Essentials of Medical Pharmacology PDF

 Essentials of Medical Pharmacology  Essentials of Medical Pharmacology Seventh Edition KD TRIPATHI MD Ex-Director-Professor and Head of Pharmacology Maulana Azad Medical College and associated...

 Essentials of Medical Pharmacology  Essentials of Medical Pharmacology Seventh 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 ® JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD New Delhi London Philadelphia 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. Jaypee Medical Inc. 83 Victoria Street London City of Knowledge, Bld. 237, Clayton The Bourse SW1H 0HW (UK) Panama City, Panama 111 South Independence Mall East Phone: +44-2031708910 Phone: +507-301-0496 Suite 835, Philadelphia, PA 19106, USA Fax: +02-03-0086180 Fax: +507-301-0499 Phone: + 267-519-9789 Email: [email protected] 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, Shaymali Shorakhute, Kathmandu Mohammadpur, Dhaka-1207 Nepal Bangladesh Phone: +00977-9841528578 Mobile: +08801912003485 Email: [email protected] Email: [email protected] Website: www.jaypeebrothers.com Website: www.jaypeedigital.com © 2013, KD Tripathi Managing Editor: M. Tripathi Inquiries for bulk sales may be solicited at: [email protected] All rights reserved. No part of this publication should be reproduced, stored in a retrieval system, or transmitted in any form or by any means: electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the author and the publisher. This book has been published in good faith that the material provided by author is original. Every effort is made to ensure accuracy of material, but the publisher, printer and author will not be held responsible for any inadvertent error(s). In case of any dispute, all legal matters to be settled under Delhi jurisdiction only. 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 ISBN: 978-93-5025-937-5 Printed at Ajanta Offset  Preface Medical pharmacology is a unique synthesis of basic pharmacology with clinical pharmacology and pharmacotherapeutics. The subject is highly dynamic. Developments are occurring both in defining molecular targets for drug action and finding targeted drugs, as well as in accruing credible evidence regarding the impact of different treatment modalities on therapeutic outcomes. These efforts have begun to crystallize into evidence based medicine and clear cut therapeutic guidelines. The present edition endeavours to amalgamate the developments with the core content of the subject. While the primary theme of the book outlined in the preface to the first edition is maintained, the successive editions have become more descriptive and more comprehensive. In preparing this edition, all chapters have been revisited and extensively updated. Latest therapeutic guidelines from authoritative sources like WHO, British National Formulary, National Formulary of India, as well as from eminent professional bodies have been incorporated, especially in areas like hypertension, dyslipidaemias, acute coronary syndromes, surgical prophylaxis, tuberculosis (including MDR-TB), MAC-infection, leprosy, HIV-AIDS, malaria, kala-azar, etc. Recent innovations have been highlighted, notably in antidiabetic drugs, psychopharmacological agents, antiplatelet drugs, treatment of inflammatory bowel disease, drugs affecting renin-angiotensin system, anticoagulants, antiviral (including anti-HIV) drugs, targeted anticancer drugs, etc. New drugs released in India have been included. Infrequently used drugs and those not available in India are presented briefly in extract type. Important points are summarized in boxes. Use of distinctive headings in a hierarchical order makes the text highly systematic. Representative trade names of drugs with available dosage forms are mentioned. Due emphasis is given to diseases prevalent in India and similar tropical countries, alongwith their current drug therapy. The most important objective of medical pharmacology is to train medical students in therapeutic decision making according to specific clinical problems in individual patients. A new feature ‘problem directed study’ has been included at the end of majority of chapters to give an exercise in therapeutic decision making for a realistic clinical scenario. The solutions provided in Appendix-1 explain how rational decisions could be arrived at. I thank students and other readers of this text for their valuable feedback and suggestions. All credit for existence of this book, especially the present edition, goes to Mr. Jitendar Pal Vij, the untiring Group Chairman and Mr. Ankit Vij (Managing Director) of M/s Jaypee Brothers. Meticulous typesetting by Ms. Sunita Katla and proof reading by Ms. Geeta Srivastava deserves special mention. Credit for improving the illustrations goes to Mr. Manoj Pahuja. The cooperation and editorial management of my wife is acknowledged. New Delhi KD Tripathi May 2013  Extract from Preface to the First Edition Pharmacology is both a basic and an applied science. It forms the backbone of rational therapeutics. 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’ approach 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 flow charts have been used with impunity. Selected chemical structures are depicted. Recent developments have been incorporated. However, discretion 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 10 3. Pharmacokinetics: Metabolism and Excretion of Drugs, Kinetics of Elimination 22 4. Pharmacodynamics: Mechanism of Drug Action; Receptor Pharmacology 37 5. Aspects of Pharmacotherapy, Clinical Pharmacology and Drug Development 61 6. Adverse Drug Effects 82 Section 2 Drugs Acting on Autonomic Nervous System 7a. Autonomic Nervous System: General Considerations 92 7b. Cholinergic System and Drugs 99 8. Anticholinergic Drugs and Drugs Acting on Autonomic Ganglia 113 9. Adrenergic System and Drugs 124 10. Antiadrenergic Drugs (Adrenergic Receptor Antagonists) and Drugs for Glaucoma 140 Section 3 Autacoids and Related Drugs 11. Histamine and Antihistaminics 159 12. 5-Hydroxytryptamine, its Antagonists and Drug Therapy of Migraine 170 13. Prostaglandins, Leukotrienes (Eicosanoids) and Platelet Activating Factor 181 14. Nonsteroidal Antiinflammatory Drugs and Antipyretic-Analgesics 192 15. Antirheumatoid and Antigout Drugs 210 viii CONTENTS Section 4 Respiratory System Drugs 16. Drugs for Cough and Bronchial Asthma 218 Section 5 Hormones and Related Drugs 17a. Introduction 234 17b. Anterior Pituitary Hormones 236 18. Thyroid Hormone and Thyroid Inhibitors 245 19. Insulin, Oral Hypoglycaemic Drugs and Glucagon 258 20. Corticosteroids 282 21. Androgens and Drugs for Erectile Dysfunction 296 22. Estrogens, Progestins and Contraceptives 306 23. Oxytocin and Other Drugs Acting on Uterus 329 24. Drugs Affecting Calcium Balance 335 Section 6 Drugs Acting on Peripheral (Somatic) Nervous System 25. Skeletal Muscle Relaxants 347 26. Local Anaesthetics 360 Section 7 Drugs Acting on Central Nervous System 27. General Anaesthetics 372 28. Ethyl and Methyl Alcohols 388 29. Sedative-Hypnotics 397 30. Antiepileptic Drugs 411 31. Antiparkinsonian Drugs 425 32. Drugs