Pharmacology for Medical Graduates, 4th Edition PDF

 PHARMACOLOGY for Medical Graduates This page intentionally left blank  FOURTH EDITION ( R E V I S E D A N D U P D AT E D E D I T I O N ) PHARMACOLOGY for Medical Graduates TARA V SHANBHAG MD Professor and Head, Department of Pharmacology Srinivas Institute of Medi...

 PHARMACOLOGY for Medical Graduates This page intentionally left blank  FOURTH EDITION ( R E V I S E D A N D U P D AT E D E D I T I O N ) PHARMACOLOGY for Medical Graduates TARA V SHANBHAG MD Professor and Head, Department of Pharmacology Srinivas Institute of Medical Sciences and Research Centre Mukka, Surathkal, Mangalore Karnataka, India Formerly, Professor, Department of Pharmacology Kasturba Medical College, Manipal, Manipal Academy of Higher Education Manipal, Karnataka, India SMITA SHENOY MD Additional Professor, Department of Pharmacology Kasturba Medical College, Manipal, Manipal Academy of Higher Education Manipal, Karnataka, India RELX India Pvt. Ltd. Registered Office: 818, 8th Floor, Indraprakash Building, 21, Barakhamba Road, New Delhi 110001 Corporate Office: 14th Floor, Building No. 10B, DLF Cyber City, Phase II, Gurgaon-122002, Haryana, India Pharmacology for Medical Graduates, 4e, Tara V Shanbhag and Smita Shenoy (Revised and Updated Edition) Copyright © 2020 by RELX India Pvt. Ltd. Previous editions Copyrighted 2019, 2015, 2013, 2008 All rights reserved. ISBN: 978-81-312-6259-7 eISBN: 978-81-312-6260-3 No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechani- cal, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permis- sions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notice Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors in relation to the adaptation or for any injury and/or damage to persons or property as a matter of products li- ability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Content Strategist - Education Solutions: Arvind Koul Content Project Manager: Goldy Bhatnagar and Shubham Dixit Production Executive: Dhan Singh Sr Graphic Designer: Milind Majgaonkar Typeset by GW India Printed and bound at FOREWORD TO THE FIRST EDITION It is common knowledge that books play a major complementary and contributing role in any educational process. While they are envisioned to facilitate self-learning beyond classroom exercises, not all of them promote learning; some, indeed, hinder it. To be useful and worthwhile, a book has to be so designed as to present an appro- priate body of knowledge in a style that suits students in a particular stage of learning: undergraduate, postgraduate, or postdoctoral. Accordingly, a book in pharmacology for MBBS phase-II students would have a body of knowledge that relates with the study-course objectives and contains ‘must know’ and ‘nice to know’ levels of factual, conceptual and applied aspects of the subject. It has a presentation style that offers an integrated composite picture of the subject interspersed with lucid explanations, cogent reasoning and logical networking of infor- mation. Contents will enable students to grasp topics in proper perspective and trigger students’ higher mental skills like critical thinking, logical reasoning, etc. Proficiency so acquired would enable the students to not only clear qualifying tests but also to wisely manage drug issues in future. Designing such a book is a challenging task, especially if it is to be concise and compre- hensive in scope. Such a version demands wise sifting, prudent pruning and meaningful condensing of the enormous and variegated knowledge base of pharmacology. Commendably, Dr (Mrs) Tara Shanbhag has accomplished this in her very first ven- ture. A fairly large number of charts, diagrams and other forms of illustrations in the text amply demonstrate this. No wonder, she has received ‘Good Teacher’ award time and again. A well written concise book as this one, serves twice as a preparatory tool: at the start of the study-course it provides a road-map of the subject to be learnt and thus tunes the students for deeper learning; and at the course-end (and examination time) it helps in rapid review and recapitulation of what is learnt. I am confident that this well thought out and well planned book, Preparatory Manual of Pharmacology for Undergraduates by Dr Tara V Shanbhag will be of tremendous use to the students. With pleasure, I compliment Dr (Mrs) Tara V Shanbhag, an erstwhile postgraduate student of mine, for such a fine piece of work. Professor DR Kulkarni Formerly: Head, Department of Medical Education, BM Patil Medical College, Bijapur; Director of PG Studies, Head, Department of Pharmacology, KMC, Manipal; Principal, Dr. Patil Medical College, Kolhapur; Head, Department of Pharmacology, JNMC, Belgaum; President, Pharmacological Society of India (1995) v This page intentionally left blank http://afkebooks.com PREFACE TO THE FOUR TH EDITION Pharmacology is a vast subject and one of the fast-growing branches of medical science and requires addition of latest information from time to time. The present fourth edition includes significant expansion and revision of the third edition. Some new topics like drug dosage forms and calculation of dosage of drugs have been included. The cardiovascular drug summary table also have been included for quick revision. The style has been retained in the form of simple diagrams, self-explanatory flowcharts, tables and student-friendly mnemonics. The textual presentation in tabular format helps in quick reading and recall. Definitions and treatment schedules have been incor- porated as per various guidelines. This extensively revised and updated edition will be useful not only for the students of medicine but also for the practicing doctors as well. This book will also help postgraduates of pharmacology and other clinical subjects for quick revision of pharmacology and therapeutics. We are extremely thankful to our students and colleagues, who had given us valuable feedback for this edition. We hope this edition will meet the requirements of the undergraduate medical students and serves as a better learning tool. We would sincerely appreciate critical appraisal of this manual and suggestions for further improvement in future. Tara V Shanbhag Smita Shenoy vii PREFACE TO THE FIRST EDITION Pharmacology is a vast subject with many crucial aspects related to drugs, their compo- sition, uses, effects, interactions, etc. which make the subject complicated and difficult to comprehend. During the course of interaction with my students as well as those of other universi- ties where I went as an examiner, I realized the difficulties faced by them while preparing for their exams due to vastness of the subject. This motivated me to write a preparatory manual that condenses this vital subject into essential elements and yet covers the undergraduate syllabus. The present book thus is a concise exam-oriented preparatory manual. The text is presented in a simple, precise and point-wise manner. This style of presentation would not only make it easier for the students to understand the subject in a better manner, but would also help them to quickly review and revise the subject before examination. Further, to make learning simpler and comprehension easier for the students, numerous tables, flowcharts and line diagrams have been included. A large number of people have helped me make this book possible. For this, I thank my postgraduate students and colleagues. I am grateful to Professor DR Kulkarni for his guidance and suggestions and for writing the Foreword. I would appreciate critical appraisal of this manual and suggestions for improvement. Tara V Shanbhag viii  BRIEF CONTENTS Foreword to the First Edition v Preface to the Fourth Edition vii Preface to the First Edition viii 1 General Pharmacology 1 2 Autonomic Pharmacology 46 3 Drugs Affecting Cardiovascular Function 98 4 Renal Pharmacology 151 5 Drugs Acting on Central Nervous System 164 6 Autacoids and Respiratory System 230 7 Drugs Used in the Treatment of Gastrointestinal Diseases 263 8 Drugs Affecting Coagulation and Blood Formation 285 9 Endocrine Pharmacology 303 10 Drugs Acting on Uterus 362 11 Chemotherapy 367 12 Miscellaneous Drugs 470 Index 505 ix This page intentionally left blank http://afkebooks.com  CONTENTS Foreword to the First Edition v Preface to the Fourth Edition vii Preface to the First Edition viii 1 General Pharmacology 1 Introduction (Definitions and Sources of Drugs) 1 Routes of Drug Administration 3 Pharmacokinetics 8 Pharmacodynamics 23 Rational Use of Medicines 36 Adverse Drug Effects 37 Poison Information Centres 42 Pharmacoeconomics 43 New Drug Development 43 2 Autonomic Pharmacology 46 Introduction to Autonomic Nervous System 46 Cholinergic System 46 Cholinergic Agents (Cholinomimetics, Parasympathomimetics) 50 Anticholinergic Agents 62 Skeletal Muscle Relaxants 69 Adrenergic Agonists (Sympathomimetic Agents) 75 Adrenergic Receptor Blockers 88 !