275 structure and function of, 272 Stomatitis, 274 Stomatitits venenata, cinnamon-induced, 1436 Stonefish, 510, 510f Stroke amphetamine-induced, 785 cocaine-induced, 760 triptan-induced, 854–855 Strontium 90 isotope, exposure to, 1469–1470 Strychnine, 204 in rodenticides, 1217–1218 Strychnos plant, toxicity of, 484 Styrene, 1368–1370 exposure to, 1368–1370 treatment protocol for, 1367b metabolism of, 1368 ototoxicity of, 1368–1369 Sublingual absorption, of drugs, 83 Substance abuse. See also Drug overdose; under specific substance, e.g., Cocaine, use/abuse of. lead exposure resulting from, 1132 Substance Abuse and Mental Health Services Administration (SAMHSA) estimates, of opioid overdose, 635–636, 636f Succimer, for lead poisoning, in children, 1141 Succinic semialdehyde dehydrogenase (SSADH) deficiency, 814 Succinylcholine, in rapid sequence intubation, 16t, 17 Sucking bugs, 451–452 Sudden death syndrome chlorinated hydrocarbons causing, 1354 inhalants causing, 1382 solvent abuse causing, 146

1555

Suicide among elderly, 377–378 by phosphorus ingestion, 235 mass, at Jonestown, 9, 9f Sulfasalazine, in breast milk, 366t Sulfhemoglobin, 295, 295t proposed formation of, 296f Sulfhemoglobinemia, 289, 295–298 background of, 295 characteristics of, 295–296, 295t clinical presentation of, 297–298 diagnosis of, 297 etiology of, 296–297, 296b treatment of, 298 Sulfonamides history of, 1019 overdose of, 882 Sulfone, in breast milk, 366t Sulfonylureas duration of action of, 318t hypoglycemia due to, 317 intoxication with, 1025, 1025b adverse effects of, 1026–1027 in elderly, 379b, 380 management of, 1029–1030 pharmacokinetics of, 1024 pharmacology of, 1022 structure and classification of, 1020, 1021f, 1022t Sulfur dioxide ocular injury due to, 305–306 uses and toxic effects of, 305t Sulfur mustard exposure to, 1502 Ct values for, 1503t decontamination following, 1505 toxic effects of, 1503, 1503t history of, 1501 ocular injury due to, 308 latency period for, 1504 Sulfuric acid ocular injury due to, 305 uses and toxic effects of, 305t Sulfuryl fluoride, 1227–1228 Sulindac, toxic effects of, 871 Sumatriptan, 849–850, 850f, 850t drug interactions with, 854t pharmacokinetics of, 852t serotonin syndrome due to, 212 Sumatriptan Pregnancy Registry, 853 Super Glue, ocular injury due to, 308 Superfund Amendments and Reauthorization Act (SARA), 1458 Superwarfarins, 1055–1057. See also Warfarin. in rodenticides, 1220 ingestion of, 1056–1057 guideline for management of, 1057f structure of, 1056f toxicokinetics of, 1055–1056 Supportive care for hymenoptera stings, 450 for poisoned patients, 29–30 for scorpion stings, 445–446 Supraventricular arrhythmias, 136 amphetamine-induced, 786 theophylline-induced, 1038 Suramin, 916 Surface-active agents. See Surfactants. Surfactants, 1443. See also Detergent(s); Soap(s). cationic, in fabric softeners, 1447 in glyphosate preparations, 1203 ocular injury due to, 308 used in synthetic detergents, 1443, 1446b SURVAD computer output, for radiation risk, 1483

