Essentials of Medical Pharmacology, 6th Edition PDF

 Essentials of Medical Pharmacology  Essentials of Medical Pharmacology Sixth Edition KD TRIPATHI MD Ex-Director-Professor and Head of Pharmacology Maulana Azad Medical Colleg...

 Essentials of Medical Pharmacology  Essentials of Medical Pharmacology Sixth Edition KD TRIPATHI MD Ex-Director-Professor and Head of Pharmacology Maulana Azad Medical College and associated LN and GB Pant Hospitals New Delhi ® JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD New Delhi Ahmedabad Bengaluru Chennai Hyderabad Kochi Kolkata Lucknow Mumbai Nagpur Published by Jitendar P Vij Jaypee Brothers Medical Publishers (P) Ltd Corporate Office 4838/24 Ansari Road, Daryaganj, New Delhi - 110002, India, +91-11-43574357 Registered Office B-3 EMCA House, 23/23B Ansari Road, Daryaganj, New Delhi 110 002, India Phones: +91-11-23272143, +91-11-23272703, +91-11-23282021, +91-11-23245672, Rel: +91-11-32558559 Fax: +91-11-23276490, +91-11-23245683 e-mail: [email protected], Visit our website: www.jaypeebrothers.com Branches  2/B, Akruti Society, Jodhpur Gam Road Satellite Ahmedabad 380 015 Phones: +91-79-26926233, Rel: +91-79-32988717 Fax: +91-79-26927094 e-mail: [email protected]  202 Batavia Chambers, 8 Kumara Krupa Road, Kumara Park East Bengaluru 560 001 Phones: +91-80-22285971, +91-80-22382956, +91-80-22372664, Rel: +91-80-32714073 Fax: +91-80-22281761 e-mail: [email protected]  282 IIIrd Floor, Khaleel Shirazi Estate, Fountain Plaza, Pantheon Road Chennai 600 008 Phones: +91-44-28193265, +91-44-28194897, Rel: +91-44-32972089 Fax: +91-44-28193231 e-mail: [email protected]  4-2-1067/1-3, 1st Floor, Balaji Building, Ramkote Cross Road Hyderabad 500 095 Phones: +91-40-66610020, +91-40-24758498, Rel:+91-40-32940929 Fax:+91-40-24758499, e-mail: [email protected]  No. 41/3098, B & B1, Kuruvi Building, St. Vincent Road Kochi 682 018, Kerala Phones: +91-484-4036109, +91-484-2395739, +91-484-2395740 e-mail: [email protected]  1-A Indian Mirror Street, Wellington Square Kolkata 700 013 Phones: +91-33-22651926, +91-33-22276404, +91-33-22276415, Rel: +91-33-32901926 Fax: +91-33-22656075, e-mail: [email protected]  Lekhraj Market III, B-2, Sector-4, Faizabad Road, Indira Nagar Lucknow 226 016 Phones: +91-522-3040553, +91-522-3040554 e-mail: [email protected]  106 Amit Industrial Estate, 61 Dr SS Rao Road, Near MGM Hospital, Parel Mumbai 400012 Phones: +91-22-24124863, +91-22-24104532, Rel: +91-22-32926896 Fax: +91-22-24160828, e-mail: [email protected]  “KAMALPUSHPA” 38, Reshimbag, Opp. Mohota Science College, Umred Road Nagpur 440 009 (MS) Phone: Rel: +91-712-3245220, Fax: +91-712-2704275 e-mail: [email protected] Essentials of Medical Pharmacology, 6th edition Managing Editor: M. Tripathi © 2008, KD Tripathi No rights reserved. Any part of this publication can 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. In fact, I encourage you to do so :P 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. First Edition: 1985 Fifth Edition: 2008 Second Edition: 1988 Sixth Edition: 2003 Third Edition: 1994 ISBN 81-8448-085-7 Fourth Edition: 1999 Updated Reprint: 2001 Typeset at JPBMP typesetting unit  Preface The unprecedented pace of developments over the recent years in the field of drugs (medicines) has further emphasized the relevance of Pharmacology to health professionals. Molecular targets of drug action are being defined at greater resolution, refining new drugs design. Practice of medicine is transforming from ‘experience (impression) based’ to ‘evidence based’, since more and more credible evidence from well designed clinical studies is now available on the impact of different treatments on mortality, morbidity and other therapeutic outcomes. The present edition is oriented to reflect the contemporary advancements. Adopting the ‘prototype drug’ approach and a structured, systematic and user-friendly format, the actions, mechanisms, kinetics and toxicological aspects of drugs are described along with the pharmacological basis of their use and role/status in the therapy of various diseases/conditions. By a unique synthesis of pharmacology with clinical medicine, the book is designed to be useful both to the uninitiated medical student, as well as to prescribing physicians. All chapters have been updated to include recently introduced drugs and published information. Latest therapeutic guidelines from leading professional bodies, WHO and National Health Programmes have been incorporated, especially in areas like hypertension, hyperlipidaemias, stroke prevention, surgical prophylaxis, tuberculosis, leprosy, malaria, and HIV-AIDS. Recent developments have been highlighted, notably in hormone replacement therapy, aromatase inhibitors, bisphosphonates, selective COX-2 inhibitors, atypical antipsychotics, therapy of diabetes mellitus, heart failure, acute coronary syndromes, Alzheimer’s disease, parkinsonism, glaucoma, kala azar, etc. A chapter is devoted to the principles of ‘rational use of medicines’, elements of ‘evidence based medicine’ and the process of ‘new drug development’ to reflect current importance of these topics. Another new chapter compiles the clinically important drug interactions. Some other topics added are drug transporters, pharmacogenomics, pharmacovigilance, expiry date of pharmaceuticals, single enantiomer drugs, biological response modifiers, prescribing in pregnancy, etc. New drugs marketed in India till mid 2007 are included, while obsolete ones are deleted. Infrequently used drugs and those not available in India are described briefly in extract type. Important points are summarized in boxes. Leading trade names with dosage forms are given. Emphasis is placed on the profile of diseases and drug use in India and other tropical countries, so as to be particularly useful to students and doctors in these regions; a need not well addressed by many texts. Thanks are due to my colleagues and students for their valuable feedback and suggestions. As previously, the major impetus for this edition has come from Shri J.P. Vij, the ever agile Chairman of Jaypee Brothers. Commendable type setting, proof reading and improvement in illustrations has been done respectively by Ms Sunita Katla, Ms Geeta Srivastava and Mr Manoj. The editorial management and moral support of my wife has been a boon. New Delhi KD Tripathi 5th Nov. 2007 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............................................................................... 3 2. Pharmacokinetics: Membrane Transport, Absorption and Distribution of Drugs...............11 3. Pharmacokinetics: Metabolism and Excretion of Drugs, Kinetics of Elimination................23 4. Pharmacodynamics: Mechanism of Drug Action; Receptor Pharmacology...........................37 5. Aspects of Pharmacotherapy; Clinical Pharmacology and Drug Development....................59 6. Adverse Drug Effects......................................................................................................................78 Section 2 Drugs Acting on Autonomic Nervous System Autonomic Nervous System: General Considerations..............................................................88 7. Cholinergic System and Drugs......................................................................................................93 8. Anticholinergic Drugs and Drugs Acting on Autonomic Ganglia........................................ 106 9. Adrenergic System and Drugs................................................................................................... 116 10. Antiadrenergic Drugs (Adrenergic Receptor Antagonists) and Drugs for Glaucoma..................................................................................................................... 132 Section 3 Autacoids and Related Drugs 11. Histamine and Antihistaminics................................................................................................. 151 12. 5-Hydroxytryptamine, its Antagonists and Drug Therapy of Migraine.............................. 162 13. Prostaglandins, Leukotrienes (Eicosanoids) and Platelet Activating Factor........................ 173 14. Nonsteroidal Antiinflammatory Drugs and Antipyretic-Analgesics................................... 184 15. Antirheumatoid and Antigout Drugs........................................................................................ 