Essentials of Medical - Fundamental Pharmacy · Pharmacology is both a basic and an applied...

Essentials ofMedical

Pharmacology

Essentials of

MedicalPharmacology

Sixth Edition

KD TRIPATHI MDEx-Director-Professor and Head of PharmacologyMaulana Azad Medical College and associated

LN and GB Pant HospitalsNew Delhi

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTDNew Delhi • Ahmedabad • Bengaluru • Chennai • Hyderabad • Kochi • Kolkata

• Lucknow • Mumbai • Nagpur

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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 ismade to ensure accuracy of material, but the publisher, printer and author will not be held responsible forany inadvertent error(s). In case of any dispute, all legal matters to be settled under Delhi jurisdiction only.

First Edition: 1985Second Edition: 1988Third Edition: 1994Fourth Edition: 1999

Updated Reprint:2001

Fifth Edition:2003Sixth Edition:

2008

ISBN 81-8448-085-7

Typeset at JPBMP typesetting unit

Preface

The unprecedented pace of developments over the recent years in the field of drugs (medicines) hasfurther emphasized the relevance of Pharmacology to health professionals. Molecular targets of drugaction are being defined at greater resolution, refining new drugs design. Practice of medicine istransforming from ‘experience (impression) based’ to ‘evidence based’, since more and more credibleevidence from well designed clinical studies is now available on the impact of different treatmentson mortality, morbidity and other therapeutic outcomes. The present edition is oriented to reflectthe 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 thepharmacological 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 usefulboth 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 HealthProgrammes have been incorporated, especially in areas like hypertension, hyperlipidaemias, strokeprevention, surgical prophylaxis, tuberculosis, leprosy, malaria, and HIV-AIDS. Recent developmentshave 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 basedmedicine’ 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 addedare drug transporters, pharmacogenomics, pharmacovigilance, expiry date of pharmaceuticals, singleenantiomer 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 addressedby many texts.

Thanks are due to my colleagues and students for their valuable feedback and suggestions. Aspreviously, the major impetus for this edition has come from Shri J.P. Vij, the ever agile Chairmanof Jaypee Brothers. Commendable type setting, proof reading and improvement in illustrations hasbeen done respectively by Ms Sunita Katla, Ms Geeta Srivastava and Mr Manoj. The editorialmanagement and moral support of my wife has been a boon.

New Delhi KD Tripathi5th Nov. 2007

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 appliedaspects, correct and skilful application of drugs is impossible without a proper understanding oftheir basic pharmacology. Medical pharmacology, therefore, must include both fundamental back-ground and clinical pharmacological information. Objective and quantitative data on the use of drugsin 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., arebeing obtained with the aim of optimising drug therapy. The concepts regarding mechanism of actionof drugs are changing. In addition, new drugs are being introduced in different countries at anexplosive pace. A plethora of information thus appears to be important. However, trying to impartall 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’ approachhas been followed by describing the representative drug of a class followed by features by whichindividual members differ from it. Leading trade names have been included. Clinically relevant druginteractions have been mentioned. Clear-cut guidelines on selection of drugs and their clinical statushave been outlined on the basis of current information. Original, simple and self-explanatoryillustrations, tables and flow charts have been used with impunity. Selected chemical structuresare depicted. Recent developments have been incorporated. However, discretion has been used inincluding only few of the multitude of new drugs not yet available in India. This is based on theirlikelihood of being marketed soon. The information and views have been arranged in an orderlysequence of distinct statements.

I hope this manageable volume book would serve to dispel awe towards pharmacology fromthe minds of medical students and provide a concise and uptodate information source for prescriberswho 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 Tripathi1st Jan., 1985

Extract fromPreface to the First Edition

Contents

Section 1General 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 2Drugs 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) andDrugs for Glaucoma ..................................................................................................................... 132

Section 3Autacoids 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

Section 4Respiratory System Drugs

16. Drugs for Cough and Bronchial Asthma ................................................................................... 213

Section 5Hormones 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 6Drugs Acting on Peripheral (Somatic) Nervous System

25. Skeletal Muscle Relaxants .......................................................................................................... 339

26. Local Anaesthetics ........................................................................................................................ 351

Section 7Drugs 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

viii Contents

Section 8Cardiovascular 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 9Drugs Acting on Kidney

Relevant Physiology of Urine Formation .................................................................................. 557

41. Diuretics ......................................................................................................................................... 561

42. Antidiuretics .................................................................................................................................. 574

Section 10Drugs 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 11Gastrointestinal Drugs

46. Drugs for Peptic Ulcer .................................................................................................................. 627

47. Drugs for Emesis, Reflux and Digestive Disorders ................................................................ 639

48. Drugs for Constipation and Diarrhoea ...................................................................................... 651

Section 12Antimicrobial Drugs

49. Antimicrobial Drugs: General Considerations ........................................................................ 667

50. Sulfonamides, Cotrimoxazole and Quinolones ....................................................................... 682

51. Beta-Lactam Antibiotics ............................................................................................................... 694

Contents ix

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 13Chemotherapy of Neoplastic Diseases

62. Anticancer Drugs .......................................................................................................................... 819

Section 14Miscellaneous 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 ..................................................................................... 903Appendix 2: Prescribing in Pregnancy ........................................................................................ 908Appendix 3: Drugs in Breastfeeding ............................................................................................ 911Appendix 4: Drugs and Fixed Dose Combinations Banned in India ........................................ 915

Index ................................................................................................................................................ 917

x Contents

List of Abbreviations

A-I/II/III Angiotensin I/II/IIIAA Amino acid

ABC ATP-binding cassette (transporter)ABLC Amphotericin B lipid complex

AB AntibodyAC Adenylyl cyclase

ACE Angiotensin II converting enzymeACh Acetylcholine

AChE AcetylcholinesteraseACT Artemisinin-based combination therapy

ACTH Adrenocorticotropic hormoneA D Alzheimer’s disease

ADE Adverse drug eventADH Antidiuretic hormoneADP Adenosine diphosphateAdr Adrenaline

ADR Adverse drug reactionADS Anti diphtheritic serumAES Atrial extrasystole

AF Atrial fibrillationAFl Atrial flutterAG Antigen

AGS Antigasgangrene serumAHG Antihaemophilic globulin

AI Aromatase inhibitorAIDS Acquired immunodeficiency syndrome

AIP Aldosterone induced proteinALA Alanine

Am AmikacinAMA Antimicrobial agentAMB Amphotericin Bamp Ampoule

AMP Adenosine mono phosphateAMPA α-Aminohydroxy methylisoxazole

propionic acidANC Acid neutralizing capacityANP Atrial natriuretic peptideANS Autonomic nervous system

AP Action potentialAPC Antigen presenting cellAPD Action potential durationaPTT Activated partial thromboplastin timeARB Angiotensin receptor blockerARC AIDS related complexARS Anti rabies serumARV Antiretrovirus

5-ASA 5-Amino salicyclic acid

Asc LH Ascending limb of Loop of HenleAT-III Antithrombin III

ATG Antithymocyte globulinATP Adenosine triphosphate

ATPase Adenosine triphosphataseATPIII Adult treatment panel III

ATS Antitetanic serumA-V Atrioventricular

AVP Arginine vasopressinAZT Zidovudine

BAL British anti lewisiteBAN British approved name

BB Borderline leprosyBCG Bacillus Calmette Guérin

BCNU Bischloroethyl nitrosourea (Carmustine)BD Twice daily

β-ARK β adrenergic receptor kinaseBHC Benzene hexachlorideBHP Benign hypertrophy of prostate

BI Bacillary indexBL Borderline lepromatous leprosy

BMD Bone mineral densityBMR Basal metabolic rateBNP Brain nartriuretic peptideBOL 2-Bromolysergic acid diethylamide

BP Blood pressureBPN Bisphosphonate

BRMs Biologic response modifiersBSA Body surface area

BT Borderline tuberculoid leprosyBuChE Butyryl cholinesterase

BW Body weightBZD Benzodiazepine

C-10 DecamethoniumCA Catecholamine

CaBP Calcium binding proteinCAD Coronary artery diseaseCAM Calmodulin

cAMP 3', 5' Cyclic adenosine monophosphatecap Capsule

CAR Conditioned avoidance responseCAse Carbonic anhydraseCAT Computerized axial tomographyCBF Cerebral blood flowCBG Cortisol binding globulin

CBS Colloidal bismuth subcitrateCCB Calcium channel blocker

CCNU Chloroethyl cyclohexyl nitrosourea(lomustine)

CD Collecting ductCFTR Cystic fibrosis transport regulatorcGMP 3', 5' Cyclic guanosine monophosphateCGRP Calcitonin gene related peptide