-Adrenergic Blockers 88 "-Adrenergic Blockers 91 3 Drugs Affecting Cardiovascular Function 98 Antihypertensive Drugs 98 Antianginal Drugs 112 Drugs Used in Congestive Cardiac Failure 122 Antiarrhythmic Drugs 131 Hypolipidaemic Drugs 138 Plasma Volume Expanders 142 4 Renal Pharmacology 151 Diuretics 152 Antidiuretics 161 5 Drugs Acting on Central Nervous System 164 Neurotransmitters and Central Nervous System 164 Sedatives and Hypnotics 165 General Anaesthetics 173 Local Anaesthetics 181 Alcohols (Ethanol and Methanol) 189 xi xii CONTENTS Antiepileptic Drugs 192 Analgesics 201 Opioid Analgesics 201 Antiparkinsonian Drugs 211 Drugs for Alzheimer Disease 215 Cognitive Enhancers (Nootropics) 216 CNS Stimulants 217 Psychopharmacology 217 6 Autacoids and Respiratory System 230 Histamine and Antihistamines 230 5-Hydroxytryptamine: Agonists and Antagonists 234 Prostaglandins and Leukotrienes (Eicosanoids) 238 Nonsteroidal Anti-Inflammatory Drugs 240 Drugs Used in the Treatment of Gout 249 Drugs Used in the Treatment of Rheumatoid Arthritis 251 Drugs Used in the Treatment of Cough 254 Drugs Used in the Treatment of Bronchial Asthma 256 7 Drugs Used in the Treatment of Gastrointestinal Diseases 263 Emetics and Antiemetics 263 Antidiarrhoeal Agents 270 Pharmacotherapy of Inflammatory Bowel Disease 272 Laxatives (Purgatives, Cathartics) 274 Pharmacotherapy of Peptic Ulcer and Gastroesophageal Reflux Disease 277 8 Drugs Affecting Coagulation and Blood Formation 285 Drugs Affecting Coagulation and Bleeding 285 Haematinics and Haematopoietic Growth Factors 297 9 Endocrine Pharmacology 303 Introduction 303 Hypothalamic and Pituitary Hormones 304 Thyroid and Antithyroid Drugs 309 Sex Hormones and Their Antagonists 316 Corticosteroids 331 Insulin and Oral Antidiabetic Agents 341 Agents Affecting Calcium Balance 354 10 Drugs Acting on Uterus 362 Uterine Stimulants and Relaxants 362 11 Chemotherapy 367 Sulphonamides 375 Quinolones and Fluoroquinolones 378 Penicillins 383 Cephalosporins 390 Carbapenems 393 CONTENTS xiii Monobactams 394 Aminoglycosides 394 Tetracyclines 398 Chloramphenicol 401 Macrolides 402 Miscellaneous Antibacterial Agents 405 Urinary Antiseptics 409 Drugs Useful in the Treatment of Sexually Transmitted Diseases 410 Antituberculosis Drugs 412 Antileprotic Drugs 419 Antifungal Agents 422 Antiviral Agents 430 Antimalarial Drugs 438 Antiamoebic Drugs 448 Anthelmintics 454 Anticancer Drugs 459 12 Miscellaneous Drugs 470 Chelating Agents 470 Immunosuppressants and Immunostimulants 472 Antiseptics and Disinfectants 476 Vitamins 479 Minerals 483 Vaccines and Antisera 485 Drugs Used in Common Skin Diseases 487 Drug Therapy of Scabies and Pediculosis 490 Topical Drugs used for Common Diseases of Eye, Nose and Ear 491 Enzymes in Therapy 493 Drug Treatment of Medical Emergencies 494 Drug Dosage Forms 495 Calculation of Dosage of Drugs 498 Index 505 This page intentionally left blank http://afkebooks.com  COMPETENCY MAP Core Chapter Code Competency Y/N No. Page No. PHARMACOLOGY Topic: Pharmacology PH1.1 Define and describe the principles of pharmacology and Y 1 1 pharmacotherapeutics. PH1.2 Describe the basis of Evidence based medicine and Y 1 21 Therapeutic drug monitoring. PH1.3 Enumerate and identify drug formulations and drug Y 1, 12 8, 495 delivery systems. PH1.4 Describe absorption, distribution, metabolism & Y 1 8 – 18 excretion of drugs. PH1.5 Describe general principles of mechanism of drug action. Y 1 23 – 27 PH1.6 Describe principles of Pharmacovigilance & ADR Y 1 41 reporting systems. PH1.7 Define, identify and describe the management of Y 1 37 – 41 adverse drug reactions (ADR). PH1.8 Identify and describe the management of drug Y 1 35 interactions. PH1.9 Describe nomenclature of drugs i.e. generic, branded Y 1 2 drugs. PH1.10 Describe parts of a correct, complete and legible generic Y - - prescription. Identify errors in prescription and correct appropriately. PH1.11 Describe various routes of drug administration, eg., oral, Y 1 3–8 SC, IV, IM, SL. PH1.12 Calculate the dosage of drugs using appropriate Y 12 498 – 503 formulae for an individual patient, including children, elderly and patient with renal dysfunction. PH1.13 Describe mechanism of action, types, doses, side Y 2 75 – 97 effects, indications and contraindications of adrenergic and anti-adrenergic drugs. PH1.14 Describe mechanism of action, types, doses, side Y 2 46 – 68 effects, indications and contraindications of cholinergic and anticholinergic drugs. PH1.15 Describe mechanism/s of action, types, doses, side Y 2 69 – 75 effects, indications and contraindications of skeletal muscle relaxants. PH1.16 Describe mechanism/s of action, types, doses, side Y 6 230 – 254 effects, indications and contraindications of the drugs which act by modulating autacoids, including: anti- histaminics, 5-HT modulating drugs, NSAIDs, drugs for gout, anti-rheumatic drugs, drugs for migraine. PH1.17 Describe the mechanism/s of action, types, doses, side Y 5 181 – 189 effects, indications and contraindications of local anesthetics. (Continued) xv xvi COMPETENCY MAP Core Chapter Code Competency Y/N No. Page No. PH1.18 Describe the mechanism/s of action, types, doses, side Y 5 173 – 181 effects, indications and contraindications of general anaesthetics, and pre- anesthetic medications. PH1.19 Describe the mechanism/s of action, types, doses, side Y 5 164 – 173, effects, indications and contraindications of the drugs 192 – 229 which act on CNS, (including anxiolytics, sedatives & hypnotics, anti-psychotic, anti- depressant drugs, anti- maniacs, opioid agonists and antagonists, drugs used for neurodegenerative disorders, anti-epileptics drugs). PH1.20 Describe the effects of acute and chronic ethanol intake. Y 5 189 – 191 PH1.21 Describe the symptoms and management of methanol Y 5 191 and ethanol poisonings. PH1.22 Describe drugs of abuse (dependence, addiction, Y 1, 5 39, 217 stimulants, depressants, psychedelics, drugs used for criminal offences). PH1.23 Describe the process and mechanism of drug Y 1, 5 39, deaddiction. 190 – 191, 204 – 205 PH1.24 Describe the mechanism/s of action, types, doses, side Y 4 151 – 163 effects, indications and contraindications of the drugs affecting renal systems including diuretics, antidiuretics- vasopressin and analogues. PH1.25 Describe the mechanism/s of action, types, doses, side Y 3, 8 285 – 296, effects, indications and contraindications of the drugs 142 – 143 acting on blood, like anticoagulants, antiplatelets, fibrinolytics, plasma expanders. PH1.26 Describe mechanisms of action, types, doses, side Y 3, 4 98 – 104, effects, indications and contraindications of the drugs 158 – 159 modulating the renin- angiotensin and aldosterone system. PH1.27 Describe the mechanisms of action, types, doses, side Y 3 98 – 111 effects, indications and contraindications of antihypertensive drugs and drugs used in shock. PH1.28 Describe the mechanisms of action, types, doses, side Y 3 112 – 122 effects, indications and contraindications of the drugs used in ischemic heart disease (stable, unstable angina and myocardial infarction), peripheral vascular disease. PH1.29 Describe the mechanisms of action, types, doses, side Y 3 122 – 131 effects, indications and contraindications of the drugs used in congestive heart failure. PH1.30 Describe the mechanisms of action, types, doses, side N 3 131 – 138 effects, indications and contraindications of the antiarrhythmics. PH1.31 Describe the mechanisms of action, types, doses, side Y 3 138 – 142 effects, indications and contraindications of the drugs used in the management of dyslipidemias. PH1.32 Describe the mechanism/s of action, types, doses, side Y 6 256 – 262 effects, indications and contraindications of drugs used in bronchial asthma and COPD. PH1.33 Describe the mechanism of action, types, doses, side Y 6 254 – 256 effects, indications and contraindications of the drugs used in cough (antitussives, expectorants/ mucolytics). COMPETENCY MAP xvii Core Chapter Code Competency Y/N No. Page No. PH1.34 Describe the mechanism/s of action, types, doses, side Y 7 277 – 284, effects, indications and contraindications of the drugs 263 – 270, used as below: 270 – 272, 1. Acid-peptic disease and GERD 274 – 276, 2. Antiemetics and prokinetics 272 – 273 3. Antidiarrhoeals 4. Laxatives 5. Inflammatory Bowel Disease 6. Irritable Bowel Disorders, biliary and pancreatic diseases. PH1.35 Describe the mechanism/s of action, types, doses, side Y 8 297 – 302, effects, indications and contraindications of drugs used 302 in hematological disorders like: 1. Drugs used in anemias 2. Colony Stimulating factors. PH1.36 Describe the mechanism of action, types, doses, side Y 9 341 – 354, effects, indications and contraindications of drugs used 309 – 315, in endocrine disorders (diabetes mellitus, thyroid 354 – 361 disorders and osteoporosis). PH1.37 Describe the mechanisms of action, types, doses, side Y 9 316 – 326, effects, indications and contraindications of the drugs 304 – 309 used as sex hormones, their analogues and anterior Pituitary hormones. PH1.38 Describe the mechanism of action, types, doses, side Y 9 331 – 341 effects, indications and contraindications of corticosteroids. PH1.39 Describe mechanism of action, types, doses, side Y 9 326 – 331 effects, indications and contraindications the drugs used for contraception. PH1.40 Describe mechanism of action, types, doses, side Y 9, 2 322, 91 effects, indications and contraindications of 1. Drugs used in the treatment of infertility, and 2. Drugs used in erectile dysfunction. PH1.41 Describe the mechanisms of action, types, doses, side Y 10 362 – 366 effects, indications and contraindications of uterine relaxants and stimulants. PH1.42 Describe general principles of chemotherapy. Y 11 367–375 PH1.43 Describe and discuss the rational use of antimicrobials Y - - including antibiotic stewardship program. PH1.44 Describe the first line antitubercular dugs, their Y 11 412 – 417 mechanisms of action, side effects and doses. PH1.45 Describe the dugs used in MDR and XDR Tuberculosis. Y 11 418 PH1.46 Describe the mechanisms of action, types, doses, side Y 11 419 – 422 effects, indications and contraindications of antileprotic drugs. PH1.47 Describe the mechanisms of action, types, doses, side Y 11 438 – 448, effects, indications and contraindications of the drugs 453, used in malaria, KALA-AZAR, amebiasis and intestinal 448 – 452, helminthiasis. 454 – 458 PH1.48 Describe the mechanisms of action, types, doses, side Y 11 409 – 410, effects, indications and contraindications of the drugs 430 – 438 used in UTI/ STD and viral diseases including HIV. (Continued) xviii COMPETENCY MAP Core Chapter Code Competency Y/N No. Page No. PH1.49 Describe mechanism of action, classes, side effects, Y 11 459 – 469 indications and contraindications of anticancer drugs. PH1.50 Describe mechanisms of action, types, doses, side Y 12 472 – 476 effects, indications and contraindications of immunomodulators and management of organ transplant rejection. PH1.51 Describe occupational and environmental pesticides, Y 2 60 – 61 food adulterants, pollutants and insect repellents. PH1.52 Describe management of common poisoning, Y 1 41 – 42, insecticides, common sting and bites. 