202 viii Contents Section 4 Respiratory System Drugs 16. Drugs for Cough and Bronchial Asthma................................................................................... 213 Section 5 Hormones and Related Drugs Introduction................................................................................................................................... 231 17. Anterior Pituitary Hormones...................................................................................................... 233 18. Thyroid Hormone and Thyroid Inhibitors............................................................................... 242 19. Insulin, Oral Hypoglycaemic Drugs and Glucagon................................................................ 254 20. Corticosteroids............................................................................................................................... 275 21. Androgens and Drugs for Erectile Dysfunction...................................................................... 288 22. Estrogens, Progestins and Contraceptives................................................................................ 297 23. Oxytocin and Other Drugs Acting on Uterus........................................................................... 319 24. Drugs Affecting Calcium Balance............................................................................................. 325 Section 6 Drugs Acting on Peripheral (Somatic) Nervous System 25. Skeletal Muscle Relaxants.......................................................................................................... 339 26. Local Anaesthetics........................................................................................................................ 351 Section 7 Drugs Acting on Central Nervous System 27. General Anaesthetics................................................................................................................... 365 28. Ethyl and Methyl Alcohols.......................................................................................................... 380 29. Sedative-Hypnotics...................................................................................................................... 388 30. Antiepileptic Drugs...................................................................................................................... 401 31. Antiparkinsonian Drugs.............................................................................................................. 414 32. Drugs Used in Mental Illness: Antipsychotic and Antimanic Drugs................................... 423 33. Drugs Used in Mental Illness: Antidepressant and Antianxiety Drugs.............................. 439 34. Opioid Analgesics and Antagonists.......................................................................................... 453 35. CNS Stimulants and Cognition Enhancers............................................................................... 469  Contents ix Section 8 Cardiovascular Drugs Cardiac Electrophysiological Considerations........................................................................... 476 36. Drugs Affecting Renin-Angiotensin System and Plasma Kinins......................................... 479 37. Cardiac Glycosides and Drugs for Heart Failure..................................................................... 493 38. Antiarrhythmic Drugs.................................................................................................................. 508 39. Antianginal and Other Anti-ischaemic Drugs......................................................................... 521 40. Antihypertensive Drugs.............................................................................................................. 539 Section 9 Drugs Acting on Kidney Relevant Physiology of Urine Formation.................................................................................. 557 41. Diuretics......................................................................................................................................... 561 42. Antidiuretics.................................................................................................................................. 574 Section 10 Drugs Affecting Blood and Blood Formation 43. Haematinics and Erythropoietin................................................................................................ 581 44. Drugs Affecting Coagulation, Bleeding and Thrombosis...................................................... 593 45. Hypolipidaemic Drugs and Plasma Expanders...................................................................... 612 Section 11 Gastrointestinal Drugs 46. Drugs for Peptic Ulcer.................................................................................................................. 627 47. Drugs for Emesis, Reflux and Digestive Disorders................................................................ 639 48. Drugs for Constipation and Diarrhoea...................................................................................... 651 Section 12 Antimicrobial Drugs 49. Antimicrobial Drugs: General Considerations........................................................................ 667 50. Sulfonamides, Cotrimoxazole and Quinolones....................................................................... 682 51. Beta-Lactam Antibiotics............................................................................................................... 694 x Contents 52. Tetracyclines and Chloramphenicol (Broad-Spectrum Antibiotics).................................... 710 53. Aminoglycoside Antibiotics........................................................................................................ 719 54. Macrolide, Lincosamide, Glycopeptide and Other Antibacterial Antibiotics; Urinary Antiseptics....................................................................................................................... 727 55. Antitubercular Drugs................................................................................................................... 739 56. Antileprotic Drugs........................................................................................................................ 751 57. Antifungal Drugs.......................................................................................................................... 757 58. Antiviral Drugs.............................................................................................................................. 767 59. Antimalarial Drugs....................................................................................................................... 780 60. Antiamoebic and Other Antiprotozoal Drugs.......................................................................... 797 61. Anthelmintic Drugs...................................................................................................................... 808 Section 13 Chemotherapy of Neoplastic Diseases 62. Anticancer Drugs.......................................................................................................................... 819 Section 14 Miscellaneous Drugs 63. Immunosuppressants, Gene Therapy...................................................................................... 837 64. Drugs Acting on Skin and Mucous Membranes..................................................................... 845 65. Antiseptics, Disinfectants and Ectoparasiticides..................................................................... 857 66. Chelating Agents........................................................................................................................... 865 67. Vitamins......................................................................................................................................... 869 68. Vaccines and Sera........................................................................................................................ 879 69. Drug Interactions.......................................................................................................................... 889 Selected References for Further Reading................................................................................. 897 Appendix 1: List of Essential Medicines..................................................................................... 903 Appendix 2: Prescribing in Pregnancy........................................................................................ 