1556

INDEX

Surveillance toxicologic testing, 77–78 Swainsonine, toxicity of, 484 Sweat bees, 447 Sympathetic activity, cardiac effects of, 135 Sympathetic-inhibiting agents, cardiac disturbances due to, 147, 147b treatment of, 148t Sympathomimetics, 196b. See also specific agent. cardiovascular complications of, 141–147, 141b, 142f treatment of, 142t toxicity of, 196 Synapse, schematic representation of, 192f Synaptic neurotransmission, 191–193, 192b, 192f Synaptic vesicles, 191 Syndrome of inappropriate ADH secretion, 116 Synthetic materials, smoke from, 1287 Syrup of ipecac, 36 for NSAID overdose, 873 Systemic agents, ocular injury due to, 309–310, 309b Systemic lupus erythematosus, procainamideinduced, 1010 Systemic toxicity, amphetamine-induced, 787 T Tabun general properties of, 1490t history of, 1487 Tachyarrhythmias management of, 137t, 138 wide complex, of uncertain origin. See Wide complex tachycardia, of uncertain origin. work-related, 1251t Tachycardia. See also Sinus tachycardia. in paraquat poisoning, 1197 Tacrine, hepatitis due to, 235b Tacrolimus drug interactions with, 944 intoxication with, 944, 944b nephrotoxicity of, 266 pharmacology and pharmacokinetics of, 943–944 Taipan bites, 429 Talcum powder, 1415–1416 in facial makeup, 1431 inhalation of, 1416–1417 Tamoxifen, 331 Tap water, for ocular injury irrigation, 310–311 Tapeworms, 912 Tarantulas, 438 Tardive dyskinesia antipsychotic agents causing, 711 management of, 716 Taxus species, cardiac toxicity of, 482, 497 Tea(s), herbal, 1080–1083, 1082t Tea tree oil, 1438, 1441t antiseptic and antimicrobial effects of, 1435 Tear gas, 1511. See also Lacrimators. Teeth whitening products, 1430 Temazepam, recommended dosage of, 672t Temperature, for decontamination fluid, 33 Tenofovir, 890t–891t, 899, 899f Teratogenicity of chlorinated hydrocarbons, 1357 of thalidomide, 8, 8f, 940 of trichloroethylene, 1357 Terminal care, in paraquat poisoning, 1198 Terpenes (plant hydrocarbons), 1344 poisoning with, management of, 1345–1346 Terpenoids, in ginkgo, 483

Terrorist attacks chemical weapons used in, 1487–1520. See also Chemical weapons; specific agent. radiation used in, patient assessment of, 1473 Tertraline derivatives, structure of, 963–965, 964f Testosterone. See also Anabolic steroids. pharmacology of, 1102 structure of, 1101–1102, 1102f testing for, 1107 Tetanus prophylaxis for marine wounds, 514 in decontamination situations, 36 Tetrachloroethane. See Tetrachloroethylene. Tetrachloroethylene, 1347, 1349t absorption of, 1351 carcinogenicity of, 1357 hepatotoxicity of, 236b Tetrachloromethane. See Carbon tetrachloride. Tetracycline for non-native Elapidae snakebites, 431 overdose of, 882 toxic effects of, in neonate, 370 Tetraethyl pyrophosphate, 1172, 1172t Δ9-Tetrahydrocannabinol, 747. See also Marijuana. cardiovascular effects of, 145–146 chemical structure of, 748f Tetrodotoxins, 511, 516 in puffer fish, 201 Teucrium polium, hepatotoxicity of, 497 Thalidomide, 938–940 history of, 938–939 pharmacology of, 939, 939f potential clinical uses for, 939b teratogenicity of, 8, 8f, 940 toxicity of, 939–940, 940b management of, 940 Thallium, 1213, 1216 gastrointestinal disturbances due to, 280 hepatotoxicity of, 235–236 in rodenticides, 1213, 1216 intoxication with, 1165–1166 management of, 1216–1217 neuropathy due to, 205, 206t The International Association of Forensic Toxicologists (TIAFT), 122 Theobromine, structure of, 1036f Theophylline, 1035–1044 drug interactions with, 1037, 1037b drug-disease interactions with, 1037 effect of isoniazid on, 920 in breast milk, 366t intoxication with acute vs. chronic, 1040–1041, 1041t cardiovascular effects of, 143–144, 144f, 1038–1039 clinical manifestations of, 1038–1040 diagnosis of, 1041 gastrointestinal effects of, 280–281, 1038 in neonate, 371 management of elimination in, 1043–1044, 1044b hemodialysis or hemoperfusion in, 58 supportive measures in, 1041–1043, 1042f treatment algorithm in, 1035b metabolic effects of, 1039–1040 musculoskeletal effects of, 1038 neurologic effects of, 1039 quantitation and interventions for, 71t signs and tests for, 64t mechanism of action of, 1038

