Essentials of Medical Pharmacology Lafi 09-10

Essentials of Medical Pharmacology Majid A. K. Lafi BSc (Hons), MPhil, PhD Department of Pharmacology College of Medi...

Author: Dr. M. Lafi

289 downloads 2325 Views 4MB Size Report

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

DOWNLOAD PDF

Essentials of Medical

Pharmacology

Majid A. K. Lafi BSc (Hons), MPhil, PhD Department of Pharmacology College of Medicine University of Al-Anbar

ABOUT THE AUTHOR Majid A K Lafi was born in Fallujah, Iraq in 1956, married with five children. He commenced studying at Kettering Technical College, Kettering, England in 1975, and obtained his "A" Level General Certificate of Education (Oxford Board) in 1978; in the same year, started a BSc (Hons) in Pharmacology at the School of Pharmacy, Portsmouth Polytechnic (now University of Portsmouth), Portsmouth, England, he has been awarded the degree in June 1981. Later on he was awarded MPhil in Pharmacology (1984), PhD in Pharmacology (1986) from the same university. I was awarded "Final Diploma" in English from the Institute of Linguists, London, in 1986. Thereafter, in 1987: Lecturer in Pharmacology, Military Medical College, Baghdad; in 1989: Lecturer in Pharmacology, College of Medicine, University of AL-Anbar, Ramadi, Iraq, in 1994: promoted to Assistant Professor of Pharmacology. His research interests in peripheral neuropharmacology (cotransmission at nerve muscle junction), unusual antimicrobial resistance, and medical education (pharmacology curriculum development).

Dr. Majid A K. Lafi

I

PREFACE When starting my carrier teaching pharmacology in Iraq, 3rd year medical school students, I confronted a problem that during the lecture most of the students were over-occupied with writing up what I was saying and not trying to understand what I was trying to deliver to them as core knowledge in pharmacology. With time, I understood that these students were very much concerned with obtaining the lecture material written more than understanding the material itself. After having long talks with them I promised to give them type-written lecture notes prior to delivering the lecture. This appeared to work very well in reassuring them that they would not lose material for "revision" paving the way for winning their attention during the lecture with consistently excellent students' attendance. This gain prompted me to continue improving my lecture notes in pharmacology to suit the need of particularly medical students in Iraq. For several years, students and colleagues have urged me to put this work in a book, only now "after 20 years" I find it is the time to do so. Teaching pharmacology at the College of Medicine, University of AL-Anbar, has been pathophysiology oriented therefore very much attention has been paid to the mechanism(s) of drugs' action. Hence, a brief account on the pathophysiology of major disorders has been mostly included in this book. Over the years of teaching this subject, it is felt that students prefer stating clinical conditions (e.g. indications, adverse effects and contraindications) in a list form rather than in a continuous text. In addition, the inclusion of a summary in a table and/or a figure form at the end of each topic has been found to be useful to recognise the core knowledge should be learned. These strategies have been largely adopted throughout this book. A considerable number of the third year medical students show very poor competence in the medical vocabulary used in delivering the core material of medical pharmacology. This prompted me to make an inclusion of an appropriate glossary at the end of this book to be handy for the reader to refer to. Undoubtedly, there are many occasions of weakness in this book, e.g. the section on antiparasitic agents as it is being very poor, particularly when taking into account the importance of parasitic infections in Iraq. It is hoped that these drawbacks and others will be dealt with in the next issue. This issue is only an initial draft awaiting feedback from students and colleagues. I am very grateful for support and assistance from a number of colleagues and students.

Majid A. K. Lafi October, 2008

CONTENTS

ABOUT THE AUTHOR PREFACE CONTENTS GENERAL PRINCIPLES Pharmacokinetics ……………………………………………………………. Pharmacodynamics ………………………………………………………… AUTONOMIC PHARMACOLOGY Cholinergic Transmission ………………………………………………….. Adrenergic Transmission …………………………………………………. Ocular Pharmacology ……………………………………………………. Drugs Used in Abnormal Micturition ………………………………………. CARDIOVASCULAR PHARMACOLOGY Antihypertensive Drugs ……………………………………………………… Antianginal Drugs …………………………………………………………... Drugs for Congestive Heart Failure …………………………………………. Antiarrhythmic Drugs ………………………………………………………. Diuretics …………………………………………………………………….. Antithrombotic Drugs ……………………………………………………….. Antihyperlipidaemic Drugs …………………………………………………. Drugs for Anaemias ANTIMICROBIAL DRUGS (GENERAL PRINCIPLES) Beta-lactam Antimicrobial Drugs …………………………………………… Sulphonamides, Trimethoprim, and Aminoglycosides ……………………… Tetracyclines, Macrolides, Metronidazole, Chloramphenicol, and others …... Antituberculosis Drugs ……………………………………………………….. Antimicrobial Drugs of Choice ……………………………………………….. Antifungal Drugs ……………………………………………………………… Antiviral Drugs ………………………………………………………………. Antiparasitic Drugs …………………………………………………………. CNS-PHARMACOLOGY (GENERAL PRINCIPLES) Antipsychotic Drugs …………………………………………………………. Drugs for Affective Disorders ……………………………………………….. Antianxiety Drugs …………………………………………………………… Sedative and Hypnotic Drugs ………………………………………………. Drugs for Parkinson s Disease ………………………………………………. Antiepileptic Drugs ………………………………………………………….. Opioids and Narcotic Analgesic Drugs ……………………………………... General Anaesthetic Drugs ………………………………………………….. Local Anaesthetic Drugs ……………………………………………………. Neuromuscular Blocking Drugs ……………………………………………… AUTACOIDS NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) DRUGS AND GASTROINTESTINAL TRACTS DRUGS AND THE RESPIRATORY SYSTEM ENDOCRINE PHARMACOLOGY Hypothalamic and Pituitary Hormones ………………………………………. Sex (Gonadal) Hormones and Inhibitors …………………………………...

III

I II III 1 1 18 24 25 25 33 35 37 46 49 54 61 65 73 77 79 88 96 101 106 110 114 117 121 124 131 135 142 146 153 156 164 170 176 178 182 190 203 212 218 223

Drugs Acting on Uterine Smooth Muscle …………………………………... Adrenocorticosteroids ……………………………………………………... Thyroid and Antithyroid Drugs …………………………………………… Agents that Affect Calcium Metabolism …………………………………… Insulin and Oral Hypoglycaemic Drugs ……………………………………. ANTICANCER DRUGS …………………………………………………… DRUG INTERACTIONS, ADVERSE DRUG REACTIONS AND ANTIDOTES GLOSSARY ……………………………………………………………… INDEX

IV

228 230 236 240 242 250 255 260 280

Essentials of Medical Pharmacology

Majid A. K. Lafi

GENERAL PRINCIPLES of the disease itself may vary from one patient to another, this difference in response is largely accounted for by variations in the metabolic handling of the drug.

Introduction This book is the result of a desire to record and update the material of lectures given upwards of twenty years to medical students. For medical students, the pharmacology course is the first confrontation with medicine and the response of patients to drugs. A drug in the widest sense is a substance used in prevention, cure and diagnosis of disease. The name pharmacon is Greek and means drug. The word drug comes from the French word drogue which means dry herb.

If the serum level of warfarin is measured in these patients a large difference may be found at the two extremes. Thus, some patients were under-treated while others were intoxicated. This phenomenon may be due to a number of factors (in addition to failure to take the prescribed dose of the drug, patient non-compliance). The rate of absorption of the drug, its distribution in various body compartments, tissue and plasma-protein binding, and the rate of metabolism and excretion of the drug all influence the steadystate level of the drug at the site where it is required. Study of these aspects of pharmacology is known as pharmacokinetics.

Pharmacology can be divided into two major parts: 1. Pharmacokinetics means what the body does to the drug . 2. Pharmacodynamics means what the drug does to the body .

Dosage Regimen Dosage regimen is the manner in which a drug is taken concerning dose, frequency, and route of administration that relate to drug level-time relationships in the body. Often, drug level in the body is reflected by plasma drug level that in turn influences the concentration of drug at the site(s) of action that relates to the magnitude of the effect(s) produced. Table 1.1. Basic pharmacological principles in empirical adult therapeutic regimens of some selected drugs. The information in this table is not intended for memorization by students rather as pharmacotherapeutic situations in which skills (critical thinking) are required in applying knowledge and understanding of basic pharmacological principles. The pharmacological principles, presented in this course of pharmacology in a manner coherently complementing each other, represent a core knowledge in which to ground skills in pharmacology as basis in therapeutics. Such knowledge and skills are expected to be learned in sequential increasing in complexity throughout the third year. Therefore, this table is expected to be referred to throughout the year.

In addition, the following topics are also covered: • Toxicology which deals with adverse effects, drug interaction, drug abuse, poisons, antidotes, industrial and environmental pollution, and therapeutic drug monitoring. • Pharmacogenetics which deals with inter-individual differences. • Pharmaceutics (drug delivery, formulation) • Pharmacognosy (plant medicine) • Prescription writing (emphasising on drug names and dosage regimen)

Pharmacokinetics If a fixed dose of a drug is given to a number of patients with a particular disease, e.g. 5 mg of warfarin daily dose in patients with deep venous thrombosis, most will show some therapeutic response as indicated by prothrombin time. A few, however, will not show obvious response, while the occasional patient may develop signs of drug intoxication (bleeding). Although the severity 1

General Principles

Ramadi, 6 October 2009

Table 1.1. Basic pharmacological principles in empirical adult therapeutic regimens of some selected drugs. Drug

Indication

Route

Warfarin t 37 hr Vd 5 L

Deep venous thrombosis

Oral

Theophylline

Asthma

Oral

Induction and maintenance of labour

Slow intravenous injection (over 20-30 min) Intravenous infusion

t 8 hr Vd 35 L

Oxytocin t

minutes Oral (control is too erratic)

Morphine t 2 hr Vd 230 L Ampicillin

Severe pain

Intramuscular Oral

Certain bacterial infections

Oral Intramuscular, intravenous, or infusion Oral

t 1.2 hr Vd 20 L Amoxicillin t 2 hr

Penicilin G t 0.5 hr

Infections due to susceptible microorganisms Infections due -lactamaseproducing amoxicillin resistant organisms

Endocarditis (prophylaxis in dental procedures) Gonorrhoea (Neisseria gonorrhoeae) Certain serious infections

Oral

Oral

Oral Intramuscular Intravenous, or infusion

Intramuscular

Phenobarbital t 4 days Vd 38 L Digoxin

Prophylaxis of recurrent rheumatic fever Syphilis (Treponema pallidum) Epilepsy

Intramuscular

Congestive heart failure

Oral

Intramuscular Oral

Dosage Regimen Individualize dosage according to PT or INR, initially 2-10 mg daily for 3 days, then; average maintenance dose: 2-5 mg at the same time each day Individualize dosage according to clinical responses and monitor serum theophylline levels. Short-acting formulation 500 mg initially, then 100-300 mg 3-4 times daily. Long-acting formulation 150-300 mg twice daily. 5-6 mg/kg (in patients not previously treated with xanthine) 0.2-4 milliunits/min infusion, gradually increased to 20 milliunits/min, if necessary, to produce 3 or 4 contractions within 10-min periods. Not used because of being rapidly destroyed by the proteolytic enzymes in GIT 10 mg when needed Not used because of being rapidly metabolised in the liver. 0.25-1 g every 6 hr 0.5 g every 4-6 hr

250

500 mg every 8 hr

250 500 mg (containing125mg of clavulanic acid, Augmentin ) every 8hr or 875 mg every12h Alternatively amoxicillin 3 g may be taken by mouth together with probenecid 1 g by mouth 4 h before the procedure Amoxicillin 3 g may be taken by mouth together with probenecid 1 g in single dose 300,000 8 million U daily 6 20 million U daily by continuous or intermittent infusion every 2 4h. Up to 60 million U daily have been given in certain serious infections. Procaine Penicillin daily in one or two doses Benzathine 2 Penicillins 1.2 2.4 million U in a single dose every 3 4 wk Benzathine 2 Penicillins 2.4 million U (1.2 million U in each buttock) in a single dose 60-180 mg at night

1.5-2 mg initially over 24 hr, then 0.25-0.5 mg once a day 2


t 39 hr Vd 440 L Amiodarone t 53 days Vd 4200

Captopril t 2.2 hr Vd 57 L Prazosin t 2.9 hr Vd 42 L Aspirin t 0.25 hr Vd 11 L (salicylic acid: t 3 hr to 13-30 hr)

Dopamine t 2 minutes

Cardiac arrhythmia (Atrial fibrillation) Ventricular arrhythmias (recurrent) Ventricular arrhythmias (existing) for not more than 48 hours because of cumulative effect Heart failure Hypertension Hypertension, Benign prostatic hyperplasia (BPH) Transient ischaemic attacks Transient ischaemic attacks Pain, fever Rheumatoid arthritis Osteoarthritis Acute rheumatic fever Renal (D1 -receptor) Cardiac ( 1-receptor) Vascular ( 1-receptor)

Omeprazole t 45 minutes

Majid A. K. Lafi

Oral Oral Intravenous

Oral Oral

6.25 mg initially then 6.25-150 mg daily 25 mg initially then 6.25-150 mg daily

Oral

1 mg 2 to 3 times daily initially, maintenance dose 6 15 mg daily

Oral (Prophylaxis) Oral

81 325 mg daily

Oral

650 mg usual single dose

Oral

2000-6000 mg 3 times daily

Oral Intravenous infusion Intravenous infusion Intravenous infusion

5000-8000 mg daily in divided doses

1300 mg 2 to 4 times daily

5 µg/kg/min >10 µg/kg/min Steady-state plasma concentration will be reached in 5 x t = 10 min 20 mg daily, 1 hr before meal (mandatory)

Oral

Insulin

Peptic ulcer Heartburn Active GI bleeding Prostate cancer Central precocious puberty Hypothalamic hypogonadotropic hypogonadism Long term regular use

Intravenous, or infusion

Glucagon

Acute or emergency situations: Diabetic ketoacidosis Hyperosmolar hyperglycemic nonketotic coma Perioperative period Severe infections Pregnancy Hypoglycaemic crisis

Nicotinic acid

Acute overdose of βblockers (heart failure) Pellagra

Goserelin t

l-l.5 mg initially over 24 hr, then 0.06250.5 mg once a day 0.8-1.2 g daily (2 to 4 weeks), then 0.2-0.4 g daily. 0.15g over 30 minutes & 1 g over the 1st day

Intravenous Subcutaneous

8 mg/hr for 72 hrs 3.6 mg every 28 days (i.e. given continuously)

Intravenous tubing (by GnRH pump) Subcutaneous

A portable battery-powered programmable pump allows pulsatile GnRH therapy every 90 minutes. Dosage individualized. Initially, 7 26 units may be given once daily. Suitable for stable biphasic insulin mixtures (e.g. short acting plus long acting) Dosage individualized. For ketoacidosis, regular insulin may be given by direct injection, intermittent infusion, or continuous infusion. One regimen involves an initial bolus injection of 10 20 units followed by a continuous low-dose infusion of 2 10 units/hr, based on hourly blood and urine glucose levels

Intramuscular Subcutaneous Intravenous (bolus) Oral

3

1 mg 5-10 mg 100-500 mg daily.

General Principles


(niacin)

Hyperlipidaemia

Oral

250 mg twice daily initially and increasing the dose monthly by 500 to 1000 mg per day to a maximum of 2 6 g daily. This regimen to reduce the intense cutaneous flush produced as an adverse effect. The latter can further be reducing by taking nicotinic acid on a full stomach (end of meal), taking aspirin before dosage, and time-release forms of nicotinic acid can reduce the severity of flushing.

Diclofenac

Pain Dysmenorrhoea

Oral

50 mg 3 times daily

Ankylosing spondylitis

Oral

Osteoarthritis

Oral

Rheumatoid arthritis

Oral

Acute renal colic

Oral

Diclofenac Immediate R (only 50mg) Diclofenac Delayed R (75mg) Extended R (100mg)

Nitroglycern t 1-3 min

Ureteral stone propulsion Relieve acute angina Prevent exercise-induced angina Long-term prophylaxis to decrease the frequency and severity of acute anginal episodes

IV, IM Oral Oral Sublingual Translingual spray

Transmucosal tablet Topical transdermal patch Hypertensive crisis Carbamazepine t 15 hr Vd 98 L

Epilepsy

Continuous Intravenous oral

Trigeminal neuralgia

oral

4

100 125 mg daily in 4-5 divided doses (e.g., 25 mg 4-5 times daily) 100 150 mg daily in divided doses (e.g., 50 mg 2 or 3 times daily, 75 mg twice or 100 mg once daily) 100 150 mg daily in divided doses (e.g., 50 mg 2 or 3 times daily, or 75 mg twice or 100 mg once daily) 50 mg 2 or 3 times daily for 5 days, then on need 75 mg once or twice daily 50 mg 2 or 3 times daily for 15 days Sustained-release tablets, 2.5 9 mg 2 or 4 times per day 0.15 0.6 mg on need for chest pain one or two metered doses (0.4 mg/dose) sprayed onto oral mucosa at onset of anginal pain, to a maximum of 3 doses in 15 min 1 mg every 3 5 hr while awake, placed between upper lip and gum or cheek and gum 5 mg applied once daily, do not rub. 5mcg/min 200 mg twice daily, increased gradually to 600 1200 mg daily if needed, in 3 or 4 divided doses 200 mg daily, increased gradually to 1200 mg if necessary


Majid A. K. Lafi

Pharmacokinetics Dosage Regimen Dose Frequency (Route of administration)

Drug Concentration at Site of Action

Plasma Drug Concentration

Pharmacodynamics

Css

Unacceptable Toxicity

Regimen C MTC Css

Regimen B

Therapeutic Window MEC

Regimen A

Css

Ineffective

Time Fig.1.1. A schematic representation of the approach to the design of dosage regimen. The pharmacokinetics and pharmacodynamics of the drugs are first defined. Then either the plasma drug concentration-time data or the effects produced are used as a feedback to modify the dosage regimen. When a drug is given at fixed time intervals (denoted by arrows), it accumulates within the body until a plateau is reached. With regimen A, the plasma drug concentration is too low therefore therapeutic failure (ineffective) is observed. With regimen B, therapeutic success is achieved although not initially. With regimen C, the therapeutic objective is more quickly achieved but the plasma drug concentration is ultimately too high.

5

General Principles


Peak 20

Nausea

Vomiting

CNS stimulation

Unacceptable Toxicity MTC Css

10

Insufficient

Trough 0

8

16 24

48 Time (hr)

bronchodilatatio n 72 96

Therapeutic Window MEC Ineffective

Fig.1.2. Different dosage regimens of theophylline showing the relationship between frequency of dosing and maximum and minimum plasma concentrations when a steady-state theophylline plasma concentration of about 10 µg/ml is desired. Regimen I- intravenous infusion of 25 mg/hr achieves smoothly rising line (dotted with black squares). Regimen II- 8-hourly administration (dark solid thin line) of doses of 200 mg. Regimen III- 24-hourly administration (dark solid thick line) of doses of 600 mg. In each of the 3 regimens, the mean steady-state plasma concentration (Css) is about 10 µg/ml. Note: in regimen III there is a large fluctuation between peak and trough and as estimation of plasma levels of drugs often not available, the former may be reflected clinically by the development of nausea, vomiting and central nervous system (CNS) stimulation as unacceptable toxicity; while trough may be reflected clinically by insufficient bronchodilatation (ineffective). Regimen IV- 12-hourly administration (dotted with black solid circles) of doses of 300 mg with oral slow release formulation to avoid the unacceptable toxicity and the insufficient bronchodilatation may be associated with regimen III. The therapeutic window lies between the minimum effective concentration (MEC) and the minimum toxic concentration (MTC). Therefore, adjustment of dosage regimen may be made depending on the clinical response. This is particularly true for drugs with low therapeutic index like theophylline.

6


Majid A. K. Lafi

Unacceptable Toxicity MTC

Css Therapeutic Window

Css MEC 0

3

6

18

12 Time (hr)

24

Fig.1.3. Different dosage regimens for a drug with large therapeutic index such as ampicillin (with t of about 1 hr). Regimen I- 1-hourly (light colour) with low total daily dose and regimen II- 6-hourly (dark colour) with higher total daily dose. Note: The steady-state plasma concentrations (Css) of the two regimens are different and regimen II shows a larger fluctuation between peak and trough comparing with that of regimen I. Both regimens exhibit Css within the therapeutic window, i.e. lies below the level expected to cause unacceptable toxicity. It follows that administering ampicillin 1-hourly would be practically inconvenient (24 times per day) and likely to result in non-compliance and consequently treatment failure. On the other hand, giving the drug 6-hourly with larger doses that attain troughs that lie at a level higher than the minimum effective concentration (MEC) and peaks lie at levels below the minimum toxic concentration (MTC), would lead to a better compliance (as a result of reducing the frequency of dosing, four times daily). This strategy can be adopted only with drugs that show large therapeutic index. In case of drugs that are with low therapeutic index other manoeuvres may be used to improve compliance; for example, sustained release formulation like for theophylline to be given twice daily instead of three times daily.

7

General Principles


The aforementioned factors are related to the question of whether generic or proprietary (brand) name should be used when prescribing.

Drugs and Medicines It is not always recognised that when prescribing a drug the patient actually receives a medicine. The drug represents only a small proportion of the total weight of the solid dosage form (e.g. tablet, capsule) or injectable dosage form (e.g. ampoule, vial). The dosage form contains other constituents, which may not be inert and may play an important role in facilitating or hindering a drug s absorption. Appropriate pharmaceutical manoeuvres of these materials may allow development of sophisticated delivery systems for delayed or position-released of the drug. The following are some of the factors involved in the production of the solid dosage form, which may influence a drug s absorption.

Absorption of Drugs When a drug is administered orally it has to pass through the gut wall which represents a complex biological barrier (complex lipid membrane) before entering the bloodstream. Dietary substances can pass through this biological barrier by one of the following ways: a. Passive diffusion concentration difference (from high to low) this is being the most important mechanism. b. Active transport e.g. amino acids, or drugs e.g. α-methyldopa that resembles endogenous substances. c. Filtration through pores, limited to molecules of small size e.g. urea. d. Pinocytosis by which small particles are engulfed by cells of the bowel.

1. Diluents e.g. lactose, calcium sulphate. 2. Granulating and binding agents e.g. syrup used for aggregation of powder into granules facilitating compression of tablet. 3. Disintegrating agents are incorporated to produce tablet disintegration in the gastrointestinal tract.

There are a number of factors which influence absorption of drugs: 1. Nature of drug polypeptides e.g. insulin is broken down by intestinal enzymes, benzylpenicillin is destroyed by gastric acid 2. Pharmaceutical formulation (see above) 3. Blood flow maintains continuous absorption by removing drug that passes through membrane. The concentration gradient across the membrane is, thereby, continuously assured. Membrane permeability of drugs also plays an important role in absorption of drugs. When the drug is lipophilic (e.g. ethanol) and thus highly membrane permeable, absorption is controlled or rate limited by perfusion (blood flow). In contrast, with streptomycin and many other polar compounds (like heparin, ipratropium and suxamethonium), absorption is controlled or rate limited by diffusion (penetration, permeability) through the membrane and not in removing the drug from other side of the membrane. Some compounds, e.g. urea, have intermediate permeability properties. At low blood flow rates, the compound has sufficient time to diffuse

moisture Starch Cocoa butter

Swelling body temperature

Melting

Sodium bicarbonate + tartaric acid moisture effervescence

4. Coating material e.g. sugar prevents disintegration before the tablet reaches the stomach or intestine (e.g. omeprazole). 5. Capsules have a gelatine envelope with no granulating excipients. 6. Sustained-release with complex pharmaceutical manoeuvres to control disintegration and dissociation rates, thus regulating the rate of a drug s absorption.

8


Majid A. K. Lafi

across the membrane so absorption is perfusion rate-limited. At higher blood flow rates, however, membrane permeability becomes the rate-limiting step, and absorption is insensitive to blood flow.

Because both ionised and unionised solutes readily pass across the capillary wall, the influence of pH on intramuscular and subcutaneous absorption of drugs is likely to be far less significant.

Absorption of drugs in solution from muscle and subcutaneous tissue is normally perfusion rate-limited. An increase in blood flow increases absorption. In this setting, absorption is impeded largely by the capillary wall. At these sites, the capillary wall, a much more loosely knit structure than the epithelial lining of the gastrointestinal tract, allows the rapid passage of all molecules below a molecular weight of about 5000, whether ionised or unionised. This molecular weight range includes essentially all drugs. Streptomycin, a relatively water-soluble polar base, has difficulty penetrating the gastrointestinal mucosa; it is rapidly absorbed from the intramuscular site.

Body fluids Gastric juice Intestine Plasma CSF Urine Prostatic secretions Vaginal secretions Weak acids

pK

pH 1.0 - 3.0 5.0 - 8.0 7.4 7.3 4.0 - 6.8 6.4 -7.4 3.4 - 4.2 Weak bases

Penicillin G Salicylic acid Warfarin

2.7 3.5 Diazepam 5.0 Chlordiazepoxide 7.3 Trimethoprim Phenobarbital 7.8 Lidocaine Theophylline 9.0 Procainamide 10 Amphetamine Permanently ionised (polar) drugs Heparin Streptomycin Ipratropium Tubocurarine Suxamethonium

4. pH and pK. Drugs are usually either weak organic acids (proton donor) or weak organic bases (proton acceptor) existing in equilibrium between undissociated molecules and as ions. This equilibrium depends on the pKa value of the drug and the pH of the surrounding medium. At a pH equals to the pKa the drug is 50% ionised. Thus, a weakly acidic drug (e.g. aspirin) in a medium of low pH (e.g. stomach) will be mainly in its undissociated form; whereas a weakly basic drugs (e.g. amphetamines) in a medium of high pH (e.g. small intestine) will be mainly in its undissociated form. Streptomycin is permanently polar and relatively strongly basic, and its pKa value greatly exceeded the highest pH reached in the intestine. This explains why some drugs (e.g. streptomycin) are very poorly absorbed from the gut, therefore they should be administered parentally. As a general rule, acids tend to ionise in basic (alkaline) media, and bases tend to ionise in acidic media.

Clinical Example Many antibiotics cannot penetrate the prostatic epithelium, therefore not achieving adequate concentration in the prostatic fluid and tissue. Hence, it is difficult to cure bacterial prsotatitis. Trimethoprim is usually effective in the treatment of bacterial prostatitis while penicillin is not. This is because trimethoprim is a basic substance with a pKa of 7.3 and prostatic secretion is relatively acidic (pH 6.4 particularly in inflammatory condition) compared to the plasma (pH 7.4); consequently, trimethoprim is about 50% non-ionised at the plasma and therefore the drug penetrates into prostate. In acidic prostatic fluid trimethoprim is ionised and thus trapped as it cannot diffuse back into plasma. On the other hand, penicillin (acidic substance with a pKa of 2.7) is largely ionised and bound to plasma protein at pH 7.4 and thus cannot penetrate into prostate.

9

General Principles


5. Gastric emptying- According to what has been described above, it follows that weak acids are absorbed more rapidly from the stomach when the pH of the contents is 1 than when the pH of the contents is closer to 8, and the converse holds for weak bases. However, absorption of acids is always much faster from the more alkaline intestine (pH 5-7) than from the stomach.

oral dose that reaches the general circulation. For example, a 50% bioavailability of a tablet of 10 mg propranolol would mean that a total of 5 mg of propranolol would reach the general circulation. The value of bioavailability may vary widely and being a characteristic of the manufacturing pharmaceutical company and in turn may have clinical implications. For the same proprietary (trade) name, a particular pharmaceutical preparation of a drug may exhibit widely different values of bioavailability due to pharmacokinetic differences in the handling of the drug by the body including concurrent medications. Three major factors are considered below.

These apparently conflicting observations may be reconciled by the following explanation. The surface area and blood flow are important determinants of the rapidity of absorption. The small intestine is favoured on both of these accounts. The total area of the small intestine represented largely by microvilli, has been estimated to be about 200 m2, and an estimated 1 litre of blood passes through the intestinal capillaries each minute. The corresponding estimates for the stomach are only 1 m2 and 150 ml/min. these increases in both surface area and blood flow more than compensate for the decreased fraction of unionised acid in the intestine. In fact, the absorption of all compounds, acids, bases, or neutral compounds, is faster from the small intestine than from the stomach. Therefore, the rate of gastric emptying is a limiting step in the rapidity of drug absorption. Consequently, food, particularly fat, slows stomach emptying. This explains why drugs are frequently recommended to be taken on an empty stomach when a rapid onset of action is desired.

Time for Absorption An orally administered drug is exposed to the gastrointestinal mucosa for no more than 1 to 2 days, and for much less time at the main absorption site, the small intestine. If a drug is poorly permeable, for example, streptomycin, heparin, suxamethonium, and ipratropium, there is insufficient time for complete absorption. There may be insufficient time for complete absorption of the vitamin, riboflavin, and of other substances absorbed by a carrier-mediated transport process. The site of the transport process is usually restricted to a certain part of the gastrointestinal tract. The system for absorbing riboflavin is located in the upper part of the small intestine. At the does taken, the concentration of riboflavin reaching the site of absorption saturates the transport process. The oral bioavailability of riboflavin can be increased by taking the vitamin with small amounts of food. The resultant slowing of stomach emptying both extends the duration and diminishes the rate of delivery of riboflavin and hence its concentration at the absorption site; both factors favour more complete absorption.

The stomach may simply be viewed as a storage organ from which pulses of drug are ejected onto the absorptive sites in the small intestine.

Factors Influencing Bioavailability

There is the situation of a drug, such as griseofulvin (and mebendazole and albendazole), that is sparingly soluble in both gastric and intestinal fluids. There may already be insufficient time for dissolution and absorption when this drug is administered as a tablet. Retaining such a drug in the stomach, by increasing the total time for dissolution, should favour increased

Bioavailability of a drug is the ease (how much of the drug and how fast, completeness of absorption) at which it reaches the general circulation. Drugs that are pharmaceutically formulated (designed) for oral administration may show different bioavailabilities. This is usually measured by the percentage of the 10


Majid A. K. Lafi

acid in a single passage through the liver, resulting in a substantial first-pass effect . Drugs that show a significant first-pass effect in man include aspirin, hydralazine, lidocaine, morphine, nitroglycerin, pentazocine, propoxyphene, and propranolol.

availability. The time available for dissolution within the intestine is probably limited to between 4 and 10 hours. Subsequently, as the intestinal fluid and contents move into the large intestine and water is reabsorbed, the resulting compaction of the solid contents limits further dissolution of drug. An additional 2 to 4 hours in the stomach, where dissolution can occur, would significantly extend the time for dissolution. Fats, particularly, delay stomach emptying, and this delay may be one of the explanations for the observed increase in the availability of griseofulvin when taken with a fatty meal or with fats.

Avoiding the first pass through the liver probably explains the activity of nitroglycerin administered sublingually. Blood perfusing the buccal cavity bypasses the liver and enters directly into the superior vena cava. This anti-anginal drug is almost completely metabolised as it passes through the liver, and any drug swallowed is not systemically available. The metabolites seen in blood are only weakly active.

The rectum has a small surface area and a drug given rectally is not always retained for a sufficient length of time to ensure complete absorption. No time limitation exists for a drug injected into muscle or subcutaneous tissue; complete absorption is anticipated unless destruction occurs at the site of administration.

The rectal route has a definite advantage over the oral route for drugs that are destroyed by gastric acidity or by enzymes in the intestinal wall and microflora. Potentially, the rectal route may also partially reduce first pass hepatic loss. Part of the rectal blood supply, particularly the inferior and middle haemorrhoidal veins, bypasses the hepatic portal circulation and dumps directly into the inferior vena cava. Achieving a reproducible availability, which is important in drug therapy, may be difficult, however, since availability is strongly dependent upon the site of absorption within the rectum.

Competing Reactions Any reactions within the gastrointestinal tract that compete with absorption may reduce the oral bioavailability of a drug. Benzylpenicillin when given orally undergoes substantial hydrolysis by gastric acid; therefore, it is administered by injection. Enzymatic hydrolysis occurs to aspirin forming salicylic acid, active antiinflammatory compound. Tetracycline undergoes complexation with polyvalent metal ions, e.g. Ca++, Al+++, forming unabsorbed insoluble complexes. Decarboxylation occurs to levodopa resulting in loss of activity (product active but not absorbed).

Distribution of Drugs Generally, drugs that are readily absorbed from the gut wall are also readily distributed throughout the body water compartments. This is applicable to most barbiturates; thiopental is highly lipid-soluble and is freely absorbed from the stomach and rectum. When it is administered intravenously, it crosses the biological barriers into the brain producing anaesthesia. Generally, centrally acting drugs have to pass through an additional lipid membrane in the blood brain barrier, and thus, are readily absorbed from the gut. These drugs can easily reach the foetal circulation, being the main offenders in causing foetal abnormalities (e.g. phocomelia caused by thalidomide).

Hepatic Extraction Over hundred years ago, acetylsalicylic acid (aspirin) was synthesised to overcome the bitter taste and the gastrointestinal irritation associated with the parent drug, salicylic acid. Only subsequently was aspirin shown to be also pharmacologically active. Aspirin, a labile ester, is rapidly hydrolysed, particularly by esterases in the liver. In fact, hepatic hydrolysis is so rapid that a significant fraction of aspirin is converted to salicylic

After being absorbed, most drugs bind to tissue and plasma proteins forming

11

General Principles


extensively bound to tissues is to have a large apparent volume of distribution (Vd). This is a theoretical volume of fluid, which would be required to contain the total body content of a drug at a concentration equal to the plasma concentration. Drugs which has a large Vd (in litres for 70 kg person) are digoxin (420), nortriptyline (1000), dothiepin (4900), amiodarone (4200) and chloroquine (13000), and drugs with small Vd are warfarin (5), heparin (5), aspirin (11), gentamicin (18), frusemide (21) and amoxicillin (28).

equilibrium with the unbound (free) drug, and the extent of binding varies from drug to drug. If a drug exhibits no appreciable tissue binding, the tissues behave as little more than water compartment in which the drug is dissolved. The pharmacological properties of a drug are greatly influenced by its being highly protein bound; this influence can be seen in the following ways: 1. Its absorption from the gut wall will be facilitated, through capturing the drug molecules by tissues and/or plasma protein molecules leading to maintenance of the concentration gradient across the gut wall.

Serum half-life

2. Since only the unbound form of the drug is the biologically active, it is essential to know the extent of binding for a drug before values given for serum levels reached for the drug in question become meaningful.

Serum half-life (t ) of a drug is the time taken for the serum concentration to halve. Metabolism and/or excretion of the drug determine it. A drug with a short t (e.g. salbutamol) produces a much steadier therapeutic action when given in at least three divided doses daily. On the other hand, a drug with a long t (e.g. digoxin) given as a single daily dose is adequate to maintain a steady response. Drugs with long t will cumulate with repeated and frequent doses and patients receiving such drugs particularly those with low therapeutic index like digoxin and phenytoin should be examined frequently for signs of overdosage.

3. Certain pathological conditions where changes in the concentration of serum proteins, e.g. hypoproteinaemia (which may occur in some renal and/or hepatic dysfunction), a higher level of unbound drug will occur in the serum unless the oral dose is lowered. This should be taken in consideration when dealing with drugs, which are highly protein bound (e.g. diazepam, frusemide, phenytoin and triamterene) and/or have low therapeutic index (e.g. theophylline and digoxin).

Thus, measurements of serum concentrations are performed routinely nowadays; these include anticonvulsants (e.g. phenytoin), antiarrhythmic drugs (e.g. quinidine), theophylline, lithium and aminoglycosides. In certain cases, measuring the response to a drug provides an easy method of monitoring its action (e.g. prothrombin time with anticoagulants like warfarin).

4. Adverse drug interactions may take place on plasma protein binding sites. This is very likely to occur with a highly protein bound drug like warfarin (99% bound) which can be displaced by certain other drugs like phenylbutazone which competes with warfarin on the same binding site. This may result in a small change in binding of warfarin that can greatly lengthen the prothrombin time. This type of drug interaction is clinically more important when the displaced drug has a small volume of distribution.

Metabolism Hepatic enzymes are responsible for the metabolism of most drugs. However, some drugs are metabolised in the plasma (e.g. procaine and suxamethonium are destroyed by pseudocholinesterase in the serum) and tissues (e.g. alcohol is destroyed by enzymes in gastric wall and liver). Metabolism in the liver can take place for those substances, which are lipid soluble and thus can enter the

5. For a drug to be effective therapeutically it has to achieve adequate plasma levels of the unbound form. Drugs vary in the period required to reach equilibrium between the body fluids and tissues. When a drug is 12


Majid A. K. Lafi

liver. Hepatic enzymes are, generally, capable of metabolising endogenous and exogenous substances that are relatively stereotyped. Each enzyme is specific for certain chemical groups, which can occur on a wide range of substances.

Inactive Substance Azathioprine Enalapril Sulphasalazine

Hepatic metabolic processes can be divided into: Phase I metabolism results in a change in drug substance by oxidation, reduction or hydrolysis and in certain cases introduces a chemically active site into it. Oxidation is the most important reaction that is usually achieved by the so-called mixed-function oxidases that are capable of metabolising a variety of compounds.

Talampicillin Acyclovir

Metronidazole

Phase II metabolism involves the union of the drug with one of several polar endogenous molecules (e.g. glucuronide, glycine or acetyl derivative) to form a watersoluble conjugate which is readily eliminated by the kidney or, if the molecular weight more than 300, in the biliary tract. Generally, phase II metabolism inactivates drugs and facilitates their excretion.

Chloramphenicol succinate Chloral hydrate Anistreplase Hexamine

When drugs undergo metabolism, they can be converted from pharmacologically active to inactive substances; this is the most likely event. Further, some pharmacologically active drugs may be converted to another active substance. While some other pharmacologically inactive drugs (prodrugs) can be converted to active ones. Active Drugs Allopurinol Amitriptyline Aspirin Acetaminophen (safe)

Codeine Chloroquine Diazepam

Active Metabolite Mercaptopurine Enalaprilat 5-aminosalicylic acid (mesalazine) plus sulphapyridine (by bacteria in the colon) Ampicillin Acyclovir triphosphate (by viral thymidine kinase) Reducedmetronidazole (by anaerobic bacteria) Chloramphenicol Trichloroethanol Deacylated anistreplase Formaldehyde (by hydrolysis in acidic urine)

Excretion Most drugs are excreted in urine, either as the parent substance or metabolites. Lipid soluble drugs, in addition to being readily absorbed from gut, appear in the glomerular filtrate, but easily pass back into the blood stream by passive diffusion at the proximal tubule. However, many of these drugs are converted by the liver into more polar, lipid insoluble metabolites. These metabolites, and other drugs which are highly polar (e.g. streptomycin), do not pass very readily into glomerular filtrate, but once they are there they have difficulty in diffusing back at the proximal tubule. These substances are usually excreted entirely by the kidney. In addition to passive diffusion, many acidic and basic drugs are actively secreted. The secretion of weakly acidic substances can be inhibited by probenecid, and this substance has been used to prolong the t of penicillin in order to reach higher tissue concentrations without increasing the dose of the antibiotic.

Active Metabolite Alloxanthine (oxypurinol) Nortriptyline Salicylic acid N-acetyl-pbenzoquinoneimine (NABQI, hepatotoxic) Morphine Hydroxychloroquine

Nordiazepam

13

General Principles


Changes in tubular pH can affect the elimination of these compounds by altering the ratio of ionised to unionised form. Normally the urine is slightly acidic and favours the excretion of weakly basic drugs (e.g. amphetamine, pethidine), while oral sodium bicarbonate will prolong their effects. On the other hand, the excretion of weakly acidic drugs (e.g. for patients who has taken overdose of barbiturates or aspirin) is accelerated by making the urine alkaline (alkaline diuresis) by giving sodium bicarbonate. As the kidney (and cardiac function) and to a lesser extent the liver are important in drug excretion, a serious consideration must be taken with impaired renal and hepatic functions. An elderly patient with congestive heart failure and a raised blood urea is likely to develop digitalis intoxication if digoxin is prescribed in full dose. It is necessary to measure repeatedly the serum level of certain drugs (e.g. gentamicin) when they are given to patients in renal failure.

14


Majid A. K. Lafi

The apparent volume of distribution (Vd)

USEFUL NOTES

D C = ------Vd

• Clearance of a drug is the rate of elimination by all routes relative to the concentration of drug in any biological fluid.

D Vd = -----C

Rate of elimination Clearance = -----------------------Concentration

C = plasma concentration of drug D = Total amount of drug in the body

Rate of elimination = Q x Ce - Q x Co

Example: if 10 mg of a drug, thus D = 10 mg, is administered and the plasma concentration is 1.0 mg/L, then the Vd = 10 mg/L = 10 L.

Blood flow = Q Entering drug concentration = Ce Exiting drug concentration = C0

Clinical applications of Vd 1. It is useful to calculate the amount of drug needed to achieve a desired plasma concentration:

Therefore: Q x Ce Q x Co Clearance = ------------------- (ml/min) Ce

Example: if supraventricular arrhythmia of a patient is not responding well due to inadequate plasma levels of digoxin. Assuming the plasma concentration of the drug is C 1 and the desired concentration is C 2, a higher one. It is important to know how additional digoxin should be administered to bring the circulating level of the drug from C1 to C2.

Ce Co = Q x ---------- = Q x ER Ce ER = extraction ratio

Clearance of a drug by an organ (e.g. kidney) means the ability of the kidney to remove the drug from a certain volume of plasma per minute. Similar to renal clearance of creatinine or urea.

D1 = Vd x C1 D1 = amount of drug initially in body D2 = Vd x C2 D2 = amount of drug in the body required to achieve the desired plasma concentration

Dosing rate = Clearance x Css (Q x Ce Q x Co ) = --------------------- x C ss Ce Css = Steady state concentration

Therefore, the additional dosage needed is the difference between the two values: (D2

C1 )

2. Since delivery of drug to the organs of elimination depends not only on blood flow but also on the fraction of the drug in plasma, therefore, the value of Vd of a drug can influence the rate of elimination. Assuming a drug with a large Vd, most of this drug is in the extraplasmic space and is unavailable to the excretory organs. Therefore, a drug with a large Vd would

Half-life (t ) is defined as the time required for the amount of drug in the body to decrease by half (50%). t

D1) = Vd (C2

= 0.693 Vd/CL CL = Clearance

15

General Principles

be expected to have a long t extended duration of action.


withdrawn, an interval equivalent to 4 t will be required for body stores of the drug to decline by 94%.

and

Clinically, the knowledge of Vd of a drug may be useful when overdosage occurs. Removing a drug by haemodialysis is likely to be of benefit if a major proportion of the total amount of the drug is in the plasma.

• When t is 6-12 hr giving half the priming dose at intervals equal to the t can indeed be a satisfactory solution because dosing every 6-12 hr is reasonable.

Example: For salicylate, which has a small Vd, (12L) haemodialysis is appropriate treatment; while for pethidine, which has a large Vd, (310L) is not appropriate one.

• When t is greater than 24 hr giving half the priming dose every day means that more drug is entering the body than is leaving it each day, and the drug will accumulate indefinitely. Thus, the maintenance dose should be adjusted to replace only that amount of drug that leaves the body in 24 hr, as for warfarin.

Students are expected to be familiar with the following terms. They are advised to make contributions in the discussion sessions on the concepts of these terms. • Therapeutic range, therapeutic window

• When t is less than 3 hr, dosing at intervals equal to the t would be so frequent as to be unacceptable, and the answer is to use continuous intravenous infusion if the t is very short, as for dopamine t , 2 min; steady-state plasma concentration will be reached in 5 x t = 10 min). Benzylpenicillin has a t of less than 1 hr but is effective in a 6-hourly regimen because the drug is very safe that it is possible to give in a dose that achieves a plasma concentration many times in excess of the minimum inhibitory concentration for sensitive organisms.

• Steady state concentrations (Css), plateau (when the quantity of drug eliminated between doses equals the dose administered, average drug levels will remain constant and plateau will have been reached. • Time to plateau (When a drug is administered repeatedly in the same dosage, plateau (steady state) will be reached in approximately 4-5 half-lives. • Techniques for reducing fluctuations in drug levels

• First and zero order (saturable) kinetics [clinical implications: (phenytoin, therapeutic index = 2, subtherapeutic plasma concentration with t of 6-24 hr and C ss reached in 2-3 days, while therapeutic plasma concentration with t of 60 hr and Css reached in 2 weeks); alcohol (due to alcohol dehydrogenase being saturable at alcohol blood concentration of about 10 mg/dL), theophylline with therapeutic index 30 55-150

6-10 6-10 6-10 20-30

1-2 1-2 1-2 4-8

* Note: Levels of aminoglycosides must be kept within a narrow range, and because of interpatient variability, the above standard doses cannot be relied upon to produce predictable levels, dosage must be carefully adjusted for each patient.

When possible, aminoglycosides should not be used for more than 10 days. Further, concurrent administration of aminoglycosides with other potentially ototoxic agents (e.g. frusemide, ethacrynic acid) should be avoided.

Ototoxicity Aminoglycosides penetrate easily to the perilymph of the inner ear, and there is a direct relationship between levels achieved in the perilymph and production of ototoxicity manifests as impairment of hearing and balance. Damage to hair cells within the cochlea results in loss of hearing, while disruption of balance is caused by damage to hair cells of vestibular apparatus.

Other adverse effects and interactions Aminoglycosides can cross the placenta and may have toxic effects on the developing foetus. They are also known to produce curare-like effects (neuromuscular block); thus, they can intensify neuromuscular blockade produced by tubocurarine and other skeletal muscle relaxants. Therefore, when using aminoglycosides together with the muscle relaxants, extreme caution must be taken to avoid respiratory arrest.

Upon giving aminoglycosides, patients should be monitored for early signs of cochlear or vestibular damage. By using audiometric testing, decreased acuity in the high-frequency range indicates loss of hearing. Auditory toxicity can also present as tinnitus or a sense of fullness in the ear. Further, damage to the vestibular system may manifest as nausea, unsteadiness, and vertigo.

Cautions

When ototoxicity is detected, aminoglycosides should be withdrawn or administered in reduced doses. If toxicity is moderate, symptoms reverse following withdrawal of aminoglycosides; however, when ototoxicity is extensive, symptoms may be permanent and even can be with complete hearing loss.

Aminoglycosides should never be mixed together with penicillins (or any β-lactam drug) in the same syringe or in the same i.v. solution because penicillins (when present in high concentrations) interact chemically with aminoglycosides rendering the latter inactive.

99

Antimicrobial Agents -Sulphonamides, Trimethoprim, and Aminoglycosides

Postantibiotic Effect Postantibiotic effect is the antibacterial activity that persists beyond the time that measurable drug is present. This phenomenon was first observed with anti-mycobacterial drugs like rifampicin and then termed the lag-period effect . This postantibiotic effect is being significant and well documented with aminoglycosides and quinolones. Therefore, a given total daily amount of aminoglycoside may have better efficacy when administered as a single large dose than when administered as multiple smaller doses. Further, the single large dose scheme produces much higher peak concentrations, which saturate an uptake mechanism into the cortex; thus, resulting in less total aminoglycoside accumulation that is thought to cause renal damage and in turn less renal toxicity. The difference in renal toxicity is a predictable consequence of the different patterns of concentration (due to different dosage regimens) and the saturable uptake mechanism in the proximal renal tubular cells.

AMINOGLYCOSIDES • Useful primarily in serious infections due to aerobic gram-negative bacteria (e.g. Pseudomonas aeruginosa) • Have to be given parenterally • Unchanged excreted renally • Adverse effects: 1. Nephrotoxicity 2. Ototoxicity 3. Neuromuscular block 4. Low therapeutic index

100



Majid A. K. Lafi

TETRACYCLINES, MACROLIDES, METRONIDAZOLE, CHLORAMPHENICOL, AND OTHERS 3. Opportunistic infections (e.g. candidiasis) 4. Tooth discoloration (tetracyclines are selectively taken up in the teeth and growing bones in the foetus and of children, given rise to inhibition of growth of bones and discoloration of teeth) 5. Inhibition of bone growth 6. Elevated blood urea (the antianabolic effect, inhibition of protein synthesis, cause blood urea to rise that is of a particular importance in uraemic patients) 7. Fatty liver 8. Photosensitisation (exposure to sunlight results in darkening of skin)

TETRACYCLINES Tetracyclines (1948) are a family of broadspectrum antibiotics with only minor differences. Tetracyclines have a 4-ring structure with small side-chains. The earliest members were chlortetracycline, oxytetracycline and tetracycline. The most recent ones are doxycycline and minocycline, which have good absorption and long t (16 h). Tetracyclines are bacteriostatic; they interfere with protein synthesis.

Resistance to Tetracycline

Caution

Bacterial resistance to tetracycline may be conferred by three possible mechanisms:

When passing the date of expiry, particularly tetracycline, becomes nephrotoxic therefore should not be used.

1. Decreased intracellular accumulation due to either impaired influx or increased efflux by an active transport protein pump 2. Ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome 3. Enzyme inactivation of tetracycline

MACROLIDES ERYTHROMYCIN

Indications

Erythromycin is one of the macrolides, which are termed after their macrocyclic lactone ring to which different sugars are attached. It was isolated in 1952 from a streptomyces strain found in the Philippine soil.

Their uses include infections with 1. Clamydiae (e.g. psittacosis, trachoma, pelvic inflammatory diseases, lymphogranuloma venereum) 2. Mycoplasma (pneumonia) 3. Rickettsia (Q fever, typhus) 4. Vibrio cholerae (cholera) 5. Haemophilus influenzae (e.g. bronchitis) 6. Brucella (brucellosis)

Absorption is best with erythromycin estolate, even if there is food in the stomach. Erythromycin is partly inactivated by gastric acid. The t (2h) is dose dependent and elimination is almost exclusively in the bile and faeces.

For a summary of pharmacokinetic properties see Table 4.6.

Erythromycin is active against gram-positive bacteria and spirochaetes. It is used instead of penicillin in patients allergic to penicillin and infections resistant to penicillin.

Adverse effects 1. GIT disturbances 2. Disorder of epithelial surfaces (sore mouth and throat, black hairy tongue, odynophagia and perianal soreness) 101

Tetracyclines, Macrolides, Metronidazole, Chloramphenicol, and Others


Table 4.6. A summary of pharmacokinetic properties of tetracyclines Group

Agent

Short-acting

Tetracycline Oxytetracycline Demeclocycline

Low Low Moderate

75 60 65

↓ ↓ ↓

Renal Renal Renal

8 9 15

50-100 50-65 40-60

Doxycycline Minocycline

High High

90-100 90-100

(No change)

Hepatic Hepatic

12-22 12-22

12-22 12-22

Intermediateacting Long-acting

t

Note: Tetracycline may achieve toxic levels in renal dysfunction, therefore, it is not suitable in such condition. Doxycycline does not accumulate in renal dysfunction, does not interact with food, and is given once or twice daily, while tetracycline should be given four times daily. These make doxycycline superior to tetracycline.

2. Gastrointestinal disturbances (particularly diarrhoea, occur in up to 28%) 3. Hepatic enzyme inhibition (unlike azithromycin, erythromycin and clarithromycin inhibit the metabolic inactivation of some drugs like warfarin, carbamazepine, theophylline, disopyramide, increasing their effects)

Resistance to Macrolides Resistance to erythromycin may be conferred by the following: 1. Decreased cellular influx or increased active efflux 2. Production of esterases that hydrolyse macrolides 3. Alteration of the ribosomal binding site

CLARITHROMYCIN Indications 1. Penicillin-allergic patients (alternative to penicillin when infections due to grampositive bacteria) 2. Pneumonia (due to Mycoplasma pneumoniae) 3. Legionnaires disease (Legionnella species, 1st choice drug) 4. Diphtheria (Corynebacterium diphtheriae) 5. Whooping cough (Bordetella pertussis) 6. Gastroenteritis (due to Campylobacter jejuni) 7. Acne

Adverse Effects 1. Cholestatic hepatitis (with abdominal pain and fever that may be confused with viral hepatitis, due to estolate; this is probably an allergic reaction, thus the estolate should not be given to a patient with liver disease. 102

Clarithromycin acts like erythromycin and also exhibits a similar antibacterial activity to the latter agent, being mainly active against gram-positive organisms. It should be noted that the t of clarithromycin is remarkably does-dependent (t 3 hours after 250 mg, 9 hours after 1200 mg). Unlike erythromycin, it is rapidly and completely absorbed from the gastrointestinal tract. Of oral clarithromycin dose, 60% is inactivated by metabolism that is saturable and the remainder is eliminated in the urine. It is useful largely in respiratory tract infection including atypical pneumonias and soft tissue infections. It exhibits fewer gastrointestinal tract adverse effects (7%) than that of erythromycin (28%). Clarithromycin, like erythromycin, also inhibits the metabolic inactivation of some drugs (See above).


Majid A. K. Lafi

2. Metallic taste 3. Peripheral neuropathy 4. Ataxia 5. Insomnia 6. Convulsion 7. Darkening of urine 8. Disulfiram-like reaction (when alcohol is consumed concurrently with metronidazole)

AZITHROMYCIN Azithromycin is a new macrolide agent that acts like erythromycin (inhibits protein synthesis) but with a broader spectrum of antibacterial activity than erythromycin. The extension of activity includes a number of important gram-negative like Haemophilus influenzae and Neisseria gonorrhoeae, and also Chlamydiae. However, it is less effective against gram-positive organisms than erythromycin. Azithromycin is rapidly absorbed and tolerated orally. Azithromycin does inhibit cytochrome P450 enzymes therefore, unlike erythromycin clarithromycin, is relatively free of the interactions.

CHLORAMPHENICOL Chloramphenicol (1948, chloromycetin) was originally obtained from a streptomyces strain from Venezuela but is now synthesised. It readily penetrates the blood brain barrier (BBB). Chloramphenicol has a wide range of antibacterial activity including. infections due to

well not and and drug

1. Typhoid (Salmonella typhi and Salmonella paratyphi) 2. Meningitis (Haemophilus influenzae) 3. Whooping Cough (Bordetella pertussis)

METRONIDAZOLE Metronidazole has for many years been successfully employed to treat protozoal infections but the outstanding activity against anaerobes has been found useful particularly in bacteroides infections, and since the recognition of toxicity from lincomycin, has been widely used in treatment of septic infections of the chest, abdomen and pelvis. Metronidazole is a prodrug activated by anaerobic bacteria and not aerobic ones. It is bactericidal agent and resistance is not a problem.

Adverse Effects

Indications 1. Septic infections 2. Antibiotic-associated enterocolitis (pseudomembraneous colitis due to Clostridium difficile) 3. Urogenital tract trichomoniasis 4. Amoebiasis (Entamoeba histolytica) 5. Giardiasis (Giardia lamblia) 6. Acute ulcerative gingivitis and dental infections 7. Vaginitis (Gardnerella vaginalis)

Adverse Effects 1. Gastrointestinal diarrhoea)

disturbances

(nausea,

103

1. Reversible bone marrow depression (dose-related) 2. Aplastic anaemia (pancytopenia and bone marrow aplasia, occurs with an incidence of 1 in 35,000 and is not related to dose; it occurs with oral, i.v., or even ophthalmic use of the drug. This reaction develops weeks or months after termination of the treatment.) 3. Grey baby syndrome (circulatory collapse, vomiting and fall in body temperature; this depends on the lower capacity to conjugate chloramphenicol in the liver in infants.) 4. Acute haemolytic anaemia in G6PD deficient patients Note: The onset of action of chloramphenicol when given orally is more rapid than when given intravenously. This is because the i.v. formulation of chloramphenicol (usually with succinate) has to be broken down in the liver to release chloramphenicol before it acts, while the capsule (usually with palmitate) form acts directly.


Ramadi, 24 February 2007

Adverse Effects LINCOSAMIDES 1. Flu-like illness 2. Hepatitis 3. Thrombocytopaenia 4. Rashes 5. Pink urine

CLINDAMYCIN AND LINCOMYCIN Clindamycin is more effective and better absorbed from the gastrointestinal tract. These drugs are effective against the following:

NITROFURANTOIN AND NALIDIXIC ACID

1. Bacteroides fragilis (first choice against gastrointestinal strains) 2. Anaerobic streptococcal infections (as an alternative) 3. Clostridium perfringens (as an alternative) 4. Staphylococcal infections (as an alternative)

These drugs are urinary tract disinfectant used for the treatment of infections with 1. Escherichia coli 2. Streptococcus faecalis 3. Proteus species Nalidixic acid also has some place in the treatment of infection with Shigella (in paediatric practice).

Adverse Effects 1. Antibiotic-associated enterocolitis (hence, these drugs should not be used indiscriminately; metronidazole is indicated to treat this condition)

Adverse Effects 1. Peripheral neuropathy (with nitrofurantoin) 2. Convulsions (with nalidixic acid)

The use of metronidazole is now preferred to that of clindamycin or lincomycin, for the treatment of anaerobic infections. Metronidazole appears to be superior because it can achieve adequate concentrations in the CSF and has not been reported to cause antibiotic-associated colitis.

SODIUM FUSIDATE Sodium fusidate is an antistaphylococcal agent, useful in severe infections caused by β-lactamase producing and methicillin resistant Staphylococcus aureus (MRSA) including osteomyelitis. It is readily absorbed from the gut and distributes widely in body tissues including bone. It is largely metaboilised and only very little is excreted in the urine. It is available as i.v. , oral, ointment and gel preparations.

RIFAMPICIN It has a broad-spectrum antibacterial activity, particularly, against mycobacterial species, and gram-positive organisms including staphylococci. With rifampicin, the rapid emergence of resistance dictates that they must always be used in combination with unrelated antimicrobial agents. It is largely reserved for mycobacterial infections. Its use in MRSA infections may be justified.

VANCOMYCIN Vancomycin is an antibiotic produced by Streptococcus orientalis, glycopeptide and is water-soluble and very stable. It inhibits cell wall synthesis. It is useful when given orally in antibiotic-associated enterocolitis, and i.v. for systemic infections. It readily crosses the BBB if there is meningeal inflammation. 104


Majid A. K. Lafi

urinary or gastrointestinal tracts, skin, soft tissues, and bones. They have also been used in the treatment of gonorrhoea and septicaemia.

Vacomycin is largely (90%) eliminated renally by being excreted by glomerular filtration. Therefore, in renal insufficiency, surprisingly high blood levels may be reached.

Adverse Effects

Indications 1. Methicillin-resistant Staphylococcus aureus (MRSA, first choice drug) 2. Enterococcal endocarditis in patients with serious penicillin allergy (in combination with gentamicin) 3. Meningitis suspected or known to be caused by a highly penicillin-resistant strains of pneumococcus (MIC > 1 µg/ml) 4. Antibiotic-associated enterocolitis (due to Clostridium difficile, administered orally)

Adverse Effects 1. Chills and fever 2. Ototoxicity (tinnitus and deafness may reverse upon withdrawal of vancomycin) 3. Nephrotoxicity 4. Red man or Red neck (a maculopapular rash possibly due to histamine release may occur upon rapid i.v. infusion)

Caution

1. Crystalluria (Therefore, adequate amount of water should be taken) 2. Cartilage deterioration (reversible arthropathy in immature animals, although such effects have not been observed in humans, prudence dictates that these drugs are contraindicated in children and in women who are pregnant or nursing. However, some authorities would state that fluoroquinolones should be used with caution in children and adolescents 1 3. Inhibition of Drug Metabolism (inhibits the metabolism of theophylline and warfarin, therefore, both of which should be monitored carefully when concurrently administered with ciprofloxacin)

Cautions 1. Oral absorption of fluoroquinolones is impaired by divalent cations including those in antacids. 2. Interacts with theophylline (inhibit hepatic metabolism of theophylline and therefore can potentiate its effects).

Administration with another ototoxic or nephrotoxic drug, such as an aminoglycoside, increases the risk of these toxicities.

FLUOROQUINOLONES These are synthetic bactericidal agents chemically related to nalidixic acid. The prototype of this group is ciprofloxacin and norfloxacin. They can easily penetrate the BBB and thus can be used as an alternative to the 3rd generation cephalosporins. Nowadays, the use of these drugs has picked up a great popularity as broad-spectrum antibacterial drugs.

Indications They have been found effective in the treatment of infections of the respiratory,

1

Laurence, D. R., Bennett, P. N. & Brown, M.J. (1997) Clinical Pharmacology. 8th edition, page 212. 105

Antimicrobial Drugs - Antimycobacterial Drugs


ANTIMYCOBACTERIAL DRUGS ANTITUBERCULOSIS DRUGS

As treatment is prolonged, if only one antituberculous drug is used there is a high risk that a drug-resistant mutants (due to spontaneous mutation, that exist in all large bacterial populations) will emerge. However, the possibility of bacilli to develop resistance to more than one drug is very low. Therefore, treatment of two or more drugs reduces the risk of developing drug-resistance. Further, drug-combination therapy also serves to reduce the incidence of relapse. A strategy for drug-combination targeting in the course of treatment of tuberculosis is presented in Fig.4.4.

Introduction The objective of antituberculous therapy is to eliminate symptoms of active disease, and to prevent relapse, and emergence of drug resistance. To achieve these goals, the following should be accomplished: 1. Killing the Actively Multiplying Tubercle Bacilli: Elimination of the actively multiplying population, which have been estimated to form about 95% of the total tubercle bacilli, and the intracellular ones within the initial phase (1st 2-3 months) of treatment.

The regimen currently recommended for the treatment of uncomplicated tuberculosis in AL-Anbar as follows:

2. Eradicating the Remaining Problematic Tubercle Bacilli: Eradicating the problematic proportion of the tubercle bacilli which is characterised by usually being at resting state but occasionally exhibits spurts of metabolic activity ; these bacilli represent, at least in part, what are described as persisters , i.e. semidormant bacilli that metabolise slowly or intermittently. It is believed that only during these spurts of activity (which have been estimated to last for about 2 minutes at a time) that drugs can kill these bugs. Therefore, the continuation (2nd) phase is directed at capturing these moments of activity. The 2nd phase usually takes 4-6 months; at the end of which this proportion of the tubercle bacilli should be eradicated (if the treatment is successful).

6-Month Regimen First 2 months (Initial Phase)

Following 4 months (Continuation Phase)

Isoniazid (INH) + rifampicin + pyrazinamide + ethambutol or streptomycin (2HRPE) Isoniazid + rifampicin (4HR)

The regimen currently recommended for the treatment of complicated tuberculosis (e.g. relapse and treatment failure cases) in ALAnbar as follows:


Further 1 or 2 Months

Success of treatment is indicated by an absence of observable tubercle bacilli in sputum (direct smear) and by failure of sputum cultures to yield any colonies of the bacilli. When sputum test results have become negative, usually within 2-6 months, therapy should continue for additional 4-6 months.

Five months (Continuation Phase)

106

Isoniazid + rifampicin + pyrazinamide + ethambutol + streptomycin (2HRZES) Isoniazid + rifampicin + pyrazinamide + ethambutol (1HRZE) Isoniazid + rifampicin + ethambutol (5HRE)


Majid A. K. Lafi

Most modern regimens for the treatment of tuberculosis include isoniazid, rifampicin, and pyrazinamide, since

Therefore, it is an essential feature of the antituberculosis regimen is that practically all drugs should be given once daily (not divided doses). For a summary of the pharmacology of antituberculosis drugs see Table 4.7.

•

Isoniazid rapidly kills large numbers of actively growing bacteria including those with only occasional spurts of activity. • Rifampicin kills actively growing bacilli including the problematic ones with only spurts of metabolic activity; and also kills intracellular bacilli. • Pyrazinamide that is converted to the active pyrazinoic acid by the activity of intrabacterial pyrazinamidase, an enzyme is most effective in an acidic environment such as the interior of cells. Thus, it is effective uniquely in zones of acute inflammation and against quiescent bacilli within macrophages (persisters, semidormant bacilli that are often within cells).

Isoniazid, pyrazinamide, and ethambutol are considered to be specific antimycobacterial drugs. Therefore, they are used in therapeutic trials for diagnostic purposes. Isoniazid is highly selective for mycobacteria; the drug can kill tubercle bacilli at concentrations 10,000 times lower than those needed to affect gram-positive bacteria.

ANTILEPROSY DRUGS Leprosy (Hansen s disease) is caused by Mycobacterium leprae. The WHO recommends that all patients receive treatment with multiple drugs.

Also, it is worth noting that: •

Ethambutol is a specific drug against mycobacteria. Generally, it is used when resistance to isoniazid and rifampicin is suspected. • Streptomycin has relatively low sterilising activity, perhaps, because of its inability to penetrate cells and not being effective against intracellular bacilli.

Dapsone (t is 27 hr, aminodiphenylsulfone) has been and remains a mainstay of therapy that requires a minimum duration of two years. The absorption of dapsone is slow but complete from the gastrointestinal tract and the drug sustains a steady blood level because it undergoes intestinal reabsorption from the bile. It is excreted in the urine. Dapsone is associated with methemoglobinemia, agranulocytosis, haemolytic anaemia, drug rash, and anorexia as adverse effects. Dapsone causes more haemolytic anaemia in slow acetylators, whereas rapid acetylators may need higher doses to control leprosy.

In general, a 6-month regimen cures the patient rapidly and these drugs are usually well tolerated. In Ramadi, this regimen has been found as the most successful one with the highest cure-rate (85%).

Rifampicin is used in combination with dapsone in the treatment of leprosy. Rifampicin in a dosage of 600 mg daily is safe and effective when given once monthly. This long interval makes acceptable the directly observed therapy with rifampicin which the above regimens require.

Postantibiotic Effect After a culture of Mycobacterium tuberculosis had been exposed to certain drugs for sometime, it took several days (the lag-period , postantibiotic effect) before growth occurred. Therefore, 600 mg of rifampicin given once daily is therapeutically superior to the same dose divided into two parts administered at 12 hours interval.

Clofazimine (t is 70 days) is a phenazine dye and it has a leprostatic action. It is absorbed from the gastrointestinal tract and 107



accumulates in tissues. Hence, dosage regimen is possible if individual doses are given in a gap separated by four weeks.

discolouration of the skin that may persist for months after the drug has been stopped.

Clofazimine is given for dapsoneresistant leprosy or when patients are intolerant to dapsone. Clofazimine therapy is associated with reddish to nearly black

Table 4.7. A summary of the pharmacology of the currently used antituberculosis drugs. Drug Isoniazid (INH)

Action Powerfully anti-TB; inhibits formation of mycolic acid in bacterial cell wall. Bacteriostatic-cidal

Rifampicin

Inhibits RNA polymerase in bacteria. Resistance develops rapidly if used on its own.

Pyrazinamide

Converted to pyrazinoic acid by intrabacterial pyrazinamidase (most effective in acidic environment) Concentrated in tubercle bacilli, mode of action not known. Resistance develops slowly. Effective against strains resistant to rifampicin and streptomycin.

Ethambutol

Streptomycin

Thiacetazone

See aminoglycosides (not effective in acidic environment) Low efficacy, delays emergence of INH resistance

108

Toxicity Insomnia Muscle twitching Peripheral neuropathy (responds to vit. B6) Hepatitis Flu-like illness Hepatitis Thrombocytopenia Rashes Pink urine Hepatotoxicity (10%) Gouty attacks

Peripheral neuropathy Colour blindness Pruritus Joint pains Abdominal pain Confusion Hallucination Contraindicated in pregnancy Nephrotoxicity Ototoxicity Neuromuscular block Hepatotoxicity


Majid A. K. Lafi

Actively multiplying population

Intracellular population

Isoniazid Rifampicin Streptomycin Ethambutol

Population with spurts of metabolic activity

Rifampicin Pyrazinamid

Isoniazid Rifampicin

This population is usually killed within the 2nd phase of therapy (4-6 months)

These 2 populations are usually killed within the 1st phase of therapy (1st 2-3 months), requiring combined isoniazid, rifampicin, pyrazinamide, & streptomycin or ethambutol.

Dormant population

Not reached by drugs

Eradication decreases relapse & resistance

Fig. 4.4. A simplified representation of the strategy of the treatment of tuberculous infections (pulmonary), different phases of treatment, antituberculous drugs, and duration of treatment are indicated. Note: The actively (rapidly) metabolising bacilli are believed to be killed within a few days: however, the intracellular bacilli (including semidormant bacilli, quiescent but with spurts of metabolic activity) are more difficult to be dealt with. Rifampicin and pyrazinamide are effective in killing the latter population within the initial phase of treatment. The continuation phase of treatment (isoniazid + rifampicin) is directed at least 4-month treatment, hopefully, to achieve eradication of bacilli and therefore decrease the possibility of relapse and drug-resistance.

109

Antimicrobial Drugs - Antimicrobial Drugs of Choice

Ramadi, 08 October, 2009

ANTIMICROBIAL DRUGS OF CHOICE Table 4.8. Antimicrobial drugs of choice; modified from Laurence, D. R., Bennett, P. N., and Brown, M. J. (1997) Clinical Pharmacology, 8th edition, page 194. * Resistance may be a problem; sensitivity test should be done. ** Suggested alternatives do not necessarily represent all options. CS = a cephalosporin Co-amoxiclav = fixed combination of amoxicillin plus clavulanic acid ± With or without FQ = a fluoroquinolone (e.g. ciprofloxacin)

Infecting organism

Drug(s) of 1st choice

Alternative drugs**

Gram-positive cocci *Enterococcus Endocarditis or other severe infections

Benzylpenicillin or amoxicillin + gentamicin, or streptomycin

Vancomycin + gentamicn or streptomycin

Uncomplicated Urinary tract infections

amoxicillin

Trimethoprim or nitrofurantoin

Non-penicillinase producing

Benzylpenicillin

CS; vancomycin; imipenem; erythromycin

Penicillinase producing

Cloxacillin

CS; vancomycin; co-amoxiclav; erythromycin; clindamycin; FQ

Methicillin-resistant

Vancomycin ± gentamicin ± rifampicin

Co-trimoxazole; a tetracycline; FQ; rifampicin; Na fusidate

Streptococcus pyogenes

Benzylpenicillin or phenoxymethylpenicillin or amoxicillin

Erythromycin; CS; vancomycin; (clindamycin, for necrotic infection of the superficial and deep fascia)

Benzylpenicillin ± gentamicin

Vancomycin; CS

Amoxicillin

Trimethoprim; nitrofurantoin; FQ

*Staphylococcus aureus or epidermidis

(Group A, and Groups C and G) Streptococcus (Group B)

Streptococcus, viridans group (endocarditis) Streptococcus faecalis (enterococci) UTI

110


Majid A. K. Lafi

Benzylpenicillin or amoxicillin + gentamicin or streptomycin Benzylpenicillin

Vancomycin + gentamicin or streptomycin

Benzylpenicillin or amoxicillin

Erythromycin; CS; vancomycin; rifampicin (or chloramphenicol for meningitis)

Moraxella (Branhamella) catarrhalis

Co-amoxiclav

Erythromycin or a tetracycline

*Neisseria gonorrhoeae (gonococcus)

Amoxicillin (+ probenecid) or FQ or ceftriaxone

Spectinomycin; cefixime or cefotaxime

Neisseria meningitis (meningococcus)

benzylpenicillin

Chloramphenicol; cefotaxime

Bacillus anthracis (anthrax)

Benzylpenicillin

Erythromycin; a tetracycline

Clostridium perfringens

Benzylpenicillin

Metronidazole; clindamycin

Benzylpenicillin

A tetracycline

Erythromycin

Benzylpenicillin

Amoxicillin ± gentamicin

Erythromycin + gentamicin

Oropharyngeal strains

Benzylpenicillin


Gastrointestinal strains

Metronidazole

Co-amoxiclav; clindamycin; imipenem; chloramphenicol Tetracycline

Endocarditis

Streptococcus, anaerobic *Streptococcus

pneumoniae (pneumococcus)

Metronidazole

Gram-negative cocci

Gram-positive bacilli

(gas gangrene)

Clostridium tetani (tetanus) Corynebacterium diphtheriae (diphtheria) Listeria monocytogenes (listeriosis)

Enteric gram-negative bacilli *Bacteroides

Erythromycin or FQ *Campylobacter jejuni *Enterobacteriaceae e.g. *Enterobacter aerogenes *Escherichia coli *Klebsiella pneumoniae *Proteus species FQ or an oral CS Lower urinary tract

Amoxicillin or trimethoprim

Septicaemia

Gentamicin or cefotaxime

FQ; imipenem

*Helicobacter pylori (peptic ulcer)

Amoxicillin + clarithromycin + metronidazole (plus omeprazole)

Amoxicillin + metronidazole + bismuth chelate; or tetracycline + clarithromycin + bismuth chelate

111



*Salmonella typhi (typhoid fever)

Ceftriaxone; FQ

Chloramphenicol; co-trimoxazole; amoxicillin

*Other Salmonella

FQ

Amoxicillin; co-trimoxazole; chloramphenicol

*Shigella

FQ

Trimethoprim; ampicillin (paediatric: nalidixic acid)

*Yersinia enterocolitica

Co-trimoxazole

FQ, gentamicin; tetracycline

*Bordetella pertussis (whooping cough)

Erythromycin

Ampicillin

*Brucella (brucellosis)

Tetracycline + streptomycin or gentamicin

Co-trimoxazole; rifampicin + tetracycline

Calymmatobacterium granulomatis (granuloma inguinale) *Fusobacterium

A tetracycline

Streptomycin or gentamicin or co-trimoxazole

Benzylpenicillin

Metronidazole or clindamycin

Gardeneralla vaginalis (anaerobic vaginosis)

Metronidazole (oral)

Topical clindamycin or metronidazole; oral clindamycin

*Haemophilus ducreyi (chancroid) *Haemophilus influenzae Meningitis, epiglotitis, arthritis or other serious infections Upper respiratory infections and bronchitis Legionella pneumophila (legionnaire s disease)

Erythromycin

FQ

Cefotaxime or ceftriaxone or amoxicillin

Chloramphenicol

Co-trimoxazole or amoxicillin

Co-amoxiclav; CS (3r generation)

Pasteurella multocida (from animal bites) *Pseudomonas aeruginosa Urinary tract infection

benzylpenicillin

Co-amoxiclav or CS

FQ

Ticarcillin; piperacillin; mezlocillin

Other infections

FQ; ticarcillin; mezlocillin; piperacillin; gentamicin; amikacin Tetracycline

Ceftazidime; imipenem

Other gram-negative bacilli

Vibrio cholerae (cholera)

Erythromycin ± rifampicin

FQ

Acid-fast bacilli *Mycobacterium tuberculosis Isoniazid + rifampicin + 112

Other antitubercular agents include cycloserine, thiacetazone, ethionamide,


Majid A. K. Lafi

Pulmonary (1st 2 months)

pyrazinamide ± ethambutol (or streptomycin) (2HRPE)

kanamycin, amikacin, capreomycin, ciprofloxacin, and ofloxacin.

