Pharmacology Mind Maps

for Medical Students and

Allied Health Professionals
 Pharmacology Mind Maps
for Medical Students and
Allied Health Professionals

Dr. Prasan Bhandari

Associate Professor, Department of Pharmacology
SDM College of Medical Sciences and Hospital, Sattur, Dharwad, Karnataka, India
CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742

© 2020 by Taylor & Francis Group, LLC

CRC Press is an imprint of Taylor & Francis Group, an Informa business

No claim to original U.S. Government works

Printed on acid-free paper

International Standard Book Number-13: 978-1-138-35124-0 (Paperback)

This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to publish reliable
data and information, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be
made. The publishers wish to make clear that any views or opinions expressed in this book by individual editors, authors or contributors are personal
to them and do not necessarily reflect the views/opinions of the publishers. The information or guidance contained in this book is intended for use
by medical, scientific or health-care professionals and is provided strictly as a supplement to the medical or other professional’s own judgement, their
knowledge of the patient’s medical history, relevant manufacturer’s instructions and the appropriate best practice guidelines. Because of the rapid
advances in medical science, any information or advice on dosages, procedures or diagnoses should be independently verified. The reader is strongly
urged to consult the relevant national drug formulary and the drug companies’ and device or material manufacturers’ printed instructions, and
their websites, before administering or utilizing any of the drugs, devices or materials mentioned in this book. This book does not indicate whether
a particular treatment is appropriate or suitable for a particular individual. Ultimately it is the sole responsibility of the medical professional to make
his or her own professional judgements, so as to advise and treat patients appropriately. The authors and publishers have also attempted to trace the
copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been
obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint.

Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any elec-
tronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information
storage or retrieval system, without written permission from the publishers.

For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or con-
tact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that
provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system
of payment has been arranged.

Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation
without intent to infringe.

Library of Congress Cataloging-in-Publication Data

Names: Bhandari, Prasan R., author.

Title: Pharmacology mind maps for medical students and allied health professionals / Prasan R Bhandari.
Description: Boca Raton, FL : CRC Press/Taylor & Francis, 2020. | Includes bibliographical references and index.
Identifiers: LCCN 2019020058| ISBN 9781138351240 (pbk. : alk. paper) | ISBN 9780429023859 (ebook)
Subjects: | MESH: Pharmacological Phenomena | Drug Therapy--methods |
Handbook | Study Guide
Classification: LCC RM301.13 | NLM QV 39 | DDC 615.1076--dc23
LC record available at https://lccn.loc.gov/2019020058

Visit the Taylor & Francis Web site at

http://www.taylorandfrancis.com
and the CRC Press Web site at
http://www.crcpress.com
 Dedicated to:
ALMIGHTY CREATOR
My parents, Mr. Ramchandra G. Bhandari and Mrs. Asha R. Bhandari
My in-laws, Mr. Dayanand A. Kamath and Mrs. Sharada D. Kamath
My sister, Mrs. Veebha (Lochan) V. Prabhu and my brother-in-law, Mr. Vishnu R. Prabhu
My sister-in-law, Mrs. Savita V. Shanbhag and my co-brother, Mr. Vinayak P. Shanbhag
My nephews, Ramnath V. Prabhu and Siddhant V. Shanbhag
My guru, guide, and philosopher, Mr. Dileep Keskar
A special thanks to Mr. Narasimha Bhat and family
(Mahalasa Narayani Temple, Mardol, Goa) for their constant guidance
Lastly, but most importantly, my wife, Mrs. Sangeeta P. Bhandari and
my two lovely daughters, Purva P. Bhandari and Neha P. Bhandari
Contents

Acknowledgments xxi
Preface xxiii
Author xxv

Part I GENERAL PHARMACOLOGY 1

1 Definitions, drug nomenclature, and sources of drugs 2

1.1 Definitions 2
1.2 Drug nomenclature 3
1.3 Sources of drugs 3
2 Routes of drug administration 4
2.1 Factors determining routes of drug administration 4
2.2 Local route 5
2.3 Systemic route 6
2.4 Specialized drug delivery 12
3 Pharmacokinetics and applied aspects 13
3.1 Introduction to pharmacokinetics 13
3.2 Transport of drugs 14
3.3 Drug absorption 15
3.4 First-pass metabolism (presystemic metabolism) 17
3.5 Absorption from parenteral route 17
3.6 Bioavailability and bioequivalence 18
3.7 Drug distribution 19
3.8 Plasma protein binding 20
3.9 Volume of distribution 21
3.10 Redistribution, blood–brain barrier, tissue binding, placental barrier 22
3.11 Factors determining distribution 23
3.12 Drug metabolism (biotransformation) 24
3.13 Pathways of metabolism and phase I reactions 25
3.14 Phase II/synthetic reactions 26
3.15 Enzymes for metabolism 27
3.16 Enzyme induction 28
3.17 Enzyme inhibition 29
3.18 Factors modifying metabolism 29
3.19 Prodrug 30
3.20 Drug excretion 30
3.21 Drug excretion by kidneys 31
3.22 Other routes of drug excretion 32
3.23 Applied pharmacokinetics 33
3.24 Drug dosing factors 34
3.25 Therapeutic drug monitoring 35
3.26 Fixed-dose combination 36
3.27 Methods of prolonging drug action 37

vii
viii Contents

4 Pharmacodynamics 38
4.1 Pharmacodynamics and principles of drug action 38
4.2 Mechanisms of drug action 39
4.3 Receptor 40
4.4 Receptor – Nature, sites, and functions 41
4.5 Drug receptor interaction theories 42
4.6 Receptor families 43
4.7 Receptor families and their transduction mechanisms – Ion channels or ligand-gated ion channels 43
4.8 G-protein coupled receptors (GPCR) 44
4.9 Enzymatic receptors 45
4.10 Nuclear receptor 46
4.11 Receptor regulation 46
4.12 Dose–response relationship 47
4.13 Drug potency 47
4.14 Drug efficacy 48
4.15 Therapeutic index (TI) 48
4.16 Therapeutic window 49
4.17 Drug synergism and antagonism 50
4.18 Factors that modify effects of drugs 51
4.19 Drug interactions 55
5 Adverse drug reactions 56
5.1 Types of adverse drug reactions (ADRs) 56
5.2 General principles of treatment of poisoning (mnemonics [ABCDEFGHI]) 60
5.3 Pharmacovigilance 61
6 New drug approval process and clinical trials 62
6.1 New drug approval process 62
6.2 Phases of clinical trials (0, 1 and 2) 63
6.3 Phases of clinical trials (3 and 4) 64

Part II AUTONOMIC NERVOUS SYSTEM (ANS) PHARMACOLOGY 65

7 Introduction to ANS 66
7.1 Introduction to ANS 66
7.2 Innervations of ANS 67
7.3 Neurotransmitters 68
8 Cholinergic system and drugs 69
8.1 Cholinergic system 69
8.2 Synthesis/transmission/metabolism of ACh 70
8.3 Cholinesterases 70
8.4 Cholinergic receptors 71
8.5 Cholinergic drugs 72
8.6 Actions of ACh 73
8.7 Uses of ACh and cholinomimetics 74
8.8 Adverse reactions of cholinomimetics 74
8.9 Cholinomimetic alkaloids 75
8.10 Glaucoma 76
8.11 Drugs for glaucoma 76
8.12 β blockers in glaucoma 77
8.13 Adrenergic agonists, miotics, and prostaglandin analogs in glaucoma 78
8.14 Carbonic anhydrase inhibitors (CAIs) 78
8.15 Anticholinesterases (AntiChE) 79
8.16 Physostigmine 80
8.17 Neostigmine 80
8.18 Edrophonium 81
8.19 Rivastigmine, donepezil, galantamine, tacrine 81
8.20 Uses of reversible AntiChE 81
8.21 Irreversible AntiChE (organophosphorus compounds) 83
 Contents ix

8.22 Organophosphorus poisoning 84

8.23 Differences between physostigmine and neostigmine 85
9 Anticholinergics 86
9.1 Introduction and classification 86
9.2 Actions 87
9.3 Adverse effects 88
9.4 Uses 89
10 Skeletal muscle relaxants 91
10.1 Introduction 91
10.2 Classification 91
10.3 Peripheral SMRs 92
10.4 Pharmacological actions 93
10.5 Adverse reactions 93
10.6 Synthetic competitive blockers 94
10.7 Depolarizing blockers – Succinylcholine (SCh) 95
10.8 Pharmacological actions 96
10.9 Adverse reactions 97
10.10 Drug interactions 97
10.11 Uses of SMRs 98
10.12 Central SMRs 99
10.13 Tizanidine 100
10.14 Mephenesin, methocarbamol, chlorzoxazone, chlormezanone 100
10.15 Uses 100
10.16 Directly acting SMRs 101
11 Adrenergic system and drugs 102
11.1 Introduction, distribution of SNS, neurotransmitters 102
11.2 Biosynthesis of catecholamines 103
11.3 Adrenergic receptors 104
11.4 Adrenergic drugs (sympathomimetics) – Classification 105
11.5 Catecholamines – Adrenaline – Pharmacological actions 106
11.6 Adverse reactions, contraindications, preparations 108
11.7 Uses of adrenaline 109
11.8 Noradrenaline 110
11.9 Isoprenaline 111
11.10 Dopamine 112
11.11 Dobutamine, fenoldopam 113
11.12 Noncatecholamines – Introduction and ephedrine 114
11.13 Amphetamine 115
11.14 ADRs, uses 116
11.15 Vasopressors 117
11.16 Nasal decongestants 118
11.17 Selective β2-stimulants, anorectics (appetite suppressants) 119
12 Alpha-adrenergic blocking agents (α blockers) 120
12.1 Classification 120
12.2 Pharmacological actions 121
12.3 ADRs 121
12.4 Nonselective α blockers 122
12.5 Selective α1 blockers 123
12.6 Selective α2 blockers 124
12.7 Uses of α blockers 124
13 Beta-adrenergic blockers (β blockers) 126
13.1 Classification 126
13.2 Pharmacological actions 127
13.3 Pharmacokinetics 128
13.4 Uses 128
13.5 Adverse reactions 130
13.6 Drug interactions 131
x Contents

13.7 Contraindications 131

13.8 Cardioselective β blockers 132
13.9 Partial agonists 132
13.10 Some individual β blockers 133

Part III CARDIOVASCULAR PHARMACOLOGY 135

14 Antihypertensives 136
14.1 Introduction 136
14.2 Classification 137
14.3 Diuretics 138
14.4 Angiotensin-converting enzyme (ACE) inhibitors (ACEIs) and ADRs 139
14.5 Angiotensin-converting enzyme (ACE) inhibitors (ACEIs) – Uses, precautions, and contraindications 140
14.6 Angiotensin II receptor blockers (ARBs) 141
14.7 Sympatholytics 142
14.8 Calcium channel blockers 144
14.9 Vasodilators 145
14.10 Management of HT 146
14.11 Drug interactions with antihypertensives, hypertensive crisis, HT in pregnancy,
combination of antihypertensives 147
15 Calcium channel blockers, drug treatment of angina pectoris, and myocardial infarction 148
15.1 Calcium channels 148
15.2 Classification of calcium channel blockers and mechanism of action 149
15.3 Pharmacological actions and pharmacokinetics 150
15.4 Indications 151
15.5 Drug interactions and ADRs 152
15.6 Angina pectoris 153
15.7 Antianginals – Classification 154
15.8 Nitrates – Pharmacological actions 155
15.9 Pharmacokinetics, ADRs, and drug interactions of nitrates 156
15.10 Uses of nitrates 157
15.11 Calcium channel blockers (CCBs), beta blockers (BBs), potassium channel openers,
and others as antianginals 158
15.12 Pharmacotherapy of angina 159
15.13 Combination of antianginals 160
15.14 Unstable angina and treatment 161
15.15 Treatment of myocardial infarction 162
16 Cardiac glycosides and treatment of cardiac failure 163
16.1 Introduction 163
16.2 Congestive cardiac failure (CCF) 164
16.3 Cardiac glycosides 165
16.4 Pharmacological actions 166
16.5 Mechanism of action, pharmacokinetics, digitalization 167
16.6 Adverse effects 168
16.7 Drug interactions, uses, precautions, and contraindications 169
16.8 Drugs for CCF, diuretics 170
16.9 Vasodilators 171
16.10 Positive inotropic agents 172
17 Antiarrhythmics 173
17.1 Arrythmias 173
17.2 Classification of antiarrythmics 174
17.3 Sodium channel blockers (Class IA) and quinidine 175
17.4 Sodium channel blockers (Class IA) and procainamide, disopyramide, and uses of class 1A drugs 176
17.5 Class IB drugs – Lignocaine, phenytoin, and mexiletine 177
17.6 Class IC drugs and Class II drugs 178
17.7 Class III drugs and amiodarone 179
17.8 Class IV drugs and miscellaneous agents 180
 Contents xi

18 Diuretics and antidiuretics 181

18.1 Classification 181
18.2 High-efficacy/high-ceiling/loop diuretics 182
18.3 Other loop diuretics and uses 183
18.4 ADRs 184
18.5 Drug interactions and contraindications 185
18.6 Thiazides and thiazide-like diuretics 186
18.7 Other thiazide diuretics and ADRs 187
18.8 Potassium-sparing diuretics 188
18.9 Carbonic anhydrase (CA) inhibitors (CAIs) 189
18.10 Osmotic diuretics 190
18.11 Newer diuretics 191
18.12 Table on differences between diuretics 192
18.13 Antidiuretics 193
19 Pharmacotherapy of shock 194
19.1 Plasma expanders 194
19.2 Dextrans 195
19.3 Gelatin products 196
19.4 Hydroxyethyl starch 196
19.5 Polyvinylpyrrolidone 197
19.6 Human albumin 197
19.7 Intravenous fluids 198

Part IV CENTRAL NERVOUS SYSTEM (CNS) PHARMACOLOGY 199

20 Introduction to CNS and alcohol 200

20.1 Introduction to CNS, CNS neurotransmitters, excitatory neurotransmitters,
inhibitory neurotransmitters 200
20.2 Alcohols, ethyl alcohol – Introduction and actions 201
20.3 Mechanism of action, pharmacokinetics, drug interaction, and uses 202
20.4 Disulfiram 203
20.5 Drugs to treat alcohol dependence 203
20.6 Methyl alcohol (methanol) 204
21 Sedative hypnotics 205
21.1 Introduction to sedative hypnotics 205
21.2 Classification 206
21.3 Mechanism of action 207
21.4 Pharmacological actions 208
21.5 Advantages of BZDs over barbiturates 209
21.6 Pharmacokinetics and ADRs 210
21.7 Uses of BZDs and BZD antagonist 211
21.8 Newer agents 212
21.9 Barbiturates classification, mechanism of action, and pharmacological action 213
21.10 Pharmacokinetics, adverse reactions, and uses 214
22 Antiepileptics 215
22.1 Antiepileptics classification and mechanism of action 215
22.2 Phenytoin 216
22.3 Phenobarbitone 217
22.4 Carbamazepine and ethosuximide 218
22.5 Valproic acid 219
22.6 Benzodiazepines 220
22.7 Newer antiepileptics 221
23 Antidepressants 222
23.1 Classification of antidepressants and selective serotonin reuptake inhibitors (SSRIs) 222
23.2 Tricyclic antidepressants (TCAs) 223
23.3 Selective serotonin – Norepinephrine reuptake inhibitors (SNRIs), 5-HT2 antagonists,
and atypical antidepressants 224
xii Contents

23.4 Monoamine oxidase (MAO) inhibitors 225

23.5 Uses of antidepressants 226
24 Mood stabilizers and lithium 227
24.1 Mood stabilizers – Introduction and lithium 227
24.2 Pharmacokinetics, ADRs, and uses 228
24.3 Riluzole and nonconventional mood stabilizers 229
25 Antipsychotics 230
25.1 Antipsychotics classification 230
25.2 Chlorpromazine (CPZ) – Mechanism of action 231
25.3 Adverse effects 233
25.4 Drug interactions and uses 235
25.5 Individual antipsychotics 236
25.6 Atypical antipsychotics 237
25.7 Other antipsychotics 238
25.8 Anxiolytics (nonbenzodiazepines) 239
26 Drug treatment of Parkinsonism and Alzheimer’s disease 240
26.1 Classification of antiparkinsonian drugs 240
26.2 Dopamine precursor – Levodopa 241
26.3 Carbidopa and benserazide, dopamine releasers 242
26.4 Dopamine receptor agonists and dopamine metabolism inhibitors 243
26.5 Central anticholinergics and drug-induced parkinsonism 244
26.6 Drugs for Alzheimer’s disease (AD) 245
27 General anesthetics (GA) 246
27.1 Mechanism of action and classification 246
27.2 Inhalational anesthetics and factors determining anesthetic PP in brain 247
27.3 Nitrous oxide 248
27.4 Halothane and congeners 249
27.5 Intravenous anesthetics and inducing agents 250
27.6 Dissociative anesthesia (ketamine) 251
27.7 Neuroleptanalgesia and benzodiazepines 252
27.8 Preanesthetic medication and balanced anesthesia 253
28 Local anesthetics (LA) 254
28.1 Local anesthetics (LA) – Introduction, history, and classification 254
28.2 Chemistry and mechanism of action 255
28.3 Actions, pharmacokinetics, and ADRs 256
28.4 Individual agents 257
28.5 Uses of LAs 258
29 Opioid analgesics 260
29.1 Opioid analgesics classification 260
29.2 Morphine and mechanism of action 261
29.3 Pharmacological actions 262
29.4 Pharmacokinetics and adverse effects 264
29.5 Dependence 265
29.6 Precautions and contraindications 266
29.7 Other opioids 267
29.8 Pethidine derivatives – Fentanyl 268
29.9 Methadone, dextropropoxyphene, and ethoheptazine 269
29.10 Uses of morphine and congeners 270
29.11 Mixed agonists and antagonists 272
29.12 Opioid antagonists 273
30 CNS stimulants/drugs of abuse 274
30.1 CNS stimulants – Classification and respiratory stimulants 274
30.2 Psychomotor stimulants/methylxanthines – Actions 275
30.3 Methylxanthines – Pharmacokinetics, adverse effects, and uses 276
30.4 Nootropics 277
30.5 Drugs of abuse – Opioids, CNS stimulants, and CNS depressants 278
 Contents xiii

30.6 Hallucinogens 279

30.7 Cannabinoids and drugs for tobacco withdrawal 280

Part V AUTACOID PHARMACOLOGY 281

31 Autacoids, histamine and antihistaminics 282

31.1 Autacoids – Introduction, classification of autacoids and histamine 282
31.2 Mechanism of action and histamine releasers 283
31.3 Actions, uses, and ADRs 284
31.4 Antihistamines – Classification and pharmacological actions 285
31.5 Adverse effects, drug interactions, and second-generation antihistaminics 286
31.6 Uses of antihistaminics 287
31.7 Drugs for vertigo 288
32 5-Hydroxytryptamine agonists and antagonists and drug treatment of migraine 289
32.1 5-Hydroxytryptamine – Introduction 289
32.2 5-HT receptors 290
32.3 5-HT agonists 291
32.4 5-HT antagonists 292
32.5 Ergot alkaloids 293
32.6 Drug treatment of migraine 294
33 Eicosanoids and leukotrienes 295
33.1 Eicosanoids – Introduction and synthesis 295
33.2 Prostaglandins and thromboxanes – Mechanism of action and actions 296
33.3 ADR 298
33.4 Uses 298
33.5 Leukotrienes – Introduction, actions, leukotriene antagonists and platelet-activating factor 299
34 Nonsteroidal anti-inflammatory drugs (NSAIDs) 300
34.1 Analgesics 300
34.2 Aspirin-type of analgesics vs. opioid-type of analgesics 300
34.3 NSAIDs classification 301
34.4 Mechanism of action 302
34.5 Salicylates 303
34.6 Pharmacological actions 304
34.7 Important pharmacokinetic aspects and doses 308
34.8 Major adverse effects 309
34.9 Precautions and contraindications 311
34.10 Indications 312
34.11 Why use of aspirin is currently restricted and drug interactions 314
34.12 Pyrazolone derivatives 315
34.13 Indole acetic acid derivatives 316
34.14 Propionic acid derivatives 317
34.15 Anthranilic acid derivatives 318
34.16 Enolic acid derivatives 319
34.17 Alkalones 320
34.18 Aryl-actetic acid derivatives 321
34.19 Preferrential COX-2 inhibitors 322
34.20 Para-aminophenol derivatives, paracetamol and pharmacokinetic aspects 323
34.21 Adverse effects 324
34.22 Uses 325
34.23 Selective COX-2 inhibitors 326
34.24 Choice of NSAIDs 327
35 Drugs used in rheumtoid arthritis and gout 328
35.1 Drugs used in rheumatoid arthritis – Classification 328
35.2 NSAIDs and immunosuppressants 329
35.3 Biological agents 330
xiv Contents

35.4 Inhibitors of T-cell activation, IL-1 antagonist, and anti-B lymphocyte antibody 332
35.5 Gold salts 333
35.6 Other antirheumatic drugs 334
35.7 Classification of drugs for gout and colchicine 335
35.8 NSAIDs, allopurinol, and febuxostat 336
35.9 Uricosuric drugs 337

Part VI RESPIRATORY PHARMACOLOGY 339

36 Drugs used in the treatment of bronchial asthma and chronic obstuctive pulmonary
disorders (COPD) 340
36.1 Classification of drugs for bronchial asthma 340
36.2 Sympathomimetics 341
36.3 Methylxanthines 342
36.4 Anticholinergics 343
36.5 Anti-inflammatory drugs 344
36.6 Anti-inflammatory drugs – Uses, inhalation steroids 345
36.7 Mast cell stabilizers 346
36.8 Leukotriene receptor antagonists (LRA) and anti-IgE antibody 347
36.9 Treatment of bronchial asthma 348
36.10 Management of chronic obstructive pulmonary disease (COPD)/chronic obstructive
lung disease (COLD) 349
36.11 Aerosols in asthma 350
37 Drugs used in the treatment of cough 351
37.1 Antitussives and central cough suppressants 351
37.2 Pharyngeal demulcents and expectorants 352
37.3 Mucolytics and drugs causing cough 353

Part VII HEMATOLOGICAL PHARMACOLOGY 355

38 Hematinics 356
38.1 Introduction and iron absorption 356
38.2 Iron metabolism and requirements 357
38.3 Iron preparations – Oral and parenteral 358
38.4 Uses of iron and ADRs 359
38.5 Maturation factors and vitamin B12 360
38.6 Deficiency, preparations, and uses 361
38.7 Folic acid (FA) 362
38.8 Hematopoietic growth factor and erythropoietin 363
38.9 Myeloid growth factors, megakaryocyte growth factors, and interleukins 364
39 Hemostatic agents 365
39.1 Local agents/styptics 365
39.2 Systemic agents 366
39.3 Sclerosing agents 368
40 Anticoagulants 369
40.1 Anticoagulants – Classification 369
40.2 Parenteral anticoagulants – Heparin 370
40.3 ADRs and contraindications of heparin 371
40.4 Low-molecular-weight heparins (LMWHs) and heparin antagonist 372
40.5 Synthetic heparin derivatives, heparinoids, and parenteral direct thrombin inhibitors 373
40.6 Oral anticoagulants – Mechanism of action and pharmacokinetics (warfarin) 374
40.7 Uses and ADRs of warfarin 375
40.8 Drug interactions of warfarin 376
40.9 Oral direct thrombin inhibitors 377
40.10 Differences between heparin vs. LMW heparin 378
40.11 Differences between heparin and dicumarol/warfarin 378
 Contents xv

41 Antiplatelet agents 379

41.1 Classification and aspirin 379
41.2 Purinergic receptor (P2Y12) antagonists/ADP antigonists and phosphodiesterase (PDE)
inhibitors 380
41.3 Glycoprotein IIB/IIIA receptor antagonists and miscellaneous 381
41.4 Uses of antiplatelet agents 382
42 Thrombolytics (fibrinolytics) and antifibrinolytics 383
42.1 Thrombolytics (fibrinolytics) – Introduction, classification, and individual agents 383
42.2 Uses, ADRs, and contraindications 384
42.3 Antifibrinolytics – Uses and contraindications 385
43 Hypolipidemic drugs 386
43.1 Classification of hypolipidemics 386
43.2 HMG-CoA reductase inhibitors (statins) 387
43.3 Fibric acids (fibrates) 388
43.4 Bile acid binding resins (BAB – resins) 389
43.5 Nicotinic acid or niacin 390
43.6 Dietary cholesterol absorption inhibitor, gugulipid, and omega-3 fatty acids 391

Part VIII GASTROINTESTINAL PHARMACOLOGY 393

44 Drug therapy of peptic ulcer and GERD 394

44.1 Classification of drugs used for peptic ulcer 394
44.2 Antacids – Introduction, types, and systemic antacids 395
44.3 Nonsystemic antacids 396
44.4 Use, ADRs, and drug interactions 397
44.5 Proton pump inhibitors (PPIs) 398
44.6 H2-receptor blockers 399
44.7 Antimuscarinic agents and prostaglandin analogs 400
44.8 Ulcer protectives 401
44.9 Miscellaneous agents 402
44.10 Anti-H. pylori agents 403
44.11 Gastroesophageal reflux disease (GERD) – Management 404
45 Emetics and antiemetics 405
45.1 Neurotransmitters and drugs involved in vomiting 405
45.2 Emetics 406
45.3 Classifications of antiemetics 407
45.4 5-HT3 receptor antagonists (5-HT3RA) 408
45.5 Dopamine D2 receptor antagonists (prokinetics) 409
45.6 Metoclopramide 410
45.7 Domperidone, cholinomimetics, anticholinesterases, and motilin receptor agonists 411
45.8 Anticholinergics and antihistaminics (H1 blockers) 412
45.9 Neuroleptic, neurokinin receptor antagonists, and cannabinoids 413
45.10 Adjuvants and preferred antiemetics 414
46 Drug treatment of constipation, treatment of IBS, and IBD 415
46.1 Introduction and classification 415
46.2 Bulk laxatives 416
46.3 Stool softeners 417
46.4 Stimulant purgatives 418
46.5 Osmotic purgatives 419
46.6 Miscellaneous agents and use of laxatives/purgatives 420
46.7 Drugs causing constipation, laxative abuse, and nonpharmacological measures 421
46.8 Treatment of irritable bowel syndrome (IBS) 422
46.9 Inflammatory bowel diseases (IBD) and treatment 423
47 Drug treatment of diarrhea 425
47.1 Principles of diarrhea treatment and ORS 425
47.2 Specific therapy 426
47.3 Antimotility and antisecretory agents and adsorbants 427
xvi Contents

47.4 Antisecretory agents and probiotics 428

47.5 Antispasmodics 429

Part IX ENDOCRINE PHARMACOLOGY 431

48 Hypothalamic and pituitary hormones 432

48.1 Hypothalamic and pituitary hormones – Types, modes, and mechanism of action 432
48.2 Hypothalamic hormones 433
48.3 Anterior pituitary hormones 434
48.4 Growth hormone (somatotrophin) 435
48.5 Corticotropin (adrenocorticotropic hormone – ACTH), thyroid-stimulating hormone
(TSH, thyrotrophin), and gonadotropins 436
48.6 Prolactin 437
48.7 Hyperprolactemia and dopamine receptor agonists 438
49 Thyroid hormones and antithyroid agents 439
49.1 Thyroid hormones – Regulation and synthesis 439
49.2 Mechanism of action, preparations, and therapeutic uses 440
49.3 Hyperthyroidism and classification of antithyroid drugs 441
49.4 Thioamides (thiourea derivatives) 442
49.5 Anion inhibitors 444
49.6 Iodine and iodides 445
49.7 Radioactive iodine (131I) 446
49.8 Management of thyrotoxic crisis (thyroid storm) 447
49.9 Differences between propylthiouracil and methimazole (carbimazole) 448
50 Estrogen, progestins, and hormonal contraceptives 449
50.1 Estrogens – Types and mechanism of action 449
50.2 Actions and pharmacokinetics 450
50.3 Uses, ADRs, and preparations 451
50.4 Antiestrogens 452
50.5 Selective estrogen receptor modulators (SERMs) and estrogen synthesis inhibitors 453
50.6 Progestins – Types, actions, and pharmacokinetics 454
50.7 Uses and ADRs of progestins 455
50.8 Antiprogestins 456
50.9 Drug treatment of menopausal symptoms 457
50.10 Types of hormonal contraceptives 458
50.11 Combined estrogen (E) and progestin (P) preparations 459
50.12 Benefits of hormonal contraception and contraindications 460
50.13 Single preparations and postcoital (emergency contraception) pill 461
50.14 Parenteral contraceptives 462
50.15 Devices and mechanism of action of contraceptives 463
50.16 Adverse effects, drug interactions, and centchroman 464
51 Androgens and anabolic steroids 465
51.1 Androgens – Physiology, classification, actions, and mechanism of action 465
51.2 Therapeutic uses, adverse effects, and precautions and contraindications 466
51.3 Anabolic steroids 467
51.4 Antiandrogens 468
51.5 Male contraceptives and drugs for male sexual dysfunction
(erectile dysfunction/impotence) 469
52 Corticosteroids 470
52.1 Corticosteroids – Introduction, structure synthesis, and release 470
52.2 Mechanism of action and pharmacokinetics 471
52.3 Glucocorticoid actions 472
52.4 Therapeutic uses 473
52.5 Adverse effects 475
52.6 Contraindications 477
52.7 Preparations and classifications 478
 Contents xvii

53 Insulin and oral antidiabetic agents 479

53.1 Insulin regulation and glucose transporters (GLUT) 479
53.2 Actions of insulin and mechanism of action 480
53.3 Pharmacokinetics and preparations 481
53.4 Unitage and dosage, human insulins, and insulin analogs 482
53.5 Insulin devices and use of insulin 483
53.6 Adverse effects and drug interactions 484
53.7 Oral antidiabetic agents – Classification 485
53.8 Sulfonylureas 486
53.9 Biguanides and meglitinide analogs 487
53.10 Thiazolidinediones (TZD) and alpha-glucosidase inhibitor 488
53.11 New drugs for diabetes mellitus 489
54 Agents affecting calcium balance 491
54.1 Calcium preparations and uses 491
54.2 Parathyroid hormone (PTH) 492
54.3 Calcitonin 493
54.4 Vitamin D 494
54.5 Bisphosphonates 495
54.6 Prevention and treatment of osteoporosis, and drugs of abuse in sports 496
55 Drugs acting on uterus 497
55.1 Uterine stimulants 497
55.2 Uterine relaxants (tocolytics) 500
55.3 Differences between oxytocin and ergometrine 501

Part X CHEMOTHERAPY 503

56 General chemotherapy 504

56.1 Definitions and classifications 504
56.2 Classifications 505
56.3 Classification, factors influencing successful chemotherapy, and antimicrobial
resistance 506
56.4 Antimicrobial resistance 507
56.5 Selection of appropriate AMA 508
56.6 AMA combinations 510
56.7 Chemoprophylaxis 511
56.8 Superinfection (suprainfection) 512
57 Beta-lactam antibiotics 513
57.1 Penicillins 513
57.2 Natural penicillins 514
57.3 Semisynthetic penicillins 515
57.4 Aminopenicillin 516
57.5 Antipseudomonal penicillins 517
57.6 Ureidopenicillins and amidinopenicillins 518
57.7 β-lactamase inhibitors 519
57.8 Cephalosporins 520
57.9 Cephalosporins – ADRs and use 521
57.10 Carbapenems 522
57.11 Carbacephems and monobactams 524
58 Sulfonamides 525
58.1 Sulfonamides – Introduction, classification, spectrum, mechanism of action,
and resistance 525
58.2 Sulfonamides – Pharmacokinetics, adverse effects, and uses 526
58.3 Cotrimoxazole 527
59 Chemotherapy of urinary tract infections and sexually transmitted diseases 528
59.1 Chemotherapy of UTI – Antimicrobials 528
59.2 Urinary analgesics 529
59.3 Chemotherapy of sexually transmitted diseases 530
xviii Contents

60 Quinolones 531
60.1 Fluoroquinolones (ciprofloxacin) 531
60.2 Individual agents 532
61 Macrolides 533
61.1 Macrolides 533
61.2 Individual macrolides and comparison 534
62 Broad-spectrum antibiotics – Tetracyclines and chloramphenicol 535
62.1 Tetracyclines – Introduction, classification, and mechanism of action 535
62.2 Spectrum of activity and resistance 536
62.3 Pharmacokinetics and administration 537
62.4 Adverse effects 538
62.5 Uses 539
62.6 Contraindications and advantages/features of doxycyline and minocycline 540
62.7 Compare/contrast – Tetracycline vs. doxycycline 541
62.8 Chloramphenicol – Mechanism of action, spectrum of activity, mechanism of resistance,
and pharmacokinetics 542
62.9 Adverse effects, drug interactions, and uses 543
62.10 Tigecycline 544
63 Aminoglycosides 545
63.1 Introduction and common properties 545
63.2 Spectrum, mechanism of action, and mechanism of resistance 546
63.3 Pharmacokinetics and ADRs 547
63.4 ADRs and precautions 548
63.5 Uses of gentamicin 549
63.6 Other aminoglycosides 550
64 Miscellaneous antibiotics 551
64.1 Lincosamides, glycopeptides, and teicoplanin 551
64.2 Polypeptide antibiotics 552
64.3 Fosfomycin, streptogramins, oxazolidinones, and daptomycin 553
65 Chemotherapy of tuberculosis (TB) 554
65.1 Introduction and classification 554
65.2 First-line drugs – Isoniazid 555
65.3 Rifampicin (rifampin) 556
65.4 Pyrazinamide, ethambutol, and streptomycin 557
65.5 Second-line drugs 558
65.6 Treatment of tuberculosis – Objectives and regimens 559
65.7 Doses of commonly used anti-TB drugs 560
65.8 WHO guidelines for TB treatment 561
65.9 DOTS, TB treatment regimens 562
65.10 Multidrug-resistant tuberculosis (MDR-TB), TB in HIV patients, TB in pregnancy, chemoprophylaxis
of TB, role of glucocorticoids in TB, and drugs for Mycobacterium avium complex (MAC) 563
66 Chemotherapy of leprosy 564
66.1 Drugs used in leprosy 564
66.2 Dapsone (DDS), rifampicin, clofazimine, ethionamide, and newer agents 565
66.3 Treatment of leprosy and lepra reactions 566
67 Chemotherapy of malaria 567
67.1 Classification of antimalarials 567
67.2 Chloroquine – Mechanism of action and resistance 568
67.3 Pharmacokinetics and adverse effects 569
67.4 Uses 570
67.5 Precautions and contraindications 571
67.6 Mefloquine and halofantrine 572
67.7 Primaquine 573
67.8 Quinine 574
67.9 Folate antagonist – Pyrimethamine 575
67.10 Proguanil (chloroguanide) and atovaquone 576
67.11 Artemisinin and derivatives 577
 Contents xix

67.12 Regimens for malaria chemoprophylaxis 579

67.13 Regimens for malaria treatment 580
68 Drugs for amebiasis/pneumocystosis/leishmaniasis/trypanosomiasis 581
68.1 Introduction and drugs – Classification 581
68.2 Metronidazole (MTZ) 582
68.3 Emetine and dehydroemetine, diloxanide furoate (DF) 583
68.4 Nitazoxanide, iodoquinol, and quiniodochlor 584
68.5 Paromomycin, tetracycline, and chloroquine 585
68.6 Treatment of amebiasis, treatment of pneumocystosis 586
68.7 Treatment of leishmaniasis 587
68.8 Drugs for dermal leishmaniasis (Oriental sore), treatment of trypanosomiasis 588
69 Antiviral drugs 589
69.1 Antiviral drugs – Classification 589
69.2 Antiherpes agent – Acyclovir 590
69.3 Other antiherpes drugs 591
69.4 Antiinfluenza virus agents 592
69.5 Antihepatitis drugs 593
69.6 Antiretroviral drugs – Introduction and classification 594
69.7 Nucleoside reverse transcription inhibitors (NRTIs) 595
69.8 Other NRTIs 596
69.9 Protease inhibitors (PIs) 597
69.10 Non-nucleoside reverse transcriptase inhibitors (NNRTIs) 598
69.11 Entry inhibitor 599
70 Antifungal drugs 600
70.1 Classification of antifungal drugs 600
70.2 Antifungal antibiotics – Amphotericin B (AMB) 601
70.3 Nystatin, Griseofulvin 602
70.4 Antimetabolites 603
70.5 Azoles 604
70.6 Ketoconazole 605
70.7 Fluconazole 606
70.8 Itraconazole 607
70.9 Topical azoles 608
70.10 Miscellaneous – Terbinafine 608
70.11 Echinocandins or pneumocandins 609
70.12 Topical antifungals and newer agents 610
70.13 Drugs used in superficial mycoses 610
70.14 Drugs for systemic fungal infections 611
71 Anthelmintics 612
71.1 Mebendazole 612
71.2 Albendazole, pyrantel pamoate, piperazine citrate 613
71.3 Praziquantel 614
71.4 Levamisole and niclosamide 615
71.5 Diethylcarbamazine (DEC) 616
71.6 Ivermectin 617
71.7 Miscellaneous 618
71.8 Preferred drugs for helmintic infestations 619
71.9 Drugs for scabies and treatment of pediculosis 620
72 Antiseptics and disinfectants 621
72.1 Definition and classification 621
72.2 Biguanides 622
72.3 Phenols 623
72.4 Halogens 624
72.5 Alcohols 625
72.6 Surface active agents 625
72.7 Metallic salts 626
72.8 Aldehydes 627
xx Contents

72.9 Acids 628

72.10 Gases 629
72.11 Oxidizing agents 630
72.12 Dyes 630
73 Cancer chemotherapy 631
73.1 Introduction and phases of cell cycles 631
73.2 Common adverse effects of anticancer agents and measures to prevent adverse effects 632
73.3 Classification of anticancer agents 633
73.4 Alkylating agents and nitrogen mustards 634
73.5 Other alkylating agents, alkyl sulfones, and nitrosureas 635
73.6 Platinum-containing compounds 636
73.7 Antimetabolites – Folate antagonists – Methotrexate (MTX) 637
73.8 Purine – Antagonists and pyrimidine antagonist 638
73.9 Natural products – Plant products: Vinca alkaloids 639
73.10 Anticancer antibiotics 640
73.11 Enzymes 641
73.12 Hormonal agents 642
73.13 Biological response modifiers 643
73.14 Miscellaneous 644
73.15 Monoclonal antibodies and radioactive isotopes 645
73.16 Resistance to anticancer drugs and general principles of cancer treatment 646

Part XI MISCELLANEOUS 647

74 Chelating agents 648

74.1 Chelating agents 648
75 Immunosuppressants and immunostimulants 649
75.1 Classification of immunosuppressants – Calcineurin inhibitors/T-cell inhibitors 649
75.2 Antiproliferative agents 650
75.3 Cytotoxic agents and glucocorticoids 651
75.4 Immunosuppressive antibodies 652
75.5 Immunostimulants 653

Index 655
Acknowledgments
I thank the management of the SDM College of Medical
Sciences and Hospital, Dharwad, Karnataka, India, espe-
cially Dr. Niranjan Kumar (Medical Director), Dr. S.K. Joshi
(Principal), Dr. P. Satyashankar (Medical Superintendent),
Dr. J.V. Chowti (former Principal), and Dr. K.R. Pravin
Chandra (Student Welfare Officer) for their support.
Thanks to my family members, relatives, friends for their
active support, suggestions, and solutions.
In addition, my sincere thanks to Shivangi Pramanik
and Mouli Sharma of CRC Press/Taylor & Francis Group,
New Delhi, India, for providing me the opportunity to
author this book.
The efforts put forth by the editorial staff, Nitasha
Devasar and Himani Dwivedi, the Project Editor, Kyle
Meyer, the Project Manager, Narayani Govindrajan, and the
production team from Nova Techset are greatly appreciated.
xxi
Preface
During my tenure of teaching pharmacology, I noticed that
undergraduate students find it difficult to read, remember,
revise, and reproduce their subject material from standard
textbooks. Empathizing with them, I wanted to write a book
to provide them with alternative/supplementary material in
a different format.
This book is designed for medical, dental, physiotherapy,
and pharmacy students and any other healthcare profession-
als whose careers involve drug therapy and related aspects.
The book presents condensed and succinct descriptions
of relevant and current information pertaining to pharma-
cology. It is not meant to be a substitute for the compre-
hensive presentation of information and difficult concepts
found in standard textbooks of pharmacology.
Students are expected to master large amounts of infor-
mation. There are few learning strategies accessible to these
students to memorize and recall essential information to
succeed in their medical colleges. When medical students
receive very large amounts of information, passive learning
results. Students remember facts rather than understanding
and applying concepts.
As the medical profession continues to change, so do
the methods by which medical students are taught. Various
authors have accepted the need for alternative teaching and
learning approaches that will help medical students to remem-
ber huge amounts of information, assimilate critical thinking
skills, and explain a range of complex clinical problems.
There is a substantial necessity for faculty to move away
from the customary teacher-centered educational method
and enhance implementation of an active, student-centered
learning environment.
One learning strategy that has been underutilized in
medical education is mind mapping. Mind maps are mul-
tisensory tools that help students to organize, integrate,
and retain information. A mind map is a diagram that rep-
resents words, concepts, ideas, or other items related to a
given topic. Recent work suggests that using mind mapping
as a note-taking strategy facilitates critical thinking.
Although the mind map as a learning strategy has not
been extensively used in medical education, the latest
research recommends using mind mapping in learning, as
it increases students’ long-term memory.
Mind maps, systematized by Tony Buzan, is a visual
technique where information and knowledge are converted
to a hierarchical formatted and illustrated diagram, with
structural key terms associated with a subject. Mind maps
are sprawling network diagrams that radiate out from a
central point. The central topic contains a label of a general
topic. Lines radiate out from that center to subtopics repre-
senting related concepts. More subtopics may radiate from
those subtopics.
Mind mapping, a form of visual outlining, may seem
superficial, but once mastered it provides a powerful tool for
managing information overload and enabling one to quickly
capture and organize a massive amount of ideas.
Mind maps are effective and can amplify productivity.
ONE SMALL STEP CAN CHANGE YOUR LIFE.
A mind map is a powerful graphic technique that can
be applied to improve learning and clarify thinking. Mind
maps can be used as self-learning methods to facilitate
understanding of difficult concepts.
Mind mapping uses visual orientation to assimilate
information and subsequently help students recall informa-
tion in an organized manner. It is ideally suited for a last-
minute study guide before examinations. This convenient
and portable distillation of knowledge aids in memorizing
and can save many hours of note taking.
We want to hear what you think. What do you like about
the book’s format—the first of its kind in the world for phar-
macology? What do you think could be improved? Please
share your feedback by emailing us at prasangeeta2012@
gmail.com.
We are grateful to our students and our other colleagues
who have taught us most of what we know about teaching.
Examinations are stressful, but if you want to succeed, you
have to put the work in.
However you choose to study, I hope you find this
resource helpful throughout your preparation for your
examinations.
Wishing you all the best for your examinations.
God Bless All.
Prasan Bhandari
xxiii
Author
Dr. Prasan Bhandari obtained his MBBS degree from one
of the oldest institutes in India, Grant Medical College and
Sir JJ Group of Hospitals, Mumbai, India. He received his
MD in Pharmacology from the academically renowned
institute Topiwala National Medical College, BYL Nair
Charitable Hospital, Mumbai, India.
Dr. Bhandari has over 23 years of academic, teaching,
research, administrative, and industry experience. He has
published several articles in both national and international
journals and has served as an examiner in several univer-
sities for both postgraduate and undergraduate medical,
dental, physiotherapy, and other allied paramedical stu-
dents. He has guided several postgraduate students in their
research work and dissertations.
He is currently Associate Professor in the Department
of Pharmacology at SDM College of Medical Sciences and
Hospital, Dharwad, India.
xxv
 I
part    

General pharmacology
 1
Definitions, drug nomenclature,
and sources of drugs

1.1 DEFINITIONS

Pharmacology – Deals with effects of Movement of drug within the body

drugs on living system

Drug – Any substance or product

that is used or intended to be
Includes process of absorption (A), distribution (D),
used to modify or explore physiological
metabolism (M), and excretion (E)
system or pathological states
for the benefit of recipient (WHO)

Pharmacokinetics Means “what the body does to the drug”

Study of drugs, their mechanism of action,

pharmacological actions, and their adverse effects
Pharmacodynamics

Means “what drug does to body”

Science that deals with preparation, preservation,

Pharmacy standardization, compounding, dispensing
and proper utilization of drugs

Definitions
Therapeutics Concerned with treatment of diseases

Toxicology Study of poisons, their actions, detection,

prevention, and treatment of poisoning

Chemotherapy Deals with treatment of

infectious diseases/cancer

Clinical pharmacology Study of drug in man, both healthy volunteers

and patients, by comparative clinical trials

Satisfy the health care needs of

majority of population
Essential drugs
Should be available at all times, in adequate
amounts, and in appropriate dosage forms (WHO)

Used for diagnosis, treatment, or prevention

Orphan drug
of rare diseases

2
 Definitions, drug nomenclature, and sources of drugs 3

1.2 DRUG NOMENCLATURE

e.g., Acetylsalicylic acid

Chemical name
Not suitable for use in
prescription

e.g., Aspirin

Also called generic

name

Non-proprietary name

Drug nomenclature Same worldwide

Assigned by U.S. Adopted

Name (USAN) Council

e.g., Dispirin

Also called brand name

Proprietary name
Given by pharmaceutical
manufacturers

A drug may have many

brand names

1.3 SOURCES OF DRUGS

i. Alkaloids – morphine,
atropine, quinine

a. Plants

ii. Glycosides – digoxin,

digitoxin

b. Animals Insulin, thyroxine

1. Natural
Ferrous sulfate, magnesium
c. Minerals
Sources of drugs sulfate

2. Synthetic: Aspirin,
paracetamol
d. Microorganisms Penicillin, streptomycin

e. Genetic engineering Human insulin, hepatitis B

(recombinant DNA technology) vaccine
 2
Routes of drug administration

2.1 FACTORS DETERMINING ROUTES OF DRUG ADMINISTRATION

Drug characteristics

Type of use –
emergency/routine

Patient condition –
unconscious, vomiting,
diarrhea
Factors determining route
of administration

Age

Co-morbid diseases

Patient/doctor choice

4
 Routes of drug administration 5

2.2 LOCAL ROUTE

One of simplest routes

Local route Given at site of desired action

Minimal side effects

Drug applied to skin/mucous

membrane for local actions

e.g., Clotrimazole troche

a. Oral cavity
for oral conditions

As non-absorbable tablet

b. GIT

e.g., Neomycin for gut

sterilization before surgery

Liquid drug is administered

in rectum

e.g., Soap water enema; soap

As evacuant enema
acts as lubricant and water
for bowel evacuation
stimulates the rectum
c. Rectum and anal canal

e.g., Methylprednisolone
1. Topical Retention enema
in ulcerative colitis

Solid dosage form drug is e.g., Bisacodyl for

Suppository
inserted in rectum bowel evacuation

As drops, ointments,
sprays, etc.
d. Eye, ear, and nose
For allergic or infective
conditions of
eye, ear, and nose

e.g., Salbutamol inhalation for

bronchial asthma and
e. Bronchi As inhalation
COPD (chronic obstructive
pulmonary disease)

f. Vagina As tablet, cream, pessary For vaginal candidiasis

g. Urethra As jelly e.g., Lignocaine

2. Deeper areas are reached e.g., Infiltration of

by using syringe and needle local anesthesia
6 Pharmacology mind maps for medical students and allied health professionals

2.3 SYSTEMIC ROUTE

Drug reaches blood and Oral, sublingual,

Systemic route e.g., A. Enteral route
produces systemic effects and rectal route

Most common and accepted e.g., Tablets, capsules, syrups, etc.

Safe

Cheap

Advantages Painless

Convenient for repeat and

long-term use

Self-administered

Slow onset, not used in

emergency

Unpalatable, highly irritant

drugs cannot be given

Unabsorbable drugs cannot

be given (e.g., neomycin)
1. Oral route Drugs destroyed by digestive
Disadvantages
juices cannot be given (e.g., insulin)

Drugs with high first-pass metabolism

cannot be given (e.g., lignocaine)
Cannot be given in unconscious/
uncooperative/unreliable patients

Cannot be given in patients with

vomiting or diarrhea

Prevents gastric irritation

Protects drug from gastric acid

Retards drug absorption and

↑ its duration of action

Done by cellulose, acetate, etc.

Sustained/controlled release
formulation
Enteric-coating of tablets
Consists of different coatings
dissolving at different time intervals

↑ Duration of action

↓ Dosing frequency

↑ Patient compliance

e.g., Sustained-release nifedipine

(Continued)
 Routes of drug administration 7

2.3 SYSTEMIC ROUTE (Continued)

Drug is kept under

tongue

Absorbed through
the buccal mucosa

Enters systemic
circulation

Bypasses first-pass
liver metabolism
Rapid onset
e.g., Nitroglycerin,
buprenorphine
Action can be
2. Sublingual route terminated by
spitting out drug
Advantages
Bypasses first-pass
liver metabolism

Self-administration
is possible

Irritant and lipid-

insoluble drugs
cannot be given

Unpalatable drugs
Disadvantages with bad smell
cannot be given

Cannot be used
in children

i.e., Retention enema e.g., Methylprednisolone

For
local effect

Solids and liquid Evacuant enema e.g., Soapy water

3. Rectal route i. Enema
dosage forms used

e.g., Diazepam for

For
febrile convulsions
systemic effect
in children

(Continued)
8 Pharmacology mind maps for medical students and allied health professionals

2.3 SYSTEMIC ROUTE (Continued)

Administered other than Injection, inhalation, and

enteral route transdermal route

Rapid onset, and can be used in

emergency

Also can be used in unconscious/unco-

operative/unreliable patients

Used in presence of vomiting and

diarrhea

Advantages Suitable for irritant drugs

Drugs with high first-pass metabolism

B. Parenteral route
can be given by this route

Drugs that are not absorbed orally

also can be given

Drugs destroyed by digestive juices

can be administered by this route

Requires sterilization and aseptic

conditions

Invasive technique, painful

Can cause local tissue injury;

Disadvantages
e.g., nerves, vessels, etc.

Requires technical experts, hence

cannot be self-administered

Expensive

(Continued)
 Routes of drug administration 9

2.3 SYSTEMIC ROUTE (Continued)

Volatile liquids and gases are

e.g., General anesthetics
administered by this route

Rapid onset

Lower dose is required,

1. Inhalation Advantages
fewer systemic side effects

Dose regulation is possible

Local irritation can cause ↑ respiratory

Disadvantages
secretions and bronchospasm

Scopolamine for motion

sickness
Patches deliver drug into
circulation for systemic effects
Nitroglycerin for angina

e.g.,
Estrogen for hormone
replacement therapy (HRT)

Fentanyl for analgesia

Self-administered

Good patient compliance

2. Transdermal route
(adhesive patches)

Advantages Prolonged action

Minimal side effects

Constant plasma concentration

Expensive

Disadvantages Local irritation (itching, dermatitis)

Patch may fall off without

being noticed

(Continued)
10 Pharmacology mind maps for medical students and allied health professionals

2.3 SYSTEMIC ROUTE (Continued)

e.g., BCG vaccination, drug sensitivity

a. Intradermal Injected into dermal layer of skin
testing

Injected into subcutaneous tissue e.g., Insulin, adrenaline

Self-administered; e.g., insulin

Advantages

Depot preparations can be used;

e.g., Norplant for contraception
b. Subcutaneous

Unsuitable for irritant drugs

3. Injection
Disadvantages

Slow onset, unsuitable

for emergency

Deltoid, gluteus maximum, lateral

Injected into large muscles
aspect of thigh in children

Rapid onset compared to oral route

Advantages
Depot preparations (used to prolong
drug action), mild irritants, soluble
c. Intramuscular substances, and suspensions can be given

Requires aseptic condition

Painful, may lead to abscess

Disadvantages

Self-administration is not possible

Local tissue injury can occur; e.g., nerves

(Continued)
 Routes of drug administration 11

2.3 SYSTEMIC ROUTE (Continued)

Bolus administration – single, large dose

e.g., Furosemide
rapidly/slowly injected as single unit

Direct injection of drug

Slow IV injection e.g., Morphine
into vein

IV infusion – addition of drug into a e.g., Dopamine infusion in

bottle containing dextrose/saline cardiogenic shock

100% bioavailability

Rapid onset, suitable for

emergencies

Large volume of fluid can be

given (IV dextrose)
Advantages
Highly irritant drugs can be
given (e.g., anticancer drugs)

Hypertonic solutions can be

given (20% mannitol)

Constant plasma levels can be maintained

(dopamine in cardiogenic shock)
d. Intravenous

Once drug is injected, drug

action cannot be stopped

Local irritation, thrombophlebitis

Strict aseptic conditions are

mandatory
Disadvantages
Self-administration is not
possible

Drug extravasation can cause

necrosis, sloughing

Depot preparations cannot be given

Administer drugs slowly,

otherwise toxicity
Caution

Ensure tip of needle is in vein

(Continued)
12 Pharmacology mind maps for medical students and allied health professionals

2.3 SYSTEMIC ROUTE (Continued)

Rarely used now

e. Intra-arterial Used diagnostically e.g., Coronary angiography

Sometimes anticancer
drugs can be given

Injection of drug in e.g., Spinal anesthesia (lignocaine),

f. Intrathecal
subarachnoid space antibiotics (in meningitis)

Direct injection of drug e.g., Hydrocortisone for

into joint space rheumatoid arthritis

g. Intra-articular Requires strict aseptic

condition

Repeated use can

damage cartilage

2.4 SPECIALIZED DRUG DELIVERY

Kept beneath lower eyelid e.g., Pilocarpine in glaucoma

1. Ocusert
Single application releases
drug for 1 wk

Intrauterine contraceptive
device
2. Progestasert
Releases progesterone
C. Specialized drug delivery
for 1 yr

Drug incorporated in minute e.g., Liposomal amphotericin

3. Liposomes
phospholipid vesicles for fungal infection

Immunoglobulins react with

specific antigen
4. Monoclonal antibiotics

Used for targeted delivery e.g., Anticancer drugs

 3
Pharmacokinetics and applied aspects

3.1 INTRODUCTION TO PHARMACOKINETICS

Derived from 2 words:

“pharmacon,” meaning drug, and
“kinesis,” meaning movement

Simply “what body does to

the drug”

Includes absorption (A),

Pharmacokinetics (PK) distribution (D), metabolism (M),
and excretion (E)

ADME involves movement of

drug across various biological
membranes

All biological membranes are

bilipid layer

13
14 Pharmacology mind maps for medical students and allied health professionals

3.2 TRANSPORT OF DRUGS

Drugs are Is bidirectional

transported across process
various biological
membranes by the Movement of drug from
following mechanisms higher to lower
concentration untill
equilibrium is achieved
1. Passive diffusion
Diffusion rate is directly
proportional to
concentration gradient
across membrane

Lipid-soluble drugs are

passively transported
(without energy)

Depends on
Transport molecular size and
of drugs weight of drug
2. Filtration
Drug are easily filtered
if they are
Movement of
smaller than pores
drug from
lower to higher
concentration
a. Active transport
e.g., Transport of
Requires energy choline to
cholinergic neurons

3. Specialized
transport Carrier-mediated
transport

Does not
require energy

Drug attaches to
b. Facilitated
carrier on
diffusion
the membrane

Carrier facilitates
diffusion e.g., Absorption of
across membrane Process of transport
vitamin B12 from
across cell in
GIT (gastrointestinal
particulate form by
tract), transport of
Drug moves from formation of vesicles
amino acids in brain
higher to lower
concentration Applicable to
Pinocytosis proteins and
other big molecules

Contributes little to
transport of most
drugs, barring few
like vit B12, which is
absorbed from the
gut after binding to
intrinsic factor
(a protein)
 Pharmacokinetics and applied aspects 15

3.3 DRUG ABSORPTION

Liquids are
a. Physical state better absorbed
than solids

Smaller particle size

e.g., Microfine
is better absorbed
griseofulvin
than larger size
Transport of drug
from site of b. Particle size
administration to Larger particle size
blood circulation anthelmintics are poorly
absorbed, hence act
Drug absorption
better on gut helminths
Factors modifying 1. Physicochemical
absorption properties Time required by the
preparation (tablet/
capsule) to disintegrate
(break) into fine particles
c. Disintegration
time
The faster the
disintegration, the
better absorption is

Time required for

preparation to
dissolve into solution
d. Dissolution time
The faster the
dissolution, the better
is the absorption

Inert substances used

with drugs such as
e. Formulation
lactose and starch may
interfere with absorption

Lipid soluble drugs

are absorbed
faster and better
f. Lipid solubility
They easily dissolve
in phospholipids
of cell membrane

(Continued)
16 Pharmacology mind maps for medical students and allied health professionals

3.3 DRUG ABSORPTION (Continued)

Ionized drugs are poorly absorbed

Un-ionized, lipid-soluble drugs, better absorbed

Strong electrolytes are completely ionized at e.g., Heparin, streptomycin

acidic and alkaline pH

g. pH and ionization However most drugs are weak electrolytes and exist
in both ionized and un-ionized forms

Degree of ionization depends on pH of medium

Acidic drugs remain un-ionized in acidic medium

e.g., Aspirin, barbiturates
of stomach and are rapidly absorbed

Basic drugs remain un-ionized in alkaline medium

e.g., Pethidine, ephedrine
of intestines and are rapidly absorbed

Larger area, more vascularity, better absorption

h. Area and vascularity of
absorbing surface
Most drugs are absorbed from small intestine

The Faster the GET, the more rapid absorption

Gastric emptying time (GET) will be, faster the drug will reach intestine
∴

i. Gastrointestinal motility
Faster the motility, ↓ absorption; e.g., in
Intestinal motility diarrhea, less contact time with intestinal
∴
surface for absorption

↓ GET, dilutes the drug, hence slows the absorption

j. Presence of food
e.g., Tetracylines
Drug food complex is incompletely absorbed
chelate calcium

Malabsorption and achlorhydria ↓ absorption

k. GI diseases

↓ Absorption of acidic drugs in achlorhydria e.g., Ketoconazole

e.g., Nitroglycerin
Drug inactivation occurs in GIT (first-pass metabolism)
(NTG), insulin
l. Metabolism
Such drugs are given in high dose or parenterally
 Pharmacokinetics and applied aspects 17

3.4 FIRST-PASS METABOLISM (PRESYSTEMIC METABOLISM)

Metabolism of drug during its

passage from site of absorption
to systemic circulation

Important aspect of orally

administered drugs

First-pass metabolism Oral drugs are metabolized in

(Presystemic metabolism) GIT wall or liver

Give higher dose

Leads to interdrug variation

Partial first-pass metabolism
and interindividual variation

e.g., Propranolol, NTG

Partial or total

Change route of drug

administration

Total first-pass metabolism

e.g., Insulin, isoprenaline

3.5 ABSORPTION FROM PARENTERAL ROUTE

Drug is directly absorbed into

IV route
systemic circulation

Drug molecules initially

dissolve in tissue fluid and are
then absorbed

Absorbed quickly muscles

∴
IM route
are highly vascular

Lipid-soluble drugs are

absorbed faster
Absorption from parenteral
route

SC route Slow but steady absorption

Lipid-soluble drugs rapidly

Inhalation route absorbed from pulmonary
epithelium

Highly lipid-soluble drugs are

e.g., Nitroglycerin
absorbed from intact skin

Slow absorption multiple

∴
Topical route
epidermal layers are present

However easy absorption

occurs from mucous membrane
18 Pharmacology mind maps for medical students and allied health professionals

3.6 BIOAVAILABILITY AND BIOEQUIVALENCE

IV – 100%
Fraction/percentage of drug that
reaches systemic circulation following
IM/SC/sublingual – >75%
administration by any route

BA of drugs from different routes Transdermal – 80%–100%

Large variations in BA can lead

Rectal – 30%–100%
to therapeutic failure or toxicity

AUC (oral) × 100 Oral – variable 30%–100%, low

BA =
AUC (IV) due to first-pass metabolism

Bioavailability (BA) Drug is given IV

Then plasma concentration is

measured at hourly interval and then
plotted against time on graph paper
To measure BA
Similarly plasma concentration–
time graph of oral dosage of same
dose is obtained

Once these curves are obtained, AUC

is measured

All factors modifying drug

Factors modifying BA
absorption also modify BA

Comparison of BA of different
formulations of same drug

Oral formulations containing same

∴
amount of drug from different
manufacturers may have different plasma
concentration they could become
non-bioequivalent

Differences may be due to differences

Bioequivalence
in rate of disintegration and/or dissolution

Non-bioequivalence or
e.g., Drugs with low safety margin
bioequivalence can lead
(digoxin, anticoagulants)
to therapeutic failure/toxicity

Hence preparations from

single manufacturer should
be used and continued
 Pharmacokinetics and applied aspects 19

3.7 DRUG DISTRIBUTION

From systemic circulation, drug is

distributed to different tissues

In this process it crosses many

barriers, then reaches the site of
action
Distribution (D) Lipid solubility
Involves same process as
absorption; i.e., filtration, diffusion,
and specialized transport
Ionization

Factors determining distribution

Vascularity

Binding to plasma and cellular

proteins
20 Pharmacology mind maps for medical students and allied health professionals

3.8 PLASMA PROTEIN BINDING

Acidic drugs are bound

to albumin

Basic drugs are bound to

α-acid glycoprotein

Free drug is available

for action, metabolism,
and excretion

Bound drug acts as a

reservoir for drug

e.g., PPB is 0% for lithium,

PPB is variable for
ethosuximide, whereas
each drug
it is 99% for warfarin
Plasma protein binding
1. Only free fraction is When free drug
(PPB)
available for action, concentration ↓,
metabolism, and excretion bound drug is released

2. Protein binding serves

as reservoir (store) for drug

3. PPB ↑ drug t½ (half-life),

hence its duration of
∴ Highly PPB drugs are
action, bound
generally long-acting
drugs are not
metabolized/excreted

∴ Drug with
higher affinity for
same binding site
4. Competition among displaces another drug
drugs for same
Clinical significance
binding sites
of PPB
e.g., Warfarin (99%
Hence displacement
bound, 1% free) if
drug interactions
co-administered
can occur
with indomethacin

5. Saturation of binding
sites after
repeated administration
6. Chronic renal failure/
chronic hepatic
dysfunction, anemia causes
hypoalbuminemia
7. In poisoning, highly PPB
drugs cannot be removed
easily by hemodialysis
Hence there is a
5-fold ↑ in warfarin
Thus there is ↑ in free Displaces warfarin,
concentration
drug concentration reducing warfarin
PPB to 95%, then 5%
warfarin will be free ∴ Toxicity of warfarin
This ↓ PPB of drugs (bleeding) ↑
Hence there should
be careful administration
of highly
protein-bound drugs
 Pharmacokinetics and applied aspects 21

3.9 VOLUME OF DISTRIBUTION

Volume necessary to accommodate

entire volume of given drug, if the
concentration throughout body were
equal to that of plasma

Formula to calculate e.g., Drug dose is 500 mg, and plasma

Amount of drug in body concentration is l0 mg/L, then
Vd = Vd = 50 L
Plasma concentration

Highly plasma protein-bound

e.g., Aspirin, phenylbutazone
drugs have small Vd

Low plasma protein-bound drugs

e.g., Pethidine
have large Vd

Volume of distribution (Vd)/

Apparent vd (Avd)

Knowledge of Vd is important
in poisoning

Drugs with large Vd are not removed

by hemodialysis easily ( they
∴
are widely distributed)

Vd changes in disease states (due to

alteration in tissue permeability and
protein binding)

Low Vd drugs have large Vd in

e.g., Aminoglycosides
edema/ascites
22 Pharmacology mind maps for medical students and allied health professionals

3.10 REDISTRIBUTION, BLOOD–BRAIN BARRIER, TISSUE BINDING, PLACENTAL BARRIER

Certain drugs bind to some tissues due to

their special affinity for them

This delays excretion/metabolism of these e.g., Lipid-soluble drugs binding to

Tissue binding
drugs which ↑ their duration of action adipose tissue

Tissue binding also serves as drug reservoir

Highly lipid-soluble drugs are redistributed

Redistribution Initially distributed to highly vascular organs Brain, heart and kidney

Later redistributed to less vascular organs

e.g., Thiopentone
(muscle, fat), which terminates their action

Tight intercellular junctions instead of pores

in endothelial cells of brain capillaries

Glial cells cover these capillaries

Together they constitute BBB

Only un-ionized lipid-soluble e.g., Barbiturates, diazepam,

Blood–brain barrier (BBB)
drugs cross BBB volatile anesthetics

Inflammation; e.g., meningitis, e.g., Penetration of penicillin

↑ permeability to BBB during meningitis ↑

Areas with weak barrier are

CTZ (Chemoreceptor Trigger Zone),
posterior pituitary, and parts of hypothalamus

pH of CSF is 7.35, hence weakly basic drug CSF

concentration is more than acidic drugs

Un-ionized lipid-soluble drugs cross placental

barrier more than lipid-insoluble drugs

Hence ↑ fetal adverse effects

Placental barrier
Lipid-soluble drugs with molecular weight
between 200–500 daltons cross easily
e.g., Anesthetics, alcohol easily
cross placental barrier
But drugs with >1000 daltons of molecular
weight hardly cross placental barrier
Whereas d-Tubocurarine, a skeletal
muscle relaxant (d-Tc), insulin
(antidiabetic) do not cross placental barrier
 Pharmacokinetics and applied aspects 23

3.11 FACTORS DETERMINING DISTRIBUTION

Un-ionized and lipid-

e.g., Lignocaine,
soluble drugs are widely
propranolol
distributed
1. Physicochemical
properties of drug
Ionized drugs are
e.g., Heparin
confined to intravascular
(strongest acid)
compartment

High PPB have low Vd

2. Plasma protein binding

Low PPB have high Vd

Factors determining
distribution Certain drugs are
e.g., Digoxin in heart;
3. Tissue storage sequestered in certain
it has Vd of 66 L/kg
tissue

Can ↑ Vd due to ↑ in
ECF volume
CCF (Congestive Cardiac
4. Diseases Failure), uremia can alter
Vd of a drug
Can ↓ Vd due to ↓ in
tissue perfusion
Highly lipid-soluble drugs
get distributed in adipose
tissue
5. Fat
∴ They have a high
Vd, fat acts as
∴
reservoir
24 Pharmacology mind maps for medical students and allied health professionals

3.12 DRUG METABOLISM (BIOTRANSFORMATION)

Biotransformation/metabolism
is the chemical alteration
of drug in living organism

Converts lipid-soluble
un-ionized drugs to
water-soluble, ionized drugs

Introduction
Water-soluble, ionized
drugs are not
reabsorbed by kidneys and
hence are excreted

If parent molecule is highly

polar, i.e., ionized, it may not
get metabolized and
is excreted as it is

Primary liver

Sites of metabolism
Drug metabolism
(biotransformation) Others–GIT, kidneys, lungs,
blood, skin, placenta, etc.

Most common

1. Active drug to Phenobarbitone →

inactive metabolite Hydroxyphenobarbitone

e.g.,

Phenytoin →
p-hydroxyphenytoin

e.g., Codeine → morphine

2. Active drug to
Consequences of active metabolite
metabolism
Diazepam → oxazepam

3. Inactive drug to active e.g., L-dopa → dopamine,

metabolite (prodrug) prednisone → prednisolone

e.g., Paracetamol →
4. Active drug to
N-acetyl-p-benzoquinone
toxic metabolite
imine (NAPQI)
 Pharmacokinetics and applied aspects 25

3.13 PATHWAYS OF METABOLISM AND PHASE I REACTIONS

Phase I or non-synthetic

Pathways of metabolism

Phase II or synthetic

Most important and

common reaction
Oxidation

Involves addition of O2 e.g., Phenytoin,

and/or removal of hydrogen phenobarbitone, propanolol

Involves removal of O2 or e.g., Chloramphenicol,

Reduction
addition of hydrogen methadone
Phase I/non-synthetic
reactions

Breakdown of compound
by addition of water

Hydrolysis

e.g., Esters: Procaine,

Common among esters and
succinylcholine. Amides:
amides
Lignocaine, procainamide
Metabolite at end of
phase I reaction may be
inactive or active
26 Pharmacology mind maps for medical students and allied health professionals

3.14 PHASE II/SYNTHETIC REACTIONS

Consists of conjugation reactions

If phase I metabolite is polar, it is

excreted by kidneys

However, many metabolites are still

lipophilic

Hence they are reabsorbed and undergo

subsequent conjugation reaction with
endogenous substrate

Endogenous substrate could either be

glucuronic acid, sulfuric acid, acetic Glucuronide conjugation Paracetamol, morphine
acid, or amino acid

Phase II/synthetic reactions INH, dapsone,

Acetylation
Conjugates are inactive, polar, water sulfonamides
soluble, hence are excreted

Glycine conjugation Salicylic acid

e.g.,

Sulfate conjugation Sex steroids

Glutathione conjugation Paracetamol

Methylation Adrenaline, dopamine

Not all drugs undergo

INH undergoes phase II
phase I and then phase II
first and then phase I
reactions in that order
 Pharmacokinetics and applied aspects 27

3.15 ENZYMES FOR METABOLISM

Mainly present in
endoplasmic reticulum

Catalyze most of phase I

and phase II glucuronide
conjugation reactions
1. Microsomal enzymes

Include cytochrome P450,

glucuronyl transferase

Are inducible

Enzymes for metabolism Present in cytoplasm,

plasma, and mitochondria of
liver cells

Catalyze all phase II

reactions except
glucuronide conjugation

Mostly reduction and

2. Non-microsomal enzymes
hydrolysis reactions

Show genetic
polymorphisms

Are non-inducible
28 Pharmacology mind maps for medical students and allied health professionals

3.16 ENZYME INDUCTION

↑ Synthesis of microsomal
enzymes due to repeated
administration of drugs

e.g., Rifampicin, phenytoin,

Slow process requiring
phenobarbitone,
around 2–3 wks
carbamazepine, griseofulvin

1. Hastens metabolism, thus reduces e.g., Rifampicin inducing

duration and efficacy of drug action, OC (Oral Contraceptive) pills,
Enzyme induction hence can lead to therapeutic failure leading to contraceptive failure

2. Autoinduction can lead to drug e.g., Carbamazepine

tolerance

3. Toxicity can occur due to ↑ production e.g., Hepatotoxicity due to

of toxic metabolites paracetamol in alcoholics

4. Osteomalacia – phenytoin ↑
∴
Clinical importance
metabolism of vitamin D

5. Porphyria can occur due to

overproduction of porphobilinogen

6. Rapid elimination of drugs can

occur due to consumption of enzyme
inducers like cabbage, spinach

Phenobarbitone when given in patients

with neonatal jaundice can induce
7. Benefit of enzyme induction glucuronyl transferase, leading to ↑
metabolism of bilirubin,
thus ↓ bilirubin levels

3.17 ENZYME INHIBITION
Drugs inhibiting activity of
metabolizing enzymes
Rapid process as compared
Enzyme inhibition
to enzyme induction
Clinical importance
3.18 FACTORS MODIFYING METABOLISM
Neonates and elderly
have ↓ metabolizing
1. Age
capacity, hence ↑
toxicity
Protein deficiency ↓
metabolism
Protein rich food ↑
2. Diet metabolism of
theophylline and caffeine
Carbohydrate rich food ↓
Factors modifying metabolism
metabolism
Liver diseases ↓
metabolism of drugs, e.g.,
3. Diseases
cirrhosis, thus ↑ duration
of action of drugs
Study of genetically
determined variation
in drug response
Genetic abnormality may
4. Pharmacogenetics
alter drug response
e.g.,
Pharmacokinetics and applied aspects 29
e.g., Erythromycin,
ketoconazole, cimetidine,
chloramphenicol, ciprofloxacin
↑ Side effects, e.g.,
warfarin + enzyme inhibitors
causes ↑ bleeding
e.g., Gray-baby
syndrome in neonates
due to ↓ glucuronyl
transferase
↑ Toxicity of propranolol
and lignocaine in elderly
e.g., Diazepam
Slow acetylators, there is
↑ in peripheral neuritis
INH
Fast acetylators require
a larger dose
SCh is depolarizing skeletal
muscle relaxant
Normally SCh is metabolized
Succinylcholine
in 3–6 min by plasma
(SCh) apnea
pseudocholinesterase
Individuals with abnormal/
atypical pseudocholinesterase,
metabolize SCh very slowly,
which leads to respiratory
paralysis → apnea
G6PD maintains RBCs integrity
G6PD (Glucose 6
Phosphate
Dehydrogenase) G6PD deficiency leads to
deficiency hemolysis in patients exposed
to primaquine, sulfonamides,
dapsone, salicylates, etc.
30 Pharmacology mind maps for medical students and allied health professionals

3.19 PRODRUG

↑ Bioavailability of drug e.g., L-dopa in parkinsonism

Inactive drug is
Has a short
metabolized
duration of action
to active drug
Prodrug ↑ Duration of action e.g., Phenothiazine
However when phenothiazine
Advantages is esterified as fluphenazine, the
e.g., Clindamycin is bitter, duration of action is ↑
Enhance taste whereas clindamycin
palmitate has better taste

e.g., Methanamine converted

Site-specific in acidic pH of urine
drug delivered to active formaldehyde
(which acts as urinary antiseptic)

3.20 DRUG EXCRETION

Removal of drug and its

metabolite from body

Drug excretion Major route–kidney

Glomerular filtration and

Minor routes–Lungs, bile,
Glomerular filtration tubular secretion facilitate
feces, sweat, saliva, milk
excretion

Passive tubular Tubular reabsorption

1. Kidney Process involved
reabsorption ↓ excretion

Active tubular secretion ↑ Excretion

 Pharmacokinetics and applied aspects 31

3.21 DRUG EXCRETION BY KIDNEYS

Smaller molecular weight

drugs are easily filtered

Glomerular filtration
Extent of filtration is directly proportional to
glomerular filtration rate and to fraction
of unbound (free) drug in plasma

Depends on pH of renal tubular fluid and

degree of ionization

Strong acids and basic drugs remain ionized at

any urinary pH and hence are excreted

Weakly acidic drugs are un-ionized at acidic

e.g., Salicylates, barbiturates
pH of urine, are reabsorbed

If urinary pH is made alkaline by giving sodium

Passive tubular
bicarbonate, weakly acidic drugs become
reabsorption
ionized and are easily excreted

Similarly, weakly basic drugs remain un-ionized

e.g., Morphine, amphetamine
in alkaline urine and hence are reabsorbed

If urine is made acidic by vitamin C

(ascorbic acid), weakly basic drugs become
ionized and hence easily excreted

This principle of acidifying/alkalinizing the urine

is employed for excretion of basic/acidic
poisons, respectively, from the kidneys

Carrier-mediated active
transport requiring energy

Unaffected by changes in urinary pH and

protein binding
Active tubular
secretion
Carrier system is non-selective
e.g., Probenecid competitively inhibits
tubular secretion of
penicillins/cephalosporins
Hence there is competition between drugs with
similar physicochemical properties for
carrier system
↑ Duration of
action/plasma concentration/
efficacy of penicillins/cephalosporins
32 Pharmacology mind maps for medical students and allied health professionals

3.22 OTHER ROUTES OF DRUG EXCRETION

Alcohol, volatile general anesthetics

2. Lungs
(ether, halothane, etc.) are excreted

Drugs not completely absorbed from e.g., Purgatives,

3. Feces
GIT are excreted by this route (senna, cascara)

Drugs are excreted from bile but are

reabsorbed from intestine to be
excreted in bile again; this cycle repeats

Such recycling is termed

4. Bile
enterohepatic circulation

Enterohepatic circulations, e.g., Erythromycin,

↑ bioavailability/duration of action phenolphthalein

5. Skin Metals like arsenic, mercury are excreted

e.g., Lithium, potassium iodide,

phenytoin, metronidazole are
excreted in saliva
6. Saliva
This principle is used for
monitoring lithium therapy

Lactating women secrete drugs in milk

Milk is acidic

Hence basic drugs like tetracycline,

7. Milk chloramphenicol, morphine,
diazepam are excreted easily

This may affect the sucking infant

e.g., Tetracyclines secreted in milk

chelates developing teeth and
bones in nursing infant
 Pharmacokinetics and applied aspects 33

3.23 APPLIED PHARMACOKINETICS

Time required for plasma concentration of the

Determines the duration of action
drug to become 50% of its original value

Clinical importance Determines dosage frequency

Plasma half-life (t½)
Drug requires approximately 4–5 t½ to
Estimates time required for
reach steady-state concentration after
steady-state concentration (PSS)
repeated administration of drug

Drug is almost completely eliminated

in 4–5 t½ after single administration

Fraction of the apparent volume of distribution

from which drug is removed in unit time
Clearance (CL)
Rate of elimination
CL =
Plasma concentration of drug

Constant fraction of drug is

eliminated per unit time

Rate of drug elimination is directly proportional

to its plasma concentration

First-order kinetics t½ will always remain constant

Most drugs are eliminated by

Pharmacokinetic first-order kinetics
parameters

e.g., Majority of the drugs

Constant amount of drug is

eliminated per unit time

Rate of elimination is independent

of its plasma concentration
( elimination process saturable)
∴
Zero-order kinetics
t½ is never constant

e.g., Alcohol, aspirin,

phenytoin, heparin

Initially first-order kinetics

at low doses

As dose ↑ elimination
processes get saturated

Mixed-order kinetics Thus, kinetics changes to zero-order,

(Michelis-Menten kinetics) i.e., saturation kinetics

e.g., Phenytoin, aspirin

Hence, therapeutic drug monitoring

(TDM) of the plasma if phenytoin
concentration has to be done
34 Pharmacology mind maps for medical students and allied health professionals

3.24 DRUG DOSING FACTORS

Drug action time mainly depends

on its route of administration

For immediate action,

drug is given IV

After repeated administration at a

constant rate, it requires 4–5 t½
to achieve steady-state
plasma concentration

Drug dosing factors

Drugs with short t½ require
frequent administration/ Initial large dose or
IV infusion series of doses

Drugs with long t½ require long Achieves rapid steady-state

time to achieve steady-state Loading dose
therapeutic concentration
concentration

e.g., Digoxin, lignocaine (for

Hence desirable to give a loading arrhythmias)
dose for raising plasma
concentration immediately to
expected therapeutic range
Usually half of loading dose

Maintenance dose

Administered at every
half-life of the drug
 Pharmacokinetics and applied aspects 35

3.25 THERAPEUTIC DRUG MONITORING

1. Drugs with narrow e.g., Phenytoin, digoxin,

therapeutic index lithium, aminoglycosides

2. In renal failure patients e.g., Aminoglycosides

Measuring plasma concentration
to monitor drug therapy

3. To ascertain bioavailability

Use for

4. To check patient compliance

5. Drugs with wide

interindividual variations
Therapeutic drug
monitoring (TDM)

6. Patient non-responsiveness

1. When clinical and biochemical

e.g., BP, blood sugar,
parameters available to monitor
prothrombin time, aPTT
drug effects

2. Drugs with tolerance e.g., Opioids

Not useful for

3. Hit-and-run drugs, like drugs
e.g., Proton Pump Inhibitors
whose effects persist longer than
(PPIs); e.g., omeprazole
drug itself

4. If estimation is expensive
36 Pharmacology mind maps for medical students and allied health professionals

3.26 FIXED-DOSE COMBINATION

Sulfamethoxazole +
trimethoprim i.e.,
Cotrimoxazole as antibiotic

Levodopa + carbidopa: For

parkinsonism
Combination of 2 or more
drugs in a single
formulation, e.g.,
Estrogen + progesterone:
Oral contraceptive

Amoxicillin + clavulanic acid

i.e., coamoxiclav as
antibiotic

↑ Patient compliance

Synergism

↑ Efficacy
Fixed-dose combination
Advantages
(FDC)

↓ Side effects

↓ Cost

↓ Resistance

Inflexible, fixed dose

Different pharmacokinetics

Disadvantages
↑ Side effects (added
toxicity on same
tissue/organ)

Ignorance of contents by
physician/patient
 Pharmacokinetics and applied aspects 37

3.27 METHODS OF PROLONGING DRUG ACTION

Prolonging drug action

helps ↓ dosing
frequency, hence
↑ patient compliance By enteric coating e.g., Erythromycin

1. Oral drugs
e.g., Diclofenac SR

Using sustained-
release preparations
Acts for 24 h compared to
12 h of diclofenac tablet

By adding a vasoconstrictor
a. By ↓ vascularity of
Methods of prolonging to drug e.g., adrenaline, with
absorbing surface
drug action local anesthetics (LA)
e.g., Penicillin G has 4–6 h
duration of action only, however,
By combining drug with
b. By ↓ solubility procaine penicillin acts for 12–24 h
water-insoluble agent
and Benzathine penicillin
has 3–4 wks duration of action

c. By injecting drug in e.g., Depot progestins (depot

oily solution medroxyprogesterone acetate)

d. Pellet implantation e.g., Norplant implantation

2. Parenteral drugs

e. Ocuserts, Progestasert,
Transdermal patch

Sulfadiazine is less protein bound,

f. By ↑ plasma hence acts for 6 h, however,
protein binding sulfadoxine, which is highly
protein bound, acts for 7 days

Anticholinesterases
g. By ↓ metabolism (physostigmine, neostigmine),
↑ action of ACh by
inhibiting cholinesterases

e.g., Probenecid ↓ excretion of

h. By ↓ renal excretion penicillin/cephalosporins, thus ↑
duration of action
 4
Pharmacodynamics

4.1 PHARMACODYNAMICS AND PRINCIPLES OF DRUG ACTION

Study of actions of drugs

on body

Concerned about the i.e., To know what drugs do

mechanisms of action and how they do it

Produce their effects by interacting

with physiological systems of organisms

Pharmacodynamics Merely modify rate of functions of

various systems
Stimulation
Do not bring about qualitative
change
Depression
Cannot change basic function of
any physiological system
Irritation
Act by
Replacement

Anti-infective (cytotoxic) action

Modification of immune status

↑ In the activity of the specialized cells

Stimulation
e.g., Adrenaline stimulates the heart

↓ In the activity of specialized cells

Depression
e.g., Quinidine depresses heart;
barbiturates depress the CNS

Some drugs stimulate one

e.g., Morphine depresses CNS but stimulates vagus
system and depress another

Irritation Can occur on all types of tissues; may result

Principles of drug action in inflammation, corrosion, necrosis

Used when there is deficiency of natural

substances like hormones, metabolites, or nutrients
Replacement
e.g., Insulin in diabetes mellitus,
iron in anemia, vitamin C in scurvy

Destroys infective organisms e.g., Penicillins

Anti-infective action
Cytotoxic effect on cancer cells e.g., Anticancer drugs

e.g., Vaccines and sera improve immunity

Modification of immune status
whereas glucocorticoids depress immunity

38
 Pharmacodynamics 39

4.2 MECHANISMS OF DRUG ACTION

e.g., Enalapril inhibits ACE

Through receptors Inhibition of enzymes (angiotensin converting
enzyme)

e.g., H+K+ ATPase inhibited by

Through enzymes and pumps Inhibition of pumps omeprazole, Na+K+ ATPase
inhibited by digoxin

e.g., Pralidoxime activates

Activation of enzymes cholinesterases and used in
organophosphorus poisoning

i.e., Drugs interfere with

movement of
Produce their effects by binding ions across specific channels
to specific target proteins like
Through ion channels
receptors, enzymes or ion
e.g., Calcium channel blockers,
channels
potassium channel openers,
GABA gated chloride channel
modulators
May act on cell membrane
or inside or outside cell
e.g., Activated charcoal in
Absorption
poisoning
Some act by complex
Mechanisms of drug action
mechanisms
e.g., Bulk laxatives like psyllium,
Mass of drug bran for relieving
constipation
Actions of some drugs are
yet to be understood
e.g., Mannitol (diuretic),
Physical action; i.e., drugs
Osmotic action magnesium
act by their physical properties
sulfate (purgative)
Some basic mechanisms
of drug action

Radioactivity e.g., I 131 (antithyroid)

e.g., Barium sulfate (as contrast

Radio opacity
media)

Antacids–neutralize gastric acid

Oxidizing agents–potassium
Chemical action permanganate acts as
germicidal

Chelating agents–bind heavy

metals to make them
nontoxic

Sulfonamides interfere with

Altering metabolic process
bacterial folic acid metabolism

Latin term means “I will please”

Dummy medicine with no

Placebo effect
pharmacological activity
Relief of psychomotor
symptoms like anxiety,
headache, pain, insomnia, etc.
Uses

Used in clinical trails in order to

minimize bias
40 Pharmacology mind maps for medical students and allied health professionals

4.3 RECEPTOR

Langley and Ehrlich put forward a concept of

“receptor substance”

Clark explained drug action based on drug

receptor occupation

Macromolecular site on cell with which an

Definition of receptor
agonist binds to bring about a change

Affinity Ability of a drug to bind to a receptor

Intrinsic activity/efficacy Ability of a drug to elicit a response after

binding to the receptor

A substance that binds to receptor and produces

a response

Agonist Has both affinity and intrinsic activity

e.g., Adrenaline is agonist at α and β adrenergic receptors,

morphine is an agonist at mu (µ) opioid receptor

A substance that binds to receptor and prevents

the action of agonist on receptor

Has affinity but no intrinsic activity

Receptor
Similar structurally to natural ligand for receptor
Antagonist
Hence receptor identifies antagonist as its ligand

e.g., Naloxone is antagonist at µ receptor, binds to

receptors, has no effect by itself, but blocks the action of
opioid agonist like morphine

e.g., Tubocurarine blocks and prevents the action

of ACh on nicotinic receptors

Binds to the receptors but has low intrinsic activity

Occupies receptor, but brings about weak effects

Partial agonist Also blocks action/binding of full agonists

Hence they are also called agonist–antagonist

e.g., Pentazocine is a partial agonist at µ opioid receptors,

pindolol is a partial agonist at β – adrenergic receptors

After binding to receptors inverse agonists produce

actions opposite to those produced by full agonist
Inverse agonist e.g., Carbolines at benzodiazepine receptors (produces anxiety,
↑ muscle tone, and convulsions, whereas diazepam the full
agonist causes antianxiety, ↓ muscle tone,
and anticonvulsant effect)
 Pharmacodynamics 41

4.4 RECEPTOR – NATURE, SITES, AND FUNCTIONS

Only a small percentage of

Ligand – a molecule that receptors are required to
binds selectively to a produce maximum
specific receptor concentration

High concentration of an
agonist can still produce
Spare receptor maximum response in
presence of irreversible
antagonist

These effects are possible

because of spare
or “reserve” receptors

Agonist binds to receptors

but does not produce a
response

This explains the

Silent receptors phenomena
of tolerance

e.g., Plasma proteins

Receptor – nature, sites,

and functions
On cell membrane,
Site of receptors
cytoplasm, nucleus

Nature of receptors Proteins

Synthesized by cells

Synthesis and life span

of receptors Definite life span, after
which they are degraded
by cell and new receptors
are synthesized

Recognition and
binding of ligand

Functions of receptors Propagation of message

Ligand-binding domain Drug molecule binds

Receptor domains (areas) to this site
for performing
above functions
This site undergoes a change
Effector domain
to propagate the message
42 Pharmacology mind maps for medical students and allied health professionals

4.5 DRUG RECEPTOR INTERACTION THEORIES

i.e., Drug specifically fits into the

Lock-and-key relationship
particular receptor (lock) like a key

i.e., Magnitude of response depends on

rate of agonist–receptor association
and dissociation

Rate theory

i.e., Rate of receptor binding is greater

initially, reaches a peak, and then
there is a ↓

i.e., Magnitude of response depends on

proportion of receptors occupied by
the drug

Occupation theory

i.e., Response will progressively

↑ till a steady state is reached

Interaction of agonist with receptor

changes receptor
Drug receptor interaction theories

This changed receptor conveys signal

to effector system

The final effect is brought about by

effector system through second
messengers

Agonist is first messenger

Transduction process which links the

Receptor exists in two states i.e.,
binding of receptor and the actual
resting and activated
response is called “coupling”

Drug–receptor interaction is Drug with greater affinity for activated

explained by “two-state” model state will function as full agonist

Drug with moderate affinity for

activated state will function as partial
agonist
 Pharmacodynamics 43

4.6 RECEPTOR FAMILIES

On stimulation of receptor, time

required to elicit response varies from
fraction of a second to hours or days

i. Ion channels (ionotropic receptors)

Because of variation in mechanisms
involved in linking receptor and
Receptor families
effector systems (transduction
mechanisms)
ii. G-protein coupled receptor
(GPCR/metabotropic receptor)
Based on this, four types or super
families of cell surface receptors are
identified
iii. Enzymatic receptor
(kinase-linked receptor)

iv. Nuclear receptors (Transcription

factors or receptor that regulate
gene transcription)

4.7 RECEPTOR FAMILIES AND THEIR TRANSDUCTION MECHANISMS – ION

CHANNELS OR LIGAND-GATED ION CHANNELS

e.g., Nicotinic cholinergic

Are proteins present
receptors → opens
on cell surface
Na+ channel → depolarization

Receptor families and Binding of agonist opens the e.g., Benzodiazepines bind to
1. Ion channels or
their transduction channel allowing ions to GABA receptor → opens Cl–
ligand-gated ion channels
mechanisms cross the membrane channel → hyperpolarization

Depolarization/hyperpolarization
e.g., Nifedipine blocks Ca+2
occurs depending on ion
channels
channels

e.g., Sulfonylureas blocks

Ca+2 K+ channels

e.g., Nicorandil opens

K+ channels
44 Pharmacology mind maps for medical students and allied health professionals

4.8 G-PROTEIN COUPLED RECEPTORS (GPCR)

Are proteins spanning plasma

membrane

Bound to inner surface of plasma

membrane

This in turn activates adenyl cyclase

Consists of 3 subunits: α, β, and γ or phospholipase C to generate
respective second messengers

Second messengers are also called

Gets activated when ligand binds
effector pathways

Thus G-proteins act as link between Second messengers in turn bring

receptors and effector systems about intracellular changes

They are of different classes, viz.