Theophylline (Cont’d) pharmacokinetics of, 1036–1037, 1036t pharmacologic actions of, 1037–1038 structural relationships of, 1036, 1036f Thiabendazole, 913 Thiamine. See Vitamin B1. Thiazide diuretics, 995–996, 995f. See also Diuretics. Thiazolidinediones, 317, 318t hepatotoxicity of, 234, 235b intoxication with, 1026 adverse effects of, 1028 management of, 1031 pharmacokinetics of, 1024–1025 pharmacology of, 1023 structure and classification of, 1020, 1021f Thienopyridine, 1060–1061 pharmacokinetics of, 1061t Thimerosal as vaccine preservative, 1115 in vaccines, autism and, 1279 Thin-layer chromatography, 68–69, 70f Thiocyanate, 984 toxicity of, 985 Thioglycolic acids, in hair products, 1427 Thiol agents, cisplatin toxicity limited with, 934–935 Thionamides, 323–324 Thiopental. See Sodium thiopental. Threshold limit values (TLVs), for industrial chemicals, 1461–1462 Throat, examination of, 23 Thrombin inhibition, 1059–1060 Thrombocytopenia, 299 antibiotic-induced, 881 cocaine-induced, 763 Crotalidae snakebite causing, 402 drug-induced, 1010 heparin-induced, 1058 Thrombosis, venous, contraceptive pills causing, 333 Thyroid antagonists, toxicology of, 1073 Thyroid cancer, childhood, near Chernobyl, 1475 Thyroid gland, 321–324 Thyroid hormones, 1065–1073. See specific hormone. commercial preparations of, 1066t dosage of, 1067t drug interactions with, 1068 intoxication with. See Thyrotoxicosis. pharmacokinetics of, 1066–1067 physiology and pharmacology of, 1065–1066 Thyroid storm, agents causing, 322, 323t Thyroiditis, 323 radiation, 324 Thyroid-stimulating hormone (TSH), 321 Thyrotoxicosis drug-induced, 323–324 gastrointestinal effects of, 281–282 mechanism of toxicity of, 322–323, 323b, 323t signs and symptoms of, 322t thyroid hormone–induced, 1068–1072 acute, 1068–1069 adverse events in, 1069–1070 chronic, 1069 clinical manifestations of, 1068–1069 diagnosis of, 1070 differential diagnosis of, 1070, 1071b epidemiology of, 1065 management of, 1071–1072 type 1, 322 type 2, 322 treatment of, 324

INDEX

Thyrotropin suppressors, 322t Thyrotropin-releasing hormone (TRH), 319, 321 physiology of, 1065 Thyroxine (T4), 321 mechanisms of toxicity of, 322–323 natural and synthetic, 321–322 pharmacokinetics of, 1066–1067 physiology and pharmacology of, 1065–1066 structure of, 1066f therapeutic dose of, 1067t toxicokinetics of, 1067–1068 Tiagabine, 204, 742 Tick(s), 452 neurotoxin producing, 201 Tick paralysis, vs. botulism, 524t Ticlopidine, 1060–1061, 1061t Tin, 1166 Tincture of opium, for neonatal opiate withdrawal, 368t Tinnitus, salicylate poisoning causing, 841 Tizanidine dosage of, 1004t intoxication with, 699 pharmacokinetics of, 1003t properties of, 696t structure of, 1002f Toluene, 1370–1374 abuse of chronic, 1370 diagnosis of, 1372 management of, 1367b, 1373 metabolic acidosis in, 109 benzene metabolic inhibition due to, 1365–1366 hepatotoxicity of, 236b metabolic products of, 1370–1371 nephrotoxicity of, 1372 neurotoxicity of, 1371–1372 occupational exposure to, markers for, 1372–1373 synonymous terms for, 1370 Toluene diisocyanate physicochemical properties of, 1317, 1318t sources of, 1317 toxicity of, 1318–1321. See also Isocyanates, intoxication with. Tonicity, of body fluids, 113 Tonics, 1087 Toothpaste, 1430 Topiramate, 204 intoxication with, 742 pharmacokinetics of, 742 pharmacology of, 741 Torsades de pointes, 136, 137f associated with long QT interval, 156–157 due to class IA antiarrhythmics, 1012–1013 organophosphates causing, 149–150 treatment of, 1016 tricyclic antidepressant intoxication causing, 541 Total iron-binding capacity, in iron poisoning, 352, 1123 Toxic epidermal necrolysis, 881 Toxic Exposure Surveillance System (TESS), 13 Toxic syndrome(s), 1275–1281 causes of, assessment of, 1276–1277, 1277f dental amalgams and, mercury in, 1277–1279, 1278f idiopathic environmental intolerance and, 1280–1281 mold as source of, 1279–1280 perception of, 1275 psychopathology of, 1275–1276 thimerosal in vaccines and, 1279