Used in Mental Illness: Antipsychotic and Antimanic Drugs 435 33. Drugs Used in Mental Illness: Antidepressant and Antianxiety Drugs 454 34. Opioid Analgesics and Antagonists 469 35. CNS Stimulants and Cognition Enhancers 486  CONTENTS ix Section 8 Cardiovascular Drugs 36a. Cardiac Electrophysiological Considerations 492 36b. Drugs Affecting Renin-Angiotensin System and Plasma Kinins 495 37. Cardiac Glycosides and Drugs for Heart Failure 512 38. Antiarrhythmic Drugs 526 39. Antianginal and Other Anti-ischaemic Drugs 539 40. Antihypertensive Drugs 558 Section 9 Drugs Acting on Kidney 41a. Relevant Physiology of Urine Formation 575 41b. Diuretics 579 42. Antidiuretics 593 Section 10 Drugs Affecting Blood and Blood Formation 43. Haematinics and Erythropoietin 599 44. Drugs Affecting Coagulation, Bleeding and Thrombosis 613 45. Hypolipidaemic Drugs and Plasma Expanders 634 Section 11 Gastrointestinal Drugs 46. Drugs for Peptic Ulcer and Gastroesophageal Reflux Disease 647 47. Antiemetic, Prokinetic and Digestant Drugs 661 48. Drugs for Constipation and Diarrhoea 672 Section 12 Antimicrobial Drugs 49. Antimicrobial Drugs: General Considerations 688 50. Sulfonamides, Cotrimoxazole and Quinolones 704 51. Beta-Lactam Antibiotics 716 x CONTENTS 52. Tetracyclines and Chloramphenicol (Broad-Spectrum Antibiotics) 733 53. Aminoglycoside Antibiotics 743 54. Macrolide, Lincosamide, Glycopeptide and Other Antibacterial Antibiotics; Urinary Antiseptics 752 55. Antitubercular Drugs 765 56. Antileprotic Drugs 780 57. Antifungal Drugs 787 58. Antiviral Drugs 798 59. Antimalarial Drugs 816 60. Antiamoebic and Other Antiprotozoal Drugs 836 61. Anthelmintic Drugs 849 Section 13 Chemotherapy of Neoplastic Diseases 62. Anticancer Drugs 857 Section 14 Miscellaneous Drugs 63. Immunosuppressant Drugs 878 64. Drugs Acting on Skin and Mucous Membranes 886 65. Antiseptics, Disinfectants and Ectoparasiticides 897 66. Chelating Agents 905 67. Vitamins 909 68. Vaccines and Sera 919 69. Drug Interactions 928 Appendices Appendix 1: Solution to Problem Directed Study 935 Appendix 2: List of Essential Medicines 957 Appendix 3: Prescribing in Pregnancy 962 Appendix 4: Drugs in Breastfeeding 965 Appendix 5: Drugs and Fixed Dose Combinations Banned in India$ (updated till Dec. 2012) 969 Selected References for Further Reading 971 Index 975  List of Abbreviations Ang-I/II/III Angiotensin I/II/III AQ Amodiaquine AA Amino acid AR Androgen receptor ABC ATP-binding cassette (transporter) ARB Angiotensin receptor blocker ABLC Amphotericin B lipid complex ARC AIDS related complex AB Antibody ARS Anti rabies serum AC Adenylyl cyclase ARV Antiretrovirus ACE Angiotensin II converting enzyme AS Artesunate ACh Acetylcholine 5-ASA 5-Amino salicyclic acid AChE Acetylcholinesterase Asc LH Ascending limb of Loop of Henle 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 -ARK  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 -Aminohydroxy methylisoxazole BOL 2-Bromolysergic acid diethylamide propionic acid BP Blood pressure ANC Acid neutralizing capacity BPN Bisphosphonate ANP Atrial natriuretic peptide BSA Body surface area ANS Autonomic nervous system BT Borderline tuberculoid leprosy ANUG Acute necrotizing ulcerative gingivitis BuChE Butyryl cholinesterase AP Action potential BW Body weight AP-1 Activator protein-1 BZD Benzodiazepine APC Antigen presenting cell APD Action potential duration C-10 Decamethonium aPTT Activated partial thromboplastin time CA Catecholamine xii ABBREVIATIONS CAB Combined androgen blockade DA Dopamine CaBP Calcium binding protein DA-B 12 Deoxyadenosyl cobalamin CAD Coronary artery disease DAD Delayed after-depolarization CAM Calmodulin DAG Diacyl glycerol cAMP 3', 5' Cyclic adenosine monophosphate DAM Diacetyl monoxime cap Capsule DAMP Diphenyl acetoxy-N-methyl piperidine CAR Conditioned avoidance response methiodide CAse Carbonic anhydrase DAT Dopamine transporter CAT Computerized axial tomography dDAVP Desmopressin CBF Cerebral blood flow DDS Diamino diphenyl sulfone (Dapsone) CBG Cortisol binding globulin DDT Dichloro diphenyl trichloroethane CBS Colloidal bismuth subcitrate DEC Diethyl carbamazine citrate CCB Calcium channel blocker DHA Dihydroartemisinin CCNU Chloroethyl cyclohexyl nitrosourea DHE Dihydroergotamine (lomustine) DHFA Dihydro folic acid CCR5 Chemokine coreceptor 5 DHFRase Dihydrofolate reductase CD Collecting duct/Cluster of differentiation DHP Dihydropyridine CDC Complement dependent cytotoxicity DHT Dihydrotestosterone CFTR Cystic fibrosis transport regulator DI Diabetes insipidus cGMP 3', 5' Cyclic guanosine monophosphate DIT Diiodotyrosine CGRP Calcitonin gene related peptide dl Decilitre CH Cholesterol DLE Disseminated lupus erythematosus ChE Cholinesterase DMA Dimethoxy amphetamine CHE Cholesterol ester DMARD Disease modifying antirheumatic drug Chy Chylomicron DMCM Dimethoxyethyl-carbomethoxy--carboline Chy. rem. Chylomicron remnants DMPA Depot medroxyprogesterone acetate CHF Congestive heart failure DMPP Dimethyl phenyl piperazinium CI Cardiac index DMT Dimethyl tryptamine/Divalent metal transporter CINV Chemotherapy induced nausea and vomiting 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 CRF Corticotropin releasing factor DVT Deep vein thrombosis CS Cycloserine DYN Dynorphin CSF Cerebrospinal fluid CTL Cytotoxic T-lymphocytes E Ethambutol CTZ Chemoreceptor trigger zone EACA Epsilon amino caproic acid CV Cardiovascular EAD Early after-depolarization 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 GM-CSF Granulocyte macrophage colony EDTA Ethylene diamine tetraacetic acid stimulating factor EEG Electroencephalogram GnRH Gonadotropin releasing hormone EGF Epidermal growth factor GPCR G-protein coupled receptor ELAM-1 Endothelial leukocyte adhesion molecule-1 G-6-PD Glucose-6-phosphate dehydrogenase -END -Endorphin 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 HAART Highly active antiretroviral therapy EPSP Excitatory postsynaptic potential Hb Haemoglobin ER Estrogen receptor HBV Hepatitis B virus ERP Effective refractory period HCG Human chorionic gonadotropin ES Extrasystole HDCV Human diploid cell vaccine ESR Erythrocyte sedimentation rate HDL High density lipoprotein ETEC Enterotoxigenic E. coli 5-HIAA 5-Hydroxyindole acetic acid Eto Ethionamide HES Hydroxyethyl starch HETE Hydroxyeicosa tetraenoic acid FA Folic acid HIV Human immunodeficiency virus FAD Flavin adenine dinucleotide HLA Human leucocyte antigen 5-FC 5-Flucytosine HMG-CoA Hydroxymethyl glutaryl coenzyme A FDC Fixed dose combination HMW High molecular weight FDT Fixed duration therapy (of leprosy) HPA axis Hypothalamo-pituitary-adrenal axis FEV1 Forced expiratory volume in 1 second HPETE Hydroperoxy eicosatetraenoic acid FFA Free fatty acid hr Hour FKBP FK 506 (tacrolimus) binding protein HR Heart rate FLAP Five-lipoxygenase activating protein HRIG Human rabies immuneglobulin FMN Favin mononucleotide HRT Hormone replacement therapy FP Ferroportin 5-HT 5-Hydroxytryptamine FQ Fluoroquinolone 5-HTP 5-Hydroxytryptophan FRase Folate reductase HVA Homovanillic acid FSH Follicle stimulating hormone 5-FU 5-Fluorouracil I Indeterminate