(next 4 months)

Isoniazid + rifampicin (4HR)

Ethionamide or cycloserine

Mycobacterium leprae (leprosy)

Dapsone + rifampicin ± clofazimine

Actinomycetes Actinomyces israelii (actinomycosis) Nocardia

Benzylpenicillin

A tetracycline

Co-trimoxazole

Amikacin; minocycline; imipenem

Chlamydiae Chlamydia psittaci (psittacosis, ornithosis)

Tetracycline

Chlamydia trachomatis Trachoma

Azithromycin

Tetracycline (oral plus oral); a sulphonamide (topical plus oral)

Inclusion conjunctivitis

Erythromycin (oral or i.v.)

A sulphonamide

Pneumonia

Erythromycin

A sulphonamide

Urethritis, cervicitis

Doxycycline or azithromycin

Erythromycin or ofloxacin

Lymphogranuloma venereum Chlamydia pneumoniae (TWAR strain)

Tetracycline

Erythromycin

Tetracycline

Erythromycin

Mycoplasma pneumoniae

Erythromycin or tetracycline

Clarithromycin; azithromycin

Ureaplasma urealyticum

Erythromycin

Tetracycline; clarithromycin

Tetracycline

Chloramphenicol; FQ

Borrelia burgdorferi (Lyme disease)

Doxycycline or amoxicillin

Ceftriaxone or cefotaxime or benzylpenicillin

Borrelia recurrentis (relapsing fever) Leptospira (leptospirosis)

Tetracycline

Benzylpenicillin

Benzylpenicillin

Tetracycline

Treponema pallidum (syphilis) Treponema pertenue (yaws)

Benzylpenicillin

Tetracycline or ceftriaxone

Benzylpenicillin

Tetracycline

Chloramphenicol

Mycoplasma

Rickettsia Q fever, typhus

Spirochaetes

113

Antimicrobial Drugs - Antifungal Drugs


ANTIFUNGAL DRUGS 1. Drugs used to treat superficial mycoses (fungal infections) a. Polyene antibiotics (e.g. nystatin and amphotericin B) b. Imidazoles (e.g. ketoconazole, clotrimazole, miconazole, and econazole) c. Others (e.g. griseofulvin, flucytosine)

Introduction Superficial fungal infections occur much more frequently than system fungal infections. The superficial mycoses are caused by two groups of organisms: 1. Candida species 2. Dermatophytes

2. Drugs used to treat systemic mycoses a. Amphotericin B b. Flucytosine c. Ketoconazole d. Miconazole

Superficial infection with dermatopytes is more common than superficial candidiasis. Candidal infections usually occur in mucous membranes or moist skin. However, candidal chronic infections may occur in scalp, skin, and nails. Dermatophytoses are generally confined to the skin, hair, and nails.

POLYENE ANTIBIOTICS Nystatin Nystatin derived from Streptomyces cultures from the soil of Virginia and its name derived from the New York State Department of Health that was responsible for its culture. It is used topically for the treatment yeast-like fungi such as Candida albicans, also for vaginal infections. It is too toxic to be used systemically.

Systemic mycoses can be classified into two types: 1. Opportunistic infections 2. Non-opportunistic infections The opportunistic mycoses, e.g. candidiasis, aspergillosis, cryptococcosis, mucormycosis, occur primarily in debilitated or immunocompromised host. While, non-opportunistic infections may occur in any subject; these infections are relatively uncommon and include sporotrichosis, blastomycosis, histoplasmosis, and coccidiodomycosis. These infections often pose a therapeutic problem because of their resistance to drugs, consequently requiring a long duration with high dose therapy with drugs that often exhibit high toxicities.

Amphotericin Amphotericin B is a polyene compound that remains the drug of choice for most serious systemic fungal infections. It has serious toxic effects, primarily nephrotoxicity. It must be given intravenously; in meningitis due to fungal infection; it has to be given intrathecally to achieve adequate concentration in the CSF.

Antifungal Drugs

IMIDAZOLES

The antifungal drugs are classified into two main groups:

The imidazole antifungal agents constitute members which are used for 114


Majid A. K. Lafi

superficial and systemic infections like ketoconazole, and to a lesser extent miconazole (rarely used systemic infections because of high toxicity); and clotrimazole and econazole are used for superficial infections and for topical application only. The imidazole agents are useful for both dermatophytic and candidal infections.

Miconazole

Ketoconazole

Econazole

Ketoconazole is the only imidazole antifungal drug that can be administered by mouth for treatment of superficial mycoses; it is active against a variety of fungal infections, dermatophytic infections and candidiasis of the skin, mouth, and vagina. Its oral absorption is variable, and only partially excreted in the urine. It carries a potential for hepatic toxicity; therefore, a regular assessment of hepatic function should be made. Because it blocks steroid synthesis, it is useful in Cushing s syndrome, and may lead to hypoadrenalism and reduction in testosterone levels (antiandrogenic activity).

Econazole is an imidazole antifungal agent applied topically only. The drug is effective in Tinea infection and for superficial candidiasis.

Miconazole is an imidazole antifungal agent available for topical and systemic administration. Because of high toxicity, the drug rarely used systemically; thus, it is a drug of first choice for dermatophytic infections, and cutaneous and vaginal candidiasis.

OTHERS Griseofulvin Griseofulvin is an antibiotic, isolated from Penicillium griseofulvin in 1939, which is active when given orally but not topically. Its only use is in the systemic treatment of dermatophytosis. The absorbed drug has an affinity for diseased skin and is deposited there, bound to keratin, making keratin resistant to fungal growth. Thus, new growth of hair or nails is free of infection. Therefore, it must be administered for 2-6 weeks for skin and hair infections. It is a hepatic enzyme inducer.

It follows that because of the serious toxicity associated with its systemic use, oral ketoconazole is reserved for fungal infections that have failed to respond to topical agents like clotrimazole and miconazole. A topical preparation of ketoconazole is now available but its use is approved only for dermatophytic infections but not for candidiasis.

Flucytosine Flucytosine is available for oral or parenteral use. It is mainly used in a synergistic combination with amphotericin against Cryptococcus neoformans. High plasma levels that often occur with renal impairment are associated with bone marrow toxicity, and monitoring of plasma concentration is therefore advised.

Clotrimazole Clotrimazole is a synthetic imidazole derivative that is topically active against dermatophytic infections and candidiasis of the skin, mouth and vagina.

115



Table 4.9. A summary of drugs of choice for superficial and systemic mycoses. Infection or organism Superficial infections

Drug of choice

Alternative Drugs

Dermatophytoses

Miconazole (topical) Clotrimazole (topical)

Tolnaftate (topical) Griseofulvin (oral) Ketoconazole (oral)

Tinea unguium (nail ringworm) Tinea capitis (scalp ringworm) Tinea pedis (athlete s foot)

(These are acid sensitive; thus, benzoic acid ointment, salicylic acid 4.65%, boric acid 2.87% in alcohol and ethyl acetate as paint)

Candidiasis of Skin and vagina

Clotrimazole (topical) Miconazole (topical)

Nystatin (topical) Ketoconazole (oral)

Mouth

Clotrimazole (topical)


Intestine

Nystatin (oral)

Systemic infections Aspergillus species

Amphotericin B

None

Blastomyces dermatitidis

Amphotericin B

Ketoconazole

Candida species

Amphotericin B

Ketoconazole

Coccidioides immitis

Amphotericin B

Ketoconazole

Histoplasma capsulatum

Amphotericin B

Ketoconazole

Cryptococcus neoformans

Amphotericin B

Ketoconazole

Mucur species

Amphotericin B

None

Paracoccidioides brasiliensis

Ketoconazole

Amphotericin B

Potassium iodide; amphotericin B

Ketoconazole

Sporothrix schenkii

116


Majid A. K. Lafi

ANTIVIRAL DRUGS with persistent HIV-1 replication despite ongoing therapy retroviral infections. Local injection site reactions are the most common side effects associated with enfuvirtide therapy.

Introduction Viruses are obligatory intracellular parasites with no growth or reproduction in vitro except in some very specialised laboratory techniques. Viruses cannot produce energy (ATP) and protein and are entirely dependent on the host. The process of viral replication includes:

Amantadine Amantadine acts by inhibiting the uncoating of the viral RNA of influenza A within host cells, therefore, preventing its replication. Amantadine is of value in the prophylaxis of infection with influenza A virus. It stimulates the CNS and can cause convulsion. Amantadine is also used in the treatment of Parkinsonism.

1. Viral penetration into host cells (blocked by enfuvirtide (HIV), γ-globulins, nonspecific) 2. Viral uncoating (blocked by amantadine, influenza A) 3. Early protein synthesis (blocked by fomivirsen, CMV) 4. Nucleic acid synthesis (replication of DNA or RNA, interfered with by purine analogues like acyclovir, pyrimidine analogues like idoxuridine, and reverse transcriptase inhibitors like zidovudine, AZT) 5. Late protein synthesis and processing (interfered with by protease inhibitors like ritonavir) 6. Assembly (maturation) of viral components 7. Release from the cell

Fomivirsen Fomivirsen binds to target mRNA resulting in inhibition of immediate early region 2 protein synthesis, thus inhibiting virus replication. Fomivirsen is injected

intravitreally for the treatment of CMV retinitis in patients with AIDS and is indicated for patients who are intolerant of or unresponsive to alternative therapies. Iritis and vitreitis as well as increased intraocular pressure and changes in vision are associated with fomivirsen therapy.

Attempts to find antiviral drugs have been very successful and their use is complicated as the virus reaches a peak titre before symptoms are observed. Therefore, a drug used to prevent viral replication is best used prophylactically rather than left till gross symptoms occur. There are a few agents, mostly in the developmental stage, which show promise of antiviral activity.

Idoxuridine Idoxuridine is a pyrimidine analogue and is preferentially incorporated in viral DNA producing material. It is very toxic and cannot be used systemically. As it is not specific for viral DNA, idoxuridine causes bone marrow depression and leucopenia.

Antiviral Drugs Enfuvirtide

Acyclovir

Enfuvirtide is a fusion inhibitor that blocks entry into the cell by preventing the

Acyclovir is a guanine analogue that is activated within herpes infected cells. Under the influence of virus thymidine kinase acyclovir is converted into active acyclovir triphosphate. This competes with

conformational changes required for the fusion of the viral and cellular membranes. It is useful in combination with other antiretroviral agents in patients 117

Antimicrobial Drugs - Antiviral Drugs


deoxyguanosine triphosphate as a substrate for viral DNA blocks replication. It is much more active against herpes DNA polymerase than that of the normal host cell, making it a highly selective antiviral agent.

Didanosine Didanosine is also a reverse transcriptase inhibitor. It may increase CD4+ counts in patients with HIV infection. Adverse effects include pancreatitis and peripheral neuropathy.

Acyclovir is active against herpes simplex virus and to a lesser extent varicella-zoster virus. It has been the drug of first choice for severe infections caused by these viruses. It can be administered topically in the eye, on the skin, orally (though poorly absorbed), or intravenously (slowly). Acyclovir is particularly useful in immunocompromised patients. It has low toxicity.

HIV Protease Inhibitors The process of HIV replication involves the production of protein and also a protease that cleaves the protein into component parts that eventually reassembled into virus particles. Protease inhibitors interfere with this essential process. Protease inhibitors have been shown to reduce viral RNA, increase CD4+ counts and improve survival compared with that observed with placebo. The representative agent of this group is ritonavir.

Famciclovir Famciclovir is similar to acyclovir except that it is well absorbed from the gut. It is a prodrug, converting to penciclovir that has a similar spectrum of activity to that of acyclovir.

Ganciclovir

Others

Ganciclovir is similar to acyclovir in its mode of action but it has a broader antiviral spectrum of activity. It is useful for the treatment of serious cytomegalovirus (CMV) infections in immunocompromised patients. However, it has dose-dependent bone marrow depression effects. Therefore, its use limited to life- or sight-threatening CMV (CMV retinitis) infection in immunocompromised patients.

Tribavirin Tribavirin is an example of antimicrobial agents that are used by inhalation (aerosol or nebulised solution) for respiratory tract infections, to avoid systemic adverse effects. It is a synthetic nucleoside useful for severe respiratory syncytial virus bronchiolitis in infants and children.

Interferons HIV Reverse Transcriptase Inhibitors

Interferons are produced by infected host cells that contain replicating viruses. They appear to protect other cells from attacks not only by the offending virus but also other viruses, irrespective of their nucleic acid composition. Interferons are expensive to produce from human white blood cells but recently have been extracted from clones of bacterial cells obtained by genetic engineering.

Zidovudine Zidovudine (azidothymidine, AZT) is a reverse transcriptase inhibitor, has been shown to prolong the life and wellbeing of patients with human immunodeficiency virus (HIV) infection. HIV replicates by converting its single stranded RNA into double stranded DNA that is incorporated into host DNA (this is the reverse of the normal cellular transcription of nucleic acids).

Interferonα2 is the most commonly used, available as subtype interferon α2a and α2b. These differ in a single amino acid but are therapeutically equivalent. They are used in the treatment of hepatitis B and hepatitis C. 118


Majid A. K. Lafi

immune response against virulent organisms, e.g. influenza, adenovirus, polio, measles, rubella, yellow fever, smallpox.

Viral Vaccines Viral vaccines are composed of killed or attenuated organisms that will induce an

Table 4.10. A summary of drugs of choice for viral infections Organism Herpes Varicella-zoster Chickenpox

Drug of Choice

Acyclovir

Important Remarks Phosphorylated acyclovir (by virus specific thymidine kinase) inhibits DNA polymerase & thus prevents viral DNA formation. Use in immunocompromised (i.v.)

Zoster (shingles)

Acyclovir

In immunocompetent (oral) In immunocompromised (i.v.)

Herpes simplex Ocular keratitis

Acyclovir

(ointment)

Labial (fever blisters)

Acyclovir

(cream and/or oral)

Genital

Acyclovir

(cream and/or oral)

Encephalitis

Acyclovir

(i.v.)

Disseminated

Acyclovir

(i.v.)

Human Deficiency (HIV)

Immuno- Zidovudine Virus Didanosine Ritonavir

Hepatitis B, C or D

Interferon α2a & α2b

Influenza A

Amantadine

Cytomegalovirus (CMV)

Ganciclovir

Respiratory Syncytial Virus Coryza (common cold)

Tribavirin Zinc

Reverse transcriptase inhibitor Reverse transcriptase inhibitor Viral protease inhibitor (Protection of foetuses from becoming infected by the virus in HIV-infected pregnant mothers) 1. Induces enzymes that degrade viral RNA (in uninfected cells) 2. Indirectly stimulates the immune system Interferes with the uncoating and release of viral genome into host cell. It is useful for prevention & treatment (debilitated persons) Similar to acyclovir in action, useful in CMVinfected immunocompromised patients; it may produce bone marrow depression. (Inhalational) Lozenges containing duration of symptoms.

119

zinc

shortens

the


Blocked by

enfuvirtide (HIV), γ-globulins (non-specific)


Blocked by amantadine (Influenza A)

Viral uptake Uncoating

Blocked by fomivirsen (CMV)

Early protein synthesis

Host cell

Nucleic acid synthesis

Late protein synthesis & processing Packaging & assembly

Viral release

Fig.4.5. The major sites of action of antiviral agents

120

Blocked by purine analogues (acyclovir), pyrimidine analogues (idoxuridine), & reverse transcriptase inhibitors (zidovudine, AZT) Blocked by protease inhibitors (ritonavir, HIV)


Majid A. K. Lafi

ANTIPARASITIC DRUGS

Table 4.11. Drugs of choice for treatment and prevention of malaria

Plasmodial strain P vivax P falciparum (chloroquinesensitive) P falciparum (chloroquineresistant)

Drugs of choice for Prevention of relapse Primaquine* NA**

Treatment of acute attack Chloroquine Chloroquine

Quinine plus pyrimethamine/ sulfadoxine or tetracycline; or i.v. quinine infusion

NA

Prophylaxis Chloroquine Chloroquine

Chloroquine plus pyrimethamine/ sulfadoxine + proguanil; or chloroquine plus doxycycline

* Primaquine is given following control of the acute attack. ** Not applicable, malaria caused by P falciparum does not relapse following successful treatment of the acute attack.

121

Antimicrobial Drugs - Antiparasitic Drugs


Table 4.12. Drugs of choice for protozoal infections

Amoebiasis

Causative protozoan and important remarks Entamoeba histoltyica

Bowel lumen

(to eradicate cyst give)

Disease

Drugs of choice

Diloxanide

Tissue-invading

Metronidazole In severe cases, to lessen the risk of opportunistic infection, perforation, & peritonitis, give

Tetracycline

Treatment of tissue-invading amoebiasis should be followed by a luminal amoebicide to eradicate the source, give

Diloxanide

Giardiasis

Giardia lamblia

Leishmaniasis Visceral

Leishmania species

Metronidazole Tinidazole Primaquine Mepacrine

Resistant cases may benefit from combining antimonials with allopurinol, pentamidine of amphotericin B.

Na stibogluconate Meglumine antimoniate

Cutaneous

Mild lesions heal spontaneously; antimonials or stibogluconate may be injected intralesionally.

Pneumocystosis (HIV-infection)

Pneumocystis carinii

Co-trimoxazole

Intolerant or resistant cases may benefit from

Pentamidine

122


Toxoplasmosis

Trichomoniasis Trypanosomiasis African (Sleeping sickness)

American (Chaga s disease)

Majid A. K. Lafi

Toxoplasma gondii

Pyrimethamine plus sulphonamide; or tetracycline

(Self-limiting, treat immunocompromised or prior to pregnancy) Trichomonas vaginalis

Metronidazole

Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense For early phase For later phase

Pentamidine, suramin Melarsoprol

Trypanosoma cruzi

Nifurtimox

Table 4.13. Drugs of choice for parasitic worms Worm Class Nematodes (round worms) Intestinal

(In immunocompromised ) Cestodes (Tapeworms) Trematodes (Flukes) Hydatid cysts (when surgery is contraindicated or when cysts rupture or spill during surgery)

Common Name Pinworm

Official Name Enterobius vermicularis

Drug of Choice Pyrantel pamoate; Mebendazole; Piperazine

Giant round worm

Ascaris lumbricoides

Mebendazole; Pyrantel pamoate; Piperazine citrate; Levamisole

Hookworm

Ancylostoma duodenale

Bephenium; Mebendazole; Pyrantel pamoate

Threadworm

Strongyloides stercoralis

Thiabendazole

Beef tapeworm Pork tapeworm Blood flukes Intestinal Urinary

Schistosoma species mansoni & japonicum haematobium Echinococcus granulosus

123

Niclosamide; Praziquantel Praziquantel

Albendazole & mebendazole or praziquantel

CNS-Pharmacology - General Principles


CNS-PHARMACOLOGY (GENERAL PRINCIPLES) potential by increasing Na+ permeability of the cell membrane (decreasing negativity inside the cell resulting in reduced value as measured by -mV). An IPSP lowers the resting membrane potential (hyperpolarisation) by increasing Cl- influx (increasing negativity inside the cell and thus increased value as measured by mV).

Introduction The resting membrane potential of the neurone in the CNS is about (-70 mV). The neurone can be affected by excitatory or inhibitory actions which give rise to an excitatory postsynaptic potential (EPSP) or an inhibitory postsynaptic potential (IPSP). An EPSP raises the resting membrane

Benzodiazepines Barbiturates Valproic acid Vigabatrin

Lamotrigine

Inhibitory neurone

Excitatory neurone

mV 0

Ethosuximide Carbamazepine Phenytoin

Action potential

Threshold potential

-60 EPSP

EPSP Resting potential

-70 IPSP Hyperpolarisation

Fig. 5.1. A simplified representation of polysynapses in the CNS showing excitatory and inhibitory neurones modulating the excitability of a primary neurone. The excitatory transmitter (e.g. glutamate) produces EPSP (excitatory postsynaptic potential) which may raise the resting potential high enough to reach the threshold and then fire an action potential. While, inhibitory transmitters (e.g. GABA) produces IPSP (inhibitory postsynaptic potential) which lowers the resting potential making it at a distance from the threshold potential (hyperpolarisation); therefore, reducing the possibility of firing action potential.

124


Majid A. K. Lafi

Transmission of electrical impulses in the neurones of the CNS mainly takes place by the action of chemical transmitter substances, neurotransmitters, which are released from presynaptic nerve endings and act on

postsynaptic membranes. In addition to distinctly released neurotransmitters there are a number of putative (suggested) neurotransmitters and neuromodulators with more diffuse actions.

Table 5.1. A summary of the possible sites of drug action in the CNS

Mechanism 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Action potential Synthesis Storage Metabolism Release Reuptake Degradation Receptor Conductance Second messenger

Drug

Specific Drug Actions

Blocks action potential Synthesis of false transmitter Depletes transmitters Blocks amine breakdown Reduces transmitter release Increase transmitter availability Blocks acetylcholinesterase Blocks postsynaptic effects Hyperpolarisation Blocks phosphodiesterase

Catecholamines

Besides the principle actions of drugs on various mechanisms, many drugs are employed because they have a specific action on one of the functions in the CNS. There are essentially three different anatomical sites in the brain to which specific function can be assigned ( Table 5.2.). There is a complex range of interrelationships, e.g. the locus caeruleus interconnects the reticular formation, hypothalamus and cortex.

The CNS contains separate neuronal systems that involve catecholamines like dopamine, noradrenaline, and adrenaline. Each system is anatomically distinct and serves separate functions.

Serotonin Serotonin (5-hydroxytryptamine, 5HT) is the chemical transmitter in the tryptaminergic systems that are found mainly in the pons and upper brain stem.

Table 5.2. An overview of the functional organisation of the brain Site Cerebral cortex Limbic system Brain stem

Action

Tetrodotoxin Methyldopa Reserpine MAO-inhibitor Ca-antagonist Cocaine Tacrine Phenothiazines Benzodiazepine Methylxanthines

Functions Motor, sensory, thought

Peptides A large number of neuromodulatory peptides have been identified as endorphinpeptides. These peptides share actions that originally were ascribed to opioids.

Emotions, visceral control Wakefulness, vasomotor & respiratory control

Other peptides: vasoactive intestinal peptide (VIP), glucagon, substance P. These substances are synthesised in the rough endoplasmic reticulum of the nerve cell body as a propeptide that is cleaved into its active form and stored in secretory vesicles.

Acetylcholine Acetylcholine (ACh) is a central neurotransmitter acting with a mixture of nicotinic and muscarinic receptors. 125



Apparently, there is no reuptake mechanism for peptides.

GABA

It is now well established that a neurone may synthesise and release one or more than one neurotransmitter (cotransmission). This is particularly true for neuropeptides.

GABA (gamma-aminobutyric acid) mediates inhibitory actions on local interneurones. Benzodiazepines potentiate the effect of GABA by interacting with GABA-receptor complex (Fig. 5.2).

Glucose

Glutamic acid

GABA vesicle

GABA

BNZ

GABA

Barbiturate -

Cl

Postsynaptic membrane -

Cl channel Fig. 5.2. A simplified schematic representation of synthesis, storage, and release of GABA from GABAergic neurone. When released GABA acts postsynaptically on a specific site that located on GABA receptor complex enhancing entry of Cl- through Cl- channel. Note: Benzodiazepines and barbiturates act allosterically on specific sites located nearby the GABA site on the GABA receptor complex to enhance the action of GABA.

126


Majid A. K. Lafi

glutamate receptor complex to enhance the excitatory effect of glutamate (Fig. 5.3).

Glycine Glycine is another amino acid with inhibitory action (increases Cl- conductance and results in hyperpolarisation) in the spinal cord. However, glycine acts allosterically on

so-called acidic amino acid receptors, glutamate receptor system , causing dislodging of Mg++ and letting Na+ and Ca++ enter, and K+ leave the cell. Glycine can also bind to this receptor system allosterically enhancing the action of glutamate and aspartate (Fig. 5.3.).

Glutamate and Aspartate Glutamate and aspartate are excitatory neuromodulators act on specific sites on the

Glycine (allosteric)

Glutamate

Agonist (NMDA +

Na ++ Ca

++

Mg Postsynaptic membrane

+

K

Fig. 5.3. A simplified schematic representation of acidic amino acid receptor system. Glutamate or aspartate (or N-methyl-D-aspartate, NMDA) can activate the ligand specific site on the receptor system leading to deployment of Mg++ and letting Na+ and Ca++ enter, and K+ leaves the cell. Allosterically, glycine enhances the action of the acidic amino acids. Mg++ ions block the channel in the resting state. Depolarisation by ligand or voltage gating dislodging Mg++. Glycine enhances the action of glutamate to open the channel.

127



Table 5.3. A summary of selected central transmitters and neuromodulators, their functions, agonists and antagonists

Transmitter

Site

Function Dysfunction

Receptor Agonists

Antagonists

Mechanism

Motor control: Nicotinic stimulation Memory: Muscarinic stimulation ↓ : Alzheimer s disease ↑ (relative): Parkinsonism

Nicotine

Dihydro-βerythroidine

Muscarine

Atropine

Muscarine

Atropine

Excitatory: ↑ cation conductance. Excitatory: ↓ K+ conductance; ↑ IP3, DAG Inhibitory: ↑ K+ conductance, ↓ cAMP

Substantia nigra Substantia nigra Pituitary gland Mesolimbic system Mesolimbic system Mesocortical system

↓ : Parkinsonism ↑ : Chorea

D1: SKF 38393

Phenothiazines SCH 23390

(Inhibitory): ↑ cAMP

D2: quinpirole

Phenothiazines Butyrophenones

Inhibitory (presynaptic): ↓ Ca2+ (postsynaptic):↑ K+ conductance, ↓ cAMP.

( (

↓ : Depression ↓:Obsessive-compulsive

5HT1A: LSD

Metergoline Spiperone

Inhibitory: ↑ K+ conductance, ↓ cAMP

5HT2A: LSD

Ketanserine

Excitatory: ↓ K+ conductance; ↑ IP3, DAG

5HT3: 2-methyl-5HT Phenylbiguanide

Ondansetrone

Excitatory: ↑ cation conductance

Prazosin


Yohimbine

Inhibitory (presynaptic): ↓ Ca2+ conductance. Inhibitory:↑ K+ efflux;↓ cAMP

Spinal cord CNS cortex

Basal ganglia

) )

Amygdala Hypothalamus Pons (raphe nuclei) Mesolimbic system

Locus caeruleus & diffuse terminals to hypothalamus & cortex

↓ : Hyperprolactinaemia ↑ : Schizophrenia ↑ : Arousal ↓ : Negative symptoms

disorder ↑ : Anxiety ↑ : Decreased appetite ↑ : Sleep ↑ : Arousal*

Arousal, mood ↓ : Depression ↑ : Mania Decrease in pressure by stimulation

(α1): Phenylephrine

blood α2 -

128

(α2): Clonidine


TransSite mitter GABA Basal ganglia

Majid A. K. Lafi

Function Dysfunction ↓ : Huntington s disease

Most inhibitory ↓ : Convulsions interneurones Amygdala

↓ : Anxiety

Glycine Spinal interneurones & Inhibitory some brain stem interneurones Relay neurones at all levels

Excitatory

Receptor Agonists

Antagonists

Type A: Muscimol

Bicuculline,

Type B: Baclofen

2-OH saclofen

Taurine

Strychnine

Ionotropic

2-Amino5phosphonovalerate

N-Methyl-Daspartate (NMDA): NMDA

picrotoxin

Metabotropic

Hypothalamus & diffuse terminals to all parts of the brain

Endings of primary afferent neurones Pain transmission (ascending) pathways Primary afferents Spinal cord Thalamus Pain inhibiting (modulating, descending) pathways Midbrain Medulla

Arousal

Nociception (algesia, tachykinins)

Antinociception (analgesia, opioid peptides)

: quisqualate

MCPG

H1: 2(m-Fphenyl) histamine H2: Dimaprit

Mepyramine

NK1:

CP99994

Ranitidine

Substance P Methylester

µ (Mu): ¾-Endorphin δ (Delta): Enkephalins

κ (Kappa): Dynorphin

Naloxone Naloxone Naloxone

Mechanism Inhibitory: conductance.

↑

Inhibitory (presynaptic): ↓ Ca2+ Inhibitory (postsynaptic):↑ in K+ conductance. Inhibitory: ↑ Clconductance Excitatory: ↑ cation conductance, (Ca2+).

Inhibitory (presynaptic): ↓ Ca2+ Conductance; ↓ cAMP. Excitatory: ↓ K+ conductance, ↑ IP3, DAG. Excitatory: ↓ K+ conductance; ↑ IP3, DAG Excitatory: ↓ K+ conductance; ↑ cAMP Excitatory: ↓ K+ conductance, ↑ IP3, DAG

Inhibitory (presynaptic): ↓ Ca2+ conductance, ↓ cAMP Inhibitory (postynaptic): ↑ K+ conductance, ↓ cAMP

NA: Noradrenaline; DA: Dopamine; 5HT: 5-hydroxytryptamine (serotonin); ACh: Acetylcholine; GABA: Gamma aminobutyric acid; ↓: Deficiency; ↑: Access. * Fluoxetine (5HT reuptake inhibitor) may produce arousal, insomnia, and reduced appetite. MCPG: α-methyl-4-carboxyphenylglycine NK: Neurokinin

129

Cl-



Table 5.4. A summary of the targets for selected centrally acting drugs Cellular Target

Drug Group/Drug

Membrane lipid Cyclooxygenase Voltage-dependent sodium channel Voltage-dependent sodium channel L-type voltage-dependent calcium channel

General anaesthetic drugs NSAIDs Local anaesthetics Phenytoin, carbamazepine Calcium channel blockers

Opioid receptors Opioid receptors GABA receptor complex GABA receptor complex GABA receptor complex GABA transaminase

Opioid analgesics Opioid antagonists Benzodiazepines (BNZ) Flumazenil ( BNZ-receptor antagonist) Barbiturates Sodium valproate

Acetylcholinesterase Adrenergic receptors Adrenergic receptors

Tacrine Clonidine (α2-agonist) Mianserin (tetracyclic antidepressant, α2antagonist?) Lecithin (ACh precursor) Antihistamine

Cholinoceptors Histamine receptors Dopamine receptors Adenosine receptors Monoamine oxidase

Antipsychotic drugs Caffeine Phenelzine, tranylcypromine, isocarboxazid & deprenyl L-DOPA L-tryptophan

Dopamine synthesis Serotonin synthesis Noradrenaline reuptake Serotonin reuptake

Viloxazine (bicyclic antidepressant) Clomipramine (tricyclic antidepressant) & fluoxetine Amantadine Lithium

Dopamine reuptake Phosphatidylinositol bisphosphate (PIP2) breakdown cAMP breakdown

Caffeine

130


Majid A. K. Lafi

ANTIPSYCHOTIC DRUGS other evidence has lead to the development of the dopamine theory of schizophrenia.

Introduction Antipsychotics are usually employed for the treatment of major psychoses such as schizophrenia. The term neuroleptic is often used for antipsychosis. They cause psychomotor slowing, emotional quietening and in higher doses, psychic indifference to the environment. It may have a sedative effect but it is not a hypnotic.

It has been known that the sympathomimetic drug amphetamine produces a psychosis rather similar to paranoid schizophrenia and this effect was shown to be related to increased release of dopamine and that he effects of this can be reduced by dopamine receptors blockade. Further experimental work suggested that in schizophrenia the dopaminergic neurone is in fact working normally and from post mortem receptors binding studies on human schizophrenia brain tissues that the density of dopamine receptors is higher than normal. In addition, there is a positive relationship between the receptor blocking activity of antipsychotic agents and their clinical effectiveness.

One of the first drugs to be used for its antipsychotic properties was reserpine (Rauwolfia alkaloid), which also reduces blood pressure. It is no longer used, partly because more effective drugs have been developed and partly because reserpine has serious side effects including the production of depressive conditions and suicidal tendencies. The central pharmacological actions of reserpine are due to the disruption of noradrenaline and dopamine storage sites in nerve terminals leading to reduced-release of these neurotransmitters.

Normally there is a balance of dopamine in the limbic system and the substantia nigra. An increased dopaminergic activity in the former gives rise to active schizophrenia and a decrease in the latter gives rise to extrapyramidal symptoms such as Parkinson s disease (Fig.5.4).

A variety of drugs are currently used in the treatment of schizophrenia, which is characterised by added features to personality known, as positive symptoms like: • Hallucination (e.g visual, olfactory and auditory) • Delusions (false unshakable belief of morbid origin not consistent with the patient s social, cultural and educational background) • Thought disorders (organisation, stream of thought; content of thought, such that it drifts away from the point)

There is a long list of antipsychotics of different groups. Within the scope of the objectives of this chapter, it is not possible to go through the pharmacology of each drug separately. Therefore, it is decided to present the essential details in Table 5.6.

Indications of antipsychotics 1. Treatment of acute and chronic schizophrenia 2. Prophylaxis of schizophrenia 3. Treatment and prophylaxis of mania 4. Psychotic depression (depression with psychotic symptoms) 5. Other psychoses (e.g. paranoid psychosis, morbid jealousy, erotomania) 6. Anxiety 7. Organic psychoses (delirium, dementia including Alzheimer s psychotic features)

Schizophrenia may also be characterised by absence of features of personality known, as negative symptoms like: • Apathy (lack of feeling or emotion; indifference) • Being withdrawn (retreat from external reality; reduced ability to relate to people) All of these drugs have in common the ability to block central dopamine receptors. This and 131

CNS-Pharmacology Antipsychotic Drugs


8. Movements disorders (Huntington s chorea, Sydenham s chorea, tics, stuttering) 9. Anorexia nervosa 10.Management of aggressive people (therapeutic restraining, chlorpromazine) 11.Personality disorder (very touchy person, small doses of antipsychotics) 12.Irritable bowel syndrome (trifluoperazine) 13.Peptic ulcer (sulpiride) Vomiting (prochlorperazine) 14.Intractable hiccup (chlorpromazine) 15.Neuroleptanalgesia (droperidol + Fentanyl) 16.Chronic pain (chlorpromazine + fentanyl) 17.Hypertensive crisis of MAO inhibitors (cheese effect)

12.Poikelothermia (disturbance in the setpoint, hypothermia and hyperthermia) 13.Eye (cornea: opacity; retina: pigmentation) 14.Iris (miosis: thioridazine; chlorpromazine: mydriasis)

Onset of Action Generally, the antipsychotic effects of neuroleptics, in the presence of adequate dosages and serum drug concentrations, take several weeks or longer to appear. This delay may be due to an inhibition of presynaptic (autoregulatory) dopamine receptors by neuroleptics leading to an enhanced release of dopamine that counteracts the postsynaptic receptor blockade. As tolerance develops to this autoregulatory receptor phenomenon, postsynaptic blockade becomes more effective. This probably also explains why only a few Parkinsonian-like side effects appear acutely in normal or psychotic subjects given neuroleptics.

Adverse effects 1. Acute dystonic reactions (use anticholinergic, e.g. benzhexol; diphenhydramine; diazepam) 2. Parkinson s syndrome 3. Akathisia (motor restlessness, severe sense of agitation), use less potent antipsychotics, β-blockers, or a benzodiazepine 4. Tardive dyskinesia (oral-facial involuntary movements, 10-30%), no satisfactory treatment 5. Anticholinergic (e.g. glaucoma, dry mouth, urinary retention, confusion in the elderly) 6. Endocrine (e.g. hyperprolactinaemia, gynaecomastia, galactorrhoea, amenorrhoea, erectile impotence) 7. Postural hypotension (α-antagonist activity) 8. Sedation (antihistamine effect) 9. Neuroleptic malignant syndrome (hyperpyrexia, disturbed consciousness, muscular rigidity, myoglobinaemia, use dantrolene, bromocriptine) 10.Proconvulsant (lower seizure threshold, particularly phenothiazines) 11.Cardiotoxicity (quinidine-like activity)

132

However, antipsychotics have rapid onset of actions for the following indications: severe anxiety, acute mania, acute psychotic states (for sedation and restraining), intractable hiccup. Note: Antipsychotics are used as therapeutic restraints in severe schizophrenia (to restrain aggressive over-excited persons) by an effect on the basal ganglia leading to generalised dystonia. For this purpose, usually a large dose and potent agent is required (e.g. fluphenazine, or chlorpromazine).


Majid A. K. Lafi

Parkinsonism Hypokinesia Dystonic syndrome Hyperprolactinaemia

Schizophrenia Dyskineasia-Chorea Tardive dyskinesia Nausea

Dopamine

Dopamine

Fig. 5.4. A simplified representation of dopamine balance in the CNS with the possible clinical consequences. If the balance is tilted in favour of dopamine then CNS disorders like schizophrenia, dyskinesia-chorea, and tardive dyskinesia may be produced; however, if the balance tilted against dopamine then CNS disorders like Parkinsonism and dystonic syndromes.

Table 5.5. Antipsychotics may produce the following extrapyramidal reactions, range of onset time and features are also listed.

Reaction Acute dystonia

Onset Hours to 5 days

Parkinsonism

5

30 days

Akathesia

5

60 days

Tarditive dyskinesia

Months to years

Features Spasm of tongue, neck, face & back Tremor, shuffling gait, drooling, stooped posture, instability Compulsive, repetitive motions; agitation Lip-smacking, worm-like tongue movement, fly-catching

133



Table 5.6. A summary of selected antipsychotics used in schizophrenia and related disorders Antipsychotics

Adverse Effects

Remarks about Uses

(mg)

Phenothiazines Chlorpromazine (Largactil) Fluphenazine (Modecate) Trifluoperazine (Stelazine)

100

+++

++

++

++

Useful in violent patients Severe anxiety (short term) Intractable hiccup Antiemetic

+

Maintenance therapy Therapeutic restraining

2

++

+++

+

5

+

+++

+

100

++

+

+++

++

useful in elderly due to low incidence of EP effects

2

+

+++

+

+

Rapid control of acute mania & other psychoses

2

+

+++

+

+

Neuroleptanalgesia

Pimozide

2

+

+

+

+

Thioxanthenes Flupenthixol

3

++

+++

+

++

Benzamides Sulpiride

50

-

+

+

+

100

+++

+

+++

+++

5

++

-

++

1

+

+

+

Thioridazine (Melleril) Butyrophenone Haloperidol (Serenace) Droperidol

Dibenzodiazepine

Clozapine* Theinobenzodiazepine

Olanzapine Benzisoxide Risperidone**

+

++

Retarded schizophrenia (-ve symptoms)

Retarded & monodelusional disorders (e.g. paranoid) Apathetic & withdrawn patients Avoid in manic or hyperactive patients Useful in ve symptoms Useful in resistant schizophrenia, lower seizure threshold, (may cause agranulocytosis, 1-2%) Useful in mania, Less incidence of blood dyscrasia Useful in ve symptoms

* Clozapine is a selective D4 receptor antagonist. ** Risperidone is an antagonist at both D2 and 5HT 2 receptors.

Note: A general rule the more potent antipsychotic drug is expected to produce more EP effects, with less anticholinergic and less sedative actions.

134


Majid A. K. Lafi

DRUGS FOR AFFECTIVE DISORDERS

inhibition of biogenic amine reuptake or degradation, in isolation, can correct the fundamental biochemical abnormalities of depression. It has been hypothesised that antidepressants increase the efficiency of transmission through 5HT and/or noradrenaline pathways but by different molecular mechanism.

Antidepressants Affective (mood) disorders are characterised by severe disturbance of mood and range from depression (unipolar affective disorder) to manic-depressive illness (bipolar affective disorder). These disorders are associated with multiple derangements of normal biological processes, neuroendocrine circadian rhythms. In severe forms, patients develop psychotic symptoms and become detached from reality, thus, these disorders represent extreme expressions (depression and manicdepressive states) of otherwise normal emotional swings, suggesting major alterations in normal biological function (Fig.5.5).

There are two major isoenzymes of MAO: types A and B. A is selectively inhibited by clorgyline and primarily degrades 5HT. B is selectively inhibited by deprenyl (used as protective therapy in Parkinson s disease) primarily degrades dopamine. The available MAO inhibitors used for treating depression are relatively nonselective for A or B isoenzymes. It has been proposed that MAO inhibitors (type A only) produce an improvement in transmission of 5HT pathways.

Typical Symptoms of Depression Depression is characterised by: • Sadness • Anhedonia (loss of interest pleasure in activities) • Crying spells • Emotional liability • Feeling of guilt • Worthlessness and hopelessness

There is a delay in onset of antidepressant effect (7-21 days). This delay may represent the time required to overcome compensatory mechanism. Hence, the initial increase in neurotransmission appears to produce, over time, a compensatory decrease in receptor activity (down-regulation of receptors). Antidepressants like selective noradrenaline reuptake inhibitors, those with mixed action on noradrenaline and 5HT.

and

Depression requiring medical treatment, is usually associated with biological abnormalities (vegetative signs, which include decreased appetite, weight loss, GI disturbances, fatigue, difficulty in concentrating, early morning awakening, and loss of libido. It is well recognised that depression may impair the immune system and may lead to increased susceptibility to infection and risk of cancer.

Tricyclic Antidepressants (TCAs) and Related Compounds These drugs are generally believed to produce their antidepressant activity by virtue of their ability to block the neuronal amine (5HT and noradrenaline) reuptake. This in turn may lead to enhanced availability of the amines in synaptic junctions, and thus, facilitates aminergic neurotransmission (i.e. correction of the disturbed balance of amines).

Two major groups of antidepressant drugs (tricyclic and related monoamine reuptake inhibiting compounds and MAO-A inhibitors) are used in the treatment of depression. No single biochemical effect can explain the mechanism of action of these antidepressant drugs. It is unlikely that

There is a long list of TCAs and related compounds and going through a detailed pharmacology of each drug is beyond the 135

CNS-Pharmacology - Drugs for Affective Disorders

scope of this volume. Therefore, it is decided to present a summary of the pharmacology of these agents in Table 5.8 and Table 5.9.


7. 8. 9. 10. 11. 12.

Indications 1. Depression (unipolar, bipolar and reactive depression) 2. Prophylaxis of depression (seasonal depression) 3. Obsessive-compulsive disorder (clomipramine, fluoxetine) 4. Phobias (an unusual or morbid fear from a condition, e.g. agoraphobia, clomipramine) 5. Anxiety (superior to diazepam because no risk of addiction, suitable for long term therapy, amitriptyline) 6. Nocturnal enuresis

13. 14. 15. 16.

Premature ejaculation Neurogenic pain Chronic pain (in cancer) Peripheral neuropathy Migraine headache Rumination disorder (in man , the regurgitation of food after almost every meal, part of it being vomited and the rest swallowed; a condition seen in infants) Attention deficit (hyperkinetic) disorder (hyperactive child) Alcoholism (as secondary to depression) Eating disorders (bulimia nervosa, fluoxetine) Sleep disorders (narcolepsy, imipramine; hypersomnia, imipramine)

Depression Mania

Amines

Amines

Fig.5.5. A simplified representation the Amine Hypothesis that proposes depression is somehow associated with underactivity of functional amine (5HT and noradrenaline)-dependent neurotransmission. While, mania may be explained by overactivity of amine-dependent neurotransmission. Note: Much of the evidence for the amine hypothesis of depression was available in the early 1950s when reserpine was used in the treatment of hypertension and schizophrenia. In hypertensive and schizophrenic patients as well as normal subjects, reserpine could produce depression and suicidal tendency that were major problems with reserpine. Reserpine interferes with aminergic neurotransmission by inhibiting the vesicular storage of amines like 5HT and noradrenaline, consequently, reducing release and hence synaptic availability of the biogenic amine neurotransmitters.

136


Selective Serotinin Inhibitors (SSRIs)

Majid A. K. Lafi

Reuptake

MAO inhibitors lie in two major groups: Irreversible MAO Inhibitors

The tricyclic antidepressant clomipramine is to certain extent selective amine reuptake inhibitor for serotonin (5HT) than noradrenaline. In recent years, a new group of drugs has emerged which characterised to be selective for serotonin reuptake. This group includes fluoxetine, paroxetine and sertraline. So there is no substantial evidence that this group provides a greater therapeutic efficacy than the older drugs. However, the SSRIs offer an advantage of their lack of antimuscarinic adverse effects.

1. Hydrazine • Phenelzine (Nardil) • Isocarboxazid (Marplan) (Leg oedema and hepatitis as adverse effects) 2. Non-hydrazine • Tranylcypromine (Parnate) (Insomnia, and addiction as adverse effects) Reversible MAO Inhibitors Moclobamide is a reversible inhibitor of MAO-A. Therefore, as tyramine is metabolised by both forms of MAO, if tyramine-containing food is consumed, tyramine is metabolised by MAO-B enzymes as well as being able to reverse the inhibition of MAO-A. Unless very large quantities of tyramine are ingested, this appears to prevent the typical hypertensive reaction seen with conventional MAOIs and tyraminecontaining foods.

A selected list of adverse effects and the possible mode of action for the TCAs and other antidepressants are presented in Table 5.9.

MAO Inhibitors MAO inhibitors were the first to be found to have antidepressant action. In 1951, iproniazid, which was then used as antituberculosis drug, was observed to elevate mood. This effect was attributed to the ability of the drug to inhibit the enzyme monoamine oxidase (MAO). The termination of the synaptic action of monoamines, such as 5HT and noradrenaline, is primarily achieved by neuronal amine-reuptake pump and the activity of MAO located intraneurally. Upon blocking MAO, the vesicular storage and consequently release and synaptic availability of the monoamine neurotransmitter is increased. In fact, this is the opposite to what happens with reserpine that reduces monoamine vesicular storage and consequently reduces release of the amine transmitter. Hence, depression may be associated with the use of reserpine.

Indications for MAO Inhibitors They have no superiority to TCAs or related agents. However, it has been suggested that MAO inhibitors may be more effective in reactive and atypical depression. Onset of action occurs in 1 to 2 weeks and persists as long as 2 to 3 weeks after stopping the treatment. A summary of the adverse effects and their possible mode of action for MAO inhibitors is presented in Table 5.7.

137



Table 5.7. A summary of the following adverse effects, the possible mode of action of MAO inhibitors Adverse effects Possible Mode of Action Hypertensive crisis (cheese Inhibit the metabolism of dietary tyramine leading to effect) enhanced systemic tyramine that causes the release of endogenous neural noradrenaline resulting in enhanced vascular α-receptor activity. Therefore, patients must carry a card stating details of treatment. Hypotension Sympathetic ganglionic block Others similar to that of TCAs •

MAOIs have anxiolytic properties; they are considered as second line drugs

CAUTION: Concomitant use of MAO inhibitors and tricyclic antidepressants may result in mutual enhancement of effects with possibility of hyperpyrexia, hypertension, seizure and death.

Antimanic Drugs

Lithium

Mania is characterised by elevated, expansive or irritable mood, accelerated speech, racing thoughts with flight of ideas, increased activity and reduced sleep. Patients may develop grandiose ideas, act recklessly with overspending, and show increased sexual drive and activity. Impaired judgement (lack of insight) is usually associated with the illness; therefore, the patient and his family should be protected by hospitalisation of the patient.

Patients with mania are at risk of physiological exhaustion and require special attention to nutrition, hydration, and rest. Lithium carbonate and a neuroleptic (or a sedative-hypnotic like diazepam) should be initiated. The additional tranquilliser is necessary because the onset of the antimanic effect of lithium is usually delayed. Further, patients with bipolar disease usually require maintenance therapy with lithium to prevent relapse into mania or depression. Those who do not respond to lithium respond to carbamazepine or sodium valproate (see antiepileptic drugs).

The antipsychotic drugs, lithium and benzodiazepines all are important in the management of mania. Antipsychotics (e.g. chlorpromazine, haloperidol) are preferred to control the acute stages; if more sedation is desired (particularly when using haloperidol) then add a benzodiazepine (e.g. diazepam). Lithium is initiated, as it is the drug of choice for long-term use to prevent relapse of manic attacks, i.e. prophylactic use.

It has been suggested that lithium produces its antimanic activity at least in part by virtue of inhibition of hydrolysis of phosphatidylinositol bisphosphate leading to reduced production of the second messenger diacylglycerol (DAG).

Adverse Effects 1. GI disturbances vomiting, diarrhoea)

138

(nausea,


Majid A. K. Lafi

2. Nontoxic goitre (hypothyroidism, inhibits iodine uptake and thyroid hormone release, affecting 5-15% of patients on long term treatment1) 3. Polyuria 4. Diabetes insipidus 5. Renal tubular impairment (failure to concentrate urine after fluid deprivation and failure to acidify urine after ingestion of ammonium chloride) 6. Leucocytosis 7. CNS toxic encephalopathy (may lead to coma)

Interactions 1. With thiazide that increases lithium renal distal tubular reabsorption leading to lithium toxicity. Note: Lithium exhibits a low therapeutic index, and haemodialysis is indicated in toxicity (apparent volume of distribution is 55 litre). 1

Walker, R. and Edwards, C. (1999) Clinical Pharmacy and Therapeutics. 2nd edition, Page 616.

139



Table 5.8. A summary of tricyclic antidepressants and related compounds, and other antidepressants Drug

Class

Important Remarks WITH SEDATIVE ACTION (useful in depression associated with agitation, or anxiety, and insomnia)

Amitriptyline (Tryptizol)

Tricyclic

More cardiotoxic (sudden death) than others Useful in nocturnal enuresis and anxiety

Dothiepin (Prothiaden)

Tri-

Most widely prescribed in the U.K. Improved adverse effects profile

Mianserin

Tetra-

α2-receptor antagonist (↑ release of transmitter1) Less cardiac risk ; (it does not affect amine reuptake)

Trazodone2

Other

Probably as for mianserin?

Trimipramine (Surmontil)

TriWITH MINIMAL SEDATIVE ACTION (useful in depression associated with retardation, hypersomnia)

Clomipramine (Anafranil) Fluoxetine (Prozac )

Tri-

5HT reuptake inhibitor Useful in obsessive-compulsive patients

SSRI

Selective 5HT reuptake inhibitor Useful in obsessive-compulsive patients

Imipramine (Tofranil) Maprotiline (Ludiomil)

Tri-

Useful in nocturnal enuresis

Tetra-

Proconvulsant activity (fit) Useful in heart disease

Nortriptyline (Aventyl)

Tri-


Viloxazine

Bi-

Noradrenaline reuptake inhibitor

Flupenthixol

Thioxanthene

Antidepressant neuroleptic

α2-adrenoceptors generally mediate inhibition on the excitability of neurones and therefore reducing transmitter release. These receptors are termed autoreceptors (or presynaptic receptors) when inhibited by α2-receptor antagonists like mianserin and probably trazodone the release of neurotransmitter is enhanced (inhibiting inhibitory mechanism). 2 Trazodone may produce priapism and may decrease appetite as adverse effects. Therefore, its use is largely restricted to female patients. 1

140


Majid A. K. Lafi

Table 5.9. A summary of adverse effects that may be encountered with the use of TCAs and other antidepressants.

Group/Drug

TCAs

Overdosage with TCAs & other antidepressants

Mode of Action

Adverse Effects

Muscarinic antagonism (especially amitriptyline, thus, avoid in the elderly, prostatism, narrow angle glaucoma) promoting sympathetic noradrenergic transmission by reuptake inhibition; while muscarinic antagonism may cause dryness in the axilla and groin regions. H1-receptor antagonism (especially doxepine, tolerance develops) ¿1-receptor antagonism3 (thus, useful in premature ejaculation) Increased catecholamine activity (cardiac overstimulation) ( Sympathomimetic) Quinidine-like action (unrelated to receptor antagonism)

Dry mouth, blurred vision, glaucoma, constipation, delayed bladder emptying, and confusion

Lowering seizure threshold in epileptic patients Shift of mood from depression to hypomania in bipolar illness Deriving from anticholinergic toxicity

Trazodone

Quinidine-like action α2-receptor antagonist (↑ release of transmitter)

SSRIs Fluoxetine

↑ synaptic availability of 5HT at certain sites in the CNS

Diaphoresis (excessive apocrine sweating, face, palm & sole, nonthermoregulatory sweating, cold sweat)

Sedation

Orthostatic hypotension Ejaculatory delay Cardiac arrhythmia Adrenergic tremor Cardiac toxicity (most serious adverse effect of TCAs, thus, avoid in patients with conduction defects and heart disease Seizure recurrence Hypomania Dilated seizure

pupil,

fever,

coma,

Cardiac toxicity Sedation, nausea, decreased appetite, priapism ( 1-blocking effect) Arousal, insomnia, decreased appetite

Caution: TCAs in a patient with bipolar illness, usually presenting as depression without history of mania, can precipitate acute mania or rapid cycling.

3

(Frohlich, D. F. (1993) Rypins Basic Science Review, 16th edition, Page 661; Mycek, M. J., Harvey, R. A. & Champe, P. C. (2000) Lippincott s Illustrated Reviews Pharmacology, 2nd edition, Page 121)

141

CNS-Pharmacology - Anxiolytics


ANTIANXIETY DRUGS system (affect), the median fore-brain bundle (reward and punishment systems) and hypothalamus.

Introduction Anxiety, fear for no adequate reason, is the most prevalent symptom in mental illnesses, but it also occurs normally and may have adaptive value. Normal anxiety, marked by dissatisfaction, unhappiness, or apprehension, is of short duration and usually event-related (e.g. as a part of the hypoglycaemic alarm, sitting an examination) and not under the subject s control. Normal subjects, under severe stress may experience periods of increased muscle tension, exaggeration of the discomfort of minor aches and pains, irritability, or sadness. There is evidence suggests that pathological anxiety is not an exaggeration of normal anxiety, because of considerable overlap in the symptoms of anxiety disorders and depressive states. However, the treatments of normal anxiety and pathological anxiety involve the same drugs.

Both BNZ and barbiturates modulate GABA type receptor complex resulting in increased chloride channel ion current. Binding of BNZ increase the frequency of chloride channel openings, whereas binding of a barbiturate like pentobarbital prolongs the duration of the chloride channel open time. The sedative, muscle relaxant, or anticonvulsant effects of BNZ show tolerance fairly rapidly upon prolonged usage, where relief of anxiety does not show tolerance. It has been suggested that a type 1 benzodiazepine receptor may be responsible for the anxiolytic actions of these drugs and a type 2 benzodiazepine receptor may be involved in other central actions. Type 3 benzodiazepine receptor has been proposed to be found in peripheral organs, e.g. stomach and heart. Serotonergic (5HT) innervation to the amygdala has been investigated with BNZ treatment which show reduced activity suggesting 5HT activity in the amygdala may be anxiety-promoting, and its interruption by a benzodiazepine drug could explain the antianxiety effect.

In the past, several drugs had been used for the treatment of anxiety; alcohol, opioids, or barbiturates. In the 1950s, meprobamate was introduced as a more selective antianxiety drug, but later it was found to have barbiturate-like actions. In the late 1960s, benzodiazepines were introduced as the first drugs to relieve anxiety without producing sedative effects. Buspirone, a more recent drug, may effectively treat anxiety with fewer side effects. The antianxiety drugs are also known as anxiolytics and have been known as minor tranquillisers (and neuroleptics as major tranquillisers).

Further evidence which lends support for the theory of the involvement of 5HT in promoting anxiety comes from the development of the second-generation antianxiety drugs like buspirone (5HT partial agonist) which affects 5HT mechanisms. Thus, it is conceivable that GABA- and 5HT modulating brain systems are involved, each having greater or lesser control according to the type of anxiety that predominates in a particular patient.

Benzodiazepines The benzodiazepines (BNZ) or barbiturates bind to GABA type A receptor/chloride channel complex (Fig.5.2.). This GABA neurotransmitter-receptor system in the CNS is the major inhibitory biochemical pathway in the mammalian brain, particularly in the amygdala region and spinal cord. BNZ may act chiefly on the brain reticular activating system (reducing sensory input), the limbic

Flumazenil A benzodiazepine receptor competitive antagonist (partial agonist) Flumazenil with a t of 1 hour, therefore, repeated i.v. doses or infusion may be needed in heavily sedated patients. Flumazenil finds use in the termination of agonist (BNZ) effect in 142


Majid A. K. Lafi

conditions like after endoscopies, and diagnosis and treatment of BNZ-overdose.

6. Paradoxical effects (agitation, overactivity, insomnia may be observed in children and elderly)

Inverse Agonists

Benzodiazepines should be avoided with alcohol as additive effects occur. Tolerance occurs with chronic use and there is a crosstolerance within the sedative-hypnotic drugs and also with ethanol. Several days (a week or more) after withdrawal seizures, rebound insomnia, and inhibition of control of aggression (disinhibition of aggression) may occur. Benzodiazepine should be avoided in pregnancy as far as possible as diazepam is known to be teratogenic in mice. A summary of the important pharmacological characteristics of BNZ is presented in Table 5.10.

Substances known as β-carbolines bind to the benzodiazepine receptor causing stimulation, anxiety, increased muscle tone and convulsions. These substances are called inverse agonist. Note: These substances produce their effects not by inhibiting the action of BNZ, rather, they appear to operate a mechanism via a benzodiazepine site that is not already in operation.

Indications for BNZ 1. Anxiety (generalised anxiety disorder, GAD) 2. Panic anxiety disorder (attack form, lasting minutes or hours, with intense fear of eminent death; high dose of BNZ, or alprazolam) 3. Phobias 4. Insomnia (a benzodiazepine with short t , e.g. midazolam, is preferred when there is no anxiety otherwise it may produce rebound anxiety) 5. Muscle relaxant (tetanus, infantile spasm; BNZ, meprobamate, or barbiturate) 6. Epilepsy (status epilepticus, diazepam i.v., lorazepam i.m., thiopental, chlormethiazole; maintenance therapy, clonazepam) 7. Premedication in anaesthesia 8. Before endoscopy (midazolam) 9. Alcohol withdrawal (BNZ, chlormethiazole)

Buspirone Buspirone is a new generation of antianxiety agents. It is believed to produce its effect by its property as a partial 5HT-receptor agonist as explained above. Unlike benzodiazepines, buspirone has no hypnotic, muscle relaxant or antiepileptic effect. The onset of its antianxiety action is delayed for 2 or more weeks. It causes little or no depression on psychomotor function. It does not benefit benzodiazepine withdrawal symptoms.

Barbiturates An account on barbiturates is presented in the following section (Sedatives and Hypnotics) and also in the section on Antiepileptic Drugs.

Adverse Effects

Others

1. Sleepiness (therefore, operating machines should be avoided) 2. Impaired psychomotor function 3. Amnesia 4. Dependence 5. Hangover (delayed drowsiness; a benzodiazepine with short t , e.g. midazolam, is preferred, less hangover particularly in the elderly)

1. ¾-blockers (e.g. propranolol) can be used where there are somatic symptoms like tremor and tachycardia. 2. Antidepressants (e.g. amitriptyline can be useful where there is depression with anxiety) 3. Antipsychotics (for their sedative action, e.g. trifluoperazine)

143



Table 5.10. A summary of the pharmacology of selected benzodiazepines Drug

Anxiolytic Action

Plasma t h

Metabolites (t h)

Alprazolam (Xanax)

16

Inactive

Chlordiazepoxide (Librium)

20

Clobazam (Frisium)

35

Active (42)

Clonazepam (Rivotril)

25

Inactive

Clorazepate (Tranxene )

Prodrug

Nordiazepam (80)

Diazepam (Valium)

43

Nordiazepam (80)

RO LA

Highly lipid soluble so quickly effective (orally), but slowly effective i.m.; short-acting as anticonvulsant i.v. (rectally, in children)

Lorazepam (Ativan)

20

Inactive

IO SA

Slowly absorbed & distributed (lower lipid solubility; thus, slower onset & offset of effect than diazepam & midazolam); quickly effective i.m., used for status epilepticus

Midazolam (Hypnovel)

3

Inactive

RO SA

Injected as adjunct in anaesthesia for endoscopies, dentistry etc; quickly effective i.m; given sublingually in status epilepticus.

Nitrazepam (Mogadon)

30

Inactive

Superseded because of long t , more sedative-hypnotic, abuse potential in Iraq; 1st choice in infantile spasm

Triazolam (Halcion )

3

Active (7)

Amnesia; psychiatric reactions; very rapid oral absorption

Important Remarks Has antidepressant activity; used in panic disorders, agoraphobia

Desmethyldiazepam

[nordiazepam (80)]

IO LA

Steady-state effect for about 3 days; low lipid solubility; slowly effective i.m.; less sedative (good anxiolytic) Used in epilepsy as well as anxiety Broad spectrum antiepileptic; useful in absence and myoclonus In stomach converted by hydrolysis to nordiazepam

Modified from Laurence, D. R., Bennett, P. N., and Brown, M. J. (1997) Clinical Pharmacology, 8th edition, page 318. R: rapid; I: intermediate; O: onset; S: short; L: long; A: action; note these generally apply to the anxiolytic action of these agents. For other actions the classification may be different, e.g. as anticonvulsant diazepam is shorter acting than lorazepam.

144


1.

Majid A. K. Lafi

Lorazepam, when given i.v., diffuses into the CNS more slowly so that the onset (15 min) and offset of effect are smoother compared to that of diazepam and midazolam both are more lipid soluble with rapid onset of action (2 min). Therefore, at sedative dose lorazepam acts longer and may produce more amnesia for which it may be superior to diazepam and midazolam. Lorazepam has a plasma t of 20 h with a single step metabolism (conjugation) suggesting that it is not seriously accumulative. This is probably why it has a substantial capacity to induce dependence and withdrawal of the drug can be troublesome for which diazepam therapy is used. Lorazepam is metabolised by conjugation (inactive metabolites), a process is less influenced by age than is oxidation of other benzodiazepines like diazepam. Cimetidine (hepatic enzyme inhibitor) does not increase plasma concentrations of lorazepam, while it may increase concentrations of diazepam and chlordiazepoxide by as much as 50%. Clonazepam, unlike diazepam, can be effective in the treatment (chronic use) of epilepsy. This is probably with diazepam tolerance to the antiepileptic action develops rapidly.

2.

3.

4.

Long t drugs/metabolites are appropriate for anxiety. Short t drugs/metabolites are appropriate for insomnia.

•

Sedative action: premedication for surgery, dental surgery (with local anaesthetic), cardioversion, endoscopies and anxiety with agitation; sedative action reduces attention; also amnesia is desired. • Hypnotic action: insomnia

145

CNS Pharmacology - Sedative and Hypnotic Drugs


SEDATIVE AND HYPNOTIC DRUGS without adverse effects such as drowsiness and hangover, and with all hypnotics there is a risk of addiction. Finally, there is no hypnotic that gives you physiological sleep as hypnotics usually cut down on the important component rapid eye movement (REM) sleep that should make up 20% of sleeping time.

Introduction To date, the physiology of sleep is still not fully understood. However, several anatomical centres are believed to be involved, as shown in the following schematic diagram (Fig.5.6). In sleep control centres, the important factor is inhibition produced by excitatory inputs that come from two major sources (reticular activating system). Both of which stimulate the reticular formation (wake centre) that in turn inhibits raphe nuclei (sleep centre):

Sedatives and Hypnotics A sedative should reduce anxiety with little or no effect on mental or motor functions. A hypnotic drug induces more marked depression on CNS function than a sedative and this can be achieved with most drugs, simply by increasing the dose. Most of the sedatives and hypnotics give a graded CNS depression, dose-related (Fig.5.7.).

1. Afferent input from sensory nerves (e.g. tactile, visual, auditory) 2. Impulses from the limbic system (e.g. emotions)

Individual sedative-hypnotic drugs differ in their dose-response to the four principle actions (Fig. 5.7.). The steep dose-response curve, for example, for a barbiturate agent would show that sedation, anaesthesia, and undesirable clinical effects (e.g. respiratory depression) fall in a narrow dose range (thus, low therapeutic index). Whereas a benzodiazepine agent would show that sedation, hypnosis, and undesirable clinical effects fall in a wide dose range (thus, a large therapeutic index) that makes the drug attractive as a sedative.

Reticular Activating System The reticular activating system is a network of neurones that extends from the spinal cord through the medulla and pons to the thalamus and hypothalamus. It receives impulses from all parts of the body, evaluates the significance of the impulses, and decides which impulses to transmit to the cerebral cortex. It also excites or inhibits motor nerves that control both reflex and voluntary movement. Stimulation of these neurones produces wakefulness and mental alertness; depression causes sedation and loss of consciousness.

Sedative-hypnotic drugs can be classified into the following chemical groups:

This means that one is able to sleep when one does not suffer pain or other discomfort, moreover it is possible to fall asleep if you are not bothered about distracting feelings from the limbic system. Also other excitatory stimuli from coffee, tea and nicotine must be considered. Hypnotics produce a state similar to physiological sleep in that the patient is rousable by external stimuli while sleep induced by anaesthetics is not rousable by external stimuli.

1. Benzodiazepines 2. Barbiturates 3. Carbamates (meprobamate) 4. Alcohols (ethanol, chloral hydrate) 5. Cyclic ethers (paraldehyde)

Benzodiazepines This class of drugs has been covered in the section on anxiolytics. Benzodiazepines are generally considered superior to barbiturates in that being characterised by:

Thus, before prescribing a sleeping pill, one should exclude other wakeful stimuli. Unfortunately, there is no sleeping pill

1. High therapeutic index 146


A

Majid A. K. Lafi

B

Cortex

Sleep Raphe Nuclei

Limbic System

+ Sensory Input

GABA Raphe Nuclei

-

+

5HT

Sleep Centre NA

Reticular Formation Wake Centre

Locus Caeruleus Nuclei

Fig.5.6. A simplified schematic representation of the sleep centre. Note: Two major stimulatory inputs coming via afferent sensory pathway (e.g tactile, visual and auditory) and input arriving from the limbic system (A). It is believed that in the raphe nuclei (sleep centre) the release of 5HT from serotonergic neurones mediates sleep. The inhibition of these serotonergic neurones by GABAergic (interneurone) activity leading to inhibition of the sleep centre, thus, wakefulness predominates. This probably explains the stimulatory effects (arousal state) of noradrenaline, 5HT, and histamine acting through the (reticular formation) interconnected with the locus caeruleus and then in turn with the sleep centre (B). 5HT in the mesolimbic system is suggested to produce arousal (it inhibits sleep as the case with the SSRI fluoxetine producing arousal and insomnia); while, in raphe nuclei it is suggested to produce sleep.

Coma -

Barbiturates

Anaesthesia -

Benzodiazepines

Hypnosis Sedation Anxiolysis -

Increasing dose Fig.5.7. A graph showing that sedative-hypnotic drugs like barbiturates (e.g. thiopental) exhibit a steep linear dose-response relationship; i.e. the dose required to produce anaesthesia and coma is close to that producing hypnosis. This type of drugs is described as having a low therapeutic index (low safety). On the other hand, drugs like benzodiazepines (e.g. diazepam) exhibit a non-linear dose-response relationship; i.e. the dose required to produce anaesthesia is very much greater than that required to produce sedation and hypnosis. This type of drugs is said to have a high therapeutic index (high safety).

147

CNS Pharmacology - Sedatives and Hypnotics


Nonbenzodiazepine Hypnotics that Act at the GABAABenzodiazepine Receptor

A list of adverse effects for barbiturates is presented in the section on Antiepileptic Drugs. It would suffice here to mention that barbiturates are characterised by:

Although structurally unrelated to the benzodiazepines, these drugs, represented by zopiclone, zolpidem and zaleplon, act on the same BNZ1 subtype of benzodiazepine receptors; their effects can be blocked by flumazenil, the receptor antagonist. They are largely effective in insomnia, have low tendency for tolerance, rebound insomnia, withdrawal symptoms and abuse potential.

1. Low therapeutic index 2. Risk for addiction

Addiction Addiction is a general term that describes the following clinical conditions that may be observed in a patient taking addictive drug:

Barbiturates

Addiction 1. Compulsion1 to use the drug 2. Using the drug taking the priority to other life activities 3. Symptoms appear upon withdrawal 4. When abstinence2 occurs, reusing the treatment leads to withdrawal symptoms more rapidly. 5. Tolerance leads to take more of the drug (higher dose), hence, withdrawal symptoms are more likely and consequently taking the drug more frequently.

Barbiturates (1903) are derivatives of barbituric acid, which is synthesised from malonic acid and urea. Barbiturates are today mostly used as antiepileptic drugs and for induction of general anaesthesia. They are too toxic to be used as sedatives or hypnotics. Phenobarbital is used as antiepileptic and thiopental for i.v. anaesthesia. Barbiturates exert a general depressant activity on cellular functions (reduce glucose oxidation), depress synaptic transmission by increasing membrane stability and by increasing GABA activity. In the brain, barbiturates predominantly depress the reticular activating system (reticular formation). The long acting phenobarbital (t : 80 hours) is more ionised and less lipid soluble than the ultrashort acting thiopental (initial t : 5 min, terminal t : 11 hr). High lipid solubility makes the drug penetrates the CNS rapidly. After entry into the CNS, thiopental is rapidly redistributed to other parts of the body that is the main reason for their ultrashort action.

Carbamates Meprobamate is a representative of the carbamate group, introduced in 1952. It has anxiolytic-sedative actions, anticonvulsant activity, and central muscle relaxant effect. It has hepatic enzyme induction activity. These days, its use is very much reduced, as this group is largely inferior to the benzodiazepines, and does not have any superiority over barbiturates. In fact, carbamates have a tendency to induce tolerance and dependence after prolonged use, and withdrawal symptoms may be precipitated if their use is terminated abruptly. Generally, its use is restricted in patients who do not respond to benzodiazepines.

Barbiturates rapidly induce tolerance since most of their effectiveness is lost with continued administration over a 2-week period and this explains why patients increase the dose. This makes the patient dependent since withdrawal induces abstinence symptoms. This tolerance depends on a metabolic factor (induction of liver enzymes) and pharmacodynamic factors (biological adaptation, see similar effects for morphine, section on Narcotic Analgesics).

1

An irresistible impulse to perform some act contrary to one s better judgement or will. 2 A refraining from the use of or indulgence in drugs. 148


Majid A. K. Lafi

5. Vomiting (Following oral or i.v. administration, therefore, this action appears to be partly central, besides local gastric irritation. Note: Because the emetic blood alcohol level is below that which induces coma, death from acute alcoholism is rare. When it occurs, it is usually due to suffocation from inhaled vomit.) 6. Hypoglycaemia (Alcohol inhibits gluconeogenesis, particularly, when heavy drinking with a meal that enhanceinsulin response to carbohydrate intake.) 7. Hyperuricaemia: Gout may be precipitated by a. Increased metabolism of adenine nucleotides (e.g. ATP) leading to the production of uric acid. b. At high alcohol level, raised blood lactate compete for renal tubular elimination resulting in reduced excretion of urate 8. Actions on sexual functions: Ethanol produces CNS disinhibition, thus, increasing libido and erection (provokes the desire).

Alcohols Ethyl alcohol behaves like general anaesthetics on the CNS. It has been suggested that the acute effect of alcohol is to block NMDA (N-methyl-D-aspartate) receptors for which the normal agonist is glutamate, the main excitatory transmitter in the brain. Preseumably as a compensatory mechanism, alcohol chronic exposure increases the number of NMDA receptors and also 'L type' calcium channels, while the action of the (inhibitory) GABA neurotransmitter is reduced. Anxiety, insomnia and craving that accompanies sudden withdrawal of alcohol may explain why resumption of drinking brings about relief, and thus perpetuating dependence.

Ethanol is hardly used as a therapeutic compound; however, it has important toxicological interest. The main effects of ethanol are on the CNS. It acts as hypnotic and anaesthetic; and it disinhibits behaviour, which appears as stimulation (an effect on the higher centres). Peripheral actions include vasodilatation, stimulation of gastric acid. The diuretic effect is due to a central action, inhibition on the release of the posterior pituitary hormone ADH.

Chronic Alcohol Consumption Chronic alcohol consumption may lead to: 1. Hepatic enzyme induction: This leads to increased metabolism of testosterone, 2. Direct toxic effect on Leydig cells: This leads to reduced production of testosterone. 3. Testicular atrophy: Both 1 and 2 (above) result in testicular atrophy leading to feminisation (takes away the performance). 4. Foetal alcohol syndrome: teratogenic effects.

Ethanol is considered to be as a rich source of calories that 1 g of ethanol produces 7 calories. The alcoholic are prone to having a variety of pathological conditions, e.g. gastritis, hepatic cirrhosis, brain damage (loss of memory, mental changes). The following list represents the important actions of ethanol. 1. Cutaneous vasodilatation (feeling of warmth, as a result of depressing the vasomotor centre, risk of rapid hypothermia) 2. Increased blood pressure (probably due to centrally mediated sympathetic stimulation) 3. Diuretic action (decreases the release of ADH from the posterior pituitary gland) 4. Gastric mucosa (erosion and petechial haemorrhages due to allowing back diffusion of acid from the gastric mucosa)

149

Withdrawal of Alcohol This may be encountered when an ill or injured alcoholic is admitted to hospital. The possible sequence of events may appear as: 1. Withdrawal syndrome (in 6 hours, craving for alcohol, tremor, and sympathetic overactivity)



2. Acute psychotic attack (delirium tremens3): (in 72 hours, seizures, agitation, anxiety, and excessive sympathetic autonomic activity.

Drugs used in treatment 1. Benzodiazepine (chlordiazepoxide, large dose for sedative action) 2. ¾-adrenoceptor blocker (propranolol for sympatholytic action) 3. Butyrophenone neuroleptic4 (haloperidol for its antipsychotic action)

Chloral Hydrate Chloral hydrate (1869) is the first synthetic hypnotic agent to be used clinically. It is usually given orally in solution. Because of its unpalatable taste a capsule is available. It is irritant to the stomach. Chloral hydrate is a prodrug, rapidly metabolised by alcohol dehydrogenase into the active hypnotic trichloroethanol. The latter undergoes conjugation with glucuronic acid to an inert form that is excreted in the urine. Therefore, avoid in serious hepatic or renal failure. Choral hydrate aggravates peptic ulcer.

Interactions As chloral hydrate is metabolised by the enzyme alcohol dehydrogenase that is also responsible for the conversion of ethanol to acetaldehyde, therefore, resulting in an increase in plasma concentration of alcohol; hence, the action of ethanol is potentiated by chloral hydrate.

3

An acute mental disturbance marked by delirium with trembling and great excitement, and attended by anxiety, mental distress, sweating, GI symptoms, and precordial pain. It is also seen in opium addiction. 4 Phenothiazines (e.g. fluphenazine and chlorpromazine) should be avoided in this condition as they are proconvulsant (lower threshold for convulsion). 150

Cyclic Ethers Paraldehyde (1882) for a long time had been used as a hypnotic (oral and injection) for control of mania, alcohol withdrawal, tetanus, and status epilepticus. These days, paraldehyde is obsolete except for status epilepticus. This is because of many major disadvantages such as unpleasant taste and smell, irritant to the stomach, causes painful muscle cramps when injected i.m., dissolves plastic syringes.