Toxicodynetics, 93 Toxicologic screens, 73–77 accuracy of clinical diagnosis in, 76 analytic accuracy of, 76 clinical reliability of, 76–77 clinical utility of, 77 comprehensive, 73–74, 73b confirmatory, 74 drugs found in, 75–76, 76t drugs-of-abuse, 74 rationale and use of, 74–75 specimen requirements for, 74, 75t types of, 73–74 Toxicologic syndromes, by drug class and tests ordered, 63t–64t Toxicologic tests situations demanding, 77–78 techniques of, 66–69, 67t, 68t, 69f–71f use of, 65–66, 65t usefulness of, 79b Toxicologists, clinical, role of, 1259 Toxicology environmental, 1257–1269. See also Environmental toxicology; Environmental toxins. medical, as subspecialty, 10–11 Toxidromes, 21, 22t Toxin(s). See Poison(s); specific poison. Traditional (folk) medicine, 1084–1085, 1085t. See also Folk remedy(ies). Tramadol, serotonin syndrome and, 573 Transferases, in drug metabolism, 86 Transfusion exchange for arsine poisoning, 1155 for cyclosporine overdose, 947 for neonatal poisoning, 372 for colchicine overdose, 862 Transplantation immunosuppressive agents used in, 943–948 liver, for acute hepatic failure, 240 Tranylcypromine, 565 cardiovascular complications of, 143 Trazodone, 550 overdose of, 554 pharmacokinetics of, 551t serotonin syndrome due to, 212, 573 Tree tobacco, 488f Trematodes, 911–912 Tremor syndrome, pyrethroid-induced, 1187 TRH (thyrotropin-releasing hormone), 319, 321 physiology of, 1065 Triage principles, in chemical disasters, 1462–1464, 1463f Trial strategies, in forensic toxicology, 124 Triazine herbicides, 1205 Triazolam recommended dosage of, 672t structure of, 673f Triazoles, 884 Trichlorfon, 1172t Trichloroethane. See Trichloroethylene. Trichloroethylene, 1347, 1349t associated with degreaser’s flush, 1356 cardiac depressant effects of, 1353 conversion of chloral hydrate to, 662 elimination of, 1352–1353 hepatotoxicity of, 236 metabolic scheme for, 1352f neuropathy due to, 205, 206t teratogenicity of, 1357 Trichlorol ethanol, structure of, 659f Trichloromethane. See Chloroform.

