K.D. Tripathi essentials of medical pharmacology, 6th ed

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1. 6thEDITION

2. 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, India JAYPEE BROTHERS MEDICAL PUBLISHERS(P)LTD StLouis (USA) • Panama City (Panama) • New Delhi • Ahmedabad • Bengaluru Chennai • Hyderabad � Kochi • Kolkata • Lucknow • Mumbai • Nagpur

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4. Preface ---�--o: c.mprecedented pace of developments over the recent years in the field of drugs (medicines) has -�:::c�er emphasized the relevance of Pharmacology to health professionals. Molecular targets of drug ·:::.on are being defined at greater resolution, refining new drugs design. Practice of medicine is -:.rc:::forming from 'experience (impression) based' to 'evidence based', since more and more credible " � :c:ence from well designed clinical studies is now available on the impact of different treatments � ::- :::1ortality, morbidity and other therapeutic outcomes. The present edition is oriented to reflect :_--o: contemporary advancements. �-dopting the 'prototype drug' approach and a structured, systematic and user-friendly format, �--2 actions, mechanisms, kinetics and toxicological aspects of drugs are described along with the ::- '- :-:rmacological basis of their use and role/status in the therapy of various diseases/conditions. :=: :-: unique synthesis of pharmacology with clinical medicine, the book is designed to be useful ::-: ::.:_--_ to the uninitiated medical student, as well as to prescribing physicians. �-II chapters have been updated to include recently introduced drugs and published information. :...�r2st therapeutic guidelines from leading professional bodies, WHO and National Health :--::- :,::rammes have been incorporated, especially in areas like hypertension, hyperlipidaemias, stroke ::-::-2·. ention, surgical prophylaxis, tuberculosis, leprosy, malaria, and HIV-AIDS. Recent developments - �'-· 2 been highlighted, notably in hormone replacement therapy, aromatase inhibitors, ::- �?hosphonates, selective COX-2 inhibitors, atypical antipsychotic&, therapy of diabetes mellitus, -2?..�t failure, acute coronary syndromes, Alzheimer's disease, parkinsonism, glaucoma, kala azar, ,c�c �-chapter is devoted to the principles of 'rational use of medicines', elements of 'evidence based -�cdicine' and the process of 'new drug development' to reflect current importance of these topics. .:._:-_other new chapter compiles the clinically important drug interactions. Some other topics added • �c drug transporters, pharmacogenornics, pharmacovigilance, expiry date of pharmaceuticals, single �::- :mtiomer drugs, biological response modifiers, prescribing in pregnancy, etc. :ew drugs marketed in India till mid 2007 are included, while obsolete ones are deleted. :::-��equently used drugs and those not available in India are described briefly in extract type. ::::-::>ortant points are summarized in boxes. Leading trade names with dosage forms are given. :=::::1rhasis is placed on the profile of diseases and drug use in India and other tropical cmmtries, � � as to be particularly useful to students and doctors in these regions; a need not well addressed -: � .- :nanv texts. Thanks are due to my colleagues and students for their valuable feedback and suggestions. As :-�2"�·iously, the major impetus for this edition has come from Shri J.P. Vij, the ever agile Chairman • c-a�pee Brothers. Commendable type setting, proof reading and improvement in illustrations has -:-o:2n done respectively by Ms Sunita Katla, Ms Geeta Srivastava and Mr Manoj. The editorial �?...:cagement and moral support of my wife has been a boon. · �2·.·: Delhi KD Tripathi =:.:- :ov. 2007

5. 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; ReceptorPharmacology ........................... 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 utacoids 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 AntigoutDrugs ........................................................................................... 202

6. viii Contents Section 4 Respiratory System Drugs 16. Drugs for Cough and Bronchial Asthma ..................................................................................... 213 Section 5 Hormones ��)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 S 25. Skeletal Muscle Relaxants ............................................................................................................. 339 26. Local Anaesthetics ........................................................................................................................... 351 Section 7 Drugs Acting on Central Nervous Sy&t�fu: 't 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

7. Secti_on 8 Cardiovascular Drugs Contents ix 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

8. 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. AntileproticDrugs ........................................................................................................................... 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 Drug 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 ofEssentialMedicines ....................................................................................... 903 Appendix2: Prescribing in Pregnancy .......................................................................................... 908 Appendix 3: Drugs inBreastfeeding .............................................................................................. 911 Appendix 4: Drugs andFixedDose CombinationsBannedin India .......................................... 915 Index ................................................................................................................................................... 917

9. List ofAbbreviations A-I/II/III AA ABC ABLC AB AC ACE ACh AChE ACT ACTH AD ADE ADH ADP Adr ADR ADS AES AF API AG AGS AHG AI AIDS AlP ALA Angiotensin 1/11/III Amino acid ATP-binding cassette (transporter) Amphotericin B lipid complex Antibody Adenylyl cyclase Angiotensin II converting enzyme Acetylcholine Acetylcholinesterase Artemisinin-based combination therapy Adrenocorticotropic hormone Alzheimer's disease Adverse drug event Antidiuretic hormone Adenosine diphosphate Adrenaline Adverse drug reaction Anti diphtheritic serum Atrial extrasystole Atrial fibrillation Atrial flutter Antigen Antigasgangrene serum Antihaemophilic globulin Aromatase inhibitor Acquired immunodeficiency syndrome Aldosterone induced protein Alanine Am Amikacin AMA Antimicrobial agent AMB Amphotericin B amp Ampoule AMP Adenosine mono phosphate AMPA a-Aminohydroxy methylisoxazole propionic acid ANC Acid neutralizing capacity ANP Atrial natriuretic peptide ANS Autonomic nervous system AP Action potential APC Antigen presenting cell APD Action potential duration aPTT Activated partial thromboplastin time ARB Angiotensin receptor blocker ARC AIDS related complex ARS Anti rabies serum ARV Antiretrovirus 5-ASA 5-Amino salicyclic acid Asc LH AT-III ATG ATP ATPase ATPIII ATS A-V AVP AZT BAL BAN BB BCG BCNU BD �-ARK BHC BHP BI BL BMD BMR BNP BOL BP BPN BRMs BSA BT BuChE BW BZD C-10 CA CaBP CAD CAM cAMP cap CAR CAse CAT CBF CBG Ascending limb of Loop of Henle Antithrombin III Antithymocyte globulin Adenosine triphosphate Adenosine triphosphatase Adult treatment panel III Antitetanic serum Atrioventricular Arginine vasopressin Zidovudine British anti lewisite British approved name Borderline leprosy Bacillus Calmette Guerin Bischloroethyl nitrosourea (Carmustine) Twice daily � adrenergic receptor kinase Benzene hexachloride Benign hypertrophy of prostate Bacillary index Borderline lepromatous leprosy Bone mineral density Basal metabolic rate Brain nartriuretic peptide 2-Bromolysergic acid diethylamide Blood pressure Bisphosphonate Biologic response modifiers Body surface area Borderline tuberculoid leprosy Butyryl cholinesterase Body weight Benzodiazepine Decamethonium Catecholamine Calcium binding protein Coronary artery disease Calmodulin 3', 5' Cyclic adenosine monophosphate Capsule Conditioned avoidance response Carbonic anhydrase Computerized axial tomography Cerebral blood flow Cortisol binding globulin