Gs, Gi, Go, and G13

2. G-protein coupled receptors

(GPCR) They are called G-proteins because
of their interaction with guanine Gs is stimulatory, Gi is inhibitory
nucleotides i.e., GTP or GDP

Adrenergic receptors and muscarinic Stimulation of AC results in formation

Second messengers are cAMP, cGMP,
cholinergic receptors are examples of and accumulation of cAMP within cell
DAG (diacylglycerol), and Ca+2
GPCR

cAMP, through protein kinases, which

Adenylyl cyclase (AC)/cAMP phosphorylate various proteins,
pathway regulate cell function

Response may be contraction,

relaxation, lipolysis, or hormone
synthesis

Activation of PLC results in formation

of second messenger IP3 and DAG
from membrane phospholipids

IP3 mobilizes Ca+2 from intracellular

Effector pathways through which sites
GPCR work are Phospholipase C/IP3–DAG
pathway
Ca+2 causes contraction, secretion,
metabolism

DAG activates protein kinase C,

which regulates cell function

Activated GPCR directly (without 2nd

messengers) opens or closes channels

Ion channel regulation

This causes depolarization or

hyperpolarization
 Pharmacodynamics 45

4.9 ENZYMATIC RECEPTORS

Are transmembrane proteins

Have an extracellular domain (site)

for ligand binding

Intracellular domain site for

catalytic activity

Two domains are linked by single

peptide chain

Enzymes are protein kinases and

3. Enzymatic receptors hence called kinase-linked
receptors

Binding of agonist to ligand domain

causes autophosphorylation of
intracellular domain

This in turn triggers phosphorylation When agonist binds to extracellular

of various intracellular proteins, domain it activates intracellular
hence cellular response domain (which forms dimers)

e.g., Insulin receptor, growth factor This in turn activates mobile JAK
receptors (Janus kinase) molecules

Second subtype of enzyme linked This activates STAT (signal

receptors is JAK-STAT kinase transducer and activation
binding receptor transcription) molecules

STATs enter nucleus and regulates

transcription

e.g., Interferons, growth hormones

46 Pharmacology mind maps for medical students and allied health professionals

4.10 NUCLEAR RECEPTOR

Regulate gene transcription

Intracellular proteins in
inactive state

4. Nuclear receptor Activated by binding of agonist

Agonist–receptor complex enters nucleus →

interacts with DNA → regulates gene
transcription → regulates activity of target cell

e.g., Receptor for steroid hormones,

thyroid hormones, vitamin D, retinoids

4.11 RECEPTOR REGULATION

Many situations alter the number of

receptors (density) and their sensitivity

Denervation/prolonged deprivation of
agonist/constant action of antagonist ↑ Called upregulation
density and sensitivity of receptors
Receptor regulation

Constant use of agonist ↓

density and sensitivity of receptors
Following long-term antagonist,
Clinical significance
Called downregulation
e.g., β blocker propranolol if suddenly
withdrawn can precipitate
angina/severe hypertensive crisis due
to upregulation of receptors
the dose should be tapered
to stop it Long-term use of β agonist like
salbutamol in bronchial asthma can down
regulate β2 receptors in respiratory system,
leading to ↓ therapeutic response
 Pharmacodynamics 47

4.12 DOSE–RESPONSE RELATIONSHIP

Clinical response to ↑
dose of drug is defined by shape
of dose–response curve (DRC)

Initially the extent of response

↑ with ↑ in the dose until the
maximum response is reached

DRC is rectangular
hyperbola shape
Dose–response
relationship
After maximum effect is
obtained further ↑ in
doses does not ↑ the response

Log DRC is sigmoid shape

In drugs having a steep slope,
a small ↑ in dose produces
large ↑ in response
Slope of DRC has clinical
significance
In drugs having a flat DRC an
↑ in dose produces little
↑ in response
Such drugs can cause toxicity,
e.g., Loop diuretics hence dose has to be
individualized
Such drugs are relatively safe,
e.g., Thiazide diuretics thus a standard dose can be
given to most patient

4.13 DRUG POTENCY

Amount of drug required to

produce a response

Potency is of little clinical

Drug potency
significance

If 1 mg of drug A produces same

effect as 50 mg of drug B, then
A is more potent than B
48 Pharmacology mind maps for medical students and allied health professionals

4.14 DRUG EFFICACY

Maximum response that can be

produced by a drug

Efficacy is of great clinical

Drug efficacy
significance

If drug A produces more response

as compared to any dose of drug B,
then A is more efficacious than B

4.15 THERAPEUTIC INDEX (TI)

Distance between beneficial effect

DRC and adverse effect DRC of same drug
indicates TI or safety margin of drug

LD50 – Median lethal dose, dose that

is lethal to 50% of population

Therapeutic index (TI)

ED50 – Median effective dose, dose
that produces desired effect in 50%
of population

TI = LD50 /ED50 (in experimental animals)

TI = TD50 /ED50 (in humans) TD50 – dose that
elicits a therapeutic response in 50 percent
of the treated individuals (TD50)
 Pharmacodynamics 49

4.16 THERAPEUTIC WINDOW

Gives idea about safety of drug

Higher the TI, safer the drug

TI > 1, drug is relatively safe

Implications of TI

Drugs with high TI: Penicillin,

paracetamol

Drugs with low TI: Digoxin,

lithium

Therapeutic index TI varies from species to species

Does not consider idiosyncrasy

Animal data cannot be applied to

humans

Limitations

For humans safety factor is

important
Range of plasma concentration
below which drug is ineffective
and above which drug is toxic
Safety factor = LD1/ED99
Hence it is desirable to have
plasma concentration of drugs
within the therapeutic window

Thus drug will have therapeutic

Therapeutic window
effect without significant toxicity

Drugs with narrow therapeutic

window; e.g., lithium, digoxin,
carbamazepine

Doses of such drugs need to be

titrated carefully
50 Pharmacology mind maps for medical students and allied health professionals

4.17 DRUG SYNERGISM AND ANTAGONISM

Effect of two or more drugs gets added up;

total effect is equal to the sum of their
individual actions
Additive effect 2+2=4

Simultaneous e.g., Ephedrine + theophylline in bronchial

administration asthma, nitrous oxide + ether as general
of two or more anesthesia
drugs can
Action of one drug is ↑ by another
result in additive,
synergistic, or
antagonist effect Total effect of two drugs is more
than the sum of their individual actions

Synergistic effect 2 + 2 >= 5

Also called “potentiation” or

“supra-additive effect”

e.g., Levodopa + carbidopa in parkinsonism,

acetylcholine + physostigmine

One drug inhibiting

Chemical antagonism
the action of another
Antagonism
Types based on
Physiological antagonism Reversible antagonism (competitive)
mechanism
Drug synergism and antagonism

Receptor antagonism Irreversible antagonism

Two drugs
e.g., Antacids neutralize gastric acid; chelating
Chemical chemically interact Non-competitive antagonism
agents inactivate heavy metals like
antagonism to inactivate
lead and mercury
the effect
Two drugs act at
e.g., Insulin and glucagon have opposite effects on blood sugar; histamine acts on H1
Physiological different sites to
receptors to produce bronchoconstriction and hypotension; these effects are antagonised by
antagonism produce opposing
adrenaline via adrenergic receptors
effects

Agonist and antagonist compete for same receptor

Response to a fixed concentration of

agonist is progressively reduced by ↑ the
dose of antagonist

However, this antagonist can be overcome

by ↑ the concentration of agonist

Reversible or competitive
Same maximum response can be
antagonism e.g., Acetylcholine
achieved by ↑ the dose of agonist
and atropine
complete at
Antagonist binds to Also called surmountable or muscarinic receptors
the receptor and equilibrium type of antagonism acetylcholine and
inhibits binding of tubocurarine
agonist to receptor DRC shifts to right in presence compete at
Receptor-level of competitive antagonist nicotinic receptors
antagonism
This antagonism is
of 2 types: Reversible Antagonist binds covalently to receptor
or irreversible
Binding is so firm that antagonist
cannot dissociate from receptor

Thus it blocks action of agonist

Irreversible antagonism But blockade cannot be overcome

by ↑ the concentration of agonist

Hence also called irreversible antagonism

e.g., Adrenaline and
Duration of action of antagonist is usually phenoxybenzamine
long because until new receptors are at α - adrenergic
synthesized, the effect of antagonist remains receptors

Also called non-equilibrium antagonism

Antagonist acts as a site beyond

the receptor and not on the receptor e.g., Verapamil blocks
calcium channels and
Non-competitive antagonism Acts on receptor-effector linkage blocks cardiac
stimulant actions of
DRC – flattening and rightward shift adrenaline and
isoprenaline

4.18 FACTORS THAT MODIFY EFFECTS OF DRUGS
1. Body weight
Same dose of a drug can
produce different degrees of
response in different patients
Same dose of a drug can
Factors that modify produce different degrees of
effects of drugs response in same patient under
different circumstances
Factors modifying
drug response
4. Species and
5. Diet and
environment
Pharmacodynamics 51
Recommended dose is generally for
medium built persons
For obese and underweight persons the
dose has to be calculated individually
Body surface area is a better parameter
for more accurate dose calculation
But it is inconvenient hence generally
not used
body weight (kg) ×
average adult dose
Dose =
70
Pharmacokinetics of many drugs
change with age
Thus, response to drugs varies in
extremes of age
In newborn, the liver and kidney are
immature, blood-brain barrier is not well
formed, gastric acidity is low, intestinal
motility is slow, skin is delicate (for topical
applications)
2. Age
e.g., Chloramphenicol causing
Hence toxicity can occur at normal
gray baby syndrome in
dosage
neonates
Age (years) ×
Young’s
Formula to calculate dose in children adult + 12
formula =
Age
In adults liver and kidney functions are
e.g., Nephrotoxicity and
reduced, hence they are more susceptible
ototoxicity
to adverse effects, so lower doses are
due to streptomycin
recommended
Hormonal effects and smaller body size
may influence drug response in women
3. Sex e.g., Purgative administered
Special precautions while prescribing during menses, ↑ menstral
drugs during pregnancy and lactation blood flow due to ↑ pelvic
congestion
Rabbits are resistant to atropine
Thus extrapolation of results
race to human becomes difficult
Blacks require higher doses of atropine
to produce mydriasis
e.g., Calcium present in milk
Food interferes with absorption
reduces absorption of
of many drugs
tetracyclines
Polycyclic hydrocarbons in cigarette
smoke ↑ metabolism of drugs
(Continued)
52 Pharmacology mind maps for medical students and allied health professionals
4.18 FACTORS THAT MODIFY EFFECTS OF DRUGS (Continued)
Change of route can alter
drug response
6. Route and time of
administration
Because of diurnal variation,
timing of drug administration
is important
Drug response can vary due
to genetic factors
Study of such genetically mediated
7. Genetic factors
variations in drug response is
called “pharmacogenetics”
Factors modifying
drug actions
These differences are mostly
due to alterations in drug
metabolizing enzyme,
∴
metabolizing enzyme, production
is under genetic control
Generally when dose is ↑,
response ↑ proportionately
until “maximum” is reached
8. Dose
However, with some drugs
↑ the dose beyond maximum
may produce opposite effect
Oral magnesium sulfate
is purgative
IV magnesium sulfate causes
CNS depression (hence used as
anticonvulsant during eclampsia
of pregnancy)
Topical magnesium sulfate reduces
e.g., local edema, rectal magnesium
sulfate reduces intracranial tension
Glucocorticoids are secreted in
∴
e.g., Oral/IV N-acetylcysteine is
morning, exogenous glucocorticoids antidote for
too are administered in morning paracetamol poisoning
Whereas inhaled N-acetylcysteine is a
Study of such co-relation of drug
mucolytic Irrigated N-acetylcysteine
response to circadian rhythm is
in urinary bladder counters cystitis
called “chronopharmacology”
caused by cyclophosphamide
e.g., Acetylation of sulfonamide
and hydralazine may be fast or slow
Slow acetylators of hydralazine
may develop lupus erythematosus
Atypical pseudocholinesterase:
Succinylcholine is normally metabolized
by typical pseudocholinesterase; when it is
administered in patients with atypical
pseudocholinesterase, they develop
prolonged apnea due to persistence
of succinylcholine action
G6PD deficiency can cause hemolysis
when sulfones, primaquine, or
quinolones are administered
Malignant hyperthermia caused
by halothane and succinylcholine
Porphyrias due to administration
of barbiturates,
griseofulvin, and carbamazepine
e.g., Normal doses of neostigmine
↑ muscle power in
myasthenia gravis patients,
but high dose can cause muscle
paralysis
e.g., Physiological doses of
vitamin D ↑ calcification,
whereas hypervitaminosis D
can lead to decalcification
(Continued)
 Pharmacodynamics 53

4.18 FACTORS THAT MODIFY EFFECTS OF DRUGS (Continued)

Gastrointestinal diseases: Drugs are

poorly absorbed in malabsorption
syndrome
↓ Drug metabolism
Liver diseases
↓ Protein binding, ↑ free drug,
hence ↑ toxicity

↓ Function of liver and kidney,

∴ ↓ tissue perfusion
Cardiac diseases
↓ Oral absorption, GIT edema
∴
9. Diseases

↑ Toxicity, drug are primarily

∴
excreted from kidneys,
hence ↓ dose
Renal diseases
e.g., Streptomycin, amphotericin B

↑ Toxicity of CNS depression in

hypothyroid patients
Endocrine diseases
↑ Urinary retention with
anticholinergics and tricyclic
antidepressants in patients
with prostatic hypertrophy

Cumulation

Can lead to Tolerance

Tachyphylaxis

Drugs which are slowly excreted

cause cumulative toxicity
Cumulation
e.g., Digoxin

Requirement of higher doses to

produce a given response Species/race shows less
sensitivity to a drug
Natural
Factors modifying
drug actions e.g., Rabbits tolerant to atropine;
Tolerance blacks tolerant to mydriatics

Tolerance on repeated administration

10. Repeated
Acquired Initially response is seen, however
dosing later there is unresponsiveness to drug

e.g., Barbiturates, opioids, nitrates

Occurs due to changes in ADME

which reduces drug concentration;
also called dispositional tolerance
Pharmacokinetic
e.g., Barbiturates ↑ own metabolism

Occurs due to changes in target tissue

Mechanisms of tolerance
Also called functional tolerance

Pharmacodynamic Due to downregulation of receptors

Tolerance to pharmacologically e.g., Opioids, due to

related drugs
Cross-tolerance
e.g., Chronic alcoholics showing
tolerance to barbiturates and
general anesthetics
compensatory mechanisms
e.g., Blunting of antihypertensive
response due to salt and water retention

Rapid development of tolerance

Tachyphylaxis Also called acute tolerance,

e.g., tyramine, ephedrine,
amphetamine
It occurs due to depletion of
noradrenaline stores from
sympathetic nerve ending due
to slow dissociation of drug
from receptor, hence
blocking the receptor

(Continued)
54 Pharmacology mind maps for medical students and allied health professionals

4.18 FACTORS THAT MODIFY EFFECTS OF DRUGS (Continued)

Depends on doctor–patient
relationship

Depends on doctor’s
confidence

Especially important in Inert dosage from with no

11. Psychological factors
psychosomatic disorder biological activity

Only resembles actual

Such patients show response
preparation in appearance
to placebo
(dummy medication)
Factors modifying drug
actions
Means “I shall be pleasing”
Placebo
(in Latin)

Used in clinical trials to

12. Presence of other drugs Drug–drug interactions
compare new compound

Benefits patients with

psychosomatic disorders and
chronic incurable diseases

4.19 DRUG INTERACTIONS
Drug interactions
In vitro drug interactions
In vivo drug interactions
Pharmacokinetic drug interactions
influencing absorption by
Pharmacokinetic drug interactions
influencing distribution by
Pharmacokinetic drug interactions
influencing metabolism by
Pharmacokinetic drug interactions
influencing excretion by
Pharmacodynamic drug interactions
Pharmacodynamics 55
Alteration in duration or magnitude of
pharmacological actions of one drug by another
Response may be greater or lesser than
the sum of their individual effects Beneficial drug interactions; e.g.,
propranolol + hydralazine for hypertension
Responses may be beneficial or harmful
Unwanted drug interactions can cause
toxicity; e.g., propanolol ephedrine ↑ BP
Occurs in the syringe before administration
Could be chemical or physical interaction
e.g., Penicillin + gentamicin
Occurs within the body
Could either be pharmacokinetic or
pharmacodynamic
e.g., Tetracyclines chelate iron and calcium
Binding drugs
↓ absorption
e.g., antacids ↑ gastric pH, hence
Altering gastric pH
↓ absorption of iron and anticoagulants
e.g., Atropine and morphine slows GI motility,
Altering GI motility thus delays absorption of drugs; purgatives
reduce absorption of riboflavin
Competition for plasma protein or tissue binding e.g., Warfarin displaced by
which results in displacement interactions phenylbutazone from protein-binding site
e.g., Enzyme inducer like rifampicin, phenytoin,
phenobarbitone, and carbamazepine
Hepatic enzyme induction and inhibition
which result in drug interactions
Enzyme inhibitors like cimetidine, ketoconazole,
erythromycin, chloramphenicol
Drugs compete for same renal tubular transport
system, hence there is prolongation of duration e.g., Penicillin and probenicid
of action
Drugs acting on same receptors or physiological
systems can lead to additive, synergistic, or
antagonistic effects
e.g., Atropine antagonizes physostigmine
Diuretics produce hypokalemia which
potentiates digoxin toxicity
Aspirin enhances bleeding risk of
anticoagulant warfarin
Alcohol enhances sedation produced by
antihistaminics
 5
Adverse drug reactions

5.1 TYPES OF ADVERSE DRUG REACTIONS (ADRs)

Undesirable or unwanted
effect due to drug
administration
Dose-related or
Types
Non-dose related

Most common

Dose-related Predictable

Less mortality

Uncommon

Non-dose related Unpredictable

High mortality

Seen with
1. Side effects e.g., Atropine causing dryness of mouth
Adverse drug therapeutic doses
reactions
(ADRs) Due to overdosing e.g., Nephrotoxicity with aminoglycosides,
2. Toxic effects
or chronic use bleeding due to anticoagulants

Ag:Ab reaction resulting

in release of various mediators
Type I, II, III: Humoral (Ab) mediated
Classified on basis of
immunological mechanism
mediating the reaction Rx promptly, as it is
Type IV: Cellular (delayed hypersensitivity)
medical emergency
mediated
Drug of choice – inj.
Rapidly occurring: Immediate adrenaline (1:1000)
Type I hypersensitivity 0.3–0.5 mL 1M
(immediate) Inj. hydrocortisone
Treatment
100–200 mL IV

Ab: Reaction of complement, Inj. diphenhydramine

Type II hypersensitivity
(cytotoxic)
3. Hypersensitivity
reactions (drug allergy)
Type III hypersensitivity
(immune complex
mediated)
which destroys cell-bound antigen 25–50 mg IV/1M
e.g., Blood transfusion reaction, hemolytic
anemia due to quinine, cephalosporins, etc. IV fluids
Ab: Involved are mainly IgG
Ab: Complex formed
e.g., Serum sickness due to penicillins,
sulfonamides, acute interstitial nephritis
with NSAIDs, Stevens–Johnson’s syndrome
due to sulfonamides

Mediated by T-lymphocytes

Type IV hypersensitivity (cell- Re-exposure to Ag leads to

mediated/delayed) local inflammation

Type II, III, and IV are treated Occurs 2–3 days after exposure; e.g.,
with corticosteroids contact dermatitis with LAs
(Continued)
56
 Adverse drug reactions 57

5.1 TYPES OF ADVERSE DRUG REACTIONS (ADRs) (Continued)

Genetically determined

4. Idiosyncrasy
e.g., Succinylcholine apnea,
aplastic anemia due to
chloramphenicol, hemolytic
anemia with primaquine

e.g., Alcohol, barbiturates,

amphetamines, opioids

Intense desire to continue

taking the drug

Psychological dependence
Adverse drug reactions
Patient feels his well-being
depends on the drug

Repeated use produces

physiological changes in the body

Physical dependence

This makes continuous presence

of the drug in the body necessary
5. Drug dependence to maintain normal function

“Withdrawal syndrome” produces

Abrupt stoppage leads to
effects opposite to that
“withdrawal syndrome”
of the abused drug

Hospitalization

Substitution therapy; e.g.,

methadone/buprenorphine for
morphine addicts

Aversion therapy; e.g., disulfiram

Treatment of dependence
for alcohol withdrawal

Blockade therapy; e.g., naltrexone

for opioid dependence

General measures: Maintain

nutrition, family
support, and rehabilitation

(Continued)
58 Pharmacology mind maps for medical students and allied health professionals

5.1 TYPES OF ADVERSE DRUG REACTIONS (ADRs) (Continued)

“Iatros” means physician

6. Iatrogenic diseases
e.g., NSAID-induced peptic ulcer,
Physician-induced disease
metoclopramide-induced
due to drug therapy
parkinsonism

Ability of drug to cause cancer–

carcinogenicity
7. Carcinogenicity and
mutagenicity
Ability of drug to produce
e.g., Anticancer drugs,
abnormal genetic materials in
estrogens, etc.
cell mutagenicity

Drug induced cutaneous reaction

8. Photosensitivity reactions

Follows exposure to ultraviolet e.g., Doxycycline,

radiation demeclocycline
Adverse drug reactions

e.g., Anti-TB drugs

(INH, rifampicin, pyrazinamide)

9. Hepatotoxic reactions

Paracetamol, halothane

e.g., Aminoglycosides
(streptomycin, gentamicin),
10. Nephrotoxic reactions
amphotericin B, cisplatin,
cyclosporine, heavy metals, etc.

e.g., Aminoglycosides, loop

11. Ototoxic reactions
diuretics (furosemide), cisplatin

e.g., Ethambutol, chloroquine,

12. Ocular reactions
glucocorticoids

(Continued)
 Adverse drug reactions 59

5.1 TYPES OF ADVERSE DRUG REACTIONS (ADRs) (Continued)

Ability of drug to cause fetal

abnormalities when administered
to pregnant woman
e.g., Thalidomide (sedative) causing
phocomelia (babies with seal limbs)

“Teratos” – means monster

Tetracyclines causing yellowish
discoloration of teeth, antithyroid
drugs leading to fetal goiter

13. Teratogenicity

Conception to 16 days – usually

resistant, if affected, causes abortion
Abnormalities produced depends
on stage of pregnancy

Period of organogenesis (17–55 days)

General rule: Avoid drugs during

first trimester of pregnancy
60 Pharmacology mind maps for medical students and allied health professionals

5.2 GENERAL PRINCIPLES OF TREATMENT OF POISONING

(MNEMONICS [ABCDEFGHI])

e.g., Atropine for organophosphorus compounds

i. Antidote – if any Flumazenil for diazepam poisoning

Naloxone for morphine poisoning

Airway cleared of tongue, secretions, vomitus

ii. Breathing assessed,
if insufficient, Insert endotracheal tube
mechanical ventilation
Aspirate secretions regularly

iii. Circulation maintained Check pulse, BP; start IV line

Promotes elimination of poison which is absorbed

Use IV mannitol or furosemide

treatment of poisoning

Any drug can

General principles of

cause poisoning iv. Diuretics

Alkalinize urine (with sodium e.g., Salicylic acid,
e.g., Barbiturates, bicarbonate) for acidic poisoning barbituric, acid
morphine, salicylate
Acidify urine (with ascorbic acid) for basic
General principles e.g., Amphetamines
drug poisoning
of treatment
In severe poisoning

Suitable only for drugs which are not highly

v. Dialysis
protein bound

vi. Electrolyte balance – e.g., Aspirin, methanol,

For drugs with low volume of distribution
maintained lithium, etc.

vii. Fluid balance – maintained Removes unabsorbed portion of drug

If patient is unconscious, endotracheal

viii. Gastric lavage – with intubation should be done before gastric lavage
normal saline
After lavage, add activated charcoal to stomach

Activated charcoal absorbs drugs and

poisons (by physical antagonism)

ix. Hospitalization This step precedes all the above steps

IV diazepam for convulsion

x. Immediate
symptomatic treatment
External cooling for hyperpyrexia

i. Physical Activated charcoal For adsorbing alkaloids

Acetic acid for alkalies

Potassium permanganate for

ii. Chemical
barbiturates, alkalies
Chelating agents for
heavy metals
Antidotes

Naloxone for morphine

iii. Pharmacological Flumazenil for diazepam

Atropine for organophosphorus

poisoning

1 part tannic acid (for alkaloids,

glycosides, heavy metals)

1 part milk of magnesia

iv. Universal
(to antidote acids)

2 parts burnt toast

(to absorb alkaloid)
 Adverse drug reactions 61

5.3 PHARMACOVIGILANCE

Safety of marketed drugs under practical

Study of
conditions of clinical use in large communities

Introduction Concerned with Development of science and regulation in area

of drug safety

Detection, assessment, and prevention of adverse

Aims at effects and other problems related to use of
medicines

Greatest of all drug disasters

Thalidomide introduced as a safe

and effective hypnotic and antiemetic

Importance Thalidomide tragedy Rapidly became popular for treatment of

of pharmacovigilance (1961–1962) nausea and vomiting in early pregnancy

Tragically drug proved to be a potent human Caused major birth defects

teratogen in an estimated 10,000 children

Phocomelia was a characteristic feature

Spontaneous reporting

Case reports

Passive surveillance

Case series

Methodologies in
pharmacovigilance Stimulated reporting Cross sectional studies

Active surveillance Comparative observational studies Case control study

The US Food and Drug Administration

FDA is an agency of the United States Cohort study
Department of Health and Human Services

The European Medicines Agency is a

EMEA decentralized body of the European Union
located in London

Important organizations MHLW Ministry of Health, Labour and Welfare, Japan

involved in
pharmacovigilance
The government of India has initiated the
national pharmacovigilance programme
CDSCO
Central Drugs Standard Control Organization
coordinates the country-wide pharmacovigilance
Uppasala Monitoring programme under the aegis of the Ministry of
Centre Health and Family Welfare, DGHS,
New Delhi, India
 6
New drug approval process and clinical trials

6.1 NEW DRUG APPROVAL PROCESS

Oversees NDA (New Drug

Application) process

Requires investigator to file Prior to testing new drugs in

Investigational NDA (IND) humans

Responsible for drugs and drug

efficacy of all prescription and
Food and Drug over-the-counter drug products
Center of Drug Evaluation
Administration (FDA)
and Research (CDER)
under FDA
Prior to marketing

Monitoring drug safety after initial

market approval
CDER is responsible for
Has authority to withdraw from
market any drug posing significant
health risk

Lead compound selection

Preclinical testing and animal testing
New drug approval of new chemicals
Overview of the drug Development process is
process
approval process divided into two sections
and clinical trials Administration of new
Clinical testing chemicals to
An IND must be filed with human beings
FDA and approved prior to
administering new drug
Investigation and new products to humans
drug applications (IND) All preclinical animal data

IND includes
Name and locations of
investigators who will be performing
the planned clinical trials
Involve administration of a
drug to humans

Clinical investigations Requires substantial financial

and time commitment

Human testing is divided into

Phase 0, Phase 1, Phase 2,
five phases each with
Phase 3, Phase 4
specific objectives

62
 New drug approval process and clinical trials 63

6.2 PHASES OF CLINICAL TRIALS (0, 1 AND 2)

Also known as human microdosing studies

A dose too low to cause any therapeutic effect

Designed to speed up the

development of promising drugs

Phase 0 clinical trials Gives no data on safety or efficacy

Distinctive features: Administration of single

subtherapeutic doses of study drug

Small number of subjects (10–15)

Preliminary data on the agent's

pharmacodynamics and pharmacokinetics

Performed in human beings

Generally 20–30 healthy volunteers are chosen

Phases of clinical trials

Starting dose is generally low, often 1/10 of the

Phase 1 clinical trials
highest no-effect dose in animal models

Additional subjects may be recruited and administered

higher doses to determine maximum tolerated
dose without significant side effect

Preliminary ADME data of the parent drug and all

metabolites are evaluated

Shifts focus from safety to efficacy

A large number of people participate (100–300),

where majority of the people suffer from
targeted illness
Phase 2 clinical trials
Side effects from new drug are also
investigated

Clinical protocols must be sent to the FDA as

amendments to the IND prior to beginning of the trial
64 Pharmacology mind maps for medical students and allied health professionals

6.3 PHASES OF CLINICAL TRIALS (3 AND 4)

Scientists review preclinical and clinical

data in evaluating the proposed
phase 3 protocol

Longest and most comprehensive trials

regarding efficacy and safety of new
compounds

Significantly greater number of people

(1000–3000 patients) who
Phase 3 clinical trials
are afflicted with targeted illness are
tested

New drug may be compared to the

existing therapeutic regimen or to placebo

Final marketed formulation of drug

Phases of clinical trials product should be optimized prior to
start of phase 3 clinical trials

Post-approval clinical trials also

called as Post Marketing Surveillance (PMS)

Specific patient population to further

Phase 4 clinical trials
assess efficacy and side effects

More fully understand how the

product compares to other commercially
available therapeutic regimens
 II
Part    

Autonomic nervous system (ANS)

pharmacology
 7
Introduction to ANS

7.1 INTRODUCTION TO ANS

Central NS

Nervous system (NS) is

categorized into
Peripheral NS

Somatic NS

Peripheral NS is classified
into
Autonomic NS (ANS)

ANS was named

by Langley

“Auto” = self, “Nomos” =

Introduction to ANS
governing (in Greek)

ANS is not under voluntary

control, i.e., is automatic
Sympathetic NS (SNS)

Controls viscera like heart,

smooth muscles
Parasympathetic NS (PSNS) Have opposing effects
Centers are present in
hypothalamus, medulla,
and spinal cord
SNS and PSNS both Are in state of equilibrium

Two important subdivisions

Innervate most organs

SNS is active i.e., Fight, flight, or

during Stress fright

PSNS is active i.e., Tissue-building

during Peace reactions

66
 Introduction to ANS 67

7.2 INNERVATIONS OF ANS

Autonomic afferents are carried in

e.g., 9th and 10th cranial nerves
visceral nerves (non-myelinated)

Myelinated preganglionic fibers →

synapse (ganglion) → postsynaptic
Autonomic efferents
fiber → receptor on organ
(neuroeffector junction)

Parasympathetic ganglia are

located near organ they supply

PSNS efferent are carried via Hence parasympathetic

CRANIOSACRAL outflow postganglionic fibers are small

Parasympathetic preganglionic
fibers are long Paravertebral

Innervations

Sympathetic ganglia are at Prevertebral

three places (T1-L3)

Sympathetic efferents carried via Sympathetic preganglionic Terminal

THORACOLUMBAR outflow fibers are short

Sympathetic postganglionic
fibers are ∴ long

Is a sympathetic ganglion

Different from other sympathetic

Adrenal medulla
ganglion

The main catecholamine

∴
is ADRENALINE
68 Pharmacology mind maps for medical students and allied health professionals

7.3 NEUROTRANSMITTERS

ANS neurotransmitters Acetylcholine, noradrenaline,

and dopamine

Adrenal medulla ADRENALINE, noradrenaline

Neurotransmitters
Other minor neurotransmitters
Nitric oxide (NO)
besides major ones

Co-transmission Modulate principle/major ATP (adenosine ATP, NO → inhibitory

neurotransmitters triphosphate) (gut)

e.g., VIP (vasoactive intestinal

peptide)

GABA (gamma amino

butyric acid)

CCK (cholecystokinin) CCK, VIP, GABA →

excitatory (gut)
 8
Cholinergic system and drugs

8.1 CHOLINERGIC SYSTEM

i. Ganglia: All preganglionic

ANS
(SNS and PSNS) fibers
Acetylcholine (ACh) is the
major neurotransmitter
of PSNS

ii. Postganglionic
parasympathetic
nerve terminals
Cholinergic nerves – synthesize,
Cholinergic system Introduction
store, and release ACh

iii. Adrenal medulla

Important ACh release sites

iv. Brain and spinal cord

v. Neuromuscular
junction (NMJ)

vi. Sympathetic
postganglionic nerve
terminals of sweat glands
(this is an unconventional site)

69
70 Pharmacology mind maps for medical students and allied health professionals

8.2 SYNTHESIS/TRANSMISSION/METABOLISM OF ACh

Acetyl CoA + choline →

acetylcholine (choline acetyl
tranferase [CAT])

Action potential at
presynaptic membrane

Release of ACh in synaptic cleft

Synthesis/transmission/ ACh binds and stimulates post-

metabolism of ACh synaptic cholinergic receptor

Depolarization of postsynaptic
membrane

Metabolism of ACh by
acetylcholinesterase
(AChE) in synaptic cleft

Repolarization of postsynaptic
membrane

8.3 CHOLINESTERASES

Acetylcholinesterase
ACh choline + acetic acid
True (acetylcholinesterase)
Cholinesterases present at neurons, ganglia, and
NMJ

2 types of AChE

Pseudo (butrylcholinesterase)
present in plasma and liver
 Cholinergic system and drugs 71

8.4 CHOLINERGIC RECEPTORS

Muscarinic

2 Types

Nicotinic

Muscarinic are of 5 subtypes M1, M2, M3, M4, and M5

Nicotinic are of 2 subtypes Nn and Nm

Muscarinic receptors are

G protein-coupled receptors

Nicotinic are ion

2α, 1β, 1γ, 1δ
channels and have 5 subunits

Cholinergic receptors
Autonomic ganglia, gastric
M1
glands, CNS

Heart, smooth muscles,

M2
nerves

Exocrine glands, smooth

M3
muscles, eye

M4,5 CNS

Nm NMJ

Autonomic ganglia, adrenal

Nn
medulla, CNS
72 Pharmacology mind maps for medical students and allied health professionals

8.5 CHOLINERGIC DRUGS

Act at same site as ACh

Mimic actions of ACh Acetylcholine,

Cholinergic i. Choline esters methacholine, carbachol,
drugs ∴ Called bethanechol
“cholinomimetics” or
Neostigmine,
“parasympathomimetics” ii. Cholinomimetic
Pilocarpine, muscarine physostigmine,
alkaloids pyridostigmine
Classification

Reversible Edrophonium
(short-acting)

Rivastigmine,
iii. Anticholinesterases CNS action, i.e., to Rx
galantamine,
Alzheimer disease
donepezil, tacrine

Echothiophate,
malathion,
Irreversible Organophosphates
toxic nerve gases
(sarin, tabun)
 Cholinergic system and drugs 73

8.6 ACTIONS OF ACh

Resembles alkaloid
muscarine present in
mushrooms

Due to stimulation of
muscarinic receptors
(M1–3) Resembles vagal
stimulation
a. Heart

Inhibits SA and AV node Hence ↓ HR and FOC Bradycardia

Due to release of
nitric oxide/EDRF
b. Blood vessels Dilatation (Endothelium
Derived Relaxing
Factor)
1. Muscarinic actions
↑ Tone and peristalsis,
GIT relaxes sphincters, hence
there is propulsion and
c. Smooth muscles ↑ Tone of all non-vascular
evacuation of GI contents
smooth muscles
Detrusor contracts, trigone
↑ Secretion of all glands, viz. Urinary bladder relaxes, hence it promotes
d. Secretory glands lacrimal, salivary, tracheo- evacuation of urine
bronchial, nasopharyngeal,
gastric, intestinal, and sweat

Constriction of sphincter
pupillae, leads to miosis

↑ Drainage of aqueous
e. Eye
humor, hence ↓ IOP

Ciliary muscle contraction

Resemble actions of
causes spasm of
alkaloid nicotine
accommodation
Actions of ACh 2. Nicotinic actions
Due to stimulation of
nicotinic receptor
i.e., Nn and Nm

Contraction of skeletal
muscles (Nm receptors)
a. NMJ
Higher doses result in
persistent contraction,
thus causing
spastic paralysis

Activates both
sympathetic and
parasympathetic ganglia
b. Autonomic ganglia
Activates adrenal
medulla

c. CNS Stimulates several sites

74 Pharmacology mind maps for medical students and allied health professionals

8.7 USES OF ACh AND CHOLINOMIMETICS

Rapidly metabolized in gut and

plasma (by pseudocholinesterase)
and at site of action
(by true cholinesterase)

Hence not used

Uses of ACh
therapeutically

Rarely used as 1% eye drops for

miosis during some eye operations

8.8 ADVERSE REACTIONS OF CHOLINOMIMETICS

Carbachol Glaucoma

Carbachol/Bethanechol
Uses of other cholinomimetics resistant to metabolism by Urinary bladder hypotonia
both cholinesterases, hence
long duration of action

Urinary retention
(mnemonic “SLUDGE”)
Bethanechol
Postoperative
S – Salivation paralytic ileus

Xerostomia (alternative to
L – Lacrimation pilocarpine)

Adverse reactions of
U – Urination
cholinomimetics

D – Diarrhea

G – GI/GU cramps

E – Emesis/Eye (miosis)
 Cholinergic system and drugs 75

8.9 CHOLINOMIMETIC ALKALOIDS

Source – Pilocarpus
microphyllus

Has prominent muscarinic

Miosis
actions

Spasm of accommodation
Actions on eye (important)
topically

↑ Sweating (diaphoresis) ↓ IOP

↑ Salivary secretion Browache due to spasm of

(sialogogue) accommodation and miosis

Cholinomimetic
Pilocarpine
alkaloids
Headache

Side effects

Corneal edema

Retinal detachment
(on long-term use)

As OCUSERT, a novel delivery

i. Glaucoma system which releases
pilocarpine for 7 days

ii. Alternatively with mydriatics To prevent/break adhesions

(pupillary dilators) between iris and lens
Uses
iii. Xerostomia (Sjögren's
syndrome)

iv. Dryness of mouth following

radiation of head and neck
76 Pharmacology mind maps for medical students and allied health professionals

8.10 GLAUCOMA

↑ In IOP (intraocular
pressure) beyond 21 mmHg

Aqueous humor is
produced by ciliary body

It drains via canal of

Glaucoma
Schlemm
Iris blocks canal of Schlemm
Acute congestive/angle
↑ In IOP leads to optic closure/narrow angle
nerve degeneration,
∴ causes blindness Should be treated urgently

2 Types of glaucoma
Slow onset

Chronic simple/open Long-term treatment is

angle/wide angle required

Surgical treatment is
usually preferred

8.11 DRUGS FOR GLAUCOMA

Timolol, betaxolol,
β blockers
levobunolol (first-line drugs)

Adrenaline, dipivefrine
Adrenergic agonists
(used with β blockers)
a. Drugs ↓ formation of
aqueous humor (all topical)

α2 adrenergic agonists Apraclonidine, brimonidine

Drugs for treatment of Carbonic anhydrase Dorzolamide (topical),

glaucoma inhibitors acetazolamide (oral)

Pilocarpine, carbachol,
Cholinergics
physostigmine, echothiophate
b. Drugs ↑ drainage of
aqueous humor
Latanoprost, bimatoprost
Prostaglandin analogs
(adjuvants)
 Cholinergic system and drugs 77

8.12 β BLOCKERS IN GLAUCOMA

e.g., Timolol

First-line drugs

↓ Aqueous production

β blockers in glaucoma Block β receptors in ciliary body

Hence there is no headache,

No miosis browache (unlike pilocarpine),
∴ preferred

Causes a smooth and sustained Can precipitate asthma, CCF,

↓ in IOP heart block

Systemic absorption via Hence are to be used carefully

nasolacrimal duct

Hence give pressure on

nasolacrimal duct
78 Pharmacology mind maps for medical students and allied health professionals

8.13 ADRENERGIC AGONISTS, MIOTICS, AND PROSTAGLANDIN

ANALOGS IN GLAUCOMA

e.g., Dipivefrine (a prodrug of

adrenaline), apraclonidine
(analog of clonidine)
Adrenergic agonists
in glaucoma
↓ IOP by reducing ciliary body
(α1-induced vasoconstriction)

e.g., Pilocarpine, physostigmine

Miotics

Thus opens up canal of Schlemm,

Constrict pupils
hence ↑ drainage

e.g., Latanoprost

Prodrug of PGF2α

Prostaglandin analogs
↑ Drainage by relaxing ciliary
muscle

Used as adjunct

8.14 CARBONIC ANHYDRASE INHIBITORS (CAIs)

e.g., Dorzolamide,
acetazolamide (oral)

Aqueous humor formation

requires HCO3– ions

Carbonic anhydrase HCO3– are produced by

H2CO3 → H+ + HCO3
inhibitors (CAIs) carbonic anhydrase

CAIs by inhibiting the

enzyme carbonic anhydrase
↓ HCO3, thus ↓ IOP

Oral acetazolamide leads

Hence topical dorzolamide
to hypokalemia, anorexia,
preferred
drowsiness
 Cholinergic system and drugs 79

8.15 ANTICHOLINESTERASES (ANTIChE)

Inhibits enzyme
cholinesterase (AChE)

Acetylcholine →
acetic acid + choline

Bind to cholinergic
AntiChE inhibits
receptors and
→ AChE
inactivates them

∴ ACh is not
Structural analogs
metabolized and
of ACh
accumulates at synapse
Anticholinesterases
(AntiChE)
∴ Their actions are
similar to ACh

AChE has 2 sites Anionic and esteratic

Physostigmine, neostigmine,
pyridostigmine, edrophonium,
Reversible Carbamates
donepezil, rivastigmine,
tacrine, galantamine

Insecticides Propoxur (Baygon),

Classification carbaryl, aldicarb
of AntiChE

Organophosphates

Irreversible
Echothiophate,
malathion, toxic nerve
gases (sarin, tabun)
80 Pharmacology mind maps for medical students and allied health professionals

8.16 PHYSOSTIGMINE

Natural alkaloid of
Source
Physostigma venenosum

Hence has a high lipid

solubility
Tertiary ammonium
compound
Thus it has a better oral,
CNS, tissue penetration

Glaucoma (with pilocarpine

nitrate)

Physostigmine Uses

Atropine poisoning

Browache

ADRs Retinal detachment

Availability – topical (0.1%–1%),

Cataract
IV injection

8.17 NEOSTIGMINE

Synthetically produced

Quarternary ammonium Hence has poor lipid

compound solubility
Neostigmine

As it has additional direct

Myasthenia gravis
action on NMJ

Postoperative paralytic
Uses
ileus

Urinary bladder atony

 Cholinergic system and drugs 81

8.18 EDROPHONIUM

Rapid and short-acting

To differentiate between
Edrophonium myasthenia crisis and
cholinergic crisis
Uses

IV for snakebite, curare

poisoning

8.19 RIVASTIGMINE, DONEPEZIL, GALANTAMINE, TACRINE

Rivastigmine, donepezil, Specifically used for

galantamine, tacrine Alzheimer's disease

8.20 USES OF REVERSIBLE ANTIChE

In glaucoma with
pilocarpine
1. As miotic
Alternating with mydratics
to prevent/break adhesions
between lens and iris ↑ Ch concentration
at NMJ
Chronic autoimmune
disorder Additionally has
direct stimulant
Characterized by nicotinic action on NMJ
receptor (NMJ) antibodies,
which ↓ NMJ receptor mass Hence muscle
Uses of reversible
AntiChE Leads to progressive skeletal power improves
muscle weakness and easy
fatigability Excessive muscle Due to infection, Can lead to
weakness surgery, stress MYASTHENIA CRISIS
Diagnosed by IV
edrophonium
Excessive muscle Due to ↑ dose of Can lead to
AntiChE; i.e.,
weakness neostigmine CHOLINERGIC CRISIS
Rx NEOSTIGMINE
15 mg QDS
CRISIS differentiated
2. Myasthenia by IV edrophonium
gravis 2 mg

IV edrophonium in Patient improves

myasthenia crisis

IV edrophonium in Patient worsens

cholinergic crisis

Rx of myasthenia
↑ Dose of AntiChE
crisis

Rx of cholinergic ↓ Dose of AntiChE,

crisis atropine
Glucocorticoids
to ↓ antibodies
Other Rx of myasthenia e.g., Azathioprine,
gravis cyclosporine
Immunosuppressants

↓ Antibodies

(Continued)
82 Pharmacology mind maps for medical students and allied health professionals

8.20 USES OF REVERSIBLE ANTIChE (Continued)

e.g., Antihistaminics, tricyclic

Toxicity of drugs with
antidepressants, and
anticholinergic actions
phenothiazine
3. Anticholinergic
poisoning/atropine
Because it has good tissue
poisoning
penetration (as it is a
tertiary amine)
Physostigmine preferred

Crosses BBB, hence it

neutralizes CNS toxicity also

As it has additional direct

4. Curare poisoning Neostigmine is preferred NMJ action besides
AntiChE action

5. Postoperative paralytic
ileus
Uses of reversible
AntiChE
6. Urinary bladder
atony/retention

Bite releases
∴
7. Cobra bite neurotoxin which paralyzes
skeletal muscles

To improve cholinergic
deficiency in CNS

8. Alzheimer’s disease

Specifically rivastigmine,
tacrine, donepezil

Irreversible AntiChE
9. Glaucoma echothiophate eye drops for
glaucoma
 Cholinergic system and drugs 83

8.21 IRREVERSIBLE ANTIChE (ORGANOPHOSPHORUS COMPOUNDS)

Powerful, irreversible inhibitors

of AntiChE

Binding is covalent to only

estaratic site and enzyme is
phosphorylated

Hence binding is stable and

irreversible

Reversible AntiChE (except

edrophonium) binds to both
Irreversible AntiChE anionic and estaratic site
(organophosphorus
compounds)
Edrophonium binds to only
anionic site, hence action is
quickly reversible and short-acting

All OP compounds (except

echothiophate) are highly lipid
soluble

Hence can be absorbed from all

routes, including intact skin

Thus, OP poisoning can also

occur by spraying of agricultural
pesticides/insecticides
84 Pharmacology mind maps for medical students and allied health professionals

8.22 ORGANOPHOSPHORUS POISONING

OP compounds are used as

agricultural insecticides/
pesticides

Hence poisoning
is frequent Similar to cholinergic
(muscarinic, nicotinic, CNS)
hyperactivity
Poisoning could be
accidental/suicidal/ i.e., SLUDGE (Salivation,
homicidal Lacrimation, Urination,
Diarrhea, GI/GU cramps,
Emesis/Eye – Miosis)
Signs/symptoms
Sweating, ↑ tracheobronchial
secretions, ↑ GI secretions,
Organophosphorus bronchospasm, hypotension,
poisoning convulsions, and coma

Respiratory paralysis can

cause death
Remove clothing

Poisoning via skin

Wash skin with soap

and water

Gastric lavage

Rx Maintain BP and
airway patency
IV 2 mg every 10 min until
pupil dilates/dryness
of mouth
ATROPINE

DRUG OF CHOICE

Poisoning via oral route

e.g., Pralidoxime

Pralidoxime combines with

cholinesterase–OP complex

Releases binding, frees

AChE enzyme

Administered within
Cholinesterase
minutes of poisoning
reactivators
(maximum 12–24 h)

Delay leads to “aging”

∴
of enzyme, cannot be freed

“Aging” is due to loss of one

chemical group from complex,
making complex stable

NOT USEFUL in carbamate

compound poisoning,
∴ they do not have a free site
(anionic site) for binding of oximes
 Cholinergic system and drugs 85

8.23 DIFFERENCES BETWEEN PHYSOSTIGMINE AND NEOSTIGMINE

Physostigmine Neostigmine

1. Natural (Physostigma venenosum) Synthetic

2. Tertiary amine Quarternary amine

3. Good oral absorption Poor oral absorption

4. Good tissue penetration Poor tissue penetration

5. Crosses BBB: CNS effects Does not cross BBB, no CNS effects

6. Main indication – glaucoma Myasthenia gravis

7. Used in atropine poisoning Used in curare poisoning

 9
Anticholinergics

9.1 INTRODUCTION AND CLASSIFICATION

Also called antimuscarinics,

parasympatholytics, or
cholinergic blocking drugs

Block effects of ACh on

Introduction
muscarinic receptors

Drugs that block nicotinic

receptors are ganglionic
blockers or neuromuscular
blockers Prototype, obtained from
Atropine Atropa belladonna, DOC
for OP poisoning
Anticholinergics Natural alkaloids

Scopolamine, for motion

Hyoscine
sickness

Homatropine (mydriatic)

Semisynthetic derivatives
Classification Ipratropium bromide, tiotropium
bromide (both for bronchial
asthma)

Mydriatics Tropicamide, cyclopentolate

Dicyclomine, propantheline,
Synthetic substitutes Antispasmodic–Antisecretory glycopyrrolate, telenzepine,
tolterodine

Benztropine, benzhexol,
Antiparkinsonian
trihexyphenidyl

86
 Anticholinergics 87

9.2 ACTIONS

↑ Heart rate,
causes tachycardia
1. CVS
Large doses lead
to hypotension

↓ All secretions, i.e., lacrimal,

salivary, gastric, tracheobronchial,
nasopharyngeal, except milk

↓ Sweating, results in fever;

ATROPINE FEVER
2. Secretions
↓ Salivary secretions lead to
dry mouth, dysphagia

↓ Lacrimal secretions lead to

dryness of eyes
↓ Tone and motility, hence
causes constipation
GIT

Relieves spasm

Relaxes ureters

Genitourinary Relaxes urinary bladder

Actions Hence they can cause urinary

retention, esp. in elderly
males with benign prostatic
3. Smooth hypertrophy (BPH)
muscles
Bronchodilation

Bronchi ↓ Tracheobronchial secretion

Hence provides symptomatic

Esp. ipratropium,
relief in chronic obstructive
tiotropium
pulmonary disease (COPD)

Relaxes smooth muscle

Biliary tract

Topical application blocks Hence relieves spasm

muscarinic receptors on sphincter
pupillae, which causes mydriasis,
4. Eye → ↑ IOP
Ciliary muscle are paralyzed;
paralysis of accommodation leads
to cycloplegia (blurring of vision)

High doses of atropine cause CNS

stimulation, leading to anxiety,
restlessness, hallucination, delirium
5. CNS
Scopolamine (hyoscine) causes
CNS depression, hence causes
sedation and drowsiness
88 Pharmacology mind maps for medical students and allied health professionals

9.3 ADVERSE EFFECTS

Dry mouth

Dysphagia

Constipation

Urinary retention

Adverse effects

Blurring of vision

Tachycardia, palpitations

Restlessness,
hallucinations, delirium

Toxicity is Rx with IV
physostigmine
 Anticholinergics 89

9.4 USES

Renal colic, along

with morphine

Biliary colic

Abdominal colic, along with

loperamide
1. Antispasmodic

Irritable bowel syndrome

Nocturnal enuresis

Post-urological surgeries

Iritis, iridocyclitis, keratitis,

Therapeutic following iridectomy
(to provide rest to eye)

Fundoscopy
Uses 2. Mydriatic and cycloplegic
Diagnostic

Testing errors of refraction

Alternating with miotics (e.g.,
pilocarpine, physostigmine) to
prevent/break adhesions
between lens and iris

Atropine 30 min before

anesthesia

↓ Salivary, tracheobronchial,
and gastric secretions

Prevents laryngospasm

3. Preanesthetic
Additional bronchodilatory
property

Prevents vasovagal attack

GLYCOPYRROLATE is
preferred

(Continued)
90 Pharmacology mind maps for medical students and allied health professionals

9.4 USES (Continued)

Drug of choice (DOC)

4. Organophosphorus (OP)
poisoning
2 mg IV every 10 min until
pupil dilates/dryness of
mouth

Transdermal (behind ear, on

5. Motion sickness mastoid) scopolamine 30 min
before journey

Ipratropium/tiotropium
bromide

Uses 6. Bronchial asthma and COPD Causes bronchodilation

Does not depress Hence there is no

mucociliary clearance inspissation of mucus in
(unlike atropine) respiratory passage

M1 blockers like
7. Peptic ulcer
pirenzepine/telenzepine

Centrally acting
anticholinergics

8. Antiparkinsonian/drug-
induced parkinsonism
e.g., Benztropine, benzhexol,
trihexyphenidyl
 10
Skeletal muscle relaxants

10.1 INTRODUCTION

↓ Muscle tone

Act peripherally at NMJ

Also act centrally on

Introduction
cerebrospinal axis

Also act directly on

contractile mechanism

↓ Spasticity in various
neurological conditions and
during operative procedures

10.2 CLASSIFICATION

d-TUBOCURARINE, vecuronium,
a. Non-depolarizing blockers
atracurium, rocuronium,
(competitive blockers)
rapacuronium, pancuronium
1. Drugs acting peripherally
at NMJ
SUCCINYLCHOLINE,
b. Depolarizing blockers
decamethonium

Classification
Diazepam, baclofen, tizanidine,
2. Drugs acting centrally
mephenesin, chlorzoxazone

3. Drugs acting directly on

DANTROLENE
skeletal muscle

91
92 Pharmacology mind maps for medical students and allied health professionals

10.3 PERIPHERAL SMRs

Curare was used as arrow poison

for hunting wild animals,
curare paralyzed them
∴

Isolated from plant

Chondrodendron tomentosum

Active principle of curare d-Tubocurarine

Natural competitive
Competitive/non- Dextrorotatory quarternary
1. Peripheral SMRs blockers/
depolarizing blockers ammonium compound
d-Tubocurarine (d-Tc)

Hence it is not well absorbed

orally and is quickly excreted
Binds to nicotinic
receptors on NMJ
∴ Administered
as IV or IM
Blocks ACh
competitively
Mechanism of action
Dissociation from
receptors is slow

Hence their actions

are reversible
 Skeletal muscle relaxants 93

10.4 PHARMACOLOGICAL ACTIONS

Muscle weakness causes Flaccid paralysis

First small muscles

are paralyzed

Later large muscles

are paralyzed

Intercostal muscles and

diaphragm also paralyzed
Skeletal muscle

Respiration stops

There is no loss of
consciousness

Recovery occurs in
Pharmacological actions reverse order

Duration of action:
30–60 min

High doses block autonomic

Autonomic ganglia Hence it leads to hypotension
ganglia and adrenal medulla

Thus there is hypotension,

Histamine is released
Histamine release bronchospasm, ↑ tracheobronchial
from mast cell
and gastric secretions

10.5 ADVERSE REACTIONS

Rx with neostigmine +
Prolonged apnea
antihistaminics

Respiratory paralysis Artificial respiration

Adverse reactions
Due to ganglion blockade and
Hypotension
histamine release

Bronchospasm and flushing Due to histamine release

94 Pharmacology mind maps for medical students and allied health professionals

10.6 SYNTHETIC COMPETITIVE BLOCKERS

More potent

Spontaneous recovery, hence

no need of neostigmine for reversal
e.g., Pancuronium, vecuronium,
atracurium, rapacuronium,
rocuronium, mivacurium
No blockade of autonomic ganglia

Advantages of synthetic
agents over d-Tc

Less histamine release

Hence less hypotension

Hence nowadays preferred over d-Tc

Pancuronium/atracurium/
Intermediate acting (2–4 min)
vecuronium

Synthetic competitive Rapacuronium and

Rapid onset
blockers rocuronium

Undergoes spontaneous HOFMANN

ELIMINATION by plasma esterases

∴ Used safely in renally

impaired patients

Atracurium

Laudanosine, a metabolite,
causes seizures

Cisatracurium, an isomer of
atracurium, causes fewer seizures, less
histamine release, thus is preferred

Short-acting and
has slow onset

Mivacurium

Significant histamine release

 Skeletal muscle relaxants 95

10.7 DEPOLARIZING BLOCKERS – SUCCINYLCHOLINE (SCh)

Neuromuscular effects are

like ACh

Quarternary ammonium SCh reacts with nicotine

compound receptors and activates NMJ

Structure resembles 2 However, SCh is metabolized

Depolarizing blockers –
molecules of ACh joined gradually (unlike ACh) by
Succinylcholine (SCh)
together pseudocholinesterase

Hence there is persistant Spastic paralysis

Mechanism of action
depolarization which leads to (phase I block)

High doses produce dual

block

Depolarizing, potentiated
Phase I block
by AntiChE

Non-depolarizing reversed
Phase II block
by AntiChE
96 Pharmacology mind maps for medical students and allied health professionals

10.8 PHARMACOLOGICAL ACTIONS

Onset within 1 min,

IV administration
duration 5–10 min

Initial transient muscle

Skeletal muscles
fasciculations, twitching

Later skeletal
muscle paralysis

Initial hypotension and

bradycardia
due to vagal stimulation
Pharmacological
actions
Later hypertension and
tachycardia due to
CVS
sympathetic ganglia
stimulation
SCh not metabolized
Causes histamine Large doses can lead to normally
release arrhythmias
Hence usual doses
SCh rapidly Genetic abnormality in leads to Respiratory paralysis
metabolized by patients with atypical prolonged SCh apnea
pseudocholinesterase pseudocholinesterase
Rx by blood transfusion
(which supplies
pseudocholinesterase)
SCh apnea

Artificial respiration
 Skeletal muscle relaxants 97

10.9 ADVERSE REACTIONS

Due to initial muscle

Postoperative pain
fasciculations

Due to liberation of K+ from

damaged intracellular
muscle fibers
Hyperkalemia

Dangerous in patients with

CCF

Cardiac arrhythmias
Adverse reactions
Rare fatal genetic disorder

Sudden excessive rise in

body temperature

Severe muscle spasm

Malignant
hyperthermia
Occurs due to release of
intracellular Ca+2 from
sarcoplasmic reticulum

Halothane, SCh, isoflurane IV DANTROLENE is drug

can precipitate of choice

Rx O2 therapy

Immediate cooling of body

10.10 DRUG INTERACTIONS

General anesthetics
↑ action

AntiChE (neostigmine)
Drug interactions
reverses action

Aminoglycosides and calcium

channel blockers ↑ action
98 Pharmacology mind maps for medical students and allied health professionals

10.11 USES OF SMRs

Adjuvant to general
anesthetics for adequate
muscle relaxation

For endotracheal intubation Short-acting SMRs like SCh

Laryngoscopy,
bronchoscopy,
esophagoscopy

Uses of SMRs

Orthopedic procedures like

fractures and dislocation
reductions

Electroconvulsion therapy
(ECT) to prevent convulsions
and trauma

Spastic disorders; e.g.,

status epilepticus,
tetanus, athetosis,
to overcome spasm
 Skeletal muscle relaxants 99

10.12 CENTRAL SMRs

Acts on cerebrospinal axis

No loss of consciousness

Possesses slight
sedative property
Depresses spinal polysynaptic
reflexes

MOA

Hence ↓ muscle tone

e.g., Diazepam, baclofen,

tizanidine, mephenesin

Useful in muscle spasm of any

Diazepam
origin

2. Central SMRs

Analog of inhibitory
Baclofen
neurotransmitter GABAb

Suppresses monosynaptic and

polysynaptic reflexes
in spinal cord

Relieves painful
muscle spasm

Administered orally

Gradually withdrawn, otherwise

anxiety, palpitations, and
hallucinations can occur

ADRs Drowsiness, ataxia

100 Pharmacology mind maps for medical students and allied health professionals

10.13 TIZANIDINE

Analog of clonidine

↑ Presynaptic inhibition
of motor neurons

Tizanidine
Spasms in stroke, multiple
Use sclerosis, amyotropic
lateral sclerosis

Sedation, hypotension,
ADRs
dry mouth

10.14 MEPHENESIN, METHOCARBAMOL, CHLORZOXAZONE, CHLORMEZANONE

All useful in acute

muscle spasms
Mephenesin, methocarbamol,
chlorzoxazone, chlormezanone

All cause sedation

10.15 USES

Myalgias, disc herniation, lumbago,

Musculoskeletal spasms strains, sprains, fibrositis (along
with analgesics)

Uses

Dislocation/fracture reduction
Orthopedic procedures (following benzodiazepines like
diazepam)
 Skeletal muscle relaxants 101

10.16 DIRECTLY ACTING SMRs

Inhibits Ca+2 release from

MOA
sarcoplasmic reticulum

Sedation, hepatotoxicity,
ADRs muscle weakness, dizziness,
fatigue

3. Directly acting SMRs Dantrolene

Drug of choice in
malignant
hyperthermia

Hemiplegia to
Uses
relieve spasm

Paraplegia
 11
Adrenergic system and drugs

11.1 INTRODUCTION, DISTRIBUTION OF SNS, NEUROTRANSMITTERS

Also called sympathetic

nervous system (SNS)

Activated during stress Prepares body for fright,

flight, or fight

↑ BP, ↑ CO, ↑ HR

Blood is shifted from skin, GIT,

kidney (less important organs)
to heart, brain, lungs, and skeletal
muscles (more important organs)

Pupils dilate

Net actions

Bronchi dilate
Introduction

↑ Sweating

↑ Blood glucose, because of

glycogenolysis

THORACOLUMBAR
outflow i.e., T1 to L2-3

Distribution of SNS
Prevertebral, paravertebral,
Ganglia
terminal, and adrenal medulla

Noradrenaline (NA) and

Major neurotransmitter dopamine (DA)

Neurotransmitters
Major neurotransmitter of
ADRENALINE (a hormone)
adrenal medulla

102
 Adrenergic system and drugs 103

11.2 BIOSYNTHESIS OF CATECHOLAMINES

Tyrosine
Tyrosine hydroxylase
NA, adrenaline,
DA DOPA
Dopa decarboxylase

3 endogenous Synthesized Dopamine

catecholamines from tyrosine
Dopamine β–hydroxylase

(Diagram of synthesis/ Noradrenaline

storage/release/ In adrenal medulla
metabolism) N-methyl transferase

Biosynthesis Adrenaline
of
catecholamines
Binding of NA to
postsynaptic receptors
generates response
(uptake 2)

80% NA is taken back

into nerve endings
Sympathetic (uptake 1)
postganglionic NA is stored in Action potential at nerve
fibers synthesize, store, vesicles of adrenergic terminals releases NA
and release NA nerve endings by exocytosis in synaptic cleft A small fraction is
(adrenergic nerves) metabolized by
catechol-O-methyl-
transferase (COMT) in
synapse

Portion of NA reuptaken
by uptake 1 is
metabolized by
monoamine oxidase
(MAO)
104 Pharmacology mind maps for medical students and allied health professionals

11.3 ADRENERGIC RECEPTORS

Classified by Ahlquist

α α1, α2
Subcategorized into
2 types
β β1, β2, β3

α receptor stimulation Excitation (except GIT)

β receptor stimulation Inhibition (except heart)

G protein coupled
α and β receptors
receptors (GPCR)

Generates inositol
α stimulation Activates phospholipase C triphosphate (IP3) and
diacylglycerol (DAG)

β stimulation Activates adenylyl cyclase ↑ cAMP

Are presynaptic
autoreceptors (major)
α2 receptor
Their stimulation leads to Hence causes a negative
inhibition of NA release feedback
Adrenergic receptors

Phenylephrine,
α1 agonist
mephenteramine

α1 antagonist Prazosin, terazosin

α2 agonist Clonidine

α2 antagonist Yohimbine

β1 agonist Dobutamine

β1 antagonist Atenolol, metoprolol

β2 agonist Salbutamol, salmeterol, etc.

β2 antagonist Butoxamine
 Adrenergic system and drugs 105

11.4 ADRENERGIC DRUGS (SYMPATHOMIMETICS) – CLASSIFICATION

Noradrenaline,
Natural
adrenaline
a. Catecholamines
Depending on Synthetic Isoprenaline
1. Chemical
Classification presence/absence of
classification
catechol nucleus
Ephedrine,
b. Non-catecholamines
amphetamine

By combining with Noradrenaline, adrenaline,

a. Directly acting
adrenergic receptors dopamine, isoprenaline

By releasing NA from
2. Based on mechanism b. Indirectly acting Amphetamine, tyramine
adrenergic neurons

c. Mixed acting Direct + indirect Ephedrine, methoxamine

a. Appetite suppressants
Fenfluramine, dexfenfluramine
(Anorectics)

Adrenaline, isoprenaline,
b. Bronchodilators salbutamol, salmeterol,
formoterol, terbutaline

Adrenaline, dopamine,
c. Cardiac stimulants dobutamine,
isoprenaline, ephedrine

3. Therapeutic classification d. CNS stimulants Amphetamine, ephedrine

Pseudoephedrine, phenylephrine,
e. Decongestants of nose (nasal
phenylpropanolamine, ephedrine,
decongestants)
oxymetazoline, xylometazoline

Noradrenaline, dopamine,
f. Vasopressors
methoxamine

g. Uterine relaxants Salbutamol, isoxuprine, ritodrine

106 Pharmacology mind maps for medical students and allied health professionals

11.5 CATECHOLAMINES – ADRENALINE – PHARMACOLOGICAL ACTIONS

Powerful cardiac
stimulant
(β1 receptor)

↑ Heart rate, force of

contraction, cardiac
output, conduction
velocity
Heart

↑ Work of heart

↑ O2 consumption

Vasoconstriction (α1)
Skin and mucous
membrane
blood vessels
Pharmacological Hence adrenaline is used
actions with local anesthetics to
Blood vessels ↑ duration action of LAs
Catecholamines Adrenaline

Skeletal muscles
1. CVS Vasodilatation (β2)
blood vessel

Due to presence of β2
receptors in skeletal muscle
Small dose ↓ BP blood vessel which are
sensitive to even minute
dose of adrenaline

Due to α1-mediated
Causes initial rise vasoconstriction

Moderate dose

Later sustained fall Due to β2 mediated

of BP vasodilatation

Blockade of α Dale’s vasomotor

receptors with ergot reversal (or) Dale’s
Blood pressure alkaloids/α blockers phenomena
produces only fall of BP

Hence there is
NA is mainly only ↑ in BP Due to baroreceptor
α agonist associated with reflex stimulation
bradycardia

On renal/pulmonary/
mesenteric vessels Vasoconstriction

↑ Cerebral and
coronary
blood flow

(Continued)
 Adrenergic system and drugs 107

11.5 CATECHOLAMINES – ADRENALINE – PHARMACOLOGICAL ACTIONS (Continued)

Powerful bronchodilation (β2) Thus ↑ vital capacity

Bronchi

Pulmonary vasoconstriction Hence ↓ bronchial congestion

On non-pregnant uterus Contraction

Uterus

On pregnant uterus Relaxation

Pilomotor muscle of Contraction

2. Smooth muscles
hair follicle

Detrusor muscle Relaxes

Bladder

Trigone Contracts

Contracts

Splenic capsule
Hence it ↑ release of RBC
into circulation

Mydriasis Due to contraction of radial

muscle of iris (α1)
3. Eye

↓ IOP

↑ Neuromuscular (α and β), it ↑

∴
4. Skeletal muscles
transmission ACh release

∴ It ↑ hepatic
↑ Blood sugar
glycogenolysis

5. Metabolic effects ↓ Insulin release

Due to ↑ breakdown of
↑ Free fatty acids triglycerides
(β3 receptors in adipocytes)

Rapidly inactivated in Hence it is not given orally

GIT and liver
Pharmacokinetics

Metabolized by MAO
and COMT
108 Pharmacology mind maps for medical students and allied health professionals

11.6 ADVERSE REACTIONS, CONTRAINDICATIONS, PREPARATIONS

Anxiety, palpitations, tremors, pallor,

dizziness, restlessness, throbbing
headache, ↑ BP

Precipitates anginal pain in ischemic

Adverse reactions
heart disease (IHD)

Arrhythmias, subarachnoid hemorrhage,

hemiplegia (if rapid IV injection), acute
pulmonary edema ( it shifts blood
∴
from systemic to pulmonary circulation)

CV diseases like angina, hypertension,

CCF, arrhythmias

∴ It can lead to hypertensive

crisis and cerebral hemorrhage due to
β blocker therapy
unopposed action of adrenaline
on α1 receptors

Contraindications

Pheochromocytoma

Thyrotoxicosis

SC/IM

1:1000, 1:10,000, 1:100,000,

solutions

Preparations Intracardiac in emergencies

Administration

Aerosol for inhalation

2% eye solution
 Adrenergic system and drugs 109

11.7 USES OF ADRENALINE

Drug of choice

0.3–0.5 mL of 1:1000 solution IM

1. Anaphylactic shock Dose
∴
( SC route is not
preferred in shock)
Relieves laryngeal edema,
bronchospasm,
reverses hypotension

SC/inhalation

2. Acute bronchial
asthma Nowadays not preferred, as
more selective agents
(like salbutamol) are available

Due to drowning,
electrocution
3. Cardiac arrest Between 4th and 5th intercostal
space, 2–3 inches away from
Intracardiac adrenaline sternum; ensure that tip of needle
is in cardiac chamber and not in
∴ the cardiac muscle by withdrawing
Adrenaline causes blood in syringe
vasoconstriction, it
↓ systemic absorption of LA

Hence there is less systemic

Uses toxicity of LA
4. ↑ Duration of
action of LA
↑ Duration of action of LA

1:10,000 to 1:20,000 solution

To control hemorrhage

1:10,000 to 1:20,000
solution is used
5. Epistaxis
It is a topical hemostatic
adrenaline
∴
causes vasoconstriction

Also used to reduce tooth

extraction bleeding

Topical application ↓ IOP

Poor absorption,
6. Glaucoma short action, Prodrug of adrenaline
rapid metabolism
Drawbacks of adrenaline
Hence dipivefrin Converted to adrenaline
preferred by corneal esterases

High lipid solubility,

hence there is good
corneal penetration
110 Pharmacology mind maps for medical students and allied health professionals

11.8 NORADRENALINE

Natural catecholamine

Major neurotransmitter in
adrenergic system

Acts on α1, α2, and

β receptor

Does not act on Hence it is a direct cardiac

β2 receptor stimulant (β1)

Causes vasoconstriction of
blood vessels (α1)

Noradrenaline
∴ There is ↑ in
systolic as well as diastolic Hence, reflex bradycardia
BP

Not effective orally

Cannot be given As it may cause necrosis and

SC/IM also sloughing at site of injection

Administered as IV infusion

However, it ↓ blood flow to

Use ↑ BP in hypotensive states vital organs due to
generalized vasoconstriction
 Adrenergic system and drugs 111

11.9 ISOPRENALINE

Synthetic catecholamine

Nonselective β-agonist
(both β1 and β2)

No action on α receptors

Hence has positive

Powerful cardiac stimulant inotropic, chronotropic and
dromotropic effects

Hence there is no change in

Dilates renal, skeletal, and
systolic BP, but diastolic BP
mesenteric blood vessels
and mean arterial pressure ↓

Relaxes bronchial and GI

smooth muscles
Isoprenaline

Extensive first-pass Hence it is not effective

metabolism orally

Given parenterally or by
aerosol

Metabolized by COMT

Heart block

Use

But selective β2 agonists like

Bronchial asthma
salbutamol preferred

ADRs Tachycardia, arrhythmias It is a cardiac stimulant

∴
112 Pharmacology mind maps for medical students and allied health professionals

11.10 DOPAMINE

Precursor of NA

Stimulates
dopaminergic and
adrenergic receptors

Also a neurotransmitter
in brain
Stimulates vascular D1
receptors in renal
Vasodilation
mesenteric and coronary
vessels
Low dose dopamine
D2 receptor stimulation
Hence renal blood
in sympathetic nerve Renal vasodilation
flow and GFR ↑
endings and CV centers

Moderate dose ∴ β1 receptors

Cardiac stimulation ∴ It ↑ HR and FC
dopamine activated

Higher dose Vasoconstriction and

Due to α1 stimulation
dopamine ↑ BP
Dopamine

No CNS effects, it
∴
does not cross BBB
∴
It has short
duration of action and
∴
it is rapidly
Administered IV metabolized by
MAO and COMT

Rx of cardiogenic/
hypovolemic/septic
shock
Use
Specially used in renal
dysfunction patients
with low cardiac output

Nausea, vomiting

Palpitation, angina,
ADRs
headache

Sudden ↑ in BP
 Adrenergic system and drugs 113

11.11 DOBUTAMINE, FENOLDOPAM

Derivative of dopamine

Selective β1 agonist

Also activates α1 receptor

in therapeutic doses
Hence, ↑ in myocardial
demand is milder as
Dobutamine compared to dopamine
However, only FO ↑,
without ↑ in HR
∴ Dobutamine is
preferred over dopamine
in cardiogenic shock

Congestive cardiac failure

(CCF)

Acute myocardial infarction

Use
(AMI)

Following cardiac surgeries,

Selective D1 agonist
if cardiac failure is present

Dilates coronary, renal,

Fenoldopam
mesenteric arteries

Severe hypertension
Use
(as IV infusion)
114 Pharmacology mind maps for medical students and allied health professionals

11.12 NONCATECHOLAMINES – INTRODUCTION AND EPHEDRINE

Devoid of catechol nucleus Orally effective

Act by direct stimulation of

Resistant to MAO
Introduction adrenergic receptors and
inactivation
indirectly by releasing NA

Compared to
Long-acting
catecholamines

Alkaloid obtained from

Cross BBB
plant of genus Ephedra

Both direct and indirect

Hence have CNS effects
action

Repeated administration
Non-catecholamines
leads to tachyphylaxis

↑ BP
(by vasoconstriction and by
↑ CO)

Leads to insomnia, anxiety,

CNS stimulant restlessness, tremors, and
↑ mental activity

But not preferred,

1. Bronchial asthma ∴ it causes side effects

Ephedrine 2. Nasal decongestion But a congener,

pseudoephedrine, is used

Eye drops produces

3. Mydriasis mydriasis
without cycloplegia

For prevention and Rx of

Uses 4. Hypotension hypotension during spinal
anesthesia, administered as
IM route

5. Narcolepsy (excessive
As it is a CNS stimulant
daytime sedation)

It ↑ bladder holding
6. Nocturnal enuresis
∴
(bedwetting) capacity

As an alternative to
7. Stokes Adams syndrome
isoprenaline

Insomnia, tremors,
ADRs palpitation,
difficulty in micturition
 Adrenergic system and drugs 115

11.13 AMPHETAMINE

Synthetic compound ↑ Mental and physical activity

Properties similar to ephedrine Alertness

↑ Concentration and
Tachyphylaxis on repeated use attention span (hence used in
attention deficit hyperactivity
disorder [ADHD])

It crosses BBB, it produces CNS Elation and euphoria

∴
effects ( ∴ it can be abused)

Powerful CNS stimulant hence ↑ Work capacity

Amphetamine

High dose can lead to confusion,

↑ Initiative and confidence
delirium, hallucinations

Stimulates respiration ↓ Fatigue

↑ Physical performance (esp. in

Depresses appetite
athletes)

∴ It is a drug of
dependence and abuse

Hence it is combined with

Weak anticonvulsant conventional anticonvulsants to ↑
efficacy and ↓ sedation
116 Pharmacology mind maps for medical students and allied health professionals

11.14 ADRs, USES

Insomnia, palpitations,
anxiety, tremors,
restlessness, confusion,
hallucinations

Psychosis on repeated
ADRs
use

Angina, arrhythmias,
hypertension, acute
High dose
psychosis, coma, and
death due to convulsion

Seen in children

↓ Concentration and
attention span

1. ADHD (attention
deficit Aggressive behavior
hyperactivity disorder)

Hyperactivity

Amphetamine ↑ Which is an indirectly

attention span and Methylphenidate acting
performance in school sympathomimetic

Amphetamine
Stimulates central
Uses preferred over
α1 receptors
ephedrine
2. Narcolepsy
Also acts on GABA
Other drugs Modafanil and 5-HT
receptors

There is appetite
∴
3. Obesity Methamphetamine Better tolerated
suppression

Adjuvant to counter
4. Epilepsy sedation Pemoline
of antiepileptics
 Adrenergic system and drugs 117

11.15 VASOPRESSORS

e.g., Noradrenaline, dopamine,

Αll these agents are
metarminol, mephenteramine,
α1 agonists
phenylephrine, methoxamine

↑ BP by ↑ peripheral
resistance and/or
cardiac output

Causes reflex bradycardia

Vasopressors

Administered parenterally

Repeated use can cause

tachyphylaxis

Hypotension following
Use cardiogenic shock/neurogenic
shock/spinal anesthesia
118 Pharmacology mind maps for medical students and allied health professionals

11.16 NASAL DECONGESTANTS

Pseudoephedrine,
Oral nasal Phenylephrine,
Administered orally
decongestants Phenylpropanolamine,
ephedrine

Administered topically on Oxymetazoline (Otrivin),

Topical nasal
nasal mucosa xylometazoline,
decongestants
naphazoline

Hence, it relieves nasal

congestion, ↓ airflow
Hence they cause resistance
vasoconstriction, shrinkage,
and ↓ volume of nasal mucosa
α1 agonists of blood Also ↓ nasal secretions
vessels in nasal mucosa
Provide symptomatic relief
in allergic rhinitis, upper
respiratory tract infection (URTI)

Orally Insomnia, tremors,

irritability

Nasal irritation

Nasal
decongestants
Due to
Nasal mucosal atrophy
vasoconstriction
ADRs
Topically (nasal drops)
On long term use

Rebound congestion
Used carefully
in hypertensives Due to
vasodilatation
Tolerance due to
Phenylpropanolamine has desensitization
been banned due to ↑
risk of hemorrhagic stroke

Allergic rhinitis

Vasomotor rhinitis

Uses
Sinusitis
(only symptomatic relief)

Rhinitis in URTI

Blocked Eustachian tubes

 Adrenergic system and drugs 119

11.17 SELECTIVE β2-STIMULANTS, ANORECTICS (APPETITE SUPPRESSANTS)

e.g., Salbutamol, terbutaline,

orciprenaline (older)

e.g., Salmeterol, formoterol,

bambuterol (newer)

Are bronchodilators

Also cause uterine relaxation

without significant cardiac
Selective β2-stimulants stimulation
Bronchial asthma (as inhalation)

Uses

Premature labor prevention

ADRs Tremors, palpitation, arrhythmias

Specifically used for preventing/

Isoxuprine, ritodrine Rx premature labor, threatened
abortion, dysmenorrhea

But not recommended for obesity

Amphetamine
due to CNS side effects

Fenfluramine, dexfenfluramine,
Others mazindol, phenylpropanolamine
(but has been banned)

ADRs Abuse, dependence

Anorectics (appetite
suppressants)

Tried in obesity

↓ Uptake of NA and 5-HT

Sibutramine
Serious, including insomnia,
ADRs anxiety, mood changes,
hypertension, CV deaths
 12
Alpha-adrenergic blocking agents (α blockers)

12.1 CLASSIFICATION

Ergot alkaloids (ergotamine),

a. Competitive (reversible) phentolamine, tolazoline,
chlorpromazine

1. Nonselective

b. Noncompetitive
Phenoxybenzamine
(irreversible)

Classification

Prazosin, terazosin,
a. α1 blocker doxazosin, alfuzosin,
tamsulosin, urapidil

2. Selective

b. α2 blocker Yohimbine

120
 Alpha-adrenergic blocking agents (α blockers) 121

12.2 PHARMACOLOGICAL ACTIONS

Vasoconstriction, pupillary
α1 (post synaptic) receptor
dilator muscle contracts
stimulation
(mydriasis)

α1 (presynaptic) receptor Negative feedback induced

stimulation inhibition of NA release

α1A receptor stimulation in

Constriction
bladder/bowel sphincters

α1B receptor stimulation in

Constriction
blood vessel muscle
Hence there is
vasodilatation, ↓ BP

α1 blockade Inhibits vasoconstriction

However fall in BP is
opposed by reflex
Pharmacological tachycardia and ↑ CO
actions

Hence there is stimulation Β1 stimulation ↑ HR

↑ NA release
of β receptors and CO

Selective α1 blockade α2 receptors are not

∴
α2 blockade causes hypotension blocked; hence there
without tachycardia is no ↑ in NA

Selective α2 blockade
Miosis causes hypertension,
∴
there is ↑ NA release

Nasal congestion

↓ Urinary resistance

12.3 ADRs

Postural hypotension

Palpitation

Nasal stuffiness

ADRs

Miosis

Impotence

Impaired ejaculation
122 Pharmacology mind maps for medical students and allied health professionals

12.4 NONSELECTIVE α BLOCKERS

Nonselective, irreversible
blockade of α receptors

Binding with α receptors is Hence blockade is

covalent non-equilibrium type

Administered both
IV and orally

Gradual fall in BP

Phenoxybenzamine

Action lasts for 3–4 days

Fall in BP is accompanied
by reflex tachycardia
and ↑ in CO

Also blocks histamine, 5-HT

and cholinergic receptors

Use Rx of pheochromocytoma

Short duration of action

Nonselective α blockers

Direct stimulation of
smooth muscles

Also associated with

Ergot alkaloids Ergotamine, ergotoxine
contraction of uterus

Imidazoline derivatives ↑ BP due to vasoconstriction

Nonselective,
and reversible blockers Gangrene of toes and fingers
of both α1 and α2 receptors

Phentolamine and
Also block 5-HT receptors
tolazoline

Stimulate GI motility and ∴ There is

↑ gastric secretion vomiting and diarrhea

Given intraoperatively IV for

As it has a rapid
hypertensive crisis during
onset and short duration
pheochromocytoma surgery
 Alpha-adrenergic blocking agents (α blockers) 123

12.5 SELECTIVE α1 BLOCKERS

Potent and highly

selective

1000 times greater

affinity for α1 receptors

Dilates arterioles Hence ↓ peripheral

resistance

Also dilates venules Hence ↓ CO

As α2 receptors are not

No significant tachycardia blocked and hence there
is no ↑ in NA

Also ↓ central
Prazosin
sympathetic outflow

Inhibits phosphodiesterase ∴ ↑ cAMP Hence ↓ BP

enzyme

Also ↓ LDL, triglycerides,

and ↑ HDL

Relaxes urinary Hence it is beneficial in

bladder neck and benign prostate
prostate capsule hypertrophy (BPH)

First dose phenomena So, start with low dose,

Hence fainting
i.e., postural hypotension at bedtime, and then
can occur
after initial dose ↑ gradually
Selective α1 blockers
ADRs Headache, dizziness

Terazosin, doxazosin, Seen with

alfusozin, tamsulosin, Abnormal ejaculation
tamsulosin
urapidil

Long-acting Hence administered as

once daily dose

Highly α1 selective

Lesser incidence of
postural hypotension
Prazosin congeners

α1A Predominant in urinary

bladder

α1B Predominant in blood

vessels

Tamsulosin, alfuzosin, Hence ∴ Preferred

Are α1A selective
urapidil uroselective in BPH

Terazosin and Hence used in

α1B selective
doxazosin hypertensives
124 Pharmacology mind maps for medical students and allied health professionals

12.6 SELECTIVE α2 BLOCKERS

Selective α2 blocker

↑ BP and HR, it ↑ Hence there is Hence it is beneficial in

∴
Selective α 2 blockers Yohimbine
NA release congestion of genitals psychogenic impotence

Use: aphrodisiac
(empirical use)

12.7 USES OF α BLOCKERS

Prazosin, terazosin, Mild/moderate essential Pheochromocytoma

doxazosin hypertension surgery
1. Hypertension
Phentolamine and Hypertensive crisis
Clonidine withdrawal
phenoxybenzamine due to

Adrenal medullary tumor Cheese reaction

Secretes large quantities of

catecholamines especially
adrenaline, hence ↑ BP

Sudden and paroxysmal severe

Signs/symptoms rise in BP, severe headache,
palpitation, ↑ sweating

24 h urine VMA levels, CT,

Diagnosis
MRI
Uses of α blockers 2. Pheochromocytoma

Phenoxybenzamine Preoperatively

Phentolamine Intraoperatively

Inhibits tyrosine Hence ↓ synthesis of

Metyrosine
hydroxylase catecholamines
Rx
Long-term
Inoperable cases phenoxybenzamine
along with β blockers
Raynaud’s phenomenon
3. Peripheral vascular ∴ α receptors will
disease remain unopposed
Provides only symptomatic
relief
∴ Stimulation
β blockers should
of α receptors can cause
not be used alone
severe vasoconstriction

Leading to severe
hypertension

(Continued)
 Alpha-adrenergic blocking agents (α blockers) 125

12.7 USES OF α BLOCKERS (Continued)

∴ They cause vasodilation

Hence there is less work on
they reduce the peripheral
heart
resistance and CO
4. Congestive cardiac failure

However, ACE inhibitors

preferred

Due to blockade of αA There is ↓ bladder sphincter

receptors in bladder, tone, hence it ↓ urinary
urethra, and prostate capsule outflow resistance

Tamsulosin, alfuzosin, and

5. Benign prostate hypertrophy
urapidil
Uses of α blockers

Preferred, it is highly
∴
Tamsulosin
selective for α1A receptor

Due to extravasation of α1
agonists

6. Tissue necrosis

Rx by local infiltration of
phentolomine

Intracavernosal
7. Male sexual dysfunction
phentolamine/papaverine
 13
Beta-adrenergic blockers (β blockers)

13.1 CLASSIFICATION

1. Non- Propranolol, timolol,

cardioselective sotalol

Atenolol, metoprolol,
2. Cardioselective
esmolol, betaxolol

3. Partial agonist Pindolol, oxprenolol

Classification

4. With additional
Labetalol, carvedilol
α blocking property

5. With additional
Celiprolol
β2 agonistic property

6. With additional
Carvedilol
antioxidant property

126
 Beta-adrenergic blockers (β blockers) 127

13.2 PHARMACOLOGICAL ACTIONS

↓ HR, FOC, CO, BP Hence ↓ cardiac work

Effect more significant in

presence of high sympathetic
tone than in normal individuals

Delays AV conduction

1. CVS ↓ Myocardial O2 requirement Hence ↓ cardiac work

↑ Exercise tolerance in angina

pectoris patients

Prevents exercise-induced
↑ in HR and FOC

Possess membrane stabilization

Hence causes direct myocardial
property (like quinidine) at high
depression
doses
Pharmacological actions

Causes bronchoconstriction Thus precipitates acute

2. Respiratory system
due to β2 blockade attacks in asthma

↓ IOP, as it ↓ aqueous humor

3. Eye
secretion from ciliary body

Blocks lipolysis

Hence nonselective β blockers

4. Metabolism Blocks glycogenolysis interfere with recovery of
(β2 action) hypoglycemia in diabetics

↑ Triglycerides, ↓ HDL
128 Pharmacology mind maps for medical students and allied health professionals

13.3 PHARMACOKINETICS

Good oral absorption

Pharmacokinetics Extensive first-pass metabolism Propranolol

Short t½ (most of them)

13.4 USES

Alone or in combination
1. Hypertension Mild to moderate with other
antihypertensives

They ↓ frequency and

severity of attacks
Prophylaxis of exertional
2. Angina pectoris
angina
They ↓ cardiac work and
O2 consumption
Uses

Ventricular/
3. Arrhythmias supraventricular Sotalol is preferred
arrhythmias

IV β blocker ↓ size of
infarct

4. Myocardial infarction

Long-term administration
↑ survival

(Continued)
 Beta-adrenergic blockers (β blockers) 129

13.4 USES (Continued)

Earlier CCF was a ∴ They possess negative

contraindication inotropic effect

Recent studies demonstrate

their benefit if used Hemodynamically stable
judiciously in select patients

↓ Sudden death
5. Congestive cardiac
failure (CCF)

↑ Survival
6. Obstructive
cardiomyopathy
Inhibits sympathetic
stimulation

Prevents cardiac remodeling This is detrimental to heart

7. Pheochromocytoma Along with α blockers

↓ Palpitations, tremors,
hence provides only
symptomatic relief

Beneficial even in thyrotoxic

8. Thyrotoxicosis
crisis or thyroid storm
Uses
Prevents peripheral T4 → T3
conversion

Topical timolol

Open angle and narrow angle

9. Glaucoma
glaucoma

First-line treatment

↓ Frequency and severity of

10. Migraine prophylaxis
attacks

↓ Acute panic symptoms of

public speaking/
examination
11. Anxiety
↓ Sympathetic stimulation
e.g., tremor, palpitations
130 Pharmacology mind maps for medical students and allied health professionals

13.5 ADVERSE REACTIONS

In heart block in patients with

conduction defects

1. Bradycardia

In patients with arrhythmia

(bradyarrhythmias)

In patients with reduced cardiac

However, β blockers ↓ this,
2. CCF function, sympathetic activity
thus aggravate cardiac failure
maintains cardiac function

Esp. in patients with peripheral

3. Cold extremities
vascular disease

4. Acute bronchial asthma
Due to blockade of β2
Esp. with nonselective
receptors; hence there is
β blockers (propanolol)
bronchoconstriction

Insomnia, depression, rarely

5. CNS
hallucinations

Due to ↓ CO, there is ↓ in

Adverse reactions 6. Fatigue
blood flow to skeletal muscles

7. Metabolic side effects ↑ Triglycerides, ↓ HDL

Dangerous side effect

8. Rebound hypertension

On abrupt withdrawal after

long-term use

Dangerous side effect

Both due to upregulation

9. Rebound angina
of β receptors
On abrupt withdrawal after
long-term use
Hence β blockers should be
10. Dizziness
gradually tapered
 Beta-adrenergic blockers (β blockers) 131

13.6 DRUG INTERACTIONS

Masks warning symptoms of e.g., Tremors,

hypoglycemia palpitations, etc.

