Pharmacology for Medical Graduates PDF (4th Edition)

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 M...

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 mechanical, 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 permissions 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 liability, 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 appropriate 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 information. 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 comprehensive 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 venture. 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 incorporated 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 composition, 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 universities 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 Preface to the Fourth Edition Preface to the First Edition 1 v vii viii 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 3 !-Adrenergic Blockers 88 "-Adrenergic Blockers 91 88 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 5 161 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 CONTENTS xii 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 Macrolides 401 402 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 Antiviral Agents 422 430 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 Code Core Y/N Competency Chapter No. Page No. PHARMACOLOGY Topic: Pharmacology PH1.1 Define and describe the principles of pharmacology and pharmacotherapeutics. Y 1 1 PH1.2 Describe the basis of Evidence based medicine and Therapeutic drug monitoring. Y 1 21 PH1.3 Enumerate and identify drug formulations and drug delivery systems. Y 1, 12 8, 495 PH1.4 Describe absorption, distribution, metabolism & excretion of drugs. Y 1 8 – 18 PH1.5 Describe general principles of mechanism of drug action. Y 1 23 – 27 PH1.6 Describe principles of Pharmacovigilance & ADR reporting systems. Y 1 41 PH1.7 Define, identify and describe the management of adverse drug reactions (ADR). Y 1 37 – 41 PH1.8 Identify and describe the management of drug interactions. Y 1 35 PH1.9 Describe nomenclature of drugs i.e. generic, branded drugs. Y 1 2 PH1.10 Describe parts of a correct, complete and legible generic prescription. Identify errors in prescription and correct appropriately. Y - - PH1.11 Describe various routes of drug administration, eg., oral, SC, IV, IM, SL. Y 1 3–8 PH1.12 Calculate the dosage of drugs using appropriate formulae for an individual patient, including children, elderly and patient with renal dysfunction. Y 12 498 – 503 PH1.13 Describe mechanism of action, types, doses, side effects, indications and contraindications of adrenergic and anti-adrenergic drugs. Y 2 75 – 97 PH1.14 Describe mechanism of action, types, doses, side effects, indications and contraindications of cholinergic and anticholinergic drugs. Y 2 46 – 68 PH1.15 Describe mechanism/s of action, types, doses, side effects, indications and contraindications of skeletal muscle relaxants. Y 2 69 – 75 PH1.16 Describe mechanism/s of action, types, doses, side effects, indications and contraindications of the drugs which act by modulating autacoids, including: antihistaminics, 5-HT modulating drugs, NSAIDs, drugs for gout, anti-rheumatic drugs, drugs for migraine. Y 6 230 – 254 PH1.17 Describe the mechanism/s of action, types, doses, side effects, indications and contraindications of local anesthetics. Y 5 181 – 189 (Continued) xv COMPETENCY MAP xvi Chapter No. Page No. Y 5 173 – 181 Describe the mechanism/s of action, types, doses, side effects, indications and contraindications of the drugs which act on CNS, (including anxiolytics, sedatives & hypnotics, anti-psychotic, anti- depressant drugs, antimaniacs, opioid agonists and antagonists, drugs used for neurodegenerative disorders, anti-epileptics drugs). Y 5 164 – 173, 192 – 229 PH1.20 Describe the effects of acute and chronic ethanol intake. Y 5 189 – 191 PH1.21 Describe the symptoms and management of methanol and ethanol poisonings. Y 5 191 PH1.22 Describe drugs of abuse (dependence, addiction, stimulants, depressants, psychedelics, drugs used for criminal offences). Y 1, 5 39, 217 PH1.23 Describe the process and mechanism of drug deaddiction. Y 1, 5 39, 190 – 191, 204 – 205 PH1.24 Describe the mechanism/s of action, types, doses, side effects, indications and contraindications of the drugs affecting renal systems including diuretics, antidiureticsvasopressin and analogues. Y 4 151 – 163 PH1.25 Describe the mechanism/s of action, types, doses, side effects, indications and contraindications of the drugs acting on blood, like anticoagulants, antiplatelets, fibrinolytics, plasma expanders. Y 3, 8 285 – 296, 142 – 143 PH1.26 Describe mechanisms of action, types, doses, side effects, indications and contraindications of the drugs modulating the renin- angiotensin and aldosterone system. Y 3, 4 98 – 104, 158 – 159 PH1.27 Describe the mechanisms of action, types, doses, side effects, indications and contraindications of