CH CholesterolChE Cholinesterase

CHE Cholesterol esterChy Chylomicron

Chy. rem. Chylomicron remnantsCHF Congestive heart failure

CI Cardiac indexCL Clearance

CLcr Creatinine clearanceCMI Cell mediated immunity

CMV CytomegalovirusCNS Central nervous system

c.o. Cardiac outputCoEn-A Coenzyme-A

COMT Catechol-O-methyl transferaseCOX Cyclooxygenasec.p.s. Cycles per secondCPS Complex partial seizuresCPZ Chlorpromazine

CRABP Cellular retinoic acid binding proteinCRBP Cellular retinol binding protein

CRF Corticotropin releasing factorCSF Cerebrospinal fluidCTZ Chemoreceptor trigger zone

CV CardiovascularCVP Central venous pressureCVS Cardiovascular system

CWD Cell wall deficientCYP450 Cytochrome P450

Cys Cycloserine

D A DopamineDA-B12 Deoxyadenosyl cobalamin

DAD Delayed after-depolarizationDAG Diacyl glycerolDAM Diacetyl monoxime

DAMP Diphenyl acetoxy-N-methyl piperidinemethiodide

DAT Dopamine transporterdDAVP Desmopressin

DDS Diamino diphenyl sulfone (Dapsone)DDT Dichloro diphenyl trichloroethaneDEC Diethyl carbamazine citrate

DHA DihydroartemisininDHE Dihydroergotamine

DHFA Dihydro folic acidDHFRase Dihydrofolate reductase

DHP DihydropyridineDHT Dihydrotachysterol

DI Diabetes insipidusDIT Diiodotyrosine

dl DecilitreDLE Disseminated lupus erythematosus

DMA Dimethoxy amphetamineDMARD Disease modifying antirheumatic drug

DMPA Depot medroxyprogesterone acetateDMPP Dimethyl phenyl piperazinium

DMT Dimethyl tryptamine/Divalent metaltransporter

DNA Deoxyribose nucleic acidDOC Deoxycholate

DOCA Desoxy corticosterone acetateDOM Dimethoxymethyl amphetaminedopa Dihydroxyphenyl alanine

DOPAC 3, 4, Dihydroxyphenyl acetic acidDOSS Dioctyl sulfosuccinateDOTS Directly observed treatment short course

DPD Dihydropyrimidine dehydrogenaseDPT Diphtheria-pertussis-tetanus triple antigenDRC Dose-response curve

DT Distal tubuleDT-DA Diphtheria-tetanus double antigen

d-TC d-TubocurarineDTIC Dacarbazine

DTPA Diethylene triamine pentaacetic acidDYN Dynorphin

E EthambutolEACA Epsilon amino caproic acid

EAD Early after-depolarizatione.c.f. Extracellular fluidECG ElectrocardiogramECT Electroconvulsive therapy

ED Erectile dysfunctionEDTA Ethylene diamine tetraacetic acid

EEG ElectroencephalogramELAM-1 Endothelial leukocyte adhesion molecule-1

β-END β-EndorphinENS Enteric nervous systemENT Extraneuronal amine transporter

EPEC Enteropathogenic E. coliEPO ErythropoietinEPP End plate potentialERP Effective refractory period

EPSP Excitatory postsynaptic potentialER Estrogen receptorES Extrasystole

ESR Erythrocyte sedimentation rateETEC Enterotoxigenic E. coli

Etm Ethionamide

FA Folic acidFAD Flavin adenine dinucleotide5-FC 5-FlucytosineFDT Fixed duration therapy (of leprosy)FEV1 Forced expiratory volume in 1 second

xii Abbreviations

FFA Free fatty acidFMN Favin mononucleotide

FP FerroportinFQ Fluoroquinolone

FRase Folate reductaseFSH Follicle stimulating hormone

5-FU 5-Fluorouracil

G GeneticGABA Gamma amino butyric acid

GAT GABA-transporterGC Guanylyl cyclase

GCP Good clinical practiceG-CSF Granulocyte colony stimulating factor

GDP Guanosine diphosphateGERD Gastroesophageal reflux disease

g.f. Glomerular filtrationg.f.r. Glomerular filtration rate

GH Growth hormoneGHRH Growth hormone releasing hormone

GHRIH Growth hormone release inhibitory hormoneGIP Gastric inhibitory peptide/Glucose-

dependent insulinotropic polypeptideg.i.t. Gastrointestinal tract

GITS Gastrointestinal therapeutic systemGLP Glucagon-like peptide

GLUT Glucose transporterGM-CSF Granulocyte macrophage colony stimulating

factorGnRH Gonadotropin releasing hormoneGPCR G-protein coupled receptor

G-6-PD Glucose-6-phosphate dehydrogenaseGPI Globus pallidus interna

GTCS Generalised tonic-clonic seizuresGTN Glyceryl trinitrateGTP Guanosine triphosphate

H Isoniazid (Isonicotinic acid hydrazide)HAART Highly active antiretroviral therapy

Hb HaemoglobinHBV Hepatitis B virusHCG Human chorionic gonadotropin

HDCV Human diploid cell vaccineHDL High density lipoprotein

5-HIAA 5-Hydroxyindole acetic acidHES Hydroxyethyl starch

HETE Hydroxyeicosa tetraenoic acidHIV Human immunodeficiency virus

HMG-CoA Hydroxymethyl glutaryl coenzyme AHMW High molecular weight

HPA axis Hypothalamo-pituitary-adrenal axisHPETE Hydroperoxy eicosatetraenoic acid

hr HourHR Heart rate

HRIG Human rabies immuneglobulinHRT Hormone replacement therapy

5-HT 5-Hydroxytryptamine

5-HTP 5-HydroxytryptophanHVA Homovanillic acid

I Indeterminate leprosyIBD Inflammatory bowel diseaseIBS Irritable bowel syndrome

ICAM-1 Intracellular adhesion molecule-1ICSH Interstitial cell stimulating hormone

i.d. Intradermal (injection)IDL Intermediate density lipoprotein

IG ImmuneglobulinIGF Insulin-like growth factor

IL InterleukinILEU Isoleucine

i.m. IntramuscularINH Isonicotinic acid hydrazideINR International normalized ratioi.o.t. Intraocular tension

IP3 Inositol trisphosphateIP4 Inositol tetrakisphosphate

IPSP Inhibitory postsynaptic potentialIPV Inactivated poliomyelitis vaccineIRS Insulin response substrateISA Intrinsic sympathomimetic activityISH Isolated systolic hypertension

IU International unitIUCD Intrauterine contraceptive device

i.v. Intravenous

JAK Janus-kinase

Kmc KanamycinKTZ Ketoconazole

LA Local anaestheticLCAT Lecithin cholesterol acyl transferase

LDL Low density lipoproteinLES Lower esophageal sphincter

leu-ENK Leucine enkephalinLH Luteinizing hormoneliq LiquidLL Lepromatous leprosy

LMW Low molecular weightLOX LipoxygenaseLSD Lysergic acid diethylamide

LT LeukotrieneLVF Left ventricular failure

MAC Minimal alveolar concentrationMAC Mycobacterium avium complexMAO Monoamine oxidaseMAP Muscle action potential

MAPKinase Mitogen activated protein kinasemax Maximum

MBC Minimum bactericidal concentrationMBL Multibacillary leprosyMDI Manic depressive illness

MDMA Methylene dioxy methamphetamine

Abbreviations xiii

MDR Multidrug resistantMDT Multidrug therapy (of leprosy)

met-ENK Methionine enkephalinmEq milliequivalent

methyl B12 Methyl cobalaminMf MicrofilariaeMF Multifactorial

MHC Major histocompatibility complexMHT Methylene dioxy methamphetamine

MI Myocardial infarctionMIC Minimal inhibitory concentrationMID Multi infarct dementiaMIF Migration inhibitory factormin MinimumMIT Monoiodo tyrosine

MLCK Myosin light chain kinaseMMF Mycophenolate mofetil6-MP 6-Mercaptopurine

MPPT Methylprednisolone pulse therapyMPTP 4-methyl-4-phenyltetrahydro pyridineMRP2 Multidrug resistance associated protein-2MRSA Methicillin resistant Staphylococcus aureus

MSH Melanocyte stimulating hormoneMtx MethotrexatemV millivolt

MW Molecular weight

NA NoradrenalineNABQI N-acetyl-p-benzoquinoneimineNADP Nicotinamide adenine dinucleotide

phosphateNADPH Reduced nicotinamide adenine dinucleotide

phosphateNAG N-acetyl glucosamineNAM N-acetyl muramic acid

NANC Nonadrenergic noncholinergicNAPA N-acetyl procainamideNaSSA Noradrenergic and specific serotonergic

antidepressantNAT N-acetyl transferase

NCEP National cholesterol education programmeNEE Norethindrone enanthateNET Norepinephrine transporter