Majid A. K. Lafi

Table 5.11. Comparison between benzodiazepines and barbiturates Nature of comparison Relatively safe Maximal ability to suppress CNS function Respiratory depressant ability Suicide potential Ability to cause physical dependence Ability to cause tolerance Abuse potential Ability to induce drug metabolism Number of drug interactions Safety in intermittent porphyria Effects increased by other CNS depressants Availability of antagonist

Benzodiazepines High Low Low Low Low Low Low Low Few ? Yes Yes

Barbiturates Low High High High High High High High Many No Yes No

Table 5.12. Barbiturates: prototypes and their clinically important pharmacological characteristics.

Sub-group

Prototype

Ultra-short acting

Thiopental (Pentothol ) Secobarbital (Seconal ) Phenobarbital (Luminal )

Short acting Long acting

Action Onset Duration minutes hours

Lipid solubility

Typical Indication

High

0.5

0.2

Induction of anesthesia; convulsion

Moderate

10-15

3-4

Insomnia

Low

60

10-12

Epilepsy

Therapeutic Coverage Anxiolytic Sedative Hypnotic Buspirone Neuroleptics, Meprobamate Benzodiazepines Barbiturates

Anaesthetic

Coma

Fig. 5.8. A simplified schematic representation of anxiolytic, sedative, hypnotic drugs and their most common therapeutic coverage. Buspirone is used for its anxiolytic action; while neuroleptics (major tranquillisers, e.g. chlorpromazine) are used for their anxiolytic-sedative actions, likewise is meprobamate. Further, benzodiazepines (e.g. diazepam) are used for therapeutic coverage including anxiolytic, sedative and hypnotic actions. Furthermore, the therapeutic objective of barbiturates (e.g. thiopental) is extended further to include their anaesthetic action. Of the major adverse effects of the CNS depressant agents are coma and depression of the respiratory and vasomotor centres; this is most apparent with barbiturates then to a much lesser extent with benzodiazepines.

151



Useful Notes • Psychotic states (manic or endogenous depressive illness and schizophrenia) • Psychoneurosis [anxiety, phobias, (exogenous) reactive depression, obsessivecompulsive disorders, and hysteria) • Neuroleptics are effective in positive symptoms, e.g. aggression, hyperactivity, delusions and hallucinations. But negative symptoms, e.g. apathy, respond less well. • In addition to schizophrenia, neuroleptics are also useful in a. Severe anxiety b. Acute mania c. Acute psychotic states d. Therapeutic restraining e. Intractable hiccup • Endogenous depression: TCA + ECT (increase postsynaptic response, if severe state) plus phenothiazine. Benzodiazepines are contraindicated except for alprazolam. • Insomnia of depression (characteristically, early waking) relieved by a sedative antidepressant drug. • Reactive (exogenous) depression (commonly associated with anxiety) is treated with anxiolytic-sedative or a TCA or MAO inhibitor. • Acute behavioural disturbances: a neuroleptic or benzodiazepine, orally, i.m. • Appetite disorders: anorexia (decrease appetite) and bulimia (increased appetite)

anticholinesterase tacrine and the ACh precursor lecithin. • Excessive sex drive in men reduced by oestrogens or by antiandrogen (cyproterone).

PSYCHOSTIMULATS These (amphetamines e.g. dexamphetamine, methylphenidate, and pemoline) increase the level of alertness and/or motivation. Indications: Narcolepsy, attention deficit disorder in children, anorectic (reduce appetite). Adverse effects: tolerance, insomnia, dependence, nausea & vomiting, increase distractibility, paranoid schizophrenia like symptoms.

PSYCHODYSLEPTICS Psychodysleptics (hallucinogens) produce mental changes that resemble those of some psychotic states. They are usually used for nonmedical purposes. • Lysergide (LSD) • Cocaine • Cannabis

a. Anorexia nervosa treated by chlorpromazine (& cyproheptadine) b. Bulimia treated by dexfenfluramine, fluoxetine, TCA. • Narcolepsy benefited by activating noradrenegic mechanisms with amphetamines (dexamphetamine, methylphenidate, mazindol or caffeine). • Attention deficit (hyperkinetic) disorder in children responds to adrenergic activation by dexamphetamine (or methylphenidate or pemoline). • Nocturnal enuresis: TCA (imipramine), desmopressin (ADH) intranasal metered aerosol (for a holiday). • Organic brain syndromes and senile dementia of Alzheimer type may be improved by the centrally acting

152


Majid A. K. Lafi

DRUGS FOR PARKINSON S DISEASE Introduction

Brain dopamine (DA) receptors operate through secondary messenger systems. DA1receptors binding Gs-protein coupled to adenylate cyclase leading to increased cAMP production. DA2-receptors coupled to adenylate cyclase but through an inhibitory Gi-protein that decreases cAMP production. DA2-receptors are also found to be coupled to a mechanism inhibiting the hydrolysis of phosphatidyl inositol bisphosphate (PI2) leading to reduced production of diacylglycerol (DAG) and inositol trisphosphate (IP3). Further, activation of D2receptors hyperpolarises neurones by increasing potassium conductance of both brainstem dopamine neurones and that receive dopamine terminals. Blockade of DA2-receptors by neuroleptic drugs or metoclopramide is associated with their ability to produce Parkinsonism in patients taking such drugs

Parkinson s disease is a progressive disorder of voluntary movement that affects 1% to 2% of the population (in the western world) over 60 years of age has an average onset age in the 50s and 60s. Clinical symptoms of Parkinson s disease manifested by most patients include: 1. Resting tremor 2. Rigidity (increased resistance to passive stretching of muscle) 3. Hypokinesia1 (slowness in initiating and carrying out voluntary movements) 4. Impaired postural reflexes (with a tendency to fall backwards or forwards easily) 1

Slowness of movements is variably called bradykinesia, hypokinesia or akinesia

Normal

Substantia nigra Dopamine (inhibitory)

Corpus striatum Acetylcholine (excitatory)

Putamen GABA (inhibitory)

Parkinsonism DA

ACh

GABA

ACh

GABA

Huntington’s disease DA

Fig. 5.9. A simplified schematic representation of nigrostriatal system of the basal ganglia. The dopaminergic neurotransmission exerts inhibitory actions on the cholinergic neurones of the corpus striatum; the latter exerts excitatory effects on the GABAergic neurones of the putamen. Normally, there is a balance between the dopaminergic and the cholinergic pathways, which is important in the extrapyramidal control of motor activity at the level of the substantia nigra and the corpus striatum. A decrease in the dopaminergic activity (degenerative loss) is believed to be the underlying cause for Parkinson s disease; while, a decrease in the GABAergic activity is believed to be responsible for Huntington s disease. It follows that an increase in dopaminergic activity may result in GABAergic underactivity and hence choreoathetosis (a condition characterised by choreic and athetoid movements ).

153

CNS Pharmacology - Drugs and Movement Disorders

Ramadi, 11 February, 2001

effects, particularly emetic effects from about 80% to less than 15%.

Therapeutic Objectives 1. Promoting dopaminergic activity that may be achieved by the use of certain drugs targeted at different dopaminergic mechanisms. This approach improves certain parkinsonian features like hypokinesia and rigidity, with little effect on tremor. 2. Reducing cholinergic activity by antimuscarinic drugs that, at least, partially redressing the imbalance created by decreased dopaminergic activity. This approach improves tremor, sailorrhoea (excessive secretion of saliva), rigidity, with little effect on hypokinesia.

At present, two fixed combined preparations are available. • Co-careldopa (carbidopa + levodopa, Sinemet) • Co-beneldopa (benserazide + levodopa, Madopar)

Dopaminergic Drugs Levodopa Levodopa (L-DOPA) is the normal physiological precursor of dopamine synthesis, being converted to dopamine by the enzyme dopa decarboxylase. Unlike dopamine, levodopa readily crosses the blood brain barrier (BBB). When levodopa is used alone, it is readily taken up and converted to dopamine by peripheral and central nervous tissues. The peripheral conversion of levodopa is undesirable as it results in peripheral adverse effects, particularly cardiovascular and emetic effects. This problem has been overcome by the concurrent administration of a levodopa decarboxylase inhibitor like carbidopa and benserazide that cannot cross the BBB. The enzyme inhibitor peripherally prevents the (extracerebral) conversion of levodopa to dopamine; therefore the required dose of levodopa is reduced to about 25%. This consequently reduces peripheral adverse

Adverse Effects 1. Postural hypotension ( ) 2. Nausea (effect DA-receptor on the CTZ, reduced by prior administration of domperidone that minimally crosses the BBB) 3. Dyskinesia (extra movements; choreoathetosis, choreic involuntary movements, involving head, lip, tongue; peak dose effect, reduced by the use of slow-release preparations) 4. Mental changes (psychosis, hallucinations; depression) 5. Wearing-off (effect of each dose becomes shorter, i.e. reduced duration of action) 6. End of Dose Akinesia (end of dosage interval; may respond to giving smaller doses of levodopa more frequently) 7. On-Off phenomenon: Severe swings in performance ranging from extra movements (dyskinesia) to complete lack of movement (total akinesia). These swings in performance often do not appear to be directly related to time of drug administration. A summary of the pharmacology of the drugs used in the treatment of Parkinson s disease is presented in Table 5.13.

154


Majid A. K. Lafi

Table 5.13. A summary of the drugs used in the treatment of Parkinson s disease. Approach Drug

Adverse Effects and Important Remarks

Action

Enhance Dopamine Activity Levodopa [+ carbidopa (Sinemet)]

Dopamine precursor [+ extracerebral decarboxylase inhibitor]

Postural hypotension Nausea Dyskinesia Psychosis Decreasing hypokinesia, rigidity, less effective on tremor

Bromocriptine (Parlodel) Lysuride Pergolide Apomorphine

Dopamine agonist

Postural hypotension Nausea Dyskinesia Psychosis

Selegiline* (Deprenyl)

MAO-B inhibitor

Amantadine

↑ dopamine synthesis & release ↓ reuptake

Increases likelihood of adverse effects caused by levodopa or dopamine agonists. Used as adjunct with levodopa (dose reduced by about 50%); improves end-ofdose akinesia1.

Confusion or agitation Benefits wears off, after about 3 months of treatment Used alone when early, and adjunct when disease progresses

Reduce Cholinergic Activity Benzhexol (trihexiphenidyl-HCl, Artane) Procyclidine Orphenadrine Benztropine

CNS (loss of memory, confusion) and HALLUCINATION →DRUG ABUSE Peripherally (dry mouth, decreased sweating, constipation, urinary retention etc.) Decreasing tremor, rigidity, less effective on hypokinesia

Muscarinic antagonist

* The claim that selegiline delays progress of the disease has lead to its use as protective therapy. This claim stemmed initially from the theory that it inhibits the oxidation (by the brain MAO-B) of the protoxin MPTP to MPP+ which results in death of dopaminergic neurones (thus, protecting the surviving dopamine neurones). However, this claim has not been supported by subsequent trials; indeed, one

study has shown an increased mortality in patients receiving selegiline2.

1 2

Laurence, D. R., Bennett, P. N. and Brown, M. J. (1997) Clinical Pharmacology. 8th edition, Page 367. Walker, R. and Edwards, C. (1999) Clinical Pharmacy and Therapeutics. 2nd edition, Page 459. 155



ANTIEPILEPTIC DRUGS seizure (e.g. head injury, tumour, hypoglycaemia, meningeal infection, or perhaps, rapid withdrawal of alcohol from an alcoholic). This is known as secondary epilepsy and is usually reversible. Status epilepticus, in which the episodes of tonicclonic seizure occur without intervening recovery of consciousness, is serious and may be fatal unless treated rapidly.

Introduction Epilepsy1 is a syndrome characterised by sudden transient alterations in brain function leading to motor, sensory, autonomic or psychic syndrome, often accompanied by unconsciousness. Seizures2 may result in abnormal perceptions if the parietal or occipital cortex is involved. However, seizures may result in abnormal movements (convulsions) if the motor cortex is involved.

Patients are treated with antiepileptic drugs. Patients with primary epilepsy are treated often for life, whereas those with secondary epilepsy are treated with antiepileptic drugs until the cause of the seizure is corrected. It is generally accepted that a patient having recurrent seizures should receive antiepileptic treatment that will be stopped only if two years elapse without any seizure. For classification of seizures see Table 5.14. and for a summary of antiepileptics and their indications (Table 5. 15).

In epilepsy, the abnormal neuronal discharge is usually localised to a specific area of the brain, known as the primary focus that usually does not show any anatomical abnormality. The functional abnormality of these foci may be triggered by different environmental factors, e.g. changes in blood gases, electrolytes, pH, glucose level. A focal cortical seizure may spread to involve the cortex and a generalised (tonic-clonic) seizure with unconsciousness, convulsions and incontinence. When the spread from the initial focus is slow, the initial focal symptoms give rise to a warning (or aura) of the impending fit. However, if the spread of the focal seizure over the cortex is rapid an aura may be absent.

Mode of Action Antiepileptic drugs inhibit the repetitive neuronal firing or its spread by one of the following three possible ways: 1. Modifying cell membrane permeability to ions like Na+ (e.g. carbamazepine, phenytoin) and Ca++ (e.g. ethosuximide) 2. Promoting the action of endogenous inhibitory neurotransmitters such as GABA producing hyperpolarisation (e.g. benzodiazepines, barbiturates, valproic acid, vigabatrin) 3. Inhibiting excitatory neurotransmitters like glutamate and aspartate (e.g. lamotrigine).

In the absence of anatomical cause (e.g. trauma or tumour) for the seizure, it is called idiopathic or primary epilepsy. However, when there is an apparent cause for the 1

Reference to the disease can be found as early as 2080 BC in the code of Hammurabi, King of Babylon. Hippocrates in about 400 BC opposed the supernatural explanation of epilepsy and correctly attributed it to abnormal cerebral function. 2 An attack of epilepsy variably called fit.

156


Majid A. K. Lafi

Table 5.14. Classification of seizure, frequency, and clinical manifestations. Frequency (%) PARTIAL (FOCAL) SEIZURES Simple partial (10%)

Clinical Manifestations

No impairment of consciousness; focal motor, sensory (e.g, olfactory hallucination), speech, psychic (e.g. delusion), and autonomic disturbances (e.g. tachycardia).

Complex partial (35%)

Impaired consciousness; complex sensory hallucinations, mental distortions, and motor dysfunctions (chewing movements).

Partial seizures secondarily generalised

(10%) Start as simple partial or partial complex and marsh to tonic clonic fit

GENERALISED SEIZURES Tonic-clonic (30%) (Grand mal)

Loss of consciousness, falling, rigidity extension of trunk and limbs (tonic phase), rhythmic contraction of arms and legs (clonic)

Absence (10%) (Petit mal) Myoclonic, atonic (4%) (Atypical absence)

Impaired consciousness with staring spells, with or without eye blinks Myclonic jerks (shock-like contractions), loss of muscle tone, falling (drop attack, Salaam attack)

Other Seizures (1-8%) frequency repetitive firing in neurones in culture (for more details see phenytoin below).

Antiepileptic Drugs All central depressant drugs like anaesthetic and hypnotics act as anticonvulsants and will suppress epileptoform convulsions. Antiepileptic drugs are special selection of anticonvulsants that are capable of suppressing epileptic seizures in doses that produce little or no sedation. An overview of the pharmacology of the important antiepileptic drugs is presented in Table 5.16.

Indications 1. Simple partial epilepsy 2. Complex partial epilepsy 3. Generalised tonic-clonic secondary) 4. Trigeminal neuralgia1 5. Postherpetic neuralgia 6. Diabetic neuropathy2 1

(primary

&

Paroxysmal pain which extends along the course of one or more nerves. Many varieties of neuralgia are distinguished according to the part affected or to the cause, as trigeminal, brachial, facial, occipital, supraorbital, etc., or postherpetic, anaemic, diabetic, gouty, malarial, syphilitic, etc. 2 A chronic, symmetrical sensory polyneuropathy affecting first the nerves of the lower limbs and often affecting autonomic nerves; pathologically, there is segmental demyelination of the peripheral nerves. An uncommon, acute form is marked by severe pain, weakness, and wasting of proximal and distal muscles, peripheral sensory impairment, and loss of tendon reflexes. With

Carbamazepine Carbamazepine is a tricyclic compound closely related to imipramine and other antidepressants. Carbamazepine was originally developed for the treatment of bipolar depression. However, it was first used in the treatment of trigeminal neuralgia and only later its anticonvulsant action has been recognised. The mechanism responsible for its anticonvulsant action appears to be related to its capability to block sodium channels at therapeutic concentrations and inhibits high157


7. Cerebellar ataxia (failure of muscular coordination due to a disease of the cerebellum) 8. Nocturnal enuresis 9. Affective disorder (unipolar depression and mania, treatment and prophylaxis) 10.Resistant schizophrenia 11.Diabetes insipidus 12.Hyperkinetic child 13.Dementia (organic loss of intellectual function) 14.Emotional incontinence (uncontrolled emotional acts, e.g. laughing) 15.Aggressive behaviour 16.Migraine (prophylaxis) 17.Impulse dyscontrol syndrome


depolarised (i.e. has more positive resting potential) cells that will recover from block Table 5.15. A summary of antiepileptic drugs and their indications Type of Epilepsy Partial (including secondarily generalised)

Antiepileptic Drug

Tonic-clonic

Carbamazepine Phenytoin Phenobarbital Primidone Valproic acid Lamotrigine ( as adjunct)

Absence

Ethosuximide Valproic acid Clonazepam Lamotrigine ACTH

Myclonic

Valproic acid Clonazepam ACTH

Febrile

Diazepam Phenobarbital Valproic acid

Status Epilepticus

Phenytoin (i.v.) Diazepam (i.v.) Phenobarbital (i.v.)

Adverse Effects Dose related (predictable) 1. Diplopia 2. drowsiness 3. Orofacial dyskinesia 4. Cardiac arrhythmias (AV depression) 5. Impairs cognition 6. Osteomalacia and folate deficiency (due to hepatic enzyme induction; with first few weeks, t 35 hours becomes 20 hours) Non-dose related (Idiosyncratic) 7. Agranulocytosis 8. Aplastic anaemia 9. Hepatotoxicity 10.Stevens-Johnson syndrome (severe form of erythema multiforme in which there is involvement of the oronasal and anogenital mucosa, the eyes, and viscera)

Carbamazepine Phenytoin Phenobarbital Primidone Valproic acid Lamotrigine Vigabatrin

Bold prints: preferred drugs In pregnancy: carbamazepine and phenobarbital are most suitable.

Phenytoin Phenytoin (1938) is a nonsedative hydantoin compound. It appears to produce its anticonvulsant action through its capability, at therapeutic concentrations, to block sodium channels and inhibit sustained highfrequency repetitive firing in neurones in culture. Like carbamazepine, phenytoin appears to exert selective inhibition on

very slowly if at all. In doing so, phenytoin increases refractory period in depolarised (sick) cells. This apparently selective action has been attributed to what is known as the use-dependent effect 3; therapeutically useful sodium channel blocking (local anaesthetic, membrane stabilising) drugs

autonomic involvement there may be orthostatic hypotension, nocturnal diarrhoea, retention of urine, impotence, and small diameter of the pupils with sluggish reaction to light.

3

Katzung, B. G. (1998) Basic & Clinical Pharmacology. 9th edition, Page 551 & 562. 158


Majid A. K. Lafi

have a high affinity for activated channels or inactivated channels but very low affinity for rested channels. Bearing in mind that an ionchannel is usually in one of three possible states:

Rested

indicator of plasma concentrations. As shown above in a, the t value cannot help the prescriber to decide the dosage regimen with reasonable safety; therefore in such condition, serial plasma concentration measurement has been recommended].

Activated

Inactivated It follows that in sick cells with abnormally high firing activity, the most likely ionchannel states would be the activated and inactivated ones. Consequently, these sodium channel-blocking drugs would preferentially bind to these channels that are in depolarised cells resulting in increased refractory period and therefore decreasing cell excitability. Indeed, this hypothesis of use-dependent effect is applied for calcium channel blocking drugs as well.

Pharmacokinetics 1. Saturation (zero-order) kinetics [At subtherapeutic (low) blood levels, phenytoin metabolism is directly proportional to the rate at which the drug is presented to the liver, i.e. first-order metabolism, the t of phenytoin is 6-24 hours. However, at therapeutic (high) blood levels the metabolic machinery becomes saturated (said to have reached zero-order kinetics), the t may reach 60 hours. Phenytoin is the most clinically important example of the drugs exhibiting zero-order kinetics. This is because it is characterised by: a. Its overall t ranges from 6-60 hours, and considering the time to reach a steady-state plasma concentration after dose increment (about 5 × t ) ranges from 2 days to 2 weeks. Consequently, the knowledge of its t is clinically not meaningful, as it is not possible to determine (reasonably) reliably the time to reach the therapeutic steadystate concentration. b. Being a drug with low therapeutic index, it should not be given without a reliable 159

2. Hepatic enzyme induction and enzyme inhibition [phenytoin is a potent hepatic enzyme inducer influencing its own metabolism as well as other drugs and dietary and naturally occurring substances such as vitamin D, folate, adrenal and gonadal steroids, thyroxine. Other drugs whose hepatic metabolism significantly increased including other antiepileptic drugs, e.g. carbamazepine, warfarin, tricyclic antidepressants, and doxycycline. It follows that hepatic enzyme inducing drugs can affect each other when administered concurrently; for example, phenobarbital, carbamazepine, rifampicin may lower phenytoin concentrations. Likewise, hepatic enzyme inhibiting drugs such as valproate, cimetidine, cotrimoxazole, isoniazid, chloramphenicol, erythromycin etc. can interact with phenytoin, and other antiepileptic drugs, causing an increase in plasma concentrations, hence increasing the possibility of toxicity].

Indications 1. Simple partial epilepsy 2. Complex partial epilepsy 3. Generalised tonic-clonic (primary secondary) 4. Status epilepticus 5. Digitalis-induced arrhythmias 6. Trigeminal neuralgia (see above)

&

Adverse Effects Dose related (predictable) 1. Ataxia, nystagmus, orofacial dyskinesia 2. Drowsiness 3. Impairment of cognitive function 4. Gingival hyperplasia (may be due to inhibition of collagen catabolism) 5. Coarsening of facial features 6. Hirsutism



7. Megaloblastic anaemia (probably due to folate deficiency as a result of hepatic enzyme induction by phenytoin) 8. Osteomalacia (due to vitamin D deficiency as a result of increased hepatic metabolism after years of therapy) 9. Teratogenic 10.Peripheral neuropathy 11.Rashes Non-dose related (idiosyncratic) 12.Hepatotoxicity

1. Dyspepsia, nausea, vomiting 2. Coagulation disorder (due to inhibition of platelet aggregation) 3. Alopecia (hair loss) 4. Increased appetite (results in weight gain) 5. Teratogenic (spina bifida) 6. Acute pancrititis 7. Hepatitis

Overdose

Barbiturates

1. Cerebellar dysfunctions 2. Coma and apnoea (may be for a long time because of zero-kinetics, maintain respiration, no antidote)

An account on barbiturates has been given in the section on sedatives and hypnotics (above). The most widely used antiepileptic member of barbiturates is phenobarbital (t 100 hours). Other members like methylphenobarbital and primidone (a prodrug) that is largely metabolised to phenobarbital. Barbiturates are potent hepatic enzyme inducers.

Valproic Acid (Sodium Valproate) Valproic acid was incidentally found to have antiepileptic activity when it was used as a solvent in the search for antiepileptic drugs. The mechanism of action of valproic acid as antiepileptic drug is not conclusively settled. However, much of the evidence now points out to its capability to block sustained high-frequency repetitive firing of neurons in culture at therapeutically relevant concentrations. Its action against partial seizures may be a consequence of this effect on sodium channel. Blockade of NMDA receptor-mediated excitation may also be important Valproic acid is a hepatic enzyme inhibitor; and it is 90% plasma protein bound with apparent volume of distribution of 9 L.

Adverse Effects

Indications 1. 2. 3. 4. 5.

Simple partial seizures Complex partial seizures Anaesthesia (e.g. thiopental) Anxiety (rarely used these days) Insomnia (rarely used these days)

Adverse Effects 1. 2. 3. 4. 5.

Indications 1. Simple partial epilepsy 2. Complex partial epilepsy 3. Generalised tonic-clonic 4. Absence 5. Myoclonic seizures 6. Affective disorders 7. Huntington s chorea 8. Peripheral neuropathy 9. Hyperkinetic child 10.Prophylaxis of migraine 11.Tardive dyskinesia 12.Impulse dyscontrol syndrome

Sedation Impaired cognition Addiction risk Enzyme induction Low therapeutic index

Benzodiazepines A detailed account on benzodiazepines has been given in the section on anxiolytics (above). Of this group, clonazepam (Rivotril, t 25 hours) is widely used as a broad-spectrum antiepileptic drug. It has the reputation to have less sedative action than most other members of benzodiazepines do. Clonazepam and diazepam are useful in status epilepticus; in this medical emergency, they should be administered i.v. slowly (30 seconds), while i.m.

160


Majid A. K. Lafi

administration is not appropriate as peak plasma concentration can be delayed as long as 2 hours making these drugs useless for the urgent control required in this medical emergency. However, lorazepam is more rapidly absorbed when administered i.m.

Adverse Effects 1. Gastric upset (Nausea, vomiting) 2. Allergic reactions (Rash, Stevens-Johnson syndrome, SLE) 3. Hepatic enzyme inhibition

Ethosuximide Lamotrigine Ethosuximide was introduced as a specific anti-absence seizure drug. To date, it remains the drug of first choice for absence seizure. The mechanism of action of ethosuximide is believed to be mediated through inhibiting the low-threshold (T-type) Ca2+ currents in the thalamic neurones; these currents are suggested to be responsible for generating the rhythmic cortical discharge of an absence seizure4. Therefore, it is useful only in absence seizure.

Lamotrigine (1993) is a voltage dependent sodium channel blocker. This action results in reduced release of excitatory amino acids like glutamate and aspartate. It is believed to have less frequent adverse effects (compared with that of carbamazepine). It finds use in partial and generalised seizures, as an adjuvant or monotherapy.

4

Katzung, B. G. (1998) Basic & Clinical Pharmacology. 9th edition, Page 567.

161



Table 5.16. A summary of the pharmacology of selected antiepileptic drugs Drug Group Drug Carbamazepine

Mechanism of Action Reduces repetitive neural firing (inhibits voltage-sensitive Na+ channel)

Phenytoin

Reduces repetitive neural firing (inhibits voltage-sensitive Na+ channel)

Partial Tonic-clonic Status epilepticus

Na valproate


Partial Tonic-clonic Absence Myclonic Febrile

Barbiturates Phenobarbital (t 100 hr) Methylphenobarbital Primidone (prodrug)

Potentiates GABA effects on Cl- influx

Partial Tonic-clonic Status epilepticus Febrile convulsion

Benzodiazepines Diazepam Lorazepam Clonazepam

GABA Clchannel receptor complex

Lamotrigine

Selected Adverse Effects and Important Remarks

Partial Tonic-clonic

Osteomalacia and folate deficiency (due to hepatic enzyme induction; with first few weeks, t 35 hours becomes 20 hours) Cardiac arrhythmias (AV depression) Impairs cognition (Idiosyncratic) Agranulocytosis Aplastic anaemia Hepatotoxicity Impairs cognition Gingival hyperplasia Coarsening of facial features Hirsutism Megaloblastic anaemia (probably due to folate deficiency as a result of hepatic enzyme induction by phenytoin) Osteomalacia (due to vitamin D deficiency as a result of increased hepatic metabolism after years of therapy) Teratogenic Peripheral neuropathy Rashes (idiosyncratic) Hepatotoxicity Coagulation disorder (due to inhibition of platelet aggregation) Alopecia (hair loss) Increased appetite (results in weight gain) Teratogenic (spina bifida) Acute pancrititis Hepatitis Hepatic enzyme inhibition

Status epilepticus Absence Myoclonic

Clonazepam

Ethosuximide

Indication

Inhibits lowthreshold (T-type) Ca2+ currents Inhibits release of glutamate & aspartate

Absence Partial Generalised seizures

162

Sedation Impaired cognition Addiction risk Enzyme induction Low therapeutic index Sleepiness Impaired psychomotor function Amnesia Dependence Gastric upset (Nausea, vomiting) Allergic reactions (Rash, StevensJohnson syndrome, SLE) Hepatic enzyme inhibition

Same as carbamazepine but probably less frequently.


Vigabatrin

Inhibits GABA transaminase (irreversibly)

Majid A. K. Lafi

Partial seizures

Sedation Weight gain Confusion, agitation & psychoses

A SUMMARY OF THE DRUGS USED IN MOVEMENT DISORDERS

Hypokinetic Movement Disorders disease. • Idiopathic Parkinson s Primary agents: carbidopa/ levodopa; bromocriptine; pergolide. Secondary agents: benzhexol; benztropine; amantadine; selegiline Hyperkinetic Movement Disorders • Tics e.g. Tourette s syndrome, which begins in childhood and is associated with vocalization, abnormal gestures, and frequently with obsessive-compulsive personality. Neuroleptic drugs e.g. haloperidol can be useful. • Myclonus (e.g. Salaam attack, infantile myclonus seizure). Benzodiazepines (clonazepam); carbidopa/5-HTP (for anoxic myclonus); baclofen (a GABA-B agonist); tetracosactrin • Essential tremor (or known as adrenergic or intentional tremor, or familial tremor). Propranolol; primidone; clonidine may be considered (advise to decrease intake of tea, coffee and smoking) • Parkinsonian tremor (rest tremor) Anticholinergics (e.g. benzhexol) • Dystonia (disordered tonicity of muscle, acute sustained contraction of muscle) may begin and remain focal, affecting only one area of the body, but can also begin focally and evolve in generalised dystonia. Two very common forms of focal dystonias involve forced eyelid closure (blepharospasm) or twisting of the neck to one side (torticolis), frequently in combination with pulling of the neck backwards (retrocollis). Trismus (clinching of teeth, lockjaw) and opisthatonus (contraction of the muscle of the back) may also be encountered. A high dose of anticholinergic drugs (e.g. benzhexol, diphenhydramine) is useful. Generalised dystonia patients surprisingly

tolerate high doses of anticholinergics with substantial improvement. If anticholinergics are not available a benzodiazepine may do. • Dyskinesia-Chorea: Dyskinesias generally refer to choreic drug side effects, whereas choreas occur in the course of natural disease. The common dyskinesia is that arising in the natural history of Parkinson s disease treated with levodopa. This dopa-dyskinesia can also be seen with direct dopamine agonist. No satisfactory treatment is available at present. • Tardive Dyskinesia: Tardive dyskinesia is a choreic movement disorder arising late in the course of neuroleptic treatment. This dyskinesia is suggested to be due to hypersensitivity (upregulation) of dopamine receptor, particularly of the substantia nigra leading to reduced GABAergic activity in the corpus striatum resulting in choreic movement. No effective specific treatment is available, however, stop giving the antipsychotics may be useful, otherwise reserpine can be used in the disabling cases; the less severe cases may respond paradoxically to carbidopa/levodopa or to clonidine treatment. • Huntington s chorea: Chorea occurs in the course of Huntington s disease, an autosomal dominantly inherited neurodegenerative disorder. The marked loss of GABA neurone in the brains of Huntington s disease patients suggests similarities to tardive dyskinesia. Neuroleptic drugs or reserpine may help.

163

CNS Pharmacology - Narcotic Analgesic Drugs


OPIOIDS AND NARCOTIC ANALGESIC DRUGS

The actions of opioids can be explained by action on specific opioid receptors in the CNS (Table 5. 17), thalamus, limbic system, hypothalamus, substantia gelatinosa of the spinal cord, nucleus tractus etc. The receptor type most responsible for analgesic properties has been designated the (mu) µ-receptor. The opioid receptors respond to natural morphinelike substances, which are peptides and act as neuromodulators. These are called enkephalins and endorphins. Endogenous analgesics like enkephalins can be detected in the CSF after certain pain-relieving procedures such as acupuncture, placebo medication and transcutaneous electrical stimulation. The endorphins are long-chain polypeptides, which also exhibit opiate activity; the best known is ¾-endorphin that is mainly found in the hypothalamus and the pituitary gland. Opioid peptides seem to be involved in many physiological functions including regulation of temperature, behaviour, gastrointestinal motility, appetite, thirst etc.

Introduction Opium is the dried latex (milky fluid) obtained from the unripe capsules of opium poppy, papaver somniferum. Opium contains 25 different alkaloids; the most important of which are morphine (15%), codeine (2%) and papaverine (1%). Papaverine is distinct from opium, it is not an analgesic and it is a potent relaxant of smooth muscle whereas the opioids induce smooth muscle contraction. Opium was initially used for its antitussive actions that were recognised. The semisynthetic opiate heroin (diacetylmorphine) was produced in 1844 with the hope of curing morphine addicts, but it was soon appreciated that it was not a cure, but on the contrary a more potent narcotic. The search for agents with analgesic qualities of morphine but without the side effects of dependence and tolerance continued and resulted in methadone and pethidine (mepiridine), which however have little advantage.

Opioids relieve pain by raising the pain threshold at the spinal cord level, and also by altering the brain s perception of pain. With morphine, the patient is still aware of the presence of pain, but the sensation is not unpleasant. It is believed that morphine acts at µ-receptors in the substantia gelatinosa of the spinal cord, decreasing the release of substance P (and probably other excitatory transmitters from terminals carrying nociceptive stimuli) which modulates pain perception in the spinal cord.

Mechanism of Action Although much remains to be learned about the neurotransmitters involved in both the afferent nociceptive pathways (primary afferent nerve fibres) and descending antinociceptive pathways, prime candidates for the afferent pathways include peptidergic neurotransmitters (e.g. substance P, somatostatin, vasoactive intestinal polypeptide, cholecystokinin, and calcitonin gene-related peptides). The descending antinociceptive pathways appear to inhibit or modulate the process of pain transmission through the afferent (spinal) nociceptive pathways. This process of modulating transmission of pain is the essential part of the gate theory of pain. Several neurotransmitters have been suggested to be involved in pain modulation, e.g. noradrenaline and serotonin, as well as endogenous opioid peptides.

Classification of Narcotic Analgesics Opiates can be classified into three groups: 1. Pure agonists: dextropropoxyphene, codeine, pethidine (meperidine), methadone, morphine, heroin, fentanyl 2. Mixed agonists/antagonists & partial agonist: pentazocine, nalorphine 3. Antagonists: naloxone, naltrexone

164


Majid A. K. Lafi

Table 5.17. A summary of responses to stimulation of the three major types of opioid receptors. Receptor Types Kappa (µ) Spinal analgesia Dysphoria/sedation Respiratory depression Miosis

Mu (³) Sigma (-) Spinal and supraspinal Dysphoria analgesia Psychotomimetic reactions* Respiratory depression Respiratory stimulation Euphoria/sedation Mydriasis Physical dependence Decreased GI motility Miosis * e.g. anxiety, strange thoughts, nightmares, hallucinations Table 5.18. Drug actions at opioid receptors Agents Pure opioid agonists: morphine, codeine etc. Mixed acting opioids: pentazocine Partial agonists nalorphine Pure opioid antagonist: naloxone, naltrexone

Mu (³) Agonist

Antagonist Weak agonist Antagonist

Agonist

Agonist

-

-

Antagonist

Antagonist

8. Respiratory depression (reduced sensitivity to CO2) 9. Miosis 10. Decreased release of LH and FSH 11. Increased release of prolactin and ADH

Principle Pharmacological Effects Desirable effects 1. 2. 3. 4. 5. 6.

Receptor Types Kappa (µ) Sigma (-) Agonist No action

Effective analgesia Sedation Sleep Euphoria Depression of Cough Relief of anxiety

Tolerance and Dependence Tolerance is characterised by decreased intensity and shortened duration of all the usual pharmacological effects of morphine. It may occur in individuals who have become socially habituated to the drug, or in patients who require continuous therapy for chronic pain (like in cancer). The pharmacokinetic parameters of morphine do not alter with its repeated use. A negative feedback system resulting in decreased production of endogenous opioid peptides may be implicated (pharmacodynamic tolerance, Fig.5.10). Different opioids exhibit crosstolerance.

Undesirable effects 1. Tolerance and dependence 2. Bronchoconstriction (due to histamine release) 3. Nausea and vomiting 4. Dysphoria 5. Depression of cough reflex 6. Spasmogenic effects (GI spasm, sphincter of Oddi spasm) 7. Constipation

165



Upon repeated dosage, cellular adaptation to the exogenously applied morphine occurs; i.e. neurotransmission (particularly the postsynaptic opioid activity that is responsible for modulating various essential biological activities) becomes dependent on the exogenous morphine. A sudden withdrawal (abstinence) of the exogenous morphine cannot be immediately compensated for, consequently results in disturbance in the regulation of these biological activities such as cardiovascular functions.

Reversal of Narcotic Effects Naloxone is the pure antagonist and the drug of choice for the treatment of narcotic overdose, or for reversing the depressant effects of narcotic agents on the neonates. The normal dose may be repeated once or twice at frequent intervals if respiratory function does not improve or relapse. It would appear that all the pharmacological actions of the narcotic agents are reversed by naloxone. If naloxone is administered to a person who has been abusing opioids, he will develop a withdrawal syndrome, but nothing happens if given to a normal person.

Withdrawal (Abstinence) Syndrome

Indications for morphine

The development of dependence to morphine can be demonstrated when the drug is suddenly withdrawn after repeated dosage. Various physical and physiological phenomena may develop, the severity of which are related to the total amount administered. Symptoms and signs include restlessness and irritability, frequent yawning, excessive sweating, gooseling of skin (piloerection), hyperpnoe, dilated pupils, tachycardia, lachrymartion and salivation, painful muscle cramps and intense and uncontrolled vomiting, diarrhoea and urination. Mild symptoms have been reported after only 48 hours therapy. Although withdrawal from opioids is unpleasant, the syndrome is rarely dangerous; on the contrary, withdrawal from other CNS depressants (e.g. alcohol, barbiturates) can be lethal.

1. Severe pain euphoria in the dying 2. Myocardial infarction (MI) or dyspnoea in acute left ventricular failure and pulmonary oedema (see later notes) 3. Premedication for surgery

Contraindications 1. Chronic obstructive lung disease 2. Liver failure 3. Raised intracranial pressure (including head injury)

Morphine and the Cardiovascular System Morphine exerts the following actions on the cardiovascular system.

Treatment of Withdrawal Syndrome

1. Decreases sympathetic vascular reflexes resulting in veno-arteriolar dilatation 2. Stimulates vagal centre leading to decreased heart rate 3. Releases histamine resulting in vasodilatation 4. Tranquillising action, thus decreasing mental distress 5. Decreases central sensitivity to afferent stimuli from the congested lung leading to decreased respiratory distress

The following drugs are essential in the treatment of the withdrawal syndrome. 1. Methadone addictive) 2. Diazepam 3. Clonidine

(oral,

long

acting,

less

166


Majid A. K. Lafi

THEREFORE, MORPHINE IS USEFUL IN DYSPNOEA DUE TO ACUTE LEFT VENTRICULAR FAILURE AND PULMONARY OEDEMA

Exogenous opioids

Pethidine versus Morphine 1. Pethidine is not useful in suppressing cough 2. Pethidine does not constipate; however, like morphine, it produces spasm of the sphincter of Oddi. 3. Pethidine is widely used in obstetrics because it does not delay labour like morphine that produces this effect centrally by reducing co-operation rather than by an action on the uterus. However, pethidine enters the foetus and can depress respiration at birth; therefore, the availability of naloxone can be essential as an antidote. 4. Pethidine is less likely to cause urinary retention which has at least partly for morphine due to the central sedation causing the patient to ignore afferent messages from a full bladder. 5. Unlike morphine, pethidine has little hypnotic effect. 6. Pethidine has shorter duration (2-3 hr) of analgesia. 7. Because of unfavourable cardiovascular effects (a transient rise in systemic arterial pressure, systemic vascular resistance and heart rate) pethidine could not be recommended for the relief of pain in myocardial infarction patients. Unlike morphine, pethidine is not considered as a venolytic agent. 8. Pethidine has considerable antimuscarinic effects that may be a problem if tachycardia would be a problem. This antimuscarinic activity is responsible for its mydriatic action (while morphine produces miosis).

167

-ve opioid Presynaptic nerve

opioid

¿2

Postsynaptic nerve

-ve

Fig. 5.10. A simplified diagrammatic representation of the effect of exogenously administered opioids (e.g. morphine) on post and presynaptic opioid receptors. Opioid-like substances are endogenously released from peptideergic nerves; therefore, when giving the first dose of an exogenous opioid the observed response would appear to be due to the exogenous opioid. This response is super-added to the basal endogenous opioid activity. As the exogenous opioid causes negative feedback effect on the release of the endogenous opioid; thus, upon subsequent administration of the opioid the effect of a particular (first) dose will be reduced (i.e. pharmacodynamic tolerance develops, a larger dose is required to produce the same effect). In this condition biological adaptation (dependence on exogenous substance) is said to have taken place. Upon withdrawal (abstinence) of the exogenous opioid, the postsynaptic opioid activity (which is responsible for modulating various essential biological activities such as regulation of cardiovascular functions) is reduced. This cannot be immediately compensated by the reduced availability of the endogenous opioid.


Ramadi, 1 March 2008

Table 5.19. A summary of the pharmacology of selected narcotic analgesics and their antagonists. Narcotic agent

t (hr) 2

Duration of analgesia (hr) 3-6

Codeine (methylmorphine)

3

4

Pethidine (meperidine)

5

2-3

Methadone

8

24

Dextropropoxyphene

5

4-6

Tramadol

6

Fentanyl

3

Morphine

Activates mu (µ) & kappa (κ) receptors; it produces analgesia, euphoria, miosis, sedation. Respiratory depression, orthostatic hypotension, cough, suppression, constipation, biliary colic, urinary retention, emesis & elevation of intracranial pressure; USES: moderate-to-severe pain, MI or dyspnoea associated with acute left ventricular failure and pulmonary oedema, & premedication for surgery. Useful in mild-to-moderate pain (codeine 30 mg is equianalgesic to 325 mg of aspirin or paracetamol), used in combination with nonopioid analgesics (e.g. aspirin) to produce greater analgesic action; & as cough suppressant (10 mg); Adverse-effects: sedation and constipation. Used primarily for its analgesic effect, preferred for obstetrical analgesia; it is less likely to cause smooth muscle spasm than morphine, thus, less constipation & urinary retention. Not preferred in MI or dyspnoea associated with acute left ventricular failure and pulmonary oedema. Synthetic, good absorption from GIT, long duration of action, used to cover opioid withdrawal & for chronic pain in palliative care. Rapidly absorbed from GIT, used for its analgesic action (similar to codeine), structurally similar to methadone Synthetic, rapidly absorbed from GIT, as effective as pethidine for postoperative pain and as morphine for moderate chronic pain, less likely to constipate, depress respiration and addict. Eighty times more potent than morphine; & more efficacious, used in surgery.

0.5-1

Increases cardiac work and oxygen demand, thus, not suitable in MI; less respiratory depression than morphine; because of sigma (-) receptor (psychotomimetic) effects, it has a low potential for abuse. It can precipitate an abstinence syndrome in a patient physically dependent on a pure opioid agonist.

Mixed agonist/antagonist Pentazocine

Principal features

5

Used to reverse depression.

Nalorphine (Partial agonist) Opioid antagonists

Naloxone

1.25

1-2

Naltrexone

4

1-3 days

narcotic

induced

respiratory

Blocks opioid actions; precipitates an immediate withdrawal reaction in a patient dependent on opioids; Useful in: 1. Opioid overdose 2. Reversal of postoperative opioid depression 3. Reversal of neonatal respiratory depression Similar to naloxone; but can be given orally; useful in former opioid addicts to prevent relapse (prevents opioid-induced euphoria, long duration of action).

168

CNS Pharmacology - Narcotic Analgesics


When combining amphetamines with morphine-like agents lead to increased analgesia, and decreased sedation. When combining antiemetics with morphine-like agents lead to suppression of nausea and vomiting. When combining CNS depressants, phenothiazines, and antidepressants with morphine-like agents leads to increased respiratory depression.

169

CNS Pharmacology - General Anaesthetic Drugs


GENERAL ANAESTHETIC DRUGS Introduction

Diaphragmatic paralysis can be induced by muscle relaxants (e.g. tubocurarine), however, an overdose with inhalational anaesthetics may produce this effect in stage IV.

Objectives: analgesia, amnesia-hypnosis (unconsciousness), muscle relaxation (loss of reflexes), and physiological homeostasis. General anaesthesia is said to be achieved when the above four objectives are met, and during which there is loss of sensation and consciousness (the subject is not rousable by external stimuli). This can be obtained by inhalation of a volatile anaesthetic agent(s) or intravenous administration of a drug or a combination of them. The order of depression in the CNS is:

Inhalational Anaesthetics Inhalation of anaesthetic drug produces a depth of anaesthesia that depends on the partial pressure of the anaesthetic agent, which will be dependent on: 1. Partial pressure of anaesthetic agent (concentration) in the inspired air 2. Solubility of anaesthetic agent in blood 3. Pulmonary ventilation (The rate of rise of anaesthetic gas tension in arterial blood is directly dependent on both the rate and depth of respiration) 4. Cardiac output (An increase in cardiac output leads to an increase in pulmonary blood flow; thus, blood capacity increases and tension rises slowly. Therefore in circulatory shock, decreased pulmonary blood flow and increased ventilation may speed up the induction of anaesthesia with some anaesthetics particularly those with high blood solubility.

Cortical centres r basal ganglia r spinal cord r medulla According to Guedel (1920) the degree of nervous depression can be divided into four different stages, as may be observed with ether, equivalent to the cumulative effect on the above-mentioned CNS-centres. Stage I: Analgesia, and amnesia from start of induction to loss of consciousness. Stage II: Excitation (delirium or confusion, but definitely the patient is amnesic), from loss of consciousness to reestablishment of regular respiration.

An anaesthetic drug with high blood solubility, such as ether and methoxyflurane, may require a long time for induction, since the blood, which acts as a reservoir, can dissolve a large amount of gas. Halothane, which has a lower solubility in blood, will equilibrate rapidly and the partial pressure of this gas in blood therefore rises quickly. Further, nitrous oxide (N2O), which has a much lower solubility will achieve a quicker induction. Nitrous oxide is the commonly used inhalational anaesthetic that is a gas at ambient temperatures and pressure. All of the other inhalational anaesthetics are liquids at room temperature and pressure, require vapourisation before use.

Stage III: Surgical anaesthesia, from the beginning of regular respiration to respiratory arrest. This stage is divided into four planes, which have been described in terms of changes in ocular movements, eye reflexes, and pupil size; these under specified conditions may represent signs of increasing depth of anaesthesia. In practice, the most important indications that surgical anaesthesia has been achieved are loss of eyelash reflex and establishment of a respiratory pattern that is regular in rate and depth.

Minimum alveolar anaesthetic concentration (MAC) is defined as that concentration of anaesthetic agent in alveolar or end-expired gas that is present when 50%

Stage IV: Overdosage (stage of medullary depression or paralysis) from onset of diaphragmatic paralysis to cardiac arrest. 170


Majid A. K. Lafi

of the subjects do not respond when exposed to the skin incision (MAC=1.0, equivalent to effective dose in 50% of patients). The value of MAC is reduced in the elderly. In general, however, the dose-response relationship for

inhaled anaesthetics is steep. Over 95% of patients may exhibit a state of anaesthesia at 1.1 MAC.

Inspired r Face mask r Alveoli r Pulmonary r Arterial Gas upper airways PAa membrane blood PAi PAfm PApm PAab

Metabolised

CNS bbr Other bbbrs tissue tissue PAcns PAt

Fig.5.11 A schematic representation of pathways for uptake, distribution, and elimination of inhalational anaesthetic agents. PA = partial pressure of agent A; other subscripts refer to anatomical regions. Note elimination of the anaesthetic agents is usually achieved by the reverse of uptake of the agent (reverse arrows to expired air are not shown).

Table 5.20. Shows the values of MAC and PC in tissues of selected general anaesthetic agents. Note: nitrous oxide is poor anaesthetic compared with other inhalational agents.

Anaesthetic Agent Nitrous oxide

MAC*

Blood/Gas PC

Brain/Gas

Metabolism

PC

101.0

0.47

0.5

None

Desflurane

6-7

0.42

1.3

70% (fluoride)

Important remarks Rapid onset & recovery; incomplete anaesthetic Low volatility; poor induction; rapid recovery Medium rate of onset & recovery Medium rate of onset & recovery Medium rate of onset & recovery Slow onset & recovery Nephrotoxic

* Expressed as partial pressure of agent (in alveolar space) divided by standard total atmospheric pressure (×100) that produces immobility in 50% of patients exposed to a noxious stimuli; PC = partition coefficient (reflecting solubility of agent in tissue).

171



cellular threshold for firing. This in turn results in a decrease in neuronal activity1.

Note: An inhalational anaesthetic agent with low solubility in blood shows fast induction time and also recovery time (e.g. nitrous oxide), and an agent with relatively high solubility in blood shows slower induction and recovery time (e.g. halothane).

Ether Ether (diethyl ether) as an anaesthetic agent was first clinically demonstrated by William Morton (Massachusetts General Hospital, Boston, 1846).

The elimination of anaesthetic gases occurs mainly by the lungs and therefore the depth of the anaesthesia is easily controlled by assisted breathing (anaesthetic machine).

Ether is a volatile liquid with an unpleasant odour. It is highly flammable and explosive, therefore, cautery should not be used in operation; for this property it is now obsolete. Otherwise, it is a safe drug because it stimulates respiration and there is a wide margin between the dose to induce surgical anaesthesia and that to cause medullary paralysis.

Elimination of the anaesthetic is also dependent on the amount of drug bound to fat tissue in the body. The biological t of most anaesthetics is about 1 hour but total elimination of metabolites may require several days.

Ether anaesthesia is associated with release of endogenous catecholamines. It therefore induces bronchial dilatation and therefore can be used in patients with severe asthma. It produces good muscle relaxation, but induction is unpleasant, and nausea and vomiting may occur frequently upon emergence.

Second Gas Effect The MAC of an inhalational anaesthetic can be reduced by a concurrent use of another inhalational agent; thus, a concurrent use of nitrous oxide with halothane would reduce the MAC for halothane and also the presence of the latter would reduce the MAC for nitrous oxide. It has been suggested that the presence of agent (gas) facilitates the uptake (transport into the pulmonary blood) of the other agent. Therefore, it is called the second gas effect. This effect is utilised for using reduced inspired partial pressure for certain agents, particularly, nitrous oxide which has a high MAC (>100%) which is practically difficult to achieve. Further, a reduction in MAC can also be achieved by the use of adjuvant drugs like narcotic analgesics or sedative-hypnotics.

Ethyl Chloride is a liquid like ether and divinyl ether. It has a boiling point below normal room temperature and can be used both for induction and refrigeration anaesthesia when sprayed from a bottle onto the skin. Like divinyl ether, it is hepatotoxic.

Nitrous Oxide Nitrous oxide (N2O) is the oldest anaesthetic compound known. Horace Wells (Massachusetts General Hospital, Boston, 1845) was the first to describe the importance of its anaesthetic property in clinical practice. Today, it is the most commonly used inhalation anaesthetic agent despite its weak anaesthetic properties: even at its maximum safe concentration of 75% it still requires some supplementation to produce adequate surgical anaesthesia and skeletal muscle relaxation. Nitrous oxide is an inert gas,

Mechanism of Action Anaesthetic agents appear to concentrate in hydrophobic regions of cell membranes, causing the membrane to swell and altering the crystalline structure of the membrane. It has been suggested that most general anaesthetic agents have a common neurophysiological action that increasing the

1

Katzung, B. G. (1998) Basic & Clinical Pharmacology. 7th edition, Page 415. 172


Majid A. K. Lafi

which is compressed to a liquid, and stored in steel cylinders, coloured blue for identification. Nitrous oxide returns to the gaseous state when released from the cylinder. The gas is colourless and tasteless but has a faintly sweet odour. Nitrous oxide is sometimes called laughing gas. It induces euphoria and a dreamy state but its effect is mostly one of analgesia. Nitrous oxide does not depress respiration and in the absence of hypoxia there is no effect on the heart.

Methoxyflurane Methoxyflurane is the most potent inhalation anaesthetic with very good skeletal muscle relaxing properties. Its disadvantage is prolonged induction and emergence. Otherwise its properties are similar to halothane.

Intravenous Anaesthetics

Prolonged exposure to nitrous oxide decreases methionine synthase activity and may lead to megaloblastic anaemia. This is of a particular importance for staff working in poorly ventilated dental operating rooms.

Barbiturates Barbiturates are used mainly for induction of anaesthesia since the ultra-short acting barbiturates act rapidly without fear of an unpleasant mask and smell of inhalational anaesthetic agents. In sufficient amounts, these drugs can accomplish all the anaesthetic stages but they may cause serious cardiovascular suppression, therefore they are mainly used in combination with inhalational agents such as nitrous oxide and oxygen. Cerebral metabolism, O2 consumption are reduced with barbiturates in proportion to the cerebral suppression and also cerebral blood flow (CBF).

Halothane Halothane (1956), a fluorinated nonflammable hydrocarbon, is a clear, colourless, potent, volatile liquid, which gives smooth induction and comfortable recovery. Anaesthesia can be induced with concentration of 4-5% halothane in oxygen (as a loading dose analogous to that with digoxin priming). For maintenance a concentration of halothane should be reduced. For convenience a hypnotic dose of an i.v. anaesthetic is often used prior to halothane administration. Muscle relaxation is not always sufficient with halothane and can be supplemented by muscle relaxant drugs such as suxamethonium. The neuromuscular blocking actions of dtubocurarine are potentiated and is therefore advisable to use a reduced dose of this component.

Thiopental sodium Thiopental is the most commonly used intravenous anaesthetic in Iraq, usually in combination with inhaled general anaesthetics. The pharmacology of barbiturates is discussed in the sections on sedatives and hypnotics, and antiepiletic drugs. It is worth noting thiopental is useful in abreaction2. Degradation takes place mainly in the liver. For distribution and redistribution of thiopental see (Fig.5.12).

Cautions 1. Postpartum haemorrhage: Halothane causes relaxation of smooth muscle including the uterine muscle, which may give rise to postpartum haemorrhage. 2. Myocardial depressant properties and may induce bradycardia. 3. Respiratory depressant, as indicated by the reduced response to various levels of carbon dioxide. 4. Liver toxicity (halothane) has been observed especially after repeated administration. 173

Adverse Effects 1. Cardiac and respiratory depression 2. Bronchospasm

2

The reliving of an experience in such a way that previously repressed emotions associated with it are released.



Propofol Methohexital Propofol as intravenous anaesthetic is very much similar to thiopental. However, it produces anaesthesia with a more rapid recovery than that obtained with thiopental. Further, in the immediate postoperative period after propofol patients feel better as compared with other intravenous anaesthetics. Perhaps, the major advantage of propofol is that it has a useful antiemetic action. This probably is responsible for the observation that postoperative vomiting is uncommon with propofol.

It is another ultra-short acting barbiturate with similar pharmacological properties but differs chemically from thiopental in that it contains no sulphur.

Ketamine Ketamine is a phencyclidine (hallucinogen) derivative and an antagonist of the NMDAreceptor. It (is a mirror image of thiopental) produces cardiovascular stimulation and increases cerebral blood flow. It is known to produce dissociative anaesthesia (the patient seems awake but dissociated from the environment, responds to verbal commands but does not respond to painful stimuli). Emergence reaction characterised by hallucination is a frequent encounter with ketamine, diazepam is used to conteract this effect.

Etomidate Etomidate is a potent hypnotic (5 minutes) used for induction of anaesthesia. Its major advantages over other agents that it causes minimal cardiovascular and respiratory depressant effects. This drug has no analgesic actions; therefore, premedication with opioid may be required. It is known as an inhibitor of steroidogenesis.

Dose % 100-

Blood

Preanaesthetic Medication

Muscle

The objectives of the drugs that may be required as adjunct to the anaesthetic agents are:

Brain

50 -

1. Allay anxiety (e.g. diazepam) 2. Reduction of secretion (e.g. oropharyngeal surgery, atropine) 3. Reduction of parasympathetic preponderance ( children tend to show parasympathetic hyperresponsiveness, thus, antimuscarinic may be used in paediatric surgery) 4. Relax muscles (muscle relaxants) 5. Rapid induction of anaesthesia (shortacting barbiturate) 6. Prevent postsurgical nausea and vomiting (antiemetics)

Fat

1.0 -

0.1

0.5

1

4

16

64

256

Time (min) Fig.5.12. Redistribution of thiopental after intravenous bolus administration (the time axis is not linear). Note: The ultra-short acting thiopental rapidly crosses the blood brain barrier because of high lipid solubility (1 min.). Then, they diffuse out of the brain to other highly vascular (highly perfused tissues like skeletal muscle) and subsequently to poorly perfused adipose tissue. It is because of this rapid removal from the CNS that a single dose is so short acting. Metabolism is much slower than redistributed.

Other Agents 1. Midazolam (slow onset and recovery; flumazenil reversal available; used in balanced anaesthesia and conscious

174


Majid A. K. Lafi

sedation; cardiovascular stability; marked amnesia. 2. Fentanyl (slow onset and recovery; naloxone reversal available; used in balanced anaesthesia and conscious sedation; marked analgesia).

Neuroleptanaesthesia When a neuroleptic drug (like droperidol) and a narcotic analgesic drug (like fentanyl that is 80 times more potent that morphine, shorter onset and duration of action), are administered together to produce a

physiological state with somnolence (sleepiness), indifference, analgesia, amnesia, and patients are responsive to commands. This state is called neuroleptanalgesia that is useful for several diagnostic or minor surgical procedures like bronchoscopy, painful dressing, cystoscopy etc. Neuroleptanalgesia can be converted to neuroleptanaesthesia by the concurrent administration of 65% nitrous oxide in oxygen.

Table 5.21. A summary of the pharmacology of selected general anaesthetic agents Effect on CVS Resp.


INDUCTION (i.v.)

Thiopental

Ketamine

YES

YES

NO

YES

YES

NO

↓

↑

↓

Contraindicated in porphyria

NO

Increases cerebral blood flow. Contraindicated in open eye surgery, neurosurgery (brain), preeclampsia (hypertension); hypertensive, hallucinogenic, emergence delirium

MAINTENANCE (inhalational)

Halothane

YES

YES*

YES*

↓

↓

Nitrous oxide

YES*

YES

NO

Variable

Variable

* Not adequate

175

Dysrhythmogenic (sensitises heart), hepatotoxicity (avoid repeated administration in short period, 90 days), malignant hyperthermia; postpartum haemorage, Myocardial depressant properties (bradycardia), Respiratory depression Megaloblastic anaemia (prolonged exposure →↓ methionine synthase activity)

CNS-Pharmacology - Local Anaesthetics


LOCAL ANAESTHETIC DRUGS Introduction

Lidocaine

The first local anaesthetic agent was cocaine (obtained from the leaves of the South American shrub E. Coca) that was introduced into clinical practice by Koller in 1884 as an ophthalmic anaesthetic. Cocaine has powerful central stimulating side effects and induces dependence. The central stimulant effect is manifested in restlessness and excitement and eventually convulsions. This effect is shared by other nitrogen containing local anaesthetics. The central action of cocaine is also related to the ability to potentiate noradrenaline, this action is not shared by other local anaesthetics. When applied to the cornea cocaine anaesthetises the surface and induces mydriasis (enlargement of the pupil). Because of its adverse effects cocaine is not used in clinical medicine.

Lignocaine (lidocaine) is most common type of local anaesthetic agents in clinical practice and it is effective in all five forms of local anaesthesia: 1. Surface (e.g. lignocaine; proparacaine, Alcaine eye drops (0.5%); cinchocaine, Nupercainal ointment (1%), Proctosedyl ointment (0.5%). 2. Infiltration (e.g. lignocaine 0.25-0.5% with adrenaline) 3. Nerve block ( lignocaine 1-2% with adrenaline, e.g. pudendal nerve block as for episiotomy1) 4. Epidural (peridural) nerve block (lignocaine 1-2% with adrenaline) requires high skills. 5. Spinal nerve block (lignocaine) with the following disadvantages: a.headache due to CSF leakage b.hypotension due to block of the sympathetic nervous system c.potential of introducing bacteria

Procaine is the first synthetic local anaesthetic was introduced in 1905 and remained the dominant local anaesthetic for the next 50 years. Procaine is an example of a local anaesthetic with an ester-bond and therefore rapidly broken down by plasma cholinesterase. Procaine still had a considerable potential for producing adverse effects like local irritation and tissue damage in addition to systemic toxicity. At present, it is only used as an amide (procainamide) for cardiac arrhythmias and in procaine penicillin (that should not be given intravenously) for slow release of penicillin.

Mechanism of Action It is believed that the mechanism of action of local anaesthetics is primarily effected by blockade of voltage-gated sodium channels. These agents block sodium channels in a voltage- and time-dependent manner. Local anaesthetics exert their effect on excitable nerve axons and neuronal cell bodies (like the membrane of cardiac muscle) mostly when these cells with high firing activity and thus at more positive membrane potential. It is noted earlier (page 150) that local anaesthetics have a much higher affinity for the activated and inactivated states (usedependence) than the rested state of sodium channels. It follows that the effect of a given concentration of a local anaesthetic is more

The continued effort to find a better local anaesthetic agent lead to the synthesis of lignocaine (1943) by L fgren. To date, lignocaine (lidocaine, xylocaine) is still considered the prototype local anaesthetic agent. Although the development of new local anaesthetic agents continues but none showed significant reduction in toxicity as compared with that of the current agents. This is probably because the most serious toxicity of local anaesthetic agents is produced by the therapeutic effect on the brain and the cardiovascular system.

1

Episiotomy: surgical incision into the perineum and vagina for obstetrical purposes.

176


Majid A. K. Lafi

marked in rapidly firing axons than in resting neurones2.

The onset of local anaesthesia is sometimes accelerated by the use of solutions saturated with carbon dioxide. The high tissue level of CO2 results in intracellular acidosis (CO2 crosses membrane readily), which results in intracellular accumulation (trapping) of cationic form of the local anaesthetic. It must be noted that the cationic (ionised) form is thought to be the most active form at the local anaesthetic receptor site located within the voltage-dependent sodium channel; this is probably because the cationic form cannot readily leave the closed channels. Further, this local anaesthetic receptor is not accessible from the external side of the cell membrane. Unlike, the cationic drug form, the uncharged form can rapidly penetrate biological membranes.

Adverse Effects 1. Seizures and convulsions (use diazepam) 2. Cardiovascular depression

Combination with Vasoconstrictors Vasoconstrictor substances such as adrenaline reduces systemic absorption of local anaesthetics resulting in enhanced neuronal uptake of the drug and reduced systemic toxic effects of the drug. Such combination should not be given for the digits. Nowadays, the vasoconstrictor agent preferred to be used is a vasopressin receptor agonist like felypressin; vasopressin is supposed to be safer in patients with coronary artery disease.

Table 5.22. A summary of the pharmacology of selected local anaesthetic agents for infiltration anaesthesia. Time course of action

Agent

Tachyphylaxis

Procaine* Tetracaine*

Repeated injection of local anaesthetics during spinal and epidural anaesthesias (and for infiltration in tissue where there is pus) results in rapid loss of effectiveness (tachyphylaxis). This is probably a consequence of local extracellular acidosis. Local anaesthetics are weak bases and marketed as hydrochloride salts (pH 4 to 6) for reasons of solubility and stability. After injection, the salts are buffered in the tissue to physiological pH, thereby providing sufficient free base for diffusion through axonal membranes. However, repeated injections deplete the local available buffer. The ensuing acidosis increases the extracellular cationic form, which diffuses poorly into axons. The clinical result is apparent tachyphylaxis, especially in areas of limited buffer reserve, such as the cerebrospinal fluid. Therefore, an agent with a long duration of action like bupivacaine is preferred in this condition to avoid repeating the dose.

Lidocaine

Onset (min) 2-5 15 100 mg/dL), emergency haemodialysis is preferred to remove the salicylate more quickly and restore acid-base balance and fluid status. Sodium nitrite rapidly converts haemoglobin to methaemoglobin that binds CN, and thiosulphate promotes the formation of less toxic thiocyanate.

Glossary and Abbreviations


GLOSSARY AND ABBREVIATIONS Incomplete list of vocabulary adapted by and large from Dorland's Medical Dictionary (2000) W.B. Saunders 1, 25-DHCC: 1, 25-dihydroxycholecalciferol. 25-HCC: 25-hydroxycholecalciferol. Abortifacient: 1. causing abortion. 2. an agent which causes abortion. Abreaction: the reliving of an experience in such a way that previously repressed emotions associated with it are released. (Thiopental) Abscess: a localized collection of pus buried in tissues, organs, or confined spaces. Absence: the seizure seen in absence epilepsy, consisting of a sudden momentary break in consciousness of thought or activity, often accompanied by automatisms or clonic movements, especially of the eyelids. On the electroencephalogram it is characterized by a specific symmetrical spike and wave type occurring at three cycles per second. Abstinence: a refraining from the use of or indulgence in food, stimulants, or sexual intercourse. ACE: angiotensin converting enzyme ACh: acetylcholine. Achlorhydria: absence of hydrochloric acid from maximally stimulated gastric secretions; a result of gastric mucosal atrophy. Acne: an inflammatory disease of the pilosebaceous unit, the specific type usually being indicated by a modifying term; frequently used alone to designate common acne, or a. vulgaris. Acromegaly: a chronic disease of adults caused by hypersecretion of growth hormone, characterized by enlargement of many parts of the skeleton, especially distal portions such as the nose, ears, jaws, fingers, and toes. ACTH: (corticotrophin) adrenocorticotropic hormone. Acute intermittent porphyria: hereditary hepatic porphyria manifested by recurrent attacks of abdominal pain, gastrointestinal dysfunction, and neurological disturbances and by excessive amounts of aminolevulinic acid and porphobilinogen in the urine; it is due to an abnormality of pyrrole metabolism transmitted as an autosomal dominant trait. (Barbiturates) Acute: having a short and relatively severe course. Addiction: 1. the state of being given up to some habit or compulsion. 2. strong physiological and psychological dependence on a drug or other psychoactive substance. Addison s disease: a chronic type of adrenocortical insufficiency, characterized by hypotension, weight loss, anorexia, weakness, and a bronzelike hyperpigmentation of the skin. It is

260

due to tuberculosis- or autoimmune-induced destruction of the adrenal cortex, which results in deficiency of aldosterone and cortisol and is fatal in the absence of replacement therapy. ADH: (vasopressin) antidiuretic hormone. Adjunct: an accessory or auxiliary agent or measure. Adjuvant: 1. assisting or aiding. 2. a substance that aids another, such as an auxiliary remedy. 3. in immunology, a non-specific stimulator of the immune response, such as BCG vaccine. Adrenal crisis: acute onset of adrenocortical insufficiency or sudden worsening of Addison's disease; manifestations include anorexia, vomiting, abdominal pain, apathy, confusion, extreme weakness, renal loss of sodium and water, and hypotension progressing to shock and, if untreated, death. Adrenergic tremor: (enhanced physiological tremor) a tremor that may appear in normal individuals under conditions of stress, such as cold, excitement, hunger, or exercise; it represents an intensification of physiological tremor to detectable levels. Affect: the external expression of emotion attached to ideas or mental representations of objects. Agitation: excessive, purposeless cognitive and motor activity or restlessness, usually associated with a state of tension or anxiety Agoraphobia: intense, irrational fear of open spaces, characterized by marked fear of being alone or of being in public places where escape would be difficult or help might be unavailable. Agranulocytosis: 1. any condition involving greatly decreased numbers of granulocytes 2. more specifically, a symptom complex characterized by marked decrease in the number of circulating granulocytes; severe neutropenia results in lesions of the throat, other mucous membranes, gastrointestinal tract, and skin; in most cases it is caused by sensitization to drugs, chemicals, or radiation affecting the bone marrow and depressing granulopoiesis. Akathesia: a condition of motor restlessness in which there is a feeling of muscular quivering, an urge to move about constantly, and an inability to sit still, a common extrapyramidal side effect of neuroleptic drugs. Akinesia: see hypokinesia Alcoholism: a disorder characterized by a pathological pattern of alcohol use that causes a serious impairment in social or occupational functioning. Algesia: 1. pain sense. 2. excessive sensitivity to


Majid A.K. Lafi

pain, a type of hyperesthesia. Allergic rhinitis: a general term used to denote any allergic reaction of the nasal mucosa; it may occur perennially (nonseasonal allergic rhinitis) or seasonally (hay fever). Alopecia: lack or loss of the hair from skin areas where it normally is present. Altitudes sickness: the condition resulting from difficulty in adjusting to diminished oxygen pressure at high altitudes. It may take the form of mountain sickness, high-altitude pulmonary oedema, or cerebral oedema. Alzheimer s disease: a progressive degenerative disease of the brain of unknown aetiology, characterized by diffuse atrophy throughout the cerebral cortex with distinctive lesions called senile plaques and clumps of fibrils called neurofibrillary tangles. There is a loss of choline acetyltransferase activity in the cortex, and many of the degenerating neurons seem to be cholinergic neurons projecting from the substantia innominata to the cortex. The first signs of the disease are slight memory disturbance or changes in personality; deterioration progresses to profound dementia over 5 to 10 years. Women are affected twice as often as men, and onset may occur at any age. Amenorrhoea: absence or abnormal stoppage of the menses. (Oestrogens) AML: Acute Myeloid Leukaemia Amnesia: lack or loss of memory; inability to remember past experiences. Amoebiasis: he state of being infected with amoebae, especially with Entamoeba histolytica. Anaemia: a reduction below normal in the concentration of erythrocytes or hemoglobin in the blood, measured per cu mm or by volume of packed red cells per 100 mL of blood; it occurs when the equilibrium is disturbed between blood loss (through bleeding or destruction) and blood production. Analgesia: 1. absence of sensibility to pain; absence of pain on noxious stimulation. 2. the relief of pain without loss of consciousness. Anaphylactic shock: a type I hypersensitivity reaction in which exposure of a sensitized individual to a specific antigen or hapten results in urticaria, pruritus, and angioedema, followed by vascular collapse and shock and often accompanied by life-threatening respiratory distress. Angina pectoris: a paroxysmal thoracic pain, often radiating to the arms, particularly the left, sometimes accompanied by a feeling of suffocation and impending death; it is most often due to ischemia of the myocardium and precipitated by effort or excitement. Angioedema: a vascular reaction involving the deep dermis or subcutaneous or submucosal tissues, representing localized edema caused by dilatation and increased permeability of capillaries, and characterized by development of giant wheals.

261

Angioneurotic oedema: see angioedema Ankylosing spondylitis: a form of degenerative joint disease that affects the spine. It is a systemic illness of unknown etiology, affecting young persons predominantly, and producing pain and stiffness as a result of inflammation of the sacroiliac, intervertebral, and costovertebral joints; paraspinal calcification, with ossification and ankylosis of the spinal joints, may cause complete rigidity of the spine and thorax. Anorexia nervosa: an eating disorder primarily affecting females, usually with onset in adolescence, characterized by refusal to maintain a normal minimal body weight, intense fear of gaining weight or becoming obese, and a disturbance of body image resulting in a feeling of being fat or having fat in certain areas even when extremely emaciated, undue reliance on body weight or shape for self-evaluation, and amenorrhea. Associated features often include denial of the illness and resistance to psychotherapy, depressive symptoms, markedly decreased libido, and obsessions or peculiar behaviour regarding food, such as hoarding. Anorexia: lack or loss of the appetite for food. Antibiotic-associated enterocolitis: that in which treatment with antibiotics alters the bowel flora and results in diarrhea or pseudomembranous enterocolitis. Called also pseudomembranous colitis and antibiotic-associated colitis. Antigenicity: the property of being able to induce a specific immune response or the degree to which a substance is able to stimulate an immune response. Antinociception: having an analgesic effect; reducing sensitivity to painful stimuli. Antipsychotic: effective in the treatment of psychosis, or an agent that so acts. Antrectomy: surgical excision of an antrum, as resection of the pyloric antrum of the stomach. Anuria: complete suppression of urinary secretion by the kidneys. Anxiety: the unpleasant emotional state consisting of psychophysiological responses to anticipation of unreal or imagined danger, ostensibly resulting from unrecognized intrapsychic conflict. Physiological concomitants include increased heart rate, altered respiration rate, sweating, trembling, weakness, and fatigue; psychological concomitants include feelings of impending danger, powerlessness, apprehension, and tension. Apathetic: indifferent; undemonstrative. Apathy: lack of feeling or emotion; indifference. Aphthous ulcer: a small ulcer, such as the round lesion with a grayish exudate surrounded by a red halo characteristic of recurrent aphthous stomatitis Aplastic anaemia: any of a diverse group of anaemias characterized by bone marrow failure with reduction of hematopoietic cells and their replacement by fat, resulting in pancytopenia, often accompanied by granulocytopenia and



thrombocytopenia. It may be hereditary; it may be secondary to causes such as toxic, radiant, or immunologic injury to bone marrow stem cells or their microenvironment; it may be associated with various diseases; or it may be idiopathic. Appetite: a natural longing or desire, especially the natural and recurring desire for food. Arousal: 1. a state of responsiveness to sensory stimulation or excitability. 2. the act or state of waking from or as if from sleep. 3. the act of stimulating to readiness or to action. Ascites: effusion and accumulation of serous fluid in the abdominal cavity. Aseptic necrosis: increasing sclerosis and cystic changes in the head of the femur which sometimes follow traumatic dislocation of the hip. A similar condition sometimes develops in the head of the humerus after shoulder dislocation. Asthma: recurrent attacks of paroxysmal dyspnea, with airway inflammation and wheezing due to spasmodic contraction of the bronchi. Asystol: absence of a heartbeat Ataxia: failure of muscular coordination; irregularity of muscular action. Atonia: see atony. Atonic bladder: a condition marked by a dilated, poorly contracting urinary bladder without evidence of a lesion of the central nervous system. Atony: lack of normal tone or strength, such as in a muscle deprived of its innervation. Atopic dermatitis: a chronic type seen in those with a hereditary susceptibility to pruritus; it may be accompanied by allergic rhinitis, hay fever, and asthma. Attention deficit (hyperkinetic) disorder: a childhood mental disorder characterized by inattention (such as distractibility, forgetfulness, not finishing tasks, and not appearing to listen), by hyperactivity and impulsivity (such as fidgeting and squirming, difficulty in remaining seated, excessive running or climbing, feelings of restlessness, difficulty awaiting one's turn, interrupting others, and excessive talking) or by both types of behaviour. Autoallergy: autoimmunity. Azotaemia: an excess of urea or other nitrogen bodies in the blood (NSAIDs) BBB: blood brain barrier. BCG: Bacille Calmette-Guerin Benign prostatic hyperplasia: see prostatism. Bilateral renal stenosis: see renal artery stenosis. Bioequivalence: the quality of being bioequivalent. Bioequivalent: having the same strength and similar bioavailability in the same dosage form as another specimen of a given drug substance. Bipolar affective disorder: pertaining to mood disorders in which both depressive episodes and manic or hypomanic episodes occur. Bizarre: peculiar, weird, absurd. Bleeding oesophageal varices: pertaining to

262

bleeding of varicosities of the branches of the azygos vein which anastomose with tributaries of the portal vein in the lower oesophagus, occurring in patients with portal hypertension. Blood dyscrasia: a pathologic condition of the blood, usually referring to disorders of the cellular elements of the blood. Blurred vision: fuzzy image. Blush: sudden, brief erythema of the face and neck, resulting from vascular dilatation due to emotion or heat. Bonchoconstriction: constriction or narrowing the lumina of the air passages of the lungs, typically as a result of bronchial smooth muscle contraction. BPH : Benign prostatic hyperplasia. Bradycardia: slowness of the heartbeat, as evidenced by slowing of the pulse rate to less than 60. Bradykinesia: see hypokinesia Bronchiectasis: chronic dilatation of the bronchi marked by fetid breath and paroxysmal coughing, with the expectoration of mucopurulent matter. Brucellosis: in humans, a generalized infection caused by species of Brucella, transmitted by contact with the natural animal reservoirs, including cattle, sheep, goats, swine, deer, and rabbits, or their infected products or tissue. It involves primarily the reticuloendothelial system and is characterized by fever, sweating, weakness, malaise, and weight loss. Bulimia nervosa: an eating disorder occurring predominantly in females, with onset usually in adolescence or early adulthood and characterized by episodic binge eating followed by behaviours designed to prevent weight gain, including purging, fasting, and excessive exercise. BUN: blood urea nitrogen CAD: coronary artery disease Calculus: an abnormal concretion occurring within the body and usually composed of mineral salts. Carcinoid tumour: a yellow circumscribed tumor arising from enterochromaffin cells, usually in the small intestine, appendix, stomach, or colon and less commonly in the bronchus. Cardiomyopathy: a general diagnostic term designating primary noninflammatory disease of the heart muscle, often of obscure or unknown etiology and not the result of ischemic, hypertensive, congenital, valvular, or pericardial disease. Cardioversion: the restoration of normal rhythm of the heart by electrical shock. Cataracts: a partial or complete opacity on or in the lens or lens capsule of the eye, especially one impairing vision or causing blindness. Cathartic: 1. causing emptying of the bowels. 2. an agent that causes emptying of the bowels, such as by increasing bulk or stimulating peristaltic action. Called also evacuant and purgative. 3. producing emotional catharsis.