antihypertensive drugs and drugs used in shock. Y 3 98 – 111 PH1.28 Describe the mechanisms of action, types, doses, side effects, indications and contraindications of the drugs used in ischemic heart disease (stable, unstable angina and myocardial infarction), peripheral vascular disease. Y 3 112 – 122 PH1.29 Describe the mechanisms of action, types, doses, side effects, indications and contraindications of the drugs used in congestive heart failure. Y 3 122 – 131 PH1.30 Describe the mechanisms of action, types, doses, side effects, indications and contraindications of the antiarrhythmics. N 3 131 – 138 PH1.31 Describe the mechanisms of action, types, doses, side effects, indications and contraindications of the drugs used in the management of dyslipidemias. Y 3 138 – 142 PH1.32 Describe the mechanism/s of action, types, doses, side effects, indications and contraindications of drugs used in bronchial asthma and COPD. Y 6 256 – 262 PH1.33 Describe the mechanism of action, types, doses, side effects, indications and contraindications of the drugs used in cough (antitussives, expectorants/ mucolytics). Y 6 254 – 256 Code Competency PH1.18 Describe the mechanism/s of action, types, doses, side effects, indications and contraindications of general anaesthetics, and pre- anesthetic medications. PH1.19 Core Y/N COMPETENCY MAP xvii Core Y/N Chapter No. Code Competency Page No. PH1.34 Describe the mechanism/s of action, types, doses, side effects, indications and contraindications of the drugs used as below: 1. Acid-peptic disease and GERD 2. Antiemetics and prokinetics 3. Antidiarrhoeals 4. Laxatives 5. Inflammatory Bowel Disease 6. Irritable Bowel Disorders, biliary and pancreatic diseases. Y 7 277 – 284, 263 – 270, 270 – 272, 274 – 276, 272 – 273 PH1.35 Describe the mechanism/s of action, types, doses, side effects, indications and contraindications of drugs used in hematological disorders like: 1. Drugs used in anemias 2. Colony Stimulating factors. Y 8 297 – 302, 302 PH1.36 Describe the mechanism of action, types, doses, side effects, indications and contraindications of drugs used in endocrine disorders (diabetes mellitus, thyroid disorders and osteoporosis). Y 9 341 – 354, 309 – 315, 354 – 361 PH1.37 Describe the mechanisms of action, types, doses, side effects, indications and contraindications of the drugs used as sex hormones, their analogues and anterior Pituitary hormones. Y 9 316 – 326, 304 – 309 PH1.38 Describe the mechanism of action, types, doses, side effects, indications and contraindications of corticosteroids. Y 9 331 – 341 PH1.39 Describe mechanism of action, types, doses, side effects, indications and contraindications the drugs used for contraception. Y 9 326 – 331 PH1.40 Describe mechanism of action, types, doses, side effects, indications and contraindications of 1. Drugs used in the treatment of infertility, and 2. Drugs used in erectile dysfunction. Y 9, 2 322, 91 PH1.41 Describe the mechanisms of action, types, doses, side effects, indications and contraindications of uterine relaxants and stimulants. Y 10 362 – 366 PH1.42 Describe general principles of chemotherapy. Y 11 367–375 PH1.43 Describe and discuss the rational use of antimicrobials including antibiotic stewardship program. Y - - PH1.44 Describe the first line antitubercular dugs, their mechanisms of action, side effects and doses. Y 11 412 – 417 PH1.45 Describe the dugs used in MDR and XDR Tuberculosis. Y 11 418 PH1.46 Describe the mechanisms of action, types, doses, side effects, indications and contraindications of antileprotic drugs. Y 11 419 – 422 PH1.47 Describe the mechanisms of action, types, doses, side effects, indications and contraindications of the drugs used in malaria, KALA-AZAR, amebiasis and intestinal helminthiasis. Y 11 438 – 448, 453, 448 – 452, 454 – 458 PH1.48 Describe the mechanisms of action, types, doses, side effects, indications and contraindications of the drugs used in UTI/ STD and viral diseases including HIV. Y 11 409 – 410, 430 – 438 (Continued) COMPETENCY MAP xviii Chapter No. Page No. Y 11 459 – 469 Describe mechanisms of action, types, doses, side effects, indications and contraindications of immunomodulators and management of organ transplant rejection. Y 12 472 – 476 PH1.51 Describe occupational and environmental pesticides, food adulterants, pollutants and insect repellents. Y 2 60 – 61 PH1.52 Describe management of common poisoning, insecticides, common sting and bites. Y 1 41 – 42, 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 Programmes including Immunisation, Tuberculosis, Leprosy, Malaria, HIV, Filaria, Kala Azar, Diarrhoeal diseases, Anaemia & nutritional disorders, Blindness, Non-communicable diseases, cancer and Iodine deficiency. Y - - PH1.56 Describe basic aspects of Geriatric and Pediatric pharmacology. Y - - 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, Fixed dose combinations, Over the counter drugs, Herbal medicines. Y 1 1, 21 – 22 PH1.60 Describe and discuss Pharmacogenomics and Pharmacoeconomics. N 