NFAT Nuclear factor of activated T-cellNLEP National leprosy eradication programme

NMDA N-methyl-D-aspartatenNOS Neural nitric oxide synthase

NNRTI Nonnucleoside reverse transcriptase inhibitorNPY Neuropeptide-Y

NR Nicotinic receptorN-REM Non rapid eye movement (sleep)

NRTI Nucleoside reverse transcriptase inhibitorNSAID Nonsteroidal antiinflammatory drug

NSTEMI Non ST-segment elevation myocardialinfarction

NTS Nucleus tractus solitariusNVBDCP National vector borne diseases control

programmeNYHA New York Heart Association

OAT Organic anion transporterOATP Organic anion transporting polypeptide

OC Oral contraceptiveOCD Obsessive-compulsive disorderOCT Organic cation transporter

OD Once dailyOPG OsteoprotegerinOPV Oral poliomyelitis vaccineORS Oral rehydration salt (solution)ORT Oral rehydration therapy

PABA Paraamino benzoic acidPAE Post antibiotic effectPAF Platelet activating factor

2-PAM PralidoximePAN Primary afferent neuronePAS Paraamino salicylic acidPBI Protein bound iodine

PBPs Penicillin binding proteinsPBL Paucibacillary leprosy

PCA Patient controlled anaesthesiaPCEV Purified chick embryo cell vaccine (rabies)

PCI Percutaneous coronary interventionPCPA Parachloro phenylalanine

PD Parkinsons’s diseasePDE Phosphodiesterase

PEMA Phenylethyl malonamidePEP Postexposure prophylaxis

PF Purkinje fibrePFOR Pyruvate: ferredoxin oxidoreductase

PG ProstaglandinPGI2 ProstacyclinPgp P-glycoprotein

PI Protease inhibitorPIG Phosphatidyl inositol glycanPIP2 Phosphatidyl inositol-4,5-bisphosphate

PKA Protein kinase: cAMP dependentPKC Protein kinase CPLA Phospholipase APLC Phospholipase C

Pl. ph. Platelet phospholipidPnG Penicillin G

POMC Pro-opio melanocortinPP Partial pressure

PPA Phenyl propanolaminePPARγ Paroxysome proliferator-activated receptor γ

PPH Post partum haemorrhagePPI Proton pump inhibitor

ppm Part per millionPPNG Penicillinase producing N. gonorrhoeae

PRA Plasma renin activityPRF Prolactin releasing factor

xiv Abbreviations

PRIH Prolactin release inhibitory hormonePSVT Paroxysmal supra-ventricular tachycardia

PT Proximal tubulePTCA Percutaneous transluminal coronary

angioplastyPTH Parathyroid hormone

PTMA Phenyl trimethyl ammoniumPTP Post-tetanic potentiationPTZ Pentylenetetrazol

PUV A Psoralen-Ultraviolet APVP Poly vinyl pyrrolidone

PVRV Purified verocell rabies vaccine

QID Four times a day

R Rifampin (Rifampicin)RANK Receptor for activation of nuclear factor κB

RANKL RANK ligandRAS Renin-angiotensin systemRBC Red blood cellsRBP Retinol binding protein

RC Respiratory centreRE Reticuloendothelial

REM Rapid eye movement (sleep)RIG Rabies immuneglobulin

RIMA Reversible inhibitor of MAO-ArINN Recommended international nonproprietary

nameRMP Resting membrane potentialRNA Ribonucleic acid

RNTCP Revised National Tuberculosis ControlProgramme

RP Refractory periodRTF Resistance transfer factorRXR Retinoid X receptorRyR Ryanodine receptor

S StreptomycinSA Sinoauricular (node)

SAARD Slow acting antirheumatic drugSABE Subacute bacterial endocarditis

s.c. SubcutaneousSCC Short course chemotherapy (of tuberculosis)SCh Succinylcholine

SCID Severe combined immunodeficiency diseaseSERDs Selective estrogen receptor down regulatorsSERM Selective estrogen receptor modulatorSERT Serotonin transporterSGA Second generation antihistaminic

SGLT Sodium-glucose transporterSHBG Sex hormone binding globulin

s.l. SublingualSLC Solute carrierSLE Systemic lupus erythematosus

SMON Subacute myelo-optic neuropathy

Abbreviations xv

SNP Single nucleotide polymorphismSN-PC Substantia nigra-pars compactaSN-PR Substantia nigra-pars reticularis

SNRI Serotonin and noradrenaline reuptakeinhibitor

s.o.s. as requiredS/P Sulfonamide + pyrimethamineSPF Sun protection factorSPS Simple partial seizures

SR Sustained releaseSRS-A Slow reacting substance of anaphylaxis

SSG Sodium stibogluconateSSI Surgical site infection

SSRIs Selective serotonin reuptake inhibitorsSTAT Signal transducer and activator of transcription

STEMI ST-segment elevation myocardial infarctionStK Streptokinase

SULT SulfotransferaseSUR Sulfonyl urea receptorsusp SuspensionSWS Slow wave sleep

syr Syrup

t½ Half lifeT3 TriiodothyronineT4 Thyroxine

tab TabletTAB Typhoid, paratyphoid A and B vaccine

TB Tubercle bacilliTBG Thyroxine binding globulinTCII Transcobalamin II

TCAs Tricyclic antidepressantsTCID50 Tissue culture infectious dose 50%

TDM Therapeutic drug monitoringTDS Three times a day

Tf TransferrinTG Triglyceride

6-TG 6-ThioguanineTHC Tetrahydrocannabinol

THFA Tetrahydro folic acidThio TEPA Triethylene thiophosphoramide

THR ThreonineTIAs Transient ischaemic attacks

TNF-α Tumour necrosis factor αTOD Target organ damageTOF Train of fourt-PA Tissue plasminogen activator

TPMT Thiopurine methyl transferaset.p.r. Total peripheral resistance

TR Thyroid hormone receptorTRE Thyroid hormone response elementTRH Thyrotropin releasing hormoneTSH Thyroid stimulating hormone

TT Tuberculoid leprosyTTS Transdermal therapeutic system

TX ThromboxaneTzn Thiacetazone

U UnitUDP Uridine diphosphateUFH Unfractionated heparin

UGDP University group diabetic programmeUGT UDP-glucuronosyl transferase

USAN United States adopted nameUTI Urinary tract infection

v VoltV Volume of distribution

VAL ValineVDR Vit D receptorVES Ventricular extrasystole

VF Ventricular fibrillationVIP Vasoactive intestinal peptideVit Vitamin

VLDL Very low density lipoprotein

VMA Vanillyl mandelic acidVMAT Vesicular monoamine transporter

VRE Vancomycin resistant enterococciVRSA Vancomycin resistant Staphylococcus aureusVRUT Vasopressin regulated urea transporter

VT Ventricular tachycardiavWF von Willebrand factor

WBC White blood cellsWCVs Water channel containing vesiclesWHO World Health OrganizationWPW Wolff-Parkinson-White syndrome

XDR-TB Extensively drug resistant-TB

Z PyrazinamideZollinger-Ellison (syndrome)

xvi Abbreviations

ZE (syndrome)

2 General Pharmacology Section 1

INTRODUCTION

PharmacologyPharmacology is the science of drugs (Greek:Pharmacon—drug; logos—discourse in) . In a broadsense, it deals with interaction of exogenouslyadministered chemical molecules (drugs) withliving systems. It encompasses all aspects ofknowledge about drugs, but most importantlythose that are relevant to effective and safe use formedicinal purposes.

For thousands of years most drugs were crudenatural products of unknown composition andlimited efficacy. Only the overt effects of thesesubstances on the body were rather impreciselyknown, but how the same were produced wasentirely unknown. Pharmacology as an experi-mental science was ushered by Rudolf Buchheimwho founded the first institute of pharmacologyin 1847 in Germany. In the later part of the 19thcentury, Oswald Schmiedeberg, regarded as the‘father of pharmacology’, together with his manydisciples like J Langley, T Frazer, P Ehrlich,AJ Clark, JJ Abel propounded some of the fun-damental concepts in pharmacology. Since thendrugs have been purified, chemically characteri-zed and a vast variety of highly potent andselective new drugs have been developed. Themechanism of action including molecular target

of many drugs has been elucidated. This has beenpossible due to prolific growth of pharmacologywhich forms the backbone of rational thera-peutics.

The two main divisions of pharmacology arepharmacodynamics and pharmacokinetics.