10. xii Abbreviations CBS CCB CCNU CD CFTR cGMP CGRP CH ChE CHE Chy Chy. rem. CHF CI CL CLcr CMI CMV CNS c.o. CoEn-A COMT cox c.p.s. CPS CPZ CRABP CRBP CRF CSF CTZ cv CVP cvs CWD CYP450 Cys DA DA-BI2 DAD DAG DAM DAMP DAT dDAVP DDS DDT DEC DHA DHE DHFA DHFRase DHP DHT Colloidal bismuth subcitrate Calcium channel blocker Chloroethyl cyclohexyl nitrosourea (!omustine) Collecting duct Cystic fibrosis transport regulator 3', 5' Cyclic guanosine monophosphate Calcitonin gene related peptide Cholesterol Cholinesterase Cholesterol ester Chylomicron Chylomicron remnants Congestive heart failure Cardiac index Clearance Creatinine clearance Cell mediated immunity Cytomegalovirus Central nervous system Cardiac output Coenzyme-A Catechol-0-methyl transferase Cyclooxygenase Cycles per second Complex partial seizures Chlorpromazine Cellular retinoic acid binding protein Cellular retinol binding protein Corticotropin releasing factor Cerebrospinal fluid Chemoreceptor trigger zone Cardiovascular Central venous pressure Cardiovascular system Cell wall deficient Cytochrome P450 Cycloserine Dopamine Deoxyadenosyl cobalamin Delayed after-depolarization Diacyl glycerol Diacetyl monoxime Diphenyl acetoxy-N-methyl piperidine methiodide Dopamine transporter Desmopressin Diarnino diphenyl sulfone (Dapsone) Dichloro diphenyl trichloroethane Diethyl carbamazine citrate Dihydroartemisinin Dihydroergotamine Dihydro folic acid Dihydrofolate reductase Dihydropyridine Dihydrotachysterol D l DIT dl DLE DMA DMARD DMPA DMPP DMT DNA DOC DOCA DOM dopa DOPAC DOSS DOTS DPD DPT DRC DT DT-DA d-TC OTIC DTPA DYN E EACA EAD e.c.f. ECG ECT ED EDTA EEG ELAM-1 P-END ENS ENT EPEC EPO EPP ERP EPSP ER ES ESR ETEC Etm FA FAD 5-FC FDT FEV1 Diabetes insipidus Diiodotyrosine Decilitre Disseminated lupus erythematosu!' Dimethoxy amphetamine Disease modifying antirheumatic dru;;: Depot medroxyprogesterone acetate Dimethyl phenyl piperaziniurn Dimethyl tryptamine/Divalent metal transporter Deoxyribose nucleic acid Deoxycholate Desoxy corticosterone acetate Dimethoxymethyl amphetamine Dihydroxyphenyl alanine 3, 4, Dihydroxyphenyl acetic acid Dioctyl sulfosuccinate Directly observed treatment short course Dihydropyrirnidine dehydrogenase Diphtheria-pertussis-tetanus triple antige:­ Dose-response curve Distal tubule Diphtheria-tetanus double antigen d-Tubocurarine Dacarbazine Diethylene triamine pentaacetic acid Dynorphin Ethambutol Epsilon amino caproic acid Early after-depolarization Extracellular fluid Electrocardiogram Electroconvulsive therapy Erectile dysfunction Ethylene diarnine tetraacetic acid Electroencephalogram Endothelial leukocyte adhesion molecule-1 P-Endorphin Enteric nervous system Extraneuronal amine transporter Enteropathogenic E. coli Erythropoietin End plate potential Effective refractory period Excitatory postsynaptic potential Estrogen receptor Extrasystole Erythrocyte sedimentation rate Enterotoxigenic E. coli Ethionamide Folic acid Flavin adenine dinucleotide 5-Flucytosine Fixed duration therapy (of leprosy) Forced expiratory volume in 1 second