1 43 PH1.61 Describe and discuss dietary supplements and nutraceuticals. N - - 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 clinical trials and Good Clinical Practice. Y 1 43 – 45 12 495 – 498 12 498 – 503 Code Competency PH1.49 Describe mechanism of action, classes, side effects, indications and contraindications of anticancer drugs. PH1.50 Core Y/N Topic: Clinical Pharmacy PH2.1 Demonstrate understanding of the use of various dosage forms (oral/local/parenteral; solid/liquid). Y PH2.2 Prepare oral rehydration solution from ORS packet and explain its use. Y PH2.3 Demonstrate the appropriate setting up of an intravenous drip in a simulated environment. Y PH2.4 Demonstrate the correct method of calculation of drug dosage in patients including those used in special situations. Y 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, pharmacological 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, preservation, 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 chemical 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 comparative clinical trials. Essential medicines: According to WHO, essential medicines are ‘those that satisfy 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 identification, purity, methods of storage, etc. Some of the pharmacopoeias are the Indian Pharmacopoeia (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 Association 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 representatives, 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 guidance 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 nonproprietary name, e.g. the opioid, pethidine and meperidine. The INN is commonly used as generic name. Ideally, generic names should be used in prescriptions because 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-paminophenol (Acetaminophen) Paracetamol Crocin Metacin Tylenol *S Kopp-Kubel. International Nonproprietary Names (INN) for pharmaceutical substances. Bull World Health Organ 1995;73(3):275–279. 3 1—GENERAL PHARMACOLOGY SOURCES OF DRUGS They are natural, semisynthetic and synthetic. Natural sources are plants, animals, minerals, 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 carminative (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 – Oral – Sublingual – Rectal Routes of drug administration Parenteral – Injection – Inhalation – Transdermal 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% lignocaine 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 conditions, 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 diagnostic 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 systemic 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, gluteus 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 D D D D D D D D D D Backing layer D D D D D D Drug reservoir 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 formulation 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 processes involve movement of the drug molecule through various biological membranes. All biological membranes are made up of a lipid bilayer. Drugs cross various biological 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 concentration 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 transport, 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 membrane 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. Absorption 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 watersoluble 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 particle 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 parenterally 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 intestine 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 peristaltic 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. Intravenous 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 (physicochemical 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 bioavailability 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 bioavailability 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. propranolol and lignocaine. 3. Enterohepatic cycling: Some drugs are excreted via bile but after reaching the intestine 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 compartments. 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) ICF (28 L) ECF (14 L) Plasma (3 L) Interstitial fluid compartment (10.5 L) Transcellular fluid compartment (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. aVd ! Total administered amount of drug 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 indicates 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 watersoluble 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, immediately gets distributed to the areas of high blood flow, such as brain, and causes general anaesthesia. 