Pharmacodynamics (Greek: dynamis—power)—What the drug does to the body.This includes physiological and biochemicaleffects of drugs and their mechanism of actionat organ system/subcellular/macromolecularlevels, e.g.—Adrenaline → interaction with adre-noceptors → G-protein mediated stimulation ofcell membrane bound adenylyl cyclase → increa-sed intracellular cyclic 3´,5´AMP → cardiac stimu-lation, hepatic glycogenolysis and hypergly-caemia, etc.

Pharmacokinetics (Greek: Kinesis—movement)— What the body does to the drug.This refers to movement of the drug in and altera-tion of the drug by the body; includes absorption,distribution, binding/localization/storage, bio-transformation and excretion of the drug, e.g.paracetamol is rapidly and almost completelyabsorbed orally attaining peak blood levels at30–60 min; 25% bound to plasma proteins, widelyand almost uniformly distributed in the body(volume of distribution ~ 1L/kg); extensively

C H A P T E R

Introduction, Routes ofDrug Administration

1


metabolized in the liver, primarily by glucuronideand sulfate conjugation into inactive metaboliteswhich are excreted in urine; has a plasma halflife (t½) of 2–3 hours and a clearance value of5 ml/kg/min.

Drug (French: Drogue—a dry herb) It is the singleactive chemical entity present in a medicine that isused for diagnosis, prevention, treatment/cure ofa disease. This disease oriented definition of drugdoes not include contraceptives or use of drugsfor improvement of health. The WHO (1966) hasgiven a more comprehensive definition—“Drug isany substance or product that is used or is intendedto be used to modify or explore physiologicalsystems or pathological states for the benefit of therecipient.”

The term ‘drugs’ is being also used to meanaddictive/abused/illicit substances. However,this restricted and derogatory sense usage isunfortunate degradation of a time honoured term,and ‘drug’ should refer to a substance that hassome therapeutic/diagnostic application.

Some other important aspects of pharmacologyare:

Pharmacotherapeutics It is the application ofpharmacological information together withknowledge of the disease for its prevention,mitigation or cure. Selection of the most appro-priate drug, dosage and duration of treatmenttaking into account the specific features of apatient are a part of pharmacotherapeutics.

Clinical pharmacology It is the scientific studyof drugs in man. It includes pharmacodynamicand pharmacokinetic investigation in healthyvolunteers and in patients; evaluation of efficacyand safety of drugs and comparative trials withother forms of treatment; surveillance of patternsof drug use, adverse effects, etc.

The aim of clinical pharmacology is togenerate data for optimum use of drugs and thepractice of ‘evidence based medicine’.

Chemotherapy It is the treatment of systemicinfection/malignancy with specific drugs that

have selective toxicity for the infecting organism/malignant cell with no/minimal effects on thehost cells.

Drugs in general, can thus be divided into:

Pharmacodynamic agents These are designedto have pharmacodynamic effects in the recipient.

Chemotherapeutic agents These are designedto inhibit/kill invading parasite/ malignant celland have no/minimal pharmacodynamic effectsin the recipient.

Pharmacy It is the art and science of compoun-ding and dispensing drugs or preparing suitabledosage forms for administration of drugs to manor animals. It includes collection, identification,purification, isolation, synthesis, standardizationand quality control of medicinal substances. Thelarge scale manufacture of drugs is called Phar-maceutics. It is primarily a technological science.

Toxicology It is the study of poisonous effect ofdrugs and other chemicals (household, environ-mental pollutant, industrial, agricultural, homi-cidal) with emphasis on detection, preventionand treatment of poisonings. It also includes thestudy of adverse effects of drugs, since the samesubstance can be a drug or a poison, dependingon the dose.

DRUG NOMENCLATURE

A drug generally has three categories of names:

(a) Chemical name It describes the substancechemically, e.g. 1-(Isopropylamino)-3-(1-naphthy-loxy) propan-2-ol for propranolol. This is cumber-some and not suitable for use in prescribing. A codename, e.g. RO 15-1788 (later named flumazenil)may be assigned by the manufacturer for con-venience and simplicity before an approved nameis coined.

(b) Non-proprietary name It is the name accep-ted by a competent scientific body/authority, e.g.the United States Adopted Name (USAN) by theUSAN council. Similarly, there is the British

Approved name (BAN) of a drug. The non-proprietary names of newer drugs are keptuniform by an agreement to use the Recommen-ded International Nonproprietary Name (rINN)in all member countries of the WHO. The BAN ofolder drugs as well has now been modified to becommensurate with rINN. However, many olderdrugs still have more than one non-proprietarynames, e.g. ‘meperidine’ and ‘pethidine’ or‘lidocaine’ and ‘lignocaine’ for the same drugs.Until the drug is included in a pharmacopoeia,the nonproprietary name may also be called theapproved name. After its appearance in the officialpublication, it becomes the official name.

In common parlance, the term generic name isused in place of nonproprietary name. Etymolo-gically this is incorrect: ‘generic’ should beapplied to the chemical or pharmacological group(or genus) of the compound, e.g. phenothiazines,tricyclic antidepressants, aminoglycoside anti-biotics, etc. However, this misnomer is unlikelyto be corrected, because of wide usage, includingthat in official parlance.

(c) Proprietary (Brand) name It is the nameassigned by the manufacturer(s) and is hisproperty or trade mark. One drug may have mul-tiple proprietary names, e.g. ALTOL, ATCARDIL,ATECOR, ATEN, BETACARD, LONOL, TENOLOL,TENORMIN for atenolol from different manufac-turers. Brand names are designed to be catchy,short, easy to remember and often suggestive, e.g.LOPRESOR suggesting drug for lowering bloodpressure. Brand names generally differ in diffe-rent countries, e.g. timolol maleate eye drops aremarketed as TIMOPTIC in USA but as GLUCOMOLin India. Even the same manufacturer may marketthe same drug under different brand names indifferent countries. In addition, combinedformulations have their own multiple brandnames. This is responsible for much confusion indrug nomenclature.

There are many arguments for using thenonproprietary name in prescribing: uniformity,convenience, economy and better comprehension(propranolol, sotalol, timolol, pindolol,metoprolol, acebutolol, atenolol are all β blockers,

but their brand names have no such similarity).However, when it is important to ensureconsistency of the product in terms of quality andbioavailability, etc. and especially when officialcontrol over quality of manufactured products isnot rigorous, it is better to prescribe by thedependable brand name.

ESSENTIAL DRUGS (MEDICINES) CONCEPT

The WHO has defined Essential Drugs* (medicines)as “those that satisfy the priority healthcare needsof the population. They are selected with dueregard to public health relevance, evidence onefficacy and safety, and comparative cost effective-ness. Essential medicines are intended to beavailable within the context of functioning healthsystems at all times and in adequate amounts, inappropriate dosage forms, with assured qualityand adequate information, and at a price theindividual and the community can afford.

It has been realized that only a handful ofdrugs out of the multitude available can meet thehealth care needs of majority of the people in anycountry, and that many well tested and cheaperdrugs are equally (or more) efficacious and safeas their newer more expensive congeners. Foroptimum utilization of resources, governments(especially in developing countries) shouldconcentrate on these drugs by identifying themas Essential medicines. The WHO has laid downcriteria to guide selection of an essential medicine.(a) Adequate data on its efficacy and safety should beavailable from clinical studies.(b) It should be available in a form in which quality,including bioavailability, and stability on storage can beassured.(c) Its choice should depend upon pattern of prevalentdiseases; availability of facilities and trained personnel;financial resources; genetic, demographic and environ-mental factors.(d) In case of two or more similar medicines, choice shouldbe made on the basis of their relative efficacy, safety,

Chapter 1 Introduction 5

* In the 12th list (2003) the terminology has been changedfrom “essential drugs” to “essential medicines” to denotepharmaceutical preparations used in clinical healthcarepractice, because often the term ‘drugs’ is understood tomean illicit substances.


quality, price and availability. Cost-benefit ratio shouldbe a major consideration.(e) Choice may also be influenced by comparative pharma-cokinetic properties and local facilities for manufactureand storage.(f) Most essential medicines should be single compounds.Fixed ratio combination products should be included onlywhen dosage of each ingradient meets the requirements ofa defined population group, and when the combinationhas a proven advantage in therapeutic effect, safety,adherence or in decreasing the emergence of drugresistance.(g) Selection of essential medicines should be a continuousprocess which should take into account the changingpriorities for public health action, epidemiologicalconditions as well as availability of better medicines/formulations and progress in pharmacological knowledge.(h) Recently, it has been emphasized to select essentialmedicines based on rationally developed treatmentguidelines.

To guide the member countries, the WHObrought out its first Model List of Essential Drugsalong with their dosage forms and strengths in1977 which could be adopted after suitablemodifications according to local needs. This hasbeen revised from time to time and the current is the15th list (2007). India produced its National EssentialDrugs List in 1996 and has revised it in 2003 withthe title “National List of Essential Medicines”. Thisincludes 354 medicines which are consideredto be adequate to meet the priority healthcareneeds of the general population of the country. Analphabetical compilation of the WHO as well asNational essential medicines is presented asAppendix-1.