11. FFA Free fatty acid FMN Favin mononucleotide FP FQ FRase FSH 5-FU G GABA GAT GC GCP G-CSF GDP GERD g.f. g.f.r. GH GHRH GHRIH GIP g.i.t. GITS GLP GLUT GM-CSF GnRH GPCR G-6-PD GPI GTCS GTN GTP H HAART Hb HBV HCG HDCV HDL 5-HIAA HES HETE HIV H'vfG-CoA HMW HPA axis HPETE hr HR HRIG HRT 5-HT Ferroportin Fluoroquinolone Folate reductase Follicle stimulating hormone 5-Fluorouracil Genetic Gamma amino butyric acid GABA-transporter Guanylyl cyclase Good clinical practice Granulocyte colony stimulating factor Guanosine diphosphate Gastroesophageal reflux disease Glomerular filtration Glomerular filtration rate Growth hormone Growth hormone releasing hormone Growth hormone release inhibitory hormone Gastric inhibitory peptide/Glucose­ dependent insulinotropic polypeptide Gastrointestinal tract Gastrointestinal therapeutic system Glucagon-like peptide Glucose transporter Granulocyte macrophage colony stimulating factor Gonadotropin releasing hormone G-protein coupled receptor Glucose-6-phosphate dehydrogenase Globus pallidus intema Generalised tonic-clonic seizures Glyceryl trinitrate Guanosine triphosphate Isoniazid (Isonicotinic acid hydrazide) Highly active antiretroviral therapy Haemoglobin Hepatitis B virus Human chorionic gonadotropin Human diploid cell vaccine High density lipoprotein 5-Hydroxyindole acetic acid Hydroxyethyl starch Hydroxyeicosa tetraenoic acid Human immunodeficiency virus Hydroxymethyl glutaryl coenzyme A High molecular weight Hypothalamo-pituitary-adrenal axis Hydroperoxy eicosatetraenoic acid Hour Heart rate Human rabies immuneglobulin Hormone replacement therapy 5-Hydroxytryptamine Abbreviations xiii 5-HTP 5-Hydroxytryptophan HVA Homovanillic acid I IBD IBS ICAM-1 ICSH i.d. IDL IG IGF IL ILEU i.m. INH INR i.o.t. IP3 IP4 IPSP IPV IRS ISA ISH IU IUCD i.v. JAK Kmc KTZ LA LCAT LDL LES leu-ENK LH liq LL LMW LOX LSD LT LVF MAC MAC MAO MAP MAPKinase max MBC MBL MDI MDMA Indeterminate leprosy Inflammatory bowel disease Irritable bowel syndrome Intracellular adhesion molecule-1 Interstitial cell stimulating hormone Intradermal (injection) Intermediate density lipoprotein Immuneglobulin Insulin-like growth factor Interleukin Isoleucine Intramuscular Isonicotinic acid hydrazide International normalized ratio Intraocular tension Inositol trisphosphate Inositol tetrakisphosphate Inhibitory postsynaptic potential Inactivated poliomyelitis vaccine Insulin response substrate Intrinsic sympathomimetic activity Isolated systolic hypertension International unit Intrauterine contraceptive device Intravenous Janus-kinase Kanamycin Ketoconazole Local anaesthetic Lecithin cholesterol acyl transferase Low density lipoprotein Lower esophageal sphincter Leucine enkephalin Luteinizing hormone Liquid Lepromatous leprosy Low molecular weight Lipoxygenase Lysergic acid diethylamide Leukotriene Left ventricular failure Minimal alveolar concentration Mycobacterium avium complex Monoamine oxidase Muscle action potential Mitogen activated protein kinase Maximum Minimum bactericidal concentration Multibacillary leprosy Manic depressive illness Methylene dioxy methamphetamine

12. xiv Abbreviations MDR Multidrug resistant MDT Multidrug therapy (of leprosy) met-ENK Methionine enkephalin mEq milliequivalent methyl B12 Methyl cobalamin Mf Microfilariae MF Multifactorial MHC Major histocompatibility complex MHT Methylene dioxy methamphetamine MI Myocardial infarction MIC Minimal inhibitory concentration MID Multi infarct dementia MIF Migration inhibitory factor min Minimum MIT Monoiodo tyrosine MLCK Myosin light chain kinase MMF Mycophenolate mofetil 6-MP 6-Mercaptopurine MPPT Methylprednisolone pulse therapy MPTP 4-methyl-4-phenyltetrahydro pyridine MRP2 Multidrug resistance associated protein-2 MRSA Methicillin resistant Staphylococcus aureus MSH Melanocyte stimulating hormone Mtx Methotrexate mV millivolt MW Molecular weight NA Noradrenaline NABQI N-acety!-p-benzoquinoneimine NADP Nicotinamide adenine dinucleotide phosphate NADPH Reduced nicotinamide adenine dinucleotide phosphate NAG N-acetyl glucosamine NAM N-acetyl muramic acid NANC Nonadrenergic noncholinergic NAPA N-acetyl procainamide NaSSA Noradrenergic and specific serotonergic antidepressant NAT N-acetyl transferase NCEP National cholesterol education programme NEE Norethindrone enanthate NET Norepinephrine transporter NFAT Nuclear factor of activated T-cell NLEP National leprosy eradication programme NMDA N-methyl-D-aspartate nNOS Neural nitric oxide synthase NNRTI Nonnucleoside reverse transcriptase inhibitor NPY Neuropeptide-Y NR Nicotinic receptor N-REM Non rapid eye movement (sleep) NRTI Nucleoside reverse transcriptase inhibitor NSAID Nonsteroidal antiinflammatory drug NSTEMI Non ST-segment elevation myocardial infarction NTS NVBDCP NYHA OAT OATP oc OCD OCT OD OPG OPV ORS ORT PABA PAE PAF 2-PAM PAN PAS PBI PBPs PBL PCA PCEV PCI PCPA PD PDE PEMA PEP PF PFOR PG PGI2 Pgp PI PIG PIP2 PKA PKC PLA PLc Pl. ph. PnG POMC pp PPA PPARy PPH PPI ppm PPNG PRA PRF Nucleus tractus solitarius National vector borne diseases control programme New York Heart Association Organic anion transporter Organic anion transporting polypeptide Oral contraceptive Obsessive-compulsive disorder Organic cation transporter Once daily Osteoprotegerin Oral poliomyelitis vaccine Oral rehydration salt (solution) Oral rehydration therapy Paraamino benzoic acid Post antibiotic effect Platelet activating factor Pralidoxime Primary afferent neurone Paraamino salicylic acid Protein bound iodine Penicillin binding proteins Paucibacillary leprosy Patient controlled anaesthesia Purified chick embryo cell vaccine (rabies) Percutaneous coronary intervention Parachloro phenylalanine Parkinsons's disease Phosphodiesterase Phenylethyl malonamide Postexposure prophylaxis Purkinje fibre Pyruvate: ferredoxin oxidoreductase Prostaglandin Prostacyclin P-glycoprotein Protease inhibitor Phosphatidyl inositol glycan Phosphatidyl inositol-4,5-bisphosphate Protein kinase: cAMP dependent Protein kinase C Phospholipase A Phospholipase C Platelet phospholipid Penicillin G Pro-opio melanocortin Partial pressure Phenyl propanolamine Paroxysome proliferator-activated receptor y Post partum haemorrhage Proton pump inhibitor Part per million Penicillinase producing N. gonorrhoeae Plasma renin activity Prolactin releasing factor