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; thiopentone and DDT – adipose tissue; chloroquine – liver and retina; digoxin – heart, etc. 13 1—GENERAL PHARMACOLOGY 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-insoluble 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 increases 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 1. Drug Absorption Enters circulation Binds to plasma protein (acidic drugs to albumin, basic drugs to α1 acid glycoprotein) Free form (pharmacologically active) Bound form (cannot exert pharmacological 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 metabolized 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. Hydroxyphenobarbitone Phenobarbitone p-Hydroxyphenytoin Phenytoin 2. Active drug to active metabolite Morphine Codeine Oxazepam Diazepam 3. Inactive drug (prodrug) to active metabolite Dopamine Levodopa Prednisolone Prednisone 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. Dopamine 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. Levodopa Levodopa Dopa decarboxylase 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 suspension has been developed for paediatric use to improve the taste. 4. To provide site-specific drug delivery: Methenamine acidic pH of urine 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. 15 1—GENERAL PHARMACOLOGY Table 1.1 Phase I reactions Oxidation Addition of oxygen/removal of hydrogen Phenytoin, phenobarbitone, pentobarbitone, propranolol Reduction Removal of oxygen/addition of hydrogen Chloramphenicol, methadone Hydrolysis Break down of compound by addition of water Esters – procaine, succinylcholine Amides – lignocaine, procainamide Cyclization Conversion of straight chain compound into ring structure Proguanil Decyclization Breaking up of the ring structure of the drug Phenobarbitone, phenytoin 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 lipophilic 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 (INH) Phase I Phase I Phase II Phase II Phase II Drug Unchanged form 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 cells, liver, kidney, lungs, e.g. cytochrome P450, monooxygenase, glucuronyl transferase Cytoplasm, mitochondria, plasma, e.g. conjugases, esterases, amidases, flavoprotein oxidases Reactions Most of the phase I reactions, Glucuronide conjugation Oxidation, reduction (few), hydrolysis. 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 elimination. 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 metabolism. 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 peripheral 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 duration 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 hepatotoxicity with paracetamol in alcoholics is due to overproduction of toxic metabolite of paracetamol. 4. Prolonged phenytoin therapy may produce osteomalacia due to enhanced metabolism of vitamin D3. 5. Enzyme inducers, e.g. barbiturates, can precipitate porphyria due to overproduction 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 inhibitors. 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 anticoagulant 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 glomerular 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 alkaline 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 requires energy. Active secretion is unaffected by changes in the pH of urine and protein binding. Most of the acidic drugs (e.g. penicillin, diuretics, probenecid, sulphonamides, etc.) and basic drugs (e.g. quinine, procaine, morphine, etc.) are secreted by the renal tubular cells. The carrier system is relatively nonselective and therefore drugs having similar physicochemical properties compete for the same carrier system, e.g. probenecid competitively inhibits the tubular secretion of penicillins, thereby increasing the duration of action as well as the plasma half-life and effectiveness of penicillins in the treatment of diseases, such as gonococcal infections. 2. Lungs: Alcohol and volatile general anaesthetics, such as ether, halothane, isoflurane, 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 lithium are excreted in saliva. Salivary estimation of lithium may be used for noninvasive 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. 19 1—GENERAL PHARMACOLOGY 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 repeated 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. Clearance ! Rate of elimination 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 kinetics of elimination and having an initial plasma concentration of 100 mcg/mL. 100 mcg/mL 1 hour ½ 50 mcg/mL 1 hour ½ 25 mcg/mL 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 constant. 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. 200 mcg/mL 1 hour 10 mcg 190 mcg/mL 1 hour 10 mcg 180 mcg/mL 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 elimination 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 carefully 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 administered 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 Steady state Plasma concentration Plasma concentration 100 50 Half-life Time (A) 0 1 2 3 4 5 6 7 8 9 Time (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, aminoglycosides, 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 anticoagulants. 