60 – 61 PH1.53 Describe heavy metal poisoning and chelating agents. N 12 470 – 472 PH1.54 Describe vaccines and their uses. Y 12 485 – 487 PH1.55 Describe and discuss the following National Health Y - - Programmes including Immunisation, Tuberculosis, Leprosy, Malaria, HIV, Filaria, Kala Azar, Diarrhoeal diseases, Anaemia & nutritional disorders, Blindness, Non-communicable diseases, cancer and Iodine deficiency. PH1.56 Describe basic aspects of Geriatric and Pediatric Y - - pharmacology. PH1.57 Describe drugs used in skin disorders. Y 12 487 – 491 PH1.58 Describe drugs used in Ocular disorders. Y 12 491 – 492 PH1.59 Describe and discuss the following: Essential medicines, Y 1 1, 21 – 22 Fixed dose combinations, Over the counter drugs, Herbal medicines. PH1.60 Describe and discuss Pharmacogenomics and N 1 43 Pharmacoeconomics. PH1.61 Describe and discuss dietary supplements and N - - nutraceuticals. PH1.62 Describe and discuss antiseptics and disinfectants. Y 12 476 – 479 PH1.63 Describe Drug Regulations, acts and other legal aspects. Y - - PH1.64 Describe overview of drug development, Phases of Y 1 43 – 45 clinical trials and Good Clinical Practice. Topic: Clinical Pharmacy PH2.1 Demonstrate understanding of the use of various dosage Y 12 495 – 498 forms (oral/local/parenteral; solid/liquid). PH2.2 Prepare oral rehydration solution from ORS packet and Y explain its use. PH2.3 Demonstrate the appropriate setting up of an Y intravenous drip in a simulated environment. PH2.4 Demonstrate the correct method of calculation of drug Y 12 498 – 503 dosage in patients including those used in special situations.  C H A P T E R 1 General Pharmacology Introduction (Definitions and Sources of Drugs) PH1.1, PH1.59 Pharmacology: It is the science that deals with the effects of drugs on living systems. Drug: World Health Organization (WHO) defines drug as ‘any substance or product that is used or intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient’. Pharmacokinetics: It means the movement of drug within the body; it includes the processes of absorption (A), distribution (D), metabolism (M) and excretion (E). It means ‘what the body does to the drug’. Pharmacodynamics: It is the study of drugs – their mechanism of action, phar- macological actions and their adverse effects. It covers all the aspects relating to ‘what the drug does to the body’. Pharmacy: It is the branch of science that deals with the preparation, preserva- tion, standardization, compounding, dispensing and proper utilization of drugs. Therapeutics: It is the aspect of medicine concerned with the treatment of diseases. Chemotherapy: It deals with treatment of infectious diseases/cancer with chemi- cal compounds that cause relatively selective damage to the infecting organism/ cancer cells. Toxicology: It is the study of poisons, their actions, detection, prevention and treatment of poisoning. Clinical pharmacology: It is the systematic study of a drug in man, both in healthy volunteers and in patients. It includes the evaluation of pharmacokinetic and pharmacodynamic data, safety, efficacy and adverse effects of a drug by com- parative clinical trials. Essential medicines: According to WHO, essential medicines are ‘those that sat- isfy the healthcare needs of majority of the population’. They should be of assured quality, available at all times, in adequate quantities and in appropriate dosage forms. They should be selected with regard to disease prevalence in a country, evidence on safety and efficacy, and comparative cost-effectiveness. The examples are iron and folic acid preparations for anaemia of pregnancy, antitubercular drugs like isoniazid, rifampicin, pyrazinamide, ethambutol, etc. Orphan drugs: Drugs that are used for diagnosis, treatment or prevention of rare diseases. The expenses incurred during the development, manufacture and marketing of drug cannot be recovered by the pharmaceutical company from selling the drug, e.g. digoxin antibody (for digoxin toxicity), fomepizole (for methyl alcohol poisoning), etc. Over-the-counter drugs (OTC drugs, nonprescription drugs): These drugs can be sold to a patient without the need for a doctor’s prescription, e.g. paracetamol, antacids, etc. Prescription drugs: These are drugs which can be obtained only upon producing the prescription of a registered medical practitioner, e.g. antibiotics, antipsychotics, etc. 1 2 PHARMACOLOGY FOR MEDICAL GRADUATES SOURCES OF DRUG INFORMATION Pharmacopoeia: It is a book which contains a list of established and officially approved drugs with description of their physical and chemical characteristics and tests for their identifica- tion, purity, methods of storage, etc. Some of the pharmacopoeias are the Indian Pharmaco- poeia (IP), the British Pharmacopoeia (BP), and the United States Pharmacopoeia (USP). Other sources of drug information are National Formulary (NF), Martindale – the Extra Pharmacopoeia, Physician’s Desk Reference (PDR), American Medical Associa- tion Drug Evaluation, textbooks and journals of pharmacology and therapeutics, drug bulletins, databases like Micromedex, Medline, Cochrane Library, etc. Information can also be obtained from pharmaceutical companies through their medical representa- tives, meetings and drug advertisements in journals. Formulary: It provides information about the available drugs in a country – their use, dose, dosage forms, adverse effects, contraindications, precautions, warnings and guid- ance on selecting the right drug for a range of conditions. DRUG NOMENCLATURE PH1.9 Drugs usually have three types of names, which are as follows: 1. Chemical name: It denotes the chemical structure of a drug, e.g. acetylsalicylic acid is the chemical name of aspirin and N-acetyl-p-aminophenol is of paracetamol. It is not suitable for use in a prescription. 2. Nonproprietary name: It is assigned by a competent scientific body/authority, e.g. the United States Adopted Name (USAN) council. WHO* along with its member countries select and recommend the International Nonproprietary Name (INN) for a drug. So, it is uniform throughout the world and denotes the active pharmaceutical ingredient. Few older drugs have more than one nonpro- prietary name, e.g. the opioid, pethidine and meperidine. The INN is commonly used as generic name. Ideally, generic names should be used in prescriptions be- cause it is economical and generally uniform all over the world than the branded counterparts. Examples are aspirin and paracetamol are generic names. 3. Proprietary name (brand name): It is given by the drug manufacturers. Brand names are short and easy to recall. Drugs sold under brand name are expensive as compared to their generic version. A drug usually has many brand names – it may have different names within a country and in different countries. Brand names can also be used in prescriptions. Disprin is a brand name of aspirin; Crocin for paracetamol. Chemical name Nonproprietary name Proprietary name/brand name Acetylsalicylic acid Aspirin Disprin Ecosprin N-acetyl-p- Paracetamol Crocin aminophenol Metacin (Acetaminophen) Tylenol *S Kopp-Kubel. International Nonproprietary Names (INN) for pharmaceutical substances. Bull World Health Organ 1995;73(3):275–279. 1—GENERAL PHARMACOLOGY 3 SOURCES OF DRUGS They are natural, semisynthetic and synthetic. Natural sources are plants, animals, min- erals, microorganisms, etc. Semisynthetic drugs are obtained from natural sources and are later chemically modified. Synthetic drugs are produced artificially. The different sources of drugs: 1. Plants: a. Alkaloids are nitrogen containing compounds, e.g. morphine, atropine, quinine, reserpine, ephedrine. b. Glycosides contain sugar group in combination with nonsugar through ether linkage, e.g. digoxin, digitoxin. c. Volatile oils have aroma. They are useful for relieving pain (clove oil), as carmi- native (eucalyptus oil), flavouring agent (peppermint oil), etc. d. Resins are sticky organic compounds obtained from plants as exudate, e.g. tincture benzoin (antiseptic). 2. Animals: Insulin, heparin, antisera. 3. Minerals: Ferrous sulphate, magnesium sulphate. 4. Microorganisms: Penicillin G, streptomycin, griseofulvin (antimicrobial agents), streptokinase (fibrinolytic). 5. Semisynthetic: Hydromorphone, hydrocodone. 6. Synthetic: Most of the drugs used today are synthetic, e.g. aspirin, paracetamol. Drugs are also produced by genetic engineering (DNA recombinant technology), e.g. human insulin, human growth hormone and hepatitis B vaccine. Routes of Drug Administration PH1.11 Most of the drugs can be administered by different routes. Drug- and patient-related factors determine the selection of routes for drug administration. These factors are 1. Characteristics of the drug. 2. Emergency/routine use. 3. Condition of the patient (unconscious, vomiting and diarrhoea). 4. Age of the patient. 5. Associated diseases. 6. Patient’s/doctor’s choice (sometimes). Routes Local Systemic Enteral Parenteral – Oral – Injection – Sublingual – Inhalation – Rectal – Transdermal Routes of drug administration 4 PHARMACOLOGY FOR MEDICAL GRADUATES LOCAL ROUTES It is the simplest mode of administration of a drug at the site where the desired action is required. Systemic side effects are minimal. 1. Topical: Drug is applied to the skin or mucous membrane at various sites for localized action. a. Oral cavity: As suspension, e.g. nystatin; as a troche, e.g. clotrimazole (for oral candidiasis); as a cream, e.g. acyclovir (for herpes labialis); as ointment, e.g. 5% lignocaine hydrochloride (for topical anaesthesia); as a spray, e.g. 10% ligno- caine hydrochloride (for topical anaesthesia). b. GI tract: As tablet which is not absorbed, e.g. neomycin (for sterilization of gut before surgery). c. Rectum and anal canal: 1) As an enema (administration of drug into the rectum in liquid form): Evacuant enema (for evacuation of bowel): For example, soap water enema – soap acts as a lubricant and water stimulates rectum. Retention enema: For example, methylprednisolone in ulcerative colitis. 