13. PRIH PSVT PT PICA PTH PIMA PIP PTZ PUV A PVP PVRV QID R RANK RANKL RAS RBC RBP RC RE REM RIG RIMA riNN Prolactin release inhibitory hormone Paroxysmal supra-ventricular tachycardia Proximal tubule Percutaneous transluminal coronary angioplasty Parathyroid hormone Phenyl trimethyl ammonium Post-tetanic potentiation Pentylenetetrazol Psoralen-Ultraviolet A Poly vinyl pyrrolidone Purified verocell rabies vaccine Four times a day Rifampin (Rifampicin) Receptor for activation of nuclear factor KB RANK ligand Renin-angiotensin system Red blood cells Retinol binding protein Respiratory centre Reticuloendothelial Rapid eye movement (sleep) Rabies irnmuneglobulin Reversible inhibitor of MAO-A Recommended international nonproprietary name RMP Resting membrane potential RNA Ribonucleic acid RNTCP Revised National Tuberculosis Control Programme RP Refractory period RTF Resistance transfer factor RXR Retinoid X receptor RyR Ryanodine receptor S Streptomycin SA Sinoauricular (node) SAARD Slow acting antirheumatic drug SABE Subacute bacterial endocarditis s.c. Subcutaneous SCC Short course chemotherapy (of tuberculosis) SCh Succinylcholine SCID Severe combined immunodeficiency disease SERDs Selective estrogen receptor down regulators SERM Selective estrogen receptor modulator SERT Serotonin transporter SGA Second generation antihistaminic SGLT Sodium-glucose transporter SHBG Sex hormone binding globulin s.l. Sublingual SLC Solute carrier SLE Systemic lupus erythematosus SMON Subacute myelo-optic neuropathy SNP SN-PC SN-PR SNRI S.O.S. SIP SPF SPS SR SRS-A SSG SSI SSRis STAT STEMI StK SULT SUR susp sws syr Abbreviations xv Single nucleotide polymorphism Substantia nigra-pars compacta Substantia nigra-pars reticularis Serotonin and noradrenaline reuptake inhibitor as required Sulfonamide + pyrimethamine Sun protection factor Simple partial seizures Sustained release Slow reacting substance of anaphylaxis Sodium stibogluconate Surgical site infection Selective serotonin reuptake inhibitors Signal transducer and activatorof transcription ST-segment elevation myocardial infarction Streptokinase Sulfotransferase Sulfonyl urea receptor Suspension Slow wave sleep Syrup tY, Half life T3 Triiodothyronine r. Thyroxine tab Tablet TAB Typhoid, paratyphoid A and B vaccine TB Tubercle bacilli TBG Thyroxine binding globulin TCII Transcobalamin II TCAs Tricyclic antidepressants TCID50 Tissue culture infectious dose 50% TDM Therapeutic drug monitoring IDS Three times a day Tf Transferrin TG Triglyceride 6-TG 6-Thioguanine THC Tetrahydrocannabinol THFA Tetrahydro folic acid Thio TEPA Triethylene thiophosphoramide THR Threonine TIAs Transient ischaernic attacks TNF-a Tumour necrosis factor a TOD Target organ damage TOF Train of four t-PA Tissue plasminogen activator TPMT Thiopurine methyl transferase t.p.r. Total peripheral resistance TR Thyroid hormone receptor IRE Thyroid hormone response element TRH Thyrotropin releasing hormone TSH Thyroid stimulating hormone TT Tuberculoid leprosy ITS Transdermal therapeutic system TX Thromboxane Tzn Thiacetazone

14. xvi Abbreviations u UDP UFH UGDP UGT USAN UTI Unit Uridine diphosphate Unfractionated heparin University group diabetic programme UDP-glucuronosyl transferase United States adopted name Urinary tract infection v Volt V Volume of distribution VAL Valine VDR Vit D receptor VES Ventricular extrasystole VF Ventricular fibrillation VIP Vasoactive intestinal peptide Vit Vitamin VLDL Very low density lipoprotein VMA VMAT VRE VRSA VRUT VT vWF WBC WCVs WHO WPW XDR-TB Vanillyl mandelic acid Vesicular monoamine transporter Vancomycin resistant enterococci Vancomycin resistant Staphylococcus aureus Vasopressin regulated urea transporter Ventricular tachycardia von Willebrand factor White blood cells Water channel containing vesicles World Health Organization Wolff-Parkinson-White syndrome Extensively drug resistant-TB Z Pyrazinamide ZE (syndrome) Zollinger-Ellison (syndrome)

15. ...,...._-------.· ---- Introduct�!ln,,ftoutes of DrugAdminis'tration INTRODUCTION Pharmacology Pharmacology is the science of drugs (Greek: Pharmacon--d.rug;logos-discoursein) .In a broad sense, it deals with interaction of exogenously adrrllnistered chemical molecules (drugs) with living systems. It encompasses all aspects of knowledge about drugs, but most importantly those that are relevant to effective and safe use for medicinal purposes. For thousands of years mostdrugs werecrude natural products of unknown composition and limited efficacy. Only the overt effects of these substances on the body were rather imprecisely known, but how the same were produced was entirely unknown. Pharmacology as an experi­ mental science was ushered by Rudolf Buchheim who founded the first institute of pharmacology in 1847 in Germany. In the later part of the 19th century, Oswald Schmiedeberg, regarded as the 'father of pharmacology', together with his many disciples like J Langley, T Frazer, P Ehrlich, :J Clark, JJ Abel propounded some of the fun­ -�amental concepts in pharmacology. Since then jrugs have been purified, chemically characteri­ zed and a vast variety of highly potent and :;.elective new drugs have been developed. The mechanism of action including molecular target of many drugs has been elucidated. This has been possible due to prolific growth of pharmacology which forms the backbone of rational thera­ peutics. The two main divisions of pharmacology are pharmacodynamics and pharmacokinetics. Pharmacodynamics (Greek: dynnmis-power) - What the drug does to the body. This includes physiological and biochemical effects of drugs and their mechanism of action at organ system/subcellularImacromolecular levels, e.g.- Adrenaline� interaction with adre­ noceptors � G-protein mediated stimulation of cell membrane bound adenylyl cyclase� increa­ sed intracellular cyclic3',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. paracetarnol is rapidly and almost completely absorbed orally attaining peak blood levels at 30-60 min; 25% bound to plasma proteins, widely and almost uniformly distributed in the body (volume of distribution - lL/kg); extensively

