KDT_Pharmacology_8th_Edition.pdf

 Essentials of Medical Pharmacology  Essentials of Medical Pharmacology Eighth Edition KD Tripathi MD Ex-Director-Professor and Head of Pharmacology Maulana Azad Medical College and associated LN and GB Pant Hospitals N...

 Essentials of Medical Pharmacology  Essentials of Medical Pharmacology Eighth Edition KD Tripathi MD Ex-Director-Professor and Head of Pharmacology Maulana Azad Medical College and associated LN and GB Pant Hospitals New Delhi, India The Health Sciences Publisher New Delhi | London | Panama  Jaypee Brothers Medical Publishers (P) Ltd Headquarters Jaypee Brothers Medical Publishers (P) Ltd 4838/24, Ansari Road, Daryaganj New Delhi 110 002, India Phone: +91-11-43574357 Fax: +91-11-43574314 Email: [email protected] Overseas Offices J.P. Medical Ltd Jaypee-Highlights Medical Publishers Inc 83 Victoria Street, London City of Knowledge, Bld. 235, 2nd Floor, Clayton SW1H 0HW (UK) Panama City, Panama Phone: +44 20 3170 8910 Phone: +1 507-301-0496 Fax: +44 (0)20 3008 6180 Fax: +1 507-301-0499 Email: [email protected] Email: [email protected] Jaypee Brothers Medical Publishers (P) Ltd Jaypee Brothers Medical Publishers (P) Ltd 17/1-B Babar Road, Block-B, Shyamoli Bhotahity, Kathmandu, Nepal Mohammadpur, Dhaka-1207 Phone: +977-9741283608 Bangladesh Email: [email protected] Mobile: +08801912003485 Email: [email protected] Website: www.jaypeebrothers.com Website: www.jaypeedigital.com © 2019, KD Tripathi Managing Editor: M. Tripathi The views and opinions expressed in this book are solely those of the original contributor(s)/author(s) and do not necessarily represent those of editor(s) of the book. All rights reserved. No part of this publication may be reproduced, stored or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission in writing of the publishers. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. Medical knowledge and practice change constantly. This book is designed to provide accurate, authoritative information about the subject matter in question. However, readers are advised to check the most current information available on procedures included and check information from the manufacturer of each product to be administered, to verify the recommended dose, formula, method and duration of administration, adverse effects and contraindications. It is the responsibility of the practitioner to take all appropriate safety precautions. Neither the publisher nor the author(s)/editor(s) assume any liability for any injury and/or damage to persons or property arising from or related to use of material in this book. This book is sold on the understanding that the publisher is not engaged in providing professional medical services. If such advice or services are required, the services of a competent medical professional should be sought. Every effort has been made where necessary to contact holders of copyright to obtain permission to reproduce copyright material. If any have been inadvertently overlooked, the publisher will be pleased to make the necessary arrangements at the first opportunity. The CD/DVD-ROM (if any) provided in the sealed envelope with this book is complimentary and free of cost. Not meant for sale. Inquiries for bulk sales may be solicited at: [email protected] Essentials of Medical Pharmacology First Edition: 1985 Second Edition: 1988 Third Edition: 1994 Fourth Edition: 1999, Updated Reprint: 2001 Fifth Edition: 2003 Sixth Edition: 2008 Seventh Edition: 2013 Reprint: 2014 Eighth Edition: 2019 ISBN: 978-93-5270-499-6  Preface Medical pharmacology is a unique blend of basic pharmacology, clinical pharmacology and pharmacotherapeutics. The subject is highly dynamic with concepts and priority drugs changing rapidly. Innovations and developments are happening at an unprecedented pace. Several new molecular targets for drug action have been identified and novel drugs produced to attack them. On the other hand, a huge body of evidence has been generated to quantify impact of various drugs and regimens on well defined therapeutic end points, so that practice of medicine is transforming from ‘impression based’ to ‘evidence based’. The present edition focuses on evidence based medicine by referring to numerous large randomized trials and other studies which have shaped current therapeutic practices. By evaluating such evidences, professional bodies, eminent health institutes, expert committees and WHO have formulated therapeutic guidelines for treating many conditions, as well as for use of specific drugs. The latest guidelines have been summarized and included in the present edition along with other developments and the core content. Adopting the ‘prototype drug’ approach and a structured, systematic and user-friendly format, all chapters have been thoroughly revised and updated. In this edition, drug classifications have been presented as eye-catching charts which help create pictorial memory. A new chapter on ‘Nitric Oxide and Vasoactive Peptide Signal Molecules’ has been added along with some recently introduced drugs which act through receptors for these molecules or by altering their turnover. Priority has been accorded to drugs that are marketed in India, and their leading brand names are mentioned along with dosage forms. All recently released drugs are included, while those not commercially available or infrequently used have been excluded or described in small type. India specific information on drugs and diseases finds a place in relevant topics. Treatment of diseases like TB, leprosy, HIV-AIDS, malaria, Kala-azar which are covered under WHO and National Health Programmes are described as per the latest recommendations of these organizations. Several new figures, charts, tables and highlight boxes have been added and many older ones have been revised/improved. The recent material and data has been authenticated by quoting its source. A brief list of useful references for further reading is provided at the end of the book. The ‘Problem directed study’ at the end of most chapters provides an exercise in therapeutic decision making. I thank my colleagues and students for providing valuable inputs and raising thoughtful queries. As ever, the driving force behind this book has been Shri Jitendar P Vij (Group Chairman) and Mr Ankit Vij (Managing Director) of M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India. The staff of Jaypee Brothers, especially Ms Sunita Katla (Executive Assistant to Group Chairman and Publishing Manager), Ms Geeta Srivastava (Proof Reader), Mr Manoj Pahuja (Graphic Designer) and Mr Kapil Dev Sharma (DTP Operator) deserve special commendation for excellent production of this text. Cooperation and participation of my wife has been pivotal. New Delhi KD Tripathi June 2018  Extract from Preface to the First Edition Pharmacology is both a basic and an applied science. It forms the backbone of rational thera- peutics. Whereas the medical student and the prescribing physician are primarily concerned with the applied aspects, correct and skilful application of drugs is impossible without a proper understanding of their basic pharmaco­logy. Medical pharmacology, therefore, must include both fundamental back­ ground and clinical pharmacological information. Objective and quantitative data on the use of drugs in man, i.e., relationship between plasma concentration and intensity of therapeutic/toxic actions, plasma half lives, relative efficacy of diffe­rent medications and incidence of adverse effects etc., are being obtained with the aim of optimising drug therapy. The concepts regarding mechanism of action of drugs are changing. In addition, new drugs are being introduced in different countries at an explosive pace. A plethora of information thus appears to be important. However, trying to impart all this to a medical student would be counter-productive. One of the important aims of this book is to delineate the essential information about drugs. The opening sentence in each chapter defines the class of drugs considered. A ‘prototype’ ap- proach has been followed by describing the representative drug of a class followed by features by which individual members differ from it. Leading trade names have been included. Clinically relevant drug interactions have been mentioned. Clear-cut guidelines on selection of drugs and their clinical status have been outlined on the basis of current information. Original, simple