Adoption of the essential medicines list forprocurement and supply of medicines, especiallyin the public sector healthcare system, hasresulted in improved availability of medicines,cost saving and more rational use of drugs.Orphan Drugs These are drugs or biological productsfor diagnosis/treatment/ prevention of a rare disease orcondition, or a more common disease (endemic only inresource poor countries) for which there is no reasonableexpectation that the cost of developing and marketing it willbe recovered from the sales of that drug. The list includessodium nitrite, fomepizole, liposomal amphotericin B, ancrod,rifabutin, succimer, somatropin, digoxin immune Fab (digoxinantibody), liothyronine (T3) and many more. Though thesedrugs may be life saving for some patients, they are

commercially difficult to obtain. Governments in developedcountries offer tax benefits and other incentives topharmaceutical companies for developing and marketingorphan drugs (e.g. Orphan Drug Act in USA).

ROUTES OF DRUG ADMINISTRATIONMost drugs can be administered by a variety ofroutes. The choice of appropriate route in a givensituation depends both on drug as well as patientrelated factors. Mostly common sense consi-derations, feasibility and convenience dictate theroute to be used.

Factors governing choice of route1. Physical and chemical properties of the drug

(solid/liquid/gas; solubility, stability, pH,irritancy).

2. Site of desired action—localized and appro-achable or generalized and not approachable.

3. Rate and extent of absorption of the drug fromdifferent routes.

4. Effect of digestive juices and first passmetabolism on the drug.

5. Rapidity with which the response is desired(routine treatment or emergency).

6. Accuracy of dosage required (i.v. and inhala-tional can provide fine tuning).

7. Condition of the patient (unconscious, vomi-ting).

Routes can be broadly divided into those for (a)Local action and (b) Systemic action.

LOCAL ROUTES

These routes can only be used for localized lesionsat accessible sites and for drugs whose systemicabsorption from these sites is minimal or absent.Thus, high concentrations are attained at thedesired site without exposing the rest of the body.Systemic side effects or toxicity are consequentlyabsent or minimal. For drugs (in suitable dosageforms) that are absorbed from these sites/routes,the same can serve as systemic route of adminis-tration, e.g. glyceryl trinitrate (GTN) applied onthe skin as ointment or transdermal patch. Thelocal routes are:

1. Topical This refers to external applicationof the drug to the surface for localized action. It isoften more convenient as well as encouraging tothe patient. Drugs can be efficiently delivered tothe localized lesions on skin, oropharyngeal/nasal mucosa, eyes, ear canal, anal canal or vaginain the form of lotion, ointment, cream, powder,rinse, paints, drops, spray, lozengens, sup-positories or pesseries. Nonabsorbable drugsgiven orally for action on g.i. mucosa (sucralfate,vancomycin), inhalation of drugs for action onbronchi (salbutamol, cromolyn sodium) andirrigating solutions/jellys (povidone iodine,lidocaine) applied to urethra are other forms oftopical medication.

2. Deeper tissues Certain deep areas can beapproached by using a syringe and needle, butthe drug should be such that systemic absorptionis slow, e.g. intra-articular injection (hydrocor-tisone acetate), infiltration around a nerve orintrathecal injection (lidocaine), retrobulbarinjection (hydrocortisone acetate).

3. Arterial supply Close intra-arterial injectionis used for contrast media in angiography;anticancer drugs can be infused in femoral orbrachial artery to localise the effect for limbmalignancies.

SYSTEMIC ROUTES

The drug administered through systemic routesis intended to be absorbed into the blood streamand distributed all over, including the site ofaction, through circulation (see Fig. 1.1).

1. OralOral ingestion is the oldest and commonest modeof drug administration. It is safer, more con-venient, does not need assistance, noninvasive,often painless, the medicament need not be sterileand so is cheaper. Both solid dosage forms(powders, tablets, capsules, spansules, dragees,moulded tablets, gastrointestinal therapeuticsystems—GITs) and liquid dosage forms (elixirs,syrups, emulsions, mixtures) can be given orally.

Limitations of oral route of administration

• Action of drugs is slower and thus not suitablefor emergencies.

• Unpalatable drugs (chloramphenicol) aredifficult to administer; drug may be filled incapsules to circumvent this.

• May cause nausea and vomiting (emetine).• Cannot be used for uncooperative/uncons-

cious/vomiting patient.• Absorption of drugs may be variable and erratic;

certain drugs are not absorbed (streptomycin).• Others are destroyed by digestive juices (peni-

cillin G, insulin) or in liver (GTN, testosterone,lidocaine).

2. Sublingual (s.l.) or buccalThe tablet or pellet containing the drug is placedunder the tongue or crushed in the mouth andspread over the buccal mucosa. Only lipid solubleand non-irritating drugs can be so administered.Absorption is relatively rapid—action can beproduced in minutes. Though it is somewhatinconvenient, one can spit the drug after thedesired effect has been obtained. The chiefadvantage is that liver is bypassed and drugs withhigh first pass metabolism can be absorbed directlyinto systemic circulation. Drugs given sublin-gually are—GTN, buprenorphine, desamino-oxytocin.

3. RectalCertain irritant and unpleasant drugs can be putinto rectum as suppositories or retention enemafor systemic effect. This route can also be usedwhen the patient is having recurrent vomiting oris unconscious. However, it is rather inconvenientand embarrassing; absorption is slower, irregularand often unpredictable, though diazepam solu-tion is rapidly and dependably absorbed fromrectum in children. Drug absorbed into externalhaemorrhoidal veins (about 50%) bypassesliver, but not that absorbed into internal haemor-rhoidal veins. Rectal inflammation can resultfrom irritant drugs. Diazepam, indomethacin,

Chapter 1 Routes of Drug Administration 7


Fig. 1.1: Vascular pathway of drugs absorbed from various systemic routes of administration andsites of first pass metabolismNote: Total drug absorbed orally is subjected to first pass metabolism in intestinal wall and liver, whileapproximately half of that absorbed from rectum passes through liver. Drug entering from any systemicroute 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 drugsare some times given rectally.

4. CutaneousHighly lipid soluble drugs can be applied overthe skin for slow and prolonged absorption. Theliver is also bypassed. The drug can be incorpo-rated in an ointment and applied over specifiedarea of skin. Absorption of the drug can beenhanced by rubbing the preparation, by usingan oily base and by an occlusive dressing.

Transdermal therapeutic systems These aredevices in the form of adhesive patches of variousshapes and sizes (5–20 cm2) which deliver thecontained drug at a constant rate into systemiccirculation via the stratum corneum (Fig. 1.2). Thedrug (in solution or bound to a polymer) is held ina reservoir between an occlusive backing film anda rate controlling micropore membrane, the undersurface of which is smeared with an adhesiveimpregnated with priming dose of the drug. Theadhesive layer is protected by another film that isto be peeled off just before application. The drug isdelivered at the skin surface by diffusion forpercutaneous absorption into circulation. Themicropore membrane is such that rate of drugdelivery to skin surface is less than the slowest rateof absorption from skin. This offsets any variationin the rate of absorption according to the propertiesof different sites. As such, the drug is delivered ata constant and predictable rate irrespective of siteof application: usually chest, abdomen, upperarm, lower back, buttock or mastoid region areutilized.

Transdermal patches of GTN, fentanyl, nicotineand estradiol are available in India, while those ofisosorbide dinitrate, hyoscine, and clonidine areavailable in other countries. These have beendesigned to last for 1–7 days in case of differentdrugs and are becoming increasingly popular,because they provide smooth plasma concentra-tions of the drug without fluctuations; minimizeinterindividual variations (drug is subjected tolittle first pass metabolism) and side effects. Theyare also more convenient—many patients prefertransdermal patches to oral tablets of the samedrug; patient compliance is better. Local irritationand erythema occurs in some, but is generallymild; can be minimized by changing the site ofapplication each time by rotation. Discontinuationhas been necessary in 2–7% cases.

5. InhalationVolatile liquids and gases are given by inhalationfor systemic action, e.g. general anaesthetics.Absorption takes place from the vast surface ofalveoli—action is very rapid. When administra-tion is discontinued the drug diffuses back and israpidly eliminated in expired air. Thus, control-led administration is possible with moment tomoment adjustment. Irritant vapours (ether) causeinflammation of respiratory tract and increasesecretion.

6. NasalThe mucous membrane of the nose can readilyabsorb many drugs; digestive juices and liver arebypassed. However, only certain drugs likeGnRH agonists and desmopressin applied as aspray or nebulized solution have been used bythis route. This route is being tried for some otherpeptide drugs, like insulin.