16. 4 General Pharmacology metabolized in the liver, primarily by glucuronide and sulfate conjugation into inactive metabolites which are excreted in urine; has a plasma half life (tVz) of 2-3 hours and a clearance value of 5 ml/kg/min. Drug (French: Drogue-adryherb) Itisthesingle activechemicalentitypresentinamedicinethatis usedfordiagnosis,prevention,treatment/cureof adisease.Thisdiseaseorienteddefinitionofdrug does not include contraceptives or use of drugs for improvement of health. The WHO(1966) has givenamorecomprehensivedefinition-"Drugis anysubstanceorproductthatisusedorisintended to be used to modify or explore physiological systemsorpathologicalstatesforthebenefitofthe recipient." The term 'drugs' is being also used to mean addictiveIabusedIillicit substances. However, this restricted and derogatory sense usage is unfortunatedegradationofa timehonouredterm, and 'drug' should refer to a substance that has some therapeutic/diagnostic application. Some other important aspects of pharmacology are: Pharmacotherapeutics It is the application of pharmacological information together with knowledge of the disease for its prevention, mitigation or cure. Selection of the most appro­ priate drug, dosage and duration of treatment taking into account the specific features of a patient are a part of pharmacotherapeutics. Clinical pharmacology It is the scientific study of drugs in man. It includes pharmacodynamic and pharmacokinetic investigation in healthy volunteers and in patients; evaluation of efficacy and safety of drugs and comparative trials with other forms of treatment; surveillance of patterns of drug use, adverse effects, etc. The aim of clinical pharmacology is to generate data for optimum use of drugs and the practice of'evidence based medicine'. Chemotherapy It is the treatment of systemic infection/malignancy with specific drugs that Section 1 have selective toxicity for the infectingorganism malignant cell with no/minimal effects on th2 host cells. Drugs in general, can thus be divided into: Pharmacodynamic agents These are designee to have pharmacodynamic effects in the recipien: Chemotherapeutic agents These are designed to inhibit/kill invading parasite/ malignant eel: and have noIminimal pharmacodynamic effect� in the recipient. Pharmacy It is the art and science of compoun­ ding and dispensing drugs or preparing suitable dosage forms for administration of drugs to man or animals. It includes collection, identification. purification, isolation, synthesis, standardization and quality control of medicinal substances. The large scale manufacture of drugs is called Phar­ maceutics. It is primarily a technological science. Toxicology It is the study of poisonous effect of drugs and other chemicals (household, environ­ mental pollutant, industrial, agricultural, homi­ cidal) with emphasis on detection, prevention and treatment of poisonings. It also includes the study of adverse effects of drugs, since the same substance can be a drug or a poison, depending on the dose. DRUG NOMENCLATURE A drug generally has three categories of names: (a) Chemical name It describes the substance chemically, e.g.1-(lsopropylamino)-3-(1-naphthy­ loxy)propan-2-olforpropranolol.Thisiscumber­ someandnotsuitableforuseinprescribing.A code name, e.g. RO 15-1788 (later named flumazenil) may be assigned by the manufacturer for con­ venienceand simplicitybeforeanapprovedname is coined. (b) Non-proprietaryname It is thenameaccep­ ted by a competent scientific bodyIauthority, e.g. the United States Adopted Name (USAN) by the USAN council. Similarly, there is the British

17. Chapter 1 Approved name (BAN) of a drug. The non­ proprietary names of newer drugs are kept uniform by an agreement to use the Recommen­ ded International Nonproprietary Name (riNN) in all member countries of the WHO. The BAN of older drugs as well has now been modified to be commensurate with riNN. However, many older drugs still have more than one non-proprietary names, 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 the approvedname. After its appearance in the official publication, it becomes the official name. In common parlance, the termgeneric name is used in place of nonproprietary name. Etymolo­ gically this is incorrect: 'generic' should be applied to thechemicalor pharmacological group (or genus) of the compound, e.g. phenothiazines, tricyclic antidepressants, aminoglycoside anti­ biotics, etc. However, this misnomer is unlikely to be corrected, because of wide usage, including that in official parlance. (c) Proprietary (Brand) name It is the name assigned by the manufacturer(s) and is his property 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 torememberand often suggestive, e.g. LOPRESOR suggesting drug for lowering blood pressure. Brand names generally differ in diffe­ rent countries, e.g. timolol maleate eye drops are marketed as TIMOPTIC in USA but as GLUCOMOL in India.Even the samemanufacturermaymarket the same drug under different brand names in different countries. In addition, combined formulations have their own multiple brand names. This is responsible for much confusion in drug nomenclature. There are many arguments for using the nonproprietary namein prescribing: uniformity, convenience,economy and better comprehension (propranolol, sotalol, timolol, pindolol, metoprolol, acebutolol, atenolol are all �blockers, Introduction 5 but their brand names have no such similarity). However, when it is important to ensure consistency ofthe product in terms of quality and bioavailability, etc. and especially when official control over quality of manufactured products is not rigorous, it is better to prescribe by the dependable brand name. ESSENTIAL DRUGS (MEDICINES) CONCEPT The WHO has defined Essential Drugs*(medicines) as "those that satisfy the priorityhealthcareneeds of the population. They are selected with due regard to public health relevance, evidence on efficacy and safety, and comparative cost effective­ ness. Essential medicines are intended to be available within the context of functioning health systems at all times and in adequate amounts, in appropriate dosage forms, with assured quality and adequate information, and at a price the individual and the community can afford. It has been realized that only a handful of drugs out of the multitude available can meet the health care needs of majority of the people in any country, and that many well tested and cheaper drugs are equally (or more) efficacious and safe as their newer more expensive congeners. For optimum utilization of resources, governments (especially in developing countries) should concentrate on these drugs by identifying them as Essential medicines. The WHO has laid down criteria to guideselection of an essentialmedicine. (a) Adequate data on its efficacy and safety should be available from clinical studies. (b) It should be available in a form in which quality, including bioavailability, and stability on storage can be assured. (c) Its choice should depend upon pattern of prevalent diseases; availability of facilities and trained personnel; financial resources; genetic, demographic and environ­ mental factors. (d) In case of two or more similar medicines, choice should be made on the basis of their relative efficacy, safety, * In the 12th list (2003) the terminology has been changed from "essential drugs" to "essential medicines" to denote pharmaceutical preparations used in clinical healthcare practice, because often the term 'drugs' is understood to mean illicit substances.

