Clinical Manual of Psychopharmacology in the Medically Ill

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Author: Stephen J. Ferrando | Stephen J. Ferrando | James L. Levenson | James A. Owen

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Clinical Manual of Psychopharmacology in the Medically Ill

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Clinical Manual of Psychopharmacology in the Medically Ill Edited by

Stephen J. Ferrando, M.D. James L. Levenson, M.D. James A. Owen, Ph.D.

Washington, DC London, England

Note: The authors have worked to ensure that all information in this book is accurate at the time of publication and consistent with general psychiatric and medical standards, and that information concerning drug dosages, schedules, and routes of administration is accurate at the time of publication and consistent with standards set by the U.S. Food and Drug Administration and the general medical community. As medical research and practice continue to advance, however, therapeutic standards may change. Moreover, specific situations may require a specific therapeutic response not included in this book. For these reasons and because human and mechanical errors sometimes occur, we recommend that readers follow the advice of physicians directly involved in their care or the care of a member of their family. Books published by American Psychiatric Publishing, Inc., represent the views and opinions of the individual authors and do not necessarily represent the policies and opinions of APPI or the American Psychiatric Association. If you would like to buy between 25 and 99 copies of this or any other APPI title, you are eligible for a 20% discount; please contact APPI Customer Service at [email protected] or 800-368-5777. If you wish to buy 100 or more copies of the same title, please e-mail us at [email protected] for a price quote. Copyright © 2010 American Psychiatric Publishing, Inc. ALL RIGHTS RESERVED Manufactured in the United States of America on acid-free paper 14 13 12 11 10 5 4 3 2 1 First Edition Typeset in Adobe’s AGaramond and Formata. American Psychiatric Publishing, Inc. 1000 Wilson Boulevard Arlington, VA 22209-3901 www.appi.org Library of Congress Cataloging-in-Publication Data Clinical manual of psychopharmacology in the medically ill / edited by Stephen J. Ferrando, James L. Levenson, James A. Owen. — 1st ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-58562-367-9 (pbk. : alk. paper) 1. Psychopharmacology. 2. Psychotropic drugs. I. Ferrando, Stephen J. II. Levenson, James L. III. Owen, James A., 1949– [DNLM: 1. Psychotropic Drugs—adverse effects. 2. Psychotropic Drugs— pharmacokinetics. 3. Comorbidity. 4. Drug Interactions. QV 77.2 C6405 2010] RM315.C5474 2010 615′.78—dc22 2010003564 British Library Cataloguing in Publication Data A CIP record is available from the British Library.

Contents Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .xix Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . xxv Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxvii

Stephen J. Ferrando, M.D. James L. Levenson, M.D. James A. Owen, Ph.D. PART I General Principles

1

Pharmacokinetics, Pharmacodynamics, and Principles of Drug–Drug Interactions . . . . . . . . . . . 3

James A. Owen, Ph.D. Pharmacodynamics. . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . . 20 Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Appendix: Drugs With Clinically Significant Pharmacokinetic Interactions. . . . . . . . . . . . . . . . . . 30

2

Severe Drug Reactions. . . . . . . . . . . . . . . . . . . . . . . 39

Stanley N. Caroff, M.D. Stephan C. Mann, M.D. E. Cabrina Campbell, M.D. Rosalind M. Berkowitz, M.D. Central Nervous System Reactions . . . . . . . . . . . . . 40 Cardiovascular Reactions . . . . . . . . . . . . . . . . . . . . . 49 Gastrointestinal Reactions . . . . . . . . . . . . . . . . . . . . 55

Renal Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 Hematological Reactions . . . . . . . . . . . . . . . . . . . . . 64 Metabolic Reactions and Body as a Whole. . . . . . . 66 Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

3

Alternate Routes of Drug Administration . . . . . . . 79

James A. Owen, Ph.D. Properties of Specific Routes of Administration . . . 80 Psychotropic Medications. . . . . . . . . . . . . . . . . . . . . 87 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

PART II Psychopharmacology in Organ System Disorders and Specialty Areas

4

Gastrointestinal Disorders . . . . . . . . . . . . . . . . . . 103

Catherine C. Crone, M.D. Michael Marcangelo, M.D. Jeanne Lackamp, M.D. Andrea F. DiMartini, M.D. James A. Owen, Ph.D. Oropharyngeal Disorders . . . . . . . . . . . . . . . . . . . . 104 Esophageal and Gastric Disorders . . . . . . . . . . . . . 106 Intestinal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . 111 Liver Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 Gastrointestinal Side Effects of Psychiatric Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 Psychotropic Drug–Induced Gastrointestinal Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

Psychiatric Side Effects of Gastrointestinal Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 132 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 138 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

5

Renal and Urological Disorders . . . . . . . . . . . . . . 149

James A. Owen, Ph.D. James L. Levenson, M.D. Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . 150 Pharmacotherapy in Renal Disease. . . . . . . . . . . . 152 Psychiatric Adverse Effects of Renal and Urological Agents. . . . . . . . . . . . . . . . . . . . . . . . . . . 161 Renal and Urological Adverse Effects of Psychotropics . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 166 Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 175 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

6

Cardiovascular Disorders . . . . . . . . . . . . . . . . . . . 181

Peter A. Shapiro, M.D. Differential Diagnostic Considerations . . . . . . . . . 182 Neuropsychiatric Side Effects of Cardiac Medications . . . . . . . . . . . . . . . . . . . . . . . . 183 Alterations in Pharmacokinetics in Heart Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 Psychotropic Medication Use in Heart Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 199 Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 207 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207

7

Respiratory Disorders . . . . . . . . . . . . . . . . . . . . . . 213

Wendy L. Thompson, M.D. Yvette L. Smolin, M.D. Differential Diagnostic Considerations . . . . . . . . . 214 Neuropsychiatric Side Effects of Respiratory Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . 216 Alteration of Pharmacokinetics . . . . . . . . . . . . . . . 219 Prescribing Psychotropic Medications in Respiratory Disease. . . . . . . . . . . . . . . . . . . . . . . . . 220 Effects of Psychotropic Drugs on Pulmonary Diseases . . . . . . . . . . . . . . . . . . . . . . . . 225 Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 227 Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 230 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230

8

Oncology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237

James A. Owen, Ph.D. Stephen J. Ferrando, M.D. Differential Diagnosis of Psychiatric Manifestations of Cancers . . . . . . . . . . . . . . . . . . . 238 Psychopharmacological Treatment of Psychiatric Disorders in Cancer Patients . . . . . . . . 239 Adverse Oncological Effects of Psychotropics. . . . 244 Neuropsychiatric Adverse Effects of Oncology Treatments . . . . . . . . . . . . . . . . . . . . . 247 Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 251 Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 260 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261

9

Central Nervous System Disorders. . . . . . . . . . . . 271

Saeed Salehinia, M.D. Vani Rao, M.D. Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 Traumatic Brain Injury. . . . . . . . . . . . . . . . . . . . . . . 276 Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . 278 Parkinson’s Disease. . . . . . . . . . . . . . . . . . . . . . . . . 280 Huntington’s Disease . . . . . . . . . . . . . . . . . . . . . . . 282 Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 Symptoms and Syndromes Common Across Neurological Disorders . . . . . . . . . . . . . . . . 285 Adverse Neurological Effects of Psychotropic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . 286 Adverse Psychiatric Effects of Neurological Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 291 Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 296 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297

10 Endocrine and Metabolic Disorders. . . . . . . . . . . 305 Stephen J. Ferrando, M.D. Jennifer Kraker, M.D., M.S. Diabetes Mellitus. . . . . . . . . . . . . . . . . . . . . . . . . . . 306 Thyroid Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 309 Pheochromocytoma . . . . . . . . . . . . . . . . . . . . . . . . 311 Antidiuretic Hormone . . . . . . . . . . . . . . . . . . . . . . . 311 Reproductive Endocrine System Disorders. . . . . . 312 Hypogonadal Disorders . . . . . . . . . . . . . . . . . . . . . 312 Endocrinological Side Effects of Psychiatric Medications. . . . . . . . . . . . . . . . . . . . . . 313 Psychiatric Side Effects of Endocrine Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320

Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 324 Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 328 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328

11 Obstetrics and Gynecology . . . . . . . . . . . . . . . . . . 339 Margaret Altemus, M.D. Mallay Occhiogrosso, M.D. Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . 340 Pharmacotherapy of Premenstrual Mood Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342 Pharmacotherapy of Menopause-Related Depression, Anxiety, and Insomnia . . . . . . . . . . . . 343 Psychopharmacology in Pregnancy and Breastfeeding . . . . . . . . . . . . . . . . . . . . . . . . . . 343 Adverse Obstetric and Gynecological Reactions to Psychotropic Drugs . . . . . . . . . . . . . . 354 Psychiatric Adverse Effects of Obstetric and Gynecological Agents and Procedures . . . . . . . . . 355 Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 358 Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 361 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362

12 Infectious Diseases . . . . . . . . . . . . . . . . . . . . . . . . 371 Stephen J. Ferrando, M.D. James L. Levenson, M.D. James A. Owen, Ph.D. Bacterial Infections . . . . . . . . . . . . . . . . . . . . . . . . . 372 Viral Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374 Parasitic Infections: Neurocysticercosis . . . . . . . . . 393 Adverse Psychiatric Effects of Antibiotics . . . . . . . 393 Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 394 Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 395 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396

13 Dermatological Disorders . . . . . . . . . . . . . . . . . . . 405 Madhulika A. Gupta, M.D., F.R.C.P.C. James L. Levenson, M.D. Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . 406 Pharmacotherapy of Specific Disorders . . . . . . . . 409 Adverse Cutaneous Drug Reactions to Psychotropic Agents . . . . . . . . . . . . . . . . . . . . . . . . 415 Adverse Psychiatric Effects of Dermatological Agents . . . . . . . . . . . . . . . . . . . . . . 420 Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 422 Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 423 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424

14 Rheumatological Disorders. . . . . . . . . . . . . . . . . . 431 James L. Levenson, M.D. Stephen J. Ferrando, M.D. Treatment of Psychiatric Disorders . . . . . . . . . . . . 432 Psychiatric Side Effects of Rheumatological Medications . . . . . . . . . . . . . . . . 433 Rheumatological Side Effects of Psychotropic Medications: Psychotropic Drug–Induced Lupus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434 Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 435 Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 435 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436

15 Surgery and Critical Care. . . . . . . . . . . . . . . . . . . . 439 Stephen J. Ferrando, M.D. James L. Levenson, M.D. James A. Owen, Ph.D. Delirium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440 Psychotropic Drugs in the Perioperative Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447 Treatment of Preoperative Anxiety . . . . . . . . . . . . 449

Acute and Posttraumatic Stress in the Critical Care Setting . . . . . . . . . . . . . . . . . . . . . . . . . 451 Adverse Neuropsychiatric Effects of Critical Care and Surgical Drugs . . . . . . . . . . . . . . . . . . . . . 453 Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 454 Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 460 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462

16 Organ Transplantation. . . . . . . . . . . . . . . . . . . . . . 469 Andrea F. DiMartini, M.D. Catherine C. Crone, M.D. Marian Fireman, M.D. Posttransplant Pharmacological Considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470 Psychotropic Medications in Transplant Patients. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475 Drug-Specific Issues . . . . . . . . . . . . . . . . . . . . . . . . 484 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491 Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 491 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492

17 Pain Management . . . . . . . . . . . . . . . . . . . . . . . . . 501 Michael R. Clark, M.D., M.P.H. James A. Owen, Ph.D. Psychiatric Comorbidity . . . . . . . . . . . . . . . . . . . . . 502 Pain Description and Management . . . . . . . . . . . . 504 Pharmacological Treatment . . . . . . . . . . . . . . . . . . 510 Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 522 Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 524 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525

18 Substance Use Disorders

. . . . . . . . . . . . . . . . . . . 537

JoséMaldonado, M.D., F.A.P.M., F.A.C.F.E. Andrea F. DiMartini, M.D. James A. Owen, Ph.D. Drugs for Substance Intoxication . . . . . . . . . . . . . . 538 Drugs for Substance Use Disorders . . . . . . . . . . . . 539 Psychiatric Adverse Effects of Drugs Used in Substance Use Disorders . . . . . . . . . . . . . . . . . . . . 547 Drug–Drug Interactions . . . . . . . . . . . . . . . . . . . . . 547 Key Clinical Points . . . . . . . . . . . . . . . . . . . . . . . . . . 549 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 552 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557


List of Tables and Figures Figure 1–1 Figure 1–2 Table 1–1 Figure 1–3 Table 1–2 Figure 1–4 Table 1–3 Table 1–4 Table Table Table Table Table Table

Relationship between pharmacokinetics and pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Concentration–response relationship . . . . . . . . . . . . . . 6 Strategies to maximize medication compliance . . . . . . 8 First-pass metabolism of orally administered drugs. .10 Conditions that alter plasma levels of albumin and alpha-1 acid glycoprotein . . . . . . . . . . . . . . . . . . .13 General pathways of metabolism and excretion . . . .16 Systemic clearance of hepatically metabolized psychotropic drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . .19 Psychotropic drugs that cause few pharmacokinetic interactions. . . . . . . . . . . . . . . . . . . .26

2–1 2–2 2–3 2–4 2–5 2–6

Central nervous system reactions . . . . . . . . . . . . . . . .41 Cardiovascular reactions . . . . . . . . . . . . . . . . . . . . . . .50 Gastrointestinal reactions. . . . . . . . . . . . . . . . . . . . . . .56 Renal reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .60 Hematological reactions . . . . . . . . . . . . . . . . . . . . . . .65 Metabolic reactions and body as a whole . . . . . . . . .68

Table 3–1

Situations potentially requiring alternate routes of administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . .80 Nonoral preparations of psychotropic medications . .82

Table 3–2 Table 4–1 Table 4–2 Table 4–3 Table 4–4

Medication absorption after Roux-en-Y gastric bypass surgery . . . . . . . . . . . . . . . . . . . . . . . Psychotropic drug dosing in hepatic insufficiency (HI) . . . . . . . . . . . . . . . . . . . . . . . . . . . Gastrointestinal adverse effects of psychiatric drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Psychiatric adverse effects of gastrointestinal drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

113 118 124 130

Table 4–5 Table 4–6 Table 5–1 Table 5–2 Table 5–3 Table 5–4 Table 5–5 Table 5–6 Table 6–1 Table Table Table Table

6–2 6–3 6–4 6–5

Table 6–6 Table 7–1

Gastrointestinal drug–psychotropic drug interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 Psychotropic drug–gastrointestinal drug interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 Psychotropic drugs in renal insufficiency (RI). . . . . Dialyzable psychotropic drugs . . . . . . . . . . . . . . . . . Psychiatric adverse effects of renal and urological drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . Renal and urological adverse effects of psychiatric drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . Renal and urological drug–psychotropic drug interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Psychotropic drug–renal and urological drug interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Selected adverse neuropsychiatric effects of cardiac medications . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacokinetic changes in heart disease. . . . . . . Cardiac adverse effects of psychotropic drugs . . . . Risk factors for torsade de pointes . . . . . . . . . . . . . Clinically relevant cardiac drug–psychotropic drug interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinically relevant psychotropic drug–cardiac drug interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . .

154 158 163 165 168 172 183 185 187 195 202 204

Table 7–4

Psychiatric symptoms often associated with respiratory diseases . . . . . . . . . . . . . . . . . . . . . . . . Neuropsychiatric side effects of drugs used to treat respiratory diseases. . . . . . . . . . . . . . . . . . Respiratory side effects of psychotropic medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Respiratory drug–psychotropic drug interactions .

Table 8–1 Table 8–2 Table 8–3

Psychiatric adverse effects of oncology drugs . . . . 249 Oncology drug–psychotropic drug interactions . . . 252 Psychotropic drug–oncology drug interactions . . . 254


. 214 . 217 . 226 . 228

Table 8–4

Oncology prodrugs activated by cytochrome P450 (CYP) metabolism . . . . . . . . . . . . . . . . . . . . . 259

Table 9–1

Neurological adverse effects of psychotropic drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Psychiatric adverse effects of neurological drugs . . Neurological drug–psychotropic drug interactions . Psychotropic drug–neurological drug interactions .

Table 9–1 Table 9–1 Table 9–1 Table 10–1 Table 10–2 Table 10–3

Table 10–4 Table 10–5 Table 10–6 Table 11–1 Table 11–2 Table 11–3 Table 11–4

Psychiatric symptoms of endocrine and metabolic disorders . . . . . . . . . . . . . . . . . . . . . . . . . Endocrinological adverse effects of psychotropic drugs. . . . . . . . . . . . . . . . . . . . . . . . . . Consensus guidelines for monitoring metabolic status in patients taking antipsychotic medications . . . . . . . . . . . . . . . . . . . . Psychiatric adverse effects of endocrinological/ hormonal treatments . . . . . . . . . . . . . . . . . . . . . . . . Psychotropic drug–endocrine drug interactions . . . Endocrine drug–psychotropic drug interactions . . . Effects of psychiatric medications on fetus/infant Psychiatric adverse effects of obstetrics and gynecology drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . Obstetrics/gynecology drug–psychotropic drug interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . Psychotropic drug–obstetrics/gynecology drug interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . .

287 290 292 294 306 313

318 321 325 327 346 356 359 360


Psychiatric adverse effects of antibiotic therapy . . . 375 Antibiotic drug–psychotropic drug interactions . . . 378

Table 13–1

Some dermatological drug–psychotherapeutic drug pharmacokinetic interactions . . . . . . . . . . . . . 410

Table 14–1

Psychiatric side effects of medications used in treating rheumatological disorders . . . . . . . . . . . 434 Rheumatology drug–psychotropic drug interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436

Table 14–2

Table 15–1 Table 15–2 Table 16–1 Table 16–2 Table 16–3 Table 16–4

Psychiatric adverse effects of drugs used in surgery and critical care . . . . . . . . . . . . . . . . . . . . 453 Critical care and perisurgical drug–psychotropic drug interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . 455 Neuropsychiatric side effects of immunosuppressants . . . . . . . . . . . . . . . . . . . . . . . Immunosuppressant metabolism and effects on metabolic systems . . . . . . . . . . . . . . . . . . . . . . . Immunosuppressant drug–psychotropic drug interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Psychotropic drug–immunosuppressant drug interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

485 488 489 490


Medications for pain management. . . . . . . . . . . . . 512 Pain drug–psychotropic drug interactions. . . . . . . . 523

Table 18–1

Neuropsychiatric adverse effects of drugs that treat substance abuse . . . . . . . . . . . . . . . . . . . 548 Psychotropic drug–drugs for substance abuse interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 550

Table 18–2

Contributors

Margaret Altemus, M.D. Associate Professor of Psychiatry, Weill Cornell Medical College, New York, New York Rosalind M. Berkowitz, M.D. Private Practice, Moorestown, New Jersey E. Cabrina Campbell, M.D. Associate Director, Inpatient Psychiatry, Philadelphia Veterans Affairs Medical Center; Associate Professor of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Stanley N. Caroff, M.D. Director, Inpatient Psychiatry, Philadelphia Veterans Affairs Medical Center; Professor of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Michael R. Clark, M.D., M.P.H. Associate Professor and Director, Adolf Meyer Chronic Pain Treatment Programs, Department of Psychiatry and Behavioral Sciences, The Johns Hopkins Medical Institutions, Baltimore, Maryland Catherine C. Crone, M.D. Associate Professor of Psychiatry, George Washington University Medical Center, Washington, D.C.; Vice Chair, Department of Psychiatry, Inova Fairxix

xx Clinical Manual of Psychopharmacology in the Medically Ill

fax Hospital, Falls Church, Virginia; Clinical Professor of Psychiatry, Virginia Commonwealth University School of Medicine, Northern Virginia Branch, Fairfax, Virginia Andrea F. DiMartini, M.D. Associate Professor of Psychiatry and of Surgery, Western Psychiatric Institute; Consultation Liaison to the Liver Transplant Program, Starzl Transplant Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Stephen J. Ferrando, M.D. Professor of Clinical Psychiatry and Public Health and Vice Chair for Psychosomatic Medicine and Departmental Operations, Payne Whitney Clinic, New York-Presbyterian Hospital, Weill Cornell Medical Center, Department of Psychiatry, New York, New York Marian Fireman, M.D. Associate Professor of Psychiatry, Oregon Health and Science University, Portland, Oregon Madhulika A. Gupta, M.D., F.R.C.P.C. Professor, Department of Psychiatry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada Jennifer Kraker, M.D., M.S. Resident in Psychiatry, Department of Psychiatry, Payne Whitney Clinic, New York-Presbyterian Hospital, New York, New York Jeanne Lackamp, M.D. Assistant Professor, Department of Psychiatry, University Hospitals/Case Medical Center, Cleveland, Ohio James L. Levenson, M.D. Professor of Psychiatry, Medicine, and Surgery, and Vice-Chair for Clinical Services, Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, Virginia

Contributors

xxi

José Maldonado, M.D., F.A.P.M., F.A.C.F.E. Associate Professor of Psychiatry and Medicine; Medical Director, Forensic Psychiatry Program; Medical Director, Psychosomatic Medicine Service; Faculty, Stanford Center for Biomedical Ethics, Stanford University School of Medicine, Stanford, California Stephan C. Mann, M.D. Medical Director, Central Montgomery Mental Health and Mental Retardation Center, Norristown, Pennsylvania; Clinical Professor, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, Kentucky Michael Marcangelo, M.D. Assistant Professor, Department of Psychiatry and Behavioral Neuroscience, and Director Of Medical Student Education, The University of Chicago Medical Center, Chicago, Illinois Mallay Occhiogrosso, M.D. Assistant Professor of Psychiatry, Weill Cornell Medical College, New York, New York James A. Owen, Ph.D. Associate Professor, Department of Psychiatry and Department of Pharmacology and Toxicology, Queen’s University; Director of Psychopharmacology, Providence Care Mental Health Services, Kingston, Ontario, Canada Vani Rao, M.D. Director, Neuropsychiatry Fellowship Program, and Section Head, Bayview Geriatric Psychiatry, Neuropsychiatry Program; Associate Professor, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland Saeed Salehinia, M.D. Physician Clinical Staff, Department of Health and Mental Hygiene, Developmental Disabilities Administration of Maryland, Secure Evaluation and Therapeutic Treatment (SETT) Program, Sykesville, Maryland

xxii Clinical Manual of Psychopharmacology in the Medically Ill

Peter A. Shapiro, M.D. Professor of Clinical Psychiatry, Columbia University; Director, Fellowship Training Program in Psychosomatic Medicine; Director, Transplant Psychiatry Programs; Associate Director, Consultation-Liaison Psychiatry Service; New York Presbyterian Hospital–Columbia University Medical Center, New York, New York Yvette L. Smolin, M.D. Director of Psychosomatic Medicine and Clinical Assistant Professor, Department of Psychiatry and Behavioral Science, New York Medical College at Westchester Medical Center, Valhalla, New York Wendy L. Thompson, M.D. Director of Education and Professor of Clinical Psychiatry, Department of Psychiatry and Behavioral Science, New York Medical College at Westchester Medical Center, Valhalla, New York

Disclosure of Competing Interests The following contributors to this book have indicated a financial interest in or other affiliation with a commercial supporter, a manufacturer of a commercial product, a provider of a commercial service, a nongovernmental organization, and/or a government agency, as listed below: Margaret Altemus, M.D. Donation of study drug from Pfizer for a clinical trial otherwise funded by NIH. E. Cabrina Campbell, M.D. Research Grant: Pfizer. Stanley N. Caroff, M.D. Research Grant: Pfizer; Consultant: Eli Lilly. Stephen J. Ferrando, M.D. Speakers Bureau: AstraZeneca, Pfizer. Jennifer Kraker, M.D., M.S. Fellowship/Award: American Psychiatric Association (APA)/Bristol-Myers Squibb Fellowship in Public Psychiatry, 2009–2011 (travel sponsorship to APA meetings, including Institute on Psychiatric Services and components meetings). James L. Levenson, M.D. Advisory Board: Eli Lilly. James A. Owen, Ph.D. Research Support/Speakers Bureau: Lundbeck. Vani Rao, M.D. Research Grants: Forest, Pfizer.

Disclosure of Competing Interests

The following contributors to this book have no competing interests to report: Rosalind M. Berkowitz, M.D. Michael R. Clark, M.D., M.P.H. Catherine C. Crone, M.D. Andrea F. DiMartini, M.D. Marian Fireman, M.D. Madhulika A. Gupta, M.D., F.R.C.P.C. Jeanne Lackamp, M.D. José Maldonado, M.D., F.A.P.M., F.A.C.F.E. Stephan C. Mann, M.D. Michael Marcangelo, M.D. Mallay Occhiogrosso, M.D. Saeed Salehinia, M.D. Peter A. Shapiro, M.D. Yvette L. Smolin, M.D. Wendy L. Thompson, M.D.

xxiii


Acknowledgments

The editors would collectively like to acknowledge multiple individuals for their support, encouragement, and thoughtful input during the preparation of this book. We thank our contributors, whose expertise has made this manual a rigorous and unique resource. We thank Charles Gross, M.A., for his outstanding editorial assistance and coordination efforts in the preparation and submission of the book manuscript. Finally, we thank Dr. Robert E. Hales, Editor in Chief of American Psychiatric Publishing, Inc. (APPI), as well as John McDuffie and the editorial staff of APPI for their enthusiastic reception of the concept of this book and for their highly professional help throughout the course of its production. Dr. Ferrando would like to acknowledge Drs. Jack D. Barchas and Philip J. Wilner for their invaluable encouragement, mentorship, and support of his professional development and work on this book. Most importantly, he would like to thank his wife, Dr. Maria Costantini-Ferrando, and children, Luke, Nicole, Marco, and David, for being his prime motivators in life and for their patience in tolerating the many hours spent writing and editing. Dr. Levenson would like to thank his wife and family for their support. Dr. Owen would like to thank his wife, Sue, for her encouragement and literary support.

xxv


Introduction

Stephen J. Ferrando, M.D. James L. Levenson, M.D. James A. Owen, Ph.D.

The mission of this book is to serve as a clinical manual and educational tool

for specialist and nonspecialist clinicians for the psychopharmacological treatment of patients with medical illness. Psychiatric comorbidity occurs in approximately 30% of medical outpatients (Spitzer et al. 1999) and 40%–50% of medical inpatients (Diez-Quevedo et al. 2001; Levenson et al. 1990). Patients with medical and psychiatric comorbidity have more functional impairment, disability days, health care services use, and medical care costs than do those without such comorbidity. Psychopharmacological agents are a mainstay of treatment for psychiatric disorders and, in keeping with the above psychiatric comorbidity rates, are often prescribed to patients who are medically ill. Approximately 10% of medical–surgical inpatients (Haggerty et al. 1986) and 5%–12% of general practice outpatients (Linden et al. 1999; Pincus et al. xxvii

xxviii Clinical Manual of Psychopharmacology in the Medically Ill

1998) are given prescribed psychotropic medication. Nearly three-fourths of patients seen in psychiatric consultation, young and old, receive psychotropic medication for broad-ranging diagnoses, including depression, anxiety, delirium, dementia with behavioral disturbances, and substance abuse and withdrawal (Schellhorn et al. 2009). Most psychotropic prescriptions are written by primary practitioners, followed by psychiatrists, then other medical specialists: of 45 million U.S. physician visits in 1993–1994 in which a psychotropic medication was prescribed, 22 million (49%) were with primary care physicians, 15 million (33%) were with psychiatrists, and 8 million (18%) were with other medical specialists (Pincus et al. 1998). Although the principles of psychotropic prescription to patients with medical illness are therefore relevant across medical specialties, physicians outside of the field of psychosomatic medicine (who represent a small subspecialty within psychiatry) often feel ill equipped to prescribe to such patients out of concerns for safety, lack of efficacy, and drug–disease and drug–drug interactions. These concerns likely contribute to the underdiagnosis, underprescription, and underdosing of psychotropic medications for widespread conditions, such as major depression, in patients who are medically ill (Mojtabai 2002; Seelig and Katon 2008). In fact, the vast majority of mainstream psychopharmacology efficacy studies on which governmental regulatory approval is based exclude medically ill individuals. Furthermore, studies of antidepressant treatment suggest that although patients with comorbid medical illness and depression improve with antidepressant medication, medical comorbidity reduces depressive symptom response and remission (Iosifescu et al. 2004). Fortunately, in recognition of the above issues, there is a growing evidence base concerning the prescription, safety, and efficacy of psychopharmacological treatments for multiple psychiatric problems in medically ill patients. Unfortunately, no current texts are specifically devoted to this topic. This is the impetus for this manual.

How to Use This Manual In this manual, we aim to provide clinically relevant information regarding psychopharmacology in patients who are medically ill, including pharmacokinetic and pharmacodynamic principles, drug–drug interactions, and organ

Introduction xxix

system disease–specific issues. Chapters are authored by experts in the field, with editorial input to maintain consistency of format and style. The manual has two sections. Part 1, “General Principles,” provides fundamental background information for prescribing psychotropic drugs across medical disease states and is suggested reading prior to advancing to the disease-specific information in the second section. Part 1 includes discussion of pharmacodynamics and pharmacokinetics, drug–drug interaction principles, major systemic adverse effects of psychotropic drugs, and alternate routes of psychotropic drug administration. Part 2, “Psychopharmacology in Organ System Disorders and Specialty Areas,” includes chapters on psychopharmacological treatment in specific organ system diseases, such as renal and cardiovascular disease, as well as other relevant subspecialty areas, such as critical care, organ transplantation, pain, and substance use disorders. With some variation, chapters are structured to include the following elements: key differential diagnostic considerations, including adverse neuropsychiatric side effects of disease-specific medications; disease-specific pharmacokinetic principles in drug prescribing; review of evidence for psychotropic drug treatment of psychiatric disorders in the specific disease state or specialty area; disease-specific adverse psychotropic drug side effects; and interactions between psychotropic drugs and disease-specific drugs. Each chapter has tables that summarize information on adverse neuropsychiatric side effects of disease-specific medications, adverse disease-specific side effects of psychotropic drugs, and drug–drug interactions. Chapters are heavily referenced with source information should readers wish to expand their knowledge in a specific area. Finally, each chapter ends with a list of key summary points pertaining to psychotropic prescribing in the specific medical disease(s) or specialty area covered in the chapter. With this structure, we hope that we have contributed a comprehensive yet practical guide for psychotropic prescribing for patients who are medically ill. We will consider this manual a success if it proves useful for a broad range of specialists: the psychosomatic medicine specialist caring for a delirious patient with cancer, the general psychiatrist in the community mental health clinic whose patient with schizophrenia develops liver disease in the setting of alcohol dependence and hepatitis C infection, and the general medical practitioner prescribing an antidepressant to a diabetic patient who recently had

xxx Clinical Manual of Psychopharmacology in the Medically Ill

a myocardial infarction. We hope that this manual, beyond serving as a clinical guide, will also become a mainstay of curricula in general psychiatric residency programs, in psychosomatic medicine fellowships, and in nonpsychiatric residency training programs that seek to provide training in psychopharmacology for medically ill patients.