2) As a suppository (administration of the drug in a solid form into the rectum), e.g. bisacodyl suppository for evacuation of bowel. d. Eye, ear and nose: As drops, ointment and spray (for infection, allergic condi- tions, etc.), e.g. gentamicin – eye and ear drops. e. Bronchi: As inhalation, e.g. salbutamol, ipratropium bromide, etc. (for bronchial asthma and chronic obstructive pulmonary disease). f. Vagina: As tablet, cream, pessary, etc. (for vaginal candidiasis). g. Urethra: As jelly, e.g. lignocaine. h. Skin: As ointment, cream, lotion, powder, e.g. clotrimazole (antifungal) for cutaneous candidiasis. 2. Intra-arterial route: This route is rarely employed. It is mainly used during diag- nostic studies, such as coronary angiography and for the administration of some anticancer drugs, e.g. for treatment of malignancy involving limbs. 3. Administration of the drug into deep tissues by injection, e.g. administration of triamcinolone directly into the joint space in rheumatoid arthritis. SYSTEMIC ROUTES Drugs administered by this route enter the blood and produce systemic effects. Enteral Routes They include oral, sublingual and rectal routes. Oral Route. It is the most common and acceptable route for drug administration. Dosage forms are tablet, capsule, powder, syrup, linctus, mixture, suspension, etc., e.g. paracetamol tablet for fever, omeprazole capsule for peptic ulcer are given orally. Tablets could be coated (covered with a thin film of another substance) or uncoated. They are also available as chewable (albendazole), dispersible (aspirin), mouth dissolving (ondansetron) and sustained release forms. Capsules have a soft or hard shell. Advantages Safer. Cheaper. Painless. 1—GENERAL PHARMACOLOGY 5 Convenient for repeated and prolonged use. Can be self-administered. Disadvantages It is not suitable for/in: unpalatable and highly irritant drugs unabsorbable drugs (e.g. aminoglycosides) drugs that are destroyed by digestive juices (e.g. insulin) drugs with extensive first-pass metabolism (e.g. lignocaine) unconscious patients uncooperative and unreliable patients patients with severe vomiting and diarrhoea emergency as onset of action of orally administrated drugs is slow Sublingual Route. The preparation is kept under the tongue. The drug is absorbed through the buccal mucous membrane and enters systemic circulation directly, e.g. nitroglycerin(for acute attack of angina) and buprenorphine. Advantages Quick onset of action of the drug. Action can be terminated by spitting out the tablet. Bypasses the first-pass metabolism. Self-administration is possible. Disadvantages It is not suitable for: irritant and lipid-insoluble drugs drugs with bad taste Rectal Route. Drugs can be given in the form of solid or liquid. 1. Suppository: It can be used for local (topical) effect (see p. 4) as well as systemic effect, e.g. indomethacin for rheumatoid arthritis. 2. Enema: Retention enema can be used for local effect (see p. 4) as well as systemic effect. The drug is absorbed through rectal mucous membrane and produces sys- temic effect, e.g. diazepam for status epilepticus in children methylprednisolone enema in ulcerative colitis. Parenteral Routes Routes of administration other than enteral route are called parenteral routes. Advantages Onset of action of drugs is faster, hence suitable for emergency. Useful in: unconscious patient uncooperative and unreliable patient patients with vomiting and diarrhoea Suitable for: irritant drugs drugs with high first-pass metabolism drugs not absorbed orally drugs destroyed by digestive juices 6 PHARMACOLOGY FOR MEDICAL GRADUATES Disadvantages Require aseptic conditions. Preparation should be sterile, and is expensive. Require invasive techniques, which are painful. Cannot be usually self-administered. Can cause local tissue injury to nerves, vessels, etc. Inhalation. Volatile liquids and gases are given by inhalation for systemic effects, e.g. general anaesthetics. Advantages Quick onset of action. Dose required is very less, so systemic toxicity is minimized. Amount of drug administered can be regulated. Disadvantages Local irritation may cause increased respiratory secretion and bronchospasm. Injections (Fig. 1.1) Intradermal Route. The drug is injected into the layers of skin, e.g. BCG vaccination and drug sensitivity tests. It is painful and a small amount of the drug can be administered. Subcutaneous (s.c.) Route. The drug is injected into the subcutaneous tissue of the thigh, abdomen, arm, e.g. adrenaline, insulin, etc. Advantages Self-administration of drug is possible, e.g. insulin. Depot preparations can be inserted into the subcutaneous tissue, e.g. norplant for contraception. Disadvantages It is suitable only for nonirritant drugs. Drug absorption is slow, hence not suitable for emergency. Intradermal Subcutaneous Intravenous Intra-arterial Intramuscular Intra-articular Fig. 1.1 Injectable routes of drug administration. 1—GENERAL PHARMACOLOGY 7 Intramuscular (i.m.) Route. Drugs are injected into large muscles, such as deltoid, glu- teus maximus and vastus lateralis, e.g. paracetamol, diclofenac, etc. A volume of 5–10 mL can be given at a time. Advantages Absorption is more rapid as compared to oral route. Mild irritants, depot injections, soluble substances and suspensions can be given by this route. Disadvantages Aseptic conditions are needed. Intramuscular (i.m.) injections are painful and may cause abscess. Self-administration is not possible. There may be injury to nerves. Intravenous (i.v.) Route. Drugs are injected directly into the blood stream through a vein. Drugs are administered as 1. Bolus: Single, relatively large dose of a drug injected rapidly or slowly into a vein, e.g. i.v. ranitidine in bleeding peptic ulcer. 2. Slow intravenous injection: For example, i.v. morphine in myocardial infarction. 3. Intravenous infusion: For example, dopamine infusion in cardiogenic shock; mannitol infusion in cerebral oedema; fluids infused intravenously in dehydration. Advantages Bioavailability is 100%. Quick onset of action, so it is the route of choice in emergency, e.g. intravenous diazepam to control convulsions in status epilepticus. Large volume of fluid can be administered, e.g. intravenous fluids in patients with severe dehydration. Highly irritant drugs, e.g. anticancer drugs can be given because they get diluted in blood. Hypertonic solution can be infused by intravenous route, e.g. 20% mannitol in cerebral oedema. By i.v. infusion, a constant plasma level of the drug can be maintained, e.g. dopamine infusion in cardiogenic shock. Disadvantages Local irritation may cause phlebitis. Self-administration is usually not possible. Strict aseptic conditions are needed. Extravasation of some drugs (e.g. noradrenaline) can cause injury, necrosis and sloughing of tissues. Depot preparations cannot be given by i.v. route. Precautions Drug should usually be injected slowly. Before injecting, make sure that the tip of the needle is in the vein. Intrathecal Route. Drug is injected into the subarachnoid space, e.g. lignocaine (spinal anaesthesia), antibiotics (amphotericin B), etc. Transdermal Route (Transdermal Therapeutic System). The drug is administered in the form of a patch or ointment that delivers the drug into the circulation for systemic effect (Fig. 1.2), e.g. scopolamine patch for sialorrhoea and motion sickness, nitroglycerin 8 PHARMACOLOGY FOR MEDICAL GRADUATES Backing layer D D D D D D D Drug reservoir D D D D D D D D D Rate controlling membrane Adhesive layer Outer layer, which is peeled off before application to skin Fig. 1.2 Transdermal drug delivery system. patch/ointment for prophylaxis of angina, oestrogen patch for hormone replacement therapy (HRT), clonidine patch for hypertension, fentanyl patch for terminal stages of cancer pain and chronic pain, nicotine patch for tobacco deaddiction, etc. Advantages Self-administration is possible. Patient compliance is better. Duration of action is prolonged. Systemic side effects are reduced. Provides a constant plasma concentration of the drug. First-pass metabolism is bypassed. Disadvantages Expensive. Local irritation may cause dermatitis and itching. Patch may fall off unnoticed. SPECIAL DRUG DELIVERY SYSTEMS PH1.3 They have been developed to prolong duration of drug action, for targeted delivery of drugs or to improve patient compliance. 1. Ocusert: It is kept beneath the lower eyelid in glaucoma. It releases the drug slowly for a week following a single application, e.g. pilocarpine ocusert. 2. Progestasert: It is an intrauterine contraceptive device that releases progesterone slowly for a period of one year. 3. Liposomes: They are minute vesicles made of phospholipids into which the drug is incorporated. They help in targeted delivery of drugs, e.g. liposomal formula- tion of amphotericin B for fungal infections. 4. Monoclonal antibodies: They are immunoglobulins, produced by cell culture, selected to react with a specific antigen. They are useful for targeted delivery of drugs, e.g. delivery of anticancer drugs using monoclonal antibodies. 5. Drug-eluting stents: e.g. paclitaxel releasing stents used in coronary angioplasty. 6. Computerized, miniature pumps, e.g. insulin pump for continuous subcutaneous delivery of insulin Pharmacokinetics PH1.4 Pharmacokinetics is derived from two words: Pharmacon meaning drug and kinesis meaning movement. In short, it is ‘what the body does to the drug’. It includes 1—GENERAL PHARMACOLOGY 9 absorption (A), distribution (D), metabolism (M) and excretion (E). All these pro- cesses involve movement of the drug molecule through various biological membranes. All biological membranes are made up of a lipid bilayer. Drugs cross various bio- logical membranes by the following mechanisms: 1. Passive diffusion: It is a bidirectional process. The drug molecules move from a region of higher to lower concentration until equilibrium is attained. The rate of diffusion is directly proportional to the concentration gradient across the membrane. Lipid-soluble drugs are transported across the membrane by passive diffusion. It does not require energy and is the process by which majority of the drugs are absorbed. 