18. 6 General Pharmacology quality, price and availability. Cost-benefit ratio should be a major consideration. (e) Choice may also be influenced by comparative pharma­ coldnetic properties and local facilities for manufacture and storage. (f) Most essential medicines should be single compounds. Fixed ratio combination products should be included only when dosage of each ingradient meets the requirements of a defined population group, and when the combination has a proven advantage in therapeutic effect, safety, adherence or in decreasing the emergence of drug resistance. (g) Selection of essential medicines should be a continuous process which should take into account the changing priorities for public health action, epidemiological conditions as well as availability of better medicines/ formulations and progress in pharmacological knowledge. (h) Recently, it has been emphasized to select essential medicines based on rationally developed treatment guidelines. To guide the member countries, the WHO brought out its first Model List ofEssential Drugs along with their dosage forms and strengths in 1977 which could be adopted after suitable modifications according to local needs. This has beenrevisedfromtimetotimeandthecurrentisthe 15thlist(2007). India produceditsNationalEssential Drugs List in 1996 and has revised it in 2003 with the title "National ListofEssentialMedicines". This includes 354 medicines which are considered to be adequate to meet the priority healthcare needsofthegeneralpopulationofthecountry.An alphabetical compilation of the WHO as well as National essential medicines is presented as Appendix-1. Adoption of the essential medicines list for procurement and supply of medicines, especially in the public sector healthcare system, has resulted in improved availability of medicines, cost saving artd more rational use of drugs. Orphan Drugs These are drugs or biological products for diagnosis/treatmenV prevention of a rare disease or condition, or a more common disease (endemic only in resource poor countries) for which there is no reasonable expectation that the cost of developing and marketing it will be recovered from the sales of that drug. The list includes sodium nitrite, fomepizole, liposomal amphotericin 8, ancrod, rifabutin, succimer, somatropin, digoxin immune Fab (digoxin antibody), liothyronine (T3) and many more. Though these drugs may be life saving for some patients, they are Section 1 commercially difficult to obtain. Governments in developed countries offer tax benefits and other incentives to pharmaceutical companies for developing and marketing orphan drugs (e.g. Orphan Drug Act in USA). ROUTES OF DRUG ADMINISTRATION Most drugs can be administered by a variety of routes. The choice of appropriate route in a given situation depends both on drug as well as patient related factors. Mostly common sense consi­ derations, feasibility and convenience dictate the route to be used. 1. Physical and chemicalproperties of the drug (solid/liquid/gas; solubility, stability, pH, irritancy). 2. Site of desired action-localized and appro­ achableorgeneralizedandnotapproachable. 3. Rateand extentofabsorptionofthedrugfrom differentroutes. 4. Effect of digestive juices and first pass metabolism on the drug. 5. Rapidity with which the response is desired (routinetreatmentoremergency). 6. Accuracyofdosage required(i.v. andinhala­ tional can provide fine tuning). 7. Conditionof thepatient(unconscious, vomi­ ting). Routes can be broadly divided into those for (a) Local action and (b) Systemic action. LOCAL ROUTES Theseroutescanonlybeusedforlocalizedlesions at accessible sites and for drugs whose systemic absorption from these sites is minimal or absent. Thus, high concentrations are attained at the desiredsitewithout exposingtherest ofthebody. Systemic side effects or toxicity are consequently absent or minimal. For drugs (in suitable dosage forms) that are absorbed from these sites/routes, the same can serve as systemic route of adminis­ tration, e.g. glyceryl trinitrate (GTN) applied on the skin as ointment or transdermal patch. The local routes are:

19. Chapter 1 1. Topical This refers to external application of the drug to the surface for localized action. It is often more convenient as well as encouraging to the patient. Drugs can be efficiently delivered to the localized lesions on skin, oropharyngeal/ nasal mucosa, eyes, ear canal, anal canal or vagina in the form of lotion, ointment, cream, powder, rinse, paints, drops, spray, lozengens, sup­ positories or pesseries. Nonabsorbable drugs given orally for action on g.i. mucosa (sucralfate, vancomycin), inhalation of drugs for action on bronchi (salbutamol, cromolyn sodium) and irrigating solutions/jellys (povidone iodine, lidocaine) applied to urethra are other forms of topical medication. 2. Deeper tissues Certain deep areas can be approached by using a syringe and needle, but the drugshould be such that systemic absorption is slow, e.g. intra-articular injection (hydrocor­ tisone acetate), infiltration around a nerve or intrathecal injection (lidocaine), retrobulbar injection (hydrocortisone acetate). 3. Arterialsupply Close intra-arterial injection is used for contrast media in angiography; anticancer drugs can be infused in femoral or brachial artery to localise the effect for limb malignancies. SYSTEMIC ROUTES The drug administered through systemic routes is intended to be absorbed into the blood stream and distributed all over, including the site of action, through circulation (see Fig.1.1). 1. Oral Oral ingestion is the oldest and commonest mode of drug administration. It is safer, more con_. venient, does not need assistance, noninvasive, oftenpainless, the medicamentneed not be sterile and so is cheaper. Both solid dosage forms (powders, tablets, capsules, spansules, dragees, moulded tablets, gastrointestinal therapeutic systems--GITs) and liquid dosage forms (elixirs, syrups, emulsions, mixtures) can be given orally. Routes of Drug Administration 7 • Action of drugs is slower and thus not uitable for emergencies. • Unpalatable drugs (chloramphenicol) ar difficult to administer; drug may be filled in capsules to circumvent this. • May cause nausea and vomiting (emetine). • Cannot be used for uncooperative/uncons­ cious/vomiting patient. • Absorptionofdrugsmaybevariableanderratic; certaindrugsare notabsorbed(streptomycin). • Others are destroyed by digestive juices (peni­ cillin G, insulin) or in liver (GTN, testosterone, lidocaine). 2. Sublingual (s.l.) or buccal The tablet or pellet containing the drug is placed under the tongue or crushed in the mouth and spreadover the buccal mucosa.Onlylipid soluble and non-irritating drugs can be so administered. Absorption is relatively rapid-action can be produced in minutes. Though it is somewhat inconvenient, one can spit the drug after the desired effect has been obtained. The chief advantage is thatliveris bypassedanddrugswith highfirstpassmetabolismcanbe absorbed directly into systemic circulation. Drugs given sublin­ gually are--GTN, buprenorphine, desamino­ oxytocin. 3. Rectal Certain irritant and unpleasant drugs can be put into rectum as suppositories or retention enema for systemic effect. This route can also be used when the patient is having recurrent vomiting or is unconscious. However, it is rather inconvenient and embarrassing; absorption is slower, irregular and often unpredictable, though diazepam solu­ tion is rapidly and dependably absorbed from rectum in children. Drug absorbed into external haemorrhoidal veins (about 50%) bypasses liver, but not that absorbed into internal haemor­ rhoidal veins. Rectal inflammation can result from irritant drugs. Diazepam, indomethacin,