7. Parenteral(Par—beyond, enteral—intestinal)This refers to administration by injection whichtakes the drug directly into the tissue fluid orblood without having to cross the intestinalmucosa. The limitations of oral administrationare circumvented.

Fig. 1.2: Illustration of a transdermal drug deliverysystem


Drug action is faster and surer (valuable inemergencies). Gastric irritation and vomiting arenot provoked. Parenteral routes can be employedeven in unconscious, uncooperative or vomitingpatient. There are no chances of interference byfood or digestive juices. Liver is bypassed.

Disadvantages of parenteral routes are—thepreparation has to be sterilized and is costlier,the technique is invasive and painful, assistanceof another person is mostly needed (though selfinjection is possible, e.g. insulin by diabetics),there are chances of local tissue injury and, ingeneral, parenteral route is more risky than oral.The important parenteral routes are:

(i) Subcutaneous (s.c.) The drug is depositedin the loose subcutaneous tissue which is richlysupplied by nerves (irritant drugs cannot beinjected) but is less vascular (absorption is slowerthan intramuscular). Only small volumes can beinjected s.c. Self-injection is possible because deeppenetration is not needed. This route should beavoided in shock patients who are vasocons-tricted—absorption will be delayed. Repository(depot) preparations that are aqueous suspen-sions can be injected for prolonged action. Somespecial forms of this route are:

(a) Dermojet In this method needle is not used;a high velocity jet of drug solution is projectedfrom a microfine orifice using a gun like imple-ment. The solution passes through the superficiallayers and gets deposited in the subcutaneoustissue. It is essentially painless and suited formass inoculations.

(b) Pellet implantation The drug in the form of asolid pellet is introduced with a trochar andcannula. This provides sustained release of thedrug over weeks and months, e.g. DOCA,testosterone.

(c) Sialistic (nonbiodegradable) and biodegradableimplants Crystalline drug is packed in tubes orcapsules made of suitable materials and implan-ted under the skin. Slow and uniform leaching ofthe drug occurs over months providing constantblood levels. The nonbiodegradable implant has

to be removed later on but not the biodegradableone. This has been tried for hormones andcontraceptives (e.g. NORPLANT).

(ii) Intramuscular (i.m.) The drug is injected inone of the large skeletal muscles—deltoid, triceps,gluteus maximus, rectus femoris, etc. Muscle isless richly supplied with sensory nerves (mildirritants can be injected) and is more vascular(absorption of drugs in aqueous solution is faster).It is less painful, but self injection is oftenimpracticable because deep penetration is needed.Depot preparations (oily solutions, aqueoussuspensions) can be injected by this route.Intramuscular injections should be avoided inanticoagulant treated patients, because it canproduce local haematoma.

(iii) Intravenous (i.v.) The drug is injected as abolus (Greek: bolos–lump) or infused slowly overhours in one of the superficial veins. The drugreaches directly into the blood stream and effectsare produced immediately (great value in emer-gency). The intima of veins is insensitive and druggets diluted with blood, therefore, even highlyirritant drugs can be injected i.v., but hazards are—thrombophlebitis of the injected vein and necrosisof adjoining tissues if extravasation occurs. Thesecomplications can be minimized by diluting thedrug or injecting it into a running i.v. line. Onlyaqueous solutions (not suspensions) can beinjected i.v. and there are no depot preparationsfor this route. The dose of the drug required issmallest (bioavailability is 100%) and even largevolumes can be infused. One big advantage withthis route is—in case response is accuratelymeasurable (e.g. BP) and the drug short acting (e.g.sodium nitroprusside), titration of the dose withthe response is possible. However, this is the mostrisky route—vital organs like heart, brain, etc. getexposed to high concentrations of the drug.

(iv) Intradermal injection The drug is injectedinto the skin raising a bleb (e.g. BCG vaccine,sensitivity testing) or scarring/multiple puncture ofthe epidermis through a drop of the drug is done.This route is employed for specific purposes only.

Pharmacokinetics is the quantitative study ofdrug movement in, through and out of the body.The overall scheme of pharmacokinetic processesis depicted in Fig. 2.1. The intensity of responseis related to concentration of the drug at the siteof action, which in turn is dependent on itspharmacokinetic properties. Pharmacokineticconsiderations, therefore, determine the route(s)of administration, dose, latency of onset, time ofpeak action, duration of action and frequency ofadministration of a drug.

All pharmacokinetic processes involve trans-port of the drug across biological membranes.

Biological membrane This is a bilayer (about100 Å thick) of phospholipid and cholesterolmolecules, the polar groups (glyceryl phosphateattached to ethanolamine/choline or hydroxylgroup of cholesterol) of these are oriented at thetwo surfaces and the nonpolar hydrocarbonchains are embedded in the matrix to form acontinuous sheet. Extrinsic and intrinsic proteinmolecules are adsorbed on the lipid bilayer

Fig. 2.1: Schematic depiction of pharmacokinetic processes

Pharmacokinetics:Membrane Transport, Absorption and

Distribution of Drugs

2


(Fig. 2.2). Glycoproteins or glycolipids are formedon the surface by attachment to polymeric sugars,aminosugars or sialic acids.The specific lipid andprotein composition of different membranesdiffers according to the cell or the organelle type.The proteins are able to freely float through themembrane: associate and organize or vice versa.Some of the intrinsic ones, which extend throughthe full thickness of the membrane, surround fineaqueous pores. Paracellular spaces or channelsalso exist between certain epithelial/endothelialcells. Other adsorbed proteins have enzymatic,carrier, receptor or signal transduction properties.Lipid molecules also are capable of lateral move-ment. Thus, biological membranes are highlydynamic structures.

Drugs are transported across the membranes by:(a) Passive diffusion and filtration(b) Specialized transport

Passive diffusionThe drug diffuses across the membrane in thedirection of its concentration gradient, themembrane playing no active role in the process.This is the most important mechanism formajority of drugs; drugs are foreign substances(xenobiotics), and specialized mechanisms aredeveloped by the body primarily for normalmetabolites.

Lipid soluble drugs diffuse by dissolving inthe lipoidal matrix of the membrane (Fig. 2.3), therate of transport being proportional to the lipid :water partition coefficient of the drug. A morelipid-soluble drug attains higher concentrationin the membrane and diffuses quickly. Also,greater the difference in the concentration of thedrug on the two sides of the membrane, faster isits diffusion.

Influence of pH Most drugs are weak electro-lytes, i.e. their ionization is pH dependent(contrast strong electrolytes that are nearlycompletely ionized at acidic as well as alkalinepH). The ionization of a weak acid HA is givenby the equation:

[A¯ ]pH = pKa + log —–— ...(1)

[HA]pKa is the negative logarithm of acidic disso-ciation constant of the weak electrolyte. If theconcentration of ionized drug [A¯ ] is equal toconcentration of unionized drug [HA], then

[A¯ ]—–— = 1[HA]

since log 1 is 0, under this conditionpH = pKa ...(2)

Fig. 2.2: Illustration of the organisation of biologicalmembrane

Fig. 2.3: Illustration of passive diffusion and filtration acrossthe lipoidal biological membrane with aqueous pores

Thus, pKa is numerically equal to the pH at whichthe drug is 50% ionized.If pH is increased by 1 scale, then—

log [A¯ ]/[HA] = 1 or [A¯ ]/[HA] = 10

Similarly, if pH is reduced by 1 scale, then—[A¯ ]/[HA] = 1/10

Thus, weakly acidic drugs, which form saltswith cations, e.g. sod. phenobarbitone, sod.sulfadiazine, pot. penicillin-V, etc. ionize more atalkaline pH and 1 scale change in pH causes 10fold change in ionization.

Weakly basic drugs, which form salts withanions, e.g. atropine sulfate, ephedrine HCl,chloroquine phosphate, etc. conversely ionize moreat acidic pH. Ions being lipid insoluble, do notdiffuse and a pH difference across a membranecan cause differential distribution of weaklyacidic and weakly basic drugs on the two sides(Fig. 2.4).

Implications of this consideration are:(a) Acidic drugs, e.g. aspirin (pKa 3.5) are largelyunionized at acid gastric pH and are absorbedfrom stomach, while bases, e.g. atropine (pKa 10)are largely ionized and are absorbed only whenthey reach the intestines.(b) The unionized form of acidic drugs whichcrosses the surface membrane of gastric mucosal

cell, reverts to the ionized form within the cell(pH 7.0) and then only slowly passes to theextracellular fluid. This is called ion trapping, i.e.a weak electrolyte crossing a membrane toencounter a pH from which it is not able to escapeeasily. This may contribute to gastric mucosal celldamage caused by aspirin.(c) Basic drugs attain higher concentrationintracellularly (pH 7.0 vs 7.4 of plasma).(d) Acidic drugs are ionized more in alkalineurine—do not back diffuse in the kidney tubulesand are excreted faster. Accordingly, basic drugsare excreted faster if urine is acidified.