1. Propanolol + insulin

Delays recovery from ∴ β blockers prevent

hypoglycemia glycogenolysis

2. Proponolol + verapamil There is severe cardiac depression,

Drug interactions
(calcium channel blocker) as both are cardiac depressants

Intense vasoconstriction because

of catecholamines

3. β blockers + catecholamines
α receptors induce
∴
unopposed stimulation of blood
vessels, as β receptors are blocked

13.7 CONTRAINDICATIONS

1. Bradycardia

2. Heart block

Contraindications 3. Bronchial asthma and COPD

4. Diabetes mellitus

5. Congestive cardiac failure

(judicious use in select patients)
132 Pharmacology mind maps for medical students and allied health professionals

13.8 CARDIOSELECTIVE β BLOCKERS

e.g., Atenolol, metoprolol,

esmolol

Selective β1 blockade, Hence there is minimal

insignificant β2 blockade bronchoconstriction

Safer in diabetics, as
Cardioselective β blockers there is less inhibition
of glycogenolysis

Lesser impairment of
exercise performance

Reduced chances of
peripheral vascular disease

13.9 PARTIAL AGONISTS

e.g., Pindolol, oxyprenolol

Hence there is minimal
Partial agonists bradycardia and cardiac
depression
Possess intrinsic
sympathomimetic activity
Thus they are preferred in
patients with bradycardia and
↓ cardiac function
 Beta-adrenergic blockers (β blockers) 133

13.10 SOME INDIVIDUAL β BLOCKERS

Possesses partial agonist

activity

Acebutalol

Used in hypertension,
arrhythmias

Possess additional β2
agonist activity

Celiprolol

Hence safe in asthmatics

Nonselective β blocker

Timolol Short-acting

Some individual
β blockers

Eye drops used in glaucoma

Blocks β1, β2, and α1 Hence acts as both

receptors α and β blocker

∴ It has both α1 and

Labetalol Causes vasodilation
β blockade activity

So there are no cold

↑ Blood flow to
extremities and peripheral
extremities
vascular disease chances

β1, β2, and α1 blockade

activity

Carvedilol

Additional antioxidant Thus beneficial in patients

property with hypertension and CCF
 III
Part    

Cardiovascular pharmacology
 14
Antihypertensives

14.1 INTRODUCTION

Hypertension is elevation
of systolic and/or diastolic BP
above 140/90 mmHg

Types:
Primary (essential)/secondary

Primary HT Cause is not known

Renal/endocrine/vascular
Secondary HT causes

Mild – diastolic BP up to
104 mmHg

Moderate – diastolic BP
Grades of HT
105–114 mmHg

Severe diastolic BP
>115 mmHg

Antihypertensives Introduction Cardiac output (CO) and

Blood pressure is
determined by total peripheral resistance
(TPR)

Baroreceptor reflex (ANS)

Blood pressure is
and renin–angiotensin–
controlled by
aldosterone system (RAAS)

Coronary artery disease

Complications of
Stroke
hypertension

Hypertension usually
Renal failure
asymptomatic

ANS

RAAS
Antihypertensives act by
influencing
Ca+2 channels

Na and H2O balance

(plasma volume)

136
 Antihypertensives 137

14.2 CLASSIFICATION

Hydrochlorothiazide,
Thiazides chlorthalidone,
indapamide

Loop diuretics Furosemide, torsemide,

1. Diuretics
bumetamide

Spironolactone,
K+ sparing diuretics amiloride, triamterene

2. Angiotensin- Captopril, enalapril,

converting enzyme, lisinopril, ramipril,
inhibitors (ACEIs) perindopril, fosinopril

3. Angiotensin II Losartan, olmesartan,

receptor blockers/ valsartan, candesartan,
antagonists (ARBs) telmisartan

Centrally acting Clonidine, methyldopa,

guanfacine

Classification
Gangion blockers Trimethaphan

4. Sympatholytics
Adrenergic neuron Phenoxybenzamine,
blockers – reserpine, α blockers phentolamine, prazosin,
guanethidine terazosin, doxazosin

Adrenergic receptor Propranolol, atenolol,

β blockers
blockers metoprolol, esmolol

Nifedipine, amlodipine,
5. Calcium channel α + β blockers –
nimodipine, nicardipine,
blockers (CCBs) labetalol, carvedilol
verapamil, diltiazem

Arteriolar dilators Hydralazine, diazoxide,

minoxidil
6. Vasodilators
Arteriolar +
Sodium nitroprusside
venodilators
138 Pharmacology mind maps for medical students and allied health professionals

14.3 DIURETICS

Antihypertensive
effect is mild

BP reduction is of
15–20 mmHg over 2–4 wks

Diuretics ↑ excretion of
Thus ↓ plasma volume Thus ↓ CO Thus ↓ BP
Na and H2O

Diuretics also cause Na+

depletion of vascular Thus ↓ TPR Thus ↓ BP
smooth muscle

Dietary salt restriction Usually first-line

will help in ↓ antihypertensives
the dose of diuretic ∴ they are very economical
Diuretics

12.5 mg initial,
Hydrochlorothiazide
25 mg maximum

Thiazide diuretics
Thiazide diuretics may have to be
combined with K+ sparing
diuretics to avoid hypokalemia
Indapamide reduces

Blood pressure in subdiuretic

doses and hence has milder
electrolyte imbalance

Powerful diuretics

Loop diuretics Poor antihypertensives

Congestive heart
Hence used in HT with
failure/chronic
CCF/CRF
renal failure
 Antihypertensives 139

14.4 ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS (ACEIs) AND ADRs

Angiotensin II is a
powerful vasoconstrictor

Aldosterone causes → Na
→ Hence ↑ plasma volume → Hence ↑ BP
and H2O retention

ACEIs inhibit production

of angiotensin II and
aldosterone, thus ↓ BP

ACE also degrades

bradykinin

Bradykinin causes
vasodilation and Well absorbed
hence ↓ BP

Blood flow to renal,

Except captopril and lisinopril
coronary, cerebral vessels
all others are prodrugs
is improved

Differences between individual drugs

Pharmacokinetics are in potency/pharmacokinetics like
bioavailability, t½, distribution, and excretion

Most ACEIs excreted

through kidneys
Angiotensin-converting
Due to ↑ bradykinin
enzyme (ACE)
levels
inhibitors (ACEIs)
So dose has to be ↓ in
renal impairment
Common in women

Persistent dry cough

May require
discontinuation

ARB used as alternative

Occurs at initiation Called FIRST-

of therapy DOSE PHENOMENA

∴ Start with
Hypotension
small dose

If patient is on diuretics,
stop diuretics

More common in patients

Hyperkalemia on K+ sparing diuretics/
K+ supplements
Adverse effects
Reversible dysguisia Swelling of lips, nose,
(altered taste sensation) larynx, and bronchospasm

Due to ↑ bradykinin
Angioneurotic edema
(0.1% incidence)
ACEI immediately stopped

Skin rashes
Severe cases Rx with
adrenaline and
corticosteroids
Teratogenicity

Acute renal failure in patients

with renal artery stenosis

Neutropenia, proteinuria in
patient with collagen diseases
140 Pharmacology mind maps for medical students and allied health professionals

14.5 ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS (ACEIs) – USES,

PRECAUTIONS, AND CONTRAINDICATIONS

First-line antihypertensives as they

are well tolerated

Rx of all grades of HT due to all

causes
Uses

Diuretics ↑ their efficacy

1. HT
K+ sparing diuretics should not be
combined as combination can lead to
hyperkalemia
Special indications
Severe HT: They are used in
combination with CCBs/diuretics/
beta blockers
2. CCF They are first-line drugs
HT with left ventricular
hypertrophy
HT with diabetes mellitus, as
it slows nephropathy
HT with renal diseases as it
slows glomerulosclerosis
HT with ischemic heart disease
and post-MI patients

Prevents CCF

3. Myocardial infarction ACEIs started within 24 h

↓ Mortality

↓ Risk of MI

4. Coronary artery diseases ↓ Risk of stroke

↓ Risk of sudden death

5. Chronic renal failure Diabetic nephropathy Slows disease progression

6. Scleroderma renal crisis ACEIs are life-saving

Pregnancy

K+ sparing diuretics

Precautions and contraindications Angioedema

Renal artery stenosis

Digoxins, ∴ ACEIs ↑ their levels

 Antihypertensives 141

14.6 ANGIOTENSIN II RECEPTOR BLOCKERS (ARBs)

Myocardium
Angiotensin II receptors
AT1 and AT2
are of 2 subtypes
Brain
AT1 receptors are Vascular smooth muscle
present on
Kidney
Losartan was the first
AT1 receptors antagonist
Adrenal glomerular
Vasodilation
cells
Net effect of ARBs
Hence ↓
↑ Salt/water excretion Thus BP ↓
plasma volume

Valsartan, candesartan,
Other ARBs
telmisartan

No ↑ in bradykinin
Advantage of ARBs
over ACEIs
Hence less dry
cough/angioedema

Generally these are well

tolerated
Angiotensin II receptor
blockers (ARBs) Less incidence of
dry cough

Less chances of
angioedema

Hypotension

Adverse effects

Hyperkalemia

Contraindicated in
pregnancy

Contraindicated along
with K+ sparing diuretics

Contraindicated in renal
Alternative to ACEIs
artery stenosis

1. HT – similar indications
First-line anti-HT agents
as ACEIs

Combined with diuretics

Uses
(except K+ sparing)

2. Cardiac failure – as In patients poorly

alternatives to ACEIs tolerating ACEIs
142 Pharmacology mind maps for medical students and allied health professionals

14.7 SYMPATHOLYTICS

Imidazoline derivative

Selective α2 agonist

Activation of α2
Hence ↓ BP
receptor in CNS Leads to ↓ release of
and
(vasomotor center noradrenaline
bradycardia
and hypothalamus)

Drowsiness

Fluid retention

Clonidine, Constipation
α-methyldopa,
Clonidine
gaunfacine,
guanabenz ADRs

Dryness of mouth,
nose, and eyes
Prodrug, an
analog of dopa

Impotence
Metabolized to
α-methylnorepinephrine,
1. Centrally an α2 agonist Sudden withdrawal
Sympatholytics
acting agents can lead to rebound HT;
hence dose should
be tapered
Properties similar
to clonidine
Mild to moderate
hypertension
It also
↓ renin levels
Opioid withdrawal
(because withdrawal
symptoms are due to
Alpha methyldopa sympathetic overactivity)
Reduces left ventricular
Uses
hypertrophy
Diabetic neuropathy
(clonidine improves
diarrhea as it absorbs salt
Drowsiness, postural and water from gut)
hypotension, impotence,
ADR
fluid retention, dryness
of mouth, and nose Preoperatively to
↓ dose of general
anesthesia
Mild to moderate HT
(in combination
with diuretic)
Uses
Safe during HT in
pregnancy (preferred
antihypertensive)

(Continued)
 Antihypertensives 143

14.7 SYMPATHOLYTICS (Continued)

Blocks both sympathetic and ∴ There is ↓

parasympathetic ganglia sympathetic tone, hence ↓ BP

They block both

∴
Frequent side effects Hence they are not
2. Ganglion blockers Trimetaphan sympathetic and
are seen preferred nowadays
parasympathetic ganglia
Hence used for controlled
Rapid and short acting hypotension during certain
operative procedures
Depletes noradrenaline
stores from
adrenergic neuron

Orthostatic hypotension,
Guanethidine Frequent side effects
diarrhea, sexual dysfunction

Hence not
preferred now

Alkaloid derived from

Indian name: Sarpagandha
plant Rauwolfia serpentina

Destroys vesicles containing Hence the monoamines leak out of Thus there is depletion of
Adrenaline, dopamine,
monoamines in adrenergic neurons which are subsequently monoamines in stores
noradrenaline, serotonin
nerve endings metabolized by MAO (monoamine oxidase) which leads to ↓ BP

Depletion of dopamine can

produce antipsychotic effects
Reserpine
Inexpensive, and is
long-acting, hence
administered as OD dose
Depression, parkinsonism,
ADR weight gain, gynecomastia,
sexual dysfunction, sedation

Due to frequent side effects

Reserpine is not used now

Phenoxybenzamine and
Nonselective agents phentolamine used for
HT due to pheochromocytoma

Prazosin, doxazosin, terazosin are

all arteriolar and venodilators
α blockers
3. Adrenergic neuron
blockers Hence ↓ TPR, Associated with reflex
Selective agents
thus ↓ BP tachycardia

First-dose phenomena is postural

Can be combined with Hence start with low dose,
hypotension, which is usually
diuretics/β blockers 0.5 mg at night
seen 30–60 min after first dose

Thereby ↓ cardiac
Blocks cardiac β1 receptors Thus ↓ CO, and hence ↓ BP
contractility

Blockade of β1 Hence additional

∴
Also ↓ renin levels
receptors on JG cells antihypertensive effect

Used in HT with angina/

arrhythmias

Used in combination with

β blockers agents causing tachycardia as
side effect (e.g., vasodilators)

First-line antihypertensives

Because of OD dosing,
Atenolol is most commonly Unlike nonselective
less CNS side effects and
used propranolol
β selective action

As sudden withdrawal Dose should always

can lead to rebound HT be tapered

e.g., Labetalol and carvedilol

α + β blockers
Used IV for Rx of HT in
pheochromocytoma and HT
emergencies
144 Pharmacology mind maps for medical students and allied health professionals

14.8 CALCIUM CHANNEL BLOCKERS

Dilate arterioles, thus

↓ peripheral resistance

Reflex tachycardia is not present

Reflex tachycardia is seen with verapamil and diltiazem, as
with nifedipine (DHP) verapamil and diltiazem
are both cardiac depressants

Can cause minimal

fluid retention

Particularly effective
in elderly

Calcium channel blockers Usage

Used as monotherapy/
combination

Well tolerated

Sublingual nifedipine/short- Used for hypertensive

acting DHPs (parenterally) emergencies

Used for once daily

Sustained release/long-acting
administration and smooth
formulation
control of BP
 Antihypertensives 145

14.9 VASODILATORS

Relax vascular smooth

muscles, hence
↓ peripheral resistance
Reflex tachycardia
∴
common
e.g., Hydralazine,
Fluid retention
minoxidil, Sodium
common
nitroprusside, diazoxide

Direct acting vasodilator

↑ Coronary, cerebral,
and renal blood flow

Metabolized by Metabolism is genetically

acetylation (like INH) determined – fast/slow acetylators

Hypotension, fluid retention,

Hydralazine flushing, dizziness, headache

Precipitation of angina due

ADRs
to reflex tachycardia

Hypersensitivity reactions like serum Common in slow

sickness and lupus erythematosus acetylators
Combined with β blocker/diuretic
( reflex tachycardia/
∴
Uses fluid retention)

Hypertension during pregnancy

Causing relaxation Thus leading to

Opens K+ channels in Leading to
MOA of vascular vasodilation and
smooth/muscles hyperpolarization
smooth muscles hence fall in BP
Reserve drugs in
unresponsive patients

Uses Combined with diuretic

Minoxidil
Vasodilators
2% topical minodixil
for alopecia

Tachycardia, fluid retention, angina

ADR
Hypertrichosis (growth of hair) Hence it is
on face, arms, legs unacceptable in women
Related to thiazide
diuretics

Potent arteriolar dilator

MOA like minoxidil

Diazoxide
IV in HT emergencies
Uses
As it has a long Monitoring of IV
duration of action infusion not required

Myocardial ischemia, tachycardia, It inhibits insulin

∴
ADR fluid retention, hyperglycemia release

Rapidly acting vasodilator

Dilates both arterioles

and venules
Hence ↓ peripheral
Thus ↓ myocardial O2
resistance and
consumption
cardiac output
Stimulates guanylate Production of
MOA Releases nitric oxide cyclase cGMP
Vasodilation ↓ BP

Acts within 30 s

Hence preferred for

Hence dose titration
Duration 3 min HT emergencies with
Sodium nitroprusside is possible
close monitoring
It decomposes Infusion bottle and tubing
∴
on exposure to light should be covered by opaque foil

Hypotension, palpitation, sweating,

nausea, vomiting

High dose nitroprusside is

ADRs Leading to toxicity
converted to cyanide

Administration of Na thiocyanate
prevents formation of cyanide

Drug of choice in HT
emergencies
Uses
Short-term Rx To ↓ myocardial
of myocardial infarction work load
146 Pharmacology mind maps for medical students and allied health professionals

14.10 MANAGEMENT OF HT

Low-salt diet

Weight reduction

Nonpharmacological

Meditation

Avoid smoking and

alcohol

Low dose of single drug

Diuretic/
β blocker
Mild HT
If no response is seen
Management of HT in 3–4 wks change
to ACEI/CCB

If monotherapy is not Combination of

adequate antihypertensive agents

Combination of
diuretic + sympatholytic
Moderate HT

If inadequate response Add third drug

Vasodilator + diuretic +
β blocker
Severe HT
Usually associated with
cardiac/renal disorder
(secondary HT)
 Antihypertensives 147

14.11 DRUG INTERACTIONS WITH ANTIHYPERTENSIVES, HYPERTENSIVE CRISIS,

HT IN PREGNANCY, COMBINATION OF ANTIHYPERTENSIVES

Sympathomimetics and
tricyclic antidepressants
antagonize effects
of sympatholytics Very high BP (210/110 mmHg) with
target organ damage
Drug interactions with NSAIDs blunt
∴
NSAIDs cause
antihypertensives antihypertensive effect fluid retention e.g., Malignant HT, hypertensive crisis
in pheochromocytoma, acute
myocardial infarction, hypertensive
Antihistaminics encephalopathy, acute LVF, dissecting
potentiate sedation aneurysm of aorta, eclampsia
HT emergencies
caused by clonidine and
alpha-methyldopa
Rx in ICU with constant BP monitoring

BP should be gradually ↓

Hypertensive crisis Includes HT emergencies

and HT urgencies
High BP without target Gradual reduction
organ damage of BP

Methyldopa is used
IV drug therapy with
for maintenance
Na nitroprusside,
Rx hydralazine,
diazoxid, esmolol,
Parenteral hydralazine labetalol, fenoldopam
HT urgencies
is used for emergency
Constant BP monitoring Sublingual NTG can
HT in pregnancy
is important be tried
Antihypertensives
used only
during 1st trimester
Switch to oral therapy
whenever possible
Cardioselective
β blockers (atenolol)
can be an alternative

When monotherapy
is inadequate

Overcome side effect

of each other
Combination of
antihypertensives
Hence lower dose Sympatholytics and
of individual drug vasodilators cause Hence are combined with diuretic
is possible fluid retension

Vasodilators and
Hence combined with
e.g., nifedipine
β blockers
cause tachycardia

ACEI causes
However combination
hyperkalemia and
of these drugs maintains a
thiazide/loop diuretics
neutral K+ status
cause hypokalemia
 15
Calcium channel blockers, drug treatment
of angina pectoris, and myocardial infarction

15.1 CALCIUM CHANNELS

4 types

Operated by
i. Voltage-gated
membrane potential

Stimulated by agonists
like adrenaline,
noradrenaline,
angiotensin II
ii. Receptor-operated Long-lasting
Agonists also ↑ current/slow
release of Ca+2 from channels
sarcoplasmic reticulum
Present in
cardiac and
Recently in blood smooth muscles
Calcium channel Calcium vessels
L type
blockers channels
Also present
iii. Stretch-operated in neurons
(also called Sensitive to stretch
leak channels)

Consists of α1, α2,

Ca+2 pumped out by β, γ, and δ subunit
Ca+2 ATPase

Transient type/fast
iv. Na+ Ca+2 channel
Operates bidirectionally;
exchange
i.e., in and out
channel

Present in neurons
Activated when T type
and endocrine cells
membrane potential
drops to –40 mv
Voltage-gated
calcium channels Blocked by
ethosuximide
3 subtypes; i.e., and flunarizine
L,T, and N

Neural channel

N type Present in neurons

Involved in
L type is
neurotransmitter
most common
release

CCBs block L type

channel

Dihydropyridine
(DHPs), verapamil and
diltiazem bind to
different sites on
α1 subunit

148
 Calcium channel blockers, drug treatment of angina pectoris, and myocardial infarction 149

15.2 CLASSIFICATION OF CALCIUM CHANNEL BLOCKERS AND MECHANISM

OF ACTION

Nifedipine (prototype) is
vasculoselective

Amlodipine
(once daily)
(most frequently
used CCB)

Nimodipine
(highly lipid soluble)

Dihydropyridines (DHPs)

Nicardipine

Felodipine
(once daily)
Classification of calcium
channel blockers
Nitrendipine
(once daily)

e.g., Verapamil (is cardio

Phenylalkylamines
selective)

Others

e.g., Diltiazem (has both

Benzothiazepine
vascular and cardiac actions)
Entry of extracellular Ca+2 into
cardiac and vascular smooth muscle
cell through Ca+2 channels

Leads to release of intracellular

Ca+2 from sarcoplasmic reticulum

Mechanism of action
CCBs inhibits entry of Ca+2 by
blocking L-type calcium channels in
cardiac and vascular smooth muscle

Thus they ↓ calcium current and

∴ CCBs ↓
entry in cardiac and vascular
contraction
smooth muscle cell
150 Pharmacology mind maps for medical students and allied health professionals

15.3 PHARMACOLOGICAL ACTIONS AND PHARMACOKINETICS

Hence ↓ in total peripheral

resistance

Relaxation of arterioles ∴ ↓ Blood pressure

1. Vascular smooth muscle

Reflex tachycardia is seen
DHPs are vasculoselective especially with short-acting
agents like nifedipine

CCBs reduce myocardial Hence they ↓ heart rate,

contractility thus ↓ cardiac work

High doses depress AV

2. Heart
conduction

Pharmacological actions
Verapamil has significant
cardioselective actions

Hence ↑ coronary blood

Dilation of coronaries
flow

3. Coronary circulation

This property is useful in

Hence it crosses BBB
variant (Prinzmetal) angina

Nimodipine is highly lipid Also dilates cerebral blood

4. Other
soluble vessels

Also relaxes the

Well absorbed orally uterus, so it is beneficial in
premature labor

Pharmacokinetics High first-pass metabolism

High plasma protein binding

 Calcium channel blockers, drug treatment of angina pectoris, and myocardial infarction 151

15.4 INDICATIONS

As prophylaxis in ∴ They ↓ O2 demand

exertional angina and ↑ coronary blood flow
1. Angina pectoris
They are also beneficial in
variant angina

Long-acting agents are Amlodipine, felodipine,

useful for nitrendipine, nisoldipine
chronic hypertension sustained-release formulations
2. Hypertension
Sublingual nifedipine
is beneficial for
hypertensive crisis

Verapamil, diltiazem have

myocardial depressant
properties, depresses SA,
AV node, and AV conduction

Property is useful for

paroxysmal
3. Arrhythmias
supraventricular
tachycardia (PSVT)

Indications Verapamil ↓ ventricular

rate in atrial
flutter/fibrillation

4. Peripheral ∴ CCBs Beneficial in

vascular diseases cause vasodilation Raynaud’s syndrome

Preterm labor

∴ It causes vasodilation of
Subarachnoid cerebral vessels that develop
Esp. nimodipine
hemorrhage vasospasm following
subarachnoid hemorrhage

Esp. verapamil and

Migraine prophylaxis
probably Flunirazine

5. Miscellaneous
Atherosclerosis
uses

Hypertrophic
cardiomyopathy

Reverses resistance of ∴ It blocks

cancer cells P-glycoprotein which is
to chemotherapy involved in efflux of drugs

Reverse chloroquine
resistance
152 Pharmacology mind maps for medical students and allied health professionals

15.5 DRUG INTERACTIONS AND ADRs

Verapamil/diltiazem + β blockers
aggravate myocardial depression,
leading to severe bradycardia
Drug interactions
Verapamil + digoxin, ↑ digoxin levels
∴ verapamil ↓ excretion of
digoxin, thereby ↑ digoxin toxicity

Hypotension

Bradycardia

Heart block

Adverse effects of
verapamil/diltiazem

CCF

Constipation

Gum hyperplasia (long-term use)

Headache

Flushing

Palpitation

Adverse effects
Dizziness
of DHPs

Hypotension

Ankle edema

Leg cramps
 Calcium channel blockers, drug treatment of angina pectoris, and myocardial infarction 153

15.6 ANGINA PECTORIS

One of the chief

symptom of ischemic
heart disease (IHD)
Sudden, severe, retrosternal
discomfort/pain with/without
Chief complaints
radiation to left shoulder
and/or left arm
Results from imbalance
between oxygen supply and
demand to cardiac muscle

Pain results from

accumulation of metabolites Preload (venous return and
(e.g., lactic acid, substance P) stretching of heart)
in cardiac muscle

Afterload (total peripheral

O2 demand determined by
resistance)

Heart rate

Angina pectoris
O2 supply determined by Coronary circulation

i. Classical/stable/exertional
angina or angina of effort
2 types of angina
ii. Variant/Prinzmetal angina
or angina at rest

Pain is induced by exercise

and/or emotion
Classical angina
Hence there is
Due to coronary Narrowing of
imbalance between O2
atherosclerosis coronary arteries
demand and supply

Pain occurs at rest

Variant angina
Hence there is
Due to spasm of coronary
imbalance between O2
arteries
demand and supply
154 Pharmacology mind maps for medical students and allied health professionals

15.7 ANTIANGINALS – CLASSIFICATION

Restore the balance between O2

supply and demant to cardiac muscle

They either ↑ O2 supply by

Antianginals
coronary vasodilation

Or they ↓ demand by reducing

preload/afterload/heart rate or
all of these

e.g., Nitroglycerin, isosorbide

dinitrate, isosorbide mononitrate,
1. Nitrates
pentaerythritol tetranitrate,
amylnitrite

e.g., Amlodipine, nifedipine,

2. Calcium channel blockers
verapamil, diltiazem

Classification 3. β blockers e.g., Propranolol, atenolol

4. Potassium channel openers Nicorandil

Aspirin, dipyridamole,
5. Others
trimetazidine
 Calcium channel blockers, drug treatment of angina pectoris, and myocardial infarction 155

15.8 NITRATES – PHARMACOLOGICAL ACTIONS

Beneficial effects are due to

vasodilation

Nitrates are converted to

nitric oxide

Nitric oxide stimulates

vascular guanylyl cyclase

This ↑ the levels of

cGMP

cGMP dephosphorylates
Mechanism of action
protein kinases

Hence interaction of actin

with myosin is prevented

It also ↓ release of Ca+2

from sarcoplasmic reticulum

It ↑ Ca+2 efflux

All these effects lead to

vasodilatation and relaxation
of other smooth muscles

1. Nitrates Predominantly causes

venodilation

∴ Venous return,
↓ the preload

Arteriolar dilation ↓
peripheral resistance; this
↓ the afterload
Net effect: ↓ Workload
on heart, thereby ↓ O2
requirement of heart

It also causes coronary

vasodilation
Pharmacological actions
This property is beneficial
in variant/Prinzmetal
angina

Skin vasodilation causes

flushing

Meningeal vasodilation
leads to headache

Bronchial smooth muscles

are also relaxed

They also inhibit platelet

aggregation
156 Pharmacology mind maps for medical students and allied health professionals

15.9 PHARMACOKINETICS, ADRs, AND DRUG INTERACTIONS OF NITRATES

Good oral absorption

Extensive first-pass
metabolism

Pharmacokinetics Good lipid solubility

Available as oral, sublingual,

parenteral, topical (ointment)
and transdermal formulation

Topical preparations are

preferred for prevention of
nocturnal episodes

Headache

Flushing

Palpitation

Adverse effects

Postural hypotension

Due to continued high plasma

Weakness
nitrate levels
Proper dosing schedule
(twice/thrice daily)

Tolerance on long-term use Prevention of tolerance

Nitrate-free period of
at least 8 h/day
Sudden withdrawal of
nitrates can precipitate
angina

Nitrates + Sildenafil (Viagra,

Drug interactions Severe hypotension Death
for erectile dysfunction)
 Calcium channel blockers, drug treatment of angina pectoris, and myocardial infarction 157

15.10 USES OF NITRATES

Drug of choice for

acute attack

Acute prophylaxis

Sublingual NTG
Relief of pain occurs
within 3 min

If there is no relief, ↑ the dose,

maximum up to 3 tablets
in 15 min

For prophylaxis

1. Classical angina
Oral nitrates Long-acting nitrates are
preferred

But can lead to tolerance

NTG ointment Prevents nocturnal

episodes

Transdermal NTG Effective for 24 h

2. Variant angina NTG relieves vasospasm

Uses
3. Unstable angina IV NTG relieves pain

∴ Nitrates cause
4. Cardiac failure
vasodilatation

IV NTG ↓ cardiac work

5. Myocardial
infarction
Dose monitoring should be Amylnitrate is given by
done to prevent tachycardia inhalation

Cyanide binds to vital cellular Na nitrate is given by IV

enzyme like cytochrome oxidase injection (10 mL of 3% solution)

This inhibits cellular respiration Na thiosulfate IV (50 mL of

6. Cyanide poisoning
and ↓ O2 utilization 25% solution)

Nitrates convert hemoglobin

Rx
to methemoglobin
Cyanmethemoglobin
Methemoglobin + cyanide is
converted to Na thiosulfate +
cyanmethemoglobin
Thiocyanate is easily forms → thiocyanate
excreted by kidneys

Immediate Rx very
important
158 Pharmacology mind maps for medical students and allied health professionals

15.11 CALCIUM CHANNEL BLOCKERS (CCBs), BETA BLOCKERS (BBs), POTASSIUM

CHANNEL OPENERS, AND OTHERS AS ANTIANGINALS

Hence ↓ cardiac work,

↓ Peripheral resistance Thus ↓ after load
so ↓ O2 requirement
Reflex tachycardia is seen especially
Cause arteriolar dilation, which with dihydropyridines
(nifedipine, amlodipine)

Coronary vasodilation↑ O2 supply But verapamil and diltiazem depress

cardiac contractility, hence ↓ heart
rate, thus ↓ O2 requirement
2. Calcium channel
Used prophylaxis of classical angina
blockers (CCBs)

Can be combined (except verapamil)

with β blockers

Also useful for variant It causes coronary

∴
(vasospastic) angina dilatation

↓ Frequency and severity

of attacks

Used for long-term prophylaxis

Prevent ↑ heart rate, force of

contraction, BP, during exercise,
emotion and other situations
which ↑ sympathetic activity

Hence they ↓ cardiac work,

3. Beta blockers (BBs)
thereby ↓ O2 requirement

Can be combined with nitrates

As it can lead to rebound

Should not be suddenly withdrawn
angina

Also useful in vasospastic

angina

e.g., Nicorandil, pinacidil

Both arteriolar and venous

dilators

Open ATP-sensitive
K+ channels

Hence relaxation of
Leads to hyperpolarization
vascular smooth muscles
4. Potassium
channel openers
They are used when other
antianginals not effective

However, they are expensive Headache

Dose: 10–20 mg BD Palpitation

Adverse effects Hypertension

Flushing

Dizziness

However, it diverts blood

Coronary vasodilator Hence it is not useful
flow from ischemic zone
Dipyridamole
∴ It is used for prevention
Also inhibits platelet aggregation
of coronary/cerebral thrombosis

Long-term low-dose aspirin is used

for prevention of myocardial infarction
Aspirin
Acts by inhibiting platelet
5. Other antianginals
aggregation

CCB with protective effect

on ischemic tissue

Maintains left ventricular

function
Trimetazidine
Used in classical angina

Dose: 20 mg thrice daily

 Calcium channel blockers, drug treatment of angina pectoris, and myocardial infarction 159

15.12 PHARMACOTHERAPY OF ANGINA

Sublingual NTG is
drug of choice

If pain relieved, spit

Acute attack
out the tablet

If pain not relieved Maximum 3 tablets in

repeat the dose 15 min

Administer sublingual
NTG 15 min prior e.g., Climbing stairs
1. Classical/exertional
to activity
angina
Acute prophylaxis
Duration of action is
30 min

Long-acting nitrates/
Pharmacotherapy
β blockers/CCBs
of angina
Chronic prophylaxis
If monotherapy is
ineffective, use
combination
NTG/Nifedipine
sublingually
2. Variant/vasospastic/
Prinzmetal angina
Given both for
prophylaxis and
treatment
160 Pharmacology mind maps for medical students and allied health professionals

15.13 COMBINATION OF ANTIANGINALS

Very effective for exertional

angina

Reflex tachycardia of
1. Nitrates + β blockers nitrates is countered by
β blockers

Ventricular dilatation of
β-blockers opposed by nitrates

Additive antianginal effects

2. Nifedipine (DHP CCB) +

β blockers
Reflex tachycardia of DHPs
is countered by β blockers
Combination of
antianginals

Additive effect

3. Nitrates + CCBs

Nitrates ↓ preload, CCBs

↓ afterload

If angina not relieved by

2 drugs, 3 drugs can be used

Nitrates ↓ preload, CCBs

4. CCBs + BBs + nitrates
↓ afterload, BBs ↓ heart rate

Combination useful in
severe angina
 Calcium channel blockers, drug treatment of angina pectoris, and myocardial infarction 161

15.14 UNSTABLE ANGINA AND TREATMENT

Pain at rest in patients of

classical/stable angina

Severe, sustained pain, but

without ECG changes associated
with myocardial infarction (MI)

Angina following myocardial 75–300 mg daily prevents

Aspirin
infarction platelet aggregation
Unstable angina
Patients are at high risk of
IV/SC heparin reduces
subsequently developing MI Heparin
thrombus formation
or sudden death

Requires immediate
Nitrates IV NTG ↓ cardiac work
hospitalization and Rx

Glycoprotein e.g., Abciximab, integrilin,

Drug Rx receptor tirofiban, inhibits final step of
antagonists platelet aggregation

Usually contraindicated,
but prolongs survival in
β blockers
hemodynamically
stable patients

Low-dose aspirin

β blockers to prevent
Long-term Rx
relapse and ↓ mortality

Prevent ventricular
ACE inhibitors remodeling
and cardiac failure
162 Pharmacology mind maps for medical students and allied health professionals

15.15 TREATMENT OF MYOCARDIAL INFARCTION

IV Morphine 10 mg or
pethidine 50 mg

Relieves anxiety

Analgesia
Reduces sympathetic
overactivity-induced
complication
Objective of Rx is to
limit myocardial
ischemia and Diazepam for sedation
consequent cell death and anxiety

Immediate Rx
Streptokinase 1.5 million
units over 1 h

O2 Alternatively urokinase/
Very expensive
alteplase 15 mg bolus
compared to
followed by 0.5 mg/kg
streptokinase
over next 90 min

Started as early as possible

Thrombolytics (within 6–12 h) to
Treatment of myocardial ↓ damage and mortality
infarction
Antiemetics/β blockers
Long-acting anistreplase
Other Rx (in hemodynamically stable
used as single dose
patients)/antiarrythmics

Aspirin 300 mg orally ↓

Stop smoking mortality, 75–150 mg as
maintenance

Control hyperlipidemia

Risk factor
↓ Body weight
management

Regular moderate
exercise

Control diabetes and

hypertension

Cardiac glycosides and treatment
of cardiac failure
16.1 INTRODUCTION
Contracting cells
Myocardium is made
up of 2 types of cells
Conducting cells
Ability to generate
electrical impulses
spontaneously
Automaticity
Present in SA node,
AV node, Purkinje fibers,
bundle of HIS
Ability of cell to
Excitability undergo depolarization
in response to a stimulus
Phase 0
Introduction
Phase 1
Phase 2
Cardiac action
potential has 5 phases
Phase 3
Phase 4
Phases 1 and 2 are absolute
refractory period; i.e., cell
does not respond to
another impulse
Phases 3 and 4 are relative
refractory period; i.e., cell
may respond to a
strong electrical impulse
16
For pumping action
For automaticity,
excitability
Rapid depolarization
Due to fast entry of Na+
into cells
Followed by repolarization
Short, initial, rapid
repolarization
Due to efflux of K+ ions
Prolonged plateau
Due to slow entry of Ca++
ions through Ca++
channels
Rapid repolarization
Due to movement of
K+ out of cells
Resting phase
During this phase K+ ions
return into cells
Resting membrane
potential (RMP)
is restored
The load on heart due to
Na+ and Ca+2 move volume reaching ventricle
out of cell
Preload
This in turn depends on
Cardiac output (CO) is venous return
SV depends on preload,
determined by heart rate
afterload, and contractility
(HR) and stroke volume (SV) The total peripheral
resistance; i.e., resistance
Afterload to the ejection of
blood by ventricles
163
164 Pharmacology mind maps for medical students and allied health professionals

16.2 CONGESTIVE CARDIAC FAILURE (CCF)

Inability of heart to provide

adequate blood supply to meet
body’s oxygen demand

Contracting ability of
ventricles is ↓

Hence there is ↑ pressure in

Thus, CO reduces, ventricles
pulmonary and systemic
are incompletely emptied
circulation

Manifested as pulmonary
edema (dyspnea), ankle Stimulation of sympathetic
edema, liver enlargement nervous system (SNS)
due to hepatic congestion

Stimulation of renin
angiotensin aldosterone
(RAAS) pathway
Compensatory mechanisms
to maintain CO
ANP ↑ renal excretion of salts
Congestive cardiac Release of atrial natiuretic
and water and dilates vascular
failure (CCF) peptide (ANP)
smooth muscles

Cardiac remodeling occurs,

Another compensatory
which leads to ventricular
mechanism i.e.,
hypertrophy

Due to ischemic heart disease,

Low output hypertension, valvular heart
disease
2 types of cardiac failure
Due to thyrotoxicosis,
High output anemia, beriberi, congenital
heart disease

Diuretics

Rx of CCF D/D/D Dilators (vasodilators)

Digitalis (cardiac glycosides)

 Cardiac glycosides and treatment of cardiac failure 165

16.3 CARDIAC GLYCOSIDES

Derived from plants of

foxglove family

William Withering described

the effects of digitalis in
CCF first in 1785

Cardiac glycosides Digitioxin, digoxin, oubain

Leaves of Digitalis purpurea Digitoxin is obtained

Cardiac glycosides
Digitoxin and digoxin are
Leaves of Digitalis lanata
obtained

Seeds of Strophanthus
Oubain is obtained
gratus

∴It has favorable

Digoxin Is most commonly used
pharmacokinetics

Possess pharmacodynamic
Aglycon
activity

Glycosides are made up of

Possess pharmacokinetic
Sugar
activity
166 Pharmacology mind maps for medical students and allied health professionals

16.4 PHARMACOLOGICAL ACTIONS

Hence are called

↑ Force of contraction Hence ↑ SV Thus ↑ CO
cardiotonic drugs

Systole duration is ↓

Hence there is more rest

Diastole duration is ↑
to ventricles

Ventricles empty
completely due to ↑ force Due to ↑ vagal tone
of systolic contractions

Due to ↓ sympathetic This occurs due to

Heart rate ↓
stimulation improved circulation

Direct action on SA and

AV node

↓ Ventricular refractory
period
1. Cardiac actions
Effects on electrophysiological
property of heart depend
↓ AV conduction
on dose and site of action
in heart

↑ Automaticity of ventricles
and Purkinje fibers

T-wave inversion

↑ PR interval

Pharmacological actions Effects on ECG

↓ QT interval
No significant change
in BP
ST segment depression

↑ Coronary circulation
(Coronaries are filled
due to ↑ CO and
during diastole)
prolongation of diastole

Hence there is relief of

Kidneys Promotes diuresis
edema
2. Extracardiac action
Hence they cause nausea Common in digitalis
CNS Stimulation of CTZ
and vomiting toxicity (earliest sign)
 Cardiac glycosides and treatment of cardiac failure 167

16.5 MECHANISM OF ACTION, PHARMACOKINETICS, DIGITALIZATION

Digitalis inhibits
Na+ K+ ATPase
(sodium pump) on
cardiac myocytes Which
Mechanism of
prevents efflux
action
of Ca+2
Inhibition of ↑ Intracellular
Na+ pump Na+ Hence there is
Hence there is more
↑ Ca+2 entry ∴ There So they are
Ca+2 intracellularly
through voltage– is ↑ intracellular cardiotonic
available for
sensitive Na+ and Ca+2 in action
contraction
Well absorbed Ca+2 channels
orally

Food ↓
absorption

Bioavailability
Hence stick to
differs between
Pharmacokinetics one
different
manufacturer
manufacturers

Low margin
of safety

Cumulative effects
frequently seen
with glycosides

Maintenance This is employed

dose generates usually for mild
response to moderate
over 5–7 days of Rx CCF
Digitalization
For severe CCF,
loading
dose is administered
Therapeutic drug followed by
monitoring maintenance dose
(TDM) is essential
to ↓ toxicity
168 Pharmacology mind maps for medical students and allied health professionals

16.6 ADVERSE EFFECTS

Extrasystoles

Bradycardia

Low safety margin, hence side

Pulses bigeminy
effects are common
Adverse effects
Side effects are common because they
inhibit Na+/K+ ATPase of all excitable tissues Cardiac toxicity: Arrhythmias AV block
(neurons, smooth muscles)

Hypokalemia – ↑ cardiotoxicity Ventricular tachycardia

Vomiting, diarrhea, diuretics leads to

Ventricular fibrillation
hypokalemia, hence ↑ toxicity

Hypercalcemia Paroxysmal atrial tachycardia

Factors influencing cardiotoxicity

Rapid digitalization

IV administration of digitals

Poor cardiac status patients

esp. elderly

GI toxicity: Anorexia, nausea, vomiting –

first symptoms (due to stimulation of CTZ)

Neurotoxicity

Vertigo, blurred vision, alteration of color

Extracardiac toxicity vision, headache, confusion, disorientation,
delirium, hallucinations, rarely convulsions

Allergic skin rashes

Long-term Rx leads to gynecomastia

Antidigoxin antibodies reverse toxicity

Stop digitalis

Oral or parenteral K+ supplements

(K+ supplements are however contraindicated
during hyperkalemia or AV block)

Oral K+ as KCI 5g in divided doses

Rx of digitalis toxicity
IV drip of K+ (along with constant
ECG monitoring)

Ventricular arrhythmias Rx with IV phenytoin

Bradycardia Rx with atropine

Supraventricular tachycardia Rx with

propranolol
 Cardiac glycosides and treatment of cardiac failure 169

16.7 DRUG INTERACTIONS, USES, PRECAUTIONS, AND CONTRAINDICATIONS

Diuretics

Calcium

Drugs that ↑ digoxin toxicity Quinidine

Verapamil ↑ Digoxin levels

Drug interactions
Methyldopa

Antacids, neomycin,
↓ Absorption
metoclopramide

Drugs that ↓ digoxin levels

↑ Metabolism

Rifampicin, phenobarbitone

As they are enzyme inducers

CCF
Digoxin ↓ AV
∴
Uses Atrial flutter/fibrillation conduction and hence
ventricular rate
Cardiac arrhythmias

Paroxysmal supraventricular
As alternative to verapamil
tachycardia (PSVT)

Hypokalemia ↑ Toxicity
∴

Myocardial infarction It ↑ arrhythmias

∴

Precautions and
contraindications

Thyrotoxicosis They ↑ arrhythmias

∴

Acid-base imbalance ↑ Toxicity

170 Pharmacology mind maps for medical students and allied health professionals

16.8 DRUGS FOR CCF, DIURETICS

1. Diuretics

2. Vasodilators Digitalis

Drugs for CCF

3. Positive inotropic
β adrenergic agonists
agents

4. Newer agents:
PDE inhibitors
Levosimendan, istaroxime

e.g., Furosemide
High-ceiling diuretics are
used
↑ Salt and water excretion Hence relieves edema

1. Diuretics
↓ The preload ∴ ↓ Venous pressure

↑ Cardiac performance
 Cardiac glycosides and treatment of cardiac failure 171

16.9 VASODILATORS

↓ Mortality
↓ Afterload
Arteriolar dilators;
e.g., hydralazine Relax arterial Hence they reduce total Thus they ↓
smooth muscle peripheral resistance the afterload

↓ The preload

Hence they ↓ stretching ↓ Myocardial O2

↓ Venous return to heart
of ventricular walls requirements
Venodilators; e.g.,
nitrates like
Used for short periods
nitroglycerine,
isosorbide dinitrate
Used IV for severe CCF

Nitrates can be combined Captopril, enalapril,

with hydralazine ramipril, lisinopril
2. Vasodilators
e.g., ACE inhibitors, Na They ↓
∴
nitroprusside, prazosin, ↓ Afterload formation of
calcium channel blockers Angiotension II

They ↓
∴
∴ ↑ Salt, Hence ↓
ACE inhibitors ↓ Preload aldosterone
water excretion plasma volume
formation

↓ Bradykinin degradation
leading to vasodilation
i.e., Compensatory
Reverses ventricular
ventricular
remodeling
hypertrophy
Dilates both
arterioles and
venules powerfully

↓ Afterload
and preload

Administered IV

Arteriolar + Na nitroprusside
venodilators Acts within 30–60 s

Duration of action
3 min

Hence used in acute

severe CCF

α1 blocker

Prazosin Hence is vasodilator

Used for longer times as

compared to nitrates

Not usually used

Calcium channel
blockers Amlodipine/felodine used
in patients for whom
other vasodilators are
contraindicated
172 Pharmacology mind maps for medical students and allied health professionals

16.10 POSITIVE INOTROPIC AGENTS

Administered in patients
not responding to diuretics
and/or vasodilators
Digitalis
Administered to patients
with associated atrial
fibrillation

e.g., Dobutamine

Activates cardiac Hence ↑ cardiac

β1 receptors contractility
β adrenergic agonists
There is no significant
↑ in heart rate

Vasodilation also occurs

due to stimulation
of β2 receptors
3. Positive inotropic
agents
CO and renal
∴
In patients with associated
Dopamine perfusion
renal failure
both are ↑

Amrinone, milrinone

PDE
Used for short periods due
to their ↑ adverse effects
and mortality chances

Use is controversial

Recent trials have

demonstrated beneficial
results
β blockers (negative
inotropic agents)
Shown to improve survival
in long-term studies

Used cautiously in
hemodynamically stable
patients of CCF
 17
Antiarrhythmics

17.1 ARRYTHMIAS

Arrythmias Abnormality of rate, rhythm, or site of origin

of cardiac impulse or impulse conduction

Abnormal generation or Altered normal

conduction of impulses automaticity

Mechanism of Abnormal
Abnormal impulse generation
arrhythmogenesis automaticity

Reentry After depolarization:

Abnormal impulse Early or delayed
conduction
Conduction block – I, II, or III degree

Myocardial hypoxia/ischemia

Electrolyte imbalance

Causes Trauma

Drugs
Introduction
Autonomic influence

Palpitation

Syncope

Clinical features Breathlessness

Cardiac failure

Cardiac arrest (in extreme cases)

Tachyarrhythmia

Bradyarrhythmias

Types of arrythmias Digitalis-induced arrhythmias

Supraventricular (SA node, AV node, atria)

Ventricular arrhythmias
(most common cause of sudden death)

173
174 Pharmacology mind maps for medical students and allied health professionals

17.2 CLASSIFICATION OF ANTIARRYTHMICS

e.g.,
Prolongs repolarization Quinidine, procainamide,
disopyramide

e.g.,
1. Class I – sodium
Shortens repolarization Lignocaine,
channel blockers
phenytoin, mexiletene

Little effect on e.g.,

repolarization Encainide, flecainide

Classification of e.g.,
2. Class II – β adrenergic
antiarrythmics (Vaughan ↓ Sympathetic tone Propanolol,
blockers
Williams classification) esmolol, acebutolol

e.g.,
3. Class III – K+ channel
Prolongs repolarization Amiodarone,
blockers
bretylium, sotalol

Prolongs conduction
4. Class IV – Ca++ e.g., Verapamil and
and refractoriness in
channel blockers diltiazem
SA and AV node
 Antiarrhythmics 175

17.3 SODIUM CHANNEL BLOCKERS (CLASS IA) AND QUINIDINE

Block Na+ channel in Hence prevent entry of

open and inactivated state Na+ ions

Resting open and

Na+ channels are in 3 states
inactivated (refractory)
Mechanism of action

Depress phase 0 depolarization

Also prolongs repolarization by

blocking K+ channels

D-isomer of quinine (antimalarial)

Obtained from cinchona bark

Blocks Na+ channels

Sodium channel
blockers (class IA) Depresses automatically excitability,
conduction velocity, and prolongs
repolarization

Membrane stabilizing properly

Inhibits propagation of action

potential

Vagolytic and α-blocking property

Additional skeletal muscle relaxant

property
Quinidine itself can
Cardiac ADRs generate arrhythmias,
Quinidine heart block
Good oral absorption

Hypotension

90% plasma protein binding

↑ QT interval, “torsades des pointes”
(polymorphic ventricular tachycardia)
(French meaning “twisting of points”)
Metabolized in liver, excreted in urine

Extra cardiac Diarrhea, nausea, vomiting

ADR

Thrombocytopenia

Bone marrow depression Due to hypersensitivity

Hepatitis

Cinchonism (high dose)

It inhibits It ↓ clearance of Hence leads to digoxin

∴
Drug interactions
microsomal enzymes digoxin toxicity
176 Pharmacology mind maps for medical students and allied health professionals

17.4 SODIUM CHANNEL BLOCKERS (CLASS IA) AND PROCAINAMIDE,

DISOPYRAMIDE, AND USES OF CLASS 1A DRUGS

Derivative of procaine (local

anesthetic)

Better tolerated than quinidine

Procainamide Lupus syndrome

It has weak vagolytic and

∴
α blocking property

Hypotension

ADR

Heart block

Torsades de pointes

Hence side effects of dry mouth,

urinary retention, constipation,
and blurred vision
Significant anticholinergic
Disopyramide
(atropine-like) property

Also causes torsades de pointes

Prophylactic for all arrhythmia Atrial flutter/fibrillation, ventricular

recurrence arrhythmias

Uses of class 1A drugs

Quinidine, procainamide not

preferred due to side effects
 Antiarrhythmics 177

17.5 CLASS IB DRUGS – LIGNOCAINE, PHENYTOIN, AND MEXILETINE

Blocks Na+ channel in open

and inactivated state

↑ Threshold for action

potential

↓ Automaticity

↑ Electrical activity of
arrhythmogenic tissues
Blocks Na+ channels and
shortens repolarization
Normal tissues are not
affected

Lignocaine

Also a local anesthetic

As it has high first-pass

Administered parenterally
metabolism

Drowsiness, hypotension,
ADR blurring of vision, confusion,
convulsions

Ventricular arrhythmias due

to AMI, open heart surgery

Class IB drugs

Digitalis-induced
Uses
arrhythmias

Atrial AP and Na+

∴
NOT useful in atrial
channel in inactive state is for
arrhythmias
very short duration
An antiepileptic

Phenytoin Ventricular arrhythmias Not preferred due to toxicity

Use

Digitalis-induced
arrhythmias

Used orally

Mexiletine Alternative to lignocaine

Neurological side effects like

ADR tremors, blurred vision,
nausea
178 Pharmacology mind maps for medical students and allied health professionals

17.6 CLASS IC DRUGS AND CLASS II DRUGS

Encainide, flecainide

Most potent Na+ channel

blocker

Class IC drugs

Can cause cardiac arrest,

Very toxic Hence not preferred
sudden death

Only used in severe

ventricular arrhythmia,
atrial flutter

Propranolol (non-
β blockers cardioselective), atenolol and
metoprolol (cardioselective)

Hence reduce cardiac

Block cardiac β receptors contractility, automaticity,
and conduction velocity

Membrane stabilization
(like class I antiarrythmics
Class II drugs at high dose)

Rx and prevention of Especially those associated

Use supraventricular with exercise, emotion, and
arrhythmias hyperthyroidism

Rapid and short-acting Hence is given IV

Esmolol
Rx of arrhythmias during
surgeries following MI and
other emergencies
 Antiarrhythmics 179

17.7 CLASS III DRUGS AND AMIODARONE

Analog of thyroid
hormone

↑ AP duration

Blocks K+ channels

ERP ↑

Variable oral
bioavailability
Blocks Na+ channels (35%–65%)

Slow onset of action

Blocks β receptors (2–3 days to several
weeks)

Demonstrates Long duration of action

complex and t½
pharmacokinetics (weeks to months)
Hence drug interactions
with concomitant
Metabolized by liver
Blocks K+ channels enzyme
inducers/inhibitors

Prolongs duration of
Itself is inhibitor of Can ↑ concentration
AP and
microsomal enzymes of warfarin and digoxin
refractory period

Amiodarone Heart block

QT prolongation

Cardiac Bradycardia

Hypotension

Cardiac failure

ADR
Bluish discoloration
Class III drugs of skin

GI disturbances

Extracardiac Hepatotoxic

It is highly toxic, Hence can lead to Hence monitoring of

∴
Blocks T4 to T3
constant monitoring thyroid conversion hypothyroidism/ thyroid
is necessary hyperthyroidism function essential

Hence only used in Rarely fatal

Uses resistant/chronic pulmonary fibrosis
ventricular
arrhythmias
Adrenergic neuron
blocker Prevention occurrence
Bretylium of AFL (Atrial Flutter),
AFib (Atrial Fibrillation)
Used in resistant
ventricular arrhythmias

β blocker

Sotalol

Prolongs AP duration
180 Pharmacology mind maps for medical students and allied health professionals

17.8 CLASS IV DRUGS AND MISCELLANEOUS AGENTS

Calcium channel blockers e.g., Verapamil, diltiazem

Inhibits entry of calcium ions in Hence ↓ contractility, automaticity,

cardiac cells and AV nodal conduction

Class IV drugs
Depresses AV nodal conduction

Terminates paroxysmal supra-

ventricular tachycardia (PSVT)
Verapamil
Controls ventricular rate in
atrial flutter/fibrillation
Displaces digoxin from tissue
binding sites
Drug interaction
Hence digoxin toxicity can occur,
↓ Renal clearance of digoxin
so ↓ digoxin dose
Purine nucleotide

Rapid onset and short duration

Hence it is administered IV
of action

↓ Automaticity AV conduction

Adenosine Dilates coronaries

Drug of choice for PSVT

Nausea, dyspnea, flushing,

ADR
dizziness

Theophylline blocks adenosine

Drug interactions
receptors hence its actions

Used in sinus bradycardia

Atropine

Blocks M2 muscarinic receptors

↓ AV conduction: Heart rate

Miscellaneous antiarrhythmics

Digitalis ↑ Force of contraction

Used in atrial fibrillation to

↓ ventricular rate

Used in Rx of digitalis-induced
arrhythmias
Magnesium sulfate

Rx of torsades de pointes

Myocardial depressant

↓ Conduction velocity, automaticity

and prolongs refractory period
Potassium
High dose induces AV conduction
defects

Hypokalemia potentiates digitalis

toxicity
 18
Diuretics and antidiuretics

18.1 CLASSIFICATION

1. Drugs acting on PCT Carbonic anhydrase inhibitor Acetazolamide

2. Drugs acting on thick

Furosemide, torsemide,
ascending limb of loop of Loop diuretics
ethacrynic acid
Henle

Chlorothiazide,
Thiazides hydrochlorothiazide,
polythiazide
3. Drugs acting on early
distal tubule
Classification based on site Chlorthalidone,
Thiazide-like
of action indapamide, metolazone

Spironolactone,
Aldosterone antagonists
eplerenone
4. Drugs acting on late distal
tubule and collecting duct
Direct Na+ channel
Amiloride, triamterene
inhibitors

5. Drugs acting on entire

nephron (but mainly loop of Osmotic diuretics Mannitol, glycerol
Henle)

Furosemide, torsemide,
1. High efficacy Loop diuretics
ethacrynic acid

Chlorothiazides,
Thiazides
hydrochlorothiazide

2. Medium efficacy

Chlorthalidone, indapamide,
Thiazide-like
metolazone

Spironolactone, eplerenone,
Potassium sparing
triamterene, amiloride

Classification based on
efficacy Carbonic anhydrase
Acetazolamide
inhibitors

3. Low efficacy

Osmotic diuretics Mannitol, glycerol, urea

Methylxanthines
theophylline

Vasopressin antagonist Conivaptan

4. Newer diuretics

Adenosine A1 receptor
Rolophyline
antagonist

181
182 Pharmacology mind maps for medical students and allied health professionals

18.2 HIGH-EFFICACY/HIGH-CEILING/LOOP DIURETICS

Sulfonamide derivative

Blocks the function

of Na+ K+ 2Cl cotransporter/
symporter from the luminal
side of TAL

Inhibits NaCl reabsorption,

hence ↑ Na and Cl excretion

↑ Excretion of K+, Ca+2, and

Mg+2

But Ca+2 is reabsorbed in DCT,

hence no hypocalcemia

High Na+ load which reaches

DCT is reabsorbed in Hence there is hypokalemia
exchange for K+
e.g., Furosemide (frusemide),
torsemide, ethacrynic acid
High-efficacy/high-ceiling/ Long-term use can lead to
loop diuretics hypomagnesemia

Furosemide

Also a weak carbonic ∴ ↑ Excretion of HCO3

anhydrase inhibitor and PO34

Also ↑ renal blood flow

↑ Renin release

Thereby relieves congestive

Thus it ↓ left ventricular filling
Causes venodilation cardiac failure (CCF) and
pressure
pulmonary edema

Hence ↓ salt reabsorption,

Stimulates PGE2 synthesis
leading to diuresis

Hence it is a powerful and

Rapid GI absorption
high-efficacy diuretic

Rapid onset; i.e., 2–5 min after

Pharmacokinetics
IV, 30–40 min after oral

Duration 2–4 h
 Diuretics and antidiuretics 183

18.3 OTHER LOOP DIURETICS AND USES

Torsemide Long-acting Hence given as OD dose

More adverse effects; i.e.,

Ethacrynic acid Hence not used nowadays
ototoxic

1. Edema of hepatic, renal, or

cardiac origin

2. Acute pulmonary edema

3. Cerebral edema, but IV

mannitol is preferred

It ↑ urine output
∴

4. Acute renal failure

Useful in impending renal failure

Associated with CCF/renal failure

Uses
5. Hypertension Hypertensive emergencies

Thiazides are preferred for primary

uncomplicated HT

As it ↑ Ca+2 and K+ excretion

6. Acute hypercalcemia and

hyperkalemia
Simultaneous replacement
of Na+ and Cl is done to avoid
hyponatremia and hypochloremia

In barbiturate/salicylate
poisoning

Fluoride/iodine/bromide
7. Forced diuresis
poisoning (anion poisoning)

Salts should be replaced to

prevent dehydration
184 Pharmacology mind maps for medical students and allied health professionals

18.4 ADRs

Most serious, dose-dependent i.e., On long-term

side effect high-dose use

Causes muscle weakness,

irritability, drowsiness, Spironolactone, amiloride,
a. Hypokalemia K+-sparing diuretics
dizziness, cardiac arrhythmias triamterene
(esp. with digitalis)

Prevention of
K+ supplementation
hypokalemia

Less K+ is available for

∴
High K+ diet
exchange with Na+ at DCT

More Na+/H+ exchange

b. Hypokalemia with occurs, hence there is
metabolic acidosis loss of H+

1. Electrolyte imbalances– Leads to metabolic

very frequent alkalosis

c. Hyponatremia Due to ↑ Na+ loss

Hence long-term use

d. Hypocalcemia ↑ Ca+2 loss
∴
will lead to osteoporosis

So give oral Mg
e. Hypomagnesemia ↑ Mg+2 loss
∴
supplements

f. Hypovolemia and
Due to loss of H2O
hypotension

a. Hyperglycemia Due to ↓ insulin secretion

2. Metabolic changes b. Hyperlipidemia ↑ LDL and TG

↓ Excretion of Patients may require

∴
c. Hyperuricemia Thereby leading to gout
uric acid allopurinol

ADRs
Deafness, vertigo, tinnitus

Due to toxic effect on

hair cells of inner ear

3. Ototoxicity Dose-dependent

Common in IV use and

renal impaired patients

Avoid other ototoxic i.e., Aminoglycosides,

drugs together cyclosporine, etc.

Skin rashes

Eosinophilia

4. Hypersensitivity

Photosensitivity
5. Weakness, fatigue,
dizziness, cramps due to
It is a sulfonamide
∴
hypokalemia
derivative (except
ethacrynic acid)
 Diuretics and antidiuretics 185

18.5 DRUG INTERACTIONS AND CONTRAINDICATIONS

1. Furosemide + digoxin leads Hence there is ↑ binding of

Leading to digoxin toxicity
to hypokalemia digoxin to Na+ K+ ATPase

2. Furosemide +
Causes ↑ ototoxicity
aminoglycosides
∴ Causes Na+ and
H2O retention
NSAIDs inhibit renal PG
3. Furosemide + NSAIDs
synthesis

Hence ↓ efficacy of diuretics

Drug interactions

Which ↑ lithium absorption

4. Furosemide + lithium Leads to hyponatremia Hence it leads to lithium toxicity
in PCT

Furosemide ↓
∴
5. Furosemide + As it has ↑ efficacy and ↓ K+; K+-sparing diuretics ↑
Is SYNERGISTIC
K+-sparing diuretics ADR K+, hence there is no change
in K+ levels

It competes for tubular

∴
6. Probenecid ↓ efficacy
secretion

1. Toxemia of pregnancy It ↓ fetal circulation

∴

Contraindications for diuretics

↑ NH3 levels cause

∴
2. Hepatic cirrhosis This worsens hepatic coma
hypokalemia and alkalosis
186 Pharmacology mind maps for medical students and allied health professionals

18.6 THIAZIDES AND THIAZIDE-LIKE DIURETICS

Thiazides Chlorothiazide, hydrochlorothiazide

Chlorthalidone, indapamide,
Thiazide-like
metolazone

90% of filtered Na is already

∴
Medium efficacy diuretics
reabsorbed before reaching DCT

Bind to Cl side of Na+ Cl symport and Hence ↑ excretion of

block them in early DCT Na and Cl

Thus more Na reaches late DCT Hence ↑ exchange with K+

Thus there is K+ loss Leading to hypokalemia

Mechanism

Weak carbonic anhydrase inhibitory

Thus there is loss of HCO3
activity

Net loss of Na+, K+, Cl, and HCO3

Thiazides

↓ Ca+2 excretion (unlike loop

Hence there is hypercalcemia
diuretics)

Given orally

Pharmacokinetics

6–48 h, as compared to loop

Longer duration of action
diuretics

↓ GFR and urine output in

diabetes insipidus

Peculiar paradoxical action

Patients with diabetes insipidus do
not respond to ADH and excrete large
volume of dilute urine

1. Hypertension They are first-line drugs

2. Congestive cardiac failure Mild to moderate cases

Uses
3. Hypercalciuria and renal stones They ↓ Ca+2 excretion
∴

There is a paradoxical benefit

4. Diabetes insipidus

It ↓ GFR and plasma

∴
volume
 Diuretics and antidiuretics 187

18.7 OTHER THIAZIDE DIURETICS AND ADRs

Hypovolemia

Hyponatremia

Hypomagnesemia

1. Electrolyte imbalance Dehydration

Hypotension

Hypokalemia

Hypercalcemia

∴
Hyperglycemia it Common with long-term
ADRs
↓ insulin secretion long-acting thiazides

2. Metabolic disturbances Hyperlipidemia

Hyperuricemia

Hence not preferred in

3. Impotence
young men

Skin rashes,
4. Allergy
photosensitivity, etc.

Chlorthalidone Long-acting

Potent, long-acting, have

lesser ADRs

Indapamide, metolazone

Used in hypertension
188 Pharmacology mind maps for medical students and allied health professionals
18.8 POTASSIUM-SPARING DIURETICS
Aldosterone antagonists
Direct inhibitors of Na channels
Spironolactone
Potassium-sparing diuretics
ADRs
Block Na+ channels in luminal
membrane of late DCT and CD cells
Amiloride and triamterene
Low-efficacy K+-sparing diuretic
GI disturbances, metabolic acidosis
Prodrug, activated to canrenone
Potassium canrenoate
Eplerenone
Spironolactone, eplerenone
Triamterene, amiloride
↑ Na reabsorption through
Na channels in late DCT and CD
Low efficacy diuretic
↓ K+ secretion
Synthetic steroid, chemically
similar to aldosterone
They bind to specific mineralocorticoid
receptor (MR) in cytoplasm
Aldosterone
This hormone-receptor complex
(MR-AL) enters nucleus
Directs synthesis of
aldosterone-induced proteins (AIPs)
AIPs retain Na, excrete potassium
Competitively blocks
MR, prevents formation of AIPs
Net effect is ↑ Na excretion
and ↑ K retention
Most effective when aldosterone levels
are high
Thus it ↓ K+ excretion due
to other diuretics (loop/thiazides)
↑ Excretion of Ca+2
Spironolactone
Given orally as microfine powder
to ↑ bioavailability (75%)
High plasma-protein binding
Canrenone has long t½ of
Active metabolite of about 18 h, spironolactone
spironolactone is canrenone has t½ of 1–2 h
Edema associated with CCF, hepatic cirrhosis, nephrotic
secondary hyperaldosteronism syndrome
Combined with loop/ To prevent hypokalemia and
Uses
thiazide diuretic ↑ efficacy in hypertension
Especially in renal impairment,
ACEIs, ARBs, β blockers, Resistant hypertension due
1. Hyperkalemia Conn’s syndrome
NSAIDs etc. to primary hyperaldosteronism
Gynecomastia, impotence, ∴It binds to androgen Hence it interferes
2. Endocrine disturbances ↓ libido, menstrual and progesterone receptors with steroidogenesis
disturbances
3. Metabolic acidosis
Directly acting agents
∴ They ↑ Na excretion
and ↑ K+ retention
In combination with loop, To prevent hypokalemia and
thiazide diuretics ↑ efficacy
Amiloride is used in ∴ It blocks lithium transport
Use lithium-induced nephrogenic
through Na+ channels in CD
diabetes inspidus
ADRs: Hyperkalemia,
Amiloride aerosol is ∴ It ↑
used in cystic fibrosis mucociliary clearance
Canrenone is the active
metabolite of spironolactone
Given parenterally
Less hormonal disturbances
Analog of spironolactone
Greater selectivity for
mineralocorticoid receptor
Less hormonal imbalances
Hypertension as
monotherapy/combination
Use
CCF
More expensive
 Diuretics and antidiuretics 189

18.9 CARBONIC ANHYDRASE (CA) INHIBITORS (CAIs)

H2O + CO2 → H2CO3 → H+ + HCO3

In tubular cell ↑
CA

H+ + HCO3 → H2CO3 → H2O + CO2

Acetazolamide In lumen ↑
CA

H+ exchanges with Na+ in

lumen by Na+H+ antiporter

Sulfonamide derivative

Hence it prevents Hence Na+ is excreted In DCT, Na exchanged with

Inhibits CA in PCT and CD Na+ H+ exchange is inhibited
formation of H+ with HCO3 in urine K+, thus there is K+ loss

Net effect is loss of Na+, K+

HCO3 To Rx acidic drug poisoning

Hence there is alkaline 1. Alkalinization of urine

urine To ↑ excretion of
uric acid and cysteine
CA is also present in ciliary
body of eyes, gastric mucosa,
Acetazolamide is given
pancreas, and other sites
orally and IV
2. Glaucoma; acute congestive
In the eye, CAIs ↓
glaucoma
aqueous formation thus
↓ IOP Dorzolamide is applied topically

Carbonic anhydrase (CA)

In brain it ↓ CSF Mountain climbers develop
inhibitors (CAIs)
formation pulmonary and cerebral edema,
3. Acute mountain sickness especially unacclimatized persons
prevention and treatment
Uses Acetazolamide ↓ CSF
and ↓ pH of CSF

Caused by ↑ use of
diuretics in patients with CCF
4. Metabolic alkalosis
Acetazolamide ↑ HCO3
excretion

Familial periodic paralysis

5. Miscellaneous Adjuvant in epilepsy

Hyperphosphatemia,
∴
acetazolamide ↑ PO4
excretion

1. Metabolic acidosis It causes HCO3 loss

∴

It ↑ Ca+ excretion
∴
2. Renal stones
and hypercalciuria

ADRs 3. Hypokalemia

4. Allergic reactions

5. Drowsiness

It precipitates hepatic
∴
coma in cirrhosis
Hepatic disease
It ↓ excretion
∴

Contraindications of NH3 in alkaline urine

Chronic obstructive It worsens metabolic

∴
pulmonary disease (COPD) acidosis
190 Pharmacology mind maps for medical students and allied health professionals

18.10 OSMOTIC DIURETICS

Pharmacologically
inert

∴
Given IV orally
Massive hemolysis
it is not absorbed
Hence it retains water
by osmotic action
Filtered by glomerulus,
Shock
e.g., Mannitol, glycerol, and not reabsorbed Hence there is ↑
urea excretion of water and
Site of action: PCT and electrolytes
Cardiovascular surgery
loop of Henle
Mannitol Maintains urine volume
and prevents acute
renal failure in Hemolytic transfusion
reaction

Rhabdomyolysis

But in patients with existing

renal failure, mannitol is
dangerous pulmonary
∴
edema and heart failure
can be precipitated
Use
Following head injury

↓ Raised
intracranial tension Tumor
(ICT)
∴
It draws fluid from brain
to circulation by osmotic effect

↓ IOP in
∴
Osmotic diuretics It draws fluid from eye
Dehydration
glaucoma into circulation
ADRs
Hence it is contraindicated in
Hence it leads to pulmonary edema, CCF,
↑ In ECF volume chronic edema, anuric renal
pulmonary edema
disease, and active
intracranial bleeding

Effective orally

↓ ICT/IOP

Glycerol (glycerine)
Also used topically
to treat corneal and
ocular edema

ADRs: Hyperglycemia

Urea Unpleasant taste Hence it is not used now

e.g., Theophylline

Methylxanthines

Mild diuretic
 Diuretics and antidiuretics 191

18.11 NEWER DIURETICS

Arginine antagonists (AVP) e.g., Conivaptan, tolvaptan

They inhibit effects of ADH Hence there is free water

in CD diuresis

V1a and V2 antagonist Conivaptan

1. Vasopressin antagonists V2 antagonist Tolvaptan

Tolvaptan is given orally

Conivaptan is given
parenterally
Syndrome of inappropriate
Newer diuretics
ADH secretion (SIADH)

Uses
Vaptans ↑ free
water clearance and corrects
hyponatremia
e.g., Rolophylline

2. Adenosine A1 receptors ↓ NaCl

antagonists reabsorption in PCT and CD

Use: Tried in CCF

192 Pharmacology mind maps for medical students and allied health professionals

18.12 TABLE ON DIFFERENCES BETWEEN DIURETICS

Thiazide Furosemide

Medium efficacy High

Acts on early DCT TALH

Inhibits Na+ Cl symport Na+ K+ 2Cl cotransport

Onset 1 h 20–40 min

Duration of action long: 8–12 h 8–6 h

No response on ↑ dose Dose dependent ↑

Causes hyperuricemia No change

↑ Blood sugar No change

No ototoxicity Ototoxic

Use: Hypertension Edema

Furosemide Spironolactone

Sulfonamide Steroid

Acts on TALH DCT and CD

Na+ K+ 2Cl cotransport blocked Aldosterone blocker

High efficacy Low efficacy

Quick onset (minutes) Slow onset (days)

Hypokalemia Hyperkalemia

Causes ototoxicity Causes gynecomastia, hirsutism

Use – edema Hyperaldosteronism, as adjuvant to diuretics

Caution: Allergy to sulfonamides Caution: Peptic ulcer

 Diuretics and antidiuretics 193

18.13 ANTIDIURETICS

Vasopressin receptors are

V1 and V2

V1 causes vasoconstriction

V2 leads to water retention in

collecting duct

Both are G protein-coupled

receptor

V1a is present in vascular

and other smooth muscles,
urinary bladder, platelets,
liver, and central
Antidiuretic nervous system (CNS)
hormone—
vasopressin V1b is present in anterior
pituitary
Vasopressin
analogs— V2 activates adenylyl cyclase, ↑ Numbers of aqueous channels
desmopressin and which leads to ↑ in cyclic in collecting duct, thus leading
terlipressin adenosine monophosphate to water reabsorption
Classification (cAMP) which
V1 receptor mediates
Thiazide diuretics vasoconstriction and
↑ blood pressure (BP)
Others –
V1 receptor induces constriction
chlorpropamide
Actions of cutaneous, coronary, celiac
and carbamazepine
and mesenteric vasculature

Antidiuretic Vasopressin V1 ↑ gastrointestinal (GI)

hormone receptors peristalsis and ↑ uterine contraction

V2 receptor mediates
water retention

Subcutaneous (SC)

Intramuscular (IM)
Route of administration
Intravenous (IV)

Intranasal

Intranasal administration leads

to rhinitis, nasal mucosal atrophy
Adverse drug reactions
Other routes of administration Bleeding esophageal
Antidiuretics

cause abdominal cramps, backache varices

Before GI radiography,
it promotes expulsion
∴
Mediated through V1 receptors
of GI gases

Asystolic cardiac arrest

Central diabetes
insipidus (DI) or
Uses
neurogenic DI or
Lifelong treatment
DI of pituitary origin
It is a short-term
treatment
Selective for V2 receptor Nocturnal enuresis Oral/Intranasal
desmopressin
Mediated through BP has to be
V2 receptor ∴
Antidiuretic hormone monitored
Hemophilia and von
Potent and longer acting (ADH) releases factor VIII
Willebrand disease
than vasopressin and controls bleeding
Desmopressin
Vasopressin If kidneys are normal,
analogs Renal small dose of
Others: Terlipressin, Route (oral/intranasal)
concentration test desmopressin ↑ urine
a prodrug of
concentration
vasopressin,
is long acting
Oral bioavailability
is 1%–2%
↓ Urine output
of both neurogenic/
Thiazide nephrogenic DI
Intranasal
diuretics availability is 10%–20%
A paradoxical effect
due to unknown
mechanism

Chlorpropamide Sensitizes kidney to

(antidiabetic) ADH action
Others
Carbamazepine It stimulates ADH
∴
(antiepileptic) secretion
 19
Pharmacotherapy of shock

19.1 PLASMA EXPANDERS

e.g., Dextrans, gelatin products,

human albumin, hydroxyethyl starch,
polyvinylpyrrolidine

Ideally whatever is lost should be i.e., Blood in hemorrhage, and

replenished plasma in burns

However, during emergencies,

Hence the use of plasma expanders
immediate volume replacement
in such circumstances
is the priority

Plasma expanders are high-molecular

weight substances

Plasma expanders Exert osmotic pressure when given IV

Remain in body for long time, hence Exerts oncotic pressure equivalent to
Dextrans
↑ volume of circulatory fluid plasma

Ideal plasma expander Pharmacologically inert

Dextrans, gelatin polymers,

hydroxyethyl starches, and
Non-antigenic and long-acting
polyvinylpyrrolidone are all colloidal
compounds

Human albumin is obtained from

pooled human plasma

194
 Pharmacotherapy of shock 195

19.2 DEXTRANS

Mol wt 70,000, dextran 40

mol wt 40,000

Polysaccharides obtained from

sugar beet

Osmotic pressure exerted is similar

Dextran 70
to plasma proteins

Dextran 70 expands plasma

volume for 24 h

However, it interferes with

coagulation, blood grouping,
and cross matching

Faster and short-acting

Improves microcirculation by
Dextran 40 preventing Rouleax formation of
RBCs and antisludging effect

However, it can block

Leading to renal failure
renal tubules

Hence can lead to allergic

Dextrans are antigenic
reactions

Easily sterilized

Of approximately 10 yrs

Long shelf life

Most commonly used

plasma expanders
196 Pharmacology mind maps for medical students and allied health professionals

19.3 GELATIN PRODUCTS

Mol wt 30,000

Duration of action 12 h

Gelatin products Stable for nearly 3 yrs

They do not interfere with

coagulation blood grouping and
cross-matching

Allergic reactions are less common

19.4 HYDROXYETHYL STARCH

Longer duration of action

Hydroxyethyl starch Allergic reactions rare

Do not interfere with coagulation, etc.