and self-explanatory illustrations, tables and flowcharts have been used with impunity. Selected chemical structures are depicted. Recent developments have been incorporated. However, discre- tion has been used in including only few of the multitude of new drugs not yet available in India. This is based on their likelihood of being marketed soon. The information and views have been arranged in an orderly sequence of distinct statements. I hope this manageable volume book would serve to dispel awe towards pharmacology from the minds of medical students and provide a concise and uptodate information source for prescribers who wish to remain informed of the current concepts and developments concerning drugs. My sincere thanks are due to my colleagues for their valuable comments and suggestions. New Delhi KD Tripathi 1st Jan., 1985  Contents Section 1 General Pharmacological Principles 1. Introduction, Routes of Drug Administration 1 2. Pharmacokinetics: Membrane Transport, Absorption and Distribution of Drugs 15 3. Pharmacokinetics: Metabolism and Excretion of Drugs, Kinetics of Elimination 28 4. Pharmacodynamics: Mechanism of Drug Action; Receptor Pharmacology 45 5. Aspects of Pharmacotherapy, Clinical Pharmacology and Drug Development 71 6. Adverse Drug Effects 92 Section 2 Drugs Acting on Autonomic Nervous System Autonomic Nervous System: General Considerations 103 7. Cholinergic Transmission and Cholinergic Drugs 110 8. Anticholinergic Drugs and Drugs Acting on Autonomic Ganglia 124 9. Adrenergic Transmission and Adrenergic Drugs 136 10. Antiadrenergic Drugs (Adrenergic Receptor Antagonists) and Drugs for Glaucoma 153 Section 3 Autacoids and Related Drugs 11. Histamine and Antihistaminics 174 12. 5-Hydroxytryptamine, its Antagonists and Drug Therapy of Migraine 185 13. Prostaglandins, Leukotrienes (Eicosanoids) and Platelet Activating Factor 197 14. Nonsteroidal Antiinflammatory Drugs and Antipyretic-Analgesics 209 15. Antirheumatoid and Antigout Drugs 227 Section 4 Respiratory System Drugs 16. Drugs for Cough and Bronchial Asthma 237 viii ESSENTIALS OF MEDICAL PHARMACOLOGY Section 5 Hormones and Related Drugs Introduction 255 17. Anterior Pituitary Hormones 257 18. Thyroid Hormones and Thyroid Inhibitors 267 19. Insulin, Oral Antidiabetic Drugs and Glucagon 280 20. Corticosteroids 306 21. Androgens and Related Drugs, Drugs for Erectile Dysfunction 320 22. Estrogens, Progestins and Contraceptives 330 23. Oxytocin and Other Drugs Acting on Uterus 354 24. Hormones and Drugs Affecting Calcium Balance 360 Section 6 Drugs Acting on Peripheral (Somatic) Nervous System 25. Skeletal Muscle Relaxants 373 26. Local Anaesthetics 386 Section 7 Drugs Acting on Central Nervous System 27. General Anaesthetics 399 28. Ethyl and Methyl Alcohols 415 29. Sedative-Hypnotics 424 30. Antiepileptic Drugs 438 31. Antiparkinsonian Drugs 452 32. Drugs Used in Mental Illness: Antipsychotic and Antimanic Drugs 462 33. Drugs Used in Mental Illness: Antidepressant and Antianxiety Drugs 481 34. Opioid Analgesics and Antagonists 497 35. CNS Stimulants and Cognition Enhancers 515 Section 8 Cardiovascular Drugs Cardiac Electrophysiological Considerations 521 36. Drugs Affecting Renin-Angiotensin System 524 37. Nitric Oxide and Vasoactive Peptide Signal Molecules 540  contents ix 38. Cardiac Glycosides and Drugs for Heart Failure 556 39. Antiarrhythmic Drugs 570 40. Antianginal and Other Anti-ischaemic Drugs 584 41. Antihypertensive Drugs 604 Section 9 Drugs Acting on Kidney Relevant Physiology of Urine Formation 621 42. Diuretics 625 43. Antidiuretics 639 Section 10 Drugs Affecting Blood and Blood Formation 44. Haematinics and Erythropoietin 645 45. Drugs Affecting Coagulation, Bleeding and Thrombosis 659 46. Hypolipidaemic Drugs 682 Section 11 Gastrointestinal Drugs 47. Drugs for Peptic Ulcer and Gastroesophageal Reflux Disease 695 48. Antiemetic, Prokinetic and Digestant Drugs 709 49. Drugs for Constipation and Diarrhoea 721 Section 12 Antimicrobial Drugs 50. Antimicrobial Drugs: General Considerations 739 51. Sulfonamides, Cotrimoxazole and Quinolones 755 52. Beta-Lactam Antibiotics 766 53. Tetracyclines and Chloramphenicol (Broad-Spectrum Antibiotics) 784 54. Aminoglycoside Antibiotics 793 55. Macrolide, Lincosamide, Glycopeptide and Other Antibacterial Antibiotics; Urinary Antiseptics 801 56. Antitubercular Drugs 815 57. Antileprotic Drugs 831 x ESSENTIALS OF MEDICAL PHARMACOLOGY 58. Antifungal Drugs 838 59. Antiviral Drugs (Non-retroviral) 849 60. Antiviral Drugs (Anti-retrovirus) 860 61. Antimalarial Drugs 873 62. Antiamoebic and Other Antiprotozoal Drugs 893 63. Anthelmintic Drugs 906 Section 13 Chemotherapy of Neoplastic Diseases 64. Anticancer Drugs 915 Section 14 Miscellaneous Drugs 65. Immunosuppressant Drugs 937 66. Drugs Acting on Skin and Mucous Membranes 946 67. Antiseptics, Disinfectants and Ectoparasiticides 957 68. Chelating Agents 964 69. Vitamins 968 70. Vaccines, Antisera and Immuneglobulins 978 71. Drug Interactions 987 Appendices Appendix 1: Solution to Problem Directed Study 995 Appendix 2: Prescribing in Pregnancy 1017 Appendix 3: Drugs in Breastfeeding 1020 Appendix 4: Drugs and Fixed Dose Combinations Banned in India 1024 Selected References for Further Reading 1033 Index 1037  List of Abbreviations AA Amino acid ARB Angiotensin receptor blocker Ab Antibody ARC AIDS related complex ABC ATP-binding cassette (transporter) ARS Anti rabies serum ABLC Amphotericin B lipid complex ART Antiretrovirus therapy AC Adenylyl cyclase ARV Antiretrovirus (drug) ACE Angiotensin II converting enzyme AS Artesunate ACh Acetylcholine 5-ASA 5-Amino salicyclic acid AChE Acetylcholinesterase ASCVD Atherosclerotic cardiovascular disease ACS Acute coronary syndromes AT-III Antithrombin III ACT Artemisinin-based combination therapy ATG Antithymocyte globulin ACTH Adrenocorticotropic hormone ATP Adenosine triphosphate AD Alzheimer’s disease ATPase Adenosine triphosphatase ADCC Antibody-dependent cellular cytotoxicity ATPIII Adult treatment panel III ADE Adverse drug event ATS Antitetanic serum ADH Antidiuretic hormone AUC Area under the plasma concentration-time ADHD Attention deficit hyperactivity disorder curve ADP Adenosine diphosphate A-V Atrioventricular Adr Adrenaline AVP Arginine vasopressin ADR Adverse drug reaction AZT Zidovudine ADS Anti diphtheritic serum AES Atrial extrasystole BAL British anti lewisite AF Atrial fibrillation BAN British approved name AFl Atrial flutter BB Borderline leprosy AG Antigen BBB Blood-brain barrier AGS Antigasgangrene serum BCG Bacillus Calmette Guérin AHG Antihaemophilic globulin BCNU Bischloroethyl nitrosourea (Carmustine) AI Aromatase inhibitor BCRP Breast cancer resistance protein AIDS Acquired immunodeficiency syndrome BD Twice daily AIP Aldosterone induced protein β-ARK β adrenergic receptor kinase ALA Alanine BHC Benzene hexachloride ALS Amyotrophic lateral sclerosis BHP Benign hypertrophy of prostate Am Amikacin BI Bacillary index AMA Antimicrobial agent BL Borderline lepromatous leprosy AMB Amphotericin B BMD Bone mineral density amp Ampoule BMR Basal metabolic rate AMP Adenosine mono phosphate BNP Brain nartriuretic peptide AMPA α-Aminohydroxy methylisoxazole BOL 2-Bromolysergic acid diethylamide propionic acid BP Blood pressure ANC Acid neutralizing capacity BPN Bisphosphonate Ang-I/II/III Angiotensin I/II/III BSA Body surface area ANP Atrial natriuretic peptide BT Borderline tuberculoid leprosy ANS Autonomic nervous system BuChE Butyryl cholinesterase ANUG Acute necrotizing ulcerative gingivitis BW Body weight AP Action potential BZD Benzodiazepine AP-1 Activator protein-1 APC Antigen presenting cell C-10 Decamethonium APD Action potential duration CA Catecholamine aPTT Activated partial thromboplastin time CAB Combined androgen blockade AQ Amodiaquine CaBP Calcium binding protein AR Androgen receptor CAD Coronary artery disease xii ESSENTIALS OF MEDICAL PHARMACOLOGY CAM Calmodulin DA Dopamine cAMP 3’, 5’ Cyclic adenosine monophosphate DA-B12 Deoxyadenosyl cobalamin CAP Community acquired pneumonia DAD Delayed after-depolarization cap Capsule DAG Diacyl glycerol CAse Carbonic anhydrase DAM Diacetyl monoxime CAT Computerized axial tomography DAMP Diphenyl acetoxy-N-methyl piperidine CBF Cerebral blood flow methiodide CBG Cortisol binding globulin DAT Dopamine transporter dDAVP Desmopressin CBS Colloidal bismuth subcitrate DDS Diamino diphenyl sulfone (Dapsone) CCB Calcium channel