908 Appendix 3: Drugs in Breastfeeding............................................................................................ 911 Appendix 4: Drugs and Fixed Dose Combinations Banned in India........................................ 915 Index................................................................................................................................................ 917  List of Abbreviations A-I/II/III Angiotensin I/II/III Asc LH Ascending limb of Loop of Henle AA Amino acid AT-III Antithrombin III ABC ATP-binding cassette (transporter) ATG Antithymocyte globulin ABLC Amphotericin B lipid complex ATP Adenosine triphosphate AB Antibody ATPase Adenosine triphosphatase AC Adenylyl cyclase ATPIII Adult treatment panel III ACE Angiotensin II converting enzyme ATS Antitetanic serum ACh Acetylcholine A-V Atrioventricular AChE Acetylcholinesterase AVP Arginine vasopressin ACT Artemisinin-based combination therapy AZT Zidovudine ACTH Adrenocorticotropic hormone AD Alzheimer’s disease BAL British anti lewisite ADE Adverse drug event BAN British approved name ADH Antidiuretic hormone BB Borderline leprosy ADP Adenosine diphosphate BCG Bacillus Calmette Guérin Adr Adrenaline BCNU Bischloroethyl nitrosourea (Carmustine) ADR Adverse drug reaction BD Twice daily ADS Anti diphtheritic serum β-ARK β adrenergic receptor kinase AES Atrial extrasystole BHC Benzene hexachloride AF Atrial fibrillation BHP Benign hypertrophy of prostate AFl Atrial flutter BI Bacillary index AG Antigen BL Borderline lepromatous leprosy AGS Antigasgangrene serum BMD Bone mineral density AHG Antihaemophilic globulin BMR Basal metabolic rate AI Aromatase inhibitor BNP Brain nartriuretic peptide AIDS Acquired immunodeficiency syndrome BOL 2-Bromolysergic acid diethylamide AIP Aldosterone induced protein BP Blood pressure ALA Alanine BPN Bisphosphonate Am Amikacin BRMs Biologic response modifiers AMA Antimicrobial agent BSA Body surface area AMB Amphotericin B BT Borderline tuberculoid leprosy amp Ampoule BuChE Butyryl cholinesterase AMP Adenosine mono phosphate BW Body weight AMPA α-Aminohydroxy methylisoxazole BZD Benzodiazepine propionic acid ANC Acid neutralizing capacity C-10 Decamethonium ANP Atrial natriuretic peptide CA Catecholamine ANS Autonomic nervous system CaBP Calcium binding protein AP Action potential CAD Coronary artery disease APC Antigen presenting cell CAM Calmodulin APD Action potential duration cAMP 3', 5' Cyclic adenosine monophosphate aPTT Activated partial thromboplastin time cap Capsule ARB Angiotensin receptor blocker CAR Conditioned avoidance response ARC AIDS related complex CAse Carbonic anhydrase ARS Anti rabies serum CAT Computerized axial tomography ARV Antiretrovirus CBF Cerebral blood flow 5-ASA 5-Amino salicyclic acid CBG Cortisol binding globulin xii Abbreviations CBS Colloidal bismuth subcitrate DI Diabetes insipidus CCB Calcium channel blocker DIT Diiodotyrosine CCNU Chloroethyl cyclohexyl nitrosourea dl Decilitre (lomustine) DLE Disseminated lupus erythematosus CD Collecting duct DMA Dimethoxy amphetamine CFTR Cystic fibrosis transport regulator DMARD Disease modifying antirheumatic drug cGMP 3', 5' Cyclic guanosine monophosphate DMPA Depot medroxyprogesterone acetate CGRP Calcitonin gene related peptide DMPP Dimethyl phenyl piperazinium CH Cholesterol DMT Dimethyl tryptamine/Divalent metal ChE Cholinesterase transporter CHE Cholesterol ester DNA Deoxyribose nucleic acid Chy Chylomicron DOC Deoxycholate Chy. rem. Chylomicron remnants DOCA Desoxy corticosterone acetate CHF Congestive heart failure DOM Dimethoxymethyl amphetamine CI Cardiac index dopa Dihydroxyphenyl alanine CL Clearance DOPAC 3, 4, Dihydroxyphenyl acetic acid CLcr Creatinine clearance DOSS Dioctyl sulfosuccinate CMI Cell mediated immunity DOTS Directly observed treatment short course CMV Cytomegalovirus DPD Dihydropyrimidine dehydrogenase CNS Central nervous system DPT Diphtheria-pertussis-tetanus triple antigen c.o. Cardiac output DRC Dose-response curve CoEn-A Coenzyme-A DT Distal tubule COMT Catechol-O-methyl transferase DT-DA Diphtheria-tetanus double antigen COX Cyclooxygenase d-TC d-Tubocurarine c.p.s. Cycles per second DTIC Dacarbazine CPS Complex partial seizures DTPA Diethylene triamine pentaacetic acid CPZ Chlorpromazine DYN Dynorphin CRABP Cellular retinoic acid binding protein CRBP Cellular retinol binding protein E Ethambutol CRF Corticotropin releasing factor EACA Epsilon amino caproic acid CSF Cerebrospinal fluid EAD Early after-depolarization CTZ Chemoreceptor trigger zone e.c.f. Extracellular fluid CV Cardiovascular ECG Electrocardiogram CVP Central venous pressure ECT Electroconvulsive therapy CVS Cardiovascular system ED Erectile dysfunction CWD Cell wall deficient EDTA Ethylene diamine tetraacetic acid CYP450 Cytochrome P450 EEG Electroencephalogram Cys Cycloserine ELAM-1 Endothelial leukocyte adhesion molecule-1 β-END β-Endorphin DA Dopamine ENS Enteric nervous system DA-B 12 Deoxyadenosyl cobalamin ENT Extraneuronal amine transporter DAD Delayed after-depolarization EPEC Enteropathogenic E. coli DAG Diacyl glycerol EPO Erythropoietin DAM Diacetyl monoxime EPP End plate potential DAMP Diphenyl acetoxy-N-methyl piperidine ERP Effective refractory period methiodide EPSP Excitatory postsynaptic potential DAT Dopamine transporter ER Estrogen receptor dDAVP Desmopressin ES Extrasystole DDS Diamino diphenyl sulfone (Dapsone) ESR Erythrocyte sedimentation rate DDT Dichloro diphenyl trichloroethane ETEC Enterotoxigenic E. coli DEC Diethyl carbamazine citrate Etm Ethionamide DHA Dihydroartemisinin DHE Dihydroergotamine FA Folic acid DHFA Dihydro folic acid FAD Flavin adenine dinucleotide DHFRase Dihydrofolate reductase 5-FC 5-Flucytosine DHP Dihydropyridine FDT Fixed duration therapy (of leprosy) DHT Dihydrotachysterol FEV1 Forced expiratory volume in 1 second  Abbreviations xiii FFA Free fatty acid 5-HTP 5-Hydroxytryptophan FMN Favin mononucleotide HVA Homovanillic acid FP Ferroportin FQ Fluoroquinolone I Indeterminate leprosy FRase Folate reductase IBD Inflammatory bowel disease FSH Follicle stimulating hormone IBS Irritable bowel syndrome 5-FU 5-Fluorouracil ICAM-1 Intracellular adhesion molecule-1 ICSH Interstitial cell stimulating hormone G Genetic i.d. Intradermal (injection) GABA Gamma amino butyric acid IDL Intermediate density lipoprotein GAT GABA-transporter IG Immuneglobulin GC Guanylyl cyclase IGF Insulin-like growth factor GCP Good clinical practice IL Interleukin G-CSF Granulocyte colony stimulating factor ILEU Isoleucine GDP Guanosine diphosphate i.m. Intramuscular GERD Gastroesophageal reflux disease INH Isonicotinic acid hydrazide g.f. Glomerular filtration INR International normalized ratio g.f.r. Glomerular filtration rate i.o.t. Intraocular tension GH Growth hormone IP 3 Inositol trisphosphate GHRH Growth hormone releasing hormone IP 4 Inositol tetrakisphosphate GHRIH Growth hormone release inhibitory hormone IPSP Inhibitory postsynaptic potential GIP Gastric inhibitory peptide/Glucose- IPV Inactivated poliomyelitis vaccine dependent insulinotropic polypeptide IRS Insulin response substrate g.i.t. Gastrointestinal tract ISA Intrinsic sympathomimetic activity GITS Gastrointestinal therapeutic system ISH Isolated systolic hypertension GLP Glucagon-like peptide IU International unit GLUT Glucose transporter IUCD Intrauterine contraceptive device GM-CSF Granulocyte macrophage colony stimulating i.v. Intravenous factor GnRH Gonadotropin releasing hormone JAK Janus-kinase GPCR G-protein coupled receptor G-6-PD Glucose-6-phosphate dehydrogenase Kmc Kanamycin GPI Globus pallidus interna KTZ Ketoconazole GTCS Generalised tonic-clonic seizures GTN Glyceryl trinitrate LA Local anaesthetic GTP Guanosine triphosphate LCAT Lecithin cholesterol acyl transferase LDL Low density lipoprotein H Isoniazid (Isonicotinic acid hydrazide) LES Lower esophageal sphincter HAART Highly active antiretroviral therapy leu-ENK Leucine enkephalin Hb Haemoglobin LH Luteinizing hormone HBV Hepatitis B virus liq Liquid HCG Human chorionic gonadotropin LL Lepromatous leprosy HDCV Human diploid cell vaccine LMW Low molecular weight HDL High density lipoprotein LOX Lipoxygenase 5-HIAA 5-Hydroxyindole acetic acid LSD Lysergic acid diethylamide HES Hydroxyethyl starch LT Leukotriene HETE Hydroxyeicosa tetraenoic acid LVF Left ventricular failure HIV Human immunodeficiency virus MAC Minimal alveolar