leprosy IAP Islet amyloid polypeptide G Genetic IBD Inflammatory bowel disease GABA Gamma amino butyric acid IBS Irritable bowel syndrome GAT GABA-transporter ICAM-1 Intracellular adhesion molecule-1 GC Guanylyl cyclase ICSH Interstitial cell stimulating hormone GCP Good clinical practice i.d. Intradermal (injection) G-CSF Granulocyte colony stimulating factor IDL Intermediate density lipoprotein GDP Guanosine diphosphate IFN Interferon GERD Gastroesophageal reflux disease IG Immuneglobulin g.f. Glomerular filtration IGF Insulin-like growth factor g.f.r. Glomerular filtration rate IL Interleukin GH Growth hormone ILEU Isoleucine GHRH Growth hormone releasing hormone i.m. Intramuscular GHRIH Growth hormone release inhibitory hormone INH Isonicotinic acid hydrazide GIP Gastric inhibitory peptide/Glucose- INR International normalized ratio dependent insulinotropic polypeptide g.i.t. Gastrointestinal tract i.o.t. Intraocular tension GITS Gastrointestinal therapeutic system IP3 Inositol trisphosphate Glc Glucocorticoid IP4 Inositol tetrakisphosphate GLP Glucagon-like peptide IPSP Inhibitory postsynaptic potential GLUT Glucose transporter IPV Inactivated poliomyelitis vaccine xiv ABBREVIATIONS IRS Insulin response substrate MQ Mefloquine ISA Intrinsic sympathomimetic activity MRP2 Multidrug resistance associated protein-2 ISH Isolated systolic hypertension MRSA Methicillin resistant Staphylococcus aureus IU International unit MSH Melanocyte stimulating hormone IUCD Intrauterine contraceptive device MT Methyl transferase i.v. Intravenous mTOR Mammalian target of rapamycin Mtx Methotrexate JAK Janus-kinase mV millivolt Km Kanamycin MW Molecular weight KTZ Ketoconazole NA Noradrenaline NADP Nicotinamide adenine dinucleotide phosphate LA Local anaesthetic NADPH Reduced nicotinamide adenine dinucleotide LCAT Lecithin cholesterol acyl transferase phosphate LC3-KAT Long chain 3-ketoacyl-CoA-thiolase NAG N-acetyl glucosamine LDL Low density lipoprotein NAM N-acetyl muramic acid LES Lower esophageal sphincter NANC Nonadrenergic noncholinergic leu-ENK Leucine enkephalin NAPA N-acetyl procainamide LH Luteinizing hormone NAPQI N-acetyl-p-benzoquinoneimine liq Liquid NaSSA Noradrenergic and specific serotonergic LL Lepromatous leprosy antidepressant LMW Low molecular weight NAT N-acetyl transferase LOX Lipoxygenase NCEP National cholesterol education programme LSD Lysergic acid diethylamide NEE Norethindrone enanthate LT Leukotriene NET Norepinephrine transporter LVF Left ventricular failure NFAT Nuclear factor of activated T-cell MAbs Monoclonal antibodies NFB Nuclear factor B MAC Minimal alveolar concentration NIS Na+ (sodium)-iodide symporter MAC Mycobacterium avium complex NLEP National leprosy eradication programme MAO Monoamine oxidase NMDA N-methyl-D-aspartate MAP Muscle action potential nNOS Neural nitric oxide synthase MAPKinase Mitogen activated protein kinase NNRTI Nonnucleoside reverse transcriptase max Maximum inhibitor MBC Minimum bactericidal concentration NPY Neuropeptide-Y MBL Multibacillary leprosy NR Nicotinic receptor MCI Mild cognitive impairment N-REM Non rapid eye movement (sleep) MDI Manic depressive illness NRTI Nucleoside reverse transcriptase inhibitor MDMA Methylene dioxy methamphetamine NSAID Nonsteroidal antiinflammatory drug MDR Multidrug resistant NSTEMI Non ST-segment elevation myocardial MDT Multidrug therapy (of leprosy) infarction met-ENK Methionine enkephalin NTS Nucleus tractus solitarius mEq milliequivalent NVBDCP National vector borne diseases control methyl B12 Methyl cobalamin programme Mf Microfilariae NYHA New York Heart Association MF Multifactorial MHC Major histocompatibility complex OAT Organic anion transporter MHT Methylene dioxy methamphetamine OATP Organic anion transporting polypeptide MI Myocardial infarction OC Oral contraceptive MIC Minimal inhibitory concentration OCD Obsessive-compulsive disorder MIF Migration inhibitory factor OCT Organic cation transporter min Minimum OD Once daily MIT Monoiodo tyrosine OPG Osteoprotegerin MLCK Myosin light chain kinase OPV Oral poliomyelitis vaccine MMF Mycophenolate mofetil ORS Oral rehydration salt (solution) 6-MP 6-Mercaptopurine ORT Oral rehydration therapy MPPT Methylprednisolone pulse therapy MPTP 4-methyl-4-phenyltetrahydro pyridine PABA Paraamino benzoic acid PAE Post antibiotic effect  ABBREVIATIONS xv PAF Platelet activating factor 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 B PAS Paraamino salicylic acid RANKL RANK ligand PBI Protein bound iodine RAS Renin-angiotensin system PBPs Penicillin binding proteins RBC Red blood cells PBL Paucibacillary leprosy RBP Retinol binding protein PCA Patient controlled anaesthesia RC Respiratory centre PCEV Purified chick embryo cell vaccine (rabies) RE Reticuloendothelial PCI Percutaneous coronary intervention REM Rapid eye movement (sleep) PCPA Parachloro phenylalanine RGS Regulator of G-protein synthesis PD Parkinsons’s disease RIG Rabies immuneglobulin PDE Phosphodiesterase 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 PPA Phenyl propanolamine SERDs Selective estrogen receptor down regulators PPAR Paroxysome proliferator-activated SERM Selective estrogen receptor modulator receptor  SERT Serotonin transporter PPH Post partum haemorrhage SGA Second generation antihistaminic PPI Proton pump inhibitor SGLT Sodium-glucose transporter ppm Part per million SHBG Sex hormone binding globulin PPNG Penicillinase producing N. gonorrhoeae SIADH Syndrome of inappropriate ADH secretion PRA Plasma renin activity s.l. Sublingual PRF Prolactin releasing factor SLC Solute carrier PRIH Prolactin release inhibitory hormone SLE Systemic lupus erythematosus PSVT Paroxysmal supra-ventricular tachycardia SMON Subacute myelo-optic neuropathy PT Proximal tubule SNP Single nucleotide polymorphism PTCA Percutaneous transluminal coronary SN-PC Substantia nigra-pars compacta angioplasty SN-PR Substantia nigra-pars reticularis PTH Parathyroid hormone SNRI Serotonin and noradrenaline reuptake PTMA Phenyl trimethyl ammonium inhibitor PTP Post-tetanic potentiation s.o.s. as required PTSD Post-traumatic stress disorder S/P Sulfonamide + pyrimethamine PTZ Pentylenetetrazol SPF Sun protection factor PUV A Psoralen-Ultraviolet A SPS Simple partial seizures PVP Poly vinyl pyrrolidone SPRM Selective progesterone receptor modulator PVRV Purified verocell rabies vaccine SR Sustained release xvi ABBREVIATIONS SRS-A Slow reacting substance of anaphylaxis TR Thyroid hormone receptor SSG Sodium stibogluconate TRE Thyroid hormone response element SSI Surgical site infection TRH Thyrotropin releasing hormone SSRIs Selective serotonin reuptake inhibitors TSH Thyroid stimulating hormone STAT Signal transducer and activator of TT Tuberculoid leprosy transcription TTS Transdermal therapeutic system STEMI ST-segment elevation myocardial infarction TX Thromboxane StK Streptokinase U Unit SU Sulfonylurea UA Unstable angina SULT Sulfotransferase UDP Uridine diphosphate SUR Sulfonyl urea receptor UFH Unfractionated heparin susp Suspension UGDP University group diabetic programme SWD Shift work disorder UGT UDP-glucuronosyl transferase SWS Slow