1557

Trichothecene mycotoxin ingestion, gastrointestinal effects of, 278 Tricyclic antidepressants, 537–545. See also specific agent. cardiac disturbances due to, 154–156, 155f, 540–541, 541f CNS disturbances due to, 541 drug interactions with, 540, 540t intoxication with, 540–542 antidote for, 15t cardiac cell action potential disturbances and, 540, 541f CNS depression in, 541 deaths from, 537 diagnosis of, 542–543, 543t disposition in, 545 dysrhythmias in, 541 fatalities due to, organ donation after, 127 management of, 543–545, 544f negative inotropy and smooth muscle contraction and, 541 signs and tests for, 64t MAO inhibitor interactions with, 572–573 over-the-counter, anticholinergic properties of, 723b pharmacodynamics of, 538–539 pharmacokinetics of, 539–540, 539t structure of, 538, 538f Tricyclic antidepressant–specific Fab antibody, for tricyclic antidepressant intoxication, 544 Triiodothyronine (T3), 321 mechanisms of toxicity of, 322–323 natural and synthetic, 321–322 pharmacokinetics of, 1066–1067 physiology and pharmacology of, 1065–1066 structure of, 1066f therapeutic dose of, 1067t toxicokinetics of, 1067–1068 Trilostane, mechanism of toxicity of, 328 Trimethoprim-sulfamethoxazole, for shigellosis, 532 Trimipramine, pharmacokinetic parameters of, 539t Trinitrotoluene, liver necrosis due to, 229 Triptan(s), 849–856. See also specific agent. drug interactions with, 853, 854t intoxication with, 853–856 cardiac disturbances due to, 161–162 diagnosis of, 855 management of, 855–856 patient disposition and, 855–856 withdrawal following, 855 pharmacokinetics of, 851, 852t, 853 pharmacology of, 851, 851t structure of, 849–851, 850f usage of FDA approval of, 850t in special populations, 853 Triptan Cardiovascular Safety Expert Panel, 854 Triterpene saponin, gastrointestinal irritation due to, 477 Tritium isotopes, exposure to, 1469 Troglitazone, hepatotoxicity of, 234 Tropane alkaloids, 483 Tryptamines, 794–795, 795t, 798t Tryptophan as food supplement, 1086–1087 metabolism of, 566, 566f Tryptophan hydroxylase, 198 TSH (thyroid-stimulating hormone), 321 Tuberculosis, isoniazid for, 919

1558

INDEX

Tumor(s). See Cancer; under anatomy. Turpentine, 1344 systemic toxicity of, 1345 Typhoid fever, Salmonella typhi associated with, 531 Typhoid Mary, 531 Tyramine, dietary, MAO inhibitor interactions with, 568–569, 569b Tyrosine hydroxylase, in dopamine synthesis, 194 U United Nations, agencies of, 1265–1266 Up-regulation, of drug receptor density, 92–93 Uranium isotopes, exposure to, 1471–1472 Urea, diminished excretion of, in acute renal failure, 250 Urea herbicides, 1205–1206, 1205f deaths from, 1206t Urginea maritima, 1081t, 1082 Urinary alkalinization for barbiturate poisoning, 692 for herbicide poisoning, 1202 for salicylate poisoning, 844–845, 846b for uranium contamination, 1472 Urinary retention, muscle relaxants associated with, 698 Urine, qualitative toxicologic methods used in, 67t Urine composition, daily, 251t Urine osmolality, changes in, 250, 251f Urticaria, 881 contact, plant-induced, 495 U.S Army Medical Research Institute of Chemical Defense (USAMRICD), 1504 U.S. Bureau of Labor Statistics, of occupational fatalities in private industry, 1237 US Department of Agriculture (USDA), 1263 U.S. fatal criticality radiation accidents, 1477–1479 V Vaccine(s), thimerosal in, 1115 autism and, 1279 Vacor (rodenticide), 1219 hypoglycemia due to, 318 neuropathy due to, 205, 206t Valacyclovir, 894t–895t, 901, 901f Valganciclovir, 894t–895t, 902, 902f Valproate, 204 intoxication with, 739 in children with fatty acid metabolic disorders, 390–391 management of, 739–740 hemodialysis or hemoperfusion in, 59 pharmacokinetics of, 739 Vancomycin overdose of, 882–883 toxic effects of, in neonate, 370 Vapona, 1172t Vapor, definition of, 170 Vasculitis, hypersensitivity, antibiotic-induced, 880, 881 Vasoconstriction, triptan-induced, 855 Vasopressin. See Antidiuretic hormone (ADH). Vasopressor therapy, in emergency care, 19–21, 20t Vecuronium, in rapid sequence intubation, 16t Venencapsan, hepatotoxicity of, 239b Venlafaxine, 550 overdose of, 555 pharmacokinetics of, 551t