Majid A.K. Lafi

CBF: cerebral blood flow. CBG: corticosteroid binding globulin. Cellulitis: an acute, diffuse, spreading, edematous, suppurative inflammation of the deep subcutaneous tissues and sometimes muscle, sometimes with abscess formation; the skin is warm and tender. Central precocious puberty: precocious puberty due to premature hypothalamic-pituitary-gonadal maturation; it is always isosexual and involves not only development of secondary sex characters but also development of the gonads. Increases in height and weight and osseous maturation are accelerated, and early closing of the epiphyses leads to short stature. CGRP: calcitonin gene related peptide. Cheese effect: cheese contains substantial amounts of sympathomimetics, most commonly tyramine, which acts by releasing tissue-stored noradrenaline. For example, degradation of the protein 'casein' by resident bacteria in well matured cheese can produce tyramine from the amino acid tyrosine, hence use of the term 'cheese effect' to describe provocation of a hypertensive crisis by orally administered sympathomimetics. CHF: Congestive heart failure Chickenpox: (varicella) a highly contagious infectious disease caused by human herpesvirus 3, usually affecting children, spread by direct contact or the respiratory route via droplet nuclei, and characterized by the appearance on the skin and mucous membranes of successive crops of typical pruritic vesicular lesions that are easily broken and become scabbed, and generally accompanied by mild constitutional symptoms. Cholinergic crisis: muscular weakness resulting from depolarization block due to overdosage of anticholinesterase agents used for myasthenia gravis; similar to but different from myasthenic crisis. CHOP: cyclophosphamide, hydroxydonorubicin (doxorubicin), Oncovin (vincristine), and prednisone. Chorea: the ceaseless occurrence of a wide variety of rapid, highly complex, jerky movements that appear to be well coordinated but are performed involuntarily. (Drugs and movement disorders) Chorionepithelioma: an epithelial malignancy of trophoblastic cells, formed by the abnormal proliferation of cuboidal and syncytial cells of the placental epithelium, without the production of chorionic villi. Chronic bronchitis: a type of chronic obstructive pulmonary disease in which there is bronchial irritation with increased secretions and a productive cough for at least three months, two years in succession; it is usually accompanied by pulmonary emphysema. The most common cause is long-term inhalation of irritants. Chronic: persisting over a long period of time. Chronotropic: affecting the time or rate, as the

263

rate of contraction of the heart. Cinchonism: poisoning by the injudicious use of cinchona bark or its alkaloids, characterized by nausea, vomiting, headache, tinnitus, deafness, symptoms of cerebral congestion, vertigo, and visual disturbances. Closed-angle glaucoma: glaucoma caused by closure of the anterior angle by contact between the iris and the inner surface of the trabecular meshwork; called also closed-angle g., narrowangle g., and pupillary block g. CMV: cytomegalovirus CNS: central nervous system. Coitus: sexual connection per vaginam between male and female. Cold sweat: a sweat produced by the apocrine sweat glands, located on the palms of the hands and a few other areas, respond to adrenoceptor stimulants with increased sweat production. These are the apocrine nonthermoregulatory glands usually associated with psychological stress, e.g. an embarrassing situation. Collapse: 1. a state of extreme prostration and depression, with failure of circulation. 2. abnormal falling in of the walls of any part or organ. Compulsion: a persistent and irresistible impulse to perform an irrational or apparently useless act. 2. a compulsive act or ritual; a repetitive and stereotyped action, such as hand-washing, touching, counting, and checking, that is engaged in for an unknown or unconscious purpose. COMT: catechol-O-methyltransferase Concomitant: accompanying; accessory; joined with another. Confusion: disturbed orientation in regard to time, place, or person, sometimes accompanied by disordered consciousness. Congestion: excessive or abnormal accumulation of fluid, as of blood in a part. Congestive heart failure: (CHF) a clinical syndrome due to heart disease, characterized by breathlessness and abnormal sodium and water retention, often resulting in oedema. The congestion may occur in the lungs or peripheral circulation or both, depending on whether the heart failure is right-sided or general. Conjunctivitis: inflammation of the conjunctiva, generally consisting of conjunctival hyperaemia associated with a discharge. Constipation: infrequent or difficult evacuation of the faeces. Contraception: the prevention of conception or impregnation. Convulsion: a violent involuntary contraction or series of contractions of the voluntary muscles. COX: cyclooxgenase. Cretinism: a chronic condition due to congenital severe hypothyroidism; manifestations begin in late infancy and include arrested physical development (dwarfism), mental retardation, dystrophy of the



bones and soft parts, and lowered basal metabolism. Crohn s disease: a chronic granulomatous inflammatory disease of unknown aetiology, involving any part of the gastrointestinal tract from mouth to anus, but commonly involving the terminal ileum with scarring and thickening of the bowel wall; it frequently leads to intestinal obstruction and fistula and abscess formation and has a high rate of recurrence after treatment. Cryptorchism: failure of testes to descend to into the scrotum. (Non-pituitary gonadotropins) Crystalluria CSF: cerebrospinal fluid. Css: steady-state concentration. CTZ: chemoreceptor trigger zone. Cushing s syndrome: a complex of symptoms caused by hyperadrenocorticism due either to a neoplasm of the adrenal cortex or adenohypophysis, or to excessive intake of glucocorticoids. Symptoms may include adiposity of the face, neck, and trunk; kyphosis from osteoporosis of the spine; hypertension; diabetes mellitus; amenorrhea and hypertrichosis in females; impotence in males; dusky complexion with purple striae; polycythemia; and muscular wasting and weakness. Cushing-like syndrome: a complex of symptoms caused by hyperadrenocorticism due either to a neoplasm of the adrenal cortex or adenohypophysis, or to excessive intake of glucocorticoids. Symptoms may include adiposity of the face, neck, and trunk; kyphosis from osteoporosis of the spine; hypertension; diabetes mellitus; amenorrhoea and hypertrichosis in females; impotence in males; dusky complexion with purple striae; polycythaemia; and muscular wasting and weakness. Cycloplegia: paralysis of the ciliary muscle; paralysis of accommodation. Cystic fibrosis: cystic fibrosis of the pancreas, an autosomal recessive disorder of infants, children, and young adults in which there is widespread dysfunction of the exocrine glands, with signs of chronic pulmonary disease (due to excess mucus production in the respiratory tract), pancreatic deficiency, abnormally high levels of electrolytes in the sweat, and occasionally biliary cirrhosis. DAG: diacylglycerol Deep venous thrombosis: DVT; thrombosis of one or more of the deep veins of the lower limb, characterized by swelling, warmth, and erythema, frequently a precursor of a pulmonary embolism. Deleterious: hurtful; injurious. Delirium tremens: (alcohol withdrawal delirium) delirium caused by cessation or reduction in alcohol consumption, typically in alcoholics with 10 years or more of heavy drinking. Clinical manifestations include autonomic hyperactivity, such as tachycardia, sweating, and hypertension; a

264

coarse, irregular tremor, and delusions, vivid hallucinations; and wild, agitated behaviour. The onset is usually 2 or 3 days after cessation of drinking; the delirium and other withdrawal symptoms usually resolve in 3 or 4 days. Delirium: an acute, transient disturbance of consciousness accompanied by a change in cognition and having a fluctuating course. Delusion of jealousy: a delusional belief that one's spouse or lover is unfaithful based on erroneous inferences drawn from innocent events imagined to be evidence and often resulting in confrontation with the accused. It is one of the subtypes of delusional disorder. Delusion: a false belief that is firmly maintained in spite of undeniable and obvious proof or evidence to the contrary and in spite of the fact that other members of the culture do not share the belief. Dementia: a general loss of cognitive abilities, including impairment of memory as well as one or more of the following: aphasia, apraxia, agnosia, or disturbed planning, organizing, and abstract thinking abilities. Demulcent: 1. soothing; bland; allaying the irritation of inflamed or abraded surfaces. 2. a soothing, mucilaginous, or oily medicine or application. Dependent oedema: oedema affecting most seriously the lowermost or dependent parts of the body. Depression: 1. a hollow or depressed area; downward or inward displacement. 2. a lowering or decrease of functional activity. 3. a mental state of depressed mood characterized by feelings of sadness, despair, and discouragement. Depression ranges from normal feelings of ''the blues'' through dysthymic disorder to major depressive disorder. It in many ways resembles the grief and mourning that follow bereavement; there are often feelings of low self-esteem, guilt, and self-reproach, withdrawal from interpersonal contact, and somatic symptoms such as eating and sleep disturbances. Dermatophytoses: any superficial fungal infection caused by a dermatophyte and involving the stratum corneum of the skin, hair, and nails, including onychomycosis and the various forms of tinea. Diabetes insipidus: any of several types of polyuria in which the volume of urine exceeds 3 litres per day, causing dehydration and great thirst, as well as sometimes emaciation and great hunger. Diabetic neuropathy: any of several clinical types of peripheral neuropathy occurring with diabetes mellitus; there are sensory, motor, autonomic, and mixed varieties. The most common kind is a chronic, symmetrical sensory polyneuropathy affecting first the nerves of the lower limbs and often affecting autonomic nerves; pathologically, there is a segmental demyelination of the


Majid A.K. Lafi

peripheral nerves. An uncommon acute form is the ischemic variety, accompanied by severe pain, weakness, and wasting of proximal and distal muscles, peripheral sensory impairment, and loss of tendon reflexes. With autonomic involvement there may be orthostatic hypotension, nocturnal diarrhea, retention of urine, impotence, and small diameter of the pupils with sluggish reaction to light. Diabetogenic: producing diabetes Diaphoresis: sweating, especially of a profuse type. Diarrhoea: abnormal frequency and liquidity of faecal discharges. DIC: Disseminated intravascular coagulation Diphtheria: an acute infectious disease caused by toxigenic strains of Corynebacterium diphtheriae, acquired by contact with an infected person or a carrier; it is usually confined to the upper respiratory tract, and characterized by the formation of a tough false membrane attached firmly to the underlying tissue that will bleed if forcibly removed. In the most serious infections the membrane begins in the faucial area on one tonsil and may spread to the other tonsil, uvula, soft palate, and pharyngeal wall, followed by the larynx, trachea, and bronchial tree, where it may cause bronchial obstruction and death by hypoxia. Diplopia: the perception of two images of a single object. Disinhibition: 1. removal of inhibitions, as reduction of the inhibitory function of the cerebral cortex by drugs such as ethyl alcohol or reduction in the severity of superego controls in psychotherapy. 2. in experimental psychology, the revival of an extinguished conditioned response by exposure to an unconditioned stimulus. Dissociative anaesthesia: loss of sensitivity to pain, heat, and cold without loss of other tactile senses. Disulfiram-like reaction: a syndrome occurring after inhalation or ingestion of disulfiram followed by drinking an alcoholic beverage, marked by intense flushing, rapid pulse and pounding heart, panting respiration, and impaired taste, unpleasant breath and perspiration, which may be followed by nausea, vomiting, and a precipitous fall in blood pressure; the extent and severity of the symptoms depend on the amount of calcium cyanamide and alcohol in the system. The reactions are due to the inhibition by disulfiram of one or more of the enzymes required for oxidation of acetaldehyde formed from alcohol, resulting in the accumulation of acetaldehyde and the altered vascular reaction to it. Dizziness: a disturbed sense of relationship to space; a sensation of unsteadiness with a feeling of movement within the head. DMARD: disease-modifying antirheumatic drug. Dosage: the determination and regulation of the

265

size, frequency, and number of doses. Dromotropic: affecting the conductivity of a nerve fiber Dropsical: oedematous. Drowsiness: sleepiness. Drug Abuse: a substance use disorder characterized by the use of a mood or behaviouraltering substance in a maladaptive pattern resulting in significant impairment or distress, such as failure to fulfil social or occupational obligations or recurrent use in situations in which it is physically dangerous to do so or which end in legal problems, but without fulfilling the criteria for substance dependence (q.v.). Specific disorders are named for their aetiology, eg., alcohol abuse, anabolic steroid abuse. Ductus arteriosus: arterial duct: a fetal blood vessel connecting the left pulmonary artery directly to the descending aorta. Dysfunctional uterine bleeding: bleeding from the uterus when no organic uterine lesions are present. Dysmenorrhoea: Painful menstruation (NSAIDs) Dyspepsia: impairment of the power or function of digestion; usually applied to epigastric discomfort following meals. Dysphoria: disquiet; restlessness; malaise (Opioids and narcotic analgesics) Dyspnoea: breathlessness or shortness of breath; difficult or laboured breathing. Dystocia: abnormal labour or childbirth (NSAIDs) Dystonia: dyskinetic movements due to disordered tonicity of muscle. ECL: enterochromaffin-like. ECT: electroconvulsive therapy. Ectopic beats: a heart beat originating at some point other than the sinus node. Emotion: a strong feeling state, such as excitement, distress, happiness, sadness, love, hate, fear, or anger, arising subjectively and directed toward a specific object, with physiological, somatic, and behavioural components. In psychoanalytic theory, it is a state of tension associated with an instinctual drive. The external manifestation of emotion is called affect; a pervasive and sustained emotional state, mood. Empirical: based on experience. Encephalopathy: any degenerative disease of the brain. Endemic: present or usually prevalent in a population or geographical area at all times; said of a disease or agent. and proliferative Endocarditis: exudative inflammatory alterations of the endocardium, usually characterized by the presence of vegetations on the surface of the endocardium or in the endocardium itself, and most commonly involving a heart valve, but sometimes affecting the inner lining of the cardiac chambers or the endocardium elsewhere. It may occur as a primary



disorder or as a complication of or in association with another disease. Endometrial cancer: carcinoma characterized by glandular patterns that resemble those of the endometrium, occurring in the uterine fundus and in the ovaries. Endometriosis: a condition in which tissue more or less perfectly resembling the uterine mucous membrane (the endometrium) and containing typical endometrial granular and stromal elements occurs aberrantly in various locations in the pelvic cavity. (Progestins, danazol) Endophathalmitis: nflammation involving the ocular cavities and their adjacent structures. Enema: a liquid injected or to be injected into the rectum Enuresis: urinary incontinence after the age at which urinary control should have been achieved; often used alone with specific reference to that occurring during sleep at night (bed-wetting; nocturnal enuresis) Eosinophilia: 1. the formation and accumulation of an abnormally large number of eosinophils in the blood. 2. the condition of being readily stained with eosin. EP: extrapyramidal. Epidural (peridural) nerve block. regional anaesthesia produced by injection of the anaesthetic agent between the vertebral spines and beneath the ligamentum flavum into the epidural space. Epilepsy: any of a group of syndromes characterized by paroxysmal transient disturbances of the brain function that may be manifested as episodic impairment or loss of consciousness, abnormal motor phenomena, psychic or sensory disturbances, or perturbation of the autonomic nervous system. Epileptoform: 1. resembling epilepsy or its manifestations. 2. occurring in severe or sudden paroxysms. Episiotomy: surgical incision into the perineum and vagina to prevent traumatic tearing during delivery. EPSP: excitatory postsynaptic potential. Erotomania: 1. a disorder in which the subject believes that a person, usually older and of higher social status, is deeply in love with them; failure of the object of the delusion to respond to the subject's advances are rationalized, and pursuit and harassment of the object of the delusion may occur. 2. occasionally, hypersexuality. ESBLs: extended spectrum -lactamases Essential tremor: a hereditary tremor with onset at varying ages, usually at about 50 years of age, beginning with a fine rapid tremor (as distinct from that of parkinsonism) of the hands, followed by tremor of the arms, tongue, head, legs, and trunk; it is aggravated by emotional factors, is accentuated by volitional movement, and in some cases is

266

temporarily improved by alcohol. Euphoria: bodily comfort; well being; absence of pain or distress. In psychiatry, an abnormal or exaggerated sense of well being, particularly common in the manic state. (Opioids and narcotic analgesics, glucocorticoids) Excipient: any more or less inert substance added to a prescription in order to confer a suitable consistency or form to the drug; called also vehicle. Expectorant: 1. promoting the ejection, by spitting, of mucus or other fluids from the lungs and trachea. 2. an agent that promotes the ejection of mucus or exudate from the lungs, bronchi, and trachea; sometimes extended to all remedies that quiet cough (antitussives). Extrasystole: a weak systole, usually premature, not associated with pulsation of a peripheral artery Extremity: an upper or lower limb ( a hand or foot) Febrile: 1. pertaining to fever. 2. characterized by fever. Fever: elevation of body temperature above the normal Fibrosis: the formation of fibrous tissue, as in repair or replacement of parenchymatous elements. Flush: 1.transient, episodic redness of the face and neck caused by certain diseases, ingestion of certain drugs or other substances, heat, emotional factors, or physical exertion. 2. to wash out with fluid. Foetal alcohol syndrome: a syndrome of altered prenatal growth and morphogenesis occurring in infants born of women who were chronically alcoholic during pregnancy; it includes maxillary hypoplasia, prominence of the forehead and mandible, short palpebral fissures, microphthalmia, epicanthal folds, severe growth retardation, mental retardation, and microcephaly. Foetal: of or pertaining to a foetus; pertaining to in utero development after the embryonic period. FSH: follicle-stimulating hormone. GABA: γ-aminobutyric acid. GAD: generalised anxiety disorder. Gastroenteritis: an acute inflammation of the lining of the stomach and intestines, characterized by anorexia, nausea, diarrhea, abdominal pain, and weakness, which has various causes, including food poisoning due to infection with such organisms as Escherichia coli, Staphylococcus aureus, and Salmonella species; consumption of irritating food or drink; or psychological factors such as anger, stress, and fear. Gastroparesis: paralysis of the stomach. GERD: gastroesophageal reflux disease. Gestational diabetes: diabetes mellitus with onset or first recognition during pregnancy; this category does not include diabetics who become pregnant or women who become lactosuric. GFR: glomerular filtration rate. GH: (somatropin) growth hormone.


Majid A.K. Lafi

Gigantism: abnormal overgrowth; excessive size and stature. Gingivitis: inflammation of the gingivae. GIT: gastrointestinal tract Glaucoma: a group of eye diseases characterized by an increase in intraocular pressure that causes pathological changes in the optic disk and typical defects in the field of vision. Glycogenolysis: the breakdown of glycogen to glucose by hydrolysis (as in digestion or within lysosomes) or phosphorolysis (as in mobilization of glycogen as a fuel). Gn: gonadotropin. GnRH: gonadotropin-releasing hormone. Goitre: an enlargement of the thyroid gland, causing a swelling in the front part of the neck. Gout: a group of disorders of purine metabolism, manifested by various combinations of (1) hyperuricaemia; (2) recurrent acute inflammatory arthritis induced by crystals of monosodium urate monohydrate; (3) tophaceous deposits of these crystals in and around the joints of the extremities, which may lead to crippling destruction of joints; and (4) uric acid urolithiasis. Granulocytopenia: reduction in the number of granular leukocytes in the blood. Graves disease: a syndrome of diffuse hyperplasia of the thyroid, with a female predominance; it usually has an autoimmune aetiology and has been linked to autoimmune thyroiditis. Characteristics include hyperthyroidism, usually with goitre and ophthalmic symptoms (Graves' orbitopathy). Grey baby syndrome: a potentially fatal condition seen in neonates, particularly premature infants, due to a reaction to chloramphenicol, characterized by an ashen gray cyanosis, listlessness, weakness, and hypotension. GTN: glyceryltrinitrate Gynaecomastia: excessive growth of the male mammary glands, in some cases including development to the stage at which milk is produced, usually associated with metabolic derangements that lead to oestrogen accumulation, testosterone deficiency, and hyperprolactinaemia. A mild form may develop transiently during normal puberty. Habitual abortion: the spontaneous expulsion of a dead or nonviable foetus in three or more consecutive pregnancies, at about the same period of development. Haematuria: blood in the urine Haemophilia: a hemorrhagic diathesis occurring in two main forms: haemophilia A, deficiency of coagulation factor VIII; and haemophilia B, deficiency of coagulation factor IX. Both forms are determined by a mutant gene near the telomere of the long arm of the X chromosome (Xq), but at different loci, and are characterized by

267

subcutaneous and intramuscular haemorrhages; bleeding from the mouth, gums, lips, and tongue; haematuria; and haemarthroses. Haemorrhoids: a varicose dilatation of a vein of the superior or inferior hemorrhoidal plexus, resulting from a persistent increase in venous pressure. Hallucination: a sense perception without a source in the external world; a perception of an external stimulus object in the absence of such an object. Hangover: extended beyond. Hashimoto s autoimmune thyroiditis: a progressive type of autoimmune thyroiditis with lymphocytic infiltration of the gland and circulating antithyroid antibodies; patients have goitre and gradually develop hypothyroidism. It has a familial predisposition, usually affects women, and sometimes precedes the onset of Graves' disease or is manifested after the major symptoms subside. Hay fever: a type of allergic rhinitis that occurs at the same time every year, marked by acute conjunctivitis with lacrimation and itching, swelling of the nasal mucosa, sneezing, and often asthmatic symptoms. hCG: human chorionic gonadotropin. Heart block: impairment of conduction of an impulse in heart excitation; often applied specifically to atrioventricular block. Hepatotoxicity: the quality or property of exerting a destructive or poisonous effect upon liver cells. Herpes simplex: a group of acute infections caused by human herpesviruses 1 and 2, characterized by the development of one or more small fluid-filled vesicles with a raised erythematous base on the skin or mucous membrane, and occurring as a primary infection or recurring because of reactivation of a latent infection. Type 1 infections usually involve nongenital regions of the body, whereas in type 2 infections the lesions are primarily seen on the genital and surrounding areas, although there is overlap between the two types. Hiatus hernia: a condition of incompetent gastrooesophageal sphincters. Hiccup: an involuntary spasmodic contraction of the diaphragm, causing a beginning inspiration that is suddenly checked by closure of the glottis, causing a characteristic sound. Hirsutism: abnormal hairiness, especially an adult male pattern of hair distribution in women. hMG: human menopausal gonadotropin. Huntington s chorea: a rare hereditary disease characterised by chronic progressive chorea and mental deterioration terminating in dementia; the age of onset is variable but usually occurs in the fourth decade of life. Death usually follows within 15 years. It is transmitted as an autosomal dominant trait. (Drugs and movement disorders) Huntington s chorea: an autosomal dominant



disease characterized by chronic progressive chorea and mental deterioration terminating in dementia; the age of onset is variable but usually in the fourth decade of life, with death within 15 years. Huntington s disease: see Huntington s chorea Hydatidiform mole: an abnormal pregnancy resulting from a pathological ovum, with proliferation of the epithelial covering of the chorionic villi and dissolution and cystic cavitation of the avascular stroma of the villi. Hydrothorax: a pleural effusion containing serous fluid. Hyperactive child: see Attention deficit (hyperkinetic) disorder Hypercalcaemia: an excess of calcium in the blood; manifestations include fatigability, muscle weakness, depression, anorexia, nausea, and constipation. Hypercalciuria: excess of calcium in the urine. Hyperchloraemic acidosis: metabolic acidosis accompanied by elevated plasma chloride. Hyperglycaemia: abnormally increased glucose in the blood, such as in diabetes mellitus. Hyperkinetic child: see Attention deficit (hyperkinetic) disorder an abnormally high Hypermagnesaemia: magnesium content of the blood; manifestations include lethargy, weakness, electrocardiographic abnormalities and, as levels increase, loss of deep tendon reflexes, somnolence, and coma. Hyperplasia: abnormal multiplication or increase in the number of normal cells in normal arrangement in a tissue. Hyperplasminaemia: abnormally increased plasmin in the blood. Hyperprolactinaemia: increased levels of prolactin in the blood; in women it is associated with amenorrhea and galactorrhoea, and in men it has been reported to cause hypogonadism, impotence, and in some cases gynaecomastia. It is often associated with microadenoma of the adenohypophysis. Hypersexuality: abnormally increased sexual desire or activity; nymphomania; satyriasis. Hypersomnia: excessive sleeping or sleepiness, as in any of a group of sleep disorders with a variety of physical and psychogenic causes. Hypertension: high arterial blood pressure; various criteria for its threshold have been suggested, ranging from 140 mm Hg systolic and 90 mm Hg diastolic to as high as 200 mm Hg systolic and 110 mm Hg diastolic. Hypertension may have no known cause (essential or idiopathic h.) or be associated with other primary diseases (secondary h.). Hypertensive crisis: dangerously high blood pressure of acute onset. Hyperthermia of anaesthesia: see malignant hyperthermia.

268

Hyperthyroidism: a condition caused by excessive production of iodinated thyroid hormones. Hypertrophy: the enlargement or overgrowth of an organ or part due to an increase in size of its constituent cells. Hyperuricaemia: excess of uric acid or urates in the blood; it is a prerequisite for the development of gout and may lead to renal disease. Hypoadrenalism: adrenal insufficiency. Hypoglycaemia: an abnormally diminished concentration of glucose in the blood, which may lead to tremulousness, cold sweat, piloerection, hypothermia, and headache; when chronic and severe it may cause central nervous system manifestations that in rare cases can even be fatal. Hypokalaemia: abnormally low potassium concentration in the blood; it may result from excessive potassium loss by the renal or the gastrointestinal route, from decreased intake, or from transcellular shifts. It may be manifested clinically by neuromuscular disorders ranging from weakness to paralysis, by electrocardiographic abnormalities (depression of the T wave and elevation of the U wave), by renal disease, and by gastrointestinal disorders. Hypokinesia: (bradykinesia, akinesia) slowness of movements (Drugs and movement disorders) Hypomania: an abnormality of mood resembling mania (persistent elevated or expansive mood, hyperactivity, inflated self-esteem, etc.) but of lesser intensity. Hypophosphotaemia: an abnormally decreased amount of phosphates in the blood; manifestations include haemolysis, lassitude, weakness, and convulsions. Hypotension: abnormally low blood pressure. Hypothalamic hypogonadotropic hypogonadism: that due to lack of gonadotropin secretion; it is caused by lack of secretion of gonadotropin-releasing hormone. Hypothyroidism: deficiency of thyroid activity, characterized by decrease in basal metabolic rate, fatigue, and lethargy; if untreated, it progresses to myxoedema. In adults it is more common in women than men, and in infants it can lead to cretinism. Hypothyroidism: deficiency of thyroid activity, characterized by decrease in basal metabolic rate, fatigue, and lethargy; if untreated, it progresses to myxoedema. In adults it is more common in women than men, and in infants it can lead to cretinism. Hypotonic bladder: a condition of diminished tone of the detrusor muscle of the urinary bladder. Hypoxia: reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. i.m.: intramuscular. i.v.: intravenous.


Majid A.K. Lafi

IDDM: insulin dependent diabetes mellitus. Idiopathic: of unknown cause or spontaneous origin; of the nature of an idiopathy. Ileus: obstruction of the intestines. Immune insulin resistance: see insulin resistance. Impulse dyscontrol syndrome: a pattern of episodic, abnormal, and often violent and uncontrollable social behaviour with little or no provocation; it may result from diseases of the limbic system or the temporal lobe or may accompany abuse of alcohol or some other psychoactive substance. Incontinence: 1. inability to control excretory functions, such as defecation (fecal i.) or urination (urinary i. ). Infant respiratory distress syndrome: dyspnoea with cyanosis in the newborn, heralded by such prodromal signs as dilatation of the alae nasi, expiratory grunt, and retraction of the suprasternal notch or costal margins, caused by a deficiency in surfactant. It is usually seen in premature infants, children of diabetic mothers, or infants delivered by caesarean section, although sometimes there is no apparent predisposing cause. Infertility: diminished or absent capacity to produce offspring; the term does not denote complete inability to produce offspring as does sterility. Inotropic: affecting the force or energy of muscular contractions. INR: international normalized ratio. Insomnia: inability to sleep; abnormal wakefulness. Insulin resistance: impairment of normal biological responses to insulin, which may result from abnormalities in the beta-cell products, binding of insulin to antagonists such as antiinsulin antibodies, defects in or reduced numbers of receptors, or defects in the insulin action cascade in the target cell. It can also be caused by excessive quantities of growth hormone, adrenocortical steroids, or some other regulators, or by chronic hyperinsulinaemia secondary to hyperphagia. Incidence is increased with conditions such as obesity, diabetes mellitus, acromegaly, uraemia, and certain rare, possibly genetic, autoimmune disorders. Insulinogenic: pertaining to, characterized by, or promoting insulinogenesis. Insulinoma: an islet cell tumor of pancreatic beta cells; although usually benign, such tumours secrete excessive amounts of insulin and are among the most important causes of hypoglycemia. Intermittent claudication: a complex of symptoms characterized by pain, tension, and weakness in a limb when walking is begun, intensification of the condition until walking becomes impossible, and disappearance of the symptoms after a period of rest. It is seen in occlusive arterial diseases of the limbs, such as

269

thromboangiitis obliterans, and in compression of the cauda equina. Intermittent: occurring at separated intervals; having periods of cessation of activity. Intractable: resistant to cure, relief, or control. IPSP: inhibitory postsynaptic potential. Iritis: inflammation of the iris, usually marked by pain, congestion in the ciliary region, photophobia, contraction of the pupil, and discoloration of the iris. Iron deficiency: deficiency of iron in the system, usually caused by blood loss, low dietary levels of iron, or a disease condition that inhibits iron uptake. Irritable bowel syndrome: irritable colon syndrome, a chronic noninflammatory disease characterized by abdominal pain, altered bowel habits consisting of diarrhea or constipation or both, and no detectable pathologic change; a variant form is characterized by painless diarrhea. It is a common disorder with a psychophysiological basis. ISA: intrinsic sympathomimetic activity Kaliuretic: 1. pertaining to, characterized by, or promoting kaliuresis. 2. an agent that promotes kaliuresis (potassium losing). Kernicterus: a condition associated with high levels of bilirubin in the blood, nearly always with severe neural symptoms, usually seen in infants as a sequela of icterus gravis neonatorum. Lactic acidosis: a metabolic acidosis occurring as a result of excess lactic acid in the blood, due to conditions causing impaired cellular respiration. It occurs most commonly in disorders in which O2 is inadequately delivered to tissues, e.g., shock, septicemia, or extreme hypoxemia, but it can also result from exogenous or endogenous metabolic defects. Initially manifesting as hyperventilation, it progresses to mental confusion and coma. Legionnaires disease: a bacterial disease caused by infection with Legionella pneumophila, and not spread by person-to-person contact; it is characterized by pneumonia, high fever, gastrointestinal pain, headache, and sometimes involvement of the kidneys, liver, or nervous system. Leucocytosis: a transient increase in the number of leukocytes in the blood; seen normally with strenuous exercise and pathologically accompanying haemorrhage, fever, infection, or inflammation. LH: luteinizing hormone. Libido: 1. sexual desire. 2. the psychic energy derived from instinctive biological drives; in early freudian theory it was restricted to the sexual drive, then expanded to include all expressions of love and pleasure, but the concept has evolved to include also the death instinct. LOX: lipoxygenase. LSD: lysergide.



Lupus erythematosus: a group of connective tissue disorders primarily affecting women aged 20 to 40 years, comprising a spectrum of clinical forms in which cutaneous disease may occur with or without systemic involvement. Luteolysis: degeneration of corpus luteum. Lymphogranuloma venereum: a sexually transmitted infection usually seen in warm climates, due to strains of Chlamydia trachomatis, characterized by a primary cutaneous or mucosal lesion at the site of infection, which may be a papular, ulcerative, herpetiform, or erosive lesion or urethritis or endocervicitis that heals spontaneously and may go unnoticed, followed by acute unilateral or bilateral lymphadenopathy. Malaise: a vague feeling of bodily discomfort. Malignant hyperthermia: an autosomal dominantly inherited condition, occurring in patients undergoing general anaesthesia, and causing a sudden, rapid rise in body temperature, associated with signs of increased muscle metabolism, such as tachycardia, tachypnoea, sweating, and cyanosis, usually, muscle rigidity. Called also hyperthermia of anaesthesia and malignant hyperpyrexia. (General anaesthetic agents, antipsychotic neuroleptic drugs, dantroline) Mania: a phase of bipolar disorder characterized by expansiveness, euphoria, agitation, hyperexcitability, hyperactivity, and increased speed of thought and speech (flight of ideas). Manic-depressive illness: older term for bipolar disorder, see bipolar affective disorder. MAO: monoamine oxidase. Megaloblastic: any anaemia characterized by the presence of megaloblasts in the bone marrow, such as pernicious anaemia. Meningitis: inflammation of the meninges, usually by either a bacterium (bacterial m.) or a virus (viral m.). Menopausal symptoms: including transient vaginal bleeding, hot flushes, and vaginal dryness. Menopausal: pertaining to or associated with the menopause. Menopause: cessation of menstruation in the human female, occurring usually between the age of 48 and 50. Menorrhagia: excessive uterine bleeding at the regular intervals of menstruation, the period of flow being greater than usual duration. (Progestins) Menstrual disorder: a derangement or abnormality of function related to menstruation. Metabolic alkalosis: any of the various kinds of acidosis in which the acid-base status of the body shifts toward the acid side because of loss of base or retention of acids other than carbonic acid (fixed or nonvolatile acids), in contrast to respiratory acidosis. Metallic: pertaining to, consisting of, or of the nature of metal.

270

Methemoglobinemia: the presence of excessive methemoglobin in the blood, resulting in cyanosis and headache, dizziness, fatigue, ataxia, dyspnea, tachycardia, nausea, vomiting, and drowsiness, which can progress to stupor, coma, and occasionally death. It may be either chemicalor drug-induced (acquired or toxic m.) or hereditary (congenital or hereditary m.). MIC: minimum inhibitory concentration Micturition: urination. Migraine: an often familial symptom complex of periodic attacks of vascular headache, usually temporal and unilateral in onset, commonly associated with irritability, nausea, vomiting, constipation or diarrhoea, and often photophobia. Attacks are preceded by constriction of the cranial arteries, often with resultant prodromal sensory (especially ocular) symptoms and the spreading depression of Le o; the migraines themselves commence with the vasodilatation that follows. Two primary types are distinguished, m. with aura and m. without aura; the variety without an aura is more common. Milk-alkali syndrome: a syndrome characterized by hypercalcaemia without hypercalciuria or hypophosphataemia, with only mild alkalosis, normal serum phosphatase, severe renal insufficiency with hyperazotaemia, and calcinosis, attributed to ingestion of milk and absorbable alkali for long periods of time. Miosis: contraction of the pupil. Mood: a pervasive and sustained emotion that, when extreme, can colour one's whole view of life and markedly affect behaviour. Mood is generally used to refer to either elation or depression. Morbid jealousy: preoccupation with gloomy or distrustful feelings or thoughts, see delusion of jealousy. Morbid: 1. pertaining to, affected with, or inducing disease; diseased. 2. unhealthy or unwholesome. 3. characterized by preoccupation with gloomy or unwholesome feelings or thoughts. Morbidity: 1. a diseased condition or state. 2. the incidence or prevalence of a disease or of all diseases in a population. Mortality: 1. the quality of being mortal. 2. the mortality rate. Motion sickness: sickness caused by motion experienced in any kind of travel, such as sea sickness, train sickness, car sickness, and air sickness. MRSA: Methicillin Resistant Staphylococcus Aureus. MSA: membrane stabilising activity. Mucolytic: destroying or dissolving mucin; an agent that so acts. Myasthenia gravis: a disorder of neuromuscular function due to the presence of antibodies to acetylcholine receptors at the neuromuscular


Majid A.K. Lafi

junction; characteristics include muscular fatigue and exhaustion tending to fluctuate in severity, without sensory disturbance or atrophy. It may be restricted to one muscle group or become generalized with severe weakness and sometimes ventilatory insufficiency. It may affect any muscle of the body, but especially those of the eye, face, lips, tongue, throat, and neck. Mydriasis: 1. physiologic dilatation of the pupil. 2. morbid dilatation of the pupil. 3. dilatation of the pupil effected by a drug. Myocardial infarction: (MI) gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. Myoclonic: relating to or marked by myoclonus. Myoclonus: shocklike contractions of a portion of a muscle, an entire muscle, or a group of muscles, restricted to one area of the body or appearing synchronously or asynchronously in several areas. It may be part of a disease process (e.g., epileptic or post-anoxic myoclonus) or be a normal physiological response (e.g., nocturnal myoclonus). Myxoedema: 1. a condition characterized by dry, waxy swelling of the skin, with abnormal deposits of glycosaminoglycans in skin (mucinosis) and other tissues, associated with primary hypothyroidism. The oedema is nonpitting, and there are distinctive facial changes including swollen lips and a thickened nose. 2. hypothyroidism in adults. NABQI: N-acetyl-benzoquinone. Narcolepsy: recurrent, uncontrollable, brief episodes of sleep often associated with hypnagogic or hypnopompic hallucinations, cataplexy, and sleep paralysis. Narcotic: 1. pertaining to or producing narcosis. 2. an agent that produces insensibility or stupor, applied especially to the opioids, i.e., to any natural or synthetic drug that has morphine-like actions. Necrosis: the sum of the morphological changes indicative of cell death and caused by the progressive degradative action of enzymes; it may affect groups of cells or part of a structure or an organ. Negative symptoms: (retarded schizophrenia) minus personality features including apathy, flattening of affect and poverty of speech. Neonatal: pertaining to the first four weeks after birth. Nephrogenic diabetes insipidus: diabetes insipidus caused by failure of the renal tubules to reabsorb water in response to antidiuretic hormone, without disturbance in the renal filtration and solute excretion rates; the condition does not respond to exogenous vasopressin. It may be inherited as an X-linked trait or be acquired as a result of drug therapy or systemic disease.

271

Nephrotic syndrome: general name for any of a group of diseases involving defective kidney glomeruli, characterized by massive proteinuria and lipiduria with varying degrees of oedema, hypoalbuminaemia, and hyperlipidaemia Nerve block: that is, injection of the anaesthetic agent close to the nerves whose conductivity is to be cut off. Neuralgia: see trigeminal neuralgia. Neurogenic: 1. forming nervous tissue. 2. originating in the nervous system or from a lesion in the nervous system. Neuroleptanaesthesia: a state of neuroleptanalgesia and unconsciousness, produced by the combined administration of a narcotic analgesic and a neuroleptic agent, together with the inhalation of nitrous oxide and oxygen. Neuroleptanalgesia: a state of quiescence, altered awareness, and analgesia produced by the administration of a combination of a narcotic analgesic and a neuroleptic agent. Neuroleptic: a term coined to refer to the effects on cognition and behaviour of the original antipsychotic agents, which produced a state of apathy, lack of initiative, and limited range of emotion and in psychotic patients caused a reduction in confusion and agitation and normalization of psychomotor activity. The term is outdated as a synonym for antipsychotic agents because newer agents do not necessarily have such effects. Neuromuscular block: a failure in neuromuscular transmission that can be induced pharmacologically or may result from pathological disturbance at the myoneural junction. Neuropathy: a functional disturbance or pathological change in the peripheral nervous system, sometimes limited to noninflammatory lesions as opposed to those of neuritis; the aetiology may be known or unknown. Neutropenia: a decrease in the number of neutrophils in the blood NIDD: non-insulin dependent diabetes mellitus. Nightmare: a terrifying dream; an anxiety attack during dreaming, accompanied by mild autonomic reactions and usually awakening the dreamer, who recalls the dream but is oriented. Nociception: pain sense. Nociceptor: a receptor for pain caused by injury to body tissues; the injury may be from physical stimuli such as mechanical, thermal, or electrical stimuli, or from chemical stimuli such as the presence of a toxin or an excess of a nontoxic substance. Most nociceptors are in either the skin (cutaneous nociceptor) or the walls of viscera (visceral nociceptor). Nocturnal: pertaining to, occurring at, or active at night. NSAID: non-steroidal anti-inflammatory drug. Nystagmus: an involuntary, rapid, rhythmic



movement of the eyeball, which may be horizontal, vertical, rotatory, or mixed, i.e., of two varieties. Obsessive-compulsive disorder: an anxiety disorder characterized by recurrent obsessions or compulsions, which are severe enough to interfere significantly with personal or social functioning. Performing compulsive rituals may release tension temporarily, and resisting them causes increased tension. Odynophagia: pain on swallowing (tetracycline) Oliguria: excretion of a diminished amount of urine in relation to the fluid intake, usually defined as less than 400 mL per 24 hours. Oliguric: pertaining to or characterized by oliguria. Open-angle glaucoma: any glaucoma in which the angle of the anterior chamber remains open, but filtration is gradually diminished because of the tissues of the angle; called also chronic g., simple g., and wide-angle g. Opportunistic infections: superinfection. Organic brain syndrome: former term for a constellation of psychological or behavioural signs and symptoms associated with brain dysfunction of unknown or unspecified aetiology and grouped according to symptoms. Organic psychoses: a psychotic disorder with a known or presumed organic aetiology. Orofacial dyskinesia: see tardive dyskinesia. Orthostatic hypotension: a fall in blood pressure associated with dizziness, blurred vision, and sometimes syncope, occurring upon standing or when standing motionless in a fixed position; it can be acquired or idiopathic. Orthostatic: pertaining to or standing erect (Antihypertensive drugs) Osteoarthritis: a noninflammatory degenerative joint disease seen mainly in older persons, characterized by degeneration of the articular cartilage, hypertrophy of bone at the margins, and changes in the synovial membrane. It is accompanied by pain, usually after prolonged activity, and stiffness, particularly in the morning or with inactivity. inadequate or delayed Osteomalacia: mineralization of osteoid in mature cortical and spongy bone; it is the adult equivalent of rickets and accompanies that disorder in children. Osteomyelitis: inflammation of bone caused by infection, usually by a pyogenic organism, although any infectious agent may be involved. It may remain localized or may spread through the bone to involve the marrow, cortex, cancellous tissue, and periosteum. Ototoxic: causing damage to the vestibulocochlear nerve or the organs of hearing and balance. Ototoxicity: the quality of causing damage to the vestibulocochlear nerve or the organs of hearing and balance PABA: p-aminobenzoic acid.

272

Paget s disease of bone: a disease of bone marked by repeated episodes of increased bone resorption followed by excessive attempts at repair, resulting in weakened deformed bones of increased mass. Pain: a more or less localized sensation of discomfort, distress, or agony, resulting from the stimulation of specialized nerve endings. It serves as a protective mechanism insofar as it induces the sufferer to remove or withdraw from the source. Palliative care: treatment designed to relieve pain and distress, but not attempting a cure. Palpitation: a subjective sensation of an unduly rapid or irregular heart beat Pancytopaenia: deficiency of all cellular elements of the blood. Panhypopituitarism: generalized or particularly severe hypopituitarism, which in its complete form leads to absence of gonadal function and insufficiency of thyroid and adrenal cortical function. Panic: acute, extreme anxiety with disorganization of personality and function. Paradox: a statement which seems to be, though it may not be, absurd or self-contradictory. Paradoxical: occurring at variance with the normal rule. Paraesthesiae: (numbness) abnormal perception, feeling, or sensation. Paralytic ileus: ileus resulting from inhibition of bowel motility, which may be produced by numerous causes, most frequently by peritonitis. Paranoid psychosis: a type of psychosis characterized by preoccupation with one or more systematized delusions or with frequent auditory hallucinations but without disorganized speech, disorganized or catatonic behaviour, or flat or inappropriate affect. Paranoid schizophrenia: a type of schizophrenia characterized by preoccupation with one or more systematized delusions or with frequent auditory hallucinations but without disorganized speech, disorganized or catatonic behaviour, or flat or inappropriate affect. Parenteral: not through the alimentary canal but rather by injection through some other route, such as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, or intravenous. Parkinson s disease: a group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. Parkinsonism: see Parkinson s disease. Paroxysm: 1. a sudden recurrence or intensification of symptoms Paroxysmal: recurring in paroxysms PBPs: penicillin binding proteins Pellagra: a clinical deficiency syndrome due to deficiency of niacin (or failure to convert tryptophan to niacin) and characterized by dermatitis, inflammation of mucous membranes,


Majid A.K. Lafi

diarrhoea, and psychic disturbances. The dermatitis occurs on the portions of the body exposed to light or trauma. Mental symptoms include depression, irritability, anxiety, confusion, disorientation, delusions, and hallucinations. Peptic: pertaining to pepsin or to digestion; related to the action of gastric juices. Peripheral neuropathy: Some conditions that are actually polyneuropathies are called neuropathies. Peritonitis: inflammation of the peritoneum, with exudations of serum, fibrin, cells, and pus, usually accompanied by abdominal pain and tenderness, constipation, vomiting, and moderate fever. Personality disorder: a category of mental disorders characterized by enduring, inflexible, and maladaptive personality traits that deviate markedly from cultural expectations, are selfperpetuating, pervade a broad range of situations, and either generate subjective distress or result in significant impairments in social, occupational, or other functioning. Onset is by adolescence or early adulthood. Pheochromocytoma: a usually benign, wellencapsulated, lobular, vascular tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. Because of increased secretion of adrenaline and noradrenaline, hypertension is a cardinal symptom; it may be persistent or intermittent. During severe attacks, there may be headache; sweating; palpitation and tremor; pallor or flushing of the face; nausea and vomiting; pain in the chest and abdomen; and paresthesias of the extremities. Phlegm: abnormally thick mucus secreted by the mucosa of the respiratory passages during certain infectious processes. Phobia: a persistent, irrational, intense fear of a specific object, activity, or situation (the phobic stimulus), fear that is recognized as being excessive or unreasonable by the individual himself. Phocomelia: a type of meromelia characterized by absence of the proximal portion of a limb or limbs, the hands or feet being attached to the trunk of the body by a single small, irregularly shaped bone. Photophobia: abnormal visual intolerance of light. Photosensitivity reactions: an abnormal cutaneous response involving the interaction between photosensitizing substances and sunlight or filtered or artificial light at wavelengths of 280 400 nm. Physiological lactation: normal; not pathological secretion of milk. Pituitary diabetes insipidus: iabetes insipidus due to injury of the neurohypophyseal system, with a deficient quantity of antidiuretic hormone being released or produced, causing failure of renal tubular reabsorption of water. It may be inherited, acquired, or idiopathic. Plankton: a collective name for the minute freefloating organisms, vegetable and animal, which

273

live in practically all natural waters. Planktonic: pertaining to plankton. PMSG: (serum gonadotropin) pregnant mare serum gonadotropin. Poikelothermia: variable or irregular body temperature. Polyarteritis nodosa: a form of systemic necrotizing vasculitis involving the small and medium-sized arteries with signs and symptoms resulting from infarction and scarring of the affected organ system. Polyarteritis: multiple inflammatory and destructive arterial lesions. Polycystic ovarian syndrome: (PCOS) a clinical symptom complex associated with polycystic ovaries and characterized by oligomenorrhea or amenorrhea, anovulation (hence infertility), and hirsutism. Both hyperestrogenism (from peripheral conversion of androgen) and hyperandrogenism are present. Polymyositis: a chronic, progressive inflammatory disease of skeletal muscle, occurring in both children and adults, and characterized by symmetrical weakness of the limb girdles, neck, and pharynx, usually associated with pain and tenderness, and sometimes preceded or followed by manifestations typical of scleroderma, arthritis, systemic lupus erythematosus, or Sj gren's syndrome. It is also sometimes associated with malignancy, and may be accompanied by characteristic skin lesions. Polyuria: the passage of a large volume of urine in a given period, a characteristic of diabetes. Porphyria: see acute intermittent porphyria. Positive symptoms: added features to personality including hallucinations, delusions and thought disorder. Postherpetic neuralgia: persistent burning pain and hyperesthesia along the distribution of a cutaneous nerve following an attack of herpes zoster; it may last for a few weeks or many months. Postmenopausal osteoporosis: that occurring in women within 3 to 20 years after menopause, affecting trabecular bone more than cortical bone, and manifested mainly by vertebral fractures of the painful crush type, hip fracture, Colles' fracture, and increased tooth loss. Postmortem: occurring or performed after death; pertaining to the period after death. Postural: pertaining to posture or position (Antihypertensive drugs) Precocious puberty: onset of sexual maturation at an earlier age than normal, defined as two standard deviations below the mean, or before age 8 in girls and 9 in boys. Premature ejaculation: ejaculation consistently occurring either prior to, upon, or immediately after penetration and before it is desired, taking into account factors such as age, novelty of the specific situation, and recent frequency of the



sexual act. Premature labour: expulsion of a viable infant before the normal end of gestation, usually applied to interruption of pregnancy between the twentieth and the thirty-seventh completed weeks after the onset of the last menstrual period. Preterm labour: labour at any time before the thirty-seventh completed week (259 days) of gestation. Priapism: persistent abnormal erection of the penis, usually without sexual desire, and accompanied by pain and tenderness. It is seen in diseases and injuries of the spinal cord, and may be caused by vesical calculus and certain injuries to the penis. Primary amenorrhoea: failure of menstruation to occur at puberty. Primary hyperaldosteronism: that arising from oversecretion of aldosterone by an adrenal cortical adenoma, characterized typically by hypokalemia, alkalosis, muscular weakness, polyuria, polydipsia, and hypertension. Called also Conn's syndrome. prn: (p.r.n.) abbreviation for L. pro re na´ta, according as circumstances may require (as needed). Proconvulsant: an agent that promote the initiation of convulsions. Prokinetic: pertaining to gastrointestinal motilityenhancing activity. Prolactin-secreting adenomas: a pituitary adenoma made up of lactotrophs that secretes excessive amounts of prolactin; this may delay puberty in either sex, cause galactorrhoeaamenorrhoea syndrome in women, or decrease libido and fertility in men. Prophylaxis: intervention aimed at the prevention of disease; called also preventive treatment, prophylactic treatment, and protective therapy. Prostatectomy: surgical removal of the prostate or of a part of it. Prostatism: a symptom complex resulting from compression or obstruction of the urethra, due most commonly to nodular hyperplasia of the prostate. Proteinuria: the presence of an excess of serum proteins in the urine; called also albuminuria. Pruritus: 1. an unpleasant cutaneous sensation that provokes the desire to rub or scratch the skin to obtain relief. Called also itching. 2. any of various conditions marked by this sensation, the specific site or type being indicated by a modifying term. Pseudomembranous colitis: see antibioticassociated enterocolitis. Pseudotumour cerebri: a condition caused by venous sinus occlusion and cerebral oedema associated with a number of pathologic conditions, marked by raised intracranial pressure with normal cerebrospinal fluid, headache, nausea, vomiting, and papilloedema, but without neurological signs except occasional abducens paralysis.

274

Psittacosis: human infection by Chlamydia psittaci, generally acquired by inhalation of dried bird excreta containing the pathogen; it may also be acquired by handling feathers or tissues of infected birds, through an open skin lesion, or from the bite of an infected bird. It may be asymptomatic, have mild influenzalike symptoms, or manifest as a severe, highly fatal pneumonia. Psychodysleptic: inducing a dreamlike or delusional state of mind. Psychosis: 1. a mental disorder characterized by gross impairment in reality testing as evidenced by delusions, hallucinations, markedly incoherent speech, or disorganized and agitated behaviour, usually without apparent awareness on the part of the patient of the incomprehensibility of his behaviour. 2. the term is also used in a more general sense to refer to mental disorders in which mental functioning is sufficiently impaired as to interfere grossly with the patient's capacity to meet the ordinary demands of life. Historically, the term has been applied to many conditions, e.g., manicdepressive psychosis, that were first described in psychotic patients, although many patients with the disorder are not judged psychotic. Psychotic depression: in the strict sense, major depressive disorder with psychotic features, such as hallucinations, delusions, mutism, or stupor. However, this term is commonly used in a broader sense to cover all severe depressions causing gross impairment of social or occupational functioning, i.e., as a rough equivalent of major depressive disorder or of endogenous depression. PT: prothrombine time. PTH: parathyroid hormone. Puberty: the period during which the secondary sex characteristics begin to develop and the capability of sexual reproduction is attained. Pulmonary embolism: the closure of the pulmonary artery or one of its branches by an embolus, sometimes associated with pulmonary infarction. Purgative: see cathartic. Purpura: 1. any of a group of conditions characterized by ecchymoses or other small haemorrhages in the skin, mucous membranes, or serosal surfaces; possible causes include blood disorders, vascular abnormalities, and trauma. 2. any of several conditions similar to the traditional purpura group, which may be caused by decreased platelet counts, platelet abnormalities, vascular defects, or reactions to drugs. PVCs: premature ventricular contractions Pyrogen: a fever-producing substance. Rash: a temporary eruption on the skin, as in urticaria; a drug eruption or viral exanthema. Raynaud s disease: a primary or idiopathic vascular disorder characterized by bilateral attacks of Raynaud's phenomenon; it affects females more often than males. Called also Raynaud's gangrene.


Majid A.K. Lafi

Rebound: a reversed response on the withdrawal of a stimulus. Reflux oesophagitis: serious and sometimes lifethreatening type of gastroesophageal reflux disease that involves damage to the esophageal mucosa, often with erosion, ulceration, and infiltration by neutrophils or eosinophils. Refraction: the act or process of refracting; specifically the determination of the refractive errors of the eye and their correction by glasses. Regimen: a strictly regulated scheme of medication, diet, exercise, or other activity designed to achieve certain ends. Relapse: the return of a disease after its apparent cessation. Renal artery stenosis: RAS; narrowing of one or both renal arteries, caused by atherosclerosis or by fibrous dysplasia or hyperplasia, so that renal function is impaired; increased renin release by the affected kidney causes renovascular hypertension, and bilateral stenosis may result in chronic renal failure. Resting tremor: a tremor occurring when a limb or other body part is at rest; it may be normal, as in some physiologic tremors, or abnormal, as in parkinsonian tremors. Retarded schizophrenia: see negative symptoms. Reye s syndrome: a rare, acute, sometimes fatal disease of childhood, characterized by recurrent vomiting and elevated serum transaminase levels, with distinctive changes in the liver and other viscera; an encephalopathic phase may follow with acute brain swelling, disturbances of consciousness, and seizures. It most often occurs as a sequel of chickenpox or a viral upper respiratory infection. Rheumatoid arthritis: a chronic systemic disease primarily of the joints, usually polyarticular, marked by inflammatory changes in the synovial membranes and articular structures and by muscle atrophy and rarefaction of the bones. In late stages deformity and ankylosis develop. The cause is unknown, but autoimmune mechanisms and virus infection have been postulated. Rhinorrhoea: the free discharge of a thin nasal mucus. Rickets: an interruption in the development and mineralization of the growth plate of bone, with radiographic abnormalities, osteomalacia, bone pain, fatigability, growth retardation, and often hypotonia, convulsions, and tetany. Rigidity: stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. s.c.: subcutaneous. Salicylism: the commonly occurring toxic effects of excessive dosage with salicylic acid or its salts, usually marked by tinnitus, nausea, and vomiting. Salmonellosis: any disease caused by infection

275

with a species of Salmonella; in humans it is most often manifested as food poisoning with acute gastroenteritis, vomiting, diarrhoea, and rarely septicaemia, or as typhoid or paratyphoid fever. Recurrent fevers and diarrhoea with more serious gastrointestinal symptoms are seen in immunocompromised patients. Sarcoidosis: a chronic, progressive, systemic granulomatous reticulosis of unknown aetiology, characterized by hard tubercles in almost any organ or tissue, including the skin, lungs, lymph nodes, liver, spleen, eyes, and small bones of the hands and feet. SC3: third generation cephalosporin. Schizophrenia: a mental disorder or heterogeneous group of disorders (the schizophrenias or schizophrenic disorders) comprising most major psychotic disorders and characterized by disturbances in form and content of thought (loosening of associations, delusions, and hallucinations), mood (blunted, flattened, or inappropriate affect), sense of self and relationship to the external world (loss of ego boundaries, dereistic thinking, and autistic withdrawal), and behaviour (bizarre, apparently purposeless, and stereotyped activity or inactivity). Secondary amenorrhoea: cessation of menstruation after it has once been established at puberty. Sedation: the production of a sedative effect; the act or process of calming. Senile dementia: that occurring in older persons, usually over the age of 65; since most cases are due to Alzheimer's disease, the term is sometimes used as a synonym of d. of the Alzheimer type, late onset. Sepsis: 1. the presence in the blood or other tissues of pathogenic microorganisms or their toxins. 2. septicemia. Septic: pertaining to sepsis Serum sickness: a hypersensitivity reaction to the administration of foreign serum or serum proteins characterized by fever, urticaria, arthralgia, edema, and lymphadenopathy. It is caused by the formation of circulating antigen-antibody complexes that are deposited in tissues and trigger tissue injury mediated by complement and polymorphonuclear leukocytes. Serum sickness is classed with the Arthus reaction and other immune complex diseases as a type III hypersensitivity reaction (Gell and Coombs classification). Although serum sickness is now rare because of the replacement of most animal-derived antisera with human immune globulins, an identical illness (serum sickness like reaction or syndrome) can be produced by hypersensitivity reactions to penicillin and other drugs. Sexual deviation: sexual behaviour or fantasy outside that which is morally, biologically, or legally sanctioned, often specifically one of the



paraphilias. Sexual dysfunction: any of a group of sexual disorders characterized by disturbance either of sexual desire or of the psychophysiological changes that usually characterize sexual response. Included are sexual desire disorders, sexual arousal disorders, orgasmic disorders, sexual pain disorders, substance-induced sexual dysfunction, and sexual dysfunction due to a general medical condition. Shingles: (herpes zoster) an acute infectious, usually self-limited, disease believed to represent activation of latent human herpesvirus 3 in those who have been rendered partially immune after a previous attack of chickenpox. It involves the sensory ganglia and their areas of innervation, is characterized by severe neuralgic pain along the distribution of the affected nerve and crops of clustered vesicles over the area of the corresponding dermatome, and is usually unilateral and confined to single or adjacent dermatomes. Postherpetic neuralgia may be a complication. In immunocompromised patients it may disseminate and be fatal. Called also acute posterior ganglionitis, shingles, zona, and zoster. Shock: 1. a sudden disturbance of mental or physical equilibrium. 2. a condition of profound hemodynamic and metabolic disturbance characterized by failure of the circulatory system to maintain adequate perfusion of vital organs. It may result from inadequate blood volume (hypovolemic shock); inadequate cardiac function (cardiogenic shock); or inadequate vasomotor tone (neurogenic shock and septic shock). SIADH: syndrome of inappropriate secretion of antidiuretic hormone. Sinus bradycardia: a slow sinus rhythm, with a heart rate of less than 60 beats per minute in an adult; it is common in young adults and in athletes but is also a manifestation of some disorders. SLE: systemic lupus erythematosus Slurred speech: speech in which the words are uncompleted Sneezing: expelling air forcibly and spasmodically through the nose and mouth. 2. an involuntary, sudden, violent, and audible expulsion of air through the mouth and nose. Spasm: 1. a sudden, violent, involuntary contraction of a muscle or a group of muscles, attended by pain and interference with function, producing involuntary movement and distortion. 2. a sudden but transitory constriction of a passage, canal, or orifice. Spasmodic: of the nature of a spasm. Spinal nerve block: 1. regional anaesthesia produced by injection of a local anesthetic into the subarachnoid space around the spinal cord; anaesthesia Called also intraspinal a. or block and subarachnoid anaesthesia or block. 2. loss of sensation due to a spinal lesion.

276

Status epilepticus: a continuous series of generalized tonic-clonic seizures without return to consciousness, a life-threatening emergency. Stevens-Johnson syndrome: a sometimes fatal form of erythema multiforme presenting with a flulike prodrome, and characterized by systemic as well as more severe mucocutaneous lesions. The oronasal and anogenital mucous membranes may become involved with a characteristic gray or white pseudomembrane, and hemorrhagic crusts often occur on the lips. Ocular lesions vary, often with injected conjunctivitis, iritis, uveitis, corneal vesicles, erosions, and perforation, which may result in corneal opacities and blindness. Pulmonary, gastrointestinal, cardiac, and renal involvement also occurs. Stomatitis: inflammation of the oral mucosa, due to local or systemic factors, which may involve the buccal and labial mucosa, palate, tongue, floor of the mouth, and the gingivae. Subarachnoid haemorrhage: intracranial hemorrhage into the subarachnoid space. Superinfection: (suprainfection, opportunistic infection, secondary infection) a new infection occurring in a patient having a preexisting infection, such as bacterial superinfection in viral respiratory disease or infection of a chronic hepatitis B carrier with hepatitis D virus. Superinfection can complicate the course of antimicrobial therapy when the new infection is by organisms resistant to the drugs in use. Suppository: a medicated mass adapted for introduction into the rectal, vaginal, or urethral orifice of the body; suppository bases are solid at room temperature but melt or dissolve at body temperature. Sydenham s chorea: an acute, usually self-limited disorder of early life, usually between the ages of 5 and 15 or during pregnancy, and closely linked with rheumatic fever. It is characterized by involuntary movements that gradually become severe, affecting all motor activities including gait, arm movements, and speech. A mild psychic component is usually present. Syncope: a temporary suspension of consciousness due to generalized cerebral ischemia; a faint. Synergistic: 1. acting together. 2. enhancing the effect of another force or agent. Systemic lupus erythematosus: (SLE) a chronic, remitting, relapsing, inflammatory, often febrile multisystemic disorder of connective tissue, acute or insidious in onset, characterized principally by involvement of the skin joints, kidneys, and serosal membranes. It is of unknown etiology, but it is thought to represent a failure of regulatory mechanisms of the autoimmune system, as suggested by the high level of numerous autoantibodies against nuclear and cytoplasmic cellular components. It is marked by a wide variety of abnormalities, including arthritis and arthralgias,


Majid A.K. Lafi

nephritis, central nervous system manifestations, pleurisy, pericarditis, leukopenia or thrombocytopenia, hemolytic anemia, elevated erythrocyte sedimentation rate, and positive LEcell preparations. Systemic sclerosis: a systemic disorder of the connective tissue characterized by induration and thickening of the skin, by abnormalities involving both the microvasculature (telangiectasia) and larger vessels (Raynaud's phenomenon), and by fibrotic degenerative changes in various body organs, including the heart, lungs, kidneys, and gastrointestinal tract. It may remain confined to the face and hands for long periods or may be progressive and spread diffusely to become generalized. t : half life. T3: triiodothyronine. T4: Tetraiodothyronine. Tachycardia: excessive rapidity in the action of the heart; the term is usually applied to a heart rate above 100 beats per minute in an adult and is often qualified by the locus of origin as well as by whether it is paroxysmal or nonparoxysmal. Tarditive dyskinesia: (orofacial dyskinesia) an iatrogenic extrapyramidal disorder caused by longterm use of antipsychotic drugs; it is characterized by oral-lingual-buccal dyskinesias that usually resemble continual chewing motions with intermittent darting movements of the tongue; there may also be choreoathetoid movements of the extremities. It is more common in women than in men and in the elderly than in the young, and incidence is related to drug dosage and duration of treatment. In some patients symptoms disappear within a few months after the drugs are withdrawn; in others symptoms may persist indefinitely. TCA: tricyclic antidepressant. TDM: therapeutic drug monitoring. Telangiectasia: permanent dilation of preexisting small blood vessels (capillaries, arterioles, venules), creating focal red lesions, usually in the skin or mucous membranes. Tenosynovitis: inflammation of a tendon sheath. Teratogenic: tending to produce congenital anomalies. Testicular teratoma: a type of germ cell tumour derived from pluripotent cells and made up of elements of different types of tissue from one or more of the three germ cell layers in the testis. Tetanus: 1. an acute, often fatal infectious disease caused by the bacillus Clostridium tetani, which produces the neurotoxin tetanospasmin; it usually enters the body through a contaminated puncture wound (such as from a metal nail, wood splinter, or insect bite), although other portals of entry include burns, surgical wounds, cutaneous ulcers, injection sites of drug abusers, the umbilical stump of neonates (t. neonatorum), and the postpartum uterus. 2. physiological tetanus; a state of

277

sustained muscular contraction without periods of relaxation caused by repetitive stimulation of the motor nerve trunk at frequencies so high that individual muscle twitches are fused and cannot be distinguished from one another. Thalassaemia: a heterogeneous group of hereditary hemolytic anemias that have in common a decreased rate of synthesis of one or more hemoglobin polypeptide chains and are classified according to the chain involved (a, b, d); the two major categories are a- and b-thalassemia. Homozygous forms are manifested by profound anemia or death in utero, and heterozygous forms by erythrocyte anomalies ranging from mild to severe. Therapeutic restraining: the use of drug therapy to control of a subject, as of a violently psychotic or irrational person. Thought disorders: a disturbance in the thought process that is most narrowly defined as disorganized thinking with altered associations, as is characteristic of schizophrenia. The term is often used much more broadly to include any disturbance of thought, such as confusion, hallucinations, or delusions, which affects possession, quantity, or content of thought. Throbbing: beating; attended with a rhythmic beating sensation. Thrombocytopenia: decrease in the number of platelets, such as in thrombocytopenic purpura. Thrombocytopenic purpura: any form of purpura in which the platelet count is decreased; it may be either primary (idiopathic) or secondary. (see purpura) Thromboembolism: obstruction of a blood vessel with thrombotic material carried by the blood stream from the site of origin to plug another vessel. Thyroiditis: inflammation of the thyroid gland. Thyrotoxicosis: the condition caused by excessive quantities of thyroid hormones (see hyperthyroidism); it may be due to overproduction by the thyroid gland as in Graves' disease, overproduction originating outside the thyroid, or loss of storage function and leakage from the gland. TIA: Transient ischaemic attack. Tics: an involuntary, compulsive, rapid, repetitive, stereotyped movement or vocalization, experienced as irresistible although it can be suppressed for some length of time; occurrence is exacerbated by stress and diminished during sleep or engrossing activities. Tics may be psychogenic or neurogenic in origin and are subclassified as either simple, such as eye blinking, shoulder shrugging, coughing, grunting, snorting, or barking, or complex, such as facial gestures, grooming motions. Tinnitus: a noise in the ears, such as ringing, buzzing, roaring, or clicking. It is usually



subjective in type. Tocolytic: pertaining to inhibition of uterine contractions. Tocolytic: uterine relaxant. Toxic adenoma: hyperthyroidism arising in a multinodular goiter, usually of long standing. Trachoma: a chronic infectious disease of the conjunctiva and cornea, producing photophobia, pain, and lacrimation, caused by a strain of Chlamydia trachomatis. Tranquilliser: a drug with a calming, soothing effect; currently it is usually used to denote a minor tranquilliser. Transient ischaemic attacks: (TIA) a brief attack (from a few minutes to an hour) of cerebral dysfunction of vascular origin, with no persistent neurological deficit; TIAs are most commonly associated with occlusive vascular disease, especially in the distribution of the carotid and vertebral-basilar systems. TRH: (protirelin) thyrotropin-releasing hormone. Trigeminal neuralgia: Paroxysmal pain that extends along the course of one or more nerves. Many varieties of neuralgia are distinguished according to the part affected or to the cause, as trigeminal, brachial, facial, occipital, supraorbital, etc., or postherpatic, anaemic, diabetic, gouty, malarial, syphilitic, etc. (carbamazepine) TSH: (thyrotropin) Thyroid-stimulating hormone. Tuberculosis: any of the infectious diseases of humans or other animals caused by species of Mycobacterium and characterized by the formation of tubercles and caseous necrosis in the tissues. The usual causative species are M. tuberculosis and M. bovis. Type I reaction: that occurring within minutes when a sensitized individual is reexposed to antigen, resulting from interaction of IgE and the antigen; clinical manifestations can range from localized dermatitis, urticaria, or angioedema to allergic rhinitis or asthma to systemic anaphylaxis. The first exposure to the antigen induces the production of IgE antibodies that bind to receptors on mast cells and basophils. Upon subsequent exposure the antigen cross-links receptor-bound IgE molecules, triggering production and release of a diverse array of mediators that act on other cells, producing symptoms such as bronchospasm, edema, mucous secretion, and inflammation. (penicillin) Type II reaction: tissue or cell damage resulting from the interaction of antibodies and antigens on cell surfaces; specific IgG or IgM against cell surface or extracellular matrix antigens or cell surface receptors binds and causes damage at the site of binding by any of several mechanisms involving either complement activation and lysis or opsonization mediated by receptors for Fc or C3b leading to phagocytosis and destruction by macrophages and neutrophils. Examples of

278

disorders caused by such tissue damage include myasthenia gravis, hemolytic anemia, Goodpasture's syndrome, and Rh incompatibility and transfusion reactions. Type III reaction: local or general inflammatory response due to formation of circulating antigenantibody complexes and their deposition in tissues; the complexes activate complement and other inflammatory mediators, initiating processes including increased vascular permeability, stimulation of mast cell degranulation and neutrophil chemotaxis and accumulation, and aggregation of platelets, and resulting in tissue damage. Ensuing diseases, called also immune complex diseases, can be roughly classified as being due to persistent infection, to autoimmunity, or to inhalation of antigenic material; examples include serum sickness, Arthus reaction, subacute bacterial endocarditis, systemic lupus erythematosus, and farmer's lung. Type IV reaction: a reaction of cell-mediated immunity, the immune response being initiated by antigen-specific T lymphocytes; in contrast to the reactions of immediate hypersensitivity, reactions take one or more days to develop and can be transferred by lymphocytes but not by serum. Reactions are mediated by T lymphocytes both through release of cytokines and through direct cytolysis. In the former mechanism, release of vasoactive and chemotactic cytokines is triggered by contact between the T cells and specific antigens on antigen-presenting cells; the cytokines attract and activate non antigen-specific monocytes and macrophages, resulting in local erythema and induration, and leading to granuloma formation and necrosis if the eliciting stimulus cannot be eliminated. A common example is the tuberculin reaction elicited in skin testing for tuberculosis. In direct cytolysis, sometimes called cell-mediated cytotoxicity, cytotoxic T lymphocytes interact with foreign antigens presented by class I MHC molecules on cell surfaces, causing lysis of these foreign cells, as in allograft rejection. Type IV reactions can be induced by intracellular parasites, such as certain viruses, mycobacteria, and fungi, foreign tissue, tumour cells, soluble proteins, and haptens. The term is often equated with delayed hypersensitivity reaction, although the latter is sometimes restricted to cytokine-mediated reactions (as contrasted with direct cytolysis). U: unit. Ulcerative colitis: chronic, recurrent ulceration in the colon, chiefly of the mucosa and submucosa, of unknown cause; it is manifested clinically by cramping abdominal pain, rectal bleeding, and loose discharges of blood, pus, and mucus with scanty fecal particles. Complications include hemorrhoids, abscesses, fistulas, perforation of the colon, pseudopolyps, and carcinoma.


Majid A.K. Lafi

Unipolar affective disorder: that unaccompanied by episodes of mania or hypomania, as in major depressive disorder. Ureteral colic: colicky pains due to obstruction of the ureter. Urinary frequency: urination at short intervals without increase in daily volume of urinary output, due to reduced bladder capacity. Urinary retention: accumulation of urine within the bladder because of inability to urinate. Urolithiasis: 1. the formation of urinary calculi (stones). 2. the diseased condition associated with the presence of urinary calculi. Urticaria: a vascular reaction in the upper dermis, usually transient, consisting of localized oedema caused by dilatation and increased capillary permeability, with development of wheals. Uterine fibroids: a benign tumour derived from smooth muscle of the uterus. Uterine rupture: forcible tearing of the uterus. Uveitis: an inflammation of part or all of the uvea, commonly involving the other tunics of the eye (sclera, cornea, and retina). Vagotomy: interruption of the impulses carried by the vagus nerve or nerves. Vertigo: an illusory sense that either the environment or one's own body is revolving; it may result from diseases of the inner ear or may be due to disturbances of the vestibular centers or pathways in the central nervous system. Visual haloes: the seeing of coloured rings around an individual light source; indicative of glaucoma. Vulvovaginitis: inflammation of the vulva and vagina, or of the vulvovaginal glands. Whooping Cough: an acute, highly contagious infection of the respiratory tract, usually affecting young children and caused by Bordetella pertussis; similar illnesses are caused by B. parapertussis and B. bronchiseptica. Wolff-Parkinson-White syndrome: the association of paroxysmal tachycardia (or atrial fibrillation) and preexcitation, in which the electrocardiogram displays a short P R interval and a wide QRS complex which characteristically shows an early QRS vector (delta wave); sometimes used synonymously with preexcitation s. Called also WPW s. Zollinger-Ellison syndrome: a triad comprising (1) intractable, sometimes fulminating, and in many ways atypical peptic ulcers; (2) extreme gastric hyperacidity; and (3) gastrin-secreting, non beta islet cell tumours of the pancreas, which may be single or multiple, small or large, benign or malignant.