wave sleep USAN United States adopted name syr Syrup UT Urea transporter UTI Urinary tract infection t½ Half life T3 Triiodothyronine v Volt T4 Thyroxine V Volume of distribution tab Tablet VAL Valine TAB Typhoid, paratyphoid A and B vaccine VDR Vit D receptor TB Tubercle bacilli VES Ventricular extrasystole TBG Thyroxine binding globulin VF Ventricular fibrillation TCII Transcobalamin II VIP Vasoactive intestinal peptide TCAs Tricyclic antidepressants Vit Vitamin TCID50 Tissue culture infectious dose 50% VKOR Vitamin K epoxide reductase TDM Therapeutic drug monitoring VL Visceral leishmaniasis TDS Three times a day VLDL Very low density lipoprotein Tf Transferrin VMA Vanillyl mandelic acid TG Triglyceride VMAT Vesicular monoamine transporter 6-TG 6-Thioguanine VRE Vancomycin resistant enterococci TGF- Transforming growth factor  VRSA Vancomycin resistant Staphylococcus aureus THC Tetrahydrocannabinol VRUT Vasopressin regulated urea transporter THFA Tetrahydro folic acid VT Ventricular tachycardia Thz Thiacetazone vWF von Willebrand factor Thio TEPA Triethylene thiophosphoramide THR Threonine WBC White blood cells TIAs Transient ischaemic attacks WCVs Water channel containing vesicles TNF- Tumour necrosis factor  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 Z Pyrazinamide t.p.r. Total peripheral resistance ZE (syndrome) Zollinger-Ellison (syndrome)  SECTION 1 GENERAL PHARMACOLOGICAL PRINCIPLES Chapter 1 Introduction, Routes of Drug Administration INTRODUCTION a vast variety of highly potent and selective new drugs have been developed. The mechanism of Pharmacology action including molecular target of many drugs Pharmacology is the science of drugs (Greek: has been elucidated. This has been possible due Pharmacon—drug; logos—discourse in). In a to prolific growth of pharmacology which forms broad sense, it deals with interaction of exo- the backbone of rational therapeutics. genously administered chemical molecules with The two main divisions of pharmacology are living systems, or any single chemical substance pharmacodynamics and pharmacokinetics. which can produce a biological response is a ‘drug’. It encompasses all aspects of knowledge Pharmacodynamics (Greek: dynamis—power) about drugs, but most importantly those that are —What the drug does to the body. relevant to effective and safe use for medicinal This includes physiological and biochemical purposes. effects of drugs and their mechanism of action For thousands of years most drugs were crude at organ system/subcellular/macromolecular natural products of unknown composition and levels, e.g.—Adrenaline → interaction with adre- limited efficacy. Only the overt effects of these noceptors → G-protein mediated stimulation of substances on the body were rather imprecisely cell membrane bound adenylyl cyclase → increa- known, but how the same were produced was sed intracellular cyclic 3´,5´AMP → cardiac stimu- entirely unknown. Pharmacology as an experi- lation, hepatic glycogenolysis and hyperglycaemia, etc. mental science was ushered by Rudolf Buchheim who founded the first institute of pharmacology Pharmacokinetics (Greek: Kinesis—move- in 1847 in Germany. In the later part of the 19th ment)—What the body does to the drug. century, Oswald Schmiedeberg, regarded as the This refers to movement of the drug in and altera- ‘father of pharmacology’, together with his many tion of the drug by the body; includes absorption, disciples like J Langley, T Frazer, P Ehrlich, AJ distribution, binding/localization/storage, bio- Clark, JJ Abel propounded some of the fundamen- transformation and excretion of the drug, e.g. tal concepts in pharmacology. Since then drugs paracetamol is rapidly and almost completely have been purified, chemically characterized and absorbed orally attaining peak blood levels at 2 GENERAL PHARMACOLOGY 30–60 min; 25% bound to plasma proteins, widely Chemotherapy It is the treatment of systemic and almost uniformly distributed in the body infection/malignancy with specific drugs that have (volume of distribution ~ 1L/kg); extensively selective toxicity for the infecting organism/ SECTION 1 metabolized in the liver, primarily by glucuronide malignant cell with no/minimal effects on the host and sulfate conjugation into inactive metabolites cells. which are excreted in urine; has a plasma half life (t½) of 2–3 hours and a clearance value of Drugs in general, can thus be divided into: 5 ml/kg/min. Pharmacodynamic agents These are designed to have pharmacodynamic effects in the recipient. Drug (French: Drogue—a dry herb) It is the single active chemical entity present in a medicine Chemotherapeutic agents These are designed that is used for diagnosis, prevention, treatment/ to inhibit/kill invading parasite/malignant cell and cure of a disease. This disease oriented definition have no/minimal pharmacodynamic effects in the of drug does not include contraceptives or use recipient. of drugs for improvement of health. The WHO Pharmacy It is the art and science of compoun- (1966) has given a more comprehensive definition—“Drug is any substance or product ding and dispensing drugs or preparing suitable that is used or is intended to be used to modify dosage forms for administration of drugs to man or explore physiological systems or pathological or animals. It includes collection, identification, states for the benefit of the recipient.” purification, isolation, synthesis, standardization and quality control of medicinal substances. The The term ‘drugs’ is being also used to mean large scale manufacture of drugs is called Phar- addictive/abused/illicit substances. However, this maceutics. It is primarily a technological science. restricted and derogatory sense usage is unfor- tunate degradation of a time honoured term, and Toxicology It is the study of poisonous effect ‘drug’ should refer to a substance that has some of drugs and other chemicals (household, environ- therapeutic/diagnostic application. mental pollutant, industrial, agricultural, homi- Some other important aspects of pharmacology cidal) with emphasis on detection, prevention and are: treatment of poisonings. It also includes the study of adverse effects of drugs, since the same Pharmacotherapeutics It is the application substance can be a drug or a poison, depending of pharmacological information together with on the dose. knowledge of the disease for its prevention, mitigation or cure. Selection of the most appro- priate drug, dosage and duration of treatment DRUG NOMENCLATURE taking into account the specific features of a A drug generally has three categories of names: patient are a part of pharmacotherapeutics. (a) Chemical name It describes the substance Clinical pharmacology It is the scientific chemically, e.g. 1-(Isopropylamino)-3-(1-napht- study of drugs (both old and new) in man. It hyloxy) propan-2-ol for propranolol. This is includes pharmacodynamic and pharmacokinetic cumbersome and not suitable for use in investigation in healthy volunteers and in patients; prescribing. A code name, e.g. RO 15-1788 (later evaluation of efficacy and safety of drugs and named flumazenil) may be assigned