Venom. See Envenomation. Veno-occlusive disease, 237 Venous thrombosis, contraceptive pills causing, 333 Venovenous hemodiafiltration, continuous for lithium poisoning, 585, 585f, 586t for salicylate poisoning, 846 Venovenous hemofiltration, continuous, 47–48, 47b, 47t, 48b Ventilation mechanical, for drug-induced pulmonary edema, 140 minute, in infants, environmental toxicants and, 1272 Ventricle, left, in anabolic steroid abusers, 1105 Ventricular arrhythmias, 136, 138 management of, 715 sedative intoxication causing, management of, 668 Ventricular tachycardia amphetamine abuse causing, 541 tricyclic antidepressant abuse causing, 541 Verapamil, in breast milk, 366t Veratridine, 482 Vesicants, 1500–1506, 1501t. See also specific agent. exposure to, 1502–1503 assessment of, 1504 manifestations of, 1503–1504 mass casualties in, management of, 1505 pathophysiology of, 1503, 1503t prenatal and pediatric issues concerning, 1504 principles of preparedness in, 1505–1506 relevant history of, 1501–1502 treatment of, 1504–1505 in national stockpile, 1502t National Research Council acute exposure guideline levels for, 1505t Vesicles, sulfur mustard–induced, 1503–1504 Vespidae, 447. See also Hymenoptera stings. Vibrio cholerae, food poisoning due to, 528–529 management of, 529 Vigabatrin, 204, 742 Villus(i), intestinal, 272 Vinblastine, pharmacologic parameters of, 929t Vincristine neurotoxicity of, 931–932 pharmacologic parameters of, 929t Vinyl chloride, carcinogenicity of, 238 Virus cell fusion inhibitors, 894t–895t, 903–904 Vision, color, styrene affecting, 1368 Visual acuity, decreased, toluene-induced, 1371–1372 Visual field constriction, peripheral, systemic substances causing, 309b Vital signs, 23 assessment of, in smoke inhalation victims, 1290 Vitamin(s), 1089–1098 definition of, 1089 fat-soluble, 1089, 1090–1096, 1091t history of, 1089–1090 reference daily intake of, 1089, 1089t supplementary, for alcohol withdrawal syndrome, 600 water-soluble, 1089, 1096–1098 Vitamin A, 1090–1095 anticarcinogenic effects of, 1091 deficiency of, 1092–1093 food sources of, 1091–1092

Vitamin A (Cont’d) history of, 1090 overdose of, 1091t clinical manifestations of, 1093–1094 diagnosis of, 1094 management of, 1094 pharmacology of, 1090–1092 structure of, 1090, 1092f Vitamin B1, 1097–1098 overdose of, 1091t, 1098 structure of, 1092f Vitamin B3, 337, 338, 1097 for pyriminil poisoning, 1219 hepatitis due to, 235b in breast milk, 366t ingestion of, gastrointestinal effects of, 278 overdose of, 1091t, 1097–1098 structure of, 1092f Vitamin B6, 1096–1097 effect of isoniazid on, 920–921 for Gyromitra mushroom poisoning, 464 for hydrazine ingestion, 1380 intravenous, for isoniazid overdose, 923 overdose of, 1091t, 1097 structure of, 1092f Vitamin C for chromium poisoning, 1161–1162 for progressive spongiform leukoencephalopathy, 652 overdose of, 1091t, 1098 structure of, 1092f Vitamin D, 324, 325, 1094–1096 analogs of, 324b overdose of, 1091t, 1095–1096 pharmacology of, 1095 structure of, 1092f Vitamin E, 1096 for progressive spongiform leukoencephalopathy, 652 overdose of, 1091t structure of, 1092f Vitamin K, 1096 and coagulation, 1052–1053, 1053f half-life of, 1056t inhibition of, 1053, 1054f overdose of, 1091t structure of, 1092f Vitreous fibers, man-made, exposure to, 182–183 Volatile inhalants, abuse of, 1381–1382 Volcanic gas, 9 Volume contraction, 116. See also Fluid balance. Volume of distribution, in decontamination, 55 Volume overload, 116. See also Fluid balance. Vomiting. See Emesis. VX agent general properties of, 1490t history of, 1488 W Warfare, chemical. See also Chemical weapons. stockpiled agents for, 1502, 1502t Warfarin, 1053–1055, 1055f. See also Superwarfarins. food interaction with, 102b in pregnancy, 1055 in rodenticides, 1056–1057, 1220 overdose of, 1055 Wasps. See also Hymenoptera. sea, 508, 509f Water for caustic alkali ingestion, 1411–1412 for soap or detergent ingestions, 1447 lead in, 1131 childhood poisoning due to, 1137