279

Essentials of Medical

Pharmacology

Majid A. K. Lafi BSc (Hons), MPhil, PhD Department of Pharmacology College of Medicine University of Al-Anbar

ABOUT THE AUTHOR Majid A K Lafi was born in Fallujah, Iraq in 1956, married with five children. He commenced studying at Kettering Technical College, Kettering, England in 1975, and obtained his "A" Level General Certificate of Education (Oxford Board) in 1978; in the same year, started a BSc (Hons) in Pharmacology at the School of Pharmacy, Portsmouth Polytechnic (now University of Portsmouth), Portsmouth, England, he has been awarded the degree in June 1981. Later on he was awarded MPhil in Pharmacology (1984), PhD in Pharmacology (1986) from the same university. I was awarded "Final Diploma" in English from the Institute of Linguists, London, in 1986. Thereafter, in 1987: Lecturer in Pharmacology, Military Medical College, Baghdad; in 1989: Lecturer in Pharmacology, College of Medicine, University of AL-Anbar, Ramadi, Iraq, in 1994: promoted to Assistant Professor of Pharmacology. His research interests in peripheral neuropharmacology (cotransmission at nerve muscle junction), unusual antimicrobial resistance, and medical education (pharmacology curriculum development).

Dr. Majid A K. Lafi

I

PREFACE When starting my carrier teaching pharmacology in Iraq, 3rd year medical school students, I confronted a problem that during the lecture most of the students were over-occupied with writing up what I was saying and not trying to understand what I was trying to deliver to them as core knowledge in pharmacology. With time, I understood that these students were very much concerned with obtaining the lecture material written more than understanding the material itself. After having long talks with them I promised to give them type-written lecture notes prior to delivering the lecture. This appeared to work very well in reassuring them that they would not lose material for "revision" paving the way for winning their attention during the lecture with consistently excellent students' attendance. This gain prompted me to continue improving my lecture notes in pharmacology to suit the need of particularly medical students in Iraq. For several years, students and colleagues have urged me to put this work in a book, only now "after 20 years" I find it is the time to do so. Teaching pharmacology at the College of Medicine, University of AL-Anbar, has been pathophysiology oriented therefore very much attention has been paid to the mechanism(s) of drugs' action. Hence, a brief account on the pathophysiology of major disorders has been mostly included in this book. Over the years of teaching this subject, it is felt that students prefer stating clinical conditions (e.g. indications, adverse effects and contraindications) in a list form rather than in a continuous text. In addition, the inclusion of a summary in a table and/or a figure form at the end of each topic has been found to be useful to recognise the core knowledge should be learned. These strategies have been largely adopted throughout this book. A considerable number of the third year medical students show very poor competence in the medical vocabulary used in delivering the core material of medical pharmacology. This prompted me to make an inclusion of an appropriate glossary at the end of this book to be handy for the reader to refer to. Undoubtedly, there are many occasions of weakness in this book, e.g. the section on antiparasitic agents as it is being very poor, particularly when taking into account the importance of parasitic infections in Iraq. It is hoped that these drawbacks and others will be dealt with in the next issue. This issue is only an initial draft awaiting feedback from students and colleagues. I am very grateful for support and assistance from a number of colleagues and students.

Majid A. K. Lafi October, 2008

CONTENTS

ABOUT THE AUTHOR PREFACE CONTENTS GENERAL PRINCIPLES Pharmacokinetics ……………………………………………………………. Pharmacodynamics ………………………………………………………… AUTONOMIC PHARMACOLOGY Cholinergic Transmission ………………………………………………….. Adrenergic Transmission …………………………………………………. Ocular Pharmacology ……………………………………………………. Drugs Used in Abnormal Micturition ………………………………………. CARDIOVASCULAR PHARMACOLOGY Antihypertensive Drugs ……………………………………………………… Antianginal Drugs …………………………………………………………... Drugs for Congestive Heart Failure …………………………………………. Antiarrhythmic Drugs ………………………………………………………. Diuretics …………………………………………………………………….. Antithrombotic Drugs ……………………………………………………….. Antihyperlipidaemic Drugs …………………………………………………. Drugs for Anaemias ANTIMICROBIAL DRUGS (GENERAL PRINCIPLES) Beta-lactam Antimicrobial Drugs …………………………………………… Sulphonamides, Trimethoprim, and Aminoglycosides ……………………… Tetracyclines, Macrolides, Metronidazole, Chloramphenicol, and others …... Antituberculosis Drugs ……………………………………………………….. Antimicrobial Drugs of Choice ……………………………………………….. Antifungal Drugs ……………………………………………………………… Antiviral Drugs ………………………………………………………………. Antiparasitic Drugs …………………………………………………………. CNS-PHARMACOLOGY (GENERAL PRINCIPLES) Antipsychotic Drugs …………………………………………………………. Drugs for Affective Disorders ……………………………………………….. Antianxiety Drugs …………………………………………………………… Sedative and Hypnotic Drugs ………………………………………………. Drugs for Parkinson s Disease ………………………………………………. Antiepileptic Drugs ………………………………………………………….. Opioids and Narcotic Analgesic Drugs ……………………………………... General Anaesthetic Drugs ………………………………………………….. Local Anaesthetic Drugs ……………………………………………………. Neuromuscular Blocking Drugs ……………………………………………… AUTACOIDS NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) DRUGS AND GASTROINTESTINAL TRACTS DRUGS AND THE RESPIRATORY SYSTEM ENDOCRINE PHARMACOLOGY Hypothalamic and Pituitary Hormones ………………………………………. Sex (Gonadal) Hormones and Inhibitors …………………………………...

III

I II III 1 1 18 24 25 25 33 35 37 46 49 54 61 65 73 77 79 88 96 101 106 110 114 117 121 124 131 135 142 146 153 156 164 170 176 178 182 190 203 212 218 223

Drugs Acting on Uterine Smooth Muscle …………………………………... Adrenocorticosteroids ……………………………………………………... Thyroid and Antithyroid Drugs …………………………………………… Agents that Affect Calcium Metabolism …………………………………… Insulin and Oral Hypoglycaemic Drugs ……………………………………. ANTICANCER DRUGS …………………………………………………… DRUG INTERACTIONS, ADVERSE DRUG REACTIONS AND ANTIDOTES GLOSSARY ……………………………………………………………… INDEX

IV

228 230 236 240 242 250 255 260 280


Majid A. K. Lafi

GENERAL PRINCIPLES of the disease itself may vary from one patient to another, this difference in response is largely accounted for by variations in the metabolic handling of the drug.

Introduction This book is the result of a desire to record and update the material of lectures given upwards of twenty years to medical students. For medical students, the pharmacology course is the first confrontation with medicine and the response of patients to drugs. A drug in the widest sense is a substance used in prevention, cure and diagnosis of disease. The name pharmacon is Greek and means drug. The word drug comes from the French word drogue which means dry herb.

If the serum level of warfarin is measured in these patients a large difference may be found at the two extremes. Thus, some patients were under-treated while others were intoxicated. This phenomenon may be due to a number of factors (in addition to failure to take the prescribed dose of the drug, patient non-compliance). The rate of absorption of the drug, its distribution in various body compartments, tissue and plasma-protein binding, and the rate of metabolism and excretion of the drug all influence the steadystate level of the drug at the site where it is required. Study of these aspects of pharmacology is known as pharmacokinetics.

Pharmacology can be divided into two major parts: 1. Pharmacokinetics means what the body does to the drug . 2. Pharmacodynamics means what the drug does to the body .

Dosage Regimen Dosage regimen is the manner in which a drug is taken concerning dose, frequency, and route of administration that relate to drug level-time relationships in the body. Often, drug level in the body is reflected by plasma drug level that in turn influences the concentration of drug at the site(s) of action that relates to the magnitude of the effect(s) produced. Table 1.1. Basic pharmacological principles in empirical adult therapeutic regimens of some selected drugs. The information in this table is not intended for memorization by students rather as pharmacotherapeutic situations in which skills (critical thinking) are required in applying knowledge and understanding of basic pharmacological principles. The pharmacological principles, presented in this course of pharmacology in a manner coherently complementing each other, represent a core knowledge in which to ground skills in pharmacology as basis in therapeutics. Such knowledge and skills are expected to be learned in sequential increasing in complexity throughout the third year. Therefore, this table is expected to be referred to throughout the year.

In addition, the following topics are also covered: • Toxicology which deals with adverse effects, drug interaction, drug abuse, poisons, antidotes, industrial and environmental pollution, and therapeutic drug monitoring. • Pharmacogenetics which deals with inter-individual differences. • Pharmaceutics (drug delivery, formulation) • Pharmacognosy (plant medicine) • Prescription writing (emphasising on drug names and dosage regimen)

Pharmacokinetics If a fixed dose of a drug is given to a number of patients with a particular disease, e.g. 5 mg of warfarin daily dose in patients with deep venous thrombosis, most will show some therapeutic response as indicated by prothrombin time. A few, however, will not show obvious response, while the occasional patient may develop signs of drug intoxication (bleeding). Although the severity 1

General Principles


Table 1.1. Basic pharmacological principles in empirical adult therapeutic regimens of some selected drugs. Drug

Indication

Route

Warfarin t 37 hr Vd 5 L

Deep venous thrombosis

Oral

Theophylline

Asthma

Oral

Induction and maintenance of labour

Slow intravenous injection (over 20-30 min) Intravenous infusion

t 8 hr Vd 35 L

Oxytocin t

minutes Oral (control is too erratic)

Morphine t 2 hr Vd 230 L Ampicillin

Severe pain

Intramuscular Oral

Certain bacterial infections

Oral Intramuscular, intravenous, or infusion Oral

t 1.2 hr Vd 20 L Amoxicillin t 2 hr

Penicilin G t 0.5 hr

Infections due to susceptible microorganisms Infections due -lactamaseproducing amoxicillin resistant organisms

Endocarditis (prophylaxis in dental procedures) Gonorrhoea (Neisseria gonorrhoeae) Certain serious infections

Oral

Oral

Oral Intramuscular Intravenous, or infusion

Intramuscular

Phenobarbital t 4 days Vd 38 L Digoxin

Prophylaxis of recurrent rheumatic fever Syphilis (Treponema pallidum) Epilepsy

Intramuscular

Congestive heart failure

Oral

Intramuscular Oral

Dosage Regimen Individualize dosage according to PT or INR, initially 2-10 mg daily for 3 days, then; average maintenance dose: 2-5 mg at the same time each day Individualize dosage according to clinical responses and monitor serum theophylline levels. Short-acting formulation 500 mg initially, then 100-300 mg 3-4 times daily. Long-acting formulation 150-300 mg twice daily. 5-6 mg/kg (in patients not previously treated with xanthine) 0.2-4 milliunits/min infusion, gradually increased to 20 milliunits/min, if necessary, to produce 3 or 4 contractions within 10-min periods. Not used because of being rapidly destroyed by the proteolytic enzymes in GIT 10 mg when needed Not used because of being rapidly metabolised in the liver. 0.25-1 g every 6 hr 0.5 g every 4-6 hr

250

500 mg every 8 hr

250 500 mg (containing125mg of clavulanic acid, Augmentin ) every 8hr or 875 mg every12h Alternatively amoxicillin 3 g may be taken by mouth together with probenecid 1 g by mouth 4 h before the procedure Amoxicillin 3 g may be taken by mouth together with probenecid 1 g in single dose 300,000 8 million U daily 6 20 million U daily by continuous or intermittent infusion every 2 4h. Up to 60 million U daily have been given in certain serious infections. Procaine Penicillin daily in one or two doses Benzathine 2 Penicillins 1.2 2.4 million U in a single dose every 3 4 wk Benzathine 2 Penicillins 2.4 million U (1.2 million U in each buttock) in a single dose 60-180 mg at night

1.5-2 mg initially over 24 hr, then 0.25-0.5 mg once a day 2


t 39 hr Vd 440 L Amiodarone t 53 days Vd 4200

Captopril t 2.2 hr Vd 57 L Prazosin t 2.9 hr Vd 42 L Aspirin t 0.25 hr Vd 11 L (salicylic acid: t 3 hr to 13-30 hr)

Dopamine t 2 minutes

Cardiac arrhythmia (Atrial fibrillation) Ventricular arrhythmias (recurrent) Ventricular arrhythmias (existing) for not more than 48 hours because of cumulative effect Heart failure Hypertension Hypertension, Benign prostatic hyperplasia (BPH) Transient ischaemic attacks Transient ischaemic attacks Pain, fever Rheumatoid arthritis Osteoarthritis Acute rheumatic fever Renal (D1 -receptor) Cardiac ( 1-receptor) Vascular ( 1-receptor)

Omeprazole t 45 minutes

Majid A. K. Lafi

Oral Oral Intravenous

Oral Oral

6.25 mg initially then 6.25-150 mg daily 25 mg initially then 6.25-150 mg daily

Oral

1 mg 2 to 3 times daily initially, maintenance dose 6 15 mg daily

Oral (Prophylaxis) Oral

81 325 mg daily

Oral

650 mg usual single dose

Oral

2000-6000 mg 3 times daily

Oral Intravenous infusion Intravenous infusion Intravenous infusion

5000-8000 mg daily in divided doses

1300 mg 2 to 4 times daily

5 µg/kg/min >10 µg/kg/min Steady-state plasma concentration will be reached in 5 x t = 10 min 20 mg daily, 1 hr before meal (mandatory)

Oral

Insulin

Peptic ulcer Heartburn Active GI bleeding Prostate cancer Central precocious puberty Hypothalamic hypogonadotropic hypogonadism Long term regular use

Intravenous, or infusion

Glucagon

Acute or emergency situations: Diabetic ketoacidosis Hyperosmolar hyperglycemic nonketotic coma Perioperative period Severe infections Pregnancy Hypoglycaemic crisis

Nicotinic acid

Acute overdose of βblockers (heart failure) Pellagra

Goserelin t

l-l.5 mg initially over 24 hr, then 0.06250.5 mg once a day 0.8-1.2 g daily (2 to 4 weeks), then 0.2-0.4 g daily. 0.15g over 30 minutes & 1 g over the 1st day

Intravenous Subcutaneous

8 mg/hr for 72 hrs 3.6 mg every 28 days (i.e. given continuously)

Intravenous tubing (by GnRH pump) Subcutaneous

A portable battery-powered programmable pump allows pulsatile GnRH therapy every 90 minutes. Dosage individualized. Initially, 7 26 units may be given once daily. Suitable for stable biphasic insulin mixtures (e.g. short acting plus long acting) Dosage individualized. For ketoacidosis, regular insulin may be given by direct injection, intermittent infusion, or continuous infusion. One regimen involves an initial bolus injection of 10 20 units followed by a continuous low-dose infusion of 2 10 units/hr, based on hourly blood and urine glucose levels

Intramuscular Subcutaneous Intravenous (bolus) Oral

3

1 mg 5-10 mg 100-500 mg daily.

General Principles


(niacin)

Hyperlipidaemia

Oral

250 mg twice daily initially and increasing the dose monthly by 500 to 1000 mg per day to a maximum of 2 6 g daily. This regimen to reduce the intense cutaneous flush produced as an adverse effect. The latter can further be reducing by taking nicotinic acid on a full stomach (end of meal), taking aspirin before dosage, and time-release forms of nicotinic acid can reduce the severity of flushing.

Diclofenac

Pain Dysmenorrhoea

Oral

50 mg 3 times daily

Ankylosing spondylitis

Oral

Osteoarthritis

Oral

Rheumatoid arthritis

Oral

Acute renal colic

Oral

Diclofenac Immediate R (only 50mg) Diclofenac Delayed R (75mg) Extended R (100mg)

Nitroglycern t 1-3 min

Ureteral stone propulsion Relieve acute angina Prevent exercise-induced angina Long-term prophylaxis to decrease the frequency and severity of acute anginal episodes

IV, IM Oral Oral Sublingual Translingual spray

Transmucosal tablet Topical transdermal patch Hypertensive crisis Carbamazepine t 15 hr Vd 98 L

Epilepsy

Continuous Intravenous oral

Trigeminal neuralgia

oral

4

100 125 mg daily in 4-5 divided doses (e.g., 25 mg 4-5 times daily) 100 150 mg daily in divided doses (e.g., 50 mg 2 or 3 times daily, 75 mg twice or 100 mg once daily) 100 150 mg daily in divided doses (e.g., 50 mg 2 or 3 times daily, or 75 mg twice or 100 mg once daily) 50 mg 2 or 3 times daily for 5 days, then on need 75 mg once or twice daily 50 mg 2 or 3 times daily for 15 days Sustained-release tablets, 2.5 9 mg 2 or 4 times per day 0.15 0.6 mg on need for chest pain one or two metered doses (0.4 mg/dose) sprayed onto oral mucosa at onset of anginal pain, to a maximum of 3 doses in 15 min 1 mg every 3 5 hr while awake, placed between upper lip and gum or cheek and gum 5 mg applied once daily, do not rub. 5mcg/min 200 mg twice daily, increased gradually to 600 1200 mg daily if needed, in 3 or 4 divided doses 200 mg daily, increased gradually to 1200 mg if necessary


Majid A. K. Lafi

Pharmacokinetics Dosage Regimen Dose Frequency (Route of administration)

Drug Concentration at Site of Action

Plasma Drug Concentration

Pharmacodynamics

Css

Unacceptable Toxicity

Regimen C MTC Css

Regimen B

Therapeutic Window MEC

Regimen A

Css

Ineffective

Time Fig.1.1. A schematic representation of the approach to the design of dosage regimen. The pharmacokinetics and pharmacodynamics of the drugs are first defined. Then either the plasma drug concentration-time data or the effects produced are used as a feedback to modify the dosage regimen. When a drug is given at fixed time intervals (denoted by arrows), it accumulates within the body until a plateau is reached. With regimen A, the plasma drug concentration is too low therefore therapeutic failure (ineffective) is observed. With regimen B, therapeutic success is achieved although not initially. With regimen C, the therapeutic objective is more quickly achieved but the plasma drug concentration is ultimately too high.

5

General Principles


Peak 20

Nausea

Vomiting

CNS stimulation

Unacceptable Toxicity MTC Css

10

Insufficient

Trough 0

8

16 24

48 Time (hr)

bronchodilatatio n 72 96

Therapeutic Window MEC Ineffective

Fig.1.2. Different dosage regimens of theophylline showing the relationship between frequency of dosing and maximum and minimum plasma concentrations when a steady-state theophylline plasma concentration of about 10 µg/ml is desired. Regimen I- intravenous infusion of 25 mg/hr achieves smoothly rising line (dotted with black squares). Regimen II- 8-hourly administration (dark solid thin line) of doses of 200 mg. Regimen III- 24-hourly administration (dark solid thick line) of doses of 600 mg. In each of the 3 regimens, the mean steady-state plasma concentration (Css) is about 10 µg/ml. Note: in regimen III there is a large fluctuation between peak and trough and as estimation of plasma levels of drugs often not available, the former may be reflected clinically by the development of nausea, vomiting and central nervous system (CNS) stimulation as unacceptable toxicity; while trough may be reflected clinically by insufficient bronchodilatation (ineffective). Regimen IV- 12-hourly administration (dotted with black solid circles) of doses of 300 mg with oral slow release formulation to avoid the unacceptable toxicity and the insufficient bronchodilatation may be associated with regimen III. The therapeutic window lies between the minimum effective concentration (MEC) and the minimum toxic concentration (MTC). Therefore, adjustment of dosage regimen may be made depending on the clinical response. This is particularly true for drugs with low therapeutic index like theophylline.

6


Majid A. K. Lafi

Unacceptable Toxicity MTC

Css Therapeutic Window

Css MEC 0

3

6

18

12 Time (hr)

24

Fig.1.3. Different dosage regimens for a drug with large therapeutic index such as ampicillin (with t of about 1 hr). Regimen I- 1-hourly (light colour) with low total daily dose and regimen II- 6-hourly (dark colour) with higher total daily dose. Note: The steady-state plasma concentrations (Css) of the two regimens are different and regimen II shows a larger fluctuation between peak and trough comparing with that of regimen I. Both regimens exhibit Css within the therapeutic window, i.e. lies below the level expected to cause unacceptable toxicity. It follows that administering ampicillin 1-hourly would be practically inconvenient (24 times per day) and likely to result in non-compliance and consequently treatment failure. On the other hand, giving the drug 6-hourly with larger doses that attain troughs that lie at a level higher than the minimum effective concentration (MEC) and peaks lie at levels below the minimum toxic concentration (MTC), would lead to a better compliance (as a result of reducing the frequency of dosing, four times daily). This strategy can be adopted only with drugs that show large therapeutic index. In case of drugs that are with low therapeutic index other manoeuvres may be used to improve compliance; for example, sustained release formulation like for theophylline to be given twice daily instead of three times daily.

7

General Principles


The aforementioned factors are related to the question of whether generic or proprietary (brand) name should be used when prescribing.

Drugs and Medicines It is not always recognised that when prescribing a drug the patient actually receives a medicine. The drug represents only a small proportion of the total weight of the solid dosage form (e.g. tablet, capsule) or injectable dosage form (e.g. ampoule, vial). The dosage form contains other constituents, which may not be inert and may play an important role in facilitating or hindering a drug s absorption. Appropriate pharmaceutical manoeuvres of these materials may allow development of sophisticated delivery systems for delayed or position-released of the drug. The following are some of the factors involved in the production of the solid dosage form, which may influence a drug s absorption.

Absorption of Drugs When a drug is administered orally it has to pass through the gut wall which represents a complex biological barrier (complex lipid membrane) before entering the bloodstream. Dietary substances can pass through this biological barrier by one of the following ways: a. Passive diffusion concentration difference (from high to low) this is being the most important mechanism. b. Active transport e.g. amino acids, or drugs e.g. α-methyldopa that resembles endogenous substances. c. Filtration through pores, limited to molecules of small size e.g. urea. d. Pinocytosis by which small particles are engulfed by cells of the bowel.

1. Diluents e.g. lactose, calcium sulphate. 2. Granulating and binding agents e.g. syrup used for aggregation of powder into granules facilitating compression of tablet. 3. Disintegrating agents are incorporated to produce tablet disintegration in the gastrointestinal tract.

There are a number of factors which influence absorption of drugs: 1. Nature of drug polypeptides e.g. insulin is broken down by intestinal enzymes, benzylpenicillin is destroyed by gastric acid 2. Pharmaceutical formulation (see above) 3. Blood flow maintains continuous absorption by removing drug that passes through membrane. The concentration gradient across the membrane is, thereby, continuously assured. Membrane permeability of drugs also plays an important role in absorption of drugs. When the drug is lipophilic (e.g. ethanol) and thus highly membrane permeable, absorption is controlled or rate limited by perfusion (blood flow). In contrast, with streptomycin and many other polar compounds (like heparin, ipratropium and suxamethonium), absorption is controlled or rate limited by diffusion (penetration, permeability) through the membrane and not in removing the drug from other side of the membrane. Some compounds, e.g. urea, have intermediate permeability properties. At low blood flow rates, the compound has sufficient time to diffuse

moisture Starch Cocoa butter

Swelling body temperature

Melting

Sodium bicarbonate + tartaric acid moisture effervescence

4. Coating material e.g. sugar prevents disintegration before the tablet reaches the stomach or intestine (e.g. omeprazole). 5. Capsules have a gelatine envelope with no granulating excipients. 6. Sustained-release with complex pharmaceutical manoeuvres to control disintegration and dissociation rates, thus regulating the rate of a drug s absorption.

8


Majid A. K. Lafi

across the membrane so absorption is perfusion rate-limited. At higher blood flow rates, however, membrane permeability becomes the rate-limiting step, and absorption is insensitive to blood flow.

Because both ionised and unionised solutes readily pass across the capillary wall, the influence of pH on intramuscular and subcutaneous absorption of drugs is likely to be far less significant.

Absorption of drugs in solution from muscle and subcutaneous tissue is normally perfusion rate-limited. An increase in blood flow increases absorption. In this setting, absorption is impeded largely by the capillary wall. At these sites, the capillary wall, a much more loosely knit structure than the epithelial lining of the gastrointestinal tract, allows the rapid passage of all molecules below a molecular weight of about 5000, whether ionised or unionised. This molecular weight range includes essentially all drugs. Streptomycin, a relatively water-soluble polar base, has difficulty penetrating the gastrointestinal mucosa; it is rapidly absorbed from the intramuscular site.

Body fluids Gastric juice Intestine Plasma CSF Urine Prostatic secretions Vaginal secretions Weak acids

pK

pH 1.0 - 3.0 5.0 - 8.0 7.4 7.3 4.0 - 6.8 6.4 -7.4 3.4 - 4.2 Weak bases

Penicillin G Salicylic acid Warfarin

2.7 3.5 Diazepam 5.0 Chlordiazepoxide 7.3 Trimethoprim Phenobarbital 7.8 Lidocaine Theophylline 9.0 Procainamide 10 Amphetamine Permanently ionised (polar) drugs Heparin Streptomycin Ipratropium Tubocurarine Suxamethonium

4. pH and pK. Drugs are usually either weak organic acids (proton donor) or weak organic bases (proton acceptor) existing in equilibrium between undissociated molecules and as ions. This equilibrium depends on the pKa value of the drug and the pH of the surrounding medium. At a pH equals to the pKa the drug is 50% ionised. Thus, a weakly acidic drug (e.g. aspirin) in a medium of low pH (e.g. stomach) will be mainly in its undissociated form; whereas a weakly basic drugs (e.g. amphetamines) in a medium of high pH (e.g. small intestine) will be mainly in its undissociated form. Streptomycin is permanently polar and relatively strongly basic, and its pKa value greatly exceeded the highest pH reached in the intestine. This explains why some drugs (e.g. streptomycin) are very poorly absorbed from the gut, therefore they should be administered parentally. As a general rule, acids tend to ionise in basic (alkaline) media, and bases tend to ionise in acidic media.

Clinical Example Many antibiotics cannot penetrate the prostatic epithelium, therefore not achieving adequate concentration in the prostatic fluid and tissue. Hence, it is difficult to cure bacterial prsotatitis. Trimethoprim is usually effective in the treatment of bacterial prostatitis while penicillin is not. This is because trimethoprim is a basic substance with a pKa of 7.3 and prostatic secretion is relatively acidic (pH 6.4 particularly in inflammatory condition) compared to the plasma (pH 7.4); consequently, trimethoprim is about 50% non-ionised at the plasma and therefore the drug penetrates into prostate. In acidic prostatic fluid trimethoprim is ionised and thus trapped as it cannot diffuse back into plasma. On the other hand, penicillin (acidic substance with a pKa of 2.7) is largely ionised and bound to plasma protein at pH 7.4 and thus cannot penetrate into prostate.

9

General Principles


5. Gastric emptying- According to what has been described above, it follows that weak acids are absorbed more rapidly from the stomach when the pH of the contents is 1 than when the pH of the contents is closer to 8, and the converse holds for weak bases. However, absorption of acids is always much faster from the more alkaline intestine (pH 5-7) than from the stomach.

oral dose that reaches the general circulation. For example, a 50% bioavailability of a tablet of 10 mg propranolol would mean that a total of 5 mg of propranolol would reach the general circulation. The value of bioavailability may vary widely and being a characteristic of the manufacturing pharmaceutical company and in turn may have clinical implications. For the same proprietary (trade) name, a particular pharmaceutical preparation of a drug may exhibit widely different values of bioavailability due to pharmacokinetic differences in the handling of the drug by the body including concurrent medications. Three major factors are considered below.

These apparently conflicting observations may be reconciled by the following explanation. The surface area and blood flow are important determinants of the rapidity of absorption. The small intestine is favoured on both of these accounts. The total area of the small intestine represented largely by microvilli, has been estimated to be about 200 m2, and an estimated 1 litre of blood passes through the intestinal capillaries each minute. The corresponding estimates for the stomach are only 1 m2 and 150 ml/min. these increases in both surface area and blood flow more than compensate for the decreased fraction of unionised acid in the intestine. In fact, the absorption of all compounds, acids, bases, or neutral compounds, is faster from the small intestine than from the stomach. Therefore, the rate of gastric emptying is a limiting step in the rapidity of drug absorption. Consequently, food, particularly fat, slows stomach emptying. This explains why drugs are frequently recommended to be taken on an empty stomach when a rapid onset of action is desired.

Time for Absorption An orally administered drug is exposed to the gastrointestinal mucosa for no more than 1 to 2 days, and for much less time at the main absorption site, the small intestine. If a drug is poorly permeable, for example, streptomycin, heparin, suxamethonium, and ipratropium, there is insufficient time for complete absorption. There may be insufficient time for complete absorption of the vitamin, riboflavin, and of other substances absorbed by a carrier-mediated transport process. The site of the transport process is usually restricted to a certain part of the gastrointestinal tract. The system for absorbing riboflavin is located in the upper part of the small intestine. At the does taken, the concentration of riboflavin reaching the site of absorption saturates the transport process. The oral bioavailability of riboflavin can be increased by taking the vitamin with small amounts of food. The resultant slowing of stomach emptying both extends the duration and diminishes the rate of delivery of riboflavin and hence its concentration at the absorption site; both factors favour more complete absorption.

The stomach may simply be viewed as a storage organ from which pulses of drug are ejected onto the absorptive sites in the small intestine.

Factors Influencing Bioavailability

There is the situation of a drug, such as griseofulvin (and mebendazole and albendazole), that is sparingly soluble in both gastric and intestinal fluids. There may already be insufficient time for dissolution and absorption when this drug is administered as a tablet. Retaining such a drug in the stomach, by increasing the total time for dissolution, should favour increased

Bioavailability of a drug is the ease (how much of the drug and how fast, completeness of absorption) at which it reaches the general circulation. Drugs that are pharmaceutically formulated (designed) for oral administration may show different bioavailabilities. This is usually measured by the percentage of the 10


Majid A. K. Lafi

acid in a single passage through the liver, resulting in a substantial first-pass effect . Drugs that show a significant first-pass effect in man include aspirin, hydralazine, lidocaine, morphine, nitroglycerin, pentazocine, propoxyphene, and propranolol.

availability. The time available for dissolution within the intestine is probably limited to between 4 and 10 hours. Subsequently, as the intestinal fluid and contents move into the large intestine and water is reabsorbed, the resulting compaction of the solid contents limits further dissolution of drug. An additional 2 to 4 hours in the stomach, where dissolution can occur, would significantly extend the time for dissolution. Fats, particularly, delay stomach emptying, and this delay may be one of the explanations for the observed increase in the availability of griseofulvin when taken with a fatty meal or with fats.

Avoiding the first pass through the liver probably explains the activity of nitroglycerin administered sublingually. Blood perfusing the buccal cavity bypasses the liver and enters directly into the superior vena cava. This anti-anginal drug is almost completely metabolised as it passes through the liver, and any drug swallowed is not systemically available. The metabolites seen in blood are only weakly active.

The rectum has a small surface area and a drug given rectally is not always retained for a sufficient length of time to ensure complete absorption. No time limitation exists for a drug injected into muscle or subcutaneous tissue; complete absorption is anticipated unless destruction occurs at the site of administration.

The rectal route has a definite advantage over the oral route for drugs that are destroyed by gastric acidity or by enzymes in the intestinal wall and microflora. Potentially, the rectal route may also partially reduce first pass hepatic loss. Part of the rectal blood supply, particularly the inferior and middle haemorrhoidal veins, bypasses the hepatic portal circulation and dumps directly into the inferior vena cava. Achieving a reproducible availability, which is important in drug therapy, may be difficult, however, since availability is strongly dependent upon the site of absorption within the rectum.

Competing Reactions Any reactions within the gastrointestinal tract that compete with absorption may reduce the oral bioavailability of a drug. Benzylpenicillin when given orally undergoes substantial hydrolysis by gastric acid; therefore, it is administered by injection. Enzymatic hydrolysis occurs to aspirin forming salicylic acid, active antiinflammatory compound. Tetracycline undergoes complexation with polyvalent metal ions, e.g. Ca++, Al+++, forming unabsorbed insoluble complexes. Decarboxylation occurs to levodopa resulting in loss of activity (product active but not absorbed).

Distribution of Drugs Generally, drugs that are readily absorbed from the gut wall are also readily distributed throughout the body water compartments. This is applicable to most barbiturates; thiopental is highly lipid-soluble and is freely absorbed from the stomach and rectum. When it is administered intravenously, it crosses the biological barriers into the brain producing anaesthesia. Generally, centrally acting drugs have to pass through an additional lipid membrane in the blood brain barrier, and thus, are readily absorbed from the gut. These drugs can easily reach the foetal circulation, being the main offenders in causing foetal abnormalities (e.g. phocomelia caused by thalidomide).

Hepatic Extraction Over hundred years ago, acetylsalicylic acid (aspirin) was synthesised to overcome the bitter taste and the gastrointestinal irritation associated with the parent drug, salicylic acid. Only subsequently was aspirin shown to be also pharmacologically active. Aspirin, a labile ester, is rapidly hydrolysed, particularly by esterases in the liver. In fact, hepatic hydrolysis is so rapid that a significant fraction of aspirin is converted to salicylic

After being absorbed, most drugs bind to tissue and plasma proteins forming

11

General Principles


extensively bound to tissues is to have a large apparent volume of distribution (Vd). This is a theoretical volume of fluid, which would be required to contain the total body content of a drug at a concentration equal to the plasma concentration. Drugs which has a large Vd (in litres for 70 kg person) are digoxin (420), nortriptyline (1000), dothiepin (4900), amiodarone (4200) and chloroquine (13000), and drugs with small Vd are warfarin (5), heparin (5), aspirin (11), gentamicin (18), frusemide (21) and amoxicillin (28).

equilibrium with the unbound (free) drug, and the extent of binding varies from drug to drug. If a drug exhibits no appreciable tissue binding, the tissues behave as little more than water compartment in which the drug is dissolved. The pharmacological properties of a drug are greatly influenced by its being highly protein bound; this influence can be seen in the following ways: 1. Its absorption from the gut wall will be facilitated, through capturing the drug molecules by tissues and/or plasma protein molecules leading to maintenance of the concentration gradient across the gut wall.

Serum half-life

2. Since only the unbound form of the drug is the biologically active, it is essential to know the extent of binding for a drug before values given for serum levels reached for the drug in question become meaningful.

Serum half-life (t ) of a drug is the time taken for the serum concentration to halve. Metabolism and/or excretion of the drug determine it. A drug with a short t (e.g. salbutamol) produces a much steadier therapeutic action when given in at least three divided doses daily. On the other hand, a drug with a long t (e.g. digoxin) given as a single daily dose is adequate to maintain a steady response. Drugs with long t will cumulate with repeated and frequent doses and patients receiving such drugs particularly those with low therapeutic index like digoxin and phenytoin should be examined frequently for signs of overdosage.

3. Certain pathological conditions where changes in the concentration of serum proteins, e.g. hypoproteinaemia (which may occur in some renal and/or hepatic dysfunction), a higher level of unbound drug will occur in the serum unless the oral dose is lowered. This should be taken in consideration when dealing with drugs, which are highly protein bound (e.g. diazepam, frusemide, phenytoin and triamterene) and/or have low therapeutic index (e.g. theophylline and digoxin).

Thus, measurements of serum concentrations are performed routinely nowadays; these include anticonvulsants (e.g. phenytoin), antiarrhythmic drugs (e.g. quinidine), theophylline, lithium and aminoglycosides. In certain cases, measuring the response to a drug provides an easy method of monitoring its action (e.g. prothrombin time with anticoagulants like warfarin).

4. Adverse drug interactions may take place on plasma protein binding sites. This is very likely to occur with a highly protein bound drug like warfarin (99% bound) which can be displaced by certain other drugs like phenylbutazone which competes with warfarin on the same binding site. This may result in a small change in binding of warfarin that can greatly lengthen the prothrombin time. This type of drug interaction is clinically more important when the displaced drug has a small volume of distribution.

Metabolism Hepatic enzymes are responsible for the metabolism of most drugs. However, some drugs are metabolised in the plasma (e.g. procaine and suxamethonium are destroyed by pseudocholinesterase in the serum) and tissues (e.g. alcohol is destroyed by enzymes in gastric wall and liver). Metabolism in the liver can take place for those substances, which are lipid soluble and thus can enter the

5. For a drug to be effective therapeutically it has to achieve adequate plasma levels of the unbound form. Drugs vary in the period required to reach equilibrium between the body fluids and tissues. When a drug is 12


Majid A. K. Lafi

liver. Hepatic enzymes are, generally, capable of metabolising endogenous and exogenous substances that are relatively stereotyped. Each enzyme is specific for certain chemical groups, which can occur on a wide range of substances.

Inactive Substance Azathioprine Enalapril Sulphasalazine

Hepatic metabolic processes can be divided into: Phase I metabolism results in a change in drug substance by oxidation, reduction or hydrolysis and in certain cases introduces a chemically active site into it. Oxidation is the most important reaction that is usually achieved by the so-called mixed-function oxidases that are capable of metabolising a variety of compounds.

Talampicillin Acyclovir

Metronidazole

Phase II metabolism involves the union of the drug with one of several polar endogenous molecules (e.g. glucuronide, glycine or acetyl derivative) to form a watersoluble conjugate which is readily eliminated by the kidney or, if the molecular weight more than 300, in the biliary tract. Generally, phase II metabolism inactivates drugs and facilitates their excretion.

Chloramphenicol succinate Chloral hydrate Anistreplase Hexamine

When drugs undergo metabolism, they can be converted from pharmacologically active to inactive substances; this is the most likely event. Further, some pharmacologically active drugs may be converted to another active substance. While some other pharmacologically inactive drugs (prodrugs) can be converted to active ones. Active Drugs Allopurinol Amitriptyline Aspirin Acetaminophen (safe)

Codeine Chloroquine Diazepam

Active Metabolite Mercaptopurine Enalaprilat 5-aminosalicylic acid (mesalazine) plus sulphapyridine (by bacteria in the colon) Ampicillin Acyclovir triphosphate (by viral thymidine kinase) Reducedmetronidazole (by anaerobic bacteria) Chloramphenicol Trichloroethanol Deacylated anistreplase Formaldehyde (by hydrolysis in acidic urine)

Excretion Most drugs are excreted in urine, either as the parent substance or metabolites. Lipid soluble drugs, in addition to being readily absorbed from gut, appear in the glomerular filtrate, but easily pass back into the blood stream by passive diffusion at the proximal tubule. However, many of these drugs are converted by the liver into more polar, lipid insoluble metabolites. These metabolites, and other drugs which are highly polar (e.g. streptomycin), do not pass very readily into glomerular filtrate, but once they are there they have difficulty in diffusing back at the proximal tubule. These substances are usually excreted entirely by the kidney. In addition to passive diffusion, many acidic and basic drugs are actively secreted. The secretion of weakly acidic substances can be inhibited by probenecid, and this substance has been used to prolong the t of penicillin in order to reach higher tissue concentrations without increasing the dose of the antibiotic.

Active Metabolite Alloxanthine (oxypurinol) Nortriptyline Salicylic acid N-acetyl-pbenzoquinoneimine (NABQI, hepatotoxic) Morphine Hydroxychloroquine

Nordiazepam

13

General Principles


Changes in tubular pH can affect the elimination of these compounds by altering the ratio of ionised to unionised form. Normally the urine is slightly acidic and favours the excretion of weakly basic drugs (e.g. amphetamine, pethidine), while oral sodium bicarbonate will prolong their effects. On the other hand, the excretion of weakly acidic drugs (e.g. for patients who has taken overdose of barbiturates or aspirin) is accelerated by making the urine alkaline (alkaline diuresis) by giving sodium bicarbonate. As the kidney (and cardiac function) and to a lesser extent the liver are important in drug excretion, a serious consideration must be taken with impaired renal and hepatic functions. An elderly patient with congestive heart failure and a raised blood urea is likely to develop digitalis intoxication if digoxin is prescribed in full dose. It is necessary to measure repeatedly the serum level of certain drugs (e.g. gentamicin) when they are given to patients in renal failure.

14


Majid A. K. Lafi

The apparent volume of distribution (Vd)

USEFUL NOTES

D C = ------Vd

• Clearance of a drug is the rate of elimination by all routes relative to the concentration of drug in any biological fluid.

D Vd = -----C

Rate of elimination Clearance = -----------------------Concentration

C = plasma concentration of drug D = Total amount of drug in the body

Rate of elimination = Q x Ce - Q x Co

Example: if 10 mg of a drug, thus D = 10 mg, is administered and the plasma concentration is 1.0 mg/L, then the Vd = 10 mg/L = 10 L.

Blood flow = Q Entering drug concentration = Ce Exiting drug concentration = C0

Clinical applications of Vd 1. It is useful to calculate the amount of drug needed to achieve a desired plasma concentration:

Therefore: Q x Ce Q x Co Clearance = ------------------- (ml/min) Ce

Example: if supraventricular arrhythmia of a patient is not responding well due to inadequate plasma levels of digoxin. Assuming the plasma concentration of the drug is C 1 and the desired concentration is C 2, a higher one. It is important to know how additional digoxin should be administered to bring the circulating level of the drug from C1 to C2.

Ce Co = Q x ---------- = Q x ER Ce ER = extraction ratio

Clearance of a drug by an organ (e.g. kidney) means the ability of the kidney to remove the drug from a certain volume of plasma per minute. Similar to renal clearance of creatinine or urea.

D1 = Vd x C1 D1 = amount of drug initially in body D2 = Vd x C2 D2 = amount of drug in the body required to achieve the desired plasma concentration

Dosing rate = Clearance x Css (Q x Ce Q x Co ) = --------------------- x C ss Ce Css = Steady state concentration

Therefore, the additional dosage needed is the difference between the two values: (D2

C1 )

2. Since delivery of drug to the organs of elimination depends not only on blood flow but also on the fraction of the drug in plasma, therefore, the value of Vd of a drug can influence the rate of elimination. Assuming a drug with a large Vd, most of this drug is in the extraplasmic space and is unavailable to the excretory organs. Therefore, a drug with a large Vd would

Half-life (t ) is defined as the time required for the amount of drug in the body to decrease by half (50%). t

D1) = Vd (C2

= 0.693 Vd/CL CL = Clearance

15

General Principles

be expected to have a long t extended duration of action.


withdrawn, an interval equivalent to 4 t will be required for body stores of the drug to decline by 94%.

and

Clinically, the knowledge of Vd of a drug may be useful when overdosage occurs. Removing a drug by haemodialysis is likely to be of benefit if a major proportion of the total amount of the drug is in the plasma.

• When t is 6-12 hr giving half the priming dose at intervals equal to the t can indeed be a satisfactory solution because dosing every 6-12 hr is reasonable.

Example: For salicylate, which has a small Vd, (12L) haemodialysis is appropriate treatment; while for pethidine, which has a large Vd, (310L) is not appropriate one.

• When t is greater than 24 hr giving half the priming dose every day means that more drug is entering the body than is leaving it each day, and the drug will accumulate indefinitely. Thus, the maintenance dose should be adjusted to replace only that amount of drug that leaves the body in 24 hr, as for warfarin.

Students are expected to be familiar with the following terms. They are advised to make contributions in the discussion sessions on the concepts of these terms. • Therapeutic range, therapeutic window

• When t is less than 3 hr, dosing at intervals equal to the t would be so frequent as to be unacceptable, and the answer is to use continuous intravenous infusion if the t is very short, as for dopamine t , 2 min; steady-state plasma concentration will be reached in 5 x t = 10 min). Benzylpenicillin has a t of less than 1 hr but is effective in a 6-hourly regimen because the drug is very safe that it is possible to give in a dose that achieves a plasma concentration many times in excess of the minimum inhibitory concentration for sensitive organisms.

• Steady state concentrations (Css), plateau (when the quantity of drug eliminated between doses equals the dose administered, average drug levels will remain constant and plateau will have been reached. • Time to plateau (When a drug is administered repeatedly in the same dosage, plateau (steady state) will be reached in approximately 4-5 half-lives. • Techniques for reducing fluctuations in drug levels

• First and zero order (saturable) kinetics [clinical implications: (phenytoin, therapeutic index = 2, subtherapeutic plasma concentration with t of 6-24 hr and C ss reached in 2-3 days, while therapeutic plasma concentration with t of 60 hr and Css reached in 2 weeks); alcohol (due to alcohol dehydrogenase being saturable at alcohol blood concentration of about 10 mg/dL), theophylline with therapeutic index 30 55-150

6-10 6-10 6-10 20-30

1-2 1-2 1-2 4-8

* Note: Levels of aminoglycosides must be kept within a narrow range, and because of interpatient variability, the above standard doses cannot be relied upon to produce predictable levels, dosage must be carefully adjusted for each patient.

When possible, aminoglycosides should not be used for more than 10 days. Further, concurrent administration of aminoglycosides with other potentially ototoxic agents (e.g. frusemide, ethacrynic acid) should be avoided.

Ototoxicity Aminoglycosides penetrate easily to the perilymph of the inner ear, and there is a direct relationship between levels achieved in the perilymph and production of ototoxicity manifests as impairment of hearing and balance. Damage to hair cells within the cochlea results in loss of hearing, while disruption of balance is caused by damage to hair cells of vestibular apparatus.

Other adverse effects and interactions Aminoglycosides can cross the placenta and may have toxic effects on the developing foetus. They are also known to produce curare-like effects (neuromuscular block); thus, they can intensify neuromuscular blockade produced by tubocurarine and other skeletal muscle relaxants. Therefore, when using aminoglycosides together with the muscle relaxants, extreme caution must be taken to avoid respiratory arrest.

Upon giving aminoglycosides, patients should be monitored for early signs of cochlear or vestibular damage. By using audiometric testing, decreased acuity in the high-frequency range indicates loss of hearing. Auditory toxicity can also present as tinnitus or a sense of fullness in the ear. Further, damage to the vestibular system may manifest as nausea, unsteadiness, and vertigo.

Cautions

When ototoxicity is detected, aminoglycosides should be withdrawn or administered in reduced doses. If toxicity is moderate, symptoms reverse following withdrawal of aminoglycosides; however, when ototoxicity is extensive, symptoms may be permanent and even can be with complete hearing loss.

Aminoglycosides should never be mixed together with penicillins (or any β-lactam drug) in the same syringe or in the same i.v. solution because penicillins (when present in high concentrations) interact chemically with aminoglycosides rendering the latter inactive.

99

Antimicrobial Agents -Sulphonamides, Trimethoprim, and Aminoglycosides

Postantibiotic Effect Postantibiotic effect is the antibacterial activity that persists beyond the time that measurable drug is present. This phenomenon was first observed with anti-mycobacterial drugs like rifampicin and then termed the lag-period effect . This postantibiotic effect is being significant and well documented with aminoglycosides and quinolones. Therefore, a given total daily amount of aminoglycoside may have better efficacy when administered as a single large dose than when administered as multiple smaller doses. Further, the single large dose scheme produces much higher peak concentrations, which saturate an uptake mechanism into the cortex; thus, resulting in less total aminoglycoside accumulation that is thought to cause renal damage and in turn less renal toxicity. The difference in renal toxicity is a predictable consequence of the different patterns of concentration (due to different dosage regimens) and the saturable uptake mechanism in the proximal renal tubular cells.

AMINOGLYCOSIDES • Useful primarily in serious infections due to aerobic gram-negative bacteria (e.g. Pseudomonas aeruginosa) • Have to be given parenterally • Unchanged excreted renally • Adverse effects: 1. Nephrotoxicity 2. Ototoxicity 3. Neuromuscular block 4. Low therapeutic index

100



Majid A. K. Lafi

TETRACYCLINES, MACROLIDES, METRONIDAZOLE, CHLORAMPHENICOL, AND OTHERS 3. Opportunistic infections (e.g. candidiasis) 4. Tooth discoloration (tetracyclines are selectively taken up in the teeth and growing bones in the foetus and of children, given rise to inhibition of growth of bones and discoloration of teeth) 5. Inhibition of bone growth 6. Elevated blood urea (the antianabolic effect, inhibition of protein synthesis, cause blood urea to rise that is of a particular importance in uraemic patients) 7. Fatty liver 8. Photosensitisation (exposure to sunlight results in darkening of skin)

TETRACYCLINES Tetracyclines (1948) are a family of broadspectrum antibiotics with only minor differences. Tetracyclines have a 4-ring structure with small side-chains. The earliest members were chlortetracycline, oxytetracycline and tetracycline. The most recent ones are doxycycline and minocycline, which have good absorption and long t (16 h). Tetracyclines are bacteriostatic; they interfere with protein synthesis.

Resistance to Tetracycline

Caution

Bacterial resistance to tetracycline may be conferred by three possible mechanisms:

When passing the date of expiry, particularly tetracycline, becomes nephrotoxic therefore should not be used.

1. Decreased intracellular accumulation due to either impaired influx or increased efflux by an active transport protein pump 2. Ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome 3. Enzyme inactivation of tetracycline

MACROLIDES ERYTHROMYCIN

Indications

Erythromycin is one of the macrolides, which are termed after their macrocyclic lactone ring to which different sugars are attached. It was isolated in 1952 from a streptomyces strain found in the Philippine soil.

Their uses include infections with 1. Clamydiae (e.g. psittacosis, trachoma, pelvic inflammatory diseases, lymphogranuloma venereum) 2. Mycoplasma (pneumonia) 3. Rickettsia (Q fever, typhus) 4. Vibrio cholerae (cholera) 5. Haemophilus influenzae (e.g. bronchitis) 6. Brucella (brucellosis)

Absorption is best with erythromycin estolate, even if there is food in the stomach. Erythromycin is partly inactivated by gastric acid. The t (2h) is dose dependent and elimination is almost exclusively in the bile and faeces.

For a summary of pharmacokinetic properties see Table 4.6.

Erythromycin is active against gram-positive bacteria and spirochaetes. It is used instead of penicillin in patients allergic to penicillin and infections resistant to penicillin.

Adverse effects 1. GIT disturbances 2. Disorder of epithelial surfaces (sore mouth and throat, black hairy tongue, odynophagia and perianal soreness) 101



Table 4.6. A summary of pharmacokinetic properties of tetracyclines Group

Agent

Short-acting

Tetracycline Oxytetracycline Demeclocycline

Low Low Moderate

75 60 65

↓ ↓ ↓

Renal Renal Renal

8 9 15

50-100 50-65 40-60

Doxycycline Minocycline

High High

90-100 90-100

(No change)

Hepatic Hepatic

12-22 12-22

12-22 12-22

Intermediateacting Long-acting

t

Note: Tetracycline may achieve toxic levels in renal dysfunction, therefore, it is not suitable in such condition. Doxycycline does not accumulate in renal dysfunction, does not interact with food, and is given once or twice daily, while tetracycline should be given four times daily. These make doxycycline superior to tetracycline.

2. Gastrointestinal disturbances (particularly diarrhoea, occur in up to 28%) 3. Hepatic enzyme inhibition (unlike azithromycin, erythromycin and clarithromycin inhibit the metabolic inactivation of some drugs like warfarin, carbamazepine, theophylline, disopyramide, increasing their effects)

Resistance to Macrolides Resistance to erythromycin may be conferred by the following: 1. Decreased cellular influx or increased active efflux 2. Production of esterases that hydrolyse macrolides 3. Alteration of the ribosomal binding site

CLARITHROMYCIN Indications 1. Penicillin-allergic patients (alternative to penicillin when infections due to grampositive bacteria) 2. Pneumonia (due to Mycoplasma pneumoniae) 3. Legionnaires disease (Legionnella species, 1st choice drug) 4. Diphtheria (Corynebacterium diphtheriae) 5. Whooping cough (Bordetella pertussis) 6. Gastroenteritis (due to Campylobacter jejuni) 7. Acne

Adverse Effects 1. Cholestatic hepatitis (with abdominal pain and fever that may be confused with viral hepatitis, due to estolate; this is probably an allergic reaction, thus the estolate should not be given to a patient with liver disease. 102

Clarithromycin acts like erythromycin and also exhibits a similar antibacterial activity to the latter agent, being mainly active against gram-positive organisms. It should be noted that the t of clarithromycin is remarkably does-dependent (t 3 hours after 250 mg, 9 hours after 1200 mg). Unlike erythromycin, it is rapidly and completely absorbed from the gastrointestinal tract. Of oral clarithromycin dose, 60% is inactivated by metabolism that is saturable and the remainder is eliminated in the urine. It is useful largely in respiratory tract infection including atypical pneumonias and soft tissue infections. It exhibits fewer gastrointestinal tract adverse effects (7%) than that of erythromycin (28%). Clarithromycin, like erythromycin, also inhibits the metabolic inactivation of some drugs (See above).


Majid A. K. Lafi

2. Metallic taste 3. Peripheral neuropathy 4. Ataxia 5. Insomnia 6. Convulsion 7. Darkening of urine 8. Disulfiram-like reaction (when alcohol is consumed concurrently with metronidazole)

AZITHROMYCIN Azithromycin is a new macrolide agent that acts like erythromycin (inhibits protein synthesis) but with a broader spectrum of antibacterial activity than erythromycin. The extension of activity includes a number of important gram-negative like Haemophilus influenzae and Neisseria gonorrhoeae, and also Chlamydiae. However, it is less effective against gram-positive organisms than erythromycin. Azithromycin is rapidly absorbed and tolerated orally. Azithromycin does inhibit cytochrome P450 enzymes therefore, unlike erythromycin clarithromycin, is relatively free of the interactions.

CHLORAMPHENICOL Chloramphenicol (1948, chloromycetin) was originally obtained from a streptomyces strain from Venezuela but is now synthesised. It readily penetrates the blood brain barrier (BBB). Chloramphenicol has a wide range of antibacterial activity including. infections due to

well not and and drug

1. Typhoid (Salmonella typhi and Salmonella paratyphi) 2. Meningitis (Haemophilus influenzae) 3. Whooping Cough (Bordetella pertussis)

METRONIDAZOLE Metronidazole has for many years been successfully employed to treat protozoal infections but the outstanding activity against anaerobes has been found useful particularly in bacteroides infections, and since the recognition of toxicity from lincomycin, has been widely used in treatment of septic infections of the chest, abdomen and pelvis. Metronidazole is a prodrug activated by anaerobic bacteria and not aerobic ones. It is bactericidal agent and resistance is not a problem.

Adverse Effects

Indications 1. Septic infections 2. Antibiotic-associated enterocolitis (pseudomembraneous colitis due to Clostridium difficile) 3. Urogenital tract trichomoniasis 4. Amoebiasis (Entamoeba histolytica) 5. Giardiasis (Giardia lamblia) 6. Acute ulcerative gingivitis and dental infections 7. Vaginitis (Gardnerella vaginalis)

Adverse Effects 1. Gastrointestinal diarrhoea)

disturbances

(nausea,

103

1. Reversible bone marrow depression (dose-related) 2. Aplastic anaemia (pancytopenia and bone marrow aplasia, occurs with an incidence of 1 in 35,000 and is not related to dose; it occurs with oral, i.v., or even ophthalmic use of the drug. This reaction develops weeks or months after termination of the treatment.) 3. Grey baby syndrome (circulatory collapse, vomiting and fall in body temperature; this depends on the lower capacity to conjugate chloramphenicol in the liver in infants.) 4. Acute haemolytic anaemia in G6PD deficient patients Note: The onset of action of chloramphenicol when given orally is more rapid than when given intravenously. This is because the i.v. formulation of chloramphenicol (usually with succinate) has to be broken down in the liver to release chloramphenicol before it acts, while the capsule (usually with palmitate) form acts directly.


Ramadi, 24 February 2007

Adverse Effects LINCOSAMIDES 1. Flu-like illness 2. Hepatitis 3. Thrombocytopaenia 4. Rashes 5. Pink urine

CLINDAMYCIN AND LINCOMYCIN Clindamycin is more effective and better absorbed from the gastrointestinal tract. These drugs are effective against the following:

NITROFURANTOIN AND NALIDIXIC ACID

1. Bacteroides fragilis (first choice against gastrointestinal strains) 2. Anaerobic streptococcal infections (as an alternative) 3. Clostridium perfringens (as an alternative) 4. Staphylococcal infections (as an alternative)

These drugs are urinary tract disinfectant used for the treatment of infections with 1. Escherichia coli 2. Streptococcus faecalis 3. Proteus species Nalidixic acid also has some place in the treatment of infection with Shigella (in paediatric practice).

Adverse Effects 1. Antibiotic-associated enterocolitis (hence, these drugs should not be used indiscriminately; metronidazole is indicated to treat this condition)

Adverse Effects 1. Peripheral neuropathy (with nitrofurantoin) 2. Convulsions (with nalidixic acid)

The use of metronidazole is now preferred to that of clindamycin or lincomycin, for the treatment of anaerobic infections. Metronidazole appears to be superior because it can achieve adequate concentrations in the CSF and has not been reported to cause antibiotic-associated colitis.

SODIUM FUSIDATE Sodium fusidate is an antistaphylococcal agent, useful in severe infections caused by β-lactamase producing and methicillin resistant Staphylococcus aureus (MRSA) including osteomyelitis. It is readily absorbed from the gut and distributes widely in body tissues including bone. It is largely metaboilised and only very little is excreted in the urine. It is available as i.v. , oral, ointment and gel preparations.

RIFAMPICIN It has a broad-spectrum antibacterial activity, particularly, against mycobacterial species, and gram-positive organisms including staphylococci. With rifampicin, the rapid emergence of resistance dictates that they must always be used in combination with unrelated antimicrobial agents. It is largely reserved for mycobacterial infections. Its use in MRSA infections may be justified.

VANCOMYCIN Vancomycin is an antibiotic produced by Streptococcus orientalis, glycopeptide and is water-soluble and very stable. It inhibits cell wall synthesis. It is useful when given orally in antibiotic-associated enterocolitis, and i.v. for systemic infections. It readily crosses the BBB if there is meningeal inflammation. 104


Majid A. K. Lafi

urinary or gastrointestinal tracts, skin, soft tissues, and bones. They have also been used in the treatment of gonorrhoea and septicaemia.

Vacomycin is largely (90%) eliminated renally by being excreted by glomerular filtration. Therefore, in renal insufficiency, surprisingly high blood levels may be reached.

Adverse Effects

Indications 1. Methicillin-resistant Staphylococcus aureus (MRSA, first choice drug) 2. Enterococcal endocarditis in patients with serious penicillin allergy (in combination with gentamicin) 3. Meningitis suspected or known to be caused by a highly penicillin-resistant strains of pneumococcus (MIC > 1 µg/ml) 4. Antibiotic-associated enterocolitis (due to Clostridium difficile, administered orally)

Adverse Effects 1. Chills and fever 2. Ototoxicity (tinnitus and deafness may reverse upon withdrawal of vancomycin) 3. Nephrotoxicity 4. Red man or Red neck (a maculopapular rash possibly due to histamine release may occur upon rapid i.v. infusion)

Caution

1. Crystalluria (Therefore, adequate amount of water should be taken) 2. Cartilage deterioration (reversible arthropathy in immature animals, although such effects have not been observed in humans, prudence dictates that these drugs are contraindicated in children and in women who are pregnant or nursing. However, some authorities would state that fluoroquinolones should be used with caution in children and adolescents 1 3. Inhibition of Drug Metabolism (inhibits the metabolism of theophylline and warfarin, therefore, both of which should be monitored carefully when concurrently administered with ciprofloxacin)

Cautions 1. Oral absorption of fluoroquinolones is impaired by divalent cations including those in antacids. 2. Interacts with theophylline (inhibit hepatic metabolism of theophylline and therefore can potentiate its effects).

Administration with another ototoxic or nephrotoxic drug, such as an aminoglycoside, increases the risk of these toxicities.

FLUOROQUINOLONES These are synthetic bactericidal agents chemically related to nalidixic acid. The prototype of this group is ciprofloxacin and norfloxacin. They can easily penetrate the BBB and thus can be used as an alternative to the 3rd generation cephalosporins. Nowadays, the use of these drugs has picked up a great popularity as broad-spectrum antibacterial drugs.

Indications They have been found effective in the treatment of infections of the respiratory,

1

Laurence, D. R., Bennett, P. N. & Brown, M.J. (1997) Clinical Pharmacology. 8th edition, page 212. 105



ANTIMYCOBACTERIAL DRUGS ANTITUBERCULOSIS DRUGS

As treatment is prolonged, if only one antituberculous drug is used there is a high risk that a drug-resistant mutants (due to spontaneous mutation, that exist in all large bacterial populations) will emerge. However, the possibility of bacilli to develop resistance to more than one drug is very low. Therefore, treatment of two or more drugs reduces the risk of developing drug-resistance. Further, drug-combination therapy also serves to reduce the incidence of relapse. A strategy for drug-combination targeting in the course of treatment of tuberculosis is presented in Fig.4.4.

Introduction The objective of antituberculous therapy is to eliminate symptoms of active disease, and to prevent relapse, and emergence of drug resistance. To achieve these goals, the following should be accomplished: 1. Killing the Actively Multiplying Tubercle Bacilli: Elimination of the actively multiplying population, which have been estimated to form about 95% of the total tubercle bacilli, and the intracellular ones within the initial phase (1st 2-3 months) of treatment.

The regimen currently recommended for the treatment of uncomplicated tuberculosis in AL-Anbar as follows:

2. Eradicating the Remaining Problematic Tubercle Bacilli: Eradicating the problematic proportion of the tubercle bacilli which is characterised by usually being at resting state but occasionally exhibits spurts of metabolic activity ; these bacilli represent, at least in part, what are described as persisters , i.e. semidormant bacilli that metabolise slowly or intermittently. It is believed that only during these spurts of activity (which have been estimated to last for about 2 minutes at a time) that drugs can kill these bugs. Therefore, the continuation (2nd) phase is directed at capturing these moments of activity. The 2nd phase usually takes 4-6 months; at the end of which this proportion of the tubercle bacilli should be eradicated (if the treatment is successful).


Following 4 months (Continuation Phase)

Isoniazid (INH) + rifampicin + pyrazinamide + ethambutol or streptomycin (2HRPE) Isoniazid + rifampicin (4HR)

The regimen currently recommended for the treatment of complicated tuberculosis (e.g. relapse and treatment failure cases) in ALAnbar as follows:


Further 1 or 2 Months

Success of treatment is indicated by an absence of observable tubercle bacilli in sputum (direct smear) and by failure of sputum cultures to yield any colonies of the bacilli. When sputum test results have become negative, usually within 2-6 months, therapy should continue for additional 4-6 months.

Five months (Continuation Phase)

106

Isoniazid + rifampicin + pyrazinamide + ethambutol + streptomycin (2HRZES) Isoniazid + rifampicin + pyrazinamide + ethambutol (1HRZE) Isoniazid + rifampicin + ethambutol (5HRE)


Majid A. K. Lafi

Most modern regimens for the treatment of tuberculosis include isoniazid, rifampicin, and pyrazinamide, since

Therefore, it is an essential feature of the antituberculosis regimen is that practically all drugs should be given once daily (not divided doses). For a summary of the pharmacology of antituberculosis drugs see Table 4.7.

•

Isoniazid rapidly kills large numbers of actively growing bacteria including those with only occasional spurts of activity. • Rifampicin kills actively growing bacilli including the problematic ones with only spurts of metabolic activity; and also kills intracellular bacilli. • Pyrazinamide that is converted to the active pyrazinoic acid by the activity of intrabacterial pyrazinamidase, an enzyme is most effective in an acidic environment such as the interior of cells. Thus, it is effective uniquely in zones of acute inflammation and against quiescent bacilli within macrophages (persisters, semidormant bacilli that are often within cells).

Isoniazid, pyrazinamide, and ethambutol are considered to be specific antimycobacterial drugs. Therefore, they are used in therapeutic trials for diagnostic purposes. Isoniazid is highly selective for mycobacteria; the drug can kill tubercle bacilli at concentrations 10,000 times lower than those needed to affect gram-positive bacteria.

ANTILEPROSY DRUGS Leprosy (Hansen s disease) is caused by Mycobacterium leprae. The WHO recommends that all patients receive treatment with multiple drugs.

Also, it is worth noting that: •

Ethambutol is a specific drug against mycobacteria. Generally, it is used when resistance to isoniazid and rifampicin is suspected. • Streptomycin has relatively low sterilising activity, perhaps, because of its inability to penetrate cells and not being effective against intracellular bacilli.

Dapsone (t is 27 hr, aminodiphenylsulfone) has been and remains a mainstay of therapy that requires a minimum duration of two years. The absorption of dapsone is slow but complete from the gastrointestinal tract and the drug sustains a steady blood level because it undergoes intestinal reabsorption from the bile. It is excreted in the urine. Dapsone is associated with methemoglobinemia, agranulocytosis, haemolytic anaemia, drug rash, and anorexia as adverse effects. Dapsone causes more haemolytic anaemia in slow acetylators, whereas rapid acetylators may need higher doses to control leprosy.

In general, a 6-month regimen cures the patient rapidly and these drugs are usually well tolerated. In Ramadi, this regimen has been found as the most successful one with the highest cure-rate (85%).

Rifampicin is used in combination with dapsone in the treatment of leprosy. Rifampicin in a dosage of 600 mg daily is safe and effective when given once monthly. This long interval makes acceptable the directly observed therapy with rifampicin which the above regimens require.

Postantibiotic Effect After a culture of Mycobacterium tuberculosis had been exposed to certain drugs for sometime, it took several days (the lag-period , postantibiotic effect) before growth occurred. Therefore, 600 mg of rifampicin given once daily is therapeutically superior to the same dose divided into two parts administered at 12 hours interval.

Clofazimine (t is 70 days) is a phenazine dye and it has a leprostatic action. It is absorbed from the gastrointestinal tract and 107



accumulates in tissues. Hence, dosage regimen is possible if individual doses are given in a gap separated by four weeks.

discolouration of the skin that may persist for months after the drug has been stopped.

Clofazimine is given for dapsoneresistant leprosy or when patients are intolerant to dapsone. Clofazimine therapy is associated with reddish to nearly black

Table 4.7. A summary of the pharmacology of the currently used antituberculosis drugs. Drug Isoniazid (INH)

Action Powerfully anti-TB; inhibits formation of mycolic acid in bacterial cell wall. Bacteriostatic-cidal

Rifampicin

Inhibits RNA polymerase in bacteria. Resistance develops rapidly if used on its own.

Pyrazinamide

Converted to pyrazinoic acid by intrabacterial pyrazinamidase (most effective in acidic environment) Concentrated in tubercle bacilli, mode of action not known. Resistance develops slowly. Effective against strains resistant to rifampicin and streptomycin.

Ethambutol

Streptomycin

Thiacetazone

See aminoglycosides (not effective in acidic environment) Low efficacy, delays emergence of INH resistance

108

Toxicity Insomnia Muscle twitching Peripheral neuropathy (responds to vit. B6) Hepatitis Flu-like illness Hepatitis Thrombocytopenia Rashes Pink urine Hepatotoxicity (10%) Gouty attacks

Peripheral neuropathy Colour blindness Pruritus Joint pains Abdominal pain Confusion Hallucination Contraindicated in pregnancy Nephrotoxicity Ototoxicity Neuromuscular block Hepatotoxicity


Majid A. K. Lafi

Actively multiplying population

Intracellular population

Isoniazid Rifampicin Streptomycin Ethambutol

Population with spurts of metabolic activity

Rifampicin Pyrazinamid

Isoniazid Rifampicin

This population is usually killed within the 2nd phase of therapy (4-6 months)

These 2 populations are usually killed within the 1st phase of therapy (1st 2-3 months), requiring combined isoniazid, rifampicin, pyrazinamide, & streptomycin or ethambutol.

Dormant population

Not reached by drugs

Eradication decreases relapse & resistance

Fig. 4.4. A simplified representation of the strategy of the treatment of tuberculous infections (pulmonary), different phases of treatment, antituberculous drugs, and duration of treatment are indicated. Note: The actively (rapidly) metabolising bacilli are believed to be killed within a few days: however, the intracellular bacilli (including semidormant bacilli, quiescent but with spurts of metabolic activity) are more difficult to be dealt with. Rifampicin and pyrazinamide are effective in killing the latter population within the initial phase of treatment. The continuation phase of treatment (isoniazid + rifampicin) is directed at least 4-month treatment, hopefully, to achieve eradication of bacilli and therefore decrease the possibility of relapse and drug-resistance.

109



ANTIMICROBIAL DRUGS OF CHOICE Table 4.8. Antimicrobial drugs of choice; modified from Laurence, D. R., Bennett, P. N., and Brown, M. J. (1997) Clinical Pharmacology, 8th edition, page 194. * Resistance may be a problem; sensitivity test should be done. ** Suggested alternatives do not necessarily represent all options. CS = a cephalosporin Co-amoxiclav = fixed combination of amoxicillin plus clavulanic acid ± With or without FQ = a fluoroquinolone (e.g. ciprofloxacin)

Infecting organism

Drug(s) of 1st choice

Alternative drugs**

Gram-positive cocci *Enterococcus Endocarditis or other severe infections

Benzylpenicillin or amoxicillin + gentamicin, or streptomycin

Vancomycin + gentamicn or streptomycin

Uncomplicated Urinary tract infections

amoxicillin

Trimethoprim or nitrofurantoin

Non-penicillinase producing

Benzylpenicillin

CS; vancomycin; imipenem; erythromycin

Penicillinase producing

Cloxacillin

CS; vancomycin; co-amoxiclav; erythromycin; clindamycin; FQ

Methicillin-resistant

Vancomycin ± gentamicin ± rifampicin

Co-trimoxazole; a tetracycline; FQ; rifampicin; Na fusidate

Streptococcus pyogenes

Benzylpenicillin or phenoxymethylpenicillin or amoxicillin

Erythromycin; CS; vancomycin; (clindamycin, for necrotic infection of the superficial and deep fascia)

Benzylpenicillin ± gentamicin

Vancomycin; CS

Amoxicillin

Trimethoprim; nitrofurantoin; FQ

*Staphylococcus aureus or epidermidis

(Group A, and Groups C and G) Streptococcus (Group B)

Streptococcus, viridans group (endocarditis) Streptococcus faecalis (enterococci) UTI

110


Majid A. K. Lafi

Benzylpenicillin or amoxicillin + gentamicin or streptomycin Benzylpenicillin

Vancomycin + gentamicin or streptomycin

Benzylpenicillin or amoxicillin

Erythromycin; CS; vancomycin; rifampicin (or chloramphenicol for meningitis)

Moraxella (Branhamella) catarrhalis

Co-amoxiclav

Erythromycin or a tetracycline

*Neisseria gonorrhoeae (gonococcus)

Amoxicillin (+ probenecid) or FQ or ceftriaxone

Spectinomycin; cefixime or cefotaxime

Neisseria meningitis (meningococcus)

benzylpenicillin

Chloramphenicol; cefotaxime

Bacillus anthracis (anthrax)

Benzylpenicillin

Erythromycin; a tetracycline

Clostridium perfringens

Benzylpenicillin


Benzylpenicillin

A tetracycline

Erythromycin

Benzylpenicillin

Amoxicillin ± gentamicin

Erythromycin + gentamicin

Oropharyngeal strains

Benzylpenicillin


Gastrointestinal strains

Metronidazole

Co-amoxiclav; clindamycin; imipenem; chloramphenicol Tetracycline

Endocarditis

Streptococcus, anaerobic *Streptococcus

pneumoniae (pneumococcus)

Metronidazole

Gram-negative cocci

Gram-positive bacilli

(gas gangrene)

Clostridium tetani (tetanus) Corynebacterium diphtheriae (diphtheria) Listeria monocytogenes (listeriosis)

Enteric gram-negative bacilli *Bacteroides

Erythromycin or FQ *Campylobacter jejuni *Enterobacteriaceae e.g. *Enterobacter aerogenes *Escherichia coli *Klebsiella pneumoniae *Proteus species FQ or an oral CS Lower urinary tract

Amoxicillin or trimethoprim

Septicaemia

Gentamicin or cefotaxime

FQ; imipenem

*Helicobacter pylori (peptic ulcer)

Amoxicillin + clarithromycin + metronidazole (plus omeprazole)

Amoxicillin + metronidazole + bismuth chelate; or tetracycline + clarithromycin + bismuth chelate

111



*Salmonella typhi (typhoid fever)

Ceftriaxone; FQ

Chloramphenicol; co-trimoxazole; amoxicillin

*Other Salmonella

FQ

Amoxicillin; co-trimoxazole; chloramphenicol

*Shigella

FQ

Trimethoprim; ampicillin (paediatric: nalidixic acid)

*Yersinia enterocolitica

Co-trimoxazole

FQ, gentamicin; tetracycline

*Bordetella pertussis (whooping cough)

Erythromycin

Ampicillin

*Brucella (brucellosis)

Tetracycline + streptomycin or gentamicin

Co-trimoxazole; rifampicin + tetracycline

Calymmatobacterium granulomatis (granuloma inguinale) *Fusobacterium

A tetracycline

Streptomycin or gentamicin or co-trimoxazole

Benzylpenicillin

Metronidazole or clindamycin

Gardeneralla vaginalis (anaerobic vaginosis)

Metronidazole (oral)

Topical clindamycin or metronidazole; oral clindamycin

*Haemophilus ducreyi (chancroid) *Haemophilus influenzae Meningitis, epiglotitis, arthritis or other serious infections Upper respiratory infections and bronchitis Legionella pneumophila (legionnaire s disease)

Erythromycin

FQ

Cefotaxime or ceftriaxone or amoxicillin

Chloramphenicol

Co-trimoxazole or amoxicillin

Co-amoxiclav; CS (3r generation)

Pasteurella multocida (from animal bites) *Pseudomonas aeruginosa Urinary tract infection

benzylpenicillin

Co-amoxiclav or CS

FQ

Ticarcillin; piperacillin; mezlocillin

Other infections

FQ; ticarcillin; mezlocillin; piperacillin; gentamicin; amikacin Tetracycline

Ceftazidime; imipenem

Other gram-negative bacilli

Vibrio cholerae (cholera)

Erythromycin ± rifampicin

FQ

Acid-fast bacilli *Mycobacterium tuberculosis Isoniazid + rifampicin + 112

Other antitubercular agents include cycloserine, thiacetazone, ethionamide,


Majid A. K. Lafi

Pulmonary (1st 2 months)

pyrazinamide ± ethambutol (or streptomycin) (2HRPE)

kanamycin, amikacin, capreomycin, ciprofloxacin, and ofloxacin.

(next 4 months)

Isoniazid + rifampicin (4HR)

Ethionamide or cycloserine

Mycobacterium leprae (leprosy)

Dapsone + rifampicin ± clofazimine

Actinomycetes Actinomyces israelii (actinomycosis) Nocardia

Benzylpenicillin

A tetracycline

Co-trimoxazole

Amikacin; minocycline; imipenem

Chlamydiae Chlamydia psittaci (psittacosis, ornithosis)

Tetracycline

Chlamydia trachomatis Trachoma

Azithromycin

Tetracycline (oral plus oral); a sulphonamide (topical plus oral)

Inclusion conjunctivitis

Erythromycin (oral or i.v.)