2. Active transport: Drug molecules move from a region of lower to higher concen- tration against the concentration gradient. It requires energy, e.g. transport of sympathomimetic amines into neural tissue, transport of choline into cholinergic neurons and absorption of levodopa from the intestine. In primary active trans- port, energy is obtained by hydrolysis of ATP. In secondary active transport, energy is derived from transport of another substrate (either symport or antiport). 3. Facilitated diffusion: This is a type of carrier-mediated transport and does not require energy. The drug attaches to a carrier in the membrane, which facilitates its diffusion across the membrane. The transport of molecules is from the region of higher to lower concentration, e.g. transport of glucose across muscle cell mem- brane by a transporter GLUT 4. 4. Filtration: Filtration depends on the molecular size and weight of the drug. If drug molecules are smaller than the pores, they are filtered easily through the membrane. 5. Endocytosis: The drug is taken up by the cell through vesicle formation. Absorp- tion of vitamin B12–intrinsic factor complex in the gut is by endocytosis. DRUG ABSORPTION PH1.4 Movement of a drug from the site of administration into the blood stream is known as absorption. Factors Influencing Drug Absorption 1. Physicochemical properties of the drug: a. Physical state: Liquid form of the drug is better absorbed than solid formulations. b. Lipid-soluble and unionized form of the drug is better absorbed than water- soluble and ionized form. c. Particle size: Drugs with smaller particle size are absorbed better than larger ones, e.g. microfine aspirin, digoxin and griseofulvin are well absorbed from the gut and produce better effects. Some of the anthelmintics have larger par- ticle size. They are poorly absorbed through gastrointestinal (GI) tract, hence they produce better effect on gut helminths. d. Disintegration time: It is the time taken for the formulation (tablet or capsule) to break up into small particles and its variation may affect the bioavailability. e. Dissolution time: It is the time taken for the particles to go into solution. Shorter the time, better is the absorption. f. Formulations: Pharmacologically inert substances like lactose, starch, calcium sulphate, gum, etc. are added to formulations as binding agents. These are not totally inert and may affect the absorption of drugs, e.g. calcium reduces the absorption of tetracyclines. 10 PHARMACOLOGY FOR MEDICAL GRADUATES Weakly acidic drugs (barbiturates) Unionized form in Acidic pH Weakly basic drugs (morphine, amphetamine) Better absorbed from the stomach Alkaline pH in Unionized form Better absorbed from the intestine Fig. 1.3 Effect of pH and ionization on drug absorption. 2. Route of drug administration: A drug administered by intravenous route bypasses the process of absorption as it directly enters the circulation. Some drugs are highly polar compounds, ionize in solution and are not absorbed through GI tract, hence are given parenterally, e.g. gentamicin. Drugs like insulin are administered paren- terally because they are degraded in the GI tract on oral administration. 3. pH and ionization: Strongly acidic (heparin) and strongly basic (aminoglycosides) drugs usually remain ionized at all pH, hence they are poorly absorbed (Fig. 1.3). 4. Food: Presence of food in the stomach can affect the absorption of some drugs. Food decreases the absorption of rifampicin, levodopa, etc., hence they should be taken on an empty stomach for better effect. Milk and milk products decrease the absorption of tetracyclines. Fatty meal increases the absorption of griseofulvin. 5. Presence of other drugs: Concurrent administration of two or more drugs may affect their absorption, e.g. ascorbic acid increases the absorption of oral iron. Antacids reduce the absorption of tetracyclines. 6. Area of the absorbing surface: Normally, drugs are better absorbed in small in- testine because of a larger surface area. Resection of the gut decreases absorption of drugs due to a reduced surface area. 7. Gastrointestinal and other diseases: In gastroenteritis, there is increased peristal- tic movement that decreases drug absorption. In achlorhydria, absorption of iron from the gut is reduced. In congestive cardiac failure, there is GI mucosal oedema that reduces absorption of drugs. BIOAVAILABILITY It is the fraction of a drug that reaches systemic circulation from a given dose. Intrave- nous route of drug administration gives 100% bioavailability as it directly enters the circulation. The term bioavailability is used commonly for drugs given by oral route. If two formulations of the same drug produce equal bioavailability, they are said to be bioequivalent. If formulations differ in their bioavailability, they are said to be bioinequivalent. Factors Affecting Bioavailability. The factors which affect drug absorption (physico- chemical properties of the drug, route of drug administration, pH and ionization, food, 1—GENERAL PHARMACOLOGY 11 Fig. 1.4 First-pass metabolism. presence of other drugs, area of absorbing surface, GI and other diseases) also affect bio- availability of a drug. Other factors that affect the bioavailability of a drug are discussed as follows: 1. First-pass metabolism (First-pass effect, presystemic elimination): When drugs are administered orally, they have to pass via gut wall n portal vein n liver n systemic circulation (Fig. 1.4). During this passage, certain drugs get metabolized and are removed or inactivated before they reach the systemic circulation. This process is known as first-pass metabolism. The net result is a decreased bioavail- ability of the drug and diminished therapeutic response, e.g. drugs like lignocaine (liver), isoprenaline (gut wall), etc. Consequences of high first-pass metabolism: 1) Drugs which undergo extensive first-pass metabolism are administered parenterally, e.g. lignocaine is administered intravenously in ventricular arrhythmias. 2) Dose of a drug required for oral administration is more than that given by other systemic routes, e.g. nitroglycerin. 2. Hepatic diseases: They result in a decrease in drug metabolism, thus increasing the bioavailability of drugs that undergo high first-pass metabolism, e.g. pro- pranolol and lignocaine. 3. Enterohepatic cycling: Some drugs are excreted via bile but after reaching the in- testine they are reabsorbed n liver n bile n intestine and the cycle is repeated – such recycling is called enterohepatic circulation and it increases bioavailability as well as the duration of action of the drug, e.g. morphine and doxycycline. DRUG DISTRIBUTION PH1.4 Distribution is defined as the reversible transfer of drugs between body-fluid compart- ments. After absorption, a drug enters the systemic circulation and is distributed in the body fluids. Various body-fluid compartments for a 70-kg person can be depicted as follows: 12 PHARMACOLOGY FOR MEDICAL GRADUATES TBW (42 L) ECF (14 L) ICF (28 L) Plasma Interstitial fluid Transcellular fluid (3 L) compartment compartment (10.5 L) (0.5 L) ECF, extracellular fluid; ICF, intracellular fluid; TBW, total body water. Apparent Volume of Distribution Apparent volume of distribution (aVd) is defined as the hypothetical volume of body fluid into which a drug is uniformly distributed at a concentration equal to that in plasma, assuming the body to be a single compartment. Total administered amount of drug aVd ! Concentration of the drug in plasma Drugs with high molecular weight (e.g. heparin) or extensively bound to plasma protein (e.g. warfarin) are largely restricted to the vascular compartment, hence their aVd is low. If aVd of a drug is about 14–16 L (0.25 mL/kg in a person weighing 70 kg), it indi- cates that the drug is distributed in the ECF, e.g. gentamicin, streptomycin, etc. Small water-soluble molecules like ethanol are distributed in total body water – aVd is approximately 42 L. Drugs which accumulate in tissues have a volume of distribution which exceeds total body water, e.g. chloroquine (13,000 L) and digoxin (500 L). Haemodialysis is not useful for removal of drugs with large aVd in case of overdosage. In congestive cardiac failure, Vd of some drugs can increase due to an increase in ECF volume (e.g. alcohol) or decrease because of reduced perfusion of tissues. In uraemia, the total body water can increase which increases Vd of small water- soluble drugs. Toxins which accumulate can displace drugs from plasma protein binding sites resulting in increased concentration of free form of drug which can leave the vascular compartment leading to an increase in Vd. Fat:lean body mass ratio – highly lipid-soluble drugs get distributed to the adipose tissue. If the ratio is high, the volume of distribution for such a drug will be higher; fat acts as a reservoir for such drugs. Redistribution (see p. 178) Highly lipid-soluble drug, such as thiopentone, on intravenous administration, immedi- ately gets distributed to the areas of high blood flow, such as brain, and causes general an- aesthesia. Immediately within few minutes, it diffuses across the blood–brain barrier (BBB) into blood and then to the less perfused tissues, such as muscle and adipose tissue. This is called redistribution, which results in termination of drug action. Thiopentone has a very short duration of action (5–10 minutes) and is used for induction of general anaesthesia. Drug Reservoirs or Tissue Storage Some drugs are concentrated or accumulated in tissues or some organs