blocker DDT Dichloro diphenyl trichloroethane CCNU Chloroethyl cyclohexyl nitrosourea DEC Diethyl carbamazine citrate (lomustine) DHA Dihydroartemisinin CCR5 Chemokine coreceptor 5 DHE Dihydroergotamine CD Collecting duct/Cluster of differentiation DHFA Dihydro folic acid CDC Complement dependent cytotoxicity DHFRase Dihydrofolate reductase CFTR Cystic fibrosis transport regulator DHP Dihydropyridine cGMP 3', 5' Cyclic guanosine monophosphate DHT Dihydrotestosterone CGRP Calcitonin gene related peptide DI Diabetes insipidus CH Cholesterol DIT Diiodotyrosine ChE Cholinesterase dl Decilitre CHE Cholesterol ester DLE Disseminated lupus erythematosus CHF Congestive heart failure DMA Dimethoxy amphetamine Chy Chylomicron DMARD Disease modifying antirheumatic drug Chy. rem. Chylomicron remnants DMCM Dimethoxyethyl-carbomethoxy-β-carboline CI Cardiac index DMPA Depot medroxyprogesterone acetate CINV Chemotherapy induced nausea and vomiting DMPP Dimethyl phenyl piperazinium CKD Chronic kidney disease DMT Dimethyl tryptamine/Divalent metal transporter DNA Deoxyribose nucleic acid CL Clearance DOC Deoxycholate CLcr Creatinine clearance DOCA Desoxy corticosterone acetate Cm Capreomycin DOM Dimethoxymethyl amphetamine CMI Cell mediated immunity dopa Dihydroxyphenyl alanine CMV Cytomegalovirus DOPAC 3, 4, Dihydroxyphenyl acetic acid CNS Central nervous system DOSS Dioctyl sulfosuccinate c.o. Cardiac output DOTS Directly observed treatment short course CoEn-A Coenzyme-A DPD Dihydropyrimidine dehydrogenase COMT Catechol-O-methyl transferase DPP-4 Dipeptidyl peptidase-4 COX Cyclooxygenase DPT Diphtheria-pertussis-tetanus triple antigen c.p.s. Cycles per second DRC Dose-response curve CPS Complex partial seizures DRI Direct renin inhibitor CPZ Chlorpromazine DST Drug sensitivity testing (for TB) CQ Chloroquine DT Distal tubule CRABP Cellular retinoic acid binding protein DT-DA Diphtheria-tetanus double antigen CRBP Cellular retinol binding protein d-TC d-Tubocurarine CrD Crohn’s disease DTIC Dacarbazine CREB Cyclic AMP response element binding protein DTPA Diethylene triamine pentaacetic acid DVT Deep vein thrombosis CRF Corticotropin releasing factor DYN Dynorphin CS Cycloserine CSF Cerebrospinal fluid E Ethambutol CTL Cytotoxic T-lymphocytes EACA Epsilon amino caproic acid CTZ Chemoreceptor trigger zone EAD Early after-depolarization CV Cardiovascular ECE Endothelin converting enzyme CVP Central venous pressure e.c.f. Extracellular fluid CVS Cardiovascular system ECG Electrocardiogram CWD Cell wall deficient ECT Electroconvulsive therapy CYP450 Cytochrome P450 ED Erectile dysfunction  Abbreviations xiii EDRF Endothelium dependent relaxing factor GLP Glucagon-like peptide EDTA Ethylene diamine tetraacetic acid GLUT Glucose transporter EEG Electroencephalogram GM-CSF Granulocyte macrophage colony EF Ejection fraction stimulating factor EGF Epidermal growth factor GnRH Gonadotropin releasing hormone ELAM-1 Endothelial leukocyte adhesion molecule-1 GPCR G-protein coupled receptor β-END β-Endorphin G-6-PD Glucose-6-phosphate dehydrogenase eNOS Endothelial nitric oxide synthase GPI Globus pallidus interna ENS Enteric nervous system GST Glutathione-S-transferase ENT Extraneuronal amine transporter GTCS Generalised tonic-clonic seizures EPAC cAMP regulated guanine nucleotide GTN Glyceryl trinitrate exchange factors GTP Guanosine triphosphate EPEC Enteropathogenic E. coli EPO Erythropoietin H Isoniazid (Isonicotinic acid hydrazide) EPP End plate potential HAP Hospital acquired pneumonia EPSP Excitatory postsynaptic potential Hb Haemoglobin ER Estrogen receptor HBV Hepatitis B virus ERA Endothelin receptor antagonist HCG Human chorionic gonadotropin ERP Effective refractory period HCV Hepatitis C virus ES Extrasystole HDCV Human diploid cell vaccine ESR Erythrocyte sedimentation rate HDL High density lipoprotein ET Endothelin HETE Hydroxyeicosa tetraenoic acid ETEC Enterotoxigenic E. coli 5-HIAA 5-Hydroxyindole acetic acid Eto Ethionamide HIV Human immunodeficiency virus HLA Human leucocyte antigen FA Folic acid HMG-CoA Hydroxymethyl glutaryl coenzyme A FAD Flavin adenine dinucleotide HMW High molecular weight 5-FC 5-Flucytosine HPA axis Hypothalamo-pituitary-adrenal axis FDC Fixed dose combination HPETE Hydroperoxy eicosatetraenoic acid FDT Fixed duration therapy (of leprosy) hr Hour FEV1 Forced expiratory volume in 1 second HR Heart rate FFA Free fatty acid HRIG Human rabies immuneglobulin FKBP FK 506 (tacrolimus) binding protein HRT Hormone replacement therapy FLAP Five-lipoxygenase activating protein 5-HT 5-Hydroxytryptamine FMN Favin mononucleotide 5-HTP 5-Hydroxytryptophan FP Ferroportin HVA Homovanillic acid FQ Fluoroquinolone FRase Folate reductase I Indeterminate leprosy FSH Follicle stimulating hormone IAP Islet amyloid polypeptide 5-FU 5-Fluorouracil IBD Inflammatory bowel disease IBS Irritable bowel syndrome G Genetic GABA Gamma amino butyric acid ICAM-1 Intracellular adhesion molecule-1 GAT GABA-transporter ICSH Interstitial cell stimulating hormone GC Guanylyl cyclase i.d. Intradermal (injection) GCP Good clinical practice IDL Intermediate density lipoprotein G-CSF Granulocyte colony stimulating factor IFN Interferon GDP Guanosine diphosphate IG Immuneglobulin GERD Gastroesophageal reflux disease IGF Insulin-like growth factor g.f. Glomerular filtration IL Interleukin g.f.r. Glomerular filtration rate ILEU Isoleucine GH Growth hormone i.m. Intramuscular GHRH Growth hormone releasing hormone INH Isonicotinic acid hydrazide GHRIH Growth hormone release inhibitory hormone INR International normalized ratio GIP Gastric inhibitory peptide/Glucose- i.o.t. Intraocular tension dependent insulinotropic polypeptide IP3 Inositol trisphosphate g.i.t. Gastrointestinal tract IP4 Inositol tetrakisphosphate GITS Gastrointestinal therapeutic system IPSP Inhibitory postsynaptic potential xiv ESSENTIALS OF MEDICAL PHARMACOLOGY IPV Inactivated poliomyelitis vaccine MRP2 Multidrug resistance associated protein-2 IRS Insulin response substrate MRSA Methicillin resistant Staphylococcus aureus ISA Intrinsic sympathomimetic activity MSH Melanocyte stimulating hormone ISH Isolated systolic hypertension mTOR Mammalian target of rapamycin IU International unit Mtx Methotrexate IUCD Intrauterine contraceptive device mV millivolt i.v. Intravenous MW Molecular weight JAK Janus-kinase NA Noradrenaline NABQI N-acetyl-p-benzoquinoneimine Km Kanamycin NADP Nicotinamide adenine dinucleotide phosphate KTZ Ketoconazole NADPH Reduced nicotinamide adenine dinucleotide phosphate LA Local anaesthetic NAG N-acetyl glucosamine LCAT Lecithin cholesterol acyl transferase NAM N-acetyl muramic acid LC3-KAT Long chain 3-ketoacyl-CoA-thiolase NANC Nonadrenergic noncholinergic LDL Low density lipoprotein NAPA N-acetyl procainamide LES Lower esophageal sphincter NaSSA Noradrenergic and specific serotonergic leu-ENK Leucine enkephalin antidepressant LH Luteinizing hormone NAT N-acetyl transferase liq Liquid NCEP National cholesterol education programme LL Lepromatous leprosy NEE Norethindrone enanthate LMW Low molecular weight NEP Neutral endopeptidase (Neprolysin) LOX Lipoxygenase NET Norepinephrine transporter LSD Lysergic acid diethylamide NFAT Nuclear factor of activated T-cell LT Leukotriene NFκB Nuclear factor κB LVF Left ventricular failure NICE National Institute for Health and Care excellence MAbs Monoclonal antibodies (UK) MAC Minimal alveolar concentration NIS Na+ (sodium)-iodide symporter NLEP National leprosy eradication programme MAC Mycobacterium avium complex NMDA N-methyl-D-aspartate MAO Monoamine oxidase nNOS Neural nitric oxide synthase MAP Muscle action potential NNRTI Nonnucleoside reverse transcriptase MAPKinase Mitogen activated protein kinase inhibitor max Maximum NPY Neuropeptide-Y MBC Minimum bactericidal concentration NR Nicotinic receptor MBL Multibacillary leprosy N-REM Non rapid eye movement (sleep) MCI Mild cognitive impairment NRTI Nucleoside reverse transcriptase inhibitor MDI Manic depressive illness NSAID Nonsteroidal antiinflammatory drug MDMA Methylene dioxy methamphetamine NSTEMI Non ST-segment elevation myocardial MDR Multidrug resistant infarction MDT Multidrug therapy (of leprosy) NTS Nucleus tractus solitarius met-ENK Methionine enkephalin NVBDCP National vector borne diseases control mEq milliequivalent programme methyl B12 Methyl cobalamin NYHA New York Heart Association Mf Microfilariae MF Multifactorial OAT Organic