References Diez-Quevedo C, Rangil T, Sanchez-Planell L, et al: Validation and utility of the Patient Health Questionnaire in diagnosing mental disorders in 1003 general hospital Spanish inpatients. Psychosom Med 63:679–686, 2001 Haggerty JJ Jr, Evans DL, McCartney CF, et al: Psychotropic prescribing patterns of nonpsychiatric residents in a general hospital in 1973 and 1982. Hosp Community Psychiatry 37:357–361, 1986 Iosifescu DV, Bankier B, Fava M: Impact of medical comorbid disease on antidepressant treatment of major depressive disorder. Curr Psychiatry Rep 6:193–201, 2004 Levenson JL, Hamer RM, Rossiter LF: Relation of psychopathology in general medical inpatients to use and cost of services. Am J Psychiatry 147:1498–1503, 1990 Linden M, Lecrubier Y, Bellantuono C, et al: The prescribing of psychotropic drugs by primary care physicians: an international collaborative study. J Clin Psychopharmacol 19:132–140, 1999 Mojtabai R: Diagnosing depression and prescribing antidepressants by primary care physicians: the impact of practice style variations. Ment Health Serv Res 4:109– 118, 2002 Pincus HA, Tanielian TL, Marcus SC, et al: Prescribing trends in psychotropic medications: primary care, psychiatry and other medical specialties. JAMA 279:526– 531, 1998 Schellhorn SE, Barnhill JW, Raiteri V, et al: A comparison of psychiatric consultation between geriatric and non-geriatric medical inpatients. Int J Geriatr Psychiatry 24:1054–1061, 2009 Seelig MD, Katon W: Gaps in depression care: Why primary care physicians should hone their depression screening, diagnosis, and management skills. J Occup Environ Med 50:451–458, 2008 Spitzer RL, Kroenke K, Williams JB: Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. Primary Care Evaluation of Mental Disorders. Patient Health Questionnaire. JAMA 282:1737–1744, 1999

PA R T I General Principles


1 Pharmacokinetics, Pharmacodynamics, and Principles of Drug–Drug Interactions James A. Owen, Ph.D.

P

sychotropic drugs are commonly employed in the management of patients who are medically ill. At least 35% of psychiatric consultations include recommendations for medication (Bronheim et al. 1998). The appropriate use of psychopharmacology in medically ill patients requires careful consideration of the underlying medical illness, potential alterations to pharmacokinetics, drug– drug interactions, and contraindications. In this chapter, we review drug action, drug pharmacokinetics, and drug interactions to provide a basis for drug–drug and drug–disease interactions presented in later disease-specific chapters. The effects of a drug—that is, the magnitude and duration of its therapeutic and adverse effects—are determined by the drug’s pharmacodynamic and 3

4 Clinical Manual of Psychopharmacology in the Medically Ill

pharmacokinetic characteristics. Pharmacodynamics describes the effects of a drug on the body. Pharmacodynamic processes determine the relationship between drug concentration and response for both therapeutic and adverse effects. Pharmacokinetics describes what the body does to the drug. It characterizes the rate and extent of drug absorption, distribution, metabolism, and excretion. These pharmacokinetic processes determine the rate of drug delivery to and the drug’s concentration at the sites of action. The relationship between pharmacokinetics and pharmacodynamics is diagrammed in Figure 1–1.

Pharmacodynamics For most drugs, the pharmacological effect is the result of a complex chain of events, beginning with the interaction of drug with receptor. Pharmacodynamic response is further modified—enhanced or diminished—by disease states, aging, and other drugs. For example, the presence of Parkinson’s disease increases the incidence of movement disorders induced by selective serotonin reuptake inhibitors (SSRIs). Pharmacodynamic disease–drug interactions are reviewed in the relevant chapters; pharmacodynamic drug–drug interactions are discussed later in this chapter in “Pharmacodynamic Drug Interactions.” A drug’s spectrum of therapeutic and adverse effects is due to its interaction with multiple receptor sites. The effects produced depend on which receptor populations are occupied by the drug; some receptor populations are readily occupied at low drug concentrations, whereas other receptor sites require high drug levels for interaction. In this way, different responses are recruited in a stepwise manner with increasing drug concentration. As drug levels increase, each effect will reach a maximum as all active receptors responsible for that effect are occupied by the drug. Further increases in drug concentration cannot increase this response but may elicit other effects. Figure 1–2 illustrates three pharmacological effects produced by a drug in a concentrationdependent manner. In this example, Effect B is the primary therapeutic effect, Effect A is a minor adverse effect, and Effect C is a significant toxic effect. Low drug concentrations recruit only Effect A; the patient experiences a nuisance side effect without any therapeutic gain. As drug concentration increases, Effect B is engaged while Effect A is maximized. Clearly, for this drug, except in the rare situation where Effect B antagonizes Effect A (e.g., where the initial sedating effect of a drug is counteracted by stimulating effects recruited at a higher

Principles of Drug–Drug Interactions

Relationship between pharmacokinetics and pharmacodynamics.

5

Figure 1–1.


Figure 1–2.

Concentration–response relationship (see text for details).


7

concentration), Effect A will always accompany a therapeutically effective dose because it is recruited at a lower concentration than that required for the therapeutic effect. Further increases in drug concentration improve the therapeutic effect until reaching its maximum but also introduce toxic Effect C. Optimum therapy requires that drug concentrations be confined to a therapeutic range to maximize the therapeutic effect and minimize any adverse and/ or toxic effects. Developing a dosage regimen to maintain drug levels within this therapeutic range requires consideration of pharmacokinetic processes. Drug–receptor interactions produce effects on several time scales. Immediate effects are the result of a direct receptor interaction. Several psychoactive drugs, including benzodiazepines, have immediate therapeutic effects and therefore are useful on an acute or as-needed basis. However, many psychoactive drugs, such as antidepressant and antipsychotic agents, require chronic dosing over several weeks for a significant therapeutic response. These drugs appear to alter neuronal responsiveness by modifying slowly adapting cellular processes. Unfortunately, many adverse effects appear immediately—the result of a direct receptor interaction. Medication adherence may be eroded when adverse effects are experienced before therapeutic effects are realized. Table 1–1 lists strategies to maximize medication compliance.

Pharmacokinetics Drug response, including the magnitude and duration of the drug’s therapeutic and adverse effects, is significantly influenced by the drug’s pharmacokinetics (absorption from administration sites, distribution throughout the body, and metabolism and excretion). Individual differences in constitutional factors, compromised organ function, and disease states, or the effects of other drugs and food, all contribute to the high variability in drug response observed across patients. Understanding the impact of these factors on a drug’s pharmacokinetics will aid in drug selection and dosage adjustment in a therapeutic environment complicated by polypharmacy and medical illness.

Absorption and Bioavailability The speed of onset and to a certain extent the duration of the pharmacological effects of a drug are determined by the route of administration. The bioavailability of a drug formulation describes the rate and extent of drug


Table 1–1. Strategies to maximize medication compliance Provide patient education Inform the patient about potential adverse effects, their speed of onset, and whether tolerance will develop over time. Indicate the time for onset of the therapeutic effect. Many psychotropic drugs have a considerable delay (weeks) before the appearance of significant therapeutic effects yet give rise to adverse effects immediately. Patients not aware of this temporal disconnect between adverse and therapeutic effects may consider the medication a failure and discontinue the drug if only adverse effects and no therapeutic effects are initially experienced. Select drugs with a convenient dosing schedule Select drugs with once-daily dosing (i.e., those with a suitably long half-life or available in an extended-release formulation) to maximize compliance. Consider the use of depot formulations for antipsychotic agents. Some antipsychotics are available in depot formulations with a dosing interval of several weeks. Compliance can be confirmed from administration records. However, the patient must have undergone a successful trial of the equivalent oral formulation to verify therapeutic response and tolerance to adverse effects, and to establish the appropriate dose. Minimize adverse effects Select drugs with minimal pharmacokinetic interaction where possible (e.g., avoid cytochrome P450 inhibitors or inducers). Gradually increase drug dosage to therapeutic levels over several days or weeks (“start low, go slow”) so that patients experience minimal adverse effects while gradually developing tolerance. Use the minimum effective dose. Select a drug with an adverse-effect profile the patient can best tolerate. Drugs within a class may be similar therapeutically but differ in their adverse-effect profile. Patients may vary in their tolerance to a particular effect. Reduce peak drug levels following absorption of oral medications. Many adverse effects are concentration dependent and are exacerbated as drug levels peak following oral dosing. Consider administering the drug with food or using divided doses or extended-release formulations to reduce and delay peak drug levels and diminish adverse effects. Schedule the dose so the side effect is less bothersome. If possible, prescribe activating drugs in the morning, and sedating drugs or those that cause gastrointestinal distress in the evening.


9

Table 1–1. Strategies to maximize medication compliance (continued) Utilize therapeutic drug monitoring Keep in mind that therapeutic drug monitoring is available for many psychotropic drugs. This is valuable for monitoring compliance and ensuring that drug levels are within the therapeutic range. Check for patient compliance Schedule office or telephone visits to discuss compliance and adverse effects for newly prescribed drugs.

delivery to the systemic circulation from the formulation. Intravenous or intra-arterial administration delivers 100% of the drug dose to the systemic circulation (100% bioavailability) at a rate that can be controlled if necessary. Bioavailability is typically less than 100%, often much less, for drugs delivered by other routes. Drug absorption is influenced by the characteristics of the absorption site and the physiochemical properties of a drug. Specific site properties affecting absorption include surface area, ambient pH, mucosal integrity and function, and local blood flow, all of which may be altered by, for example, peptic ulcer disease or inflammatory bowel disease, and their drug treatment. Orally administered drugs face several pharmacokinetic barriers that limit drug delivery to the systemic circulation. Drugs must dissolve in gastric fluids to be absorbed, and drug dissolution in the stomach and gut may be incomplete (e.g., after gastric bypass surgery). Drugs may be acid labile and degrade in the acidic stomach environment, or may be partially metabolized by gut flora. Drugs absorbed through the gastrointestinal tract may be extensively altered by “first-pass” metabolism before entering the systemic circulation (see Figure 1–3). First-pass metabolism refers to the transport and metabolism of drugs from the gut lumen to the systemic circulation via the portal vein and liver. Drug passage from the gut lumen to the portal circulation may be limited by two processes: 1) a P-glycoprotein (P-gp) efflux transport pump, which serves to reduce the absorption of many compounds (some P-gp substrates are listed in the appendix to this chapter) by countertransporting them back into the intestinal lumen, and 2) metabolism within the gut wall by cytochrome P450 (CYP) 3A4 enzymes. Because P-gp is co-localized with and shares similar substrate affinity with CYP 3A4, drug substrates of CYP 3A4


Figure 1–3.

First-pass metabolism of orally administered drugs.

Many drugs undergo a “first-pass effect” as they are absorbed from the intestinal lumen before they are delivered to the systemic circulation. The first-pass effect limits oral bioavailability through countertransport by P-glycoprotein (P-gp) back into the intestinal lumen, and by gut wall (mainly cytochrome P450 3A4 [CYP 3A4]) and hepatic metabolism.


11

typically have poor bioavailability. Bioavailability may be further decreased by hepatic extraction of drugs as they pass through the liver before gaining access to the systemic circulation. Sublingual and topical drug administration minimizes this first-pass effect, and rectal delivery, although often resulting in erratic absorption, may reduce first-pass effect by 50%. Bioavailability can be markedly altered by disease states and drugs that alter gut and hepatic function. As with the CYP and uridine 5′-diphosphate glucuronosyltransferase (UGT) enzyme systems involved in drug metabolism, drugs can also inhibit or induce the P-gp transporter. Common P-gp inhibitors include paroxetine, sertraline, trifluoperazine, verapamil, and proton pump inhibitors. Because intestinal P-gps serve to block absorption in the gut, inhibition of these transporters can dramatically increase the bioavailability of poorly bioavailable drugs. For example, oral fentanyl absorption in humans is increased 2.7-fold when administered with quinidine, a known intestinal P-gp inhibitor (Kharasch et al. 2004). P-gp inhibitors are listed in the appendix to this chapter. For drugs administered chronically, the extent of drug absorption is the key factor in maintaining drug levels within the therapeutic range. In situations where bioavailability may be significantly altered, parenteral administration of drugs may be preferable. Drug formulation, drug interactions, gastric motility, and the characteristics of the absorptive surface all influence the rate of absorption, a key factor when rapid onset is desired. Oral medications are absorbed primarily in the small intestine due to its large surface area. Delayed gastric emptying or drug dissolution will slow absorption and therefore blunt the rise in drug levels following an oral dose. In this way, the occurrence of transient concentration-related adverse effects following an oral dose may be reduced by administering a drug with food, whereas the common practice of dissolving medications in juice may produce higher peak levels and exacerbate these transient adverse reactions.

Distribution Following absorption into the systemic circulation, the drug is distributed throughout the body in accordance with its physiochemical properties and the extent of protein binding. The volume of distribution describes the relationship between the bioavailable dose and the plasma concentration. Lipophilic drugs, including most psychotropic medications, are sequestered into lipid compartments of the body. Because of their low plasma concentrations relative to dose,


these drugs appear to have a large volume of distribution. In contrast, hydrophilic drugs (e.g., lithium, oxazepam, valproate), being confined mainly to the vascular volume and other aqueous compartments, have a high plasma concentration relative to dose, suggesting a small volume of distribution. Volume of distribution is often unpredictably altered by disease-related changes in organ and tissue perfusion or body composition. Edema (e.g., in congestive heart failure, cirrhosis, nephrotic syndrome) causes expansion of the extracellular fluid volume and may significantly increase the volume of distribution for hydrophilic drugs. Lipophilic drugs experience an increase in volume of distribution with obesity, which is sometimes iatrogenic (e.g., with corticosteroids or antipsychotics), and age-related increases in body fat. P-gp, a major component of the blood–brain barrier, may limit entry of drugs into the central nervous system (CNS). Many antiretroviral agents have limited CNS penetration because they are P-gp substrates (see the appendix to this chapter). Most drugs bind, to varying degrees, to the plasma proteins albumin or alpha-1 acid glycoprotein. Acidic drugs (e.g., valproic acid, barbiturates) bind mostly to albumin, and more basic drugs (e.g., phenothiazines, tricyclic antidepressants, amphetamines, most benzodiazepines) bind to globulins. Drug in plasma circulates in both bound and free (unbound to plasma proteins) forms. Generally, only free drug is pharmacologically active. The amount of drug bound to plasma proteins is dependent on the presence of other compounds that displace the drug from its protein binding sites (a protein-binding drug interaction) and the plasma concentration of albumin and alpha-1 acid glycoprotein. Medical conditions may alter plasma concentrations of albumin or alpha-1 acid glycoprotein (see Table 1–2) or increase the levels of endogenous displacing compounds. For example, uremia, chronic liver disease, and hypoalbuminemia may significantly increase the proportion of free drug relative to total drug in circulation (Dasgupta 2007). Changes in drug protein binding, either disease induced or the result of a protein-binding drug interaction, were once considered a common cause of drug toxicity because therapeutic and toxic effects increase with increasing concentrations of free drug. These interactions are now seen as clinically significant only in very limited cases involving rapidly acting, highly proteinbound (>80%), narrow-therapeutic-index drugs with high hepatic extraction (possible candidates include propafenone, verapamil, and intravenous lidocaine) (Benet and Hoener 2002; Rolan 1994). For drugs with low hepatic


Table 1–2. Conditions that alter plasma levels of albumin and alpha-1 acid glycoprotein Decrease albumin Surgery Burns Trauma Pregnancy Alcoholism Sepsis Bacterial pneumonia Acute pancreatitis Uncontrolled diabetes Hepatic cirrhosis Nephritis, nephrotic syndrome, renal failure Increase albumin Hypothyroidism Decrease alpha-1 acid glycoprotein Pancreatic cancer Pregnancy Uremia Hepatitis, cirrhosis Cachexia Increase alpha-1 acid glycoprotein Stress response to disease states Inflammatory bowel disease Acute myocardial infarction Trauma Epilepsy Stroke Surgery Burns Cancer (except pancreatic) Acute nephritic syndrome, renal failure Rheumatoid arthritis, systemic lupus erythematosus Source. Compiled in part from Dasgupta 2007; Israili and Dayton 2001.

13


extraction, such as warfarin (Greenblatt and Von Moltke 2005) and phenytoin (Tsanaclis et al. 1984) (see Table 1–3 later in this chapter), metabolism is not limited by hepatic blood flow, and a reduction in protein binding serves to increase the amount of free drug available for metabolism and excretion. Consequently, hypoalbuminemia or the presence of a displacing drug enhances drug elimination, which generally limits changes in circulating unbound drug levels to only a transient, and clinically insignificant, increase. (Many warfarin drug interactions previously thought to be protein-binding interactions are now recognized as pharmacodynamic and CYP 2C9 and CYP 1A2 metabolic interactions.) However, although free drug levels may remain unchanged, changes in protein binding will reduce plasma levels of total drug (free + bound fractions). Although of no consequence therapeutically, therapeutic drug monitoring procedures that measure total drug levels could mislead the clinician by suggesting lower, possibly subtherapeutic levels and might prompt a dosage increase with possible toxic effects. For this reason, in patients with uremia, chronic hepatic disease, hypoalbuminemia, or a protein-binding drug interaction, the use of therapeutic drug monitoring for dose adjustment requires caution; clinical response to the drug (e.g., international normalized ratio [INR] for warfarin), rather than laboratory-determined drug levels, should guide dosage. Where therapeutic drug monitoring is employed, methods selective for unbound drug should be used, if available, for phenytoin, valproate, tacrolimus, cyclosporine, amitriptyline, haloperidol, and possibly carbamazepine (Dasgupta 2007). Disease-related changes to a drug’s protein binding have little effect on steady-state plasma concentrations of free drug as long as the disease does not affect metabolic and excretory processes (Benet and Hoener 2002). However, most diseases that affect protein binding also affect metabolism and excretion, with clinically significant consequences, especially for drugs with a low therapeutic index.

Drug Elimination: Metabolism and Excretion The kidney is the primary organ of drug excretion, with fecal and pulmonary excretion being of less importance. Hydrophilic compounds are removed from the body through excretion into the aqueous environment of urine and feces. In contrast, lipophilic drugs, including most psychoactive medications, are readily reabsorbed through the intestinal mucosa (enterohepatic recirculation) and renal tubules, which limits their excretion. Because all drugs un-


15

dergo glomerular filtration, lipophilic drugs would experience significant renal elimination were it not for renal resorption. Renal resorption, and thus the elimination, of several drugs, including amphetamines, meperidine, and methadone, can be significantly changed by altering urine pH (discussed under “Pharmacokinetic Drug Interactions” later in this chapter). The general function of metabolism is to convert lipophilic molecules into more polar water-soluble compounds that can be readily excreted. Although biotransformation often results in less active or inactive metabolites, this is not always true. For some drugs, metabolites have pharmacological activities similar to, or even greater than, the parent compound, and thus contribute to the therapeutic effect. Indeed, some metabolites are separately marketed, including paliperidone (principal active metabolite of risperidone) and temazepam and oxazepam (both metabolites of diazepam). Some drugs are administered as prodrugs—inactive compounds requiring metabolic activation—including lisdexamfetamine (metabolized to amphetamine), tramadol, codeine, and fosphenytoin (metabolized to phenytoin). Other drug metabolites may have pharmacological effects considerably different from those of the parent drug and may cause unique toxicities (e.g., the meperidine metabolite normeperidine has proconvulsant activity). Metabolism Biotransformation occurs throughout the body, with the greatest activity in the liver and gut wall. Most psychotropic drugs are eliminated by hepatic metabolism followed by renal excretion. Hepatic biotransformation processes are of two types, identified as Phase I and Phase II reactions. Phase I reactions typically convert the parent drug into a more polar metabolite by introducing or unmasking a polar functional group in preparation for excretion or further metabolism by Phase II pathways. Phase II metabolism conjugates the drug or Phase I metabolite with an endogenous acid such as glucuronate, acetate, or sulfate. The resulting highly polar conjugates are usually inactive and are rapidly excreted in urine and feces (see Figure 1–4). Phase I metabolism. Phase I reactions include oxidation, reduction, and hydrolysis. Most Phase I oxidation reactions are carried out by the hepatic CYP system, with a lesser contribution from the monoamine oxidases (MAOs). CYP enzymes exist in a variety of body tissues, including the gastrointestinal tract, liver, lung, and brain. The CYP system includes 11 enzyme


Figure 1–4. General pathways of metabolism and excretion. UGTs=uridine 5′-diphosphate glucuronosyltranferases.


17

families, three of which are important for drug metabolism in humans: CYP 1, CYP 2, and CYP 3. These families are divided into subfamilies identified by a capital letter (e.g., CYP 3A). Subfamilies are further subdivided into isozymes based on the homology between subfamily proteins. Isozymes are denoted by a number following the subfamily letter (e.g., CYP 3A4). In humans, CYP 1A2, 2C9, 2C19, 2D6, and 3A4 are the most important enzymes for drug metabolism. These enzymes exhibit substrate specificity. Many drugs undergo Phase I metabolism primarily through one CYP isozyme. Functional deficiencies in one CYP enzyme will impact the metabolism of only those compounds that are substrate for that enzyme. Because some of these enzymes exist in a polymorphic form, a small percentage of the population, varying with ethnicity, has one or more CYP enzymes with significantly altered activity. For example, polymorphisms of the 2D6 gene give rise to populations with the capacity to metabolize CYP 2D6 substrates extensively (normal condition), poorly (5%–14% of Caucasians, ~1% of Orientals), or ultraextensively (1%–3% of the population) (Zanger et al. 2004). CYP enzyme activity can also be altered (inhibited or enhanced through induction) by environmental compounds or drugs, giving rise to many drug– drug interactions (discussed below in “Drug Interactions”). Phase II metabolism. Phase II conjugation reactions mainly involve enzymes belonging to the superfamily of UGTs. UGT enzymes are located hepatically (primarily centrizonal) (Debinski et al. 1995) and in the kidney and small intestine (Fisher et al. 2001). The UGT enzyme superfamily is classified in a manner similar to the CYP system. There are two clinically significant UGT subfamilies: 1A and 2B. As with the CYP system, there can be substrates, inhibitors, and inducers of UGT enzymes. For example, those benzodiazepines that are primarily metabolized by conjugation (oxazepam, lorazepam, and temazepam) are glucuronidated by UGT2B7. Valproic acid, tacrolimus, cyclosporine, and a number of nonsteroidal anti-inflammatory drugs (NSAIDs), including diclofenac, flurbiprofen, and naproxen, are competitive inhibitors of UGT2B7. Carbamazepine, phenytoin, rifampin (rifampicin), phenobarbital, and oral contraceptives are general inducers of UGTs (Kiang et al. 2005). Drug interactions involving Phase II UGT-mediated conjugation reactions are increasingly becoming recognized. These interactions between crit-


ical substrates, inducers, and inhibitors follow the same rationale as for CYP interactions (discussed in “Drug Interactions” later in this chapter). Effect of disease on metabolism. Hepatic clearance of a drug may be limited by either the rate of delivery of the drug to the hepatic metabolizing enzymes (i.e., hepatic blood flow) or the intrinsic capacity of these enzymes to metabolize the substrate. Reduced hepatic blood flow impairs the clearance of drugs with high hepatic extraction (>6 mL/min/kg; flow-limited drugs) but has little effect on drugs with low hepatic extraction (6 mL/min/kg) Amitriptyline Bupropion Buspirone Chlorpromazine Clozapine Codeine Desipramine Diphenhydramine Doxepin Fentanyl Flumazenil

Fluoxetine Fluvoxamine Haloperidol Hydrocodone Hydromorphone Imipramine Meperidine Midazolam Morphine Nortriptyline Olanzapine

Paroxetine Quetiapine Rizatriptan Ropinirole Sertraline Sumatriptan Venlafaxine Zaleplon Zolmitriptan

Intermediate extraction ratio (clearance 3–6 mL/min/kg) Bromocriptine Citalopram Clonidine

Flunitrazepam Flurazepam Protriptyline

Risperidone Triazolam Zolpidem

Low extraction ratio (clearance 200 mg/day)

TCAs Amitriptyline Clomipramine (slight CYP 2D6 inhibition) Desipramine (slight CYP 2D6 inhibition) Doxepin Imipramine Maprotiline Nortriptyline Protriptyline Trimipramine

Venlafaxine Novel action agents Amoxapine Mirtazapine Trazodone Antipsychotics All antipsychotics Agents for drug-induced extrapyramidal symptoms Benztropine Procyclidine Biperiden Trihexyphenidyl Ethopropazine Anxiolytics/sedative-hypnotics All benzodiazepines Zaleplon Buspirone Zolpidem Eszopiclone Zopiclone Cognitive enhancers Donepezil Memantine Galantamine Rivastigmine Opiate analgesics All opiate analgesics Psychostimulants Amphetamine Methamphetamine Dextroamphetamine Methylphenidate Lisdexamfetamine

Note. CYP 2D6= cytochrome P450 3D6; SSRI/SNRI=selective serotonin reuptake inhibitor/ serotonin–norepinephrine reuptake inhibitor; TCA =tricyclic antidepressant.


27

• For a drug administered chronically, the therapeutic effect is a function of the extent of absorption, not the speed of absorption. Rapid absorption is likely to cause transient, concentrationdependent adverse effects. • Drug interactions involving displacement of highly proteinbound drugs are clinically significant for only a very few drugs; propafenone, verapamil, and intravenous lidocaine are possible candidates. • Therapeutic drug monitoring should employ methods selective for free (unbound) drug.