by the comparative trials with other forms of treatment; manufacturer for convenience and simplicity surveillance of patterns of drug use, adverse before an approved name is coined. effects, etc. The aim of clinical pharmacology is to (b) Non-proprietary name It is the name accep- generate data for optimum use of drugs and the ted by a competent scientific body/authority, e.g. practice of ‘evidence based medicine’. the United States Adopted Name (USAN) by the  INTRODUCTION, ROUTES OF DRUG ADMINISTRATION 3 USAN council. Similarly, there is the British However, when it is important to ensure Approved name (BAN) of a drug. The non- consistency of the product in terms of quality proprietary names of newer drugs are kept uniform and bioavailability, etc. and especially when CHAPTER 1 by an agreement to use the Recommended official control over quality of manufactured International Nonproprietary Name (rINN) in all products is not rigorous, it is better to prescribe member countries of the WHO. The BAN of older by the dependable brand name. drugs as well has now been modified to be commensurate with rINN. However, many older DRUG COMPENDIA drugs still have more than one non-proprietary These are compilations of information on drugs names, e.g. ‘meperidine’ and ‘pethidine’ or in the form of monographs; without going into ‘lidocaine’ and ‘lignocaine’ for the same drugs. the theoretical concepts, mechanisms of action Until the drug is included in a pharmacopoeia, the and other aspects which help in understanding nonproprietary name may also be called the the subject. Pharmacopoeias and Formularies are approved name. After its appearance in the official broughtout by the Government in a country, hold publication, it becomes the official name. legal status and are called official compendia. In common parlance, the term generic name In addition, some non-official compendia are is used in place of nonproprietary name. Etymolo- published by professional bodies, which are gically this is incorrect: ‘generic’ should be applied supplementary and dependable sources of to the chemical or pharmacological group (or information about drugs. genus) of the compound, e.g. phenothiazines, tricyclic antidepressants, aminoglycoside antibio- Pharmacopoeias They contain description of tics, etc. However, this misnomer is widely chemical structure, molecular weight, physical and accepted and used even in official parlance. chemical characteristics, solubility, identification and assay methods, standards of purity, storage (c) Proprietary (Brand) name It is the name conditions and dosage forms of officially approved assigned by the manufacturer(s) and is his property drugs in a country. They are useful to drug or trade mark. One drug may have multiple pro- manufacturers and regulatory authorities, but not prietary names, e.g. ALTOL, ATCARDIL, ATECOR, to doctors, most of whom never see a ATEN, BETACARD, LONOL, TENOLOL, TENORMIN for pharmacopoeia. Examples are Indian (IP), British atenolol from different manufacturers. Brand (BP), European (Eur P), United States (USP) names are designed to be catchy, short, easy to pharmacopoeias. remember and often suggestive, e.g. LOPRESOR suggesting drug for lowering blood pressure. Brand Formularies Generally produced in easily names generally differ in different countries, e.g. carried booklet form, they list indications, dose, timolol maleate eye drops are marketed as TIMOPTIC dosage forms, contraindications, precautions, in USA but as GLUCOMOL in India. Even the adverse effects and storage of selected drugs that same manufacturer may market the same drug are available for medicinal use in a country. Drugs under different brand names in different countries. are categorized by their therapeutic class. Some In addition, combined formulations have their own rational fixed-dose drug combinations are multiple brand names. This is responsible for much included. A brief commentary on the drug class confusion in drug nomenclature. and clinical conditions in which they are used There are many arguments for using the generally preceeds specifics of individual drugs. nonproprietary name in prescribing: uniformity, Brief guidelines for treatment of selected convenience, economy and better comprehension conditions are provided. While British National (propranolol, sotalol, timolol, pindolol, Formulary (BNF) also lists brand names metoprolol, acebutolol, atenolol are all β blockers, with costs, the National Formulary of India (NFI) but their brand names have no such similarity). does not include these. Most formularies have 4 GENERAL PHARMACOLOGY informative appendices as well. Formularies can (b) It should be available in a form in which quality, including be considerably helpful to prescribers. bioavailability, and stability on storage can be assured. (c) Its choice should depend upon pattern of prevalent Martindale: The Complete Drug Reference diseases; availability of facilities and trained personnel; SECTION 1 financial resources; genetic, demographic and environmental (Extrapharmacopoeia) Published every 2–3 factors. years by the Royal Pharmaceutical Society of Great (d) In case of two or more similar medicines, choice should Britain, this non-official compendium is an be made on the basis of their relative efficacy, safety, quality, exhaustive and updated compilation of unbiased price and availability. Cost-benefit ratio should be a major consideration. information on medicines used/registered all over (e) Choice may also be influenced by comparative pharma- the world. It includes new launches and contains cokinetic properties and local facilities for manufacture and pharmaceutical, pharmacological as well as storage. therapeutic information on drugs, which can serve (f) Most essential medicines should be single compounds. Fixed ratio combination products should be included only as a reliable reference book. when dosage of each ingradient meets the requirements of Physicians Desk Reference (PDR) and Drug: a defined population group, and when the combination has a proven advantage in therapeutic effect, safety, adherence Facts and Comparisons (both from USA), etc. or in decreasing the emergence of drug resistance. are other useful non-official compendia. (g) Selection of essential medicines should be a continuous process which should take into account the changing priorities for public health action, epidemiological conditions as well ESSENTIAL MEDICINES (DRUGS) as availability of better medicines/formulations and progress CONCEPT in pharmacological knowledge. (h) Recently, it has been emphasized to select essential The WHO has defined Essential Medicines medicines based on rationally developed treatment guidelines. (drugs) as “those that satisfy the priority healthcare To guide the member countries, the WHO needs of the population. They are selected with brought out its first Model List of Essential Drugs due regard to public health relevance, evidence along with their dosage forms and strengths in on efficacy and safety, and comparative cost 1977 which could be adopted after suitable effectiveness. Essential medicines are