anion transporter MHC Major histocompatibility complex OATP Organic anion transporting polypeptide MHT Methylene dioxy methamphetamine OC Oral contraceptive MI Myocardial infarction OCD Obsessive-compulsive disorder MIC Minimal inhibitory concentration OCT Organic cation transporter MIF Migration inhibitory factor OD Once daily min Minimum OPG Osteoprotegerin MIT Monoiodo tyrosine OPV Oral poliomyelitis vaccine MLCK Myosin light chain kinase ORS Oral rehydration salt (solution) MMF Mycophenolate mofetil ORT Oral rehydration therapy 6-MP 6-Mercaptopurine MPPT Methylprednisolone pulse therapy PABA Paraamino benzoic acid MPTP 4-methyl-4-phenyltetrahydro pyridine PAE Post antibiotic effect MQ Mefloquine PAF Platelet activating factor  Abbreviations xv PAH Pulmonary arterial hypertension QID Four times a day PAI-1 Plasminogen activator inhibitor-1 2-PAM Pralidoxime R Rifampin (Rifampicin) PAN Primary afferent neurone RANK Receptor for activation of nuclear factor κB PAS Paraamino salicylic acid RANKL RANK ligand PBI Protein bound iodine RAS Renin-angiotensin system PBL Paucibacillary leprosy RBC Red blood cells PBPs Penicillin binding proteins RBP Retinol binding protein PCA Patient controlled anaesthesia RC Respiratory centre PCEV Purified chick embryo cell vaccine (rabies) RCT Randomized clinical trial PCI Percutaneous coronary intervention RE Reticuloendothelial PCPA Parachloro phenylalanine REM Rapid eye movement (sleep) PD Parkinsons’s disease RGS Regulator of G-protein synthesis PDE Phosphodiesterase RIG Rabies immuneglobulin RIMA Reversible inhibitor of MAO-A PE Pulmonary embolism rINN Recommended international PEMA Phenylethyl malonamide nonproprietary name PEP Postexposure prophylaxis RMP Resting membrane potential PF Purkinje fibre RNA Ribonucleic acid PFOR Pyruvate: ferredoxin oxidoreductase RNTCP Revised National Tuberculosis Control PG Prostaglandin Programme PGI2 Prostacyclin RP Refractory period Pgp P-glycoprotein RTF Resistance transfer factor PI Protease inhibitor RTKs Receptor tyrosine kinases PIG Phosphatidyl inositol glycan RXR Retinoid X receptor PIP2 Phosphatidyl inositol-4,5-bisphosphate RyR Ryanodine receptor PKA Protein kinase: cAMP dependent PKC Protein kinase C S Streptomycin PLA Phospholipase A SA Sinoauricular (node) PLC Phospholipase C SABE Subacute bacterial endocarditis Pl. ph. Platelet phospholipid s.c. Subcutaneous pMDI pressurized multidose inhaler SCC Short course chemotherapy (of tuberculosis) PnG Penicillin G SCh Succinylcholine POMC Pro-opio melanocortin SCID Severe combined immunodeficiency disease PONV Postoperative nausea and vomiting SERCA Sarcoplasmic-endoplasmic reticular calcium PP Partial pressure ATPase PPARγ Paroxysome proliferator-activated SERDs Selective estrogen receptor down regulators receptor γ SERM Selective estrogen receptor modulator PPH Post partum haemorrhage SERT Serotonin transporter PPI Proton pump inhibitor SGA Second generation antihistaminic ppm Part per million SGLT Sodium-glucose transporter PPNG Penicillinase producing N. gonorrhoeae SHBG Sex hormone binding globulin PRA Plasma renin activity SIADH Syndrome of inappropriate ADH secretion PrEP Pre-exposure prophylaxis (of HIV) s.l. Sublingual SLC Solute carrier PRF Prolactin releasing factor SLE Systemic lupus erythematosus PRIH Prolactin release inhibitory hormone SMON Subacute myelo-optic neuropathy PSVT Paroxysmal supra-ventricular tachycardia SNP Single nucleotide polymorphism PT Proximal tubule SN-PC Substantia nigra-pars compacta PTCA Percutaneous transluminal coronary SN-PR Substantia nigra-pars reticularis angioplasty SNRI Serotonin and noradrenaline reuptake PTH Parathyroid hormone inhibitor PTMA Phenyl trimethyl ammonium s.o.s. as required PTP Post-tetanic potentiation S/P Sulfonamide + pyrimethamine PTSD Post-traumatic stress disorder SP Substance P PTZ Pentylenetetrazol SPF Sun protection factor PUV A Psoralen-Ultraviolet A SPRM Selective progesterone receptor modulator PVRV Purified verocell rabies vaccine SPS Simple partial seizures xvi ESSENTIALS OF MEDICAL PHARMACOLOGY SR Sustained release TRE Thyroid hormone response element SRS-A Slow reacting substance of anaphylaxis TRH Thyrotropin releasing hormone SSG Sodium stibogluconate TSH Thyroid stimulating hormone SSI Surgical site infection TT Tuberculoid leprosy SSRIs Selective serotonin reuptake inhibitors TTS Transdermal therapeutic system STAT Signal transducer and activator of TX Thromboxane transcription STEMI ST-segment elevation myocardial infarction U Unit StK Streptokinase UA Unstable angina SU Sulfonylurea UDP Uridine diphosphate SULT Sulfotransferase UFH Unfractionated heparin SUR Sulfonyl urea receptor UGDP University group diabetic programme susp Suspension UGT UDP-glucuronosyl transferase SVR Sustained viral response USAN United States adopted name SWD Shift work disorder UT Urea transporter SWS Slow wave sleep UTI Urinary tract infection syr Syrup v Volt t½ Half life V Volume of distribution T3 Triiodothyronine VAL Valine T4 Thyroxine VAP Ventilator associated pneumonia tab Tablet VDR Vit D receptor TAB Typhoid, paratyphoid A and B vaccine VES Ventricular extrasystole TAL Thick ascending limb (loop of Henle) VF Ventricular fibrillation TB Tubercle bacilli VIP Vasoactive intestinal peptide TBG Thyroxine binding globulin Vit Vitamin TCII Transcobalamin II VKOR Vitamin K epoxide reductase TCAs Tricyclic antidepressants VL Visceral leishmaniasis TCID50 Tissue culture infectious dose 50% VLDL Very low density lipoprotein TDM Therapeutic drug monitoring VMA Vanillyl mandelic acid TDS Three times a day VMAT Vesicular monoamine transporter Tf Transferrin VRE Vancomycin resistant enterococci TG Triglyceride VRSA Vancomycin resistant Staphylococcus aureus 6-TG 6-Thioguanine VRUT Vasopressin regulated urea transporter TGF-β Transforming growth factor β VT Ventricular tachycardia THC Tetrahydrocannabinol VTE Venous thromboembolism THFA Tetrahydro folic acid vWF von Willebrand factor Thio TEPA Triethylene thiophosphoramide THR Threonine WBC White blood cells TIAs Transient ischaemic attacks WCVs Water channel containing vesicles TNF-α Tumour necrosis factor α WHO World Health Organization TOD Target organ damage WPW Wolff-Parkinson-White syndrome TOF Train-of-four t-PA Tissue plasminogen activator XDR-TB Extensively drug resistant-TB TPMT Thiopurine methyl transferase t.p.r. Total peripheral resistance Z Pyrazinamide TR Thyroid hormone receptor ZE (syndrome) Zollinger-Ellison (syndrome)  GENERAL PHARMACOLOGICAL PRINCIPLES Introduction, Routes of Chapter 1 Drug Administration INTRODUCTION of the fundamental concepts in pharmacology. Since then drugs have been purified, chemically characterized and a vast variety of highly potent Pharmacology and selective new drugs have been developed. Pharmacology is the science of drugs (Greek: The mechanism of action including molecular Pharmacon-drug; logos-discourse in). In target of many drugs has been elucidated. This a broad sense, it deals with interaction of has been possible due to prolific growth of exogenously administered chemical molecules pharmaco ogy which forms the backbone of with living systems, and any single chemi­ ational therapeutics. cal substance which can produce a biological The two main divisions of pharmacology response is a 'drug'. Pharmacology encompasses are pharmacodynamics and pharmacokinetics. all aspects of knowledge about drugs, butlrQ importantly those that are relevart_ to ef(ecti\l_e Pharmacodynamics (Greek: dynamis-power) and safe use of drugs for medicinal purposes. -What the drug does to the body. For thousands of years most drugs were crude This includes physiological and biochemical natural products of unknown composition and effects of drugs and their mechanism of action limited efficacy. Only the overt effects of these at organ system/subcellular/macromolecular substances on the body were rather imprecisely levels, e.g.