 Pharmacotherapy of shock 197

19.5 POLYVINYLPYRROLIDONE

Synthetic polymer

Polyvinylpyrrolidone Releases histamine Hence can lead to allergic reactions

Interferes with coagulation

Hence it is not preferred
grouping and cross-matching

19.6 HUMAN ALBUMIN

Derived from pooled human blood

Does not interfere with coagulation

grouping and cross-matching

Human albumin (5%–20% solution)

Useful in burns, hypovolemic shock,

hypoproteinemia, acute liver failure,
dialysis, and edema

Allergic reactions are less common

Plasma substitutes in extensive

fluid loss

Uses of plasma expanders

Emergency restoration of plasma

e.g., Burns, hypovolemic shock, etc.
volume
198 Pharmacology mind maps for medical students and allied health professionals

19.7 INTRAVENOUS FLUIDS

Sterile solutions

Variable content of solutes

Used for replacement of fluid, electrolytes, and nutrition

3 types of IV fluids, depending on osmolality Isotonic, hypotonic, or hypertonic

Intravenous fluids If osmolality = ECF Isotonic IV fluid

Electrolytes (cations + anions) = 310 mEq/L Isotonic

Electrolytes <250 mEq/L Hypotonic

Electrolytes >375 mEq/L Hypertonic

Plasma osmolality is approximately 300 mmol/L

Hence they do not alter size of RBCs

Normal saline, ringer lactate solution However, it quickly diffuses into ECF

∴ Plasma volume effectively

Osmolality = ECF
↑ by only 25%

Hence 3 L of isotonic fluid is required to

replace 1 L of lost blood volume

Careful monitoring is needed in patients with hypertension

and cardiac failure to avoid volume overload

Isotonic fluids
0.9% NaCl

Normal saline Used in hypotremia

Caution/avoid in CCF, renal failure,

pulmonary edema

Contains K, Ca, and NaCl

Ringer lactate solution
Corrects dehydration, hyponatremia, and
gastrointestinal fluid losses
0.45% NaCl solution

Half normal saline

Hypotonic fluids
Used in hypernatremia and similar hyperosmolar situations

Overdose can lead to fluid depletion, hypotension,

cellular edema, and later on cell death can occur

5% Dextrose in normal saline or ringer lactate solutions or in

hypotonic solution

Osmolality is more than ECF

Once dextrose is metabolized, normal saline becomes isotonic,

ringer lactate solution becomes hypotonic

45%–50% dextrose is given in situations like hypoglycemia or to

Hypertonic fluids
supplement calories

As these are hypertonic they must be infused into large

central veins for immediate dilution

They are hypertonic, cells shrink

∴

Should be infused gradually to prevent any volume overload

 IV
Part    

Central nervous system (CNS)

pharmacology
 20
Introduction to CNS and alcohol

20.1 INTRODUCTION TO CNS, CNS NEUROTRANSMITTERS, EXCITATORY

NEUROTRANSMITTERS, INHIBITORY NEUROTRANSMITTERS

One of the most complex systems

Drugs are used for either therapy

Introduction to or pleasure
CNS Drugs may either stimulate
or depress CNS
Important to understand
neurotransmitters and receptors

Excitatory neurotransmitter Glutamate

Inhibitory neurotransmitter GABA, glycine

Noradrenaline, 5-HT, dopamine, acetylcholine,

Others
histamine, adenosine, nitric oxide

Main excitatory neurotransmitter is Glutamate

Acts on specific glutamate receptors

4 subtypes of excitatory amino acid

NMDA, AMPA, kainite, metabotropic
receptors
NMDA, AMPA, kainite are
ionotropic receptors
Glycine and glutamate act on different
sites at NMDA receptor
NMDA receptor stimulation induces
Excitatory neurotransmitters
slow excitation
NMDA receptors play a role in long-term
adaptive changes
CNS
neurotransmitters Ketamine, memantine, phencyclidine,
magnesium block NMDA receptor channels
AMPA and kainite are involved in fast
excitatory transmission

Both are activated by glutamate

Metabotropic receptors are G-protein Involved in long-term adaptive changes

coupled receptors
Chief inhibitory
neurotransmitter in brain
Agonists attach to different sites on
GABA receptor
2 subtypes of GABA receptor –
GABAa and GABAb
GABA, glycine
GABAa Ligand gated chloride channel
GABA
GABAb G-protein coupled receptor

GABAa agonist Benzodiazepines, barbiturates

Inhibitory neurotransmitters
GABAa antagonist Flumazenil

GABAb agonist Baclofen, a skeletal muscle

relaxant
Inhibitory neurotransmitter in
brain stem and spinal cord

Glycine Stimulates glycine receptor A ligand-gated Cl channel

Tetanus toxin prevents release Hence it causes powerful

of glycine in SPINAL CORD muscle spasms

200
 Introduction to CNS and alcohol 201

20.2 ALCOHOLS, ETHYL ALCOHOL – INTRODUCTION AND ACTIONS

Monohydroxy alcohol

Produced by
fermentation of sugars
Introduction
Colorless, volatile, inflammable
liquid Quickly evaporated

Ethanol content of various

alcoholic bevarages ranges Cooling effect
from 4%–55%
Astringent, hence hardens
1. Local (topical application) skin
Rubefacient and counter
irritant action (40%–50%
alcohol)
Antiseptic action
(70% alcohol)

CNS depressant

Euphoria, reduces anxiety/social

Ethyl alcohol (Ethanol) Small dose
inhibition

Impairs muscle coordination

Moderate dose
and visual acuity
Mental clouding, impaired
judgement, drowsiness, and High dose Avoid driving
2. CNS lack of self control

Stupor and coma Toxic dose

Precipitates convulsion
in epileptics

Death due to respiratory

depression

Tolerance on prolonged usage

Actions
Actions are dose-dependent

Small dose produces cutaneous Hence produces flushing and

3. CVS
vasodilation feeling of warmth

Due to depression of
Large dose causes hypotension myocardium
and vasomotor center

↑ Gastric secretion
as it is an irritant

Acts as an APPETIZER

Peptic ulceration on
4. GIT and liver
long-term use

Leads to liver enlargement,

Long-term use causes fat subsequently fatty
accumulation in liver degeneration,
finally liver cirrhosis

Microsomal enzyme inducer

Probably acts as an aphrodisiac Due to loss of inhibition

↑ HDL and
Long-term low dose
↓ LDL

Induces diuresis It inhibits ADH

∴

5. Miscellaneous
Interferes with folate
Megaloblastic anemia
metabolism

↑ Heat loss due to Hence not recommended for

cutaneous vasodilation warming in cold environment

Food value: 7 calories/g

202 Pharmacology mind maps for medical students and allied health professionals

20.3 MECHANISM OF ACTION, PHARMACOKINETICS, DRUG INTERACTION,

AND USES

Inhibits central nicotinic receptors

Mechanism of action

Alcohol dehydrogenase, aldehyde

Inhibits excitatory NMDA
dehydrogenase
and kainite receptors

Metabolism of alcohol
Alcohol
Rapid absorption Alcohol
dehydrogenase
Acetaldehyde

Acetaldehyde
Metabolized in liver by zero-order dehydrogenase
Pharmacokinetics
kinetics
Acetic acid

Carbon dioxide
Excreted via kidneys and lungs +
Water and energy

Potentiates other CNS

depressants like hypnotics, Zero-order kinetics
opioids, antipsychotics

Constant amount (10 mL/h) is

metabolized per unit time
Drug interaction Disulfiram-like effects seen

With metronidazole,
sulfonylureas, griseofulvin,
cefoperazone
Microsomal enzyme inducer

1. Antiseptic 70% Topical application

2. Bed sores

Alcohol sponges reduce

3. Fever
temperature

Uses

4. Appetite stimulant 50 mL of 6%–10% alcohol

5. Neuralgias Injection of alcohol around nerve

6. Methanol poisoning
 Introduction to CNS and alcohol 203

20.4 DISULFIRAM

Inhibits aldehyde dehydrogenase

If alcohol is consumed Due to inhibition of Acetaldehyde

after taking disulfiram aldehyde dehydrogenase accumulates

This leads to flushing, throbbing

headache, nausea, vomiting,
sweating, hypotension,
and confusion

This is called ANTABUSE

Disulfiram (brand name
Antabuse)
REACTION
Used to treat alcohol
dependence
Hence disulfiram Rx should be
given in hospital

Hence alcohol-dependent
Effect lasts 7 days after stopping
patient develops aversion
disulfiram
for alcohol, and gives up habit

Drugs causing antabuse reaction:

Chlorpropamide, griseofulvin,
cephalosporin, phenylbutazone

Liver disease, physical

Contraindications
dependence on alcohol

20.5 DRUGS TO TREAT ALCOHOL DEPENDENCE

Disulfiram

Benzodiazepines As they reduce anxiety

Reduces release of
Clonidine sympathetic
neurotransmitter

Reduces tremors and

Propranolol
tachycardia
Drugs for alcohol
dependence
Should not be combined with
Naltrexone disulfiram, as both are
hepatotoxic

Nalmefene is an alternative

It is a NMDA receptor
Acamprosate
antagonist; it prevents relapse

↓ Alcohol
Ondansetron
consumption
204 Pharmacology mind maps for medical students and allied health professionals

20.6 METHYL ALCOHOL (METHANOL)

Used to denature ethyl alcohol

No therapeutic value

Ingestion leads to methanol

poison
Methanol
(–) Fomepizole (Antizol)
Alcohol dehydrogenase (ADH) or Ethanol
(both competitive inhibitors)
Alcohol dehydrogenase
Formaldehyde
Aldehyde dehydrogenase
Aldehyde dehydrogenase (ALDH)

Formic acid
Folic acid (Vit B9)

CO2 + H2O

Vomiting, headache, abdominal

Methyl alcohol Toxicity pain, hypotension, vertigo,
(methanol) delirium, acidosis, coma

Formic acid has affinity for Hence it causes retinal damage

optic nerve which could lead to blindness
Acidosis hastens retinal
∴
damage
Even 15 mL can cause
1. Correction of acidosis
blindness

IV NaHCO3

2. Gastric lavage
It competes with methanol
∴
for alcohol dehydrogenase due
to its higher affinity
3. Ethyl alcohol
Hence it slows metabolism of
methanol and reduces
concentration of toxic formic acid

Rx of toxicity
Fomepizole, which inhibits
4. Antidote
alcohol dehydrogenase

5. Hemodialysis

6. BP and ventilation
maintenance

7. Protection of eyes Keep patient in dark room

 21
Sedative hypnotics

21.1 INTRODUCTION TO SEDATIVE HYPNOTICS

Produces calming/quieting
Sedative actions, ↓ excitement,
produces drowsiness

Induces sleep, mimicking

Hypnotic
natural sleep

Both sedation and hypnosis

are different grades of
CNS depression
NREM (non-rapid eye
movement)

Classification of sleep
Introduction
REM (rapid eye movement)
(associated with dreaming)
Alternating NREM and
REM sleep, cycles
are present for short duration

From lying down to falling

Stage 0
asleep

Less eye movement,

Stage 1
neck muscles are relaxed

Still less eye movement,

Stages/levels of NREM sleep Stage 2
but person easily aroused

Minimal eye movement,

Stage 3 deeper sleep, person not
arousable

Deepest level of sleep, slow

wave sleep, lowest metabolic
Stage 4
rate, highest growth
hormone secretion

205
206 Pharmacology mind maps for medical students and allied health professionals

21.2 CLASSIFICATION

a. Ultra short-acting (<6 h) Triazolam, midazolam

Alprazolam, lorazepam,
1. Benzodiazepines b. Short-acting (12–24 h)
nitrazepam

Diazepam, clonazepam,
c. Long-acting (24–48 h)
flurazepam, chlordiazepoxide

a. Ultra short-acting Thiopentone

Classification 2. Barbiturates b. Short-acting Pentobarbitone

c. Long-acting Phenobarbitone

3. New agents Zolpidem, zopiclone, zaleplon

Paraldehyde, chloralhydrate,
4. Miscellaneous
meprobamate (rarely used)
 Sedative hypnotics 207

21.3 MECHANISM OF ACTION

GABA is the principle

inhibitory neurotransmitter
in CNS

GABA acts via GABA

receptors (GABAa and GABAb)

BZDs bind to GABAa

receptors

However this binding site

is different from
GABA-binding site

BZDs ↑ affinity of
Mechanism of action
GABA for receptor

GABA ↑ chloride ion

conduction through receptor

This action is potentiated

by BZDs

BZDs enhance frequency of

chloride channel opening in
response to GABA

↑ Chloride entry in
neurons leads to
hyperpolarization
208 Pharmacology mind maps for medical students and allied health professionals

21.4 PHARMACOLOGICAL ACTIONS

Induces calming effect

Hastens onset of sleep

Produces sleep

1. Sedation and
Enhances duration of sleep
hypnosis

↑ Stage 2 NREM and

↓ REM sleep (though very little)

Resembles natural sleep

Tolerance is seen after

1–2 wks

Reduces anxiety and

aggression

2. Anxiolytic effect Induces calming effect

Alprazolam has additional

antidepressant action

Dose-dependent CNS
depression

Sedation Hypnosis Stupor Anesthesia Coma

Higher dose produces general

anesthesia (GA)
3. Anesthesia
Midazolam is administered
as IV anesthetic
Pharmacological
actions BZDs can also be used as
adjuvants to GA

Slight risk of respiratory

depression prolongation

↓ Muscle tone by central action

Inhibits spinal polysynaptic Which maintains

4. Muscle relaxation
reflexes muscle tone

Anxiety associated with

↑ muscle tone is also reduced

↓ Seizure threshold

5. Anticonvulsant IV diazepam is used for

action status epilepticus
Clonazepam is used
for absence seizures and
myoclonic seizures in children

Anterograde amnesia is the

loss of memory for the events
occurring after giving BZDs
6. Amnesia As patient will not
Beneficial during surgical
remember
procedures
unpleasant events
High dose reduces BP, HR, and
respiration
7. Miscellaneous
↓ Nocturnal gastric acid
secretion
 Sedative hypnotics 209

21.5 ADVANTAGES OF BZDs OVER BARBITURATES

1. Induces sleep resembling

natural sleep

2. Less hangover

3. Less suppression of REM

sleep

4. Hypnotic dose does not

alter RS/CVS functions

Advantages of BZDs over

5. Higher margin of safety
barbiturates

6. Mild respiratory depression

in overdoses

7. BZD antagonist,
flumazenil, is present for
overdose

8. No microsomal enzyme
Hence lesser drug interactions
induction

9. Lower abuse potential

210 Pharmacology mind maps for medical students and allied health professionals

21.6 PHARMACOKINETICS AND ADRs

Significant PK differences Because of their differing

among BZDs lipid solubility

Oral absorption is better

than IM

Pharmacokinetics

High plasma protein binding

Long-acting BZDs (diazepam)

have active metabolites

Generally well tolerated

Drowsiness, confusion, amnesia,

lethargy, weakness, blurred
Common ADRs Hence avoid driving
vision, ataxia, daytime sedation,
impaired motor coordination

Paradoxical irritability and Less potential compared to

anxiety is seen in few patients barbiturates

Withdrawal symptoms are

mild and slow in onset for
long-acting BZDs

Withdrawal symptoms more

ADR Tolerance and dependence intensive and abrupt in
short-acting BZDs

Anxiety, nervousness, dizziness,

Withdrawal symptoms
anorexia

When administered to Neonate can develop hypotonia

pregnant women during labor and respiratory depression

Induces sleep

There is mild respiratory

Acute overdosage
depression

Rx by BZD antagonist Hence they are safer compared

flumazenil to barbiturates
 Sedative hypnotics 211

21.7 USES OF BZDs AND BZD ANTAGONIST

e.g., Triazolam,
1. Insomnia Drugs of choice
lorazepam

However, ultra
2. Anxiolytic Most commonly used short-acting agents
are not preferred

IV diazepam is drug Are used as adjuvants

3. Anticonvulsants Clonazepam/clobazam
of choice with other antiepileptics

For chronic muscle

spasm
4. Muscle relaxant

Spasticity
Uses of BZDs

5. Pre-anesthetic For sedation, anxiolytic,

medication and amnestic action

IV midazolam used

6. General anesthesia
Also used as adjuvant
to other general
anesthetics

Withdrawal of other
sedative hypnotics
7. Alcohol withdrawal

Opioid withdrawal

Competes with BZDs

for receptors

Blocks actions of BZDs

Administered IV

BZD antagonist Flumazenil

Rapid and short-acting

Rarely induces
convulsions
BZDs overdose

Use
Reverse BZD
sedation/anesthesia
212 Pharmacology mind maps for medical students and allied health professionals

21.8 NEWER AGENTS

e.g., Zolpidem, zopiclone,

zaleplone

Non-BZDs

But produce their effects

Bind to GABAa receptor

Facilitate inhibitory
transmission

Lesser incidence of dependence

and tolerance compared to BZDs

Insignificant alteration of
sleep pattern

Used for short duration in

insomnia

Rapid onset and short duration Hence there is less

of action hangover

Flumazenil blocks/
Good hypnotic
reverses actions

Weak anticonvulsant,
anxiolytic, and muscle relaxant

Does not suppress stage 3

and 4 of NREM sleep
Newer agents Negligible suppression
of REM sleep
Zolpidem
Short-acting (t½ of 2 h)

Sleep duration – 8 h

Dose is reduced in hepatic

dysfunction

ADR Dizziness, diarrhea

Short t½ of 1 h Hence has rapid onset

Minimal withdrawal
symptoms

No tolerance
Zaleplon
Insignificant side effects

Useful for patients with

Long time to fall sleep
long sleep latency

Duration of sleep is not ↑

Actions similar to BZDs

Zopiclone Dry mouth, metallic taste,
ADR impaired
psychomotor function
 Sedative hypnotics 213

21.9 BARBITURATES CLASSIFICATION, MECHANISM OF ACTION, AND

PHARMACOLOGICAL ACTION

1. Ultra short-acting Thiopentone

Barbiturates

Classification 2. Short-acting Pentobarbitone

3. Long-acting Phenobarbitone

Bind to specific site on GABA

Different from BZD binding site
receptor-Cl channel complex
Mechanism of action

Hence they hyperpolarize

the neuron
Prolongs duration of opening
of Cl channels by GABA
Hence facilitates inhibitory
transmission
Induces sleep
Directly ↑ Cl conductance,
Only at high dose
i.e., GABA-mimetic action Prolongs duration of sleep

Alters NREM–REM sleep cycle

Depress all excitable tissues CNS is most sensitive

↓ REM sleep, ↑ NREM sleep

Sedation and hypnosis
Residual sedation and
hangover on awakening

Reduces anxiety, impairs short-term

memory and judgment

Hence has addiction

Produces euphoria
potential

Paradoxical dysphoria, hyperalgesia

1. CNS in some patients

In high doses
Pharmacological action

Anesthesia
Seen with conventional doses
IV thiopentone
of ultra short-acting barbiturates

All barbiturates are anticonvulsants

in conventional doses
Anticonvulsant
Seen with sub-hypnotic
doses of phenobarbitone
Significant respiratory
depression
2. Respiratory system
Additional direct paralysis
of medullary center

Hypnotic doses,
causes slight ↓ in BP and HR

3. CVS Toxic doses, causes significant

↓ in BP due to direct
depression of myocardium
and vasomotor center

4. Skeletal muscles ↓ Excitability

214 Pharmacology mind maps for medical students and allied health professionals

21.10 PHARMACOKINETICS, ADVERSE REACTIONS, AND USES

Good oral absorption

Pharmacokinetics

Wide tissue distribution

High lipid solubility Hence have a rapid onset e.g., Thiopentone

Redistributed to adipose Hence have a short duration

Thiopentone
tissue of action
Potent microsomal
enzyme inducers

Hangover due to residual

CNS depression

Mood distortion

Impaired judgment and

fine motor skills

Excitement and irritability In children

Severe in patients with respiratory

Respiratory depression
disorders even in therapeutic dose
Adverse reactions

They ↑ porphyrin synthesis

∴
Contraindicated in porphyrias

Tolerance on prolonged use

Physical and psychological

Hence there is high abuse potential
dependence

Anxiety, restlessness, hallucinations,

Withdrawal symptoms
delirium and convulsions

Fatal dose 6–10 g

Respiratory depression withslow, shallow breathing,
Manifestation
hypotension, CV collapse, renal failure, skin eruptions

Unlike BZD (i.e.,

No specific antidote
Acute barbiturate poisoning flumazenil)
Gastric lavage

Activated charcoal, reduces

further absorption ∴
Barbiturates
are acidic
Rx Forced alkaline diuresis
By NaHCO3 diuretic
and IV fluids
Because of respiratory depression
Not preferred nowadays
and abuse potential i. Maintain BP

1. Sedation and hypnosis
2. Anesthesia
3. Pre-anesthetic medication
Uses
However, BZD are preferred ii. Patent airway
General supportive
IV thiopentone measures iii. Adequate/artificial
ventilation
BZDs are preferred Hemodialysis, if renal failure

iv. Oxygen
4. Anticonvulsant Phenobarbitone

Phenobarbitone is a microsonal enzyme inducer

∴

Reduces production of glucoronyl transferase

5. Neonatal jaundice
This enzyme metabolizes and excretes excess bilirubin

Hence helps in clearance of jaundice

 22
Antiepileptics

22.1 ANTIEPILEPTICS CLASSIFICATION AND MECHANISM OF ACTION

1. Hydantoins Phenytoin

2. Barbiturates Phenobarbitone

3. Deoxybarbiturate Primidone

4. Iminostilbene Carbamazepine

5. Succinimide Ethosuximide

6. GABA transaminase Valproic acid, vigabatrin

inhibitors
Antiepileptics classification

7. Benzodiazepines Diazepam, clonazepam

Gabapentin,
8. GABA analogs
tiagabine

Newer
Lamotrigine, felbamate,
9. Miscellaneous zonisamide,
levetiracetam

1. Blockade of Na+ channels e.g., Phenytoin,

causes prolongation of their inactive carbamazepine,
state, this delays their recovery lamotrigine

2. Blockade of low threshold Ca+2 This controls absence

e.g., Ethosuximide
current (T-type) in thalamic neurons seizures

Mechanism of action

Acts on GABA e.g., Benzodiazepines

receptors

3. Enhances GABA Inhibits GABA e.g., Valproic acid,

inhibition metabolism vigabatrin

Blocks excitatory e.g., Topiramate

glutamate receptors

215
216 Pharmacology mind maps for medical students and allied health professionals

22.2 PHENYTOIN

Blockade of voltage-gated ∴ Delays recovery

Na+ channels in inactive state from inactive state
Preferentially blocks high
Mechanism frequency firing
of action Reduces number of Na+ This causes neuronal
channels for producing AP membrane stabilization

Inhibits repetitive action

potential generation
Most effective for generalized tonic
Pharmacological clonic seizures and partial seizures
actions There is no associated CNS
depression
Slow oral absorption due to
poor water solubility

90% plasma protein binding This can lead to drug

interactions
Pharmacokinetics
Metabolized initially by first-order Hence it is important to
kinetics and as dose ↑ it is monitor plasma concentration
metabolized by zero-order kinetics
Hence can lead to drug
Induces microsomal enzymes interactions
Depends on dose, duration, and
route

Nystagmus, diplopia, ataxia

Gum hyperplasia Esp. in children

Hirsutism, acne, thickening of

Peripheral neuropathy
facial features

Hyperglycemia As it ↓ insulin release

Phenytoin Endocrinal side effects Reduced secretion of ADH

(Diphenylhydantoin)
Adverse effects Due to ↓ sensitivity
Osteomalacia
of target tissues to vitamin D
∴ It reduces absorption
Hypocalcemia
of Ca+2 from GIT
∴ It ↓ the absorption of
Megaloblastic anemia
and ↑ the excretion of folic acid
Hypersensitivity – SLE, hepatic
necrosis
Cleft palate, microcephaly,
Teratogenecity Fetal hydantion syndrome
harelip, hypoplastic phalanges

Cerebellar/vestibular effects
Toxic dose
Drowsiness, delirium, hallucinations,
behavioral changes, coma
1. Generalized tonic – clonic seizures

2. Partial seizures But not absence seizures

Uses 3. Status epilepticus IV phenytoin

4. Trigeminal neuralgia Second choice after carbamazepine

5. Digitalis-induced cardiac
arrhythmias
↑ The metabolism of
As it is an enzyme inducer
phenobarbitone, carbamazepine

Valproate displaces phenytoin from protein

binding leading to phenytoin toxicity
Drug interactions
Cimetidine, ketoconazole (both enzyme
inhibitors), ↑ phenytoin toxicity
Antacids reduce phenytoin
absorption
 Antiepileptics 217

22.3 PHENOBARBITONE

Mechanism ↑ Activation of
Hence promotes Hence ↑ CNS
GABA-mediated Cl inhibitory
of action GABAa receptors
channel opening neurotransmission

↑ Seizures
threshold

Pharmacological Effective in tonic-clonic

actions seizures

Not effective in absence

seizures

Slow but complete oral

absorption
Pharmacokinetics
Induces microsomal Hence there are frequent
Phenobarbitone
enzymes drug interactions

Sedation

Tolerance on
Adverse effects
long-term use

Nystagmus, ataxia,
megaloblastic anemia,
osteomalacia

Widely used as it is
efficacious and cheap

Generalized
Uses
tonic-clonic seizures

Partial seizures
218 Pharmacology mind maps for medical students and allied health professionals

22.4 CARBAMAZEPINE AND ETHOSUXIMIDE

Tricyclic compound,
similar to imipramine

Commonly used

MOA similar
to phenytoin

Slow and
erratic absorption

Hence t½ 20–30 h
Induces microsomal
reduces to 15 h due
enzymes
to autoinduction

Sedation, vertigo, Hence caution

ADR ataxia, diplopia, blurring is advised
of vision, dizziness while driving
Carbamazepine
Due to antidiuretic
Water retention
action

Aplastic anemia,
Hematological
leucopenia,
side effects
thrombocytopenia

Grand mal epilepsy

(tonic-clonic seizures)

Simple partial seizures

Complex partial seizures

(temporal lobe epilepsy)

Trigeminal Drug
Uses
neuralgia of choice

Glossopharyngeal
neuralgia

Chronic
neuropathic pain

Bipolar mood Alternative

disorder to lithium

Responsible for
absence seizures

↑ Seizure
threshold
↓ Low threshold
Ethosuximide calcium currents (T-currents)
in thalamic neurons
Drug of choice for Epigastric pain, ∴ Start
absence seizures gastric irritation with low dose

Drowsiness, lethargy
ADR fatigue, dizziness, Dose-related
euphoria, hiccup

Leucopenia, Hypersensitivity
thrombocytopenia reactions
 Antiepileptics 219

22.5 VALPROIC ACID

↑ GABA synthesis
by ↑ GABA synthetase

Reduces GABA
metabolism by inhibiting
GABA transminase
MOA
Blocks Na+ channels
(like phenytoin)

Reduces T-currents (like

ethosuximide)

Nausea, vomiting,
epigastric irritation Hence frequent
monitoring of LFTs
should be done
Fatal in
ADR Idiosyncratic reactions Hepatoxicity
children <2 yrs
Avoid in patients with
hepatic dysfunction
Neural tube defects,
Teratogenic
spina bifida

Generalized seizures
Valproic acid

Partial seizures

Uses Absence seizures Very effective

Generalized tonic-clonic
seizures with absence Drug of choice
seizures

Bipolar mood disorders

Combination of valproic
acid and Na valproate

Divalproex
Better bioavailability
sodium

Better tolerated
220 Pharmacology mind maps for medical students and allied health professionals

22.6 BENZODIAZEPINES

Drug of choice in
Diazepam status epilepticus

Used in absence seizures,

Clonazepam and myoclonic seizures

Benzodiazepines

Used as adjuvant to
other antiepileptics

Causes less
Clobazam sedation

Effective in most
epilepsies
 Antiepileptics 221

22.7 NEWER ANTIEPILEPTICS

Analog of GABA

Highly lipid soluble

Effective in tonic-clonic seizures

Does not act on GABA receptors

Absorption does not ↑ with

dose as it is based on carrier protein

Hence, it is well tolerated and safe

Gabapentin
Tolerance develops on
ADR Ataxia, drowsiness, dizziness, fatigue
continued use of 1–2 wks

As adjunct with other antiepileptics

Migraine
Use
Neuropathic pain

Bipolar mood disorders

Prodrug, more potent

Pregabalin
than gabapentin

Acts by inhibiting Na+ channels

Also inhibits release of excitatory

amino acids (glutamate)
Lamotrigine
Broad spectrum antiepileptic

Used alone or as adjunct

GABA analog
Inhibits GABA transaminase, hence
Vigabatrin ↑ brain GABA concentration
Beneficial in non-responders
to other antiepileptics

Newer Effective against partial and

antiepileptics secondarily generalized seizures
Unkown MOA
Levetiracetam
Does not induce enzymes, has
minimal drug interactions

Used as adjunct in refractory patients

GABA analog

Inhibits GABA reuptake, hence

Tiagabine
↑ GABA concentration

Used in non-responders, as add-on therapy

Monosaccharide Blocks Na+ channels

Topiramate Has multiple MOAs ↑ GABA receptors currents

Used as add-on therapy Blocks glutamate receptor

Analog of meprobamate
(sedative-hypnotic category)

Felbamate Blocks NMDA receptor

Serious aplastic anemia,

ADRs
hepatic toxicity

Sulfonamide derivative

Zonisamide Inhibits T type Ca+2

currents and Na+ channels

Used in refractory partial seizures

 23
Antidepressants

23.1 CLASSIFICATION OF ANTIDEPRESSANTS AND SELECTIVE SEROTONIN

REUPTAKE INHIBITORS (SSRIs)

1. Selective Serotonin Reuptake Fluoxetine, fluvoxamine, sertraline,

Inhibitors (SSRIs) citalopram, escitalopram

2. Tricyclic antidepressants Imipramine, desipramine, clomipramine,

(TCAs) amitriptyline, nortriptyline, doxepin
antidepressants
Classification of

3. Selective Serotonin Norepinephrine

Venlafaxine, duloxetine, milnacipran
Reuptake Inhibitors (SNRIs)

4. 5-HT2 antagonists Trazodone, nefazodone

Mianserin, bupropion, amineptine,

5. Atypical antidepressants
mirtazepine, amoxapine, maprotiline

6. Monoamine oxidase (MAO) Moclobemide, phenelzine, tranylcypromine,

inhibitors isocarboxazid, clorgyline, selegiline

Inhibits serotonin transport (SERT)

Fluoxetine, fluvoxamine, sertraline,
citalopram, escitalopram
Hence blocks reuptake of serotonin
into serotonergic nerve endings
Mechanism of action
Thus synaptic serotonin concentration ↑

Also ↑ production of BDNF

Now are first-line drugs for
depression
Less sedation

Less constipation, urinary

Fewer anticholinergic side effects retention hence preferred
in elderly patients

Become 1st line drugs as they have many Fewer cardiovascular side effects
advantages over TCAs such as
Especially in patients with
Safe in overdose
suicidal tendencies
1. Selective serotonin

inhibitors (SSRIs)

Better patient compliance

reuptake

Thus due to fewer

side effects
Hence higher efficacy

Microsomal enzyme inhibitors

Hence duration of action

Fluoxetine is converted to active norfluoxetine
is 7–10 days
Pharmacokinetics
Escitalopram 1000 times more potent than citalopram

Unlike other SSRIs, drug interactions

are uncommon with escitalopram

Insomnia

Anxiety

Adverse effects Restlessness

Sexual dysfunction (interferes with ejaculation)

Ecchymosis ( ∴ they inhibit platelet function)

222
 Antidepressants 223

23.2 TRICYCLIC ANTIDEPRESSANTS (TCAs)

Binds and blocks serotonin

transporter (SERT) and
norepinephrine
transporter (NET)
Used in the past
Hence inhibits uptake
of both serotonin and
∴ They are norepinephrine
economical, they
are still preferred Thus they ↑ synaptic
concentration of
both 5-HT and NE
Mechanism of action

Binding to SERT and

NET variable for each TCA

Blockade of α1 adrenergic Leads to postural

and hypotension and
muscarinic receptors tachycardia

Leads to dry mouth,

Blockade of muscarinic
constipation, urinary
receptors
retention, blurred vision

High plasma protein Hence frequent drug

binding interactions

Metabolized by
Pharmacokinetics microsomal
enzymes

Thus administered as
Active metabolites Hence has a long action
once daily dose

Dry mouth, constipation,

Anticholinergic
2. Tricyclic urinary retention, blurred
side effects such as
antidepressants vision, palpitation
(TCAs)

Postural hypotension,
Due to α1 blockade –
tachycardia

Sedation, confusion, weight

gain, sweating

↓ Seizure threshold
hence precipitates
Adverse effects convulsions To sedative and
anticholinergic
effects after 2–3 wks
Tolerance and dependence
occurs
Gradual withdrawal - Gastric lavage
after long-term therapy

Mimics symptoms
of atropine IV fluids
poisoning

Delirium, excitement,
convulsion, fever,
Overdosage hypotension, Respiratory support
arrhythmias, respiratory
depression, coma

Potentiate action of
Reduces anticholinergic
anticholinergics Rx Physostigmine
side effects
and antihistaminics

Potentiate action of alcohol

Sodium bicarbonate Reduces acidosis
and CNS depressants
Drug interactions

Potentiate Hence precipitates

Diazepam/phenytoin To control seizures
sympthomimetics hypertension

Highly protein-bound-
drugs like phenytoin, Lignocaine/propranolol To control arrhythmias
sulfonylureas,
phenylbutazone displace
TCAs and cause toxicity
224 Pharmacology mind maps for medical students and allied health professionals

23.3 SELECTIVE SEROTONIN – NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIs),

5-HT2 ANTAGONISTS, AND ATYPICAL ANTIDEPRESSANTS

e.g., Venlafaxine, duloxetine, Like TCAs (block SERT and

milnacipran NET)

But no blockade of α1, muscarinic Hence they have minimal

Mechanism of action
and H1 histaminic receptors side effects

3. Selective serotonin
Also beneficial for chronic
–norepinephrine
pain
reuptake inhibitors (SNRIs)

t½ 5 h, hence it is short-acting ∴ It is given twice daily

Venlafaxine Withdrawal symptoms

common

Beneficial for non-responders

e.g., Trazodone and nefazodone
other antidepressants

Earlier classified as atypical

antidepressants

Now known to act as 5-HT2

Short (6 h) t½
antagonists and weak 5-HT
reuptake inhibitors

Safe in overdosage
Trazodone
4. 5-HT2 antagonists
Postural hypotension

ADR
Priapism (sustained erection)
due to α1 blockade

Nefazodone ADRs Sedation, hepatotoxicity

Both not preferred nowadays ↑ NA and 5-HT

↑ Monoamines in CNS by
↓ reuptake/degradation
Blocks 5-HT2, 5-HT3, and α 2
receptors
Mirtazapine

Fast onset (within 1 wk)

Sedation is common, whereas

other side effects are minimal

Weak DA reuptake inhibitor

CNS stimulant

Amoxapine, bupropion, Bupropion Used in depression with

5. Atypical antidepressants mianserin, mirtazapine, comorbid anxiety
maprotiline
Reduces smoking craving
(along with nicotine patch)

ADR Insomnia, agitation, no sexual

disturbances

Derivative of antipsychotic
loxapine
Amoxapine

ADRs like TCAs Hence not preferred

Blocks presynaptic α2 auto Hence ↑ monoamines

receptors

Mianserin
Hepatotoxicity, seizures, blood
dyscrasias
ADR

So not used
 Antidepressants 225

23.4 MONOAMINE OXIDASE (MAO) INHIBITORS

Monoamine oxidase (MAO) metabolizes/degrades NA, 5-HT, and DA

Hence MOA inhibitors ↑ neuronal concentration of monoamines

MAOa Selective for 5-HT

MAO
MAOb Selective for dopamine
Reversible and selective
Moclobemide
MAOa inhibitor

Selective MAOb inhibitor Selegiline Used in parkinsonism

Phenelzine, tranylcypromine, isocarboxazid

6. Monoamine oxidase (MAO) inhibitors

Irreversibly and nonselectively inhibit MAO

↑ Neuronal concentration of 5-HT, NA, and DA

Nonselective and irreversible
MAO inhibitors
Very slow onset of action (2–3 wks)

Slow recovery after stopping (1–2 wks)

There is withdrawal on
Excitement, psychosis
abrupt stoppage which is manifested as

Postural hypotension, weight gain, anxiety, restlessness,

Common side effects anticholinergic side effects (dry mouth, constipation,
urinary retention, blurred vision), hepatotoxicity

Drug/food interactions Cheese, beer, wines, yeast, fish,

Patients concomitantly taking tyramine–rich food taking
buttermilk

Cheese reaction Leads to severe hypertension Hence, MAO inhibitors ↑

concentration of tyramine
Normally tyramine is metabolized in GIT by MAO
Tyramine displaces NA from
nerve endings, causing hypertension
Due to concomitant SSRIs and MAOIs
There is both inhibition of reuptake
∴
and metabolism of serotonin
Severe ↑ in synaptic serotonin concentration
Leads to hyperthermia, muscle rigidity,
tremor, restlessness, sweating, aggression,
Serotonin syndrome seizures, coma, which could be fatal

Reversible, competitive, Buspirone, sumatriptan (5-HT agonist)

selective MAO inhibitor
Can also occur with Tryptophan (5-HT synthesis)
Short-acting
∴ Avoid such combinations Amphetamines, cocaine (5-HT release)
Fast recovery (1–2 days)
after withdrawal
Moclobemide

No sedation, anticholinergic,
cardiovascular side effects

No drug–food interactions Hence it is well tolerated

ADR Insomnia, dizziness, hepatic dysfunction

Mild–moderate depression

Use Alternative to TCA

Anxiety-related mood disorders

226 Pharmacology mind maps for medical students and allied health professionals

23.5 USES OF ANTIDEPRESSANTS

Effects seen after 2–3 wks

1. Endogenous depression

ECT is given for severe depression

Acute, recurrent, brief anxiety attacks

2. Panic attacks

Post-traumatic stress disorder (PTSD)

Repetitive anxiety – provoking thoughts and

compulsive behavior to overcome such thoughts
3. Obsessive compulsive disorders (OCDs)
Clomipramine is used along with
counseling

Phobias

4. Other anxiety disorders Social anxiety

BZDs may also be used

Fibromyalgia

Diabetic neuropathy backache

5. Chronic pain

Postherpetic neuralgia

SNRIs preferred (duloxetine)

Uses of antidepressants

Irritable bowel syndrome

Chronic fatigue

6. Psychosomatic disorders Sleep apnea

Tics

Newer antidepressants are tried

SSRIs given 2 wks before menstruation

7. Premenstrual syndrome

Also effective in perimenopausal symptoms

8. Smoking withdrawal Bupropion is used

9. Nocturnal enuresis TCAs such as imipramine used

10. Bulimia nervosa Episodic bouts of excessive eating

Attention deficit-hyperactivity disorder (ADHD)

11. Miscellaneous Chronic alcoholism

Migraine
 24
Mood stabilizers and lithium

24.1 MOOD STABILIZERS – INTRODUCTION AND LITHIUM

Also called antimanic

drugs

Controls mood swings

seen in
bipolar disorders

Lithium salts
Introduction Conventional drugs
(as carbonate, citrate)

Antiepileptics
(carbamazepine,
valproic acid,
gabapentin)

Antipsychotics
Unconventional
(aripiprazole,
drugs
olanzapine, risperidone)

Mood stabilizers
Chlorpromazine, ↓ Of membrane phosphatidyl
Monovalent cation, haloperidol inositol causes inhibition of
a mood stabilizer are used for acute receptor mediated actions through
attacks of mania IP3 and DAG

Prophylactically used Hence ↓ the formation of

in bipolar disorder inositol, ∴ regeneration
of PI pathway

Reduces mood
Lithium swings i.e.,
mania and depression ∴ Reduces second messenger;
i.e., inositol triphosphate
(IP3) and diacylglycerol (DAG)

In acute mania,
reduces attacks
after few weeks
Inhibits phosphoinositol (PI)
pathway
Complex, not fully
understood
Mechanism of action
Following are some
hypotheses
Also reduces hormone-induced
cAMP production

227
228 Pharmacology mind maps for medical students and allied health professionals

24.2 PHARMACOKINETICS, ADRs, AND USES

Mimics action in excitable

tissues

Has good oral absorption

Filtered by glomerulus, but

reabsorbed like Na
Small ion, similar
Pharmacokinetics
to sodium (Na+)
Steady-state concentration is
achieved in 5–6 days

Secreted in sweat, saliva,

breast milk
Hence frequent monitoring of
Narrow margin of safety Low therapeutic index plasma concentration
(therapeutic drug monitoring)

Hence frequent side effects

Nausea, vomiting, diarrhea

Edema, thirst, polyuria As it has actions like Na

Tremors Controlled by propranolol

Low therapeutic Due to reversible inhibition of

ADRs
index thyroid function
Hypothyroidism
Hence regular monitoring of TSH
to be done (every 6 months)

Nephrogenic diabetes
Hence avoid dehydration
insipidus on long-term use

Weight gain
Initially drowsiness, giddiness, confusion,
ataxia, blurred vision, nystagmus
Overdose
Later delirium, muscle twitching,
convulsions, arrhythmias, renal failure

i. Prophylaxis of
↓ Severity
bipolar disorders

The action of lithium is

∴
ii. Acute mania
delayed, neuroleptics are preferred

As add-on therapy in severe

iii. Depression
recurrent depression

Uses iv. Leukopenia following It ↑ leukocyte count

∴
cancer chemotherapy

Recurrent neuropsychiatric
disorders

Pediatric mood disorders

v. Miscellaneous
Hyperthyroidism

SIADH (syndrome of
inappropriate ADH secretion)
 Mood stabilizers and lithium 229

24.3 RILUZOLE AND NONCONVENTIONAL MOOD STABILIZERS

Prevents relapse of
Tried in mood disorder
bipolar mood disorder

Neuroprotective agent

Used in amyotrophic
Rx of acute mania
lateral sclerosis

Combined with lithium

Carbamazepine
(but ↑ toxicity)

Unknown mechanism

Mood stabilizer in mild cases Safe

As monotherapy in
Well tolerated
mild–moderate cases

Combined with lithium in

Sodium valproate Rapid uptitration of dose
refractory cases

Nonconventional mood
stabilizers First-line mood stabilizer
due to the following Mild ADR compared to lithium
advantages

Can be safely combined

with antipsychotics

Effective in lithium
nonresponders

Comparable efficacy to lithium

Lamotrigine, gabapentin,
Antiepileptics
topiramate

Others

Risperidone, olanzapine,
Antipsychotics
quetiapine
 25
Antipsychotics

25.1 ANTIPSYCHOTICS CLASSIFICATION

i. Aliphatic Chlorpromazine,
side chain trifluopramazine

ii. Piperidine
a. Phenothiazines Thioridazine
side chain

iii. Diperazine Trifluoperazine,

side chain fluphenazine
1. Classical/typical/first-
generation neuroleptics Haloperidol,
b. Butyrophenones droperidol,
trifluoperidol

Thiothixene,
Antipsychotics c. Thioxanthene
Classification flupenthixol
(neuroleptics)
Clozapine, olanzapine,
2. Atypical/second-
risperidone, quetiapine,
generation neuroleptic
ziprasidone, aripiprazole

3. Miscellaneous Pimozide, loxapine,

reserpine

230
 Antipsychotics 231

25.2 CHLORPROMAZINE (CPZ) – MECHANISM OF ACTION

↓ Motor activity;
Normal drowsiness,
Act by blocking individuals indifference
Typical/1st-generation
D2 receptors in to surroundings
antipsychotics
mesolimbic area

↓ Aggression,
DA hyperactivity in initiative,
limbic area is thought impulsiveness
to be responsible
for schizophrenia
Chlorpromazine Mechanism
(CPZ) of action ↓ Motor
Also responsible activity
D2 blockade for extrapyramidal
side effects (EPS)

↓ Anxiety
Pharmacological
CNS
actions

Causes emotional
quieting

Drowsiness

↓ Hallucinations
and delusions
Psychotic
patients
Hence can
↓ Seizures
precipitate
threshold
convulsions (cortex)

Hence can lead to

↓ Gonadotropin amenorrhea
secretion (hypothalamus)

Hence can cause

galactorrhea,
↓ Prolactin
gynecomastia
(hypothalamus)

Hence can cause EPS;

i.e., drug-induced
DA antagonist
parkinsonism
(basal ganglia)

Depresses
∴ ↓ BP (brain stem)
vasomotor reflexes

DA antagonist Hence is an
in CTZ antiemetic (CTZ)

(Continued)
232 Pharmacology mind maps for medical students and allied health professionals

25.2 CHLORPROMAZINE (CPZ) – PHARMACOLOGICAL ACTIONS (Continued)

α blocker

Varies with individual

ANS Anticholinergic property
drugs

Also has H1 blocker

property

It has α blocking Orthostatic hypotension,

∴
property reflex tachycardia

CVS
Direct myocardial
depressant action
like quindine

Reduces ADH, hence is a

Kidney
weak diuretic

Tolerance develops to
sedation and hypotension

However, there is no
tolerance to antipsychotic
effects
 Antipsychotics 233

25.3 ADVERSE EFFECTS

Orthostatic
Due to α blockade and
hypotension
central effects
and palpitation

Hence arrhythmias (in high dose), hence caution with

1. CVS and ANS

QTC prolongation
mefloquine, halofantrine, quinine, and antiarrhythmics

Nasal stuffiness Due to α blockade

Dry mouth,
constipation Facial grimacing, tics,
Anticholinergic effects
urinary retention, protruding of tongue,
reduced sweating muscle spasms
a. Acute dystonias
Rx by central
Seen in first few days anticholinergics
Adverse effects

(benztropine, benzhexol)
Bradykinesia, rigidity,
tremors, parkinsonian face
b. Parkinsonism
Rx by central
Seen in first few weeks
anticholinergics
Rabbit syndrome
c. Perioral tremors
Rx by central
After several months
anticholinergics
Drowsiness,
confusion
2. CNS

Feeling of intense discomfort

Extrapyramidal
d. Akathesia
symptoms Rx by ↓ dose of
Compels patient to
antipsychotic,
move/walk constantly
or giving propranolol
Seen months or years later
e. Tardive dyskinesia
Involuntary movements of
Use atypical
face, tongue, eyelids,
antipsychotics
trunks, limbs

Immobility, rigidity,
tremors, fever, dysphagia,
stupor, coma

Fluctuating BP and HR

Frequent with high potency

parenteral antipsychotics
f. Malignant neuroleptic
syndrome (MNS)
Rare, but fatal
Probably due to sudden
↓ DA activity and
↑ Ach activity
Rx
Stop neuroleptic
immediately
Tepid water sponging,
reduces temperature
Dantrolene, a skeletal
muscle relaxant,
is drug of choice

Diazepam

Bromocriptine

(Continued)
234 Pharmacology mind maps for medical students and allied health professionals

25.3 ADVERSE EFFECTS (Continued)

Gynecomastia

Due to blockade of DA
3. Endocrinal changes Galactorrhea receptors in pituitary
lactotrophs

Amenorrhea

Due to long-term high

dose antipsyhotic

Corneal/lenticular
4. Ocular toxicity
opacities

Retinal pigmentation/
degeneration

Agranulocytosis

5. Hypersensitivity
Jaundice
reactions

Skin rashes
 Antipsychotics 235

25.4 DRUG INTERACTIONS AND USES

↑ Sedative effects of CNS

depressants

Additive effect with α blockers,

Drug interactions
anticholinergics

↓ Actions of DA
agonists and L-DOPA

Schizophrenia

1. Psychiatric conditions

Organic brain syndrome

CPZ for DINV (drug-induced nausea

2. Nausea and vomiting and vomiting), RINV (radiation-
induced nausea and vomiting)

Uses
3. Intractable hiccough CPZ

Tourette syndrome

4. Neuropsychiatric syndromes Huntington disease

Chronic alcoholism
236 Pharmacology mind maps for medical students and allied health professionals

25.5 INDIVIDUAL ANTIPSYCHOTICS

Less potent, but

Aliphatic side chain
produce more sedative
derivatives
and weight gain

More potent
and selective
Piperazine derivatives
Used as
Differ in their potency, Triflupromazine
antiemetic
sedative, autonomic, and
extra-pyramidal effects and
pharmacokinetic profile Prominent
anticholinergic
effects, less EPS
Phenothiazines
Lenticular
opacities
Piperidine side chain Thioridazine
Retinal
degeneration
Trifluoperazine,
fluphenazine
Not preferred
for long term
High potency

Piperazine
Fewer autonomic
side effects
Individual Haloperidol,
antipsychotics trifluperidol
High EPS

High potency

Low autonomic Hence preferred

Butyrophenones
side effects in elders

Long t½ haloperidol;
penfluridol
is given once a week
Drug of choice in
Tourette syndrome
Haloperidol
and Huntington
disease

Additional
antidepressant
property
Thioxanthines Flupenthixol
Hence suitable
Available as depot
for maintainance
preparations
therapy
 Antipsychotics 237

25.6 ATYPICAL ANTIPSYCHOTICS

Clozapine, olanzapine, risperidone,

Less EPS
quetiapine, aripiprazole

Weak D2 blockade No ↑ prolactin

Prominent 5-HT2
Reduces both positive and negative symptoms
antagonistic actions

Following advantages over

Effective in resistant cases
typical/1st generation

First line in newly diagnosed patients

Preferred in patients with EPS due to typical agents

Efficacy similar to typical antipsychotics

Blocks D1 and D4 receptors > D2
Also block 5-HT2a, α-adrenergic,
muscarinic and H1 histaminic receptors
Hence less chance of EPS,
low sedation and minimal
endocrinal changes

Clozapine Effective in patients not responding

to typical antipsychotics

ADR Fatal agranulocytosis

Epileptogenic
antipsychotics

Hence weekly monitoring

Atypical

Similar to clozapine of WBC count for

first 18 wks
Given once daily (t½ 24–30 h)
Olanzapine
No agranulocytosis

Anticholinergic side effects,

weight gain, hyperglycemia can occur

Quetiapine t½ 6 h, hence given twice daily

Blocks D2 and 5-HT2a receptors

Effectively against positive and negative symptoms

Risperidone
Low EPS and sedation

Most commonly used atypical antipsychotic

Partial agonist of D2 and 5-HT2a receptors

Aripiprazole Side effects – tachycardia, dyspepsia, hypothyroidism

Long t½ of 3 days

Schizophrenia

Use Mania

Bipolar mood disorders

238 Pharmacology mind maps for medical students and allied health professionals

25.7 OTHER ANTIPSYCHOTICS

Loxapine Fast onset, short duration

D2 blocker, weak α receptor

and muscarinic blocker

Pimozide
Other antipsychotics
Long duration of action

Depletes monoamines
(NA and DA)

Reserpine

Serious ADR-like depression Hence not used nowadays

 Antipsychotics 239

25.8 ANXIOLYTICS (NONBENZODIAZEPINES)

Azapirone derivative

Selective 5-HT1a partial

agonist

5-HT1a receptors are

inhibitory auto receptors

Binding of buspirone,
reduces release of 5-HT

They are also a weak D2

antagonists

Buspirone, ipsapirone,
gepirone Useful in mild–moderate
anxiety, where sedation is
to be avoided
Not skeletal muscle
relaxants
Slow onset of action; i.e.,
about 2 wks

Not anticonvulsants

Unlike BZD

Does not produce sedation,

dependence, or tolerance

Not useful for panic attacks

Anxiolytics
(nonbenzodiazepines)
Headache, dizziness,
ADR
tachycardia, paresthesias

High sedation, hence not

Others Meprobamate
used now

Antihistaminic, high
Hydroxyzine
sedation, hence not used

In patients with prominent Tremors, palpitation,

autonomic symptoms hypertension

May be combined
β blockers Propanolol
with BZD

Useful before public

speaking, stage
performance
 26
Drug treatment of Parkinsonism
and Alzheimer’s disease

26.1 CLASSIFICATION OF ANTIPARKINSONIAN DRUGS

a. Dopamine
Levodopa
precursor

b. Dopamine
Amantadine
releasers
1. Drugs that enhance
dopamine activity c. Dopamine Bromocriptine, lisuride,
agonists pergolide, ropinirole

MOAb inhibitors Selegiline

d. Dopamine
Classification metabolism inhibitors
Entocapone,
COMT inhibitors
tolcapone

a. Central Benztropine, benzhexol,

anticholinergics biperidine, trihexyphenidyl
2. Drugs depressing
cholinergic activity
Diphenhydramine,
b. Antihistaminics
promethazine

240
 Drug treatment of Parkinsonism and Alzheimer’s disease 241

26.2 DOPAMINE PRECURSOR – LEVODOPA

Dopamine has no ∴
It does not cross BBB
therapeutic value

Levodopa is a prodrug Which is able to cross the BBB

In the brain levodopa is

converted by dopa
decarboxylase to dopamine
This dopamine is taken Improvement of rigidity
into nigrostriatal neurons and bradykinesia

Sialorrhea and seborrhea

Pharmacological actions
subsides

General motor activity

is enhanced

Activates CTZ Hence causes vomiting

∴ Postural hypotension,
Dopamine is
Miscellaneous actions tachycardia,
a catecholamine
arrhythmias

Inhibits prolactin release

Hence amino acids

Absorbed actively by transport
compete for absorption
process meant for amino acids
and transport to brain

Food delays absorption

Pharmacokinetics
99% metabolized by peripheral
Dopamine
Levodopa (i.e., intestinal, plasma) dopa
precursor
decarboxylase, MAO, and COMT

1% crosses BBB and reaches CNS

Nausea, vomiting

Postural hypotension, palpitation, As it is a

arrhythmias catecholamine

Tolerance on long-term use

ADR Anxiety, depression

hallucinations, psychosis
Facial tics, grimacing,
Abnormal involuntary
choreo-athetoid
movements
movements
Develops 2–5 yrs
after use
“On–off phenomena”
Swinging of response
from good to poor
Only useful for
idiopathic parkinsonism
Uses
Not beneficial for
drug-induced parkinsonism

Pyridoxine ↑ peripheral Thus activity of

decarboxylation of L-dopa L-dopa ↓
Drug interactions
Dopamine antagonists like
phenothiazines and metoclopramide
reverse effects of L-dopa
242 Pharmacology mind maps for medical students and allied health professionals

26.3 CARBIDOPA AND BENSERAZIDE, DOPAMINE RELEASERS

Peripheral dopa
decarboxylase inhibitors

Inhibit the formation of

dopamine in periphery

Hence they allow

Do not cross BBB levodopa to be converted
to dopamine in CNS

∴ Combination of
75% reduction of
levodopa + carbidopa/
levodopa dose
benserazide is synergistic
Carbidopa and
benserazide
Early symptomatic relief
Benefits of
combination
Reduction in
side effects

No interference
of pyridoxine

10 mg carbidopa +
100 mg levodopa
Fixed dose combination
ratio 1:4 or 1:10 i.e.,
25 mg carbidopa +
100/250 mg levodopa

Antiviral agent

↑ release and ↓ reuptake of

dopamine in CNS

Dopamine Early response and

Amantadine
releasers minimal side effects

Used in mild cases/

add-on with levodopa
Insomnia, dizziness,
hallucinations
ADR
Vomiting, postural
hypotension,
ankle edema
 Drug treatment of Parkinsonism and Alzheimer’s disease 243

26.4 DOPAMINE RECEPTOR AGONISTS AND DOPAMINE METABOLISM INHIBITORS

Bromocriptine, pergolide,
lisuride, ropinirole

Are ergot derivatives

D2 receptor agonist + D1
Bromocriptine
partial agonist

D2 receptor agonist + D1
Pergolide
agonist

Newer agents e.g.,

ropinirole, pramipexole

Dopamine receptor Better tolerated

agonists Selective D2 agonist
Show an early response

Minimal side effects

(e.g., sleep disruption)

All agents are Hence beneficial for

long-acting “on-off” phenomena

Nausea, vomiting,
hallucinations

Postural hypotension
ADR
Hypertension

Hence they can cause

First-dose phenomena
sudden CV collapse

e.g., Selegiline

Selective MAOb inhibitor

MAOb is present in dopamine-

containing areas of CNS

Selegiline inhibits Hence ↑ duration

MAOb inhibitors levodopa metabolism of action

Slows progression
of parkinsonism

ADR Nausea, postural hypotension,

confusion, hallucinations

Dopamine metabolism Mild cases as monotherapy

inhibitors Use
As add-on to levodopa
e.g., Entacapone/
tolcapone

Prevent peripheral Hence ↑

degradation of levodopa levodopa bioavailability
COMT inhibitors
Use Adjunct therapy

Nausea, postural hypotension,

hallucination, confusion
ADR
Hepatotoxicity
(with tolcapone)
244 Pharmacology mind maps for medical students and allied health professionals

26.5 CENTRAL ANTICHOLINERGICS AND DRUG-INDUCED PARKINSONISM

Atropine derivatives – benztropine,

benzhexol, biperidine,
trihexyphenidyl

Antihistaminics: e.g.,
diphenhydramine, promethazine,
they benefit because of their
anticholinergic activity

Reduce cholinergic hyperactivity

in CNS

Central anticholinergics

↓ Tremors, sialorrhea,
seborrhea more than rigidity

ADR – dry mouth, constipation,

urinary retention, blurring of vision

Drug of choice in drug-

induced parkinsonism

Use

Add-on to levodopa

Causative agents –
phenothiazines,
metoclopramide, reserpine

Phenothiazines, metoclopramide
are dopamine antagonists

Drug-induced parkinsonism

Reserpine depletes catecholamine

Withdrawal of causative agent
(dopamine) stores

Central anticholinergics:
Rx Benztropine, benzhexol,
biperidine, trihexyphenidyl

Levodopa/dopamine agonists
are not effective dopamine
∴
receptors are already blocked
 Drug treatment of Parkinsonism and Alzheimer’s disease 245

26.6 DRUGS FOR ALZHEIMER’S DISEASE (AD)

1. Cholinesterase Tacrine, rivastigmine,

inhibitors donepezil, galatamine

2. Nootropic agents
Piracetam, aniracetam
(improve memory)

3. Investigational Memantine, ibuprofen,

agents indomethacin

Centrally acting
cholinesterase inhibitor

↑ Cholinergic
activity in CNS

Tacrine

Short-acting

Nausea, vomiting, abdominal

ADR cramps, diarrhea, hepatotoxicity
Drugs for AD (peripheral cholinergic effects)

Rivastigmine, donepezil,
galantamine

As they are selective,

there are less
GI side effects
Selective central
cholinesterase inhibitors
(newer agents)
No hepatotoxicity

Long-acting

NMDA
Memantine
receptor antagonist

Have shown inconsistent

results in
improving memory
Nootropic agents

Hence are sometimes

used empirically
 27
General anesthetics (GA)

27.1 MECHANISM OF ACTION AND CLASSIFICATION

↑ Inhibitory
neurotransmission in brain
1. Binding to GABAa
receptor chloride channels

Depress CNS

Exact mechanism unclear,

Mechanism of action accepted theories are as ↑ Inhibitory
follows 2. ↑ Sensitivity of glycine
neurotransmission in brain
gated chloride channels
stem

3. Ketamine, nitrous oxide

inhibit NMDA receptors

e.g., Nitrous oxide,

Gases
cyclopropane

1. Inhalational anesthetics
e.g., Ether, halothane,
Liquids enflurane, isoflurane,
desflurane, sevoflurane

e.g., Thiopentone sodium,

Classification Inducing agents
propofol, etomidate

Dissociative anesthesia Ketamine

2. Intravenous anesthetics

Neuroleptanalgesia Fentanyl + droperidol

Diazepam, lorazepam,
Benzodiazepines
midazolam

246
 General anesthetics (GA) 247

27.2 INHALATIONAL ANESTHETICS AND FACTORS DETERMINING ANESTHETIC

PP IN BRAIN

Given at a specific concentration

Brain is highly perfused

∴
Steady-state is achieved quickly

Inhalational At steady-state concentration, partial pressure Hence, monitoring of anesthetic

anesthetics (PP) of anesthetic in lung and brain are similar concentration is easier

However, for anesthetics with high solubility Hence induction

in blood and tissues, ↑ alveolar partial pressure is slower

These anesthetics ∴ should be

administered at higher pressures

Determines concentration in
1. Pulmonary ventilation
alveoli and is directly proportional

Higher the PP, greater the

2. PP in inspired gas
concentration in blood

Free diffusion of anesthetic across

3. Alveolar exchange alveoli is dependent on adequate
ventilation perfusion ratio
Factors determining
anesthetic PP in brain Lower the solubility, more rapid is
4. Solubility of anesthetic in Hence longer time for
the rise of PP in blood,
blood induction and recovery
and faster is induction

5. Solubility of anesthetic Higher solubility of anesthetic Longer time to

in tissues in tissues like adipose tissue achieve steady state

6. Cerebral blood flow Higher blood flow results in Hence rapid induction
higher concentration in brain

Concentration that results in immobilization of 50% of individuals

in response to surgical skin incision
Minimum alvelolar
concentration (MAC)
Used for describing potencies of volatile anesthetics

Seen especially when nitrous oxide

is administered in high concentration
Secondary gas effect
Other anesthetic gases are Hence their alveolar tension
also sucked in rises faster

Rapid rise in alveolar tension following the administration of high

concentration anesthetic
Concentration effect
(e.g., 75% N2O) compared to low concentration anesthetic (e.g., 50% N2O)

Following discontinuation, recovery depends on rate of elimination from brain

Recovery is determined by similar factors that govern induction

Elimination
Inhalation anesthetics are eliminated from lungs

Elimination, hence recovery is slower for agents with high solubility

in adipose and other tissues
248 Pharmacology mind maps for medical students and allied health professionals

27.3 NITROUS OXIDE

Potent analgesia

Rapid and smooth induction

and recovery
Used by Horace Wells in
1944
Non-irritating

Slightly sweetish odor

Non-flammable

Advantages

No significant
postoperative nausea

Nontoxic to liver, kidney

and brain

Quickly eliminated from

lungs

Hence there is no depression

Produces light anesthesia of vasomotor center or
respiration
Nitrous oxide

Less potent Hence used in combination

Inadequate muscle
relaxation

N2O rapidly displaces Hence can lead to

Disadvantages nitrogen from cavities pneumothorax,
even before air embolism
nitrogen escapes

Bone marrow depression

on repeated use

Long-term exposure to
Hence fetal abnormalities e.g., Staff in operation
low doses can
at conception theaters
damage DNA

As adjuvant with other

agents

Usage pattern

Used along with O2 (30%)

 General anesthetics (GA) 249

27.4 HALOTHANE AND CONGENERS

Potent

Non-inflammable

Advantages Non-irritant

Smooth and rapid induction

and recovery
Insignificant postoperative
nausea and vomiting

Inadequate analgesia and

muscle relaxation

Myocardial and respiratory

Halothane depression

Sensitizes heart to adrenaline,

Disadvantages hence can lead to arrhythmia
Genetically determined
Fatal hepatitis, because of its
metabolite
Succinylcholine potentiates it
Malignant hyperthermia Hence there is muscle
Caused due to release of contraction and
intracellular Ca+2 heat production
Most frequently used
Usage pattern Drug of choice for
Combined with analgesics treatment is dantrolene
and muscle relaxants
Similar to halothane

Hence less incidence of

Less metabolism hepatitis
Enflurane
Does not sensitize heart to
adrenaline
However, may produce
seizures

Isomer of enflurane

More potent

Does not sensitize heart to

adrenaline

Less metabolism Hence lesser incidence of

Isoflurane hepatitis
No seizures

However, expensive and

produces hypotension

Widely used

Congener of isoflurane,
hence similar
Hence it produces cough and Hence it is not preferred for
However, it is pungent induction, but used for
laryngospasm
Desflurane maintainance
Requires special vaporizer
for administration

Produces sympathetic
stimulation and tachycardia

Recently introduced

Not pungent

Rapid and smooth induction Hence it is preferred for day-

and recovery case surgeries and children
Sevoflurane
However, it is chemically
unstable
Its metabolite produces
nephrotoxicity

Fluoride ions produced during

metabolism can cause
nephrotoxicity
250 Pharmacology mind maps for medical students and allied health professionals

27.5 INTRAVENOUS ANESTHETICS AND INDUCING AGENTS

Extremely rapid induction

Cannot be eliminated Hence elimination of

Intravenous anesthetics rapidly like inhalational inhalational agents can be
agents ↑ hyperventilation

This is not possible for IV ∴ IV agents are used

anesthetics for induction and inhalational
agents for maintainance

Ultra short-acting
barbiturate

Rapidly produces
hypnosis

No analgesia

Hence rapidly
Thiopentone sodium Highly lipid-soluble
distributed in tissues

Inadequate analgesia and

Onset of action: 20–30 s
muscle relaxation

Respiratory and circulatory

Duration of action: 4–7 min
depression

Rx with head – low position,

Disadvantages Severe hypotension plasma expanders and
vasopressor agents

Extravasation can produce

local necrosis, gangrene

Should not be combined Barbiturates are

∴
with acidic drugs precipitated

Total IV anesthesia as
Oily liquid continuous infusion or
intermittent injection
Inducing agents
Rapid induction and Induction as well as
Propofol
recovery maintenance

Uses Short procedures of up to

1 h duration (day-cases)

Additional antiemetic
property

Used safely in pregnant

women

Rapid metabolism Hence has rapid recovery

Less cardiorespiratory Hence preferred in patients

depression with CVS/RS disorders

Cause excitation and

Etomidate involuntary movements
during induction

Pain at site of injection

Long-term use can result in

adrenocortical suppression
 General anesthetics (GA) 251

27.6 DISSOCIATIVE ANESTHESIA (KETAMINE)

Phencyclidine derivative

“Trance-like” state manifested by

profound analgesia;
immobilization and amnesia

Feeling of dissociation from ones

own body and surroundings
with/without actual loss
of consciousness

MOA Blocks excitatory NMDA

receptor

Hence rapidly distributed to highly

Highly lipid soluble vascular organs, then redistributed
to less perfused organs

Onset of action is
3–5 min

Duration lasts for

10–15 min

Amnesia lasts for 1–2 h

Premedication with
atropine essential

Dissociative
Ketamine
anesthesia Actions Recovery is gradual

Delirium with vivid dreams This is avoided by pre/post-op

may be there diazepam

Sympathetic stimulation
↑ BP, HR, CO

There is no CVS/RS
depression

Less incidence of
postoperative
nausea/vomiting
Used alone for minor operations

Uses
Valuable in pediatrics asthmatics
and vulnerable patients
with poor risk
Hallucinations, delirium,
Avoided by pre/postoperative
involuntary movements, and
diazepam
nystagmus during recovery

Produces hypertension

Raises intracranial tension

Drawbacks
Hypertension, cardiac failure
Contraindications cerebral hemorrhage, psychiatric
disorders, and pregnancy

Monitor HR and BP

Caution
Patients should be undisturbed
and observed during recovery
252 Pharmacology mind maps for medical students and allied health professionals

27.7 NEUROLEPTANALGESIA AND BENZODIAZEPINES

Fentanyl Short-acting analgesic

Combination of neuroleptic
(droperidol) and analgesic
(fentanyl)
Rapidly acting neuroleptic
Droperidol
(like haloperidol)
It is quieting, mental
indifference, profound
analgesia, loss of
consciousness

Patient is drowsy, but

cooperative

Associated with respiratory

depression
Neuroleptanalgesia

Negligible fall of BP and HP

due to vagal stimulation

Extrapyramidal symptoms
may be present during recovery

Endoscopies, burn dressing,

Uses angiographies, diagnostic
procedures, minor operations

Above combination +
Neuroleptanesthesia
65% N2O + 35% O2

e.g., Diazepam, lorazepam,

midazolam

For induction or combination

Produce sedation, amnesia,

Benzodiazepines
↓ anxiety
Sole agent for reduction of
fractures, endoscopies, cardiac
catheterization and cardioversion
Uses
IV midazolam preferred it is
∴
short-acting and rapid, there is no
cardiorespiratory depression

Also used as preanesthetic

medication
 General anesthetics (GA) 253

27.8 PREANESTHETIC MEDICATION AND BALANCED ANESTHESIA

1. Sedatives/anxiolytics e.g., Diazepam

Makes anesthesia safe e.g., Metaclopramide,

2. Antiemetics
domperidone, ondansetron

↓ Adverse effects e.g., Promethazine has sedative,

of anesthetic 3. Antihistaminics antiemetic, and anticholinergic
properties

Minimizes gastric acidity

Reduce salivary and respiratory
secretions produced by irritant
anesthetics (like ether)
Preanesthetic
Reduce anxiety
medication
Hence also reduce
laryngospasm
Produces amnesia of
preoperative period Also reduce aspiration
pneumonia
Allays preoperative pain,
if any Reduce bradycardia due
4. Anticholinergics
to vagal stimulation

Agents e.g., Atropine 0.6 mg IM

Scopolamine 0.6 mg IM Causes more sedation

Causes less sedation,

Glycopyrrolate 0.2 mg IM
(longer acting)

Anesthetics provoke vomiting

and ↓ protective
respiratory reflexes

Hence ↑ risk of aspiration

5. Drugs to reduce acidity of acidic gastric contents
leading to pneumonia

Hence reduce gastric acidity by

H2 blockers (ranitidine) or PPIs
(omeprazole) administered at
night before surgery

↑ Gastric motility,
emptying and tone
6. Prokinetics
Hence, combined with H2
blockers/PPIs to ↓
aspirations

Preanesthetic
medication

IV anesthesia for
Multiple drugs are used to induction
achieve ideal anesthesia
Balanced Inhalational agents for
anesthesia maintainance
Agents
O2

Skeletal muscle
relaxants and

Analgesics
 28
Local anesthetics (LA)

28.1 LOCAL ANESTHETICS (LA) – INTRODUCTION, HISTORY, AND CLASSIFICATION

Reversible loss of sensation

without loss of consciousness or
impairment of vital functions

Block nerve conduction when

applied topically to nerve tissue

Act on axons, cell body, dendrites,

synapses, and other excitable
membranes that utilize
Na+ channels as primary means
of action potential generation

Both sensory motor paralysis

Introduction and history

First agent used was cocaine,

in 1860 by Niemann

Cocaine was used for 30 yrs,

in spite of addiction liability

Procaine is without addiction

liability, was synthesized in 1905
Local anesthetics (LA) and used for 50 yrs

Lignocaine was produced in 1943 Short-acting e.g., Procaine, chlorprocaine

and is currently used

1. Injectable LAs Intermediate e.g., Lignocaine, prilocaine

e.g., Tetracaine, bupivacaine,

Classification Long-acting dibucaine, ropivacaine,
etidocaine

Lignocaine, cocaine,
2. Surface LAs tetracaine, benzocaine,
oxethazine

254
 Local anesthetics (LA) 255

28.2 CHEMISTRY AND MECHANISM OF ACTION

Are weak bases

Aromatic ring Ester linkage

Lipophilic —COO—
Intermediate chain
Amino group Amide linkage
Hydrophilic —NHCO—

Esters are liable to be

hydrolyzed by esterases

Hence esters are of short

duration and amides are
Chemistry long-acting Cocaine, procaine, tetracaine,
benzocaine, chlorprocaine
Esters
There is no “I” in prefix
to caine

L“I”gnocaine, bup“I”vacaine,
“I” is present in prefix to
Amides rop“I”vacaine, pr“I”locaine,
“caine”
et“I”docaine

LAs are weak bases, hence

they ionize in acidic medium

Thus there is low concentration

Infected tissues are acidic
of unionized LAs for action

Hence, they are less effective

in infected tissues

Penetrate through cell

membrane
Hence, impulse conduction slows
Prevents ↑ in
Na+ permeability
Rate of rise of action
potential reduces
↑ Threshold
for excitation
Amplitude of action
Block the generation and potential ↓
propagation of nerve
impulses
Generation of action potential
Blocks the voltage-gated Na blockade
Mechanism of action channels from inner side of
cell membrane
Hence autonomic fibers
Smaller fibers are blocked first are blocked first
they provide a larger
∴
surface area per unit volume Later, sensory fibers conducting
This is called
pain, temperature, touch,
“differential blockade”
Sensory and motor fibers pressure, vibration
are equally sensitive

Nonmyelinated more than

myelinated nerves ↑ Duration of action
by reducing absorption of LA
Adrenaline (1:1,00,000 to from site of administration
1:2,00,000) or phenylephrine
(1:20,000) due to
↓ Systemic side effects,
vasoconstriction
absorption is reduced
∴
256 Pharmacology mind maps for medical students and allied health professionals

28.3 ACTIONS, PHARMACOKINETICS, AND ADRs

Depress cortical inhibitory pathway,

hence there is unopposed excitation

Manifested as restlessness,
CNS
tremors, convulsions
Leading to
Stimulation is followed by CNS respiratory
Systemic actions are produced depending on its concentration depression depression,
leading to death
Actions

Affect the function of all organs where Myocardial depressant, arteriolar

conduction/transmission of impulses occur dilatation

e.g., CNS, CVS, autonomic ganglia, NMJ, smooth muscles ↓ Excitability, conduction rate and
CVS
force of contraction (similar to quinidine)
Hence
Rapidly absorbed from mucous membrane and abraded skin procainamide
Procaine is short-acting
is used as
Absorption depends on blood supply to that area antiarrhythmic
Pharmacokinetics

Thus, vasoconstrictions (adrenaline/ phenylephrine) Relaxes intestinal muscles

Smooth
↓ absorption
muscle
Relaxes bronchial muscles
Ester LAs are metabolized rapidly by plasma/liver
pseudocholinesterase

Amide LAs are metabolized by dealkylation in liver microsomes

Extensive first pass metabolism Hence are not effective orally

Depends on balance between absorption and metabolism

Metabolism reduces LAs systemic concentration Hence adverse events

Tissue binding reduces systemic concentration Hence toxicity

Manifested as rashes, dermatitis, asthma, rarely anaphylaxis

∴ They are metabolized
More common with esters
to PABA derivatives
PABA derivatives cause hypersensitivity

Rare with amide LAs

Hypersensitivity
Intradermal sensitivity should be done before giving LAs

Drugs to manage hypersensitivity, hence should be kept ready

Preservative methylparaben, too is responsible for hypersensitivity

Adverse effects

Preservative free LAs are now available

Dizziness

Auditory/visual disturbances

CNS Mental confusion

Anxiety, tremors, convulsion

Respiratory failure

Hypotension

Bradycardia
CVS
Arrhythmias

Rarely cardiac arrest

Pain at site of injection

Local
Delayed wound healing
 Local anesthetics (LA) 257

28.4 INDIVIDUAL AGENTS

Most commonly used

Rapid and long-acting

Used for all types of blocks

Onset of action 2–5 min

1. Lignocaine
Duration of action 30–45 min
4% topical solution
Causes drowsiness and mental clouding
2% jelly
Not used for corneal anesthesia,
as it can cause irritation
5% ointment
Availability
1% and 2% injection
More potent and longer acting
5% for spinal anesthesia
2. Bupivacaine More cardiotoxicity
10% spray
Levobupivacaine is less toxic

3. Ropivacaine Less toxic than bupivacaine

Used for epidural/regional/infilt

4. Etidocaine
ration anesthesia
Use is restricted to dental
5. Prilocaine
A. Injectable procedures
Hence has addiction
Causes euphoria
liability

Used as surface anesthetic

6. Cocaine It is a protoplasmic poison It cannot be injected

∴

Previously used as corneal

anesthetic
However, it causes conjunctival
Hence nowadays not used
vasoconstriction and corneal sloughing

Widely used in the past

Hence reduces action of

7. Procaine Metabolized to PABA
sulfonamides

Not useful as surface anesthetic

Individual agents
PABA derivative

8. Tetracaine (Amethocaine) Used on eye/spinal anesthesia

10 times more potent and toxic

Benoxinate, proparacaine
than procaine
B. LAs used only on eye
For tonometry

Dibucaine, pramoxine
C. LAs on skin and mucous
membrane For anal/genital pruritus, poison ivy
rashes, acute/chronic dermatoses

Benzocaine (PABA derivative)

For wounds and ulcerated surfaces

D. Poorly soluble LAs
For anesthetizing skin and
mucous membrane

Poorly water soluble Hence remains at site for longer time Hence is less toxic
258 Pharmacology mind maps for medical students and allied health professionals

28.5 USES OF LAs

Of eye, nose, mouth, tracheobronchial

Anesthesia of mucus membrane
tree, esophagus, genitourinary tract

Tetracaine 2%, lignocaine

2%–10% are commonly used

Phenylephrine combination ↑
duration and reduces systemic toxicity Tonometry, preoperative,
Eye
foreign body removal
Indications
1. Surface anesthesia Nasal lesions, stomatitis, sore throat,
tonsillectomy, endoscopies, intubation,
gastric ulcer, burns, proctoscopy

Combination of 2.5% lignocaine +

2.5% prilocaine

Combination has lower melting

point than single drug

Combination is emulsified and

Eutectic mixture
applied to intact skin

Administration of LA directly Occlusive dressing should be used

into skin, either superficial or deep
Used for venipuncture, skin graft harvesting
LA is combined with adrenaline

Combination should not be used

around end arteries to prevent Tip of fingers, toes, nose, ear, penis
necrosis/gangrene

Lignocaine, bupivacaine,
2. Infiltration anesthesia
prilocaine are used

Provides anesthesia without

Benefits
disturbing normal body functions

Drawbacks Systemic toxicity if large amounts are

Uses of LAs

used in major surgeries

Minor procedures like incision/

Use
drainage (I/D) of abscess, excision, etc.