intended modifications according to local needs. This has to be available within the context of functioning been revised from time to time and the current health systems at all times and in adequate is the 17th list (2011). India produced its National amounts, in appropriate dosage forms, with Essential Drugs List in 1996 and has revised assured quality and adequate information, and at it in 2011 with the title “National List of Essential a price the individual and the community can Medicines”. This includes 348 medicines which afford. are considered to be adequate to meet the priority It has been realized that only a handful of healthcare needs of the general population of the medicines out of the multitude available can meet country. An alphabetical compilation of the WHO the health care needs of majority of the people as well as National essential medicines is presented in any country, and that many well tested and as Appendix-2. cheaper medicines are equally (or more) Adoption of the essential medicines list for efficacious and safe as their newer more expensive procurement and supply of medicines, especially congeners. For optimum utilization of resources, in the public sector healthcare system, has resulted in improved availability of medicines, cost saving governments (especially in developing countries) and more rational use of drugs. should concentrate on these medicines by identifying them as Essential medicines. The Prescription and non-prescription drugs WHO has laid down criteria to guide selection As per drug rules, majority of drugs including of an essential medicine. all antibiotics must be sold in retail only against (a) Adequate data on its efficacy and safety should be available a prescription issued to a patient by a registered from clinical studies. medical practitioner. These are called ‘prescription  INTRODUCTION, ROUTES OF DRUG ADMINISTRATION 5 drugs’, and in India they have been placed in LOCAL ROUTES the schedule H of the Drugs and Cosmetic Rules These routes can only be used for localized lesions (1945) as amended from time to time. However, at accessible sites and for drugs whose systemic CHAPTER 1 few drugs like simple analgesics (paracetamol absorption from these sites is minimal or absent. aspirin), antacids, laxatives (senna, lactulose), Thus, high concentrations are attained at the vitamins, ferrous salts, etc. are considered relatively desired site without exposing the rest of the body. harmless, and can be procured without a Systemic side effects or toxicity are consequently prescription. These are ‘non-prescription’ or ‘over- absent or minimal. For drugs (in suitable dosage the-counter’ (OTC) drugs; can be sold even by forms) that are absorbed from these sites/routes, grocery stores. the same can serve as systemic route of adminis- Orphan Drugs These are drugs or biological products tration, e.g. glyceryl trinitrate (GTN) applied on for diagnosis/treatment/ prevention of a rare disease or the skin as ointment or transdermal patch. The condition, or a more common disease (endemic only in resource poor countries) for which there is no reasonable local routes are: expectation that the cost of developing and marketing it will 1. Topical This refers to external application be recovered from the sales of that drug. The list includes of the drug to the surface for localized action. It sodium nitrite, fomepizole, liposomal amphotericin B, miltefosine, rifabutin, succimer, somatropin, digoxin immune is often more convenient as well as encouraging Fab (digoxin antibody), liothyronine (T3) and many more. to the patient. Drugs can be efficiently delivered Though these drugs may be life saving for some patients, to the localized lesions on skin, oropharyngeal/ they are commercially difficult to obtain as a medicinal nasal mucosa, eyes, ear canal, anal canal or vagina product. Governments in developed countries offer tax benefits and other incentives to pharmaceutical companies for in the form of lotion, ointment, cream, powder, developing and marketing orphan drugs (e.g. Orphan Drug rinse, paints, drops, spray, lozengens, suppositories Act in USA). or pesseries. Nonabsorbable drugs given orally for action on g.i. mucosa (sucralfate, vancomycin), ROUTES OF DRUG ADMINISTRATION inhalation of drugs for action on bronchi (salbutamol, cromolyn sodium) and irrigating Most drugs can be administered by a variety of solutions/jellys (povidone iodine, lidocaine) routes. The choice of appropriate route in a given applied to urethra are other forms of topical situation depends both on drug as well as patient medication. related factors. Mostly common sense consi- 2. Deeper tissues Certain deep areas can be derations, feasibility and convenience dictate the approached by using a syringe and needle, but route to be used. the drug should be in such a form that systemic Routes can be broadly divided into those for absorption is slow, e.g. intra-articular injection (a) Local action and (b) Systemic action. (hydrocortisone acetate in knee joint), infiltration Factors governing choice of route around a nerve or intrathecal injection (lidocaine), retrobulbar injection (hydrocortisone acetate 1. Physical and chemical properties of the drug (solid/ behind the eyeball). liquid/gas; solubility, stability, pH, irritancy). 2. Site of desired action—localized and approach- 3. Arterial supply Close intra-arterial injec- able or generalized and not approachable. tion is used for contrast media in angiography; 3. Rate and extent of absorption of the drug from anticancer drugs can be infused in femoral or different routes. brachial artery to localise the effect for limb 4. Effect of digestive juices and first pass metabolism on the drug. malignancies. 5. Rapidity with which the response is desired (routine treatment or emergency). SYSTEMIC ROUTES 6. Accuracy of dosage required (i.v. and inhalational can provide fine tuning). The drug administered through systemic routes 7. Condition of the patient (unconscious, vomiting). is intended to be absorbed into the blood stream 6 GENERAL PHARMACOLOGY and distributed all over, including the site of action, inconvenient and embarrassing; absorption is through circulation (see Fig. 1.1). slower, irregular and often unpredictable, though diazepam solution and paracetamol suppository 1. Oral SECTION 1 are rapidly and dependably absorbed from the Oral ingestion is the oldest and commonest mode rectum in children. Drug absorbed into external of drug administration. It is safer, more convenient, haemorrhoidal veins (about 50%) bypasses liver, does not need assistance, noninvasive, often but not that absorbed into internal haemorrhoidal painless, the medicament need not be sterile and veins. Rectal inflammation can result from irritant so is cheaper. Both solid dosage forms (powders, drugs. Diazepam, indomethacin, paracetamol, tablets, capsules, spansules, dragees, moulded ergotamine and few other drugs are some times tablets, gastrointestinal therapeutic systems— given rectally. GITs) and liquid dosage forms (elixirs, syrups, emulsions, mixtures) can be given orally. 