-Adrenaline ➔ interaction with known, but how the same ere produced was adrenoceptors ➔ G-protein mediated stimu­ lation of cell membrane bound adenylyl cyclase entirely unknown. Animal experiments, primarily ➔ increased intracellular cyclic 3',5'AMP ➔ aimed at understanding pn siological processes, cardiac stimulation, hepatic glycogenolysis and were started in the 18th century. These were hyperglycaemia, etc. pioneered by F. Magendie and Claude Bernard, who also adapted them to study effects of Pharmacokinetics (Greek: Kinesis-move­ certain drugs. Pharmacology as an experimental ment)-What the body does to the drug. science was ushered by Rudolf Buchheim who This refers to movement of the drug in and founded the first institute of pharmacology alteration of the drug by the body; includes in 1847 in Germany. In the later part of the absorption, distribution, binding/localization/stor­ 19th century, Oswald Schmiedeberg, regarded age, biotransformation and excretion of the drug, as the 'father of pharmacology', together with e.g. paracetamol is rapidly and almost completely his many disciples like J Langley, T Frazer, P absorbed orally attaining peak blood levels at Ehrlich, AJ Clark, JJ Abel propounded some 30-60 min; 25% bound to plasma proteins, 3 2 GENERAL PHARMACOLOGY widely and almost uniformly distri­buted in the of drugs and comparative trials with other body (volume of distribution ~ 1L/kg); exten­ forms of treatment; surveillance of patterns of sively metabolized in the liver, prima­rily by drug use, adverse effects, etc. are also part of glucuronide and sulfate conju­gation into inac- clinical pharmacology. tive metabolites which are excreted in urine; The aim of clinical pharmacology is to gen- has a plasma half life (t½) of 2–3 hours and erate data for optimum use of drugs and the a clearance value of 5 ml/kg/min. practice of ‘evidence based medicine’. Drug (French: Drogue—a dry herb) It is Chemotherapy It is the treatment of sys- the single active chemical entity present in a temic infection/malignancy with specific drugs medicine that is used for diagnosis, prevention, that have selective toxicity for the infecting treatment/cure of a disease. orga­nism/malignant cell with no/minimal effects This disease oriented definition of drug does on the host cells. not include contraceptives or use of drugs for Drugs in general, can thus be divided into: improvement of health. The WHO (1966) has Pharmacodynamic agents These are designed given a more comprehensive definition—“Drug to have pharmacodynamic effects in the reci­pient. is any substance or product that is used or is intended to be used to modify or explore Chemotherapeutic agents These are designed physiological systems or pathological states for to inhibit/kill invading parasites/malignant cell, SECTION 1 the benefit of the recipient.” but have no/minimal pharmacodynamic effects The term ‘drugs’ is being also used to mean in the recipient. addic­­­­tive/abused/illicit substances. However, Pharmacy It is the art and science of this res­tric­ted and dero­gatory sense usage is compoun­ding and dispensing drugs or prepar- unfor­ tunate degradation of a time honoured ing suitable dosage forms for administration of term, and ‘drug’ should refer to a substance drugs to man or animals. It includes collection, that has some health promoting/therapeutic/ identification, purification, isolation, synthesis, diagnostic application. Nevertheless, to avoid standardization and quality control of medicinal any misinterpretation, the term ‘medicine’ is substances. The large scale manufacture of drugs being employed to designate such a substance is called Phar­ma­ceutics, which is primarily a in place of the term ‘drug’. technological science. Some other important aspects of pharmacol- Toxicology It is the study of poisonous ogy are: effect of drugs and other chemicals (household, Pharmacotherapeutics It is the application environ­­mental pollutant, industrial, agricultural, of phar­ma­cological information together with homi­cidal) with emphasis on detection, pre- know­ ledge of the disease for its prevention, vention and treatment of poisonings. It also mitigation or cure. Selection of the most appro­ includes the study of adverse effects of drugs, priate drug, dosage and duration of treatment since the same substance can be a drug or a taking into account the stage of disease and poison, depending on the dose. the specific features of a patient are a part of pharmacotherapeutics. nature of drugs Clinical pharmacology It is the scientific All drugs are chemical entities with simple or study of drugs (both old and new) in man. It complex molecules. While majority are organic includes pharma­codynamic and pharmacokinetic compounds, some are purely inorganic, like investigation in healthy volun­teers as well as lithium carbonate, ferrous sulfate, magnesium in patients. Evaluation of efficacy and safety hydroxide, etc. Organic drugs may be weakly  Introduction, Routes of DRUG Administration 3 acidic (aspirin, penicillin) or weakly basic (mor- a. Alkaloids: These are alkaline nitrogenous phine, chloroquine) or nonelectrolytes (alcohol, bases having potent activity, and are the diethyl-ether). Most drugs are normally solids, most important category of vegetable e.g. paracetamol, propranolol, furosemide, ampi- origin drugs. Prominent examples are: cillin, etc., but some such as ethanol, glyceryl morphine, atropine, ephedrine, nicotine, trinitrate, propofol, castor oil are liquids, and ergotamine, reserpine, quinine, vincristine, few like nitrous oxide are gaseous. etc. They are mostly used as their water The molecular weight of majority of drugs soluble hydrochloride/ sulfate salts. falls in the range of 100-1000 D, because b. Glycosides: These compounds consist of molecules smaller than 100 D do not generally a heterocyclic nonsugar moiety (aglycone) have sufficiently specific features in terms of linked to a sugar moiety through ether shape, size, configuration, chirality, distribution linkage. Cardiac glycosides (digoxin, of charges, etc. to selectively bind to only one/ ouabain) are the best known glycosidic few closely related target biomolecules, to the drugs. The active principle of senna and exclusion of others. On the other hand, larger similar plant purgatives are anthraquinone molecules than 1000 D do not readily pass glycosides. Aminoglycosides (gentamicin, through membranes/barriers in the body to reach etc.) are antibiotics obtained from the target sites in various tissues/cells. However, microorganisms, and have an aminosugar CHAPTER 1 few drugs are as small as lithium ion (7D), and in place of a sugar moiety. some like heparin (10-20 KD), gonadotropins c. Oils: These are viscous, inflammable liquids, (>30 KD), enzymes, proteins, antibodies (>50 insoluble in water. Fixed (nonvolatile) KD) are much bigger. Bulky molecule drugs oils are calorie yielding triglycerides of have to be administered parenterally. higher fatty acids; mostly used for food Drugs are generally perceived to be chemical and as emollients, e.g. groundnut oil, substances foreign to the body (Xenobiotics). coconut oil, sesame oil, etc. Castor oil is However, many endogenous chemicals like a stimulant purgative. Essential (volatile) hormones, autacoids, metabolites and nutrients oils, mostly obtained from flowers or are also used as drugs. Chemical congeners of leaves by steam distillation are aromatic these metabolites/signal molecules are an im- (fragrant) terpene hydrocarbons that have portant class of drugs which act by modifying no food value. They are used as flavouring the synthesis, storage, degradation or action of agents, carminatives, counterirritants and these metabolites/signal molecules. astringents; examples are eucalyptus oil, pepermint oil, nilgiri oil, etc. Clove oil is sources of drugs used to allay dental pain. Menthol, thymol, Drugs are obtained from a variety of sources: camphor are volatile oils that are solids at 1. Plants Many plants contain biologically room temperature. active substances and are the oldest source Mineral oils are not plant products, but of drugs. Clues about medicinal plants were obtained from petroleum; liquid paraffin is obtained from traditional systems of medicine a lubricant laxative, soft and hard paraffin prevalent in various parts of the world; e.g. are used as emollient and as ointment use of opium, belladonna, ephedra, cinchona, bases. curare, foxglove, sarpagandha, qinghaosu Other plant products like tanins are astringent; has been learnt from Egyptian, Greek, Aztec, gums are demulcents and act as suspending agents Ayurvedic, chinese and other systems of in liquid dosage forms. Glycerine is a viscous, medicine. Chemically the active ingredients sweet liquid used as vehicle for gum/throat paint. of plants fall in several categories: Resins and balsams are used as antiseptic and in  4 GENERAL PHARMACOLOGY cough mixtures. The antimalarial drug