20. 8 General Pharmacology Intranasal --�2 spray . . ·. Flrst pass metabolism In lungs (mlnor.extent) Transdermal patch =--- Flrst pass metabolism �--1' inllver . . ./.. . . -- Portal vein -=:---7---f'---- First pass · - - ·"''-------- metabolism in intestinal wall -50% subtec!ed to first pass metabolism Suppository 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 t11rough liver Drug entenng from any systemic route is exposed to first pass metabolism in lungs, but its extent is minor for most drugs.

21. Chapter 1 paraldehyde, ergotamine and few other drugs are some times given rectally. 4. Cutaneous Highly lipid soluble drugs can be applied over the skin for slow and prolonged absorption. The liver is also bypassed. The drug can be incorpo­ rated in an ointment and applied over specified area of skin. Absorption of the drug can be enhanced by rubbing the preparation, by using an oily base and by an occlusive dressing. Transdermal therapeutic systems These are devicesintheform ofadhesivepatchesofvarious shapes and sizes (5-20 cm2) which deliver the contained drug at a constant rate into systemic circulationviathestratumcorneum (Fig.1.2).The drug (insolutionorboundtoapolymer) isheldin areservoirbetweenanocclusivebackingfilm and aratecontrollingrnicroporemembrane,theunder surface of which is smeared with an adhesive impregnated with priming dose of the drug. The adhesive layer is protectedby another film that is tobepeeledoff justbeforeapplication.Thedrug is delivered at the skin surface by diffusion for percutaneous absorption into circulation. The micropore membrane is such that rate of drug deliverytoskinsurfaceislessthantheslowestrate ofabsorption fromskin.Thisoffsets anyvariation intherateofabsorptionaccordingtotheproperties of different sites. As such, the drug is delivered at a constantandpredictablerateirrespectiveofsite of application: usually chest, abdomen, upper arm, lower back, buttock or mastoid region are utilized. --���-_r--- Backing film Drug reservorr ,..--------""":�·/ R�te controJiin %./ m1cropore membrane Adhesive layer with priming dose Capillary Fig. 1.2: Illustration of a transdermal drug delivery system Routes of Drug Administration 9 TransderrnalpatchesofGTN,fentanyl,nicotine andestradiol areavailableinIndia, whilethoseof isosorbide dinitrate, hyoscine, and clonidine are available in other countries. These have been designed to last for 1-7 days in case of different drugs and are becoming increasingly popular, because they provide smooth plasma concentra­ tions of the drug without fluctuations; minimize interindividual variations (drug is subjected to little first pass metabolism) andside effects. They are also more convenient-many patients prefer transdermal patches to oral tablets of the same drug;patientcomplianceisbetter. Localirritation and erythema occurs in some, but is generally mild; can be minimized by changing the site of applicationeachtimebyrotation. Discontinuation has been necessary in 2-7% cases. 5. Inhalation Volatileliquids and gases are given byinhalation for systemic action, e.g. general anaesthetics. Absorption takes place from the vast surface of alveoli-action is very rapid. When administra­ tion is discontinued the drug diffuses ba . ck and is rapidly eliminated in expired air. Thus, control­ led administration is possible with moment to moment adjustment. Irritantvapours (ether) cause inflammation of respiratory tract and increase secretion. 6. Nasal The mucous membrane of the nose can readily absorb many drugs; digestive juices and liver are bypassed. However, only certain drugs like 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 mucosa. The limitations of oral administration are circumvented.