A sulphonamide

Pneumonia

Erythromycin

A sulphonamide

Urethritis, cervicitis

Doxycycline or azithromycin

Erythromycin or ofloxacin

Lymphogranuloma venereum Chlamydia pneumoniae (TWAR strain)

Tetracycline

Erythromycin

Tetracycline

Erythromycin

Mycoplasma pneumoniae

Erythromycin or tetracycline

Clarithromycin; azithromycin

Ureaplasma urealyticum

Erythromycin

Tetracycline; clarithromycin

Tetracycline

Chloramphenicol; FQ

Borrelia burgdorferi (Lyme disease)

Doxycycline or amoxicillin

Ceftriaxone or cefotaxime or benzylpenicillin

Borrelia recurrentis (relapsing fever) Leptospira (leptospirosis)

Tetracycline

Benzylpenicillin

Benzylpenicillin

Tetracycline

Treponema pallidum (syphilis) Treponema pertenue (yaws)

Benzylpenicillin

Tetracycline or ceftriaxone

Benzylpenicillin

Tetracycline

Chloramphenicol

Mycoplasma

Rickettsia Q fever, typhus

Spirochaetes

113



ANTIFUNGAL DRUGS 1. Drugs used to treat superficial mycoses (fungal infections) a. Polyene antibiotics (e.g. nystatin and amphotericin B) b. Imidazoles (e.g. ketoconazole, clotrimazole, miconazole, and econazole) c. Others (e.g. griseofulvin, flucytosine)

Introduction Superficial fungal infections occur much more frequently than system fungal infections. The superficial mycoses are caused by two groups of organisms: 1. Candida species 2. Dermatophytes

2. Drugs used to treat systemic mycoses a. Amphotericin B b. Flucytosine c. Ketoconazole d. Miconazole

Superficial infection with dermatopytes is more common than superficial candidiasis. Candidal infections usually occur in mucous membranes or moist skin. However, candidal chronic infections may occur in scalp, skin, and nails. Dermatophytoses are generally confined to the skin, hair, and nails.

POLYENE ANTIBIOTICS Nystatin Nystatin derived from Streptomyces cultures from the soil of Virginia and its name derived from the New York State Department of Health that was responsible for its culture. It is used topically for the treatment yeast-like fungi such as Candida albicans, also for vaginal infections. It is too toxic to be used systemically.

Systemic mycoses can be classified into two types: 1. Opportunistic infections 2. Non-opportunistic infections The opportunistic mycoses, e.g. candidiasis, aspergillosis, cryptococcosis, mucormycosis, occur primarily in debilitated or immunocompromised host. While, non-opportunistic infections may occur in any subject; these infections are relatively uncommon and include sporotrichosis, blastomycosis, histoplasmosis, and coccidiodomycosis. These infections often pose a therapeutic problem because of their resistance to drugs, consequently requiring a long duration with high dose therapy with drugs that often exhibit high toxicities.

Amphotericin Amphotericin B is a polyene compound that remains the drug of choice for most serious systemic fungal infections. It has serious toxic effects, primarily nephrotoxicity. It must be given intravenously; in meningitis due to fungal infection; it has to be given intrathecally to achieve adequate concentration in the CSF.

Antifungal Drugs

IMIDAZOLES

The antifungal drugs are classified into two main groups:

The imidazole antifungal agents constitute members which are used for 114


Majid A. K. Lafi

superficial and systemic infections like ketoconazole, and to a lesser extent miconazole (rarely used systemic infections because of high toxicity); and clotrimazole and econazole are used for superficial infections and for topical application only. The imidazole agents are useful for both dermatophytic and candidal infections.

Miconazole

Ketoconazole

Econazole

Ketoconazole is the only imidazole antifungal drug that can be administered by mouth for treatment of superficial mycoses; it is active against a variety of fungal infections, dermatophytic infections and candidiasis of the skin, mouth, and vagina. Its oral absorption is variable, and only partially excreted in the urine. It carries a potential for hepatic toxicity; therefore, a regular assessment of hepatic function should be made. Because it blocks steroid synthesis, it is useful in Cushing s syndrome, and may lead to hypoadrenalism and reduction in testosterone levels (antiandrogenic activity).

Econazole is an imidazole antifungal agent applied topically only. The drug is effective in Tinea infection and for superficial candidiasis.

Miconazole is an imidazole antifungal agent available for topical and systemic administration. Because of high toxicity, the drug rarely used systemically; thus, it is a drug of first choice for dermatophytic infections, and cutaneous and vaginal candidiasis.

OTHERS Griseofulvin Griseofulvin is an antibiotic, isolated from Penicillium griseofulvin in 1939, which is active when given orally but not topically. Its only use is in the systemic treatment of dermatophytosis. The absorbed drug has an affinity for diseased skin and is deposited there, bound to keratin, making keratin resistant to fungal growth. Thus, new growth of hair or nails is free of infection. Therefore, it must be administered for 2-6 weeks for skin and hair infections. It is a hepatic enzyme inducer.

It follows that because of the serious toxicity associated with its systemic use, oral ketoconazole is reserved for fungal infections that have failed to respond to topical agents like clotrimazole and miconazole. A topical preparation of ketoconazole is now available but its use is approved only for dermatophytic infections but not for candidiasis.

Flucytosine Flucytosine is available for oral or parenteral use. It is mainly used in a synergistic combination with amphotericin against Cryptococcus neoformans. High plasma levels that often occur with renal impairment are associated with bone marrow toxicity, and monitoring of plasma concentration is therefore advised.

Clotrimazole Clotrimazole is a synthetic imidazole derivative that is topically active against dermatophytic infections and candidiasis of the skin, mouth and vagina.

115



Table 4.9. A summary of drugs of choice for superficial and systemic mycoses. Infection or organism Superficial infections

Drug of choice

Alternative Drugs

Dermatophytoses

Miconazole (topical) Clotrimazole (topical)

Tolnaftate (topical) Griseofulvin (oral) Ketoconazole (oral)

Tinea unguium (nail ringworm) Tinea capitis (scalp ringworm) Tinea pedis (athlete s foot)

(These are acid sensitive; thus, benzoic acid ointment, salicylic acid 4.65%, boric acid 2.87% in alcohol and ethyl acetate as paint)

Candidiasis of Skin and vagina

Clotrimazole (topical) Miconazole (topical)


Mouth

Clotrimazole (topical)


Intestine

Nystatin (oral)

Systemic infections Aspergillus species

Amphotericin B

None

Blastomyces dermatitidis

Amphotericin B

Ketoconazole

Candida species

Amphotericin B

Ketoconazole

Coccidioides immitis

Amphotericin B

Ketoconazole

Histoplasma capsulatum

Amphotericin B

Ketoconazole

Cryptococcus neoformans

Amphotericin B

Ketoconazole

Mucur species

Amphotericin B

None

Paracoccidioides brasiliensis

Ketoconazole

Amphotericin B

Potassium iodide; amphotericin B

Ketoconazole

Sporothrix schenkii

116


Majid A. K. Lafi

ANTIVIRAL DRUGS with persistent HIV-1 replication despite ongoing therapy retroviral infections. Local injection site reactions are the most common side effects associated with enfuvirtide therapy.

Introduction Viruses are obligatory intracellular parasites with no growth or reproduction in vitro except in some very specialised laboratory techniques. Viruses cannot produce energy (ATP) and protein and are entirely dependent on the host. The process of viral replication includes:

Amantadine Amantadine acts by inhibiting the uncoating of the viral RNA of influenza A within host cells, therefore, preventing its replication. Amantadine is of value in the prophylaxis of infection with influenza A virus. It stimulates the CNS and can cause convulsion. Amantadine is also used in the treatment of Parkinsonism.

1. Viral penetration into host cells (blocked by enfuvirtide (HIV), γ-globulins, nonspecific) 2. Viral uncoating (blocked by amantadine, influenza A) 3. Early protein synthesis (blocked by fomivirsen, CMV) 4. Nucleic acid synthesis (replication of DNA or RNA, interfered with by purine analogues like acyclovir, pyrimidine analogues like idoxuridine, and reverse transcriptase inhibitors like zidovudine, AZT) 5. Late protein synthesis and processing (interfered with by protease inhibitors like ritonavir) 6. Assembly (maturation) of viral components 7. Release from the cell

Fomivirsen Fomivirsen binds to target mRNA resulting in inhibition of immediate early region 2 protein synthesis, thus inhibiting virus replication. Fomivirsen is injected

intravitreally for the treatment of CMV retinitis in patients with AIDS and is indicated for patients who are intolerant of or unresponsive to alternative therapies. Iritis and vitreitis as well as increased intraocular pressure and changes in vision are associated with fomivirsen therapy.

Attempts to find antiviral drugs have been very successful and their use is complicated as the virus reaches a peak titre before symptoms are observed. Therefore, a drug used to prevent viral replication is best used prophylactically rather than left till gross symptoms occur. There are a few agents, mostly in the developmental stage, which show promise of antiviral activity.

Idoxuridine Idoxuridine is a pyrimidine analogue and is preferentially incorporated in viral DNA producing material. It is very toxic and cannot be used systemically. As it is not specific for viral DNA, idoxuridine causes bone marrow depression and leucopenia.

Antiviral Drugs Enfuvirtide

Acyclovir

Enfuvirtide is a fusion inhibitor that blocks entry into the cell by preventing the

Acyclovir is a guanine analogue that is activated within herpes infected cells. Under the influence of virus thymidine kinase acyclovir is converted into active acyclovir triphosphate. This competes with

conformational changes required for the fusion of the viral and cellular membranes. It is useful in combination with other antiretroviral agents in patients 117



deoxyguanosine triphosphate as a substrate for viral DNA blocks replication. It is much more active against herpes DNA polymerase than that of the normal host cell, making it a highly selective antiviral agent.

Didanosine Didanosine is also a reverse transcriptase inhibitor. It may increase CD4+ counts in patients with HIV infection. Adverse effects include pancreatitis and peripheral neuropathy.

Acyclovir is active against herpes simplex virus and to a lesser extent varicella-zoster virus. It has been the drug of first choice for severe infections caused by these viruses. It can be administered topically in the eye, on the skin, orally (though poorly absorbed), or intravenously (slowly). Acyclovir is particularly useful in immunocompromised patients. It has low toxicity.

HIV Protease Inhibitors The process of HIV replication involves the production of protein and also a protease that cleaves the protein into component parts that eventually reassembled into virus particles. Protease inhibitors interfere with this essential process. Protease inhibitors have been shown to reduce viral RNA, increase CD4+ counts and improve survival compared with that observed with placebo. The representative agent of this group is ritonavir.

Famciclovir Famciclovir is similar to acyclovir except that it is well absorbed from the gut. It is a prodrug, converting to penciclovir that has a similar spectrum of activity to that of acyclovir.

Ganciclovir

Others

Ganciclovir is similar to acyclovir in its mode of action but it has a broader antiviral spectrum of activity. It is useful for the treatment of serious cytomegalovirus (CMV) infections in immunocompromised patients. However, it has dose-dependent bone marrow depression effects. Therefore, its use limited to life- or sight-threatening CMV (CMV retinitis) infection in immunocompromised patients.

Tribavirin Tribavirin is an example of antimicrobial agents that are used by inhalation (aerosol or nebulised solution) for respiratory tract infections, to avoid systemic adverse effects. It is a synthetic nucleoside useful for severe respiratory syncytial virus bronchiolitis in infants and children.

Interferons HIV Reverse Transcriptase Inhibitors

Interferons are produced by infected host cells that contain replicating viruses. They appear to protect other cells from attacks not only by the offending virus but also other viruses, irrespective of their nucleic acid composition. Interferons are expensive to produce from human white blood cells but recently have been extracted from clones of bacterial cells obtained by genetic engineering.

Zidovudine Zidovudine (azidothymidine, AZT) is a reverse transcriptase inhibitor, has been shown to prolong the life and wellbeing of patients with human immunodeficiency virus (HIV) infection. HIV replicates by converting its single stranded RNA into double stranded DNA that is incorporated into host DNA (this is the reverse of the normal cellular transcription of nucleic acids).

Interferonα2 is the most commonly used, available as subtype interferon α2a and α2b. These differ in a single amino acid but are therapeutically equivalent. They are used in the treatment of hepatitis B and hepatitis C. 118


Majid A. K. Lafi

immune response against virulent organisms, e.g. influenza, adenovirus, polio, measles, rubella, yellow fever, smallpox.

Viral Vaccines Viral vaccines are composed of killed or attenuated organisms that will induce an

Table 4.10. A summary of drugs of choice for viral infections Organism Herpes Varicella-zoster Chickenpox

Drug of Choice

Acyclovir

Important Remarks Phosphorylated acyclovir (by virus specific thymidine kinase) inhibits DNA polymerase & thus prevents viral DNA formation. Use in immunocompromised (i.v.)

Zoster (shingles)

Acyclovir

In immunocompetent (oral) In immunocompromised (i.v.)

Herpes simplex Ocular keratitis

Acyclovir

(ointment)

Labial (fever blisters)

Acyclovir

(cream and/or oral)

Genital

Acyclovir

(cream and/or oral)

Encephalitis

Acyclovir

(i.v.)

Disseminated

Acyclovir

(i.v.)

Human Deficiency (HIV)

Immuno- Zidovudine Virus Didanosine Ritonavir

Hepatitis B, C or D

Interferon α2a & α2b

Influenza A

Amantadine

Cytomegalovirus (CMV)

Ganciclovir

Respiratory Syncytial Virus Coryza (common cold)

Tribavirin Zinc

Reverse transcriptase inhibitor Reverse transcriptase inhibitor Viral protease inhibitor (Protection of foetuses from becoming infected by the virus in HIV-infected pregnant mothers) 1. Induces enzymes that degrade viral RNA (in uninfected cells) 2. Indirectly stimulates the immune system Interferes with the uncoating and release of viral genome into host cell. It is useful for prevention & treatment (debilitated persons) Similar to acyclovir in action, useful in CMVinfected immunocompromised patients; it may produce bone marrow depression. (Inhalational) Lozenges containing duration of symptoms.

119

zinc

shortens

the


Blocked by

enfuvirtide (HIV), γ-globulins (non-specific)


Blocked by amantadine (Influenza A)

Viral uptake Uncoating

Blocked by fomivirsen (CMV)

Early protein synthesis

Host cell

Nucleic acid synthesis

Late protein synthesis & processing Packaging & assembly

Viral release

Fig.4.5. The major sites of action of antiviral agents

120

Blocked by purine analogues (acyclovir), pyrimidine analogues (idoxuridine), & reverse transcriptase inhibitors (zidovudine, AZT) Blocked by protease inhibitors (ritonavir, HIV)


Majid A. K. Lafi

ANTIPARASITIC DRUGS

Table 4.11. Drugs of choice for treatment and prevention of malaria

Plasmodial strain P vivax P falciparum (chloroquinesensitive) P falciparum (chloroquineresistant)

Drugs of choice for Prevention of relapse Primaquine* NA**

Treatment of acute attack Chloroquine Chloroquine

Quinine plus pyrimethamine/ sulfadoxine or tetracycline; or i.v. quinine infusion

NA

Prophylaxis Chloroquine Chloroquine

Chloroquine plus pyrimethamine/ sulfadoxine + proguanil; or chloroquine plus doxycycline

* Primaquine is given following control of the acute attack. ** Not applicable, malaria caused by P falciparum does not relapse following successful treatment of the acute attack.

121

Antimicrobial Drugs - Antiparasitic Drugs


Table 4.12. Drugs of choice for protozoal infections

Amoebiasis

Causative protozoan and important remarks Entamoeba histoltyica

Bowel lumen

(to eradicate cyst give)

Disease

Drugs of choice

Diloxanide

Tissue-invading

Metronidazole In severe cases, to lessen the risk of opportunistic infection, perforation, & peritonitis, give

Tetracycline

Treatment of tissue-invading amoebiasis should be followed by a luminal amoebicide to eradicate the source, give

Diloxanide

Giardiasis

Giardia lamblia

Leishmaniasis Visceral

Leishmania species

Metronidazole Tinidazole Primaquine Mepacrine

Resistant cases may benefit from combining antimonials with allopurinol, pentamidine of amphotericin B.

Na stibogluconate Meglumine antimoniate

Cutaneous

Mild lesions heal spontaneously; antimonials or stibogluconate may be injected intralesionally.

Pneumocystosis (HIV-infection)

Pneumocystis carinii

Co-trimoxazole

Intolerant or resistant cases may benefit from

Pentamidine

122


Toxoplasmosis

Trichomoniasis Trypanosomiasis African (Sleeping sickness)

American (Chaga s disease)

Majid A. K. Lafi

Toxoplasma gondii

Pyrimethamine plus sulphonamide; or tetracycline

(Self-limiting, treat immunocompromised or prior to pregnancy) Trichomonas vaginalis

Metronidazole

Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense For early phase For later phase

Pentamidine, suramin Melarsoprol

Trypanosoma cruzi

Nifurtimox

Table 4.13. Drugs of choice for parasitic worms Worm Class Nematodes (round worms) Intestinal

(In immunocompromised ) Cestodes (Tapeworms) Trematodes (Flukes) Hydatid cysts (when surgery is contraindicated or when cysts rupture or spill during surgery)

Common Name Pinworm

Official Name Enterobius vermicularis

Drug of Choice Pyrantel pamoate; Mebendazole; Piperazine

Giant round worm

Ascaris lumbricoides

Mebendazole; Pyrantel pamoate; Piperazine citrate; Levamisole

Hookworm

Ancylostoma duodenale

Bephenium; Mebendazole; Pyrantel pamoate

Threadworm

Strongyloides stercoralis

Thiabendazole

Beef tapeworm Pork tapeworm Blood flukes Intestinal Urinary

Schistosoma species mansoni & japonicum haematobium Echinococcus granulosus

123

Niclosamide; Praziquantel Praziquantel

Albendazole & mebendazole or praziquantel



CNS-PHARMACOLOGY (GENERAL PRINCIPLES) potential by increasing Na+ permeability of the cell membrane (decreasing negativity inside the cell resulting in reduced value as measured by -mV). An IPSP lowers the resting membrane potential (hyperpolarisation) by increasing Cl- influx (increasing negativity inside the cell and thus increased value as measured by mV).

Introduction The resting membrane potential of the neurone in the CNS is about (-70 mV). The neurone can be affected by excitatory or inhibitory actions which give rise to an excitatory postsynaptic potential (EPSP) or an inhibitory postsynaptic potential (IPSP). An EPSP raises the resting membrane

Benzodiazepines Barbiturates Valproic acid Vigabatrin

Lamotrigine

Inhibitory neurone

Excitatory neurone

mV 0

Ethosuximide Carbamazepine Phenytoin

Action potential

Threshold potential

-60 EPSP

EPSP Resting potential

-70 IPSP Hyperpolarisation

Fig. 5.1. A simplified representation of polysynapses in the CNS showing excitatory and inhibitory neurones modulating the excitability of a primary neurone. The excitatory transmitter (e.g. glutamate) produces EPSP (excitatory postsynaptic potential) which may raise the resting potential high enough to reach the threshold and then fire an action potential. While, inhibitory transmitters (e.g. GABA) produces IPSP (inhibitory postsynaptic potential) which lowers the resting potential making it at a distance from the threshold potential (hyperpolarisation); therefore, reducing the possibility of firing action potential.

124


Majid A. K. Lafi

Transmission of electrical impulses in the neurones of the CNS mainly takes place by the action of chemical transmitter substances, neurotransmitters, which are released from presynaptic nerve endings and act on

postsynaptic membranes. In addition to distinctly released neurotransmitters there are a number of putative (suggested) neurotransmitters and neuromodulators with more diffuse actions.

Table 5.1. A summary of the possible sites of drug action in the CNS

Mechanism 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Action potential Synthesis Storage Metabolism Release Reuptake Degradation Receptor Conductance Second messenger

Drug

Specific Drug Actions

Blocks action potential Synthesis of false transmitter Depletes transmitters Blocks amine breakdown Reduces transmitter release Increase transmitter availability Blocks acetylcholinesterase Blocks postsynaptic effects Hyperpolarisation Blocks phosphodiesterase

Catecholamines

Besides the principle actions of drugs on various mechanisms, many drugs are employed because they have a specific action on one of the functions in the CNS. There are essentially three different anatomical sites in the brain to which specific function can be assigned ( Table 5.2.). There is a complex range of interrelationships, e.g. the locus caeruleus interconnects the reticular formation, hypothalamus and cortex.

The CNS contains separate neuronal systems that involve catecholamines like dopamine, noradrenaline, and adrenaline. Each system is anatomically distinct and serves separate functions.

Serotonin Serotonin (5-hydroxytryptamine, 5HT) is the chemical transmitter in the tryptaminergic systems that are found mainly in the pons and upper brain stem.

Table 5.2. An overview of the functional organisation of the brain Site Cerebral cortex Limbic system Brain stem

Action

Tetrodotoxin Methyldopa Reserpine MAO-inhibitor Ca-antagonist Cocaine Tacrine Phenothiazines Benzodiazepine Methylxanthines

Functions Motor, sensory, thought

Peptides A large number of neuromodulatory peptides have been identified as endorphinpeptides. These peptides share actions that originally were ascribed to opioids.

Emotions, visceral control Wakefulness, vasomotor & respiratory control

Other peptides: vasoactive intestinal peptide (VIP), glucagon, substance P. These substances are synthesised in the rough endoplasmic reticulum of the nerve cell body as a propeptide that is cleaved into its active form and stored in secretory vesicles.

Acetylcholine Acetylcholine (ACh) is a central neurotransmitter acting with a mixture of nicotinic and muscarinic receptors. 125



Apparently, there is no reuptake mechanism for peptides.

GABA

It is now well established that a neurone may synthesise and release one or more than one neurotransmitter (cotransmission). This is particularly true for neuropeptides.

GABA (gamma-aminobutyric acid) mediates inhibitory actions on local interneurones. Benzodiazepines potentiate the effect of GABA by interacting with GABA-receptor complex (Fig. 5.2).

Glucose

Glutamic acid

GABA vesicle

GABA

BNZ

GABA

Barbiturate -

Cl

Postsynaptic membrane -

Cl channel Fig. 5.2. A simplified schematic representation of synthesis, storage, and release of GABA from GABAergic neurone. When released GABA acts postsynaptically on a specific site that located on GABA receptor complex enhancing entry of Cl- through Cl- channel. Note: Benzodiazepines and barbiturates act allosterically on specific sites located nearby the GABA site on the GABA receptor complex to enhance the action of GABA.

126


Majid A. K. Lafi

glutamate receptor complex to enhance the excitatory effect of glutamate (Fig. 5.3).

Glycine Glycine is another amino acid with inhibitory action (increases Cl- conductance and results in hyperpolarisation) in the spinal cord. However, glycine acts allosterically on

so-called acidic amino acid receptors, glutamate receptor system , causing dislodging of Mg++ and letting Na+ and Ca++ enter, and K+ leave the cell. Glycine can also bind to this receptor system allosterically enhancing the action of glutamate and aspartate (Fig. 5.3.).

Glutamate and Aspartate Glutamate and aspartate are excitatory neuromodulators act on specific sites on the

Glycine (allosteric)

Glutamate

Agonist (NMDA +

Na ++ Ca

++

Mg Postsynaptic membrane

+

K

Fig. 5.3. A simplified schematic representation of acidic amino acid receptor system. Glutamate or aspartate (or N-methyl-D-aspartate, NMDA) can activate the ligand specific site on the receptor system leading to deployment of Mg++ and letting Na+ and Ca++ enter, and K+ leaves the cell. Allosterically, glycine enhances the action of the acidic amino acids. Mg++ ions block the channel in the resting state. Depolarisation by ligand or voltage gating dislodging Mg++. Glycine enhances the action of glutamate to open the channel.

127



Table 5.3. A summary of selected central transmitters and neuromodulators, their functions, agonists and antagonists

Transmitter

Site

Function Dysfunction

Receptor Agonists

Antagonists

Mechanism

Motor control: Nicotinic stimulation Memory: Muscarinic stimulation ↓ : Alzheimer s disease ↑ (relative): Parkinsonism

Nicotine

Dihydro-βerythroidine

Muscarine

Atropine

Muscarine

Atropine

Excitatory: ↑ cation conductance. Excitatory: ↓ K+ conductance; ↑ IP3, DAG Inhibitory: ↑ K+ conductance, ↓ cAMP

Substantia nigra Substantia nigra Pituitary gland Mesolimbic system Mesolimbic system Mesocortical system

↓ : Parkinsonism ↑ : Chorea

D1: SKF 38393

Phenothiazines SCH 23390

(Inhibitory): ↑ cAMP

D2: quinpirole

Phenothiazines Butyrophenones

Inhibitory (presynaptic): ↓ Ca2+ (postsynaptic):↑ K+ conductance, ↓ cAMP.

( (

↓ : Depression ↓:Obsessive-compulsive

5HT1A: LSD

Metergoline Spiperone

Inhibitory: ↑ K+ conductance, ↓ cAMP

5HT2A: LSD

Ketanserine


5HT3: 2-methyl-5HT Phenylbiguanide

Ondansetrone

Excitatory: ↑ cation conductance

Prazosin


Yohimbine

Inhibitory (presynaptic): ↓ Ca2+ conductance. Inhibitory:↑ K+ efflux;↓ cAMP

Spinal cord CNS cortex

Basal ganglia

) )

Amygdala Hypothalamus Pons (raphe nuclei) Mesolimbic system

Locus caeruleus & diffuse terminals to hypothalamus & cortex

↓ : Hyperprolactinaemia ↑ : Schizophrenia ↑ : Arousal ↓ : Negative symptoms

disorder ↑ : Anxiety ↑ : Decreased appetite ↑ : Sleep ↑ : Arousal*

Arousal, mood ↓ : Depression ↑ : Mania Decrease in pressure by stimulation

(α1): Phenylephrine

blood α2 -

128

(α2): Clonidine


TransSite mitter GABA Basal ganglia

Majid A. K. Lafi

Function Dysfunction ↓ : Huntington s disease

Most inhibitory ↓ : Convulsions interneurones Amygdala

↓ : Anxiety

Glycine Spinal interneurones & Inhibitory some brain stem interneurones Relay neurones at all levels

Excitatory

Receptor Agonists

Antagonists

Type A: Muscimol

Bicuculline,

Type B: Baclofen

2-OH saclofen

Taurine

Strychnine

Ionotropic

2-Amino5phosphonovalerate

N-Methyl-Daspartate (NMDA): NMDA

picrotoxin

Metabotropic

Hypothalamus & diffuse terminals to all parts of the brain

Endings of primary afferent neurones Pain transmission (ascending) pathways Primary afferents Spinal cord Thalamus Pain inhibiting (modulating, descending) pathways Midbrain Medulla

Arousal

Nociception (algesia, tachykinins)

Antinociception (analgesia, opioid peptides)

: quisqualate

MCPG

H1: 2(m-Fphenyl) histamine H2: Dimaprit

Mepyramine

NK1:

CP99994

Ranitidine

Substance P Methylester

µ (Mu): ¾-Endorphin δ (Delta): Enkephalins

κ (Kappa): Dynorphin

Naloxone Naloxone Naloxone

Mechanism Inhibitory: conductance.

↑

Inhibitory (presynaptic): ↓ Ca2+ Inhibitory (postsynaptic):↑ in K+ conductance. Inhibitory: ↑ Clconductance Excitatory: ↑ cation conductance, (Ca2+).

Inhibitory (presynaptic): ↓ Ca2+ Conductance; ↓ cAMP. Excitatory: ↓ K+ conductance, ↑ IP3, DAG. Excitatory: ↓ K+ conductance; ↑ IP3, DAG Excitatory: ↓ K+ conductance; ↑ cAMP Excitatory: ↓ K+ conductance, ↑ IP3, DAG

Inhibitory (presynaptic): ↓ Ca2+ conductance, ↓ cAMP Inhibitory (postynaptic): ↑ K+ conductance, ↓ cAMP

NA: Noradrenaline; DA: Dopamine; 5HT: 5-hydroxytryptamine (serotonin); ACh: Acetylcholine; GABA: Gamma aminobutyric acid; ↓: Deficiency; ↑: Access. * Fluoxetine (5HT reuptake inhibitor) may produce arousal, insomnia, and reduced appetite. MCPG: α-methyl-4-carboxyphenylglycine NK: Neurokinin

129

Cl-



Table 5.4. A summary of the targets for selected centrally acting drugs Cellular Target

Drug Group/Drug

Membrane lipid Cyclooxygenase Voltage-dependent sodium channel Voltage-dependent sodium channel L-type voltage-dependent calcium channel

General anaesthetic drugs NSAIDs Local anaesthetics Phenytoin, carbamazepine Calcium channel blockers

Opioid receptors Opioid receptors GABA receptor complex GABA receptor complex GABA receptor complex GABA transaminase

Opioid analgesics Opioid antagonists Benzodiazepines (BNZ) Flumazenil ( BNZ-receptor antagonist) Barbiturates Sodium valproate

Acetylcholinesterase Adrenergic receptors Adrenergic receptors

Tacrine Clonidine (α2-agonist) Mianserin (tetracyclic antidepressant, α2antagonist?) Lecithin (ACh precursor) Antihistamine

Cholinoceptors Histamine receptors Dopamine receptors Adenosine receptors Monoamine oxidase

Antipsychotic drugs Caffeine Phenelzine, tranylcypromine, isocarboxazid & deprenyl L-DOPA L-tryptophan

Dopamine synthesis Serotonin synthesis Noradrenaline reuptake Serotonin reuptake

Viloxazine (bicyclic antidepressant) Clomipramine (tricyclic antidepressant) & fluoxetine Amantadine Lithium

Dopamine reuptake Phosphatidylinositol bisphosphate (PIP2) breakdown cAMP breakdown

Caffeine

130


Majid A. K. Lafi

ANTIPSYCHOTIC DRUGS other evidence has lead to the development of the dopamine theory of schizophrenia.

Introduction Antipsychotics are usually employed for the treatment of major psychoses such as schizophrenia. The term neuroleptic is often used for antipsychosis. They cause psychomotor slowing, emotional quietening and in higher doses, psychic indifference to the environment. It may have a sedative effect but it is not a hypnotic.

It has been known that the sympathomimetic drug amphetamine produces a psychosis rather similar to paranoid schizophrenia and this effect was shown to be related to increased release of dopamine and that he effects of this can be reduced by dopamine receptors blockade. Further experimental work suggested that in schizophrenia the dopaminergic neurone is in fact working normally and from post mortem receptors binding studies on human schizophrenia brain tissues that the density of dopamine receptors is higher than normal. In addition, there is a positive relationship between the receptor blocking activity of antipsychotic agents and their clinical effectiveness.

One of the first drugs to be used for its antipsychotic properties was reserpine (Rauwolfia alkaloid), which also reduces blood pressure. It is no longer used, partly because more effective drugs have been developed and partly because reserpine has serious side effects including the production of depressive conditions and suicidal tendencies. The central pharmacological actions of reserpine are due to the disruption of noradrenaline and dopamine storage sites in nerve terminals leading to reduced-release of these neurotransmitters.

Normally there is a balance of dopamine in the limbic system and the substantia nigra. An increased dopaminergic activity in the former gives rise to active schizophrenia and a decrease in the latter gives rise to extrapyramidal symptoms such as Parkinson s disease (Fig.5.4).

A variety of drugs are currently used in the treatment of schizophrenia, which is characterised by added features to personality known, as positive symptoms like: • Hallucination (e.g visual, olfactory and auditory) • Delusions (false unshakable belief of morbid origin not consistent with the patient s social, cultural and educational background) • Thought disorders (organisation, stream of thought; content of thought, such that it drifts away from the point)

There is a long list of antipsychotics of different groups. Within the scope of the objectives of this chapter, it is not possible to go through the pharmacology of each drug separately. Therefore, it is decided to present the essential details in Table 5.6.

Indications of antipsychotics 1. Treatment of acute and chronic schizophrenia 2. Prophylaxis of schizophrenia 3. Treatment and prophylaxis of mania 4. Psychotic depression (depression with psychotic symptoms) 5. Other psychoses (e.g. paranoid psychosis, morbid jealousy, erotomania) 6. Anxiety 7. Organic psychoses (delirium, dementia including Alzheimer s psychotic features)

Schizophrenia may also be characterised by absence of features of personality known, as negative symptoms like: • Apathy (lack of feeling or emotion; indifference) • Being withdrawn (retreat from external reality; reduced ability to relate to people) All of these drugs have in common the ability to block central dopamine receptors. This and 131



8. Movements disorders (Huntington s chorea, Sydenham s chorea, tics, stuttering) 9. Anorexia nervosa 10.Management of aggressive people (therapeutic restraining, chlorpromazine) 11.Personality disorder (very touchy person, small doses of antipsychotics) 12.Irritable bowel syndrome (trifluoperazine) 13.Peptic ulcer (sulpiride) Vomiting (prochlorperazine) 14.Intractable hiccup (chlorpromazine) 15.Neuroleptanalgesia (droperidol + Fentanyl) 16.Chronic pain (chlorpromazine + fentanyl) 17.Hypertensive crisis of MAO inhibitors (cheese effect)

12.Poikelothermia (disturbance in the setpoint, hypothermia and hyperthermia) 13.Eye (cornea: opacity; retina: pigmentation) 14.Iris (miosis: thioridazine; chlorpromazine: mydriasis)

Onset of Action Generally, the antipsychotic effects of neuroleptics, in the presence of adequate dosages and serum drug concentrations, take several weeks or longer to appear. This delay may be due to an inhibition of presynaptic (autoregulatory) dopamine receptors by neuroleptics leading to an enhanced release of dopamine that counteracts the postsynaptic receptor blockade. As tolerance develops to this autoregulatory receptor phenomenon, postsynaptic blockade becomes more effective. This probably also explains why only a few Parkinsonian-like side effects appear acutely in normal or psychotic subjects given neuroleptics.

Adverse effects 1. Acute dystonic reactions (use anticholinergic, e.g. benzhexol; diphenhydramine; diazepam) 2. Parkinson s syndrome 3. Akathisia (motor restlessness, severe sense of agitation), use less potent antipsychotics, β-blockers, or a benzodiazepine 4. Tardive dyskinesia (oral-facial involuntary movements, 10-30%), no satisfactory treatment 5. Anticholinergic (e.g. glaucoma, dry mouth, urinary retention, confusion in the elderly) 6. Endocrine (e.g. hyperprolactinaemia, gynaecomastia, galactorrhoea, amenorrhoea, erectile impotence) 7. Postural hypotension (α-antagonist activity) 8. Sedation (antihistamine effect) 9. Neuroleptic malignant syndrome (hyperpyrexia, disturbed consciousness, muscular rigidity, myoglobinaemia, use dantrolene, bromocriptine) 10.Proconvulsant (lower seizure threshold, particularly phenothiazines) 11.Cardiotoxicity (quinidine-like activity)

132

However, antipsychotics have rapid onset of actions for the following indications: severe anxiety, acute mania, acute psychotic states (for sedation and restraining), intractable hiccup. Note: Antipsychotics are used as therapeutic restraints in severe schizophrenia (to restrain aggressive over-excited persons) by an effect on the basal ganglia leading to generalised dystonia. For this purpose, usually a large dose and potent agent is required (e.g. fluphenazine, or chlorpromazine).


Majid A. K. Lafi

Parkinsonism Hypokinesia Dystonic syndrome Hyperprolactinaemia

Schizophrenia Dyskineasia-Chorea Tardive dyskinesia Nausea

Dopamine

Dopamine

Fig. 5.4. A simplified representation of dopamine balance in the CNS with the possible clinical consequences. If the balance is tilted in favour of dopamine then CNS disorders like schizophrenia, dyskinesia-chorea, and tardive dyskinesia may be produced; however, if the balance tilted against dopamine then CNS disorders like Parkinsonism and dystonic syndromes.

Table 5.5. Antipsychotics may produce the following extrapyramidal reactions, range of onset time and features are also listed.

Reaction Acute dystonia

Onset Hours to 5 days

Parkinsonism

5

30 days

Akathesia

5

60 days

Tarditive dyskinesia

Months to years

Features Spasm of tongue, neck, face & back Tremor, shuffling gait, drooling, stooped posture, instability Compulsive, repetitive motions; agitation Lip-smacking, worm-like tongue movement, fly-catching

133



Table 5.6. A summary of selected antipsychotics used in schizophrenia and related disorders Antipsychotics

Adverse Effects

Remarks about Uses

(mg)

Phenothiazines Chlorpromazine (Largactil) Fluphenazine (Modecate) Trifluoperazine (Stelazine)

100

+++

++

++

++

Useful in violent patients Severe anxiety (short term) Intractable hiccup Antiemetic

+

Maintenance therapy Therapeutic restraining

2

++

+++

+

5

+

+++

+

100

++

+

+++

++

useful in elderly due to low incidence of EP effects

2

+

+++

+

+

Rapid control of acute mania & other psychoses

2

+

+++

+

+

Neuroleptanalgesia

Pimozide

2

+

+

+

+

Thioxanthenes Flupenthixol

3

++

+++

+

++

Benzamides Sulpiride

50

-

+

+

+

100

+++

+

+++

+++

5

++

-

++

1

+

+

+

Thioridazine (Melleril) Butyrophenone Haloperidol (Serenace) Droperidol

Dibenzodiazepine

Clozapine* Theinobenzodiazepine

Olanzapine Benzisoxide Risperidone**

+

++

Retarded schizophrenia (-ve symptoms)

Retarded & monodelusional disorders (e.g. paranoid) Apathetic & withdrawn patients Avoid in manic or hyperactive patients Useful in ve symptoms Useful in resistant schizophrenia, lower seizure threshold, (may cause agranulocytosis, 1-2%) Useful in mania, Less incidence of blood dyscrasia Useful in ve symptoms

* Clozapine is a selective D4 receptor antagonist. ** Risperidone is an antagonist at both D2 and 5HT 2 receptors.

Note: A general rule the more potent antipsychotic drug is expected to produce more EP effects, with less anticholinergic and less sedative actions.

134


Majid A. K. Lafi

DRUGS FOR AFFECTIVE DISORDERS

inhibition of biogenic amine reuptake or degradation, in isolation, can correct the fundamental biochemical abnormalities of depression. It has been hypothesised that antidepressants increase the efficiency of transmission through 5HT and/or noradrenaline pathways but by different molecular mechanism.

Antidepressants Affective (mood) disorders are characterised by severe disturbance of mood and range from depression (unipolar affective disorder) to manic-depressive illness (bipolar affective disorder). These disorders are associated with multiple derangements of normal biological processes, neuroendocrine circadian rhythms. In severe forms, patients develop psychotic symptoms and become detached from reality, thus, these disorders represent extreme expressions (depression and manicdepressive states) of otherwise normal emotional swings, suggesting major alterations in normal biological function (Fig.5.5).

There are two major isoenzymes of MAO: types A and B. A is selectively inhibited by clorgyline and primarily degrades 5HT. B is selectively inhibited by deprenyl (used as protective therapy in Parkinson s disease) primarily degrades dopamine. The available MAO inhibitors used for treating depression are relatively nonselective for A or B isoenzymes. It has been proposed that MAO inhibitors (type A only) produce an improvement in transmission of 5HT pathways.

Typical Symptoms of Depression Depression is characterised by: • Sadness • Anhedonia (loss of interest pleasure in activities) • Crying spells • Emotional liability • Feeling of guilt • Worthlessness and hopelessness

There is a delay in onset of antidepressant effect (7-21 days). This delay may represent the time required to overcome compensatory mechanism. Hence, the initial increase in neurotransmission appears to produce, over time, a compensatory decrease in receptor activity (down-regulation of receptors). Antidepressants like selective noradrenaline reuptake inhibitors, those with mixed action on noradrenaline and 5HT.

and

Depression requiring medical treatment, is usually associated with biological abnormalities (vegetative signs, which include decreased appetite, weight loss, GI disturbances, fatigue, difficulty in concentrating, early morning awakening, and loss of libido. It is well recognised that depression may impair the immune system and may lead to increased susceptibility to infection and risk of cancer.

Tricyclic Antidepressants (TCAs) and Related Compounds These drugs are generally believed to produce their antidepressant activity by virtue of their ability to block the neuronal amine (5HT and noradrenaline) reuptake. This in turn may lead to enhanced availability of the amines in synaptic junctions, and thus, facilitates aminergic neurotransmission (i.e. correction of the disturbed balance of amines).

Two major groups of antidepressant drugs (tricyclic and related monoamine reuptake inhibiting compounds and MAO-A inhibitors) are used in the treatment of depression. No single biochemical effect can explain the mechanism of action of these antidepressant drugs. It is unlikely that

There is a long list of TCAs and related compounds and going through a detailed pharmacology of each drug is beyond the 135


scope of this volume. Therefore, it is decided to present a summary of the pharmacology of these agents in Table 5.8 and Table 5.9.


7. 8. 9. 10. 11. 12.

Indications 1. Depression (unipolar, bipolar and reactive depression) 2. Prophylaxis of depression (seasonal depression) 3. Obsessive-compulsive disorder (clomipramine, fluoxetine) 4. Phobias (an unusual or morbid fear from a condition, e.g. agoraphobia, clomipramine) 5. Anxiety (superior to diazepam because no risk of addiction, suitable for long term therapy, amitriptyline) 6. Nocturnal enuresis

13. 14. 15. 16.

Premature ejaculation Neurogenic pain Chronic pain (in cancer) Peripheral neuropathy Migraine headache Rumination disorder (in man , the regurgitation of food after almost every meal, part of it being vomited and the rest swallowed; a condition seen in infants) Attention deficit (hyperkinetic) disorder (hyperactive child) Alcoholism (as secondary to depression) Eating disorders (bulimia nervosa, fluoxetine) Sleep disorders (narcolepsy, imipramine; hypersomnia, imipramine)

Depression Mania

Amines

Amines

Fig.5.5. A simplified representation the Amine Hypothesis that proposes depression is somehow associated with underactivity of functional amine (5HT and noradrenaline)-dependent neurotransmission. While, mania may be explained by overactivity of amine-dependent neurotransmission. Note: Much of the evidence for the amine hypothesis of depression was available in the early 1950s when reserpine was used in the treatment of hypertension and schizophrenia. In hypertensive and schizophrenic patients as well as normal subjects, reserpine could produce depression and suicidal tendency that were major problems with reserpine. Reserpine interferes with aminergic neurotransmission by inhibiting the vesicular storage of amines like 5HT and noradrenaline, consequently, reducing release and hence synaptic availability of the biogenic amine neurotransmitters.

136


Selective Serotinin Inhibitors (SSRIs)

Majid A. K. Lafi

Reuptake

MAO inhibitors lie in two major groups: Irreversible MAO Inhibitors

The tricyclic antidepressant clomipramine is to certain extent selective amine reuptake inhibitor for serotonin (5HT) than noradrenaline. In recent years, a new group of drugs has emerged which characterised to be selective for serotonin reuptake. This group includes fluoxetine, paroxetine and sertraline. So there is no substantial evidence that this group provides a greater therapeutic efficacy than the older drugs. However, the SSRIs offer an advantage of their lack of antimuscarinic adverse effects.

1. Hydrazine • Phenelzine (Nardil) • Isocarboxazid (Marplan) (Leg oedema and hepatitis as adverse effects) 2. Non-hydrazine • Tranylcypromine (Parnate) (Insomnia, and addiction as adverse effects) Reversible MAO Inhibitors Moclobamide is a reversible inhibitor of MAO-A. Therefore, as tyramine is metabolised by both forms of MAO, if tyramine-containing food is consumed, tyramine is metabolised by MAO-B enzymes as well as being able to reverse the inhibition of MAO-A. Unless very large quantities of tyramine are ingested, this appears to prevent the typical hypertensive reaction seen with conventional MAOIs and tyraminecontaining foods.

A selected list of adverse effects and the possible mode of action for the TCAs and other antidepressants are presented in Table 5.9.

MAO Inhibitors MAO inhibitors were the first to be found to have antidepressant action. In 1951, iproniazid, which was then used as antituberculosis drug, was observed to elevate mood. This effect was attributed to the ability of the drug to inhibit the enzyme monoamine oxidase (MAO). The termination of the synaptic action of monoamines, such as 5HT and noradrenaline, is primarily achieved by neuronal amine-reuptake pump and the activity of MAO located intraneurally. Upon blocking MAO, the vesicular storage and consequently release and synaptic availability of the monoamine neurotransmitter is increased. In fact, this is the opposite to what happens with reserpine that reduces monoamine vesicular storage and consequently reduces release of the amine transmitter. Hence, depression may be associated with the use of reserpine.

Indications for MAO Inhibitors They have no superiority to TCAs or related agents. However, it has been suggested that MAO inhibitors may be more effective in reactive and atypical depression. Onset of action occurs in 1 to 2 weeks and persists as long as 2 to 3 weeks after stopping the treatment. A summary of the adverse effects and their possible mode of action for MAO inhibitors is presented in Table 5.7.

137



Table 5.7. A summary of the following adverse effects, the possible mode of action of MAO inhibitors Adverse effects Possible Mode of Action Hypertensive crisis (cheese Inhibit the metabolism of dietary tyramine leading to effect) enhanced systemic tyramine that causes the release of endogenous neural noradrenaline resulting in enhanced vascular α-receptor activity. Therefore, patients must carry a card stating details of treatment. Hypotension Sympathetic ganglionic block Others similar to that of TCAs •

MAOIs have anxiolytic properties; they are considered as second line drugs

CAUTION: Concomitant use of MAO inhibitors and tricyclic antidepressants may result in mutual enhancement of effects with possibility of hyperpyrexia, hypertension, seizure and death.

Antimanic Drugs

Lithium

Mania is characterised by elevated, expansive or irritable mood, accelerated speech, racing thoughts with flight of ideas, increased activity and reduced sleep. Patients may develop grandiose ideas, act recklessly with overspending, and show increased sexual drive and activity. Impaired judgement (lack of insight) is usually associated with the illness; therefore, the patient and his family should be protected by hospitalisation of the patient.

Patients with mania are at risk of physiological exhaustion and require special attention to nutrition, hydration, and rest. Lithium carbonate and a neuroleptic (or a sedative-hypnotic like diazepam) should be initiated. The additional tranquilliser is necessary because the onset of the antimanic effect of lithium is usually delayed. Further, patients with bipolar disease usually require maintenance therapy with lithium to prevent relapse into mania or depression. Those who do not respond to lithium respond to carbamazepine or sodium valproate (see antiepileptic drugs).

The antipsychotic drugs, lithium and benzodiazepines all are important in the management of mania. Antipsychotics (e.g. chlorpromazine, haloperidol) are preferred to control the acute stages; if more sedation is desired (particularly when using haloperidol) then add a benzodiazepine (e.g. diazepam). Lithium is initiated, as it is the drug of choice for long-term use to prevent relapse of manic attacks, i.e. prophylactic use.

It has been suggested that lithium produces its antimanic activity at least in part by virtue of inhibition of hydrolysis of phosphatidylinositol bisphosphate leading to reduced production of the second messenger diacylglycerol (DAG).

Adverse Effects 1. GI disturbances vomiting, diarrhoea)

138

(nausea,


Majid A. K. Lafi

2. Nontoxic goitre (hypothyroidism, inhibits iodine uptake and thyroid hormone release, affecting 5-15% of patients on long term treatment1) 3. Polyuria 4. Diabetes insipidus 5. Renal tubular impairment (failure to concentrate urine after fluid deprivation and failure to acidify urine after ingestion of ammonium chloride) 6. Leucocytosis 7. CNS toxic encephalopathy (may lead to coma)

Interactions 1. With thiazide that increases lithium renal distal tubular reabsorption leading to lithium toxicity. Note: Lithium exhibits a low therapeutic index, and haemodialysis is indicated in toxicity (apparent volume of distribution is 55 litre). 1

Walker, R. and Edwards, C. (1999) Clinical Pharmacy and Therapeutics. 2nd edition, Page 616.

139



Table 5.8. A summary of tricyclic antidepressants and related compounds, and other antidepressants Drug

Class

Important Remarks WITH SEDATIVE ACTION (useful in depression associated with agitation, or anxiety, and insomnia)

Amitriptyline (Tryptizol)

Tricyclic

More cardiotoxic (sudden death) than others Useful in nocturnal enuresis and anxiety

Dothiepin (Prothiaden)

Tri-

Most widely prescribed in the U.K. Improved adverse effects profile

Mianserin

Tetra-

α2-receptor antagonist (↑ release of transmitter1) Less cardiac risk ; (it does not affect amine reuptake)

Trazodone2

Other

Probably as for mianserin?

Trimipramine (Surmontil)

TriWITH MINIMAL SEDATIVE ACTION (useful in depression associated with retardation, hypersomnia)

Clomipramine (Anafranil) Fluoxetine (Prozac )

Tri-

5HT reuptake inhibitor Useful in obsessive-compulsive patients

SSRI

Selective 5HT reuptake inhibitor Useful in obsessive-compulsive patients

Imipramine (Tofranil) Maprotiline (Ludiomil)

Tri-


Tetra-

Proconvulsant activity (fit) Useful in heart disease

Nortriptyline (Aventyl)

Tri-


Viloxazine

Bi-

Noradrenaline reuptake inhibitor

Flupenthixol

Thioxanthene

Antidepressant neuroleptic

α2-adrenoceptors generally mediate inhibition on the excitability of neurones and therefore reducing transmitter release. These receptors are termed autoreceptors (or presynaptic receptors) when inhibited by α2-receptor antagonists like mianserin and probably trazodone the release of neurotransmitter is enhanced (inhibiting inhibitory mechanism). 2 Trazodone may produce priapism and may decrease appetite as adverse effects. Therefore, its use is largely restricted to female patients. 1

140


Majid A. K. Lafi

Table 5.9. A summary of adverse effects that may be encountered with the use of TCAs and other antidepressants.

Group/Drug

TCAs

Overdosage with TCAs & other antidepressants

Mode of Action

Adverse Effects

Muscarinic antagonism (especially amitriptyline, thus, avoid in the elderly, prostatism, narrow angle glaucoma) promoting sympathetic noradrenergic transmission by reuptake inhibition; while muscarinic antagonism may cause dryness in the axilla and groin regions. H1-receptor antagonism (especially doxepine, tolerance develops) ¿1-receptor antagonism3 (thus, useful in premature ejaculation) Increased catecholamine activity (cardiac overstimulation) ( Sympathomimetic) Quinidine-like action (unrelated to receptor antagonism)

Dry mouth, blurred vision, glaucoma, constipation, delayed bladder emptying, and confusion

Lowering seizure threshold in epileptic patients Shift of mood from depression to hypomania in bipolar illness Deriving from anticholinergic toxicity

Trazodone

Quinidine-like action α2-receptor antagonist (↑ release of transmitter)

SSRIs Fluoxetine

↑ synaptic availability of 5HT at certain sites in the CNS

Diaphoresis (excessive apocrine sweating, face, palm & sole, nonthermoregulatory sweating, cold sweat)

Sedation

Orthostatic hypotension Ejaculatory delay Cardiac arrhythmia Adrenergic tremor Cardiac toxicity (most serious adverse effect of TCAs, thus, avoid in patients with conduction defects and heart disease Seizure recurrence Hypomania Dilated seizure

pupil,

fever,

coma,

Cardiac toxicity Sedation, nausea, decreased appetite, priapism ( 1-blocking effect) Arousal, insomnia, decreased appetite

Caution: TCAs in a patient with bipolar illness, usually presenting as depression without history of mania, can precipitate acute mania or rapid cycling.

3

(Frohlich, D. F. (1993) Rypins Basic Science Review, 16th edition, Page 661; Mycek, M. J., Harvey, R. A. & Champe, P. C. (2000) Lippincott s Illustrated Reviews Pharmacology, 2nd edition, Page 121)

141



ANTIANXIETY DRUGS system (affect), the median fore-brain bundle (reward and punishment systems) and hypothalamus.

Introduction Anxiety, fear for no adequate reason, is the most prevalent symptom in mental illnesses, but it also occurs normally and may have adaptive value. Normal anxiety, marked by dissatisfaction, unhappiness, or apprehension, is of short duration and usually event-related (e.g. as a part of the hypoglycaemic alarm, sitting an examination) and not under the subject s control. Normal subjects, under severe stress may experience periods of increased muscle tension, exaggeration of the discomfort of minor aches and pains, irritability, or sadness. There is evidence suggests that pathological anxiety is not an exaggeration of normal anxiety, because of considerable overlap in the symptoms of anxiety disorders and depressive states. However, the treatments of normal anxiety and pathological anxiety involve the same drugs.

Both BNZ and barbiturates modulate GABA type receptor complex resulting in increased chloride channel ion current. Binding of BNZ increase the frequency of chloride channel openings, whereas binding of a barbiturate like pentobarbital prolongs the duration of the chloride channel open time. The sedative, muscle relaxant, or anticonvulsant effects of BNZ show tolerance fairly rapidly upon prolonged usage, where relief of anxiety does not show tolerance. It has been suggested that a type 1 benzodiazepine receptor may be responsible for the anxiolytic actions of these drugs and a type 2 benzodiazepine receptor may be involved in other central actions. Type 3 benzodiazepine receptor has been proposed to be found in peripheral organs, e.g. stomach and heart. Serotonergic (5HT) innervation to the amygdala has been investigated with BNZ treatment which show reduced activity suggesting 5HT activity in the amygdala may be anxiety-promoting, and its interruption by a benzodiazepine drug could explain the antianxiety effect.

In the past, several drugs had been used for the treatment of anxiety; alcohol, opioids, or barbiturates. In the 1950s, meprobamate was introduced as a more selective antianxiety drug, but later it was found to have barbiturate-like actions. In the late 1960s, benzodiazepines were introduced as the first drugs to relieve anxiety without producing sedative effects. Buspirone, a more recent drug, may effectively treat anxiety with fewer side effects. The antianxiety drugs are also known as anxiolytics and have been known as minor tranquillisers (and neuroleptics as major tranquillisers).

Further evidence which lends support for the theory of the involvement of 5HT in promoting anxiety comes from the development of the second-generation antianxiety drugs like buspirone (5HT partial agonist) which affects 5HT mechanisms. Thus, it is conceivable that GABA- and 5HT modulating brain systems are involved, each having greater or lesser control according to the type of anxiety that predominates in a particular patient.

Benzodiazepines The benzodiazepines (BNZ) or barbiturates bind to GABA type A receptor/chloride channel complex (Fig.5.2.). This GABA neurotransmitter-receptor system in the CNS is the major inhibitory biochemical pathway in the mammalian brain, particularly in the amygdala region and spinal cord. BNZ may act chiefly on the brain reticular activating system (reducing sensory input), the limbic

Flumazenil A benzodiazepine receptor competitive antagonist (partial agonist) Flumazenil with a t of 1 hour, therefore, repeated i.v. doses or infusion may be needed in heavily sedated patients. Flumazenil finds use in the termination of agonist (BNZ) effect in 142


Majid A. K. Lafi

conditions like after endoscopies, and diagnosis and treatment of BNZ-overdose.

6. Paradoxical effects (agitation, overactivity, insomnia may be observed in children and elderly)

Inverse Agonists

Benzodiazepines should be avoided with alcohol as additive effects occur. Tolerance occurs with chronic use and there is a crosstolerance within the sedative-hypnotic drugs and also with ethanol. Several days (a week or more) after withdrawal seizures, rebound insomnia, and inhibition of control of aggression (disinhibition of aggression) may occur. Benzodiazepine should be avoided in pregnancy as far as possible as diazepam is known to be teratogenic in mice. A summary of the important pharmacological characteristics of BNZ is presented in Table 5.10.

Substances known as β-carbolines bind to the benzodiazepine receptor causing stimulation, anxiety, increased muscle tone and convulsions. These substances are called inverse agonist. Note: These substances produce their effects not by inhibiting the action of BNZ, rather, they appear to operate a mechanism via a benzodiazepine site that is not already in operation.

Indications for BNZ 1. Anxiety (generalised anxiety disorder, GAD) 2. Panic anxiety disorder (attack form, lasting minutes or hours, with intense fear of eminent death; high dose of BNZ, or alprazolam) 3. Phobias 4. Insomnia (a benzodiazepine with short t , e.g. midazolam, is preferred when there is no anxiety otherwise it may produce rebound anxiety) 5. Muscle relaxant (tetanus, infantile spasm; BNZ, meprobamate, or barbiturate) 6. Epilepsy (status epilepticus, diazepam i.v., lorazepam i.m., thiopental, chlormethiazole; maintenance therapy, clonazepam) 7. Premedication in anaesthesia 8. Before endoscopy (midazolam) 9. Alcohol withdrawal (BNZ, chlormethiazole)

Buspirone Buspirone is a new generation of antianxiety agents. It is believed to produce its effect by its property as a partial 5HT-receptor agonist as explained above. Unlike benzodiazepines, buspirone has no hypnotic, muscle relaxant or antiepileptic effect. The onset of its antianxiety action is delayed for 2 or more weeks. It causes little or no depression on psychomotor function. It does not benefit benzodiazepine withdrawal symptoms.

Barbiturates An account on barbiturates is presented in the following section (Sedatives and Hypnotics) and also in the section on Antiepileptic Drugs.

Adverse Effects

Others

1. Sleepiness (therefore, operating machines should be avoided) 2. Impaired psychomotor function 3. Amnesia 4. Dependence 5. Hangover (delayed drowsiness; a benzodiazepine with short t , e.g. midazolam, is preferred, less hangover particularly in the elderly)

1. ¾-blockers (e.g. propranolol) can be used where there are somatic symptoms like tremor and tachycardia. 2. Antidepressants (e.g. amitriptyline can be useful where there is depression with anxiety) 3. Antipsychotics (for their sedative action, e.g. trifluoperazine)

143



Table 5.10. A summary of the pharmacology of selected benzodiazepines Drug

Anxiolytic Action

Plasma t h

Metabolites (t h)

Alprazolam (Xanax)

16

Inactive

Chlordiazepoxide (Librium)

20

Clobazam (Frisium)

35

Active (42)

Clonazepam (Rivotril)

25

Inactive

Clorazepate (Tranxene )

Prodrug

Nordiazepam (80)

Diazepam (Valium)

43

Nordiazepam (80)

RO LA

Highly lipid soluble so quickly effective (orally), but slowly effective i.m.; short-acting as anticonvulsant i.v. (rectally, in children)

Lorazepam (Ativan)

20

Inactive

IO SA

Slowly absorbed & distributed (lower lipid solubility; thus, slower onset & offset of effect than diazepam & midazolam); quickly effective i.m., used for status epilepticus

Midazolam (Hypnovel)

3

Inactive

RO SA

Injected as adjunct in anaesthesia for endoscopies, dentistry etc; quickly effective i.m; given sublingually in status epilepticus.

Nitrazepam (Mogadon)

30

Inactive

Superseded because of long t , more sedative-hypnotic, abuse potential in Iraq; 1st choice in infantile spasm

Triazolam (Halcion )

3

Active (7)

Amnesia; psychiatric reactions; very rapid oral absorption

Important Remarks Has antidepressant activity; used in panic disorders, agoraphobia

Desmethyldiazepam

[nordiazepam (80)]

IO LA

Steady-state effect for about 3 days; low lipid solubility; slowly effective i.m.; less sedative (good anxiolytic) Used in epilepsy as well as anxiety Broad spectrum antiepileptic; useful in absence and myoclonus In stomach converted by hydrolysis to nordiazepam

Modified from Laurence, D. R., Bennett, P. N., and Brown, M. J. (1997) Clinical Pharmacology, 8th edition, page 318. R: rapid; I: intermediate; O: onset; S: short; L: long; A: action; note these generally apply to the anxiolytic action of these agents. For other actions the classification may be different, e.g. as anticonvulsant diazepam is shorter acting than lorazepam.

144


1.

Majid A. K. Lafi

Lorazepam, when given i.v., diffuses into the CNS more slowly so that the onset (15 min) and offset of effect are smoother compared to that of diazepam and midazolam both are more lipid soluble with rapid onset of action (2 min). Therefore, at sedative dose lorazepam acts longer and may produce more amnesia for which it may be superior to diazepam and midazolam. Lorazepam has a plasma t of 20 h with a single step metabolism (conjugation) suggesting that it is not seriously accumulative. This is probably why it has a substantial capacity to induce dependence and withdrawal of the drug can be troublesome for which diazepam therapy is used. Lorazepam is metabolised by conjugation (inactive metabolites), a process is less influenced by age than is oxidation of other benzodiazepines like diazepam. Cimetidine (hepatic enzyme inhibitor) does not increase plasma concentrations of lorazepam, while it may increase concentrations of diazepam and chlordiazepoxide by as much as 50%. Clonazepam, unlike diazepam, can be effective in the treatment (chronic use) of epilepsy. This is probably with diazepam tolerance to the antiepileptic action develops rapidly.

2.

3.

4.

Long t drugs/metabolites are appropriate for anxiety. Short t drugs/metabolites are appropriate for insomnia.

•

Sedative action: premedication for surgery, dental surgery (with local anaesthetic), cardioversion, endoscopies and anxiety with agitation; sedative action reduces attention; also amnesia is desired. • Hypnotic action: insomnia

145

CNS Pharmacology - Sedative and Hypnotic Drugs


SEDATIVE AND HYPNOTIC DRUGS without adverse effects such as drowsiness and hangover, and with all hypnotics there is a risk of addiction. Finally, there is no hypnotic that gives you physiological sleep as hypnotics usually cut down on the important component rapid eye movement (REM) sleep that should make up 20% of sleeping time.

Introduction To date, the physiology of sleep is still not fully understood. However, several anatomical centres are believed to be involved, as shown in the following schematic diagram (Fig.5.6). In sleep control centres, the important factor is inhibition produced by excitatory inputs that come from two major sources (reticular activating system). Both of which stimulate the reticular formation (wake centre) that in turn inhibits raphe nuclei (sleep centre):

Sedatives and Hypnotics A sedative should reduce anxiety with little or no effect on mental or motor functions. A hypnotic drug induces more marked depression on CNS function than a sedative and this can be achieved with most drugs, simply by increasing the dose. Most of the sedatives and hypnotics give a graded CNS depression, dose-related (Fig.5.7.).

1. Afferent input from sensory nerves (e.g. tactile, visual, auditory) 2. Impulses from the limbic system (e.g. emotions)

Individual sedative-hypnotic drugs differ in their dose-response to the four principle actions (Fig. 5.7.). The steep dose-response curve, for example, for a barbiturate agent would show that sedation, anaesthesia, and undesirable clinical effects (e.g. respiratory depression) fall in a narrow dose range (thus, low therapeutic index). Whereas a benzodiazepine agent would show that sedation, hypnosis, and undesirable clinical effects fall in a wide dose range (thus, a large therapeutic index) that makes the drug attractive as a sedative.

Reticular Activating System The reticular activating system is a network of neurones that extends from the spinal cord through the medulla and pons to the thalamus and hypothalamus. It receives impulses from all parts of the body, evaluates the significance of the impulses, and decides which impulses to transmit to the cerebral cortex. It also excites or inhibits motor nerves that control both reflex and voluntary movement. Stimulation of these neurones produces wakefulness and mental alertness; depression causes sedation and loss of consciousness.

Sedative-hypnotic drugs can be classified into the following chemical groups:

This means that one is able to sleep when one does not suffer pain or other discomfort, moreover it is possible to fall asleep if you are not bothered about distracting feelings from the limbic system. Also other excitatory stimuli from coffee, tea and nicotine must be considered. Hypnotics produce a state similar to physiological sleep in that the patient is rousable by external stimuli while sleep induced by anaesthetics is not rousable by external stimuli.

1. Benzodiazepines 2. Barbiturates 3. Carbamates (meprobamate) 4. Alcohols (ethanol, chloral hydrate) 5. Cyclic ethers (paraldehyde)

Benzodiazepines This class of drugs has been covered in the section on anxiolytics. Benzodiazepines are generally considered superior to barbiturates in that being characterised by:

Thus, before prescribing a sleeping pill, one should exclude other wakeful stimuli. Unfortunately, there is no sleeping pill

1. High therapeutic index 146


A

Majid A. K. Lafi

B

Cortex

Sleep Raphe Nuclei

Limbic System

+ Sensory Input

GABA Raphe Nuclei

-

+

5HT

Sleep Centre NA

Reticular Formation Wake Centre

Locus Caeruleus Nuclei

Fig.5.6. A simplified schematic representation of the sleep centre. Note: Two major stimulatory inputs coming via afferent sensory pathway (e.g tactile, visual and auditory) and input arriving from the limbic system (A). It is believed that in the raphe nuclei (sleep centre) the release of 5HT from serotonergic neurones mediates sleep. The inhibition of these serotonergic neurones by GABAergic (interneurone) activity leading to inhibition of the sleep centre, thus, wakefulness predominates. This probably explains the stimulatory effects (arousal state) of noradrenaline, 5HT, and histamine acting through the (reticular formation) interconnected with the locus caeruleus and then in turn with the sleep centre (B). 5HT in the mesolimbic system is suggested to produce arousal (it inhibits sleep as the case with the SSRI fluoxetine producing arousal and insomnia); while, in raphe nuclei it is suggested to produce sleep.

Coma -

Barbiturates

Anaesthesia -

Benzodiazepines

Hypnosis Sedation Anxiolysis -

Increasing dose Fig.5.7. A graph showing that sedative-hypnotic drugs like barbiturates (e.g. thiopental) exhibit a steep linear dose-response relationship; i.e. the dose required to produce anaesthesia and coma is close to that producing hypnosis. This type of drugs is described as having a low therapeutic index (low safety). On the other hand, drugs like benzodiazepines (e.g. diazepam) exhibit a non-linear dose-response relationship; i.e. the dose required to produce anaesthesia is very much greater than that required to produce sedation and hypnosis. This type of drugs is said to have a high therapeutic index (high safety).

147



Nonbenzodiazepine Hypnotics that Act at the GABAABenzodiazepine Receptor

A list of adverse effects for barbiturates is presented in the section on Antiepileptic Drugs. It would suffice here to mention that barbiturates are characterised by:

Although structurally unrelated to the benzodiazepines, these drugs, represented by zopiclone, zolpidem and zaleplon, act on the same BNZ1 subtype of benzodiazepine receptors; their effects can be blocked by flumazenil, the receptor antagonist. They are largely effective in insomnia, have low tendency for tolerance, rebound insomnia, withdrawal symptoms and abuse potential.

1. Low therapeutic index 2. Risk for addiction

Addiction Addiction is a general term that describes the following clinical conditions that may be observed in a patient taking addictive drug:

Barbiturates

Addiction 1. Compulsion1 to use the drug 2. Using the drug taking the priority to other life activities 3. Symptoms appear upon withdrawal 4. When abstinence2 occurs, reusing the treatment leads to withdrawal symptoms more rapidly. 5. Tolerance leads to take more of the drug (higher dose), hence, withdrawal symptoms are more likely and consequently taking the drug more frequently.

Barbiturates (1903) are derivatives of barbituric acid, which is synthesised from malonic acid and urea. Barbiturates are today mostly used as antiepileptic drugs and for induction of general anaesthesia. They are too toxic to be used as sedatives or hypnotics. Phenobarbital is used as antiepileptic and thiopental for i.v. anaesthesia. Barbiturates exert a general depressant activity on cellular functions (reduce glucose oxidation), depress synaptic transmission by increasing membrane stability and by increasing GABA activity. In the brain, barbiturates predominantly depress the reticular activating system (reticular formation). The long acting phenobarbital (t : 80 hours) is more ionised and less lipid soluble than the ultrashort acting thiopental (initial t : 5 min, terminal t : 11 hr). High lipid solubility makes the drug penetrates the CNS rapidly. After entry into the CNS, thiopental is rapidly redistributed to other parts of the body that is the main reason for their ultrashort action.

Carbamates Meprobamate is a representative of the carbamate group, introduced in 1952. It has anxiolytic-sedative actions, anticonvulsant activity, and central muscle relaxant effect. It has hepatic enzyme induction activity. These days, its use is very much reduced, as this group is largely inferior to the benzodiazepines, and does not have any superiority over barbiturates. In fact, carbamates have a tendency to induce tolerance and dependence after prolonged use, and withdrawal symptoms may be precipitated if their use is terminated abruptly. Generally, its use is restricted in patients who do not respond to benzodiazepines.

Barbiturates rapidly induce tolerance since most of their effectiveness is lost with continued administration over a 2-week period and this explains why patients increase the dose. This makes the patient dependent since withdrawal induces abstinence symptoms. This tolerance depends on a metabolic factor (induction of liver enzymes) and pharmacodynamic factors (biological adaptation, see similar effects for morphine, section on Narcotic Analgesics).

1

An irresistible impulse to perform some act contrary to one s better judgement or will. 2 A refraining from the use of or indulgence in drugs. 148


Majid A. K. Lafi

5. Vomiting (Following oral or i.v. administration, therefore, this action appears to be partly central, besides local gastric irritation. Note: Because the emetic blood alcohol level is below that which induces coma, death from acute alcoholism is rare. When it occurs, it is usually due to suffocation from inhaled vomit.) 6. Hypoglycaemia (Alcohol inhibits gluconeogenesis, particularly, when heavy drinking with a meal that enhanceinsulin response to carbohydrate intake.) 7. Hyperuricaemia: Gout may be precipitated by a. Increased metabolism of adenine nucleotides (e.g. ATP) leading to the production of uric acid. b. At high alcohol level, raised blood lactate compete for renal tubular elimination resulting in reduced excretion of urate 8. Actions on sexual functions: Ethanol produces CNS disinhibition, thus, increasing libido and erection (provokes the desire).

Alcohols Ethyl alcohol behaves like general anaesthetics on the CNS. It has been suggested that the acute effect of alcohol is to block NMDA (N-methyl-D-aspartate) receptors for which the normal agonist is glutamate, the main excitatory transmitter in the brain. Preseumably as a compensatory mechanism, alcohol chronic exposure increases the number of NMDA receptors and also 'L type' calcium channels, while the action of the (inhibitory) GABA neurotransmitter is reduced. Anxiety, insomnia and craving that accompanies sudden withdrawal of alcohol may explain why resumption of drinking brings about relief, and thus perpetuating dependence.

Ethanol is hardly used as a therapeutic compound; however, it has important toxicological interest. The main effects of ethanol are on the CNS. It acts as hypnotic and anaesthetic; and it disinhibits behaviour, which appears as stimulation (an effect on the higher centres). Peripheral actions include vasodilatation, stimulation of gastric acid. The diuretic effect is due to a central action, inhibition on the release of the posterior pituitary hormone ADH.

Chronic Alcohol Consumption Chronic alcohol consumption may lead to: 1. Hepatic enzyme induction: This leads to increased metabolism of testosterone, 2. Direct toxic effect on Leydig cells: This leads to reduced production of testosterone. 3. Testicular atrophy: Both 1 and 2 (above) result in testicular atrophy leading to feminisation (takes away the performance). 4. Foetal alcohol syndrome: teratogenic effects.

Ethanol is considered to be as a rich source of calories that 1 g of ethanol produces 7 calories. The alcoholic are prone to having a variety of pathological conditions, e.g. gastritis, hepatic cirrhosis, brain damage (loss of memory, mental changes). The following list represents the important actions of ethanol. 1. Cutaneous vasodilatation (feeling of warmth, as a result of depressing the vasomotor centre, risk of rapid hypothermia) 2. Increased blood pressure (probably due to centrally mediated sympathetic stimulation) 3. Diuretic action (decreases the release of ADH from the posterior pituitary gland) 4. Gastric mucosa (erosion and petechial haemorrhages due to allowing back diffusion of acid from the gastric mucosa)

149

Withdrawal of Alcohol This may be encountered when an ill or injured alcoholic is admitted to hospital. The possible sequence of events may appear as: 1. Withdrawal syndrome (in 6 hours, craving for alcohol, tremor, and sympathetic overactivity)



2. Acute psychotic attack (delirium tremens3): (in 72 hours, seizures, agitation, anxiety, and excessive sympathetic autonomic activity.

Drugs used in treatment 1. Benzodiazepine (chlordiazepoxide, large dose for sedative action) 2. ¾-adrenoceptor blocker (propranolol for sympatholytic action) 3. Butyrophenone neuroleptic4 (haloperidol for its antipsychotic action)

Chloral Hydrate Chloral hydrate (1869) is the first synthetic hypnotic agent to be used clinically. It is usually given orally in solution. Because of its unpalatable taste a capsule is available. It is irritant to the stomach. Chloral hydrate is a prodrug, rapidly metabolised by alcohol dehydrogenase into the active hypnotic trichloroethanol. The latter undergoes conjugation with glucuronic acid to an inert form that is excreted in the urine. Therefore, avoid in serious hepatic or renal failure. Choral hydrate aggravates peptic ulcer.

Interactions As chloral hydrate is metabolised by the enzyme alcohol dehydrogenase that is also responsible for the conversion of ethanol to acetaldehyde, therefore, resulting in an increase in plasma concentration of alcohol; hence, the action of ethanol is potentiated by chloral hydrate.

3

An acute mental disturbance marked by delirium with trembling and great excitement, and attended by anxiety, mental distress, sweating, GI symptoms, and precordial pain. It is also seen in opium addiction. 4 Phenothiazines (e.g. fluphenazine and chlorpromazine) should be avoided in this condition as they are proconvulsant (lower threshold for convulsion). 150

Cyclic Ethers Paraldehyde (1882) for a long time had been used as a hypnotic (oral and injection) for control of mania, alcohol withdrawal, tetanus, and status epilepticus. These days, paraldehyde is obsolete except for status epilepticus. This is because of many major disadvantages such as unpleasant taste and smell, irritant to the stomach, causes painful muscle cramps when injected i.m., dissolves plastic syringes.


Majid A. K. Lafi

Table 5.11. Comparison between benzodiazepines and barbiturates Nature of comparison Relatively safe Maximal ability to suppress CNS function Respiratory depressant ability Suicide potential Ability to cause physical dependence Ability to cause tolerance Abuse potential Ability to induce drug metabolism Number of drug interactions Safety in intermittent porphyria Effects increased by other CNS depressants Availability of antagonist

Benzodiazepines High Low Low Low Low Low Low Low Few ? Yes Yes

Barbiturates Low High High High High High High High Many No Yes No

Table 5.12. Barbiturates: prototypes and their clinically important pharmacological characteristics.

Sub-group

Prototype

Ultra-short acting

Thiopental (Pentothol ) Secobarbital (Seconal ) Phenobarbital (Luminal )

Short acting Long acting

Action Onset Duration minutes hours

Lipid solubility

Typical Indication

High

0.5

0.2

Induction of anesthesia; convulsion

Moderate

10-15

3-4

Insomnia

Low

60

10-12

Epilepsy

Therapeutic Coverage Anxiolytic Sedative Hypnotic Buspirone Neuroleptics, Meprobamate Benzodiazepines Barbiturates

Anaesthetic

Coma

Fig. 5.8. A simplified schematic representation of anxiolytic, sedative, hypnotic drugs and their most common therapeutic coverage. Buspirone is used for its anxiolytic action; while neuroleptics (major tranquillisers, e.g. chlorpromazine) are used for their anxiolytic-sedative actions, likewise is meprobamate. Further, benzodiazepines (e.g. diazepam) are used for therapeutic coverage including anxiolytic, sedative and hypnotic actions. Furthermore, the therapeutic objective of barbiturates (e.g. thiopental) is extended further to include their anaesthetic action. Of the major adverse effects of the CNS depressant agents are coma and depression of the respiratory and vasomotor centres; this is most apparent with barbiturates then to a much lesser extent with benzodiazepines.