Subcutaneous injection of LA
proximal to site of operation

Blocks nerve impulses distally

Forearm, lower limbs, scalp, anterior

3. Field block e.g.,
abdominal wall

Hence, knowledge of
neuroanatomy is important

Benefit Small dose results in larger area of anesthesia

Sensory cranial nerve (neuralgia)

Administration of LA in and around Cervical plexus (neck)

individual peripheral nerves
or nerve plexus
Brachial plexus (arm)
Small dose provides larger
4. Nerve block
region of anesthesia Radial/ulnar nerve (lower arm)

e.g., Facial/lingual nerve (neuralgia)

Inferior alveolar nerve (extraction of lower teeth)

Wrist/ankle (hand/foot)

Sciatic/femoral nerve (knee)

Intercostal nerve (anterior abdominal wall)

(Continued)
 Local anesthetics (LA) 259

28.5 USES OF LAs (Continued)

LA injected in subarachnoid
space between L2-3/L3-4
Drug acts on nerve roots,
below spinal cord
Lower abdomen, lower limbs
anesthetized and paralysed

Level of anesthesia altered by Volume of injection, specific gravity

of solution and posture of patient

Solution Hyperbaric, isobaric, hypobaric

Lignocaine, tetracaine, bupivacaine,

Agents used
ropivacaine

Sympathetic blockade

2 segments

Sensory blockade

2 segments
5. Spinal anesthesia
Motor blockade

Surgical procedures on lower

Uses abdomen, lower limb, pelvis, obstetric
procedures, caesarean section
Safe, good anesthesia, muscle
relaxation, no loss of consciousness
Benefits
Preferred over GA in patients with
cardio/pulmonary/renal diseases

Sepsis, meningitis

Headache Due to leakage of CSF

Hypotension and bradycardia Due to sympathetic blockade

which ↓ venous return
Complications
Due to hypotension and ischemia
of respiratory center
Respiratory paralysis
LA is injected into spinal Additionally paralysis of abdominal Hence accumulation of
extradural space muscles results in loss of cough reflex respiratory secretions and
respiratory infections
Technically it is more Results in loss of control over bowel
Cauda equina syndrome
difficult than SA and bladder sphincters
6. Epidural anesthesia
Sensory blockade is 4–5 segments
Large volume of LA required
higher than motor
Mother has painless labor but
∴
Benefits This difference is useful for
can still cooperate in process of labor
obstetric analgesia and is conscious
Meningeal coverings are not
∴
breached no chance of infection
Rubber bandage is tied over upper
extremity which exanguinates
(removes blood) from extremity

Rapid anesthesia of extremity Tourniquet applied to limb to

prevent re-entry of blood
Dilute LA injected intravenous in
Technique that extremity

This diffuses extravascularly

7. Intravenous regional Onset of action: 2 min

anesthesia (Biers’ block)
Used on extremity for ∴
Pain is produced by tourniquet
procedures less than 1 h
25% drug is absorbed into
systemic circulation
More commonly used for
upper limbs than legs/thighs
 29
Opioid analgesics

29.1 OPIOID ANALGESICS CLASSIFICATION

Relieve pain without loss

Opioid analgesics
of consciousness

Provide symptomatic relief

Analgesics without tackling the
cause of pain
Opioid/morphine type

Two categories of analgesics

Non-opioid/aspirin type

“Opus” – meaning juice

in Greek

Dark brown gummy exudate

from unripe seed capsule of
papaver somniferum

Morphine is a pure
Opium
opium alkaloid

“Morpheus,” is Greek
god of dreams

Opium contains nearly 20

alkaloids with various
agonists, partial agonists,
antagonist property
Natural Morphine, codeine

Agonists

Synthetic Pethidine, methadone

Classification of analgesics
based on activity
Antagonists Naloxone, naltrexone

Mixed agonists Pentazocine, buprenorphine,

antagonists butorphanol, nalorphine

Morphine, codeine,
Natural
noscapine

Classification based Heroin, pholcodeine,

Semisynthetic
on source oxymorphone

Pethidine, methadone, tramadol,

fentanyl, diphenoxylate,
Synthetic
dextropropoxyphene,
loperamide, ethoheptazine

260
 Opioid analgesics 261

29.2 MORPHINE AND MECHANISM OF ACTION

Endorphins,
3 endogenous
enkephalins,
opioid peptides
dynorphins

3 specific mu (µ), kappa (κ),

opioid receptors delta (δ)

Endogenous ligands
Endorphins
for µ receptors

Endogenous ligands
Enkephalins
for δ receptors

Endogenous ligands
Most important Dynorphins
for κ receptors
alkaloid
of opium
Morphine 4th new opioid Nociception (N)/
receptor has been orphanin FQ
Mechanism identified
of action

All are G-protein

coupled
receptors (GPCR)

Peri-aqueductal gray
Opioid receptors are area, substantia
abundant in gelatinosa,
and spinal cord ↓ Intracellular
cAMP
Stimulation of Inhibits adenylate
GPCR cyclase ↓ Release of neurotransmitters
↓ Intracellular involved in transmission of
Ca+2 pain (glutamate, GABA,
substance P, NA, DA, 5-HT)

↓ Ca+ entry into cells/

Also facilitates K+ ↓ Neurotransmitters
Hyperpolarization ↓ opening of Ca+
channel opening of pain
channels

Inhibit pain
transmission in
dorsal horn
ascending pathway
262 Pharmacology mind maps for medical students and allied health professionals

29.3 PHARMACOLOGICAL ACTIONS

Relieves pain without

loss of consciousness
Dull pain relieved
better than sharp pain

↑ Pain threshold
1. Analgesia
Changes both pain
perception and pain reaction

Alters emotional reaction to pain

Euphoria and sedation adds

to its analgesic effect
Feeling of well-being
Causes euphoria
Hence it is a
drug of abuse

Gives a highly pleasurable sensation “high”/“rush”/“kick”

Loss of rational thinking

Sees colorful daydreams

2. Euphoria, sedation
and hypnosis Induces drowsiness, calming effect

↓ Concentration

Feeling of detachment

Indifference to environment

May produce paradoxical

dysphoria in few
Produces significant
respiratory depression
Pharmacological
A. CNS
actions Depresses brain stem

Depresses rate, tidal volume

3. Respiration
Hence there is irregular
Alters respiratory rhythm
breathing
Inhibits neurogenic,
chemical, and hypoxic drive
Sedation and indifference contributes
to respiratory depression
Suppression of cough
4. Cough center
center reduces cough

Stimulates CTZ in medulla

Hence there is no
5. Nausea and vomiting
High doses inhibit vomiting in poisoning
vomiting center Hence emetics are not
Characteristic “pinpoint” recommended in poisoning
pupils in toxic doses
It stimulates Edinger -
∴
Westphal nucleus of 3rd cranial nerve
6. Pupils
Central effect produces miosis

But morphine eyedrops do not

produce miosis

7. Vagus Stimulation, hence there is bradycardia

Reduces body temperature

8. Miscellaneous
Toxic doses induce convulsions

(Continued)
 Opioid analgesics 263

29.3 PHARMACOLOGICAL ACTIONS (Continued)

Hypotension due to direct

arteriolar dilation and inhibition Standard dose
of baroreceptor reflexes

High dose depresses

vasomotor center
B. CVS
Release of histamine also
adds to hypotension

Postural hypotension
and fainting

Reduces GI motility, ↑ tone of

antrum and first part of duodenum

↑ Gastric emptying time

↓ Gastric secretion

Slows oral absorption

of drugs
C. GIT
↓ Intestinal
secretions and motility

Slows digestion of food

↑ Tone of sphincters

Inattention to Hence there is

defecation reflex severe constipation

Hence there is
Spasm of sphincter of Oddi
biliary colic

Colic reduced
↑ Biliary pressure
by atropine

↑ Ureteric tone and Relieved by opioid

amplitude of contractions antagonists
D. Other smooth
muscles
↑ Tone of sphincters

Esp. in elderly and

Hence there is urinary
Suppresses voiding reflex patients with
retention
prostatic enlargement

Hence causes It is unsafe

Releases histamine
bronchoconstriction in asthmatics

Hence ↓ concentration of
↓ Release of GNRH and CRF FSH, LH, ACTH,
β endorphins

E. Neuroendocrine
Tolerance on prolonged use
effects

Normalizes after stopping

264 Pharmacology mind maps for medical students and allied health professionals

29.4 PHARMACOKINETICS AND ADVERSE EFFECTS

Slow and incomplete oral

absorption

High first-pass
metabolism

20%–40% bioavailability

Pharmacokinetics Enterohepatic circulation

Metabolized by
glucoronide conjugation

Metabolite morphine-
6-glucoronide is more
potent than morphine
SC injections, rectal
Preparations suppositories,
transdermal patches

Nausea, vomiting

Dizziness, drowsiness

Constipation

Respiratory depression

Urinary retention

Hypotension
Adverse effects

Mental clouding,
confusion
Respiratory
depression
As it causes histamine
Allergic manifestations
release
Analgesia
Tolerance to following
effects
Sedation
No tolerance to
constipation and miosis
Euphoria
Cross-tolerance among
different opioids
Tolerance
Tolerance is
pharmacodynamic

Cells adapt at receptor level

∴ An addict requires
higher doses progressively
to achieve the same effect
 Opioid analgesics 265

29.5 DEPENDENCE

Lacrimation, sweating, rhinorrhea

Occurs due to its
euphoriant action Anxiety, restlessness, tremors
∴ Sudden cessation, or
both physical and Fever, abdominal colic, diarrhea
administration of opioid antagonist
psychological
causes withdrawal reactions
Severe sneezing, yawning
Manifested by
Mydriasis, hypertension,
palpitation

Severe dehydration

Withdrawal symptoms are Goose-flesh (pilomotor activity)

seen after 8–12 h resembling plucked turkey

Bone and muscle pain

Babies born to mothers who

were addicts before delivery
Withdrawal in neonates Irritability, crying, tremors,
suckling of fists, diarrhea,
Manifested as
sneezing,
yawning, vomiting, and fever

Effective orally

Long-acting
Gradual withdrawal of morphine
over many days
No kick
Substitution by oral methadone ∴
Slow release from tissues

Dependence
More potent

Hence there is no withdrawal

1 mg methadone for every 4 mg

Rx of addiction
of morphine (once daily)
Methadone dose depends on Methadone then gradually
severity of dependence tapered and withdrawn
Most addicts completely
withdrawn in about 10 days

Central α agonist
Clonidine
Reduces autonomic symptoms
Concomitant benzodiazepines of withdrawal
like diazepam at night Shallow breathing (respiratory
Could be accidental, homicidal depression)
or suicidal
Pinpoint pupils
Lethal dose – 250 mg
(in non-addicts)
Hypotension
Addicts can tolerate higher
amounts
Shock
Signs/symptoms
Cyanosis
Acute morphine
Hypothermia
poisoning
Flaccidity

Due to respiratory depression

Stupor–coma-death
and pulmonary edema

Positive pressure breathing

Maintain BP
Rx
Gastric lavage with
potassium permanganate
Naloxone (0.4–0.8 mg IV
Specific antidote
repeat every 10–15 min)
266 Pharmacology mind maps for medical students and allied health professionals

29.6 PRECAUTIONS AND CONTRAINDICATIONS

1. Respiratory dysfunction COPD, bronchial asthma

As they are prone for

2. Extremes of age
respiratory depression

i. It ↑ CSF, ∴ ↑ ICT

ii. There is marked respiratory

3. Head injury depression, which interferes
∴
with signs of head injury
Precautions and
contraindications
iii. Vomiting, miosis, mental
clouding interferes with
diagnosis and prognosis

Morphine ↓ BP
∴
4. Hypovolemic shock

5. Concomitant CNS
Interferes with diagnosis
depressants

6. Undiagnosed acute Induces vomiting and

abdomen as morphine is spasmogenic

Hence administer
morphine only after
confirmation of diagnosis
 Opioid analgesics 267

29.7 OTHER OPIOIDS

Converted to morphine
in body

Hence faster
1. Heroin Higher lipid solubility
euphoric effects

Higher abuse liability

Naturally occurring
opium alkaloid

Depresses cough center Hence used as

in sub-analgesic doses an antitussive

Less respiratory
2. Codeine
depression

10% codeine is
converted morphine

Constipation Very frequent

Naturally occurring
opium alkaloid

Hence it is used
No significant CNS effects,
3. Noscapine frequently as
except cough suppression
antitussive agent

Nausea is frequent

Other opioids Synthetic opioid

derivatives
4. Dextromethorphan,
pholcodeine
Centrally acting
antitussives

Synthetic codeine
analog
Hence used in
acute/chronic pain,
Effective analgesic
postoperative
pain, neuralgias

Weak opioid agonist

Also inhibits reuptake of

5. Tramadol noradrenaline and 5-HT
Drowsiness, dryness
of mouth, nausea,
ADRs
dependence,
precipitation of seizures
It has better oral Hence preferred
∴
Pain
efficacy, less spasmogenic over morphine

It causes less respiratory

∴
Use depression in neonate, and
Labor
There is no interference
Phenylpiperidine with uterine contractions
derivative of morphine Pre-anesthetic
6. Pethidine medication
Similar to morphine, but
some difference
268 Pharmacology mind maps for medical students and allied health professionals

29.8 PETHIDINE DERIVATIVES – FENTANYL

Pethidine congener

100 times more potent

than morphine as analgesic

Rapid acting (within 5 min)

∴it is highly lipid soluble

Causes less interference

with CV functions hence
preferred in CV surgeries

No ↑ in intracranial pressure

Does not release histamine

Available as transdermal
patch which acts for 48 h

Pethidine derivatives Fentanyl Combined with droperidol for

neuroleptanalgesia (Fixed Neuroleptonalgesia in
Dose Combination of 0.05 mg poor risk patients
fentanyl + 2.5 mg droperidol)

Epidural fentanyl for

postoperative and obstetrical
Use
analgesia (combined with
local anesthesia)

Chronic pain, where

opioids are recommended

Reduce by avoiding
Muscle rigidity
bolus dose

Adverse effects Nausea vomiting

Respiratory depression

e.g., Sufentanil, alfentanil

Congeners of fentanyl
Hence they are
Faster acting (1 min)
preferred for short
and has a rapid recovery
surgical procedures
 Opioid analgesics 269

29.9 METHADONE, DEXTROPROPOXYPHENE, AND ETHOHEPTAZINE

Synthetic opioid derivative

Effective analgesic

Effective orally

90% plasma protein

binding
Hence it has a
slow release
Gradual accumulation
is tissue Hence, it causes milder
withdrawal reactions
Methadone following discontinuation
Less incidence
of euphoria

Slow development
of tolerance

Hence it is beneficial to
Long duration of action
manage morphine
(t½ 24–36 h)
withdrawal symptoms

Substitution therapy
in opioid addicts

Opioid maintainance
Uses
Analgesic
A methadone
Congener of methadone
derivative
LAAM (L-α–acetyl–
methadone) Hence administered
Longer acting and Longer acting than
thrice a week in
orally efficacious methadone
opioid addicts

Less constipation
Dextropropoxyphene

Abuse liability

Large doses cause

CNS stimulation

Used in mild to Usually in combination

moderate pain with aspirin/paracetamol

Related to pethidine

Mild analgesic
Ethoheptazine
Less addiction liability

Used in combination
with NSAIDs
270 Pharmacology mind maps for medical students and allied health professionals

29.10 USES OF MORPHINE AND CONGENERS

IM/SC, tablet (ethylmorphine)

Most potent analgesic

Provides symptomatic relief

It ↓ reflex
∴
Myocardial infarction It ↓ pain, anxiety sympathetic
stimulation
To relieve spasm of
Renal and biliary colic Along with atropine
sphincter of Oddi

Segmental block
in spinal cord
∴ There is no
interference with motor
autonomic functions
1. Analgesic Epidural analgesia
No systemic side effects

Small dose required

Pethidine is preferred
Obstetric analgesia
to morphine

Cancer pain Terminal stages

Fractures, burns, pulmonary

embolism, spontaneous
pneumothorax, postoperative pain
Uses of morphine
and congeners
Should not be used for chronic
pain as it can cause addiction
Intraspinal infusion, rectal,
Other routes of transmucosal, transdermal,
administration inhalation, patient
controlled analgesia (PCA)
Pethidine is preferred
over morphine

∴ It allays anxiety

Affords analgesia Respiratory depression

2. Pre-anesthetic
medication
Reduces anesthetic dose Vasomotor depression

Provides smoother induction Bronchospasm

Drawbacks Vomiting

Constipation

Urinary retention

Interferes with pupillary ∴

It produces miosis
response to anesthesia

(Continued)
 Opioid analgesics 271

29.10 USES OF MORPHINE AND CONGENERS (Continued)

Reduces anxiety and reflex

Hence ↓ work on heart
sympathetic stimulation
Relieves dyspnea and
pulmonary edema

Mechanism unclear, however

3. Acute left
there are
ventricular failure
the following hypotheses Hence there is shunting
↓ Peripheral resistance of blood from pulmonary
However, morphine is to systemic circulation
contraindicated in pulmonary
edema due to
respiratory irritants Changes patient
perception to reduced
pulmonary function

Provides symptomatic
4. Diarrhea Diphenoxylate, loperamide
relief

5. Cough Codeine, noscapine

↓ Anxiety in threatened
6. Sedative abortion without affecting
uterine contractions

High-dose IV morphine

Neuroleptanalgesia
7. Special anesthesia neuroleptanesthesia
(fentanyl + droperidol)

Epidural morphine for

postoperative and
chronic pain
272 Pharmacology mind maps for medical students and allied health professionals

29.11 MIXED AGONISTS AND ANTAGONISTS

K receptor agonist, weak

µ–receptor antagonist

Similar to morphine

20 mg morphine = 10 mg
pentazocine
Low dose causes euphoria,
high dose causes dysphoria
Less respiratory
depression and sedation
1. Pentazocine Less constipation and
biliary spasm

It ↑ BP and heart rate Hence cannot be used in MI

As it has less
Postoperative and chronic pain
abuse liability
Use
Given both orally and parenterally
Tolerance, dependence on
long-term use
Sweating nausea, dysphoria, anxiety,
Adverse effects
nightmares, hallucinations
More potent than
pentazocine
Produces respiratory
depression
2. Nalbuphine
Dysphoria can occur
at higher doses

Used as analgesic

Synthetic thebaine congener

Highly lipid soluble

Mixed agonists and

antagonists Partial μ agonist

25 times more potent

than morphine
Slow onset, long duration
3. Buprenorphine of action
Less respiratory depression,
tolerance and dependence

Mild withdrawal symptoms

Maintenance drug in
opioid addicts
Use
Terminal cancer pain

Administration SC/IM/sublingual

Agonist–Antagonist
∴ It is a K agonist and produces
dysphoria even at low doses
4. Nalorphine
Respiratory depression Hence it cannot be
even at low doses used as analgesic
At high doses, Hence it is used in acute morphine
it acts as antagonist poisoning diagnosis of opioid addiction
Short-acting analgesic, causes Hence it is used for
5. Meptazinol
less respiratory depression obstetric analgesia
 Opioid analgesics 273

29.12 OPIOID ANTAGONISTS

Competitive
antagonist to all
opioid receptors

Pure antagonist

No actions in
normal individuals

However, it antagonizes
all actions of morphine
in addicts

1. Naloxone Also antagonizes Endorphins,

actions of endopenous enkephalins,
opioids dynorphins

∴ It has high first-

Administered IV pass metabolism,
duration 3–4 h

Morphine poisoning

Reverse neonatal
asphyxia due to opioid
use during labor
Uses
∴ It precipitates
Diagnosis of opioid
withdrawal
dependence
symptoms
Pure opioid
Opioid
antagonist
antagonists Stress induced
hypotension/
shock reversal
More potent than
naloxone

2. Naltrexone Effective orally

Longer duration of
action (1–2 days)
Opioid blockade
therapy in post
opioid addict
Uses

Alcohol dependence
Effective orally and
3. Nalmefane
long-acting
 30
CNS stimulants/drugs of abuse

30.1 CNS STIMULANTS – CLASSIFICATION AND RESPIRATORY STIMULANTS

1. Respiratory
Doxapram, nikethamide
stimulants

2. Psychomotor Amphetamine, cocaine,

CNS stimulants Classification
stimulants methylxanthines

3. Convulsants Leptazol, strychnine

Stimulate respiration

Used for
respiratory failure

Provide temporary relief,

however ∴ is no
reduction in mortality

Low therapeutic index

Acts mainly on brain

stem and spinal cord
Precipitates convulsions

1. Respiratory Also called Stimulates medullary

stimulants analeptics Availability of ventilators respiratory and
has reduced vasomotor center
the need for analeptics

Administered via
IV infusion
Doxapram

Cough, restlessness,
muscle twitching,
ADR
hypertension, tachycardia,
arrhythmias, convulsions

Acute respiratory
failure

Uses
Apnea in premature
infants not responding to
theophylline
Not used as it causes
Nikethamide
convulsions

274
 CNS stimulants/drugs of abuse 275

30.2 PSYCHOMOTOR STIMULANTS/METHYLXANTHINES – ACTIONS

Amphetamine –
sympathomimetic
agent (see CNS stimulant
ANS – under
adrenergic drugs)
Caffeine and
Cocaine Euphoriant theophylline
are CNS stimulants

Drug of abuse
↑ Mental
(see local
alertness
anesthetics)

Caffeine,
Naturally occurring
theophylline, ↓ Fatigue
2. Psychomotor xanthine alkaloids
theobromine
stimulants

Coffee contains Produces sense of

1. CNS
caffeine well-being

Tea contains
theophylline and ↑ Motor activity
caffeine

Cocoa contains Stimulates

caffeine and respiration
theobromine
Methylxanthines Nervousness,
restlessness, irritability,
Overdose insomnia, excitement,
headache, convulsions
(very high dose)

↑ Force of
contraction

↑ Heart rate

↑ Cardiac
2. CVS
output
Actions

Also causes Hence

peripheral Hence reduces BP inconsistent/variable
vasodilation effect on BP

Cerebral
vasoconstriction
(caffeine)

3. Kidneys Diuretic action

↑ Power of
contraction
4. Smooth
muscle ↑ Work capacity
(central + peripheral
actions)

↑ Gastric
acid and pepsin
secretion
5. GIT
Hence causes
gastric irritation
276 Pharmacology mind maps for medical students and allied health professionals

30.3 METHYLXANTHINES – PHARMACOKINETICS, ADVERSE EFFECTS, AND USES

Good oral absorption

Wide distribution

Pharmacokinetics

t½ 7–12 h

Due to saturation of
↑ t½ at higher dose
metabolism enzymes

Insomnia, nervousness,
tremors, tachycardia, headache,
arrhythmias, gastritis, nausea,
vomiting, epigastric pain, diuresis

High dose can produce

Adverse effects
convulsions

Tolerance on long-term use

∴ Caffeine causes cerebral

vasoconstriction

i. Headache
Hence caffeine combined
Caffeine is combined with
with ergotamine for migraine
aspirin/paracetamol
headache

ii. Bronchial asthma Theophylline

Uses

Prolonged apnea
(>15–20 s) can lead to
neurologic damage/other
tissue damage

iii. Apnea of premature Caffeine/theophylline used

infants orally/IV

Used for 1–3 wks,

↓ duration of episodes
 CNS stimulants/drugs of abuse 277

30.4 NOOTROPICS

They enhance cognition,

Improves learning and
improve memory, and
memory
cognition

Protects cerebral cortex

Piracetam
from hypoxia

Inhibits platelet
aggregation (high dose)

Insomnia, nervousness,
ADR
depression, weight-gain
Nootropics

Dementia

Alzheimer’s disease

Behavioral disorders in
children
Use

Learning difficulty

Stroke

Cerebrovascular
accidents
278 Pharmacology mind maps for medical students and allied health professionals

30.5 DRUGS OF ABUSE – OPIOIDS, CNS STIMULANTS, AND CNS DEPRESSANTS

Used for recreational

purpose/pleasurable effects

Associated with dependence

(addiction)

Cause either physical or

Drugs of abuse
psychological dependence
Morphine, heroin, pethidine
Lead to withdrawal symptoms
1. Opioids
on abrupt stoppage
Amphetamine, methylphenidate,
cocaine, caffeine, nicotine
Drugs of dependence
Alcohol, barbiturates,
2. CNS depressants
benzodiazepine, methaqualone
(Drugs not discussed here, are
1. Opioids
in their respective chapters) LSD, phencyclidine (PCP), mescaline,
3. Hallucinogens cannabinoids, dimethyltryptamine, (DMT),
diethytryptamine (DET), psilocybin
Cocaine, amphetamine, and their
Long-term use can lead to
analogs methamphetamine,
personality changes,
methylphenidate, methylene dioxy
paranoia, psychosis
methamphetamine (MDMA – “ecstasy”)
Dependence on long-term
Caffeine use and withdrawal on
abrupt discontinuation

Is an alkaloid
smoked in cigarettes
Nicotine
Also used as nasal
snuff and chewing
2. CNS stimulants
Chemically related
to amphetamine

Releases intracellular
catecholamine

Additionally directly
stimulates
adrenergic receptors

Methylphenidate ↑ Attention and alertness

Reduces fatigue, irritability,

and appetite (anorectic)

Causes insomnia

Can lead to convulsions

(in high dose)

e.g., Barbiturates,
benzodiazepines,
meprobamate
Sedative-hypnotics
Euphoriants, and anxiolytic Hence they are abused

3. CNS depressants
Most common and oldest
substance of abuse
Ethanol
Withdrawal symptoms seen
in chronic alcoholics
following sudden stoppage

30.6 HALLUCINOGENS
Psychogenic drugs causing psychosis
Also termed as psychomimetics,
psychodelics, or psychodysleptics
LSD (lysergic acid diethylamide),
PCP (phencyclidine), mescaline
LSD
4. Hallucinogens
PCP
Mescaline
CNS stimulants/drugs of abuse 279
Very potent
20–30 mg causes euphoria, visual illusion,
altered perception, impaired judgement,
impaired thinking, altered mood,
emotional outbursts
Feeling of detachment
Sympathetic stimulation causes anxiety,
tremors
Duration of action 8–12 h
Abused either orally or parenterally
CNS stimulation
Auditory hallucination
Dissociative feeling (ketamine-like,
ketamine is a PCP analog)
Sweating, tachycardia, hypertension,
nystagmus
Overdose is fatal
Obtained from cactus
Effects are like LSD
Rapid tolerance, even after 3–4 doses
Dependence is not seen
280 Pharmacology mind maps for medical students and allied health professionals

30.7 CANNABINOIDS AND DRUGS FOR TOBACCO WITHDRAWAL

Hemp plant
Source
(Cannabis sativa)

Produces euphoria,
uncontrolled
laughing, relaxation, dreamy
status, drowsiness, ↓
motor coordination
Obtained from dried
i. Marijuana leaves and flowering
heads of plant

Obtained from dried

ii. Hashish or charas solid, black resinous
substance from plant

Dried female
5. Cannabinoids iii. Ganja
inflorescence
Acts on cannabinoid
(CB) receptors in CNS
All the above three are
smoked
Endogenous substance
Anandamide binds to
Obtained from dried cannabinoid receptors
iv. Bhang leaves of cannabis and
is consumed orally
Causes tachycardia

Inter-individual
variability in response
Causes vasodilation Hence ∴ is
Tetrahydrocannabinoid conjunctival redness
Mechanism of
(THC) is active constituent
action/pharmacological
of cannabis responsible
actions
for effects Produces
Chronic marijuana bronchodilation
smokers develop
bronchitis, precancerous
lesions in lungs,
precipitation of angina ↓ Intraocular pressure

As patch, spray,
Nicotine
chewing gum, lozenges
Has analgesic effect

Weak DA reuptake
Bupropion
inhibitor
Has antiemetic property
(dronabinole)
6. Drugs for tobacco Cannabinoid (CB) receptor
withdrawal antagonist
Rimonabant
Also used as appetite
suppressant
(anorexiant) in obesity

Nicotinic (Nn) receptor

Varenidine
partial agonist
 V
Part    

Autacoid pharmacology

Autacoids, histamine and antihistaminics
31.1 AUTACOIDS – INTRODUCTION, CLASSIFICATION OF AUTACOIDS
AND HISTAMINE
Word “autacoid” is derived
from greek word
Formed in various tissues
Have diverse physiological
and pathological roles
Introduction
Synthesized and act
locally
Hence they are called
local hormones
e.g.,
Autacoids
Biogenic amine, tissue
amine (histos = tissue)
Present in many animal
and plant tissues
Histamine
Also present in venoms
and stings
Synthesis, storage,
distribution, and metabolism
present in brain, serves as
deamination and methylation
282
31
“Autos” meaning self and
“akos” meaning remedy
Histamine
Amine autacoids
5-HT
Angiotensin
Peptide autacoids
Kinins
Prostaglandins
Phospholipid-derived
Leukotrienes
autacoids
Synthesized by
Platelet activating factor
decarboxylation of
(PAF)
amino acid histidine
Stored in mast cells and
basophils
Present in lungs, skin
intestines, and liver
Non-mast cell histamine
neurotransmitter
Metabolized by
to inactive compounds
 Autacoids, histamine and antihistaminics 283

31.2 MECHANISM OF ACTION AND HISTAMINE RELEASERS

Present in smooth muscle, blood vessels

Acts on 4 subtypes of histamine

Endothelium, lungs, brain
receptors

H1 ↑ Ca+2

Smooth muscle contraction

↑ Capillary permeability

Stomach (gastric glands, parietal cells)

H2 ↑ cAMP
Mechanism of action
↑ Gastric acid secretion

Presynaptic autoreceptors

H3 ↓ cAMP

↓ Histamine levels in brain, skin,

lungs, gastric mucosa

Eosinophils, neutrophils, CD4 cells

H4 ↓ cAMP

Ag:Ab reaction Chemotaxis, cytokine secretion

Insect stings, venoms

Seafood (crabs, fish)

Histamine releasers Morphine
Cold temperature
d-Tubocurarine
Bile salts
Quinine
Drugs
Dextran

Radiocontrast media

Vancomycin, etc.
284 Pharmacology mind maps for medical students and allied health professionals

31.3 ACTIONS, USES, AND ADRs

Dilates small blood vessels

causing hypotension and
reflex tachycardia Flush-red spot at site Due to local capillary
dilation

Dilates cerebral blood vessels

CVS
causing throbbing headache
Surrounding the flush

Flare
Triple response
(on intradermal injection)
Due to arteriolar dilation

Local edema

Contraction of non-vascular Wheal

smooth muscle
Smooth muscle Due to extravasation of
capillary fluid
Hence leads to
No significant effect on
bronchospasm,
uterus in humans
↑ GI motility
Actions
↑ Gastric acid
secretion (H2 receptor)
Glands

↑ Pepsin and
intrinsic factor

Functions as
neurotransmitter
CNS
Hence antihistamines
Maintains wakefulness
produce sedation/drowsiness

Hence causes pain

Stimulates sensory nerve
Nerve endings and itching
endings
(esp. healing wounds)

Histamine no valid Testing gastric acid secretion

clinical use

However was used occasionally Diagnosis of

Uses
in some diagnostic tests pheochromocytoma

Betahistine, a histamine analog

(H2 agonist), used orally to treat Test bronchial hyper
vertigo in Meniere disease reactivity

Hypotension, flushing,
tachycardia, headache

Wheal

ADRs

Bronchospasm

Diarrhea
 Autacoids, histamine and antihistaminics 285

31.4 ANTIHISTAMINES – CLASSIFICATION AND PHARMACOLOGICAL ACTIONS

Competitively block
H1 receptors

Antagonize the effects

of histamine Diphenhydramine,
Sedative dimenhydrinate,
Histamine (agonist) → H1 promethazine
receptors ← antihistamines 1st generation
(antagonists) Chlorpheniramine,
Less sedative pheniramine,
Classification meclizine, buclizine

Cetirizine, levocetirizine, terfenadine,

2nd generation loratadine, desloratadine,
fexofenadine, azelastine

Blocks action of histamine Blocks effects on GIT, bronchi,

on H1 receptors blood vessels, and triple response

Nausea and vomiting due to

Antihistamines

motion sickness
Antimotion sickness
Vomiting of pregnancy; i.e., morning
sickness (doxylamine)

↓ Tremors, rigidity, and sialorrhea

Antiparkinsonian
Probably due to anticholinergic effects
effects

Only early and mild cases respond

Responsible for both beneficial

and side effects

Hence used in rhinorrhea, sialorrhea

(antisecretory effects)
Anticholinergic effects
Also causes urinary retention,
Pharmacological actions constipation, and dryness of mouth
(antisecretory action)

2nd-generation antihistamines have

minimal anticholinergic property

Due to CNS depression (histamine in

brain is involved in wakefulness)

Reduces concentration,
coordination
Sedation
Alcohol and other CNS depressants
potentiate this action

2nd generation have no/less

sedation

Hence have local

Block sodium channels in
anesthetic property
high doses
(not used clinically)

Hence can cause

arrhythmias Erythromycin,
Block potassium channels ketoconazole, etc.
Esp. when given
with enzyme
Miscellaneous inhibitors like Hence terfenadine,
Some agents also block α1 and astemizole are
5-HT receptors banned
Hence reverses
Chlorpheramine inhibits
resistance in
P-glycoprotein
cancer cells
Reduces resistance in
chloroquine-resistant malaria
286 Pharmacology mind maps for medical students and allied health professionals

31.5 ADVERSE EFFECTS, DRUG INTERACTIONS, AND SECOND-GENERATION

ANTIHISTAMINICS

Sedation, muscle incoordination,

Due to CNS depression
difficulty in concentration
Adverse effects
Dry mouth, blurring of vision, urinary retention, Due to anticholinergic
constipation actions

Alcohol, barbiturates, benzodiazepine,

Potentiate action
antidepressants

Terfenadine, astemizole + enzyme inhibitors

Drug interactions Can cause arrhythmias
(erythromycin, ketoconazole, grapefruit)

Anticholinergics ↑ antimuscarinic effects

e.g., Cetirizine, levocetirizine, loratadine,

desloratadine, fexofenadine

Highly selective for H1 receptors

Do not cross BBB, hence less/no

sedation or drowsiness

No psychomotor impairment

Do not have anticholinergic property

No antiemetic action

Uses are limited to allergic disorders

Not effective in motion sickness,

cough, rhinorrhea
Second-generation
antihistaminics
More expensive
With terfenadine and
astemizole
Cardiac arrhythmias, esp. torsades de
pointes can occur
Potentiated by enzyme Erythromycin,
inhibitors like ketoconazole, etc.
Loratadine has longer duration of action

Desloratadine Metabolite of loratadine

Hydroxyzine An antipruritic

Cetirizine Metabolite of hydroxyzine

Metabolite of terfenadine

Fewer chances of QTc

Fexofenadine
prolongation

Long duration of action

 Autacoids, histamine and antihistaminics 287

31.6 USES OF ANTIHISTAMINICS

Prevention and treatment of symptoms

Allergic rhinitis, allergic conjunctivitis, hayfever,

1. Allergic disorders
urticaria, pruritus, pollinosis, allergic skin disorders
Other mediators are involved
Not useful in bronchial asthma
Additionally they make Hence difficult
mucus thick to cough
Reduce rhinorrhea (antisecretory effect)

Produces drowsiness
2. Common cold
Provide only symptomatic relief

∴ They have no
2nd-generation agents are ineffective
anticholinergic action

By ↓ postnasal drip
3. Cough
However, not effective in productive It causes thickening of
∴
cough mucus, difficulty in expectoration

Drug-induced nausea/vomiting

Postoperative nausea/vomiting Promethazine

4. Antiemetic
Chemotherapy-induced nausea/vomiting Promethazine

Pregnancy-induced nausea/vomiting Doxylamine

Uses of antihistaminics

Promethazine is used
5. Preanesthetic
medication
Due to sedative, anticholinergic, and
antiemetic action

Used due to
Diphenhydramine, promethazine
anticholinergic property

6. Parkinsonism Early and mild cases benefit

Reduces sialorrhea, rigidity, tremors

7. Motion sickness Promethazine, meclizine, cyclizine

Caused due to antipsychotic drugs

8. Dystonia
Drugs with prominent anticholinergic
activity like promethazine are beneficial

Cinnarizine, meclizine, dimenhydrinate

9. Vertigo
Vertigo of Meniere disease and other
vestibular disturbances

Induces sleep, esp. in children for

minor surgical procedures
10. Sedative and
hypnotic
Hydroxyzine is an anxiolytic
288 Pharmacology mind maps for medical students and allied health professionals

31.7 DRUGS FOR VERTIGO

Cinnarizine,
promethazine
H1 blockers
↓ Entry of
calcium in vestibular Hence reduces vertigo
cells

Anticholinergics Hyoscine

Vetigo is sensation of rotation Phenothiazines Prochlorperazine

or movement of one’s self
or surrounding in any plane
Drugs for vertigo
H1 analog Betahistine
Drugs

Furosemide, thiazides,
Diuretics
acetazolamide

Benzodiazepines Diazepam

Tricyclic antidepressants Amitriptyline

Glucocorticoids
 32
5-Hydroxytryptamine agonists and antagonists
and drug treatment of migraine

32.1 5-HYDROXYTRYPTAMINE – INTRODUCTION

5-HT is also called serotonin

Important neurotransmitter

Widely distributed in plants and

animals (banana, pineapple,
wasp, scorpion sting)

In humans, 90% is present in

intestines, rest in platelets and
brain

Synthesized from amino acid

tryptophan

Introduction

Stored in serotonergic neurons

Stored in enterochromaffin
cells of GI mucosa

Released into serotonergic

synapses

Reuptake in serotonergic
neurons, by serotonergic
transporter, SERT

Degraded primarily by MAO

289
290 Pharmacology mind maps for medical students and allied health professionals

32.2 5-HT RECEPTORS

4 types with further Present in brain,

subtypes cranial blood vessels

5-HT 1,2,4–7 are GPCR They are autoreceptors

5-HT3 is ligand-gated ↓ 5-HT release from nerve endings,

ion channels reduces release of peptides

Causes constriction of cranial

5-HT1
blood vessels

5-HT1a partial agonist Buspirone

5-HT1b/d agonist Triptans

Partial agonist/antagonist at
Ergotamine
all subtypes of 5-HT1 receptors

Present in platelets, 5-HT2a present in cerebral

Activation of neurons
causes aggregation cortex

Present in smooth muscle 5-HT2b present in stomach

Contraction
causes contraction fundus
5-HT receptors

5-HT2c present in choroid Production of CSF

5-HT2

5-HT2a antagonist Ketanserin/cyproheptadine

5-HT2a/2c antagonist Methysergide

5-HT2a antagonist Atypical antipsychotics

Present in CTZ, NTS (nucleus tractus

solitarius), parasympathetic
nerve terminals (GIT)

5-HT3 Causes vomiting and peristalsis

5-HT3 antagonists Ondansetron, granisetron

Present in GIT, CNS

5-HT4 Induces peristalsis

Metoclopramide, cisapride,
5-HT4 agonists
tegaserod
 5-Hydroxytryptamine agonists and antagonists and drug treatment of migraine 291

32.3 5-HT AGONISTS

5-HT1B/1D agonist

Useful in acute migraine

and cluster headaches
(first-line Rx)

Reduces release of
vasodilator peptides

Constricts cerebral blood

vessels

↓ Stretching of
pain nerve endings

Route of administration Oral/SC

↓ Nausea and
vomiting of migraine also

Bioavailability about 14%

1. Sumatriptan t½–2 h

Chest discomfort, dizziness,

ADRs
neck pain

Contraindications Coronary artery disease

Zolmitriptan, almotriptan,
Other triptans frovatriptan

5-HT1a agonist/antagonist
Buspirone
Antianxiety agent

Prokinetic agent
Cisapride/metaclopramide
5-HT4 agonist

5-HT4 agonist
2. Other agonists
Tegaserod
Used in irritable bowel
syndrome

e.g., Fluoxetine, sertraline,

citalopram, escitalopram
Selective serotonin
reuptake inhibitors (SSRIs)
Used in treatment of
depression

Is an appetite suppressant,
Dexfenfluramine
used in obesity
292 Pharmacology mind maps for medical students and allied health professionals

32.4 5-HT ANTAGONISTS

Blocks 5-HT2, H1 histamine and

Carcinoid tumors
cholinergic receptors

↓ Appetite, promotes
Serotonin syndrome
weight gain

Postgastrectomy dumping
Other uses
syndrome

Pruritus

1. Cyproheptadine

Seasonal allergy

Sedation

Drowsiness

ADRs Dizziness

Blocks 5-HT2 receptor, also

Ataxia
α1 receptor

Causes vasoconstriction and

Dryness of mouth
platelet aggregation
2. Ketanserin
5-HT antagonists
Used in hypertension

Selective 5-HT2 blocker

Retanserin

No α1 blocking effect
5-HT3 antagonist

3. Ondansetron Used in prevention and

treatment of chemotherapy/
radiation-induced nausea
and vomiting

Blocks 5-HT2A/2C receptors

4. Clozapine

Atypical antipsychotic

Antihistamines,
5. Miscellaneous phenoxybenzamine
(non-selective α blocker)
 5-Hydroxytryptamine agonists and antagonists and drug treatment of migraine 293

32.5 ERGOT ALKALOIDS

Produced by fungus Claviceps

purpurea, that infects rye, Ergotism
millet, and other grains

Consumption leads to Gangrene of hands and feet

Isolated by Dale and Barger

Hallucinations
in 1906

Ergometrine, ergotamine,
Natural
ergotoxine
Classification
Dihydroergotamine,
Semisynthetic
bromocriptine
Partial agonists, agonist,
antagonists at 5-HT and
α adrenergic receptors

Antagonist at CNS dopamine

receptors

Hence they have complex

actions
Actions
Lysergic acid diethylamide
Cause hallucinations
(LSD)

Stimulate uterine muscles Hence used in PPH

Constrict vascular smooth

Hence leads to gangrene
Ergot alkaloids muscles

Nausea, vomiting, and diarrhea

(common)

Gangrene

Retroperitoneal/mediastinal
ADRs
fibrosis (methysergide)

Parkinsonism Bromocriptine (D2 agonist)

Galactorrhea Bromocriptine (D2 agonist)

Ergotamine (oral/SL, rectal)

migraine
Dihydroergotamine
Uses (oral/IM/SC)

Postpartum hemorrhage
Ergometine (IM/IV)
(PPH)

IHD

HT
Contraindications
Peripheral vascular disease
(PVD)

Renal disease
294 Pharmacology mind maps for medical students and allied health professionals
32.6 DRUG TREATMENT OF MIGRAINE
Common disorder
Signs/symptoms
Triggers
Release of vasoactive
Food (chocolate, cheese)
peptides from nerve endings
Calcitonin – gene related
protein (CGRP) is a powerful
Hormonal imbalances
vasodilator which
is also released
Exact pathophysiology –
unclear
Drug treatment
Treatment of acute attack Sumatriptan/ergotamine
of migraine
If patient has 2–3 attacks/
Migraine prophylaxis
Severe, throbbing,
unilateral headache
associated nausea,
vomiting, giddiness
Brief “aura” or premonitory
Classical migraine symptoms of visual
disturbances (photophobia)
Stress
Anxiety
Excitement
Paracetamol, aspirin Mild attack
Analgesics
Moderate to severe attack
Ibuprofen, diclofenec,
naproxen,
mefanamic acid
Caffeine enhances NSAID
absorption
Severe attack with
antiemetics
(metoclopramide)
is given for
Is short-acting Repeat dose if
Sumatriptan
(as t½ is 2 h), is given SC pain recurs
Administered either
orally, SL, or rectally
Ergotamine
Effective alternative
to triptans
Propranolol reduces
frequency and severity
of attack
month and are severe MOA – unclear
1. β blockers Dose – 40 mg BD
160 mg BD (maximum)
Most commonly used
2. Calcium channel Flunarizine, as it is
blockers CNS selective
Sodium valproate,
3. Anticonvulsants
gabapentin, topiramate
Tricyclic antidepressants
like amitriptyline
4. Antidepressants Only as an alternative
Used in patients with
comorbid depression
Methysergide
(5-HT antagonist)
Cyproheptadine
5. Miscellaneous
(5-HT + H1 antagonist)
Used only as alternative
 33
Eicosanoids and leukotrienes

33.1 EICOSANOIDS – INTRODUCTION AND SYNTHESIS

“Eicosa” in greek
means 20

These are 20 carbon

unsaturated fatty acids
Introduction Prostaglandins (PGs)
Synthesized mostly from
arachidonic acid of cell
membrane
Prostacyclin (PGIs)

e.g.,

Eicosanoids Thromboxanes (TX)

Locally from arachidonic
acid
Leukotrienes (LT)
Cyclooxygenase (COX)
synthesize PGs and TX
Synthesis
Lipoxygenase (LOX)
COX 1 and COX 2
synthesize LTs

2 COX subtypes COX 1 Has a physiological

role

COX 2 Has a pathological Induced by

role inflammation

295
296 Pharmacology mind maps for medical students and allied health professionals

33.2 PROSTAGLANDINS AND THROMBOXANES – MECHANISM OF ACTION

AND ACTIONS

Substance present in prostate/human semen

which contracts uterine smooth muscle

Hence are called “prostaglandin”

Act via prostanoid receptors
However, it was later found that it is
present in many tissues with varied roles
They are GPCR
DP for PGD2: DP1 and DP2
Mechanism of action
Some act via cAMP, some
through IP3 pathway EP for PGE2: EP1-4

There are 5 types of receptors FP for PGF2

IP for PGI2

TP for TXA2

Stimulate GI smooth muscles Hence there is colic and diarrhea

Prostaglandins and

1. GIT
thromboxanes

PGE2 ↓ acid secretion, ↑ mucus production Hence are cytoprotective

PGI2 and PGE2 causes vasodilatation

PGE2 and PGI2 produced in ducts Hence maintain patency during

arteriosus in fetal life this period
2. CVS
TXA2 causes vasoconstriction

PGF2α constricts pulmonary veins

PGI2 inhibits platelet aggregation

3. Platelets
TXA2 induces platelet aggregation Inhibited by low-dose aspirin

PGE2 and PGF2α

Hence used in mid-trimester
Contracts pregnant uterus abortion, missed abortion,
hydatiform mole
Induces labor at term
Actions 4. Uterus
Promotes cervical ripening

Controls PPH (15 methy PGF2α/ carboprost)

Also play a role in dysmenorrhea

and menorrhagia

PGs present in prostate, seminal

5. Male vesicle, and testes
reproductive system
PGs in semen facilitate movement
of sperms, coordinate fertilization

PGE and PGF2α reduces intraocular tension

6. Eye
(IOT) by improving drainage of aqueous humor

PGE2 and PGI2

Causes renal vasodilation Hence is a diuretic

Opposes ADH action

Regulates renal function during impairment

7. Kidneys
Maintains BP

Regulate Na/H2O excretion

Releases renin

Hence long-term use leads

NSAIDs inhibits PG synthesis
to renal impairment

(Continued)
 Eicosanoids and leukotrienes 297

33.2 PROSTAGLANDINS AND THROMBOXANES – MECHANISM OF ACTION

AND ACTIONS (Continued)

↑ Blood flow in inflamed tissue

8. Inflammation Enhances leucocyte infiltration

hence causing edema

↓ Lymphocyte activity, proliferation,

and cytokine release, hence
inhibits immunological response

↑ Body temperature

Promotes sleep (PGD2)

9. CNS
Sensitizes sensory nerve endings
to pain

↓ Release of noradrenaline

Relaxes bronchial muscle

(PGE2 and PGI2)

10. Respiratory system Constricts bronchial muscle

(PGF2α and TXA2)

Implicated in bronchial asthma

11. Bone Cause bone formation and resorption

↑ Release of insulin
growth hormone and steroids
12. Endocrine system

Thyrotropin-like effects on thyroid

PGE2–pro-oncogenic

13. Cancer

NSAIDs use reduces tumor

298 Pharmacology mind maps for medical students and allied health professionals

33.3 ADR

Diarrhea

Abdominal pain, uterine, and

GI contraction
ADRs

Fever

Hypotension

33.4 USES

PGE2 (dinoprostone) vaginal

Induction of labor
tab/pessary

PGE2 (dinoprostone) vaginal

tab/pessary

Mid-term abortion

Intra-amniotic misoprostol
(PGE 1)
Obstetric uses

PGE2 (dinoprostone) vaginal

Termination of pregnancy
tab/pessary

Control of PPH Misoprostol/15-methylPGF2α

(carboprost) IM

Cervical ripening PGE1 (gemprost) as vaginal

pessary
Uses

Erectile dysfunction Intracavernosal PGE1 (alprostadil)

NSAID-induced peptic ulcer Misoprostol (oral)

Maintain patent ductus IV alprostadil

arteriosus

Other uses

IV/inhalation epoprostenol/
Pulmonary hypertension treprostinil/iloprost (PGI2)

Glaucoma Topical latanoprost/bimatoprost/

unoprostone (PGF2α)

Peripheral vascular disease IV PGI2

 Eicosanoids and leukotrienes 299

33.5 LEUKOTRIENES – INTRODUCTION, ACTIONS, LEUKOTRIENE ANTAGONISTS

AND PLATELET-ACTIVATING FACTOR

Produced from arachidonic

acid through LOX pathway

“Leuko” – present in WBCs

“Trines” – contain 3 double

bonds
Introduction
Present in lungs, mast cells,
platelets and WBCs

LTA4 forms
LTB4, LTC4, LTD4, LTE4, LTF4

LTC-E4 is slow reacting substance

of anaphylaxis (SRS-A)

Vasoconstriction

Bronchoconstriction

↑ Airway mucus
Leukotrienes
Actions
↑ Vascular
Hence leads to edema
permeability

Rheumatoid arthritis

Psoriasis

Role in inflammation

Ulcerative colitis

e.g., Montelukast, zarfirlukast Bronchial asthma

Block actions of LTC4 and LTD4 Hence beneficial orally in

on bronchial smooth muscle bronchial asthma (as adjuvants)
Leukotriene antagonists

∴ ↓ LTs

Zileuton inhibits LOX

Hence it is useful in bronchial
asthma and allergic rhinitis
 34
Nonsteroidal anti-inflammatory drugs (NSAIDs)

34.1 ANALGESICS

Analgesics are agents which

relieve pain

Aspirin-type analgesics and

2 Types of analgesics
opioid-type analgesics

Nonsteroidal anti-
Analgesics
inflammatory drugs
Aspirin-type of analgesics is
NSAIDs, i.e.,
Are also called non-narcotic/
non-opioid type
analgesics

Morphine/narcotic type of
Opioid analgesics are
analgesics

34.2 ASPIRIN-TYPE OF ANALGESICS vs. OPIOID-TYPE OF ANALGESICS

Aspirin-type of analgesics
do not depress the CNS

Do not have physical

dependence or abuse liability

Aspirin-type of
Are weaker analgesics
analgesics vs opioid-
(except for inflammatory pain)
type of analgesics

Primarily act on peripheral

pain mechanisms

More commonly used

300
 Nonsteroidal anti-inflammatory drugs (NSAIDs) 301

34.3 NSAIDs CLASSIFICATION

Aspirin (PROTOTYPE)

Salicylates

Sodium salicylate

Pyrazolone Phenylbutazone

Indole acetic acid Indomethacin, sulindac

Non-selective COX
inhibitors Ibuprofen, naproxen,
Propionic acid
ketoprofen

Fenamates (arthranillic
Mefanamic acid
acids)

Enolic acid derivatives/ Piroxicam, meloxicam,

oxicams tenoxicam

Alkalones Nabumetone
NSAIDs classification

Diclofenac, aceclofenac,
Arylacetic acid
ketorolac
Preferrential COX-2
inhibitors
Nimesulide

Paracetamol
Analgesic antipyretic but
(para-aminophenol
poor anti-inflammatory
derivative)

Selective COX-2 Celecoxib, rofecoxib,

inhibitors etoricoxib
302 Pharmacology mind maps for medical students and allied health professionals

34.4 MECHANISM OF ACTION

During inflammation there is

release of arachidonic acid (AA)
from membrane phospholipids

Cyclo-oxygenase (COX) enzyme

converts AA to prostaglandins
(PGs)

PGs sensitize nerve endings to

∴ Hyperalgesia
bradykinin, histamine

NSAIDs inhibits COX ∴ PG synthesis ∴ ↓ Pain and inflammation

Two isoforms of COX COX-1 and COX-2

Constitutive, found in
most normal cells
Mechanism of action normal cells
COX-1

Maintains tissue
homeostasis

Inducible by inflammatory
mediators like cytokines

COX-2

Synthesizes prostaglandins,
the mediators of inflammation
Aspirin irreversibly inhibits
both COX-1 and COX-2
(by acetylation)

Other NSAIDs are reversible,

non-selective COX inhibitors

Newer agents like rofecoxib,

celecoxib are selective COX-2
inhibitors
 Nonsteroidal anti-inflammatory drugs (NSAIDs) 303

34.5 SALICYLATES

e.g., Acetyl salicylic acid

(aspirin/ASA)

Others Sodium salicylate, methyl salicylate

Aspirin is a prototypical/classical
Salicylates
NSAID

Aspirin (acetyl salicylic acid) is rapidly

converted in body to salicylic acid,
which is responsible for the action

One of the oldest analgesic-

anti-inflammatory drugs
304 Pharmacology mind maps for medical students and allied health professionals

34.6 PHARMACOLOGICAL ACTIONS

↓ Pain of inflammatory origin

↓ Pain from integumental

structures viz bones, muscles,
joints, connective tissue

1. Analgesia Is ineffective in relieving vague,

visceral pain

No euphoria, sedation, tolerance,

dependence (as compared to
morphine)

Weaker analgesic as compared to

morphine

↓ Fever, burning, hyperthermia

No change in temperature in normal

afebrile individuals

Pyrogen, a protein, ↑ PGs in

hypothalamus, during fever

2. Antipyretic ∴ ↑ Temperature set point

Pharmacological actions

Fever disturbs hypothalamic

thermostatic set point

Aspirin ↓ PG synthesis in
hypothalamus

↑ Sweating and cutaneous

vasodilation promotes heat loss,
∴ ↓ fever

At higher doses (4–6 g/day)

↓ Signs/symptoms of inflammation
→ pain, tenderness, swelling,
erythema caused due to PGs

However disease progression

unaffected

3. Anti-inflammatory Aspirin ↓ chemical mediators of

inflammation like PGs, kallikrein

↓ Granulocyte adhesion to
endothelium

Stabilizes lysosomes

↓ Migration of leucocytes,
macrophages to site of inflammation

(Continued)
 Nonsteroidal anti-inflammatory drugs (NSAIDs) 305

34.6 PHARMACOLOGICAL ACTIONS (Continued)

Therapeutic doses of 4–6 g/

day aspirin ↑ O2 consumption
by skeletal muscles

∴ ↑ CO2, leading to
respiratory stimulation

Stage of compensatory
respiratory alkalosis
Direct stimulation of
respiratory center

4. Respiration
Normal pH
∴ Dose dependent ↑ in
rate and depth of respiration

Compensatory ↑ in HCO3
Due to respiratory urinary excretion (along with
Plasma CO2 ↓ Respiratory alkalosis
stimulation Na+, K+, H2O)

Toxic doses depresses

respiratory center, pH alkaline
∴ respiratory failure

Therapeutic doses ↑ Respiratory stimulation ↑ CO2 wash-out Respiratory alkalosis

Directly depress respiratory

Toxic doses CO2 accumulation ↑ Plasma CO2
center

5. Acid–base and electrolyte

balance H2O excreted in urine with Na+,
K+, HCO3 ↓ pH

Plasma HCO3
∴
↑ Sweating
concentration already low due
All these are associated with to renal excretion
dehydration ∴
Water loss due to
hyperventilation (respiratory
stimulation) Uncompensated respiratory
acidosis

∴ Severe dehydration with

acidosis Additional metabolic
↑ Cellular metabolism due to acidosis due to accumulation
uncoupling of oxidative of acids
phosphorylation
Hyperpyrexia, ↑ protein
catabolism
↑ O2 use, ↑ CO2
6. Metabolic effects production, ↑ heat production
(esp. in skeletal muscles)
∴ Aminoaciduria, negative
nitrogen balance

Toxic doses

↑ Glucose utilization,
∴ hypoglycemia (normal doses)

Hyperglycemia, central
∴
sympathetic stimulation which
↑ adrenaline levels

(Continued)
306 Pharmacology mind maps for medical students and allied health professionals

34.6 PHARMACOLOGICAL ACTIONS (Continued)

Gastric irritant, ∴ epigastric

distress, nausea, vomiting
In acidic pH of stomach,
salicylates remains non-ionized
(ion trapping)
Stimulates CTZ ∴ vomiting
These drug particles stick to
7. Gastrointestinal tract mucosa leading to gastric
ADR: Erosive gastritis, mucosal irritation
congestion, peptic ulceration,
G1 bleeding, rarely malena,
hematemesis
They also cause local back
diffusion of acid

Mechanism of hyperacidity

↓ Production of
mucoprotective PGs

Inhibits platelet aggregation,

∴ easy bleeding

Uric acid reabsorbed by

Selective COX-2 inhibitors
proximal tubules and secreted
cause less gastric irritation
by distal tubules

1–2 g/day aspirin ↓ Uric acid secretion Causes urate retention ∴ ↑ Plasma uric acid levels

Variable effect, often

8. Uric acid 2–5 g
no change

Inhibits uric acid reabsorption

>5 g/day ∴ Uricosuria, urate excretion
by proximal tubules

This effect cannot be used

therapeutically because of high
dose leading to toxic effects

(Continued)
 Nonsteroidal anti-inflammatory drugs (NSAIDs) 307

34.6 PHARMACOLOGICAL ACTIONS (Continued)

Single small dose inhibits

irreversibly platelet aggregation
∴ ↑ Bleeding time
and TXA2 synthesis by platelets
(for 8–12 days, i.e., platelet life)
Hence no protein synthesis
Platelets contain only
∴
COX-1, fresh platelets have to be This is because platelets do not
produced to regain TXA2 activity have nucleus

9. Hematological ∴ COX-1 cannot be produced

Additionally aspirin inhibits
∴
Even a small dose (40 mg) can
platelet COX in portal
inhibit platelets aggregation
circulation itself

Other NSAIDs cause reversible

inhibition of platelet COX

Inhibits several Ag–Ab

reactions

↓ Ab production, release of
10. Immunological
histamine

∴ May benefit rheumatic

fever

No effects in therapeutic
dose

11. Cardiovascular system

Toxic dose depresses
circulation by inhibiting
vasomotor center

Keratolytic effects

12. Local (salicylic acid)

Mild antiseptic, fungistatic

308 Pharmacology mind maps for medical students and allied health professionals

34.7 IMPORTANT PHARMACOKINETIC ASPECTS AND DOSES

Salicylic acid being acid is

immediately absorbed from
stomach

However, aspirin is not well

absorbed

Microfine particles are well

absorbed

Salicylic acid and methyl

salicylate are absorbed from
intact skin

Important
Highly plasma protein bound
pharmacokinetic aspects

Deacetylated to active
salicylic acid

Small dose: First order kinetics

Dose-dependent excretion in
urine

High dose: Zero order kinetics

∴ Anti-inflammatory doses,
t½ ↑ to 12 h (normal dose
t½ 3–5 h)

Alkalinization of urine ↑ its

excretion (esp. during
poisoning)

50–300 mg per day

Antiplatelet
(low-dose)

Important doses of 2–3 g per day in divided

Analgesic
aspirin doses

4–6 g per day in divided

Anti-inflammatory
doses
 Nonsteroidal anti-inflammatory drugs (NSAIDs) 309

34.8 MAJOR ADVERSE EFFECTS

Dose-dependent,
duration-dependent

Nausea, vomiting, epigastric distress,

1. GIT mucosal erosion, ulceration, occult
blood loss (malena, hematemesis)

Aspirin inhibits only COX

Arachidonic acid converted by LOX

(lipoxygenase pathway)
to leukotrines (LTs)

2. RS LTs are bronchoconstrictors

Precipitation of bronchial asthma in

susceptible individuals

However diclofenac and

indomethacin
inhibit both PGs and LTs

Major adverse effects Analgesic nephropathy on

long-term use

3. Renal

Salt and water retention ( blunts

∴
effects of antihypertensives)

4. Liver Hepatoxicity on long-term use

Fatal hepatic encephalopathy

esp. in children

Usually seen after viral fever

5. Reye's syndrome
(influenza, varicella)

∴ Aspirin contraindicated, whereas

paracetamol preferred in pediatric
age group

↓ PGs which are required for

∴
Delays onset of labor
initiation of labor

Premature closure of ductus Portal hypertension

6. Pregnancy and infancy
arteriosus in fetus

↑ Postpartum hemorrhage ∴ It inhibits platelet aggregation

(Continued)
310 Pharmacology mind maps for medical students and allied health professionals

34.8 MAJOR ADVERSE EFFECTS (Continued)

Headache, dizziness,
7. CNS
confusion

Rashes, urticaria, pruritus,

rhinorrhea, photosensitivity,
asthma, angioedema

8. Allergic manifestations

Esp. in patients with

history of allergies

High dose for Esp. in Rx of

long-term rheumatoid arthritis

Headache, vertigo, tinnitus,

Chronic salicylate Signs/symptoms mental confusion, vomiting,
intoxication diarrhea, perspiration, hearing
loss, thirst, dehydration
Reversible, after
discontinuation
of aspirin

Suicidal/accidental

More common in Gastrointestinal irritation,

9. Salicylism children vomiting

Fatal dose: 15–30 g Hyperpyrexia, dehydration

Sign/symptoms Acid-base imbalance,

metabolic acidosis

Restlessness, delirium
Acute salicylate tremors, hallucinations,
intoxication convulsions, coma

Death due to RS/CV failure

To eliminate
Gastric lavage
unabsorbed drug

External cooling with alcohol

To ↓ temperature
or cold water sponges

To reverse acid–base
IV Fluids containing Na+,
imbalance and
Management K+, HCO3 and glucose
dehydration

Blood transfusion If hemorrhagic

and vitamin K complications

Forced alkaline diuresis Sodium bicarbonate

∴
with NaHCO3 and ionizes salicylates
In severe cases
Potent diuretics like Makes them water
furosemide and IV fluids soluble

Promotes their renal

excretion
 Nonsteroidal anti-inflammatory drugs (NSAIDs) 311

34.9 PRECAUTIONS AND CONTRAINDICATIONS

Peptic ulceration

Liver disease

Bleeding tendency

Precautions and
contraindications

Viral infections in children To avoid Reye’s syndrome

To avoid premature closure

Pregnancy
of ductus arteriosus in fetus

Stop NSAID 1 wk To ↓ risk of bleeding due

Surgery
before surgery to antiplatelet effect
312 Pharmacology mind maps for medical students and allied health professionals

34.10 INDICATIONS

Of all integumental origin

∴ PGs cause cerebral

Headache
vasodilation

1. Analgesic Backache, toothache

Myalgias, neuralgias

↓ PG synthesis which
∴
Dysmenorrhea are responsible for
dysmenorrheal

Provides symptomatic relief

2. Antipyretic
of hyperpyrexia

3. Anti-inflammatory Arthritis, fibromyositis

Initial dose 100 mg/day in 4–6

divided doses for 4–7 days
4. Acute rheumatic fever
Maintenance dose 50 mg/day
for 2–3 wks

↓ Pain, swelling, redness

Indications Improves joint mobility

↓ Morning stiffness

5. Rheumatic arthritis

↓ Fever

Does not stop progress

Provides only
symptomatic relief

6. Osteoarthritis Only symptomatic relief

Low dose: 50–300 mg/day

∴ Inhibition of platelet
aggregation

7. Post-myocardial infarction, ↓ lncidence of transient

post-stroke ischemic attacks (TIA)

Post angina pectoris,

↓ myocardial infarction (MI)

Prevents deep vein thrombosis

(Continued)
 Nonsteroidal anti-inflammatory drugs (NSAIDs) 313

34.10 INDICATIONS (Continued)

Mesalamine and sulfasalazine

Given orally for local effects, not

absorbed and acts locally in
ulcerative colitis
8. Inflammatory bowel disease (IBD)
Sulfasalazine converted to active
metabolite in colon which has local
action

Rectal suppository or enema

(mesalamine)
PGs initiate labor

To delay labor
However, ↑ risk of postpartum
bleeding and premature
closure of ductus arteriosus in fetus

Chemoprophylaxis in hereditary Colonic polyps in young age develop

Colon cancer prevention
familial adenomatous polyposis to colonic cancer in older age

Patent ductus arteriosus (PDA) to

cause closure of PDA in newborn
60–100 mg/day, ↓ BP

Eclampsia

PGs responsible for eclampsia

∴
and hypertension

Due to ↑ renal PG production

Bartter syndrome
Characterized by ↑ plasma
renin and aldosterone and hypokalemia

↑ Proliferation of mast cells

in reticuloendothelial and bone marrow

Systemic mastocytosis ∴ Sudden episodes of hypotension Due to release or PGs from mast cells

9. Miscellaneous
H1 and H2 blockers, should be given NSAIDs degranulate mast cells
∴
before aspirin/ NSAID therapy and release histamine

Niacin used for hypolipidemia

Releases PGD2 from skin

Niacin flush

∴ Infuse flushing

NSAIDs ↓ PGs, flushing

Slows progress

Cataract Protects lens proteins

However high dose required, leading

to toxicity

Salicylic acid 3% ( with benzoic acid

Local
6% as Whitfield’s ointment )
314 Pharmacology mind maps for medical students and allied health professionals

34.11 WHY USE OF ASPIRIN IS CURRENTLY RESTRICTED AND DRUG INTERACTIONS

Short duration of action

Large dose requirement

Frequent dosing

Why is use of aspirin

currently restricted?

High incidence of GI ADRs

Aggravates bronchial
asthma

Cannot be used in children

with viral infections

Like warfarin, heparin,

Displaces highly plasma
naproxen, phenytoin, ↑ Toxicity
protein-bound drugs
sulfonylureas

Oral anticoagulants ↑ Risk of bleeding

Drug interactions Corticosteroids, alcohol ↑ Risk of GI bleeding

Blunts antihypertensives
efficacy of diuretics, beta
blockers, ACE inhibitors

↓ Uricosuric effects of
↓ Uric acid secretion
∴
probenecid
 Nonsteroidal anti-inflammatory drugs (NSAIDs) 315

34.12 PYRAZOLONE DERIVATIVES

e.g., Phenylbutazone

Potent anti-inflammatory,
Complete oral absorption
weak analgesic, antipyretic

98% plasma protein

Pharmacokinetic aspects
binding

t½–60 h

More toxic, poorly

Edema
tolerated

Precipitate congestive
Na+, H2O retention
cardiac failure (CCF)
Agranulocytosis
Blunts efficacy of
Pyrazolone antihypertensives
derivatives
Aplastic anemia
Hematological
Adverse effects Hypersensitivity
complications
Thrombocytopenia
Serum sickness, hepatitis,
nephritis, dermatitis,
jaundice
Bone marrow
depression
Inhibit iodine uptake by
thyroid, hypothyroidism,
and goiter on long-term use

Due to toxicity, banned

by many countries

Rheumatoid arthritis

Osteoarthiritis

Uses

Ankylosing spondylitis

Other musculoskeletal
disorders
316 Pharmacology mind maps for medical students and allied health professionals

34.13 INDOLE ACETIC ACID DERIVATIVES

e.g., Indomethacin, sulindac (weaker

action, alternative to indomethacin)

Potent anti-inflammatory, good

analgesic, prompt antipyretic
Frequently seen (up to 50%)
Inhibits PG synthesis and
suppresses neutrophil motility
Gastrointestinal irritation,
Common
bleeding, ulcers
90% plasma protein binding

Frontal headache
Undergoes entero-hepatic circulation,
hence ↑ duration of action
Ataxia, confusion,
CNS
hallucinations, psychoses
Dose: 50 mg TDS

Hypersensitivity Rashes, leucopenia, asthma

Adverse effects
∴ Inhibits platelet
Bleeding
aggregation

Na+, H2O retention

Indole acetic acid

Avoid in patients with renal failure, hepatic
derivatives
dysfunction, psychiatric patients, epileptics,
machinery operators

Blunts efficacy of diuretics Na+, H2O

∴
Drug interactions
and antihypertensives retention

↑ Bleeding with warfarin

Used as reserve drug,

∴ prominent adverse effects

Rheumatoid arthritis

Psoriatic arthritis

Very effective, potent

∴
Ankylosing spondylitis
anti-inflammatory

Gout

Uses Closure of patent ductus arteriosus Most common use

Epidural indomethacin for pain

relief following laminectomy

Eye drops ↓ Ocular inflammation

Oral rinse ↓ Gingival inflammation

Malignancy associated with fever

may respond

Dramatic response, like other

Bartter syndrome
PG synthesis inhibitors
 Nonsteroidal anti-inflammatory drugs (NSAIDs) 317

34.14 PROPIONIC ACID DERIVATIVES

Better tolerated than aspirin

Does not cause Reye’s syndrome

e.g., Ibuprofen, ketoprofen, Lower analgesic/antipyretic/anti-inflammatory

fluribiprofen, naproxen activity than aspirin

Ibuprofen 99% Plasma protein binding

Reaches synovial fluid

Dosage forms: Oral, parenteral, topical

(gel, cream)

Dose: 400–600 mg TDS

Available as patch, tablet

Ketoprofen
Also stabilizes lysosomes, and inhibits LOX

Fluribiprofen Used topically in eye

Potent in inhibiting leucocyte migration

Propionic acid
derivatives Strong anti-inflammatory

Valuable in acute gout

Naproxen
Also recommended in ankylosing
spondylitis and rheumatoid arthritis

Long t½

Low incidence, mild,

Uses and adverse effects
similar to NSAIDs

Analgesic in painful conditions

Fever

Soft tissue injuries

Fractures
Uses
Postoperative pain

Osteoarthritis

Dysmenorrhea

Gout
318 Pharmacology mind maps for medical students and allied health professionals

34.15 ANTHRANILIC ACID DERIVATIVES

e.g., Fenamates: Mefanamic acid

Efficacious as analgesic/antipyretic
but weak anti-inflammatory

Has both peripheral and central

actions

More toxic Contraindicated in children

Anthranilic acid derivatives Not used for >1 wk

Dose: 250–500 mg TDS

Diarrhea is common

ADRs

Similar, but milder than aspirin

Analgesic in muscle, joint, and soft

tissue pain where strong anti-
inflammatory action is not required

Uses

Mefanamic acid for dysmenorrhea

 Nonsteroidal anti-inflammatory drugs (NSAIDs) 319

34.16 ENOLIC ACID DERIVATIVES

Good
e.g., Piroxicam, meloxicam,
analgesic/antipyretic/anti-inflammatory
tenoxicam
activity

Lowers PG concentration in synovial

Piroxicam
fluid

Inhibits production of IgM rheumatoid

No significant drug interactions
factor, and leucocyte chemotaxis

Less ulcerogenic

Well tolerated

99% protein bound

Entero-hepatic circulation

t½ nearly 2 days

Hence administered once daily

Enolic acid derivatives Slow onset, longer duration

Dose: 20 mg OD

Rheumatoid arthritis

Osteoarthritis

Ankylosing spondylitis

Uses

Acute musculoskeletal pain

Postoperative pain

Painful dental conditions

Preferential COX-2 inhibition

Meloxicam

Well tolerated
320 Pharmacology mind maps for medical students and allied health professionals

34.17 ALKALONES

e.g., Nabumetone

Good anti-inflammatory

Preferred for rheumatoid

Alkalones
arthritis, osteoarthritis

Fewer side effects

Selective COX-2 inhibitor

Less ulcerogenicity

Prodrug, generates active

metabolite 6-MNA
 Nonsteroidal anti-inflammatory drugs (NSAIDs) 321

34.18 ARYL-ACTETIC ACID DERIVATIVES

Good analgesic, antipyretic,

potent anti-inflammatory

Somewhat COX-2 selective

Reduces neutrophil chemotaxis and superoxide

production at inflammatory site

Good tissue penetrability

Good and longer synovial fluid concentration,

hence preferred in inflammatory arthritis

Good absorption, rapid therapeutic concentration

Only 50% bioavailability, high

∴
Diclofenac
first-pass metabolism
Tablets

High plasma protein binding

Extended-release tablets

Mild adverse effects (like other NSAIDs)

Gels

Preparations

Eye drops

Dose: 50 mg BD or 100 mg sustained release OD

Rectal suppositories

Most extensively used NSAID

Mouthwashes
Combination with misoprostol
(PGE1analog) reduces GI adverse effects

Gastric friendly ( COX-2 selective)

∴
e.g., Diclofenac,
aceclofenac, ketorolac

↑ Glycosaminoglycan synthesis,
hence additional chondroprotective property
Aceclofenac

Longer acting

Preferred over diclofenac

Potent analgesic, as effective as

morphine, but modest anti-inflammatory action

No action on opioid receptors, only Short duration postoperative,

Aryl-actetic acid
peripheral actions pain
derivatives

But no respiratory depression, dependence, or

Renal colic
hypotension, unlike morphine

Used orally/parenterally for Metastatic cancer pain

Ketorolac
Use for more than 5 days is not
Dental pain
recommended
Acute musculoskeletal pain

Dose: 10–20 mg QDS Acute musculoskeletal pain

Painful dental lesions

Eye drops for ocular inflammation
Uses
(non-infective conditions)
Postoperative pain and
inflammation
Also available as IM, transdermal patch
Ocular inflammation
(eye drops)
322 Pharmacology mind maps for medical students and allied health professionals

34.19 PREFERRENTIAL COX-2 INHIBITORS

e.g., Nimesulide
Reduces generation of superoxide by
neutrophils
Moderately COX-2 selective
Inhibits PAF synthesis and TNFα
release
Mechanism

Free radical scavenging

99% protein bound

Inhibition of metalloproteinase activity in
cartilage
Analgesic/antipyretic/anti-inflammatory
activity comparable to other NSAIDs
Sports injuries

ENT disorders

Sinusitis

Dental surgery
Preferrential COX-2
inhibitors

Used primarily for short duration painful

Bursitis
conditions e.g.,

Dose: 100 mg BD Dysmenorrhea

Safer in asthmatics, as compared to aspirin Low backache

Fever

Postoperative pain

Similar but less prevalent as compared to

Adverse effects
other NSAIDs

Banned in many countries, including India,

Fulminant hepatitis has been reported
esp. in children

Hence not marketed in many countries like

USA, UK, Australia, Canada
 Nonsteroidal anti-inflammatory drugs (NSAIDs) 323

34.20 PARA–AMINOPHENOL DERIVATIVES, PARACETAMOL AND

PHARMACOKINETIC ASPECTS

e.g., Paracetamol, phenacetin

Analgesic abuse nephropathy
Phenacetin had severe adverse effect
Banned
Paracetamol, a metabolite of
phenacetin, is safer and effective

Paracetamol also called acetaminophen

But weak anti-inflammatory

Good analgesic, antipyretic
(unlike aspirin, other NSAIDs)

Inhibits brain COX-3 Good antipyretic, analgesic

Raises pain threshold

Poor inhibition of peripheral COX Weak anti-inflammatory

Peroxides present at site of inflammation (but not generated

Weak anti-inflammatory
in brain), ↓ activity
Para-aminophenol
derivatives
No inhibition of platelet activity

Mild gastric irritation

No uricosuric effect

No hypersensitivity reactions

No drug interactions

Does not stimulate respiration

No action on acid-base balance,

cellular metabolism, CVS

Dose: 500 mg QDS

Can be safely used during pregnancy

Good oral absorption

Pharmacokinetic
Low protein binding (30%)
aspects

Metabolized by glucuronide conjugation (60%) and

glutathione conjugation (20%)
324 Pharmacology mind maps for medical students and allied health professionals

34.21 ADVERSE EFFECTS

Generally safe and well-

tolerated in therapeutic Observed with large doses
doses

>150 mg/kg or >10 g in

Acute paracetamol poisoning
adult

Also common in chronic

Low glucoronide
∴
alcoholics and premature Esp. in children
conjugation ability
infants

↑ Serum
Reversible on treatment
transaminases

Nausea, vomiting, anorexia

Jaundice
within 24 h

Signs/symptoms

Severe hepatic damage

Liver tenderness
within 2–4 days

Nephrotoxicity in some
Adverse effects ↑ Prothrombin time
(renal tubular necrosis)

Progress to liver failure in

some

Highly reactive metabolite

Detoxified by glutathione
Normal dose metabolized to i.e., N-acetyl p-
conjugation
benzoquinoneimine (NAPQI)
Mechanism of paracetamol-
induced hepatotoxicity
Toxic metabolite binds to
Large dose of paracetamol Centrilobular hepatic
sulfhydryl group in hepatic
depletes glutathione necrosis
proteins

Gastric lavage

Activated charcoals 150 mg/kg IV infusion over

absorption (orally 15 min, repeated if
or by tube) required

Antidote, N-acetyl Oral loading

Management
cysteine dose – 140 mg/kg

N-acetyl cysteine
Maintenance
replenishes glutathione
dose – 70 mg/kg every 4 h
stores

Prevents binding of toxic

metabolite to cellular
constituents
 Nonsteroidal anti-inflammatory drugs (NSAIDs) 325

34.22 USES

Most commonly used

“over the counter”

Toothache, headache,
Analgesic
myalgias

Antipyretic

Safe analgesic/antipyretic
Uses
during pregnancy/lactation

Drug of first choice for But ineffective for ∴ Poor anti-inflammatory

osteoarthritis rheumatoid arthritis

No risk of Reye’s
∴
Best antipyretic in children
syndrome

Used in conditions where

aspirin is contraindicated
326 Pharmacology mind maps for medical students and allied health professionals

34.23 SELECTIVE COX-2 INHIBITORS

e.g., Celecoxib, rofecoxib,

valdecoxib, etoricoxib

Long-term NSAIDs are

poorly tolerated

NSAIDs use limited due

to gastric irritation

COX-1 is gastroprotective

COX-2 is involved in
inflammation

Selective COX-2 inhibitors

have analgesic/antipyretic/
anti-inflammatory activity,
Selective COX-2 but less GI side effects
inhibitors
Additionally they do not
inhibit TXA2 production
∴
by platelets ( COX-1
is involved)

Does not inhibit platelet

aggregation or prolong
bleeding time

However reduces PGI2

production by vascular
endothelium, prothrombotic
influence

Used only with lowest

dose and shortest period

Avoid in patients with history ↑ Risk of cardiovascular

of IHD/CVD/hypertension/
cardiac failure
Rofecoxib, celecoxib,
↑ MI and stroke
∴
and cerebrovascular PGI2 is inhibited
withdrawn from market
thrombotic events

Others are under

Drawbacks
supervision

Hepatoxicity on
long-term use
 Nonsteroidal anti-inflammatory drugs (NSAIDs) 327

34.24 CHOICE OF NSAIDs

Only paracetamol

Children

Avoid aspirin

Geriatric patients Low dose of NSAIDs Look out for drug interactions

Usually empirical

Mild–moderate pain without

Paracetamol
inflammation
∴ Minor differences between
NSAIDs efficacy and large inter-
individual variations
Ketorolac

No one drug is better than the other

in terms of efficacy

Acute/short duration pain Diclofenac

However differences in side effects

Choice of NSAIDs
are beneficial in choosing the drug

Nimesulide
Cause/nature of pain, presence/
absence of inflammation help
in selection
Paracetamol or diclofenac
Pain due to injury
(if inflammation)
Age, allergy, comorbid disorders, past
acceptance, acceptability, individual
preference also help in deciding
Paracetamol

Certain guidelines

Pain in patients with GI

Selective COX-2 inhibitors
intolerance

Additional gastroprotectives
like PPIs beneficial

COX-2 inhibitors

Pain in asthmatics

Nimesulide

Avoid COX-2 inhibitors

Pain in patients with CVS/CNS

disorders

Use low-dose aspirin

Pain during pregnancy Paracetamol

Sustained release
formulations

Chronic pain

Long-acting NSAIDs
 35
Drugs used in rheumtoid arthritis and gout

35.1 DRUGS USED IN RHEUMATOID ARTHRITIS – CLASSIFICATION

Methotrexate

Cyclophosphamide

a. Immunosuppressants

Azathioprine

Leflunomide Etanercept

i. TNF α blockers Infliximab

Adalimumab

b. Biological agents ii. Inhibitors of Abatacept

T-cell activation

iii. IL-1 antagonist Anakinra

1. NSAIDs

Classification
2. DMARDs (disease iv. Anti-B lymptocyte Rituximab
modifying antibody
antirheumatic drugs)
Auranofin

c. Gold salts

Aurothiomalate

Penicillamine

Sulfasalazine

d. Others

Chloroquine

Hydroxychloroquine

e. Adjuvants Corticosteroids

328
 Drugs used in rheumtoid arthritis and gout 329

35.2 NSAIDs AND IMMUNOSUPPRESSANTS

First line drugs

Provide symptomatic relief

Do not halt disease progress

Anti-inflammatory doses used for this purpose

Aspirin
NSAIDs

Prolonged use is associated with toxicity Ibuprofen

Agents used Diclofenac

Naproxen

Piroxicam

Selective COX-2 inhibitors Are banned due to toxicity

e.g., Methotrexate, cyclophosphamide,

azathioprine, leflunomide

Cytotoxic drugs
Doses used are lower than that used for cancers

Used after conventional agents have failed

Inhibits cytokines
Reserved for serious crippling
disease with reversible lesions Directly suppresses cells involved in
inflammatory and immunological process Nausea
Methotrexate (MTX)
Stimulates apoptosis of these cells Mucosal ulcers

ADR Bone marrow suppression

Weekly doses are better tolerated Hepatotoxicity

Purine analog Leucovorin (Folinic acid)

reduces toxicity
Prodrug converted to active 6-thioguanine
Immunosuppressants

Azathioprine Inhibits cell mediated immunity

Suppresses T and B cell function

Alternative to methotrexate

Alkylating agent
Cyclophosphamide
Suppresses T and B cell activity

Prodrug

Inhibits autoimmune T cell proliferation

Reduces production of autoantibodies by B cells

Leflunomide Diarrhea
Long t½ of 5–40 days
Weight gain
ADR
Alopecia
Used in combination with methotrexate
↑ Hepatic
Cyclosporine enzyme levels
Other agents
Mycophenolate mofetil
330 Pharmacology mind maps for medical students and allied health professionals

35.3 BIOLOGICAL AGENTS

Cytokines, TNFα
(tumor necrosis factor)
play an important role
in inflammation

TNFα is produced
by macrophages and
activated T cells

Stimulates
TNFα receptor

Monoclonal antibody

1. TNFα blocking Produces other

Biological agents
agents cytokines

Binds to TNFα

TNFα blockers hence

are useful in RA
Combined with
methotrexate
e.g., Etanercept,
infliximab,
adalimumab
t½ is 9–12 days

↑ Susceptibility
Infliximab
to upper
respiratory infections
Dose: IV infusion
3–5 mg/kg over 8 h

Activation of viral
hepatitis
ADR

Antinuclear, anti-DNA
Ankylosing spondylitis
antibodies

Allergic reaction – cough,

Crohn’s disease
rashes, sinusitis

Autoimmune disease
Uses Psoriasis
such as

Ulcerative colitis

Sarcoidosis

(Continued)
 Drugs used in rheumtoid arthritis and gout 331

35.3 BIOLOGICAL AGENTS (Continued)

Recombinant fusion protein

Binds to TNFα

Slows RA progression

Other uses – psoriatic and

Etanercept
juvenile arthritis

Used in combination with MTX

Pain at injection site

Administered SC

Allergic reactions
ADR

Anti-DNA antibodies
Anti-TNF monoclonal antibody

Anti-etanercept antibodies
Similar to infliximab

Adalimumab Less immunogenic

Administered SC – 40 mg/wk

Combined with MTX

332 Pharmacology mind maps for medical students and allied health professionals

35.4 INHIBITORS OF T-CELL ACTIVATION, IL-1 ANTAGONIST, AND ANTI-B

LYMPHOCYTE ANTIBODY

Inhibits T-cell activation

Long t½ of 13–16 days IV infusion 800–1000 mg

Dose Repeated after 2 and 4 wks

Inhibitors of T-cell activation Abatacept

Then repeat at monthly

intervals

Hypersensitivity and
ADR
↑ upper respiratory infections

Do not combine with

TNFα blockers

Recombinant IL-1 receptor

IL-1 antagonist Anakinra
antagonist

Monoclonal antibody
against B cells

Suppresses release of
cytokines

Anti-B lymphocyte antibody Rituximab Inhibits inflammatory process

Used in combination with

MTX in moderate to severe RA

Also used in lymphomas

 Drugs used in rheumtoid arthritis and gout 333

35.5 GOLD SALTS

Were introduced in 1920s

Used in 1960s

Most effective in halting

disease progress
Introduction
However, toxicity and availability of
safer agents has reduced their use
They ↓ signs and Concentrate in tissues rich in
symptoms of RA phagocytes
Reduces rheumatoid factor and Accumulate in lysosomes of
immunoglobulins synovial cells
Reduce the migration and
Mechanism of action Unclear, probable hypothesis
activity of phagocytes

↓ Lysosomal enzyme activity

Inhibit cell-mediated immunity

Kidney Glomerulonephritis, hematuria

Liver Hepatitis, jaundice

Aplastic anemia, leukopenia,

Blood
thrombocytopenia, agranulocylosis

CVS Postural hypotension

Lungs Pulmonary fibrosis

ADR

Dermatitis

Stomatitis

Gold salts
Pharyngitis

Glossitis
Skin and mucous membrane
Gastritis
Pregnancy
Colitis
Contraindications Blood dyscrasias
Vaginitis
Liver, kidney, skin diseases
Grey-blue pigmentation of
exposed skin

↓ Disease progress

↓ Morning stiffness
RA
↑ Grip strength
Juvenile RA
Prevents affliction of unaffected
joints
Uses Psoriatic arthritis

Pemphigus

Lupus erythematosus

Auranofin–orally
Preparations
Aurathioglucose/aurat
hiomalate – IM/IV
334 Pharmacology mind maps for medical students and allied health professionals

35.6 OTHER ANTIRHEUMATIC DRUGS

Analog of amino acid

cysteine

Metabolite of penicillin

Chelates copper

Actions and toxicities

similar to gold
Antirheumatic However, they are less Hence they are not
drugs – pencillamine efficacious preferred
Alternative to gold in early, Drug fever
mild, non-erosive disease

Rashes

Proteinuria

ADR Blood dyscrasias

Autoimmune diseases Lupus erythematosus,

Antimalarials thyroiditis, hemolytic anemia

Useful in mild non-erosive Loss of taste

RA
Chloroquine and Achieve remission in 50% Alopecia
hydroxychloroquine patients Hence eye examination
should be done every
MOA: Unknown, ? inhibits Retinal damage on 3 months
CMI prolonged use
Fewer side effects with Hence
hydroxychloroquine than hydroxychloroquine
ADR Myopathy, neuropathy chloroquine is preferred

Compound of sulfapyridine Irritable bowel syndrome

and 5-amino salicylic acid
In colon, bacteria splits
sulfasalazine and liberates
Other antirheumatic sulfapyridine
Sulfasalazine
drugs Sulfapyridine is absorbed,
and causes
anti-inflammatory effect

ADR GI upset, rashes

Act by anti-inflammatory and

immunosuppressive actions
Provide rapid relief in
symptoms
Do not halt disease
progress
Associated with long-term
Adjuvants Corticosteroids
side effects
Extracorporeal immune Exarcerbation of RA on Hence they are used
adsorption of plasma withdrawal only as adjuvants

Removes lgG containing Used to treat flare-up of

Immunoadsorption immunocomplexes disease
apheresis Used for moderate to Intra-articular steroids
severe RA reduces pain
Mild and tolerable
side effects
Diet rich in unsaturated
fatty acids (marine fish)
Unsaturated fatty acids
∴
Diet compete with arachidonic
acids for uptake and
metabolism
For people who do not eat 1–4 g/day of
fish eicosapentanoic acid tablets
 Drugs used in rheumtoid arthritis and gout 335

35.7 CLASSIFICATION OF DRUGS FOR GOUT AND COLCHICINE

Colchicine

Acute gout
NSAIDs
Allopurinol
Classification of drugs
for gout Uric acid synthesis inhibitor
Febuxostat

Chronic gout
Probenecid

Alkaloid of colchicum
autumnale Uricosuric drugs Sulfinpyrazone

Unique anti-inflammatory
property Benzbromarone

Effective only against

acute gouty arthritis

Not an analgesic
Inhibits migration of
granulocytes to
No effect on uric acid inflamed area
production
Inhibits phagocytosis
Rapid relief of pain
Suppresses release of
glycoprotein
Mechanism of action
Binds to tubulin, prevents
polymerization to
microtubules
Binds to microtubules and
arrests cell division in
metaphase

↑ Gastrointestinal
Colchicine Other action
motility

Hemorrhagic
gastroenteritis

Dose-related nausea,
vomiting, diarrhea, Nephrotoxicity
abdominal pain

Anemia, leukopenia,
ADR Muscular paralysis
thrombocytopenia

High-dose Acute renal failure

Respiratory failure

Shock

Fatal CNS depression

Followed by 0.5 mg every

Acute gout 1 mg orally initially
2–3 h
Uses
Prophylaxis 0.6 mg once daily/thrice
daily
336 Pharmacology mind maps for medical students and allied health professionals

35.8 NSAIDs, ALLOPURINOL, AND FEBUXOSTAT

Provide symptomatic relief due to

anti-inflammatory activity

Indomethacin is commonly used

Other NSAIDs used Diclofenac, naproxen, piroxicam

NSAIDs
Relieve pain in 12–24 h

Better tolerated than colchicine

Not given long-term, only low dose

are given for 2–4 wks

Analog of hypoxanthine
Allopurinol
Inhibits uric acid production

Mechanism of action Purine nucleotides Hypoxanthine Xanthine Uric acid

Xanthine oxidase

Inhibits Inhibits

Allopurinol Alloxanthine

Hypersensitivity – fever, rashes

t½ of allopurinol is 2–3 h, and

GI irritation
alloxanthine is 24 h

ADR Headache

Dizziness
Allopurinol, alloxanthine
Anticancer drugs (6-mercaptopurine
and azathioprine) are metabolized by
xanthine oxidase hence ↑ their dose
Drug interaction Precipitation of acute gouty
arthritis during initial months of
treatment with allopurinol

Chronic gout

Secondary hyperuricemia 100 mg/day ↑ to 300 mg/day

Uses

A non-purine xanthine oxidase To prevent acute gouty arthritis

inhibitor Colchicine/NSAID is administered in
initial few weeks with allopurinol Then there is gradual absorption
Reduces the formation of uric acid of tophi

Like allopurinol there is initial

Febuxostat
flareup of gout

ADR Nausea, diarrhea, headache,

↑ liver enzymes

Use: Chronic gout

 Drugs used in rheumtoid arthritis and gout 337

35.9 URICOSURIC DRUGS

Organic acid

Developed to inhibit renal

secretion of penicillin
Thus ↓ plasma
uric acid
Blocks renal tubular
reabsorption of uric acid
hence promotes their
excretion
Hence there is gradual
reabsorption of tophi

1. Probenecid GI irritation, rashes

ADR

Prevented by drinking
Renal stones
large quantity of water

Chronic gout

Secondary hyperuricemia

Use

500 mg OD,
↑ to 1 g/day

Uricosuric drugs
It causes flareup of
acute gouty arthritis

Actions similar to
probenecid

2. Sulfinpyrazone Pyrazolone derivative

Given in dose
of 200–800 mg
once/twice daily
inhibits renal tubular uric
acid reabsorption

Potent uricosuric

3. Benzbromarone Dose: 40–80 mg OD

Used as alternative in
patients allergic to other
drugs

Can also be combined with

allopurinol
 VI
Part    

Respiratory pharmacology
 36
Drugs used in the treatment of bronchial
asthma and chronic obstuctive pulmonary
disorders (COPD)

36.1 CLASSIFICATION OF DRUGS FOR BRONCHIAL ASTHMA

Salbutamol
Short-acting
terbutaline
i. Selective β2
agonists
Salmeterol
Long-acting
formeterol
a. Sympathomimetics

Adrenaline,
ii. Nonselective isoprenaline,
ephedrine

1. Bronchodilators
Aminophylline,
b. Methylxanthines
theophylline

Ipratropium bromide,
c. Anticholinergics
tiotroprium bromide

Glucocorticoids
a. Systemic (hydrocortisone,
prednisolone)
2. Anti-
inflammatory
Classification of drugs Beclomethasone,
for bronchial asthma b. Inhalational budesonide, fluticasone,
triamcinolone, mometasone

Sodium
3. Mast cell
chromoglycate,
stabilizers
Ketotifen, Nedocromil

4. LT receptor Montelukast,
antagonists zafirlukast

5. Anti-IgE
Omalizumab
antibody

340
 Drugs used in the treatment of bronchial asthma and chronic obstuctive pulmonary disorders (COPD) 341

36.2 SYMPATHOMIMETICS

Stimulates β2 receptors in Stimulation of adenylyl

cAMP Bronchodilation
bronchial smooth muscle cyclase

↑ cAMP in mast cell

causes ↓ in release
of inflammatory mediators
They have a rapid
∴
Most commonly
onset, and are safe and
used agents
convenient

Oral

Injections

Metered dose inhalers

(MDI)
Routes of administration
Nebulizer solution
Usually first-line drugs
Rotacaps

Subcutaneous

Long-term use leads Due to downregulation

to tolerance of β2 receptors

Inhaled agents are

Tremors
well tolerated

Tachycardia

Sympathomimetics Mechanism of action

Palpitations

Oral agents cause Restlessness

Anxiety

Hypokalemia

Arrhythmias (rare)
Hence they are
Rapid onset on inhalation
preferred
(within 1–5 min)
for acute attacks
Short-acting agents Salbutamol
Dose 100–200 μg every 6 h
as MDI (or as required)
They are long-acting,
∴
they are not preferred
for acute attacks
Salmeterol, formeterol
Long-acting agents Hence they are beneficial
Dose: 50 μg BD for maintenance therapy
as inhalation

Adrenaline, isoprenaline,
ephedrine

Powerful and prompt

bronchodilation

Route SC/inhalation
Nonselective agents
Palpitations

Anxiety

Not preferred due

Tremors
to ADRs like

Restlessness

Arrhythmias
342 Pharmacology mind maps for medical students and allied health professionals

36.3 METHYLXANTHINES

Inhibits
phosphodiesterase
5 (PDE5)
e.g., Aminophylline,
theophylline
Hence there is This leads to ↓ In
PDE degrades cAMP ↑ in levels bronchodilation, inflammatory
of cAMP and mediators release
MOA
Adenosine causes
They
bronchoconstriction
also block
and histamine release
adenosine receptors
from airway mast cells