of the body, which can lead to toxicity on chronic use, e.g. tetracyclines – bones and teeth; thiopen- tone and DDT – adipose tissue; chloroquine – liver and retina; digoxin – heart, etc. 1—GENERAL PHARMACOLOGY 13 Blood–Brain Barrier The capillary boundary that is present between blood and brain is called blood—brain barrier (BBB). In the brain capillaries, the endothelial cells are joined by tight junctions. Only the lipid-soluble and unionized form of drugs can pass through BBB and reach the brain, e.g. barbiturates, diazepam, volatile anaesthetics, amphetamine, etc. Lipid-insol- uble and ionized particles do not cross the BBB, e.g. dopamine and aminoglycosides. Pathological states like meningitis and encephalitis increase the permeability of the BBB and allow the normally impermeable substances to enter the brain, e.g. penicillin G in normal conditions has poor penetration through BBB, but its penetrability in- creases during meningitis and encephalitis. Placental Barrier Drugs administered to a pregnant woman can cross placenta and reach the fetus. Passage across placenta is affected by lipid solubility, degree of plasma protein binding, presence of transporters, etc. Quaternary ammonium compounds, e.g. d-tubocurarine (d-TC) and substances with high molecular weight like insulin cannot cross the placental barrier. PLASMA PROTEIN BINDING PH1.4 Many drugs bind to plasma proteins like albumin, "1 acid glycoprotein, etc. Clinical importance of plasma protein binding Absorption 1. Drug Enters circulation Binds to plasma protein (acidic drugs to albumin, basic drugs to α1 acid glycoprotein) Free form (pharma- Bound form (cannot exert pharmacological cologically active) action, acts as a ‘temporary store’ of the drug) 2. Drugs that are highly bound to plasma proteins have a low volume of distribution. 3. Plasma protein binding delays the metabolism of drugs. 4. Bound form is not available for filtration at the glomeruli. Hence, excretion of highly plasma protein bound drugs by filtration is delayed. 5. Highly protein bound drugs have a longer duration of action, e.g. sulphadiazine is less plasma protein bound and has a duration of action of 6 hours, whereas sulphadoxine is highly plasma protein bound and has a duration of action of 1 week. 6. In case of poisoning, highly plasma protein bound drugs are difficult to be removed by haemodialysis. 7. In disease states like anaemia, renal failure, chronic liver diseases, etc. plasma albumin levels are low (hypoalbuminaemia). So, there will be a decrease in bound form and an increase in free form of the drug, which can lead to drug toxicity. 8. Plasma protein binding can cause displacement interactions. More than one drug can bind to the same site on plasma protein. The drug with higher affinity will displace the one having lower affinity and may result in a sudden increase in the free concentration of the drug with lower affinity. 14 PHARMACOLOGY FOR MEDICAL GRADUATES BIOTRANSFORMATION (Drug Metabolism) PH1.4 Chemical alteration of the drug in a living organism is called biotransformation. The metabolism of a drug usually converts lipid-soluble and unionized compounds into water-soluble and ionized compounds, hence not reabsorbed in the renal tubules and are excreted. If the parent drug is highly polar (ionized), then it may not get metabo- lized and is excreted as such. Sites: Liver is the main site for drug metabolism; other sites are GI tract, kidney, lungs, blood, skin and placenta. The end result of drug metabolism is inactivation, but sometimes a compound with pharmacological activity may be formed as shown below: 1. Active drug to inactive metabolite: This is the most common type of metabolic transformation. Phenobarbitone Hydroxyphenobarbitone Phenytoin p-Hydroxyphenytoin 2. Active drug to active metabolite Codeine Morphine Diazepam Oxazepam 3. Inactive drug (prodrug) to active metabolite Levodopa Dopamine Prednisone Prednisolone Prodrug It is an inactive form of a drug, which is converted to an active form after metabolism. Uses of Prodrugs (Advantages) 1. To improve bioavailability: Parkinsonism is due to deficiency of dopamine. Dopa- mine itself cannot be used since it does not cross BBB. So, it is given in the form of a prodrug, levodopa. Levodopa crosses the BBB and is then converted into dopamine. Dopa decarboxylase Levodopa Levodopa Dopamine BBB 2. To prolong the duration of action: Phenothiazines have a short duration of action, whereas esters of phenothiazine (fluphenazine) have a longer duration of action. 3. To improve taste: Clindamycin has a bitter taste, so clindamycin palmitate sus- pension has been developed for paediatric use to improve the taste. 4. To provide site-specific drug delivery: acidic pH of urine Methenamine Formaldehyde (acts as urinary antiseptic) Pathways of Drug Metabolism. Drug metabolic reactions are grouped into two phases. They are Phase I or nonsynthetic reactions and Phase II or synthetic reactions. Phase I Reactions (Table 1.1). Oxidation: Addition of oxygen or removal of hydrogen is called oxidation. It is the most important and common metabolic reaction. Oxidation reactions are mainly carried out by cytochrome P450, cytochrome P450 reductase, molecular O2 and NADPH. There are several cytochrome P450 isoenzymes. 1—GENERAL PHARMACOLOGY 15 Table 1.1 Phase I reactions Oxidation Addition of oxygen/removal of Phenytoin, phenobarbitone, pento- hydrogen barbitone, propranolol Reduction Removal of oxygen/addition of Chloramphenicol, methadone hydrogen Hydrolysis Break down of compound by Esters – procaine, succinylcholine addition of water Amides – lignocaine, procainamide Cyclization Conversion of straight chain Proguanil compound into ring structure Decyclization Breaking up of the ring structure Phenobarbitone, phenytoin of the drug They are numbered as 1,2,3,4… (to denote families) and each as A, B, C, D (subfamilies). More than 50% of drugs undergo biotransformation reactions by CYP3A4/5. Other enzymes include CYP2D6, CYP2C9, CYP2E1, CYP2C19, etc. Reduction: Removal of oxygen or addition of hydrogen is known as reduction. Hydrolysis: Breakdown of the compound by addition of water is called hydrolysis. This is common among esters and amides. Cyclization: Conversion of a straight chain compound into ring structure. Decyclization: Breaking up of the ring structure of the drug. At the end of phase I, the metabolite may be active or inactive. Phase II Reactions (Table 1.2). Phase II consists of conjugation reactions. If the phase I metabolite is polar, it is excreted in urine or bile. However, many metabolites are lipo- philic and undergo subsequent conjugation with an endogenous substrate, such as glucuronic acid, sulphuric acid, acetic acid or amino acid. These conjugates are polar, usually water-soluble and inactive. Not all drugs undergo phase I and phase II reactions in that order. In case of isoniazid (INH), phase II reaction precedes phase I reaction (Fig. 1.5). Table 1.2 Phase II reactions Conjugation reaction Enzyme Examples Glucuronidation UDP glucuronosyl transferase Aspirin Morphine Acetylation N-acetyltransferase Isoniazid Dapsone Sulphation Sulphotransferase Paracetamol Methyldopa Methylation Transmethylase Adrenaline Dopamine Glutathione conjugation Glutathione transferase Paracetamol Glycine conjugation Acyl CoA glycine transferase Salicylates 16 PHARMACOLOGY FOR MEDICAL GRADUATES Drug Drug Drug Drug Drug (INH) Phase I Phase I Unchanged Phase II form Phase II Phase II Phase I Metabolite excreted Fig. 1.5 Phases of biotransformation. Table 1.3 Microsomal and nonmicrosomal enzymes Microsomal enzymes Nonmicrosomal enzymes Location Smooth endoplasmic reticulum of Cytoplasm, mitochondria, plasma, e.g. conjugases, cells, liver, kidney, lungs, e.g. esterases, amidases, flavoprotein oxidases cytochrome P450, monooxygen- ase, glucuronyl transferase Reactions Most of the phase I reactions, Oxidation, reduction (few), hydrolysis. Glucuronide conjugation All conjugations except glucuronide conjugation Inducible Not inducible – may show genetic polymorphism Drug-Metabolizing Enzymes They are broadly divided into two groups – microsomal and nonmicrosomal enzyme systems (Table 1.3). Hofmann Elimination Drugs can be inactivated without the need of enzymes – this is known as Hofmann elimi- nation. Atracurium, a skeletal muscle relaxant, undergoes Hofmann elimination. Factors Affecting Drug Metabolism 1. Age: Neonates and elderly metabolize some drugs to a lesser extent than adults. In these cases, it is due to diminished amount/activity of hepatic microsomal enzymes. Neonates conjugate chloramphenicol more slowly, hence develop toxicity – grey baby syndrome. Increased incidence of toxicity with propranolol and lignocaine in elderly is due to their decreased hepatic metabolism. 2. Diet: Poor nutrition can decrease enzyme function. 3. Diseases: Chronic diseases of liver may affect hepatic metabolism of some drugs, e.g. increased duration of action of diazepam, in patients with cirrhosis, due to its impaired metabolism. 1—GENERAL PHARMACOLOGY 17 4. Genetic factors (pharmacogenetics): These factors also influence drug metabo- lism. The study of genetically determined variation in drug response is called pharmacogenetics a. Slow and fast acetylators of isoniazid: There is an increased incidence of pe- ripheral neuritis with isoniazid in slow acetylators. The fast acetylators require a larger dose of the drug to produce therapeutic effect. b. Succinylcholine apnoea: Succinylcholine, a neuromuscular blocker, is metabolized by plasma pseudocholinesterase enzyme. The duration of action of succinylcholine is 3–6 minutes. However, some individuals have atypical pseudocholinesterase that metabolizes the drug very slowly. This results in prolonged succinylcholine apnoea due to paralysis of respiratory muscles, which is dangerous. c. Glucose-6-phosphate dehydrogenase (G6PD) deficiency and haemolytic anaemia: G6PD activity is important to maintain the integrity of the RBCs. A person with G6PD deficiency may develop haemolysis when exposed to certain drugs like sulphonamides, primaquine, salicylates, dapsone, etc. 5. Simultaneous administration of drugs: This can result in increased or decreased metabolism of drugs (see enzyme induction or inhibition). Enzyme Induction. Repeated administration of certain drugs increases the synthesis of microsomal enzymes. This is known as enzyme induction. The drug is referred to as an enzyme inducer, e.g. rifampicin, phenytoin, barbiturates, carbamazepine, griseofulvin, etc. Clinical Importance of Microsomal Enzyme Induction 1. Enzyme induction may accelerate the metabolism of drugs, thus reducing the du- ration and intensity of drug action leading to therapeutic failure, e.g. rifampicin and oral contraceptives. Rifampicin induces the drug metabolizing enzyme of oral contraceptives, thus enhancing its metabolism and leading to contraceptive failure. 