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 2. Prevents development of microbial resistance in diseases like TB, AIDS, etc. as missing of single drug is prevented 3. Increased efficacy 4. Reduced side effects 5. Reduced cost 6. Synergistic effect 1. Inflexible fixed-dose ratio 2. Incompatible pharmacokinetics can interfere with action of the drug 3. Increased toxicity due to inappropriate combinations. If adverse effect occurs, difficult to identify the component of FDC causing it 4. The preparation cannot be used if there is a contraindication for use of one component 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 preparations 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 anaesthetics. 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 administration resulting in prolonged action. Injecting the drug in oily solution, e.g. depot progestins (depot medroxyprogesterone 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. 23 1—GENERAL PHARMACOLOGY 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 probenecid (see p. 36). Pharmacodynamics Pharmacodynamics (Greek pharmacon: drug; dynamis: power). It covers all aspects relating 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 complexes, 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, enalapril, etc. act by inhibiting ACE. They are used in the treatment of hypertension, 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. Selective 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 neutrophils (hence useful in acute gout). Receptor-Mediated Mechanism of Action of Drugs Receptors are macromolecules, present either on the cell surface, cytoplasm or in the nucleus with which the drug binds and interacts to produce cellular changes. !! Drug (D) # Receptor (R) # → Response !" ! Drug-receptor complex  For example, adrenergic receptors (" and $), cholinergic receptors (muscarinic and nicotinic), opioid receptors, etc. Affinity: The ability of the drug to get bound to receptor is known as affinity. Intrinsic activity: The ability of the drug to produce pharmacological action after combining with the receptor is known as intrinsic activity of the drug. Agonist: A drug that is capable of producing pharmacological action after binding to the receptor is called an agonist. Agonist has high affinity # high intrinsic activity (e.g. morphine and adrenaline). Antagonist: A drug that prevents binding of agonist to its receptor or blocks its effect/s is called an antagonist. It does not by itself produce any effect. 25 1—GENERAL PHARMACOLOGY Competitive antagonist has high affinity without intrinsic activity (e.g. naloxone and atropine). It produces receptor blockade. Partial agonist: A drug that binds to the receptor but produces an effect less than that of an agonist is called partial agonist. It inhibits the effect of agonist. Partial agonist has affinity # less intrinsic activity (e.g. pindolol and buprenorphine). Inverse agonist: It has full affinity towards the receptor but produces effect opposite to that of an agonist, e.g. benzodiazepines (BZDs) produce antianxiety and anticonvulsant effects by interacting with BZD receptors, but $-carbolines act as inverse agonist at BZD receptor and produce anxiety and convulsions. Inverse agonist has affinity # intrinsic activity between 0 and –1 (e.g. $-carboline). RECEPTOR FAMILIES (Table 1.5) PH1.5 1. Ligand-gated ion channels (inotropic receptors) 2. G protein-coupled receptors (GPCRs; metabotropic receptors) 3. Enzymatic receptors 4. Receptor-regulating gene expression (transcription factors) or the nuclear receptor Ligand-Gated Ion Channels (Inotropic Receptors). Examples are nicotinic (NM) acetylcholine receptors at neuromuscular junction, GABA (gamma amino butyric acid) and glutamate receptors in the CNS. Binding of agonist to inotropic receptors Opens the ion channels (Na+, K+, Ca2+, Cl–) Tissue response Flow of ions through channels Hyperpolarization/ Depolarization The onset of action of a drug is fastest through this receptor. G Protein-Coupled Receptors (GPCRs, Metabotropic Receptors). GPCRs are transmembrane receptors which control cell function via adenylyl cyclase, phospholipase C, ion channels, etc. They are coupled to intracellular effectors through G proteins. G proteins are membrane proteins and have three subunits (", $, %) with GDP bound to " subunit. Table 1.5 Characteristics of various receptor families Ligand-gated ion channels G proteincoupled receptors Enzymatic receptors Nuclear receptors Location Membrane Membrane Membrane Intracellular Effector Ion channel Channel or enzyme Enzyme Gene transcription Examples Nicotinic, GABAA receptors Muscarinic, adrenergic receptors Insulin epidermal growth factor receptors Steroid, thyroid hormone receptors Time required for response Milliseconds Seconds Minutes to hours Hours 26 PHARMACOLOGY FOR MEDICAL GRADUATES The agonist that binds to the receptor is the first messenger. It results in the formation or recruitment of molecules (second messengers) that initiate