4. Cutaneous Highly lipid soluble drugs can be applied over Limitations of oral route of administration the skin for slow and prolonged absorption. The Action of drugs is slower and thus not suitable for liver is also bypassed. The drug can be incorpo- emergencies. rated in an ointment and applied over specified Unpalatable drugs (chloramphenicol) are difficult to administer; drug may be filled in capsules to area of skin. Absorption of the drug can be circumvent this. enhanced by rubbing the preparation, by using May cause nausea and vomiting (emetine). an oily base and by an occlusive dressing. Cannot be used for uncooperative/unconscious/ vomiting patient. Transdermal therapeutic systems (TTS) Absorption of drugs may be variable and erratic; These are devices in the form of adhesive patches certain drugs are not absorbed (streptomycin). Others are destroyed by digestive juices (penicillin G, of various shapes and sizes (5–20 cm2) which insulin) or in liver (GTN, testosterone, lidocaine). deliver the contained drug at a constant rate into systemic circulation via the stratum corneum (Fig. 2. Sublingual (s.l.) or buccal 1.2). The drug (in solution or bound to a polymer) The tablet or pellet containing the drug is placed is held in a reservoir between an occlusive backing under the tongue or crushed in the mouth and film and a rate controlling micropore membrane, spread over the buccal mucosa. Only lipid soluble the under surface of which is smeared with an and non-irritating drugs can be so administered. adhesive impregnated with priming dose of the Absorption is relatively rapid—action can be pro- drug. The adhesive layer is protected by another duced in minutes. Though it is somewhat incon- film that is to be peeled off just before applica- venient, one can spit the drug after the desired tion. The drug is delivered at the skin surface effect has been obtained. The chief advantage by diffusion for percutaneous absorption into is that liver is bypassed and drugs with high first circulation. The micropore membrane is such that pass metabolism can be absorbed directly into rate of drug delivery to skin surface is less than systemic circulation. Drugs given sublingually the slowest rate of absorption from the skin. This are—GTN, buprenorphine, desamino-oxytocin. offsets any variation in the rate of absorption according to the properties of different sites. As 3. Rectal such, the drug is delivered at a constant and Certain irritant and unpleasant drugs can be put predictable rate irrespective of site of application. into rectum as suppositories or retention enema Usually chest, abdomen, upper arm, lower back, for systemic effect. This route can also be buttock or mastoid region are utilized. used when the patient is having recurrent vomiting Transdermal patches of GTN, fentanyl, or is unconscious. However, it is rather nicotine and estradiol are available in India, while  INTRODUCTION, ROUTES OF DRUG ADMINISTRATION 7 CHAPTER 1 Fig. 1.1: Vascular pathway of drugs absorbed from various systemic routes of administration and sites of first pass metabolism Note: Total drug absorbed orally is subjected to first pass metabolism in intestinal wall and liver, while approximately half of that absorbed from rectum passes through liver. Drug entering from any systemic route is exposed to first pass metabolism in lungs, but its extent is minor for most drugs. 8 GENERAL PHARMACOLOGY drugs like insulin, as well as to bypass the blood- brain barrier. 7. Parenteral SECTION 1 (Par—beyond, enteral—intestinal) Conventionally, parenteral refers to administration by injection which takes the drug directly into the tissue fluid or blood without having to cross the enteral mucosa. The limitations of oral administration are circumvented. Fig. 1.2: Illustration of a transdermal drug delivery system Drug action is faster and surer (valuable in emergencies). Gastric irritation and vomiting are those of isosorbide dinitrate, hyoscine, and not provoked. Parenteral routes can be employed clonidine are marketed elsewhere. For different even in unconscious, uncooperative or vomiting drugs, TTS have been designed to last for patient. There are no chances of interference by 1–3 days. Though more expensive, they provide food or digestive juices. Liver is bypassed. smooth plasma concentrations of the drug without Disadvantages of parenteral routes are—the fluctuations; minimize interindividual variations preparation has to be sterilized and is costlier, (drug is subjected to little first pass metabolism) the technique is invasive and painful, assistance and side effects. They are also more convenient— of another person is mostly needed (though self many patients prefer transdermal patches to oral injection is possible, e.g. insulin by diabetics), tablets of the same drug; patient compliance is there are chances of local tissue injury and, in better. Local irritation and erythema occurs in general, parenteral route is more risky than oral. some, but is generally mild; can be minimized The important parenteral routes are: by changing the site of application each time by rotation. Discontinuation has been necessary in (i) Subcutaneous (s.c.) The drug is deposited 2–7% cases. in the loose subcutaneous tissue which is richly supplied by nerves (irritant drugs cannot be 5. Inhalation injected) but is less vascular (absorption is slower Volatile liquids and gases are given by inhalation than intramuscular). Only small volumes can be for systemic action, e.g. general anaesthetics. injected s.c. Self-injection is possible because deep Absorption takes place from the vast surface of penetration is not needed. This route should be alveoli—action is very rapid. When administra- avoided in shock patients who are vasocons- tion is discontinued the drug diffuses back and tricted—absorption will be delayed. Repository is rapidly eliminated in expired air. Thus, control- (depot) preparations that are aqueous suspensions led administration is possible with moment to can be injected for prolonged action. Some special moment adjustment. Irritant vapours (ether) cause forms of this route are: inflammation of respiratory tract and increase (a) Dermojet In this method needle is not used; secretion. a high velocity jet of drug solution is projected 6. Nasal from a microfine orifice using a gun like imple- The mucous membrane of the nose can readily ment. The solution passes through the superficial absorb many drugs; digestive juices and liver are layers and gets deposited in the subcutaneous bypassed. However, only certain drugs like GnRH tissue. It is essentially painless and suited for mass agonists and desmopressin applied as a spray or inoculations. nebulized solution have been used by this route. (b) Pellet implantation The drug in the form This route is being tried for some other peptide of a solid pellet is introduced with a trochar and  INTRODUCTION, ROUTES OF DRUG ADMINISTRATION 9 cannula. This provides sustained release of the drug reaches directly into the blood stream and drug over weeks and months, e.g. DOCA, effects are produced immediately (great value in testosterone. emergency). The intima of veins is