concentration HMG-CoA Hydroxymethyl glutaryl coenzyme A MAC Mycobacterium avium complex HMW High molecular weight MAO Monoamine oxidase HPA axis Hypothalamo-pituitary-adrenal axis MAP Muscle action potential HPETE Hydroperoxy eicosatetraenoic acid MAPKinase Mitogen activated protein kinase hr Hour max Maximum HR Heart rate MBC Minimum bactericidal concentration HRIG Human rabies immuneglobulin MBL Multibacillary leprosy HRT Hormone replacement therapy MDI Manic depressive illness 5-HT 5-Hydroxytryptamine MDMA Methylene dioxy methamphetamine xiv Abbreviations MDR Multidrug resistant NTS Nucleus tractus solitarius MDT Multidrug therapy (of leprosy) NVBDCP National vector borne diseases control met-ENK Methionine enkephalin programme mEq milliequivalent NYHA New York Heart Association methyl B12 Methyl cobalamin Mf Microfilariae OAT Organic anion transporter MF Multifactorial OATP Organic anion transporting polypeptide MHC Major histocompatibility complex OC Oral contraceptive MHT Methylene dioxy methamphetamine OCD Obsessive-compulsive disorder MI Myocardial infarction OCT Organic cation transporter MIC Minimal inhibitory concentration OD Once daily OPG Osteoprotegerin MID Multi infarct dementia OPV Oral poliomyelitis vaccine MIF Migration inhibitory factor ORS Oral rehydration salt (solution) min Minimum ORT Oral rehydration therapy MIT Monoiodo tyrosine MLCK Myosin light chain kinase PABA Paraamino benzoic acid MMF Mycophenolate mofetil PAE Post antibiotic effect 6-MP 6-Mercaptopurine PAF Platelet activating factor MPPT Methylprednisolone pulse therapy 2-PAM Pralidoxime MPTP 4-methyl-4-phenyltetrahydro pyridine PAN Primary afferent neurone MRP2 Multidrug resistance associated protein-2 PAS Paraamino salicylic acid MRSA Methicillin resistant Staphylococcus aureus PBI Protein bound iodine MSH Melanocyte stimulating hormone PBPs Penicillin binding proteins Mtx Methotrexate PBL Paucibacillary leprosy mV millivolt PCA Patient controlled anaesthesia MW Molecular weight PCEV Purified chick embryo cell vaccine (rabies) PCI Percutaneous coronary intervention NA Noradrenaline PCPA Parachloro phenylalanine NABQI N-acetyl-p-benzoquinoneimine PD Parkinsons’s disease NADP Nicotinamide adenine dinucleotide PDE Phosphodiesterase phosphate PEMA Phenylethyl malonamide NADPH Reduced nicotinamide adenine dinucleotide PEP Postexposure prophylaxis phosphate PF Purkinje fibre NAG N-acetyl glucosamine PFOR Pyruvate: ferredoxin oxidoreductase NAM N-acetyl muramic acid PG Prostaglandin PGI2 Prostacyclin NANC Nonadrenergic noncholinergic Pgp P-glycoprotein NAPA N-acetyl procainamide PI Protease inhibitor NaSSA Noradrenergic and specific serotonergic PIG Phosphatidyl inositol glycan antidepressant PIP 2 Phosphatidyl inositol-4,5-bisphosphate NAT N-acetyl transferase PKA Protein kinase: cAMP dependent NCEP National cholesterol education programme PKC Protein kinase C NEE Norethindrone enanthate PL A Phospholipase A NET Norepinephrine transporter PLC Phospholipase C NFAT Nuclear factor of activated T-cell Pl. ph. Platelet phospholipid NLEP National leprosy eradication programme PnG Penicillin G NMDA N-methyl-D-aspartate POMC Pro-opio melanocortin nNOS Neural nitric oxide synthase PP Partial pressure NNRTI Nonnucleoside reverse transcriptase inhibitor PPA Phenyl propanolamine NPY Neuropeptide-Y PPARγ Paroxysome proliferator-activated receptor γ NR Nicotinic receptor PPH Post partum haemorrhage N-REM Non rapid eye movement (sleep) PPI Proton pump inhibitor NRTI Nucleoside reverse transcriptase inhibitor ppm Part per million NSAID Nonsteroidal antiinflammatory drug PPNG Penicillinase producing N. gonorrhoeae NSTEMI Non ST-segment elevation myocardial PRA Plasma renin activity infarction PRF Prolactin releasing factor  Abbreviations xv PRIH Prolactin release inhibitory hormone SNP Single nucleotide polymorphism PSVT Paroxysmal supra-ventricular tachycardia SN-PC Substantia nigra-pars compacta PT Proximal tubule SN-PR Substantia nigra-pars reticularis PTCA Percutaneous transluminal coronary SNRI Serotonin and noradrenaline reuptake angioplasty inhibitor PTH Parathyroid hormone s.o.s. as required PTMA Phenyl trimethyl ammonium S/P Sulfonamide + pyrimethamine PTP Post-tetanic potentiation SPF Sun protection factor PTZ Pentylenetetrazol SPS Simple partial seizures PUV A Psoralen-Ultraviolet A SR Sustained release SRS-A Slow reacting substance of anaphylaxis PVP Poly vinyl pyrrolidone SSG Sodium stibogluconate PVRV Purified verocell rabies vaccine SSI Surgical site infection SSRIs Selective serotonin reuptake inhibitors QID Four times a day STAT Signal transducer and activator of transcription STEMI ST-segment elevation myocardial infarction R Rifampin (Rifampicin) StK Streptokinase RANK Receptor for activation of nuclear factor κB SULT Sulfotransferase RANKL RANK ligand SUR Sulfonyl urea receptor RAS Renin-angiotensin system susp Suspension RBC Red blood cells SWS Slow wave sleep RBP Retinol binding protein syr Syrup RC Respiratory centre RE Reticuloendothelial t½ Half life REM Rapid eye movement (sleep) T3 Triiodothyronine RIG Rabies immuneglobulin T4 Thyroxine RIMA Reversible inhibitor of MAO-A tab Tablet rINN Recommended international nonproprietary TAB Typhoid, paratyphoid A and B vaccine name TB Tubercle bacilli RMP Resting membrane potential TBG Thyroxine binding globulin RNA Ribonucleic acid TCII Transcobalamin II RNTCP Revised National Tuberculosis Control TCAs Tricyclic antidepressants Programme TCID50 Tissue culture infectious dose 50% RP Refractory period TDM Therapeutic drug monitoring RTF Resistance transfer factor TDS Three times a day Tf Transferrin RXR Retinoid X receptor TG Triglyceride RyR Ryanodine receptor 6-TG 6-Thioguanine THC Tetrahydrocannabinol S Streptomycin THFA Tetrahydro folic acid SA Sinoauricular (node) Thio TEPA Triethylene thiophosphoramide SAARD Slow acting antirheumatic drug THR Threonine SABE Subacute bacterial endocarditis TIAs Transient ischaemic attacks s.c. Subcutaneous TNF-α Tumour necrosis factor α SCC Short course chemotherapy (of tuberculosis) TOD Target organ damage SCh Succinylcholine TOF Train of four SCID Severe combined immunodeficiency disease t-PA Tissue plasminogen activator SERDs Selective estrogen receptor down regulators TPMT Thiopurine methyl transferase SERM Selective estrogen receptor modulator t.p.r. Total peripheral resistance SERT Serotonin transporter TR Thyroid hormone receptor SGA Second generation antihistaminic TRE Thyroid hormone response element SGLT Sodium-glucose transporter TRH Thyrotropin releasing hormone SHBG Sex hormone binding globulin TSH Thyroid stimulating hormone s.l. Sublingual TT Tuberculoid leprosy SLC Solute carrier TTS Transdermal therapeutic system SLE Systemic lupus erythematosus TX Thromboxane SMON Subacute myelo-optic neuropathy Tzn Thiacetazone xvi Abbreviations U Unit VMA Vanillyl mandelic acid UDP Uridine diphosphate VMAT Vesicular monoamine transporter UFH Unfractionated heparin VRE Vancomycin resistant enterococci UGDP University group diabetic programme VRSA Vancomycin resistant Staphylococcus aureus UGT UDP-glucuronosyl transferase VRUT Vasopressin regulated urea transporter USAN United States adopted name VT Ventricular tachycardia UTI Urinary tract infection vWF von Willebrand factor v Volt WBC White blood cells V Volume of distribution WCVs Water channel containing vesicles VAL Valine WHO World Health Organization VDR Vit D receptor WPW Wolff-Parkinson-White syndrome VES Ventricular extrasystole VF Ventricular fibrillation XDR-TB Extensively drug resistant-TB VIP Vasoactive intestinal peptide Vit Vitamin Z Pyrazinamide VLDL Very low density lipoprotein ZE (syndrome) Zollinger-Ellison (syndrome) 2 General Pharmacology Section 1 CHAPTER 1 Introduction, Routes of Drug Administration INTRODUCTION of many drugs has been elucidated. This has been possible due to prolific growth of pharmacology Pharmacology which forms the backbone of rational thera- Pharmacology is the science of drugs (Greek: peutics. Pharmacon—drug; logos—discourse in). In a broad The two main divisions of pharmacology are sense, it deals with interaction of exogenously pharmacodynamics and pharmacokinetics. administered chemical molecules (drugs) with living systems. It encompasses all aspects of Pharmacodynamics (Greek: dynamis—power) knowledge about drugs, but most importantly —What the drug does to the body. those that are relevant to effective and safe use for This includes physiological and