the signalling mechanism in a cell. Examples of second messengers are cAMP (generated by adenylyl cyclase), cGMP (generated by guanylyl cyclase), Ca2#, IP3-DAG (generated by phospholipase C), nitric oxide, etc. Binding of agonist to receptors GDP bound to α subunit exchanges with GTP Coupling of G protein to the receptors Dissociation of G protein subunits from occupied receptor; α-GTP also dissociates from βγ subunit α-GTP and βγ subunits are released Bind to target enzyme/ion channel Stimulation of GTPase associated with α subunit GTP GDP α subunit associates with βγ subunit Gs ! Gi " Effects produced depends on the type of G protein (Gs, Gi, Gq and Go), which associates with agonist occupied receptor (see below) Gq ! Adenylyl cyclase Adenylyl cyclase Phospholipase C ↑cAMP, e.g. β-adrenergic receptors ↓cAMP, e.g. α2-adrenergic receptors in smooth muscle ↑IP3 and ↑DAG, e.g. muscarinic (M1) receptors !" !/" Enzymes and ion channels, e.g. all GPCRs Transmembrane Enzyme-Linked Receptors. Transmembrane enzyme-linked receptors have enzymatic activity in their intracellular portion. The enzyme is mainly tyrosine kinase, e.g. receptor tyrosine kinases for insulin, epidermal growth factor, etc.). 27 1—GENERAL PHARMACOLOGY Binding of agonist (e.g. insulin) to extracellular domain of receptors Dimerization of the receptor Stimulates intrinsic kinase activity in intracellular part of the receptor Phosphorylation of tyrosine residues on the receptor and other intracellular proteins (when insulin/EGF, etc. are agonists) Tissue response Gene transcription Activates intracellular signalling pathways Transmembrane JAK (Janus kinase)-STAT (signal transducer and activator of transcription) receptors, e.g. receptors for cytokines, growth hormone, etc. These receptors do not have intrinsic enzymatic activity in their intracellular part. On activation, they dimerize followed by their binding to kinases in the cytoplasm, e.g. JAK n phosphorylates tyrosine residues on the receptor n binding of receptor to STAT which gets phosphorylated n dissociation of STAT from receptor n binds to gene to alter transcription. Nuclear Receptors – Regulate Gene Expression. Examples: receptors for thyroxine, vitamins A and D, sex steroids and glucocorticoids. Steroids n bind to receptors in cytoplasm n steroid-receptor complex n migrates to nucleus n binds to specific site on the DNA n regulate protein synthesis n response Regulation of Receptors Receptors can be regulated by various mechanisms resulting in either their upregulation or downregulation (Table 1.6). Table 1.6 Regulation of receptors Receptor downregulation Receptor upregulation Prolonged use of agonists g gg Receptor number and sensitivity g gg Drug effect For example, chronic use of salbutamol downregulates $2-adrenoceptors, which may be responsible for decreased effect of salbutamol in asthmatics. Prolonged use of antagonists g hh Receptor number and sensitivity; On sudden stoppage of the antagonist g hh Response to agonist For example, when propranolol is stopped after prolonged use, some patients experience symptoms, such as nervousness, anxiety, palpitation, tachycardia, rise in BP, increased incidence of angina or even myocardial infarction may be precipitated. This is due to upregulation or supersensitivity of $-adrenoceptors to catecholamines. Therefore, propranolol should not be discontinued abruptly. 28 PHARMACOLOGY FOR MEDICAL GRADUATES DOSE–RESPONSE RELATIONSHIP The pharmacological effect of a drug depends on its concentration at the site of action, which in turn is determined by dose of the drug administered. Such a relationship is called ‘dose–response relationship’. TYPES OF DOSE–RESPONSE CURVES 1. Graded dose–response: This curve when plotted on a graph takes the form of a rectangular hyperbola, whereas log dose–response curve (DRC) is sigmoid shaped (Fig. 1.7A and B). 2. Quantal DRC: Certain pharmacological effects which cannot be quantified but can only be said to be present or absent (all or none) are called as quantal responses, e.g. a drug causing ovulation (Fig. 1.7C). Therapeutic Index Therapeutic index (TI) is an index of drug safety. TI ! Median lethal dose (LD 50 ) of the drug Median effective dose (ED 50 ) of the drug It is the ratio of median lethal dose to the median effective dose (Fig. 1.8). 1. LD50: It is the dose of a drug, which is lethal for 50% of the population. 