2. Autoinduction may lead to development of drug tolerance, e.g. carbamazepine enhances its own metabolism. 3. Enzyme induction can lead to drug toxicity, e.g. increased incidence of hepatotox- icity with paracetamol in alcoholics is due to overproduction of toxic metabolite of paracetamol. 4. Prolonged phenytoin therapy may produce osteomalacia due to enhanced me- tabolism of vitamin D3. 5. Enzyme inducers, e.g. barbiturates, can precipitate porphyria due to overproduc- tion of porphobilinogen. 6. Enzyme induction can also be beneficial, e.g. phenobarbitone in neonatal jaundice – phenobarbitone induces glucuronyl transferase enzyme, hence bilirubin is conjugated and jaundice is resolved. Enzyme Inhibition. Certain drugs, e.g. chloramphenicol, ciprofloxacin, erythromycin, etc. inhibit the activity of drug metabolizing enzymes and are known as enzyme in- hibitors. Inhibition of metabolism of one drug by another can occur when both are metabolized by the same enzyme. Enzyme inhibition is a rapid process as compared to enzyme induction. Clinical Relevance of Enzyme Inhibition. Enzyme inhibition can result in drug toxicity, e.g. increased incidence of bleeding with warfarin, due to concomitant administration of erythromycin or chloramphenicol, etc. These drugs inhibit drug metabolizing enzyme of warfarin resulting in increased plasma concentration of warfarin and enhanced anticoagu- lant effect (bleeding). Toxicity following inhibition of metabolism is significant for those 18 PHARMACOLOGY FOR MEDICAL GRADUATES drugs which have saturation kinetics of metabolism. Enzyme inhibition can be beneficial, e.g. boosted protease inhibitor regimen used for treatment of HIV infection (see p. 436). DRUG EXCRETION PH1.4 Removal of the drug and its metabolite from the body is known as drug excretion. The main channel of excretion of drugs is the kidney; others include lungs, bile, faeces, sweat, saliva, tears, milk, etc. 1. Kidney: The processes involved in the excretion of drugs via kidney are glo- merular filtration, passive tubular reabsorption and active tubular secretion. Glomerular filtration and active tubular secretion facilitate drug excretion, whereas tubular reabsorption decreases drug excretion. Rate of renal excretion ! (Rate of filtration # Rate of secretion) – Rate of reabsorption 1) Glomerular filtration: Drugs with small molecular size are more readily filtered. The extent of filtration is directly proportional to the glomerular filtration rate (GFR) and to the fraction of the unbound drug in plasma. 2) Passive tubular reabsorption: The main factor affecting passive reabsorption is the pH of renal tubular fluid and the degree of ionization. Strongly acidic and strongly basic drugs remain in ionized form at any pH of urine, hence are excreted in urine. a) Weakly acidic drugs (e.g. salicylates, barbiturates) in acidic urine remain mainly in ‘unionized’ form, so they are reabsorbed into the circulation. If the pH of urine is made alkaline by sodium bicarbonate, the weakly acidic drugs get ‘ionized’ and are excreted easily. b) Similarly, weakly basic drugs (e.g. morphine, amphetamine, etc.) in alka- line urine remain in ‘unionized’ form, hence are reabsorbed. If the pH of urine is made acidic by vitamin C (ascorbic acid), these weakly basic drugs get ‘ionized’ and are excreted easily. 3) Active tubular secretion: It is a carrier-mediated active transport which re- quires energy. Active secretion is unaffected by changes in the pH of urine and protein binding. Most of the acidic drugs (e.g. penicillin, diuretics, pro- benecid, sulphonamides, etc.) and basic drugs (e.g. quinine, procaine, mor- phine, etc.) are secreted by the renal tubular cells. The carrier system is rela- tively nonselective and therefore drugs having similar physicochemical properties compete for the same carrier system, e.g. probenecid competi- tively inhibits the tubular secretion of penicillins, thereby increasing the duration of action as well as the plasma half-life and effectiveness of penicil- lins in the treatment of diseases, such as gonococcal infections. 2. Lungs: Alcohol and volatile general anaesthetics, such as ether, halothane, isoflu- rane, sevoflurane and ether are excreted via lungs. 3. Faeces: Drugs like purgatives, e.g. senna, cascara, etc. are excreted in faeces 4. Bile: Some drugs are secreted in bile. They are reabsorbed in the gut while a small portion is excreted in faeces, e.g. tetracyclines. 5. Skin: Metals like arsenic and mercury are excreted through skin. 6. Saliva: Certain drugs like potassium iodide, phenytoin, metronidazole and lith- ium are excreted in saliva. Salivary estimation of lithium may be used for nonin- vasive monitoring of lithium therapy. 7. Milk: Drugs taken by lactating women may appear in milk. They may or may not adversely affect the breast fed infant. Drugs like penicillins, erythromycin, etc. are safe for use but amiodarone is to be avoided in mothers during breast feeding. 1—GENERAL PHARMACOLOGY 19 PHARMACOKINETIC PARAMETERS The important pharmacokinetic parameters are bioavailability, volume of distribution, plasma half-life (t1/2) and clearance. Plasma Half-Life (t1/2) It is the time required for the plasma concentration of a drug to decrease by 50% of its original value (Fig. 1.6A). Plasma half-life of lignocaine is 1 hour and for aspirin it is 4 hours. Clinical Importance of Plasma Half-Life. It helps to determine the duration of drug action. determine the frequency of drug administration. estimate the time required to reach the steady state. At steady state, the amount of drug administered is equal to the amount of drug eliminated in the dose interval. It takes approximately four to five half-lives to reach the steady state during re- peated administration of the drug. A drug is almost completely eliminated in four to five half-lives after single administration. Clearance Clearance (CL) of a drug is defined as that volume of plasma from which the drug is removed in unit time. Rate of elimination Clearance ! Plasma concentration of the drug 1. First-order kinetics: A constant fraction of the drug in the body is eliminated per unit time. For example, assume drug ‘A’ with plasma t1/2 of 1 hour following first-order kinet- ics of elimination and having an initial plasma concentration of 100 mcg/mL. 1 hour 1 hour 100 mcg/mL 50 mcg/mL 25 mcg/mL ½ ½ If its concentration is increased to 200 mcg/mL, a constant fraction (1/2) gets eliminated in unit time, i.e. after 1 hour, concentration is 100 mcg/mL. The rate of drug elimination is directly proportional to its plasma concentration. The t1/2 of the drugs following first-order kinetics will always remain con- stant. The drug will be almost completely eliminated in four to five plasma half-lives if administered at a constant rate at each half-life. Most of the drugs follow first-order kinetics. 2. Zero-order kinetics: A constant amount of a drug in the body is eliminated per unit time. For example, ethanol is eliminated from the body at the rate of about 10 mL/h. Assume a drug ‘B’ with an initial plasma concentration of 200 mcg/mL and eliminated at a constant amount of 10 mcg per unit time. The concentration will be 190 mcg/mL after 1 hour and 100 mcg/mL after 10 hours. So, half-life is 10 hours. 1 hour 1 hour 200 mcg/mL 190 mcg/mL 180 mcg/mL 10 mcg 10 mcg If its concentration is increased to 300 mcg/mL, concentration will be 290 mcg/mL after 1 hour (as constant amount 10 mcg per unit time is eliminated) and 20 PHARMACOLOGY FOR MEDICAL GRADUATES 150 mcg/mL after 15 hours. The half-life increases to 15 hours. Thus, the t1/2 of the drug following zero-order kinetics is never constant. The rate of elimina- tion is independent of plasma drug concentration Drugs like phenytoin and aspirin At low doses, follow first-order kinetics As the plasma concentration increases Elimination processes get saturated Kinetics changes over to zero order (saturation kinetics) Note: Phenytoin exhibits saturation kinetics and its plasma concentration has to be care- fully monitored (therapeutic drug monitoring, TDM) when used in the treatment of epilepsy. Once the kinetics changes to zero order, an increase in dose will result in a marked increase in plasma concentration leading to drug toxicity. Steady-State Concentration If constant dose of a drug is given at constant intervals at its t1/2, plasma concentration of the drug increases due to its absorption and falls due to elimination in each dosing interval. Finally, the amount of drug eliminated will equal the amount of drug admin- istered in the dosing interval. The drug is said to have reached steady-state or plateau level (Fig. 1.6B). It is attained after approximately four to five half-lives. Target Level Strategy The dosage of drug is calculated to achieve the desired plasma steady state concentration of the drug which produces therapeutic effect with minimal side effects. Loading dose: Initially, a large dose or series of doses of a drug is given with the aim of rapidly attaining the target level in plasma. This is known as loading dose. A loading dose is administered if the time taken to reach steady state is relatively more as 100 Steady state Plasma concentration Plasma concentration 50 0 1 2 3 4 5 6 7 8 9 Half-life Time Time (A) (B) Fig. 1.6 (A) Plasma half-life of a drug after single intravenous injection. (B) Steady state: achieved after approximately four to five half-lives during repeated administration at a constant rate. 1—GENERAL PHARMACOLOGY 21 compared to the patient’s condition, e.g. the half-life of lignocaine is more than 1 hour, so it takes more than 4–6 hours to reach the target concentration at steady state. When a patient has life-threatening ventricular arrhythmias after myocardial infarction, initially a large dose of lignocaine has to be given to achieve desired plasma concentration quickly. Once it is achieved, it is maintained by giving the drug as an intravenous infusion. Maintenance dose: The dose of a drug which is repeated at fixed intervals or given as a continuous infusion to maintain target level in plasma or steady-state concentration is known as maintenance dose. The dose administered is equal to dose eliminated in a dosing interval. Therapeutic Drug Monitoring PH1.2 Monitoring drug therapy by measuring plasma concentration of a drug is known as therapeutic drug monitoring (TDM). Indications of TDM 1. Drugs with narrow therapeutic index, e.g. lithium, digoxin, phenytoin, aminogly- cosides, etc. 2. Drugs showing wide interindividual variations, e.g. tricyclic antidepressants. 