Restore the
sensitivity of
glucocorticoids

Deriphyllin
Acute attack (etophylline +
theophylline), IM

Oral theophylline
Chronic asthma (monitor
Rapid injection
∴
Methylxanthines plasma levels)
can lead to hypotension,
Uses Very slowly
arrhythmias,
IV aminophylline convulsions, death
Severe asthma (status
250 mg slowly over
asthmaticus) Administered only
15–20 min
when there is no
response to
Apnea of Theophylline β2 agonists
premature infants or caffeine

Narrow
therapeutic index

GI irritation, nausea,
vomiting

Insomnia, tremors,
ADRs
palpitation

Diuresis

Hypotension
 Drugs used in the treatment of bronchial asthma and chronic obstuctive pulmonary disorders (COPD) 343

36.4 ANTICHOLINERGICS

e.g., Ipratropium
bromide, tiotropium
bromide

Thus it causes thickening

It inhibits
∴
Atropine not of mucus and inspissation
mucociliary
preferred of mucus in respiratory
clearance
passage

Slow action as
compared to
sympathomimetics

Anticholinergics

Hence given
Poor GI absorption
as inhalation

Preferred in chronic
bronchitis and COPD

Adjunct to β2 agonists
Use (available
as combination)

Tiotropium is longer Hence given as

acting OD dose
344 Pharmacology mind maps for medical students and allied health professionals

36.5 ANTI-INFLAMMATORY DRUGS

Systemic Hydrocortisone,
Oral/IV
corticosteroids prednisolone

MDI

Spacer
Beclomethasone,
Inhalational
budesonide, fluticasone,
corticosteroids
ciclesonide, mometasone
Nebulizer
Inhibit inflammatory
response to Ag:
Ab reaction
Rotacaps
Anti-inflammatory
drugs Reduce bronchial
hyperactivity

↓ Mucosal edema

Not bronchodilators, but

anti-inflammatory agents

Drug receptor This leads to

They bind to steroid Complex attaches Anti-inflammatory
complex goes into synthesis of specific
receptors in cytoplasm to DNA action
nucleus mRNA

Cytokines stimulate
Mechanism ↓ Cytokine
eosinophils and ↑
of action synthesis
antibody formation

Thus reduces PG
Inhibit COX-2
formation in airways

Stimulate lipocortin Hence ↓ LTs and PAF

↓ IL-3
production

Improve the β2
agonists If there is tolerance
responsiveness

↓ Eosinophils, Hence they reduce

lymphocytes and mast the release of
cells in airways inflammatory mediators
 Drugs used in the treatment of bronchial asthma and chronic obstuctive pulmonary disorders (COPD) 345

36.6 ANTI-INFLAMMATORY DRUGS – USES, INHALATION STEROIDS

IV hydrocortisone
Status asthmaticus later oral predisolone
hemisuccinate

Oral prednisolone
Uses Acute asthma (for 5–7 days) along
with β2 agonists

Inhalational steroids for

Chronic asthma
prevention

Hence have minimal Small dose

∴
Local effects
systemic toxicity is required

Only for prevention, not Onset of action is

∴
for acute attack seen after few days

Hoarseness of voice

Sore throat

ADRs
Prevented by rinsing of
Oropharyngeal
mouth and throat with
candiasis
Inhalation steroids water after each use

HPA axis suppression may

Prevented by
No HPA axis suppression be seen in children given
use of spacer
large dose for long time

High topical effects

Budesonide

Also used as nasal

spray in allergic rhinitis

No systemic side effects

Fluticasone
Poor GI absorption and
high first-pass
metabolism
346 Pharmacology mind maps for medical students and allied health professionals

36.7 MAST CELL STABILIZERS

e.g., Sodium cromoglycate

nedocromil, ketotifen

Hence they ↓ release

Prevent degranulation
of inflammatory Esp. histamine
of mast cells
mediators

Inhibit exaggerated
neuronal reflexes

Reduces leukocyte
infiltration in respiratory
passages

↓ Release
of cytokines

Hence they inhibit

bronchial
hyperreactivity

Hence they are used for

Not a bronchodilator
prophylaxis, as inhaler

Also used for prophylaxis

As nasal spray
of allergic rhinitis

Used in allergic
As eye drops
Mast cell stabilizers conjunctivitis

Slow onset of action Approximately 2–4 wks

∴ Use has
↓ as inhaled
steroids are safe and effective
Children/young patients
with extrinsic asthma
respond better

Cough, throat irritation,

ADRs
bronchospasm

Antihistaminic agent

Actions similar to
cromoglycate

Prophylaxis of
Used orally
bronchial asthma

Onset of action after

Allergic rhinitis
6–12 wks
Ketotifen
Use Conjunctivitis

Urticaria

Atopic dermatitis

Drowsiness, dry mouth,

ADRs
weight gain
 Drugs used in the treatment of bronchial asthma and chronic obstuctive pulmonary disorders (COPD) 347

36.8 LEUKOTRIENE RECEPTOR ANTAGONISTS (LRA) AND ANTI-IgE ANTIBODY

Bronchospasm

e.g., Montelukast, zafirlukast

Mucus production

LTs cause

Mucosal edema
LRAs block the effect of
LT on respiratory tract
↑ In inflammatory
cells in airways
They ↓ response
to allergens

They inhibit exercise/aspirin-

induced bronchospasm
(LTs production)

Leukotriene receptor Used as adjuvants to

antagonists (LRA) β2 agonists

Used for prophylaxis of

mild–moderate asthma

Administration – oral

They reduce the

requirement
of corticosteroids
Inhibits LOX
Montelukast is preferred
due to its OD dosing
Reduces production of LTs

Zileuton

Frequent dosing (QDS) Hence not preferred

e.g., Omalizumab

ADRs Raised liver enzymes

Monoclonal antibody
against IgE

Hence IgE cannot bind to

Bind to IgE to form complex
mast cells/basophils

Allergic process and response

does not occur
Anti-IgE antibody

t½–26 h

SC injection once
Dose
in 2–4 wks

Moderate to severe asthma

Use
for prophylaxis

? Can lead to development

ADRs
of cancers
348 Pharmacology mind maps for medical students and allied health professionals

36.9 TREATMENT OF BRONCHIAL ASTHMA

Occasional acute attack

of bronschospasm

Treated by β2
agonist inhalation
Mild attack

No need of prophylaxis

Chronic asthma requires

regular prophylaxis with
steroids/cromoglycate

Acute episode treated

with β2 agonist inhalation

Regular prophylaxis
with cromoglycate
Moderate attack
Regular prophylaxis with
inhaled steroids, if no
response to cromoglycate

If inhaled steroids
Leukotriene antagonist
are contraindicated

Frequent and repeated attacks

of bronchospasm

Regular daily activities

are interfered

β2 agonists frequently
Treatment of (3–4 times/day)
bronchial asthma Severe attack
Additional inhaled
steroids

Short-term oral steroids

may be tried

Adjuvants like inhaled

ipratropium bromide/oral Acute RTI
theophylline could be considered

Medical emergency Drugs

Triggering factors Allergens

Nebulization with β2 agonist +

Stress
ipratropium

Abrupt withdrawal of
long-term steroids

IM/SC salbutamol Monitor heart rate

IV hydrocortisone Later follow-up with

Status asthmaticus
hemisuccinate, until crisis subsides oral steroids

O2 inhalation

To correct dehydration
IV fluids
and acidosis

Slow IV aminophylline infusion Over 15–20 min Not preferred

Antibiotics if infection

If respiratory failure
Artificial respiration
(severe cases)
 Drugs used in the treatment of bronchial asthma and chronic obstuctive pulmonary disorders (COPD) 349

36.10 MANAGEMENT OF CHRONIC OBSTRUCTIVE PULMONARY

DISEASE (COPD)/CHRONIC OBSTRUCTIVE LUNG DISEASE (COLD)

Nonpharmacological
Stop smoking
Rx

Long-acting β2
agonist or
tiotropium inhalation

During acute
Inhaled steroids
episodes

Rx

Antibiotics During RTI

Oral theophylline to
relieve bronchospasm
350 Pharmacology mind maps for medical students and allied health professionals

36.11 AEROSOLS IN ASTHMA

Have reduced risk of

systemic side effects
β2 agonists, corticosteroids,
ipratropium bromide, and
cromoglycale used as inhalation

Inhalation By MDI, nebulizers

Dry powder inhalation

Rotacaps
(DPI)

Particle size 2–5 micrometers

Are pressurized aerosols

Economical and portable

Use requires proper

breathing coordination

Chlorofluorocarbon (CFC)
MDI
propellant is unsafe

Propellant used now – hydrofluoro

Particles size
alkine it is safe
∴

Aerosols in asthma Effectiveness of inhalation

Breath-holding capacity
depends on

Only 2%–10% of active drug

Rate of breathing
reaches bronchioles

No need of breathing
coordination

More amount of drug

reaches bronchioles

Used in severe
bronchospasm
Nebulizers
CFC is not used

Overdose/abuse
Use is monitored
∴
prevented

Expensive, not portable,

generates large particles

Dry powder inhalation

Requires deep and forceful

inspiration
Rotacaps
Not suitable in children
Remove cap from
mouthpiece
Dry power causes
throat irritation
Shake the device

Exhale slowly and gently

Keep mouth piece in mouth

and cover it with lips

During inhalation press the

Technique of inhalation plunger to release drug

Hold breath for at least 10 s

or until patient comfortable

Repeat after few minutes

if no response
 37
Drugs used in the treatment of cough

37.1 ANTITUSSIVES AND CENTRAL COUGH SUPPRESSANTS

Codeine

Pholcodeine

Noscapine
1. Central cough
suppressants
Dextromethorphan

Antihistamine

Benzonatate
Drugs used in the
Antitussives
treatment of cough 2. Pharyngeal Lozenge, cough drops,
demulcents linctuses

Potassium iodide

Ammonium chloride
3. Expectorants
Guaiphenesin

Ipecacunanha

Effective cough
suppressant in
subanalgesic dose

Codeine Causes less dependence

Drowsiness, nausea,
vomiting
ADRs
Respiratory Hence avoid in
depression bronchial asthma
Natural opium alkaloid
Noscapine
No significant CNS side
effects
Synthetic opioid
derivative
Similar to codeine, but
less side effects
Dextromethorphan
No constipation or
1. Central cough Inhibit cough center in addiction
suppressants medulla
ADRs: Drowsiness

Similar to codeine, but

Pholcodeine
longer acting
Chemically similar to
procaine
(local anesthetic)
Peripheral action –
Benzonatate inhibits cough
receptors in lungs

Additional central action

Chlorpheniramine,
diphenhydramine,
promethazine

Antihistamines Useful in allergic cough

Hence it causes
However, it thickens
difficulty in
secretions
expectoration

351
352 Pharmacology mind maps for medical students and allied health professionals

37.2 PHARYNGEAL DEMULCENTS AND EXPECTORANTS

“Demulcere” means to
caress
soothingly in Latin

Hence there is soothing

↑ The salivary flow effect on irritated
pharyngeal mucosa
2. Pharyngeal demulcents

They suppress afferent

cough impulses

e.g., Candy, sugar,

lemon drops

“Expectorare” – means to
drive from chest

↑ Respiratory secretions,
this covers the
irritated mucosa

Makes secretions thin

and less viscid, hence it is
easily coughed out
↑ Secretions directly
when given as inhalation

Direct stimulants

e.g., Eucalyptus oil,

alcohol, cedar wood oil

Are gastric irritants, hence They are gastric

∴
Reflex expectorants they ↑ the respiratory irritation, nausea,
3. Expectorants secretions by reflex action vomiting is common

Potassium iodide Direct + reflex expectorant

Not preferred as it causes

Ammonium chloride
nausea, anorexia

Emetic in therapeutic dose

Ipecacuanha

Expectorant in
subtherapeutic dose

Guaiaphenesin Plant product

 Drugs used in the treatment of cough 353

37.3 MUCOLYTICS AND DRUGS CAUSING COUGH

Depolymerizes mucopolysaccharides
in mucus

Releases lysosomal enzymes,

which makes mucus thin

Liquefies sputum, makes it less viscid Hence there is easy expectoration

e.g., Bromhexine, ambroxol, acetylcysteine,

Semisynthetic compound
carbocysteine, pancreatic dornase

Isolated from vasicine

(alkaloid from plant adhatoda vasica)

Bromhexine Highly bitter, hence given as tablet

Most commonly used mucolytic

ADRs – rhinorrhea, lacrimation

Metabolite of bromhexine
Ambroxol
Route-both oral and inhalation

Administered by inhalation
Mucolytics

Breaks disulfide bond in mucoproteins

Acetylcysteine
and makes mucus thin

Not preferred due to side effects

Similar to acetylcysteine
Carbocysteine
Given orally

Deoxyribonuclease obtained from

beef pancreas

Deoxyribonuclease protein is an important

constituent of thick respiratory secretions
Pancreatic dornase
Breaks DNA into smaller parts,
makes secretion thin

Given as inhalation

Humidifies sputum

↓ Mucosal irritation
Steam inhalation
Assists expectoration
ACE inhibitors (ramipril, captopril)
Cost-effective substitute to
drugs
Amiodarone
Drugs causing cough
β blockers

Ether vapors
 VII
Part    

Hematological pharmacology
 38
Hematinics

38.1 INTRODUCTION AND IRON ABSORPTION

Average dietary iron is about

Of which about 10%
10–20 mg is present as either
is absorbed
heme or inorganic iron

Is better and faster absorption

Heme iron
as there is no need to be
(iron in meat)
dissociated to elemental iron

Is poorly absorbed as it is
Inorganic iron
bound to organic compounds
(vegetable/grains)
and needs to be dissociated

Is converted by enzyme ferro

Required for blood Non-heme iron
reductase to heme iron acid
formation (ferric form )
(ferrous form) ferro reductase

Absorbed by active
Used in treatment of
Hematinics Introduction transport by apoferritin
anemia
(in upper GI)

Ferrous iron is then oxidized

e.g., Iron, vitamin B12,
in mucosal cells to ferric
folic acid
iron (ferroxidase)

Liver, egg yolk, meat, fish,

Dietary source Ferric iron combines with
spinach, dry fruits, wheat,
of iron apoferritin to form ferritin
apple, jaggery, banana, etc.
Iron
Iron is slowly released from
Pharmacokinetics Absorption Vitamin C
ferritin

Transported to bone
marrow to Iron deficiency state
synthesize hemoglobin

Factors ↑ iron
Gastric acidity
absorption

Amino acids

Meat

Antacids

Tetracycline

Factors ↓ iron
Food in stomach
absorption

Phytates, oxalates,
phosphates

Milk

356
 Hematinics 357

38.2 IRON METABOLISM AND REQUIREMENTS

Transported via glyprotein

transferrin

2 molecules of ferric iron

coupled with transferrin

This complex engulfed by

Transport and storage
RBCs

There is ↑ in transferrin
levels during iron deficiency
Ferritin in intestinal mucosal
cells

Excess is stored as 66% as hemoglobin

Hemosiderin in liver, spleen, and
bone marrow
(reticuloendothelial cells)
25% as ferritin, hemosiderin

Distribution Total body iron 2.5–5 g

0.3% as enzymes (cytochrome)

Adult male 0.5–1 mg

0.3% as myoglobin (muscles)

Daily iron requirement Adult female 1–2 mg

Pregnancy and lactation 3–5 mg

0.5–1 mg daily

Shed in intestinal epithelial

Major
cells

Excretion

Bile, skin, and urine Minor

Menstruation In female
358 Pharmacology mind maps for medical students and allied health professionals

38.3 IRON PREPARATIONS – ORAL AND PARENTERAL

20% hydrated salt + 32%

dried salt elemental
iron
i. Ferrous sulfate

Is oldest and economical

ii. Ferrous gluconate 12% elemental iron

iii. Ferrous fumarate 33% elemental iron

Ferrous succinate

Oral Ferric ammonium citrate

iv. Others

Iron choline citrate

Ferrous salts better
absorbed than
ferric salts and are
Iron hydroxyl polymaltose
economical

200 mg of elemental
Adults iron/day in
divided dose
3–5 mg/kg elemental
Children iron/day in
divided dose
Dose Iron supplements should be
maintained for 3–6 months
Requires 4–8 wks To replenish iron stores
Iron preparations after normalization of
hemoglobin

0.7–1 g/100mL/wk
Rise in Hb

Iron dextran
IM/IV
(imferon)

Intolerance to oral iron

Malabsorption

Indications for
parenteral Noncompliance
iron therapy

Severe anemia

Gastrectomy patients

With erythropoietin in
kidney disease patients

Iron sorbitol
Parenteral citric acid IM/IV
complex (jectofer)
Iron requirement (mg)
Total dose of = 4.4 x body
parenteral iron weight (kg) x
Hb deficit (g/dL)
Iron dextran complex,
iron–sorbitol–citric acid
complex

Recommended 100 mg daily (2 mL) or Until total required dose is

IM iron on alternate days given or maximum 2 g
adult dose

Deep IM “Z” technique To prevent staining

in buttock of skin

Iron dextran complex

Total daily dose diluted Given IV slowly over

in 500 mL normal saline 6–8 h, under continuous
supervision
IV iron
Initial test dose 0.5 mL,
over 5–10 min

Sodium ferric gluconate,

Less allergenic
iron sucrose
 Hematinics 359

38.4 USES OF IRON AND ADRs

Pregnancy

Bleeding
i. Treatment of iron-
deficiency anemia Dietary iron
(microcytic deficiency
hemolytic anemia)
due to
Reduced GI
absorption

Uses of iron
200 mg/daily

Pregnancy 100 mg/day from 2nd

ii. Prevention of trimester
iron-deficiency
anemia during Infancy 0.5 mg/day folic acid
from 1st trimester

i. Staining of teeth
(with liquid
formulations)

ii. Metallic taste

iii. Nausea,
Oral iron vomiting, epigastric
distress, dyspepsia
Vomiting
iv. Diarrhea/
constipation

v. Blackening Abdominal pain

of stools
Frequently seen in
ADRs i. Pain at site of young children, Hemetemesis
injection infants
10 tablets (1–2 g)
Bloody diarrhea
ii. Skin pigmentation is fatal

Signs/symptoms Shock
iii. Sterile abscess

Parenteral iron
iv. Fever, headache, Cyanosis
arthralgia,
lymphadenopathy,
urticaria, flushing, Dehydration
palpitation,
bronchospasm
Hyperventilation
v. Anaphylaxis (rare)

CVS collapse and

vi. Acute iron Death
coma
poisoning

Maintain airway

Breathing

General Circulation

Gastric lavage with Fluid/electrolyte

sodium bicarbonate balance
Rx
Whole bowel
irrigation to flush Acid–base balance
out unabsorbed
pills from GIT
Is a potent iron
Desferrioxamine chelating agent Enhances iron
Specific
(antidote) IM/IV binds to iron excretion
in blood and
360 Pharmacology mind maps for medical students and allied health professionals

38.5 MATURATION FACTORS AND VITAMIN B12

Vitamin B12 and

folic acid

Both are water-

soluble vitamins
Maturation factors Glossitis
Required for DNA
synthesis
Stomatitis
Deficiency leads to Thus defective maturation Hence it can lead to Presence of RBC precursors
abnormal of RBCs and other rapidly megaloblastic anemia in blood and bone marrow
DNA synthesis multiplying cells i.e., manifested as
Malabsorption
It is a cobalt
∴
Also called
containing
cyanocobalamin
compound
Neurological problems
Synthesized by
colonic bacteria

Liver, fish, meat, egg yolk,

Dietary source
cheese, pulses, etc.

Absorbed in terminal ileum with

Vitamin B12 or
help of intrinsic factor secreted
extrinsic factor
by stomach (parietal cells)
Vitamin B12
Acts as co-enzyme in
Transported in plasma by
certain
transcobalamin
metabolic pathways
Methylcobalamin
(methyl B12)
Stored in liver, excreted
in bile, and undergoes Co-enzyme forms
enterohepatic cycling
Deoxyadenosylcobalamin
(DAB12)

Essential for conversion

Methyl B12 of homocysteine to
Functions methionine

Essential for conversion

DAB12 of methylmalonyl CoA
to succinyl CoA

Essential for synthesis

of purine

Essential for normal

hematopoiesis and
maintenance
of normal myelin
 Hematinics 361

38.6 DEFICIENCY, PREPARATIONS, AND USES

Addisons pernicious Destruction of parietal Hence ↓ in intrinsic ∴ Reduced B12

anemia cells factor absorption
Chronic gastritis,
Causes gastrectomy,
malabsorption
∴ Tapeworm consumes
Tapeworm infestation
B12

Megaloblastic anemia
with hypercellular marrow

Weakness, fatigue,
tachycardia, angina

Neurological problems

Tingling numbness of
hands and feet

Deficiency
Presentation Spasticity

Ataxia

Loss of memory

Confusion, delusion,
hallucinations

Psychosis

Peripheral smear
Diagnosis
Vitamin B12 levels
Methylcobalamin (oral)

Hydroxycobalamin It is long-acting, can

Preparations
(IM) cause Ab formation

Cyanocobalamin
Can lead to anaphylaxis
(IM/SC)

Prevention and treatment

of vitamin B12 deficiency ∴ Oral B12 is not
Parenteral B12
absorbed
Pernicious anemia
Lifelong Rx

Immediate treatment

IM (Intramuscular)
Cyanocobalamin 100 mg
Severe deficiency and 1 m + 5 mg oral folic acid
neurological problems
3–4 wks treatment
B12 stimulates and
∴
Cyanocobalamin ↑ hematopoiesis
↑ requirement
Uses of folic acid and iron Hence supplementation
with iron and folic acid
Topical neuropathy is mandatory

Trigeminal neuralgia

Neuropathies Multiple sclerosis

Certain psychiactric
Empirical
disorders

Alcohol and tobacco

Weekly hydroxycobalamin
amblyopia

Prevention 3–10 mcg daily

362 Pharmacology mind maps for medical students and allied health professionals

38.7 FOLIC ACID (FA)

Green leafy vegetables, esp. spinach

(hence called folic acid; “foliage”
means leaf)
Combination of glutamic acid,
para-aminobenzoic acid, Liver
and pteridine nucleus
Fruits
Source
Yeast
Destroyed by cooking
Egg

Milk

Adults 50–100 mcg/day

Requirements
Pregnancy and lactation 500–800 mcg/day

Polyglutamates in dietary folic acid is

cleaved into monoglutamates by
intestinal folate conjugase

Then absorbed from upper intestine

Jejunal mucosa converts it to

tetrahydrofolate and it
then gets methylated

Transported as methyltetra
Pharmacokinetics hydrofolate (MTHF)

Stored in liver

Hence deficiency manifestation

Stores exhausted in 3–4 months
appear after 3–4 months

Folic acid is inactive Active form is tetrahydrofolate

Folic acid (FA) Synthesis of amino acids, purines,

pyrimidine, choline, DNA
Functions
Essential for cell multiplication

Dietary deficiency (most common)

Malabsorption

↓ Storage Liver disease, vitamin C deficiency

Causes of deficiency
Phenytoin, phenobarbitone,
Reduced utilization
oral contraceptive pills

Children, pregnancy, lactation,

↑ Requirement
hemolytic anemia

Drug induced e.g., Methotrexate,

Antifolates
trimethoprim, pyrimethamine
Oral ulcers, diarrhea, lethargy,
weight loss
Signs/symptoms
Megaloblastic anemia, blood picture
similar to B12 deficiency

Preparation Folic acid 5 mg tablet

Along with vitamin B12
Megaloblastic anemia
In folic acid deficiency due to
FA is given IM
malabsorption

During infancy, pregnancy, lactation,

and during ↑ requirements
Uses Prophylactically
1st trimester to prevent neural tube
defects

Folinic acid is given

Methotrexate toxicity
Folinic acid is active form of Also called citrovorum
FA (n-formy tetrahydro FA) factor or leucovorin
 Hematinics 363

38.8 HEMATOPOIETIC GROWTH FACTOR AND ERYTHROPOIETIN

Stimulate growth and differentiation

of blood cells

e.g., Erythropoietin, thrombopoietin,

myeloid growth factors

Hematopoietic growth factor Usually given SC

Are glycoproteins, produced by

recombinant DNA technology

Regular monitoring of blood counts

mandatory during treatment

Synthesized by peritubular interstitial

kidney cells

Triggers for synthesis Anemia, hypoxia

Binds to erythropoietin receptors on

Anemia of chronic kidney disease
red cell progenitors

↑ Red cell production, by acting

Anemia due to zidovudine therapy In AIDS patient
on erythropoietic stem cells

Given as IV/SC Anemia due to anticancer drugs

Aplastic anemia, multiple

Anemia due to bone marrow disorders
myeloma

Uses Anemia due to cancers

Anemia of prematurity

Erythropoietin Anemia due to chronic

inflammation in AIDS

↓ Need for blood transfusion in

high-risk patients undergoing surgeries

Treatment of iron overload

Epoetin alpha given thrice

weekly

Darbopoetin α once a
Preparations
week as it has long t½

Epoetin β once in
2–3 wks

Rise in BP

Monitor Hb level, should

↑ Hematocrit
not be >12g%
ADRs
Thromboembolic complications Myocardial infarcation, stroke,
such as venous thrombosis

Allergic reactions
364 Pharmacology mind maps for medical students and allied health professionals

38.9 MYELOID GROWTH FACTORS, MEGAKARYOCYTE GROWTH FACTORS,

AND INTERLEUKINS

Granulocyte macrophage
colony stimulating
factor (GM-CSF)

Granulocyte colony
stimulating factor (G-CSF)

Monocyte colony stimulating

factor (M-CSF)

Sargramostim Stimulates neutrophils and

GM-CSF
monocytes

G-CSF Filgrastim Stimulates neutrophils

Stimulates monocytes and Bone marrow

macrophages transplantations
M-CSF
Myeloid growth factors
Causes splenomegaly and
Anticancer drug
thrombocytopenia
Given SC/IV infusion

Aplastic anemia

Uses Neutropenia due to

AIDS

Bone pain

Congenital neutropenia

Fever

Myelodysplastic syndrome

Arthralgia, myalgia

Capillary leak syndrome

ADRs
with edema

Pericardial effusion In high dose

Pleural effusion

Heart failure

Stimulates platelet
production

Megakaryocyte growth Thrombopoietin Attaches to platelet

factors progenitor cell

Interleukin-2
Thrombocytopenia following
↑ production of Used in
anticancer drugs
megakaryocytes and platelets

e.g., Oprelvekin
Interleukins
Thrombocytopenia due to
Used in
anticancer agents

ADRs Sodium retention Hence can cause edema

 39
Hemostatic agents

39.1 LOCAL AGENTS/STYPTICS

Arrest bleeding and

promote coagulation

Hemostatic agents Also called coagulants

Local agents Also called styptics
Classification
Systemic agents Hence controls
Causes vasoconstriction
bleeding

Cotton pad soaked in 0.1% (1:10,000) is used Hypertension

1. Adrenaline
Congestive
cardiac failure

Avoid in patients with Arrhythmias

Freeze-dried powder obtained Ischemic

from bovine/human plasma heart disease
Uncontrolled
Dusted over bleeding surface after skin graft
hyperthyroidism
2. Thrombin
Can lead to allergic reactions

Should not be injected

Contains fibrinogen, factor XIII, thrombin,

Ca+2, and other clotting agents
3. Fibrin
Available as sheets/spray

Absorbed
Absorbable hemostatic protein
after 6 wk
Left in place after suturing wound
Used locally to control
4. Gelatin
bleeding from capillaries and
small blood vessels Being porous and spongy, it provides
Local agents/styptics physical meshwork on which clotting occurs
e.g., bleeding after tooth
extraction, epistaxis,
small wounds etc. Can lead to infection, granuloma and fibrosis

Enzyme complex obtained from

venom of bothrops atrax (viper)

Converts fibrinogen to fibrin

5. Hemocoagulase
↓ Bleeding and clotting time

Can be used locally as well as systemically

i.e., IV/IM/SC

Precipitates local proteins in bleeding site

6. Astringents
e.g., Tannic acid, ferric chloride, etc.

Absorbable

Swells up and assists clot formation

7. Oxidized cellulose
Used where arterioles cannot be ligated
Vascular block,
ADRs tissue necrosis,
nerve damage
8. Calcium alginate Absorbable hemostatic
sourced from seaweed

365
366 Pharmacology mind maps for medical students and allied health professionals

39.2 SYSTEMIC AGENTS

Vitamin K1 (phytonadione) From plant and animal source

Exists in different forms (all

are naphthoquinone derivative) Vitamin K2 (menaquinone) From intestinal bacteria

Vitamin K3 (menadione) Synthetic compound

Spinach, cabbage, cauliflower

Dietary source Meat, liver, milk, butter

Average daily intake 70–140 mcg/day

Bile is required to absorb

vitamin K1 and k2

Transported with LDL

Pharmacokinetics Stored in liver

Metabolized by glucoronide/
sulfate conjugation

Excreted in bile and urine

Essential for synthesis of

clotting factors (II, VII, IX)
Actions
Important for bone
development (osteocalcin)

Reduced absorption, due to

absence of bile salts

Liver disease Obstructive jaundice

Malabsorption, long-term
Necessary for synthesis of parenteral nutrition
clotting factors
Long-term broad spectrum As they inhibit commensal Required for vitamin K
Deficiency causes
antibiotics bacteria synthesis

↑ Bleeding tendency

Epistaxis

Signs/symptoms Hematuria

GI bleeding

Postoperative bleeding

Vitamin K1 (phytonadione) Oral, SC, IM, IV

Preparations
Vitamin K3 (menadiol
Water-soluble oral, IM IV
sodium diphosphate)
1. Prophylaxis and treatment of
bleeding associated with
vitamin K deficiency
vitamin K1 1 mg IM As they have underdeveloped
2. Newborn babies
is given routinely intestinal flora

Uses 3. Oral anticoagulant toxicity

4. Salicylate poisoning
associated hemorrhage

5. Obstructive jaundice
associated hemorrhage
Hypersensitivity reactions
Oral vitamin K is safe
ADRs Hemolysis
Parenteral therapy can cause
Hyperbilirubinemia

Esp. menadione
Kernicterus in newborn
hence it is not used

(Continued)
 Hemostatic agents 367

39.2 SYSTEMIC AGENTS (Continued)

Hemophilla

Antihemophilic globulin (AHG)

Sourced from pooled human plasma Use
deficiency

Acute hypofibrinogenemia
Contains factor VII with von
Willebrand’s factor
Hemophilia
Source from pooled human
Use
plasma/recombinant DNA technology
AHG deficiency
Given as IV infusion

Normalizes platelet adhesion

PPH
Inhibits PGIs synthesis, hence
↑ platelet aggregation
Menorrhagia
Use
Stabilizes capillary wall by Epistaxis
anti-hyaluronidase action No antifibrinolytic activity
Following tooth extraction

Route Oral, IM, IV

ADRs Hypotension, skin rashes

↑ Von Willebrand’s
Von Willebrand’s disease
factor and factors VIII

Normalizes bleeding time Hemophilia A

Use Congenital platelet defects

Uremia-induced bleeding

Synthetic analog of vasopression

NSAID-induced bleeding

Hypertension

Tachycardia

Hyponatremia
ADRs
Flushing

Water retention

Headache
Oxidation product of adrenaline
Epistaxis
6. Adenochrome monosemicarbazone Use
After tooth extraction, hematuria
Route: oral, parenteral

They contain all clotting factors

7. Fresh plasma/whole blood Concentrated plasma fractions of
fibrinogen factor VII, VIII, IX, and X
(for specific deficiencies)

Analog of amino acid lysine

Interacts with lysine binding Hence it inhibits both and

site of plasminogen and plasma hence stabilizes clot
Controls bleeding due to
8. Epsilon amino caproic acid (EACA) Given oral and IV
excess fibrinolytics

Surgery in hemophiliacs

Use Following tooth extraction

Hematuria, conjunctival
erythema, myopathy, muscle necrosis
Bleeding associated with
obstetric complications
Bleeding due to ↑ fibrinolytic activity
Use
Following tonsillectomy, prostatectomy,
9. Tranexemic acid Analog of EACA
More potent and long-acting tooth extraction, menorrhagia
than EACA
368 Pharmacology mind maps for medical students and allied health professionals

39.3 SCLEROSING AGENTS

Irritant substances

Injected locally in varicose

veins, piles, esophageal Sodium tetradecyl sulfate
varices

Sclerosing agents

This leads to local

inflammation, fibrosis and Phenol 5%
blockade of vein

e.g., Ethanolamineolate 5%

Polydocanol 3%

Sodium linoleate
 40
Anticoagulants

40.1 ANTICOAGULANTS – CLASSIFICATION

Heparin

Used in blood banks

1. In vitro Sodium citrate
to store blood

Sodium Heparin (unfractionated

Used in laboratory
oxalate/edetate heparin, UFH)

i. Indirect thrombin Low-molecular-weight

Enoxaparin, dalteparin
inhibitors heparins (LMWH)

Classification
Synthetic Fondaparinux

a. Parenteral

Lepirudin

ii. Direct thrombin

Bivalirudin
inhibitors

2. In vivo
Agratroban

i. Coumarin Warfarin, dicumarol,

derivatives acenocoumarol

ii. Inandione
b. Oral Phenindione
derivatives

iii. Direct thrombin

Dibigatran
inhibitors

369
370 Pharmacology mind maps for medical students and allied health professionals

40.2 PARENTERAL ANTICOAGULANTS – HEPARIN

Discovered by McLean,
a medical student

It was first isolated and high

∴
concentration was present in
liver, it was named “heparin”

Sulfated mucopolysaccharide,
glycosaminoglycan
Introduction
Strongest acid in body, strong
electronegative compound

Present in mast cells of liver,

lungs, and intestinal mucosa

Commercially sourced
from ox lung and
pig intestinal mucosa

Activates plasma
antithrombin III

Antithrombin III inhibits

LMWH selectively inhibits
activated thrombin and factors
factor X and not thrombin
IXa and Xa

Heparin accelerates this Hence there is ↑

reaction 1000 times clotting time, bleeding time
Mechanism of action
Selectively inhibits conversion
of prothrombin to thrombin
(low dose)

Antiplatelet activity
is seen (in high dose)

Stimulates lipoprotein lipase

Thus ↓
which hydrolyzes
plasma lipids
triglycerides and

It has high
∴
Parenteral i. Indirect thrombin Hence is given
Heparin Not absorbed orally molecular weight and a
anticoagulants inhibitors IV/SC
strong negative charge

As it can lead to
It is not to be given IM
hematoma formation

Onset after IV route Immediate

Onset after SC route 1–2 h

Pharmacokinetics

Metabolized by heparinase

Normalization of clotting time

after 2–4 h

Rx has to be monitored by
measuring aPTT or clotting time

As it has a large molecular

Hence can be used in
weight it does not
pregnancy
cross placenta

Then 1000–1500
IV infusion 5000 units bolus
units/hr

aPTT is maintained
at 1.5–2 times of control
Route and dose
Clotting time maintained
at 1.8–2.5 times the
normal mean aPTT value

SC route is used for 5000 units every

prophylaxis 8–12 h
 Anticoagulants 371

40.3 ADRs AND CONTRAINDICATIONS OF HEPARIN

Heparin has narrow

∴
therapeutic index

1. Bleeding Most common side effect

Prevented by dose control

and careful supervision

2. Hypersensitivity As it is sourced from bovine

reactions lung or porcine intestine

It induces platelet aggregation Hence there is a systemic

∴
∴ ↑ Venous thrombosis
and antiplatelet antibodies hypercoagulable state

Confirmed by heparin independent

platelet activation assay

1%–4 % more in patients who

3. Heparin-induced Circulating antibodies
∴
Incidence have received heparin in
thrombocytopenia (HIT) are already present
previous 3–4 months

This is less common with

LMWH

Immediate withdrawal of
ADRs Rx
heparin

Dose-dependent

4. Osteoporosis

Reversible

Seen in 0.5% patients

5. Alopecia Reversible

Occurs within 5–10 days of

treatment

As it inhibits aldosterone

6. Hypoaldosteronism This leads to hyperkalemia

Threatened abortion Heparin resistance

Hemophilia

Infective endocarditis

Hemorrhage (intracranial)

Contraindications Cirrhosis

Renal failure

HIT

Active TB

Neurosurgery
372 Pharmacology mind maps for medical students and allied health professionals

40.4 LOW-MOLECULAR-WEIGHT HEPARINS (LMWHs) AND HEPARIN ANTAGONIST

e.g., Enoxaparin, dalteparin,

reviparin etc.

Produced by chemical/enzymatic
treatment of standard
unfractionated heparin (UFH)

Similar efficacy to (UFH)

Better pharmacokinetic profile

Shorter chain

Inhibits only factor Xa and not

thrombin
Hence there is no need of monitor

Low-molecular-weight heparins aPTT/clotting time is unchanged

(LMWHs) However, monitoring is required in
renal failure patients
Levels of LMWH are measured by
anti Xa assay
Higher SC bioavailability

Longer duration of action

Advantages over UFH

No need of aPTT monitoring

Lower incidence of HIT,

osteoporosis

Prophylaxis and treatment of venous

thrombosis and pulmonary embolism

Uses Unstable angina

Maintain patency of tubes

during dialysis

Sourced from fish sperm

Given IV

1 mg neutralizes 100 units of

heparin

It is a strong base which

∴
Heparin antagonist Protamine sulfate It is a chemical antagonism
neutralizes strong acid

Recommended only for severe

heparin overdose

For mild overdose, stop heparin

Protamine itself is weak

Hence its overdose is avoided
anticoagulant
 Anticoagulants 373

40.5 SYNTHETIC HEPARIN DERIVATIVES, HEPARINOIDS, AND PARENTERAL DIRECT

THROMBIN INHIBITORS

e.g., Fondaparinux

Synthetic
pentasaccharide

Factor Xa inhibitor, acts by

binding to antithrombin

Given SC OD (as t½ is
17–21 h)
Synthetic heparin
derivatives
No need of monitoring
laboratory parameters

Low incidence of HIT

(lower than LMWH also)

Avoid in patients with

renal dysfunction
Prevention and treatment of
DVT and pulmonary embolism
Use
Thromboprophylaxis for patients
undergoing hip/knee surgery

Is similar to heparin

Heparinoids Heparin sulfate

May be responsible for
antithrombolytic activity
on vascular endothelium
Mixture of heparinoids

Recombinant hirudin
Inhibits Xa
analogs

Donaparoids Long-acting Directly inhibits thrombin

Used as alternative to
Inhibits its protease activity
heparin

Their activity is
∴
Inactivate fibrin-bound
Given SC Present in leech saliva independent of
thrombin in clots
antithrombin III

Produced by recombinant
Hirudin Given IV
DNA technology

Lepirudin and bivalirudin Requires aPTT monitoring

Parenteral direct
thrombin inhibitors Synthetic direct thrombin
No antidote is available
inhibitor

Given IV Used in patients with HIT

Agratroban
Caution is needed in patients
Used in HIT
with renal dysfunction

Bivalirudin is used in patients

Needs aPTT monitoring
undergoing coronary angioplasty

Due to the development There is risk of

of antibodies anaphylaxis
374 Pharmacology mind maps for medical students and allied health professionals

40.6 ORAL ANTICOAGULANTS – MECHANISM OF ACTION

AND PHARMACOKINETICS (WARFARIN)

e.g., Warfarin, dicumarol,

acenocumarol

Coumadin derivatives are

It has only in vivo activity
commonly used
Hence it is a vitamin K
antagonist
Warfarin has a structure similar
Mechanism of action
to vitamin K
Hence it competively interfere
with synthesis of vitamin K
It inhibits gamma carboxylation dependent clotting factors
of glutamate residue in
prothrombin, factor VII, IX, and X

Oral anticoagulants
Slow onset of action i.e., 1–3 days

Does not act on already

existing clotting factors

Complete oral absorption

t½ long, i.e., 40 h

High plasma protein

binding (99%)
Hence has a long duration of
action, nearly 2–5 days
Pharmacokinetics

Metabolism shows genetic

variation

Metabolized by CYP2CP

Slow metabolizers have

↑ risk of bleeding

As it crosses placental It is contraindicated during Unlike heparin,

barrier pregnancy which is safe

Warfarin available in 2 isoforms,

Levo form is more potent
levo and dextro
 Anticoagulants 375

40.7 USES AND ADRs OF WARFARIN

Prevents formation of
intravascular thrombus or
extension of already existing clot

It does not lyse already

Uses
formed clot

Treatment initiated with Along with simultaneous For delayed and continued
For immediate action
heparin/LMWH warfarin action

Prolonged hospitalization

Prolonged immobilization

Major surgery
i. Deep vein thrombosis (DVT)
and pulmonary embolism (PE)
Major trauma

Hemodialysis With low-dose aspirin

Prosthetic heart valves

Reduces incidence of myocardial

infarction
ii. Unstable angina

LMWH/UFH is used

↓ Extension
of thrombus

Reduces recurrence of MI and stroke

(combined with low-dose aspirin)
iii. Myocardial infarction (MI)
Also used during coronary
angioplasty

Heparin/LMWH is used

Long-term oral anticoagulants

iv. Atrial fibrillation
reduce the risk of stroke

Low-dose heparin inhibits

thrombin formation
v. Disseminated intravascular
Most serious and common
coagulation (DIC)
↓ Consumption of
clotting factors
Can occur anywhere

Bleeding Treatment is monitored by

frequent measuring of INR Stop treatment
(international normalized
ratio) of PT
Fresh frozen plasma/blood
To replenish clotting factors
Treatment depends on severity transfusion

Helps synthesize fresh

clotting factors
Fetal hemorrhage
∴
Antidote vitamin K1
ADRs
oxide IV
Onset after few hours
Teratogenicity Abortion

Skin necrosis Intrauterine death

Alopecia
376 Pharmacology mind maps for medical students and allied health professionals

40.8 DRUG INTERACTIONS OF WARFARIN

Drugs which inhibit

NSAIDs (aspirin)
platelet activity

Erythromycin

Ketoconazole

Cimetidine
Inhibitors of warfarins
hepatic metabolism
Chloramphenicol
Drugs potentiating
warfarin effect
Metronidazole

Alcohol

Salicylates
Drugs which displace
warfarin from
protein binding
Sulfonamides

Drug interactions Drugs which ↓

Tetracyclines By destroying GI flora
vitamin K

Rifampicin

Barbiturates

Enzyme inducers

Carbamazepine

Griseofulvin
Drugs reducing warfarin
effect

Drugs which ↓
Cholestyramine
warfarin GI absorption

Drugs which ↑
Oral contraceptives
clotting factors
 Anticoagulants 377

40.9 ORAL DIRECT THROMBIN INHIBITORS

e.g., Dabigatran

Rapid onset

Long-acting Hence used once daily

Oral direct thrombin Hence plasma levels is

Predictable absorption
inhibitors constant

No need of monitoring
Hence it is preferred and may
laboratory parameters
replace warfarin
for clotting

No major drug interaction

Prevention and treatment of

Use venous thromboembolism in
hip/knee replacement surgeries
378 Pharmacology mind maps for medical students and allied health professionals

40.10 DIFFERENCES BETWEEN HEPARIN vs. LMW HEPARIN

Heparin Low-molecular-weight heparin

1. Mol wt High Low

2. Source Natural Semi-synthetic
3. Thrombin inhibition Present Absent
4. Clotting parameters Effected Not effected
5. Laboratory monitoring Needed Not needed

6. SC bioavailability Low High

7. Duration of action 2–4 h (Short) 18–24 h (long)
8. Dose 4–6/day Once daily
9. Bleeding complications High Minimal

10. Thrombocytopenia High Low

40.11 DIFFERENCES BETWEEN HEPARIN AND DICUMAROL/WARFARIN

Heparin Dicaumarol/warfarin

1. Source Natural Synthetic

2. Chemistry Mucopolysaccharide Coumarin

3. Action In vitro and in vivo Only in vivo

4. Administration Parenteral (IV/SC) Oral

5. Onset Rapid (3–6 h) Slow (1–3 days)

6. Duration Short (2–4 h) Long (4–7 days)

7. Mechanism Stimulates antithrombin III Inhibits clotting factors

8. Antidote Protamine sulfate Vitamin K1 oxide

9. Usage For initiation For maintenance

10. Usage in pregnancy Used Not used as it is teratogenic

11. Cost Expensive Economical

12. Monitoring Measuring aPTT/clotting time Synthetic

 41
Antiplatelet agents

41.1 CLASSIFICATION AND ASPIRIN

i. Thromboxane synthesis
Low-dose aspirin
(TXA2) inhibitors

ii. Purnergic (P2Y12)

receptor antagonists/ADP Ticlopidine, clopidogrel
antagonists

iii. Phosphodiesterase
Antiplatelet agents Classification Dipyridamole
inhibitor

iv. Glycoprotein IIb/IIIa Abciximab, eptifibatide,

receptor antagonists tirofiban

v. Miscellaneous PGI2, cilostazol

Thromboxane A2 (TXA2)
causes platelet aggregation
Irreversibly acetylates
cyclooxygenase-1
Low-dose aspirin
(50–325 mg)
Hence inhibits the
formation of TXA2

This effect lasts for 7–10 Until fresh platelets are

days produced

PGI2 is responsible for

platelet inhibition
Aspirin

High dose aspirin inhibits

Hence efficacy ↓
both TXA2 and PGI2

When thrombosis occurs Termed aspirin

in spite of aspirin resistance (30% incidence)

Prophylaxis of MI
Use
and stroke

GI irritation and bleeding

ADRs
(dose related)

379
380 Pharmacology mind maps for medical students and allied health professionals

41.2 PURINERGIC RECEPTOR (P2Y12) ANTAGONISTS/ADP ANTIGONISTS

AND PHOSPHODIESTERASE (PDE) INHIBITORS

e.g., Ticlopidine, clopidogrel

Thienopyridine derivatives

Prodrugs, and structurally related

It inhibits ADP-induced platelet

aggregation by blocking purinergic
(P2Y12) receptors on platelets

Antiplatelet effect continues for 7–10 h

despite drug discontinuation

Given orally it has a slow onset,

i.e., 3–7 days

Action is dose-dependent Hence initial loading doses of 300 mg

produces effect within 5 h

Acute coronary syndrome

Purinergic receptor (P2Y12) Expensive as compared to aspirin

antagonists/ADP antagonists

MI

Additive effect with aspirin

Hence combination used in

Coronary angioplasty

Neutropenia

Transient ischemic attacks

Thrombocytopenia

ADRs

Bleeding

Clopidogrel is preferred over

ticlopidine it is safer
∴

Prasugrel Has a rapid onset of action

Newer agent Cangrelor is given as IV infusion

e.g., Dipyridamole

Levels, Hence inhibits platelet aggregation and

It inhibits PDE
∴ ↑ platelet cAMP causes vasodilation

With aspirin/warfarin to prevent

Phosphodiesterase (PDE) inhibitors thromboembolism patients with
prosthetic heart valves
Use

Transient ischemic attacks (TIAs) to

prevent stoke

ADRs Headache, no bleeding

 Antiplatelet agents 381

41.3 GLYCOPROTEIN IIB/IIIA RECEPTOR ANTAGONISTS AND MISCELLANEOUS

e.g., Abciximab, eptifibatide,

tirofiban

Fibrinogen and von Willebrand’s Induced by platelet agonists

And causes platelet
factor bind to GP IIb/receptor like thrombin, collagen, TXA2,
aggregation
on platelet surface etc.

This final step of platelet

aggregation is blocked

Abciximab Is a monoclonal antibody

Is a synthetic derivative
Eptifibatide
(peptide)

Tirofiban Is a non-peptide

Glycoprotein IIb/IIIa receptor

antagonists

They are given as IV infusion Coronary angioplasty

Percutaneous coronary
intervention

Use Unstable angina

Acute coronary syndromes

MI

ADRs Bleeding

e.g., Epoprostenol

Used during hemodialysis, as

an alternative to heparin

Prevents platelet aggregation,

and is a potent vasodilator
Prostacyclin i.e., PGI2

Short duration of action of

Hence given as IV infusion
2–3 min

Severe pulmonary hypertension

Miscellaneous
Other use

Circulatory shock As it is a vasodilator

PDE 3 inhibitor

Vasodilator and antiplatelet

Cilostazol
agent

Where it ↑ pain-free
Used in Intermittent claudication
walking distance
382 Pharmacology mind maps for medical students and allied health professionals

41.4 USES OF ANTIPLATELET AGENTS

As thromboprophylaxis

Stable angina pectoris To prevent MI Aspirin 75–150 mg/daily

1. Ischemic heart disease

Unstable angina pectoris 300 mg aspirin immediately With clopidogrel/abciximab

Reduces
Myocardial infarction reinfarction/mortality,
↑ survival

After angioplasty, stenting,

Post MI 75–150 mg aspirin long-term
coronary bypass surgery

2. Angioplastic coronary
intervention

Either alone or with

clopidogrel/abciximab/heparin

Dipyridamole/aspirin with
warfarin

3. Prosthetic heart valves

Reduces thromboembolic
complications

Also called “mini stroke”

Uses of antiplatelet agents

4. Transient ischemic attacks Aspirin ± dipyridamole

(TIAs) reduces frequency

Clopidogrel is an alternative

Oral anticoagulants/
5. Atrial fibrillation
antiplatelets

6. Intermittent claudication Cilostazol

7. Vascular grafts

8. Hemodialysis Epoprostenol (PGIs)

9. Severe pulmonary
Epoprostenol (PGIs)
hypertension
 42
Thrombolytics (fibrinolytics) and antifibrinolytics

42.1 THROMBOLYTICS (FIBRINOLYTICS) – INTRODUCTION, CLASSIFICATION,

AND INDIVIDUAL AGENTS

Breakdown the clot/thrombi

Activate natural fibrinolytic

system

Plasminogen circulates in plasma as

Introduction
well as is bound to fibrin

Tissue plasminogen activator (tPA)

promotes conversion of
plasminogen to plasmin

Plasmin lyses fibrin to fibrin

Hence lyses clot
Thrombolytics (fibrinolytics) degration products

Streptokinase
1st generation thrombolytics
Urokinase

Classification Alteplase

Reteplase
2nd generation thrombolytics
Tenecteplase

Sourced from β-hemolytic

Anistreplase
streptococci

As it is antigenic/pyrogenic It forms antibodies Hence leads to allergy

1. Streptokinase
Given as IV infusion Hence inactivates streptokinase

Past streptococcal infection ∴ Other

produces antibodies thrombolytics are preferred

Antibodies remain in circulation

for around 5 yrs

Initially isolated from human

Hence the name
urine

Now prepared from cultured

2. Urokinase
human kidney cells

Given initially as IV bolus, later

IV infusion

Anisoylated plasminogen
It is APSAC, i.e.,
streptokinase activator complex
3. Anistreplase
It is a long-acting streptokinase Hence suitable to use

Hence it preferentially activates

fibrin-bound plasminogen
It is a tPA
It spares free circulating
Produced by recombinant DNA plasminogen
4. Alteplase
technology

Given as initial IV bolus, then IV

infusion

Causes quicker reperfusion

5. Reteplase
Fewer chances of bleeding
complications

6. Tenecteplase Longer duration of action

383
384 Pharmacology mind maps for medical students and allied health professionals

42.2 USES, ADRs, AND CONTRAINDICATIONS

Aimed to restore coronary artery

patency

Immediate Rx reduces chances of

i. Acute MI
death

ii. Deep vein thrombosis and large Administered within 6 h of

The earlier the better
pulmonary embolism symptoms
Uses

iii. Ascending thrombophlebitis

iv. Peripheral vascular disease Intra-arterial therapy

Bleeding Major, serious, and common

Hypotension

ADRs

Fever

Hypersensitivity with
streptokinase

Bleeding disorders

Severe hypertension/diabetes

Recent trauma/surgery/
Contraindications
abortion/stroke

Liver damage

Peptic ulcers

Plasminogen

Streptokinase/ Fibrinolytics Antifibrinolytics EACA

Urokinase/tPAs (stimulate) (inhibit) Tranexemic acid

Plasmin
 Thrombolytics (fibrinolytics) and antifibrinolytics 385

42.3 ANTIFIBRINOLYTICS – USES AND CONTRAINDICATIONS

Inhibit fibrin/clot dissolution

Block conversion of
plasminogen to plasmin

e.g., EACA, tranexemic acid, Naturally occurring

aprotinin polypeptide

EACA (see previous

A protease inhibitor
pages)

Tranexemic acid (see Inhibits plasmin, trypsin,

previous pages) chymotrypsin, kallikrein

Protects platelets from

Aprotinin
mechanical injury

Prevents generation of clot

Cardiac surgeries (CABG)
and fibrinolysis
Antifibrinolytics

Used in Heart valve replacement

It is sourced from
∴
bovine lung and can lead to Overdose of fibrinolytics
hypersensitivity reaction

Overdose of fibrinolytics

PPH, menorrhagia

Tonsillectomy, prostate
surgery

After dental procedures (as

mouthwash) in hemophiliacs

Uses

Cardiac surgeries

Intravascular coagulation

Contraindications Bleeding peptic ulcer

Hematuria

Epistaxis, ocular bleeding

∴
Plasmin causes
Hereditary angioedema uncontrolled stimulation
of complement system
 43
Hypolipidemic drugs

43.1 CLASSIFICATION OF HYPOLIPIDEMICS

Atorvastatin

Simvastatin
1. HMG-CoA
reductase inhibitors
Rosuvastatin

Lovastatin

Gemfibrozil

2. Fibric acids Fenofibrate

Clofibrate

Classification of
Cholestyramine
hypolipidemics

3. Bile acid-binding
Colestipol
resins

Colesevalam

4. Inhibitors of VLDL
Nicotinic acid
synthesis and lipolysis

5. Dietary cholesterol
Ezetimibe
absorption inhibitor

Gugulipid

6. Miscellaneous

Omega-3 fatty acids

386
 Hypolipidemic drugs 387

43.2 HMG-CoA REDUCTASE INHIBITORS (STATINS)

Rate controlling
HMG-CoA reductase
enzyme in synthesis
enzyme
of cholesterol

Statins are structurally

Hence they ∴ There is ↓ in liver Hence there is ↑ So LDL from Hence there is ↓
competitively cholesterol in expression of LDL plasma goes to in plasma LDL
similar to HMG-CoA
inhibit the enzyme synthesis receptors in liver liver cholesterol and TG

HDL levels ↑ 10%

Also inhibit proliferation

of arterial smooth muscle

Anti-inflammatory antioxidant
effect stabilizes plaque

Mechanism
↑ Nitric oxide production by
endothelium, hence have
antiplatelet and
cardioprotective effects

As the synthesis of
Statins are
cholesterol is more in
administered at night
evening

Lovastatin and simvastatin

are prodrugs

Rosuvastatin is most
potent and long-acting

Atorvastatin is most
commonly used

First line in familial and

secondary hyperlipidemias
HMG-CoA reductase inhibitors (statins)

Uses Reduces mortality and

morbidity in CHD

MI, angina, stroke,

TIAs to ↓ LDL-C

Hepatotoxicity ↑ Serum
transaminase levels

ADRs Myalgia,
weakness

Myopathy Rhabdomyolysis
(0.1% incidence)

↑ Plasma
creatinine

Fibrates and
↑ Myopathy
nicotinic acid
Drug
interactions
Erythromycin,
Enzyme inhibitors ketoconazole, ↑ Toxicity
cyclosporine

Contraindications Pregnancy and

lactation
388 Pharmacology mind maps for medical students and allied health professionals

43.3 FIBRIC ACIDS (FIBRATES)

Stimulate peroxisome
Hence they ↑
proliferator-activated Leads degradation
lipoprotein lipase Which ↓ TG by 40%
receptor α (PPAR-α ) of TG rich VLDL
activity
in liver

Reduces hepatic
secretion of VLDL
e.g., Gemfibrozil,
clofibrate, fenofibrate
↑ HDL by 10%–15%

Mechanism
↑ Oxidation
of fatty acids in
liver and muscle

Reduces lipolysis
in adipocytes

Inhibit coagulation
and ↑ thrombolysis

Type III, IV, and V

hyperlipidemias Which ↑ TGs
Fibric acids (Fibrates)
Use
Severe hyper
DOC
triglyceridemias

Dyspepsia, GI upset Most common

Renal failure patients

Rhabdomyolysis in
ADRs
Patients on statins
↑ Risk of
Contraindicated in gall stones
pregnancy

↑ Effect of
warfarin and oral
hypoglycemics
 Hypolipidemic drugs 389

43.4 BILE ACID-BINDING RESINS (BAB – RESINS)

Hence they bind to

Resins are highly
bile acids, which are
positively charged
negatively charged

Bile acid is required for Hence cholesterol is Interrupt

And ↑
intestinal absorption not absorbed, binds enterohepatic
their excretion
of cholesterol bile acids in gut circulation
e.g., Cholestyramine,
colestipol, colesevalam
↑ Conversion of
cholesterol to bile acids
in liver
Mechanism
Hence ↑ hepatic
↑ Formation of ∴ ↓ Plasma
uptake of cholesterol
LDL receptor in liver LDL-C levels
from plasma

There is no effect
on HDL-C

It ↑ TG levels So avoid in patients

with raised TG levels

Primary
Bile acid-binding hypercholesterolemias
(BAB) resins

Taken with water/fruit

Uses Available as powders
juice before meals

Colesevelam is a tablet

Not absorbed, hence

Thiazides
no systemic side effects
ADRs
Unpalatability, bloating,
flatulence, constipation Digitalis
drug interactions

Drug interactions Hence reduces their Hence their

They bind to drugs e.g., Anticoagulants
absorption efficacy

Fat-soluble vitamin

Thyroxine, etc.
390 Pharmacology mind maps for medical students and allied health professionals

43.5 NICOTINIC ACID OR NIACIN

↓ TGs, LDL-C, and

High dose
HDL-C

Inhibits lipolysis in Hence ↓ VLDL

adipose tissue production in liver
Mechanism

Stimulates lipoprotein ∴ ↑ Hydrolysis

Thus reduces VLDL levels
lipase of TGs of VLDL

Most effective for

↑ HDL levels

Hypertriglyceridemia

Use

Low HDL levels

Prostaglandin induced

Niacin is Vitamin B Flushing Most common

Reduced by taking aspirin
30 min before niacin or To delay absorption
taking niacin after food
Itching

Hyperpigmentation

Hyperuricemia

ADRs

Hyperglycemia
Contraindicated during
pregnancy
Hepatotoxicity

Peptic ulcer

Arrhythmias
 Hypolipidemic drugs 391

43.6 DIETARY CHOLESTEROL ABSORPTION INHIBITOR, GUGULIPID,

AND OMEGA-3 FATTY ACIDS

It inhibits absorption
of dietary biliary
cholesterol by
enterocytes

It inhibits specific protein Hence it reduces Thereby ↑ plasma

NPC1L1, which absorbs hepatic cholesterol cholesterol clearance
luminal cholesterol

Mechanism

↓ LDL-C Statins inhibit But ↑ cholesterol

by 15%–20% cholesterol synthesis absorption from
intestine

Its effect is synergistic

Ezetimibe reduces
with statins,
cholesterol absorption But ↑ cholesterol
↓ LDL-C synthesis
from intestine
by 50%–60%

This combination prevents

intestinal cholesterol
absorption caused by statins
and ↑ cholesterol
synthesis caused by ezetimibe
Dietary cholesterol Ezetimibe
absorption inhibitor Mild
As monotherapy
hypercholesterolemia

Use

Partial statin responders As combination

ADRs Hepatic dysfunction

Dose 10 mg OD

“Gum guggul”
Source
(a plant resin)

Gugulipid ↓ Cholesterol and TGs

ADRs Diarrhea

Source Fish oils

Hence reduces TG
Activate PPAR-α
synthesis in liver

Additional
anti-inflammatory,
antiplatelet,
Omega-3 fatty acids antiarrhythmic property
Hypertriglyceridemia

Use

Rheumatoid arthritis

ADRs Nausea, belching

 VIII
Part    

Gastrointestinal pharmacology
 44
Drug therapy of peptic ulcer and GERD

44.1 CLASSIFICATION OF DRUGS USED FOR PEPTIC ULCER

Omeprazole

Pantoprazole

a. Proton pump inhibitors (PPIs) Esomeprazole

Lansoprazole

Rabeprazole

Cimetidine

Ranitidine

1. Inhibitor of gastric acid secretion b. H2 receptor blockers

Famotidine

Nizatidine

Pirenzepine

c. Antimuscarinic drugs

Telenzepine

d. Prostaglandin analogs Misoprostol

a. Systemic antacids Sodium bicarbonate, sodium citrate

Classification of drugs used

for peptic ulcer Magnesium hydroxide
2. Drugs that neutralize gastric acid
(antacids)

Aluminium hydroxide

b. Non-systemic antacids

Calcium carbonate

Sucralfate

3. Ulcer protective Magnesium trisilicate

Colloidal bismuth subcitrate (CBS)

Amoxicillin, metronidazole,
4. Anti-H. pylori agents clarithromycin,
H2 blockers, PPIs, tetracycline,
tinidazole, bismuth subsalicylate

Simethicone
5. Miscellaneous
Carbonoxolone

394
 Drug therapy of peptic ulcer and GERD 395

44.2 ANTACIDS – INTRODUCTION, TYPES, AND SYSTEMIC ANTACIDS

Weak bases, neutralize

gastric acid,
↑ gastric pH

No effect on acid
production

↓ Peptic activity

Introduction

Only symptomatic
relief

Rebound hyperacidity
due to
↑ gastric levels
30–60 min

Duration

Taken on empty stomach

Sodium bicarbonate,
1. Systemic
sodium citrate
Types of antacids
Aluminium hydroxide,
magnesium hydroxide,
2. Nonsystemic
Antacids magnesium trisilicate,
(drugs that neutralize calcium carbonate
gastric acid)
Sodium bicarbonate
(NaHCO3)

Rapid symptomatic
relief, short duration

Very effective

NaHCO3 + HCI → NaCl + Hence systemic

Intestinal absorption
H2O + CO2 alkalosis

CO2 released comes

out as eructation Rebound hyperacidity

Systemic antacids
Abdominal
Drawbacks Due to released CO2
distention and belching

Caution in patients
Sodium retention with MI and CCF

Due to simultaneous
Hypercalcemia, alkalosis, consumption of
Milk-alkali syndrome
renal impairment calcium-rich products or
calcium carbonate

Hyperacidity

Peptic ulcer

Use
Alkalinize urine,
to treat acidic
drugs poisoning

Metabolic acidosis
396 Pharmacology mind maps for medical students and allied health professionals

44.3 NONSYSTEMIC ANTACIDS

Reacts with HCI – chloride

salt and H2O

Mg (OH) + 2HCI → MgCl2 + 2H2O

CaCO3 + 2HCI → CaCl2 + H2O

Chloride salts react with

Hence no HCO3 present Hence no systemic alkalosis
intestinal HCO3

Slow acting

Astringent and demulcent,

protective coat over ulcers
Aluminium hydroxide
Relaxes GI smooth muscles Thus causes constipation

Binds phosphate absorption,

hypophosphatemia

Osmotic purgatives Mild diarrhea

Quick and prolonged action

Magnesium salts
Less rebound hyperacidity

Nonsystemic antacids Insoluble compounds Hypermagnesemia in renal

impairment

Rapid effect, long duration

Chalky taste

Released CO2 causes belching,

Calcium carbonate
distention

Constipation, hypercalcemia

Milk-alkali syndrome, kidney

On long-term use
stones

Aluminium salts – slow and

lon-acting + Magnesium salts –
fast acting

Aluminium salts – constipation +

Magnesium salts – diarrhea
Antacid combinations
Aluminium salts – delays gastric
emptying + Magnesium salts –
hastens gastric emptying

Combination has additive

effects, lower dose of each
 Drug therapy of peptic ulcer and GERD 397

44.4 USE, ADRs, AND DRUG INTERACTIONS

Adjuvant in hyperacidity reflux

esophagitis, peptic ulcer

Tablets to be
chewed and swallowed

Use

Gels more effective than

tablets

Given after food for

longer action

Systemic alkalosis

Sodium retention NaHCO3

Constipation,
Al salts
hypophosphatemia

ADRs

Mg salts Diarrhea

Ca carbonate Hypercalcemia, hypercalciuria

Rebound acidity

Hence ↓ absorbed iron,

Form insoluble and
Drug interactions
non-absorbable complexes
tetracyclines, digoxin, So 2 h gap between
fluoroquinolones, ketoconazole, administration
sulfonamides and anticholinergic of these drugs and antacids
drugs
398 Pharmacology mind maps for medical students and allied health professionals

44.5 PROTON PUMP INHIBITORS (PPIs)

Proton pump or H+K+ATpase is

membrane-bound enzyme

Final pathway in gastric acid secretion

(PPIs most efficacious to inhibit gastric acid secretion basal and stimulated both)

e.g., Omeprazole (prototype) esomeprazole, lansoprazole, pantoprazole, rabeprazole

Proton pump
Inhibitors (PPIs) PPIs are inactive prodrugs

Mechanism Accumulate in parietal cells

Activated in acidic environment

to sulfonamide

Sulfonamide binds covalently to SH group of H+K+ATpase

Binding irreversible

Single dose inhibits gastric acid secretion by 90%–95%

Acid secretion resumed after 3–4 days of stopping After new H+ K+ATpase enzyme is synthesized

Given orally 30 min before food as enteric coated/delayed release capsules/tablets Avoids degradation by gastric acid

Maximum number of proton

pumps are active

Food absorption by 50%

Pharmacokinetics t½ short i.e., 1.5 h, but effect lasts for 24 h irreversible inhibition and accumulation in parietal cell
(hit and run drugs)

High plasma protein binding Hence drug interactions with

phenytoin, warfarin, benzodiazepines
Microsomal enzyme inhibitors
Causes toxicity
Pantoprazole, lansoprazole, rabeprazole,
and esomeprazole available for IV use Most powerful acid suppressants
Drugs inhibiting
acid secretion

Inhibits all phases of acid secretion

Better than H2 blockers in terms of onset and healing

Duodenal ulcers 4 wks therapy for healing

i. Peptic ulcer disease Gastric ulcers 6–8 wks therapy for healing

Acute bleeding ulcers IV PPIs

Stress ulcers (Curling’s ulcer) Prophylactic in critically ill patients

NSAID-induced ulcers Prevention and treatment

H. pylori-induced ulcers Combined with 2/3 antibiotics

Uses ii. Dyspepsia H2 blockers (PPIs)

Better than H2 blockers

iii. Gastro esophageal reflux disease (GERD)
May require long-term maintenance therapy

Hypergastrinemia with multiple pepticulcers (gastric secreting tumor)

Drugs of choice
iv. Zollinger–Ellison syndrome
High dose for healing ulcers
Generally well tolerated
Definitive treatment – surgery
Long-term treatment ↓ vitamin B12
absorption Long-term treatment – inoperative cases

Hypergastrinemia – gastric tumors

ADRs
Atrophic gastritis

Drug interactions
∴
It is enzyme inhibitor Toxicity of phenytoin,
warfarin, benzodiazepines
Antacids, H2 blockers reduces acidity, thus ↓ efficacy of PPI
 Drug therapy of peptic ulcer and GERD 399

44.6 H2-RECEPTOR BLOCKERS

Competitively blocks
H2 receptors
on parietal cell surface

↓ Acid secretion – basal,

stimulated,
and nocturnal

Reduces pepsin and

intrinsic factor secretion

More effective in
inhibiting nocturnal
acid secretion

Less efficacious as
e.g., Cimetidine, compared to PPIs
ranitidine,
famotidine, nizatidine Single dose causes
60%–70% reduction
in acid secretion
Cimetidine
Cimetidine – prototype
but many side effects

Short duration of
action 6–8 h

↑ Levels of phenytoin,
Potent enzyme
digoxin, warfarin,
inhibitor
theophylline, etc.

Displaces
∴
Antiandrogenic effect testosterone from Thus ↑ prolactin
androgenic receptors levels

∴ Causes gynecomastia,
↓ Estrogen impotence, ↓ sperm
metabolism count, loss of libido,
galactorrhea Like headache, Symptomatic relief in
confusion, hallucinations days, healing in weeks
Crosses BBB ∴ CNS side effects
Seen esp. in
H2 receptor Duodenal ulcer 4–6 wks
elderly
blockers

i. Peptic ulcer disease Gastric ulcer 6–8 wks

In critically ill patients

Stress ulcer IV for prevention
and treatment

Less effective
NSAID induced ulcers
than PPIs

But PPIs more effective

ii. GERD
and commonly used
Uses
Surgery definitive
treatment
iii. Zollinger–Ellison
syndrome
PPIs DOC

iv. Prevent aspiration

Used pre-operatively
More potent and longer pneumonia
Ranitidine
acting than cimetidine

v. Dyspepsia PPIs preferred

Generally well
tolerated

ADRs Dyscrasias (rare)

Contraindicated in
pregnancy and lactation
400 Pharmacology mind maps for medical students and allied health professionals

44.7 ANTIMUSCARINIC AGENTS AND PROSTAGLANDIN ANALOGS

e.g., Pirenzepine,
telenzepine

Selectively block M1,

muscarinic receptor,
inhibit acid secretion

Low efficacy,
Antimuscarinic agents
acid inhibition 40%–50%

Used as adjuvant

Dry mouth, constipation,

Anticholinergic side
ADRs blurring of vision,
effects
retention of urine

PGE2 and PGI2 secreted

by gastric mucosa

Inhibit acid secretion

↑ Mucus
production and
mucosal blood flow

Cytoprotective

Bind to PG receptor (EP3)

on parietal cell–cAMP

Synthetic PGE analog Misoprostol

Prostaglandin analogs PGE2 analog Enprostil

All given orally

Use – prevention of
NSAID-induced ulcers

ADRs–diarrhea,
abdominal cramps

Uterine contractions, hence

contraindicated in
pregnancy

Expensive

Rarely used
 Drug therapy of peptic ulcer and GERD 401

44.8 ULCER PROTECTIVES

Complex of aluminium hydrated

sucrose
In acidic gastric medium (pH 4)
sucralfate polymerizes to form
sticky gel
Gel adheres to ulcer
base and protects it
Negatively charged sucralfate
attaches to positively charged
proteins in ulcer base
Sucralfate
Also precipitates proteins at Forms a barrier against
ulcer base acid pepsin

Releases PG and epidermal

growth factor locally Promotes healing

Enhances mucus and bicarbonate

secretion, mucosal defense

One tablet (1 g) given 1 h

before meal

Prevention of bleeding from

stress ulcers

Reduce risk of aspiration

pneumonia

GERD with esophagitis

Oral mucositis
Use
Radiation proctitis

Rectal ulcer

Burns
Ulcer protective

Bed sores

Nausea

ADRs Constipation Due to aluminium

Aluminium toxicity Long-term in renal failure

↓ Absorption of digoxin,
tetracyclines, ketoconazole,
fluoroquinolones, etc.
Drug interactions
Antacids, H2 blockers, Acid pH is required for
∴
PPIs ↓ absorption activation

e.g., Bismult subsalicylate,

colloidal bismuth subcitrate (CB)

Chelate proteins on ulcer base Protective coat on ulcer base

Enhances mucus and PGs

Inhibits growth of H. pylori

Promote ulcer healing in

Bismult salts 4–6 wks
Bismuth–excreted through gut
Bismuth subsalicylate
dissociates in stomach to
Salicylate–absorbed

Constipation, black stools,

ADRs Bismuth black tongue, dizziness

Combination regimens for H. pylori

infections

Use Prevention of traveler’s diarrhea

Should be used for short duration

402 Pharmacology mind maps for medical students and allied health professionals

44.9 MISCELLANEOUS AGENTS

Contains simethicone Used in combination

and dimethicone with antacids
Methylpolysiloxane
(MPS)

Reduces foaming Relieves flatulence

Local anesthetic on
gastric mucosa

1. Antifoaming agents Oxethazine Reduces pain in gastritis

Combined with antacids

Forms froth on gastric

contents

Sodium alginate

Prevents effects of GERD

Miscellaneous Steroid-like compound

Obtained from
glycyrrhizic
acid in root of licorice

Alters mucus
composition, makes
it viscid

Attaches to ulcer
base and protects it

2. Carbenoxolone

Inhibits pepsin activity

Enhances PGs action

duration

Hence Na/H2O
Steroid-like effect Edema, weight gain
retention

Not preferred
 Drug therapy of peptic ulcer and GERD 403

44.10 ANTI-H. PYLORI AGENTS

Prevents/delays resistance

Prevents relapse

Hastens healing

H. pylori–Gm –ve, rod-shaped

Triple/quadruple therapy Eradicate H. pylori infection
bacteria

Causes gastritis, gastric ulcer,

2 wks (1 wk not so
duodenal/gastric carcinoma, Efficacy up to 95% Duration
effective)
recurrence of ulcers
Anti-H. pylori agents
Amoxicillin, clarithromycin,
Ammonia produced by urease
Antimicrobials tetracyclines, metronidazole,
activity damages cells
tinidazole

Combination regimens for

PPIs, H2 blockers, CBS
H. pylori eradication

Lansoprazole 30 mg BD +
Triple therapy (2 wks) clarithromycin 500 mg BD +
amoxicillin 1 g BD

Lansoprazole 30 mg BD four
Quadruple therapy (2 wks) times a day + bismuth
subsalicylate 525 mg QID

Following the regimen, PPIs to

be continued for 6 wks to
promote healing
404 Pharmacology mind maps for medical students and allied health professionals

44.11 GASTROESOPHAGEAL REFLUX DISEASE (GERD) – MANAGEMENT

Antacids

Forms a protective
Sodium alginate mechanical barrier between
mucosa and acid

PPI’s provide
symptomatic relief
hastens healing in 4–8 wks

Usually long-term Rx
MILD GERD treated with Moderate to severe GERD
needed (years)

Prokinetics as adjuvants

Avoid heavy meals

Non-pharmacological
Avoid late night dinner
therapy

Stop smoking and alcohol

 45
Emetics and antiemetics

45.1 NEUROTRANSMITTERS AND DRUGS INVOLVED IN VOMITING

Acetylcholine

Histamine

Neurotransmitters
involved in vomiting
5-Hydroxytryptamine
(serotonin)

Dopamine

Anticancer drugs

Opioids

Ergot derivatives

Cholinomimetics

Drugs inducing
vomiting

Emetine

Levodopa

Dopamine agonists

Bromocriptine

405
406 Pharmacology mind maps for medical students and allied health professionals

45.2 EMETICS

Induce vomiting

e.g., Mustard powder,

hypertonic salt solution,
apomorphine, and ipecac
Derivative of morphine

Used in certain poisoning

Given SC/IM

Apomorphine
Stimulate dopamine
receptors in brain

Emetics As it is a morphine
derivative it causes
respiratory depression

Source is root of Cephalis

ipeccuanha

Contains alkaloid emetine

Given as syrup

Ipecac Acts within 15 min

Acts directly on CTZ and

reflexly by irritating Children
gastric mucosa

Safe in children Unconscious patients

Corrosive and caustic

Contraindications
poisons

Poisoning due to CNS

stimulants

Kerosene poisoning
 Emetics and antiemetics 407

45.3 CLASSIFICATIONS OF ANTIEMETICS

Vomiting is a protective reflex

It removes toxic substances

from GIT
Antiemetics
At certain times vomiting is
not useful, but troublesome
It leads to dehydration, electrolyte Hence it needs to be
disturbances, fatigue controlled by antiemetics

Ondensetron
1. 5-HT3 antagonists
Granisetron

Metoclopramide
2. Dopamine D2 antagonists
(prokinetics)
Domperidone

Scopolamine (hyoscine)
3. Anticholinergics
Dicyclomine

Promethazine

Dimenhydrinate

Diphenhydramine
4. H1 blockers
(antihistaminics)
Cyclizine

Doxylamine
Classification

Cinnarizine

Chlorpromazine

5. Neuroleptics Haloperidol

Prochlorperazine

Aprepitant
6. Neurokinin receptor
antagonists
Fosaprepitant

Dronabinol
7. Cannabinoids
Nabilone
Dexamethasone
a. Corticosteroids
Betamethasone
8. Adjuvants
Lorazepam
b. Benzodiazepines
Alprazolam
408 Pharmacology mind maps for medical students and allied health professionals

45.4 5-HT3 RECEPTOR ANTAGONISTS (5-HT3RA)

GI nerve endings including

vagal afferents are rich in
5-HT3 receptor

e.g., Ondansetron, 5-HT3 liberated in GIT is an

granisetron important inducer of vomiting

Which stimulates 5-HT3 receptors

Anticancer agents, radiation, and
Mechanism in gut, nucleus tractus solitarius Thereby initiates vomiting
GI infection releases GI 5-HT
(NTS) and area postrema in brain

5-HT3 RA blocks 5-HT3 receptor in

Thereby prevents vomiting
GIT, CTZ, and NTS

They are powerful antiemetics

Given orally and parenterally (IV)

Granisetron is more potent and

long-acting than ondansetron

Pharmacokinetics

Palonosetron is longest acting

Transdermal patch of granisetron

I. 5-HT3 receptor antagonists
for prophylaxis of chemotherapy-
(5-HT3 RA)
induced vomiting

i. Chemotherapy-induced
nausea/vomiting (CINV)

ii. Radiation-induced
nausea/vomiting (RINV)

Used for prevention and iii. Postoperative nausea/

treatment of vomiting (PINV)

iv. Drug-induced nausea/

vomiting (DINV)

v. Hyperemesis of pregnancy

Generally well tolerated

ADRs Headache, dizziness

QT prolongation (dolasetron)
 Emetics and antiemetics 409

45.5 DOPAMINE D2 RECEPTOR ANTAGONISTS (PROKINETICS)

Hastens gastroduodenal
Prokinetics motility and gastric
emptying
Metoclopramide

i. D2 receptor blockers

Domperidone
II. Dopamine D2 receptor
antagonists (prokinetics)

ii. Cholinomimetics Bethanechol

iii. Anticholinesterases Neostigmine

Classification of prokinetics

iv. Motilin receptor

Erythromycin
agonists

Cisapride

v. Others Mosapride

Itopride
410 Pharmacology mind maps for medical students and allied health professionals

45.6 METOCLOPRAMIDE

Acts as antiemetic/prokinetic
by central and peripheral actions
Blocks D2 receptor in CTZ
Central actions
High dose also blocks 5-HT3
receptors in CTZ and NTS

Blocks D2 receptors
(antagonist)
Peripheral (GIT) actions
Stimulates 5-HT4 receptors Hence ↑ Ach release
Mechanism
(agonist) from myenteric neurons

↑ Gastro-duodenal emptying

↑ Pressure in lower
esophageal sphincter (LES)

↑ Forward peristalsis of
esophagus
Both central and peripheral actions
has following effects on upper GIT
↑ Tone and amplitude of
antral contraction
Rapid oral absorption
Relaxes pyloric sphincter
Hence promotes forward
Can be given IM/IV movement of upper GI contents
No/mild ↑ in peristalsis of
small intestine and colon
Onset of action within minutes after Hence prevents reflux
Pharmacokinetics
IV and 30–60 min after oral route esophagitis

Short t½ of 4 h CINV

Crosses BBB and placenta and is Except levodopa-induced

secreted in milk DINV
vomiting

i. Antiemetic (prophylaxis and

RINV
treatment)

PONV

Disease-associated nausea
vomiting (DANV)

Symptomatic relief by
Metoclopramide

↑ tone of LES
ii. GERD
As adjuvant to PPIs/
H2 blockers

Diabetic (autonomic
neuropathy)
Uses

Postoperative gastroparesis
iii. Gastric stasis due to
Vagotomy

Antrectomy

iv. Endoscopy To assist passage of tubes

To prevent aspiration pneumonia

v. Pre-anesthetic before general anesthesia in
emergency surgeries

vi. Intractable hiccups

Drowsiness, dizziness, diarrhea

Treated with central
Acute dystonias, due to D2 Spasm of muscles of face, anticholenergics (benztropine)
blockade tongue, neck, and back
ADRs
Due to D2 blockade in basal
Extrapyramidal symptoms (EPS) Rigidity, tremors, etc.
ganglia

Gynecomastia, galactorrhea, Inhibitory effect of dopamine

Due to D2 blockade
menstrual disturbances in prolactin release is removed

↑ Absorption of diazepam
∴ Not used to treat
Drug interaction ↓ Absorption of digoxin L-dopa-induced vomiting

Metoclopramide blocks D2 Hence it interferes with actions

Levodopa
receptor in basal ganglia of L-dopa
 Emetics and antiemetics 411

45.7 DOMPERIDONE, CHOLINOMIMETICS, ANTICHOLINESTERASES,

AND MOTILIN RECEPTOR AGONISTS

Similar actions like

metoclopramide

Blocks D2 receptor in CTZ

But does not cross BBB

EPS and other neuropsychiatric

side effects are minimal

However, ↑ prolactin
Domperidone levels

It is a preferred antiemetic

Controls vomiting induced by

∴
L–dopa/bromocriptine without It does not cross BBB
reducing their efficacy

Dryness of mouth

Diarrhea
ADRs
Galactorrhea

e.g., Bethanachol Menstrual disturbances

Stimulates M3 muscarinic
Hence ↑ GI motility
receptor in gut
Cholinomimetics
Used in past to treat
gastroparesis

Not preferred presently due to

cholinergic side effects

e.g., Neostigmine

↑ GI motility, causes
Anticholinesterases
colonic evacuation

Acute colonic pseudo-

Use
obstruction (Ogilvie’s syndrome)

e.g., Erythromycin

Motilin is a peptide hormone

It hastens peristalsis
in upper GIT

Motilin receptor agonists Erythromycin stimulates motilin

Hence it hastens peristalsis
receptors

Diabetic gastroparesis
Use
↓ Small intestinal
motility
412 Pharmacology mind maps for medical students and allied health professionals

45.8 ANTICHOLINERGICS AND ANTIHISTAMINICS (H1 BLOCKERS)

Effective in motion
sickness, not in other
types of vomiting

It blocks afferent impulses

from vestibular apparatus to
vomiting center
e.g., Hyoscine (scopolamine),
dicyclomine
It also relaxes GI smooth
muscles

Hyoscine

It is taken 30 min
Duration is 6 h
before journey

III. Anticholinergics
Transdermal patch is
Duration is 3 days
applied behind ear

ADRs Sedation, dry mouth

Used for vomiting of

Dicyclomine pregnancy and motion
sickness

e.g., Promethazine,
diphenhydramine, cyclizine,
doxylamine, cinnarizine

Blocks H1 receptors in
area postrema

Also possess central

anticholinergic properties

IV. Antihistaminics
(H1 blockers) Acts due to sedative
action also

Motion sickness

Use

Postoperative vomiting

Combined with pyridoxine

Doxylamine
for morning sickness
 Emetics and antiemetics 413

45.9 NEUROLEPTIC, NEUROKININ RECEPTOR ANTAGONISTS, AND CANNABINOIDS

e.g., Prochlorperazine

It acts by blocking D2
receptor in CTZ
Drug/disease-induced
vomiting
It has additional anticholinergic
and antihistaminic property
Vomiting due to Uremia
Use
Not effective in motion
V. Neuroleptic
sickness

Not as effective as 5-HT3

RA in CINV and RINV

Sedation

EPS
ADRs
Dry mouth
e.g., Aprepitant, fosaprepitant
Hypotension
It blocks neurokinin receptor 1
(NK1) in area postrema
Given IV
Fosaprepitant
VI. Neurokinin receptor Converted to aprepitant
antagonists

Aprepitant Given orally

CINV (in combination with

Use
5-HT3 RA + corticosteroids)

Dizziness, weakness,
ADRs
diarrhea

Major psychoactive
constituent of marijuana

It is ∆ 9
tetrahydrocannabinol

Stimulates cannabinoid
receptor (CB1) in NC

Stimulates appetite
e.g., Dronabinol, nabilone
VII. Cannabinoids Given orally
CINV (reserve antiemetic
Dronabinol
when others do not respond)
Use
Appetite stimulant

Hallucinations

Euphoria

Dysphoria
ADRs
Behavioral changes

Hypotension

Drug dependence
414 Pharmacology mind maps for medical students and allied health professionals

45.10 ADJUVANTS AND PREFERRED ANTIEMETICS

e.g., Dexamethasone, betamethasone,

methylprednisolone

Used in combination with

5-HT3 RA/D2 blockers for CINV

i. Corticosteroids Controls delayed vomiting

MOA – unclear Anti-inflammatory property or

May act due to Inhibition of PG synthesis or

VIII. Adjuvants

Stimulating glucocorticoid
e.g., Lorazepam, alprazolam
receptor in NTS

It controls psychogenic/
anticipatory vomiting
ii. Benzodiazepines
Acts by sedative, amnesic,
and antianxiety properties

Used as adjuvants with other

antiemetics to control CINV

5-HT3 RA + aprepitant +
corticosteroids
1. CINV
D2 blockers + corticosteroids +
H1 blockers + lorazepam

Chlorpromazine

2. DINV

Metoclopramide

5-HT3 RA (ondansetron)

3. PONV
Preferred antiemetics
Metoclopramide

Doxylamine

4. Morning sickness

Pyridoxine

Hyoscine

5. Motion sickness Cinnarizine

Promethazine
 46
Drug treatment of constipation, treatment
of IBS, and IBD

46.1 INTRODUCTION AND CLASSIFICATION

Facilitate evacuation of formed

Laxatives
stools, they have mild action

Purgatives/cathartics Cause evacuation of watery

Drug treatment of Introduction stools; they have a powerful action
constipation These terms are used
interchangeably