151



Useful Notes • Psychotic states (manic or endogenous depressive illness and schizophrenia) • Psychoneurosis [anxiety, phobias, (exogenous) reactive depression, obsessivecompulsive disorders, and hysteria) • Neuroleptics are effective in positive symptoms, e.g. aggression, hyperactivity, delusions and hallucinations. But negative symptoms, e.g. apathy, respond less well. • In addition to schizophrenia, neuroleptics are also useful in a. Severe anxiety b. Acute mania c. Acute psychotic states d. Therapeutic restraining e. Intractable hiccup • Endogenous depression: TCA + ECT (increase postsynaptic response, if severe state) plus phenothiazine. Benzodiazepines are contraindicated except for alprazolam. • Insomnia of depression (characteristically, early waking) relieved by a sedative antidepressant drug. • Reactive (exogenous) depression (commonly associated with anxiety) is treated with anxiolytic-sedative or a TCA or MAO inhibitor. • Acute behavioural disturbances: a neuroleptic or benzodiazepine, orally, i.m. • Appetite disorders: anorexia (decrease appetite) and bulimia (increased appetite)

anticholinesterase tacrine and the ACh precursor lecithin. • Excessive sex drive in men reduced by oestrogens or by antiandrogen (cyproterone).

PSYCHOSTIMULATS These (amphetamines e.g. dexamphetamine, methylphenidate, and pemoline) increase the level of alertness and/or motivation. Indications: Narcolepsy, attention deficit disorder in children, anorectic (reduce appetite). Adverse effects: tolerance, insomnia, dependence, nausea & vomiting, increase distractibility, paranoid schizophrenia like symptoms.

PSYCHODYSLEPTICS Psychodysleptics (hallucinogens) produce mental changes that resemble those of some psychotic states. They are usually used for nonmedical purposes. • Lysergide (LSD) • Cocaine • Cannabis

a. Anorexia nervosa treated by chlorpromazine (& cyproheptadine) b. Bulimia treated by dexfenfluramine, fluoxetine, TCA. • Narcolepsy benefited by activating noradrenegic mechanisms with amphetamines (dexamphetamine, methylphenidate, mazindol or caffeine). • Attention deficit (hyperkinetic) disorder in children responds to adrenergic activation by dexamphetamine (or methylphenidate or pemoline). • Nocturnal enuresis: TCA (imipramine), desmopressin (ADH) intranasal metered aerosol (for a holiday). • Organic brain syndromes and senile dementia of Alzheimer type may be improved by the centrally acting

152


Majid A. K. Lafi

DRUGS FOR PARKINSON S DISEASE Introduction

Brain dopamine (DA) receptors operate through secondary messenger systems. DA1receptors binding Gs-protein coupled to adenylate cyclase leading to increased cAMP production. DA2-receptors coupled to adenylate cyclase but through an inhibitory Gi-protein that decreases cAMP production. DA2-receptors are also found to be coupled to a mechanism inhibiting the hydrolysis of phosphatidyl inositol bisphosphate (PI2) leading to reduced production of diacylglycerol (DAG) and inositol trisphosphate (IP3). Further, activation of D2receptors hyperpolarises neurones by increasing potassium conductance of both brainstem dopamine neurones and that receive dopamine terminals. Blockade of DA2-receptors by neuroleptic drugs or metoclopramide is associated with their ability to produce Parkinsonism in patients taking such drugs

Parkinson s disease is a progressive disorder of voluntary movement that affects 1% to 2% of the population (in the western world) over 60 years of age has an average onset age in the 50s and 60s. Clinical symptoms of Parkinson s disease manifested by most patients include: 1. Resting tremor 2. Rigidity (increased resistance to passive stretching of muscle) 3. Hypokinesia1 (slowness in initiating and carrying out voluntary movements) 4. Impaired postural reflexes (with a tendency to fall backwards or forwards easily) 1

Slowness of movements is variably called bradykinesia, hypokinesia or akinesia

Normal

Substantia nigra Dopamine (inhibitory)

Corpus striatum Acetylcholine (excitatory)

Putamen GABA (inhibitory)

Parkinsonism DA

ACh

GABA

ACh

GABA

Huntington’s disease DA

Fig. 5.9. A simplified schematic representation of nigrostriatal system of the basal ganglia. The dopaminergic neurotransmission exerts inhibitory actions on the cholinergic neurones of the corpus striatum; the latter exerts excitatory effects on the GABAergic neurones of the putamen. Normally, there is a balance between the dopaminergic and the cholinergic pathways, which is important in the extrapyramidal control of motor activity at the level of the substantia nigra and the corpus striatum. A decrease in the dopaminergic activity (degenerative loss) is believed to be the underlying cause for Parkinson s disease; while, a decrease in the GABAergic activity is believed to be responsible for Huntington s disease. It follows that an increase in dopaminergic activity may result in GABAergic underactivity and hence choreoathetosis (a condition characterised by choreic and athetoid movements ).

153


Ramadi, 11 February, 2001

effects, particularly emetic effects from about 80% to less than 15%.

Therapeutic Objectives 1. Promoting dopaminergic activity that may be achieved by the use of certain drugs targeted at different dopaminergic mechanisms. This approach improves certain parkinsonian features like hypokinesia and rigidity, with little effect on tremor. 2. Reducing cholinergic activity by antimuscarinic drugs that, at least, partially redressing the imbalance created by decreased dopaminergic activity. This approach improves tremor, sailorrhoea (excessive secretion of saliva), rigidity, with little effect on hypokinesia.

At present, two fixed combined preparations are available. • Co-careldopa (carbidopa + levodopa, Sinemet) • Co-beneldopa (benserazide + levodopa, Madopar)

Dopaminergic Drugs Levodopa Levodopa (L-DOPA) is the normal physiological precursor of dopamine synthesis, being converted to dopamine by the enzyme dopa decarboxylase. Unlike dopamine, levodopa readily crosses the blood brain barrier (BBB). When levodopa is used alone, it is readily taken up and converted to dopamine by peripheral and central nervous tissues. The peripheral conversion of levodopa is undesirable as it results in peripheral adverse effects, particularly cardiovascular and emetic effects. This problem has been overcome by the concurrent administration of a levodopa decarboxylase inhibitor like carbidopa and benserazide that cannot cross the BBB. The enzyme inhibitor peripherally prevents the (extracerebral) conversion of levodopa to dopamine; therefore the required dose of levodopa is reduced to about 25%. This consequently reduces peripheral adverse

Adverse Effects 1. Postural hypotension ( ) 2. Nausea (effect DA-receptor on the CTZ, reduced by prior administration of domperidone that minimally crosses the BBB) 3. Dyskinesia (extra movements; choreoathetosis, choreic involuntary movements, involving head, lip, tongue; peak dose effect, reduced by the use of slow-release preparations) 4. Mental changes (psychosis, hallucinations; depression) 5. Wearing-off (effect of each dose becomes shorter, i.e. reduced duration of action) 6. End of Dose Akinesia (end of dosage interval; may respond to giving smaller doses of levodopa more frequently) 7. On-Off phenomenon: Severe swings in performance ranging from extra movements (dyskinesia) to complete lack of movement (total akinesia). These swings in performance often do not appear to be directly related to time of drug administration. A summary of the pharmacology of the drugs used in the treatment of Parkinson s disease is presented in Table 5.13.

154


Majid A. K. Lafi

Table 5.13. A summary of the drugs used in the treatment of Parkinson s disease. Approach Drug


Action

Enhance Dopamine Activity Levodopa [+ carbidopa (Sinemet)]

Dopamine precursor [+ extracerebral decarboxylase inhibitor]

Postural hypotension Nausea Dyskinesia Psychosis Decreasing hypokinesia, rigidity, less effective on tremor

Bromocriptine (Parlodel) Lysuride Pergolide Apomorphine

Dopamine agonist

Postural hypotension Nausea Dyskinesia Psychosis

Selegiline* (Deprenyl)

MAO-B inhibitor

Amantadine

↑ dopamine synthesis & release ↓ reuptake

Increases likelihood of adverse effects caused by levodopa or dopamine agonists. Used as adjunct with levodopa (dose reduced by about 50%); improves end-ofdose akinesia1.

Confusion or agitation Benefits wears off, after about 3 months of treatment Used alone when early, and adjunct when disease progresses

Reduce Cholinergic Activity Benzhexol (trihexiphenidyl-HCl, Artane) Procyclidine Orphenadrine Benztropine

CNS (loss of memory, confusion) and HALLUCINATION →DRUG ABUSE Peripherally (dry mouth, decreased sweating, constipation, urinary retention etc.) Decreasing tremor, rigidity, less effective on hypokinesia

Muscarinic antagonist

* The claim that selegiline delays progress of the disease has lead to its use as protective therapy. This claim stemmed initially from the theory that it inhibits the oxidation (by the brain MAO-B) of the protoxin MPTP to MPP+ which results in death of dopaminergic neurones (thus, protecting the surviving dopamine neurones). However, this claim has not been supported by subsequent trials; indeed, one

study has shown an increased mortality in patients receiving selegiline2.

1 2

Laurence, D. R., Bennett, P. N. and Brown, M. J. (1997) Clinical Pharmacology. 8th edition, Page 367. Walker, R. and Edwards, C. (1999) Clinical Pharmacy and Therapeutics. 2nd edition, Page 459. 155



ANTIEPILEPTIC DRUGS seizure (e.g. head injury, tumour, hypoglycaemia, meningeal infection, or perhaps, rapid withdrawal of alcohol from an alcoholic). This is known as secondary epilepsy and is usually reversible. Status epilepticus, in which the episodes of tonicclonic seizure occur without intervening recovery of consciousness, is serious and may be fatal unless treated rapidly.

Introduction Epilepsy1 is a syndrome characterised by sudden transient alterations in brain function leading to motor, sensory, autonomic or psychic syndrome, often accompanied by unconsciousness. Seizures2 may result in abnormal perceptions if the parietal or occipital cortex is involved. However, seizures may result in abnormal movements (convulsions) if the motor cortex is involved.

Patients are treated with antiepileptic drugs. Patients with primary epilepsy are treated often for life, whereas those with secondary epilepsy are treated with antiepileptic drugs until the cause of the seizure is corrected. It is generally accepted that a patient having recurrent seizures should receive antiepileptic treatment that will be stopped only if two years elapse without any seizure. For classification of seizures see Table 5.14. and for a summary of antiepileptics and their indications (Table 5. 15).

In epilepsy, the abnormal neuronal discharge is usually localised to a specific area of the brain, known as the primary focus that usually does not show any anatomical abnormality. The functional abnormality of these foci may be triggered by different environmental factors, e.g. changes in blood gases, electrolytes, pH, glucose level. A focal cortical seizure may spread to involve the cortex and a generalised (tonic-clonic) seizure with unconsciousness, convulsions and incontinence. When the spread from the initial focus is slow, the initial focal symptoms give rise to a warning (or aura) of the impending fit. However, if the spread of the focal seizure over the cortex is rapid an aura may be absent.

Mode of Action Antiepileptic drugs inhibit the repetitive neuronal firing or its spread by one of the following three possible ways: 1. Modifying cell membrane permeability to ions like Na+ (e.g. carbamazepine, phenytoin) and Ca++ (e.g. ethosuximide) 2. Promoting the action of endogenous inhibitory neurotransmitters such as GABA producing hyperpolarisation (e.g. benzodiazepines, barbiturates, valproic acid, vigabatrin) 3. Inhibiting excitatory neurotransmitters like glutamate and aspartate (e.g. lamotrigine).

In the absence of anatomical cause (e.g. trauma or tumour) for the seizure, it is called idiopathic or primary epilepsy. However, when there is an apparent cause for the 1

Reference to the disease can be found as early as 2080 BC in the code of Hammurabi, King of Babylon. Hippocrates in about 400 BC opposed the supernatural explanation of epilepsy and correctly attributed it to abnormal cerebral function. 2 An attack of epilepsy variably called fit.

156


Majid A. K. Lafi

Table 5.14. Classification of seizure, frequency, and clinical manifestations. Frequency (%) PARTIAL (FOCAL) SEIZURES Simple partial (10%)

Clinical Manifestations

No impairment of consciousness; focal motor, sensory (e.g, olfactory hallucination), speech, psychic (e.g. delusion), and autonomic disturbances (e.g. tachycardia).

Complex partial (35%)

Impaired consciousness; complex sensory hallucinations, mental distortions, and motor dysfunctions (chewing movements).

Partial seizures secondarily generalised

(10%) Start as simple partial or partial complex and marsh to tonic clonic fit

GENERALISED SEIZURES Tonic-clonic (30%) (Grand mal)

Loss of consciousness, falling, rigidity extension of trunk and limbs (tonic phase), rhythmic contraction of arms and legs (clonic)

Absence (10%) (Petit mal) Myoclonic, atonic (4%) (Atypical absence)

Impaired consciousness with staring spells, with or without eye blinks Myclonic jerks (shock-like contractions), loss of muscle tone, falling (drop attack, Salaam attack)

Other Seizures (1-8%) frequency repetitive firing in neurones in culture (for more details see phenytoin below).

Antiepileptic Drugs All central depressant drugs like anaesthetic and hypnotics act as anticonvulsants and will suppress epileptoform convulsions. Antiepileptic drugs are special selection of anticonvulsants that are capable of suppressing epileptic seizures in doses that produce little or no sedation. An overview of the pharmacology of the important antiepileptic drugs is presented in Table 5.16.

Indications 1. Simple partial epilepsy 2. Complex partial epilepsy 3. Generalised tonic-clonic secondary) 4. Trigeminal neuralgia1 5. Postherpetic neuralgia 6. Diabetic neuropathy2 1

(primary

&

Paroxysmal pain which extends along the course of one or more nerves. Many varieties of neuralgia are distinguished according to the part affected or to the cause, as trigeminal, brachial, facial, occipital, supraorbital, etc., or postherpetic, anaemic, diabetic, gouty, malarial, syphilitic, etc. 2 A chronic, symmetrical sensory polyneuropathy affecting first the nerves of the lower limbs and often affecting autonomic nerves; pathologically, there is segmental demyelination of the peripheral nerves. An uncommon, acute form is marked by severe pain, weakness, and wasting of proximal and distal muscles, peripheral sensory impairment, and loss of tendon reflexes. With

Carbamazepine Carbamazepine is a tricyclic compound closely related to imipramine and other antidepressants. Carbamazepine was originally developed for the treatment of bipolar depression. However, it was first used in the treatment of trigeminal neuralgia and only later its anticonvulsant action has been recognised. The mechanism responsible for its anticonvulsant action appears to be related to its capability to block sodium channels at therapeutic concentrations and inhibits high157


7. Cerebellar ataxia (failure of muscular coordination due to a disease of the cerebellum) 8. Nocturnal enuresis 9. Affective disorder (unipolar depression and mania, treatment and prophylaxis) 10.Resistant schizophrenia 11.Diabetes insipidus 12.Hyperkinetic child 13.Dementia (organic loss of intellectual function) 14.Emotional incontinence (uncontrolled emotional acts, e.g. laughing) 15.Aggressive behaviour 16.Migraine (prophylaxis) 17.Impulse dyscontrol syndrome


depolarised (i.e. has more positive resting potential) cells that will recover from block Table 5.15. A summary of antiepileptic drugs and their indications Type of Epilepsy Partial (including secondarily generalised)

Antiepileptic Drug

Tonic-clonic

Carbamazepine Phenytoin Phenobarbital Primidone Valproic acid Lamotrigine ( as adjunct)

Absence

Ethosuximide Valproic acid Clonazepam Lamotrigine ACTH

Myclonic

Valproic acid Clonazepam ACTH

Febrile

Diazepam Phenobarbital Valproic acid

Status Epilepticus

Phenytoin (i.v.) Diazepam (i.v.) Phenobarbital (i.v.)

Adverse Effects Dose related (predictable) 1. Diplopia 2. drowsiness 3. Orofacial dyskinesia 4. Cardiac arrhythmias (AV depression) 5. Impairs cognition 6. Osteomalacia and folate deficiency (due to hepatic enzyme induction; with first few weeks, t 35 hours becomes 20 hours) Non-dose related (Idiosyncratic) 7. Agranulocytosis 8. Aplastic anaemia 9. Hepatotoxicity 10.Stevens-Johnson syndrome (severe form of erythema multiforme in which there is involvement of the oronasal and anogenital mucosa, the eyes, and viscera)

Carbamazepine Phenytoin Phenobarbital Primidone Valproic acid Lamotrigine Vigabatrin

Bold prints: preferred drugs In pregnancy: carbamazepine and phenobarbital are most suitable.

Phenytoin Phenytoin (1938) is a nonsedative hydantoin compound. It appears to produce its anticonvulsant action through its capability, at therapeutic concentrations, to block sodium channels and inhibit sustained highfrequency repetitive firing in neurones in culture. Like carbamazepine, phenytoin appears to exert selective inhibition on

very slowly if at all. In doing so, phenytoin increases refractory period in depolarised (sick) cells. This apparently selective action has been attributed to what is known as the use-dependent effect 3; therapeutically useful sodium channel blocking (local anaesthetic, membrane stabilising) drugs

autonomic involvement there may be orthostatic hypotension, nocturnal diarrhoea, retention of urine, impotence, and small diameter of the pupils with sluggish reaction to light.

3

Katzung, B. G. (1998) Basic & Clinical Pharmacology. 9th edition, Page 551 & 562. 158


Majid A. K. Lafi

have a high affinity for activated channels or inactivated channels but very low affinity for rested channels. Bearing in mind that an ionchannel is usually in one of three possible states:

Rested

indicator of plasma concentrations. As shown above in a, the t value cannot help the prescriber to decide the dosage regimen with reasonable safety; therefore in such condition, serial plasma concentration measurement has been recommended].

Activated

Inactivated It follows that in sick cells with abnormally high firing activity, the most likely ionchannel states would be the activated and inactivated ones. Consequently, these sodium channel-blocking drugs would preferentially bind to these channels that are in depolarised cells resulting in increased refractory period and therefore decreasing cell excitability. Indeed, this hypothesis of use-dependent effect is applied for calcium channel blocking drugs as well.

Pharmacokinetics 1. Saturation (zero-order) kinetics [At subtherapeutic (low) blood levels, phenytoin metabolism is directly proportional to the rate at which the drug is presented to the liver, i.e. first-order metabolism, the t of phenytoin is 6-24 hours. However, at therapeutic (high) blood levels the metabolic machinery becomes saturated (said to have reached zero-order kinetics), the t may reach 60 hours. Phenytoin is the most clinically important example of the drugs exhibiting zero-order kinetics. This is because it is characterised by: a. Its overall t ranges from 6-60 hours, and considering the time to reach a steady-state plasma concentration after dose increment (about 5 × t ) ranges from 2 days to 2 weeks. Consequently, the knowledge of its t is clinically not meaningful, as it is not possible to determine (reasonably) reliably the time to reach the therapeutic steadystate concentration. b. Being a drug with low therapeutic index, it should not be given without a reliable 159

2. Hepatic enzyme induction and enzyme inhibition [phenytoin is a potent hepatic enzyme inducer influencing its own metabolism as well as other drugs and dietary and naturally occurring substances such as vitamin D, folate, adrenal and gonadal steroids, thyroxine. Other drugs whose hepatic metabolism significantly increased including other antiepileptic drugs, e.g. carbamazepine, warfarin, tricyclic antidepressants, and doxycycline. It follows that hepatic enzyme inducing drugs can affect each other when administered concurrently; for example, phenobarbital, carbamazepine, rifampicin may lower phenytoin concentrations. Likewise, hepatic enzyme inhibiting drugs such as valproate, cimetidine, cotrimoxazole, isoniazid, chloramphenicol, erythromycin etc. can interact with phenytoin, and other antiepileptic drugs, causing an increase in plasma concentrations, hence increasing the possibility of toxicity].

Indications 1. Simple partial epilepsy 2. Complex partial epilepsy 3. Generalised tonic-clonic (primary secondary) 4. Status epilepticus 5. Digitalis-induced arrhythmias 6. Trigeminal neuralgia (see above)

&

Adverse Effects Dose related (predictable) 1. Ataxia, nystagmus, orofacial dyskinesia 2. Drowsiness 3. Impairment of cognitive function 4. Gingival hyperplasia (may be due to inhibition of collagen catabolism) 5. Coarsening of facial features 6. Hirsutism



7. Megaloblastic anaemia (probably due to folate deficiency as a result of hepatic enzyme induction by phenytoin) 8. Osteomalacia (due to vitamin D deficiency as a result of increased hepatic metabolism after years of therapy) 9. Teratogenic 10.Peripheral neuropathy 11.Rashes Non-dose related (idiosyncratic) 12.Hepatotoxicity

1. Dyspepsia, nausea, vomiting 2. Coagulation disorder (due to inhibition of platelet aggregation) 3. Alopecia (hair loss) 4. Increased appetite (results in weight gain) 5. Teratogenic (spina bifida) 6. Acute pancrititis 7. Hepatitis

Overdose

Barbiturates

1. Cerebellar dysfunctions 2. Coma and apnoea (may be for a long time because of zero-kinetics, maintain respiration, no antidote)

An account on barbiturates has been given in the section on sedatives and hypnotics (above). The most widely used antiepileptic member of barbiturates is phenobarbital (t 100 hours). Other members like methylphenobarbital and primidone (a prodrug) that is largely metabolised to phenobarbital. Barbiturates are potent hepatic enzyme inducers.

Valproic Acid (Sodium Valproate) Valproic acid was incidentally found to have antiepileptic activity when it was used as a solvent in the search for antiepileptic drugs. The mechanism of action of valproic acid as antiepileptic drug is not conclusively settled. However, much of the evidence now points out to its capability to block sustained high-frequency repetitive firing of neurons in culture at therapeutically relevant concentrations. Its action against partial seizures may be a consequence of this effect on sodium channel. Blockade of NMDA receptor-mediated excitation may also be important Valproic acid is a hepatic enzyme inhibitor; and it is 90% plasma protein bound with apparent volume of distribution of 9 L.

Adverse Effects

Indications 1. 2. 3. 4. 5.

Simple partial seizures Complex partial seizures Anaesthesia (e.g. thiopental) Anxiety (rarely used these days) Insomnia (rarely used these days)

Adverse Effects 1. 2. 3. 4. 5.

Indications 1. Simple partial epilepsy 2. Complex partial epilepsy 3. Generalised tonic-clonic 4. Absence 5. Myoclonic seizures 6. Affective disorders 7. Huntington s chorea 8. Peripheral neuropathy 9. Hyperkinetic child 10.Prophylaxis of migraine 11.Tardive dyskinesia 12.Impulse dyscontrol syndrome

Sedation Impaired cognition Addiction risk Enzyme induction Low therapeutic index

Benzodiazepines A detailed account on benzodiazepines has been given in the section on anxiolytics (above). Of this group, clonazepam (Rivotril, t 25 hours) is widely used as a broad-spectrum antiepileptic drug. It has the reputation to have less sedative action than most other members of benzodiazepines do. Clonazepam and diazepam are useful in status epilepticus; in this medical emergency, they should be administered i.v. slowly (30 seconds), while i.m.

160


Majid A. K. Lafi

administration is not appropriate as peak plasma concentration can be delayed as long as 2 hours making these drugs useless for the urgent control required in this medical emergency. However, lorazepam is more rapidly absorbed when administered i.m.

Adverse Effects 1. Gastric upset (Nausea, vomiting) 2. Allergic reactions (Rash, Stevens-Johnson syndrome, SLE) 3. Hepatic enzyme inhibition

Ethosuximide Lamotrigine Ethosuximide was introduced as a specific anti-absence seizure drug. To date, it remains the drug of first choice for absence seizure. The mechanism of action of ethosuximide is believed to be mediated through inhibiting the low-threshold (T-type) Ca2+ currents in the thalamic neurones; these currents are suggested to be responsible for generating the rhythmic cortical discharge of an absence seizure4. Therefore, it is useful only in absence seizure.

Lamotrigine (1993) is a voltage dependent sodium channel blocker. This action results in reduced release of excitatory amino acids like glutamate and aspartate. It is believed to have less frequent adverse effects (compared with that of carbamazepine). It finds use in partial and generalised seizures, as an adjuvant or monotherapy.

4

Katzung, B. G. (1998) Basic & Clinical Pharmacology. 9th edition, Page 567.

161



Table 5.16. A summary of the pharmacology of selected antiepileptic drugs Drug Group Drug Carbamazepine

Mechanism of Action Reduces repetitive neural firing (inhibits voltage-sensitive Na+ channel)

Phenytoin


Partial Tonic-clonic Status epilepticus

Na valproate


Partial Tonic-clonic Absence Myclonic Febrile

Barbiturates Phenobarbital (t 100 hr) Methylphenobarbital Primidone (prodrug)

Potentiates GABA effects on Cl- influx

Partial Tonic-clonic Status epilepticus Febrile convulsion

Benzodiazepines Diazepam Lorazepam Clonazepam

GABA Clchannel receptor complex

Lamotrigine

Selected Adverse Effects and Important Remarks

Partial Tonic-clonic

Osteomalacia and folate deficiency (due to hepatic enzyme induction; with first few weeks, t 35 hours becomes 20 hours) Cardiac arrhythmias (AV depression) Impairs cognition (Idiosyncratic) Agranulocytosis Aplastic anaemia Hepatotoxicity Impairs cognition Gingival hyperplasia Coarsening of facial features Hirsutism Megaloblastic anaemia (probably due to folate deficiency as a result of hepatic enzyme induction by phenytoin) Osteomalacia (due to vitamin D deficiency as a result of increased hepatic metabolism after years of therapy) Teratogenic Peripheral neuropathy Rashes (idiosyncratic) Hepatotoxicity Coagulation disorder (due to inhibition of platelet aggregation) Alopecia (hair loss) Increased appetite (results in weight gain) Teratogenic (spina bifida) Acute pancrititis Hepatitis Hepatic enzyme inhibition

Status epilepticus Absence Myoclonic

Clonazepam

Ethosuximide

Indication

Inhibits lowthreshold (T-type) Ca2+ currents Inhibits release of glutamate & aspartate

Absence Partial Generalised seizures

162

Sedation Impaired cognition Addiction risk Enzyme induction Low therapeutic index Sleepiness Impaired psychomotor function Amnesia Dependence Gastric upset (Nausea, vomiting) Allergic reactions (Rash, StevensJohnson syndrome, SLE) Hepatic enzyme inhibition

Same as carbamazepine but probably less frequently.


Vigabatrin

Inhibits GABA transaminase (irreversibly)

Majid A. K. Lafi

Partial seizures

Sedation Weight gain Confusion, agitation & psychoses

A SUMMARY OF THE DRUGS USED IN MOVEMENT DISORDERS

Hypokinetic Movement Disorders disease. • Idiopathic Parkinson s Primary agents: carbidopa/ levodopa; bromocriptine; pergolide. Secondary agents: benzhexol; benztropine; amantadine; selegiline Hyperkinetic Movement Disorders • Tics e.g. Tourette s syndrome, which begins in childhood and is associated with vocalization, abnormal gestures, and frequently with obsessive-compulsive personality. Neuroleptic drugs e.g. haloperidol can be useful. • Myclonus (e.g. Salaam attack, infantile myclonus seizure). Benzodiazepines (clonazepam); carbidopa/5-HTP (for anoxic myclonus); baclofen (a GABA-B agonist); tetracosactrin • Essential tremor (or known as adrenergic or intentional tremor, or familial tremor). Propranolol; primidone; clonidine may be considered (advise to decrease intake of tea, coffee and smoking) • Parkinsonian tremor (rest tremor) Anticholinergics (e.g. benzhexol) • Dystonia (disordered tonicity of muscle, acute sustained contraction of muscle) may begin and remain focal, affecting only one area of the body, but can also begin focally and evolve in generalised dystonia. Two very common forms of focal dystonias involve forced eyelid closure (blepharospasm) or twisting of the neck to one side (torticolis), frequently in combination with pulling of the neck backwards (retrocollis). Trismus (clinching of teeth, lockjaw) and opisthatonus (contraction of the muscle of the back) may also be encountered. A high dose of anticholinergic drugs (e.g. benzhexol, diphenhydramine) is useful. Generalised dystonia patients surprisingly

tolerate high doses of anticholinergics with substantial improvement. If anticholinergics are not available a benzodiazepine may do. • Dyskinesia-Chorea: Dyskinesias generally refer to choreic drug side effects, whereas choreas occur in the course of natural disease. The common dyskinesia is that arising in the natural history of Parkinson s disease treated with levodopa. This dopa-dyskinesia can also be seen with direct dopamine agonist. No satisfactory treatment is available at present. • Tardive Dyskinesia: Tardive dyskinesia is a choreic movement disorder arising late in the course of neuroleptic treatment. This dyskinesia is suggested to be due to hypersensitivity (upregulation) of dopamine receptor, particularly of the substantia nigra leading to reduced GABAergic activity in the corpus striatum resulting in choreic movement. No effective specific treatment is available, however, stop giving the antipsychotics may be useful, otherwise reserpine can be used in the disabling cases; the less severe cases may respond paradoxically to carbidopa/levodopa or to clonidine treatment. • Huntington s chorea: Chorea occurs in the course of Huntington s disease, an autosomal dominantly inherited neurodegenerative disorder. The marked loss of GABA neurone in the brains of Huntington s disease patients suggests similarities to tardive dyskinesia. Neuroleptic drugs or reserpine may help.

163



OPIOIDS AND NARCOTIC ANALGESIC DRUGS

The actions of opioids can be explained by action on specific opioid receptors in the CNS (Table 5. 17), thalamus, limbic system, hypothalamus, substantia gelatinosa of the spinal cord, nucleus tractus etc. The receptor type most responsible for analgesic properties has been designated the (mu) µ-receptor. The opioid receptors respond to natural morphinelike substances, which are peptides and act as neuromodulators. These are called enkephalins and endorphins. Endogenous analgesics like enkephalins can be detected in the CSF after certain pain-relieving procedures such as acupuncture, placebo medication and transcutaneous electrical stimulation. The endorphins are long-chain polypeptides, which also exhibit opiate activity; the best known is ¾-endorphin that is mainly found in the hypothalamus and the pituitary gland. Opioid peptides seem to be involved in many physiological functions including regulation of temperature, behaviour, gastrointestinal motility, appetite, thirst etc.

Introduction Opium is the dried latex (milky fluid) obtained from the unripe capsules of opium poppy, papaver somniferum. Opium contains 25 different alkaloids; the most important of which are morphine (15%), codeine (2%) and papaverine (1%). Papaverine is distinct from opium, it is not an analgesic and it is a potent relaxant of smooth muscle whereas the opioids induce smooth muscle contraction. Opium was initially used for its antitussive actions that were recognised. The semisynthetic opiate heroin (diacetylmorphine) was produced in 1844 with the hope of curing morphine addicts, but it was soon appreciated that it was not a cure, but on the contrary a more potent narcotic. The search for agents with analgesic qualities of morphine but without the side effects of dependence and tolerance continued and resulted in methadone and pethidine (mepiridine), which however have little advantage.

Opioids relieve pain by raising the pain threshold at the spinal cord level, and also by altering the brain s perception of pain. With morphine, the patient is still aware of the presence of pain, but the sensation is not unpleasant. It is believed that morphine acts at µ-receptors in the substantia gelatinosa of the spinal cord, decreasing the release of substance P (and probably other excitatory transmitters from terminals carrying nociceptive stimuli) which modulates pain perception in the spinal cord.

Mechanism of Action Although much remains to be learned about the neurotransmitters involved in both the afferent nociceptive pathways (primary afferent nerve fibres) and descending antinociceptive pathways, prime candidates for the afferent pathways include peptidergic neurotransmitters (e.g. substance P, somatostatin, vasoactive intestinal polypeptide, cholecystokinin, and calcitonin gene-related peptides). The descending antinociceptive pathways appear to inhibit or modulate the process of pain transmission through the afferent (spinal) nociceptive pathways. This process of modulating transmission of pain is the essential part of the gate theory of pain. Several neurotransmitters have been suggested to be involved in pain modulation, e.g. noradrenaline and serotonin, as well as endogenous opioid peptides.

Classification of Narcotic Analgesics Opiates can be classified into three groups: 1. Pure agonists: dextropropoxyphene, codeine, pethidine (meperidine), methadone, morphine, heroin, fentanyl 2. Mixed agonists/antagonists & partial agonist: pentazocine, nalorphine 3. Antagonists: naloxone, naltrexone

164


Majid A. K. Lafi

Table 5.17. A summary of responses to stimulation of the three major types of opioid receptors. Receptor Types Kappa (µ) Spinal analgesia Dysphoria/sedation Respiratory depression Miosis

Mu (³) Sigma (-) Spinal and supraspinal Dysphoria analgesia Psychotomimetic reactions* Respiratory depression Respiratory stimulation Euphoria/sedation Mydriasis Physical dependence Decreased GI motility Miosis * e.g. anxiety, strange thoughts, nightmares, hallucinations Table 5.18. Drug actions at opioid receptors Agents Pure opioid agonists: morphine, codeine etc. Mixed acting opioids: pentazocine Partial agonists nalorphine Pure opioid antagonist: naloxone, naltrexone

Mu (³) Agonist

Antagonist Weak agonist Antagonist

Agonist

Agonist

-

-

Antagonist

Antagonist

8. Respiratory depression (reduced sensitivity to CO2) 9. Miosis 10. Decreased release of LH and FSH 11. Increased release of prolactin and ADH

Principle Pharmacological Effects Desirable effects 1. 2. 3. 4. 5. 6.

Receptor Types Kappa (µ) Sigma (-) Agonist No action

Effective analgesia Sedation Sleep Euphoria Depression of Cough Relief of anxiety

Tolerance and Dependence Tolerance is characterised by decreased intensity and shortened duration of all the usual pharmacological effects of morphine. It may occur in individuals who have become socially habituated to the drug, or in patients who require continuous therapy for chronic pain (like in cancer). The pharmacokinetic parameters of morphine do not alter with its repeated use. A negative feedback system resulting in decreased production of endogenous opioid peptides may be implicated (pharmacodynamic tolerance, Fig.5.10). Different opioids exhibit crosstolerance.

Undesirable effects 1. Tolerance and dependence 2. Bronchoconstriction (due to histamine release) 3. Nausea and vomiting 4. Dysphoria 5. Depression of cough reflex 6. Spasmogenic effects (GI spasm, sphincter of Oddi spasm) 7. Constipation

165



Upon repeated dosage, cellular adaptation to the exogenously applied morphine occurs; i.e. neurotransmission (particularly the postsynaptic opioid activity that is responsible for modulating various essential biological activities) becomes dependent on the exogenous morphine. A sudden withdrawal (abstinence) of the exogenous morphine cannot be immediately compensated for, consequently results in disturbance in the regulation of these biological activities such as cardiovascular functions.

Reversal of Narcotic Effects Naloxone is the pure antagonist and the drug of choice for the treatment of narcotic overdose, or for reversing the depressant effects of narcotic agents on the neonates. The normal dose may be repeated once or twice at frequent intervals if respiratory function does not improve or relapse. It would appear that all the pharmacological actions of the narcotic agents are reversed by naloxone. If naloxone is administered to a person who has been abusing opioids, he will develop a withdrawal syndrome, but nothing happens if given to a normal person.

Withdrawal (Abstinence) Syndrome

Indications for morphine

The development of dependence to morphine can be demonstrated when the drug is suddenly withdrawn after repeated dosage. Various physical and physiological phenomena may develop, the severity of which are related to the total amount administered. Symptoms and signs include restlessness and irritability, frequent yawning, excessive sweating, gooseling of skin (piloerection), hyperpnoe, dilated pupils, tachycardia, lachrymartion and salivation, painful muscle cramps and intense and uncontrolled vomiting, diarrhoea and urination. Mild symptoms have been reported after only 48 hours therapy. Although withdrawal from opioids is unpleasant, the syndrome is rarely dangerous; on the contrary, withdrawal from other CNS depressants (e.g. alcohol, barbiturates) can be lethal.

1. Severe pain euphoria in the dying 2. Myocardial infarction (MI) or dyspnoea in acute left ventricular failure and pulmonary oedema (see later notes) 3. Premedication for surgery

Contraindications 1. Chronic obstructive lung disease 2. Liver failure 3. Raised intracranial pressure (including head injury)

Morphine and the Cardiovascular System Morphine exerts the following actions on the cardiovascular system.

Treatment of Withdrawal Syndrome

1. Decreases sympathetic vascular reflexes resulting in veno-arteriolar dilatation 2. Stimulates vagal centre leading to decreased heart rate 3. Releases histamine resulting in vasodilatation 4. Tranquillising action, thus decreasing mental distress 5. Decreases central sensitivity to afferent stimuli from the congested lung leading to decreased respiratory distress

The following drugs are essential in the treatment of the withdrawal syndrome. 1. Methadone addictive) 2. Diazepam 3. Clonidine

(oral,

long

acting,

less

166


Majid A. K. Lafi

THEREFORE, MORPHINE IS USEFUL IN DYSPNOEA DUE TO ACUTE LEFT VENTRICULAR FAILURE AND PULMONARY OEDEMA

Exogenous opioids

Pethidine versus Morphine 1. Pethidine is not useful in suppressing cough 2. Pethidine does not constipate; however, like morphine, it produces spasm of the sphincter of Oddi. 3. Pethidine is widely used in obstetrics because it does not delay labour like morphine that produces this effect centrally by reducing co-operation rather than by an action on the uterus. However, pethidine enters the foetus and can depress respiration at birth; therefore, the availability of naloxone can be essential as an antidote. 4. Pethidine is less likely to cause urinary retention which has at least partly for morphine due to the central sedation causing the patient to ignore afferent messages from a full bladder. 5. Unlike morphine, pethidine has little hypnotic effect. 6. Pethidine has shorter duration (2-3 hr) of analgesia. 7. Because of unfavourable cardiovascular effects (a transient rise in systemic arterial pressure, systemic vascular resistance and heart rate) pethidine could not be recommended for the relief of pain in myocardial infarction patients. Unlike morphine, pethidine is not considered as a venolytic agent. 8. Pethidine has considerable antimuscarinic effects that may be a problem if tachycardia would be a problem. This antimuscarinic activity is responsible for its mydriatic action (while morphine produces miosis).

167

-ve opioid Presynaptic nerve

opioid

¿2

Postsynaptic nerve

-ve

Fig. 5.10. A simplified diagrammatic representation of the effect of exogenously administered opioids (e.g. morphine) on post and presynaptic opioid receptors. Opioid-like substances are endogenously released from peptideergic nerves; therefore, when giving the first dose of an exogenous opioid the observed response would appear to be due to the exogenous opioid. This response is super-added to the basal endogenous opioid activity. As the exogenous opioid causes negative feedback effect on the release of the endogenous opioid; thus, upon subsequent administration of the opioid the effect of a particular (first) dose will be reduced (i.e. pharmacodynamic tolerance develops, a larger dose is required to produce the same effect). In this condition biological adaptation (dependence on exogenous substance) is said to have taken place. Upon withdrawal (abstinence) of the exogenous opioid, the postsynaptic opioid activity (which is responsible for modulating various essential biological activities such as regulation of cardiovascular functions) is reduced. This cannot be immediately compensated by the reduced availability of the endogenous opioid.


Ramadi, 1 March 2008

Table 5.19. A summary of the pharmacology of selected narcotic analgesics and their antagonists. Narcotic agent

t (hr) 2

Duration of analgesia (hr) 3-6

Codeine (methylmorphine)

3

4

Pethidine (meperidine)

5

2-3

Methadone

8

24

Dextropropoxyphene

5

4-6

Tramadol

6

Fentanyl

3

Morphine

Activates mu (µ) & kappa (κ) receptors; it produces analgesia, euphoria, miosis, sedation. Respiratory depression, orthostatic hypotension, cough, suppression, constipation, biliary colic, urinary retention, emesis & elevation of intracranial pressure; USES: moderate-to-severe pain, MI or dyspnoea associated with acute left ventricular failure and pulmonary oedema, & premedication for surgery. Useful in mild-to-moderate pain (codeine 30 mg is equianalgesic to 325 mg of aspirin or paracetamol), used in combination with nonopioid analgesics (e.g. aspirin) to produce greater analgesic action; & as cough suppressant (10 mg); Adverse-effects: sedation and constipation. Used primarily for its analgesic effect, preferred for obstetrical analgesia; it is less likely to cause smooth muscle spasm than morphine, thus, less constipation & urinary retention. Not preferred in MI or dyspnoea associated with acute left ventricular failure and pulmonary oedema. Synthetic, good absorption from GIT, long duration of action, used to cover opioid withdrawal & for chronic pain in palliative care. Rapidly absorbed from GIT, used for its analgesic action (similar to codeine), structurally similar to methadone Synthetic, rapidly absorbed from GIT, as effective as pethidine for postoperative pain and as morphine for moderate chronic pain, less likely to constipate, depress respiration and addict. Eighty times more potent than morphine; & more efficacious, used in surgery.

0.5-1

Increases cardiac work and oxygen demand, thus, not suitable in MI; less respiratory depression than morphine; because of sigma (-) receptor (psychotomimetic) effects, it has a low potential for abuse. It can precipitate an abstinence syndrome in a patient physically dependent on a pure opioid agonist.

Mixed agonist/antagonist Pentazocine

Principal features

5

Used to reverse depression.

Nalorphine (Partial agonist) Opioid antagonists

Naloxone

1.25

1-2

Naltrexone

4

1-3 days

narcotic

induced

respiratory

Blocks opioid actions; precipitates an immediate withdrawal reaction in a patient dependent on opioids; Useful in: 1. Opioid overdose 2. Reversal of postoperative opioid depression 3. Reversal of neonatal respiratory depression Similar to naloxone; but can be given orally; useful in former opioid addicts to prevent relapse (prevents opioid-induced euphoria, long duration of action).

168

CNS Pharmacology - Narcotic Analgesics


When combining amphetamines with morphine-like agents lead to increased analgesia, and decreased sedation. When combining antiemetics with morphine-like agents lead to suppression of nausea and vomiting. When combining CNS depressants, phenothiazines, and antidepressants with morphine-like agents leads to increased respiratory depression.

169



GENERAL ANAESTHETIC DRUGS Introduction

Diaphragmatic paralysis can be induced by muscle relaxants (e.g. tubocurarine), however, an overdose with inhalational anaesthetics may produce this effect in stage IV.

Objectives: analgesia, amnesia-hypnosis (unconsciousness), muscle relaxation (loss of reflexes), and physiological homeostasis. General anaesthesia is said to be achieved when the above four objectives are met, and during which there is loss of sensation and consciousness (the subject is not rousable by external stimuli). This can be obtained by inhalation of a volatile anaesthetic agent(s) or intravenous administration of a drug or a combination of them. The order of depression in the CNS is:

Inhalational Anaesthetics Inhalation of anaesthetic drug produces a depth of anaesthesia that depends on the partial pressure of the anaesthetic agent, which will be dependent on: 1. Partial pressure of anaesthetic agent (concentration) in the inspired air 2. Solubility of anaesthetic agent in blood 3. Pulmonary ventilation (The rate of rise of anaesthetic gas tension in arterial blood is directly dependent on both the rate and depth of respiration) 4. Cardiac output (An increase in cardiac output leads to an increase in pulmonary blood flow; thus, blood capacity increases and tension rises slowly. Therefore in circulatory shock, decreased pulmonary blood flow and increased ventilation may speed up the induction of anaesthesia with some anaesthetics particularly those with high blood solubility.

Cortical centres r basal ganglia r spinal cord r medulla According to Guedel (1920) the degree of nervous depression can be divided into four different stages, as may be observed with ether, equivalent to the cumulative effect on the above-mentioned CNS-centres. Stage I: Analgesia, and amnesia from start of induction to loss of consciousness. Stage II: Excitation (delirium or confusion, but definitely the patient is amnesic), from loss of consciousness to reestablishment of regular respiration.

An anaesthetic drug with high blood solubility, such as ether and methoxyflurane, may require a long time for induction, since the blood, which acts as a reservoir, can dissolve a large amount of gas. Halothane, which has a lower solubility in blood, will equilibrate rapidly and the partial pressure of this gas in blood therefore rises quickly. Further, nitrous oxide (N2O), which has a much lower solubility will achieve a quicker induction. Nitrous oxide is the commonly used inhalational anaesthetic that is a gas at ambient temperatures and pressure. All of the other inhalational anaesthetics are liquids at room temperature and pressure, require vapourisation before use.

Stage III: Surgical anaesthesia, from the beginning of regular respiration to respiratory arrest. This stage is divided into four planes, which have been described in terms of changes in ocular movements, eye reflexes, and pupil size; these under specified conditions may represent signs of increasing depth of anaesthesia. In practice, the most important indications that surgical anaesthesia has been achieved are loss of eyelash reflex and establishment of a respiratory pattern that is regular in rate and depth.

Minimum alveolar anaesthetic concentration (MAC) is defined as that concentration of anaesthetic agent in alveolar or end-expired gas that is present when 50%

Stage IV: Overdosage (stage of medullary depression or paralysis) from onset of diaphragmatic paralysis to cardiac arrest. 170


Majid A. K. Lafi

of the subjects do not respond when exposed to the skin incision (MAC=1.0, equivalent to effective dose in 50% of patients). The value of MAC is reduced in the elderly. In general, however, the dose-response relationship for

inhaled anaesthetics is steep. Over 95% of patients may exhibit a state of anaesthesia at 1.1 MAC.

Inspired r Face mask r Alveoli r Pulmonary r Arterial Gas upper airways PAa membrane blood PAi PAfm PApm PAab

Metabolised

CNS bbr Other bbbrs tissue tissue PAcns PAt

Fig.5.11 A schematic representation of pathways for uptake, distribution, and elimination of inhalational anaesthetic agents. PA = partial pressure of agent A; other subscripts refer to anatomical regions. Note elimination of the anaesthetic agents is usually achieved by the reverse of uptake of the agent (reverse arrows to expired air are not shown).

Table 5.20. Shows the values of MAC and PC in tissues of selected general anaesthetic agents. Note: nitrous oxide is poor anaesthetic compared with other inhalational agents.

Anaesthetic Agent Nitrous oxide

MAC*

Blood/Gas PC

Brain/Gas

Metabolism

PC

101.0

0.47

0.5

None

Desflurane

6-7

0.42

1.3

70% (fluoride)

Important remarks Rapid onset & recovery; incomplete anaesthetic Low volatility; poor induction; rapid recovery Medium rate of onset & recovery Medium rate of onset & recovery Medium rate of onset & recovery Slow onset & recovery Nephrotoxic

* Expressed as partial pressure of agent (in alveolar space) divided by standard total atmospheric pressure (×100) that produces immobility in 50% of patients exposed to a noxious stimuli; PC = partition coefficient (reflecting solubility of agent in tissue).

171



cellular threshold for firing. This in turn results in a decrease in neuronal activity1.

Note: An inhalational anaesthetic agent with low solubility in blood shows fast induction time and also recovery time (e.g. nitrous oxide), and an agent with relatively high solubility in blood shows slower induction and recovery time (e.g. halothane).

Ether Ether (diethyl ether) as an anaesthetic agent was first clinically demonstrated by William Morton (Massachusetts General Hospital, Boston, 1846).

The elimination of anaesthetic gases occurs mainly by the lungs and therefore the depth of the anaesthesia is easily controlled by assisted breathing (anaesthetic machine).

Ether is a volatile liquid with an unpleasant odour. It is highly flammable and explosive, therefore, cautery should not be used in operation; for this property it is now obsolete. Otherwise, it is a safe drug because it stimulates respiration and there is a wide margin between the dose to induce surgical anaesthesia and that to cause medullary paralysis.

Elimination of the anaesthetic is also dependent on the amount of drug bound to fat tissue in the body. The biological t of most anaesthetics is about 1 hour but total elimination of metabolites may require several days.

Ether anaesthesia is associated with release of endogenous catecholamines. It therefore induces bronchial dilatation and therefore can be used in patients with severe asthma. It produces good muscle relaxation, but induction is unpleasant, and nausea and vomiting may occur frequently upon emergence.

Second Gas Effect The MAC of an inhalational anaesthetic can be reduced by a concurrent use of another inhalational agent; thus, a concurrent use of nitrous oxide with halothane would reduce the MAC for halothane and also the presence of the latter would reduce the MAC for nitrous oxide. It has been suggested that the presence of agent (gas) facilitates the uptake (transport into the pulmonary blood) of the other agent. Therefore, it is called the second gas effect. This effect is utilised for using reduced inspired partial pressure for certain agents, particularly, nitrous oxide which has a high MAC (>100%) which is practically difficult to achieve. Further, a reduction in MAC can also be achieved by the use of adjuvant drugs like narcotic analgesics or sedative-hypnotics.

Ethyl Chloride is a liquid like ether and divinyl ether. It has a boiling point below normal room temperature and can be used both for induction and refrigeration anaesthesia when sprayed from a bottle onto the skin. Like divinyl ether, it is hepatotoxic.

Nitrous Oxide Nitrous oxide (N2O) is the oldest anaesthetic compound known. Horace Wells (Massachusetts General Hospital, Boston, 1845) was the first to describe the importance of its anaesthetic property in clinical practice. Today, it is the most commonly used inhalation anaesthetic agent despite its weak anaesthetic properties: even at its maximum safe concentration of 75% it still requires some supplementation to produce adequate surgical anaesthesia and skeletal muscle relaxation. Nitrous oxide is an inert gas,

Mechanism of Action Anaesthetic agents appear to concentrate in hydrophobic regions of cell membranes, causing the membrane to swell and altering the crystalline structure of the membrane. It has been suggested that most general anaesthetic agents have a common neurophysiological action that increasing the

1

Katzung, B. G. (1998) Basic & Clinical Pharmacology. 7th edition, Page 415. 172


Majid A. K. Lafi

which is compressed to a liquid, and stored in steel cylinders, coloured blue for identification. Nitrous oxide returns to the gaseous state when released from the cylinder. The gas is colourless and tasteless but has a faintly sweet odour. Nitrous oxide is sometimes called laughing gas. It induces euphoria and a dreamy state but its effect is mostly one of analgesia. Nitrous oxide does not depress respiration and in the absence of hypoxia there is no effect on the heart.

Methoxyflurane Methoxyflurane is the most potent inhalation anaesthetic with very good skeletal muscle relaxing properties. Its disadvantage is prolonged induction and emergence. Otherwise its properties are similar to halothane.

Intravenous Anaesthetics

Prolonged exposure to nitrous oxide decreases methionine synthase activity and may lead to megaloblastic anaemia. This is of a particular importance for staff working in poorly ventilated dental operating rooms.

Barbiturates Barbiturates are used mainly for induction of anaesthesia since the ultra-short acting barbiturates act rapidly without fear of an unpleasant mask and smell of inhalational anaesthetic agents. In sufficient amounts, these drugs can accomplish all the anaesthetic stages but they may cause serious cardiovascular suppression, therefore they are mainly used in combination with inhalational agents such as nitrous oxide and oxygen. Cerebral metabolism, O2 consumption are reduced with barbiturates in proportion to the cerebral suppression and also cerebral blood flow (CBF).

Halothane Halothane (1956), a fluorinated nonflammable hydrocarbon, is a clear, colourless, potent, volatile liquid, which gives smooth induction and comfortable recovery. Anaesthesia can be induced with concentration of 4-5% halothane in oxygen (as a loading dose analogous to that with digoxin priming). For maintenance a concentration of halothane should be reduced. For convenience a hypnotic dose of an i.v. anaesthetic is often used prior to halothane administration. Muscle relaxation is not always sufficient with halothane and can be supplemented by muscle relaxant drugs such as suxamethonium. The neuromuscular blocking actions of dtubocurarine are potentiated and is therefore advisable to use a reduced dose of this component.

Thiopental sodium Thiopental is the most commonly used intravenous anaesthetic in Iraq, usually in combination with inhaled general anaesthetics. The pharmacology of barbiturates is discussed in the sections on sedatives and hypnotics, and antiepiletic drugs. It is worth noting thiopental is useful in abreaction2. Degradation takes place mainly in the liver. For distribution and redistribution of thiopental see (Fig.5.12).

Cautions 1. Postpartum haemorrhage: Halothane causes relaxation of smooth muscle including the uterine muscle, which may give rise to postpartum haemorrhage. 2. Myocardial depressant properties and may induce bradycardia. 3. Respiratory depressant, as indicated by the reduced response to various levels of carbon dioxide. 4. Liver toxicity (halothane) has been observed especially after repeated administration. 173

Adverse Effects 1. Cardiac and respiratory depression 2. Bronchospasm

2

The reliving of an experience in such a way that previously repressed emotions associated with it are released.



Propofol Methohexital Propofol as intravenous anaesthetic is very much similar to thiopental. However, it produces anaesthesia with a more rapid recovery than that obtained with thiopental. Further, in the immediate postoperative period after propofol patients feel better as compared with other intravenous anaesthetics. Perhaps, the major advantage of propofol is that it has a useful antiemetic action. This probably is responsible for the observation that postoperative vomiting is uncommon with propofol.

It is another ultra-short acting barbiturate with similar pharmacological properties but differs chemically from thiopental in that it contains no sulphur.

Ketamine Ketamine is a phencyclidine (hallucinogen) derivative and an antagonist of the NMDAreceptor. It (is a mirror image of thiopental) produces cardiovascular stimulation and increases cerebral blood flow. It is known to produce dissociative anaesthesia (the patient seems awake but dissociated from the environment, responds to verbal commands but does not respond to painful stimuli). Emergence reaction characterised by hallucination is a frequent encounter with ketamine, diazepam is used to conteract this effect.

Etomidate Etomidate is a potent hypnotic (5 minutes) used for induction of anaesthesia. Its major advantages over other agents that it causes minimal cardiovascular and respiratory depressant effects. This drug has no analgesic actions; therefore, premedication with opioid may be required. It is known as an inhibitor of steroidogenesis.

Dose % 100-

Blood

Preanaesthetic Medication

Muscle

The objectives of the drugs that may be required as adjunct to the anaesthetic agents are:

Brain

50 -

1. Allay anxiety (e.g. diazepam) 2. Reduction of secretion (e.g. oropharyngeal surgery, atropine) 3. Reduction of parasympathetic preponderance ( children tend to show parasympathetic hyperresponsiveness, thus, antimuscarinic may be used in paediatric surgery) 4. Relax muscles (muscle relaxants) 5. Rapid induction of anaesthesia (shortacting barbiturate) 6. Prevent postsurgical nausea and vomiting (antiemetics)

Fat

1.0 -

0.1

0.5

1

4

16

64

256

Time (min) Fig.5.12. Redistribution of thiopental after intravenous bolus administration (the time axis is not linear). Note: The ultra-short acting thiopental rapidly crosses the blood brain barrier because of high lipid solubility (1 min.). Then, they diffuse out of the brain to other highly vascular (highly perfused tissues like skeletal muscle) and subsequently to poorly perfused adipose tissue. It is because of this rapid removal from the CNS that a single dose is so short acting. Metabolism is much slower than redistributed.

Other Agents 1. Midazolam (slow onset and recovery; flumazenil reversal available; used in balanced anaesthesia and conscious

174


Majid A. K. Lafi

sedation; cardiovascular stability; marked amnesia. 2. Fentanyl (slow onset and recovery; naloxone reversal available; used in balanced anaesthesia and conscious sedation; marked analgesia).

Neuroleptanaesthesia When a neuroleptic drug (like droperidol) and a narcotic analgesic drug (like fentanyl that is 80 times more potent that morphine, shorter onset and duration of action), are administered together to produce a

physiological state with somnolence (sleepiness), indifference, analgesia, amnesia, and patients are responsive to commands. This state is called neuroleptanalgesia that is useful for several diagnostic or minor surgical procedures like bronchoscopy, painful dressing, cystoscopy etc. Neuroleptanalgesia can be converted to neuroleptanaesthesia by the concurrent administration of 65% nitrous oxide in oxygen.

Table 5.21. A summary of the pharmacology of selected general anaesthetic agents Effect on CVS Resp.


INDUCTION (i.v.)

Thiopental

Ketamine

YES

YES

NO

YES

YES

NO

↓

↑

↓

Contraindicated in porphyria

NO

Increases cerebral blood flow. Contraindicated in open eye surgery, neurosurgery (brain), preeclampsia (hypertension); hypertensive, hallucinogenic, emergence delirium

MAINTENANCE (inhalational)

Halothane

YES

YES*

YES*

↓

↓

Nitrous oxide

YES*

YES

NO

Variable

Variable

* Not adequate

175

Dysrhythmogenic (sensitises heart), hepatotoxicity (avoid repeated administration in short period, 90 days), malignant hyperthermia; postpartum haemorage, Myocardial depressant properties (bradycardia), Respiratory depression Megaloblastic anaemia (prolonged exposure →↓ methionine synthase activity)

CNS-Pharmacology - Local Anaesthetics


LOCAL ANAESTHETIC DRUGS Introduction

Lidocaine

The first local anaesthetic agent was cocaine (obtained from the leaves of the South American shrub E. Coca) that was introduced into clinical practice by Koller in 1884 as an ophthalmic anaesthetic. Cocaine has powerful central stimulating side effects and induces dependence. The central stimulant effect is manifested in restlessness and excitement and eventually convulsions. This effect is shared by other nitrogen containing local anaesthetics. The central action of cocaine is also related to the ability to potentiate noradrenaline, this action is not shared by other local anaesthetics. When applied to the cornea cocaine anaesthetises the surface and induces mydriasis (enlargement of the pupil). Because of its adverse effects cocaine is not used in clinical medicine.

Lignocaine (lidocaine) is most common type of local anaesthetic agents in clinical practice and it is effective in all five forms of local anaesthesia: 1. Surface (e.g. lignocaine; proparacaine, Alcaine eye drops (0.5%); cinchocaine, Nupercainal ointment (1%), Proctosedyl ointment (0.5%). 2. Infiltration (e.g. lignocaine 0.25-0.5% with adrenaline) 3. Nerve block ( lignocaine 1-2% with adrenaline, e.g. pudendal nerve block as for episiotomy1) 4. Epidural (peridural) nerve block (lignocaine 1-2% with adrenaline) requires high skills. 5. Spinal nerve block (lignocaine) with the following disadvantages: a.headache due to CSF leakage b.hypotension due to block of the sympathetic nervous system c.potential of introducing bacteria

Procaine is the first synthetic local anaesthetic was introduced in 1905 and remained the dominant local anaesthetic for the next 50 years. Procaine is an example of a local anaesthetic with an ester-bond and therefore rapidly broken down by plasma cholinesterase. Procaine still had a considerable potential for producing adverse effects like local irritation and tissue damage in addition to systemic toxicity. At present, it is only used as an amide (procainamide) for cardiac arrhythmias and in procaine penicillin (that should not be given intravenously) for slow release of penicillin.

Mechanism of Action It is believed that the mechanism of action of local anaesthetics is primarily effected by blockade of voltage-gated sodium channels. These agents block sodium channels in a voltage- and time-dependent manner. Local anaesthetics exert their effect on excitable nerve axons and neuronal cell bodies (like the membrane of cardiac muscle) mostly when these cells with high firing activity and thus at more positive membrane potential. It is noted earlier (page 150) that local anaesthetics have a much higher affinity for the activated and inactivated states (usedependence) than the rested state of sodium channels. It follows that the effect of a given concentration of a local anaesthetic is more

The continued effort to find a better local anaesthetic agent lead to the synthesis of lignocaine (1943) by L fgren. To date, lignocaine (lidocaine, xylocaine) is still considered the prototype local anaesthetic agent. Although the development of new local anaesthetic agents continues but none showed significant reduction in toxicity as compared with that of the current agents. This is probably because the most serious toxicity of local anaesthetic agents is produced by the therapeutic effect on the brain and the cardiovascular system.

1

Episiotomy: surgical incision into the perineum and vagina for obstetrical purposes.

176


Majid A. K. Lafi

marked in rapidly firing axons than in resting neurones2.

The onset of local anaesthesia is sometimes accelerated by the use of solutions saturated with carbon dioxide. The high tissue level of CO2 results in intracellular acidosis (CO2 crosses membrane readily), which results in intracellular accumulation (trapping) of cationic form of the local anaesthetic. It must be noted that the cationic (ionised) form is thought to be the most active form at the local anaesthetic receptor site located within the voltage-dependent sodium channel; this is probably because the cationic form cannot readily leave the closed channels. Further, this local anaesthetic receptor is not accessible from the external side of the cell membrane. Unlike, the cationic drug form, the uncharged form can rapidly penetrate biological membranes.

Adverse Effects 1. Seizures and convulsions (use diazepam) 2. Cardiovascular depression

Combination with Vasoconstrictors Vasoconstrictor substances such as adrenaline reduces systemic absorption of local anaesthetics resulting in enhanced neuronal uptake of the drug and reduced systemic toxic effects of the drug. Such combination should not be given for the digits. Nowadays, the vasoconstrictor agent preferred to be used is a vasopressin receptor agonist like felypressin; vasopressin is supposed to be safer in patients with coronary artery disease.

Table 5.22. A summary of the pharmacology of selected local anaesthetic agents for infiltration anaesthesia. Time course of action

Agent

Tachyphylaxis

Procaine* Tetracaine*

Repeated injection of local anaesthetics during spinal and epidural anaesthesias (and for infiltration in tissue where there is pus) results in rapid loss of effectiveness (tachyphylaxis). This is probably a consequence of local extracellular acidosis. Local anaesthetics are weak bases and marketed as hydrochloride salts (pH 4 to 6) for reasons of solubility and stability. After injection, the salts are buffered in the tissue to physiological pH, thereby providing sufficient free base for diffusion through axonal membranes. However, repeated injections deplete the local available buffer. The ensuing acidosis increases the extracellular cationic form, which diffuses poorly into axons. The clinical result is apparent tachyphylaxis, especially in areas of limited buffer reserve, such as the cerebrospinal fluid. Therefore, an agent with a long duration of action like bupivacaine is preferred in this condition to avoid repeating the dose.

Lidocaine

Onset (min) 2-5 15 100 mg/dL), emergency haemodialysis is preferred to remove the salicylate more quickly and restore acid-base balance and fluid status. Sodium nitrite rapidly converts haemoglobin to methaemoglobin that binds CN, and thiosulphate promotes the formation of less toxic thiocyanate.



GLOSSARY AND ABBREVIATIONS Incomplete list of vocabulary adapted by and large from Dorland's Medical Dictionary (2000) W.B. Saunders 1, 25-DHCC: 1, 25-dihydroxycholecalciferol. 25-HCC: 25-hydroxycholecalciferol. Abortifacient: 1. causing abortion. 2. an agent which causes abortion. Abreaction: the reliving of an experience in such a way that previously repressed emotions associated with it are released. (Thiopental) Abscess: a localized collection of pus buried in tissues, organs, or confined spaces. Absence: the seizure seen in absence epilepsy, consisting of a sudden momentary break in consciousness of thought or activity, often accompanied by automatisms or clonic movements, especially of the eyelids. On the electroencephalogram it is characterized by a specific symmetrical spike and wave type occurring at three cycles per second. Abstinence: a refraining from the use of or indulgence in food, stimulants, or sexual intercourse. ACE: angiotensin converting enzyme ACh: acetylcholine. Achlorhydria: absence of hydrochloric acid from maximally stimulated gastric secretions; a result of gastric mucosal atrophy. Acne: an inflammatory disease of the pilosebaceous unit, the specific type usually being indicated by a modifying term; frequently used alone to designate common acne, or a. vulgaris. Acromegaly: a chronic disease of adults caused by hypersecretion of growth hormone, characterized by enlargement of many parts of the skeleton, especially distal portions such as the nose, ears, jaws, fingers, and toes. ACTH: (corticotrophin) adrenocorticotropic hormone. Acute intermittent porphyria: hereditary hepatic porphyria manifested by recurrent attacks of abdominal pain, gastrointestinal dysfunction, and neurological disturbances and by excessive amounts of aminolevulinic acid and porphobilinogen in the urine; it is due to an abnormality of pyrrole metabolism transmitted as an autosomal dominant trait. (Barbiturates) Acute: having a short and relatively severe course. Addiction: 1. the state of being given up to some habit or compulsion. 2. strong physiological and psychological dependence on a drug or other psychoactive substance. Addison s disease: a chronic type of adrenocortical insufficiency, characterized by hypotension, weight loss, anorexia, weakness, and a bronzelike hyperpigmentation of the skin. It is

260

due to tuberculosis- or autoimmune-induced destruction of the adrenal cortex, which results in deficiency of aldosterone and cortisol and is fatal in the absence of replacement therapy. ADH: (vasopressin) antidiuretic hormone. Adjunct: an accessory or auxiliary agent or measure. Adjuvant: 1. assisting or aiding. 2. a substance that aids another, such as an auxiliary remedy. 3. in immunology, a non-specific stimulator of the immune response, such as BCG vaccine. Adrenal crisis: acute onset of adrenocortical insufficiency or sudden worsening of Addison's disease; manifestations include anorexia, vomiting, abdominal pain, apathy, confusion, extreme weakness, renal loss of sodium and water, and hypotension progressing to shock and, if untreated, death. Adrenergic tremor: (enhanced physiological tremor) a tremor that may appear in normal individuals under conditions of stress, such as cold, excitement, hunger, or exercise; it represents an intensification of physiological tremor to detectable levels. Affect: the external expression of emotion attached to ideas or mental representations of objects. Agitation: excessive, purposeless cognitive and motor activity or restlessness, usually associated with a state of tension or anxiety Agoraphobia: intense, irrational fear of open spaces, characterized by marked fear of being alone or of being in public places where escape would be difficult or help might be unavailable. Agranulocytosis: 1. any condition involving greatly decreased numbers of granulocytes 2. more specifically, a symptom complex characterized by marked decrease in the number of circulating granulocytes; severe neutropenia results in lesions of the throat, other mucous membranes, gastrointestinal tract, and skin; in most cases it is caused by sensitization to drugs, chemicals, or radiation affecting the bone marrow and depressing granulopoiesis. Akathesia: a condition of motor restlessness in which there is a feeling of muscular quivering, an urge to move about constantly, and an inability to sit still, a common extrapyramidal side effect of neuroleptic drugs. Akinesia: see hypokinesia Alcoholism: a disorder characterized by a pathological pattern of alcohol use that causes a serious impairment in social or occupational functioning. Algesia: 1. pain sense. 2. excessive sensitivity to


Majid A.K. Lafi

pain, a type of hyperesthesia. Allergic rhinitis: a general term used to denote any allergic reaction of the nasal mucosa; it may occur perennially (nonseasonal allergic rhinitis) or seasonally (hay fever). Alopecia: lack or loss of the hair from skin areas where it normally is present. Altitudes sickness: the condition resulting from difficulty in adjusting to diminished oxygen pressure at high altitudes. It may take the form of mountain sickness, high-altitude pulmonary oedema, or cerebral oedema. Alzheimer s disease: a progressive degenerative disease of the brain of unknown aetiology, characterized by diffuse atrophy throughout the cerebral cortex with distinctive lesions called senile plaques and clumps of fibrils called neurofibrillary tangles. There is a loss of choline acetyltransferase activity in the cortex, and many of the degenerating neurons seem to be cholinergic neurons projecting from the substantia innominata to the cortex. The first signs of the disease are slight memory disturbance or changes in personality; deterioration progresses to profound dementia over 5 to 10 years. Women are affected twice as often as men, and onset may occur at any age. Amenorrhoea: absence or abnormal stoppage of the menses. (Oestrogens) AML: Acute Myeloid Leukaemia Amnesia: lack or loss of memory; inability to remember past experiences. Amoebiasis: he state of being infected with amoebae, especially with Entamoeba histolytica. Anaemia: a reduction below normal in the concentration of erythrocytes or hemoglobin in the blood, measured per cu mm or by volume of packed red cells per 100 mL of blood; it occurs when the equilibrium is disturbed between blood loss (through bleeding or destruction) and blood production. Analgesia: 1. absence of sensibility to pain; absence of pain on noxious stimulation. 2. the relief of pain without loss of consciousness. Anaphylactic shock: a type I hypersensitivity reaction in which exposure of a sensitized individual to a specific antigen or hapten results in urticaria, pruritus, and angioedema, followed by vascular collapse and shock and often accompanied by life-threatening respiratory distress. Angina pectoris: a paroxysmal thoracic pain, often radiating to the arms, particularly the left, sometimes accompanied by a feeling of suffocation and impending death; it is most often due to ischemia of the myocardium and precipitated by effort or excitement. Angioedema: a vascular reaction involving the deep dermis or subcutaneous or submucosal tissues, representing localized edema caused by dilatation and increased permeability of capillaries, and characterized by development of giant wheals.

261

Angioneurotic oedema: see angioedema Ankylosing spondylitis: a form of degenerative joint disease that affects the spine. It is a systemic illness of unknown etiology, affecting young persons predominantly, and producing pain and stiffness as a result of inflammation of the sacroiliac, intervertebral, and costovertebral joints; paraspinal calcification, with ossification and ankylosis of the spinal joints, may cause complete rigidity of the spine and thorax. Anorexia nervosa: an eating disorder primarily affecting females, usually with onset in adolescence, characterized by refusal to maintain a normal minimal body weight, intense fear of gaining weight or becoming obese, and a disturbance of body image resulting in a feeling of being fat or having fat in certain areas even when extremely emaciated, undue reliance on body weight or shape for self-evaluation, and amenorrhea. Associated features often include denial of the illness and resistance to psychotherapy, depressive symptoms, markedly decreased libido, and obsessions or peculiar behaviour regarding food, such as hoarding. Anorexia: lack or loss of the appetite for food. Antibiotic-associated enterocolitis: that in which treatment with antibiotics alters the bowel flora and results in diarrhea or pseudomembranous enterocolitis. Called also pseudomembranous colitis and antibiotic-associated colitis. Antigenicity: the property of being able to induce a specific immune response or the degree to which a substance is able to stimulate an immune response. Antinociception: having an analgesic effect; reducing sensitivity to painful stimuli. Antipsychotic: effective in the treatment of psychosis, or an agent that so acts. Antrectomy: surgical excision of an antrum, as resection of the pyloric antrum of the stomach. Anuria: complete suppression of urinary secretion by the kidneys. Anxiety: the unpleasant emotional state consisting of psychophysiological responses to anticipation of unreal or imagined danger, ostensibly resulting from unrecognized intrapsychic conflict. Physiological concomitants include increased heart rate, altered respiration rate, sweating, trembling, weakness, and fatigue; psychological concomitants include feelings of impending danger, powerlessness, apprehension, and tension. Apathetic: indifferent; undemonstrative. Apathy: lack of feeling or emotion; indifference. Aphthous ulcer: a small ulcer, such as the round lesion with a grayish exudate surrounded by a red halo characteristic of recurrent aphthous stomatitis Aplastic anaemia: any of a diverse group of anaemias characterized by bone marrow failure with reduction of hematopoietic cells and their replacement by fat, resulting in pancytopenia, often accompanied by granulocytopenia and



thrombocytopenia. It may be hereditary; it may be secondary to causes such as toxic, radiant, or immunologic injury to bone marrow stem cells or their microenvironment; it may be associated with various diseases; or it may be idiopathic. Appetite: a natural longing or desire, especially the natural and recurring desire for food. Arousal: 1. a state of responsiveness to sensory stimulation or excitability. 2. the act or state of waking from or as if from sleep. 3. the act of stimulating to readiness or to action. Ascites: effusion and accumulation of serous fluid in the abdominal cavity. Aseptic necrosis: increasing sclerosis and cystic changes in the head of the femur which sometimes follow traumatic dislocation of the hip. A similar condition sometimes develops in the head of the humerus after shoulder dislocation. Asthma: recurrent attacks of paroxysmal dyspnea, with airway inflammation and wheezing due to spasmodic contraction of the bronchi. Asystol: absence of a heartbeat Ataxia: failure of muscular coordination; irregularity of muscular action. Atonia: see atony. Atonic bladder: a condition marked by a dilated, poorly contracting urinary bladder without evidence of a lesion of the central nervous system. Atony: lack of normal tone or strength, such as in a muscle deprived of its innervation. Atopic dermatitis: a chronic type seen in those with a hereditary susceptibility to pruritus; it may be accompanied by allergic rhinitis, hay fever, and asthma. Attention deficit (hyperkinetic) disorder: a childhood mental disorder characterized by inattention (such as distractibility, forgetfulness, not finishing tasks, and not appearing to listen), by hyperactivity and impulsivity (such as fidgeting and squirming, difficulty in remaining seated, excessive running or climbing, feelings of restlessness, difficulty awaiting one's turn, interrupting others, and excessive talking) or by both types of behaviour. Autoallergy: autoimmunity. Azotaemia: an excess of urea or other nitrogen bodies in the blood (NSAIDs) BBB: blood brain barrier. BCG: Bacille Calmette-Guerin Benign prostatic hyperplasia: see prostatism. Bilateral renal stenosis: see renal artery stenosis. Bioequivalence: the quality of being bioequivalent. Bioequivalent: having the same strength and similar bioavailability in the same dosage form as another specimen of a given drug substance. Bipolar affective disorder: pertaining to mood disorders in which both depressive episodes and manic or hypomanic episodes occur. Bizarre: peculiar, weird, absurd. Bleeding oesophageal varices: pertaining to

262

bleeding of varicosities of the branches of the azygos vein which anastomose with tributaries of the portal vein in the lower oesophagus, occurring in patients with portal hypertension. Blood dyscrasia: a pathologic condition of the blood, usually referring to disorders of the cellular elements of the blood. Blurred vision: fuzzy image. Blush: sudden, brief erythema of the face and neck, resulting from vascular dilatation due to emotion or heat. Bonchoconstriction: constriction or narrowing the lumina of the air passages of the lungs, typically as a result of bronchial smooth muscle contraction. BPH : Benign prostatic hyperplasia. Bradycardia: slowness of the heartbeat, as evidenced by slowing of the pulse rate to less than 60. Bradykinesia: see hypokinesia Bronchiectasis: chronic dilatation of the bronchi marked by fetid breath and paroxysmal coughing, with the expectoration of mucopurulent matter. Brucellosis: in humans, a generalized infection caused by species of Brucella, transmitted by contact with the natural animal reservoirs, including cattle, sheep, goats, swine, deer, and rabbits, or their infected products or tissue. It involves primarily the reticuloendothelial system and is characterized by fever, sweating, weakness, malaise, and weight loss. Bulimia nervosa: an eating disorder occurring predominantly in females, with onset usually in adolescence or early adulthood and characterized by episodic binge eating followed by behaviours designed to prevent weight gain, including purging, fasting, and excessive exercise. BUN: blood urea nitrogen CAD: coronary artery disease Calculus: an abnormal concretion occurring within the body and usually composed of mineral salts. Carcinoid tumour: a yellow circumscribed tumor arising from enterochromaffin cells, usually in the small intestine, appendix, stomach, or colon and less commonly in the bronchus. Cardiomyopathy: a general diagnostic term designating primary noninflammatory disease of the heart muscle, often of obscure or unknown etiology and not the result of ischemic, hypertensive, congenital, valvular, or pericardial disease. Cardioversion: the restoration of normal rhythm of the heart by electrical shock. Cataracts: a partial or complete opacity on or in the lens or lens capsule of the eye, especially one impairing vision or causing blindness. Cathartic: 1. causing emptying of the bowels. 2. an agent that causes emptying of the bowels, such as by increasing bulk or stimulating peristaltic action. Called also evacuant and purgative. 3. producing emotional catharsis.