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Debinski HS, Lee CS, Danks JA, et al: Localization of uridine 5´-diphosphate-glucuronosyltransferase in human liver injury. Gastroenterology 108:1464–1469, 1995 DeVane CL, Nemeroff CB: 2002 Guide to psychotropic drug interactions. Prim Psychiatry 9:28–57, 2002 Ebert U, Thong NQ, Oertel R, et al: Effects of rifampicin and cimetidine on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects. Eur J Clin Pharmacol 56:299–304, 2000 Eli Lilly: Strattera (atomoxetine) home page. Available at: http://www.strattera.com. Accessed October 25, 2009 Fisher MB, Paine MF, Strelevitz TJ, et al: The role of hepatic and extrahepatic UDPglucuronosyltransferases in human drug metabolism. Drug Metab Rev 33:273– 297, 2001 Freudenthaler S, Meineke I, Schreeb KH, et al: Influence of urine pH and urinary flow on the renal excretion of memantine. Br J Clin Pharmacol 46:541–546, 1998 Gardner DM, Shulman KI, Walker SE, et al: The making of a user friendly MAOI diet. J Clin Psychiatry 57:99–104, 1996 Gillman PK: Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br J Anaesth 95:434–441, 2005 Greenblatt DJ, Von Moltke LL: Interaction of warfarin with drugs, natural substances, and foods. J Clin Pharmacol 45:127–132, 2005 Guedon-Moreau L, Ducrocq D, Duc MF, et al: Absolute contraindications in relation to potential drug interactions in outpatient prescriptions: analysis of the first five million prescriptions in 1999. Eur J Clin Pharmacol 59:689–695, 2003 Israili ZH, Dayton PG: Human alpha-1-glycoprotein and its interactions with drugs. Drug Metab Rev 33:161–235, 2001 Kharasch ED, Hoffer C, Altuntas TG, et al: Quinidine as a probe for the role of Pglycoprotein in the intestinal absorption and clinical effects of fentanyl. J Clin Pharmacol 44:224–233, 2004 Kiang TK, Ensom MH, Chang TK: UDP-glucuronosyltransferases and clinical drugdrug interactions. Pharmacol Ther 106:97–132, 2005 McEvoy G (ed): American Hospital Formulary Service (AHFS) Drug Information 2008. Bethesda, MD, American Society of Health-System Pharmacists, 2008 Michalets E: Clinically significant cytochrome P-450 drug interactions. Pharmacotherapy 18:84–112, 1998 Morris RG, Black AB, Lam E, et al: Clinical study of lamotrigine and valproic acid in patients with epilepsy: using a drug interaction to advantage? Ther Drug Monit 22:656–660, 2000 Nilsson MI, Widerlov E, Meresaar U, et al: Effect of urinary pH on the disposition of methadone in man. Eur J Clin Pharmacol 22:337–342, 1982


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Owen JA: Psychopharmacology, in The American Psychiatric Publishing Textbook of Psychosomatic Medicine: Psychiatric Care of the Medically Ill, 2nd Edition. Edited by Levenson JL. Arlington, VA, American Psychiatric Publishing, 2010 (in press) Pal D, Mitra AK: MDR- and CYP3A4-mediated drug-drug interactions. J Neuroimmune Pharmacol 1:323–339, 2006 Papadakis MA, Arieff AI: Unpredictability of clinical evaluation of renal function in cirrhosis: prospective study. Am J Med 82:945–952, 1987 Physicians’ Desk Reference 2009, 63rd edition. Montvale, NJ, Thomson Reuters, 2008 Pichette V, Leblond FA: Drug metabolism in chronic renal failure. Curr Drug Metab 4:91–103, 2003 Repchinsky C (ed): CPS 2008: Compendium of Pharmaceuticals and Specialties: The Canadian Drug Reference for Health Professionals. Ottawa, ON, Canadian Pharmacists Association, 2008 Rolan PE: Plasma protein binding displacement interactions: why are they still regarded as clinically important? Br J Clin Pharmacol 37:125–128, 1994 Rudolph JL, Salow MJ, Angelini MC, et al: The anticholinergic risk scale and anticholinergic adverse effects in older persons. Arch Intern Med 168:508–513, 2008 Sokoll LJ, Russell RM, Sadowski JA, et al: Establishment of creatinine clearance reference values for older women. Clin Chem 40:2276–2281, 1994 Thummel KE, Shen DD, Isoherranen N, et al: Appendix II, Design and optimization of dosage regimens: pharmacokinetic data, in Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 11th Edition. Edited by Brunton LL, Lazo JS, Parker KL. New York, McGraw-Hill, 2005, pp 1787–1888 Tsanaclis LM, Allen J, Perucca E, et al: Effect of valproate on free plasma phenytoin concentrations. Br J Clin Pharmacol 18:17–20, 1984 Tune L, Carr S, Hoag E, et al: Anticholinergic effects of drugs commonly prescribed for the elderly: potential means for assessing risk of delirium. Am J Psychiatry 149:1393–1394, 1992 USP DI Editorial Board (eds): United States Pharmacopeia Dispensing Information Volume 1: Drug Information for the Health Care Professional, 27th edition. Greenwood Village, CO, Thomson Micromedex, 2007 Yasui-Furukori N, Saito M, Niioka T, et al: Effect of itraconazole on pharmacokinetics of paroxetine: the role of gut transporters. Ther Drug Monit 29:45–48, 2007 Zanger UM, Raimundo S, Eichelbaum M: Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol 369:23–37, 2004


Appendix: Drugs With Clinically Significant Pharmacokinetic Interactions

Drug

Cytochrome P450 isozyme 1A2 2Ca 2D6 3A4 MAO-A

ACE inhibitor Captopril Antianginal Ranolazine Antiarrhythmics Amiodarone X S, X X Disopyramide Flecainide S Lidocaine S, X Mexiletine X S Propafenone X S, X Quinidine X Anticoagulants and antiplatelet agents R-warfarin S S S-warfarin S Ticlopidine X Anticonvulsants and mood stabilizers Carbamazepine I I Ethosuximide Felbamate Lamotrigine Phenytoin I S, I Tiagabine S S Valproate I Antidepressants Amitriptyline S S S Bupropion X Clomipramine S S S, X Desipramine S, X Desvenlafaxine

UGT

P-gp X

S, X

S, X

S, X S

X

S

X

S S

S

X S, X

S, I

S

S I

S S S

S

S, I S, I

I S

S, X S S S

S, X

X S


Drug Doxepin Duloxetine Fluoxetine Fluvoxamine Gepirone Imipramine Maprotiline Mirtazapine Moclobemide Nefazodone Nortriptyline Paroxetine Phenelzine Sertraline Tranylcypromine Trazodone Trimipramine Venlafaxine Antidiarrheal agent Loperamide Antiemetic Ondansetron Antihyperlipidemics Atorvastatin Fenofibrate Fluvastatin Gemfibrozil Lovastatin Pravastatin Simvastatin Antihyponatremic Conivaptan

Cytochrome P450 isozyme 1A2 2Ca 2D6 3A4 MAO-A S S S, X X X S, X S, X S, X X X S S S S S S S S S X X S, X S S, X X

UGT

P-gp

S X X

S S, X X

X

X S S S

S

I

S

S S S

S X X X X

31

X X

S S S S

S, X X

S, X

X


Drug Antimicrobials Chloramphenicol Ciprofloxacin Clarithromycin Co-trimoxazole Enoxacin Erythromycin Fluconazole Grepafloxacin Griseofulvin Isoniazid Itraconazole Ketoconazole Levofloxacin Linezolid Metronidazole Miconazole Nafcillin Norfloxacin Ofloxacin Posaconazole Rifabutin Rifampin (rifampicin) Roxithromycin Sulfaphenazole Sulfonamides Troleandomycin Valinomycin Antimigraine Eletriptan Ergotamine Frovatriptan


UGT

P-gp

X X X

X S, X

S X

X X X X

S S, X

S, X X

S I X

I S, X S, X

X X

X S, X X X

S, X X X

I

I

X S, X S, I X X I S, I

S

X S

I

S, I

X X X X

S, X S S S

S

S


Cytochrome P450 isozyme 1A2 2Ca 2D6 3A4 MAO-A S S S S

Drug Rizatriptan Sumatriptan Zolmitriptan Antineoplastic agents Dactinomycin Dasatinib Docetaxel Doxorubicin Etoposide Gefitinib Ifosfamide Imatinib Irinotecan Lapatinib Methotrexate Nilotinib Paclitaxel Procarbazine Sorafenib Sunitinib Tamoxifen Tegafur (ftorafur) S, I Teniposide Topotecan Vinblastine Vincristine Vinorelbine Antiparkinsonian agents Rasagiline S Selegiline Antipsychotics Aripiprazole Asenapine S

UGT

P-gp

S, X S, X S

X

X S

X

S S, X S

S S S S, X S S, X

S

S, X S

X

S S S, X S S, X S

X X S

S S S I S

S, X S, X S S S, X S S

S S S

X S

S S

33


Cytochrome P450 isozyme Drug 1A2 2Ca 2D6 3A4 MAO-A Antipsychotics (continued) Chlorpromazine S S Clozapine S S S Haloperidol S S, X Iloperidone S S Olanzapine S S Perphenazine S Pimozide S Quetiapine S Risperidone S Thioridazine S S S Trifluoperazine Ziprasidone S Antiretroviral agents Amprenavir S Atazanavir X S, X Darunavir S, X Delavirdine X S, X Efavirenz X S, X Indinavir S, X Lopinavir S Maraviroc S Nelfinavir S, X Nevirapine S, I Raltegravir Ritonavir I X X S, X Saquinavir S, X Tipranavir/ritonavir X S, X Zidovudine Anxiolytics and sedative-hypnotics Alprazolam S Bromazepam S Buspirone S

UGT

P-gp X X

S

S X S S X

X

S, I X

S S S S, X S S, X S, X S, I S


Cytochrome P450 isozyme 1A2 2Ca 2D6 3A4 MAO-A S S S S

Drug Clonazepam Diazepam Hexobarbital Lorazepam Midazolam Oxazepam Phenobarbital I Temazepam Triazolam Beta-blockers Alprenolol Bisoprolol Bufuralol Labetalol Metoprolol Pindolol Propranolol S Talinolol Timolol Bronchodilator Theophylline S Calcium channel blockers Amlodipine Diltiazem Felodipine Isradipine Nicardipine Nifedipine Nimodipine Nisoldipine Verapamil S Cardiac glycoside Digoxin

UGT

P-gp

S S

X S

I

I S S

S

S S S S S S S, X

S

S

X S, X

S S S, X S S S S S S S

35

S, X X X

S, X S



Drug Cognitive enhancer Tacrine S Gastrointestinal motility modifier Domperidone Gout therapy Colchicine Probenecid Sulfinpyrazone X Histamine H2 antagonists Cimetidine X X X X Ranitidine Immunosuppressive agents Cyclosporine S, X Sirolimus S Tacrolimus S Muscle relaxant Cyclobenzaprine S S S Nonsteroidal anti-inflammatory drugs and analgesic agents Acetaminophen Diclofenac X Flurbiprofen X Naproxen Phenylbutazone S, X Opiate analgesics Alfentanil S Codeine S S Fentanyl S Hydrocodone S Meperidine S Methadone S S Morphine Oxycodone S Tramadol S

UGT

P-gp

S S, X X

X

S S S, X S

S X X X

S X

S

X S



Drug Oral hypoglycemics Chlorpropamide Glimepiride Glipizide Glyburide Pioglitazone Tolbutamide Proton pump inhibitors Esomeprazole Lansoprazole I Omeprazole I Pantoprazole Psychostimulants Armodafinil I Atomoxetine Modafinil I Steroids Aldosterone Cortisol Dexamethasone Estradiol Estrogen Ethinyl estradiol Hydrocortisone Prednisolone Prednisone Progesterone Testosterone Triamcinolone

UGT

P-gp

S S S S S S, X

S S, X

X S, X S, X S, X

S

X

S, I S, X

X

S, I

S I S S S, X S S S S

37

S S S, I S I S, X S S X S


Cytochrome P450 isozyme Drug 1A2 2Ca 2D6 3A4 MAO-A UGT P-gp Foods and herbal medicines Caffeine S S Cannabinoids S S, X Cruciferous I vegetablesb Grapefruit juice X X Smoking (tobacco, I S etc.) St. John’s wort I I Tyramine-containing S foodsc Note. Pharmacokinetic drug interactions: I, inducer; S, substrate; X, inhibitor. Only significant interactions are listed. ACE=angiotensin-converting enzyme; MAO-A=monoamine oxidase type A; P-gp=Pglycoprotein efflux transporter; UGT=uridine 5′-diphosphate glucuronosyltransferase. aCombined properties on 2C8/9/10 and 2C19 cytochrome P450 isozymes. bCruciferous vegetables include cabbage, cauliflower, broccoli, brussels sprouts, kale, etc. cTyramine-containing foods include banana peel, beer (all tap, “self-brew,” and nonalcoholic), broad bean pods (not beans), fava beans, aged cheese (tyramine content increases with age), sauerkraut, sausage (fermented or dry), soy sauce and soy condiments, concentrated yeast extract (Marmite). Source. Compiled in part from Armstrong and Cozza 2002; Balayssac et al. 2005; Bezchlibnyk-Butler et al. 2007; Bristol-Myers Squibb 2009; Cozza et al. 2003; DeVane and Nemeroff 2002; Eli Lilly 2009; Gardner et al. 1996; Gillman 2005; GuedonMoreau et al. 2003; Kiang et al. 2005; McEvoy 2008; Michalets 1998; Pal and Mitra 2006; Repchinsky 2008; USP DI Editorial Board 2007.

2 Severe Drug Reactions Stanley N. Caroff, M.D. Stephan C. Mann, M.D. E. Cabrina Campbell, M.D. Rosalind M. Berkowitz, M.D.

This chapter diverges from others in this book by reviewing not how psy-

chotropic drugs are useful in treating patients with medical illnesses, but rather how psychotropic drugs occasionally cause medical disorders. Although many important, common side effects are associated with psychotropic drugs, the discussion in this chapter is limited to rare, severe, acute, and potentially lifethreatening drug reactions that occur at therapeutic dosages and require emergency medical treatment. Mirroring the book as a whole, the discussion is organized by specific organ systems. Severe drug-induced dermatological reactions are covered in Chapter 13, “Dermatological Disorders.” In reading this chapter, clinicians should keep in mind that psychotropic drugs, when indicated, are potentially beneficial for the majority of patients 39


and should not be withheld because of the risk of these rare reactions. Instead, the best defense against adverse reactions consists of careful monitoring of patients, informed by familiarity with adverse signs and symptoms to allow prompt recognition, rapid drug discontinuation, and supportive treatment.

Central Nervous System Reactions Although psychotropic drugs are selected and developed for their therapeutic effects on specific neurotransmitter pathways in the brain, several severe and life-threatening drug reactions have been reported stemming either from an abnormal exaggeration of the desired effect on a single neurotransmitter system (e.g., neuroleptic malignant syndrome) or from an unexpected action on systemic or other central nervous system mechanisms that affect brain function (e.g., seizures) (Table 2–1). These reactions have been associated mostly with potent antipsychotic and antidepressant drugs.

Neuroleptic Malignant Syndrome Neuroleptic malignant syndrome (NMS) has been the subject of numerous clinical reports and reviews (Caroff 2003b; Strawn et al. 2007). The incidence of NMS is about 0.02% among patients treated with antipsychotic drugs. NMS may also result from treatment with other dopamine-blocking drugs, such as the phenothiazine antiemetics (promethazine, prochlorperazine) and metoclopramide. Risk factors include dehydration, exhaustion, agitation, catatonia, previous episodes, and large dosages of high-potency drugs given parenterally at a rapid rate of titration. The effect of concurrent administration of multiple antipsychotics and other drugs, including lithium and selective serotonin reuptake inhibitors (SSRIs) or serotonin–norepinephrine reuptake inhibitors (SNRIs), in enhancing the risk of NMS has been suggested but is unproven (Stevens 2008). NMS may develop within hours but usually evolves over days. About two-thirds of cases occur during the first 1–2 weeks after drug initiation. Classic signs are elevated temperatures (from moderate to life-threatening hyperthermia), generalized rigidity with tremors, altered consciousness with catatonia, and autonomic instability. Laboratory findings may include muscle enzyme elevations (primarily creatine phosphokinase, median elevations 800 IU/L; Meltzer et al. 1996), myoglobinuria, leukocytosis, metabolic acidosis, hypoxia, elevated serum catecholamines, and low serum iron levels.

Table 2–1. Central nervous system reactions Implicated drugs

Neuroleptic malignant syndrome (NMS)

Hyperthermia, rigidity, Dopamine antagonists Dehydration, mental status changes, exhaustion, (antipsychotics, dysautonomia agitation, antiemetics) catatonia, prior episodes, dose and parenteral route

Enzyme elevations Specific agents? (lorazepam, (CPK), ↑WBC, dopamine acidosis, ↓iron, agonists, hypoxia dantrolene, ECT)

Parkinsonian hyperthermia syndrome

Dopamine withdrawal Parkinson’s disease Hyperthermia, rigidity, Reduced CSF HVA mental status changes, dysautonomia

—a

Dopaminergic therapy

Neuroleptic sensitivity syndrome

Antipsychotics

Signs and symptoms

Lewy body dementia

Confusion, immobility, rigidity, postural instability, falls, fixedflexion posture, poor oral uptake

—a

—b

Same as for NMS plus lithium toxicity

Same as for NMS plus lithium toxicity (ataxia, dysarthria, myoclonus, and seizures)

Lithium level

—b

Severe Drug Reactions

Antipsychotics plus Lithium– lithium neuroleptic encephalopathy

Risk factors

Diagnostic studiesa Managementb

Disorders

41

Risk factors

Implicated drugs

Serotonin syndrome

Overdose, Antidepressants polypharmacy (MAOIs, SNRIs, SSRIs, TCAs) Linezolid Triptans Some opiates (dextromethorphan, fentanyl, meperidine, tramadol)

—a Behavioral (delirium, agitation, restlessness) Neuromotor (tremor, myoclonus, hyperreflexia, ataxia, rigidity, shivering) Dysautonomia (tachycardia, tachypnea, hyperthermia, mydriasis, blood pressure lability) Gastrointestinal (diarrhea, nausea, vomiting, incontinence)

Mortality in dementiarelated psychosis

Antipsychotics

Cerebrovascular events Cardiovascular (heart failure, sudden death) Infections (pneumonia)

Elderly

Signs and symptoms

Diagnostic studiesa Managementb

Disorders

—a

Serotonin antagonists? (cyproheptadine)

—b


Table 2–1. Central nervous system reactions (continued)

Table 2–1. Central nervous system reactions (continued) Disorders

Implicated drugs

Risk factors

Signs and symptoms

Seizures

Antipsychotics (chlorpromazine, clozapine) Antidepressants (bupropion, clomipramine) Lithium toxicity Withdrawal of anticonvulsants or benzodiazepines Flumazenil

Epilepsy, substance — abuse, brain injury, overdose, drug interactions, dose and rate of titration

Diagnostic studiesa Managementb Brain imaging, EEG

—b


Note. CPK =creatine phosphokinase; CSF HVA= cerebrospinal fluid homovanillic acid; ECT=electroconvulsive therapy; EEG= electroencephalogram; MAOIs =monoamine oxidase inhibitors; SNRIs =serotonin–norepinephrine reuptake inhibitors; SSRIs= selective serotonin reuptake inhibitors; TCAs =tricyclic antidepressants; WBC= white blood cell count. aStandard imaging and laboratory studies to rule out other conditions in the differential diagnosis or complications are assumed. Only studies associated with or specific for each reaction are listed. bMainstay of management in all reactions includes careful monitoring, prompt recognition, rapid cessation of the offending drug, and supportive medical care. Only specific therapies that have been reported are listed. ?= lack of evidence of safety and efficacy.

43


The differential diagnosis of NMS is complex, including other disorders with elevated temperatures and encephalopathy, such as malignant catatonia due to psychosis, infections, benign extrapyramidal side effects, agitated delirium of diverse causes, heatstroke, serotonin syndrome, and withdrawal from dopamine agonists, sedatives, or alcohol. Although no single laboratory test is diagnostic for NMS, a thorough laboratory assessment and neuroimaging are essential to exclude other serious medical conditions. Several lines of evidence strongly implicate drug-induced dopamine blockade as the primary triggering mechanism in the pathogenesis of NMS. Once dopamine-blocking drugs are withheld, two-thirds of NMS cases resolve within 1–2 weeks, with an average duration of 7–10 days (Caroff 2003b). Patients may experience prolonged symptoms if injectable long-acting drugs are implicated. Occasional patients develop a residual catatonic and parkinsonian state that can last for weeks unless electroconvulsive therapy (ECT) is administered (Caroff et al. 2000). NMS is still potentially fatal in some cases due to renal failure, cardiorespiratory arrest, disseminated intravascular coagulation, pulmonary emboli, or aspiration pneumonia. Treatment consists of early diagnosis, discontinuing dopamine antagonists, and supportive medical care. Benzodiazepines, dopamine agonists, dantrolene, and ECT have been advocated in clinical reports, but randomized, controlled trials comparing these agents with supportive care have not been done and may not be feasible because NMS is rare, often self-limited after drug discontinuation, and heterogeneous in presentation, course, and outcome. We have proposed that these agents may be considered empirically in individual cases, based on symptoms, severity, and duration of the episode (see Strawn et al. 2007 for details). For additional information about the diagnosis and management of NMS, the Neuroleptic Malignant Syndrome Information Service offers access to volunteer consultants at a toll-free hotline (888-667-8367) and provides educational material and E-mail access through their Web site (http:// www.nmsis.org).

Neuroleptic Sensitivity Syndromes in Parkinson’s Disease and Lewy Body Dementia In view of the underlying nigrostriatal dopamine deficiency in Parkinson’s disease and Lewy body dementia, patients with these disorders are at risk for


45

severe exacerbations of extrapyramidal motor symptoms as well as NMS. In Parkinson’s disease, there are few reports of NMS attributable to antipsychotics alone without concomitant withdrawal of dopamine agonist therapy or addition of cholinesterase inhibitors. However, following withdrawal of dopaminergic drugs alone or during “off” episodes, patients with Parkinson’s disease may develop a parkinsonian-hyperthermia syndrome that is indistinguishable from NMS (Harada et al. 2003). Reports suggest an incidence of 2%–3%, including several deaths. Ueda et al. (2001) showed that Parkinson’s disease patients with reductions in cerebrospinal fluid homovanillic acid concentrations are more likely to develop the syndrome after drug withdrawal. The neuroleptic sensitivity syndrome is considered a supporting criterion in the diagnosis of Lewy body dementia (McKeith et al. 1992). McKeith et al. (1992) reported that 4 (29%) of 14 patients receiving antipsychotics showed mild extrapyramidal symptoms, but 8 (57%) showed severe symptoms with half the survival of untreated patients. Neuroleptic sensitivity is defined as sedation followed by rigidity, postural instability, and falls. Rapid deterioration with increased confusion, immobility, rigidity, fixed-flexion posture, and decreased food and fluid intake was not reversed by anticholinergic medications. Death resulted usually from complications of immobility and/or reduced food and fluid intake. If antipsychotics must be used for patients with Parkinson’s disease or Lewy body dementia, clozapine or quetiapine should be selected due to reduced risk, and patients should be carefully monitored for worsening motor symptoms and mental status changes (Weintraub and Hurtig 2007) (see also Chapter 9, “Central Nervous System Disorders”).

Lithium–Neuroleptic Encephalopathy In 1974, a severe encephalopathic syndrome was reported in four patients treated with lithium and haloperidol, suggesting synergistic toxic effects (Cohen and Cohen 1974). Subsequently, Miller and Menninger (1987) reported neurotoxicity consisting of delirium, extrapyramidal symptoms, and ataxia in 8 (19.5%) of 41 patients receiving concurrent treatment with lithium and antipsychotics. Similar cases, most often associated with haloperidol, have continued to be reported (Caroff 2003a). The manifestations of neurotoxicity in these cases include stupor, delirium, catatonia, rigidity, ataxia, dysarthria, myoclonus, seizures, and fever. Spring and Frankel (1981) proposed two types of combined lithium–antipsy-


chotic drug toxicity: an NMS-like reaction associated with haloperidol and other high-potency antipsychotics, and a separate reaction associated with phenothiazines, especially thioridazine, resulting in lithium toxicity. Goldman (1996) reviewed 237 cases of neurotoxicity ascribed to lithium with or without antipsychotics and found support for Spring and Frankel’s bipartite concept. However, the heterogeneity of cases led Goldman to suggest that adverse reactions to combination therapy form a continuum ranging from predominantly antipsychotic-induced to largely lithium-induced reactions. The mechanism for possible toxic synergy remains unknown. Lithium–neuroleptic encephalopathy is extremely rare, and concern about this effect should not outweigh the potential benefit and tolerance of this drug combination in the vast majority of patients presenting with mania and psychosis. Rather, the clinician is obligated to carefully monitor the response to treatment, including lithium levels, and to promptly recognize this reaction in order to rapidly discontinue medications and institute supportive medical care.

Serotonin Syndrome The serotonin syndrome generally results when two or more serotonergic drugs are taken concurrently but also occurs following overdose and during single drug exposure. Nearly all serotonergic drugs have been implicated. Agents associated with severe or fatal cases include combinations of monoamine oxidase inhibitors (MAOIs) and other antidepressants or certain opioids that potentiate serotonergic activity (meperidine, tramadol, dextromethorphan, fentanyl), as well as abuse of “ecstasy” (Boyer and Shannon 2005). Morphine has not been implicated in this interaction and is a reasonable choice for pain control in the context of concurrent serotonergic treatment, provided an allowance is made for possible potentiation of its depressive narcotic effect (Browne and Linter 1987). Some nonpsychiatric drugs that increase serotonergic activity, including triptans and linezolid, also have been implicated in serotonin syndrome. The incidence among patients on selective serotonin reuptake inhibitor (SSRI) monotherapy has been estimated in the range of 0.5–0.9 cases per 1,000 patient-months of treatment (Mackay et al. 1999), but increases to 14%–16% in persons who overdose on SSRIs (Boyer and Shannon 2005). The onset of symptoms is usually abrupt, and clinical manifestations range from mild to fatal.


47

Sternbach (1991) developed diagnostic criteria based on a triad of cognitive-behavioral, neuromuscular, and autonomic abnormalities. Serotonin syndrome presents with alterations in consciousness and mood, restlessness, and agitation. Gastrointestinal symptoms include diarrhea, incontinence, nausea, and vomiting. Autonomic disturbances include tachycardia, labile blood pressure, diaphoresis, shivering, tachypnea, mydriasis, sialorrhea, and hyperthermia. Neurological signs include tremor, myoclonus, ankle clonus, hyperreflexia, ataxia, incoordination, and muscular rigidity. The differential includes NMS, anticholinergic toxicity, heat stroke, the carcinoid syndrome, infection, drug or alcohol withdrawal, lithium toxicity, and SSRI withdrawal. Management entails cessation of serotonergic medications and supportive care. Based on anecdotal clinical reports, moderate cases appear to benefit from administration of 5-HT2A antagonists such as cyproheptadine (Graudins et al. 1998).

Cerebrovascular Events and Mortality Associated With Antipsychotics in Elderly Patients With Dementia-Related Psychosis In 2003, the U.S. Food and Drug Administration (FDA) issued an advisory that the incidence of cerebrovascular adverse events, including fatalities, was significantly higher in elderly patients with dementia-related psychosis treated with atypical antipsychotics. Collectively, 11 risperidone and olanzapine trials indicated that 2.2% of drug-treated subjects experienced cerebrovascular adverse events compared with 0.8% taking placebo (Jeste et al. 2008). In 2005, the FDA analyzed 17 placebo-controlled trials and followed with a black-box warning of increased mortality (relative risk of 1.6–1.7 vs. placebo), due primarily to cardiovascular (heart failure, sudden death) or infectious (pneumonia) causes, associated with atypical antipsychotics in elderly patients with dementia-related psychosis (U.S. Food and Drug Administration 2005). Although these data implicated newer drugs, higher or equivalent mortality with typical as compared with atypical antipsychotics among older adults was reported in retrospective analyses of large health system databases (Kales et al. 2007; Schneeweiss et al. 2007; Wang et al. 2005). In a community sample, Rochon et al. (2008) reported that compared with controls, older adults who received atypical antipsychotics were 3 times more likely and those who


received typical antipsychotics were almost 4 times more likely to experience a serious adverse advent within 30 days of starting therapy. The use of antipsychotic drugs to treat psychosis, aggression, and agitation in elderly patients with dementia is a standard off-label practice. Data from randomized, controlled trials are inconclusive on the risk–benefit ratio of these drugs in elderly patients (Schneider et al. 2006; Sink et al. 2005; Sultzer et al. 2008). However, given the lack of evidence to support the efficacy and safety of other agents or psychosocial treatments, the use of antipsychotics after informed discussion with patients and caregivers, and with careful clinical monitoring, is reasonable (Jeste et al. 2008). Several mechanisms may be suggested for antipsychotic-associated cerebrovascular adverse events and death, including cardiac conduction disturbances, sedation leading to venous stasis or aspiration pneumonia, metabolic disturbances, orthostatic hypotension, tachycardia, and increased platelet aggregation.

Seizures The risk of drug-induced seizures is difficult to estimate due to predisposing factors, such as epilepsy, drug interactions, or substance abuse, which are infrequently cited in clinical trials (Alper et al. 2007; Montgomery 2005; Stimmel and Dopheide 1996). Thus, if a seizure occurs in a given patient, a thorough history and neurological investigation are necessary to identify underlying risk factors. Patients with epilepsy are at risk of drug-induced seizures; however, psychotropic drugs are not contraindicated but require more careful monitoring of anticonvulsant therapy, and have been shown to improve seizure control once psychiatric symptoms are controlled (Alper et al. 2007; Stimmel and Dopheide 1996). As a rule, seizures correlate with drug dosage and rate of titration, and are more likely to be observed after overdosage. Clozapine is associated with the highest rate of seizures among antipsychotics, followed by chlorpromazine (Stimmel and Dopheide 1996; Wong and Delva 2007). Olanzapine and quetiapine may have proconvulsant effects compared with other atypical drugs (Alper et al. 2007). Because clozapine is most often indicated and most effective for patients with treatment-refractory schizophrenia, lowering the dosage or adding valproic acid may be worthwhile prior to switching to a different antipsychotic if a seizure occurs. Among antidepressants, tricyclic drugs at therapeutic dosages were associated with an incidence of seizures of about 0.4%–2% and are particularly


49

hazardous in overdose (Montgomery 2005). Clomipramine is considered most likely to be associated with seizures. MAOIs are considered to have low risk for seizures. Bupropion has a 10-fold increase in seizure risk in dosages over 600 mg/day and is relatively contraindicated in patients with epilepsy or severe eating disorders, or at least requires careful documentation and monitoring in these patients (Alper et al. 2007). Venlafaxine is not associated with seizures at therapeutic dosages. The SSRIs have a low risk of seizures, even in overdose, and have been associated with reduction in seizure frequency compared with placebo (Alper et al. 2007). However, some SSRIs can increase plasma levels of other drugs, with potential for increasing seizure activity. Among mood stabilizers, lithium is associated with seizures only during intoxication. Carbamazepine has been associated with seizures after overdose and can increase the risk of seizures during withdrawal; as a rule, the risk of withdrawal seizures can be minimized by not abruptly stopping carbamazepine, valproic acid, or any anticonvulsant, and by slowly tapering the drug over a 2-week period (Stimmel and Dopheide 1996). Short- and intermediate-acting benzodiazepines, especially alprazolam, have been associated with withdrawal seizures. Finally, seizure induction is a serious complication of the benzodiazepine receptor antagonist flumazenil, with fatal cases of status epilepticus having been reported.

Cardiovascular Reactions Severe adverse cardiovascular reactions in association with sudden death are often the most unexpected and catastrophic reactions to psychotropic drugs (Table 2–2). Cardiac reactions are observed primarily with antipsychotic drugs, especially clozapine, and with tricyclic antidepressants, whereas hypertensive crises are associated with nonselective and irreversible monoamine oxidase inhibitors.

Ventricular Arrhythmias and Sudden Cardiac Death Reports of sudden death in patients receiving antipsychotic drugs emerged soon after the drugs’ introduction. Several studies have confirmed a twofold to fivefold increased risk of sudden cardiac death in patients receiving antipsychotics (Hennessy et al. 2002; Liperoti et al. 2005; Mehtonen et al. 1991; Modai et al. 2000; Ray et al. 2001; Reilly et al. 2002; Straus et al. 2004). The risk is dosage related

Disorders Ventricular arrhythmias and sudden death QTc prolongation and torsade de pointes

Brugada syndrome

Heart block

Signs and symptoms Diagnostic studiesa Managementb

Implicated drugs

Risk factors

Antipsychotics (chlorpromazine, clozapine, droperidol, haloperidol, mesoridazine, pimozide, sulpiride, thioridazine, ziprasidone) Antipsychotics Antidepressants

Long QT syndrome; Palpitations, syncope, ECGs in at-risk chest pain patients cardiac, renal, or hepatic disease; family history; syncope; drug history; electrolytes; drug interactions; abnormal ECG; QTc>500 msec

—b

ECG (RBBB, ST elevations)

ECGs in at-risk patients

—b

Heart block

ECGs in at-risk patients

—b

Antidepressants (TCAs)

Genetic predisposition, overdose, drug combinations Intraventricular conduction defects


Table 2–2. Cardiovascular reactions

Table 2–2. Cardiovascular reactions (continued) Disorders

Implicated drugs

Risk factors

Signs and symptoms Diagnostic studiesa Managementb

Hypertensive crisis

MAOIs

Tyramine-containing food Sympathomimetic drugs

Blood pressure Hypertension, stiff monitoring neck, nausea, palpitations, diaphoresis, confusion, seizures, arrhythmias, headache, stroke

Myocarditis, cardiomyopathy, and pericarditis

Antipsychotics (clozapine)

Cardiovascular and pulmonary disease

Fever, dyspnea, flulike symptoms, chest pain, fatigue

Phentolamine iv, nifedipine for headache

Note. ECG= electrocardiogram; iv= intravenous; MAOIs=monoamine oxidase inhibitors; RBBB= right bundle branch block; TCAs=tricyclic antidepressants. a Standard imaging and laboratory studies to rule out other conditions in the differential diagnosis or complications are assumed. Only studies associated with or specific for each reaction are listed. b Mainstay of management in all reactions includes careful monitoring, prompt recognition, rapid cessation of the offending drug, and supportive medical care. Only specific therapies that have been reported are listed.