INDEX

Water (Cont’d) total-body. See also Fluid entries. intracellular and extracellular movement of, 114 redistribution of, 114–115 regulation of, 113–114, 113f Water hemlock, 489f cicutoxin in, 498 Water loss, restoration of, in acute renal failure, 258 Water solubility, in dialyzability, 55 Water-reactive materials, cutaneous decontamination from, 34, 36 Water-soluble drug hepatotoxicity, molecular adsorbents recirculating system for, 240 Water-soluble vitamins, 1089, 1096–1098. See also specific vitamin. Weapons, chemical, 1487–1520. See also Chemical weapons; specific agent. Weever fish, 510 Wernicke’s encephalopathy, 594–595 White phosphorus. See Phosphorus. Whole bowel irrigation for body stuffers and packers, 768 for calcium channel blocker toxicity, 969 for iron poisoning, 1126 for lithium poisoning, 584 in decontamination, 39 Wide complex tachycardia, of uncertain origin, 138, 138f, 139f Wild cherry, hallucinogenic effects of, 499 Wilson’s disease, 1162 Wisteria, 489f Withdrawal headaches, following triptan overuse, 855 Withdrawal syndrome(s), neonatal cocaine and, 367–368 opioids and, 367, 368t selective serotonin reuptake inhibitors and, 368

Wolf spider, 438 Wolff-Chaikoff effect, 1390 Woolly (pus) caterpillar, 451, 451f, 452f Workplace, surveillance toxicologic testing in, 77–78 Work-related illness. See also Industrial poisoning. causative agents, associative uses, occupations, and industries associated with, 1248t–1253t chemical exposure levels and monitoring in, 1244 environmental history in, 1242 evaluation of, principles in, 1242–1243 World Health Organization (WHO), 1266 World Health Organization (WHO) classification, of organophosphates, 1173 Wound(s). See also specific type, e.g., Snakebite(s). inflicted by pressurized paint, decontamination of, 36 Wound botulism, 521, 526. See also Botulism. Wyeth-Ayerst Antivenin (Crotalidae) Polyvalent, 409–413 complications of, 409–411 dosage of, 411 infusion guidelines for, 411–412, 412b route of administration of, 411 skin test for, 411 Wyeth-Ayerst Elapidae antivenin, for coral snakebites, 425 X Ximelagatran, 1059–1060 X-ray fluorescence, of lead poisoning, 1134 Xylene, 1374–1375 Y Yanango hydroelectric power plant, industrial radiation accident at, 1479–1480 Yarrow oil, 1441t