artemisinin 6. Biotechnology Several drugs, especially is a sesquiterpene endoperoxide obtained from a peptides and proteins are now produced by Chinese plant. recombinant DNA technology, e.g. human 2. Animals Though animal parts have been used growth hormone, human insulin, altaplase, as cures since early times, it was exploration interferon, etc. Monoclonal antibodies, of activity of organ extracts in the late 19th and regulator peptides, erythropoietin and early 20th century that led to introduction of other growth factors are the newer drugs of animal products into medicine, e.g. adrenaline, biotechnological origin. protein therapeutics thyroxine, insulin, liver extract (vit. B12). Antisera is rapidly expanding, because specifically and few vaccines are also produced from animals. designed and customized proteins can now be 3. Microbes Most antibiotics are obtained produced. from fungi, actinomycetes and bacteria, e.g. penicillin, gentamicin, tetracycline, Drug nomenclature erythromycin, polymyxin B, actinomycin D A drug generally has three categories of names: (anticancer). Some enzymes, e.g. diastase from a fungus and streptokinase from streptococci (a) Chemical name It describes the sub- have a microbial source. Vaccines are produced stance che­mically, e.g. 1-(Isopropylamino)-3- by the use of microbes. (1-napht­hy­­­loxy) propan-2-ol for propranolol. SECTION 1 4. Minerals Few minerals, e.g. iron salts, This is cumber­some and not suitable for use calcium salts, lithium carbonate, magnesium/ in prescribing. A code name, e.g. RO 15-1788 aluminium hydroxide, iodine are used as (later named flumazenil) may be assigned by medicinal substances. the manufacturer for con­venience and simplicity 5. Synthetic chemistry Synthetic chemistry before an approved name is coined. made its debut in the 19th century, and (b) Non-proprietary name It is the name is now the largest source of medicines. accep­ted by a competent scientific body/ Synthetic drugs have the advantage of purity authority, e.g. the United States Adopted Name and uniformity of the product. They can be (USAN) by the USAN council. Similarly, manufactured in any quantity as per need, there is the British Approved name (BAN) of in contrast to drugs from natural sources a drug. The non-proprietary names of newer whose availability may be limited. Not only drugs are kept uniform by an agreement to use diverse congeners of naturally obtained the Recommen­ded International Nonproprie­tary drugs (atropine substitutes, adrenergic b 2 Name (rINN) in all member countries of the agonists, synthetic glucocorticoids/progestins/ WHO. The BAN of older drugs as well has cephalosporins, etc.) have been introduced now been modified to be commensurate with to achieve greater selectivity of action rINN. However, many older drugs still have or even novel type of activity, but many more than one non-proprietary names, e.g. entirely synthetic families of drugs, e.g. ‘meperidine’ and ‘pethidine’ or ‘lidocaine’ benzodiazepines, thiazides, benzimidazoles, and ‘lignocaine’ for the same drugs. Until fluoroquinolones, etc. have been produced. the drug is included in a pharmacopoeia, the Many drugs are being synthesized to target nonproprie­tary name may also be called the specific biomolecules, e.g. ACE inhibitors, approved name. After its appearance in the glycoprotein IIb/IIIa receptor antagonists, official publication, it becomes the official HIV-reverse transcriptase inhibitors, etc. name. Synthetic drugs that are chiral can also be In common parlance, the term generic produced as single active enantiomer products, name is used in place of nonproprietary name. which may be therapeutically superior. Etymolo­g ically this is incorrect: ‘generic’  Introduction, Routes of DRUG Administration 5 should be applied to the chemical or pharma- drug COMPENDIA cological group (or genus) of the compound, These are compilations of information on drugs e.g. pheno­ thiazines, tricyclic anti­depressants, in the form of monographs; without going into aminoglycoside anti­bio­tics, etc. However, this the theoretical concepts, mechanisms of action misnomer is widely accepted and used even and other aspects which help in understanding in official parlance. the subject. Pharmacopoeias and Formularies (c) Proprietary (Brand) name It is the are broughtout by the Government in a country, name assig­­ned by the manufacturer(s) and is hold legal status and are called official compen­ his property or trade mark. One drug may dia. In addition, some non-official compendia have mul­tiple pro­prietary names, e.g. AMCARD, are published by professional bodies, which AMLOGARD, AMLOCOR, AMLONG, AMLOPIN, are supplementary and dependable sources of AMLOVAS, STAMLO for amlodipine from different information about drugs. manufac­ turers. Brand names are designed to Pharmacopoeias They contain description of be catchy, short, easy to remember and often chemical structure, molecular weight, physical suggestive, e.g. LOPRESOR suggesting drug for and chemical characteristics, solubility, identifi­ lowering blood pressure. Brand names gener- cation and assay methods, standards of purity, ally differ in diffe­rent countries, e.g. timolol storage conditions and dosage forms of officially CHAPTER 1 maleate eye drops are marketed as TIMOPTIC in approved drugs in a country. They are useful to USA but as GLUCOMOL in India. Even the same drug manufacturers and regulatory authorities, manufacturer may mar­ket the same drug under but not to doctors, most of whom never see different brand names in different countries. In a pharmacopoeia. Examples are Indian (IP), addition, combined formulations have their own British (BP), European (Eur P), United States multiple brand names. This is responsible for (USP) pharmacopoeias. much confusion in drug nomen­ clature. There are many arguments for using the Formularies Generally produced in easily nonproprietary name in prescribing: uniformity, carried booklet form, they list indications, dose, convenience, economy and better comprehen­sion dosage forms, contraindications, precautions, (propranolol, sotalol, timolol, pindolol, meto- adverse effects and storage of selected drugs prolol, acebutolol, atenolol are all β blockers, that are available for medicinal use in a country. but their brand names have no such similarity). Drugs are categorized by their therapeutic class. Drugs marketed under nonproprietary name Some rational fixed-dose drug combinations (called generic products) are much cheaper than are included. A brief commentary on the their branded counterparts, partly because the drug class and clinical conditions in which they are used generally precedes specifics of manufacturer invests a lot of money in promot- individual drugs. Brief guidelines for treatment ing the brand name. However, when a drug is of selected conditions are provided. While British prescribed by the generic name, the chemist National Formulary (BNF) also lists brand names is free to dispense the generic product from with costs, the National Formulary of India (NFI) any manufacturer, but not so when the drug is does not include these. Most formularies have prescribed by a brand name. Thus, when it is informative appendices as well. Formularies can important to ensure consistency of the product be consid­erably helpful to prescribers. in terms of quality and bioavailability, etc. and especially when official control over quality Martindale: The Complete Drug Reference of manufac­tured products is not rigorous, it (Extrapharmacopoeia) Published every 2–3 is better to prescribe by the dependable brand years by the Royal Pharmaceutical Society of name. Great Britain, this non-official compendium is  6 GENERAL PHARMACOLOGY an exhaustive and updated compilation of un- financial resources; genetic, demographic and environ­ biased information on medicines used/registered mental factors. (d) In case of two or more similar medicines, choice all over the world. It includes new launches and should be made on the basis of their relative efficacy, contains pharmaceutical, pharma­cological as well safety, quality, price and availability. Cost-benefit ratio as therapeutic information on drugs, which can should be a major consideration. serve as a reliable reference book. (e) Choice may also be influenced by comparative pharma­ cokinetic properties and local facilities for manufacture Physicians Desk Reference (PDR) and