Lipid-soluble nonelectrolytes (e.g. ethanol,diethyl-ether) readily cross biological membranesand their transport is pH independent.

FiltrationFiltration is passage of drugs through aqueouspores in the membrane or through paracellularspaces. This can be accelerated if hydrodynamicflow of the solvent is occurring under hydrostaticor osmotic pressure gradient, e.g. across mostcapillaries including glomeruli. Lipid-insolubledrugs cross biological membranes by filtration iftheir molecular size is smaller than the diameterof the pores (Fig. 2.3). Majority of cells (intestinalmucosa, RBC, etc.) have very small pores (4 Å)and drugs with MW > 100 or 200 are not able topenetrate. However, capillaries (except those inbrain) have large paracellular spaces (40 Å) andmost drugs (even albumin) can filter through these(Fig. 2.8). As such, diffusion of drugs acrosscapillaries is dependent on rate of blood flowthrough them rather than on lipid solubility ofthe drug or pH of the medium.

Specialized transportThis can be carrier mediated or by pinocytosis.

Carrier transportAll cell membranes express a host of transmem-brane proteins which serve as carriers ortransporters for physiologically important ions,nutrients, metabolites, transmitters, etc. across themembrane. At some sites, certain transporters also

Fig. 2.4: Influence of pH difference on two sides of abiological membrane on the steady-state distribution of aweakly acidic drug with pKa = 6

Chapter 2 Pharmacokinetics: Membrane Transport 13


a. Facilitated diffusion The transporter,belonging to the super-family of solute carrier(SLC) transporters, operates passively withoutneeding energy and translocates the substrate inthe direction of its electrochemical gradient, i.e.from higher to lower concentration (Fig. 2.5A). Itmearly facilitates permeation of a poorly diffusiblesubstrate, e.g. the entry of glucose into muscle andfat cells by GLUT 4.b. Active transport It requires energy, isinhibited by metabolic poisons, and transportsthe solute against its electrochemical gradient(low to high), resulting in selective accumulationof the substance on one side of the membrane.Drugs related to normal metabolites can utilize

Fig. 2.5: Illustration of different types of carrier mediated transport across biological membraneABC—ATP-binding cassettee transporter; SLC—Solute carrier transporter; M—MembraneA. Facilitated diffusion: the carrier (SLC) binds and moves the poorly diffusible substrate along its concentration gradient(high to low) and does not require energyB. Primary active transport: the carrier (ABC) derives energy directly by hydrolysing ATP and moves the substrateagainst its concentration gradient (low to high)C. Symport: the carrier moves the substrate ‘A’ against its concentration gradient by utilizing energy from downhillmovement of another substrate ‘B’ in the same directionD. Antiport: the carrier moves the substrate ‘A’ against its concentration gradient and is energized by the downhillmovement of another substrate ‘B’ in the opposite direction

translocate xenobiotics, including drugs and theirmetabolites. In contrast to channels, which openfor a finite time and allow passage of specific ions,transporters combine transiently with theirsubstrate (ion or organic compound)—undergo aconformational change carrying the substrate tothe other side of the membrane where the substratedissociates and the transporter returns back to itsoriginal state (Fig. 2.5). Carrier transport is specificfor the substrate (or the type of substrate, e.g. anorganic anion), saturable, competitively inhibitedby analogues which utilize the same transporter,and is much slower than flux through channels.Depending on requirement of energy, carriertransport is of two types:

the transport processes meant for these, e.g.levodopa and methyl dopa are actively absorbedfrom the gut by the aromatic amino acidtransporter. In addition, the body has developedsome relatively nonselective transporters, likeP-glycoprotein (P-gp), to deal with xenobiotics.Active transport can be primary or secondarydepending on the source of the driving force.i. Primary active transport Energy is obtaineddirectly by the hydrolysis of ATP (Fig. 2.5B). Thetransporters belong to the superfamily of ATPbinding cassettee (ABC) transporters whose intra-cellular loops have ATPase activity. They mediateonly efflux of the solute from the cytoplasm, eitherto extracellular fluid or into an intracellularorganelli (endoplasmic reticulum, mitochondria,etc.)

Encoded by the multidrug resistance 1 (MDR1) gene,P-gp is the most well known primary active transporterexpressed in the intestinal mucosa, renal tubules, bilecanaliculi, choroidal epithelium, astrocyte foot processesaround brain capillaries (the blood-brain barrier), testicularand placental microvessels, which pumps out manydrugs/metabolites and thus limits their intestinal absorp-tion, penetration into brain, testes and foetal tissues aswell as promotes biliary and renal elimination. Manyxenobiotics which induce or inhibit P-gp also have a similareffect on the drug metabolizing isoenzyme CYP3A4,indicating their synergistic role in detoxification ofxenobiotics.

Other primary active transporters of pharmacologicalsignificance are multidrug resistance associated protein 2(MRP 2) and breast cancer resistance protein (BCRP).ii. Secondary active transport In this type ofactive transport effected by another set of SLCtransporters, the energy to pump one solute isderived from the downhill movement of anothersolute (mostly Na+). When the concentrationgradients are such that both the solutes move inthe same direction (Fig. 2.5C), it is called symportor cotransport, but when they move in oppositedirections (Fig. 2.5D), it is termed antiport orexchange transport. Metabolic energy (fromhydrolysis of ATP) is spent in maintaining hightransmembrane electrochemical gradient of thesecond solute. The SLC transporters mediate bothuptake and efflux of drugs and metabolites.

The organic anion transporting polypeptide (OATP)and organic cation transporter (OCT), highly expressed in

liver canaliculi and renal tubules, are secondary activetransporters important in the metabolism and excretionof drugs and metabolites (especially glucuronides). TheNa+,Cl– dependent neurotransmitter transporters forserotonin and dopamine (SERT and DAT) as well as thevesicular transporter for biogenic amines are active SLCtransporters that are targets for action of drugs like tricyclicantidepressants and reserpine, etc. The absorption ofglucose in intestines and renal tubules is through secondaryactive transport by sodium-glucose transporters (SGLT1and SGLT2).

As indicated earlier, carrier transport (bothfacilitated diffusion and active transport) issaturable and follows the Michaelis-Mentenkinetics. The maximal rate of transport isdependent on the density of the transporter in aparticular membrane, and its rate constant (Km),i.e. the substrate concentration at which rate oftransport is half maximal, is governed by itsaffinity for the substrate. Genetic polymorphismcan alter both the density and affinity of thetransporter protein for different substrates andthus affect the pharmacokinetics of drugs.Moreover, tissue specific drug distribution canoccur due to the presence of specific transportersin certain cells.

Pinocytosis It is the process of transport across the cellin particulate form by formation of vesicles. This is applicableto proteins and other big molecules, and contributes littleto transport of most drugs.

ABSORPTIONAbsorption is movement of the drug from its siteof administration into the circulation. Not onlythe fraction of the administered dose that getsabsorbed, but also the rate of absorption isimportant. Except when given i.v., the drug hasto cross biological membranes; absorption isgoverned by the above described principles. Otherfactors affecting absorption are:

Aqueous solubility Drugs given in solid formmust dissolve in the aqueous biophase before theyare absorbed. For poorly water soluble drugs(aspirin, griseofulvin) rate of dissolution governsrate of absorption. Obviously, a drug given aswatery solution is absorbed faster than when thesame is given in solid form or as oily solution.

Chapter 2 Pharmacokinetics: Drug Absorption 15


Concentration Passive diffusion depends onconcentration gradient; drug given as concen-trated solution is absorbed faster than from dilutesolution.

Area of absorbing surface Larger it is, faster isthe absorption.

Vascularity of the absorbing surface Blood circu-lation removes the drug from the site of absorptionand maintains the concentration gradient acrossthe absorbing surface. Increased blood flowhastens drug absorption just as wind hastensdrying of clothes.

Route of administration This affects drug absorp-tion, because each route has its own peculiarities.

OralThe effective barrier to orally administered drugsis the epithelial lining of the gastrointestinal tract,which is lipoidal. Nonionized lipid solubledrugs, e.g. ethanol are readily absorbed fromstomach as well as intestine at rates proportionalto their lipid : water partition coefficient. Acidicdrugs, e.g. salicylates, barbiturates, etc. arepredominantly unionized in the acid gastric juiceand are absorbed from stomach, while basicdrugs, e.g. morphine, quinine, etc. are largelyionized and are absorbed only on reaching theduodenum. However, even for acidic drugsabsorption from stomach is slower, because themucosa is thick, covered with mucus and thesurface area is small. Absorbing surface area ismuch larger in the small intestine due to villi.Thus, faster gastric emptying accelerates drugabsorption in general. Dissolution is a surfacephenomenon, therefore, particle size of the drug insolid dosage form governs rate of dissolution andin turn rate of absorption.