Echocardiography —b (reduced ejection fraction, ventricular dysfunction), ECG (T wave changes), leukocytosis, eosinophilia, cardiac enzyme elevations

51


and heightened by preexisting cardiovascular disease and use of some firstgeneration drugs. Implicated drugs include thioridazine, mesoridazine, pimozide, sertindole, sulpiride, clozapine, and low-potency phenothiazines, whereas other atypical drugs appear to have reduced risk. Butyrophenones, including haloperidol and droperidol used parenterally, have also been implicated. The reasons for increased risk of arrhythmias and sudden death have been attributed to specific drug effects on cardiac conduction (Glassman and Bigger 2001; Sicouri and Antzelevitch 2008). QTc prolongation predicts risk of torsade de pointes, ventricular fibrillation, syncope, and death. Although QTc is the best available predictor, it is imperfect; the threshold for increased risk is usually set at 500 msec, but other risk factors (see below) may determine occurrence of torsade (De Ponti et al. 2001; Glassman and Bigger 2001). Among psychotropic drugs, the antipsychotic drugs, particularly thioridazine, have the highest potential for QTc prolongation and resulting arrhythmias. Although ziprasidone has not been associated with torsade, this drug does prolong the QTc interval and is considered contraindicated in patients with a history of QTc prolongation, recent myocardial infarction, or uncompensated heart failure. A second mechanism for sudden death may be the Brugada syndrome, which is characterized by right bundle branch block and ST elevation in right precordial leads, but relatively normal QTc intervals. This syndrome has been associated with genetic predisposition, as well as with the use of antipsychotic and antidepressant drugs, mostly in the context of overdose or use of drug combinations. Early concerns over cardiac effects of tricyclic antidepressants derived primarily from the occurrence of heart block and arrhythmias observed after drug overdoses. However, subsequent studies suggested that risk of conduction disturbances also existed when therapeutic dosages were used (Roose et al. 1989). QTc prolongation and torsade have been reported with tricyclics, but far less often than with antipsychotics (Sala et al. 2006). QTc prolongation with tricyclics is due primarily to prolonged QRS conduction, which along with increased PR intervals reflects delays in the intraventricular HisPurkinje conduction system involved in depolarization. Tricyclics proved to be effective Type 1A quinidine-like antiarrhythmics, capable of suppressing ventricular ectopy. Although in patients with healthy hearts, tricyclic-induced suppression of conduction at therapeutic dosages is of no consequence, there


53

is a 10-fold risk of significant atrioventricular block in patients with preexisting intraventricular conduction defects (Roose et al. 1989). Newer antidepressants have less risk of arrhythmias and sudden death (Feinstein et al. 2002; Sala et al. 2006); however, there have been isolated reports of torsade following SSRI overdose (Lherm et al. 2000; Tarabar et al. 2008). Patients who are considered for antipsychotic and antidepressant treatment should be screened for heart disease, congenital long QT or Brugada syndrome, family history of sudden death, syncope, prior drug history of adverse cardiac effects, electrolyte imbalance (especially hypokalemia, hypocalcemia, or hypomagnesemia), and renal or hepatic disease. The list of drugs implicated in QTc prolongation and torsade when used concurrently can be divided into the following: drugs that prolong QTc, including antiarrhythmics (quinidine, procainamide, sotalol, amiodarone), antihistamines (diphenhydramine), antibiotics/antivirals (erythromycin, clarithromycin, amantadine), and others (cisapride, methadone); drugs that interfere with metabolism of agents associated with torsade, including antifungals (ketoconazole), antivirals (indinavir, ritonavir), calcium antagonists (diltiazem, verapamil), antibiotics (erythromycin, clarithromycin), and grapefruit juice; and drugs that may affect electrolytes or other risk factors (diuretics) (Kao and Furbee 2005). An electrocardiogram (ECG) should be obtained at baseline and after drug administration in patients with any of these risk factors. Conservative dosages of psychotropic drugs should be prescribed and polypharmacy should be minimized, with close clinical monitoring and warnings for patients to report promptly any new symptoms, such as palpitations or near-syncope, as well as the prescription of new medications. Cessation and change of medication should be considered if the ECG shows significant prolongation of the QTc, a QTc intervalgreater than 500 msec, new T wave abnormalities, marked bradycardia, or a Brugada phenotype.

Hypertensive Crisis Due to Monoamine Oxidase Inhibitors Irreversible MAOIs may produce a potentially fatal hypertensive crisis. Symptoms include throbbing headaches with marked blood pressure elevations, nausea, neck stiffness, palpitations, diaphoresis, and confusion, sometimes complicated by seizures, cardiac arrhythmias, intracerebral hemorrhage, and death. Episodes follow ingestion of sympathomimetic drugs or foods containing high concentrations of tyramine (Rapaport 2007). Prior to recognition of


the need for dietary restrictions, rates of hypertensive reactions were estimated to range from 2.4% to 25% (Krishnan 2007). Previous MAOI diets were probably overly conservative, but more recent dietary restrictions are less daunting (Gardner et al. 1996). Monoamine oxidase (MAO) is the principal enzyme responsible for the oxidative deamination of monoamines. There are two subtypes of MAO isoenzymes: MAO-A and MAO-B. MAO-A occurs primarily in the brain, where its primary substrates are epinephrine, norepinephrine, dopamine, and serotonin, and in the intestine and liver, where it plays a critical role in the catabolism of dietary tyramine. Inhibition of MAO-A by MAOIs permits uptake of tyramine into the systemic circulation, triggering a significant release of norepinephrine from sympathetic nerve terminals with resultant hypertensive crisis. All sympathomimetic drugs may cause a hypertensive crisis in MAOItreated patients. Intravenous phentolamine is the preferred treatment to reverse the acute rise in blood pressure in hypertensive crisis. Patients are often provided with nifedipine to take in case they have a hypertensive headache. Several selective and reversible inhibitors of MAO-A that do not require dietary restrictions have been developed but are not currently marketed in the United States. Selegiline, a selective but irreversible inhibitor of MAO-B at dosages used to increase dopaminergic activity in Parkinson’s disease, becomes an inhibitor of both MAO-A and MAO-B at dosages needed to treat depression. A transdermal delivery system has become available that allows selegiline to be directly absorbed into the systemic circulation, bypassing the gastrointestinal tract and avoiding the need for dietary restrictions (see Chapter 3, “Alternate Routes of Drug Administration”). However, dietary restrictions are still required at higher dosages. Rasagiline is similar and still contains the tyramine warning.

Myocarditis, Cardiomyopathy, and Pericarditis Disorders of the myocardium and pericardium are associated primarily with clozapine (Haas et al. 2007; Merrill et al. 2005). The risk of myocarditis from clozapine ranges from 0.015% to 1.2%, with a mortality rate of 10%–51%. The median age of affected patients has been 30–36 years. Myocarditis occurs at therapeutic dosages, and the median time of onset is less than 3 weeks after initiation of treatment. Symptoms can be diverse and nonspecific, such as fever, dyspnea, flulike illness, chest discomfort, and fatigue. Laboratory studies


55

may reveal ventricular dysfunction and reduced ejection fraction on echocardiography; ECG abnormalities, particularly T wave changes; leukocytosis and eosinophilia; and elevations in cardiac enzymes. Symptoms may improve following discontinuation of clozapine, but several recurrences on rechallenge have been reported. The exact pathophysiology has yet to be determined but is thought to reflect an acute hypersensitivity reaction to the drug. Dilated or congestive cardiomyopathy, characterized by ventricular dilatation, contractile dysfunction, and congestive heart failure, has also been associated with clozapine (Merrill et al. 2005). As with myocarditis, the median age of patients with clozapine-related cardiomyopathy is in the 30s, and dosages are within the therapeutic range. However, the duration of treatment with clozapine before cardiomyopathy onset ranges from weeks to years, with a median duration of 9 months. Improvement after clozapine discontinuation has been described. Cardiomyopathy could represent a direct cardiotoxic effect of clozapine, but more likely evolves from clozapine-induced myocarditis. Pericarditis and polyserositis (involving the pleura as well) have also been described in association with clozapine (Merrill et al. 2005; Wehmeier et al. 2005). These inflammations occur within the first few weeks after drug initiation and appear to resolve after drug discontinuation. Clozapine should be used cautiously in patients with cardiovascular and pulmonary disease. Patients and families should be informed of symptoms and questioned for any signs of cardiac dysfunction. A baseline ECG should be obtained prior to starting clozapine and repeated 2–4 weeks afterward. The value of repeat ECGs, echocardiography, magnetic resonance imaging, serum cardiac enzymes, and eosinophilia has not been substantiated but should be considered together with cardiology consultation if new symptoms of cardiovascular disease develop. If myocarditis, pericarditis, or cardiomyopathy is suspected, clozapine should be discontinued immediately and should not be reinstituted if the diagnosis is confirmed.

Gastrointestinal Reactions While mild gastrointestinal upset is not uncommon as a side effect associated with several psychotropic drug classes (e.g., SSRIs, lithium), severe hepatic and pancreatic toxicity is rarely reported but is most often described following administration of anticonvulsant drugs, particularly valproic acid (Table 2–3).

Disorders

Implicated drugs

Risk factors

Signs and symptoms

Diagnostic studiesa

Managementb

Hepatotoxicity

Anticonvulsants (carbamazepine, lamotrigine, topiramate, valproic acid) Antipsychotics (phenothiazines)

Children, multiple anticonvulsants

Lethargy, jaundice, nausea, vomiting, anorexia, hemorrhages, seizures, fever, facial edema

Transaminitis, hyperbilirubinemia

L-Carnitine

Hyperammonemic encephalopathy

Valproic acid

—

Decreased consciousness, focal deficits, impaired cognition, lethargy, vomiting, seizures

Serum ammonia, EEG

L-Carnitine

Acute pancreatitis

Valproic acid

Abdominal pain, nausea, vomiting, anorexia, fever

Serum amylase, lipase

Children, multiple anticonvulsants

for valproate toxicity?

for valproate toxicity?

—b

Note. EEG =electroencephalogram. a Standard imaging and laboratory studies to rule out other conditions in the differential diagnosis or complications are assumed. Only studies associated with or specific for each reaction are listed. bMainstay of management in all reactions includes careful monitoring, prompt recognition, rapid cessation of the offending drug, and supportive medical care. Only specific therapies that have been reported are listed. ?= lack of evidence of safety and efficacy.


Table 2–3. Gastrointestinal reactions


57

Hepatotoxicity Transient elevations in transaminases are common with drugs metabolized by the liver. Severe hepatotoxicity is much less common but has been reported with older phenothiazines, nefazodone, and anticonvulsant drugs, including carbamazepine, lamotrigine, topiramate, and valproic acid (Dreifuss et al. 1987; Fayad et al. 2000; Konig et al. 1999; Lheureux et al. 2005; MoralesDiaz et al. 1999). Drug-induced liver failure associated with anticonvulsants is more common in children and in patients taking multiple agents. Valproic acid, the drug that has been most often implicated in druginduced hepatotoxicity, occurs in two forms. Reversible elevations in transaminases without clinical symptoms occur in up to 44% of patients (Dreifuss et al. 1987). Less commonly, irreversible, idiosyncratic, and potentially fatal hepatic failure occurs. The onset is usually within 6 months of treatment initiation. The incidence has been estimated to be 1 per 5,000 to 1 per 50,000 patients, but may increase in high-risk groups, including children under age 2 years, those with concomitant neurological or metabolic illness, and those taking multiple anticonvulsant drugs (Dreifuss et al. 1987; Lheureux et al. 2005). Among reported cases in adults, patients’ ages ranged from 17 to 62 years, duration of treatment ranged from 7 weeks to 6 years, and most patients had concomitant illnesses and received more than one anticonvulsant (Konig et al. 1999). Symptoms of hepatotoxicity include lethargy, jaundice, nausea, vomiting, hemorrhages, worsening seizures, anorexia, fever, and facial edema. Liver function test results are variable; transaminases and bilirubin vary from mild to extreme elevations and are not reliable predictors of progression to fatal hepatotoxicity. Regular clinical monitoring for prodromal symptoms is essential, followed by withholding of the suspected drug if symptoms emerge or enzyme elevations are found. The mechanisms of hepatotoxicity are incompletely understood, but it may result either from direct drug toxicity or from a hypersensitivity reaction. Evidence suggests that valproic acid–induced lipid peroxidation, glutathione depletion, and accumulation of toxic metabolites contribute to hepatic damage. Valproic acid also decreases levels and stores of carnitine, an amino acid derivative involved in mitochondrial metabolism, resulting in accumulation of toxic metabolites of the drug and ammonia (Lheureux et al. 2005). Recent evidence suggests that supplementation with L-carnitine may improve survival.


Hyperammonemic Encephalopathy Although hyperammonemia occurs in nearly 50% of patients receiving valproic acid, it remains asymptomatic in most cases (Lheureux et al. 2005). Rare patients develop hyperammonemic encephalopathy, characterized by decreased consciousness, focal neurological deficits, cognitive slowing, vomiting, lethargy, and increased seizure frequency (Segura-Bruna et al. 2006). These symptoms should prompt screening for blood ammonia levels, which can be elevated despite normal liver functions. Signs of severe encephalopathy, which are evident on an electroencephalogram, can be reversed once valproic acid is discontinued. Carnitine supplementation has shown promise in reducing ammonia levels and associated symptoms.

Acute Pancreatitis Acute pancreatitis has been reported as an idiosyncratic reaction to therapeutic dosages of valproic acid in 1 per 40,000 treated patients (Gerstner et al. 2007). Pancreatitis is most common in children, especially when treated with multiple anticonvulsants. Onset is variable, ranging from drug initiation to several years of treatment. Diagnosis is based clinically on abdominal pain, nausea, vomiting, anorexia, and fever, and is associated with elevations in amylase and lipase. Mortality may reach 15%–20%. Treatment is supportive after discontinuation of valproic acid. The mechanisms are unknown.

Renal Reactions Severe renal toxicity, including renal insufficiency and nephrogenic diabetes insipidus, has been associated primarily with lithium administration (Table 2–4). However, the syndrome of inappropriate antidiuretic hormone secretion (SIADH) leading to hyponatremia has been associated with several drug classes. These disorders necessitate careful clinical and laboratory monitoring to prevent irreversible kidney damage.

Chronic Renal Insufficiency Lithium has been implicated in several disorders of kidney function, including renal tubular acidosis, interstitial nephritis, proteinuria with nephrotic syndrome, acute renal failure after intoxication, nephrogenic diabetes insipi-


59

dus, and chronic renal insufficiency progressing to end-stage renal disease (Boton et al. 1987; Raedler and Wiedemann 2007). Histopathological studies reveal that about 10%–20% of patients receiving long-term lithium therapy demonstrate changes including tubular atrophy, interstitial fibrosis, cysts, and glomerular sclerosis. Recent studies have confirmed an association between long-term lithium treatment and progressive renal insufficiency (Raedler and Wiedemann 2007). Studies have shown that about 15%–20% of patients show evidence of reduced renal function after 10 years of taking lithium. Abnormalities may develop as early as 1 year after beginning treatment. Kidney dysfunction is related to duration of lithium treatment and is progressive, even after lithium is discontinued in some cases. The rate of progression is variable; although many patients show a decreased filtration rate, few develop renal insufficiency, and frank renal failure is rare. In a study among dialysis patients, 0.22% had lithium-induced nephropathy (Presne et al. 2003). No reliable risk factors predict renal failure, but decreased renal function has been associated with duration of treatment, age, concomitant medications (e.g., nonsteroidal anti-inflammatory drugs, especially indomethacin), and episodes of lithium toxicity. Management focuses on prevention by screening patients for underlying kidney disease, discussing risks and benefits of treatment, using lowest effective dosages, avoiding lithium intoxication, careful monitoring of lithium levels, measurement of serum creatinine and creatinine clearance every 6 months or as indicated by the patient’s condition, and reassessing risks of lithium if renal function declines.

Nephrogenic Diabetes Insipidus In early studies, impairment in urine concentration with resulting polyuria, which was observed in 20%–30% of patients receiving lithium, was considered benign (Khanna 2006). However, lithium is the most common cause of nephrogenic diabetes insipidus (NDI). NDI is defined as the inability of the kidneys to concentrate urine, resulting in excessive volumes of dilute urine due to the insensitivity of the distal nephron to the antidiuretic hormone vasopressin. Although mild cases can be compensated by increased fluid intake, severe cases can result in dehydration, neurological symptoms, encephalopathy, and lithium intoxication. NDI can be congenital or acquired from drugs including pimozide and alcohol apart from lithium. The diagnosis of NDI can

Management b

Implicated drugs

Risk factors

Chronic renal insufficiency

Lithium

— Elderly, duration of treatment, concomitant drugs (NSAIDs), lithium toxicity

Creatinine, creatinine —b clearance (at least every 6 months)

Nephrogenic diabetes insipidus

Alcohol Lithium Pimozide

—

Volume depletion

Water deprivation Serum vasopressin Response to exogenous vasopressin

Monitor urinary output Specific agents? (amiloride, NSAIDs, thiazides)

Nausea, vomiting, anorexia, dysgeusia, disorientation, confusion, fatigue, headaches, weakness, irritability, lethargy, muscle cramps, → delirium, hallucinations, diminished consciousness, seizures, coma, respiratory arrest

Hyponatremia, elevated urine/ reduced plasma osmolality

Hyponatremic encephalopathy, hypertonic fluidsc Specific agents? (conivaptan, demeclocycline)

Hyponatremia (SIADH) — Acute Antidepressants (SSRIs or SNRIs, TCAs) Antipsychotics Opiates

Signs and symptoms

Diagnostic studies a

Disorders


Table 2–4. Renal reactions

Table 2–4. Renal reactions (continued) Disorders Chronic

Implicated drugs

Risk factors

— Antidepressants (SSRIs or SNRIs, TCAs) Antipsychotics Opiates

Signs and symptoms

Diagnostic studies a

Management b

Impaired cognition, falls, mood change

—a

Fluid restriction c Specific agents? (clozapine, conivaptan, demeclocycline, tolvaptan)


Note. NSAID= nonsteroidal anti-inflammatory drug; SIADH= syndrome of inappropriate antidiuretic hormone secretion; SNRIs= serotonin–norepinephrine reuptake inhibitors; SSRIs =selective serotonin reuptake inhibitors; TCAs= tricyclic antidepressants. a Standard imaging and laboratory studies to rule out other conditions in the differential diagnosis or complications are assumed. Only studies associated with or specific for each reaction are listed. bMainstay of management in all reactions includes careful monitoring, prompt recognition, rapid cessation of the offending drug, and supportive medical care. Only specific therapies that have been reported are listed. ?= lack of evidence of safety and efficacy. c Risk of central or extrapontine myelinolysis (mood changes, lethargy, mutism, dysarthria, pseudobulbar palsy, and quadriplegia) if serum sodium corrected at >12 mMol/L over 24-hour period.

61


be confirmed and distinguished from primary psychogenic polydipsia by comparing urine and plasma osmolality during a water deprivation or dehydration test (Garofeanu et al. 2005; Khanna 2006); in primary polydipsia, patients will show concentration of urine (osmolality >500 mOsmol/kg, with plasma osmolality >295 mOsmol/kg) after water deprivation, whereas patients with NDI will continue to show a dilute urine (50 mL/min; moderate RI is 10–50 mL/min; severe RI is 100–120 beats per minute (Lee et al 2005). Delirium tremens is typically an agitated hyperactive delirium—that is, mental status changes with associated cognitive impairment—with pronounced autonomic hyperactivity (including fever and increased heart rate and blood pressure); it is often accompanied by visual (although sometimes tactile) hallucinations or other perceptual distortions. The duration of confusion may persist days to weeks after resolution of the physical symptoms of withdrawal. Death may result from infections, cardiac arrhythmia, shock, hyperpyrexia, or suicide in response to hallucinations or delusions. The most commonly used measures of alcohol withdrawal severity include the Alcohol Withdrawal Assessment Scale (Wetterling et al. 1997) and

Substance Use Disorders

541

the revised Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) (Sullivan et al. 1989). Management of Alcohol Withdrawal No single standardized protocol is used for the treatment of alcohol withdrawal, and standardized monitoring of patients’ withdrawal severity is not common practice (Saitz et al. 1995). Before initiating any specific treatment for alcohol withdrawal, a thorough assessment of the patient’s medical condition is required to identify acute (i.e., dehydration, hypoglycemia, subdural hematoma, Mallory-Weiss tear, gastritis) and long-term (e.g., cirrhosis, malnutrition, neuropathy) sequelae of alcohol abuse. Admission blood alcohol level and toxicology screening are indicated, the latter to identify other abused substances (particularly benzodiazepines and opioids) that may complicate the withdrawal syndrome and its treatment. A 100-mg dose of thiamine hydrochloride should be given parenterally before the administration of dextrose-containing solutions, to avoid precipitating acute Wernicke-Korsakoff syndrome (a medical emergency). Thiamine 100 mg/day (administered intravenously, intramuscularly, or orally) should be continued indefinitely, because no data are available to indicate how long it is required. Folate and other B vitamins should also be supplemented daily. Fluid and electrolytes should be replaced as needed. Most patients in alcohol withdrawal can be managed with supportive care alone. However, malnourished alcoholic patients may be hypoglycemic, and when they receive intravenous glucose, they are at high risk for the refeeding syndrome, including hypophosphatemia and hypomagnesemia. Benzodiazepines are the mainstay of alcohol withdrawal treatment. In patients who are medically ill, short-acting benzodiazepines are preferred, particularly those requiring only Phase II glucuronidation, such as lorazepam. Lorazepam has no active metabolites; can be administered by multiple routes, including intravenous drip; and can be easily titrated upward or downward based on symptom severity. Symptom-driven protocols in the general hospital and ICU setting call for frequent AWS severity measurement, followed by dosing per protocol of lorazepam, and have been shown to reduce time to symptom control, amount of sedative required, and time spent receiving benzodiazepine infusion, compared with historical control subjects (DeCarolis


et al. 2007). Lorazepam appears to have longer duration of seizure control compared with diazepam (Alldredge et al. 2001). When standing lorazepam is required, dosing should be administered at least every 4 hours; when tapered, the dose per administration should be decreased, but the timing should not change because breakthrough symptoms may occur with longer intervals. Once lorazepam-treated patients are stabilized, and they have no severe liver disease and are reliably taking oral medication (generally for 2–4 days), lorazepam can be switched to an equivalent dosage of a longer-acting agent such as chlordiazepoxide or clonazepam. This change will allow for widening the dosing interval and autotapering if the patient leaves the hospital prematurely. For this reason, some experts also advocate the use of phenobarbital. However, this medication is less desirable in patients who are severely medically ill, including those who are at greater risk for respiratory suppression, those with impaired liver function, and those receiving polypharmacy. Alternatively, a slow titration off lorazepam is also an acceptable treatment method. Several drugs in other classes, including anticonvulsants (e.g., carbamazepine), beta-blockers (e.g., propranolol), alpha-2 agonists (e.g., clonidine, dexmedetomidine), and propofol, have been reported as effective in a few small studies or case series, but patients were usually experiencing mild withdrawal and had minimal medical comorbidity, and validated instruments for assessing withdrawal were often not used. Thus, no definite conclusions can be drawn about the effectiveness and safety of the use of these drugs for alcohol withdrawal (Polycarpou et al. 2005), and none are recommended as firstline therapy, especially in medically ill patients. A review of 57 randomized trials of benzodiazepines compared with placebo or other drugs found that benzodiazepines offered a large benefit against alcohol withdrawal seizures compared with placebo and offered a significant benefit for seizure control when compared with nonanticonvulsants, but not when compared with anticonvulsants (Ntais et al. 2005). An anticonvulsant should be added if seizures are not adequately controlled with benzodiazepines. Beta-blockers and alpha-2 agonists may serve as adjunctive treatments for autonomic hyperactivity that is not fully responding to benzodiazepine management. Beta-blockers reduce autonomic manifestations of acute alcohol withdrawal, and most arrhythmias that patients have during AWS are responsive to them (Mayo-Smith et al. 2004). However, beta-blockers do not mitigate the central nervous system effects, especially delirium and seizures. Beta-

Substance Use Disorders 543

blockers are contraindicated in patients with asthma, chronic obstructive pulmonary disease, hypoglycemia, bradycardia, and atrioventricular block, as well as some forms of heart failure. The alpha-2 adrenergic agonist clonidine has been found to be effective in managing the physical (i.e., autonomic hyperactivity) as well as psychological (i.e., anxiety) symptoms associated with AWS (Baumgartner and Rowen 1991; Bjorkqvist 1975; Braz et al 2003; Dobrydnjov et al 2004; Nutt and Glue 1986; Manhem et al. 1985; Walinder et al. 1981; Wilkins et al. 1983). In fact, transdermal clonidine patch has been found to be more effective than chlordiazepoxide (Baumgartner and Rowen 1991) and diazepam (Dobrydnjov et al. 2004) in all withdrawal symptoms. Clonidine is contraindicated in patients with bradycardia and atrioventricular block. It is important to monitor for hypotension during clonidine therapy and then to taper clonidine gradually to avoid hypertensive rebound (Gowing et al. 2004). In addition to orthostatic hypotension, side effects of clonidine include sedation, dry mouth, and constipation; these are more likely at higher doses. There are several reports (although no controlled studies) of the effectiveness of dexmedetomidine (Baddigam et al. 2005; Darrouj et al. 2008; Maccioli 2003; Rovasalo 2006), but use of this agent is limited to the ICU. Continuous infusion of propofol has been reported to be effective for delirium tremens in ICU patients who are refractory to lorazepam, but controlled studies are lacking (McCowan and Marik 2000). The addition of an antipsychotic on an as-needed basis may be useful in severely agitated patients or in those experiencing severe hallucinosis that is not responding to an adequate benzodiazepine regimen. Because they can lower seizure threshold, antipsychotic agents should not be administered alone to patients with AWS. Although intravenous ethanol has been reported to be effective for the treatment of withdrawal symptoms (Dissanaike et al. 2006), as well as less sedating than benzodiazepines, no controlled trials have been reported. Intravenous alcohol has a relatively narrow therapeutic index and is toxic, and its use seems to give a mixed message to alcoholic patients. Therefore, intravenous alcohol is inappropriate for treatment or prevention of AWS in patients who are medically ill (Hodges and Mazur 2004). The alcohol-dependent patient with cirrhosis who presents with acute withdrawal presents a therapeutic dilemma. Benzodiazepines and barbiturates


are contraindicated in patients with cirrhosis because these drugs can precipitate hepatic encephalopathy, but untreated delirium tremens has a high risk of morbidity and mortality. A prudent plan is to treat with lorazepam for the reasons outlined above, but to use the lowest effective dosage. New data are finally accumulating on the use of antidepressant agents for the management of AWS. Carbamazepine is the most studied antiepileptic agent. Randomized double-blind studies have suggested that carbamazepine is equal in efficacy to lorazepam in decreasing the symptoms of alcohol withdrawal and superior to lorazepam in preventing posttreatment relapse to drinking and reducing withdrawal-related anxiety symptoms (Malcolm et al. 2002). A Cochrane review suggests that carbamazepine has a small but statistically significant protective edge over benzodiazepines (Polycarpou et al. 2005). Other agents studied in this class include valproic acid (Reoux et al. 2001), topiramate (Krupitsky et al. 2007), and gabapentin (Bozikas et al. 2002). Anticraving and Abstinence-Promoting Medications for Alcohol Dependence Disulfiram (Antabuse) inhibits the enzyme aldehyde dehydrogenase, elevating levels of aldehydes in the liver, thus inducing the “Antabuse reaction,” which consists of flushing, headache, nausea, weakness, dizziness, anxiety, vertigo, and ataxia. Disulfiram is not advised in most patients with serious medical illnesses because of the potential for serious cardiac, hepatic, and neurological effects. For example, disulfiram is contraindicated in severe myocardial disease or coronary occlusion. Multiple cases of hepatitis, both cholestatic and fulminant types, as well as hepatic failure resulting in transplantation or death, have been reported with disulfiram. In patients with preexisting liver disease, the inactivation of aldehydes is impaired, leading to excessive accumulation of acetaldehyde and making a disulfiram reaction more severe. Disulfiram may cause a variety of neurological symptoms that mimic multiple sclerosis (e.g., optic neuritis, polyneuritis). Many oral medications in liquid form and some intravenous infusions contain small amounts of alcohol, which would provoke the disulfiram reaction. Acamprosate, a structural analog of gamma-aminobutyric acid and glutamate, is thought to interact with these neurotransmitter systems in the central nervous system to attenuate glutamatergic excitation that occurs with abstinence, and thus to reduce alcohol craving. In randomized controlled trials, acamprosate has been found to reduce craving and to increase and maintain


abstinence rates compared with placebo (Mann et al. 2004). It can be initiated immediately after detoxification and managed in a structured alcoholism treatment program. Acamprosate’s primary side effects are diarrhea and anxiety, usually only at high doses. Rare cases of cardiomyopathy, heart failure, and renal failure have occurred. Acamprosate is renally eliminated, not hepatically metabolized, so it can be used in patients with liver disease (U.S. Department of Health and Human Services 2005). However, in renal impairment (creatinine clearance 30–50 mL/minute), dosage must be reduced by half. It is contraindicated in patients with creatinine clearance ≤30 mL/minute (Herve et al. 1986). Acamprosate has few known drug interactions. Compared with disulfiram and naltrexone, which have multiple contraindications, acamprosate may be a good choice for patients with medical comorbidity, especially those taking other medications. Naltrexone, an opioid antagonist used to reduce alcohol craving, is subject to a U.S. Food and Drug Administration black-box warning contraindicating its use in severe hepatic disease and warning of possible hepatotoxicity when administered above the recommended dosage (Alkermes 2009). Several studies support its hepatic safety at the recommended dosage for the treatment of alcoholism (Yen et al. 2006). However, acute worsening of hepatic function has been noted when used in therapeutic dosages to treat itching in patients with hepatic failure (McCabe 2006). Postoperative use is contraindicated, because naltrexone will block postoperative opioid analgesia.

Drugs for Opioid Withdrawal Methadone is the most widely used drug for treatment of opioid withdrawal; its use in patients with particular medical illnesses is discussed in Chapter 17, “Pain Management.” Methadone’s risk for QT prolongation is of particular concern when given intravenously, especially if the patient is receiving other drugs that can increase the QT interval. In patients with renal and hepatic failure, dosage adjustment may be needed to minimize side effects and prevent worsening uremic or hepatic encephalopathy. Perioperatively, patients who were undergoing chronic methadone maintenance therapy require careful attention to pain control. The dose can be increased for pain control or continued at maintenance dose with a different opioid added for acute postoperative pain. Sedation, respiratory depression, and other symptoms of opioid toxicity should be monitored. Drug–drug interactions are common (Cherpitel 2007).