biochemical medicinal 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 hypergly- mental science was ushered by Rudolf Buchheim caemia, etc. who founded the first institute of pharmacology Pharmacokinetics (Greek: Kinesis—movement) in 1847 in Germany. In the later part of the 19th — 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, distribution, binding/localization/storage, bio- AJ Clark, JJ Abel propounded some of the fun- transformation and excretion of the drug, e.g. damental concepts in pharmacology. Since then paracetamol is rapidly and almost completely drugs have been purified, chemically characteri- absorbed orally attaining peak blood levels at zed and a vast variety of highly potent and 30–60 min; 25% bound to plasma proteins, widely selective new drugs have been developed. The and almost uniformly distributed in the body mechanism of action including molecular target (volume of distribution ~ 1L/kg); extensively 4 General Pharmacology Section 1 metabolized in the liver, primarily by glucuronide have selective toxicity for the infecting organism/ and sulfate conjugation into inactive metabolites malignant cell with no/minimal effects on the which are excreted in urine; has a plasma half host cells. life (t½) of 2–3 hours and a clearance value of 5 ml/kg/min. Drugs in general, can thus be divided into: Drug (French: Drogue—a dry herb) It is the single Pharmacodynamic agents These are designed active chemical entity present in a medicine that is to have pharmacodynamic effects in the recipient. used for diagnosis, prevention, treatment/cure of Chemotherapeutic agents These are designed a disease. This disease oriented definition of drug to inhibit/kill invading parasite/ malignant cell does not include contraceptives or use of drugs and have no/minimal pharmacodynamic effects for improvement of health. The WHO (1966) has in the recipient. given a more comprehensive definition—“Drug is Pharmacy It is the art and science of compoun- any substance or product that is used or is intended ding and dispensing drugs or preparing suitable to be used to modify or explore physiological dosage forms for administration of drugs to man systems or pathological states for the benefit of the or animals. It includes collection, identification, recipient.” purification, isolation, synthesis, standardization The term ‘drugs’ is being also used to mean and quality control of medicinal substances. The addictive/abused/illicit substances. However, large scale manufacture of drugs is called Phar- this restricted and derogatory sense usage is maceutics. It is primarily a technological science. unfortunate degradation of a time honoured term, and ‘drug’ should refer to a substance that has Toxicology It is the study of poisonous effect of some therapeutic/diagnostic application. drugs and other chemicals (household, environ- mental pollutant, industrial, agricultural, homi- Some other important aspects of pharmacology cidal) with emphasis on detection, prevention are: and treatment of poisonings. It also includes the Pharmacotherapeutics It is the application of study of adverse effects of drugs, since the same pharmacological information together with substance can be a drug or a poison, depending knowledge of the disease for its prevention, on the dose. 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 patient are a part of pharmacotherapeutics. A drug generally has three categories of names: Clinical pharmacology It is the scientific study (a) Chemical name It describes the substance of drugs in man. It includes pharmacodynamic chemically, e.g. 1-(Isopropylamino)-3-(1-naphthy- and pharmacokinetic investigation in healthy loxy) propan-2-ol for propranolol. This is cumber- volunteers and in patients; evaluation of efficacy some and not suitable for use in prescribing. A code and safety of drugs and comparative trials with name, e.g. RO 15-1788 (later named flumazenil) other forms of treatment; surveillance of patterns may be assigned by the manufacturer for con- of drug use, adverse effects, etc. venience and simplicity before an approved name The aim of clinical pharmacology is to is coined. generate data for optimum use of drugs and the (b) Non-proprietary name It is the name accep- practice of ‘evidence based medicine’. ted by a competent scientific body/authority, e.g. Chemotherapy It is the treatment of systemic the United States Adopted Name (USAN) by the infection/malignancy with specific drugs that USAN council. Similarly, there is the British Chapter 1 Introduction 5 Approved name (BAN) of a drug. The non- but their brand names have no such similarity). proprietary names of newer drugs are kept However, when it is important to ensure uniform by an agreement to use the Recommen- consistency of the product in terms of quality and ded International Nonproprietary Name (rINN) bioavailability, etc. and especially when official in all member countries of the WHO. The BAN of control over quality of manufactured products is older drugs as well has now been modified to be not rigorous, it is better to prescribe by the commensurate with rINN. However, many older dependable brand name. drugs still have more than one non-proprietary names, e.g. ‘meperidine’ and ‘pethidine’ or ESSENTIAL DRUGS (MEDICINES) CONCEPT ‘lidocaine’ and ‘lignocaine’ for the same drugs. Until the drug is included in a pharmacopoeia, The WHO has defined Essential Drugs* (medicines) the nonproprietary name may also be called the as “those that satisfy the priority healthcare needs approved name. After its appearance in the official of the population. They are selected with due publication, it becomes the official name. regard to public health relevance, evidence on In common parlance, the term generic name is efficacy and safety, and comparative cost effective- used in place of nonproprietary name. Etymolo- ness. Essential medicines are intended to be gically this is incorrect: ‘generic’ should be available within the context of functioning health applied to the chemical or pharmacological group systems at all times and in adequate amounts, in (or genus) of the compound, e.g. phenothiazines, appropriate dosage forms, with assured quality tricyclic antidepressants, aminoglycoside anti- and adequate information, and at a price the biotics, etc. However, this misnomer is unlikely individual and the community can afford. to be corrected, because of wide usage, including It has been realized that only a handful of that in official parlance. drugs out of the multitude available can meet the health care needs of majority of the people in any (c) Proprietary (Brand) name It is the name country, and that many well tested and cheaper assigned by the manufacturer(s) and is his drugs are equally (or more) efficacious and safe property or trade mark. One drug may have mul- as their newer more expensive congeners. For tiple proprietary names, e.g. ALTOL, ATCARDIL, optimum utilization of resources, governments ATECOR, ATEN, BETACARD, LONOL, TENOLOL, TENORMIN for atenolol from different manufac- (especially in developing countries) should turers. Brand names are designed to be catchy, concentrate on these drugs by identifying them short, easy to remember and often suggestive, e.g. as Essential medicines. The WHO has laid down LOPRESOR suggesting drug for lowering blood criteria to guide selection of an essential medicine. pressure. Brand names generally differ in diffe- (a) Adequate data on its efficacy and safety should be available from clinical studies. rent countries, e.g. timolol maleate eye drops are (b) It should be available in a form in which quality, marketed as TIMOPTIC in USA but as GLUCOMOL including bioavailability, and stability on storage can be in India. Even the same manufacturer may market assured. the same drug under different brand names in (c) Its choice should depend upon pattern of prevalent different countries. In addition, combined diseases; availability of facilities and trained personnel; financial resources; genetic, demographic and environ- formulations have their own multiple brand mental factors. names. This is responsible for much confusion in (d) In case of two or more similar medicines, choice should drug nomenclature. be made on the basis of their relative efficacy, safety, There are many arguments for using the * In the 12th list (2003) the terminology has been changed nonproprietary name in prescribing: uniformity, from “essential drugs” to “essential medicines” to denote convenience, economy and better comprehension pharmaceutical preparations used in clinical healthcare (propranolol, sotalol, timolol, pindolol, practice, because often the term ‘drugs’ is understood to metoprolol, acebutolol, atenolol are all β blockers, mean illicit substances. 