2. ED50: It is the dose of drug, which produces the desired effect in 50% of the population. Higher the value of therapeutic index, safer is the drug, e.g. penicillin G has a high therapeutic index; digitalis, lithium and phenytoin have narrow therapeutic index. Drug Potency Dose (A) Fig. 1.7 curve. Sigmoid curve Log dose (B) No. of responders Hyperbolic curve % Response % Response The amount of a drug required to produce a desired response is called potency of the drug. Lower the dose required for a given response, more potent is the drug, e.g. analgesic dose of morphine is 10 mg and that of pethidine is 100 mg. Therefore, morphine is ten times more potent than pethidine as an analgesic. DRC of drug A (morphine) and drug B (pethidine, rightward DRC) as analgesic is compared (Fig. 1.9). Dose (C) (A) Dose–response curve. (B) Log dose–response curve. (C) Quantal dose–response 29 % Maximal response 1—GENERAL PHARMACOLOGY A 100 B 50 0 Therapeutic range Log dose Fig. 1.8 Dose–response curves of therapeutic effect (A) and adverse effect (B). B A % Maximal effect % Maximal effect A Log dose Fig. 1.9 Relative potency of two drugs. B Log dose Fig. 1.10 Relative efficacy of two drugs. Drug Efficacy It is the maximum effect of a drug, e.g. morphine is more efficacious than aspirin as an analgesic (Fig. 1.10). DRC of drug A (morphine) and drug B (aspirin) as an analgesic is compared. Therapeutic Range It is the range of concentration of the drug which produces desired response with minimal toxicity. COMBINED EFFECT OF DRUGS A combination of two or more drugs can result in an increase or a decrease in response. Increased Response 1. Additive effect: The combined effect of two or more drugs is equal to the sum of their individual effect. Effect of drugs A # B ! Effect of drug A # Effect of drug B For example, combination of ibuprofen and paracetamol as analgesic. 30 PHARMACOLOGY FOR MEDICAL GRADUATES 2. Potentiation (supra-additive): The enhancement of action of one drug by another drug which is inactive is called potentiation. Effect of drugs A # B & Effect of drug A # Effect of drug B For example, levodopa # carbidopa; acetylcholine # physostigmine. Carbidopa and physostigmine inhibit breakdown of levodopa and acetylcholine, respectively, thus enhancing their effects. 3. Synergism: When two or more drugs are administered simultaneously, their combined effect is greater than that elicited by either drug alone. For example, sulphamethoxazole # trimethoprim; pyrimethamine # sulphadoxine. Decreased Response (Drug Antagonism) In antagonism, the effect of one drug is decreased or abolished in the presence of another drug. 1. Physical antagonism: The opposing action of two drugs is due to their physical property, e.g. adsorption of alkaloids by activated charcoal – useful in alkaloid poisoning. 2. Chemical antagonism: The opposing action of two drugs is due to their chemical property, e.g. antacids are weak bases; they neutralize gastric acid and are useful in peptic ulcer; chelating agents complex metals and are useful in heavy metal poisoning (dimercaprol in arsenic poisoning). 3. Physiological (functional) antagonism: Here, two drugs act at different receptors or by different mechanisms on the same physiological system and produce opposite effects, e.g. insulin and glucagon on blood sugar; adrenaline and histamine on bronchial smooth muscle – histamine produces bronchoconstriction (via histamine receptors), whereas adrenaline produces bronchodilatation by acting through adrenergic ($2) receptors – hence, adrenaline helps to reverse bronchospasm in anaphylactic shock. 4. Receptor antagonism: The antagonist binds to the same receptor as the agonist and inhibits its effects. It can be competitive or noncompetitive. a. Competitive antagonism (equilibrium type): In competitive antagonism, both agonist and the antagonist bind reversibly to same site on the receptor. For example, Acetylcholine Morphine (Agonists) Muscarinic receptors Opioid receptors Atropine Naloxone (Antagonists) Equilibrium type of competitive antagonism can be overcome (reversible) by increasing concentration of the agonist. The log DRC of the agonist shows a rightward parallel shift in the presence of competitive antagonist (Fig. 1.11). Nonequilibrium antagonism: The antagonist binds to the same site on the receptor as agonist but binding is irreversible. The antagonist forms strong covalent bond with the receptor, e.g. phenoxybenzamine is an irreversible antagonist of adrenaline at " receptors. b. Noncompetitive antagonism: The antagonist binds to a different site on the receptor and prevents the agonist from interacting with the receptor. In this type, the antagonistic effect cannot be overcome by increasing the concentration of the agonist. There is a flattening of the DRC in noncompetitive antagonism, e.g. diazepam and bicuculline (Fig. 1.12). 31 1—GENERAL PHARMACOLOGY Agonist % Maximal effect Agonist + competitive antagonist Log dose Fig. 1.11 Competitive antagonism. (Adapted from Alfred Gilman Sr. and Louis S. Goodman: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th edition, Mcgraw Hill, 2018.) % Maximal effect Agonist Agonist + noncompetitive antagonist (increasing dose) Log dose Fig. 1.12 Noncompetitive antagonism. (Adapted from Alfred Gilman Sr. and Louis S. Goodman: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12e.) Factors Modifying Drug Action There are a number of factors which can influence drug response. Individuals may often show quantitative variations in drug response but rarely show qualitative variations. The important factors are described in Table 1.7. DRUG FACTORS 1. Route of administration: When a drug is administered by different routes, it commonly exhibits quantitative variations, but sometimes it may also result in qualitative variations in response. a. Quantitative variation: Oral dose of drugs are usually larger than intravenous dose (since i.v. route produces 100% bioavailability), e.g. for analgesic effect, intravenous dose of morphine required is 5–10 mg whereas oral dose is 30–60 mg. Onset of drug action following intravenous administration is rapid. 