Buprenorphine, a mixed agonist–antagonist opioid used for treatment of opioid dependence, has a lower potential for causing respiratory depression and QTc prolongation (Wedam et al. 2007) than methadone. A few cases of buprenorphine-induced hepatotoxicity have occurred in patients with known hepatitis C. Buprenorphine is metabolized by cytochrome P450 (CYP) 3A4, and drug–drug interactions must be considered (Moss and Burnham 2006). Buprenorphine is not recommended perioperatively because it may precipitate withdrawal in patients previously taking opioids and will block agonist opioids given for postoperative analgesia. Clonidine is another option for mitigating signs of opioid withdrawal, and its contraindications are the same as when used for AWS. Naltrexone’s risks in the medically ill patient with opioid dependence are the same as in alcohol dependence, except that the potential for blocking opioid analgesia is even greater in the former (see “Anticraving and AbstinencePromoting Medications for Alcohol Dependence,” earlier in this chapter).

Drugs for Nicotine Dependence Nicotine replacement therapy (NRT) is often used in medically hospitalized smokers to treat acute nicotine withdrawal symptoms and to treat dependence (Rigotti et al. 2008). NRT is safe in patients with hypertension and stable cardiovascular disease (Joseph and Fu 2003). NRT is generally contraindicated in patients with acute heart disease because of the potential for increasing heart rate, angina, and possibly arrhythmias. Caution is advised, especially in heart transplant patients. Bupropion and varenicline reduce nicotine craving. Because bupropion may lower the seizure threshold, especially at rarely given doses of >450 mg/ day, it is relatively contraindicated in patients with epilepsy or a recent seizure, and should be used with caution in patients at risk for seizures (e.g., those at risk for acute alcohol withdrawal). Varenicline is a nicotinic receptor partial agonist approved as an aid to smoking cessation. Because of its partial agonist properties, varenicline relieves the symptoms of nicotine withdrawal and cigarette craving while blocking the reinforcing effects of nicotine in patients who relapse (Rollema et al. 2007). Serious psychiatric adverse effects, including depression, mania, psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide,


547

have been reported in patients with and without mild psychiatric disorders, and have prompted a black-box warning. Patients with preexisting psychiatric illness receiving varenicline should be closely monitored because the drug may worsen existing psychopathology. Clinical trials have not investigated its safety in patients with serious psychiatric illness, such as schizophrenia, bipolar disorder, or major depressive disorder (Pfizer 2009), or in patients with serious medical illness. Varenicline is renally excreted, and dose reductions are recommended in patients with renal insufficiency or undergoing dialysis. It is without significant drug interactions. Side effects (i.e., nausea and vomiting) may be problematic in patients who are medically ill. Rare cases of angioedema leading to respiratory compromise, Stevens-Johnson syndrome, and erythema multiforme have been reported with varenicline (Pfizer 2009).

Psychiatric Adverse Effects of Drugs Used in Substance Use Disorders A variety of drugs used in treating substance use disorders have neuropsychiatric adverse effects. These effects are summarized in Table 18–1.

Drug–Drug Interactions Acamprosate and varenicline are without significant pharmacokinetic drug interactions. Drug interactions between other drugs used to treat substance abuse and psychotropic drugs are listed in Table 18–2. See Chapter 1, “Pharmacokinetics, Pharmacodynamics, and Principles of Drug–Drug Interactions,” for a detailed discussion of drug interactions.


Table 18–1. Neuropsychiatric adverse effects of drugs that treat substance abuse Medication Acamprosate

Neuropsychiatricadverseeffect(s)

Common: anxiety, insomnia Serious: suicidality, depression Common: drowsiness, sedation, nervousness, agitation, Alpha-2 agonists sexual dysfunction (e.g., clonidine, Serious: depression dexmedetomidine) Common: depression, sedation, confusion, fatigue, appetite/ Anticonvulsants weight changes (e.g., carbamazepine, Serious: seizure exacerbation, suicidality, psychosis, delirium valproic acid, topiramate) Barbiturates Common: drowsiness, somnolence, dependence (e.g., phenobarbital) Serious: suicidality, respiratory depression Common: sedation, lethargy Benzodiazepines Serious: dependence, seizures, depression, delirium, (e.g., lorazepam, impaired memory diazepam) Beta-blockers Common: depression, insomnia, disorientation, sexual (e.g., propranolol) dysfunction Buprenorphine Common: sedation, insomnia, withdrawal symptoms, depression Serious: seizures, respiratory depression Bupropion Common: anxiety, insomnia, weight loss Serious: seizures, suicidality, worsening depression, agitation, psychosis, hallucinations, paranoia Disulfiram Common: alcohol–disulfiram reaction, drowsiness Serious: psychosis, respiratory depression, seizures Flumazenil Common: agitation, anxiety, fatigue, confusion Serious: seizures, re-sedation (due to short half-life), benzodiazepine withdrawal syndrome Naltrexone Common: insomnia, anxiety, fatigue, somnolence Serious: suicidality, depression, opioid withdrawal syndrome Propofol Common: respiratory depression, sedation, cognitive impairment Serious: propofol infusion syndrome, opisthotonus, unconsciousness


Table 18–1. Neuropsychiatric adverse effects of drugs that treat substance abuse (continued) Medication

Neuropsychiatricadverseeffect(s)

Varenicline

Common: insomnia, abnormal dreams, appetite changes, somnolence, emotional disturbances Serious: suicidality, depression, agitation, behavioral disturbances, exacerbation of underlying psychiatric disorder, seizures, hallucinations

Source. McEvoy 2008.

Key Clinical Points • Alcohol withdrawal syndrome (AWS) occurs after a period of absolute or, in some cases, relative abstinence or attempted selftapering from alcohol. Therefore, patients can experience AWS even though they may have a high blood alcohol level on presentation. • The mortality rate of delirium tremens is about 1% when timely treated, but it may be as high as 20% in nontreated patients. • Although benzodiazepines are considered the treatment of choice for alcohol withdrawal, several drugs in other classes, including anticonvulsants (e.g., carbamazepine), beta-blockers (e.g., propranolol), alpha-2 agonists (e.g., clonidine, dexmedetomidine), and propofol, have shown effectiveness and promise. • Nicotine replacement therapy is safe in patients with hypertension and stable cardiovascular disease but is generally contraindicated in patients with acute heart disease because of the potential for increasing heart rate, angina, and arrhythmias. • Because most available pharmacological agents used to treat addiction or prevent withdrawal syndromes have considerable potential for neuropsychiatric side effects, providers must use caution when prescribing them.

Psychotropic drug–drugs for substance abuse interactions

Medication

Interactionmechanism

Buprenorphine See Methadone below

Clonidine

Opioid antagonism Additive hypotensive effect Inhibits norepinephrine release

Disulfiram

Flumazenil

Inhibits CYP 2E1, 1A2, and possibly other CYP enzymes Inhibits acetaldehyde metabolism Inhibits dopamine beta-hydroxylase GABA antagonism

Methadone

Opioid antagonism Induces CYP 3A4

Inhibits CYP 3A4

Effect(son ) psychotropicdrugsandmanagement Similar drug interaction profile to methadone (see below), although generally attenuated effects, particularly less concomitant sedation and QT prolongation. May induce withdrawal in patients on opioid analgesics and methadone. Increased risk of hypotensive effects with antipsychotics, TCAs, and MAOIs; increased risk of dry mouth and eyes with TCAs and antipsychotics. Clonidine may decrease the therapeutic effect of TCAs and NRIs, including atomoxetine. Similarly, TCAs and NRIs may decrease the effects of clonidine. Increased levels and toxicity of phenytoin (and possibly mephenytoin and fosphenytoin), olanzapine, and risperidone. Many oral medications in liquid form and some intravenous infusions contain small amounts of alcohol, which would provoke a disulfiram reaction. Increased seizure potential with illicit cocaine use. Flumazenil is contraindicated in patients receiving a benzodiazepine for control of intracranial pressure or status epilepticus, or in cases of TCA overdose. Decreased methadone effect and possibly withdrawal in combination with naloxone, naltrexone, pentazocine, nalbuphine, butorphanol, and buprenorphine. Decreased serum levels of methadone and possible withdrawal in combination with phenytoin, St. John’s wort, phenobarbital, carbamazepine, rifampin, and some antiretroviral medications (see Chapter 12, “Infectious Diseases”). Increased serum levels of methadone and potential excessive sedation and respiratory suppression with CYP 3A4 inhibitors such as fluvoxamine and nefazodone.


Table 18–2.

Table 18–2. Medication

Psychotropic drug–drugs for substance abuse interactions (continued) Interactionmechanism Potentiation of opioid sedation QT prolongation

Naltrexone

Opioid antagonism

Unknown

Effect(son ) psychotropicdrugsandmanagement Coadministration with benzodiazepines or strong antihistamines (e.g., tertiary amine TCAs, quetiapine, diphenhydramine) can potentiate opioid sedation. Additive risk for QT prolongation and electrolyte disturbances with psychotropics that increase QT interval, including TCAs, typical antipsychotics, pimozide, risperidone, paliperidone, iloperidone, quetiapine, ziprasidone, and lithium (see also Chapter 6, “Cardiovascular Disorders”). Naltrexone blocks the effect of opioids administered for pain, cough and diarrhea. Use of naltrexone should be avoided in patients dependent on opioids for control of severe pain. Naltrexone increases area under the plasma concentration–time curve of acamprosate by 25%.a Substance Use Disorders

Note. CYP= cytochrome P450; GABA= gamma-aminobutyric acid; MAOIs =monoamine oxidase inhibitors; NRIs= norepinephrine reuptake inhibitors; TCAs =tricyclic antidepressants. aAcamprosate product monograph (Prempharm 2007).

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Index Page numbers printed in boldface type refer to tables or figures.

intramuscular form of, 81 intravenous form of, 80–81 for mood stabilizers, 92–93 for psychostimulants, 94 reasons for, 79, 80, 94–95 rectal form of, 81, 86 sublingual form of, 81 for surgical patients, 449 Adverse cutaneous drug reactions (ACDRs), 415–420 Adverse effects of medications. See also Anticholinergic effects; Drug–drug interactions; Drug reactions; Extrapyramidal symptoms; Neuroleptic malignant syndrome; Serotonin syndrome of chronic opioid therapy, 514–515 medication compliance and minimization of, 8 pharmacodynamics and, 4, 7 psychiatric manifestations of antibiotic therapy for infectious diseases, 375–377, 393–394 cancer treatments, 247–251 cardiac medications, 183–184 critical care and surgical drugs, 453–454 dermatological agents, 420–422

Abacavir, 376 Absorption, and pharmacokinetics, 9, 10, 11, 115, 185. See also Malabsorption Acamprosate alcohol dependence and, 199, 483, 544–545 drug–drug interactions and, 547, 551 medical side effects of, 483 neuropsychiatric adverse effects of, 548 ACE inhibitors, and drug–drug interactions, 30, 202 Acetaminophen, 36 Acetazolamide, 203, 217, 219 Acne, 408, 415 Acromegaly, 306 Acute pain, 504–505 Acyclovir, 377, 393 Addison’s disease, 306 Administration, alternative routes of. See also Transdermal patch for antidepressants, 89–91 for antipsychotics, 91–92 for anxiolytics and sedativehypnotics, 87–89 for children, 451 for cognitive enhancers, 94

557


Adverse effects of medications, psychiatric manifestations of (continued) endocrine treatments, 320–324 gastrointestinal medications, 130, 131 immunosuppressant medications for organ transplantation, 484–487 neurological drugs, 289–291 obstetric and gynecological agents and procedures, 355–358 renal and urological agents, 161–162, 163 respiratory medications, 216–219 rheumatological medications, 433, 434 substance use disorder drugs, 547, 548–549 psychotropic drugs and cancer risk, 244–247 cardiovascular disorders, 187 endocrinological disorders, 313–320 gastrointestinal disorders, 123–126 neurological disorders, 286–289 renal and urological disorders, 164–166 respiratory disorders, 225–227 rheumatological disorders, 434–435 sexual dysfunction, 166, 319, 326, 355 Adverse Event Reporting System database (Food and Drug Administration), 245 Affective disorders, and complex regional pain syndrome, 507

Aggression, and testosterone replacement therapy, 323–324 Agitation Alzheimer’s disease and, 273–274 traumatic brain injury and, 277–278 Agranulocytosis, 64–66, 295 Albumin, 12, 13 Albuterol, 217, 228 Alcohol and alcohol use disorders. See also Substance use disorders interferon-alpha therapy and abstinence from, 122 medications for treatment of, 199, 483, 539–545 plasma levels of albumin and, 13 renal drug reactions to, 60 Alcohol Withdrawal Assessment Scale, 540 Alcohol withdrawal syndrome (AWS), 540–545 Aldosterone, and drug–drug interactions, 37 Alemtuzumab, 252, 485 Alfentanil, 36, 202, 203 Alfuzosin, 169, 171, 172, 173 Alkylating agents, 249 Almotriptan, 294, 523 Alopecia areata, 408, 414, 417 Alosetron, 137 Alpha-adrenergic blocking agents, 183 Alpha-glucosidase inhibitors, 321 Alpha-lipoic acid, 104 5-alpha reductase inhibitors, 162, 163, 172 Alpha-1 acid glycoprotein, 12, 13 Alpha-1 adrenergic antagonists, 162, 163, 167, 169, 455, 456, 457 Alpha-2 adrenergic sedatives, 456 Alpha-2 agonists, 290, 542, 543, 548

Index

Alprazolam anxiety in cancer patients and, 242 diabetic patients and, 309 drug–drug interactions and, 34 hepatic insufficiency and, 119 nonoral preparations of, 82 seizures and, 49 systemic clearance of, 19 Alprenolol, 35 Alternative medications, and anxiety in preoperative patients, 450. See also Herbal medicines; Melatonin; St. John’s wort Alternative routes. See Administration Altretamine, 249 Alzheimer’s disease anticholinergic medications and, 24 treatment of psychiatric symptoms of, 272–274 Amantadine adverse psychiatric effects of, 290, 377 drug–drug interactions and, 292, 294, 295 renal insufficiency and, 157 American Psychiatric Association, 272 Amiloride, 168, 316 Aminoglycosides, 375 Aminophylline, 217 Aminotransferase, and drug-induced liver injury, 128 Amiodarone drug–drug interactions and, 183, 202, 205 neuropsychiatric side effects of, 184 pharmacokinetics and, 30 Amisulpride, 104 Amitriptyline drug–drug interactions and, 26, 30, 168, 382, 383, 410

559

gastric bypass surgery and, 113 incontinence and, 114–115 neuropathic pain and, 505, 506 nonoral preparations of, 82, 90 pain management and, 512 rheumatological disorders and, 432 systemic clearance of, 19 Amlodipine, 35 Amoxapine, 26, 287 Amphetamines drug–drug interactions and, 26, 135, 168, 295 gastrointestinal adverse effects of, 125 pregnancy and, 352 Amphotericin B, 377 Amprenavir, 34, 381 Amrinone, 453, 457 Analgesic agents, 455, 504 Anastrozole, 250 Anemia drug reactions and, 65 fatigue in cancer patients and, 243 Anesthetic agents. See also Inhalational anesthetics discontinuation of psychotropic drugs before surgery and, 448 pain management and local forms of, 521, 523 psychiatric adverse effects of, 453 Anger, and chronic pain, 504 Angioedema, 408 Angiotensin-converting enzyme inhibitors, 183, 184 Angiotensin II receptor blockers, 202 Antacids, 23, 133 Antianginal drugs, and drug–drug interactions, 30, 202 Antiarrhythmic agents, 53, 183, 184, 202, 204


Antibiotics adverse psychiatric effects of, 375–377, 393–394 drug–drug interactions and, 378–384, 410 Lyme disease and, 373 neuropsychiatric side effects of, 218 Anticholinergic effects atypical antipsychotics and, 67 delirium in hospitalized patients and, 447 drug–drug interactions and, 24, 134, 169, 228, 455 gastrointestinal symptoms and, 124, 134 metabolic reactions and, 68 neurological symptoms and, 287 neuropsychiatric symptoms and, 217, 218 renal and urological symptoms and, 165 respiratory disorders and, 221, 228, 229 Anticoagulants, and drug–drug interactions, 30 Anticonvulsants adverse psychiatric effects of, 290, 548 alcohol withdrawal syndrome and, 542 diabetic peripheral neuropathy and, 505 drug–drug interactions and, 30, 292, 294, 295, 327 epilepsy and, 284, 285 gastrointestinal reactions and, 56 hematological reactions and, 65 HIV/AIDS patients and, 395 pain management and, 512, 518–520

pancreatitis and, 129 psychiatric adverse effects of, 289, 291 rectal administration of, 93 renal insufficiency and, 156 trigeminal neuralgia and, 506 Antidepressants. See also Tricyclic antidepressants alcohol withdrawal syndrome and, 544 breastfeeding and, 353 cancer risk and, 246 cardiac reactions to, 50, 187, 188–193 central nervous system reactions to, 42, 43 diabetic patients and, 308 drug–drug interactions and cardiac medications, 204–205 dermatological medications, 411 endocrine medications, 325, 327 gastrointestinal medications, 136 neurological drugs, 294 pharmacokinetics of, 26, 30–31 renal and urological drugs, 60, 61, 165, 172 endocrinological adverse effects of, 313 functional dyspepsia and, 108 gastrointestinal adverse effects of, 124 hematological reactions to, 65 hepatic insufficiency and, 118 hypothyroidism and, 309 inflammatory bowel disease and, 112–113 irritable bowel syndrome and, 114 liver injury and, 127 neurological adverse effects of, 287, 294

Index

nonoral preparations of, 82–83, 89–91 organ transplantation and, 476–480 pain management and, 512, 515–518 pancreatitis and, 129 pregnancy and, 344, 346, 348–349 renal disease and, 153, 154, 157, 159 respiratory disorders and, 220–221 rheumatological disorders and, 432–433 sexual dysfunction and, 166 xerostomia and, 105 Antidiarrheal agents, 31, 130, 133 Antiemetics chemotherapy-induced nausea and vomiting, 260 drug–drug interactions and, 134 hyperprolactinemia and, 319 neuroleptic malignant syndrome and, 40, 41 psychiatric adverse effects of, 130 Antiepileptic agents, 350 Antifungal agents, 377, 410 Antihelminthic agents, 377, 393 Antiherpetic agents, 377 Antihistamines, 411, 421, 551. See also Diphenhydramine Antihyperlipidemics, 31, 203 Antihyponatremics, 31 Anti-infective agents, 227 Antimetabolites, 249 Antimicrobials, 32. See also Antibiotics Antimigraine drugs, 32, 523 Antimuscarinic effects, and delirium, 447 Antinauseants, 134 Antineoplastic agents, 33 Antiparkinsonian agents, 33, 157, 292

561

Antiplatelet agents, 30 Antipsychotics. See also Atypical antipsychotics breastfeeding and, 353 cancer risk and, 244–245 cardiac effects of, 187, 193–196, 205 central nervous system reactions to, 41, 42, 43 corticosteroids and, 323 drug–drug interactions and cardiac medications, 205 dermatological medications, 411 endocrine medications, 326, 327 gastrointestinal medications, 136 neurological medications, 293, 295 obstetrics/gynecology drugs, 359 pain management, 523 pharmacokinetics of, 26, 33–34 renal and urological medications, 60, 61, 165, 173 dysphagia and, 105 endocrinological adverse effects of, 313 extrapyramidal symptoms and, 286 gastrointestinal reactions and, 56, 124 heatstroke induced by, 67, 68, 69 hematological reactions and, 64, 65 hepatic insufficiency and, 119 HIV/AIDS patients and, 390 hyperemesis gravidarum and, 110 hyperprolactinemia and, 317, 319–320 hyperthyroidism and, 310–311 intravenous administration of, 81 metabolic reactions and, 68, 70, 316–317, 318, 319–320


Antipsychotics (continued) mortality of elderly patients with dementia-related psychosis and, 47–48, 195, 224, 273 neuroleptic malignant syndrome and, 40 neurological adverse effects of, 287, 295 nonoral preparations of, 83, 91–92 organ transplantation and, 480–481 pain management and, 513, 520–521 Parkinson’s disease or Lewy body dementia, 45 pregnancy and, 347, 349–350 renal insufficiency and, 155, 159 respiratory disorders and, 223–224 ventricular arrhythmias and sudden cardiac death, 49, 50, 52 xerostomia and, 105 Antiretroviral agents depression and, 394 drug–drug interactions and, 34, 380 HIV-associated mania and, 388 neuropsychiatric side effects of, 377, 385 Antispasmodics drug–drug interactions and, 133, 167, 169, 172 psychiatric adverse effects of, 131, 161–162, 163 Antithyroid antibodies, 340 Antithyroid medications, 321 Antitubercular drugs, 218, 374, 375, 378 Antiviral agents, 376–377, 380. See also Antiretroviral agents

Anxiety and anxiety disorders. See also Anxiolytics Alzheimer’s disease and, 273 cancer patients and, 242–243 complex regional pain syndrome and, 507 diabetes and, 308–309 epilepsy and, 284–285 HIV/AIDS patients and, 387–388 hyperthyroidism and, 310 menopause and, 343 organ transplantation and, 475 pain and, 503 premenstrual exacerbation of, 342–343 renal disease patients and, 150 respiratory disease patients and, 214–215, 222 stroke and, 276 surgery and preoperative patients and, 449–451 Anxiolytics breastfeeding and, 353 cancer risk and, 245 cardiovascular disorders and, 187–188 drug–drug interactions and, 26, 34–35 gastrointestinal adverse effects of, 124 globus hystericus and, 106 hepatic insufficiency and, 119–120 neurological adverse effects of, 287 nonoral preparations of, 82, 87–89 pregnancy and, 344–345, 346 renal disease and, 155, 159–160 respiratory disorders and, 221–222 Apathetic hyperthyroidism, 310

Index

Apathy, and central nervous system disorders, 285 Aprepitant, 130, 136, 137 Aquaporin-2, and lithium, 62 Arformoterol, 217 Aripiprazole cardiac effects of, 194, 196 delirium in hospitalized patients and, 444 drug–drug interactions and, 33, 202 hyperprolactinemia and, 320 nonoral preparations of, 83 renal insufficiency and, 155 Arizona Center for Education and Research on Therapeutics, 167, 259, 291, 446 Armodafinil drug–drug interactions and, 137, 174, 254, 360, 490 gastrointestinal adverse effects of, 125 hepatic insufficiency and, 121 organ transplantation and, 490 pharmacokinetics and, 37 renal insufficiency and, 157 Arrhythmias cardiac drug reactions and, 49, 50, 52 gastrointestinal drug interactions and, 136 neurological drug interactions and, 292 renal and urological drug interactions and, 168, 173, 174 surgical and critical care drugs and, 456 Arsenic trioxide, 252 Asenapine drug–drug interactions and, 33

563

nonoral preparations of, 83, 92 renal insufficiency and, 155 sublingual form of, 81 Asparaginase, 249, 251, 252, 256 Asthma, 214, 215, 223 Atazanavir, 34, 376 Atomoxetine drug–drug interactions and cardiac medications, 202 dermatological medications, 411 gastrointestinal medications, 133, 137 neurological agents, 295 obstetric/gynecology drugs, 360 oncology drugs, 253, 255 renal and urological drugs, 174 gastrointestinal adverse effects of, 125 hepatic insufficiency and, 121 pharmacokinetics and, 37 renal insufficiency and, 157 respiratory disorders and, 224 Atopic dermatitis, 407, 413 Atorvastatin, 31 Atrioventricular block, and heart transplant, 472 Atropine, 217, 218, 228 Attapulgite, 133 Atypical antipsychotics anticholinergic activity of, 67 cancer risk and, 245 cardiac effects of, 205 drug–drug interactions and, 173, 205, 295, 326, 360 endocrinological adverse effects of, 313 extrapyramidal symptoms and, 286 gastrointestinal adverse effects of, 124


Atypical antipsychotics (continued) hepatic insufficiency and, 118–119 HIV/AIDS patients and, 389, 391 neurological adverse effects of, 287, 295 nonoral preparations of, 83, 91 organ transplantation and, 481 psychogenic polydipsia and, 152 renal insufficiency and, 155 Autoimmune thyroiditis, 385 Azathioprine, 434, 436, 485, 486 Azithromycin, 372 Azole antifungals, 410 Bacterial infections neuroborreliosis and, 372–373 neurosyphilis and, 373 pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) and, 372 plasma levels of albumin in pneumonia and, 13 tuberculosis in central nervous system and, 374 Barbiturates neuropsychiatric adverse effects of, 548 renal disease and, 160 respiratory disorders and, 222 Bariatric surgery, 111 Basal ganglia disorders, 282 Basiliximab, 485 Beck Depression Inventory, 191 Behavior, benzodiazepines and disinhibition of, 289. See also Aggression; Agitation; Anger; Apathy; Compliance Bendroflumethiazide, 163

Benzodiazepines alcohol withdrawal treatment and, 541–542 antipsychotics administered in conjunction with, 91 anxiety before surgery and, 449–450, 451 anxiety in cancer patients and, 242 cardiac effects of, 188 drug–drug interactions and antibiotics, 379, 380, 381, 383 cardiac medications, 202, 203 dermatological medications, 410 endocrine medications, 327 gastrointestinal medications, 135 immunosuppressant drugs, 489 neurological medications, 292 oncology medications, 253 pharmacokinetics of, 26 renal and urological drugs, 170 substance abuse treatments, 551 functional dyspepsia and, 108 hematological reactions to, 65 hepatic encephalopathy and, 117 HIV/AIDS patients and, 387–388, 391 hyperthyroidism and, 310 intoxication with, 538–539 intravenous administration of, 81, 87 neuroleptic malignant syndrome and, 44 neurological adverse effects of, 287, 289 neuropsychiatric adverse effects of, 548 organ transplantation and, 480 pain management and, 520 pregnancy and, 345, 346 rectal administration of, 88

Index

renal disease and, 155, 160 respiratory disorders and, 221–222, 226 seizures and, 49 sublingual administration of, 88–89 xerostomia and, 105 Benztropine drug–drug interactions and, 26 gastrointestinal adverse effects of, 124 neurological adverse effects of, 287 renal and urological adverse effects of, 165 Beta-adrenergic blocking agents, 183 Beta-agonists drug–drug interactions and, 228, 356, 357, 359 neuropsychiatric adverse effects of, 216, 217, 218 Beta-blockers alcohol withdrawal syndrome and, 542–543 drug–drug interactions and, 35, 201, 204, 206 hyperthyroidism and, 310 neuropsychiatric effects of, 184, 548 psychogenic polydipsia and, 152 respiratory disorders and, 218 traumatic brain injury and, 278 Beta-lactam agents, 375 Biguanides, 321 Bioavailability drug–drug interactions and, 253, 489, 490 pharmacokinetics and, 7, 9, 11, 115, 257 Biological response modifiers, and dermatological disorders, 422 Biotransformation, 15

565

Biperiden, 26, 124 Bipolar disorder, 307, 310, 314 Bisoprolol, 35 Bisphosphonates, 507, 510 Black box warnings on antipsychotics and metabolic syndrome, 316 on antipsychotic use in elderly patients with dementia, 195, 224, 273 on naltrexone and severe hepatic disease, 545 on triptans in combination with serotonergic antidepressants, 296 on varenicline and preexisting psychiatric illness, 547 Blood dyscrasias, 64 Blood pressure, and drug–drug interactions, 200. See also Hypertension; Hypotension Body dysmorphic disorder, 406, 408 Bone marrow suppression, and clozapine, 295 Borrelia burgdorferi, 372 Bortezomib, 249 Brain tumors, psychiatric symptoms of, 238 Breast cancer, 240, 258, 319, 320 Breastfeeding, approach to psychopharmacology during, 352–354 Bromazepam, 34 Bromocriptine, 19, 321 Bronchodilators drug–drug interactions and, 35, 228 neuropsychiatric side effects of, 216, 217, 218


Brugada syndrome, 50 Budesonide, 136 Bufuralol, 35 Buprenorphine drug–drug interactions and, 550 neuropsychiatric adverse effects of, 548 nicotine dependency and, 546 organ transplantation and, 484 Bupropion bariatric surgery and, 112, 113 breastfeeding and, 353 cancer patients and, 241, 255 cardiac adverse effects of, 187, 191, 193, 204 drug–drug interactions and antibiotics, 380, 382, 383 cardiac medications, 204 gastrointestinal medications, 136 neurological drugs, 294 obstetric/gynecological drugs, 360 oncology drugs, 253, 255 renal and urological medications, 172 gastrointestinal adverse effects of, 124 hepatic insufficiency and, 118 inflammatory bowel disease and, 113 interferon-alpha and, 123 multiple sclerosis and, 279 neurological adverse effects of, 287, 294 neuropsychiatric adverse effects of, 548 nicotine dependence and, 546 organ transplantation and, 478 pain management and, 512, 517 pharmacokinetics of, 30 pregnancy and, 346

psoriasis and, 414 renal insufficiency and, 154 seizures and, 49, 288 systemic clearance of, 19 Burning mouth syndrome (BMS), 104, 409 Burns, and plasma levels of albumin and alpha-1 acid glycoprotein, 13 Buserelin, 356 Buspirone Alzheimer’s disease and, 273 drug–drug interactions and antibiotics, 379, 383 cardiac drugs, 202, 203 dermatological drugs, 410 gastrointestinal medications, 135 immunosuppressants, 489 neurological drugs, 292 pharmacokinetics of, 26, 34 renal and urological drugs, 170 functional dyspepsia and, 108 gastrointestinal adverse effects of, 124 hepatic insufficiency and, 119 HIV/AIDS patients and, 387 neurological adverse effects of, 287 renal insufficiency and, 155 respiratory disorders and, 222 systemic clearance of, 19 Butyrophenones, 52, 226 Cabergoline, 321 Caffeine, and drug–drug interactions, 37 Cachexia, and plasma levels of alpha-1 acid glycoprotein, 13 Calcineurin-inhibiting immunosuppressants, 473, 485–487

Index

Calcitonin, 507 Calcium acetate, 169 Calcium carbonate, 169 Calcium channel blockers, 35, 203, 204, 521 Cancer. See also Breast cancer; Chemotherapy; Pancreatic cancer; Prostate cancer drug–drug interactions and, 251–260 HIV-associated neuropsychiatric disorders and, 377 malignant pain and, 510 nausea and vomiting in, 110–111 neuropsychiatric adverse effects of oncology treatments, 247–251 plasma levels of alpha-1 acid glycoprotein and, 13 psychiatric symptoms in patients with, 237, 238–239 psychopharmacological treatment of psychiatric disorders in patients with, 239–244 testosterone replacement therapy and, 324 Cannabinoids, and drug–drug interactions, 37 Capecitabine, 252 Capsaicin, 104, 521–522 Captopril, 30 Carbamazepine alcohol withdrawal syndrome and, 544 breastfeeding and, 354 cardiac adverse effects of, 187, 197, 206 discontinuation of prior to surgery, 448