6 General Pharmacology Section 1 quality, price and availability. Cost-benefit ratio should commercially difficult to obtain. Governments in developed be a major consideration. countries offer tax benefits and other incentives to (e) Choice may also be influenced by comparative pharma- pharmaceutical companies for developing and marketing cokinetic properties and local facilities for manufacture orphan drugs (e.g. Orphan Drug Act in USA). and storage. (f) Most essential medicines should be single compounds. ROUTES OF DRUG ADMINISTRATION Fixed ratio combination products should be included only when dosage of each ingradient meets the requirements of Most drugs can be administered by a variety of a defined population group, and when the combination routes. The choice of appropriate route in a given has a proven advantage in therapeutic effect, safety, situation depends both on drug as well as patient adherence or in decreasing the emergence of drug related factors. Mostly common sense consi- resistance. (g) Selection of essential medicines should be a continuous derations, feasibility and convenience dictate the process which should take into account the changing route to be used. priorities for public health action, epidemiological conditions as well as availability of better medicines/ Factors governing choice of route formulations and progress in pharmacological knowledge. (h) Recently, it has been emphasized to select essential 1. Physical and chemical properties of the drug medicines based on rationally developed treatment (solid/liquid/gas; solubility, stability, pH, guidelines. irritancy). To guide the member countries, the WHO 2. Site of desired action—localized and appro- brought out its first Model List of Essential Drugs achable or generalized and not approachable. along with their dosage forms and strengths in 3. Rate and extent of absorption of the drug from 1977 which could be adopted after suitable different routes. modifications according to local needs. This has 4. Effect of digestive juices and first pass been revised from time to time and the current is the metabolism on the drug. 15th list (2007). India produced its National Essential 5. Rapidity with which the response is desired Drugs List in 1996 and has revised it in 2003 with (routine treatment or emergency). the title “National List of Essential Medicines”. This 6. Accuracy of dosage required (i.v. and inhala- includes 354 medicines which are considered tional can provide fine tuning). to be adequate to meet the priority healthcare 7. Condition of the patient (unconscious, vomi- needs of the general population of the country. An ting). alphabetical compilation of the WHO as well as Routes can be broadly divided into those for (a) National essential medicines is presented as Local action and (b) Systemic action. Appendix-1. Adoption of the essential medicines list for LOCAL ROUTES procurement and supply of medicines, especially These routes can only be used for localized lesions in the public sector healthcare system, has at accessible sites and for drugs whose systemic resulted in improved availability of medicines, absorption from these sites is minimal or absent. cost saving and more rational use of drugs. Thus, high concentrations are attained at the Orphan Drugs These are drugs or biological products for diagnosis/treatment/ prevention of a rare disease or desired site without exposing the rest of the body. condition, or a more common disease (endemic only in Systemic side effects or toxicity are consequently resource poor countries) for which there is no reasonable absent or minimal. For drugs (in suitable dosage expectation that the cost of developing and marketing it will forms) that are absorbed from these sites/routes, be recovered from the sales of that drug. The list includes the same can serve as systemic route of adminis- sodium nitrite, fomepizole, liposomal amphotericin B, ancrod, rifabutin, succimer, somatropin, digoxin immune Fab (digoxin tration, e.g. glyceryl trinitrate (GTN) applied on antibody), liothyronine (T3) and many more. Though these the skin as ointment or transdermal patch. The drugs may be life saving for some patients, they are local routes are: Chapter 1 Routes of Drug Administration 7 1. Topical This refers to external application Limitations of oral route of administration of the drug to the surface for localized action. It is often more convenient as well as encouraging to Action of drugs is slower and thus not suitable the patient. Drugs can be efficiently delivered to for emergencies. the localized lesions on skin, oropharyngeal/ Unpalatable drugs (chloramphenicol) are nasal mucosa, eyes, ear canal, anal canal or vagina difficult to administer; drug may be filled in in the form of lotion, ointment, cream, powder, capsules to circumvent this. rinse, paints, drops, spray, lozengens, sup- May cause nausea and vomiting (emetine). positories or pesseries. Nonabsorbable drugs Cannot be used for uncooperative/uncons- given orally for action on g.i. mucosa (sucralfate, cious/vomiting patient. vancomycin), inhalation of drugs for action on Absorption of drugs may be variable and erratic; bronchi (salbutamol, cromolyn sodium) and certain drugs are not absorbed (streptomycin). irrigating solutions/jellys (povidone iodine, Others are destroyed by digestive juices (peni- lidocaine) applied to urethra are other forms of cillin G, insulin) or in liver (GTN, testosterone, topical medication. lidocaine). 2. Deeper tissues Certain deep areas can be approached by using a syringe and needle, but 2. Sublingual (s.l.) or buccal the drug should be such that systemic absorption The tablet or pellet containing the drug is placed is slow, e.g. intra-articular injection (hydrocor- under the tongue or crushed in the mouth and tisone acetate), infiltration around a nerve or spread over the buccal mucosa. Only lipid soluble intrathecal injection (lidocaine), retrobulbar and non-irritating drugs can be so administered. injection (hydrocortisone acetate). Absorption is relatively rapid—action can be produced in minutes. Though it is somewhat 3. Arterial supply Close intra-arterial injection inconvenient, one can spit the drug after the is used for contrast media in angiography; desired effect has been obtained. The chief anticancer drugs can be infused in femoral or advantage is that liver is bypassed and drugs with brachial artery to localise the effect for limb high first pass metabolism can be absorbed directly malignancies. into systemic circulation. Drugs given sublin- gually are—GTN, buprenorphine, desamino- SYSTEMIC ROUTES oxytocin. The drug administered through systemic routes 3. Rectal is intended to be absorbed into the blood stream and distributed all over, including the site of Certain irritant and unpleasant drugs can be put action, through circulation (see Fig. 1.1). into rectum as suppositories or retention enema for systemic effect. This route can also be used 1. Oral when the patient is having recurrent vomiting or Oral ingestion is the oldest and commonest mode is unconscious. However, it is rather inconvenient of drug administration. It is safer, more con- and embarrassing; absorption is slower, irregular venient, does not need assistance, noninvasive, and often unpredictable, though diazepam solu- often painless, the medicament need not be sterile tion is rapidly and dependably absorbed from and so is cheaper. Both solid dosage forms rectum in children. Drug absorbed into external (powders, tablets, capsules, spansules, dragees, haemorrhoidal veins (about 50%) bypasses moulded tablets, gastrointestinal therapeutic liver, but not that absorbed into internal haemor- systems—GITs) and liquid dosage forms (elixirs, rhoidal veins. Rectal inflammation can result syrups, emulsions, mixtures) can be given orally. from irritant drugs. Diazepam, indomethacin, 8 General Pharmacology Section 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. Chapter 1 Routes of Drug Administration 9 paraldehyde, ergotamine and few other drugs Transdermal patches of GTN, fentanyl, nicotine are some times given rectally. and estradiol