32 PHARMACOLOGY FOR MEDICAL GRADUATES Table 1.7 Factors influencing drug response Drug factors Patient factors Route of administration Age Presence of other drugs Body weight Cumulation Sex Environment Genetic factor Psychological factor Pathological state Tolerance Drug dependence b. Qualitative variation: The drug may produce an entirely different response when administered by different routes, e.g. magnesium sulphate administered orally produces purgative effect; parenterally, it causes CNS depression and on local application reduces oedema in the inflamed area. 2. Presence of other drugs: See addition, potentiation, synergism and antagonism. 3. Cumulation: If the elimination of a drug is slow, then repeated administration of such drug will result in its accumulation in the body causing toxicity, e.g. digoxin, emetine and chloroquine. PATIENT FACTORS 1. Age: In neonates, metabolizing function of liver and excretory function of kidney is not fully developed, e.g. chloramphenicol can cause grey baby syndrome when given to neonates as the metabolizing enzymes are not fully developed. In adults, penicillin G is given 6 hourly, but in infants it is given 12 hourly as the excretory function is not completely developed. In the elderly, renal and hepatic functions progressively decline. The incidence of adverse effect of drugs is also relatively more, and hence drug doses have to be reduced accordingly, e.g. dose of aminoglycosides in elderly is less than normal adult dose. The dose of a drug for a child can be calculated as follows: Young's formula: Child dose ! Age # adult dose Age " 12 Dilling's formula: Child dose ! Age " adult dose 20 2. Body weight and body surface: An average dose of a drug is usually calculated in terms of body weight (mg/kg). Dose ! Body weight (kg) " Average adult dose 70 In obese individuals and in patients with dehydration or oedema, dose calculation on the basis of body weight is not very appropriate. A more accurate method 1—GENERAL PHARMACOLOGY 3. 4. 5. 6. 7. 33 for calculating a dose is on the basis of the body surface area (BSA) of the patient. Nomograms are available to calculate BSA from height and weight of the patient. Since it is inconvenient to calculate BSA, dose is routinely calculated on body weight basis. Dose of anticancer drugs and a few other drugs are calculated on the basis of BSA. Sex: Drugs like $ blockers, diuretics and clonidine can cause decreased libido in males. Diet and environmental factors: Milk reduces absorption of tetracyclines; fatty meal increases the absorption of griseofulvin (antifungal agent). Cigarette smoke induces hepatic microsomal enzymes and increases metabolism of drugs, such as theophylline. So, the dose of the drug administered may be inadequate in smokers. Genetic factor: For example, fast and slow acetylators of isoniazid, prolonged succinylcholine apnoea, primaquine induced haemolysis in G6PD deficiency individuals (see p. 17 under metabolism). Other examples are as follows Acute porphyria Barbiturates may precipitate attacks of acute intermittent porphyria in susceptible individuals by inducing ALA (aminolevulinic acid) synthase enzyme that catalyses the production of porphyrins. Malignant hyperthermia In some patients, dangerous rise in body temperature (malignant hyperthermia) may occur especially when halothane–succinylcholine combination is used due to genetic abnormality. In person with shallow anterior chamber/and or narrow iridocorneal angle, mydriatics may precipitate acute congestive glaucoma. There is an increased risk of bleeding with coumarin anticoagulants due reduced activity of metabolizing enzyme, CYP2C9. Psychological factor: Personality of the doctor as well as the patient can affect response to a drug. Some patients respond to inert dosage forms (placebo) in conditions like pain, bronchial asthma, anxiety, etc. Placebo effect: ‘Placebo’ is a Latin term that means ‘I will please’. It is a dummy medicine having no pharmacological activity. The effect produced by placebo is called placebo effect. Sugar tablets and distilled water injection are used as placebos. 1) Uses a) Placebos are used for the relief of subjective symptoms like anxiety, headache, tremors, pain, insomnia, etc. b) Placebos are used in clinical trials in order to minimize bias. 2) Factors affecting placebo effect are: a) Patient factor: Patients with neurotic symptoms often respond to placebos. b) Drug factor: The placebo response can be affected by the physical presentation or route of