567

drug–drug interactions and antibiotics, 379, 380, 382, 383 cardiac medications, 206 dermatological medications, 410 endocrine drugs, 325 gastrointestinal medications, 137 immunosuppressants, 490 neurological medications, 292, 294, 295 obstetrical/gynecology drugs, 360 oncology drugs, 252, 254, 255 pharmacokinetics of, 30 renal and urological drugs, 168, 170, 174 surgical and critical care drugs, 455 endocrinological adverse effects of, 313 gastrointestinal adverse effects of, 124, 125 hematological reactions to, 64 hepatic insufficiency and, 120 HIV/AIDS patients and, 388 neurological adverse effects of, 287, 292 nonoral preparations of, 84, 93 organ transplantation and, 482, 490 pain management and, 512, 518 pregnancy and, 347, 350–351 renal insufficiency and, 156, 158 renal and urological adverse effects of, 165, 174 respiratory disorders and, 224, 225, 227, 229 seizures and, 49 systemic clearance of, 19 trigeminal neuralgia and, 506 xerostomia and, 105 ziprasidone and, 25


Carbimazole, 321 Carbonic anhydrase inhibitor diuretics, 23, 168, 171 Carboplatin, 252 Cardiac glycosides, and drug–drug interactions, 35, 203 Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial, 190 Cardiomyopathy, 51, 54–55 Cardiovascular disorders. See also Cardiovascular system; Heart disease; Stroke comorbidity of psychiatric disorders with, 181 differential diagnosis of psychiatric problems in, 182–183 drug–drug interactions and, 199–201, 202–206 hyperprolactinemia and, 319, 320 metabolism and, 18 neuropsychiatric side effects of medications for, 183–184 pharmacokinetics and, 184–186 psychotropic medication use in, 187–199 sildenafil and, 395 Cardiovascular system, and drug reactions, 49–55. See also Arrhythmias; Cardiovascular disorders; QTc prolongation; Torsade de pointes Ceftriaxone, 373 Celecoxib, 523 Celiac disease, 112 Central nervous system. See also Central nervous system disorders drug reactions and, 40–49

heatstroke and, 67 tuberculosis in, 374 Central nervous system (CNS) depressants, 135 Central nervous system disorders. See also Central nervous system adverse effects of psychotropic drugs and, 286–289 apathy and, 285 dementia and, 272–275 drug–drug interactions and, 291–296 epilepsy and, 283–285 frequency of, 271 Huntington’s disease and, 282–283 multiple sclerosis and, 278–280 Parkinson’s disease and, 280–282 pathological laughter and crying, 285–286 sexual disinhibition and, 286 stroke and, 275–276 traumatic brain injury and, 276–278 Central poststroke pain, 505–506 Cephalosporins, 375 Cerebral edema, and hyponatremia, 63 Cerebrovascular adverse events, and antipsychotics for elderly patients with dementia-related psychosis, 47–48 Cesarean section, and antipsychotics, 350 Cetuximab, 252 Chemotherapy drug metabolism and, 256–257 nausea and vomiting induced by, 110–111 neuropsychiatric adverse effects of, 247–248, 250–251 renal elimination of drugs and, 257

Index

Child-Pugh score (CPS), 116–117 Children. See also Infants cyclic vomiting syndrome and, 109 pancreatitis as reaction to valproic acid in, 58 PANDAS and recurrent streptococcal infections in, 372 prenatal exposure to carbamazepine and cognitive impairment in, 351 preoperative anxiety and, 450–451 rectal administration of benzodiazepines for seizures in, 88 transdermal methylphenidate for, 94 Chloramphenicol, 32 Chlordiazepoxide gastrointestinal drug interactions and, 134 hepatic insufficiency and, 119 renal insufficiency and, 155 systemic clearance of, 19 Chlorothiazide, 163 Chlorpheniramine, 411 Chlorpropamide, 37 Chlorpromazine agranulocytosis and, 64 anemia and, 66 delirium in hospitalized patients and, 443 drug–drug interactions and, 34, 133 HIV/AIDS patients and, 391 liver toxicity and, 127 nonoral preparations of, 83 rheumatological disorders and, 434 seizures and, 48 systemic clearance of, 19 Cholinesterase inhibitors adverse psychiatric effects of, 290

569

Alzheimer’s disease and, 272 cancer patients and, 242 cardiac effects of, 198, 206 discontinuation of prior to surgery, 448–449 drug–drug interactions and cardiac medications, 201, 202, 203, 206 gastrointestinal medications, 134 respiratory medications, 228 surgical and critical care drugs, 455, 458–459 gastrointestinal adverse effects of, 125 hepatic insufficiency and, 120 multiple sclerosis and, 278 Parkinson’s disease and, 282 renal disease and, 156, 160–161 respiratory disorders and, 224–225 traumatic brain injury and, 277 Chronic daily headache, 508 Chronic fatigue syndrome, 392 Chronic obstructive pulmonary disease, 214 Chronic renal insufficiency, 58–59, 60 Cigarettes. See Smoking cessation Cimetidine, 36, 131, 133 Ciprofloxacin, 32, 375, 379 Cirrhosis. See also Hepatic cirrhosis alcohol-dependent patients and, 543–544 drug monitoring and dosage reductions in, 117 metabolism and, 18 selective serotonin reuptake inhibitors and, 477 Cisplatin, 252, 257


Citalopram cardiac effects of, 190, 192 drug–drug interactions and, 26, 477 irritable bowel syndrome and, 114 nonoral preparations of, 82, 90 pain management and, 512, 517 respiratory disorders and, 220 systemic clearance of, 19 traumatic brain injury and, 277 Clarithromycin, 32, 375, 379, 410 Clidinium, 134 Clinical Antipsychotic Trials of Intervention Effectiveness— Alzheimer’s Disease (CATIE-AD), 273–274 Clinical Global Impression of Change scale, 273 Clinical Global Impressions Improvement Scale, 189 Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar), 541 Clomiphene, 356 Clomipramine drug–drug interactions and, 26, 30, 294 nonoral preparations of, 82 seizures and, 49 Clonazepam anxiety in cancer patients and, 243 burning mouth syndrome and, 104 drug–drug interactions and, 34 gastric bypass surgery and, 113 hepatic insufficiency and, 119 HIV/AIDS patients and, 389, 390 nonoral preparations of, 82 organ transplantation and, 480 pain management and, 520 systemic clearance of, 19

Clonidine adverse psychiatric effects of, 290 alcohol withdrawal syndrome and, 543 anxiety in preoperative patients and, 450, 451 drug–drug interactions and, 204, 205, 550 systemic clearance of, 19 Clorazepate, 19, 450 Clozapine anemia and, 66 cardiac effects of, 193, 195 discontinuation of prior to surgery, 448 drug–drug interactions and antibiotics, 379, 381, 382 cardiac drugs, 202 gastrointestinal medications, 133 neurological agents, 292, 295 oncology drugs, 253 pain medications, 523 pharmacokinetics of, 34 gastric bypass surgery and, 113 gastrointestinal adverse effects of, 124 hepatic insufficiency and, 118 infectious disease and, 394 myocarditis and, 54–55 neutropenia and, 64, 66 Parkinson’s disease and, 281 renal insufficiency and, 155 rhabdomyolysis and, 70 seizures and, 48 systemic clearance of, 19 urological effects of, 166 Coagulation disorders, and drug monitoring, 66 Cocaine, and colonic toxicity, 129–130

Index

Codeine, 19, 36, 202, 379 Cognitive dysfunction Alzheimer’s disease and, 272 anticholinergics for overactive bladder and, 162 antihistamines and, 421 cancer patients and, 244 epilepsy and, 283–284 HIV-associated neuropsychiatric disorders and, 377 multiple sclerosis and, 278 neurological adverse effects of, 289 organ transplantation and, 476 Parkinson’s disease and, 280 prenatal exposure to valproic acid and, 351 renal disease and, 151 respiratory disorders and, 216 stroke and, 275 traumatic brain injury and, 276–277 Cognitive enhancers cardiac effects of, 198 drug–drug interactions and, 26, 36, 293 nonoral preparations of, 85, 94 respiratory disorders and, 224–225 Colchicine, 36 Colonic toxicity, 129–130 Combined therapy. See Psychotherapy Comorbidity, psychiatric anxiety in cancer patients and, 242 burning mouth syndrome and, 104 cardiovascular disorders and, 181 chronic pain and, 502–504 dermatological disorders and, 405, 408 diabetes and, 306–307 functional dyspepsia and, 107–108 Complete blood count (CBC), 64, 66

571

Complex regional pain syndrome (CRPS), 507 Compliance, with medication routes of administration and, 79, 80, 94–95 strategies to maximize, 8–9 COMT inhibitors, 290 Conduction delay, and heart transplant, 472 Congestive heart failure, 55, 184, 312, 477 Conivaptan, 31, 162, 163, 170, 171, 172, 173, 174 Constipation, 115, 126 Contraceptives. See Oral contraceptives Corticosteroids. See also Steroids complex regional pain syndrome and, 507 drug–drug interactions and, 136, 137, 325 psychiatric adverse effects of, 130, 216, 217, 321–323, 420, 434, 485 immunosuppressant drug interactions and, 488, 489 PTSD in hospitalized surgical trauma patients and, 452 Cortisol, and drug–drug interactions, 37 Co-trimoxazole, 32 Creatine phosphokinase (CPK), and rhabdomyolysis, 70, 71 Creatinine, and drug elimination, 18–20, 475 Crohn’s disease, 112 Current Opioid Misuse Measure (COMM), 511 Cushing’s disease, 306 Cutaneous delusions, 406


Cutaneous dysesthesias, 409 Cutaneous excoriation, 412 Cyclic vomiting syndrome, 109–110 Cyclobenzaprine, 36, 509 Cyclophosphamide, 254, 255, 259, 434 Cycloserine, 375 Cyclosporine bioavailability of paclitaxel and, 257 drug–drug interactions and, 489, 490 organ transplantation and, 481, 485–486, 488, 489, 490 pharmacokinetics and, 36 psychiatric side effects of, 422, 434 CYP 2D6 substrates, 17 Cystic fibrosis, 214, 219, 473 Cytarabine, 249 Cytochrome P450 (CYP) 3A4 enzymes drug absorption and, 9, 10, 11 drug–drug interactions and, 20–21, 30–38, 171 drug elimination and, 15, 17 Cytomegalovirus, 392 Dacarbazine, 259 Daclizumab, 485 Dactinomycin, 33 Dapsone, 375 Darifenacin, 162, 169, 172 Darunavir, 34, 381 Dasatinib, 33, 252, 256 Daunorubicin, 252 Death, asthma and risk of, 223. See also Mortality; Sudden death Dehydroepiandrosterone (DHEA), 386, 387 Delavirdine, 376, 380 Delayed graft function (DGF), 471

Delirium alternative routes of drug administration and, 80 anticholinergic drugs and, 24, 421 chemotherapy and, 247 corticosteroids and, 322 HIV/AIDS patients and, 390–391 neurological adverse effects of psychotropic drugs and, 289 in postsurgical and critical care patients, 440–47 posttransplant organ rejection and, 471 renal failure and, 150 Delirium Rating Scale (DRS), 441, 442, 444 Delirium tremens, 540 Delusions central nervous system disorders and, 282, 283 dermatological disorders and, 409 Dementia. See also Alzheimer’s disease; Dementia with Lewy bodies; Frontotemporal dementia; Vascular dementia hormone replacement therapy and, 357–358 neurosyphilis and, 373 Dementia-related psychosis, 42, 47–48, 273–274 Dementia with Lewy bodies (DLB), 44–45, 274–275 Denileukin, 252 Depolarizing neuromuscular blocking agents, 455, 459 Depression Alzheimer’s disease and, 272–273 antiretroviral medications and, 394

Index

cancer patients and, 238, 239–242, 250 corticosteroids and, 322, 323 dermatological disorders and, 420–421 diabetes patients and, 307–308 epilepsy and, 284 HIV/AIDS patients and, 385–387 Huntington’s disease and, 282–283 hyperthyroidism and, 310 inflammatory bowel disease and, 112 interferon-alpha and, 122 isotretinoin and, 420–421 menopause and, 343 multiple sclerosis and, 278–279 organ transplantation and, 473, 475 pain symptoms and, 503 Parkinson’s disease and, 280–281 polycystic ovarian syndrome and, 340 pregnancy and, 340–341 premenstrual exacerbation of, 342–343 renal disease and, 150 respiratory disorders and, 215 rheumatological disorders and, 432–433 stroke and, 275–276 traumatic brain injury and, 277 Dermatitis artefacta, 407 Dermatological disorders adverse psychiatric effects of dermatological agents, 420–422 differential diagnosis of psychiatric manifestations of, 406–408 drug–drug interactions and, 410–411, 422–423

573

drug reactions to psychotropic agents and, 415–420 exacerbation of by psychotropic medications, 419–420 pharmacotherapy for psychiatric manifestations of, 409, 412–415 psychiatric and psychosocial comorbidity in, 405 Desflurane, 453, 455 Desipramine cancer patients and, 240 diarrhea and, 115 drug–drug interactions and, 26, 30, 382 multiple sclerosis and, 278 pain management and, 512 Parkinson’s disease and, 281 renal failure and, 159 systemic clearance of, 19 Desvenlafaxine drug–drug interactions and, 26, 30 gastrointestinal adverse effects of, 124 hepatic insufficiency and, 118 renal insufficiency and, 154 respiratory effects of, 226 Developmental and Reproductive Toxicology (DART) Database, 344 Dexamethasone, 37 Dexmedetomidine delirium in hospitalized patients and, 442, 443, 444–445, 446–447 drug–drug interactions and, 456, 459 Dextroamphetamine, 26, 85, 94 Dextromethorphan, 523


Diabetes. See also Nephrogenic diabetes insipidus gastroparesis and, 109 gestational, 350 metabolic drug reactions and, 69 plasma levels of albumin and, 13 psychogenic polydipsia and, 151 treatment of psychiatric symptoms and, 306–309 Diabetic ketoacidosis, 68, 69 Diabetic peripheral neuropathy, 308, 505 Diagnosis, Intractability, Risk, Efficacy (DIRE) screening scale, 511 Dialyzable psychotropics, 153, 158 Diarrhea, 115, 125–126 Diazepam anxiety before surgery and, 449–450 delirium in hospitalized patients and, 443 drug–drug interactions and, 35, 133 gastroesophageal reflux disorder and, 107 hepatic insufficiency and, 119 nonoral preparations of, 82, 86 systemic clearance of, 19 Diclofenac, 36 Dicyclomine, 131, 134 Didanosine, 376 Diet. See also Foods alcoholism and, 541 celiac disease and, 112 constipation and, 115 Differential diagnosis of neuroleptic malignant syndrome, 44 of psychiatric symptoms in cancer patients, 238–239

in cardiovascular patients, 182–183 in dermatological disorder patients, 406–408 in diabetes patients, 307 in HIV-infected patients, 374, 377, 385 in renal disease patients, 150–152 in reproductive disorder patients, 340–342 in respiratory disease patients, 214–216 of rhabdomyolysis, 71 Digoxin, 35, 183, 184, 203 Diltiazem, 35, 203 Dimenhydrinate, 131, 134 Diphenhydramine drug–drug interactions and, 134, 411 gastrointestinal adverse effects of, 124 pregnancy and, 345 psychiatric adverse effects of, 131, 421 systemic clearance of, 19 Diphenoxylate, 130 Discontinuation. See also Withdrawal of antipsychotics, 223, 323 of opioids, 511 of psychotropic drugs before surgery, 448–449 Disease. See Infectious diseases; Medical conditions Disopyramide, 30, 202 Distribution, and pharmacokinetics, 11–14, 185, 251, 256 Disulfiram, 483, 544, 548, 550

Index

Diuretics. See also Osmotic diuretics; Thiazide diuretics drug–drug interactions and, 168, 172, 203 hyponatremia and, 162 neuropsychiatric effects of, 183, 184 pharmacokinetics and, 186 Dobutamine, 453, 456, 460 Dolasetron, 131, 134, 136 Domperidone breast milk production and, 357 drug–drug interactions and, 131, 135, 359 pharmacokinetics of, 36 psychiatric adverse effects of, 131 Donepezil adverse psychiatric effects of, 290 Alzheimer’s disease and, 272 cancer patients and, 242, 244 delirium in hospitalized patients and, 442, 443, 447 drug–drug interactions and, 26, 293 hepatic insufficiency and, 120 multiple sclerosis and, 278 renal insufficiency and, 156 respiratory disorders and, 224 systemic clearance of, 19 Dopamine agonists adverse psychiatric effects of, 289, 290 Parkinson’s disease and, 280 psychiatric adverse effects of, 321 renal disease and, 161 Dopamine antagonists, 41, 44 Dopamine dysregulation syndrome, 289 Dose and dosages antipsychotics and metabolic syndrome, 317

575

cardiovascular disorders and, 192 compliance and use of minimum effective, 8 delirium as side effect of chemotherapy and, 247 of haloperidol for delirium in hospitalized patients, 445–446 liver disease and, 116–121 of lorazepam for alcohol withdrawal syndrome, 542 protein binding and, 14 renal disease and, 153 smoking and, 219–220 of venlafaxine for pain, 516 Dothiepin, 432 Doxazosin, 162, 163, 172, 173 Doxepin dermatological disorders and, 413, 414 drug–drug interactions and, 26, 31, 410 nonoral preparations of, 82, 90 systemic clearance of, 19 Doxorubicin, 33 Dronabinol, 131, 135 Droperidol drug–drug interactions and, 135, 136 nonoral preparations of, 83, 91 psychiatric adverse effects of, 131 Drug administration. See Administration Drug–drug interactions, and psychotropic medications antibiotics and, 378–384, 394–395 cancer therapy and, 251–260 cardiovascular drugs and, 199–201, 202–206 central nervous system disorders and, 291–296


Drug–drug interactions, and psychotropic medications (continued) dermatological disorders and, 410–411, 422–423 endocrine system and, 324, 325–327 gastrointestinal drugs and, 132, 133–137 obstetric and gynecological drugs and, 358–360 organ transplantation and, 476, 487–491 pain management and, 522–524 Phase II UGT-mediated conjugation and, 17–18 pharmacodynamics of, 24–25 pharmacokinetics of, 20–23, 25, 26, 30–38 renal and urological medications and, 166–171, 172–174 respiratory drugs and, 227–229 rheumatological medications and, 435, 436 substance abuse drugs and, 547, 550–551 surgical and critical care drugs and, 454–460 Drug elimination, and pharmacokinetics, 14–20, 185, 257 Drug hypersensitivity syndrome (DRESS), 417, 418 Drug hypersensitivity vasculitis, 418–419 Drug-induced lupus, 434–435. See also Systemic lupus erythematosus Drug-induced pigmentation, 416

Drug reactions. See also Adverse effects cardiovascular system and, 49–55 central nervous system and, 40–49 dermatological conditions and, 415–420 gastrointestinal system and, 55–58 hematological system and, 64–66 metabolism and, 66–71 obstetric and gynecological care and, 354–355 renal toxicity and, 58–64 Drug-seeking behavior, and pain control, 503 Drugs and Lactation Database (LactMed), 353 Duloxetine cardiac effects of, 191, 204 drug–drug interactions and cardiac drugs, 204 gastrointestinal medications, 136 obstetric/gynecology drugs, 360 oncology drugs, 255 pharmacokinetics of, 31 renal and urological drugs, 172 fibromyalgia and, 509 gastrointestinal adverse effects of, 124 hepatic insufficiency and, 118 liver injury and, 127 organ transplantation and, 478 pain management and, 512, 516 renal insufficiency and, 154 rheumatological disorders and, 433 Dutasteride, 162, 163, 172 Dyspnea, and opioids, 225 Dysphagia, 105–106 Eating disorders, 341, 342, 408 Ebstein’s anomaly, 350

Index

Ecstasy. See 3,4methylenedioxymethamphetamine (MDMA) Eczema, 407, 413 Edema, and renal disease, 152 Education, and medication compliance, 8 Efavirenz drug–drug interactions and, 380 insomnia and, 391 pharmacokinetics of, 34 psychiatric adverse effects of, 376, 385 Elderly patients. See also Alzheimer’s disease antipsychotics for dementia-related psychosis and mortality of, 47–48, 195, 224, 273 delirium and hip fracture in, 440 sleep–wake cycle disturbance and postoperative delirium in, 442–443 syndrome of inappropriate antidiuretic hormone secretion and, 63 Eletriptan, 32 Electrocardiographs (ECGs), and psychotropic drugs with cardiac effects, 53, 55 Electroconvulsive therapy (ECT) neuroleptic malignant syndrome and, 44 pregnancy and, 344, 347 Electroencephalograms, and differential diagnosis of encephalopathies and depression, 183 Electrolytes, and drug–drug interactions, 168, 551 Eletriptan, 294, 523

577

Emtricitabine, 376 Endocrine disorders adverse effects of psychiatric medications and, 313–320 diabetes mellitus and, 306–309 drug–drug interactions and, 324, 325–327 hypogonadal disorders and, 312–313 pheochromocytoma and, 311 psychiatric side effects of treatments for, 320–324 psychiatric symptoms of, 305, 306 thyroid disorders and, 309–311 Endocrinopathies, and HIV/AIDS patients, 385 End-stage renal disease (ESRD), 150. See also Renal disease Enflurane, 453, 455 Enhancing Recovery in Coronary Heart Disease (ENRICHD) trial, 190 Enoxacin, 32, 379 Entacapone, 290, 294 Epidemiology. See Prevalence Epilepsy anxiety and, 284–285 caution on use of psychotropics in patients with, 288 cognitive deficits and, 283–284 depression and, 284 drug-induced seizures and, 48 mania and, 284 plasma levels of alpha-1 acid glycoprotein and, 13 Epinephrine, 217, 453, 456 Eplerenone, 168, 172 Epstein-Barr virus infection, 392 Ergotamine, 32 Erythema multiforme (EM), 417–418


Erythromycin drug–drug interactions and, 379, 395, 410 pharmacokinetics of, 32 psychiatric adverse effects of, 375 Escitalopram, 26, 192, 477 Esomeprazole, 37, 131, 133 Esophageal disorders alternative routes of drug administration and, 80 psychotropic medications and treatment of, 106–111 Esophageal motility disorders, 107 Estradiol, 37 Estrogen, and drug–drug interactions, 37, 358, 359, 360. See also Hormone replacement therapy Estrogen receptor modulators, 356 Eszopiclone drug–drug interactions and, 26, 202, 203 gastrointestinal adverse effects of, 124 hepatic insufficiency and, 120 HIV/AIDS patients and, 391 menopause and, 343 renal insufficiency and, 155 Ethambutol, 375 Ethanol, and alcohol withdrawal syndrome, 543 Ethinyl estradiol, 37 Ethionamide, 375 Ethopropazine, 26 Ethosuximide, 19, 30, 292 Etomidate, 453, 456 Etoposide, 33, 252 Exanthematous rashes, 415–416

Excretion, and drug elimination, 14–20 Exfoliative dermatitis, 417, 418 Extrapyramidal symptoms adverse neurological effects of psychotropic drugs, 286, 288 gastrointestinal drug–psychotropic drug interactions and, 135 haloperidol and patients with delirium, 445–446 neurological drug–psychotropic drug interactions and, 293, 295 obstetrical drug–psychotropic drug interactions and, 359 psychotropic drugs for druginduced, 26 Fatigue. See also Chronic fatigue syndrome cancer patients and, 238, 243–244 multiple sclerosis and, 280 Parkinson’s disease and, 282 Felbamate, 30, 292, 294, 295 Felodipine, 35 Fenofibrate, 31 Fentanyl bioavailability of, 11 drug–drug interactions and, 36, 252, 253, 489, 523 pain management and, 513, 514, 523 systemic clearance of, 19 Fenugreek, 357 Fibromyalgia, 509 Finasteride, 162, 163, 172, 422 First-pass metabolism, and drug absorption, 9, 115

Index

Fixed drug eruptions, 416 Flavoxate, 163 Flecainide, 30, 168 Fluconazole, 32, 383 Fluid-attenuated inversion recovery (FLAIR) MRI sequences, 486 Flumazenil benzodiazepine intoxication and, 538–539 central nervous system reactions and, 43, 49 drug–drug interactions and, 550 neuropsychiatric adverse effects of, 548 systemic clearance of, 19 Flunitrazepam, 82, 87, 133 Fluoroquinolones, 375 5-Fluorouracil, 252 Fluoxetine breastfeeding and, 353 cancer patients and, 240, 241, 255 cardiac effects of, 189, 204 diabetic patients and, 308 drug–drug interactions and cardiac medications, 204 gastrointestinal medications, 136 neurological drugs, 294 obstetrics/gynecology medications, 360 oncology drugs, 255 organ transplantation drugs, 487–488, 490 pharmacokinetics of, 31 renal and urological drugs, 172 gastric bypass surgery and, 113 nonoral preparations of, 83, 90–91

579

organ transplantation and, 487–488, 490 pain management and, 512, 517 systemic clearance of, 19 Flupenthixol, 83 Fluphenazine, 84 Flurazepam, 19, 119 Flurbiprofen, 36 Fluvastatin, 31, 203 Fluvoxamine drug–drug interactions and, 31, 136, 204, 294, 325, 490 nifedipine and, 21 organ transplantation and, 490 respiratory disorders and, 229 systemic clearance of, 19 Folate supplementation, 351, 541 Food and Drug Administration (FDA). See Adverse Event Reporting System; Black box warnings Foods. See also Diet drug–drug interactions and, 37–38, 380 MAOIs and, 21, 53–54 Formoterol, 217 Fosamprenavir, 376, 381 Foscarnet, 377 Fosphenytoin, 292, 294, 295 Frontotemporal dementia, 275 Frovatriptan, 32, 294, 523 Functional dyspepsia, 107–108 Furosemide, 203 Gabapentin adverse psychiatric effects of, 290 anxiety in preoperative patients and, 450 fibromyalgia and, 509


Gabapentin (continued) hepatic insufficiency and, 120 menopause and, 343 neuropathic pain and, 505 organ transplantation and, 482–483 pain management and, 512, 518, 520 pregnancy and, 345 renal and biliary excretion of, 16 renal insufficiency and, 156, 158 Galactogogues, 356, 357 Galactorrhea, and antipsychotics, 359 Galantamine adverse psychiatric effects of, 290 drug–drug interactions and, 26, 293 nonoral preparations of, 85 renal disease and, 156, 160–161 Ganciclovir, 377 Gastric bypass surgery, 111–112 Gastric disorders, 106–111 Gastroesophageal reflux disease (GERD), 106–107 Gastrointestinal disorders adverse effects of psychiatric drugs and, 123–126 drug–drug interactions and, 132, 133–137 esophageal and gastric disorders, 106–111 immunosuppressant medications and, 491 intestinal disorders and, 111–115 liver disorders and, 115–123 oropharyngeal disorders and, 104–106 psychiatric side effects of gastrointestinal medications, 130, 131

psychotropic drug–induced complications of, 126–130 Gastrointestinal motility modifiers, 36 Gastrointestinal system, and drug reactions, 55–58. See also Gastrointestinal disorders Gastroparesis, 108–109 Gefitinib, 33, 258 Gemfibrozil, 31, 203 Gepirone, 31 Gestational diabetes, 350 Glatiramer, 290 Glimepiride, 37, 325 Glipizide, 37, 325 Globus hystericus, 106 Glomerular filtration rate (GFR), 19–20 Glossodynia, 409, 412 Glucocorticoids, 135, 487 Glyburide, 37, 325 Glycopyrrolate, 131, 134 Gold, and rheumatological medications, 434 Gonadotropin-releasing hormone agonists, 342, 356 Goserelin, 356 Gout therapy, 36 Granisetron, and drug–drug interactions, 131, 134, 136, 137 Grapefruit juice, 38 Graves’ disease. See Autoimmune thyroiditis; Hyperthyroidism Grepafloxacin, 32 Group A beta-hemolytic streptococci (GABHS), 372 Growth hormone disorders, 306 Growth hormone–inhibiting hormones, 321, 324, 326 Guanfacine, 290

Index

Hallucinations central nervous system disorders and, 282, 283 Parkinson’s disease and, 281 renal failure and, 150 Halothane, 453, 455, 458 Haloperidol cardiac effects of, 194, 196 delirium in hospitalized patients and, 441, 443, 444, 445–446 drug–drug interactions and, 34 extrapyramidal symptoms and, 286 hepatic insufficiency and, 119 HIV/AIDS patients and, 390, 391 hyperprolactinemia and, 319 lithium–neuroleptic encephalopathy and, 45 nonoral preparations of, 84 organ transplantation and, 480–481 renal insufficiency and, 155 systemic clearance of, 19 Hamilton Rating Scale for Depression (Ham-D), 189, 191 Hashimoto’s thyroiditis, 309 Headache, and chronic pain, 508–510 Health care. See Intensive care units; Medical conditions; Surgery and critical care Heart block, 50 Heart disease. See also Cardiovascular disease; Congestive heart failure metabolism and failure of, 18 pharmacokinetics and failure of, 185, 186 use of psychotropic drugs in patients with, 53, 187–199, 200, 478 Heart transplant, 472 Heatstroke, and antipsychotics, 67, 68, 69

581

Hematological reactions, to psychotropic drugs, 64–66 Hemodynamics, and liver transplant, 472 Hepatic cirrhosis, 13. See also Cirrhosis Hepatic disease. See also Liver disease black box warning on naltrexone and, 545 metabolism and, 18 Hepatic encephalopathy, 116 Hepatic insufficiency, 118–121 Hepatitis, and metabolism, 18 Hepatitis C virus (HCV), 121–123 Hepatocellular jaundice, 128 Hepatotoxicity, and gastrointestinal reactions to psychotropic drugs, 56, 57, 126–128 Herbal medicines, and drug–drug interactions, 37–38. See also Alternative medications; Melatonin; St. John’s wort Herpes encephalitis (HSE), 392–393 Herpes zoster, 505 Hexobarbital, 35 Hip fractures, delirium in elderly patients with, 440 His-Purkinje conduction system, 52 Histamine H 2 antagonists, 36, 131, 421 Histrelin, 356 HIV/AIDS, psychopharmacological treatments in patients with, 374, 377, 385–391, 395 HIV-associated mania, 388–389 Homoharringtonine, 252 Hormonal contraceptives, 355–356, 415 Hormone replacement therapy (HRT), 343, 357–358. See also Estrogen