Presence of food dilutes the drug and retardsabsorption. Further, certain drugs form poorlyabsorbed complexes with food constituents, e.g.tetracyclines with calcium present in milk;moreover food delays gastric emptying. Thus,most drugs are absorbed better if taken in emptystomach. Highly ionized drugs, e.g. gentamicin,

neostigmine are poorly absorbed when givenorally.

Certain drugs are degraded in the gastrointes-tinal tract, e.g. penicillin G by acid, insulin bypeptidases, and are ineffective orally. Entericcoated tablets (having acid resistant coating) andsustained release preparations (drug particlescoated with slowly dissolving material) can beused to overcome acid lability, gastric irritancyand brief duration of action.

The oral absorption of certain drugs is lowbecause a fraction of the absorbed drug is extru-ded back into the intestinal lumen by the effluxtransporter P-gp located in the gut epithelium.The low oral bioavailability of digoxin and cyclo-sporine is partly accounted by this mechanism.Inhibitors of P-gp like quinidine, verapamil,erythromycin, etc. enhance while P-gp inducerslike rifampin and phenobarbitone reduce the oralbioavailability of these drugs.

Absorption of a drug can be affected by otherconcurrently ingested drugs. This may be aluminal effect: formation of insoluble complexes,e.g. tetracyclines with iron preparations andantacids, phenytoin with sucralfate. Suchinteraction can be minimized by administeringthe two drugs at 2–3 hr intervals. Alteration ofgut flora by antibiotics may disrupt theenterohepatic cycling of oral contraceptives anddigoxin. Drugs can also alter absorption by gutwall effects: altering motility (anticholinergics, tri-cyclic antidepressants, opioids, metoclopramide)or causing mucosal damage (neomycin,methotrexate, vinblastine).

Subcutaneous and IntramuscularBy these routes the drug is deposited directly inthe vicinity of the capillaries. Lipid soluble drugspass readily across the whole surface of thecapillary endothelium. Capillaries having largeparacellular spaces do not obstruct absorption ofeven large lipid insoluble molecules or ions (Fig.2.8A). Very large molecules are absorbed throughlymphatics. Thus, many drugs not absorbed orallyare absorbed parenterally. Absorption from s.c.site is slower than that from i.m. site, but both are

generally faster and more consistent/ predictablethan oral absorption. Application of heat andmuscular exercise accelerate drug absorption byincreasing blood flow, while vasoconstrictors, e.g.adrenaline injected with the drug (local anaes-thetic) retard absorption. Incorporation of hyalu-ronidase facilitates drug absorption from s.c.injection by promoting spread. Many depot pre-parations, e.g. benzathine penicillin, protaminezinc insulin, depot progestins, etc. can be givenby these routes.

Topical sites (skin, cornea, mucous membranes)Systemic absorption after topical applicationdepends primarily on lipid solubility of drugs.However, only few drugs significantly penetrateintact skin. Hyoscine, fentanyl, GTN, nicotine,testosterone, and estradiol (see p. 9) have beenused in this manner. Corticosteroids applied overextensive areas can produce systemic effects andpituitary-adrenal suppression. Absorption can bepromoted by rubbing the drug incorporated in anolegenous base or by use of occlusive dressingwhich increases hydration of the skin. Organo-phosphate insecticides coming in contact withskin can produce systemic toxicity. Abradedsurfaces readily absorb drugs, e.g. tannic acidapplied over burnt skin has produced hepaticnecrosis.

Cornea is permeable to lipid soluble, unioni-zed physostigmine but not to highly ionizedneostigmine. Drugs applied as eye drops may getabsorbed through the nasolacrimal duct, e.g.timolol eye drops may produce bradycardia andprecipitate asthma. Mucous membranes of mouth,rectum, vagina absorb lipophilic drugs: estrogencream applied vaginally has produced gynaeco-mastia in the male partner.

BIOAVAILABILITY

Bioavailability refers to the rate and extent ofabsorption of a drug from a dosage form asdetermined by its concentration-time curve inblood or by its excretion in urine (Fig. 2.6). It is ameasure of the fraction (F ) of administered dose

of a drug that reaches the systemic circulation inthe unchanged form. Bioavailability of druginjected i.v. is 100%, but is frequently lower afteroral ingestion because—(a) the drug may be incompletely absorbed.(b) the absorbed drug may undergo first passmetabolism in the intestinal wall/liver or beexcreted in bile.

Fig. 2.6: Plasma concentration-time curves depictingbioavailability differences between three preparations of adrug containing the same amountNote that formulation B is more slowly absorbed than A,and though ultimately both are absorbed to the sameextent (area under the curve same), B may not producetherapeutic effect; C is absorbed to a lesser extent—lowerbioavailability

Incomplete bioavailability after s.c. or i.m. injectionis less common, but may occur due to localbinding of the drug.

Oral formulations of a drug from differentmanufacturers or different batches from the samemanufacturer may have the same amount of thedrug (chemically equivalent) but may not yieldthe same blood levels—biologically inequivalent.Two preparations of a drug are consideredbioequivalent when the rate and extent of bioavai-lability of the drug from them is not significantlydifferent under suitable test conditions.

Before a drug administered orally in soliddosage form can be absorbed, it must break intoindividual particles of the active drug (disinte-gration). Tablets and capsules contain a number

Chapter 2 Pharmacokinetics: Drug Absorption 17


of other materials—diluents, stabilizing agents,binders, lubricants, etc. The nature of these as wellas details of the manufacture process, e.g. forceused in compressing the tablet, may affectdisintegration. The released drug must then dissolvein the aqueous gastrointestinal contents. The rateof dissolution is governed by the inherentsolubility, particle size, crystal form and otherphysical properties of the drug. Differences inbioavailability may arise due to variations indisintegration and dissolution rates.

Differences in bioavailability are seen mostlywith poorly soluble and slowly absorbed drugs.Reduction in particle size increases the rate ofabsorption of aspirin (microfine tablets). Theamount of griseofulvin and spironolactone in thetablet can be reduced to half if the drug particle ismicrofined. There is no need to reduce the particlesize of freely water soluble drugs, e.g. paracetamol.

Bioavailability variation assumes practicalsignificance for drugs with low safety margin(digoxin) or where dosage needs precise control(oral hypoglycaemics, oral anticoagulants). It mayalso be responsible for success or failure of anantimicrobial regimen.

However, in the case of a large number ofdrugs bioavailability differences are negligibleand the risks of changing formulation have oftenbeen exaggerated.

DISTRIBUTION

Once a drug has gained access to the bloodstream, it gets distributed to other tissues thatinitially had no drug, concentration gradientbeing in the direction of plasma to tissues. Theextent of distribution of a drug depends on itslipid solubility, ionization at physiological pH (afunction of its pKa), extent of binding to plasmaand tissue proteins, presence of tissue-specifictransporters and differences in regional bloodflow. Movement of drug proceeds until anequilibrium is established between unbound drug

in plasma and tissue fluids. Subsequently, thereis a parallel decline in both due to elimination.

Apparent volume of distribution (V) Presumingthat the body behaves as a single homogeneouscompartment with volume V into which drug getsimmediately and uniformly distributed

dose administered i.v. V = ——————————– ...(3)plasma concentration

Since in the example shown in Fig. 2.7, the drugdoes not actually distribute into 20 L of bodywater, with the exclusion of the rest of it, this isonly an apparent volume of distribution whichcan be defined as “the volume that wouldaccommodate all the drug in the body, if theconcentration throughout was the same as inplasma”. Thus, it describes the amount of drugpresent in the body as a multiple of that containedin a unit volume of plasma. Considered togetherwith drug clearance, this is a very usefulpharmacokinetic concept.

Lipid-insoluble drugs do not enter cells—V approximates extracellular fluid volume, e.g.streptomycin, gentamicin 0.25 L/kg.

Distribution is not only a matter of dilution,but also binding and sequestration. Drugsextensively bound to plasma proteins are largelyrestricted to the vascular compartment and havelow values, e.g. diclofenac and warfarin (99%bound) V = 0.15 L/kg.

Drugs sequestrated in other tissues may have,V much more than total body water or even bodymass, e.g. digoxin 6 L/kg, propranolol 4 L/kg,morphine 3.5 L/kg, because most of the drug ispresent in other tissues, and plasma concen-tration is low. Therefore, in case of poisoning,drugs with large volumes of distribution are noteasily removed by haemodialysis.

Pathological s

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