1559

Yeast extracts, tyramine in, 569, 569b Yellow oleander, 488f Yellow oleander fruit, 489f Yersinia enterocolitis sepsis, deferoxamineinduced, 1127 Yew, 489f Yew toxins, 482, 497 Yohimbine, for clonidine overdose, 1007 Z Zalcitabine, 890t–891t, 898–899, 898f Zaleplon adverse effects of, 666 drug interactions with, 663t, 666 intoxication with, 666 pharmacokinetics of, 662t, 665–666 structure of, 659f Zanamivir, 896t–897t, 905, 905f Zebra fish, 510, 510f Zidovudine, 890t–891t, 899, 899f toxic effects of, in neonate, 371 Zinc, 1166–1167 Zinc phosphide, in rodenticides, 1218 Zinc-desferrioxamine, for ocular mustard injury, 312 Zolmitriptan, drug interactions with, 854t Zolpidem adverse effects of, 666 drug interactions with, 663t, 666 intoxication with, 666 pharmacokinetics of, 662t, 665–666 structure of, 659f Zonisamide, 743 Zopiclone adverse effects of, 666 drug interactions with, 663t, 666 history and structure of, 659f, 660 intoxication with, 666 pharmacokinetics of, 662t, 665–666 Zykon-B, 6–7, 7f

Haddad and Winchester's Clinical Management of Poisoning and Drug Overdose, 4th Edition

Poisoning and Drug Overdose

Poisoning and Drug Overdose

Poisoning & Drug Overdose

Poisoning & Drug Overdose, 5 e 2006

Clinical Anesthesiology, 4th Edition

Clinical Interviewing, 4th edition

Clinical Dermatology, 4th edition

Clinical Anesthesiology, 4th Edition

Clinical Anesthesiology, 4th Edition

Understanding Normal and Clinical Nutrition 4th Edition

Criminal Poisoning: Clinical and Forensic Perspectives

Project Management, 4th Edition

Horse and Stable Management 4th Edition

Logistics and Supply Chain Management, 4th Edition

Logistics and Supply Chain Management, 4th Edition

Construction Contracts: Law and Management, 4th Edition

Essential Clinical Anatomy, 4th Edition

Clinical Nuclear Medicine 4th Edition

Abeloff's Clinical Oncology, 4th Edition

Abeloff's Clinical Oncology, 4th Edition

Basic Clinical Radiobiology, 4th edition

Fundamentals of Clinical Trials (4th edition)

Tietz Textbook of Clinical Chemistry and Molecular Diagnostics 4th edition

Principles and Practice of Clinical Virology, 4th Edition

Clinical Anatomy of the Lumbar Spine and Sacrum (4th Edition)

Fundamentals of Clinical Trials 4th Edition

Anticancer Drug Toxicity: Prevention, Management, and Clinical Pharmacokinetics

Practical General Practice: Guidelines for Effective Clinical Management 4th Edition

Management: An Introduction, 4th Edition

Energy Management Handbook, 4th edition

Haddad and Winchester's Clinical Management of Poisoning and Drug Overdose, 4th Edition

Poisoning and Drug Overdose

Poisoning and Drug Overdose

Poisoning & Drug Overdose

Poisoning & Drug Overdose, 5 e 2006

Clinical Anesthesiology, 4th Edition

Clinical Interviewing, 4th edition

Clinical Dermatology, 4th edition

Clinical Anesthesiology, 4th Edition

Clinical Anesthesiology, 4th Edition

Understanding Normal and Clinical Nutrition 4th Edition

Criminal Poisoning: Clinical and Forensic Perspectives

Project Management, 4th Edition

Horse and Stable Management 4th Edition

Logistics and Supply Chain Management, 4th Edition

Logistics and Supply Chain Management, 4th Edition

Construction Contracts: Law and Management, 4th Edition

Essential Clinical Anatomy, 4th Edition

Clinical Nuclear Medicine 4th Edition

Abeloff's Clinical Oncology, 4th Edition

Abeloff's Clinical Oncology, 4th Edition

Basic Clinical Radiobiology, 4th edition

Fundamentals of Clinical Trials (4th edition)

Tietz Textbook of Clinical Chemistry and Molecular Diagnostics 4th edition

Principles and Practice of Clinical Virology, 4th Edition

Clinical Anatomy of the Lumbar Spine and Sacrum (4th Edition)

Fundamentals of Clinical Trials 4th Edition

Anticancer Drug Toxicity: Prevention, Management, and Clinical Pharmacokinetics

Practical General Practice: Guidelines for Effective Clinical Management 4th Edition

Management: An Introduction, 4th Edition

Energy Management Handbook, 4th edition

Recommend Documents