22. 1 0 General Pharmacology Drug action is faster and surer (valuable in emergencies). Gastric irritation and vomiting are not provoked. Parenteral routes can be employed even in unconscious, uncooperative or vomiting patient. There are no chances of interference by food or digestive juices. Liver is bypassed. Disadvantages of parenteral routes are-the preparation has to be sterilized and is costlier, the technique is invasive and painful,assistance of another person is mostly needed (though self injection is possible, e.g. insulin by diabetics), there are chances of local tissue injury and, in general,parenteral route is more risky than oral. The important parenteral routes are: (i) Subcutaneous (s.c.) The drug is deposited in the loose subcutaneous tissue which is richly supplied by nerves (irritant drugs cannot be injected) but is less vascular (absorption is slower than intramuscular). Only small volumes can be injected s.c. Self-injection is possible because deep penetration is not needed. This route should be avoided 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. Some special forms of this route are: (a) Dermojet In this method needle is not used; a high velocity jet of drug solution is projected from a microfine orifice using a gun like imple­ ment. The solution passes through the superficial layers and gets deposited in the subcutaneous tissue. It is essentially painless and suited for mass inoculations. (b) Pellet implantation The drug in the form of a solid pellet is introduced with a trochar and cannula. This provides sustained release of the drug over weeks and months, e.g. DOCA, testosterone. (c) Sialistic (nonbiodegradable) andbiodegradable implants Crystalline drug is packed in tubes or capsules made of suitable materials and implan­ ted under the skin. Slow and uniform leaching of the drug occurs over months providing constant blood levels. The nonbiodegradable implant has Section 1 to be removed later on but not the biodegradable one. This has been tried for hormones and contraceptives (e.g. NORPLANT). (ii) Intramuscular (i.m.) The drug is injectedin one ofthelargeskeletal muscles-deltoid,triceps, gluteus maximus, rectus femoris, etc. Muscle is less richly supplied with sensory nerves (mild irritants can be injected) and is more vascular (absorption ofdrugsin aqueous solution is faster). It is less painful, but self injection is often impracticable becausedeeppenetration is needed. Depot preparations (oily solutions, aqueous suspensions) can be injected by this route. Intramuscular injections should be avoided in anticoagulant treated patients, because it can produce local haematoma. (iii) Intravenous (i.v.) The drug is injected as a bolus (Greek: bolos-lump) or infused slowly over hours in one of the superficial veins. The drug reaches directly into the blood stream and effects are produced immediately (great value in emer­ gency).Theintimaofveinsisinsensitiveanddrug gets diluted with blood, therefore, even highly irritantdrugscanbeinjectedi.v.,buthazardsare­ thrombophlebitisoftheinjectedveinandnecrosis of adjoiningtissuesifextravasationoccurs. These complications can be minimized by diluting the drug or injecting it into a running i.v. line. Only aqueous solutions (not suspensions) can be injected i.v. and there are no depot preparations for this route. The dose of the drug required is smallest (bioavailability is 100%) and even large volumes can be infused. One big advantage with this route is-in case response is accurately measurable (e.g. BP)andthedrugshortacting (e.g. sodium nitroprusside),titration of the dose with theresponse is possible. However,this isthe most risky route-vital organslike heart,brain,etc.get exposed to high concentrations of the drug. (iv) Intradermal injection The drug is injected into the skin raising a bleb (e.g. BCG vaccine, sensitivity testing) or scarring/multiplepunctureof the epidermis through a drop of the drug is done. This route is employed for specific purposes only.

23. c Pharmacokinetics: Membrane Transport, Absorption and Distribution ofDrugs Pharmacokinetics is the quantitative study of drug movement in,through and out of the body. Theoverallschemeof pharmacokinetic processes is depicted in Fig. 2.1. The intensity of respon11e is related to concentration of the drug at the site of action, which in turn is dependent on its pharmacokinetic properties. Pharmacokinetic considerations,therefore,determine the route(s) of administration,dose,latency of onset,time of peak action,duration of action and frequency of administration of a drug. All pharmacokinetic processes involve trans­ port of the drug across biological membranes. Biological membrane This is a bilayer (about 100 A thick) of phospholipid and cholesterol molecules,the polar groups (glyceryl phosphate attached to ethanolamine/choline or hydroxyl group of cholesterol) of these are oriented at the two surfaces and the nonpolar hydrocarbon chains are embedded in the matrix to form a continuous sheet. Extrinsic and intrinsic protein molecules are adsorbed on the lipid bilayer 1BSORPTIOIJ DISTRIBUTION� STORAGE EXCRETION 11 ,_--- 1 Release Site- of action Storage tissue Bound� Free Free � Bound � 1--Drug in -----'�------+ FREEDRUG solution II Bile Faeces ____P_r o _fe_l_!_(�ou _n�d--1·--M- e - T o l lt e • } Urine -l--+ Sweat Saliva BIOTRANSFORMATION Fig. 2.1: Schematic depiction of pharmacokinetic processes

24. 12 General Pharmacology Fig. 2.2: Illustration of the organisation of biological membrane (Fig. 2.2). Glycoproteins or glycolipids areformed on thesurface by attachment to polymeric sugars, aminosugars or sialic acids.The specific lipid and protein composition of different membranes differs according to the cell or the organelle type. The proteins are able to freely float through the membrane: associate and organize or vice versa. Some of theintrinsic ones, which extend through the fullthicknessof themembrane,surround fine aqueous pores. Paracellular spaces or channels also exist between certain epithelial/endothelial cells. Other adsorbed proteins have enzymatic, carrier,receptororsignal transduction properties. Lipid molecules also are capable of lateral move­ ment. Thus, biological membranes are highly dynamic structures. Drugs are transported across the membranes by: (a) Passive diffusion and filtration (b) Specialized transport Passive diffusion The drug diffuses across the membrane in the direction of its concentration gradient, the membrane playing no active role in the process. This is the most important mechanism for majority of drugs; drugs are foreign substances (xenobiotics), and specialized mechanisms are developed by the body primarily for normal metabolites. Higher cone. Lower cone. 0 Section 1 Lipid-soluble drug Nonlipid- soluble drug o 0 o 0 0 0 0 0 0 Aqueous pore/ 0 paracellular 0 0 0 0 space 0 0 0 0 Fig. 2.3: Illustration of passive diffusion and filtration across the lipoidal biological membrane with aqueous pores Lipid soluble drugs diffuse by dissolving in the lipoidal matrix of the membrane (Fig. 2.3), the rate of transport being proportional to the lipid : water partition coefficient of the drug. A more lipid-soluble drug attains higher concentration in the membrane and diffuses quickly. Also, greater the difference in the concentration of the drug on the two sides of the membrane, faster is its diffusion. Influence of pH Most drugs are weak electro­ lytes, i.e. their ionization is pH dependent (contrast strong electrolytes that are nearly completely ionized at acidic as well as alkaline pH). The ionization of a weak acid HA is given by the equation: [K] pH=pKa +log [HA] . ..(1) pKa is the negative logarithm of acidic disso­ ciation constant of the weak electrolyte. If the concentration of ionized drug [A-] is equal to concentration of unionized drug [HA], then [A-] [HA] =1 since log 1 is 0, under this condition pH=pKa .. (2)

25. Chapter 2 pH7 UNIONIZED UNIONIZED 10 10 1l 1l100 IONIZED IONIZED TOTAL" 11 TOTAL= 110

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