Drug: and storage. Facts and Comparisons (both from USA), (f) Most essential medicines should be single compounds. etc. are other useful non-official compendia. Fixed ratio combination products should be included only when dosage of each ingredient meets the requirements of a defined population group, and when the combina- Essential medicines (drugS) tion has a proven advantage in therapeutic effect, safety, concept adherence or in decreasing the emergence of drug resistance. (g) Selection of essential medicines should be a continu- The WHO has defined Essential Medicines ous process which should take into account the changing (drugs) as “those that satisfy the priority priorities for public health action, epidemiological conditions healthcare needs of the population.” They as well as availability of better medicines/formulations and progress in pharmacological knowledge. are selected with due regard to public health (h) Recently, it has been emphasized to select essential relevance, evidence on efficacy and safety, medicines based on rationally developed treatment guide- SECTION 1 and comparative cost effective­ness. Essential lines. medicines are intended to be available within To guide the member countries, the WHO the context of functioning health systems at all brought out its first Model List of Essential times and in adequate amounts, in appropriate Drugs along with their dosage forms and dosage forms, with assured quality and adequate strengths in 1977 which could be adopted information, and at a price the individual and after suitable modifications according to local the community can afford. needs. This has been revised from time to time It has been realized that only a handful of and the current is the 20th list (2017)$ which medicines out of the multitude available can has 433 medicines, including 25 fixed dose meet the health care needs of majority of the drug combinations (FDCs). India produced its people in any country, and that many well National Essential Drugs List in 1996, and has tested and cheaper medicines are equally (or revised it in 2011, and now in 2015 with the more) efficacious and safe as their newer more title “National List of Essential Medicines”.£ expensive congeners. For optimum utilization of The latest list includes 376 medicines, of which resources, governments (especially in developing 20 are FDCs. These medicines have been countries) should concentrate on these medicines by identifying them as Essential medicines. The marked into 3 categories for being available WHO has laid down criteria to guide selection at primary, secondary and tertiary levels of of an essential medicine.* health care facility. (a) Adequate data on its efficacy and safety should be Adoption of the essential medicines list for available from clinical studies. procurement and supply of medicines, especially (b) It should be available in a form in which quality, includ- in the public sector healthcare system, has ing bioavailability, and stability on storage can be assured. (c) Its choice should depend upon pattern of prevalent resulted in improved availability of medicines, diseases; availability of facilities and trained personnel; cost saving and more rational use of drugs. *The use of Essential Drugs (including the 8th model list of essential drugs); WHO Technical report series 850, 1995, Geneva. $ www.who.int>20th—essential med-list (pub. 6 Jun 2017). £ National list of Essential Medicines (2015) [http//www.cdsco.nic.in]  Introduction, Routes of DRUG Administration 7 Prescription and non-prescription drugs vehicles, etc.) according to a specific recipe and As per drug rules, majority of drugs includ- packaged into a specific ‘dosage form’ such as ing all antibiotics must be sold in retail only tablet, elixir, ointment, injection vial, etc. which against a prescription issued to a patient by a is then administered to the subject. The dosage registered medical practitioner. These are called form provides body to the drug, demarkates single ‘prescription drugs’, and in India they have doses, protects the active ingredient(s), and makes been placed in the schedule H of the Drugs it suitable for administration in various ways. and Cosmetic Rules (1945) as amended from The important dosage forms are briefly described time to time. However, few drugs like simple below. analgesics (paracetamol aspirin), antacids, laxa- tives (senna, lactulose), vitamins, ferrous salts, Solid dosage forms etc. are considered relatively harmless, and can 1. Powders The drug is in a dry and finely be procured without a prescription. These are pulverised state. If the drug is for oral ‘non-prescription’ or ‘over-the-counter’ (OTC) drugs; can be sold even by grocery stores. administration, each dose has to be wrapped separately or packed in sachets; therefore this Orphan Drugs These are drugs or biological products for diagnosis/treatment/ prevention of a rare disease or condi- dosage form is inconvenient and unpopular tion, or a more common disease (endemic only in resource except when the quantity is several grams, poor countries or areas) for which there is no reasonable e.g. oral rehydration salts. Powders for topical CHAPTER 1 expectation that the cost of developing and marketing it will be recovered from the sales of that drug. As per Or- application (dusting powders) are supplied as phan Drug Amendment (1983) Act of USA, a rare disease/ bulk powders in metallic or plastic containers condition is one that affects less than 0.2 million people with holes for sprinkling. Effervescent powders in the USA. Though these drugs may be life saving for some patients, they are commercially difficult to obtain as contain granulated sod. bicarbonate and citric a medicinal product. Governments in developed countries or tartaric acid. They react when dissolved in offer tax benefits and other incentives to pharmaceutical companies for developing and marketing orphan drugs. water to liberate CO2 causing bubbling. Orphan drug status has been awarded to many drugs in the 2. Tablets The drug is powdered or granulated, USA, Europe and some other countries. Few examples of mixed with binding agents, and other drugs granted ‘Orphan Drug’ status are listed in the box. excipients, and compressed/moulded into Abridged list of Orphan drugs discoid, oblong or other shapes suitable for Azacitidine Icatibant swallowing. The tablet may be plain or sugar coated or film coated. Other specialized types Bevacizumab Iloprost of tablets are: Bortezomib Nilotinib Chewable tablets—can be chewed and Busulfan Paromomycin swallowed, ingredients must be pleasent Carboprost Rifaximin tasting. Clofazimine Rituximab Dispersible tablets—the tablet is dropped in Colchicine Sodium stibogluconate a small quantity of water, wherein it disperses Eltrombopag Sodium thiosulfate quickly; the solution is then gulped. Fomivirsen ThioTEPA Sublingual tablets—put under the tongue, the drug is rapidly absorbed from the mouth. Enteric coated tablet—the tablet is coated with Dosage forms of drugs a material that does not dissolve in the acidic Dosage form is a product suitable for administration medium of the stomach; the tablet disintegrates of a drug to a patient. Every active ingredient only on reaching the duodenum. (drug) has to be formulated by adding other Sustained/Extended release tablets—These substances (excipients, diluents, preservatives, contain drug particles which are coated to  8 GENERAL PHARMACOLOGY dissolve at different rates. The active ingredient oral, topical or parenteral administration. is made available for absorption over a longer Oral drug solutions often contain sweetening period of time. The duration of action of short and flavouring agents. Preservatives have to acting (2-6 hours) drugs can be extended to 12 be mostly added because shelf-life of watery hours or more. solutions is short. Controlled release tablets—A semipermeable 2. Suspensions are dispersion of insoluble membrane controls the release of the drug – drugs in water with the help of a suspending prolonging its duration of action. agent. Emulsions are uniform mixtures of two 3. Pills These are archaic dosage forms in which immiscible liquids (mostly oil and water) in the drug powder is mixed with honey/syrup which droplets of one (dispersed phase) are to make a sticky mass. This is then rolled into suspended in the other (continuous phase) spherical/oval bodies meant to be swallowed. with