insensitive CHAPTER 1 (c) Sialistic (nonbiodegradable) and bio- and drug gets diluted with blood, therefore, even degradable implants Crystalline drug is highly irritant drugs can be injected i.v., but hazards packed in tubes or capsules made of suitable are—thrombophlebitis of the injected vein and materials and implanted under the skin. Slow and necrosis of adjoining tissues if extravasation occurs. uniform leaching of the drug occurs over months These complications can be minimized by diluting providing constant blood levels. The nonbio- the drug or injecting it into a running i.v. line. degradable implant has to be removed later on Only aqueous solutions (not suspensions, because but not the biodegradable one. This has been tried drug particles can cause embolism) are to be for hormones and contraceptives (e.g. NORPLANT). injected i.v. and there are no depot preparations for this route. Chances of causing air embolism (ii) Intramuscular (i.m.) The drug is injected is another risk. The dose of the drug required in one of the large skeletal muscles—deltoid, is smallest (bioavailability is 100%) and even large triceps, gluteus maximus, rectus femoris, etc. volumes can be infused. One big advantage with Muscle is less richly supplied with sensory nerves (mild irritants can be injected) and is more this route is—in case response is accurately measur- vascular (absorption of drugs in aqueous solution able (e.g. BP) and the drug short acting (e.g. is faster). It is less painful, but self injection is sodium nitroprusside), titration of the dose with often impracticable because deep penetration is the response is possible. However, this is the most needed. Depot preparations (oily solutions, risky route—vital organs like heart, brain, etc. aqueous suspensions) can be injected by this route. get exposed to high concentrations of the drug. Intramuscular injections should be avoided in (iv) Intradermal injection The drug is anticoagulant treated patients, because it can injected into the skin raising a bleb (e.g. BCG produce local haematoma. vaccine, sensitivity testing) or scarring/multiple (iii) Intravenous (i.v.) The drug is injected puncture of the epidermis through a drop of the as a bolus (Greek: bolos–lump) or infused slowly drug is done. This route is employed for specific over hours in one of the superficial veins. The purposes only. ) PROBLEM DIRECTED STUDY 1.1. A 5-year-old child is brought to the hospital with the complaint of fever, cough, breathlessness and chest pain. On examination he is found to be dull, but irritable with fast pulse (116/min), rapid breathing (RR 50/min) and indrawing of lower chest during inspiration, wheezing, crepitations and mild dehydration. Body temperature is 40°C (104°F). The paediatrician makes a provisional diagnosis of acute pneumonia and orders relevant haematological as well as bacteriological investig- ations. He decides to institute antibiotic therapy. (a) In case he selects an antibiotic which can be given orally as well as by i.m. or i.v. injection, which route of administration will be most appropriate in this case? (b) Should the paediatrician administer the antibiotic straight away or should he wait for the laboratory reports? (see Appendix-1 for solution)  Chapter 2 Pharmacokinetics: Membrane Transport, Absorption and Distribution of Drugs Pharmacokinetics is the quantitative study of drug group of cholesterol) of these are oriented at the movement in, through and out of the body. The two surfaces and the nonpolar hydrocarbon chains overall scheme of pharmacokinetic processes is are embedded in the matrix to form a continuous depicted in Fig. 2.1. The intensity of response sheet. This imparts high electrical resistance is related to concentration of the drug at the site and relative impermeability to the membrane. of action, which in turn is dependent on its Extrinsic and intrinsic protein molecules are pharmacokinetic properties. Pharmacokinetic adsorbed on the lipid bilayer (Fig. 2.2). Glyco- considerations, therefore, determine the route(s) proteins or glycolipids are formed on the surface of administration, dose, latency of onset, time by attachment to polymeric sugars, aminosugars of peak action, duration of action and frequency or sialic acids. The specific lipid and protein of administration of a drug. composition of different membranes differs All pharmacokinetic processes involve trans- according to the cell or the organelle type. The port of the drug across biological membranes. proteins are able to freely float through the membrane: associate and organize or vice versa. Biological membrane This is a bilayer (about Some of the intrinsic ones, which extend through 100 Å thick) of phospholipid and cholesterol the full thickness of the membrane, surround fine molecules, the polar groups (glyceryl phosphate aqueous pores. Paracellular spaces or channels attached to ethanolamine/choline or hydroxyl also exist between certain epithelial/endothelial Fig. 2.1: Schematic depiction of pharmacokinetic processes  MEMBRANE TRANSPORT, ABSORPTION AND DISTRIBUTION OF DRUGS 11 CHAPTER 2 Fig. 2.2: Illustration of the organisation of biological membrane cells. Other adsorbed proteins have enzymatic, Fig. 2.3: Illustration of passive diffusion and filtration across the lipoidal biological membrane with aqueous carrier, receptor or signal transduction properties. pores Lipid molecules also are capable of lateral move- ment. Thus, biological membranes are highly ionized at acidic as well as alkaline pH). The dynamic structures. ionization of a weak acid HA is given by the Drugs are transported across the membranes by: equation: (a) Passive diffusion and filtration [A¯ ] (b) Specialized transport pH = pKa + log —–—...(1) [HA] Passive diffusion The drug diffuses across the membrane in the pKa is the negative logarithm of acidic disso- direction of its concentration gradient, the ciation constant of the weak electrolyte. If the membrane playing no active role in the process. concentration of ionized drug [A¯ ] is equal to This is the most important mechanism for majority concentration of unionized drug [HA], then of drugs; drugs are foreign substances [A¯ ] (xenobiotics), and specialized mechanisms are —–— = 1 [HA] developed by the body primarily for normal metabolites. since log 1 is 0, under this condition Lipid soluble drugs diffuse by dissolving in pH = pKa...(2) the lipoidal matrix of the membrane (Fig. 2.3), Thus, pKa is numerically equal to the pH at which the rate of transport being proportional to the the drug is 50% ionized. lipid : water partition coefficient of the drug. A more lipid-soluble drug attains higher concentra- If pH is increased by 1 scale, then— tion in the membrane and diffuses quickly. Also, log [A¯ ]/[HA] = 1 or [A¯ ]/[HA] = 10 greater the difference in the concentration of the drug on the two sides of the membrane, faster Similarly, if pH is reduced by 1 scale, then— is its diffusion. [A¯ ]/[HA] = 1/10 Influence of pH Most drugs are weak electro- Thus, weakly acidic drugs, which form salts lytes, i.e. their ionization is pH dependent (contrast with cations, e.g. s