Carminatives Promote expulsion of gases from gut

Bran

Methylcellulose

Husk
1. Dietary fiber
Isphagula (isabgol)

Agar

Plantago seeds

Sodium (DOSS)
2. Stool softeners–docusate
Liquid paraffin (emollients/
stool-wetting agents)

Phenolphthalein

Bisacodyl

3. Stimulant or irritant
Castor oil
purgatives
Sodium picosulfate
Senna
Anthraquinone derivatives
Cascara sagrada
Magnesium sulfate
Classification
Magnesium hydroxide

Magnesium citrate

Sodium phosphate

Sodium sulfate

4. Osmotic purgatives Sodium potassium tartarate

Lactulose

Sorbitol

Polyethylene glycol (PEG)

5-HT4 agonists Prucalopride, cisapride (banned)

5. Miscellaneous Opioid antagonists Methylnaltrexone, alvimopan

Chloride channel activator Lubiprostone

415
416 Pharmacology mind maps for medical students and allied health professionals

46.2 BULK LAXATIVES

Dietary fiber consists of cell

walls and other parts of
fruits and vegetables

These are indigestible,

hydrophilic vegetables
e.g., Bran, methylcellulose, substances
agar, isphagula,
plantago seeds They absorb water, swell up
and ↑ the bulk of stools
Mechanism
They ↑ the volume,
and ↓ the viscosity of
intestinal contents

They forms large, soft, and

solid stools

This causes mechanical Thus stimulates peristalsis

distention and promotes defecation

Bulk laxatives
Onset 1–3 days

Helpful in irritable bowel

syndrome symptoms like
constipation and diarrhea

Sufficient water intake

prevents intestinal
obstruction

Avoid in patients with GI

obstruction

Interferes with
absorption of many drugs

Residue of flour of cereals

1. Bran
contains 40% fiber

Contains natural mucilage

2. Isphaghula, plantago Forms gelatinous mass

seeds (psyllium) with water

More palatable than bran

Semisynthetic derivative
3. Methylcellulose
of cellulose

Mucilaginous substance
from marine algae
4. Agar

Contains hemicellulose
 Drug treatment of constipation, treatment of IBS, and IBD 417

46.3 STOOL SOFTENERS

An anion detergent

Hence there is
Reduces the surface
accumulation of ∴ It
tension of intestinal
fluid and fat softens stools
contents
in feces

Onset 1–3 days

1. Docusate sodium
(dioctyl sodium ↑ Absorption of
sulfosuccinate or many drugs
DOSS)

↑ Absorption of Hence they are not

liquid paraffin given together

Given orally or
retention enema

Hence it can cause

It is bitter nausea, abdominal
Stool softeners
pain

Mineral oil, and

is unpalatable

Chemically inert,
and not digested

Hence helps smooth

Lubricant action
evacuation
2. Liquid paraffin

Useful in cardiac Due to its Hence avoid at

patients, because it Lipoid pneumonia aspiration bedtime and lying
avoids straining into lungs down position

Malabsorption of
fat-soluble vitamins
A,D,E, and K
ADRs

Leakage of fecal Hence soiling of

matter from anus undergarments

∴
They can get
Intestinal
absorbed into
paraffinomas
intestines
418 Pharmacology mind maps for medical students and allied health professionals

46.4 STIMULANT PURGATIVES

Direct action on GI mucosa

and neurons

↑ PGs and cAMP

Inhibit Na+ K+ ATPase Hence they ↑ secretion Thereby stimulates

activity in intestinal mucosa of water and electrolytes peristalsis

Act on colon
Mechanism
Produce semifluid stools

Long-term use can lead

to atonic colon
High–dose can cause
fluid/electrolyte imbalances
Contraindicated during As it can cause reflex
pregnancy stimulation of uterus

e.g., Cascara sagrada, senna

Sourced from plants

Bacteria liberate active Which stimulate myentric

anthraquinones intestines plexus in colon
1. Anthraquinones
So the effect is
Onset 6–7 h Hence it is given at bedtime
seen in morning
Hence it is contraindicated
Secreted in milk
during lactation
Discoloration of urine and melanotic
Long-term use can lead to
(black) pigmentation of colon
An indicator, and was
discovered accidentally
Acts on large intestine,
onset 6–8 h
Produces soft,
semiliquid stools

2. Phenolphthalein Produces cramps

Undergoes enterohepatic
Which prolongs duration
circulation

Stimulant purgatives Pink color skin lesions

ADRs Cardiac toxicity

Similar to phenolphthalein Colic

Activated in bowel
Which stimulates colon
by esterases

Onset 6–8 h Hence given at bed-time

Given as oral tablet (enteric

coated) or rectal suppository
Rectal suppository acts
3. Bisacodyl
within 15–30 min
Local inflammation and
Popular agent
irritation (proctitis)
Anal soreness, due to
ADRs
leakage of contents
Hence not used for
10 days at a time
To empty bowel before endoscopy,
Use
surgery or radiological investigations

Similar to bisacodyl

4. Sodium picosulfate Activated by colonic bacteria

Used orally at bedtime

onset after 6–8 h
∴

Metabolized in upper
intestine to ricinoleic acid
Local irritant, hence it
stimulates intestinal motility
5. Castor oil
One of the most powerful
and oldest agents
However, it causes cramps,
so is not used
 Drug treatment of constipation, treatment of IBS, and IBD 419

46.5 OSMOTIC PURGATIVES

Powerful and fast-acting

Solutes that are not absorbed,

retained in intestinal lumen

Osmotically retain water hence

Mechanism
the intestinal contents ↑

Hence they distend the bowel,

Magnesium salts release
stimulate peristalsis,
cholecystokinin also
and assist evacuation

Evacuation of fluid stools

is within 1–3 h
Non-absorbable salts
Osmotic purgatives
These include
Non-absorbable sugars
Saline purgatives like Mg
hydroxide (milk of magnesia)
Mg sulfate (epsum salt), Na
phosphate, Na sulfate, Na K
tartarate (Rochelle’s salt)
Lactulose, sorbitol, glycerine

Polyethylene glycol

They can cause

∴
Avoid in children, renal failure
CNS/CVS depression

Na salts avoided in
cardiac patients

Synthetic disaccharide of
fructose and galactose

Not absorbed

Colonic bacteria convert it

to lactic, acetic acids and
short-chain fatty acids

These exert osmotic effect

Lactulose
Also inhibits growth of colonic
ammonia-producing bacteria

Reduces absorption of
ammonia by ↓ pH

Thus lowers blood

ammonia levels

Hence used in hepatic coma,

ammonia worsens coma
∴

Sorbitol Similar to lactulose

Similar to lactulose,
Lactilol
more palatable

Used as rectal suppository

Glycerine
or enema

Non-absorbable sugar

Balanced isotonic solution

is given with PEG

This avoids electrolyte

disturbances
Cleaning bowel before
Polyethylene Glycol (PEG)
endoscopy
Use
3–4 L is given over 2 h
PEG powder + water for
chronic constipation

There is no flatulence or
abdominal cramps
420 Pharmacology mind maps for medical students and allied health professionals

46.6 MISCELLANEOUS AGENTS AND USE OF LAXATIVES/PURGATIVES

e.g., Prucalopride,
cisapride

1. 5-HT4 receptor
Have a prokinetic action
agonist

Used in severe chronic

constipation, not responding
to other laxatives

e.g., Lubiprostone

Derivative of prostanoic acid

2. Chloride channel
activator This stimulates
Opens chloride channels in Hence causes secretion
intestinal motility
small intestine of chloride-rich fluid
in 24 h
Miscellaneous
Chronic constipation,
Use
irritable bowel syndrome

e.g., Methylnaltrexone,
alvimopan

Block opioid receptors in GIT

Hence does not

There is no crossing of BBB antagonize analgesic
effect of opioids

Opioid-induced In comatose and

3. Opioid antagonists Use
constipation terminally ill patients

Methylnaltrexone Given SC once in 2 days

Given orally

Alvimopan Postoperative ileus

Short-term use (1 wk)

1. Acute functional
Bulk laxatives as it can cause
constipation
CVS toxicity
2. Avoid straining at
stools (CVS patients, eye Bulk laxatives/docusates
surgery, hernia)
3. Hepatic coma (to
reduce blood Lactulose
ammonia)
4. Pre-operative (GI
Use of laxatives/
surgery, radiology Osmotic purgatives/bisacodyl
purgatives
investigation)
5. Following
anthelmintics to expel Osmotic purgatives
worms

6. Drug poisoning
Osmotic purgatives
elimination from gut

7. Constipation in
Lactulose
children/pregnancy

Intestinal obstruction

Contraindications
Undiagnosed acute
abdomen
 Drug treatment of constipation, treatment of IBS, and IBD 421

46.7 DRUGS CAUSING CONSTIPATION, LAXATIVE ABUSE,

AND NONPHARMACOLOGICAL MEASURES

Opioids

Anticholinergics

Iron

Drugs causing
constipation

Calcium channel blockers

Due to anticholinergic
Tricyclic antidepressants
action

Due to anticholinergic
Antihistamines
action

Due to stimulant laxatives

Causes loss of electrolytes, loss

of calcium, malabsorption,
irritable bowel syndrome
Laxative abuse

Clear patient misconception

of bowel habits

Normal variations in bowel

motions 3/day to 2/wk

Fiber-rich diet

Adequate fluid intake

Nonpharmacological
measures

Physical activity

Use laxatives/purgatives
if above measures fail
422 Pharmacology mind maps for medical students and allied health professionals

46.8 TREATMENT OF IRRITABLE BOWEL SYNDROME (IBS)

No specific cause

Manifested as abnormal
bowel functions

Diarrhea/constipation,
abdominal pain

Stress, food allergy,

Cause emotional disturbances,
lack of dietary fiber

For constipation Isphagula (dietary fiber)

For diarrhea Loperamide

Benzodiazepines, newer
For anxiety
antidepressants

Selective 5-HT3 receptor

antagonist

Inhibits reflex activation Hence ↓ colonic

of GI smooth muscle motility
Aloesetron
Women with IBS prominent
Use diarrhea unresponsive
to other drugs

ADRs Constipation, colitis

Partial 5-HT4 agonist

↑ Gastric emptying

Treatment of Irritable
bowel syndrome (IBS) ↑ Chloride
secretion in colon
Tegaserod

Use IBS prominent constipation

Diarrhea

10-fold ↑ risk of
ADRs
heart attacks and stroke

Hence it has been

This is due to inhibition
Reserpine derivative withdrawn in many
of 5-HT1B
countries

An antispasmodic

Also a direct GI relaxant

Indirectly reduces colonic

hypermotility

Mebeverine ↓ Na+ ion

permeability of
smooth muscle

↓ K+ ion efflux
of smooth muscle

Use IBS, dysentery

Dizziness, constipation,
gastritis
ADRs
No anticholinergic side
effects
Other antispasmodics Dicyclomine, drotaverine
 Drug treatment of constipation, treatment of IBS, and IBD 423

46.9 INFLAMMATORY BOWEL DISEASES (IBD) AND TREATMENT

Comprise ulcerative colitis

and Crohn’s disease

Diarrhea, bleeding, abdominal

Manifestations discomfort, anemia,
weight loss
Inflammatory bowel
diseases (IBD) i. Aminosalicylates Sulphasalazine, mesalamine

ii. Glucocorticoids Prednisolone, budesonide

Classification
Azathloprine, methotrexate,
iii. Immunosuppressants
6-mercaptopurine (6-MP)

iv. Biological response Anti-TNF therapy,

modifiers anti-integrin therapy

Prodrug

Colonic bacteria breaks

it down
5-ASA acts locally as
Aminosalicylates It liberates 2 components – anti-inflammatory
5-aminosalicylate (5-ASA) +
sulfapyridine Sulfapyridine is absorbed
systemically

Diarrhea, allergy,
Hence it produces side
megaloblastic anemia,
effects
SJ syndrome

Is 5-ASA

Delayed-release capsules
Well tolerated, has minor
Mesalamine
side effects
pH-dependent tablets

Given as
1. Aminosalicylates
Retention enema
Made up of 2 molecules of
5-ASA with azo link
Suppository

Olsalazine Colonic bacteria splits

2 molecules

Has poor absorption, hence

has less side effects

Contain mesalamine and

inert carrier

Split into 5-ASA, released

Balsalazide
into colon

Used in mild–moderate IBD

(Continued)
424 Pharmacology mind maps for medical students and allied health professionals
46.9 INFLAMMATORY BOWEL DISEASES (IBD) AND TREATMENT (Continued)
Prednisolone (oral)
Methylprednisolone (oral,
parenteral)
Hydrocortisone (enema,
suppository)
Budesonide (oral)
2. Glucocorticoids
Used for short-term in
moderate–severe IBD
IBD of distal bowel (distal
ileum and colon)
IBD of sigmoid colon or
rectum
Long-term therapy in
steroid-dependent IBD
e.g., Azathioprine,
methotrexate,
6-mercaptopurine (6-MP) of remission in active IBD
3. Immunosuppressants
Uses
Steroid-unresponsive IBD
i. Anti-tumor necrosis
factors (anti-TNF) therapy
4. Biological response
modifiers
ii. Anti-integrin therapy
Oral therapy
Retention enema
For induction and
maintenance
Steroid-dependent IBD
∴
TNF is pro-inflammatory
e.g., Infliximab
in IBD
These agents are
monoclonal antibodies
to TNF
Moderate–severe IBD
Use unresponsive to other
therapies
Expensive,
ADRs
↑ infection risk
e.g., Natalizumab
Are adhesion molecules
on leukocyte surface
Integrins
They bind to other
adhesion molecules on
These agents are vascular endothelium
monoclonal antibodies
to integrins
They bind integrins on Hence block their migration
inflammatory cells and inflammatory process
Crohn's disease
Use unresponsive
to other therapies
Expensive,
ADRs ↑ susceptibility to
infections
 47
Drug treatment of diarrhea

47.1 PRINCIPLES OF DIARRHEA TREATMENT AND ORS

i. Fluid and electrolyte replacement

ii. Specific therapy to treat the cause

Principles of diarrhea
treatment
iii. Antimotility and antisecretory agents

∴
It is life-saving in infants death
Fluid and electrolyte replacement
is usually due to dehydration

NaCl 2.6 g

Simple, safe, cheap, and life-saving KCl 1.5 g

WHO–formula Na citrate 2.9 g

Glucose and citrate

Glucose 13.5 g
↑ Na absorption in ileum

Citrate is more stable than bicarbonate Water 1 L

5 g table salt (one pinch)

Home-made ORS 20 g sugar

Dissolve both in 1 L of boiled and cooled

For severe dehydration – IV fluids
water

Oral rehydration solution Improved ORS

(ORS)

Additional amino acids Na absorption

Super ORS But are expensive

Rice-based ORS (40–50 g/L)

Cheap
provides glucose and amino acids
Wheat, maize, or potato can be used as Hence is preferred in
alternative to rice developing countries
Also used in heat stroke, burns, after
ORS
trauma/surgery

5 mL/kg/h in children 50 mL/kg over 4–6 h

Dose 50 mL/kg over 4–6 h in mild dehydration

100 mL/kg over 4–6 h in moderate

dehydration

425
426 Pharmacology mind maps for medical students and allied health professionals

47.2 SPECIFIC THERAPY

Viral, bacterial or
Cause of diarrhea
protozoal infection

Viral cause is usually Hence no antibiotics are

self-limiting required

Ciprofloxacin 500 mg BD ×
i. Shigella
5 days

Ciprofloxacin 500 mg BD ×
ii. Campylobacter jejuni
5 days

Mild bacterial diarrhea Ciprofloxacin 500 mg BD ×

ii. Specific therapy iii. E.coli
too is self-limiting 5 days

Ciprofloxacin 500 mg BD ×
iv. Salmonella
5 days

Doxycycline 100 mg BD ×
v. Vibrio cholerae
5 days

Metronidazole 400 mg Followed by diloxanide

Entamoeba histolytica
BD × 5 days furoate 500 mg TDS × 7

Metronidazole 200 mg
Giardia lamblia
TDS × 5 days
 Drug treatment of diarrhea 427

47.3 ANTIMOTILITY AND ANTISECRETORY AGENTS AND ADSORBANTS

e.g., Pectin, kaolin, chalk,

and activated charcoal

Pectin Sourced from apples

Offer only symptomatic
relief in non-infective
diarrhea Hydrated magnesium and
Kaolin
aluminium silicate
Adsorbants
Adsorbs intestinal
microorganisms and
toxins, and coats them
They are not absorbed
hence no systemic
side effects
They ↓ Hence 2-h interval
absorption of concurrent between their
medications administration

↑ Systemic invasion

Intestinal perforation
Avoided in infective
diarrheas
∴
Slow clearance of
iii. Antimotility and pathogens
antisecretory agents and
adsorbants
Toxic megacolon

Natural opium alkaloid

Stimulates opioid receptors Hence reduces GI

i. Codeine peristalsis and
in GI smooth muscles
↓ secretions
Used for symptomatic
treatment of diarrhea

Structurally similar to
pethidine

Very potent antidiarrheal

Abuse liability in high Hence it is combined with ∴

Atropine will cause
atropine to discourage
ii. Diphenoxylate doses abuse side effects
Antimotility agents
Respiratory depression

Paralytic ileus in children

ADRs
Hence contraindicated in
Toxic megacolon
children

Analog of opiate, acts

Banned in many countries
on µ-receptors in GIT

There is no crossing
∴
Selective GI action Hence less CNS actions
of BBB

Powerful antidiarrheal

Reduces GI motility,
↑ anal sphincter
tone
↓ Secretion induced
by E. coli and cholera
toxin
iii. Loperamide
Less sedating and less
addicting

Most commonly used

Used in acute, chronic, and

traveler’s diarrhea

Onset: 1–2 h
Duration: 12–18 h

Contraindicated in As it can lead to paralytic

ileus, toxic megacolon, and
children 4 < years
abdominal distention
428 Pharmacology mind maps for medical students and allied health professionals

47.4 ANTISECRETORY AGENTS AND PROBIOTICS

Active metabolite thiorphan

Prevents degradation of enkephalins
(µ/δ agonist)
Inhibit enkephalinase
(in gut and peripheral tissues)
↓ Intestinal secretions
Enkephalins are GI neurotransmitters

Hence it corrects hypersecretion of

They have antisecretory property
water and electrolytes

There is no change in intestinal

motility
i. Racecadrotil (prodrug)
Quick onset

Used in symptomatic treatment

of secretory diarrhea

Used only for short duration

not >7 days

Can be used in children

ADRs Flatulence, nausea, drowsiness

Synthetic analog of somatostatin

↓ GI motility and secretions

Somatostatin actions ↓ Secretion of gastrin, secretin,

cholecystokinin, growth hormone,
insulin, glucagon, 5-HT, pancreatic
ii. Octreotide Octreotide is long-acting polypeptide and vasoactive intestinal
peptide (VIP)

Given SC
Antisecretory agents
GI secreting tumors causing diarrhea
Use
Diarrhea due to vagotomy, dumping
syndrome and AIDS
It is antisecretory and antimotility
Diarrhea due to opioid withdrawal
Use
iii. Clonidine Diarrhea due to diabetic autonomic
neuropathy

ADRs Hypotension, mental depression

Lactobacillus acidophilus,
Lactobacillus sporogenes

They colonize the intestine

↑ Growth of commensal
saprophytic flora

It alters gut pH
iv. Probiotics
Inhibits the growth of pathogenic
organisms in gut

Used in antibiotic-associated
diarrhea

Available as tablets, powders

Curd/buttermilk

Home-based probiotics
They are cheap alternative to
synthetic probiotics
 Drug treatment of diarrhea 429

47.5 ANTISPASMODICS

Atropine derivatives Propantheline, dicyclomine

Related to papaverine

Antispasmodics
Direct smooth muscle relaxant

Also an analgesic

Drotaverine

Hence ↑ cAMP/cGMP,
Inhibits PDE
causing relaxation

Renal, intestinal, biliary colic,

Uses
IBS

Dizziness, flushing,
ADRs
constipation
 IX
Part    

Endocrine pharmacology
 48
Hypothalamic and pituitary hormones

48.1 HYPOTHALAMIC AND PITUITARY HORMONES – TYPES, MODES,

AND MECHANISM OF ACTION

Hypothalamic
regulatory
hormones

Pituitary
hormones

Peptides Insulin

Glucagon
Hormone is
substance
produced
by specialized
cells in specific Parathyroid
glands and hormones
transported
in circulation to
distance where
it acts on
Adrenocortical
target tissues
hormones

Types of
Steroids
hormones

Sex steroids

Adrenaline

Catecholamines

Noradrenaline

Hypothalamic
and
pituitary
hormones Thyroxine (T4),
Others triiodothyronine
(T3)

e.g., Somatostatin

Cell membrane

Bind to cell
↑ cAMP
membrane Effects
concentration
receptors

Site and mode

of action Steroid hormones Steroid receptor Binds to a specific
Synthesis of
Cytoplasm bind to receptors complex enters binding site Effects
proteins
in cytoplasm nucleus on DNA

Bind to
Thyroid Synthesis of
Nucleus nuclear Effects
hormones proteins
receptor

432
 Hypothalamic and pituitary hormones 433

48.2 HYPOTHALAMIC HORMONES

Growth hormone release-

inhibiting hormone

Stimulates anterior Present in hypothalamus,

pituitary to parts of
secrete growth hormone CNS, pancreas and GIT

Sermorelin is GHRH Inhibits secretion of GH,

Growth hormone-
analog used TSH, PRL, insulin, glucagon
releasing hormone (GHRH)
to diagnose GH deficiency and intestinal secretions

Somatostatin Very short-acting Synthetic analog

Octreotide Long-acting Acromegaly

Secreted by hypothalamus Used in Hormone-secreting tumors

Stimulates release of
Thyrotropin-releasing TSH (thyroid-stimulating GH receptor antagonist
Pegvisomant Bleeding esophageal varices
hormone (TRH) hormone) from used in acromegaly
anterior pituitary

Used in diagnosis of
Protirelin Synthetic analog of TSH
thyroid disorders

Releases ACTH and

β-endorphins from
anterior pituitary
Corticotropin-releasing
Hypothalamic hormones factor (CRF)
Used in diagnosing
Cushing’s disease

Secreted in pulsatile
manner

Regulates secretion of
gonadotropins i.e.,
FSH and LH

Used in diagnosing
hypogonadism

For treatment of
Administered in
infertility and delayed
pulsatile manner
puberty

Inhibits gonadotrophin
secretion
Continuous
administration
Used in prostatic
Gonadotrophin–
cancers
releasing
hormone (GnRH)
Pharmacological
More potent GnRH
orchiectomy/oophorectomy
analog
in prostate cancer
Leuprolide

Used for Uterine fibroids

Endometriosis

Is a synthetic compounds
Hence, ↓ secretion
Cetrorelix that binds and blocks Hence delays ovulation
of LH, FSH
pituitary GnRH receptors

Used in in vitro
fertilization

GnRH antagonist

Produces less ovarian

hyperstimulation

Also used in uterine

fibroids and
endometriosis
434 Pharmacology mind maps for medical students and allied health professionals

48.3 ANTERIOR PITUITARY HORMONES

1. Growth hormone (GH)

2. Prolactin (PRL)

3. Gonadotropins
(FSH and LH)
Anterior pituitary
hormones
4. Adrenocorticotropic
Hormone (ACTH)

5. Thyroid-stimulating
hormone (TSH)

6. Melanocyte-stimulating
hormone (MSH)
 Hypothalamic and pituitary hormones 435

48.4 GROWTH HORMONE (SOMATOTROPHIN)

Peptide hormone secreted

by anterior pituitary

Regulated by 2 i.e., GHRH and somatostatin

hypothalamic hormones (GHRIH)

Promotes growth of all

organs and tissues except brain

Are mediated by somatomedin or

Anabolic actions insulin-like growth factors (IGF)
produced in liver
Functions
Causes lipolysis and protein
synthesis

Due to peripheral insulin

Hyperglycemia
antagonistic action

Deficiency in children leads to Dwarfism

Hypersecretion in children leads to Gigantism

Growth hormone
(somatotrophin)
Hypersecretion in adults leads to Acromegaly

GH deficiency in children
and adults

Chronic renal failure

Uses

Catabolic conditions Burns, AIDS

Abused by athletes to
promote growth

Somatostatin analogs Like octreotide

Inhibits synthesis and release

of GH
Like bromocriptine and
cabergoline
Dopamine receptor
Drugs to treat acromegaly
agonists
Paradoxically ↓ GH
secretion

A GH receptor antagonist

Pegvisomant
For patients not responding
to somatostatin analogs
436 Pharmacology mind maps for medical students and allied health professionals

48.5 CORTICOTROPIN (ADRENOCORTICOTROPIC HORMONE – ACTH), THYROID-

STIMULATING HORMONE (TSH, THYROTROPHIN), AND GONADOTROPINS
Controls synthesis and
release of glucocorticoids,
mineralocorticoids, and
androgens from adrenal
Corticotropin cortex
(adrenocorticotropic
hormone – ACTH)
Used in diagnosis
adrenocortical
insufficiency

Simulates
Thus regulates thyroid
production and secretion of
function
thyroid hormones

Thyroid-stimulating
hormone (TSH,
thyrotropin)
To test thyroid function

Used

↑ Uptake of
radioactive iodine
in thyroid carcinoma
Follicle-stimulating
hormone (FSH) and
luteinizing hormone (LH)

Produced by anterior
pituitary

Regulate gonadal function

Stimulate follicular
Gonadotropins
development in hormone

Stimulate ovarian
steroidogenesis

Amenorrhea and infertility

Promote spermatogenesis
in men

In vitro fertilization To time ovulation

Menotropins, i.e.,
combination of FSH and
Uses
LH is obtained from urine
of postmenopausal women
Undescended testes

Gonadotropin deficiency
in males
 Hypothalamic and pituitary hormones 437

48.6 PROLACTIN

Also called lactogenic

Peptide hormone
hormone

Promotes growth and

development of breasts during
pregnancy

Stimulates milk production

along with other hormones like
estrogens and progesterones

Deficiency leads to Lactational failure

Prolactin Excess leads to Galactorrhea

Release prolactin releasing

Suckling stimulus
factor from hypothalamus

Estrogens and progesterones

also stimulate prolactin
release
Unlike other anterior
pituitary hormones
Control of prolactin is mostly
Regulation of secretion
inhibitory
Dopamine is inhibitory
hormone secreted by
hypothalamus
Dopamine agonist inhibit
Not used clinically
prolactin secretion

Dopamine antagonist Chlorpromazine, haloperidol,

↑ prolactin secretion metoclopramide
438 Pharmacology mind maps for medical students and allied health professionals

48.7 HYPERPROLACTEMIA AND DOPAMINE RECEPTOR AGONISTS

Semisynthetic ergot-
derived dopamine
agonist

Acts on D2 receptors

Relatively common
disorder
Dopamine is
Dopamine is a Produces various
∴
↓ Prolactin ∴
It is dopamine prolactin
neurotransmitter in motor, behavioral, and secretion agonist release inhibiting
brain endocrine effects
Caused by prolactin- hormone (PRIH)
secreting pituitary
tumors or dopamine
antagonists Paradoxically
Pharmacological ↓ GH ↑ GH levels in
Hyperprolactemia Endocrine actions
actions levels in patients of normal people
acromegaly
Tumors treated by
surgery,
radiation, or drugs
Relieves symptoms of
Hyperprolactinemia parkinsonism due to
dopamine deficiency
Postoperatively most
patients require
dopamine
receptor agonists
Following delivery like
To suppress lactation
in still birth or abortion

Dopamine receptor
Bromocriptine
agonists

Acromegaly

Uses

Parkinsonism

Restless leg syndrome

Prolactinomas

Nausea, vomiting Due to CTZ stimulation

Due to α adrenergic
Adverse effects Postural hypotension
block

Hallucinations,
confusion, and
psychosis
 49
Thyroid hormones and antithyroid agents

49.1 THYROID HORMONES – REGULATION AND SYNTHESIS

Thyroxine (T4) and triiodothyronine Are secreted by thyroid gland

(T3)

Calcitonin is secreted by Parafollicular, “C” cells

Calcitonin Regulates calcium metabolism

T4 is less active precursor of T3

Their secretion is regulated by TSH

which is secreted by anterior pituitary

TSH secretion is inhibited by free

Thyroid hormones
thyroid hormone levels
Children leads to cretinism
Deficiency in
Adults leads to myxedema

Excess hormones Leads to thyrotoxicosis

Drugs for treating hyperthyroidism

are called antithyroid drugs

Hyperthyroidism is caused due to

benign or malignant conditions of thyroid
Active transport of iodide ions (I) into follicular cells
1. Iodide trapping
Done by basement membrane protein sodium/iodide Inhibited by thiocyanate and perchlorate
symporter ions by competing with iodide

Iodide ion is oxidized to iodine by peroxidase enzyme

Iodine combines with tyrosine residues of

thyroglobulin molecule
2. Oxidation and iodination
Forms monoiodotyrosine (MIT) and
diiodotyrosine (DIT)

High levels of iodide in follicular Thiourea drugs persistently blocks

cells transiently inhibits peroxidase peroxidase

It is the final step of synthesis

Synthesis of thyroid hormones

3. Coupling MIT + DIT → T3

DIT + DIT → T4

Is controlled by TSH

Involves proteolysis of iodinated thyroglobulin

4. Hormone release
and exocytosis

It releases MIT, DIT, T3, and T4 Proteolysis in inhibited by high

levels of intrafollicular iodide

Most of hormone released from thyroid is T4

5. Peripheral conversion of T4 to T3 T4 is less active

Propylthiouracil, propranolol, and glucocorticoids

inhibit peripheral T4 → T3 conversion

439
440 Pharmacology mind maps for medical students and allied health professionals

49.2 MECHANISM OF ACTION, PREPARATIONS, AND THERAPEUTIC USES

Similar to steroid
hormones
Mechanism of
action
T3 combines with Synthesis of various
T3 and T4 enters cell T4 is converted to T3 Activation of genes Responses
nuclear receptor proteins

Levothyroxine (T4)
Tablets and IV
available as

Liothyronine (T3, Not commonly

Preparations Tablets, parenteral
triiodothyronine) available as available

Combination of T4 and T3
It could be sporadic or
tablets are available in
endemic
ratio 4:1
Congenital absence of
Sporadic thyroid, or defective
thyroid hormone synthesis

Extreme deficiency
Endemic
of iodine
Replacement therapy
in hypothyroid states Should be started
Rx immediately to avoid
mental retardation
1. Cretinism
Early detention and Rx
ensures normal physical and
mental development

Levothyroxine 10–15 mg/kg daily

Replacement Lifelong

Cretinism due to hypothyroidism

in mother can be prevented
by treating the mother
By levothyroxine
50 mcg daily
Results from ↓
thyroid activity ↑ Gradually over
2. Hypothyroidism
2–3 wks depending
in adults
on TSH levels
Rx
Full single dose orally
Young adults in morning on
empty stomach
Elderly and patients with
Medical emergency coronary artery Low dose 12.5–25 mg
disease
Infection, trauma,
Therapeutic uses Precipitated by exposure to cold or
inadequate treatment
Hypothermia, Hypotension,
Hypoglycemia, Hypoventilation,
Manifestations Bradycardia, Lactic acidosis
and Coma

3. Myxedema coma IV levothyroxine or via

nasogastric tube

IV hydrocortisone

Rewarming with
blankets without
direct heat
Rx
Correction of electrolyte
e.g., Hyponatremia
imbalance
Due to deficiency if
iodine in diet
Ventilator support
Prevented by iodination of
4. Endemic goiter
common salt (iodized salt)
Antibiotics, if infection is
precipitating factor
T4 suppresses TSH and
non-toxic goiter regresses

T4 causes temporary
remission
5. Thyroid carcinoma

Used after surgery

 Thyroid hormones and antithyroid agents 441

49.3 HYPERTHYROIDISM AND CLASSIFICATION OF ANTITHYROID DRUGS

Excess of circulating
thyroid hormones
Hyperthyroidism Autoimmune disorder

Most common cause Graves disease

Hyperthyroidism, diffuse
Characterized by goiter, IgG antibodies that
activate TSH receptors
1. Thyroid hormone
↓ The levels of synthesis inhibitors Propylthiouracil,
thyroid hormone (thioamides or thiourea methimazole, carbimazole
derivatives)

2. Inhibitors of iodide
Antithyroid Reduce synthesis or
trapping (anion Thiocyanates, perchlorates
drugs release or both
inhibitors)

Iodine, Na or K iodine,
Classification 3. Release inhibitors
organic iodide

4. Thyroid tissue-
Radioactive iodine (131 I)
destroying agents

β blockers (propranolol,
5. Others
atenolol), dexamethasone
442 Pharmacology mind maps for medical students and allied health professionals

49.4 THIOAMIDES (THIOUREA DERIVATIVES)

Inhibit peroxidase enzyme,

which convert iodide to iodine

Inhibit iodination of tyrosine

residues in thyroglobulin

Inhibit coupling of
iodotyrosines (MIT and DIT)
Mechanism of
action Propylthiouracil inhibit peripheral
deiodination of T4 to T3 more as
compared to other thioamides
Large doses stimulate release
of TSH, causing thyroid
enlargement

Signs and symptoms subside

after 3–4 wks of treatment

Well absorbed orally

Gets accumulated in
thyroid gland

Propylthiouracil is highly
bound to plasma proteins

Very little crosses the placenta

1. Thioamides e.g., Propylthiouracil, Pharmacokinetics
and milk concentration is minimal
(thiourea derivatives) methimazole, carbimazole
However, carbimazole and
methimazole cross the
placenta and is secreted in milk

Propylthiouracil is fast-acting
but carbimazole is long-acting

Carbimazole is a prodrug
of methimazole

Skin rashes Are most common

Include fever, joint pain,

Allergic reactions
hepatitis, nephritis, etc.

Most dangerous but Agranulocytosis

rare side effect (incidence 0.1%)

Can occur during first few weeks

Adverse effects But can occur later also
or months of therapy

Regular WBC counts should be

performed and monitored

Reversible on stopping drug

Drug should be stopped i.e., Sore throat

at first sign of agranulocytosis or fever

(Continued)
 Thyroid hormones and antithyroid agents 443

49.4 THIOAMIDES (THIOUREA DERIVATIVES) – USES (Continued)

Needs long-term treatment

i. Graves disease Patients euthyroid after

(diffuse toxic goiter) 8–12 wks

Later, small maintenance dose

is adequate

ii. Toxic nodular As an alternative to surgery,

goiter e.g., elderly patients

Patients of hyperthyroidism are

iii. Preoperatively
made euthyroid and then operated

Rare but severe

iv. Hyperthyroidism
Propylthiouracil is preferred As it does not cross placenta
during pregnancy

Uses
Preferred in lactating mother As it is not secreted in milk

Thyroid crisis

Sudden, severe flareup of

thyrotoxicosis

Can be life-threatening

By stress, infection, trauma, surgery,

Precipitated
inadequate Rx of thyrotoxicosis

Fever, tachycardia, profuse sweating, restless-

Manifestation ness, confusion, nausea, vomiting, diarrhea,
v. Thyroid storm pulmonary edema, CCF, later coma and death

Propylthiouracil

Potassium iodide (Oral/rectal)

IV hydrocortisone

Controls symptoms and

Propranolol (β blocker) ↓ conversion
of T4 to T3
Rx

Tepid sponging

IV fluids

Sedation

Immediate supportive therapy

444 Pharmacology mind maps for medical students and allied health professionals

49.5 ANION INHIBITORS

e.g., Thiocyanates,
perchlorates

Block uptake of iodide by

thyroid

2. Anion inhibitors

Are highly toxic, and have

Hence not used clinically
unpredictable effects

Cabbage, cigarette smoke,

Na nitroprusside ↑ May cause hypothyroidism
the levels of thiocyanate
 Thyroid hormones and antithyroid agents 445

49.6 IODINE AND IODIDES

Oldest agents to
treat Inhibit almost all steps of thyroid hormone synthesis and release
hyperthyroidism
Inhibits organification of
Produce
iodine
paradoxical
effects in Action is transient Thus thyroid escape
therapeutic doses occurs after 2 days
Gland becomes firm, less
Mechanism of
vascular and shrinks in size
action
over 10–14 days

Given Orally as Lugol’s iodine or Potassium iodide solution 3 drops 3 times daily

Iodine is converted in intestine to iodide which is then absorbed

Iodides also inhibit the

synthesis of thyroid
hormone for 1–2 days
Lugol’s iodine
Known as Wolff-Chaikoff effect
5% iodine with 10% potassium
iodide

Preparations Povidone iodine 5%-10% solution

2% iodine with 2.4% sodium

Tincture iodine
iodide

Preoperative before
thyroidectomy

Iodine is started 10 days To make thyroid firm and less

3. Iodine and iodides

before surgery vascular

Iodide acts rapidly to reduce the

Thyroid storm
release of thyroid hormones

Prophylaxis iodized salt to

Uses
prevent endemic goiter Tincture iodine Used to clean skin before surgery

Used to treat pharyngitis and

Antiseptic Mandl’s paint
tonsillitis

Iodine ointment As fungicide in ringworm

Potassium iodide for treating

Expectorant
cough

Type III hypersensitivity

Allergic reactions
Skin rashes, conjunctivitis, swelling
of lips, rhinitis, vasculitis, Nausea, vomiting, diarrhea,
fever, and lymphadenopathy metallic taste

Metallic taste, excessive salivation, Corrosion, perforation of mouth

Chronic overdose can
cause iodism
lacrimation, burning sensation in
oral cavity, running nose,
sore throat, and GIT
Acute toxicity with 3–4 gms can
be fatal
Manifestations (as it is an irritant)
Vesication, desquamation and
corrosion of skin and mucous
membrane with brownish
yellow stains
Emesis induction or
Inhalation causes edema of lungs gastric lavage is Contraindicated
nephritis, renal failure contraindicated

Anaphylactic reactions Administer starch or

flour solution
Adverse effects (30 g/L of water)
Delirium and stupor
Milk can also
Iodine toxicity
benefit
Management
Sodium thiosulfate Converts iodine to
Hypothyroidism
1%–5% is antidote harmless iodide

20% alcohol for skin

Chronic poisoning with iodide salts
lesions
Erythema, urticaria, acne, Supportive
Iodism (mimics coryza; stomatitis, conjunctions, rhinorrhea, management
i.e., common cold) parotid swelling, lymphadenopathy,
anorexia, and insomnia Liberal intake of This promotes
NaCI excretion of iodides
Fetal goiter If used during pregnancy Rx
Chloride competes
∴
with iodide for
excretion at renal
tubular level
446 Pharmacology mind maps for medical students and allied health professionals

49.7 RADIOACTIVE IODINE (131I)

Given orally, concentrated

γ rays pass through the tissue
in thyroid follicles

β rays penetrate only 0.5–2 mm

Emits both γ and β rays
of tissue

Hence they destroy only Without damaging

thyroid tissue surrounding structures

But radioactivity is present

t½ – 8 days
for 2 months

Administered as single
dose

Therapeutic response seen

after 1–2 months
Therapeutically for hyperthyroidism
Alternative to surgery
and thyroid carcinoma
Use
Diagnostically for thyroid
function tests (small dose)
4. Radioactive iodine (131I)
Treatment is simple and
convenient

Can be given on OPD basis

Advantages Inexpensive

No risk of surgery and scar

Permanently cures
hyperthyroidism

Slow response (after 3 months)

Hypothyroidism after months

Rx with thyroid hormones
or years (high incidence)
Disadvantages
Not suitable for pregnant women,
children, and young patients

Local soreness in the neck

 Thyroid hormones and antithyroid agents 447

49.8 MANAGEMENT OF THYROTOXIC CRISIS (THYROID STORM)

Severe hypermetabolic
condition

Hyperpyrexia

Because of high concentration

of circulating thyroid hormone
Cardiac arrhythmias (atrial
fibrillation)
Classical signs/symptoms of
Manifestations
hyperthyroidism

Nausea, vomiting, diarrhea

Infection, surgery, trauma,
Precipitated by diabetic ketoacidosis,
myocardial infarction, etc.
Management of thyrotoxic Mental confusion
crisis (thyroid storm)
Hospitalization

Propylthiouracil Via nasogastric tube

Inhibits release of thyroid

Oral iodides
hormones

Propranolol, IV or oral Controls symptoms

Management

Inhibits peripheral conversion

Parenteral dexamethasone
of T4 to T3

Paracetamol for hyperpyrexia Cooling blankets

Hydration

Supportive therapy

Sedation

Antibiotics to treat infection

448 Pharmacology mind maps for medical students and allied health professionals

49.9 DIFFERENCES BETWEEN PROPYLTHIOURACIL AND METHIMAZOLE

(CARBIMAZOLE)

Features Propylthiouracil Methimazole

i. Onset Fast Slow

ii. Potency Less More

iii. t½ 1–2 h 6h

iv. Protein binding High Low

v. Duration of action Short (4–8 h) Long (12–24 h)

vi. Placenta transfer Negligible Easy

vii. Secretion in milk Negligible Significant

viii. Pregnancy Preferred Not Preferred

ix. Lactation Preferred Not Preferred

x. Dose Tid – qid Od – bid

 50
Estrogen, progestins, and hormonal
contraceptives

50.1 ESTROGENS – TYPES AND MECHANISM OF ACTION

Produced mainly by Ovaries, placenta

Also produced by adrenals,

Small amounts testes, and peripheral
aromatization of androgens

By aromatization of androgens
Produced by granulosa
derived from thecal cells in the
cells
initial part of menstrual cycle

Major estrogens Estradiol, estrone, and estriol

Estradiol (most potent) Is converted in liver Estrone, estriol

Estrogen types

Natural estrogens Chemical alterations Synthetic estrogens

Nonsteroidal compounds Diethyl stilbesterol,

with estrogenic activity dinestrol

Natural estrogens Estradiol, estrone, estriol

Ethinyl estradiol

Synthetic estrogens Stilbestrol (oral)

Dienestrol (topical)

Bind to specific estrogen Regulate protein

Estrogens Enters nucleus Response
receptor synthesis

Mechanism of action
Uterus, vagina, ovary,
ERα breast, hypothalamus,
Types and location of blood vessels
estrogen ERα and ERβ
receptors (ER)
ERβ Prostate, ovaries

449
450 Pharmacology mind maps for medical students and allied health professionals

50.2 ACTIONS AND PHARMACOKINETICS

i. Growth and development of sex

of organs in females

ii. Stimulates development of

secondary sex characteristics

iii. Responsible for proliferative

phase of endometrium

iv. Promotes rhythmic

contractions of fallopian tubes
and myometrium

v. Makes cervical secretion thin,

watery and alkaline, and
facilitates entry of sperms

vi. Growth of ducts and stroma in

breast

Actions

vii. Inhibits activity of osteoclasts ↓ Bone resorption

viii. ↑ HDL and ↓ LDL

ix. Na+ and water retention

By ↑ clotting factors (II, VII,

x. ↑ Blood coagulability
IX and X) and ↓ antithrombin III

xi. Negative feedback control

on anterior pituitary

xii. Stimulates progesterone

receptor synthesis

Due to high first pass

Natural estrogens Are not effective orally Hence have a short t½
metabolism

Are orally effective and

Synthetic estrogens

Long-acting

Undergo glucoronide and sulfate

conjugation
Pharmacokinetics

Excreted in urine and bile

Undergo deconjugation by
intestinal bacterial flora

They are reabsorbed, resulting Hence ↑ duration

in enterohepatic circulation of action
 Estrogen, progestins, and hormonal contraceptives 451

50.3 USES, ADRs, AND PREPARATIONS

Cessation of normal Lead to menopause and its associated

ovarian function manifestations
Like hot flashes, sleep disturbances,
Vasomotor symptoms
genital atrophy, osteoporosis (fractures)
Night sweats, depression,
irritability

Incidence of CV disease

↓ Menopausal
Short-term HRT
1. Postemenopausal hormone symptoms
replacement therapy Reduces osteoporosis,
Long-term HRT
atherosclerosis and Alzheimer disease
2. Oral contraceptive
Progestin (medroxyprogesterone Added for the last Reduces endometrial and
or norethisterome) 12–14 days of each month breast cancer

Estrogen alone Is used in hysterectomised women

Oral conjugated estrogens (sulfate

esters) are most effective
Transdermal patch has fewer
systemic side effects
Anovulatory cycles
∴
are painless
3. Dysmenorrhea
Estrogens with progestions
Uses suppresses ovulation
Turner syndrome and
hypopituitarism
Estrogens develop secondary sex
characteristics
4. Delayed puberty in girls
Reduces chances of osteoporosis

Cyclic treatment is given

Topical estrogens ↓
5. Senile vaginitis
dyspareunia and urethral syndrome

Palliative treatment

Fosfeterol, a prodrug, is
6. Prostate carcinoma concentrated in prostate, activated
to stilbestrol
Venous thromboembolism GnRH agonists are preferred

Uterine bleeding

Breast cancer/tenderness

Gallstones (cholestasis)

Liver diseases

Mood changes
ADRs
Endometrial cancer

Migraine headaches

Gynecomastia and feminization In men

Edema and weight gain Due to Na and H2O retention

When given to pregnant woman

Teratogenicity ↑ Incidence of vaginal and

cervical cancer in female child
Conjugated estrogens (premarin) Genital abnormalities in
oral tablets, vaginal cream, injections male child

Transdermal patch
Preparations
Has estrogenic, progestogenic and
Vaginal cream/pessaries
weak androgenic activity

Tibolone No endometrial proliferation

Used continuously without cyclic

progesterone
452 Pharmacology mind maps for medical students and allied health professionals

50.4 ANTIESTROGENS

Compete with natural

estrogens for receptors
in target organs
They include
androgens and
clomiphene citrate Inhibit ovarian function
at anterior pituitary
Androgens
Oppose actions of
estrogens on target
organs

Antiestrogens Nonsteroidal
Infertility due to
antiestrogenic
anovulation
compound

Uses In vitro fertilization

↑ Sperm count
Male infertility and
testosterone secretion
Induces ovulation
Stimulates
Blocks both ERα and ERβ Blocks negative
Mechanism gonadotropin
Clomiphene citrate – (pure antagonist) feedback of estrogens
secretion (FSH and LH) Also ↑ sperm
50 mg OD from second count in men
day of menstrual cycle
for 5 days
Dose
Not to used for 6 cycles
due to risk of
ovarian cancer

Hot flushes,
hyperstimulation
syndrome, multiple
pregnancy,
ovarian cyst/malignancy
ADRs
Weight gain, breast
discomfort
 Estrogen, progestins, and hormonal contraceptives 453

50.5 SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs) AND ESTROGEN

SYNTHESIS INHIBITORS

Act as an agonist,
antagonist or partial
agonist depending on site

Bone, lipid metabolism,

Agonist
brain, liver

e.g., Tamoxifen, raloxifene

Breast, pituitary,
Antagonist
endometrium

Genitourinary epithelium,
Partial agonist bone remodeling,
cholesterol metabolism
Antiresorptive effect
Bone
(inhibit osteoclasts)

↓ LDL levels,
Estrogenic Lipid
reduces CV risk

Endometrium Causes proliferation

Actions

Breast cancer cells Reduces tumor size

Antiestrogenic

Periphery – Hot flushes

Tamoxifen

As palliation in advanced Both pre- and post-

Breast cancer (ER+ve)
cases menopausal women
Selective estrogen
receptor modulators
(SERMs) Hot flushes, vaginal
Uses
dryness

↑ Risk of
ADRs
endometrial cancer and

Thromboembolism

Antiresorptive hence
Bone reduces risk of vertebral
fractures

Estrogenic Lipid ↓ LDL cholesterol

↑ Risk of
Blood
thromboembolism

Antiproliferative on ER+ve
Breast
breast tumors

Antiestrogenic
Raloxifene Actions
Endometrium No proliferation

Continuous administration
of GnRH agonist inhibits
estrogen synthesis Prevention and treatment
Uses
of osteoporosis

Inhibits aromatase an
Aminoglutethimide enzyme essential for
estrogen synthesis Hot flushes, ↑ risk
Estrogen synthesis of thromboembolism
inhibitors
e.g., Anastrozole, ADRs
Selective aromatase
letrozole block production
inhibitors
of estrogens Does not ↑ risk of
endometrial cancer

Used in treatment of
breast cancer
454 Pharmacology mind maps for medical students and allied health professionals

50.6 PROGESTINS – TYPES, ACTIONS, AND PHARMACOKINETICS

Is secreted by ovary in second half

of menstrual cycle and

Placenta during pregnancy

Natural progesterone
Also synthesized by testis and
adrenals

Acts as precursor of various

steroid hormones

Natural Progesterone
Types

Medroxy progesterone acetate,

megestrol, hydroxyl progesterone
acetate
Synthetic progesterone
derivatives
Norethidrone
Synthetic 19-nortestosterone
(norethisterone),
derivatives
Norgestrel, Levonorgestrel

Newer progestins (with no

Gestodene, Norgestimate
androgenic activity)

Progestin means favors

i. Maintains pregnancy
pregnancy

ii. Secretory phase of endometrium

iii. Negative feedback on

hypothalamus and anterior
pituitary

iv. ↓ Tubal motility

and uterine contractions

v. Cervical mucus becomes scanty,

thick, viscous, and acidic, hence
Progestins
hostile to sperm penetration

vi. Proliferation of acini in

↓ Glucose tolerance
breast
Actions

vii. Metabolic ↑ LDL levels

viii. Sodium and water Stimulates lipase activity

retention hence fat deposition

ix. ↑ Body
temperature

x. Slight induction of
hypnosis

xi. ↓ Synthesis of
estrogen receptors

xii. Stimulate respiratory

center ( high dose)

Hence high dose oral

Pharmacokinetics High first-pass metabolism Hence not effective orally micronized progesterone
preparations are available
 Estrogen, progestins, and hormonal contraceptives 455

50.7 USES AND ADRs OF PROGESTINS

As combined pill With estrogen

Minipill
1. Contraception

Injectable (depot preparations)

Available as

Implants

Adjuvants with estrogens
2. HRT in postmenopausal women
Long-term therapy
Intrauterine contraceptive
devices (IUCD)
Prevents endometrial
proliferation/carcinoma because
of estrogen therapy

Norethisterone or norethynodrel

Initial high dose arrests bleeding

3. Dysfunctional uterine
Later maintainance dose for 20 days
bleeding (DUB)

After 2–5 days of stopping

Withdrawal bleeding occurs
therapy

Treatment cycle continued for

Uses 3–6 months

Progestins alone or combination pills

Started 5 days before expected

period
4. Postponement of periods
Continued until required time as
needed

72 h after stopping
Withdrawal bleeding occurs
therapy

Dysmenorrhea, menorrhagia,
infertility, and dyspareunia

Continuous long-term oral

5. Endometriosis
progestins

Regresses lesions by causing

anovulation

Better than chemotherapy in

advanced stages

6. Endometrial carcinoma Oral progestins daily

IM medroxy progesterone
acetate weekly

Acne, irregular menses, depression,

breast tenderness, fluid retention, Androgenic actions
weight gain, hirsutism

↑ Risk of thromboembolism

ADRs
Older progestins ↑ lipid
Thus ↑ CV risk
levels

Newer progestins little or no

CV risk
456 Pharmacology mind maps for medical students and allied health professionals

50.8 ANTIPROGESTINS

∴ Competitive antagonist
of progesterone
receptors at
target organs

Has luteolytic property

When given during Hence decidual

Blocks progesterone
early pregnancy breakdown,
receptors in uterus
causes abortion detaches blastocyst

Mechanism of
This ↑
Mechanism of action termination of
prostaglandin levels
pregnancy

HCG ( human choronic

Hence uterine
gonadatropins) and
contractions occur
progesterone levels fall

It prevents midcycle This softens cervix and

Administered during
surge of gonadotropins causes expulsion
follicular phase
and delays ovulation of blastocyst

Also binds to
Early pregnancy up to
glucocorticoid
9 wks
receptors

Single oral dose

of 600 mg
i. Termination
of pregnancy
48 h later give
prostaglandins

Antiprogestins Mifepristone This ↑ uterine

contractions and helps in
expulsion of blastocyst

When given within

Prevents implantation
72 h after coitus
ii. Postcoital
Uses
contraception
Causes sloughing and Hence brings
shedding of decidua about abortion
iii. Monthly
contraceptive or
“morning after pill”

iv. Induction of labor in

case of intrauterine
fetal death

v. For cervical ripening

before abortion or
induction of labor

Uterine bleeding,
ADRs teratogenicity abdominal
pain, nausea, vomiting
 Estrogen, progestins, and hormonal contraceptives 457

50.9 DRUG TREATMENT OF MENOPAUSAL SYMPTOMS

Hormone replacement
Caused due to ↓
therapy
synthesis of estrogens
with estrogen

Hot flushes, sweating,

Reduces menopausal
anxiety, fatigue, vaginitis,
Manifestations symptoms
dryness, musculoskeletal
pain

Osteoporosis, urogenital ↓ Osteoporosis

atropy, dyspareunia, and CV risk
Long–term effects ↑ Risk of uterine
psychological disturbances fibroids and endometrial
and ↑ CV risk carcinoma
Drug treatment of Estrogen alone HRT
menopausal Menopause Hormonal Hence combination of
symptoms estrogen + progestin
reduces this risk

Orally, transdermally or
Administered
subcutaneous implants

Given continuously if
withdrawal
bleeding is undesirable Synthetic steroid with
effects like estrogen
Treatment – hormonal/ and progesterone
nonhormonal Tibolone
Reduces menopausal
symptoms

Clonidine α adrenergic agonists

Proponalol Non-selective β blockers

Nonhormonal agents

Dopamine antagonist

Veralipride
↓ Hot flushes and
palpitation
458 Pharmacology mind maps for medical students and allied health professionals

50.10 TYPES OF HORMONAL CONTRACEPTIVES

Mini pill

Single preparations
(progestin-only pill)

Emergency (postcoital) pill

1. Oral Monophasic

Biphasic

Combined estrogen and

progestin preparation

Triphasic
Most effective
contraceptive methods

Emergency (postcoital) pill

Greatly contribute
Hormonal contraceptives
to population control

Depot medroxyprogesterone
Implants: Norplant
acetate (DMPA)
Types
2. Parenteral

NET-EN (norethindrone
Injections (IM, SC)
enanthate)

Once a month
medroxyprogesterone
25 mg + estradiol
cypionate 5 mg

Progestasert

Intrauterine device (IUD)

Levonorgestrel (LNG)

3. Devices Transvaginal ring

Transdermal patch
 Estrogen, progestins, and hormonal contraceptives 459

50.11 COMBINED ESTROGEN (E) AND PROGESTIN (P) PREPARATIONS

Widely used, most

effective

Estrogen used Ethinyl estradiol (EE)

Norethisterone,
Progestin used levonorgestrel,
desogestrel, gestodene

Fixed amount if E and

Monophasic Efficacy 98%–99.9%
P in each pill

E is constant

Biphasic Day 1–10 EE (35 mcg) + N (0.5)

P varies according to
menstrual phase
Monophasic, biphasic, or
Day 11–21 EE (35 mcg) + N (1.0)
triphasic
E dose is slightly more
during midcycle
1. Combined estrogen (E)
E content ranges from
and progestin (P)
20–50 mcg
preparations P dose successively
↑ in 3
phases of menstrual cycle
P content ranges from
0.75–1.0 mg
EE (35 mcg) +
Triphasic Day 1–7
Noret (0.5 mg)

EE (40 mcg) +
Low-dose pills E is less than 35 mcg Day 8–14
Noret (0.75 mg)

Desogestrel, gestodene, EE (35 mcg) +

Day 15–24
norgestimate Noret (1.0 mg)

They ↑ HDL
∴
Newer progestins Lipid–friendly and ↓
atherogenic risk

Schedule for use

Menstrual cycle

Day 1 Day 21 Day 28

1 tablet orally for Pill-free/iron

Withdrawal bleeding
21 consecutive days iron/placebo
460 Pharmacology mind maps for medical students and allied health professionals

50.12 BENEFITS OF HORMONAL CONTRACEPTION AND CONTRAINDICATIONS

Avoids unwanted
pregnancy

↓ Menstrual blood
loss, anemia

↓ Dysmenorrhea,
premenstrual tension
Benefits of hormonal
contraception
↓ Pelvic inflammatory
disease

↓ Ovarian and endometrial

carcinoma

↓ Ovarian cyst and

benign breast tumors

Venous thromboembolism

Hypertension, cardiac
disease

Diabetes mellitus

Chronic liver diseases,

gallstones

Contraindications Epilepsy

Genital tract malignancy

Breast cancer

Migraine

Thyroid disease
 Estrogen, progestins, and hormonal contraceptives 461

50.13 SINGLE PREPARATIONS AND POSTCOITAL (EMERGENCY CONTRACEPTION)

PILL

Progestin only pill

(mini pill)

Very low dose of P

Safe in lactation and

women >35 yrs
Single preparations
1 tablet orally daily
Schedule
without a break

Efficacy 96%

Menstrual irregularities,
ADR
ectopic pregnancy

Morning-after pill

Oral P alone or with EE If taken within 72 h of

effective unprotected intercourse

Following rape

Unprotected intercourse

Use
Accidental condom
rupture during coitus
Postcoital (emergency
contraception) pill Mifepristone
(antiprogestin)
also is effective

Contraindication Confirmed pregnancy

ADR Nausea, vomiting E dose is high Use antiemetics

∴

Postcoital pill acts by

preventing implantation

If postcoital pill fails, LNG (0.75 mg)

pregnancy should be one pill
terminated (as OCPs are i. 2 one pill doses
teratogenic) 12 h
(within 72 h)

IUD within 5 days of LNG (0.75 mg)

coitus can also prevent one pill
implantation and
pregnancy
LNG (0.25 mg) +
EE (0.05 mg) 2 pills
ii. 2 two pill doses 12 h
Schedules of use (within 72 h)
LNG (0.25 mg) +
EE (0.05 mg) 2 pills
iii. Mifepristone 600 mg
single dose
Selective progesterone
receptor modulators
(SPRM)
iv. Ulipristal
30 mg single dose within
12 h or 5 days after
unprotected coitus
462 Pharmacology mind maps for medical students and allied health professionals

50.14 PARENTERAL CONTRACEPTIVES

150 mg IM once in
DMPA
3 months

Dose 30% less; once in

Injectables Subcutaneous DMPA
3 months

200 mg IM once in
NET-EN
2 months

Better patient compliance

∴
it avoids regular oral
medicines

Safe during lactation

Benefits
Reduced endometrial
On long-term use
carcinoma

Reduced dysmenorrhea,
menorrhagia

Menstrual irregularities

2. Parenteral
contraceptives
Mood changes, weight gain

Drawbacks Osteoporosis

↑ LDL, ↓ HDL

Delayed (6–8 months)

return of fertility on
stopping pills

Norplant

6 flexible rods containing

Subdermal implant
216 mg LNG

Contraceptive effects lasts

for 5 yrs
Implants
Immediate return of
fertility on removal of pill

Pain, irritation, infection at

ADRs site, headache, mood
changes, weight gain, acne

Single rod of 68 mg
Implanon desogestrel is effective for
3 yrs
 Estrogen, progestins, and hormonal contraceptives 463

50.15 DEVICES AND MECHANISM OF ACTION OF CONTRACEPTIVES

“T” shaped, inserted in uterine

IUD LNG device
cavity, effect lasts for 5 yrs

Low efficacy, has to be

Progestasert IUD contains progesterone
replaced yearly

Combination of EE and
desogestrel

Transvaginal ring
3. Devices
Effect lasts for a month

Contains EE and norgestimate

Applied over buttocks, upper

outer arm, lower abdomen,
etc.
Transdermal patch

Applied weekly for 3 wks

Then 1 week patch free Then withdrawal bleeding

Negative feedback on
→ Inhibits FSH and LH release Prevents ovulation
hypothalamus of E and P

Hence ovarian follicle

E suppresses FSH
fails to develop

P inhibits E-induced midcycle

LH surge

Mechanism of action
P makes cervical mucus thick
and unfavorable for sperm
penetration

Makes endometrium
unfavorable for implantation

Causes incordinated Hence transport of ovum,

contraction of cervix, uterus, sperm, fertilization,
and fallopian tubes implantation affected
464 Pharmacology mind maps for medical students and allied health professionals

50.16 ADVERSE EFFECTS, DRUG-INTERACTIONS, AND CENTCHROMAN

Dose-related

Current low-dose preparations have

minimal side effects i.e., Desogestrel, gestodene, and
norgestimate
Newer progestins
Are lipid friendly Hence reduces CV risk

Migraine headache

Nausea, vomiting

Edema
Adverse effects

Mild Weight gain

Breast tenderness

Amenorrhea

Irregular cycles

Venous thromboembolism

↑ Risk of MI

↑ Blood coagulability

Severe Hypertension

↑ Risk of breast, cervical, endometrial cancers

Cholestatic jaundice, gallstones

Impaired glucose tolerance

∴ Use alternative forms

Drug interactions

Enzyme inducers (rifampicin, phenytoin) ↓ Efficacy Hence can lead to contraceptive failure
of contraception

E is conjugated in liver Excreted via bile into gut Deconjugated by intestinal bacterial flora

Antibiotics which are incompletely absorbed

Destroy deconjugating bacteria Hence ↓ absorption of OCPs Hence contraceptive failure
from gut (ampicillin, tetracyclines)

Chroman synthetic nonsteroidal contraceptive

Developed by CDRI, Lucknow

Antiestrogenic and antiprogestogenic

Acts by preventing implantations

Onset quick i.e., < than 60 min

Duration if action – 7 days 30 mg twice weekly for 3 months

Then once weekly until contraception

Dosage
is desired
Tablet should be continued without
stopping during menses
Centchroman

Return of fertility Within 6 months of stopping drug

Efficacy 97%–99%

Devoid of side effects of hormonal

contraceptives

Benefits Well tolerated

No teratogenecity, carcinogenecity,
mutagenicity

Once-daily dosage, hence better compliance

ADRs Prolongation of menstrual cycles (10%)

Ovarian enlargement

Polycystic ovaries

Contraindications Hepato-renal dysfunction

Tuberculosis

Lactation
 51
Androgens and anabolic steroids

51.1 ANDROGENS – PHYSIOLOGY, CLASSIFICATION, ACTIONS, AND MECHANISM

OF ACTION

Mainly in testis and

Androgens are
synthesized
Small amount in
adrenal cortex

Small amounts are

In females synthesized in ovary
and adrenal cortex

Main androgen
Testosterone
Physiology in men

Synthesized by Leydig
Testosterone is
cells (interstitial cells)

Interstitial cell-stimulating
Regulated by hormone (ICSH, LH) of
anterior pituitary
FSH is responsible
Testosterone
for spermatogenesis

Dihydrotestosterone
1. Natural
Dehydroepiandrosterone

Classification Androstenedione

Methyltestosterone

Androgens 2. Synthetic Fluoxymesterone

Testosterone
undecanoate

Has both androgenic

Testosterone
and anabolic actions

Development of secondary
sexual characteristics and sex
organs (androgenic)

Normal
spermatogenesis
Physiological
actions
Maintaining
sexual function

↑ Mass and strength

of skeletal muscles, protein Anabolic
synthesis, and positive
nitrogen balance

Erythropoiesis

Mechanism Similar to other Binds to androgen Complex moves Stimulates protein

of action steroids receptor to nucleus synthesis

465
466 Pharmacology mind maps for medical students and allied health professionals

51.2 THERAPEUTIC USES, ADVERSE EFFECTS, AND PRECAUTIONS

AND CONTRAINDICATIONS

Replacement therapy in
Testicular failure
hypogonadism
primary and secondary
(transdermal patch)
∴
Testosterone is
physiologic antagonist
Therapeutic uses of estrogens
Ca breast in women
Only estrogen receptor
positive tumors respond
Senile osteoporosis

Masculinization

Hirsuitism

Menstrual irregularities

Females

Breast atrophy

Acne

Deepening of voice

Precocious puberty

Children
Adverse effects Premature closure of Hence impairment
epiphyses of growth

Due to salt and water

Edema
retention

Suppression of
Hence infertility
spermatogenesis
∴
Some androgens
Feminizing effects like
are converted
gynecomastia
to estrogens

Cholestatic jaundice

Pregnancy Virilization of fernale fetus

Ca prostate
Precautions and
contraindications
Ca breast in men

Renal and cardiac

diseases
 Androgens and anabolic steroids 467

51.3 ANABOLIC STEROIDS

Are synthetic
androgens

Promote protein
synthesis

↑ Muscle mass,
Introduction hence causes
weight gain

Anabolic to
androgenic ratio of
testosterone is 1

Have greater anabolic

Synthetic androgens and lesser androgenic
activity

Nandrolone
decanoate : IM

Nandrolone
Preparations Following surgery
phenylpropionate : IM

Oxandrolone,
Trauma
Stanozolol : Oral

1. Catabolic states Prolonged illness

Anabolic steroids
2. Postmenopausal and
Convalescence
senile osteoporosis

Improves appetite,
Debilitating conditions
feeling of well-being

Actual benefit in
3. Growth stimulation
improving final
in children
Therapeutic uses height is doubtful

4. Chronic renal failure

Improves athletic
to reduce nitrogen load
performance
on kidney

5. Refractory anemias ↑ Muscle mass

with bone (when combined
marrow failure with exercise)
∴
High dose is used, there
are frequent adverse effects
(similar to that of androgens)
6. Abuse in athletes
However, no proven
benefit
Adverse effects and
Similar to androgens
contraindications
Hence, medically not
recommended
and banned

↑ Risk of
coronary heart disease,
aggressiveness,
psychotic behavior
468 Pharmacology mind maps for medical students and allied health professionals

51.4 ANTIANDROGENS

Inhibits gonadotropin
1. Estrogens
secretion

Potent competitive antagonist

at androgen receptors
2. Flutamide
Used with GnRH/leuprolide
in Rx of Ca prostate

5–α reductase inhibitor

↓ Prostate size
Inhibits activation of testosterone to
3. Finasteride
dehydrotestosterone in genital tract
Improves urinary flow
Used in benign prostatic
hypertrophy
Combined with
α1 - adrenergic blockers
Irreversibly inhibits
aromatase enzyme
Long-term Rx necessary to
prevent regrowth of prostate
4. Exemestane Hence ↓ estrogen levels

Used in Ca breast in
postmenopausal women

Antiandrogens
Progesterone derivative

Competitively binds to Thus, blocks actions

androgen receptor of androgens
5. Cyproterone acetate
Hypersexuality in males

Use Ca prostate

GnRH or leuprolide Hirsuitism in females

6. Inhibitors of Administered continuously, they Hence they cause

androgen synthesis inhibit LH and testosterone secretion pharmacological castration

Used in men with Ca prostate

Spironolactone Aldosterone antagonist

Ketoconazole Antifungal
7. Spironolactone and
ketoconazole
Both are inhibitors of Hyperkalemia
testosterone synthesis

ADR Gynecomastia

Menstrual irregularities
 Androgens and anabolic steroids 469

51.5 MALE CONTRACEPTIVES AND DRUGS FOR MALE SEXUAL DYSFUNCTION

(ERECTILE DYSFUNCTION/IMPOTENCE)

Cottonseed
derivative

Produces
oligospermia

Impairs sperm
motility
Male
Gossypol
contraceptives
Documented in
Chinese studies

Inability of man to
Reversible on
have satisfying
discontinuation
sexual intercourse
Inability to produce
and maintain Major side effects Hypokalemia
erection

Major cause Psychological

Minor cause Physical/organic

Testosterone

Yohimbine

Drugs tried Papaverine

Drugs for male Antidepressants

sexual dysfunction
(erectile dysfunction/
impotence) Sildenafil (Viagra)

Orally effective
Thus ↑ cGMP
first agent

Inhibits penile Hence there is smooth

enzyme muscle relaxation of
phosphodiesterase corpus cavernosum

This leads to Thus cavernosal

Penile erection
vasodilation engorgement and

Sildenafil
Headache

Dizziness

Nasal stuffiness
ADR and
precautions
Hypotension Potentiated by nitrates

Others Tadalafil, vardanafil

In patients on nitrates
Contraindicated and with coronary
artery disease

Elderly, liver/renal
disease, Deaths have been
Precautions
bleeding disorders documented

Corticosteroids
52.1 CORTICOSTEROIDS – INTRODUCTION, STRUCTURE SYNTHESIS, AND RELEASE
Adrenal gland consists of
cortex and medulla
Cortex
Medulla
Cortex
Zona glomerulosa
Introduction
Zona fasciculata
Zona reticularis
Chronic deficiency of adrenocortical
hormones leads to
Adrenocortical hormones are more
necessary than medullary hormones
Corticosteroids
Mineralocorticoids are more
important than glucocorticoids
Cyclopenta(a)phenanthrenes
(CPP/steroid) ring
Synthesized
Synthesis and release
ACTH secretion
Glucocorticoids
10–20 mg of hydrocortisone and
Structure
0.125 mg of aldosterone is
synthesis and release
secreted every day
Secretion of glucocorticoids
Mineralocorticoids (aldosterone)
release
Large dose of long-term
corticosteroids
470
52
Secretes steroidal hormones
Secretes adrenaline and Zona glomerulosa
noradrenaline
Is divided in 3 zones i.e., Zona fasciculata
Secretes mineralocorticoids, Zona reticularis
aldosterone, deoxycortisone
Hypersecretion leads to
Regulates water and primary hyperaldosteronism Involved in
electrolyte balance Conn’s syndrome carbohydrate, fat, and
protein metabolism
Secretes glucocorticoids Hydrocortisone (cortisol)
Has anti-inflammatory,
immunosuppressant and
Hypersecretion leads to
Cushing’s syndrome antiallergic actions
Hypersecretion leads to
Secretes androgens Precocious puberty
adrenogenital syndrome
Addison’s disease
In adrenal cortex from
cholesterol
Controlled by ACTH (adreno-
cortico tropic hormone)
released by anterior pituitary
Controlled by corticotrophin- Produced by
releasing factor (CRF) hypothalamus
Have a negative feedback
on release of ACTH and CRF
Maximum in early
morning and
Lowest in late evening
Circadian rhythm
Released in response
to stress
Controlled by renin-angiotensin
aldosterone system (RAAS)
↓ ACTH secretion Hence sudden withdrawal is
leading to gradual dangerous it precipitates
∴
adrenocortical atrophy acute adrenal insufficiency
 Corticosteroids 471

52.2 MECHANISM OF ACTION AND PHARMACOKINETICS

Corticosteroids enter the target

organ by simple diffusion
↓

Bind to specific cytoplasmic receptor

Steroid–receptor complex activated

Complex transported to nucleus

Mechanism of action Binds to specific site on DNA

Induces synthesis of specific RNA

Synthesis of new proteins

Response

Well absorbed orally

High first–pass metabolism

95% is plasma protein bound to

Pharmacokinetics corticosteroid binding globulin (CBG)

Metabolized first by oxidation

followed by conjugation

Short/intermediate/long
Variable t½
(depending on agent/preparation)
472 Pharmacology mind maps for medical students and allied health professionals
52.3 GLUCOCORTICOID ACTIONS
Natural
Glucocorticoids
Synthetic
Hydrocortisone has both
glucocorticoid and
mineralocorticoid actions
1. Carbohydrate metabolism
2. Lipid metabolism
3. Protein metabolism
4. Water and electrolyte balance
Synthetic glucocorticoids have no mineralocorticoid activity
5. Cardiovascular system
6. Central nervous system
Glucocorticoid actions
7. Gastrointestinal tract
8. Calcium metabolism
9. Skeletal muscles
10. Blood and lymphoid tissue
This effect prevents/inhibits clinical manifestations of inflammation
11. Anti-inflammatory effect
12. Immunosuppressant effect
Hydrocortisone
Prednisolone
Triamcinolone
Dexamethasone
Betamethasone
↑ Glycogen deposition in liver
↑ Gluconeogenesis (from amino acids)
↓ Peripheral utilization of glucose Hyperglycemia
Net effect Insulin resistance
Hence they
Precipitation or exacerbation of DM are contraindicated
in diabetics
Redistribution of body fat over neck, face, and
shoulder (long-term) Hence “moon face,” buffalo
hump, and “fish mouth” with thin limbs
↑ Lipolysis
↑ Protein breakdown i.e., Catabolic
↑ Nitrogen excretion Hence –ve nitrogen balance
Thinning of skin
Osteoporosis
Muscle wasting
Mobilization of amino acids from skin, bone,
muscle, lymphoid tissue hence
Lympholysis
Growth retardation
↓ Wound healing
Hence it leads to
Na+ and H2O retention, K+ excretion Due to its weak mineralocorticoid action edema and hypertension
on long-term use
e.g., Dexamethasone, betamethasone and
triamcinolone
↑ The action of adrenaline and angiotensin ∴ Long-term use can lead to hypertension
and congestive cardiacfailure (CCF)
Indirect effect due to maintanence of blood pressure,
blood glucose and electrolyte levels
Influence mood and behavior – direct action
↓ Glucocorticoid levels i.e., Addison’s disease leads to depression,
irritability
↑ Glucocorticoids Leads to euphoria, insomnia, restlessness
↓ Prostaglandins
↑ Gastric acid and pepsin
Aggravates peptic ulcers
↓ Local immunity against H. pylori
↓ GI Ca+2 absorption Hence ↓ blood Ca+2 levels
↑ Renal Ca+2 excretion
Reduces osteoblasts (bone-forming cells)
↑ Osteoclasts (bone-resorption cells)
∴ Osteoporosis, pathological
Anti-vitamin D action Esp. of vertebral bodies
fractures
Corticosteroids are essential for normal function Inadequate circulation
Reduced corticosteroids
Muscle weakness and fatigue
↑ Corticosteroids
Muscle wasting and weakness, termed “steroid myopathy” Hypokalemia
↓ Circulating lymphocytes,
eosinophils, basophils, and monocytes
↑ Platelets and RBCs This occurs due to redistribution of cells
Marked lympholytic effect Hence used in lymphomas and leukemias
This a powerful effect
Capillary permeability, edema, cellular
Suppresses early phenomena infiltration, and phagocytosis
Inhibits late responses Capillary proliferation, collagen deposition,
fibroblast activity, and scar formation
Inhibits development of inflammation to all types of stimuli
Lipocortin inhibits phospholipase A2
Inhibits synthesis of lipocortin
Hence there is reduced formation of
Also inhibits COX-2 in inflammatory cells prostaglandins and leukotrines
↓ Production of inflammatory cytokines like IL6, ILb
Reduces TNFα
Suppresses both T and B lymphocyte function
Inhibits cell and humoral immunity
Inhibits all types of hypersensitivity and allergic reactions
 Corticosteroids 473

52.4 THERAPEUTIC USES

Medical emergency Infection

Trauma
Precipitated by
Hemorrhage, or
Sudden withdrawal of corticosteroids

Nausea
Vomiting
1. Acute adrenal
insufficiency Weakness
Signs/symptoms
Hypotension

Hypo Na+
Hyper K+
Endocrinal uses

IV hydrocortisone hemisuccinate Followed by 100 mg

100 mg bolus infusion every 4–6 h

Rx Correction of fluid and electrolyte balance

On recovery, oral preparation
of corticosteroids
2. Chronic adrenal 20–40 mg oral hydrocortisone Correction of precipitating factors
insufficiency
(Addison’s disease) Additional fludrocortisone For mineralocorticoid action

Reduced synthesis of corticosteroids

3. Congenital adrenal Due to deficiency of some

hyperplasia enzymes involved in synthesis Hence ACTH levels ↑

Rx Daily hydrocortisone + a mineralocorticoid

They do not halt progression of disease

But provide immediate and

1. Rheumatoid dramatic symptomatic relief
arthritis
Intra-articular injection
(only if 1–2 joints involved)
Therapeutic uses

Used as adjunct to NSAIDs and DMARDs

Rarely used now In acute episodes with

2. Osteoarthritis strict aseptic precaution
Intra-articular injection
Should be at least 3 months interval Otherwise there could be
Provides rapid between intra-articular injections joint destruction
symptomatic relief than aspirin
3. Rheumatic
Indicated in carditis and CCF
carditis (fever)
Continued until ESR comes
down to normal
Hay fever
Reserve drugs
4. Acute gout Drug reaction
In NSAID non-responders
Urticaria
Reduces manifestations
Contant dermatitis
However, slow onset
Angioneurotic edema
Non-endrocinal uses

5. Allergic disorders
Anaphylaxis

Severe allergic reactions Rx by adrenaline

Mild allergic reactions Rx by antihistamine

Leads to severe inflammatory reaction

6. Shock
Prompt IV glucocorticoids are life-saving They sensitize vascular smooth muscle
receptors to sympathomimetics

e.g., Polymyositis, polyarthritis nodosa, dermatomyosis, Wegeners granulomatosis

7. Collagen disease First-line drugs

Given usually for 6 wks, then tapered

Used due to its anti-inflammatory and antiallergic property

Reduces mucosal edema and bronchial hyperirritability

Acute attacks IV hydrocortisone + β2 agonist nebulization

8. Bronchial asthma

Status asthmaticus 100–200 mg hydrocortisone Repeated after 8 h

hemisuccinate IV

Inhalational steroids Followed by 40–60 mg

Chronic asthma prednisolone till patient recovers
Beclomethasone, ∴ They have minimal
9. Renal diseases Drug of choice in nephrotic syndrome budesonide, fluticasone systemic side effects

(Continued)
474 Pharmacology mind maps for medical students and allied health professionals

52.4 THERAPEUTIC USES (Continued)

Allergic conjunctivitis
Uveitis

Optic neuritis

Other inflammatory diseases

10. Ocular disorders
Suppresses inflammation, preserves vision
Topically, sub conjunctivally, systemically
Given
or by retrobulbar injection
Contraindicated in Herpes simplex keratitis and ocular injuries

Monitor IOP in long-term therapy

Atopic dermatitis, seborrhic dermatitis, other

inflammatory dermatoses, allergic dermatoses

Topical steroids preferred

11. Dermatological disorder
Life-saving in severe conditions like Pemphigus, exfoliative dermatitis, dermatomyositis Systemic therapy

Psoriasis, keloids, hypertrophic scar Intralesional steroids

Disorders with immunological etiology

12. Hematological disorders
e.g., Purpura, autoimmune hemolytic anemia

Mild inflammatory intestinal disorders

Retention enema
e.g., Ulcerative colitis
13. Gastrointestinal disorders
Oral enteric coated capsules To release in ileum and colon

Severe cases Systemic therapy

Autoimmune chronic active hepatitis

14. Hepatic disorders
Alcoholic hepatitis

Depends on underlying etiology

Brain tumors, metastatic
Highly effective in edema due to
lesions and tubercular meningitis
16. Cerebral edema Least effective in edema due to Head injuries

Large doses of dexamethasone preferred

Or anyone without Na and H2O retention activity

17. Respiratory disorders
(Besides bronchial asthma)
Aspiration pneumonia
Prevention of infant respiratory
distress syndrome (IRDS)
Due to lympholytic effect and
inhibition of cell proliferation

Lymphomas, leukemias As adjunct to chemotherapy

18. Malignancies
Breast carcinoma Rapid symptomatic relief

Others Hodgkin’s disease, multiple myeloma

Prevent and Rx graft-versus- Started before surgery along with

19. Organ transplantation
host disease (GVHD) other immunosuppressants

Hypercalcemia of malignant diseases

Sarcoidosis

Vitamin D intoxication

Bell’s palsy
20. Miscellaneous
Acute polyneuritis

Myotonia

Pneumocystis carinii pneumonia Reduces respiratory failure and mortality

Test HPA function Dexamethasone

 Corticosteroids 475

52.5 ADVERSE EFFECTS

Dose, duration, and relative

Depends on potency of additional
mineralocorticoid activity

Giving topical therapy,

Reduced by
wherever possible

Short-term and single Moon face, buffalo hump,

doses well tolerated fish mouth, thin limbs

Truncal obesity

Muscle wasting
1. Cushing’s habitus
(characteristic)/Cushing’s
syndrome
Easy bruising

Purple striae

Acne

Hyperglycemia

2. Metabolic
Precipitation or aggravation
of diabetes mellitus

Adverse effects Due to immunosuppression Fungal Candidiasis, cryptococcosis

Opportunistic infections Viral Herpes, viral hepatitis

3. Susceptibility to infections Reactivation of dormant

Bacterial
tuberculosis

Candidiasis of oropharynx

Inhalational steroids Prevented by using spacer

and rinsing the mouth
after inhalation

Due to mineralocorticoid Hence it leads to edema,

property hypertension, CCF
4. Salt and water retention
Reduced by using synthetic Dexamethasone,
steroids betamethasone

On prolonged therapy with/

5. Peptic ulceration
without NSAIDs concurrently

Pathologic fractures of
6. Osteoporosis
vertebral bodies

Due to impairment of blood

flow

Usually on head of femur,

7. Avascular necrosis humerus, or distal
part of femur

Growth retardation in
children

(Continued)
476 Pharmacology mind maps for medical students and allied health professionals

52.5 ADVERSE EFFECTS (Continued)

Hence frequent monitoring

8. Cataract and glaucoma On long-term therapy
of eye

Due to hypokalemia there is

9. Muscle muscle weakness and Steroid myopathy
fatigability

Mental disturbances

10. CNS
Insomnia, anxiety,
restlessness, nervousness,
euphoria, psychosis
11. Delayed wound healing

Most dangerous side effect

of long-term therapy

∴
Adrenal cortex
Flareup of underlying
gradually atrophies due to
disease
feedback inhibition

Fever, bodyache, malaise,

Abrupt stoppage causes Withdrawal symptoms
etc.