3. To ascertain patient compliance. 4. For drugs whose toxicity is increased in the presence of renal failure, e.g. aminoglycosides. 5. In patients who do not respond to therapy without any known reason. In drug poisoning, estimation of plasma drug concentration is done. TDM is not required in the following situations: 1. When clinical and biochemical parameters are available to assess response: a. Blood pressure measurement for antihypertensives. b. Blood sugar estimation for antidiabetic agents. c. Prothrombin time, aPTT and International Normalized Ratio (INR) for anti- coagulants. 2. Drugs producing tolerance, e.g. opioids. 3. Drugs whose effect persists longer than the drug itself, e.g. omeprazole. Fixed-Dose Combinations (FDCs; Fixed-Dose Ratio Combinations) PH1.59 It is the combination of two or more drugs in a fixed-dose ratio in a single formulation. Some of the examples of WHO approved FDCs are Levodopa # carbidopa for parkinsonism Isoniazid # rifampicin # pyrazinamide # ethambutol for tuberculosis. Ferrous sulphate # folic acid for anaemia of pregnancy Sulphamethoxazole # trimethoprim in cotrimoxazole (antimicrobial agent) Amoxicillin # clavulanic acid (antimicrobial agent) Oestrogen # progesterone (oral contraceptive) Advantages and disadvantages of FDCs are explained in Table 1.4, p. 22. Methods to Prolong the Duration of Drug Action Prolongation of action of a drug helps to reduce the frequency of drug administration. to improve patient compliance. to minimize fluctuations in plasma concentration. 22 PHARMACOLOGY FOR MEDICAL GRADUATES Table 1.4 Advantages and disadvantages of FDCs Advantages Disadvantages 1. Increased patient compliance 1. Inflexible fixed-dose ratio 2. Prevents development of mi- 2. Incompatible pharmacokinetics can interfere with crobial resistance in diseases action of the drug like TB, AIDS, etc. as missing 3. Increased toxicity due to inappropriate combina- of single drug is prevented tions. If adverse effect occurs, difficult to identify 3. Increased efficacy the component of FDC causing it 4. Reduced side effects 4. The preparation cannot be used if there is a 5. Reduced cost contraindication for use of one component 6. Synergistic effect 5. Physician and pharmacist’s ignorance of the contents Various methods to prolong the duration of drug action are 1. By retarding drug absorption: a. For orally administered drugs: Using sustained release/controlled release preparations: Sustained release prep- arations consist of drug particles, which have different coatings that dissolve at different intervals of time. It prolongs the duration of action of the drug, reduces the frequency of administration and improves patient compliance, e.g. tab. diclofenac has a duration of action of 12 hours, whereas diclofenac sustained release preparation has a duration of action of 24 hours. b. For parenterally administered drugs: By decreasing the vascularity of the absorbing surface: This is achieved by adding a vasoconstrictor to the drug, e.g. adrenaline with local anaesthet- ics. When adrenaline is added to a local anaesthetic, the vasoconstriction produced by adrenaline will delay the removal of the local anaesthetic from the site of administration and prolongs the duration of its action. It also reduces the systemic toxicity of the local anaesthetic and minimizes bleeding in the operative field. By decreasing the solubility of the drug: by combining it with a water-insoluble compound, e.g. combining procaine/benzathine with penicillin G. Injection penicillin G has a duration of action of 4–6 hours. Injection procaine penicillin G: It has a duration of action of 12–24 hours. Injection benzathine penicillin G: It has a duration of action of 3–4 weeks. By combining the drug with a protein, e.g. protamine zinc insulin – the complexed insulin is released slowly from the site of administration, thus prolonging its action. By esterification: Esters of testosterone, e.g. testosterone propionate and testosterone enanthate are slowly absorbed following intramuscular admin- istration resulting in prolonged action. Injecting the drug in oily solution, e.g. depot progestins (depot medroxypro- gesterone acetate). Pellet implantation: e.g. norplant for contraception. Transdermal patch (see p. 7) 2. By increasing the plasma protein binding of the drug, e.g. sulphadiazine is less bound to plasma proteins and has duration of action of 6 hours. Sulphadoxine is highly protein bound and so has duration of action of 1 week. 1—GENERAL PHARMACOLOGY 23 3. By inhibiting drug metabolism: For example, allopurinol # 6-mercaptopurine (6-MP). 6-MP is metabolized by xanthine oxidase. Allopurinol (xanthine oxidase inhibitor) n inhibits metabolism of 6-MP n prolongs action of 6-MP. 4. By delaying renal excretion of the drug, e.g. penicillin/cephalosporins with pro- benecid (see p. 36). Pharmacodynamics Pharmacodynamics (Greek pharmacon: drug; dynamis: power). It covers all aspects re- lating to ‘what the drug does to the body’. It is the study of drugs – their mechanism of action, pharmacological actions and adverse effects. TYPES OF EFFECTS OF A DRUG 1. Stimulation: Some drugs act by increasing the activity of specific organ/system, e.g. adrenaline stimulates the heart resulting in an increase in heart rate and force of contraction. 2. Depression: Some drugs act by decreasing the activity of specific organ/system, e.g. alcohol, barbiturates, general anaesthetics, etc. depress the central nervous system. 3. Irritation: Certain agents on topical application can cause irritation of the skin and adjacent tissues. When an agent on application to the skin relieves deep seated pain, it is known as counterirritant, e.g. eucalyptus oil, methyl salicylate, etc. They are useful in sprain, joint pain and myalgia. They exert their action by reflexly increasing local circulation in deeper structures. blocking impulse conduction in the spinal cord. 4. Cytotoxic: Drugs are selectively toxic for the infecting organism/cancer cells, e.g. antibiotics/anticancer drugs. 5. Replacement: When there is a deficiency of endogenous substances, they can be replaced by drugs, e.g. insulin in diabetes mellitus, thyroxine in cretinism and myxoedema, etc. MECHANISM OF DRUG ACTION PH1.5 Mechanism of action of drugs Nonreceptor mediated Receptor mediated Nonreceptor-Mediated Mechanism of Action of Drugs 1. By physical action: a. Osmosis: Some drugs act by exerting an osmotic effect, e.g. 20% mannitol in cerebral oedema and acute congestive glaucoma. b. Adsorption: Activated charcoal adsorbs toxins; hence, it is used in the treatment of drug poisoning. c. Demulcent: Cough syrup produces a soothing effect in pharyngitis by coating the inflamed mucosa. d. Radioactivity: Radioactive isotopes emit rays and destroy the tissues, e.g. 131I in hyperthyroidism. 24 PHARMACOLOGY FOR MEDICAL GRADUATES 2. By chemical action: a. Antacids are weak bases – they neutralize gastric acid – useful in peptic ulcer. b. Metals like iron, copper, mercury, etc. are eliminated from the body with the help of chelating agents. These agents trap metals and form water-soluble com- plexes, which are rapidly excreted from the body, e.g. dimercaprol (BAL) in arsenic poisoning, desferrioxamine in iron poisoning and d-penicillamine in copper poisoning. 3. Through enzymes: Some drugs act by inhibiting the enzyme activity. a. Angiotensin-converting enzyme (ACE) inhibitors, such as captopril, enala- pril, etc. act by inhibiting ACE. They are used in the treatment of hyperten- sion, congestive heart failure, etc. b. Xanthine and hypoxanthine are oxidized to uric acid by the enzyme xanthine oxidase, which is inhibited by allopurinol. Allopurinol (competitive inhibitor) is used in the treatment of chronic gout to reduce the synthesis of uric acid. Xanthine Hypoxanthine Uric acid Xanthine oxidase ! Allopurinol 4. Through ion channels: Some drugs directly bind to ion channels and alter the flow of ions, e.g. local anaesthetics block sodium channels in neuronal membrane to produce local anaesthesia. 5. Through antibody production: Vaccines produce their effect by stimulating the formation of antibodies, e.g. vaccine against tuberculosis (BCG), oral polio vaccine, etc. 6. Transporters: Some drugs produce their effect by binding to transporters. Selec- tive serotonin reuptake inhibitors (SSRIs) n bind to 5-HT transporter n block 5-HT reuptake into neurons n antidepressant effect. 7. Others: Drugs, like colchicine, bind to tubulin and prevent migration of neutro-