the help of an amphiphilic emulsifying The term is often loosely applied to tablets as agent. Milk is a naturally occurring emulsion. well. Both suspensions and emulsions tend to settle down on keeping; should be shaken thoroughly 4. Capsules These are water soluble cylindrical before use. containers made of gelatin which are filled with powdered or liquid medicament. The container 3. Elixirs are hydro-alcoholic solutions of drugs, dissolves on swallowing so that the drug is usually sweetened with syrup and flavoured by SECTION 1 released in the stomach. Soft gelatine capsules fruit extracts. Syrups have higher concentration of sugar and are thicker in consistency. Drugs dissolve very rapidly and generally contain that deteriorate in aqueous medium can be liquid medicament. Enteric coated capsules dispensed as ‘dry syrups’ which is reconstituted are designed to dissolve only on reaching the by adding water and shaking. The reconstituted ileum. Spansules are extended release capsules syrup must be used within a few days. Linctus which are packed with granules of the drug is a viscous syrupy liquid meant to be licked having different coatings to dissolve over a slowly for soothing the throat. It generally has range of time periods. menthol to impart cooling sensation, and an 5. Lozenges These are tablet-like bodies of antitussive. various shapes containing the drug along with 4. Drops These are relatively more concentrated a suitable gum, sweetening and flavouring solutions of medicaments meant for oral agents. They are to be retained in the mouth ingestion or external application to eye, nose or and allowed to dissolve slowly, providing the ear canal. Oral drops are the preferred dosage drug for local action in the mouth and throat. form for infants and young children. Eye/ 6. Suppositories These are conical bullet- shaped nasal drops should be isotonic. Eye drops need dosage forms for insertion into the anal canal, sterilization. Drops are supplied in vials with in which the drug is mixed with a mouldable a nozzle or alongwith a dropper for accurate firm base that melts at body temperature and dosing. releases the contained drug. Oval or suitably 5. Lotions These are solutions, suspensions or shaped bodies for vaginal insertion are called emulsions meant for external application to ‘pessaries’, while elongated pencil-like cones the skin without rubbing. They generally have meant for insertion into male or female urethra soothing, cooling, protective or emollient are called bougies. property and are better suited than creams or ointments for hairy skin. Liniments are Liquid dosage forms similar preparations which generally contain 1. Aqueous solutions They contain the drug counterirritants, and are to be rubbed on the dissolved in water, and may be meant for skin to relieve pain and cause rubefaction.  Introduction, Routes of DRUG Administration 9 6. Injections These are sterile solutions or and mucous membranes. Toothpastes are items suspensions in aqueous or oily medium for of personal hygiene, and medicated toothpastes subcutaneous or intramuscular administration. are extensively used in dentistry. Only aqueous solutions (not suspensions) 3. Gels The medicament is incorporated in are suitable for intravenous (i.v.) injection, a viscous colloidal solution of gelatin or because particles in suspension and oils similar material and is usually dispensed in injected i.v. can cause embolism. Injections collapsible tubes. They are meant for external are supplied in sealed glass ampoules or application to the skin or mucosa and provide air tight rubber capped vials. Ampoules are longer duration contact, but are nongreasy broken just before injection, and usually and washable with water. Gels are suitable for contain a single dose. Drug from the vial is application to hairy skin, and are commonly sucked in a syringe by piercing the rubber applied to oral ulcers because they are better cap. Vials may be single or multi-dose. Drugs retained than aqueous solutions. which are unstable in solution are supplied as dry powder vials. Sterile solvent is injected Inhalations in the vial just before it is to be administered, Drugs which are gases or volatile liquids can and the dissolved/suspended drug is then be administered by inhalation carried into air or sucked out into the syringe. Some drugs like oxygen with the help of a mouth piece, face mask, CHAPTER 1 insulin are also supplied in prefilled syringes hood or endotracheal tube. Nonvolatile liquids and pen injectors. Large volume i.v. infusions and fine particle solids can be aerosolized using are marketed in glass/polypropylene bottles. a metered dose inhaler, jet nebulizer, rotahaler or spinhaler for inhalation through the mouth. Semisolid dosage forms Pressurized metered dose inhalers (PMDIs) 1. Ointments These are greasy semisolid are hand-held devices which use a propellant, preparations meant for external application to mostly hydrofluoroalkane (HFA), and deliver a the skin, eye, nasal mucosa, ear or anal canal. specified dose of the drug in aerosol form per The drug is incorporated in an oily base, such actuation. Jet nebulizers produce a mist of the as soft or hard paraffin, wool fat, bee’s wax, drug solution generated by pressurized air or etc. Ointments are not suitable for oozing oxygen. Rotahaler is also a portable device in surfaces, because they are more occlusive and which a capsule (rotacap) containing very fine donot allow evaporation of water. Rather they powder of the drug is punctured during actuation are good for dry, chronic lesions. Creams are and the released particles are aerosolized by the similar to ointment but the base is a water in oil inspiratory airflow of the patient. A propellant can emulsion. The medicament is better absorbed also be used in some spin halers. Efficacy of the into the skin from creams than from ointments, aerosolized drug depends on the particle size: 1–5 and creams are cosmetically more acceptable mm diameter particles deposit on the bronchioles than ointments. and effectively deliver the drug. Larger particles 2. Pastes These are nongreasy preparations settle on the oropharynx, while 100 or 200 are not able to penetrate. However, capillaries (except those in brain) have large paracellular spaces (40 Å) and most drugs (even albumin) can filter through these (Fig. 2.8). As such, diffusion of drugs across capillaries is Fig. 2.4: Influence of pH difference on two sides of a dependent on rate of blood flow through them biological membrane on the steady-state distribution of rather than on lipid solubility of the drug or a weakly acidic drug with pKa = 6 pH of the medium. Implications of this consideration are: (a) Acidic drugs, e.g. aspirin (pKa 3.5) are Specialized transport largely unionized at acid gastric pH and are This can be carrier mediated or by vesicular absorbed from stomach, while bases, e.g. transport (endocytosis, exocytosis). atropine (pKa 10) are largely ionized and are absorbed only when they reach the intestines. Carrier transport (b) The unionized form of acidic drugs which All cell membranes express a host of transmem­ crosses the surface membrane of gastric mucosal brane proteins which serve as carriers or cell, reverts to the ionized form within the cell transporters for physiologically important ions,  18 GENERAL PHARMACOLOGY SECTION 1 Fig. 2.5: Illustration of different types of carrier mediated transport across biological membrane ABC—ATP-binding cassette transporter; SLC—Solute carrier transporter; M—Membrane A. Facilitated diffusion: the carrier (SLC) binds and moves the poorly diffusible substrate along its concentration gradient (high to low) and does not require energy B. Primary active transport: the carrier (ABC) derives energy directly by hydrolysing ATP and moves the substrate against its concentration gradient (low to high) C. Symport: the carrier moves the substrate ‘A’ against its concentration gradient by utilizing energy from downhill movement of another substrate ‘B’ in the same direction D. Antiport: the carrier moves the substrate ‘A’ against its concentration gradient and is energized by the downhill movement of another substrate ‘B’ in the opposite direction nutrients, metabolites, transmitters, etc. across through channels. Depending on requirement the membrane. At some sites, certain transport­ of energy, carrier transport is of two types: ers also translocate