Hormone therapy, and cancer patients, 250. See also Testosterone 5-HT3 antagonists, 134 Huntington’s disease, 282–283 Hydrochlorothiazide, 163 Hydrocodone, 19, 36, 514 Hydrocortisone, 37, 452 Hydroflumethiazide, 163 Hydromorphone, 19, 515 Hydrophilic drugs, 12 Hydroxychloroquine, 434 Hydroxyurea, 509 Hydroxyzine, 411 Hyoscyamine, 134 Hyperammonemia, and valproate, 292 Hyperammonemic encephalopathy, 56, 58 Hypercalcemia, 315 Hyperemesis gravidarum, 110, 340–341 Hyperhidrosis, 419–420 Hypernatremia, 164–165, 482 Hyperparathyroidism, 306, 311, 315 Hyperprolactinemia antipsychotics and, 244, 245, 246–247, 317, 319–320 drug–drug interactions and, 326, 359 psychiatric symptoms of, 306 Hyperpyrexia, 523 Hypertension. See also Blood pressure antidepressants and, 191 drug–drug interactions and, 204, 205, 254, 295, 380 monoamine oxidase inhibitors and, 51, 53–54 Hyperthyroidism, 306, 310–311, 315 Hyperventilation syndrome, 214 Hypnotics, nonoral preparations of, 82. See also Sedative-hypnotics

Hypoalbuminemia, 14 Hypoglycemia, 325, 541. See also Oral hypoglycemics Hypogonadism, 306, 312–313 Hypokalemia, 168 Hypomagnesemia, 168 Hyponatremia drug–drug interactions and, 200, 168, 205 renal drug reactions and, 60, 62–64, 151, 164 thiazide diuretics and, 162 Hyponatremic encephalopathy, 63 Hypotension. See also Blood pressure; Orthostatic hypotension anticancer drugs and, 260 antipsychotics and, 193 drug–drug interactions and, 168, 173, 204, 293, 455, 456, 457 Hypothyroidism interferon-alpha and, 122 lithium-induced, 314–315, 325 mood and cognitive problems in, 182 plasma levels of albumin and, 13 psychiatric symptoms of, 306, 309–310 Ibuprofen, 523 Ibutilide, 205 Idarubicin, 252 Idiopathic localized cutaneous dysesthesias, 407 Ifosfamide drug–drug interactions and, 249, 252, 254, 255 neuropsychiatric adverse effects of, 248 pharmacokinetics of, 33, 259 renal elimination of drugs and, 257

Index

Iloperidone drug–drug interactions and, 136, 173, 252, 253, 360, 489 hepatic insufficiency and, 118 pharmacokinetics of, 34 renal insufficiency and, 155 Imatinib, 33, 253, 256, 258 Imipenem, 375 Imipramine cancer patients and, 240 drug–drug interactions and, 26, 31, 168, 410 HIV/AIDS patients and, 385, 386 irritable bowel syndrome and, 114 nonoral preparations of, 83 pain management and, 512 systemic clearance of, 19 Immunoglobulin, 434 Immunomodulators, 290 Immunosuppressive agents drug–drug interactions and, 36, 482 neuropsychiatric effects of organ transplantation medications and, 484–487 posttransplant organ rejection and, 473 Incontinence, 114–115, 166 Indapamide, 163, 168, 173 Indinavir, 34, 376, 381 Infants. See also Children; Pregnancy; Teratogenicity benzodiazepines and, 345 lithium and, 351, 354 psychopharmacology during lactation and, 352–354 selective serotonin reuptake inhibitors and, 349

583

Infectious diseases adverse psychiatric effects of antibiotics and, 393–394 bacterial forms of, 372–374 drug–drug interactions and, 394–395 parasitic infections and, 393 psychiatric symptoms as part of, 371 viral forms of, 374, 377, 385–393 Infertility treatment, 356 Inflammatory bowel disease (IBD), 13, 112–113 Infliximab, 112 Inhalational anesthetics, 453, 454, 455, 458 Inositol, and psoriasis, 419 Insomnia, 224, 343, 391, 478 Insulin, and drug–drug interactions, 325, 326 Intensive care units (ICUs), 440, 446, 539. See also Surgery and critical care Interferon(s) drug metabolism and, 256 psychiatric adverse effects of, 248, 249, 250, 290 Interferon-alpha (IFN-), neuropsychiatric effects of, 121–123, 249, 250, 253, 256 Interferon-alpha-2a, 376, 385 Interferon-beta-1a/1b, 290, 291 Interleukin-2, 248, 249, 253, 256–257 Intestinal disorders, 111–115 Intoxication, and substance use disorders, 538–539 Intracranial pressure, and vasodilator hypotensive agents, 454


Intramuscular administration of antidepressants, 90 of antipsychotics, 91–92 of anxiolytics and sedativehypnotics, 87–88 properties of, 81 of testosterone, 387 Intranasal administration, 86, 89, 92 Intravenous administration of antipsychotics, 91, 445–446 of anxiolytics and sedativehypnotics, 87 of mood stabilizers, 93 properties of, 80–81 Iproniazid, 213 Irinotecan, 33, 254, 255, 258–259 Irritable bowel syndrome, 113–114, 131, 133 Ischemic cerebrovascular disease, 183 Isoflurane, 453, 455 Isoniazid, 32, 229, 375, 378 Isoproterenol, 217, 453, 456 Isosorbide, 202, 453, 457 Isotretinoin, 250, 415, 420–421 Isradipine, 35 Itraconazole, 23, 32, 383, 410 Kaolin, 133 Ketoconazole, 32, 377, 383, 410 Ketamine, 452 Kidney. See also Renal disease drug elimination and, 14–15, 18–20, 23 organ transplantation and, 470–471, 472, 475 Klüver-Bucy syndrome, 392 Labetalol, 35

Laboratory tests of hepatic enzymes and liver functions, 127–128 for neuroleptic malignant syndrome, 44 Lactam antibiotics, 375 Lamivudine, 376 Lamotrigine adverse psychiatric effects of, 290 breastfeeding and, 354 cardiac effects of, 196–197 dermatological disorders and, 418 drug–drug interactions and, 30, 382 gastrointestinal adverse effects of, 124 hepatic insufficiency and, 120 HIV/AIDS patients and, 389 nonoral preparations of, 84, 93 pain management and, 512, 519 phase II metabolism of, 16 pregnancy and, 347, 351 renal insufficiency and, 156, 158 systemic clearance of, 19 trigeminal neuralgia and, 506 valproate and, 21–22 Lanreotide, 321 Lansoprazole, 37, 131, 133 Lanthanum carbonate, 169 Lapatinib, 33 Laryngeal dystonia, 223 Leflunomide, 434 Leukopenia, and carbamazepine, 482 Leukotriene inhibitors, 217, 219, 228 Leuprolide, 356 Levalbuterol, 217 Levetiracetam, 19, 290, 291 Levodopa, 290, 292, 295 Levofloxacin, 32, 375

Index

Lidocaine drug–drug interactions and, 30 neuropathic pain and, 505, 506 nociceptive pain and, 510 pain management and, 521 Linezolid central nervous system reactions to, 42 drug–drug interactions and, 380, 395 pharmacokinetics of, 32 serotonin syndrome and, 46 Lipophilic drugs, 11–12 Lisdexamfetamine, 26 Lithium bariatric surgery and, 112, 113 breastfeeding and, 354 cancer and, 245–246 cardiac adverse effects of, 187, 196 corticosteroids and, 323 cystic fibrosis and, 219 dermatological disorders and, 419 discontinuation of prior to surgery, 448 drug–drug interactions and cardiac medications, 200 endocrine medications, 325 gastrointestinal drugs, 137 immunosuppressants, 491 neurological medications, 292, 294 obstetric/gynecology drugs, 360 oncology drugs, 252, 254 pain medications, 523 renal and urological drugs, 174 surgical and critical care drugs, 455 endocrinological adverse effects of, 313, 314–315

585

gastrointestinal adverse effects of, 124, 125 heart failure and elimination of, 186 hematological reactions and, 66 hepatic insufficiency and, 120 HIV/AIDS patients and, 388 hypernatremia and, 164–165 hyperthyroidism and, 310 hypothyroidism and, 310, 314–315 lithium–neuroleptic encephalopathy and, 41, 45–46 multiple sclerosis and, 279 nephrogenic diabetes insipidus and, 62, 316 neuroleptic malignant syndrome and coadministration with antipsychotics, 40 neurological adverse effects of, 287, 289, 294 nonoral administration of, 92–93 organ transplantation and, 481–482, 491 pregnancy and, 344, 347, 350 renal and biliary excretion of, 16 renal disease and, 156, 158, 160, 165 renal reactions to, 58–59, 60, 165, 174 seizures and, 43, 49 steroid-induced neuropsychiatric reactions and, 322 xerostomia and, 105 Lithium–neuroleptic encephalopathy, 41, 45–46 Liver disease. See also Cirrhosis; Hepatic disease dosing and, 116–121 drug elimination and, 19–20 drug-induced failure of, 57


Liver disease (continued) organ transplantation and, 470–471, 472, 474 pharmacokinetics and, 115–116 psychotropic drug–induced forms of, 126–128 Living organ donation, 474–475 LJP394, 434 Local anesthetics, 521, 523 Loop diuretics, 168, 171, 186 Loperamide, 31, 130 Lopinavir, 34, 382 Lorazepam alcohol withdrawal treatment and, 541–542, 544 anxiety in cancer patients and, 242–243 delirium in hospitalized patients and, 443 drug–drug interactions and, 35, 135 hepatic insufficiency and, 119 HIV/AIDS patients and, 387–388, 390, 391 nonoral preparations of, 82, 87, 88, 89 organ transplantation and, 480 phase II metabolism of, 16 sublingual form of, 81 Lormetazepam, 82 Lovastatin, 31, 203 Loxapine, 84 Lundbeck Institute, 80 Lupus cerebritis, 433. See also Drug-induced lupus; Systemic lupus erythematosus Lyme disease, 372–373 Macrolide antibiotics, 375, 410

Magnetic resonance imaging, and paraneoplastic limbic encephalitis, 239 Major depression, and chronic respiratory disease, 215 Malabsorption, and alternative routes of administration, 80 Malignant hyperthermia syndrome, and inhalational anesthetics, 454, 458 Malignant pain, 510 Mania corticosteroids and, 322, 323 epilepsy and, 284 HIV/AIDS patients and, 388–389 Huntington’s disease and, 283 hyperthyroidism and, 310 multiple sclerosis and, 279 stroke and, 276 traumatic brain injury and, 277 MAO-B inhibitors, 290 Maprotiline drug–drug interactions and, 26, 31, 133, 294 neurological adverse effects of, 287 nonoral preparations of, 83 Maraviroc, 34 Medical conditions. See also Cancer; Cardiovascular disorders; Central nervous system disorders; Dermatological disorders; Diabetes; Endocrine disorders; Epilepsy; Gastrointestinal disorders; Infectious diseases; Pain and pain management; Renal disease; Reproductive disorders; Respiratory disorders; Rheumatological disorders; Urological disorders Phase II metabolism and, 18

Index

plasma levels of albumin and alpha-1 acid glycoprotein and, 13 Medical emergency, hyponatremic encephalopathy as, 63 Meglitinides, 321 Melatonin, 222, 450, 451 Memantine Alzheimer’s disease and, 272 cardiac effects of, 198 drug–drug interactions and, 26, 134, 168, 202, 203 gastrointestinal adverse effects of, 125 hepatic insufficiency and, 120 renal disease and, 156, 160–161 Menopause, psychiatric manifestations of, 341, 343, 357 Meperidine drug–drug interactions and, 168, 252, 253, 380, 489, 523 pain management and, 514, 515, 523 pharmacokinetics of, 36 systemic clearance of, 19 Mephenytoin, 133 Metabolic syndrome antipsychotics and, 194, 316–317, 318 psoriasis and, 414 Metabolism and metabolic disorders cardiovascular disorders and, 185 chemotherapeutic agents and, 256–257, 258 drug–drug interactions and, 21–22, 167, 171, 206 drug elimination and, 14–20 drug reactions and, 66–71 immunosuppressant drugs and, 491 renal disease and, 152–153 Metabolites, 15

587

Metaproterenol, 217 Metformin, 317 Methadone and methadone maintenance therapy drug–drug interactions and antibiotics, 379, 380, 381, 395 drugs for substance abuse, 550–551 pain medications, 522, 523, 524 pharmacokinetics of, 36 renal and urological drugs, 168 opioid withdrawal and, 545 organ transplantation and, 474, 484 pain management and, 513, 514, 520, 522, 523, 524 systemic clearance of, 19 Methamphetamine, 26, 85 Methicillin-resistant Staphylococcus aureus, 395 Methimazole, 321 Methotrexate, 258, 33, 252, 255, 434 Methotrimeprazine, 84 Methoxyflurane, 453, 455 Methscopolamine, 131, 134 Methylene blue, 248 3,4-methylenedioxymethamphetamine (MDMA), 395 Methylphenidate cancer patients and, 241–242, 243, 244 cardiac effects of, 198 drug–drug interactions and, 26, 135, 295, 479 hepatic insufficiency and, 121 nonoral preparations of, 85, 86, 94 organ transplantation and, 479 Parkinson’s disease and, 282 renal insufficiency and, 157 respiratory effects of, 225, 226, 227


Metoclopramide drug–drug interactions and, 135, 359, 360 gastroparesis and, 109 psychiatric adverse effects of, 131, 356, 357 Metolazone, 163 Metoprolol, 35 Metronidazole, 32, 375 Mexiletine, 30, 202, 521, 523 Mianserin, 240 Miconazole, 32, 384 Midazolam anxiety before surgery and, 449, 451 delirium in hospitalized patients and, 442 drug–drug interactions and, 35, 170, 383, 456 nonoral preparations of, 82, 87, 89 psychiatric adverse effects of, 453 systemic clearance of, 19 Migraine, 508 Milnacipran, 509, 516–517 Milrinone, 453, 457 Mineralocorticoids, 325 Mirtazapine anxiety in preoperative patients and, 450 cancer patients and, 241 cardiac effects of, 191, 204 depression and nausea in cancer patients, 111 drug–drug interactions and, 26, 31, 133, 204, 292 gastrointestinal adverse effects of, 124 gastroparesis and, 109 hepatic insufficiency and, 118 hyperemesis gravidarum and, 110 nonoral preparations of, 83, 90, 91

organ transplantation and, 477–478 pain management and, 512, 517 renal insufficiency and, 154 respiratory disorders and, 220 Mitoxantrone, 252, 290 Mixed alpha- and beta-agonists, 216, 217, 218 Moclobemide cardiac effects of, 204 drug–drug interactions and, 136, 172, 204, 255, 294, 360 pharmacokinetics of, 31 psoriasis and, 414 Modafinil cancer patients and, 242, 243, 244, 254 drug–drug interactions and cardiac medications, 202, 203 gastrointestinal drugs, 137 obstetrics/gynecology drugs, 360 oncology drugs, 254 organ transplantation drugs, 490 pharmacokinetics of, 37 renal and urological drugs, 174 gastrointestinal adverse effects of, 125 hepatic insufficiency and, 120 neuropsychiatric side effects of, 217, 219 organ transplantation and, 479–480 respiratory disorders and, 224 systemic clearance of, 19 Molindone, 390 Monitoring, of therapeutic drugs. See also Laboratory tests compliance and, 9 liver disease and, 116 of metabolic status in patients taking antipsychotics, 318 Monoamine oxidase (MAO), 54

Index

Monoamine oxidase inhibitors (MAOIs) cardiovascular reactions to, 51, 53–54, 187, 191, 205 discontinuation of prior to surgery, 448 drug–drug interactions and cardiac medications, 205 endocrine drugs, 325 neurological medications and, 292, 294 nondepolarizing neuromuscular blocking agents, 460 organ transplantation, 479 pain medications, 522 renal and urological drugs, 173 surgical and critical care drugs and, 456 hepatic insufficiency and, 118 hypoglycemic effects of, 307 neurological adverse effects of, 287, 294 organ transplantation and, 479 pain management and, 522 pharmacokinetic interactions and, 21 renal insufficiency and, 154 serotonin syndrome and, 46 Monoclonal antibodies, 249, 485, 486 Montelukast, 217, 219 Montgomery-Åsberg Depression Rating Scale, 240 Mood. See also Anger hormonal contraceptives and, 355 hormone replacement therapy and, 357 Mood stabilizers. See also Carbamazepine; Lithium breastfeeding and, 354

589

cancer risk and, 245–246 cardiac adverse effects of, 187, 196–197, 206 drug–drug interactions and, 137, 174, 206, 294, 325 endocrinological adverse effects of, 313 gastrointestinal adverse effects of, 124–125 hepatic insufficiency and, 120 neurological adverse effects of, 287, 294 nonoral preparations of, 84, 92–93 organ transplantation and, 481–483 pregnancy and, 344, 347, 350–352 renal disease and, 160 renal and urological adverse effects of, 165, 174 respiratory disorders and, 224 self-induced dermatoses and, 412–413 Morphine drug–drug interactions and, 36, 202, 379, 523 neuropathic pain and, 506 pain management and, 514, 515 phantom limb pain and, 508 serotonin syndrome and, 46 stress in surgical patients and, 452 systemic clearance of, 19 Mortality. See also Death; Sudden death; Suicide and suicidal ideation antipsychotics in elderly patients with dementia-related psychosis and, 47–48 dementia-related psychosis and, 42 drug hypersensitivity syndrome and, 418


Moxifloxacin, 375 Mucosal dysesthesias, 409, 412 Mucosal sensory syndromes, 407 Multiple sclerosis, 278–280 Muromonab-CD3 (OKT3), 485, 486 Muscle relaxants, and drug–drug interactions, 36 Musculoskeletal pain, 509–510 Mycobacterium tuberculosis, 374 Myocardial infarction, and plasma levels of alpha-1 acid glycoprotein, 13 Myocardial Infarction and Depression—Intervention Trial (MIND-IT), 191 Myocarditis, 51, 54–55, 195 Myoglobinuria, 70, 71 Mycophenolate, 434, 485 Nabilone, 131, 135 Nafarelin, 356 Nafcillin, 32 Naloxone, 538 Naltrexone, 199, 483 alcohol dependence and, 199, 483, 545 black box warning on hepatic disease and, 545 drug–drug interactions and, 551 hepatic disease and, 483 neuropsychiatric adverse effects of, 548 opioid withdrawal and, 546 Naproxen, 36, 523 Naratriptan, 294, 523 Natalizumab, 290 Nateglinide, 325 National Survey on Drug Use and Health, 537

Nausea and vomiting adverse effects of psychiatric drugs and, 123, 125 causes and treatment of, 109–111 chemotherapy and, 260 Nefazodone drug–drug interactions and cardiac medications, 204 endocrine drugs, 325 gastrointestinal medications, 136 oncology drugs, 255 organ transplantation drugs, 490 pharmacokinetics of, 31 renal and urological drugs, 172 gastrointestinal adverse effects of, 124 hepatic insufficiency and, 118 HIV/AIDS patients and, 386 liver injury and, 127 organ transplantation and, 478, 488 renal insufficiency and, 154 Nelfinavir, 34, 382 Nephrectomy, 475 Nephritic syndrome, and plasma levels of alpha-1 acid glycoprotein, 13 Nephritis, and plasma levels of albumin, 13 Nephrogenic diabetes insipidus (NDI), 59, 60, 62, 316 Nephrotic syndrome, and plasma levels of albumin, 13 Nephrotoxicity, and immunosuppressant drugs, 490 Nesiritide, 453, 457 Neural tube defects, and carbamazepine, 351 Neurocysticercosis, 393

Index

Neuroleptic malignant syndrome (NMS) central nervous system drug reactions and, 40, 41, 44, 45 dysphagia and, 105 Neuroleptic Malignant Syndrome Information Service, 44 Neuroleptic Sensitivity Syndrome, 41, 44–45 Neuromuscular blockers, 453, 455 Neuropathic pain, 505–508 Neurosyphilis, 373 Neurotic excoriations, 406 Neurotoxicity, and lithium–neuroleptic encephalopathy, 45–46 Neutropenia, 64–66 Nevirapine, 34, 376, 380 Nicardipine, 35 Nicotine dependence, 546–547. See also Smoking cessation Nicotine replacement therapy (NRT), 484, 546 Nifedipine drug–drug interactions and, 35, 203 fluvoxamine and, 21 hypertensive crisis and, 54 Nilotinib, 33, 252, 256 Nilutamide, 253, 256 Nimodipine, 35 Nisoldipine, 35 Nitrazepam, 19 Nitrogen mustards, 248, 249 Nitroglycerin, 453, 457 Nitroprusside, 453, 457 Nitrous oxide, 453–454, 455, 458 Nizatidine, 131 Nociceptive pain, 509–510 Noncardiac chest pain, and esophageal disorders, 107 Nonclassic alkylating agents, 248, 249

591

Nondepolarizing neuromuscular blocking agents, 455, 458–459 Non-nucleoside reverse transcription inhibitors, 376 Nonsteroidal anti-inflammatory drugs (NSAIDs) complex regional pain syndrome and, 507 drug–drug interactions and, 23, 36, 436, 522, 523 migraine and, 508 pain management and, 508, 509, 510, 522, 523 rheumatological disorders and, 434, 436 Norepinephrine, 453, 456 Norfloxacin, 32, 379 Nortriptyline breastfeeding and, 353 cardiac effects of, 189, 192 diabetic patients and, 307–308 drug–drug interactions and, 26, 31, 383, 479 organ transplantation and, 479 pain management and, 512 Parkinson’s disease and, 281 poststroke depression and, 276 renal failure and, 159 systemic clearance of, 19 NPO (nothing per oral) orders, 80 Nucleoside reverse transcription inhibitors, 376 Obsessive-compulsive disorder, 372, 407 Obstetrics/gynecology. See Pregnancy; Menopause; Reproductive disorders Obstructive sleep apnea (OSA), 214, 215, 219, 223


Octreotide, 321, 324, 327 Ofloxacin, 32, 375 Olanzapine cardiac effects of, 196 corticosteroids and, 323 delirium in hospitalized patients and, 442, 443–444, 445 drug–drug interactions and antibiotics, 379, 382 cardiac drugs, 202 gastrointestinal medications, 133 neurological agents, 292 oncology drugs, 253 pain medications, 523 pharmacokinetics of, 34 gastric bypass surgery and, 113 hepatic insufficiency and, 119 HIV/AIDS patients and, 390 hyperprolactinemia and, 319 mortality associated with antipsychotics in elderly patients with dementia-related psychosis, 47 nonoral preparations of, 83 pain management and, 513 renal insufficiency and, 155 rhabdomyolysis and, 70 systemic clearance of, 19 Omeprazole, 37, 131, 133 Oncology. See Cancer Ondansetron, and drug–drug interactions, 31, 134, 136, 137 Onychophagia, 406 Onychotillomania, 406–407 Opiates central nervous system reactions and, 42 drug–drug interactions and, 26, 36, 202, 254

renal drug reactions and, 60, 61 Opioid Risk Tool (ORT), 511 Opioids drug–drug interactions and, 135, 326, 327, 522, 523, 551 drugs for withdrawal from, 545–546 pain management and, 504–505, 509, 510–511, 513, 514–515, 520, 522, 523 respiratory disorders and, 225 treatment of overdose, 538 Oral contraceptives, 355–356, 358, 360, 415 Oral disintegrating tablets (ODTs), 92 Oral hypoglycemics, 37, 320–321, 325, 326 Organ transplantation drug–drug interactions and, 487–491 neuropsychiatric side effects of immunosuppressants for, 484–487 posttransplant pharmacological considerations and, 470–475 psychotropic medications and, 475–484 Oropharyngeal disorders, 104–106 Orthostatic hypotension. See also Hypotension antipsychotics and, 193 mirtazapine and, 191 Osmotic demyelination, and hyponatremia, 63 Osmotic diuretics, 168, 203 Osteoarthritis, 432–433, 510 Osteoporosis, 319, 320, 482 Ovariectomy, 357 Oxazepam drug–drug interactions and, 35, 135, 410

Index

hepatic insufficiency and, 119 organ transplantation and, 480 phase II metabolism of, 16 systemic clearance of, 19 Oxcarbazepine anemia and, 66 drug–drug interactions and cardiac medications, 206 gastrointestinal medications, 137 obstetric/gynecology drugs, 360 oncology drugs, 254 organ transplantation drugs, 490 renal and urological drugs, 168, 174 gastrointestinal adverse effects of, 125 hepatic insufficiency and, 120 organ transplantation and, 482 pain management and, 512, 519 renal insufficiency and, 156 renal and urological adverse effects of, 165 systemic clearance of, 19 trigeminal neuralgia and, 506 Oxybutynin, 163, 169, 171, 172 Oxycodone, 36, 513, 514 Oxygen therapy, and respiratory disorders, 216 Oxymorphone, 513 Paclitazel, 33, 257 Pain Assessment and Documentation Tool, 511 Pain and pain management categories and treatment of, 504–510 drug–drug interactions and, 522–524 organ transplantation and, 474 pharmacological treatment of, 510–522

593

prevalence of, 501 psychiatric comorbidity and, 502–504 undertreatment of, 502, 503 Paliperidone drug–drug interactions and, 136, 173, 295, 360 hepatic insufficiency and, 119 nonoral preparations of, 83 renal insufficiency and, 155, 159 Palonosetron, and drug–drug interactions, 131, 134, 136, 137 Pancreatic cancer, and plasma levels of alpha-1 acid glycoprotein, 13 Pancreatitis gastrointestinal reactions to psychotropic drugs and, 56, 58, 128–129 plasma levels of albumin and, 13 Pancuronium, 455, 458 Pancytopenia, 66 Panic attacks, and dermatological conditions, 406 Panic disorder cardiovascular disorders and, 182 noncardiac chest pain and, 107 Pantoprazole, 37, 131 Paraneoplastic limbic encephalitis (PLE), 239 Paranoid delusions, and Parkinson’s disease, 281 Parasitic infections, 393 Parasitosis, delusional, 409 Parathyroidectomy, 315 Parkinsonian hyperthermia syndrome, 41 Parkinsonism, drug-induced, 105 Parkinson’s disease atypical antipsychotics and, 295


Parkinson’s disease (continued) behavioral problems and dopamine receptor stimulation, 289 cognitive deficits and, 280 depression and, 280–281 neuroleptic sensitivity syndrome and, 44–45 psychosis and, 281–282 Paroxetine burning mouth syndrome and, 104 cancer patients and, 240, 255 cardiac effects of, 189, 204 drug–drug interactions and antibiotics, 381 cardiac medications, 204 gastrointestinal medications, 136 obstetric/gynecology drugs, 360 oncology drugs, 253, 255 pharmacokinetics of, 31 renal and urological drugs, 172 gastric bypass surgery and, 113 gastrointestinal adverse effects of, 124 inflammatory bowel disease and, 112–113 irritable bowel syndrome and, 114 itraconazole and, 23 menopause and, 343 organ transplantation and, 477 pain management and, 512, 517 psoriasis and, 414 renal insufficiency and, 154, 159 respiratory disorders and, 220–221 rheumatological disorders and, 432 systemic clearance of, 19 Paroxysmal supraventricular tachycardia, 182 Pathological laughter and crying, 285–286

Pathways Study, 308 Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), 372 Pegvisomant, 321, 326 Penicillamine, 434 Penicillin, 372, 373, 375 Pentamidine, 377 Peptic ulcer disease, 108 Pericarditis, 51, 54–55 Perimenopause, 341, 342 Perphenazine, 34 P-glycoprotein (P-gp) efflux transport pump, 9, 10, 11, 23 Phantom limb pain, 507–508 Pharmacodynamics adverse effects and, 4, 7 anticancer drugs and, 259–260 concentration–response relationship in, 4, 6, 7 definition of, 4 drug–drug interactions and, 24–25, 360, 522 drug–receptor interactions and, 7 overview of issues in, 4 pain medications and, 522 relationship between pharmacokinetics and, 5 renal disease and, 153 urological agents and, 166–167 Pharmacokinetics absorption and, 9, 10, 11 bioavailability and, 7, 9, 11, 115, 257 cancer therapy and, 251, 256–259 cardiovascular disorders and, 184–186 definition of, 4

Index

drug distribution and, 11–14 drug–drug interactions and, 20–23, 25, 26, 30–38, 358, 360, 394 drug elimination and, 14–20 liver disease and, 115–116 posttransplant organ functioning and, 470–475 relationship between pharmacodynamics and, 5 renal disease and, 152–153 renal and urological agents and, 167, 171 respiratory disorders and, 219–220 Phase I and Phase II metabolism, 15, 16, 17–18, 21, 186 Phenelzine, 31, 113, 294 Phenobarbital, and drug–drug interactions, 35, 229, 292, 294, 325 Phenothiazines beta-blockers and, 201 cardiac effects of, 194 colonic toxicity of, 130 hematological reactions to, 64 respiratory effects of, 226, 227 Phentolamine, 54 Phenylbutazone, 36 Phenylephrine, 217 Phenylpropanolamine, 217 Phenytoin cardiac effects and, 206 drug–drug interactions and antibiotics, 380, 381, 383, 384 cardiac medications, 202, 203, 206 endocrine drugs, 325 gastrointestinal medications, 133, 137 neurological drugs, 292, 294

595

obstetrics/gynecology drugs, 359, 360 oncology medications and, 252, 253, 254 organ transplantation drugs, 490 pharmacokinetics of, 30 renal and urological drugs, 174 organ transplantation and, 490 pain management and, 518 respiratory effects of, 226 systemic clearance of, 19 therapeutic drug monitoring and, 14 Pheochromocytoma, 306, 311 Phosphate binders, 169, 171 Phosphodiesterase type 5 (PDE5) inhibitors cardiovascular disorders, 199 drug–drug interactions and, 169, 171, 172, 173, 187, 457 Photosensitivity reactions, and dermatological conditions, 416 Physostigmine, 447 Pimozide delusional parasitosis and, 409 drug–drug interactions and antibiotics, 379, 381 dermatological medications, 410, 423 gastrointestinal medications, 135, 136 neurological drugs, 292 obstetrics/gynecology drugs, 360 oncology drugs, 252, 253 organ transplantation drugs, 489 pharmacokinetics of, 34 renal and urological drugs, 170, 173 renal drug reactions to, 60, 173 Pindolol, 35