Majid A.K. Lafi

CBF: cerebral blood flow. CBG: corticosteroid binding globulin. Cellulitis: an acute, diffuse, spreading, edematous, suppurative inflammation of the deep subcutaneous tissues and sometimes muscle, sometimes with abscess formation; the skin is warm and tender. Central precocious puberty: precocious puberty due to premature hypothalamic-pituitary-gonadal maturation; it is always isosexual and involves not only development of secondary sex characters but also development of the gonads. Increases in height and weight and osseous maturation are accelerated, and early closing of the epiphyses leads to short stature. CGRP: calcitonin gene related peptide. Cheese effect: cheese contains substantial amounts of sympathomimetics, most commonly tyramine, which acts by releasing tissue-stored noradrenaline. For example, degradation of the protein 'casein' by resident bacteria in well matured cheese can produce tyramine from the amino acid tyrosine, hence use of the term 'cheese effect' to describe provocation of a hypertensive crisis by orally administered sympathomimetics. CHF: Congestive heart failure Chickenpox: (varicella) a highly contagious infectious disease caused by human herpesvirus 3, usually affecting children, spread by direct contact or the respiratory route via droplet nuclei, and characterized by the appearance on the skin and mucous membranes of successive crops of typical pruritic vesicular lesions that are easily broken and become scabbed, and generally accompanied by mild constitutional symptoms. Cholinergic crisis: muscular weakness resulting from depolarization block due to overdosage of anticholinesterase agents used for myasthenia gravis; similar to but different from myasthenic crisis. CHOP: cyclophosphamide, hydroxydonorubicin (doxorubicin), Oncovin (vincristine), and prednisone. Chorea: the ceaseless occurrence of a wide variety of rapid, highly complex, jerky movements that appear to be well coordinated but are performed involuntarily. (Drugs and movement disorders) Chorionepithelioma: an epithelial malignancy of trophoblastic cells, formed by the abnormal proliferation of cuboidal and syncytial cells of the placental epithelium, without the production of chorionic villi. Chronic bronchitis: a type of chronic obstructive pulmonary disease in which there is bronchial irritation with increased secretions and a productive cough for at least three months, two years in succession; it is usually accompanied by pulmonary emphysema. The most common cause is long-term inhalation of irritants. Chronic: persisting over a long period of time. Chronotropic: affecting the time or rate, as the

263

rate of contraction of the heart. Cinchonism: poisoning by the injudicious use of cinchona bark or its alkaloids, characterized by nausea, vomiting, headache, tinnitus, deafness, symptoms of cerebral congestion, vertigo, and visual disturbances. Closed-angle glaucoma: glaucoma caused by closure of the anterior angle by contact between the iris and the inner surface of the trabecular meshwork; called also closed-angle g., narrowangle g., and pupillary block g. CMV: cytomegalovirus CNS: central nervous system. Coitus: sexual connection per vaginam between male and female. Cold sweat: a sweat produced by the apocrine sweat glands, located on the palms of the hands and a few other areas, respond to adrenoceptor stimulants with increased sweat production. These are the apocrine nonthermoregulatory glands usually associated with psychological stress, e.g. an embarrassing situation. Collapse: 1. a state of extreme prostration and depression, with failure of circulation. 2. abnormal falling in of the walls of any part or organ. Compulsion: a persistent and irresistible impulse to perform an irrational or apparently useless act. 2. a compulsive act or ritual; a repetitive and stereotyped action, such as hand-washing, touching, counting, and checking, that is engaged in for an unknown or unconscious purpose. COMT: catechol-O-methyltransferase Concomitant: accompanying; accessory; joined with another. Confusion: disturbed orientation in regard to time, place, or person, sometimes accompanied by disordered consciousness. Congestion: excessive or abnormal accumulation of fluid, as of blood in a part. Congestive heart failure: (CHF) a clinical syndrome due to heart disease, characterized by breathlessness and abnormal sodium and water retention, often resulting in oedema. The congestion may occur in the lungs or peripheral circulation or both, depending on whether the heart failure is right-sided or general. Conjunctivitis: inflammation of the conjunctiva, generally consisting of conjunctival hyperaemia associated with a discharge. Constipation: infrequent or difficult evacuation of the faeces. Contraception: the prevention of conception or impregnation. Convulsion: a violent involuntary contraction or series of contractions of the voluntary muscles. COX: cyclooxgenase. Cretinism: a chronic condition due to congenital severe hypothyroidism; manifestations begin in late infancy and include arrested physical development (dwarfism), mental retardation, dystrophy of the



bones and soft parts, and lowered basal metabolism. Crohn s disease: a chronic granulomatous inflammatory disease of unknown aetiology, involving any part of the gastrointestinal tract from mouth to anus, but commonly involving the terminal ileum with scarring and thickening of the bowel wall; it frequently leads to intestinal obstruction and fistula and abscess formation and has a high rate of recurrence after treatment. Cryptorchism: failure of testes to descend to into the scrotum. (Non-pituitary gonadotropins) Crystalluria CSF: cerebrospinal fluid. Css: steady-state concentration. CTZ: chemoreceptor trigger zone. Cushing s syndrome: a complex of symptoms caused by hyperadrenocorticism due either to a neoplasm of the adrenal cortex or adenohypophysis, or to excessive intake of glucocorticoids. Symptoms may include adiposity of the face, neck, and trunk; kyphosis from osteoporosis of the spine; hypertension; diabetes mellitus; amenorrhea and hypertrichosis in females; impotence in males; dusky complexion with purple striae; polycythemia; and muscular wasting and weakness. Cushing-like syndrome: a complex of symptoms caused by hyperadrenocorticism due either to a neoplasm of the adrenal cortex or adenohypophysis, or to excessive intake of glucocorticoids. Symptoms may include adiposity of the face, neck, and trunk; kyphosis from osteoporosis of the spine; hypertension; diabetes mellitus; amenorrhoea and hypertrichosis in females; impotence in males; dusky complexion with purple striae; polycythaemia; and muscular wasting and weakness. Cycloplegia: paralysis of the ciliary muscle; paralysis of accommodation. Cystic fibrosis: cystic fibrosis of the pancreas, an autosomal recessive disorder of infants, children, and young adults in which there is widespread dysfunction of the exocrine glands, with signs of chronic pulmonary disease (due to excess mucus production in the respiratory tract), pancreatic deficiency, abnormally high levels of electrolytes in the sweat, and occasionally biliary cirrhosis. DAG: diacylglycerol Deep venous thrombosis: DVT; thrombosis of one or more of the deep veins of the lower limb, characterized by swelling, warmth, and erythema, frequently a precursor of a pulmonary embolism. Deleterious: hurtful; injurious. Delirium tremens: (alcohol withdrawal delirium) delirium caused by cessation or reduction in alcohol consumption, typically in alcoholics with 10 years or more of heavy drinking. Clinical manifestations include autonomic hyperactivity, such as tachycardia, sweating, and hypertension; a

264

coarse, irregular tremor, and delusions, vivid hallucinations; and wild, agitated behaviour. The onset is usually 2 or 3 days after cessation of drinking; the delirium and other withdrawal symptoms usually resolve in 3 or 4 days. Delirium: an acute, transient disturbance of consciousness accompanied by a change in cognition and having a fluctuating course. Delusion of jealousy: a delusional belief that one's spouse or lover is unfaithful based on erroneous inferences drawn from innocent events imagined to be evidence and often resulting in confrontation with the accused. It is one of the subtypes of delusional disorder. Delusion: a false belief that is firmly maintained in spite of undeniable and obvious proof or evidence to the contrary and in spite of the fact that other members of the culture do not share the belief. Dementia: a general loss of cognitive abilities, including impairment of memory as well as one or more of the following: aphasia, apraxia, agnosia, or disturbed planning, organizing, and abstract thinking abilities. Demulcent: 1. soothing; bland; allaying the irritation of inflamed or abraded surfaces. 2. a soothing, mucilaginous, or oily medicine or application. Dependent oedema: oedema affecting most seriously the lowermost or dependent parts of the body. Depression: 1. a hollow or depressed area; downward or inward displacement. 2. a lowering or decrease of functional activity. 3. a mental state of depressed mood characterized by feelings of sadness, despair, and discouragement. Depression ranges from normal feelings of ''the blues'' through dysthymic disorder to major depressive disorder. It in many ways resembles the grief and mourning that follow bereavement; there are often feelings of low self-esteem, guilt, and self-reproach, withdrawal from interpersonal contact, and somatic symptoms such as eating and sleep disturbances. Dermatophytoses: any superficial fungal infection caused by a dermatophyte and involving the stratum corneum of the skin, hair, and nails, including onychomycosis and the various forms of tinea. Diabetes insipidus: any of several types of polyuria in which the volume of urine exceeds 3 litres per day, causing dehydration and great thirst, as well as sometimes emaciation and great hunger. Diabetic neuropathy: any of several clinical types of peripheral neuropathy occurring with diabetes mellitus; there are sensory, motor, autonomic, and mixed varieties. The most common kind is a chronic, symmetrical sensory polyneuropathy affecting first the nerves of the lower limbs and often affecting autonomic nerves; pathologically, there is a segmental demyelination of the


Majid A.K. Lafi

peripheral nerves. An uncommon acute form is the ischemic variety, accompanied by severe pain, weakness, and wasting of proximal and distal muscles, peripheral sensory impairment, and loss of tendon reflexes. With autonomic involvement there may be orthostatic hypotension, nocturnal diarrhea, retention of urine, impotence, and small diameter of the pupils with sluggish reaction to light. Diabetogenic: producing diabetes Diaphoresis: sweating, especially of a profuse type. Diarrhoea: abnormal frequency and liquidity of faecal discharges. DIC: Disseminated intravascular coagulation Diphtheria: an acute infectious disease caused by toxigenic strains of Corynebacterium diphtheriae, acquired by contact with an infected person or a carrier; it is usually confined to the upper respiratory tract, and characterized by the formation of a tough false membrane attached firmly to the underlying tissue that will bleed if forcibly removed. In the most serious infections the membrane begins in the faucial area on one tonsil and may spread to the other tonsil, uvula, soft palate, and pharyngeal wall, followed by the larynx, trachea, and bronchial tree, where it may cause bronchial obstruction and death by hypoxia. Diplopia: the perception of two images of a single object. Disinhibition: 1. removal of inhibitions, as reduction of the inhibitory function of the cerebral cortex by drugs such as ethyl alcohol or reduction in the severity of superego controls in psychotherapy. 2. in experimental psychology, the revival of an extinguished conditioned response by exposure to an unconditioned stimulus. Dissociative anaesthesia: loss of sensitivity to pain, heat, and cold without loss of other tactile senses. Disulfiram-like reaction: a syndrome occurring after inhalation or ingestion of disulfiram followed by drinking an alcoholic beverage, marked by intense flushing, rapid pulse and pounding heart, panting respiration, and impaired taste, unpleasant breath and perspiration, which may be followed by nausea, vomiting, and a precipitous fall in blood pressure; the extent and severity of the symptoms depend on the amount of calcium cyanamide and alcohol in the system. The reactions are due to the inhibition by disulfiram of one or more of the enzymes required for oxidation of acetaldehyde formed from alcohol, resulting in the accumulation of acetaldehyde and the altered vascular reaction to it. Dizziness: a disturbed sense of relationship to space; a sensation of unsteadiness with a feeling of movement within the head. DMARD: disease-modifying antirheumatic drug. Dosage: the determination and regulation of the

265

size, frequency, and number of doses. Dromotropic: affecting the conductivity of a nerve fiber Dropsical: oedematous. Drowsiness: sleepiness. Drug Abuse: a substance use disorder characterized by the use of a mood or behaviouraltering substance in a maladaptive pattern resulting in significant impairment or distress, such as failure to fulfil social or occupational obligations or recurrent use in situations in which it is physically dangerous to do so or which end in legal problems, but without fulfilling the criteria for substance dependence (q.v.). Specific disorders are named for their aetiology, eg., alcohol abuse, anabolic steroid abuse. Ductus arteriosus: arterial duct: a fetal blood vessel connecting the left pulmonary artery directly to the descending aorta. Dysfunctional uterine bleeding: bleeding from the uterus when no organic uterine lesions are present. Dysmenorrhoea: Painful menstruation (NSAIDs) Dyspepsia: impairment of the power or function of digestion; usually applied to epigastric discomfort following meals. Dysphoria: disquiet; restlessness; malaise (Opioids and narcotic analgesics) Dyspnoea: breathlessness or shortness of breath; difficult or laboured breathing. Dystocia: abnormal labour or childbirth (NSAIDs) Dystonia: dyskinetic movements due to disordered tonicity of muscle. ECL: enterochromaffin-like. ECT: electroconvulsive therapy. Ectopic beats: a heart beat originating at some point other than the sinus node. Emotion: a strong feeling state, such as excitement, distress, happiness, sadness, love, hate, fear, or anger, arising subjectively and directed toward a specific object, with physiological, somatic, and behavioural components. In psychoanalytic theory, it is a state of tension associated with an instinctual drive. The external manifestation of emotion is called affect; a pervasive and sustained emotional state, mood. Empirical: based on experience. Encephalopathy: any degenerative disease of the brain. Endemic: present or usually prevalent in a population or geographical area at all times; said of a disease or agent. and proliferative Endocarditis: exudative inflammatory alterations of the endocardium, usually characterized by the presence of vegetations on the surface of the endocardium or in the endocardium itself, and most commonly involving a heart valve, but sometimes affecting the inner lining of the cardiac chambers or the endocardium elsewhere. It may occur as a primary



disorder or as a complication of or in association with another disease. Endometrial cancer: carcinoma characterized by glandular patterns that resemble those of the endometrium, occurring in the uterine fundus and in the ovaries. Endometriosis: a condition in which tissue more or less perfectly resembling the uterine mucous membrane (the endometrium) and containing typical endometrial granular and stromal elements occurs aberrantly in various locations in the pelvic cavity. (Progestins, danazol) Endophathalmitis: nflammation involving the ocular cavities and their adjacent structures. Enema: a liquid injected or to be injected into the rectum Enuresis: urinary incontinence after the age at which urinary control should have been achieved; often used alone with specific reference to that occurring during sleep at night (bed-wetting; nocturnal enuresis) Eosinophilia: 1. the formation and accumulation of an abnormally large number of eosinophils in the blood. 2. the condition of being readily stained with eosin. EP: extrapyramidal. Epidural (peridural) nerve block. regional anaesthesia produced by injection of the anaesthetic agent between the vertebral spines and beneath the ligamentum flavum into the epidural space. Epilepsy: any of a group of syndromes characterized by paroxysmal transient disturbances of the brain function that may be manifested as episodic impairment or loss of consciousness, abnormal motor phenomena, psychic or sensory disturbances, or perturbation of the autonomic nervous system. Epileptoform: 1. resembling epilepsy or its manifestations. 2. occurring in severe or sudden paroxysms. Episiotomy: surgical incision into the perineum and vagina to prevent traumatic tearing during delivery. EPSP: excitatory postsynaptic potential. Erotomania: 1. a disorder in which the subject believes that a person, usually older and of higher social status, is deeply in love with them; failure of the object of the delusion to respond to the subject's advances are rationalized, and pursuit and harassment of the object of the delusion may occur. 2. occasionally, hypersexuality. ESBLs: extended spectrum -lactamases Essential tremor: a hereditary tremor with onset at varying ages, usually at about 50 years of age, beginning with a fine rapid tremor (as distinct from that of parkinsonism) of the hands, followed by tremor of the arms, tongue, head, legs, and trunk; it is aggravated by emotional factors, is accentuated by volitional movement, and in some cases is

266

temporarily improved by alcohol. Euphoria: bodily comfort; well being; absence of pain or distress. In psychiatry, an abnormal or exaggerated sense of well being, particularly common in the manic state. (Opioids and narcotic analgesics, glucocorticoids) Excipient: any more or less inert substance added to a prescription in order to confer a suitable consistency or form to the drug; called also vehicle. Expectorant: 1. promoting the ejection, by spitting, of mucus or other fluids from the lungs and trachea. 2. an agent that promotes the ejection of mucus or exudate from the lungs, bronchi, and trachea; sometimes extended to all remedies that quiet cough (antitussives). Extrasystole: a weak systole, usually premature, not associated with pulsation of a peripheral artery Extremity: an upper or lower limb ( a hand or foot) Febrile: 1. pertaining to fever. 2. characterized by fever. Fever: elevation of body temperature above the normal Fibrosis: the formation of fibrous tissue, as in repair or replacement of parenchymatous elements. Flush: 1.transient, episodic redness of the face and neck caused by certain diseases, ingestion of certain drugs or other substances, heat, emotional factors, or physical exertion. 2. to wash out with fluid. Foetal alcohol syndrome: a syndrome of altered prenatal growth and morphogenesis occurring in infants born of women who were chronically alcoholic during pregnancy; it includes maxillary hypoplasia, prominence of the forehead and mandible, short palpebral fissures, microphthalmia, epicanthal folds, severe growth retardation, mental retardation, and microcephaly. Foetal: of or pertaining to a foetus; pertaining to in utero development after the embryonic period. FSH: follicle-stimulating hormone. GABA: γ-aminobutyric acid. GAD: generalised anxiety disorder. Gastroenteritis: an acute inflammation of the lining of the stomach and intestines, characterized by anorexia, nausea, diarrhea, abdominal pain, and weakness, which has various causes, including food poisoning due to infection with such organisms as Escherichia coli, Staphylococcus aureus, and Salmonella species; consumption of irritating food or drink; or psychological factors such as anger, stress, and fear. Gastroparesis: paralysis of the stomach. GERD: gastroesophageal reflux disease. Gestational diabetes: diabetes mellitus with onset or first recognition during pregnancy; this category does not include diabetics who become pregnant or women who become lactosuric. GFR: glomerular filtration rate. GH: (somatropin) growth hormone.


Majid A.K. Lafi

Gigantism: abnormal overgrowth; excessive size and stature. Gingivitis: inflammation of the gingivae. GIT: gastrointestinal tract Glaucoma: a group of eye diseases characterized by an increase in intraocular pressure that causes pathological changes in the optic disk and typical defects in the field of vision. Glycogenolysis: the breakdown of glycogen to glucose by hydrolysis (as in digestion or within lysosomes) or phosphorolysis (as in mobilization of glycogen as a fuel). Gn: gonadotropin. GnRH: gonadotropin-releasing hormone. Goitre: an enlargement of the thyroid gland, causing a swelling in the front part of the neck. Gout: a group of disorders of purine metabolism, manifested by various combinations of (1) hyperuricaemia; (2) recurrent acute inflammatory arthritis induced by crystals of monosodium urate monohydrate; (3) tophaceous deposits of these crystals in and around the joints of the extremities, which may lead to crippling destruction of joints; and (4) uric acid urolithiasis. Granulocytopenia: reduction in the number of granular leukocytes in the blood. Graves disease: a syndrome of diffuse hyperplasia of the thyroid, with a female predominance; it usually has an autoimmune aetiology and has been linked to autoimmune thyroiditis. Characteristics include hyperthyroidism, usually with goitre and ophthalmic symptoms (Graves' orbitopathy). Grey baby syndrome: a potentially fatal condition seen in neonates, particularly premature infants, due to a reaction to chloramphenicol, characterized by an ashen gray cyanosis, listlessness, weakness, and hypotension. GTN: glyceryltrinitrate Gynaecomastia: excessive growth of the male mammary glands, in some cases including development to the stage at which milk is produced, usually associated with metabolic derangements that lead to oestrogen accumulation, testosterone deficiency, and hyperprolactinaemia. A mild form may develop transiently during normal puberty. Habitual abortion: the spontaneous expulsion of a dead or nonviable foetus in three or more consecutive pregnancies, at about the same period of development. Haematuria: blood in the urine Haemophilia: a hemorrhagic diathesis occurring in two main forms: haemophilia A, deficiency of coagulation factor VIII; and haemophilia B, deficiency of coagulation factor IX. Both forms are determined by a mutant gene near the telomere of the long arm of the X chromosome (Xq), but at different loci, and are characterized by

267

subcutaneous and intramuscular haemorrhages; bleeding from the mouth, gums, lips, and tongue; haematuria; and haemarthroses. Haemorrhoids: a varicose dilatation of a vein of the superior or inferior hemorrhoidal plexus, resulting from a persistent increase in venous pressure. Hallucination: a sense perception without a source in the external world; a perception of an external stimulus object in the absence of such an object. Hangover: extended beyond. Hashimoto s autoimmune thyroiditis: a progressive type of autoimmune thyroiditis with lymphocytic infiltration of the gland and circulating antithyroid antibodies; patients have goitre and gradually develop hypothyroidism. It has a familial predisposition, usually affects women, and sometimes precedes the onset of Graves' disease or is manifested after the major symptoms subside. Hay fever: a type of allergic rhinitis that occurs at the same time every year, marked by acute conjunctivitis with lacrimation and itching, swelling of the nasal mucosa, sneezing, and often asthmatic symptoms. hCG: human chorionic gonadotropin. Heart block: impairment of conduction of an impulse in heart excitation; often applied specifically to atrioventricular block. Hepatotoxicity: the quality or property of exerting a destructive or poisonous effect upon liver cells. Herpes simplex: a group of acute infections caused by human herpesviruses 1 and 2, characterized by the development of one or more small fluid-filled vesicles with a raised erythematous base on the skin or mucous membrane, and occurring as a primary infection or recurring because of reactivation of a latent infection. Type 1 infections usually involve nongenital regions of the body, whereas in type 2 infections the lesions are primarily seen on the genital and surrounding areas, although there is overlap between the two types. Hiatus hernia: a condition of incompetent gastrooesophageal sphincters. Hiccup: an involuntary spasmodic contraction of the diaphragm, causing a beginning inspiration that is suddenly checked by closure of the glottis, causing a characteristic sound. Hirsutism: abnormal hairiness, especially an adult male pattern of hair distribution in women. hMG: human menopausal gonadotropin. Huntington s chorea: a rare hereditary disease characterised by chronic progressive chorea and mental deterioration terminating in dementia; the age of onset is variable but usually occurs in the fourth decade of life. Death usually follows within 15 years. It is transmitted as an autosomal dominant trait. (Drugs and movement disorders) Huntington s chorea: an autosomal dominant



disease characterized by chronic progressive chorea and mental deterioration terminating in dementia; the age of onset is variable but usually in the fourth decade of life, with death within 15 years. Huntington s disease: see Huntington s chorea Hydatidiform mole: an abnormal pregnancy resulting from a pathological ovum, with proliferation of the epithelial covering of the chorionic villi and dissolution and cystic cavitation of the avascular stroma of the villi. Hydrothorax: a pleural effusion containing serous fluid. Hyperactive child: see Attention deficit (hyperkinetic) disorder Hypercalcaemia: an excess of calcium in the blood; manifestations include fatigability, muscle weakness, depression, anorexia, nausea, and constipation. Hypercalciuria: excess of calcium in the urine. Hyperchloraemic acidosis: metabolic acidosis accompanied by elevated plasma chloride. Hyperglycaemia: abnormally increased glucose in the blood, such as in diabetes mellitus. Hyperkinetic child: see Attention deficit (hyperkinetic) disorder an abnormally high Hypermagnesaemia: magnesium content of the blood; manifestations include lethargy, weakness, electrocardiographic abnormalities and, as levels increase, loss of deep tendon reflexes, somnolence, and coma. Hyperplasia: abnormal multiplication or increase in the number of normal cells in normal arrangement in a tissue. Hyperplasminaemia: abnormally increased plasmin in the blood. Hyperprolactinaemia: increased levels of prolactin in the blood; in women it is associated with amenorrhea and galactorrhoea, and in men it has been reported to cause hypogonadism, impotence, and in some cases gynaecomastia. It is often associated with microadenoma of the adenohypophysis. Hypersexuality: abnormally increased sexual desire or activity; nymphomania; satyriasis. Hypersomnia: excessive sleeping or sleepiness, as in any of a group of sleep disorders with a variety of physical and psychogenic causes. Hypertension: high arterial blood pressure; various criteria for its threshold have been suggested, ranging from 140 mm Hg systolic and 90 mm Hg diastolic to as high as 200 mm Hg systolic and 110 mm Hg diastolic. Hypertension may have no known cause (essential or idiopathic h.) or be associated with other primary diseases (secondary h.). Hypertensive crisis: dangerously high blood pressure of acute onset. Hyperthermia of anaesthesia: see malignant hyperthermia.

268

Hyperthyroidism: a condition caused by excessive production of iodinated thyroid hormones. Hypertrophy: the enlargement or overgrowth of an organ or part due to an increase in size of its constituent cells. Hyperuricaemia: excess of uric acid or urates in the blood; it is a prerequisite for the development of gout and may lead to renal disease. Hypoadrenalism: adrenal insufficiency. Hypoglycaemia: an abnormally diminished concentration of glucose in the blood, which may lead to tremulousness, cold sweat, piloerection, hypothermia, and headache; when chronic and severe it may cause central nervous system manifestations that in rare cases can even be fatal. Hypokalaemia: abnormally low potassium concentration in the blood; it may result from excessive potassium loss by the renal or the gastrointestinal route, from decreased intake, or from transcellular shifts. It may be manifested clinically by neuromuscular disorders ranging from weakness to paralysis, by electrocardiographic abnormalities (depression of the T wave and elevation of the U wave), by renal disease, and by gastrointestinal disorders. Hypokinesia: (bradykinesia, akinesia) slowness of movements (Drugs and movement disorders) Hypomania: an abnormality of mood resembling mania (persistent elevated or expansive mood, hyperactivity, inflated self-esteem, etc.) but of lesser intensity. Hypophosphotaemia: an abnormally decreased amount of phosphates in the blood; manifestations include haemolysis, lassitude, weakness, and convulsions. Hypotension: abnormally low blood pressure. Hypothalamic hypogonadotropic hypogonadism: that due to lack of gonadotropin secretion; it is caused by lack of secretion of gonadotropin-releasing hormone. Hypothyroidism: deficiency of thyroid activity, characterized by decrease in basal metabolic rate, fatigue, and lethargy; if untreated, it progresses to myxoedema. In adults it is more common in women than men, and in infants it can lead to cretinism. Hypothyroidism: deficiency of thyroid activity, characterized by decrease in basal metabolic rate, fatigue, and lethargy; if untreated, it progresses to myxoedema. In adults it is more common in women than men, and in infants it can lead to cretinism. Hypotonic bladder: a condition of diminished tone of the detrusor muscle of the urinary bladder. Hypoxia: reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. i.m.: intramuscular. i.v.: intravenous.


Majid A.K. Lafi

IDDM: insulin dependent diabetes mellitus. Idiopathic: of unknown cause or spontaneous origin; of the nature of an idiopathy. Ileus: obstruction of the intestines. Immune insulin resistance: see insulin resistance. Impulse dyscontrol syndrome: a pattern of episodic, abnormal, and often violent and uncontrollable social behaviour with little or no provocation; it may result from diseases of the limbic system or the temporal lobe or may accompany abuse of alcohol or some other psychoactive substance. Incontinence: 1. inability to control excretory functions, such as defecation (fecal i.) or urination (urinary i. ). Infant respiratory distress syndrome: dyspnoea with cyanosis in the newborn, heralded by such prodromal signs as dilatation of the alae nasi, expiratory grunt, and retraction of the suprasternal notch or costal margins, caused by a deficiency in surfactant. It is usually seen in premature infants, children of diabetic mothers, or infants delivered by caesarean section, although sometimes there is no apparent predisposing cause. Infertility: diminished or absent capacity to produce offspring; the term does not denote complete inability to produce offspring as does sterility. Inotropic: affecting the force or energy of muscular contractions. INR: international normalized ratio. Insomnia: inability to sleep; abnormal wakefulness. Insulin resistance: impairment of normal biological responses to insulin, which may result from abnormalities in the beta-cell products, binding of insulin to antagonists such as antiinsulin antibodies, defects in or reduced numbers of receptors, or defects in the insulin action cascade in the target cell. It can also be caused by excessive quantities of growth hormone, adrenocortical steroids, or some other regulators, or by chronic hyperinsulinaemia secondary to hyperphagia. Incidence is increased with conditions such as obesity, diabetes mellitus, acromegaly, uraemia, and certain rare, possibly genetic, autoimmune disorders. Insulinogenic: pertaining to, characterized by, or promoting insulinogenesis. Insulinoma: an islet cell tumor of pancreatic beta cells; although usually benign, such tumours secrete excessive amounts of insulin and are among the most important causes of hypoglycemia. Intermittent claudication: a complex of symptoms characterized by pain, tension, and weakness in a limb when walking is begun, intensification of the condition until walking becomes impossible, and disappearance of the symptoms after a period of rest. It is seen in occlusive arterial diseases of the limbs, such as

269

thromboangiitis obliterans, and in compression of the cauda equina. Intermittent: occurring at separated intervals; having periods of cessation of activity. Intractable: resistant to cure, relief, or control. IPSP: inhibitory postsynaptic potential. Iritis: inflammation of the iris, usually marked by pain, congestion in the ciliary region, photophobia, contraction of the pupil, and discoloration of the iris. Iron deficiency: deficiency of iron in the system, usually caused by blood loss, low dietary levels of iron, or a disease condition that inhibits iron uptake. Irritable bowel syndrome: irritable colon syndrome, a chronic noninflammatory disease characterized by abdominal pain, altered bowel habits consisting of diarrhea or constipation or both, and no detectable pathologic change; a variant form is characterized by painless diarrhea. It is a common disorder with a psychophysiological basis. ISA: intrinsic sympathomimetic activity Kaliuretic: 1. pertaining to, characterized by, or promoting kaliuresis. 2. an agent that promotes kaliuresis (potassium losing). Kernicterus: a condition associated with high levels of bilirubin in the blood, nearly always with severe neural symptoms, usually seen in infants as a sequela of icterus gravis neonatorum. Lactic acidosis: a metabolic acidosis occurring as a result of excess lactic acid in the blood, due to conditions causing impaired cellular respiration. It occurs most commonly in disorders in which O2 is inadequately delivered to tissues, e.g., shock, septicemia, or extreme hypoxemia, but it can also result from exogenous or endogenous metabolic defects. Initially manifesting as hyperventilation, it progresses to mental confusion and coma. Legionnaires disease: a bacterial disease caused by infection with Legionella pneumophila, and not spread by person-to-person contact; it is characterized by pneumonia, high fever, gastrointestinal pain, headache, and sometimes involvement of the kidneys, liver, or nervous system. Leucocytosis: a transient increase in the number of leukocytes in the blood; seen normally with strenuous exercise and pathologically accompanying haemorrhage, fever, infection, or inflammation. LH: luteinizing hormone. Libido: 1. sexual desire. 2. the psychic energy derived from instinctive biological drives; in early freudian theory it was restricted to the sexual drive, then expanded to include all expressions of love and pleasure, but the concept has evolved to include also the death instinct. LOX: lipoxygenase. LSD: lysergide.



Lupus erythematosus: a group of connective tissue disorders primarily affecting women aged 20 to 40 years, comprising a spectrum of clinical forms in which cutaneous disease may occur with or without systemic involvement. Luteolysis: degeneration of corpus luteum. Lymphogranuloma venereum: a sexually transmitted infection usually seen in warm climates, due to strains of Chlamydia trachomatis, characterized by a primary cutaneous or mucosal lesion at the site of infection, which may be a papular, ulcerative, herpetiform, or erosive lesion or urethritis or endocervicitis that heals spontaneously and may go unnoticed, followed by acute unilateral or bilateral lymphadenopathy. Malaise: a vague feeling of bodily discomfort. Malignant hyperthermia: an autosomal dominantly inherited condition, occurring in patients undergoing general anaesthesia, and causing a sudden, rapid rise in body temperature, associated with signs of increased muscle metabolism, such as tachycardia, tachypnoea, sweating, and cyanosis, usually, muscle rigidity. Called also hyperthermia of anaesthesia and malignant hyperpyrexia. (General anaesthetic agents, antipsychotic neuroleptic drugs, dantroline) Mania: a phase of bipolar disorder characterized by expansiveness, euphoria, agitation, hyperexcitability, hyperactivity, and increased speed of thought and speech (flight of ideas). Manic-depressive illness: older term for bipolar disorder, see bipolar affective disorder. MAO: monoamine oxidase. Megaloblastic: any anaemia characterized by the presence of megaloblasts in the bone marrow, such as pernicious anaemia. Meningitis: inflammation of the meninges, usually by either a bacterium (bacterial m.) or a virus (viral m.). Menopausal symptoms: including transient vaginal bleeding, hot flushes, and vaginal dryness. Menopausal: pertaining to or associated with the menopause. Menopause: cessation of menstruation in the human female, occurring usually between the age of 48 and 50. Menorrhagia: excessive uterine bleeding at the regular intervals of menstruation, the period of flow being greater than usual duration. (Progestins) Menstrual disorder: a derangement or abnormality of function related to menstruation. Metabolic alkalosis: any of the various kinds of acidosis in which the acid-base status of the body shifts toward the acid side because of loss of base or retention of acids other than carbonic acid (fixed or nonvolatile acids), in contrast to respiratory acidosis. Metallic: pertaining to, consisting of, or of the nature of metal.

270

Methemoglobinemia: the presence of excessive methemoglobin in the blood, resulting in cyanosis and headache, dizziness, fatigue, ataxia, dyspnea, tachycardia, nausea, vomiting, and drowsiness, which can progress to stupor, coma, and occasionally death. It may be either chemicalor drug-induced (acquired or toxic m.) or hereditary (congenital or hereditary m.). MIC: minimum inhibitory concentration Micturition: urination. Migraine: an often familial symptom complex of periodic attacks of vascular headache, usually temporal and unilateral in onset, commonly associated with irritability, nausea, vomiting, constipation or diarrhoea, and often photophobia. Attacks are preceded by constriction of the cranial arteries, often with resultant prodromal sensory (especially ocular) symptoms and the spreading depression of Le o; the migraines themselves commence with the vasodilatation that follows. Two primary types are distinguished, m. with aura and m. without aura; the variety without an aura is more common. Milk-alkali syndrome: a syndrome characterized by hypercalcaemia without hypercalciuria or hypophosphataemia, with only mild alkalosis, normal serum phosphatase, severe renal insufficiency with hyperazotaemia, and calcinosis, attributed to ingestion of milk and absorbable alkali for long periods of time. Miosis: contraction of the pupil. Mood: a pervasive and sustained emotion that, when extreme, can colour one's whole view of life and markedly affect behaviour. Mood is generally used to refer to either elation or depression. Morbid jealousy: preoccupation with gloomy or distrustful feelings or thoughts, see delusion of jealousy. Morbid: 1. pertaining to, affected with, or inducing disease; diseased. 2. unhealthy or unwholesome. 3. characterized by preoccupation with gloomy or unwholesome feelings or thoughts. Morbidity: 1. a diseased condition or state. 2. the incidence or prevalence of a disease or of all diseases in a population. Mortality: 1. the quality of being mortal. 2. the mortality rate. Motion sickness: sickness caused by motion experienced in any kind of travel, such as sea sickness, train sickness, car sickness, and air sickness. MRSA: Methicillin Resistant Staphylococcus Aureus. MSA: membrane stabilising activity. Mucolytic: destroying or dissolving mucin; an agent that so acts. Myasthenia gravis: a disorder of neuromuscular function due to the presence of antibodies to acetylcholine receptors at the neuromuscular


Majid A.K. Lafi

junction; characteristics include muscular fatigue and exhaustion tending to fluctuate in severity, without sensory disturbance or atrophy. It may be restricted to one muscle group or become generalized with severe weakness and sometimes ventilatory insufficiency. It may affect any muscle of the body, but especially those of the eye, face, lips, tongue, throat, and neck. Mydriasis: 1. physiologic dilatation of the pupil. 2. morbid dilatation of the pupil. 3. dilatation of the pupil effected by a drug. Myocardial infarction: (MI) gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. Myoclonic: relating to or marked by myoclonus. Myoclonus: shocklike contractions of a portion of a muscle, an entire muscle, or a group of muscles, restricted to one area of the body or appearing synchronously or asynchronously in several areas. It may be part of a disease process (e.g., epileptic or post-anoxic myoclonus) or be a normal physiological response (e.g., nocturnal myoclonus). Myxoedema: 1. a condition characterized by dry, waxy swelling of the skin, with abnormal deposits of glycosaminoglycans in skin (mucinosis) and other tissues, associated with primary hypothyroidism. The oedema is nonpitting, and there are distinctive facial changes including swollen lips and a thickened nose. 2. hypothyroidism in adults. NABQI: N-acetyl-benzoquinone. Narcolepsy: recurrent, uncontrollable, brief episodes of sleep often associated with hypnagogic or hypnopompic hallucinations, cataplexy, and sleep paralysis. Narcotic: 1. pertaining to or producing narcosis. 2. an agent that produces insensibility or stupor, applied especially to the opioids, i.e., to any natural or synthetic drug that has morphine-like actions. Necrosis: the sum of the morphological changes indicative of cell death and caused by the progressive degradative action of enzymes; it may affect groups of cells or part of a structure or an organ. Negative symptoms: (retarded schizophrenia) minus personality features including apathy, flattening of affect and poverty of speech. Neonatal: pertaining to the first four weeks after birth. Nephrogenic diabetes insipidus: diabetes insipidus caused by failure of the renal tubules to reabsorb water in response to antidiuretic hormone, without disturbance in the renal filtration and solute excretion rates; the condition does not respond to exogenous vasopressin. It may be inherited as an X-linked trait or be acquired as a result of drug therapy or systemic disease.

271

Nephrotic syndrome: general name for any of a group of diseases involving defective kidney glomeruli, characterized by massive proteinuria and lipiduria with varying degrees of oedema, hypoalbuminaemia, and hyperlipidaemia Nerve block: that is, injection of the anaesthetic agent close to the nerves whose conductivity is to be cut off. Neuralgia: see trigeminal neuralgia. Neurogenic: 1. forming nervous tissue. 2. originating in the nervous system or from a lesion in the nervous system. Neuroleptanaesthesia: a state of neuroleptanalgesia and unconsciousness, produced by the combined administration of a narcotic analgesic and a neuroleptic agent, together with the inhalation of nitrous oxide and oxygen. Neuroleptanalgesia: a state of quiescence, altered awareness, and analgesia produced by the administration of a combination of a narcotic analgesic and a neuroleptic agent. Neuroleptic: a term coined to refer to the effects on cognition and behaviour of the original antipsychotic agents, which produced a state of apathy, lack of initiative, and limited range of emotion and in psychotic patients caused a reduction in confusion and agitation and normalization of psychomotor activity. The term is outdated as a synonym for antipsychotic agents because newer agents do not necessarily have such effects. Neuromuscular block: a failure in neuromuscular transmission that can be induced pharmacologically or may result from pathological disturbance at the myoneural junction. Neuropathy: a functional disturbance or pathological change in the peripheral nervous system, sometimes limited to noninflammatory lesions as opposed to those of neuritis; the aetiology may be known or unknown. Neutropenia: a decrease in the number of neutrophils in the blood NIDD: non-insulin dependent diabetes mellitus. Nightmare: a terrifying dream; an anxiety attack during dreaming, accompanied by mild autonomic reactions and usually awakening the dreamer, who recalls the dream but is oriented. Nociception: pain sense. Nociceptor: a receptor for pain caused by injury to body tissues; the injury may be from physical stimuli such as mechanical, thermal, or electrical stimuli, or from chemical stimuli such as the presence of a toxin or an excess of a nontoxic substance. Most nociceptors are in either the skin (cutaneous nociceptor) or the walls of viscera (visceral nociceptor). Nocturnal: pertaining to, occurring at, or active at night. NSAID: non-steroidal anti-inflammatory drug. Nystagmus: an involuntary, rapid, rhythmic



movement of the eyeball, which may be horizontal, vertical, rotatory, or mixed, i.e., of two varieties. Obsessive-compulsive disorder: an anxiety disorder characterized by recurrent obsessions or compulsions, which are severe enough to interfere significantly with personal or social functioning. Performing compulsive rituals may release tension temporarily, and resisting them causes increased tension. Odynophagia: pain on swallowing (tetracycline) Oliguria: excretion of a diminished amount of urine in relation to the fluid intake, usually defined as less than 400 mL per 24 hours. Oliguric: pertaining to or characterized by oliguria. Open-angle glaucoma: any glaucoma in which the angle of the anterior chamber remains open, but filtration is gradually diminished because of the tissues of the angle; called also chronic g., simple g., and wide-angle g. Opportunistic infections: superinfection. Organic brain syndrome: former term for a constellation of psychological or behavioural signs and symptoms associated with brain dysfunction of unknown or unspecified aetiology and grouped according to symptoms. Organic psychoses: a psychotic disorder with a known or presumed organic aetiology. Orofacial dyskinesia: see tardive dyskinesia. Orthostatic hypotension: a fall in blood pressure associated with dizziness, blurred vision, and sometimes syncope, occurring upon standing or when standing motionless in a fixed position; it can be acquired or idiopathic. Orthostatic: pertaining to or standing erect (Antihypertensive drugs) Osteoarthritis: a noninflammatory degenerative joint disease seen mainly in older persons, characterized by degeneration of the articular cartilage, hypertrophy of bone at the margins, and changes in the synovial membrane. It is accompanied by pain, usually after prolonged activity, and stiffness, particularly in the morning or with inactivity. inadequate or delayed Osteomalacia: mineralization of osteoid in mature cortical and spongy bone; it is the adult equivalent of rickets and accompanies that disorder in children. Osteomyelitis: inflammation of bone caused by infection, usually by a pyogenic organism, although any infectious agent may be involved. It may remain localized or may spread through the bone to involve the marrow, cortex, cancellous tissue, and periosteum. Ototoxic: causing damage to the vestibulocochlear nerve or the organs of hearing and balance. Ototoxicity: the quality of causing damage to the vestibulocochlear nerve or the organs of hearing and balance PABA: p-aminobenzoic acid.

272

Paget s disease of bone: a disease of bone marked by repeated episodes of increased bone resorption followed by excessive attempts at repair, resulting in weakened deformed bones of increased mass. Pain: a more or less localized sensation of discomfort, distress, or agony, resulting from the stimulation of specialized nerve endings. It serves as a protective mechanism insofar as it induces the sufferer to remove or withdraw from the source. Palliative care: treatment designed to relieve pain and distress, but not attempting a cure. Palpitation: a subjective sensation of an unduly rapid or irregular heart beat Pancytopaenia: deficiency of all cellular elements of the blood. Panhypopituitarism: generalized or particularly severe hypopituitarism, which in its complete form leads to absence of gonadal function and insufficiency of thyroid and adrenal cortical function. Panic: acute, extreme anxiety with disorganization of personality and function. Paradox: a statement which seems to be, though it may not be, absurd or self-contradictory. Paradoxical: occurring at variance with the normal rule. Paraesthesiae: (numbness) abnormal perception, feeling, or sensation. Paralytic ileus: ileus resulting from inhibition of bowel motility, which may be produced by numerous causes, most frequently by peritonitis. Paranoid psychosis: a type of psychosis characterized by preoccupation with one or more systematized delusions or with frequent auditory hallucinations but without disorganized speech, disorganized or catatonic behaviour, or flat or inappropriate affect. Paranoid schizophrenia: a type of schizophrenia characterized by preoccupation with one or more systematized delusions or with frequent auditory hallucinations but without disorganized speech, disorganized or catatonic behaviour, or flat or inappropriate affect. Parenteral: not through the alimentary canal but rather by injection through some other route, such as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, or intravenous. Parkinson s disease: a group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. Parkinsonism: see Parkinson s disease. Paroxysm: 1. a sudden recurrence or intensification of symptoms Paroxysmal: recurring in paroxysms PBPs: penicillin binding proteins Pellagra: a clinical deficiency syndrome due to deficiency of niacin (or failure to convert tryptophan to niacin) and characterized by dermatitis, inflammation of mucous membranes,


Majid A.K. Lafi

diarrhoea, and psychic disturbances. The dermatitis occurs on the portions of the body exposed to light or trauma. Mental symptoms include depression, irritability, anxiety, confusion, disorientation, delusions, and hallucinations. Peptic: pertaining to pepsin or to digestion; related to the action of gastric juices. Peripheral neuropathy: Some conditions that are actually polyneuropathies are called neuropathies. Peritonitis: inflammation of the peritoneum, with exudations of serum, fibrin, cells, and pus, usually accompanied by abdominal pain and tenderness, constipation, vomiting, and moderate fever. Personality disorder: a category of mental disorders characterized by enduring, inflexible, and maladaptive personality traits that deviate markedly from cultural expectations, are selfperpetuating, pervade a broad range of situations, and either generate subjective distress or result in significant impairments in social, occupational, or other functioning. Onset is by adolescence or early adulthood. Pheochromocytoma: a usually benign, wellencapsulated, lobular, vascular tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. Because of increased secretion of adrenaline and noradrenaline, hypertension is a cardinal symptom; it may be persistent or intermittent. During severe attacks, there may be headache; sweating; palpitation and tremor; pallor or flushing of the face; nausea and vomiting; pain in the chest and abdomen; and paresthesias of the extremities. Phlegm: abnormally thick mucus secreted by the mucosa of the respiratory passages during certain infectious processes. Phobia: a persistent, irrational, intense fear of a specific object, activity, or situation (the phobic stimulus), fear that is recognized as being excessive or unreasonable by the individual himself. Phocomelia: a type of meromelia characterized by absence of the proximal portion of a limb or limbs, the hands or feet being attached to the trunk of the body by a single small, irregularly shaped bone. Photophobia: abnormal visual intolerance of light. Photosensitivity reactions: an abnormal cutaneous response involving the interaction between photosensitizing substances and sunlight or filtered or artificial light at wavelengths of 280 400 nm. Physiological lactation: normal; not pathological secretion of milk. Pituitary diabetes insipidus: iabetes insipidus due to injury of the neurohypophyseal system, with a deficient quantity of antidiuretic hormone being released or produced, causing failure of renal tubular reabsorption of water. It may be inherited, acquired, or idiopathic. Plankton: a collective name for the minute freefloating organisms, vegetable and animal, which

273

live in practically all natural waters. Planktonic: pertaining to plankton. PMSG: (serum gonadotropin) pregnant mare serum gonadotropin. Poikelothermia: variable or irregular body temperature. Polyarteritis nodosa: a form of systemic necrotizing vasculitis involving the small and medium-sized arteries with signs and symptoms resulting from infarction and scarring of the affected organ system. Polyarteritis: multiple inflammatory and destructive arterial lesions. Polycystic ovarian syndrome: (PCOS) a clinical symptom complex associated with polycystic ovaries and characterized by oligomenorrhea or amenorrhea, anovulation (hence infertility), and hirsutism. Both hyperestrogenism (from peripheral conversion of androgen) and hyperandrogenism are present. Polymyositis: a chronic, progressive inflammatory disease of skeletal muscle, occurring in both children and adults, and characterized by symmetrical weakness of the limb girdles, neck, and pharynx, usually associated with pain and tenderness, and sometimes preceded or followed by manifestations typical of scleroderma, arthritis, systemic lupus erythematosus, or Sj gren's syndrome. It is also sometimes associated with malignancy, and may be accompanied by characteristic skin lesions. Polyuria: the passage of a large volume of urine in a given period, a characteristic of diabetes. Porphyria: see acute intermittent porphyria. Positive symptoms: added features to personality including hallucinations, delusions and thought disorder. Postherpetic neuralgia: persistent burning pain and hyperesthesia along the distribution of a cutaneous nerve following an attack of herpes zoster; it may last for a few weeks or many months. Postmenopausal osteoporosis: that occurring in women within 3 to 20 years after menopause, affecting trabecular bone more than cortical bone, and manifested mainly by vertebral fractures of the painful crush type, hip fracture, Colles' fracture, and increased tooth loss. Postmortem: occurring or performed after death; pertaining to the period after death. Postural: pertaining to posture or position (Antihypertensive drugs) Precocious puberty: onset of sexual maturation at an earlier age than normal, defined as two standard deviations below the mean, or before age 8 in girls and 9 in boys. Premature ejaculation: ejaculation consistently occurring either prior to, upon, or immediately after penetration and before it is desired, taking into account factors such as age, novelty of the specific situation, and recent frequency of the



sexual act. Premature labour: expulsion of a viable infant before the normal end of gestation, usually applied to interruption of pregnancy between the twentieth and the thirty-seventh completed weeks after the onset of the last menstrual period. Preterm labour: labour at any time before the thirty-seventh completed week (259 days) of gestation. Priapism: persistent abnormal erection of the penis, usually without sexual desire, and accompanied by pain and tenderness. It is seen in diseases and injuries of the spinal cord, and may be caused by vesical calculus and certain injuries to the penis. Primary amenorrhoea: failure of menstruation to occur at puberty. Primary hyperaldosteronism: that arising from oversecretion of aldosterone by an adrenal cortical adenoma, characterized typically by hypokalemia, alkalosis, muscular weakness, polyuria, polydipsia, and hypertension. Called also Conn's syndrome. prn: (p.r.n.) abbreviation for L. pro re na´ta, according as circumstances may require (as needed). Proconvulsant: an agent that promote the initiation of convulsions. Prokinetic: pertaining to gastrointestinal motilityenhancing activity. Prolactin-secreting adenomas: a pituitary adenoma made up of lactotrophs that secretes excessive amounts of prolactin; this may delay puberty in either sex, cause galactorrhoeaamenorrhoea syndrome in women, or decrease libido and fertility in men. Prophylaxis: intervention aimed at the prevention of disease; called also preventive treatment, prophylactic treatment, and protective therapy. Prostatectomy: surgical removal of the prostate or of a part of it. Prostatism: a symptom complex resulting from compression or obstruction of the urethra, due most commonly to nodular hyperplasia of the prostate. Proteinuria: the presence of an excess of serum proteins in the urine; called also albuminuria. Pruritus: 1. an unpleasant cutaneous sensation that provokes the desire to rub or scratch the skin to obtain relief. Called also itching. 2. any of various conditions marked by this sensation, the specific site or type being indicated by a modifying term. Pseudomembranous colitis: see antibioticassociated enterocolitis. Pseudotumour cerebri: a condition caused by venous sinus occlusion and cerebral oedema associated with a number of pathologic conditions, marked by raised intracranial pressure with normal cerebrospinal fluid, headache, nausea, vomiting, and papilloedema, but without neurological signs except occasional abducens paralysis.

274

Psittacosis: human infection by Chlamydia psittaci, generally acquired by inhalation of dried bird excreta containing the pathogen; it may also be acquired by handling feathers or tissues of infected birds, through an open skin lesion, or from the bite of an infected bird. It may be asymptomatic, have mild influenzalike symptoms, or manifest as a severe, highly fatal pneumonia. Psychodysleptic: inducing a dreamlike or delusional state of mind. Psychosis: 1. a mental disorder characterized by gross impairment in reality testing as evidenced by delusions, hallucinations, markedly incoherent speech, or disorganized and agitated behaviour, usually without apparent awareness on the part of the patient of the incomprehensibility of his behaviour. 2. the term is also used in a more general sense to refer to mental disorders in which mental functioning is sufficiently impaired as to interfere grossly with the patient's capacity to meet the ordinary demands of life. Historically, the term has been applied to many conditions, e.g., manicdepressive psychosis, that were first described in psychotic patients, although many patients with the disorder are not judged psychotic. Psychotic depression: in the strict sense, major depressive disorder with psychotic features, such as hallucinations, delusions, mutism, or stupor. However, this term is commonly used in a broader sense to cover all severe depressions causing gross impairment of social or occupational functioning, i.e., as a rough equivalent of major depressive disorder or of endogenous depression. PT: prothrombine time. PTH: parathyroid hormone. Puberty: the period during which the secondary sex characteristics begin to develop and the capability of sexual reproduction is attained. Pulmonary embolism: the closure of the pulmonary artery or one of its branches by an embolus, sometimes associated with pulmonary infarction. Purgative: see cathartic. Purpura: 1. any of a group of conditions characterized by ecchymoses or other small haemorrhages in the skin, mucous membranes, or serosal surfaces; possible causes include blood disorders, vascular abnormalities, and trauma. 2. any of several conditions similar to the traditional purpura group, which may be caused by decreased platelet counts, platelet abnormalities, vascular defects, or reactions to drugs. PVCs: premature ventricular contractions Pyrogen: a fever-producing substance. Rash: a temporary eruption on the skin, as in urticaria; a drug eruption or viral exanthema. Raynaud s disease: a primary or idiopathic vascular disorder characterized by bilateral attacks of Raynaud's phenomenon; it affects females more often than males. Called also Raynaud's gangrene.


Majid A.K. Lafi

Rebound: a reversed response on the withdrawal of a stimulus. Reflux oesophagitis: serious and sometimes lifethreatening type of gastroesophageal reflux disease that involves damage to the esophageal mucosa, often with erosion, ulceration, and infiltration by neutrophils or eosinophils. Refraction: the act or process of refracting; specifically the determination of the refractive errors of the eye and their correction by glasses. Regimen: a strictly regulated scheme of medication, diet, exercise, or other activity designed to achieve certain ends. Relapse: the return of a disease after its apparent cessation. Renal artery stenosis: RAS; narrowing of one or both renal arteries, caused by atherosclerosis or by fibrous dysplasia or hyperplasia, so that renal function is impaired; increased renin release by the affected kidney causes renovascular hypertension, and bilateral stenosis may result in chronic renal failure. Resting tremor: a tremor occurring when a limb or other body part is at rest; it may be normal, as in some physiologic tremors, or abnormal, as in parkinsonian tremors. Retarded schizophrenia: see negative symptoms. Reye s syndrome: a rare, acute, sometimes fatal disease of childhood, characterized by recurrent vomiting and elevated serum transaminase levels, with distinctive changes in the liver and other viscera; an encephalopathic phase may follow with acute brain swelling, disturbances of consciousness, and seizures. It most often occurs as a sequel of chickenpox or a viral upper respiratory infection. Rheumatoid arthritis: a chronic systemic disease primarily of the joints, usually polyarticular, marked by inflammatory changes in the synovial membranes and articular structures and by muscle atrophy and rarefaction of the bones. In late stages deformity and ankylosis develop. The cause is unknown, but autoimmune mechanisms and virus infection have been postulated. Rhinorrhoea: the free discharge of a thin nasal mucus. Rickets: an interruption in the development and mineralization of the growth plate of bone, with radiographic abnormalities, osteomalacia, bone pain, fatigability, growth retardation, and often hypotonia, convulsions, and tetany. Rigidity: stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. s.c.: subcutaneous. Salicylism: the commonly occurring toxic effects of excessive dosage with salicylic acid or its salts, usually marked by tinnitus, nausea, and vomiting. Salmonellosis: any disease caused by infection

275

with a species of Salmonella; in humans it is most often manifested as food poisoning with acute gastroenteritis, vomiting, diarrhoea, and rarely septicaemia, or as typhoid or paratyphoid fever. Recurrent fevers and diarrhoea with more serious gastrointestinal symptoms are seen in immunocompromised patients. Sarcoidosis: a chronic, progressive, systemic granulomatous reticulosis of unknown aetiology, characterized by hard tubercles in almost any organ or tissue, including the skin, lungs, lymph nodes, liver, spleen, eyes, and small bones of the hands and feet. SC3: third generation cephalosporin. Schizophrenia: a mental disorder or heterogeneous group of disorders (the schizophrenias or schizophrenic disorders) comprising most major psychotic disorders and characterized by disturbances in form and content of thought (loosening of associations, delusions, and hallucinations), mood (blunted, flattened, or inappropriate affect), sense of self and relationship to the external world (loss of ego boundaries, dereistic thinking, and autistic withdrawal), and behaviour (bizarre, apparently purposeless, and stereotyped activity or inactivity). Secondary amenorrhoea: cessation of menstruation after it has once been established at puberty. Sedation: the production of a sedative effect; the act or process of calming. Senile dementia: that occurring in older persons, usually over the age of 65; since most cases are due to Alzheimer's disease, the term is sometimes used as a synonym of d. of the Alzheimer type, late onset. Sepsis: 1. the presence in the blood or other tissues of pathogenic microorganisms or their toxins. 2. septicemia. Septic: pertaining to sepsis Serum sickness: a hypersensitivity reaction to the administration of foreign serum or serum proteins characterized by fever, urticaria, arthralgia, edema, and lymphadenopathy. It is caused by the formation of circulating antigen-antibody complexes that are deposited in tissues and trigger tissue injury mediated by complement and polymorphonuclear leukocytes. Serum sickness is classed with the Arthus reaction and other immune complex diseases as a type III hypersensitivity reaction (Gell and Coombs classification). Although serum sickness is now rare because of the replacement of most animal-derived antisera with human immune globulins, an identical illness (serum sickness like reaction or syndrome) can be produced by hypersensitivity reactions to penicillin and other drugs. Sexual deviation: sexual behaviour or fantasy outside that which is morally, biologically, or legally sanctioned, often specifically one of the



paraphilias. Sexual dysfunction: any of a group of sexual disorders characterized by disturbance either of sexual desire or of the psychophysiological changes that usually characterize sexual response. Included are sexual desire disorders, sexual arousal disorders, orgasmic disorders, sexual pain disorders, substance-induced sexual dysfunction, and sexual dysfunction due to a general medical condition. Shingles: (herpes zoster) an acute infectious, usually self-limited, disease believed to represent activation of latent human herpesvirus 3 in those who have been rendered partially immune after a previous attack of chickenpox. It involves the sensory ganglia and their areas of innervation, is characterized by severe neuralgic pain along the distribution of the affected nerve and crops of clustered vesicles over the area of the corresponding dermatome, and is usually unilateral and confined to single or adjacent dermatomes. Postherpetic neuralgia may be a complication. In immunocompromised patients it may disseminate and be fatal. Called also acute posterior ganglionitis, shingles, zona, and zoster. Shock: 1. a sudden disturbance of mental or physical equilibrium. 2. a condition of profound hemodynamic and metabolic disturbance characterized by failure of the circulatory system to maintain adequate perfusion of vital organs. It may result from inadequate blood volume (hypovolemic shock); inadequate cardiac function (cardiogenic shock); or inadequate vasomotor tone (neurogenic shock and septic shock). SIADH: syndrome of inappropriate secretion of antidiuretic hormone. Sinus bradycardia: a slow sinus rhythm, with a heart rate of less than 60 beats per minute in an adult; it is common in young adults and in athletes but is also a manifestation of some disorders. SLE: systemic lupus erythematosus Slurred speech: speech in which the words are uncompleted Sneezing: expelling air forcibly and spasmodically through the nose and mouth. 2. an involuntary, sudden, violent, and audible expulsion of air through the mouth and nose. Spasm: 1. a sudden, violent, involuntary contraction of a muscle or a group of muscles, attended by pain and interference with function, producing involuntary movement and distortion. 2. a sudden but transitory constriction of a passage, canal, or orifice. Spasmodic: of the nature of a spasm. Spinal nerve block: 1. regional anaesthesia produced by injection of a local anesthetic into the subarachnoid space around the spinal cord; anaesthesia Called also intraspinal a. or block and subarachnoid anaesthesia or block. 2. loss of sensation due to a spinal lesion.

276

Status epilepticus: a continuous series of generalized tonic-clonic seizures without return to consciousness, a life-threatening emergency. Stevens-Johnson syndrome: a sometimes fatal form of erythema multiforme presenting with a flulike prodrome, and characterized by systemic as well as more severe mucocutaneous lesions. The oronasal and anogenital mucous membranes may become involved with a characteristic gray or white pseudomembrane, and hemorrhagic crusts often occur on the lips. Ocular lesions vary, often with injected conjunctivitis, iritis, uveitis, corneal vesicles, erosions, and perforation, which may result in corneal opacities and blindness. Pulmonary, gastrointestinal, cardiac, and renal involvement also occurs. Stomatitis: inflammation of the oral mucosa, due to local or systemic factors, which may involve the buccal and labial mucosa, palate, tongue, floor of the mouth, and the gingivae. Subarachnoid haemorrhage: intracranial hemorrhage into the subarachnoid space. Superinfection: (suprainfection, opportunistic infection, secondary infection) a new infection occurring in a patient having a preexisting infection, such as bacterial superinfection in viral respiratory disease or infection of a chronic hepatitis B carrier with hepatitis D virus. Superinfection can complicate the course of antimicrobial therapy when the new infection is by organisms resistant to the drugs in use. Suppository: a medicated mass adapted for introduction into the rectal, vaginal, or urethral orifice of the body; suppository bases are solid at room temperature but melt or dissolve at body temperature. Sydenham s chorea: an acute, usually self-limited disorder of early life, usually between the ages of 5 and 15 or during pregnancy, and closely linked with rheumatic fever. It is characterized by involuntary movements that gradually become severe, affecting all motor activities including gait, arm movements, and speech. A mild psychic component is usually present. Syncope: a temporary suspension of consciousness due to generalized cerebral ischemia; a faint. Synergistic: 1. acting together. 2. enhancing the effect of another force or agent. Systemic lupus erythematosus: (SLE) a chronic, remitting, relapsing, inflammatory, often febrile multisystemic disorder of connective tissue, acute or insidious in onset, characterized principally by involvement of the skin joints, kidneys, and serosal membranes. It is of unknown etiology, but it is thought to represent a failure of regulatory mechanisms of the autoimmune system, as suggested by the high level of numerous autoantibodies against nuclear and cytoplasmic cellular components. It is marked by a wide variety of abnormalities, including arthritis and arthralgias,


Majid A.K. Lafi

nephritis, central nervous system manifestations, pleurisy, pericarditis, leukopenia or thrombocytopenia, hemolytic anemia, elevated erythrocyte sedimentation rate, and positive LEcell preparations. Systemic sclerosis: a systemic disorder of the connective tissue characterized by induration and thickening of the skin, by abnormalities involving both the microvasculature (telangiectasia) and larger vessels (Raynaud's phenomenon), and by fibrotic degenerative changes in various body organs, including the heart, lungs, kidneys, and gastrointestinal tract. It may remain confined to the face and hands for long periods or may be progressive and spread diffusely to become generalized. t : half life. T3: triiodothyronine. T4: Tetraiodothyronine. Tachycardia: excessive rapidity in the action of the heart; the term is usually applied to a heart rate above 100 beats per minute in an adult and is often qualified by the locus of origin as well as by whether it is paroxysmal or nonparoxysmal. Tarditive dyskinesia: (orofacial dyskinesia) an iatrogenic extrapyramidal disorder caused by longterm use of antipsychotic drugs; it is characterized by oral-lingual-buccal dyskinesias that usually resemble continual chewing motions with intermittent darting movements of the tongue; there may also be choreoathetoid movements of the extremities. It is more common in women than in men and in the elderly than in the young, and incidence is related to drug dosage and duration of treatment. In some patients symptoms disappear within a few months after the drugs are withdrawn; in others symptoms may persist indefinitely. TCA: tricyclic antidepressant. TDM: therapeutic drug monitoring. Telangiectasia: permanent dilation of preexisting small blood vessels (capillaries, arterioles, venules), creating focal red lesions, usually in the skin or mucous membranes. Tenosynovitis: inflammation of a tendon sheath. Teratogenic: tending to produce congenital anomalies. Testicular teratoma: a type of germ cell tumour derived from pluripotent cells and made up of elements of different types of tissue from one or more of the three germ cell layers in the testis. Tetanus: 1. an acute, often fatal infectious disease caused by the bacillus Clostridium tetani, which produces the neurotoxin tetanospasmin; it usually enters the body through a contaminated puncture wound (such as from a metal nail, wood splinter, or insect bite), although other portals of entry include burns, surgical wounds, cutaneous ulcers, injection sites of drug abusers, the umbilical stump of neonates (t. neonatorum), and the postpartum uterus. 2. physiological tetanus; a state of

277

sustained muscular contraction without periods of relaxation caused by repetitive stimulation of the motor nerve trunk at frequencies so high that individual muscle twitches are fused and cannot be distinguished from one another. Thalassaemia: a heterogeneous group of hereditary hemolytic anemias that have in common a decreased rate of synthesis of one or more hemoglobin polypeptide chains and are classified according to the chain involved (a, b, d); the two major categories are a- and b-thalassemia. Homozygous forms are manifested by profound anemia or death in utero, and heterozygous forms by erythrocyte anomalies ranging from mild to severe. Therapeutic restraining: the use of drug therapy to control of a subject, as of a violently psychotic or irrational person. Thought disorders: a disturbance in the thought process that is most narrowly defined as disorganized thinking with altered associations, as is characteristic of schizophrenia. The term is often used much more broadly to include any disturbance of thought, such as confusion, hallucinations, or delusions, which affects possession, quantity, or content of thought. Throbbing: beating; attended with a rhythmic beating sensation. Thrombocytopenia: decrease in the number of platelets, such as in thrombocytopenic purpura. Thrombocytopenic purpura: any form of purpura in which the platelet count is decreased; it may be either primary (idiopathic) or secondary. (see purpura) Thromboembolism: obstruction of a blood vessel with thrombotic material carried by the blood stream from the site of origin to plug another vessel. Thyroiditis: inflammation of the thyroid gland. Thyrotoxicosis: the condition caused by excessive quantities of thyroid hormones (see hyperthyroidism); it may be due to overproduction by the thyroid gland as in Graves' disease, overproduction originating outside the thyroid, or loss of storage function and leakage from the gland. TIA: Transient ischaemic attack. Tics: an involuntary, compulsive, rapid, repetitive, stereotyped movement or vocalization, experienced as irresistible although it can be suppressed for some length of time; occurrence is exacerbated by stress and diminished during sleep or engrossing activities. Tics may be psychogenic or neurogenic in origin and are subclassified as either simple, such as eye blinking, shoulder shrugging, coughing, grunting, snorting, or barking, or complex, such as facial gestures, grooming motions. Tinnitus: a noise in the ears, such as ringing, buzzing, roaring, or clicking. It is usually



subjective in type. Tocolytic: pertaining to inhibition of uterine contractions. Tocolytic: uterine relaxant. Toxic adenoma: hyperthyroidism arising in a multinodular goiter, usually of long standing. Trachoma: a chronic infectious disease of the conjunctiva and cornea, producing photophobia, pain, and lacrimation, caused by a strain of Chlamydia trachomatis. Tranquilliser: a drug with a calming, soothing effect; currently it is usually used to denote a minor tranquilliser. Transient ischaemic attacks: (TIA) a brief attack (from a few minutes to an hour) of cerebral dysfunction of vascular origin, with no persistent neurological deficit; TIAs are most commonly associated with occlusive vascular disease, especially in the distribution of the carotid and vertebral-basilar systems. TRH: (protirelin) thyrotropin-releasing hormone. Trigeminal neuralgia: Paroxysmal pain that extends along the course of one or more nerves. Many varieties of neuralgia are distinguished according to the part affected or to the cause, as trigeminal, brachial, facial, occipital, supraorbital, etc., or postherpatic, anaemic, diabetic, gouty, malarial, syphilitic, etc. (carbamazepine) TSH: (thyrotropin) Thyroid-stimulating hormone. Tuberculosis: any of the infectious diseases of humans or other animals caused by species of Mycobacterium and characterized by the formation of tubercles and caseous necrosis in the tissues. The usual causative species are M. tuberculosis and M. bovis. Type I reaction: that occurring within minutes when a sensitized individual is reexposed to antigen, resulting from interaction of IgE and the antigen; clinical manifestations can range from localized dermatitis, urticaria, or angioedema to allergic rhinitis or asthma to systemic anaphylaxis. The first exposure to the antigen induces the production of IgE antibodies that bind to receptors on mast cells and basophils. Upon subsequent exposure the antigen cross-links receptor-bound IgE molecules, triggering production and release of a diverse array of mediators that act on other cells, producing symptoms such as bronchospasm, edema, mucous secretion, and inflammation. (penicillin) Type II reaction: tissue or cell damage resulting from the interaction of antibodies and antigens on cell surfaces; specific IgG or IgM against cell surface or extracellular matrix antigens or cell surface receptors binds and causes damage at the site of binding by any of several mechanisms involving either complement activation and lysis or opsonization mediated by receptors for Fc or C3b leading to phagocytosis and destruction by macrophages and neutrophils. Examples of

278

disorders caused by such tissue damage include myasthenia gravis, hemolytic anemia, Goodpasture's syndrome, and Rh incompatibility and transfusion reactions. Type III reaction: local or general inflammatory response due to formation of circulating antigenantibody complexes and their deposition in tissues; the complexes activate complement and other inflammatory mediators, initiating processes including increased vascular permeability, stimulation of mast cell degranulation and neutrophil chemotaxis and accumulation, and aggregation of platelets, and resulting in tissue damage. Ensuing diseases, called also immune complex diseases, can be roughly classified as being due to persistent infection, to autoimmunity, or to inhalation of antigenic material; examples include serum sickness, Arthus reaction, subacute bacterial endocarditis, systemic lupus erythematosus, and farmer's lung. Type IV reaction: a reaction of cell-mediated immunity, the immune response being initiated by antigen-specific T lymphocytes; in contrast to the reactions of immediate hypersensitivity, reactions take one or more days to develop and can be transferred by lymphocytes but not by serum. Reactions are mediated by T lymphocytes both through release of cytokines and through direct cytolysis. In the former mechanism, release of vasoactive and chemotactic cytokines is triggered by contact between the T cells and specific antigens on antigen-presenting cells; the cytokines attract and activate non antigen-specific monocytes and macrophages, resulting in local erythema and induration, and leading to granuloma formation and necrosis if the eliciting stimulus cannot be eliminated. A common example is the tuberculin reaction elicited in skin testing for tuberculosis. In direct cytolysis, sometimes called cell-mediated cytotoxicity, cytotoxic T lymphocytes interact with foreign antigens presented by class I MHC molecules on cell surfaces, causing lysis of these foreign cells, as in allograft rejection. Type IV reactions can be induced by intracellular parasites, such as certain viruses, mycobacteria, and fungi, foreign tissue, tumour cells, soluble proteins, and haptens. The term is often equated with delayed hypersensitivity reaction, although the latter is sometimes restricted to cytokine-mediated reactions (as contrasted with direct cytolysis). U: unit. Ulcerative colitis: chronic, recurrent ulceration in the colon, chiefly of the mucosa and submucosa, of unknown cause; it is manifested clinically by cramping abdominal pain, rectal bleeding, and loose discharges of blood, pus, and mucus with scanty fecal particles. Complications include hemorrhoids, abscesses, fistulas, perforation of the colon, pseudopolyps, and carcinoma.


Majid A.K. Lafi

Unipolar affective disorder: that unaccompanied by episodes of mania or hypomania, as in major depressive disorder. Ureteral colic: colicky pains due to obstruction of the ureter. Urinary frequency: urination at short intervals without increase in daily volume of urinary output, due to reduced bladder capacity. Urinary retention: accumulation of urine within the bladder because of inability to urinate. Urolithiasis: 1. the formation of urinary calculi (stones). 2. the diseased condition associated with the presence of urinary calculi. Urticaria: a vascular reaction in the upper dermis, usually transient, consisting of localized oedema caused by dilatation and increased capillary permeability, with development of wheals. Uterine fibroids: a benign tumour derived from smooth muscle of the uterus. Uterine rupture: forcible tearing of the uterus. Uveitis: an inflammation of part or all of the uvea, commonly involving the other tunics of the eye (sclera, cornea, and retina). Vagotomy: interruption of the impulses carried by the vagus nerve or nerves. Vertigo: an illusory sense that either the environment or one's own body is revolving; it may result from diseases of the inner ear or may be due to disturbances of the vestibular centers or pathways in the central nervous system. Visual haloes: the seeing of coloured rings around an individual light source; indicative of glaucoma. Vulvovaginitis: inflammation of the vulva and vagina, or of the vulvovaginal glands. Whooping Cough: an acute, highly contagious infection of the respiratory tract, usually affecting young children and caused by Bordetella pertussis; similar illnesses are caused by B. parapertussis and B. bronchiseptica. Wolff-Parkinson-White syndrome: the association of paroxysmal tachycardia (or atrial fibrillation) and preexcitation, in which the electrocardiogram displays a short P R interval and a wide QRS complex which characteristically shows an early QRS vector (delta wave); sometimes used synonymously with preexcitation s. Called also WPW s. Zollinger-Ellison syndrome: a triad comprising (1) intractable, sometimes fulminating, and in many ways atypical peptic ulcers; (2) extreme gastric hyperacidity; and (3) gastrin-secreting, non beta islet cell tumours of the pancreas, which may be single or multiple, small or large, benign or malignant.

279

Essentials of Medical Pharmacology Lafi 09-10

Essentials of Medical Genomics

Essentials of Medical Genomics

Viva Voce in Medical Pharmacology

Clinical Physiology and Pharmacology: The Essentials

Essentials Medical Statistics (Second Edition)

Medical Retina (Essentials in Ophthalmology)

Essentials in Ophthalmology - Medical Retina

The Marks' Essentials of Medical Biochemistry

Essentials of Pharmacology for Health Occupations, Sixth Edition

Pharmacology

Musculoskeletal Ultrasound: The Essentials (Greenwich Medical Media)

Essentials of Banking (Essentials Series)

Color Atlas of Pharmacology

Color Atlas of Pharmacology

Color atlas of pharmacology

Principles of clinical pharmacology

Principles of Clinical Pharmacology

Color Atlas of Pharmacology

Color Atlas of Pharmacology

Color Atlas Of Pharmacology

Schaum's Outline of Pharmacology

Clinical Pharmacology of Sleep

Color Atlas of Pharmacology

Color Atlas of Pharmacology

Color atlas of pharmacology

Color atlas of pharmacology

Color Atlas of Pharmacology

Essentials of Medical Pharmacology Lafi 09-10

Essentials of Medical Genomics

Essentials of Medical Genomics

Viva Voce in Medical Pharmacology

Clinical Physiology and Pharmacology: The Essentials

Essentials Medical Statistics (Second Edition)

Medical Retina (Essentials in Ophthalmology)

Essentials in Ophthalmology - Medical Retina

The Marks' Essentials of Medical Biochemistry

Essentials of Pharmacology for Health Occupations, Sixth Edition

Pharmacology

Musculoskeletal Ultrasound: The Essentials (Greenwich Medical Media)

Essentials of Banking (Essentials Series)

Color Atlas of Pharmacology

Color Atlas of Pharmacology

Color atlas of pharmacology

Principles of clinical pharmacology

Principles of Clinical Pharmacology

Color Atlas of Pharmacology

Color Atlas of Pharmacology

Color Atlas Of Pharmacology

Schaum's Outline of Pharmacology

Clinical Pharmacology of Sleep

Color Atlas of Pharmacology

Color Atlas of Pharmacology

Color atlas of pharmacology

Color atlas of pharmacology

Color Atlas of Pharmacology

Recommend Documents