are available in India, while those of isosorbide dinitrate, hyoscine, and clonidine are 4. Cutaneous available in other countries. These have been Highly lipid soluble drugs can be applied over designed to last for 1–7 days in case of different the skin for slow and prolonged absorption. The drugs and are becoming increasingly popular, liver is also bypassed. The drug can be incorpo- because they provide smooth plasma concentra- rated in an ointment and applied over specified tions of the drug without fluctuations; minimize area of skin. Absorption of the drug can be interindividual variations (drug is subjected to enhanced by rubbing the preparation, by using little first pass metabolism) and side effects. They an oily base and by an occlusive dressing. are also more convenient—many patients prefer Transdermal therapeutic systems These are transdermal patches to oral tablets of the same devices in the form of adhesive patches of various drug; patient compliance is better. Local irritation shapes and sizes (5–20 cm2) which deliver the and erythema occurs in some, but is generally contained drug at a constant rate into systemic mild; can be minimized by changing the site of circulation via the stratum corneum (Fig. 1.2). The application each time by rotation. Discontinuation drug (in solution or bound to a polymer) is held in has been necessary in 2–7% cases. a reservoir between an occlusive backing film and 5. Inhalation a rate controlling micropore membrane, the under Volatile liquids and gases are given by inhalation surface of which is smeared with an adhesive for systemic action, e.g. general anaesthetics. impregnated with priming dose of the drug. The Absorption takes place from the vast surface of adhesive layer is protected by another film that is alveoli—action is very rapid. When administra- to be peeled off just before application. The drug is tion is discontinued the drug diffuses back and is delivered at the skin surface by diffusion for rapidly eliminated in expired air. Thus, control- percutaneous absorption into circulation. The led administration is possible with moment to micropore membrane is such that rate of drug moment adjustment. Irritant vapours (ether) cause delivery to skin surface is less than the slowest rate inflammation of respiratory tract and increase of absorption from skin. This offsets any variation secretion. in the rate of absorption according to the properties of different sites. As such, the drug is delivered at 6. Nasal a constant and predictable rate irrespective of site The mucous membrane of the nose can readily of application: usually chest, abdomen, upper absorb many drugs; digestive juices and liver are arm, lower back, buttock or mastoid region are bypassed. However, only certain drugs like utilized. GnRH agonists and desmopressin applied as a spray or nebulized solution have been used by this route. This route is being tried for some other peptide drugs, like insulin. 7. Parenteral (Par—beyond, enteral—intestinal) This refers to administration by injection which takes the drug directly into the tissue fluid or blood without having to cross the intestinal Fig. 1.2: Illustration of a transdermal drug delivery mucosa. The limitations of oral administration system are circumvented. 10 General Pharmacology Section 1 Drug action is faster and surer (valuable in to be removed later on but not the biodegradable emergencies). Gastric irritation and vomiting are one. This has been tried for hormones and not provoked. Parenteral routes can be employed contraceptives (e.g. NORPLANT). even in unconscious, uncooperative or vomiting (ii) Intramuscular (i.m.) The drug is injected in patient. There are no chances of interference by one of the large skeletal muscles—deltoid, triceps, food or digestive juices. Liver is bypassed. gluteus maximus, rectus femoris, etc. Muscle is Disadvantages of parenteral routes are—the less richly supplied with sensory nerves (mild preparation has to be sterilized and is costlier, irritants can be injected) and is more vascular the technique is invasive and painful, assistance of another person is mostly needed (though self (absorption of drugs in aqueous solution is faster). injection is possible, e.g. insulin by diabetics), It is less painful, but self injection is often there are chances of local tissue injury and, in impracticable because deep penetration is needed. general, parenteral route is more risky than oral. Depot preparations (oily solutions, aqueous The important parenteral routes are: suspensions) can be injected by this route. Intramuscular injections should be avoided in (i) Subcutaneous (s.c.) The drug is deposited anticoagulant treated patients, because it can in the loose subcutaneous tissue which is richly produce local haematoma. supplied by nerves (irritant drugs cannot be injected) but is less vascular (absorption is slower (iii) Intravenous (i.v.) The drug is injected as a than intramuscular). Only small volumes can be bolus (Greek: bolos–lump) or infused slowly over injected s.c. Self-injection is possible because deep hours in one of the superficial veins. The drug penetration is not needed. This route should be reaches directly into the blood stream and effects avoided in shock patients who are vasocons- are produced immediately (great value in emer- tricted—absorption will be delayed. Repository gency). The intima of veins is insensitive and drug (depot) preparations that are aqueous suspen- gets diluted with blood, therefore, even highly sions can be injected for prolonged action. Some irritant drugs can be injected i.v., but hazards are— special forms of this route are: thrombophlebitis of the injected vein and necrosis of adjoining tissues if extravasation occurs. These (a) Dermojet In this method needle is not used; complications can be minimized by diluting the a high velocity jet of drug solution is projected drug or injecting it into a running i.v. line. Only from a microfine orifice using a gun like imple- aqueous solutions (not suspensions) can be ment. The solution passes through the superficial injected i.v. and there are no depot preparations layers and gets deposited in the subcutaneous for this route. The dose of the drug required is tissue. It is essentially painless and suited for smallest (bioavailability is 100%) and even large mass inoculations. volumes can be infused. One big advantage with (b) Pellet implantation The drug in the form of a this route is—in case response is accurately solid pellet is introduced with a trochar and measurable (e.g. BP) and the drug short acting (e.g. cannula. This provides sustained release of the sodium nitroprusside), titration of the dose with drug over weeks and months, e.g. DOCA, the response is possible. However, this is the most testosterone. risky route—vital organs like heart, brain, etc. get exposed to high concentrations of the drug. (c) Sialistic (nonbiodegradable) and biodegradable implants Crystalline drug is packed in tubes or (iv) Intradermal injection The drug is injected capsules made of suitable materials and implan- into the skin raising a bleb (e.g. BCG vaccine, ted under the skin. Slow and uniform leaching of sensitivity testing) or scarring/multiple puncture of the drug occurs over months providing constant the epidermis through a drop of the drug is done. blood levels. The nonbiodegradable implant has This route is employed for specific purposes only.  2 Pharmacokinetics: Membrane Transport, Absorption and Distribution of Drugs Pharmacokinetics is the quantitative study of All pharmacokinetic processes involve trans- drug movement in, through and out of the body. port of the drug across biological membranes. The overall scheme of pharmacokinetic processes Biological membrane This is a bilayer (about is depicted in Fig. 2.1. The intensity of response 100 Å thick) of phospholipid and cholesterol is related to concentration of the drug at the site molecules, the polar groups (glyceryl phosphate of action, which in turn is dependent on its attached to ethanolamine/choline or hydroxyl pharmacokinetic properties. Pharmacokinetic group of cholesterol) of these are oriented at the considerations, therefore, determine the route(s) two surfaces and the nonpolar hydrocarbon of administration, dose, latency of onset, time of chains are embedded in the matrix to form a peak action, duration of action and frequency of continuous sheet. Extrinsic and intrinsic protein