Pioglitazone, 37, 325 Pipotiazine, 84 Pirbuterol, 217 Platelet abnormalities, and drug reactions, 66 Polycystic ovarian syndrome, 340, 355 Polypharmacy, and drug–drug interactions, 20, 21, 25 Polyserositis, 55 Porphyria, 420 Posaconazole, 32 Posterior reversible leukoencephalopathy syndrome, 486 Postherpetic neuralgia, 505 Postpartum thyroiditis, 340 Poststroke depression, 275–276 Posttraumatic stress disorder chronic pain and, 504 critical care patients and, 451–452 dermatological disorders and, 408 renal disease and, 150 Pramipexole, 157, 290, 293, 295 Pravastatin, 31 Prazepam, 82 Prednisolone, 37 Prednisone, 37, 485 Pregabalin anxiety in preoperative patients and, 450 fibromyalgia and, 509 pain management and, 512, 518–519 renal and biliary excretion of, 16 renal insufficiency and, 156, 158 Pregnancy depression and, 341–342 management of psychiatric disorders during, 343–345, 348–352

nausea and vomiting, 110 plasma levels of albumin and, 13 psychiatric issues related to, 340–341 teratogenicity of psychiatric medications, 346–347 Premenstrual dysphoric disorder (PMDD), 340, 342 Prevalence of anxiety in cancer patients, 242 of anxiety in diabetic patients, 308–309 of chronic pain, 501 of cutaneous drug reactions, 415 of delirium in hospitalized patients, 440 of depression in epilepsy, 284 of depression in Parkinson’s disease, 280 of depression in renal disease patients, 150 of lithium-induced hyperthyroidism and hypothyroidism, 314, 315 of neuropsychiatric disorders in patients with rheumatological disorders, 431 of poststroke depression, 275 of preexisting psychiatric disorders in cancer patients, 238 of psychiatric disorders in HIVinfected patients, 374 of psychiatric and psychosocial comorbidity in dermatological conditions, 405, 408 of psychiatric symptoms of corticosteroids, 322 of psychiatric symptoms in diabetes patients, 306–307 of psychosis in HIV/AIDS patients, 389

Index

Prevention of delirium in hospitalized patients, 441–443 of PTSD in hospitalized surgical trauma victims, 452 of substance use disorders, 537–538 Primary psychogenic polydipsia, 62 Primidone, 294 Probenecid, 36 Procainamide, 202 Procarbazine chemotherapeutic agents and, 257 drug–drug interactions and, 249, 254, 255, 259, 260 pharmacokinetics of, 33 Prochlorperazine, 86, 131, 134 Procyclidine, 26 Prodrugs, 15, 259, 260 Progesterone, and drug–drug interactions, 37 Progressive renal insufficiency, 59 Promethazine, 131, 134 Propafenone, 30, 202 Propofol, 442, 455, 543, 548 Propoxyphene, 523 Propranolol drug–drug interactions and, 35, 456 hyperthyroidism and, 310 psychiatric adverse effects of, 453 Propylthiouracil, 321 Prostate cancer, 324 Protease inhibitors, 376, 381, 395 Protein binding, and drug toxicity, 12, 14 Proton pump inhibitors, 37, 131 Protriptyline, 19, 26, 220–221 Pruritus, 407, 415 Psoriasis, 408, 413–414, 419

597

Psychiatric disorders and psychiatric symptoms. See also Adverse effects; Anxiety and anxiety disorders; Bipolar disorder; Comorbidity; Depression; Differential diagnosis; Mania; Obsessive-compulsive disorder; Panic disorder; Posttraumatic stress disorder; Psychosis; Schizophrenia cancer patients and, 237, 239–244 diabetes mellitus and, 306–309 endocrine and metabolic disorders, 305, 306 HIV/AIDS patients and, 385–391 interferon-alpha and preexisting, 123 obstetric and gynecological disorders and, 341–342 renal disease and, 150–152 respiratory disorders and, 214 Psychodermatological disorders, 405–406 Psychogenic polydipsia (PPD), 151–152, 164 Psychomotor retardation, and organ transplantation, 476 Psychopharmacology. See Administration; Adverse effects; Bioavailability; Dose and dosages; Drug–drug interactions; Drug reactions; Medical conditions; Pharmacodynamics; Pharmacokinetics Psychosis. See also Schizophrenia Alzheimer’s disease and, 273–274 corticosteroids and, 322, 323 drug–drug interactions and, 292, 293 epilepsy and, 285


Psychosis (continued) HIV/AIDS patients and, 389–390 Huntington’s disease and, 283 hyperthyroidism and, 310 hypothyroidism and, 309 multiple sclerosis and, 279 Parkinson’s disease and, 281–282 renal disease and, 150–151 traumatic brain injury and, 277–278 Psychostimulants breastfeeding and, 354 cancer patients and, 241–242 cardiac effects of, 197–198 drug–drug interactions and, 26, 37, 174, 254, 295, 479 gastrointestinal adverse effects of, 125 hepatic insufficiency and, 121 HIV/AIDS patients and, 386 interferon-alpha and, 123 nonoral preparations of, 85, 94 organ transplantation and, 479 pregnancy and, 347, 352 renal insufficiency and, 157 respiratory disorders and, 224 Psychotherapy, combined with medication for chronic daily headache, 508 for HIV/AIDS patients, 386 Psychotropic-induced metabolic syndrome, 316–317 Pulmonary disease, and metabolism, 18 Pulmonary embolus, 215 Pyrimidine analogs, 249 QTc prolongation anticancer drugs and, 259–260 antipsychotics and, 50, 52, 53, 194, 446

dermatological medication interactions and, 411 immunosuppressant drug interactions and, 489 methadone and, 545 neurological drug interactions and, 294, 295 obstetrics/gynecology drug interactions and, 359 oncology drug interactions and, 252, 253 pain medication interactions and, 523 pimozide and, 409 respiratory drug interactions and, 228 substance abuse drugs and, 551 Quetiapine cardiac effects of, 193 delirium in hospitalized patients and, 444 drug–drug interactions and gastrointestinal medications, 135 neurological agents, 295 obstetric/gynecology drugs, 360 oncology drugs, 252, 254 organ transplantation drugs, 489 pharmacokinetics of, 34 renal and urological drugs, 170, 173 gastric bypass surgery and, 113 hematological reactions and, 66 hepatic insufficiency and, 119 hyperprolactinemia and, 319 pain management and, 513, 520–521 Parkinson’s disease and, 281–282 renal insufficiency and, 155 systemic clearance of, 19

Index

Quinidine, 11, 30, 136, 202 Quinolones, 375 Radiotherapy, 247 Raltegravir, 34 Ramelteon, 119, 155 Ramosetron, 134, 136 Randomized controlled trials (RCTs), 240 Ranitidine, 36, 131 Ranolazine, 30 Rasagiline, 33, 54, 292 Recombinant human growth hormone, 321, 327 Rectal administration of antidepressants, 90 of antipsychotics, 92 of anxiolytics and sedativehypnotics, 88 of mood stabilizers, 93 properties of, 81, 86 Rejection, of transplanted organ, 471–472, 473 Renal disease. See also Kidneys; Renal insufficiency adverse effects of psychotropic drugs and, 164–166 antidepressants and, 153, 157, 159 antipsychotics and, 159 anxiolytics and sedative-hypnotics, 159–160

599


Respiratory disorders (continued) psychiatric symptoms associated with, 214 psychotropic medications used in, 220–225 Restless legs syndrome (RLS), 151, 345 Retinoic acid compounds, 249, 250, 420–421 Rhabdomyolysis, 68, 70–71 Rheumatoid arthritis, 13, 432 Rheumatological disorders adverse effects of psychotropic medications on, 434–435 drug–drug interactions and, 435, 436 prevalence of neuropsychiatric disorders in patients with, 431 psychiatric side effects of medications for, 433, 434 treatment of psychiatric disorders in patients with, 432–433 Rifabutin, 32, 378 Rifampin, 21–22, 32, 375, 378 Risk factors for cancer in patients with schizophrenia, 244 for cardiac effects of antipsychotics, 194, 195, 196 for central nervous system drug reactions, 41–43 for diabetic ketoacidosis in patients receiving antipsychotics, 69 for drug-induced hyperprolactinemia, 319 for lithium-induced hypothyroidism, 314 for neuroleptic malignant syndrome, 40, 41 for renal drug reactions, 60–61

Risperidone anemia and, 66 cancer risk and, 245 delirium in hospitalized patients and, 443, 445 drug–drug interactions and, 133, 136, 173, 202, 253, 360 gastric bypass surgery and, 113 hepatic insufficiency and, 119 HIV/AIDS patients and, 389, 390 hyperprolactinemia and, 319 mortality associated with antipsychotics in elderly patients with dementia-related psychosis and, 47 nonoral preparations of, 83 pain management and, 513 pharmacokinetics of, 34 renal insufficiency and, 155 smoking and, 20 systemic clearance of, 19 urinary effects of, 166 Ritonavir, 34, 376, 382, 395 Rituximab, 252, 485, 486 Rivastigmine adverse psychiatric effects of, 290 drug–drug interactions and, 26, 292 hepatic insufficiency and, 120 nonoral preparations of, 85, 86, 94 renal disease and, 156, 160 Rizatriptan, 19, 33, 523 Ropinirole, 19, 290, 293, 295 Rosiglitazone, 325 Roux-en-Y procedures, 111, 112 Roxithromycin, 32 St. John’s wort dermatological disorders and, 415, 421

Index

drug–drug interactions and, 173, 254, 360, 421, 488, 490 HIV/AIDS patients and, 387 oncology drugs and, 259 organ transplantation and, 488, 490 pharmacokinetics of, 38 respiratory medications and, 229 Salmeterol, 217 Saquinavir, 34, 376 Scalp dysesthesia, 412 Schizoaffective disorder, 307 Schizophrenia pregnancy and, 342 premenstrual dysphoric disorder and, 340 psychogenic polydipsia and, 151 rate of diabetes in patients with, 69, 307 risk factors for cancer and, 244 Screener and Opioid Assessment for Patients in Pain (SOAPP), 511 Seborrheic dermatitis, 419 Sedative-hypnotics. See also Benzodiazepines; Hypnotics breastfeeding and, 353 cardiovascular disorders and, 187– 188 drug–drug interactions and, 26, 34–35, 455, 456, 459 gastrointestinal adverse effects of, 124 hepatic insufficiency and, 119–120 nonoral preparations of, 87–89 pregnancy and, 344–345 renal disease and, 155, 159–160 respiratory disorders and, 221–222 Seizures. See also Epilepsy alcohol withdrawal syndrome and, 540

601

bupropion and, 478 central nervous system reactions to psychotropic medications and, 43, 48–49, 288 drug–drug interactions and, 294, 295 Selective serotonin reuptake inhibitors (SSRIs) Alzheimer’s disease and, 272–273 cancer patients and, 240–241 cardiac adverse effects of, 187, 189, 200–201, 205 coadministration with antipsychotics and neuroleptic malignant syndrome, 40 discontinuation of prior to surgery, 448 drug–drug interactions and antibiotics, 380 cardiac medications, 205 neurological medications, 292, 294 obstetrics/gynecology drugs, 359 oncology medications, 254 pain medications, 523 pharmacokinetics of, 26 endocrinological adverse effects of, 313 epilepsy and, 284, 285 frontotemporal dementia and, 275 gastrointestinal adverse effects of, 124, 126 gastroparesis and, 109 hematological reactions and, 66 hepatic insufficiency and, 118 HIV/AIDS patients and, 385, 387 Huntington’s disease and, 282–283 hypoglycemic effects of, 307 interferon-alpha and, 122–123


Selective serotonin reuptake inhibitors (SSRIs) (continued) irritable bowel syndrome and, 114 neurological adverse effects of, 287, 294 organ transplantation and, 476–477 pain management and, 512, 517 Parkinson’s disease and, 281 pathological laughter and crying, 285 pregnancy and, 346, 348, 349 premenstrual dysphoric disorder and, 342 renal insufficiency and, 154 renal and urological adverse effects of, 165 rheumatological disorders and, 433 seizures and, 49 serotonin syndrome and, 46, 254, 292, 395, 523 sexual side effects of, 166, 355 syndrome of inappropriate antidiuretic hormone secretion and, 63 Selegiline adverse psychiatric effects of, 290 drug–drug interactions and, 33, 292, 479 hepatic insufficiency and, 118 hypertensive crisis and, 54 nonoral preparations of, 83, 86, 89 organ transplantation and, 479 renal insufficiency and, 154 sublingual form of, 81 Self-induced dermatoses, 412–413 Sepsis, and plasma levels of albumin, 13 Serotonin–norepinephrine reuptake inhibitors (SNRIs) cardiac adverse effects of, 187, 205

coadministration with antipsychotics and neuroleptic malignant syndrome, 40 drug–drug interactions and antibiotics, 380 cardiac medications, 205, 206 neurological agents, 292, 294 obstetric/gynecology drugs, 359 oncology drugs, 254 pain medications, 523 endocrinological adverse effects of, 313 gastrointestinal adverse effects of, 124 neurological adverse effects of, 287, 294 organ transplantation and, 478 pain management and, 512, 516–517 pregnancy and, 346 premenstrual dysphoric disorder and, 342 renal insufficiency and, 154 renal and urological adverse effects of, 165, 166 rheumatological disorders and, 433 serotonin syndrome and, 254, 292, 395 sexual dysfunction and, 355 Serotonin syndrome diagnostic criteria for, 47 drug–drug interactions and, 254, 292, 380, 523 dysphagia and, 105 linezolid coadministered with SSRIs and SNRIs, 395 psychotropic drugs implicated in, 42, 46 triptans in combination with serotonergic antidepressants and, 293, 296

Index

Sertraline anemia and, 66 burning mouth syndrome and, 104 cancer patients and, 241 cardiac effects of, 190, 192 diabetic patients and, 308 drug–drug interactions and, 26, 31, 325, 381, 382, 477 gastric bypass surgery and, 113 multiple sclerosis and, 278–279 organ transplantation and, 477 pregnancy and, 349 rheumatological disorders and, 432 systemic clearance of, 19 Sertraline Antidepressant Heart Attack Randomized Trial (SADHART), 189–190 Sevoflurane, 453, 455 Sexual disinhibition, and central nervous system disorders, 286 Sexual dysfunction, as side effect of psychotropic drugs, 166, 319, 326, 355 Shingles, and neuropathic pain, 505 Sickle cell anemia, 509 Side effects. See Adverse effects Sildenafil cardiovascular side effects of, 171, 395 drug–drug interactions and, 169, 172, 173 drug-induced sexual dysfunction and, 166, 355 Simvastatin, 31, 203 Sinus node dysfunction, and heart transplant, 472 Sirolimus, 36, 485, 486, 488

603

Sleep disorders. See also Insomnia; Obstructive sleep apnea dermatological disorders and, 413 HIV/AIDS patients and, 391 pain and sleep deprivation, 504 postoperative delirium in elderly patients and, 442–443 renal disease and, 151 respiratory disorders and, 215 Small-for-size syndrome (SFSS), and liver transplants, 474 Smoking cessation. See also Nicotine dependence; Nicotine replacement therapy bupropion and, 193, 478 drug–drug interactions and, 38, 227 pharmacodynamics and pharmacokinetics, 219–220 risperidone and, 20 varenicline and, 198–199 Solifenacin, 163, 169, 172 Somatic pain, 509 Somatization disorder, 502 Somatostatin, 321, 324 Sorafenib, 33, 255 Spinal cord injury, and neuropathic pain, 505–506 Spironolactone, 168 Statins, 201, 204 Status epilepticus, and benzodiazepines, 87 Steroids. See also Corticosteroids drug–drug interactions and, 37 HIV/AIDS patients and, 387 posttransplant organ rejection and, 471 psychiatric adverse effects of, 321 Stevens-Johnson syndrome (SJS), 417


Stimulants. See also Psychostimulants cardiac adverse effects of, 187 drug–drug interactions and, 380 seizures and, 288 Stress. See also Posttraumatic stress disorder dermatological disease and, 407 surgical and critical care patients and, 451–452 Stroke neuropsychiatric disturbances in 275–276 plasma levels of alpha-1 acid glycoprotein and, 13 Sublingual administration of antidepressants, 90–91 of antipsychotics, 92 of anxiolytics and sedativehypnotics, 88–89 properties of, 81 Substance use disorders. See also Alcohol and alcohol use disorders chronic pain and, 502–503, 507 drug–drug interactions and, 547, 550–551 drug intoxications and, 538–539 incidence of, 537–538 medications for treatment of, 539–547 organ transplantation and medications for treatment of, 483–484 psychiatric adverse effects of drugs used in, 547, 548–549 Substrate drugs, and drug–drug interactions, 22 Succinylcholine, 453, 454, 455, 459 Sucralfate, 133

Sudden death. See also Mortality antipsychotics and, 49, 50, 52, 194–195, 196 pimozide and, 409 Suicide and suicidal ideation corticosteroids and, 322 dermatological disorders and, 407, 408 interferon-alpha therapy and, 122 multiple sclerosis and rate of, 278 pain comorbid with depression and risk of, 503 substance use disorders and, 538 Sulfamethoxazole, 375, 384 Sulfaphenazole, 32 Sulfasalazine, 131, 434, 436 Sulfinpyrazone, 36 Sulfonamides, 32, 375 Sulfonylureas, 321 Sumatriptan, 19, 33, 523 Sunitinib, 33 Supportive therapy, for HIV/AIDS patients, 386 Surgery and critical care acute and posttraumatic stress, 451–452 alcohol use disorders and, 539 delirium and, 440–447 difficulty of psychopharmacological treatment and, 439 drug–drug interactions and, 454–460 menopause and, 357 neuropsychiatric effects of drugs for, 453–454 plasma levels of albumin and alpha-1 acid glycoprotein and, 13 preoperative anxiety and, 449–451 psychotropic drugs in perioperative period and, 447–449

Index

Suxamethonium, 455, 459 Sweating, anticholinergic-induced inhibition of, 67 Swedish National Birth Register, 349 Sympathomimetic agents drug–drug interactions and, 254, 380, 455, 456, 459–460 psychiatric adverse effects of, 453, 454 Symptom Checklist–90, 191, 240 Syndrome of inappropriate antidiuretic hormone secretion (SIDH), 60, 62–64, 164, 205, 206 Syphilis, 373 Systemic lupus erythematosus, and plasma levels of alpha-1 acid glycoprotein, 13 Systemic viral infections, 392 Tacrine, 36 Tacrolimus drug–drug interactions and, 436, 489 metabolic systems and, 488 neuropsychiatric adverse effects of, 434, 485–486 pharmacokinetics of, 36 Tactile hallucinations, 406 Tadalafil, 169, 172, 173 Taenia solium, 393 Talinolol, 35 Tamoxifen cognitive effects of, 250 drug–drug interactions and, 252, 254, 255, 258, 359, 360 pharmacokinetics of, 33, 258, 259 Tamsulosin, 162, 163, 171, 172, 173, 174

605

Tardive dyskinesia discontinuation of antipsychotics and, 286, 288 dysphagia and, 105–106 respiratory disorders and, 223 Tegafur, 33 Tegaserod, 133 Telithromycin, 379 Temazepam drug–drug interactions and, 35, 135 hepatic insufficiency and, 119 nonoral preparations of, 82 phase II metabolism of, 16 systemic clearance of, 19 Teniposide, 33, 258 Tennessee, and data on sudden deaths in antipsychotic drug users, 195 Teratogenicity, of psychiatric medications, 344–345, 346–347, 348–352 Terazosin, 173 Terbinafine, 411 Terbutaline, 356, 359, 423 Testosterone drug–drug interactions and, 37 HIV/AIDS patients and, 386–387 hypogonadism and replacement therapy, 312–313 menopause and, 358 psychiatric adverse effects of, 321, 323–324 Tetracyclines, 375 Theophylline drug–drug interactions and, 228, 229 neuropsychiatric adverse effects of, 217, 218 pharmacokinetics of, 35 Thiabendazole, 377


Thiamine hydrochloride, 541 Thiazide diuretics. See also Diuretics drug–drug interactions and, 168, 171, 203, 205, 206 pharmacokinetics and, 167, 186 psychiatric adverse effects of, 163 Thiazolidinediones, 321 Thioridazine cardiovascular reactions to, 52 drug–drug interactions and, 34, 295 HIV/AIDS patients and, 390 lithium toxicity and, 46 ThioTEPA, 254, 255 Thiothixene, 84 Thrombocytopenia, 65, 66 Thyroid disorders, 309–311. See also Hyperparathyroidism; Hyperthyroidism; Hypothyroidism Thyroid hormone, and drug–drug interactions, 325 Tiagabine, 30, 519 Ticlopidine, 30 Timolol, 35 Tipranavir, 34, 376, 383 Tocolytics, 357, 360 Tolbutamide, 37, 325 Tolcapone, 290, 294 Tolerance, and long-term opioid administration, 515 Tolterodine, 163, 169 Tolvaptan, 162, 172, 173, 174 Topical administration, of drugs, 86 Topiramate adverse psychiatric effects of, 289, 290, 291 alcohol dependence and, 199 drug–drug interactions and, 292 hepatic insufficiency and, 120

nonoral preparations of, 84, 93 organ transplantation and, 483 pain management and, 512, 519 pregnancy and, 351 renal insufficiency and, 156, 158 systemic clearance of, 19 Topotecan, 33 Torsade de pointes antipsychotics and, 50, 194, 446 drugs implicated in, 53 QTc prolongation as predictor of, 52 risk factors for, 195 Toxic epidermal necrolysis (TEN), 417, 418, 418 Toxicity. See also Hepatotoxicity; Nephrotoxicity; Neurotoxicity; Teratogenicity immunosuppressant drugs and, 489, 490 lithium in infants and, 354 liver injury and, 127 oncology medications and, 274 protein binding and, 12, 14 theophylline and, 218 Tramadol anticonvulsants and, 520 drug–drug interactions and, 252, 253, 489, 523 fibromyalgia and, 509 pharmacokinetics of, 36 Transaminases, and hepatotoxicity, 57 Transdermal patch amitriptyline and, 90 continuous drug delivery by, 86 haloperidol and, 92 psychostimulants and, 94 selegiline and, 89 testosterone replacement therapy and, 312

Index

Tranylcypromine, 31, 294 Trauma, and plasma levels of albumin, 13. See also Posttraumatic stress disorder Traumatic brain injury (TBI), 276–278 Trazodone cardiac adverse effects of, 187, 192, 205 drug–drug interactions and antibiotics, 381, 382 cardiac medications, 205 gastrointestinal medications, 133 neurological drugs, 292 pharmacokinetics of, 26, 31 hepatic insufficiency and, 118 nonoral preparations of, 83 organ transplantation and, 478 pain management and, 518 renal insufficiency and, 154 respiratory effects of, 226, 227 systemic clearance of, 19 Tretinoin, 249, 250, 252 Triamcinolone, 37 Triazolam drug–drug interactions and, 35, 383 hepatic insufficiency and, 119 nonoral preparations of, 82 systemic clearance of, 19 Trichlormethiazide, 163 Trichotillomania, 407, 412 Tricyclic antidepressants cardiac effects of, 52–53, 187, 189, 192, 205 colonic toxicity of, 130 diabetes patients and, 307, 308 discontinuation of prior to surgery, 448

607

drug–drug interactions and antibiotics and, 380 cardiac medications, 202, 205 endocrine drugs, 325 gastrointestinal medications, 133, 135, 136 inhalational anesthetics, 458 neurological medications and, 292, 293, 294 obstetric/gynecology drugs, 360 oncology medications and, 253, 254 pain medications and, 523 pharmacokinetics of, 26 renal and urological drugs, 168, 173 respiratory agents, 228 endocrinological adverse effects of, 313 gastrointestinal adverse effects of, 124 globus hystericus and, 106 hepatic insufficiency and, 118 irritable bowel syndrome and, 114 neurological adverse effects of, 287, 294 neuropathic pain and, 505 organ transplantation and, 479 pain management and, 512, 515–516 peptic ulcer disease and, 108 pheochromocytoma and, 311 pregnancy and, 346, 348–349 renal insufficiency and, 155, 157, 159 renal and urological adverse effects of, 165, 173 respiratory disorders and, 221, 226, 227


Tricyclic antidepressants (continued) rheumatological disorders and, 432, 433 seizures and, 48–49 serotonin syndrome and, 254 surgery and critical care, 458 Trifluoperazine, 34 Trigeminal neuralgia, 506 Trihexyphenidyl drug–drug interactions and, 26 gastrointestinal adverse effects of, 124 neurological adverse effects of, 287 renal and urological adverse effects of, 165 Trimethobenzamide, 131, 134 Trimethoprim, 375 Trimipramine, 26 Triptans central nervous system reactions to, 42 drug–drug interactions and, 293, 294 migraine and, 508 serotonin syndrome and, 293 Trofosfamide, 259 Troleandomycin, 32, 379 Tropisetron, 136, 137 Trospium, 163 Tuberculosis, 214, 374 Tubocurarine, 455 Tyramine, and MAOIs, 21, 38, 53 UGT2B7, 17 Ulcerative colitis, 112 U.S. National Library of Medicine, 344, 353 Upper gastrointestinal bleeding, 126 Uremia cognitive dysfunction and, 151 plasma levels of alpha-1 acid glycoprotein and, 13, 14

Uridine 5′-diphosphate glucuronosyltransferase (UGT) enzyme system, 11, 17, 21–22 Urine. See also Uremia; Urological disorders drug–drug interactions and changes in pH of, 23, 171 psychotropic drugs and retention of, 166 Urological disorders adverse effects of psychotropic drugs and, 164–166 drug–drug interactions and, 166–171, 172–174 psychiatric adverse effects of medications for, 161–162, 163 psychiatric symptoms of, 149 Urticaria, 408, 414, 416 Valacyclovir, 377 Valinomycin, 32 Valproate cancer risk and, 246 drug–drug interactions and, 30, 252, 255, 292, 522 gastrointestinal adverse effects of, 125 hematological reactions and, 66 hepatic insufficiency and, 120 HIV/AIDS patients and, 388 intravenous administration of, 81 lamotrigine and, 21–22 liver injury and, 127 neurological adverse effects of, 287, 290, 292 nonoral preparations of, 84, 93 pain management and, 512, 518, 522 polycystic ovarian syndrome and, 355

Index

pregnancy and, 350 renal insufficiency and, 156, 158 systemic clearance of, 19 Valproic acid breastfeeding and, 354 cardiac effects of, 196 drug–drug interactions and, 294 endocrinological adverse effects of, 313 gastrointestinal reactions and, 56, 57, 58 HIV/AIDS patients and, 388–389 intravenous administration of, 93 organ transplantation and, 482 pain management and, 518 pancreatitis and, 129 pregnancy and, 347, 350, 351 Vardenafil, 169, 171, 172, 173 Varenicline black box warning on preexisting psychiatric illness and, 547 neuropsychiatric adverse effects of, 549 nicotine dependence and, 198–199, 484, 546–547 Vascular dementia, 151, 275 Vasculitis, 417 Vasoconstriction, and psychostimulants, 295 Vasodilator hypotensive agents, 453, 454, 457, 460 Vasomotor symptoms, of menopause, 343 Vasopressin drug–drug interactions and, 325, 326 nephrogenic diabetes insipidus and, 62

609

Vasopressin antagonists, 162, 163, 170, 172 Venlafaxine cardiac effects of, 191 drug–drug interactions and, 26, 31, 133, 253, 294, 478 gastrointestinal adverse effects of, 124 hepatic insufficiency and, 118 menopause and, 343 organ transplantation and, 478 pain management and, 512, 516 renal insufficiency and, 154, 159 respiratory effects of, 226 systemic clearance of, 19 Ventricular arrhythmias, 49, 50, 52 Verapamil, 203, 351, 521 Veterans Affairs health care system, 69 Viloxazine, 83 Vinblastine, 33 Vinca alkaloids, 251 Vincristine, 33 Vinorelbine, 33 Viral encephalitis, 392 Viral infections herpes encephalitis (HSE) and, 392–393 HIV/AIDS and, 374, 377, 385–391 metabolic effects of hepatitis, 18 Visceral pain, 509 Visual hallucinations, and Parkinson’s disease, 281 Vitamin B supplements, 541 Vocal cord dysfunction (VCD), 214, 215 Volume of distribution, 11–12 Von Willebrand disease, 66 Vulvodynia, 412


Warfarin, 14, 30, 201, 204 Water deprivation test, for nephrogenic diabetes insipidus, 316 Weight gain, and antipsychotics, 223, 317 Wernicke-Korsakoff syndrome, 541 White blood cells, and hematological toxicity, 64 Withdrawal. See also Alcohol withdrawal syndrome; Discontinuation corticosteroids and, 323 opioids and, 545–546 Women’s Health Initiative (WHI), 358 World Health Organization, and Adverse Drug Reactions database, 245 Xerostomia, 104–105 Yasmin, 342 Yaz-24, 342 Young Mania Rating Scale, 389 Zafirlukast, 219, 228 Zaleplon drug–drug interactions and, 26 hepatic insufficiency and, 120 renal insufficiency and, 155 systemic clearance of, 19 Ziconotide, 521 Zidovudine, 34, 376 Ziprasidone carbamazepine and, 25 cardiovascular reactions to, 52, 194 drug–drug interactions and gastrointestinal medications, 135, 136

immunosuppressants, 489 neurological agents, 295 obstetrics/gynecology drugs, 360 oncology drugs, 252, 253 pharmacokinetics of, 34 renal and urological drugs, 170, 173 gastric bypass surgery and, 113 hepatic insufficiency and, 119 nonoral preparations of, 83 pain management and, 513 renal insufficiency and, 155 Zolmitriptan, 19, 33, 523 Zolpidem drug–drug interactions and, 26, 292, 379 gastrointestinal adverse effects of, 124 hepatic insufficiency and, 120 HIV/AIDS patients and, 391 menopause and, 343 nonoral preparations of, 82, 89 pregnancy and, 345 renal insufficiency and, 155 respiratory disorders and, 222 sublingual form of, 81 systemic clearance of, 19 Zonisamide, 519 Zopiclone drug–drug interactions and, 26, 202, 203 gastrointestinal adverse effects of, 124 hepatic insufficiency and, 120 HIV/AIDS patients and, 391 renal insufficiency and, 155 Zuclopenthixol, 84

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