administration of a drug. molecules are adsorbed on the lipid bilayer Fig. 2.1: Schematic depiction of pharmacokinetic processes 12 General Pharmacology Section 1 Fig. 2.2: Illustration of the organisation of biological membrane Fig. 2.3: Illustration of passive diffusion and filtration across (Fig. 2.2). Glycoproteins or glycolipids are formed the lipoidal biological membrane with aqueous pores on the surface by attachment to polymeric sugars, aminosugars or sialic acids.The specific lipid and Lipid soluble drugs diffuse by dissolving in protein composition of different membranes the lipoidal matrix of the membrane (Fig. 2.3), the differs according to the cell or the organelle type. rate of transport being proportional to the lipid : The proteins are able to freely float through the water partition coefficient of the drug. A more membrane: associate and organize or vice versa. lipid-soluble drug attains higher concentration Some of the intrinsic ones, which extend through in the membrane and diffuses quickly. Also, the full thickness of the membrane, surround fine greater the difference in the concentration of the aqueous pores. Paracellular spaces or channels drug on the two sides of the membrane, faster is also exist between certain epithelial/endothelial its diffusion. cells. Other adsorbed proteins have enzymatic, carrier, receptor or signal transduction properties. Influence of pH Most drugs are weak electro- Lipid molecules also are capable of lateral move- lytes, i.e. their ionization is pH dependent ment. Thus, biological membranes are highly (contrast strong electrolytes that are nearly dynamic structures. completely ionized at acidic as well as alkaline pH). The ionization of a weak acid HA is given Drugs are transported across the membranes by: by the equation: (a) Passive diffusion and filtration (b) Specialized transport [A¯ ] pH = pKa + log —–—...(1) [HA] Passive diffusion pKa is the negative logarithm of acidic disso- The drug diffuses across the membrane in the ciation constant of the weak electrolyte. If the direction of its concentration gradient, the concentration of ionized drug [A¯ ] is equal to membrane playing no active role in the process. concentration of unionized drug [HA], then This is the most important mechanism for majority of drugs; drugs are foreign substances [A¯ ] —–— = 1 (xenobiotics), and specialized mechanisms are [HA] developed by the body primarily for normal since log 1 is 0, under this condition metabolites. pH = pKa...(2) Chapter 2 Pharmacokinetics: Membrane Transport 13 cell, reverts to the ionized form within the cell (pH 7.0) and then only slowly passes to the extracellular fluid. This is called ion trapping, i.e. a weak electrolyte crossing a membrane to encounter a pH from which it is not able to escape easily. This may contribute to gastric mucosal cell damage caused by aspirin. (c) Basic drugs attain higher concentration intracellularly (pH 7.0 vs 7.4 of plasma). (d) Acidic drugs are ionized more in alkaline urine—do not back diffuse in the kidney tubules and are excreted faster. Accordingly, basic drugs are excreted faster if urine is acidified. Fig. 2.4: Influence of pH difference on two sides of a biological membrane on the steady-state distribution of a Lipid-soluble nonelectrolytes (e.g. ethanol, weakly acidic drug with pKa = 6 diethyl-ether) readily cross biological membranes and their transport is pH independent. Thus, pKa is numerically equal to the pH at which the drug is 50% ionized. Filtration If pH is increased by 1 scale, then— Filtration is passage of drugs through aqueous pores in the membrane or through paracellular log [A¯ ]/[HA] = 1 or [A¯ ]/[HA] = 10 spaces. This can be accelerated if hydrodynamic Similarly, if pH is reduced by 1 scale, then— flow of the solvent is occurring under hydrostatic [A¯ ]/[HA] = 1/10 or osmotic pressure gradient, e.g. across most capillaries including glomeruli. Lipid-insoluble Thus, weakly acidic drugs, which form salts drugs cross biological membranes by filtration if with cations, e.g. sod. phenobarbitone, sod. their molecular size is smaller than the diameter sulfadiazine, pot. penicillin-V, etc. ionize more at of the pores (Fig. 2.3). Majority of cells (intestinal alkaline pH and 1 scale change in pH causes 10 mucosa, RBC, etc.) have very small pores (4 Å) fold change in ionization. and drugs with MW > 100 or 200 are not able to Weakly basic drugs, which form salts with penetrate. However, capillaries (except those in anions, e.g. atropine sulfate, ephedrine HCl, brain) have large paracellular spaces (40 Å) and chloroquine phosphate, etc. conversely ionize more most drugs (even albumin) can filter through these at acidic pH. Ions being lipid insoluble, do not (Fig. 2.8). As such, diffusion of drugs across diffuse and a pH difference across a membrane capillaries is dependent on rate of blood flow can cause differential distribution of weakly through them rather than on lipid solubility of acidic and weakly basic drugs on the two sides the drug or pH of the medium. (Fig. 2.4). Specialized transport Implications of this consideration are: This can be carrier mediated or by pinocytosis. (a) Acidic drugs, e.g. aspirin (pKa 3.5) are largely unionized at acid gastric pH and are absorbed Carrier transport from stomach, while bases, e.g. atropine (pKa 10) All cell membranes express a host of transmem- are largely ionized and are absorbed only when brane proteins which serve as carriers or they reach the intestines. transporters for physiologically important ions, (b) The unionized form of acidic drugs which nutrients, metabolites, transmitters, etc. across the crosses the surface membrane of gastric mucosal membrane. At some sites, certain transporters also 14 General Pharmacology Section 1 Fig. 2.5: Illustration of different types of carrier mediated transport across biological membrane ABC—ATP-binding cassettee 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 translocate xenobiotics, including drugs and their a. Facilitated diffusion The transporter, metabolites. In contrast to channels, which open belonging to the super-family of solute carrier for a finite time and allow passage of specific ions, (SLC) transporters, operates passively without transporters combine transiently with their needing energy and translocates the substrate in substrate (ion or organic compound)—undergo a the direction of its electrochemical gradient, i.e. conformational change carrying the substrate to from higher to lower concentration (Fig. 2.5A). It the other side of the membrane where the substrate mearly facilitates permeation of a poorly diffusible dissociates and the transporter returns back to its substrate, e.g. the entry of glucose into muscle and original state (Fig. 2.5). Carrier transport is specific fat cells by GLUT 4. for the substrate (or the type of substrate, e.g. an b. Active transport It requires energy, is organic anion), saturable, competitively inhibited inhibited by metabolic poisons, and transports by analogues which utilize the same transporter, the solute against its electrochemical gradient and is much slower than flux through channels. (low to high), resulting in selective accumulation Depending on requirement of energy, carrier of the substance on one side of the membrane. transport is of two types: Drugs related to normal metabolites can utilize Chapter 2 Pharmacokinetics: Drug Absorption 15 the transport processes meant for these, e.g. liver canaliculi and renal tubules, are secondary active transporters important in the metabolism and excretion levodopa and methyl dopa are actively absorbed of drugs and metabolites (especially glucuronides). The from the gut by the aromatic amino acid Na+,Cl– dependent neurotransmitter transporters for transporter. In addition, the body has developed serotonin and dopamine (SERT and DAT) as well as the some relatively nonselective transporters, like vesicular transporter for biogenic amines are active SLC transporters that are targets for action of drugs like tricyclic P-glycoprotein (P-gp), to deal with xenobiotics. antidepressants and reserpine, etc. The absorption of Active transport can be primary or secondary glucose in intestines and renal tubules is through secondary depending on the source of the driving force. active transport by sodium-glucose transporters (SGLT1 i. Primary active transport Energy is obtained and SGLT2). directly by the hydrolysis of ATP (Fig. 2.5B). The