Hence there should be

Acute adrenal insufficiency
12. Hypothalamo–pituitary– tapering of dose before
on exposure to stress
adrenal (HPA) axis withdrawal
suppression

>20 mg/day for >2 wks Use topical therapy

requires tapering wherever possible

Lowest possible dose

Shortest possible duration

To minimize HPA axis

suppression

Give single dose in morning

If daily dose is high, 2/3 dose

in morning and 1/3 dose in
evening

Alternate-day therapy in
chronic conditions
 Corticosteroids 477

52.6 CONTRAINDICATIONS

1. Hypertension

2. Diabetes mellitus

3. Infections

4. Peptic ulceration

5. Osteoporosis

6. Tuberculosis

Contraindications

7. Herpes simplex keratitis

8. Glaucoma

9. Epilepsy

10. Psychoses

11. CCF

12. Renal failure

478 Pharmacology mind maps for medical students and allied health professionals

52.7 PREPARATIONS AND CLASSIFICATIONS

Anti-inflammatory activity 1 Rapid onset, short duration

Mineralocorticoid activity 1
Anti-inflammatory dose: 20 mg DOC acute adrenal insufficiency
a. Hydrocortisone
(cortisol) Use Status asthraticus

Anaphylactic shock

Routes Oral, IM, IV, intra-articular, topical

1. Short-acting
glucocorticoids (8–12 h)
Anti-inflammatory activity: 0.8

Mineralocorticoid activity: 0.8

Anti-inflammatory: 25 mg
b. Cortisone dose
It is economical

It is a pro-drug, converted to hydrocortisone

Rarely used now

Anti-inflammatory activity: 4 Allergic, inflammatory,
autoimmune
Anti-inflammatory dose: 5 mg disorders and malignancies
a. Prednisolone Mineralocorticoid activity: 0.8

Use Most common for

Route Oral, IM, intra-articular, topical

Anti-inflammatory activity: 5

Anti-inflammatory dose: 5 mg

b. Prednisone Mineralocorticoid activity: 0.8

It is a pro-drug, converted to prednisolone

Less efficacious, hence rarely used now

2. Intermediate-acting
glucocorticoids (12–36 h) Anti-inflammatory activity: 5

Anti-inflammatory dose: 4 mg

c. Methyl prednisolone Mineralocorticoid activity: 0.5

Anti-inflammatory immunosuppressant activity is used for therapy

Used as high-dose pulse therapy in renal transplant, pemphigus

Anti-inflammatory activity: 5
Preparations

Anti-inflammatory dose: 4 mg

Mineralocorticoid activity: 0
d. Triamcinolone
More potent, more toxic

No mineralocorticoid property

Used Oral, IM, intra-articular, topical

Anti-inflammatory activity: 30

Anti-inflammatory dose: 0.75 mg

3. Long-acting
glucocorticoids (36-72 h)
Mineralocorticoid activity: 0
∴ No mineralocorticoid activity
Long-acting
a. Dexamethasone
Potent anti-inflammatory and immunosuppressant properly
As there is no water retention
No mineralocorticoid activity

Causes severe HPA axis suppression

Cerebral edema due to neoplasms
Use
Promote lung maturation in
premature neonates
Used as inhalation in bronchial asthma

Used as nasal spray in allergic rhinitis

a. Beclomethasone,
budesonide Applied as ointment for skin, mucous membrane disorders

4. Local-acting Others Mometasone, clobetasol, desonide

glucocorticoids
Used as inhalation in bronchial asthma and COPD
b. Fluticasone Used orally for inflammatory bowel disease

Applied as ointment for skin and mucous membrane lesions

a. Deoxycorticosterone 0:100 glucocorticoid (anti-inflammatory): mineralocorticoid activity

acetate (DOCA)
Used as replacement therapy in Addison’s disease
Anti-inflammatory activity: 10

Mineralocorticoid activity: 125

b. Fludrocorticosone
5. Mineralocorticoids
Anti-inflammatory dose: 2 mg

Used with hydrocortisone as replacement in Addison’s disease

Anti-inflammatory activity: 0.3

c. Aldosterone Mineralocorticoid activity: 3000

Not used clinically

 53
Insulin and oral antidiabetic agents

53.1 INSULIN REGULATION AND GLUCOSE TRANSPORTERS (GLUT)

Discovered by
Banting and Best in 1921
Chain A – 21 amino acids
Consists of 2 polypeptide
chains – chain A and B
Chain B – 30 amino acids

C–chain (connecting
2 chains linked by
chain) can produce
disulfide bridges
immunogenic reactions

Insulin in β-cell is initially Preproinsulin Removal of

i.e., Preproinsulin Proinsulin Insulin
a single polypeptide chain converted to C-peptide

Glucose

Amino acids

Chemical
Fatty acids
stimulate

Hypokalemia
inhibits
Insulin
Glucagon-like
peptide (GLP-1)

GI inhibitory
peptide

Regulation of Gastrin
insulin secretion
Hormonal
Human insulin differs
Cholecystokinin
from bovine insulin
by 3 amino acids

Secretin

Cystokinin

Parasympathetic ↑ Insulin

Neural β2
↑ Insulin
stimulation
Human insulin differs Sympathetic
Hence porcine insulin
from porcine insulin α2
is closer to human insulin ↓ Insulin
by 1 amino acid stimulation
They are proteins present
on different tissue

Glucose enters pancreatic

β-cells with help of
Glucose glucose transporters
transporters
(GLUT) There are 5 subtypes:
1 to 5

GLUT-4: Present in
muscle and fat, promotes
uptake of glucose

479
480 Pharmacology mind maps for medical students and allied health professionals

53.2 ACTIONS OF INSULIN AND MECHANISM OF ACTION

Except RBCs,
Facilitates glucose entry
WBCs, liver, and
in all cells of the body
brain cells

Exercise facilitates entry of

glucose into muscle cells
without need of insulin

Inhibits hepatic
1. Carbohydrate glycogenolysis and
metabolism gluconeogenesis

Promotes hepatic and

muscle glycogenesis

Net effect reduces

blood sugar

Inhibits lipolysis in
adipose tissue

Thus in diabetes, In liver This results in

2. Lipid Promotes lipogenesis, Hence, free fatty Acetyl Ketone
large concentration FFA is ketonemia,
metabolism synthesis of triglycerides acids are formed CoA bodies
of fat is broken down converted to ketonuria

Hence there is Hence in insulin

Enhances lipoprotein
↑ clearance of deficiency there is
lipase
VLDL and chylomicrons hypertriglyceridemia

Facilitates amino acid

uptake

Enhances protein
synthesis

3. Protein Inhibits protein

metabolism breakdown

Actions
of Insulin
Net effect Anabolic

Catabolic state
Hence diabetes is with negative
nitrogen balance

Hypoglycemic
Insulin
hormones

Glucagon

Growth hormones
Hyperglycemic
hormones
Corticosteriods

Thyroxine

Binds with specific

insulin receptor
Entirely
α-unit
extracellular
Insulin receptor has
2α and 2β subunits
Transmembrane
Mechanism of
β-unit with tyrosine
insulin action
Binding of insulin to α kinase activity
unit activates tyrosine
kinase
Through complex series of
phosphorylation, it
promotes glucose
entry into cell
 Insulin and oral antidiabetic agents 481

53.3 PHARMACOKINETICS AND PREPARATIONS

As it is destroyed by gut
proteolytic enzymes
Not effective orally
Hence usually given
subcutaneously (SC)

Emergencies IV administration

Pharmacokinetics
Soluble injection t½ is 6 min

Addition of protamine Isophane insulin

Addition of zinc Insulin zinc suspension

Differs from human insulin

Bovine insulin (beef) Hence more antigenic
by 3 amino acids
Differs from human by
Porcine insulin (pig) Hence less antigenic
1 amino acid
1. Based on source
Enzymatic modification
of porcine insulin

Human insulin Produced by use of DNA

recombinant technology

Least antigenic

Peak due to pancreatic

“a”
proteins
Processing of conventional
insulin (i.e., bovine and porcine
“b” Peak due to preinsulin
insulin) by gel chromatography
shows impurities in 3 peaks i.e.,
Peak due to insulin fragment
“c”
and other pancreatic hormones
2. Based on purity
Single-peak insulin Highly purified

Monocomponent insulin More purified

Preparations
Insulin lispro

i. Ultrashort-acting Insulin aspart

Onset: 15 min; peak:

0.5–2 h

Regular soluble (crystalline)

Onset : 30 min–1 h
ii. Short-acting
Peak : 2–4 hr

Duration : 6–8 hr

NPH/isophane (neutral
protamine hagedorn)
3. Based on onset and
duration Lente (mixture of ultralente
and semilente in ratio 70:30)

iii. Intermediate-acting Onset: 1–2 h

Peak: 6–12 h

Duration: 18–24 h

Ultralente

Protamine zinc insulin

Insulin glargine
iv. Long-acting
Onset: 4–6 h

Peak: 16–20 h

Duration: 24–36 h

Regular, lente, and

Most commonly used
isophane insulin
Regular and isophane
It forms a complex
∴
insulins should not be
and delays absorption
mixed together
482 Pharmacology mind maps for medical students and allied health professionals

53.4 UNITAGE AND DOSAGE, HUMAN INSULINS, AND INSULIN ANALOGS

Dose is measured in
units (U)
SC
Given
IV (only regular insulin)

Available in concentration
Preparation of 100 u/mL or 40 u/mL

Regular insulin 500 u/mL

Requirement calculated based on

Unitage and dosage blood glucose and glycosylated Hb
Several regimens including
mixtures are being used
Multiple doses offer better
glycemic control

IDDM Daily requirement is

0.2 to 1 u/kg

Higher requirement in obese

Mixtures of short-and intermediate-/ Rapid onset and long

long-acting preparations duration of action
Antigenic (due to impurities
Disadvantages of and animal origin)
conventional insulins
Unstable

Mostly porcine insulin

Purified by gel filtration and ion-

exchange chromatography
Less immunogenic
Both short and long-acting
preparations available
Stable
Advantages
Highly purified insulin Less resistance
Single-peak insulin
Less lipodystrophy
Monocomponent insulin

Expensive

Actrapid, Lentard, Actrapid Human proinsulin gene

MC, Monotard MC
Produced by recombinant
DNA technology
Available as regular, NPH,
lente and ultralente
Enzymatic treatment of porcine
insulin can be done to obtain
human insulin
introduced in E. coli
E. coli is cultured and
proinsulin extracted
Proinsulin is modified
to obtain insulin

Less antigenic

Rapid absorption

Lesser dose required

Allergy to conventional
Human insulins preparation
But more expensive
Lipodystrophy
Use
Pregnancy

Insulin resistance

Favorable pharmacokinetic
profile

Faster absorption

Insulin analogs Lesser hypoglycemia Lispro differs from human

Better glycemic control
e.g., Insulin lispro/aspart
insulin by transposition of lysine Hence called “lispro”
and proline amino acid in β-chain
Aspart is obtained by
substituting aspartic acid in Long-acting (24 h)
place of proline in β-chain
Peakless
Glargine
Broad plasma concentrated
plateau
Should not be mixed with any
other insulin in same syringe
 Insulin and oral antidiabetic agents 483

53.5 INSULIN DEVICES AND USE OF INSULIN

Designed for convenience

Portable pen injections

Pen-size devices

Carried while traveling

Multiple insulin doses

Delivers appropriate doses

Insulin devices Rectractable needles
of insulin

Continuous subcutaneous Based on blood glucose

insulin infusion (CSII) (self-monitored)

Inserted subcutaneously

Inhalation

Nasal spray

Trial insulin Oral

1. IDDM Rectal

2. Non-obese NIDDM Subcutaneous pellet

unresponsive to drugs implants

3. Diabetic ketoacidosis

4. Nonketotic
hyperglycemic coma

5. Diabetes during
pregnancy

6. Stress of surgery,
Use of insulin
infections, and trauma

K+ deficiency leads
∴
7. Myocardial infarction Insulin, glucose and K+ drip
to arrhythmias

Insulin coma induced for Followed by glucose

8. Schizophrenia
20 min administration

To reduce nitrogen and K+

9. Burns
loss, along with glucose

10. Hyperkalemia

11. Anorexia nervosa

484 Pharmacology mind maps for medical students and allied health professionals

53.6 ADVERSE EFFECTS AND DRUG INTERACTIONS

Large doses
Most common
Inappropriate time
Due to
Small meal

Vigorous exercise

Sweating
1. Hypoglycemia
Palpitations

Tremors

Blurred vision
Symptoms
Weakness
Rx : Oral/IV glucose
Hunger

Difficulty in
concentration
Adverse effects
Due to contaminating proteins Convulsions and coma

2. Allergy Manifested as Urticaria, angioedema,

rarely anaphylaxis

Rare with purified and human insulin

Atropy of subcutaneous fat

Occurs at site of injection

Due to immune response to

contaminating proteins

3. Lipodystrophy Lipohypertrophy: Enlargement of

subcutaneous tissue

Irregular insulin absorption from

these sites

Prevented by frequent changing

of injection sites

Rare with purified preparations

Masks warning symptoms of Like palpitations,

hypoglycemia tremors
1. β blockers
They also prolong hypoglycemia by
inhibiting compensatory mechanisms
Drug interactions acting through β2 receptors
Exert hypoglycemic effect by
2. Salicylates ↑ sensitivity of β-cells to
glucose and enhancing insulin release
 Insulin and oral antidiabetic agents 485

53.7 ORAL ANTIDIABETIC AGENTS – CLASSIFICATION

Tolbutamide,
a. First generation
chlorpropamide
1. Sulfonylureas
Glibenclamide, glipizide,
b. Second generation
gliclazide, glimepiride

Metformin

2. Biguanides

Phenformin (banned)

Oral antidiabetic 3. Meglitinides Repaglinide, nateglinide

Classification
agents

Troglitazone (banned)

4. Thiazolidinediones Rosiglitazone (banned)

Pioglitazone

5. Alpha-glucosidase Acarbose, miglitol,

inhibitors voglibose
486 Pharmacology mind maps for medical students and allied health professionals

53.8 SULFONYLUREAS

Sulfonamide This led to

derivative produced development of sulfonylureas
hypoglycemia

All have same But differ in potency and

mechanism duration
This causes Degranulation
2nd generation 100 Bind to sulfonylurea SUR are ATP-sensitive Binds to SUR1 Closes K+ Hence leads to Ca++ influx from and release
times more potent receptors (SUR) on β- K+ channels (KATP) subunit channels depolarization voltage-dependent of insulin
than 1st generation cells of islets of pancreas on cell membrane calcium channels (secretagogues)
Also ↑ sensitivity
of peripheral tissues of insulin
Mechanism
of action
↑ Number
of insulin receptors

↓ Hepatic
gluconeogenesis
Hence lesser
Short-acting hypoglycemia
Tolbutamide
Safer in elderly
diabetics
1st-generation
agents
Long-acting
(t½ 32 h)
Chlorpropamide
Causes prolonged
hypoglycemia in
elderly
More potent

Lesser ADRs and

drug interactions

Contraindicated
in hepatic and renal
dysfunction
Commonly used
Glibenclamide
2nd-generation Long-acting hence
given as OD
Sulfonylureas

Short-acting
Glipizide
Lesser
hypoglycemia

Glimepiride Long-acting hence

given as OD

Hypoglycemia (lesser with

2nd generation)

Weight gain

Cholestatic
jaundice

ADRs Allergic reactions

Teratogenicity

↑ Risk of CV death
(controversial)

Hence patients
Disulfiram-like should abstain
reaction with alcohol from alcohol
NSAIDs, sulfonamides, ∴
They displace
warfarin ↑ sulfonylureas from
hypoglycemia protein-binding sites
Alcohol, cimetidine,
They
∴
erythromycin
↑ hypoglycemia inhibit metabolism
Drug
interactions Diuretics and
corticosteroids ↑
blood sugar levels Thus delays recovery
from hypoglycemia
Propranolol blocks β2 Hence it inhibits
receptors in liver glycogenolysis Also masks the Tachycardia,
symptoms of palpitation,
Use hypoglycemia tremors, etc.
THIN NIDDM patients
 Insulin and oral antidiabetic agents 487

53.9 BIGUANIDES AND MEGLITINIDE ANALOGS

Metformin

Phenformin (banned)
Insulinomimetic
Metformin, only used
clinically
Inhibits hepatic
gluconeogenesis
Mechanism of action
↓ Gastrointestinal
glucose absorption

↑ Peripheral
glucose utilization

Anorexia, nausea,
Biguanides vomiting, diarrhea

Metallic taste

Loss of weight as it
causes anorexia
ADRs
Lactic acidosis

Vitamin B12 deficiency Only long-term use

Does not cause In conventional

hypoglycemia doses

Use OBESE NIDDM patients

Repaglinide, nateglinide

Structurally unrelated
to sulfonylureas

i.e., Insulin secretagogues by

But they have similar
closure of ATP-sensitive K+ Depolarization Insulin release
mechanism
channels in β-cells of pancreas
∴
They are metabolized
Avoid in hepatic failure
in liver

Rapid onset and short

Meglitinide duration
analogs Used either alone or with
biguanides
Less potent than
sulfonylureas
Used as alternatives when
sulfonylureas cause allergy
Use
They cause insulin release only
in presence of glucose

Used only to control post-

prandial hyperglycemia

ADR Lowest chances of hypoglycemia

488 Pharmacology mind maps for medical students and allied health professionals

53.10 THIAZOLIDINEDIONES (TZD) AND ALPHA-GLUCOSIDASE INHIBITOR

Agonists of PPAR receptors

(peroxisome proliferator-
activated receptors)
PPAR-nuclear receptors
Also called Hence modulates expression of
present mostly in adipose
glitazones insulin-sensitive genes
tissue, muscle, and liver

TZD stimulate PPAR-γ Hence it stimulates synthesis of

MOA
genes that ↑ insulin action

Inhibits hepatic Hence ↑ glucose transport to

gluconeogenesis muscle and adipose tissue (by GLUT-4)

↑ Lipogenesis

Fluid retention

Weight gain

Thiazolidinediones ADRs Anemia

(TZD)

Precipitates congestive
cardiac failure

Hepatotoxicity

Adjuvants to
sulfonylurea/biguanides
OD dose
Monotherapy in mild NIDDM
Lesser hypoglycemia
Benefits
↑ HDL cholesterol
Use
Minimal drug interactions

Maximum efficacy only after

6–12 wks

Weight gain and anemia

Drawbacks
Precipitates CCF

As it could be
Regular monitoring of LFT
hepatotoxic
Breakdown of disaccharides and
α-glucosidases (e.g., sucrase,
oligosaccharides to monosaccharides
maltase, glycoamylase)
(glucose and fructose)
Acarbose, miglitol, These agents competitively Hence prevents carbohydrate
voglibose inhibit enzyme α-glucosidase absorption
on intestinal brush border
They are administered just
MOA before or with food (either
alone or with OHA or insulin)
Hence they reduce post-
Alpha-glucosidase prandial hyperglycemia
inhibitor
They do not cause
hypoglycemia

GI disturbances are
frequent and common
ADRs
Abdominal distention,
∴
Undigested carbohydrates
flatulence, bloating, diarrhea are fermented in colon

53.11 NEW DRUGS FOR DIABETES MELLITUS
Oral glucose provokes 4
times higher insulin release
than intravenous glucose
GLP-1 secretion is
reduced in patients
with type 2 diabetes
Incretins like GLP-1 have little
stimulatory effect on insulin
secretion at normoglycemic
concentration
Apart from releasing
insulin, GLP-1 has
following actions
diabetes mellitus
New drugs for
Endogenous GLP-1 is
1. Incretins rapidly broken by
dipeptidyl peptidase-4
So, two strategies by
which incretin effect
can be strengthened are
Insulin and oral antidiabetic agents 489
This is because oral
This amplifies glucose-
glucose releases GLP-1
induced insulin release
(glucagon-like peptide-1)
This is unlike Hence, GLP-1 has lower
sulfonylureas and other risk of causing
insulin secretagogues hypoglycemia
Suppresses glucagon e.g., Exenatide and
secretion liraglutide
Preserves islet cell
Administered
integrity and
subcutaneously
↓ apoptosis
Delays gastric
Act by mechanism similar
emptying resulting in
to GLP-1
reduced appetite
New drugs of this
Thus has a half-life
category include albiglutide
of 1–2 min only
and dulaglutide
Promote weight loss
Nausea
A. GLP-1 receptor
agonists Most common adverse
effect
Acute pancreatitis
Personal or family
Contraindicated history of medullary
thyroid cancer or MEN-2
Liraglutide is longer acting
(once daily) compared
to exenatide (twice daily)
Liraglutide does not require dose
adjustment in renal failure whereas
exenatide dose should be reduced
Recently, liraglutide has been
approved for management
of obesity
Sitagliptin, vildagliptin,
saxagliptin, alogliptin,
empagliflozin, and linagliptin
Prolong action of endogenous
GLP-1 by inhibiting its
metabolism through DPP-4
Unlike incretin-mimetic
drugs, these do not cause
nausea or weight loss
Nasopharyngitis and
Most common adverse
B. DPP-4 inhibitors upper respiratory tract
effect
infections
Effective orally
Require dose adjustment
in renal failure except
linagliptin
Vildagliptin can cause
hepatitis
(Continued)
490 Pharmacology mind maps for medical students and allied health professionals

53.11 NEW DRUGS FOR DIABETES MELLITUS (Continued)

Dapagliflozin and canagliflozin

Glucose is freely filtered across glomerulus

and is reabsorbed in proximal tubules by
sodium-glucose cotransporter-2 (SGLT-2)

Act by inhibiting this transporter and

cause glucosuria in diabetics

2. Sodium-glucose
Also result in weight loss
cotransporter-2 inhibitors

Effective orally

Efficacy reduced in renal failure

Incidence of urinary tract infections and
genital infections
Main adverse effects
Higher rates of breast and bladder
cancers with dapagliflozin
e.g., Pramlintide

Synthetic analog of islet amyloid

polypeptide (IAPP)

Also called amylin ↓ Glucagon secretion

Acts by Delaying gastric emptying

3. Amylin analogs

↓ Appetite

Administered by subcutaneous
route

Cause weight loss

Important points
Approved for treatment of type 2 as well
as type 1 diabetes mellitus (only drug
Bile acid metabolism is abnormal in apart from insulin)
patients with type 2 diabetes mellitus
Cause hypoglycemia
Bile acid-binding agents lower
blood glucose
4. Bile acid-binding resins
Colesevelam is specifically approved for
type 2 diabetes

Result in hypertriglyceridemia

Adjunct to diet and exercise to improve

glycemic control in type 2 diabetes
5. Bromocriptine
Found that dopamine alters insulin
resistance by acting on hypothalmus and
bromocriptine targets D2 receptors
 54
Agents affecting calcium balance

54.1 CALCIUM PREPARATIONS AND USES

Calcium citrate

Calcium gluconate

Oral

Calcium lactate
Most cost-
effective
Calcium carbonate
Has high percentage
of calcium

Non-irritant hence
Calcium gluconate
preferred
Parental IV
An irritant hence can
Calcium chloride
cause tissue necrosis

In children, pregnancy,
lactation, post-
menopausal
Calcium
preparations Due to dietary
deficiency

In rickets and
Prevent and treat
osteomalacia with
calcium deficiency
vitamin D
Following long-term
corticosteroid therapy
with vitamin D

Following removal of
parathyroid gland

As antacid Calcium carbonate

IV calcium
gluconate
Uses of calcium
5–10 mL followed by
50–100 mL
(slow infusion)

Tetany Relieves muscle spasm

Feeling of warmth

Follow up with oral

calcium 1.5 g daily
for few wks

Urticaria and IV calcium Relief could be due to

dermatoses gluconate placebo effect

491
492 Pharmacology mind maps for medical students and allied health professionals

54.2 PARATHYROID HORMONE (PTH)

Polypeptide, secreted
by chief cells of
parathyroid gland
Secretion is controlled
by concentration of
free Ca+2 in plasma
Introduction
Low plasma
↑ Ca+2 secretion

High plasma
↓ Ca+2 secretion

Mobilizes calcium
from bone

↑ Renal
Ca+2 reabsorption

Stimulates calcitriol
synthesis which
↑ GI Ca+2 absorption
Actions
Which induces ↑ Number and activity
Stimulates
protein RANK of osteoclasts
osteoblasts
ligand which

Stimulates bone
Parathyroid remodeling
hormone
(PTH)
↑ Phosphate
excretion

10–20 mL of 10% calcium Follow up with

Acute attack
gluconate IV slowly oral calcium
(tetany)
Treatment of till tetany subsides supplements
hypoparathyroidism i.e., Ergocalciferol,
Chronic Vitamin D2 (drug
oral calcium
hypoparathyroidism of choice)
supplements

Calcimimetic
agent
Surgical resection
of tumor Binds to receptor
on parathyroid
gland
Cinacalcet
Reduces PTH
secretion hence
↓ serum Ca+2

Used orally
Hyperparathyroidism Rx

Recombinant
PTH

Administered
SC OD

↑ Bone
Teriparatide
formation

Rx of severe
Use osteoporosis
(↑ bone density)

However, it is
costly
 Agents affecting calcium balance 493

54.3 CALCITONIN

It is a peptide hormone

Synthesized by “C”
cells of thyroid
Introduction
Regulated by plasma
calcium concentration

High plasma calcium

↑ calcitonin
release and vice versa

Opposite of PTH
↑
Serum calcium
and phosphate by direct
action on bone and kidney
Actions
↑ ↑
Inhibits bone Bone Plasma
osteoclasts resorption calcium and phosphate
↑
Ca+2 and
Reduces plasma
phosphate reabsorption
Ca+2 and phosphate
in renal tubules

Synthetic human
calcitonin

Synthetic salmon
calcitonin
Calcitonin
Preparations Natural porcine Hence causes
Antigenic
calcitonin antibody formation

IM/SC
Given
Nasal spray (only
salmon calcitonin)
Hypercalcemia
(due to cancers)

But bisphosphonates
Paget’s disease of bone
are DOC
Uses
Nasal spray of salmon
Postmenopausal
calcitonic + Ca
osteoporosis
+ vitamin D
Nasal spray of salmon
Corticosteroid-induced
calcitonic + Ca
osteoporosis
vitamin D

Nausea, vomiting

Side effects Flushing

Pain at injection site

494 Pharmacology mind maps for medical students and allied health professionals

54.4 VITAMIN D

Mechanism of action Vitamin D binds Complex goes to Stimulates synthesis This leads to
(similar to corticosteroids) vitamin D receptors nucleus of specific mRNA protein synthesis
↑ Ca and phosphate
absorption in small intestines
↑ Synthesis of calcium channels and
calcium binding protein (calbindin) in GIT
Calbindin is carrier protein for
calcium
Mobilizes calcium from
Physiological role ↓
bone by osteoclastic action
↑
This Ca+2 and phosphate
reabsorption from renal tubules
Normal bone mineralization
(calcitriol)
Cellular growth and
differentiation
↑
Plasma and
phosphate levels

Deficiency Causes rickets in children

Immediate withdrawal of
vitamin D
Causes osteomalacia in adults
Low-calcium diet
Hypervitaminosis D Rx
IV hydration

Glucocorticoids

Oral capsules 400 IU/day

Vitamin D2 (ergocalciferol)
for rickets and osteomalacia
Vitamin D
Vitamin D3 (cholecalciferol) Oral, IM

Calcitriol Oral capsule

Are prodrugs

Preparations
Are effective orally
Alfacalcidol and dihydrotachysterol
Liver then converts
to calcitriol

Used in hypoparathyroidism
of renal bone disease

Calcipotriol
Prevention (400 IU/day) and treatment (4000
IU/day) of nutritional rickets and osteomalacia
Vitamin D-resistant rickets
Vitamin D-dependent rickets
Vitamin D analog
Used topically in psoriasis
It is an X-linked disorder of calcium
and phosphate metabolism
Rx with large doses of
vitamin D and phosphate
Inborn error of vitamin
metabolism
Failure of conversion of
calcifediol to calcitriol
Rx with calcitriol or
alfacalcidol

Due to chronic renal failure

Uses Hence inability to convert

Renal rickets
calcifediol to calcitriol
Rx with calcitriol or
alfacalcidol
There is hypocalcemia and
hyperphosphatemia
Hypoparathyroidism
Calcitriol or alfacalcidol
(temporary treatment)

Along with calcium

Senile or postmenopausal
osteoporosis
Reduces risk of fractures

Psoriasis Topical calcipotriol

 Agents affecting calcium balance 495

54.5 BISPHOSPHONATES

Etidronate (oral, IV)

They are analogs of

Alendronate (oral)
pyrophosphate

e.g., Pamidronate (IV infusion)

Risedronate (oral)

Zoledronate (IV infusion)

Inhibit bone resorption (antiresorptive)

Have high affinity for bone calcium

Hence accumulate in areas of bone

resorption
Mechanism of action
Imbibed by osteoclasts, promote
their apoptosis
↓ Formation and dissolution of
hydroxyapatite crystals
Interferes with mevalonate pathway of
cholesterol synthesis which is required
for normal function of osteoclasts

Highly polar Hence poorly absorbed from GIT (about 10%)

Pharmacokinetics Food reduces absorption Hence given on empty stomach

Gets incorporated in bone Stays there for months to years

Drug of choice
Bisphosphonates

Paget’s disease of bone Given cyclically

Reduces pain and alkaline

phosphate levels

↑ Bone mineral density

Prevention and Rx of postmenopausal

Reduces risk of fractures
osteoporosis

Given with calcium and vitamin D

Uses
Can be life-threatening

Immediate Rx required
Hypercalcemia of malignancy
IV pamidronate infusion
↓ plasma Ca+2 levels

IV fluids, frusemide beneficial

Hypercalcemia of hyperparathyroidism Relieves pain of lytic bone diseases

Hence taken with full glass of water, patient

Esophagitis is most common
should remain upright for at least 30 min

Fever, flu-like symptoms

Osteomalacia (long-term)
Adverse effects
Hypocalcemia

Osteonecrosis of jaw (high dose)

Thrombophlebitis (IV administration)

496 Pharmacology mind maps for medical students and allied health professionals

54.6 PREVENTION AND TREATMENT OF OSTEOPOROSIS, AND DRUGS OF ABUSE

IN SPORTS

Calcium (↑ BMD)

Vitamin D (↑ Ca+2
absorption)

Estrogen (prevents
Prevention and treatment osteoporosis)
Agents preventing
of osteoporosis bone resorption
SERMs (↑ BMD, e.g.,
raloxifene)

Calcitonin (prevents bone

resorption)

Bisphosphonates
(↓ Bone resorption)

Small doses,
↑ osteoblastic activity
Fluorides
But not preferred

Agents promoting
bone formation Testosterone In hypogonadal men

Anabolic steroids In postmenopausal women

Anabolic agents (clenbuterol,

tibolone): ↑ Lean body mass

Peptide hormones, growth Erythropoietin, insulin-like growth

factors factors, chronic gonadotropin

β2 agonists Salbutamol, etc.

Aromatase inhibitors,
antiestrogens
Hormones and metabolic
modulators
Diuretics reduce weight

Ephedrine, amphetamine,
Stimulants
caffeine, cocaine
Drugs and methods
Drugs of abuse
prohibited by WADA (World Narcotics (opioids) Protect against pain
in sports
Anti-Doping Agency)

Cannabinoids Protect against pain

Anti-inflammatory and
Glucocorticoids
euphoric actions

Blood doping ↑ O2 transfer

Transfer of nucleic acids and

Gene doping
genetically modified cells

Prohibited in specific
Alcohol
sports

e.g., Archery, billiards,

β blockers
shooting, golf, etc.

Drugs acting on uterus
55.1 UTERINE STIMULANTS
Also called oxytocics or ecbolics
Uterine stimulants Stimulate uterine contractions
e.g.,
Nonapeptide hormone
Synthesized in hypothalamus
Stored and secreted by posterior pituitary
with antidiuretic hormone (ADH)
Released by stimuli such as
suckling, parturition, and coitus
Physiological actions
Oxytocin Preparations and
administration
Uses
Side effects
55
Oxytocin
Ergot derivatives Ergometrine, methylergometrine
Prostaglandins PGE2, PGF2α, 15-methyl PGF2α, misoprostol
Acts on oxytocin receptors
Stimulates contraction
of pregnant uterus
Nonpregnant uterus is resistant
At full-term uterus is
highly sensitive
Supraoptic and Estrogen ↑ number and
paraventricular nuclei sensitivity of oxytocin receptors
Uterus Effects of oxytocin are
dose-dependent
Contraction of fundus and body
Relaxation lower segment-low dose
↑ Both force and frequency
of uterine contractions
Produces sustained
Complete relaxation between contractions contractions
maintain blood flow to placenta and fetus
No relaxation inbetween
High-dose
Hence there is no
blood flow to fetus
Contracts myoepithelial cells
This leads to fetal
distress/asphyxia and death
Breast Facilitates milk ejection
Suckling stimulates oxytocin release
High dose has mild ADH-like action
CVS Hence ↓ urine output and
Not effective orally Causes Na and H2O retention
Synthetic oxytocin (syntocinon) IV infusion
Syntometrine: Syntocinon + IM
ergometrine
Given as IV infusion
Initial low dose, later
adjusted as per response
Rule out cephalopelvic disproportion and
malpresentation before administration
Induction of labor
Monitor fetomaternal heart
rate and maternal BP Rate of infusion can be adjusted
Monitor uterine contractions Hence action can be If uterine overstimulation/
Short t½
terminated immediately fetal asphyxia
Syntocinon is DOC because
Complete uterine relaxation between
uterine contractions (at low dose), hence
Abortion As an alternative to induce no fetal distress
midtrimester abortion
Does not contract lower uterine segment,
If they are inadequate during labor hence no interference with fetal descent
To ↑ uterine contractions
For prevention (IM) or
treatment (IV infusion)
Postpartum
hemorrhage (PPH)
Methylergometrine is
Milk ejection–as an alternative
intranasal spray
Uterine rupture Due to overstimulation
(high-dose)
Fetal asphyxia/death In high dose
Water intoxication Due to ADH-like action
(Continued)
497
498 Pharmacology mind maps for medical students and allied health professionals

55.1 UTERINE STIMULANTS (Continued)

e.g., Ergometrine and

methylergometrine (Methergine)

Ergometrine (E) Natural alkaloid

Methylergometrine (ME) Semisynthetic (is more potent)

Acts by binding to 5HT

receptors

Powerful uterine stimulant

↑ Force, frequency, and

duration of uterine contractions
Actions
Contractions involve both Powerful, sustained contractions
upper and lower segment which can lead to uterine tetany
Ergot derivatives
Low dose: Rhythmic ↑ GI motility
contractions + relaxations

High dose ↑ BP by causing

vasoconstriction

Postpartum hemorrhage (PPH)

Administered orally, IM, or IV
for prevention and treatment

Uses Prevent uterine atony Rapid and short-acting

following caesarean section

Hasten uterine involution Oral ergometrine/methylergotamine

for 7 days

Side effects Nausea, vomiting,

hypertension

Contraindication Hypertension, PVD, pre-

eclampsia, eclampsia

Synthesized by uterus

They play an important role during

menstruation and parturition

PGE2 and PGF2 stimulate Pregnant >> than nonpregnant

uterine contractions
Prostaglandins
Soften cervix and hasten
dilatation (called ripening)

PGs produced by fetal tissues help in

initiation and progression of labor

Involved in dysmenorrhea and

menorrhagia Hence NSAIDs are beneficial

(Continued)
 Drugs acting on uterus 499

55.1 UTERINE STIMULANTS (Continued)

Intravaginal or extra-amniotic
dinoprostone (PGE2)

Deep IM carboprost
Preparations
(15 methyl PGF2α)

Intravaginal misoprostol
(PGE)

Side effects Nausea, vomiting, diarrhea

PPH
(alternative to ergometrine)

Cervical ripening (prior to

induction of labor)

Uses

Induction of labor
Vaginal suppositories
(alternative to oxytocin)

Dinoprostone
Abortion (mid-trimester)
(intravaginal/extra-amniotic)

With mifepristone in MTP

(up to 9 wks)
500 Pharmacology mind maps for medical students and allied health professionals

55.2 UTERINE RELAXANTS (TOCOLYTICS)

e.g., Salbutamol, terbutaline

isoxsuprine, ritodrine
Tachycardia
Acts by ↑ cAMP
Palpitations
Inhibit uterine contractions
Side effects
and relax the uterus
Hypotension
β2 adrenergic agonists
Hyperglycemia

Ischemic heart disease

Diabetes mellitus
Contraindications/caution
Thyrotoxicosis

Hypokalemia

When β2 agonists are

Alternative
contraindicated

Given as IV infusion

Also causes CNS and CVS Hence used to control convulsions

Magnesium sulfate depression and BP in toxemia of pregnancy

Hypotension

Arrhythmias
ADRs
CNS and respiratory depression

e.g., Nifedipine Hypothermia

Given sublingually 10 mg Repeated every 20 min

for 3 doses
Uterine relaxants (tocolytics) Calcium channel blockers (CCBs)
Inhibits Ca+2 entry into
myometrial cells

it ↓ placental perfusion It is not preferred

∴

Oxytocin receptor antagonist

Atosiban Given as IV infusion Alternative to β2 agonists

ADRs Hypotension, headache

e.g., NSAIDs like indomethacin

They inhibit Hence has both beneficial

prostaglandin synthesis and adverse effects
Prostaglandin synthesis inhibitors
Also useful in dysmenorrhea

Premature closure of ductus Hence subsequent

ADRs
arteriosus development of pulmonary HT

Alcohol But produces CNS depression

Nitric oxide donors e.g., Nitroglycerin and other nitrates But causes maternal hypotension
Miscellaneous

Inhibits cytokine synthesis

and cervical ripening
Progesterone
ADRs Masculinization of female fetus
Threatened abortion

Uses Delay premature labor

Dysmenorrhea
 Drugs acting on uterus 501

55.3 DIFFERENCES BETWEEN OXYTOCIN AND ERGOMETRINE

Oxytocin Ergometrine

1. Synthetic (commercial) Natural

2. Peptide Alkaloid

3. Acts on oxytocin receptors 5-HT receptors

4. Endogenous Exogenous

5. Only IV Oral, IM and IV

6. Short duration t½ 15 min Long duration t½ 2 h

7. Contracts body & fundus Contracts whole uterus

8. Relaxes lower segment No relaxation

9. Induces labor, milk ejection PPH, uterine involution

 X
Part    

Chemotherapy
 56
General chemotherapy

56.1 DEFINITIONS AND CLASSIFICATIONS

Use of chemicals in infectious

diseases to destroy
1. Chemotherapy
microorganisms without
damaging the host tissue
Definitions
Substances produced by
microorganisms which inhibit Penicillins, cephalosporins,
2. Antibiotics
the growth of or destroy glycopepties (vancomycin)
other microorganisms

Louis Pasteur 1. Drugs that inhibit β-lactams Weakens bacterial cell wall
cell wall synthesis

Paul Ehrlich – father of Polymyxins, amphotericin B, Hence they swell and burst
modern chemotherapy nystatin due to difference in tonicity

Notable scientists

General 2. Drugs that affect cell Alter membrane

Gerhard domagk
chemotherapy membrane function permeability

Leakage of cell contents,

Alexander Fleming
hence leads to cell death

Bacterial ribosome has

30S and 50S subunit

3. Drugs that inhibit Mammalian ribosome

protein synthesis has 40S and 60S subunit
Classification of
A. Based on mechanism
antimicrobials
of action
agents (AMAs) Macrolides, tetracyclines,
chloramphenicol inhibit 30S/50S
subunit hence protein synthesis

4. Drugs that cause misreading

of mRNA code and alter Aminoglycosides
protein synthesis

5. Drugs that inhibit DNA Acyclovir, ganciclovir,

(nucleic acid) synthesis zidovudine

6. Drugs that inhibit

Rifampicin, metronidazole
DNA function

7. Drugs that inhibit

Fluoroquinolones
DNA gyrase

8. Drugs that interfere Sulfonamides, dapsone,

with metabolic pathway trimethoprim, pyrimethamine

504
 General chemotherapy 505

56.2 CLASSIFICATIONS

Tetracyclines, chloramphenicol,
1. Bacteriostatic Suppresses growth of bacteria
macrolides, sulfonamides

Cephalosporins, aminoglycosides,
2. Bacteriocidal Kills the bacteria: Penicillins fluoroquinolones, metronidazole,
rifampicin

3. However at high concentrations e.g., Chloramphenicol is “static,”

B. Classification based
“static” drugs may produce but ”cidal” against H. influenzae,
on type of action
“cidal” effect N. meningitidis, and S. pneumoniae

For most patients use of

“static”/“cidal” drugs may not
make significant difference

However, for patients with

impaired host defense, “cidal”
drugs must be used
506 Pharmacology mind maps for medical students and allied health professionals

56.3 CLASSIFICATION, FACTORS INFLUENCING SUCCESSFUL CHEMOTHERAPY,

AND ANTIMICROBIAL RESISTANCE

Penicillin G Gm +ve organisms

1. Narrow-spectrum
antimicrobials
Aminoglycosides Gm –ve organisms

Gm +ve, Gm –ve,
Tetracyclines Chlamydiae,
C. Classification based Mycoplasma, Rickettsiae
on spectrum 2. Broad-spectrum
antimicrobials

Chloramphenicol

3. However, in practice, the

term broad-spectrum i.e., Both Gm +ve and
includes all antimicrobials Gm –ve
with wide spectrum of organisms, e.g., ampicillin
activity

Drug should reach site

1. Site
of infection

Drug must achieve

2. Concentration adequate concentration
Factors influencing at site of infection
successful
chemotherapy
Good host defense reduces
3. Host defense
antibiotic dosage

Microorganism must be
4. Sensitivity sensitive to
antimicrobial agent

Unresponsiveness of
Resistance microorganism to
antimicrobial agent

Organisms have never

Natural/acquired responded to
antimicrobial

Due to absence of specific

enzyme or target site
affected by the drug
Natural
Gm –ve organisms not
Spontaneous genetic
e.g., responding to
change
Antimicrobial resistance penicillin G

Not a clinical problem, as Few mutants are normally

alternative present in a
drugs are available population of bacteria

Organisms initially sensitive, Antibiotics destroy

later develop resistance sensitive bacteria

Mutation

A major clinical problem Resistant bacteria multiply

Acquired
Bacteria acquires
Mutation occurs in e.g., S. aureus acquiring
resistance via
single step resistance to rifampicin
alterations in their DNA

Such DNA changes Mutations also occur in e.g., Gonococci to

may occur by multiple steps penicillin G

Bacteria contain
extrachromosomal genetic
material called plasmids in
cytoplasm

They carry genes encoding

for resistance

Gene transfer
DNA is transferred by
1. Transduction
bacteriophage (virus)
Called R-factors

Resistant bacteria releases

genetic material in medium,
2. Transformation
which is taken up
R-factors are transferred by by sensitive organisms
the following mechanisms

It is most important mode

of transfer
3. Conjugation
Transfer occurs via direct
contact between cells
through sex pilus or bridge
 General chemotherapy 507

56.4 ANTIMICROBIAL RESISTANCE

1. Production of inactivating enzymes e.g., β-lactamase by staphylococci

e.g., Resistant bacteria producing folic

2. Altered metabolic pathway acid by alternative pathway and
acquiring resistance to sulfonamides

e.g., Alteration of ribosomal binding

Resistance exhibited by 3. Altered binding site
site for aminoglycosides

Change in penicillin-binding protein

(PBP) of Pneumococci, sensitivity for
penicillins

4. ↓ Accumulation/efflux e.g., Resistance of Gm +ve and Gm –ve

pump organisms to tetracyclines

Resistance among chemically related

drugs

When organism develops resistance

e.g., Resistance to one tetracycline
to one drug, it is also resistant to
means resistance to all other
other drugs of same group, even when
tetracyclines
not exposed to them

Tetracycline
(two-way)
Cross-resistance

Doxycycline (two-way)

Sulfadoxine
(two-way)

Cross-resistance could be one-way or

Sulfadiazine (two-way)
two-way

1. Use AMA only when indicated/ Gentamicin

necessary (one-way)

Streptomycin (one-way)
2. Selecting right AMA

Gentamicin-resistant organisms may

be resistant to streptomycin
Prevention of resistance 3. Give correct dose

But many streptomycin-resistant

organisms still respond to
4. Give correct duration gentamicin

5. Judicious combination of AMA e.g., Tuberculosis, leprosy, H. pylori

508 Pharmacology mind maps for medical students and allied health professionals

56.5 SELECTION OF APPROPRIATE AMA

Chloramphenicol can cause

gray baby syndrome in
premature infants

Sulfonamides can cause

kernicterus in neonates
1. Age
Ototoxicity and
nephrotoxicity are
common in elderly

These are due to reduced

hepatorenal functions

Asthma, allergic rhinitis,

hay fever, etc.
↑ risk of allergy

Antibiotics are derived

∴
Hence history of allergy
2. History of allergy from microorganisms allergic
should be taken
reactions are expected

If allergy is known, avoid

that agent,
use an alternative AMA

Primaquine, pyrimethamine,
sulfonamides can lead to
3. Genetic abnormalities
hemolysis in G6PD-deficient
patients
Tetracyclines (abnormal
fetal dentition and
∴
AMA can cross bone growth)
Selection of appropriate
A. Patient factors placental barrier and
AMA
affect the developing fetus Chloramphenical
(gray baby
Risk of teratogenicity is syndrome)
4. Pregnancy highest Hence avoid
during first trimester
Aminoglycosides (fetal
ototoxicity/nephrotoxicity)
Relatively safer AMAs –
penicillins,
some cephalosporins
Sulfonamides (kernicterus)
In patients with AIDS, leukemias, other
immunocompromised malignancies, anticancer
5. Host defense – status
status prefer drug therapy, corticosteroid
use of bactericidal agents therapy

Avoid aminoglycosides,
tetracycline
6. Renal dysfunction
(except doxycycline),
vancomycin, fluoroquinolones

Avoid erythromycin,
7. Hepatic dysfunction rifampicin,
chloramphenicol

Activity of sulfonamides
Pus is rich in PABA, purines
↓ in
and thymidine
presence of pus
8. Local factors
Efficacy of
aminoglycosides
↑ at alkaline pH

(Continued)
 General chemotherapy 509

56.5 SELECTION OF APPROPRIATE AMA (Continued)

Depending on site and

severity of infection

1. Route of administration Mild–moderate infection Oral route

Severe infections Parenteral initially, later oral

Broad-spectrum AMA during

2. Spectrum of activity empirical
therapy

3. Bacteriostatic/
Immunocompromised patients Bactericidal agent
bactericidal effect

e.g., Agents crossing BBB are

4. Pharmacokinetics useful for meningitis or
anaerobic brain abscess

Prefer drugs with least toxicity

5. Toxicity

B. Drug factors This will improve patient

compliance

Prefer cheap and effective AMA

6. Cost
Newer expensive ones should
only be used when
absolutely necessary

Adequate enough to attain

plasma concentration above
minimum inhibitory
concentration (MIC)

Lowest concentration of AMA

that prevents visible
MIC
growth of microorganisms
after 18–24 h of incubation

Bactericidal effects of many i.e., Higher the concentration,

AMA are greater is the bactericidal
dose–dependent effect, e.g., aminoglycosides As concentration of AMA
↑ above MIC, rate and extent of e.g., Aminoglycosides
7. Dose of AMA bactericidal effect also ↑
a. Concentration-
dependent killing
Hence they should be
1. Infecting organism should be administered once daily
sensitive to the antibiotic used

Longer the presence of AMA

2. Bacteriological culture and above MIC, the longer is the e.g., β-lactams, vancomycin
sensitivity tests (C and S) should bactericidal effect
guide drug selection b. Time-dependent killing
Hence they should be
Bactericidal effect is also
3. When C and S not available/ administered
dependent on 2 factors
feasible, empirical therapy more frequently
should be considered
Microbe-/organism- AMAs with PAE continue to
related factors suppress the multiplication of
4. In severe infections organisms even after their plasma
empirical therapy should be concentration falls below MIC
started

Indicates time required for e.g., Aminoglycosides,

5. In empiric therapy, antibiotic bacteria to return carbapenems,
must cover all likely pathogens; a to normal growth quinolones
combination or broad-spectrum c. Post-antibiotic effect
antibiotic must be used (PAE)
Hence dosage interval
6. When organisms are should be kept longer
identified, use Persistence of drug at site
definitive therapy of action or
periplasmic space
Reasons for PAE
Regeneration of inhibited
enzymes
requires time, e.g., DNA gyrase
510 Pharmacology mind maps for medical students and allied health professionals

56.6 AMA COMBINATIONS

2 bacteriocidal agents are e.g., Penicillin +

generally synergistic gentamicin

Not useful, avoid

Bacteriostatic +
Bacteriostatic agent inhibits
∴
bactericidal
bacterial multiplication, hence
They act on
∴
antagonizes bacteriocidal drug
multiplying bacteria
effect

β-lactamase Amoxicillin + clavulanic

producing organisms acid

Tuberculosis INH + rifampicin

Carbenicillin +
1. Synergism Pseudomonas infection
gentamicin

Pneumocystis carinii Sulfamethoxazole +

AMA combinations pneumonia trimethoprim

Bacterial endocarditis Penicillin + gentamicin

Intra-abdominal
infections

Genitourinary
2. Mixed infections
infections

Abscesses – brain, pelvic,

lung, liver

AMAs covering both

Gm +ve and Gm –ve
organisms, or

3. Initial treatment of Both aerobes and

Situations requiring severe infections anaerobes used
combination therapy
e.g., Penicillin/
cephalosporin +
Until culture and sensitivity
gentamicin ±
report is available
metronidazole (to
cover anaerobes, if any)

e.g., Tuberculosis, leprosy,

4. Prevent resistance
HIV, H. pylori

Lower dose is used in

combination therapy

5. Reduce toxicity Hence ↓ toxicity

e.g., Amphotericin B +
flucytosine in
cryptococcal meningitis
e.g., INH + rifampicin ↑ Hepatotoxicity
1. ↑ Toxicity –
esp. if overlapping,
it adds up Vancomycin
+ ↑ Nephrotoxicity
Gentamicin
2. Selection of resistant
strains
Drawbacks of
combination
3. Emergence of resistant
organisms for
multiple drugs

4. ↑ Cost
 General chemotherapy 511

56.7 CHEMOPROPHYLAXIS

Penicillin G as post-exposure
prophylaxis to prevent
gonorrhea/syphilis
Rifampicin to prevent
meningococcal infection
1. To protect healthy during epidemic
individuals
Chloroquine to prevent
malaria in healthy people
visiting endemic area
Fluoroquinolones/penicillin/
cotrimoxazole reduce incidence
of bacterial infections in AIDS, anticancer/
neutropenic patients immunosuppressive
To prevent bacterial endocarditis
in patients with valvular heart
diseases, chemoprophylaxis
before dental extraction,
Used to prevent tonsillectomy, or endoscopies
infection 2. To prevent infection
in high-risk patients Before catheterization
Chemoprophylaxis
Done in following
situations Contaminated/exposed
wounds (road accidents)

To ↓ bacterial
Burn patients
colonization

Children with close contacts

3. In close contacts
of open cases of TB/leprosy

To prevent surgical
wound infection

Large proportion of a. Dirty, contaminated

nosocomial infection
4. Surgical prophylaxis
Reduces morbidity,
↑ success of surgery
Guidelines for surgical
prophylaxis
and clean contaminated
Effective against
wounds in immuno-
likely organisms
compromised patients
b. Prosthetic implants Low toxicity
c. Low-risk caesarean
section – may Inexpensive
not require
Adequate concentration
d. Selection of AMA above MIC at site of
infection perioperatively
AMA used for shortest
duration and preferably
single dose
AMA used for 5 days in
contaminated/
dirty wounds Cefazolin 1 gm
at induction of
Agent conventionally anesthesia
used
Vancomycin, where
MRSA is prevalent
512 Pharmacology mind maps for medical students and allied health professionals

56.8 SUPERINFECTION (SUPRAINFECTION)

New infection due to use of

AMA

AMAs alter/destroy normal

Produce bacteriocins, which
commensal flora of GIT,
inhibit pathogenic organisms
respiratory, and genitourinary tract

Normal flora prevent

Compete for nutrients
superinfection by the following

↑ Chances with broad-

spectrum AMAs

GIT, genitourinary, respiratory

Sites involved
tract

AIDS

Diabetes mellitus

Superinfection (suprainfection)

Use of broad-spectrum AMAs

Common in following situations

Use of anticancer drugs

Use of corticosteroids for long

time

Immunocompromised patients

Candida albicans, Clostridium

Organisms involved difficile, Staphylococci,
Pseudomonas

Use narrow-spectrum/specific
AMAs wherever possible

Use AMAs only when absolutely

Prevention of superinfection
necessary

Use AMAs for right duration

(avoid prolonged use)
 57
Beta-lactam antibiotics

57.1 PENICILLINS

β-lactam antibiotics Have a β-lactam ring in their structure e.g., Penicillins, cephalosporins, monobactams, carbapenems

Discovered Sir Alexander Fleming in 1928

Sourced Fungus Penicillium notatum

Used therapeutically in 1941

Currently obtained From Penicillium chrysogenum

Consists of thiazolidine ring (1)
Attached to β-lactam ring (2)

Structure With a side chain (R)

1+2 → 6-aminopenicillanic acid (APA) or penicillin nucleus

R → determines some of the pharmacokinetic properties;

its modifications result in semisynthetic penicillins

Activity present in 0.6 g of crystalline sodium penicillin = 1 U

Unitage
1 million units (MU) of penicillin – 0.6 mcg

Rigid cell wall of bacteria maintains integrity and shape

It protects it from lysis due to osmotic pressure

Peptidoglycan is an important component of cell wall

Glycan chains cross-linked by peptide chains

Glycan chains composed of alternating sugars

N-acetylglucosamine and N-acetylmuramic acid
Penicillins

Cross-linking is synthesized by enzyme transpeptidases

Cross-linking is done with help of enzyme

transpeptidases, the “penicillin-binding proteins” (PBPs)
Mechanism of action β-lactams covalently bind to and inhibit PBPs
Hence there is inhibition of cell wall synthesis

This leads to formation of cell wall-deficient bacteria → bacterial lysis

Thus penicillins are bactericidal

They act on actively multiplying bacteria

Gm +ve organisms have thick cell wall, hence are susceptible

Gm –ve organisms have thin cell wall, hence are less susceptible

Peptiglycans are absent in humans, hence penicillins are relatively safe

Organisms (staphylococci) produce penicillinase, a β-lactamase, which

opens β-lactam ring hence inactivates penicillin

Some β-lactamases also inactivate cephalosporins

Mechanism of resistance Reduced affinity of PBPs

Poor penetration

Efflux of penicillin by efflux pump

A. Natural Penicillin G

Classification 1. Acid resistant Penicillin V

2. Penicillinase resistant Methicillin, cloxacillin

B. Semisynthetic
3. Aminopenicillins Ampicillin, bacampicillin, amoxycillin

Carbenicillin, ticarcillin,
Carboxypenicillins
carbenicillin indanyl
4. Antipseudomonal
Piperacillin, azlocillin,
Ureidopenicillins
mezlocillin

513
514 Pharmacology mind maps for medical students and allied health professionals

57.2 NATURAL PENICILLINS

Penicillin G Narrow spectrum

(benzylpenicillin)
Gm –ve cocci and bacilli, few Gm –ve cocci
Spectrum of activity
Streptococci, Pneumococci, Meningococci, Gonococci, C. diphthariae, Clostridia, B. anthracis, Listeria, Spirochetes

Some anaerobes

Inactivated by gastric acid, hence less bioavailability ∴ Given usually parenterally

Normally does not cross BBB

Wide tissue distribution, mostly extracellularly
But during inflammation, therapeutic concentrations are achieved, as BBB weakens
Pharmacokinetics

Around 10% by glomerular filtration and 90% by renal tubular secretion, ∴ penicillins are organic acids
Rapidly excreted by kidneys
Probenecid competes with penicillin for excretion Hence ↑ duration of actions of penicillin

Oral penicillins used only in minor infections

Benzylpenicillin is short-acting

Repository penicillins are long-acting

Repository penicillins e.g., Procaine penicillins and benzathine penicillin

Given deep IM

Procaine penicillin – once daily

Benzathine penicillin effective for 3–4 wks

Hence are safe

High therapeutic index
Confusion, convulsion, Except hypersensitivity,
coma (only large doses) which can be fatal

Suprainfection Rare, as it has narrow spectrum

In patients with syphilis

Jarisch–Herxheimer reaction Sudden release of lytic products from spirochetes

Fever, myalgia, shivering, vascular collapse, and aggravation of syphilitic lesions

PnG is most common cause of drug allergy

Adverse effects

Penicilloic acid, a metabolite of penicillin, is antigenic

Natural penicillins

Skin rashes, urticarial, pruritus, fever, bronchospasm

Rarely exfoliative dermatitis and anaphylaxis

All forms of penicillin can cause allergy

Anaphylaxis is more common with parenteral therapy

Highest incidence with procaine penicillin

Procaine too is antigenic

Topical penicillins are also highly sensitizing,
hence are banned

Cross-sensitivity among different penicillins

Hypersensitivity History of allergy should be elicited before prescribing

Higher incidence in atopic individuals

Scratch test/intradermal sensitivity with

2–10 units should be done

Even if negative, does not rule out allergy

Syringe loaded with adrenaline should be kept ready

Best to avoid penicillins; if not, desensitization/hyposensitization to be done

Anaphylactic shock

Bronchospasm, laryngeal edema, severe hypotension

Immediate hypersensitivity (type-1) reaction

IgE mediated Inj. Adrenaline 0.3–0.5 mL 1:1000 solution IM

Rx Inj. Hydrocortisone 200 mg IV

1. Pneumococcal infections Drug of choice, pneumonia, meningitis, osteomyelitis Inj. Diphenhydramine 50–100 mg IM/IV

2. Streptococcal infections Pharyngitis, endocarditis with aminoglycosides for S. viridans endocarditis

3. Meningococcal infections Drug of choice

4. Syphilis Procaine/benzathine penicillin

5. Diphtheria Along with antitoxin, PnG eliminates carrier state

6. Tetanus Along with antitoxin

Uses

7. Gas gangrene PnG is drug of choice

8. Staphylococcal infections Penicillinase resistant-penicillin to be used

9. Other infections Anthrax, trench mouth, rat bite fever, Listeria infections Drugs of choice

Drug of choice
10. Actinomycosis
Rx for 6 wks (12–20 MU)

Rheumatic fever Benzathine penicillin 1.2 MU every month

for 5 yrs or more
11. Prophylactic Gonorrhea and syphilis Within 12 h of exposure Rx sexual contacts
Before dental extraction, endoscopies and other
Valvular heart diseases minor surgeries that may cause bacteremia
 Beta-lactam antibiotics 515

57.3 SEMISYNTHETIC PENICILLINS

Narrow spectrum

Acid labile
(not effective orally)
Produced to overcome
following limitations of
natural penicillins
Penicillinase susceptible

Risk of hypersensitivity

Penicillin V
(phenoxymethylpenicillin)

Acid stable, given orally

1. Acid-resistant penicillins Low bioavailability

Semisynthetic Narrow spectrum

penicillins

Only used in mild Streptococcal pharyngitis,

infections sinusitis, trench mouth

Resistant to penicillinase

Less effective than PnG

against non-penicillinase
producing organisms
Acid labile Hence given parenterally

Methicillin
However nowadays
methicillin resistance is
also common (MRSA)

Oxacillin, dicloxacillin,
Acid stable Hence given orally
2. Penicillinase-resistant dicloxacillin
penicillins

Effective against
penicillinase-producing
and non-penicillinase
Nafcillin producing organisms

Given parenterally

Infections due to
penicillinase-producing
staphylococci

For severe staphylococcal

Use infections
(nafcillin/oxacillin)

For MRSA Use vancomycin

516 Pharmacology mind maps for medical students and allied health professionals

57.4 AMINOPENICILLIN

Extended-spectrum Both Gm +ve and

penicillin Gm –ve organisms

Wider spectrum
including Streptococci, Meningococci,
Gm –ve organisms Pneumococci, H. influenzae

E. coli, Proteus,
Orally effective Spectrum Shigella, Salmonella
Klebsiella, Enterobacter
But inactivated by But most strains are
β-lactamases now resistant

Spectrum ↑ by addition of
Ampicillin
β-lactamase inhibitor

Diarrhea due to irritation

of unabsorbed drug
Skin rashes in patients with
ADR AIDS, infectious mononucleosis
and those on allopurinol

3. Aminopenicillin Prodrug of ampicillin Rashes are self-limiting

Better absorbed
Bacampicillin
Less diarrhea

Longer-acting

Better absorption
Bronchitis, sinusitis,
i. RTI
otitis media
Food does not interfere
with absorption
Was drug of choice earlier
High blood levels ii. UTI
However now many
organisms developed
resistance
Amoxicillin Less protein bound
With cephalosporin
Less diarrhea (better
iii. Meningitis
absorbed)
Now organisms are
resistant
Less frequent dosing
Alternative to ciprofloxacin/
iv. Typhoid
chloramphenicol
Uses
Due to Shigella

But now several

v. Bacillary dysentery
strains are resistant

Hence now not

preferred

With aminoglycoside /3rd-

vi. Gm –ve septicemia
generation cephalosporin

Parenteral ampicillin +
vii. Bacterial endocarditis
gentamicin

Amoxicillin (as component

viii. H. pylori infections
of various regimens)
 Beta-lactam antibiotics 517

57.5 ANTIPSEUDOMONAL PENICILLINS

Effective against
Pseudomonas and Proteus

Also effective against

Gm +ve and
Gm –ve organisms

Given parenterally,
Carbenicillin combined with
aminoglycoside

Carbenicillin indanyl
is effective orally

Severe pseudomonal/
Use Proteus
infections in burns

Analog of carbenicillin

Better activity than

carbenicillin against
Pseudomonas
4. Antipseudomonal
Carboxypenicillins
penicillins Combined with
Ticarcillin
aminoglycoside

Reaches CSF, pleural

fluid, and sputum

Severe UTI due to

Use
Pseudomonas

All above mentioned

carbenicillins are
susceptible to penicillinase

However temocillin is
penicillinase resistant
Temocillin
Effective against
H. influenzae and
Enterobacter Na+ salt of
carbenicillin
causes edema, CCF
ADRs
Bleeding due to
abnormal
platelet aggregation
518 Pharmacology mind maps for medical students and allied health professionals

57.6 UREIDOPENICILLINS AND AMIDINOPENICILLINS

e.g., Piperacillin,
azlocillin, mezlocillin
Effective against
Pseudomonas, Proteus,
Klebsiella, H. influenzae
Wider spectrum
Better activity against
Pseudomonas than
ticarcillin
Lower sodium content

Preferred over
carboxypenicillin
Ureidopenicillins
Broadest spectrum when
combined with
β-lactamase inhibitor

Crosses BBB Useful for meningitis

Severe infections due to

Pseudomonas, Proteus

Combined with
Use β-lactamase inhibitor
(Tazobactam)

Severe Gm –ve infections in

immunocompromised patients
(with aminoglycoside)

High efficacy against Gm –ve

but not Gm +ve organisms

Salmonella, Shigella, E. coli,

Proteus, Klebsiella, Aerobacter

Not effective against

Mecillinam
Pseudomonas

Inhibits cell wall synthesis,

but different from
penicillins

Poor oral absorption,

5. Amidinopenicillins
hence given IM

A prodrug is effective
orally

Pivmecillinam

Tried in UTI, typhoid,

Use
dysentery

57.7 β-LACTAMASE INHIBITORS
β-lactamases are enzymes
produced by bacteria
They open up β-lactam ring
β-lactamase inhibitors bind
and inactivate β-lactamases
Broadens antibacterial
spectrum of penicillin
3 β-Lactamase inhibitors
No significant antibacterial activity
Combined with penicillin
with suitable
pharmacokinetic properties
Clavulanic acid
β-lactamase
inhibitors
Sulbactam
Tazobactam
Beta-lactam antibiotics 519
Hence inactivate
β-lactam antibiotics
Hence prevents destruction
of β-lactam antibiotics
Spectrum includes penicillinase
producing Staphylococci, Gonococci,
E. coli, H. influenzae, and others
Not effective against β-lactamase
produced by Pseudomonas,
Enterobacter, and MRSA
Clavulanic acid, sulbactam, tazobactam
Obtained from It gets inactivated
Streptomyces clavuligerus in the process
Binds and inactivates Hence called “suicide”
β-lactamases inhibitor
Binding is covalent – hence
it is irreversible
Given both orally and
Combined with amoxicillin
parenterally
Combined with ticarcillin Only parenterally
Minor GI disturbances,
ADRs
occasional superinfection
Cellulitis
Diabetic foot
Skin and soft tissue
infections
RTI
Use
Genitourinary infection
Nosocomial infections
Mixed aerobic–anaerobic
infections
Gonorrhea (amoxicillin
Similar to clavulanic acid 3 g + clavulanic acid
0.5 g + probenecid 1g)
Unreliable oral absorption Hence given parenterally
Suitable for mixed intraabdominal
and pelvic infections
Other indications similar to
clavulanic acid
Reduce dose in renal dysfunction
Given parenterally in
combination with piperacillin
Active against several
β-lactamases
520 Pharmacology mind maps for medical students and allied health professionals

57.8 CEPHALOSPORINS

Effective against Gm +ve organisms

Used in minor RTI, UTI, skin, and soft tissue infections Additional activity against E. coli, Klebsiella, Enterobacter

Cefazolin Agent of choice for surgical prophylaxis

1. First-Generation

Longer t½, and good tissue penetration

cephalosporins

Effective orally
Less effective against penicillinase-
Cephalexin
producing staphylococci
For minor infections like abscesses
Used
or cellulitis
Analog of cephalexin, similar to it

Good concentration in plasma and urine

Cefadroxil
Long duration of action (given BD)
Effective against Gm –ve organisms, some anaerobes
Use UTI, RTI, minor infections
More resistant to β-lactamases
Resistant to β-lactamases
Effective against H. influenzae, E. coli, Proteus, Meningitis due to H. influenzae,
Klebsiella, Enterobacter, but not Pseudomonas Good CSF concentration N. meningitidis, C. pneumoniae
2. Second-Generation
cephalosporins

Cefuroxime Useful
Also effective against Enterobacter,
Given orally
Citrobacter and gonorrhea
Cefuroxime axetil, a prodrug of
cefuroxime, is effective orally
Effective against H. influenzae, Proteus, E.coli
Cefaclor
Effective orally
Effective against anaerobes
Cefoxitin
Used in mixed aerobic-anaerobic
infectious lung abscess
Highly resistant to β-lactamases

Effective against Gm –ve organisms and anaerobes

β-lactamase producing H. influenzae, N. gonorrhoeae, Pseudomonas, Serratia, Citrobacter, Enterobacter

Weak activity against Gm +ve organisms
But effective against streptococci
Crosses BBB Hence useful in meningitis
Life-saving in serious Gm –ve infections including
aminoglycoside-resistant ones Resistant to several β-lactamases
Cephalosporins

Cefotaxime Metabolized to active metabolite

Crosses BBB Used for meningitis

Long-acting (t½ 8 h) hence given once daily

Good CSF concentration

Ceftriaxone Hence no dosage adjustment
50% biliary excretion in renal dysfunction
3. Third-Generation

Gonorrhea (single dose)

cephalosporins

Use
Meningitis
Orally effective prodrug

Cefpodoxime proxetil Ester of cefpodoxime

Use RTI, skin infections

Prodrug
Cefditoren pivoxil
Use Uncomplicated RTI and skin infections
More effective against Pseudomonas
Hence no dose adjustment in
Cefoperazone Major excretion in bile renal dysfunction
Requires
Hypoprothrombinemia (bleeding) vitamin K
ADR prophylaxis
Disulfiram-like reactions
Orally effective

Cefixime Effective against Gm +ve cocci, enterobacteriaceae

Use UTI, RTI, and infections of biliary tract
Effective against Gm +ve cocci including
β-lactamase-producing organisms
Cefdinir
Use RTI, ENT infections, typhoid
Ceftazidime Excellent activity against Pseudomonas and
Enterobacteriaceae
Cefepime, cefpirome

Effective against Gm +ve and Gm –ve organisms

4. Fourth-Generation

Given parenterally
cephalosporins

Excreted completely by kidneys

Cefepime Good CSF concentration

Cefpirome Good tissue penetration

More effective against Gm –ve organisms

Use Septicemia, nosocomial infections; serious RTI, UTI,

skin infections in immunocompromised patients
 Beta-lactam antibiotics 521

57.9 CEPHALOSPORINS – ADRs AND USE

Well tolerated

20% of patients allergic to

Hypersensitivity
penicillins

Hence avoid combining

Nephrotoxicity
with aminoglycosides

Esp. cefoperazone,
Diarrhea
it is excreted in bile
∴

ADRs of cephalosporins
Common in malnourished
Bleeding due to
hypoprothrombinemia
Prevented by vitamin K,
10 mg BD
Low WBC count

Pain at site of injection

Disulfiram-like reactions
with alcohol

1. Gm –ve infections like

UTI, RTI, soft 3rd-generation CP
tissue infections

2. Surgical prophylaxis Cefazolin

Ceftriaxone as an
Use 3. Typhoid
alternative to ciprofloxacin

Single-dose ceftriaxone
4. Gonorrhea
is drug of choice

5. Mixed aerobic–anaerobic
infections, following 3rd-generation CP
pelvic surgeries

3rd-generation CP like
Combined with
6. Meningitis cefotaxime, ceftriaxone,
aminoglycosides
ceftazidime

7. Nosocomial infections 3rd-generation CP

522 Pharmacology mind maps for medical students and allied health professionals

57.10 CARBAPENEMS

β-lactam fused with

5-membered penem ring

e.g., Imipenem,
meropenem, ertapenem
Wide spectrum

Spectrum
Gm +ve, Gm –ve, and
anaerobes
Mechanism–similar to
penicillins
Not absorbed orally Given IV
Carbapenems
Highly resistant to most
β-lactamases
Cilastatin is inhibitor
∴
Good CSF concentration Hence combined with
cilastatin of dehydropeptidase

Inactivated by
Hence it ↑ the t½
dehydropeptidases
of imipenem
in renal tubules

Additionally there are

matching
pharmacokinetics of
imipenem and cilastatin

Reduce its dose in renal As it is excreted by

Imipenem
dysfunction kidneys

Allergic manifestations,
ADRs
seizures (in high dose)

UTI, RTI, bone, soft

tissue, intra-abdominal,
gynecological infections

Infections with penicillin-

resistant pneumococci

Nosocomial infections
Uses
resistant to other AMAs

Pseudomonas infections With aminoglycoside

It is resistant to
∴
Drug of choice in
β-lactamases produced
Enterobacter infections
by enterococci

(Continued)
 Beta-lactam antibiotics 523

57.10 CARBAPENEMS (Continued)

Hence not combined

with cilastatin
Not destroyed by
dehydropeptidase
Hence ↓ risk
Meropenem
of seizures
Similar indications like
imipenem

Similar to meropenem

But not useful against

Pseudomonas
Ertapenem
Long-acting, hence
given OD
Hence IM injections are
painful
Irritant
∴ Combined
with 1% lignocaine
524 Pharmacology mind maps for medical students and allied health professionals

57.11 CARBACEPHEMS AND MONOBACTAMS

Loracarbef

Synthetic agent

Carbacephems
Similar to 2nd-generation CP Effective against Gm –ve bacilli
(cefaclor) including Pseudomonas

Included in 2nd-generation CP Resistant to β-lactamases

by some produced by Gm –ve bacteria

High efficacy against

Contains only single
H. influenzae, Enterobacter,
β-lactam ring
gonococci
Monobactams
Also effective against Gm +ve
e.g., Aztreonam
organisms and anaerobes

Acts by inhibiting cell wall

synthesis like penicillins

Given parenterally

No cross-allergenicity Hence used in patients

with β-lactams allergic to penicillins
 58
Sulfonamides

58.1 SULFONAMIDES – INTRODUCTION, CLASSIFICATION, SPECTRUM, MECHANISM

OF ACTION, AND RESISTANCE

First effective antibacterials to be

used systemically in man

Introduced by Domagk in 1935

Presently limited use because of

Introduction
resistance and availability of safer agents

Structural analogs of PABA

(para-aminobenzoic acid)

H2N – SO2 NH2

1. Short-acting Sulfadiazine (4–8 h)

2. Intermediate-acting Sulfamethoxazole (8–12 h)

Classification 3. Long-acting Sulfadoxine (7 days)

Sulfasalazine (acts both locally and

4. Poorly absorbed
systemically)

Sulfacetamide, mafenide, silver

5. Topical
sulfadiazine

Gm +ve and Gm –ve organisms like

Streptococci, H. influenzae, H. ducreyi, E. coli,
Salmonella, Shigella, Proteus, V. cholerae

Few strains of Staphylococci, Gonococci,

Spectrum
Meningococci, and Pneumococci

Sulfonamides Also effective against Chlamydiae,

P. falciparum, and Toxoplasma gondii

Folic acid is essential for nucleic acid

synthesis

Bacteria synthesize their own

folic acid from PABA
Hence they competitively inhibit
enzyme folic acid synthetase
Sulfonamides are structural
analogs of PABA
This leads to folic acid deficiency,
hence inhibition of bacterial growth
Mechanism of action Sulfonamides are bacteriostatic

Humans cannot synthesize their

own folic acid

Humans use preformed

Hence human cells are not affected
folic acid from diet

Pus, blood, tissue breakdown Hence their presence reduces the

products are rich in PABA efficacy of sulfonamides

1. Mutation Leading to overproduction of PABA

2. Use of alternative metabolic

pathway to produce PABA
Resistance
3. Folic acid synthetase with lower
affinity for sulfonamides

4. ↓ Penetration of
sulfonamides

525
526 Pharmacology mind maps for medical students and allied health professionals
58.2 SULFONAMIDES – PHARMACOKINETICS, ADVERSE EFFECTS, AND USES
Good oral absorption
High plasma protein binding
Pharmacokinetics
Metabolized by acetylation
and glucuronidation
Excreted in kidneys
1. Renal irritation, hematuria,
crystalluria, albuminuria
2. Hypersensitivity
Adverse effects
3. Hemolytic anemia in
G6PD-deficient patients
4. Kernicterus
5. Drug interactions
Resistance and availability of safer
AMAs has reduced their usage
Uses
However, combinations with
trimethoprim and pyrimethamine
still used
Except sulfasalazine
Hence many drug interactions
Hence dosage reduction
in renal dysfunction
Due to precipitation of
drug in acidic urine
Avoided by ↑ water intake and alkalinizing
urine with sodium bicarbonate
Allergic nephritis or
nephrosis can also occur
Rashes, fever, urticaria,
anaphylactoid reactions
Photosensitivity, Stevens–Johnson
syndrome (SJS), exfoliative
dermatitis (could be fatal)
Sulfonamides displace
∴
It is poorly developed
∴
bilirubin from protein binding
Bilirubin crosses BBB in
This leads to kernicterus
neonates
Sulfonamides potentiate effects of
Hence sulfonamides are
phenytoin, oral anticoagulants, oral
contraindicated in
hypoglycemic agents, methotrexate by
pregnancy and infants
displacing them from protein-binding sites
1. Urinary tract infections (UTIs) Uncomplicated UTI
2. Nocardiosis High dose, as alternative
Combined with pyrimethamine
Due to sequential blockage and
synergistic effects
3. Toxoplasmosis
Rx given for 4–6 wks
(high-dose)
Supplemented by leucovorin
rescue
4. Trachoma and inclusion As alternative to tetracyclines,
conjunctivitis which are drugs of choice
5. Lymphogranuloma As alternative to tetracyclines,
venereum and chancroid which are drugs of choice
Silver sulfadiazine/mafenide in
Sulfacetamide eyedrops for
6. Topical burns to prevent infection; silver ions
bacterial conjunctivitis
are also toxic to microorganisms
7. Ulcerative colitis Sulfasalazine For local action
Sulfasalazine
8. Rheumatoid arthritis
5-ASA component is beneficial
Sulfadoxine with pyrimethamine
9. Malaria
In chloroquine-resistant malaria
Streptococcal pharyngitis in
rheumatic fever
10. Prophylactic
In patients allergic to penicillin
 Sulfonamides 527

58.3 COTRIMOXAZOLE

WHO approved fixed-dose combination

Combination of trimethoprim and sulfamethoxazole
Trimethoprim effective against both Gm +ve and Gm –ve organisms
However, resistance develops if used alone

Several Gm +ve and Gm –ve organisms

Spectrum S. aureus, Streptococci, Meningococci, C. diphtheriae,
E. coli, Proteus, H. influenzae, Salmonella, and Shigella
Sulfonamides inhibit conversion of PABA to By blocking folic acid synthetase (FAS)
dihydrofolic acid
Trimethoprim inhibits conversion of dihydrofolic acid By blocking dihydrofolate reductase
to tetrahydrofolic acid (DHFR)
Thus, both block sequential steps in folic acid synthesis

Combination is synergistic

Sulfonamides Bacteriostatic

Trimethoprim Bacteriostatic
Mechanism of action
Combination, i.e., cotrimoxozole Bactericidal
Trimethoprim has high selectivity for bacterial DHFR
compared to human DHFR
Ratio of trimethoprim: sulfamethoxazole is 1:5
This ratio attains correct plasma concentration
Optimum peak plasma concentration of the
combination is 1:20 (trimethoprim: sulfamethoxazole)
Sulfamethoxazole is preferred as its pharmacokinetics
closely match trimethoprim
Slower, when compared to individual drugs
Resistance
Cotrimoxazole

Mutation or gene transfer for an altered DHFR

Administered orally as well as parenterally

Good absorption

Pharmacokinetics Wide distribution even into prostatic and vaginal fluids

∴ Trimethoprim is basic, it concentrates
in acidic fluids
Hence reduce the dose in renal
Both drugs and its metabolites are excreted in kidneys
dysfunction
Skin rashes and GI disturbances
Precipitates megaloblastic anemia in folate- Alcoholics, malnourished patients
deficient patients
Uremia in patients with renal dysfunction
Adverse effects
Hematological reaction like anemia, granulocytopenia,
thrombocytopenia
Allergic reactions like glossitis, stomatitis
Adverse effects are frequent in patients with AIDS Hence they are contraindicated in pregnancy

Due to E. coli, Proteus, Enterobacter spp.

Acute uncomplicated 7–10 days

1. UTI Daily or
Chronic and recurrent Small dose as prophylaxis thrice
weekly
Bacterial prostatitis As it achieves good
concentration of
Due to S. pneumoniae and H. influenzae trimethoprim
2. Respiratory tract
Upper respiratory tract infections (URTIs)
infections
Lower respiratory tract infections (LRTIs)

Due to Shigella, Salmonella

3. Bacterial
gastroenteritis
Uses But fluoroquinolones preferred

4. Typhoid Alternative to fluoroquinolones/3rd generation

cephalosporins (ceftriaxone, cefoperazone)
Prophylaxis
5. Pneumocystis jiroveci
(carinii) infections Treatment (high-dose)
(AIDS patients) Pentamidine, clindamycin, primaquine,
atovaquone are alternatives
Caused by H. ducreyi

Drug of choice

6. Chanchroid Rx for 7 days (DS [double strength], twice daily)

Azithromycin also is drug of choice

Ceftriaxone, ciprofloxacin are alternatives


Chemotherapy of urinary tract infections
and sexually transmitted diseases
59.1 CHEMOTHERAPY OF UTI – ANTIMICROBIALS
Acute or chronic UTI
Urinary antiseptics have only
local antibacterial activity,
but no systemic activity
e.g., Nitrofurantoin,
methanamine mandelate
Nitrofurantoin
Chemotherapy of UTI
Methanamine mandelate
Neutralizes action of
sulfonamides
Drug interactions
Precipitates sulfonamides in
acidic urine
Chronic UTI resistant to
Use
other drugs
Cotrimoxazole, nalidixic acid,
Other agents for UTI fluoroquinolones, tetracyclines,
and cephalosporins
528
59
Bacteriostatic, but bactericidal
at high concentration
Effective against Gm +ve and
Gm –ve bacteria
Rapidly reduced by bacteria
to highly reactive derivatives
These derivatives damage
DNA and RNA synthesis
Attains high concentration
Hemolysis in G6PD deficiency
in urine
Urine turns dark brown
ADRs
(due to metabolites)
Pneumonitis, interstitial pulmonary
fibrosis (on long term)
Acute UTI
∴
Alkaline urine reduces efficacy,
acidify urine with ascorbic acid
Use
Long-term suppression of
chronic UTI
A salt of mandelic acid and
methanamine
Prophylaxis of UTI
Releases formaldehyde in
acidic urine (pH 5.5)
Formaldehyde is bactericidal
Urea-splitting organisms like
Proteus ↑ urinary pH Nausea and epigastric distress (due to
release of formaldehyde in stomach)
Hence acidify urine with
ascorbic acid, mandelic acid,
or hippuric acid Hence given as enteric-coated
tablets to reduce side effects
ADRs
Hematuria, chemical cystitis,
painful micturition (on long-term use)
Avoid in renal failure
∴
( mandelic acid adds to acidosis)
 Chemotherapy of urinary tract infections and sexually transmitted diseases 529

59.2 URINARY ANALGESICS

An azo dye

Has an analgesic action on

urinary tract

Urinary analgesics Phenazopyridine No antibacterial action

Reduces dysuria, urgency

of cystitis, and UTI

Colors urine orange-red

530 Pharmacology mind maps for medical students and allied health professionals

59.3 CHEMOTHERAPY OF SEXUALLY TRANSMITTED DISEASES

Ceftriaxone 250 mg
IM single dose

Or

1. Gonorrhea Cefixime 400 mg oral,

single dose

Or

Ciprofloxacin 500 mg oral,

single dose

Benzathine penicillin G 2.4 MU

IM single dose

2. Syphilis Or

Doxycycline 100 mg
BD oral × 2 wks

Ceftriaxone 250 mg
IM single dose
Chemotherapy of sexually
3. Chancroid Or
transmitted diseases
Cotrimoxazole DS
BD oral × 1 wk

Doxycycline 100 mg
BD oral × 3 wks

4. Granuloma inguinale Or

Cotrimoxazole DS
BD oral × 2 wks

5. Lymphogranuloma Doxycycline 100 mg

venereum BD oral × 3 wks

6. Trichomoniasis Metronidazole/secnidazole
2 g oral, single dose

Penicillin 4–8 MU IM

Chemoprophylaxis Post-exposure prophylaxis of

syphilis/gonorrhea Or

For post-exposure prophylaxis of

Doxycycline 100 mg syphillis/gonorrhea/
BD × 15 days lymphogranuloma venereum/
chancroid/granuloma inguinale
 60
Quinolones

60.1 FLUOROQUINOLONES (CIPROFLOXACIN)

Are synthetic agents

Introduction e.g., Nalidixic acid, the
oldest agent
among quinolones
Bactericidal against Gm –ve
E. coli, Shigella, Proteus, Klebsiella, and Enterobacter
organisms like

Good oral absorption Hence high urinary concentration

But rapid renal excretion So there is inadequate plasma concentration

Nalidixic acid (quinolone)
Hence they are not effective systemically
ADR Hemolytic anemia in G6PD deficiency

Urinary antiseptic E. coli, Shigella, Proteus

Uses
Diarrhea E. coli, Shigella, Proteus

They have a wider spectrum

Fluorinated quinolones Higher therapeutic plasma concentration
Quinolones

Compared to quinolones Better tissue penetration

Fewer side effects

Lower incidence of resistance

1. First generation Norfloxacin, ciprofloxacin,

ofloxacin, pefloxacin

Classification 2. Second generation Lomefloxacin, sparfloxacin,

gatifloxacin, moxifloxacin

3. Third generation Levofloxacin

Bactericidal

Inhibits bacterial DNA gyrase and Topoisomerase IV

These enzymes are required for DNA

replication and transcription
There is excessive positive supercoiling
of DNA during replication
This is corrected by DNA gyrase
Fluoroquinolones (FQs) DNA gyrase introduces negative supercoils
Mechanism of action
By inhibiting DNA gyrase, FQs inhibit DNA transcription

Humans have topoisomerase II instead of DNA gyrase

500–1000 times higher
concentration is required Hence FQs are safer in humans
to inhibit topoisomerase II
Bacterial topoisomerase IV is required for daughter cell
separation following replication

FQs inhibit topoisomerase IV in Gm +ve bacteria

FQs inhibit DNA gyrase in Gm –ve bacteria

↓ Affinity of FQs for target enzymes
Resistance Reduced permeability of FQs into bacteria
Protection of DNA gyrase by some proteins

Gonococci, meningococci, E. coli, H. influenzae,

Gm –ve
Salmonella, Shigella, Proteus

Gm +ve Staphylococci, Vibrio cholerae

Legionella, Chlamydiae,
Spectrum of activity
Mycoplasma
M. tuberculosis, M. avium
Mycobacteria
complex (MAC)
Some anaerobes and
Streptococcus pneumoniae

531
532 Pharmacology mind maps for medical students and allied health professionals

60.2 INDIVIDUAL AGENTS

Narrow spectrum

Does not achieve adequate plasma

1. Norfloxacin concentration

Higher concentration in GIT and GUT Hence used in diarrhea, UTI, prostatitis

Most commonly used

2. Ciprofloxacin Drug of choice for typhoid fever

Hence 3rd-generation
Salmonella has now developed resistance
cephalosporin (ceftriaxone) used

Highly lipid-soluble derivative of norfloxacin

3. Pefloxacin Bioavailability >90%

High CSF concentration Hence used for meningeal infection

Active against Gm +ve organisms, M. tuberculosis, Hence used in regimens for TB

M. leprae, atypical mycobacteria,
and leprosy
Mycoplasma and Chlamydia
Used in chlamydia infections, gonorrhea, pelvic
inflammatory diseases (with metronidazole)

4. Ofloxacin Bioavailability >95%

Long-acting

Excreted unchanged by kidneys Hence ↓ dose in renal dysfunction

Levoisomer of ofloxacin
RTI
5. Levofloxacin Bioavailability 100%
Community-acquired pneumonia
Use
UTI
Difluorinated FQ
Skin and soft tissue infections
Bioavailability >90%

Longer tissue distribution, hence given

6. Lomefloxacin
once daily

Excreted by kidneys Hence ↓ dose in renal failure

Use UTI, RTI

Difluorinated FQ
Individual agents
Good activity against Gm +ve and Gm –ve
organisms
Streptococci, Legionella, Chlamydiae,
Moraxella
Also against M. tuberculosis, M. leprae,
MAC

Bioavailability >90%
7. Sparfloxacin
t½ 15–21 h Hence given once daily

ADR Photosensitivity, ↑ QTc interval

RTI, including pneumonia S. pneumoniae and atypical pneumonia

Sinusitis, bronchitis, otitis

Use M. tuberculosis

Effective against S. pneumoniae, Chlamydia

MAC in AIDS patients
pneumoniae, M. tuberculosis, some anaerobes

90%–95% bioavailability Leprosy

8. Gatifloxacin
Use RTI, GU infections

ADR QTc prolongation

Effective against Gm +ve bacilli

and some anaerobes

9. Moxifloxacin Use RTI, soft tissue infections

ADR QTc prolongation

 61
Macrolides

61.1 MACROLIDES

Introduction Large (macrocyclic) lactone ring with e.g., Erythromycin, roxithromycin, clarithromycin,
linked sugars azithromycin

Source Streptomyces erythreus

Narrow spectrum
Erythromycin
Spectrum Aerobic Gm +ve bacteria, few Gm –ve organisms

Bacteriostatic at low and bactericidal at high

concentrations Staphylococci, Gonococci,
Legionella, C. diphtheria,
Alkaline pH ↑ its efficacy C. jejuni, Mycoplasma, Chlamydiae,
atypical mycobacteria, B. pertussis, T. pallidum
Binds to 50S ribosomal subunit
Hence they compete for
Mechanism of action binding site
∴
Inhibits protein synthesis Chloramphenicol and clindamycin
also bind to 50S subunit
∴ May antagonize each
Macrolides inhibit translocation of other, thus their combination
growing peptide chain from A site to P site should not be used
A site is not available for binding of next amino
acid (presented by tRNA)

Reduced permeability
Mechanism of Production of drug-inactivating enzymes
resistance
↓ Affinity of target site, i.e., ribosomal 50S subunit

Food ↓ absorption

Acid destroys erythromycin Hence given as enteric-coated tablets

Macrolides

Pharmacokinetics
Good tissue penetration, except brain and CSF

Excreted from bile Hence no dosage adjustment

required in renal dysfunction

Hepatitis and cholestatic jaundice

Epigastric distress, nausea, vomiting, diarrhea

Adverse effects Stimulation of motilin receptors in intestine Hence leads to diarrhea

Cardiac arrhythmias in patients with cardiac Terfenadine, mefloquine, halofantrine, etc.

disease or other arrhythmogenic drugs
Reversible hearing loss
Carbamazepine, valproate,
Drug interactions Erythromycin and clarithromycin are Hence ↑ concentration/toxicity of terfenadine, theophylline,
potent microsomal enzyme inhibitors digoxin, and warfarin

Uses Due to Mycoplasma (drug of choice),

1. Atypical pneumonia
Chlamydia, Legionella

2. Legionnaires’ pneumonia Azithromycin is drug of choice

Erythromycin is drug of choice for treatment

3. Whooping cough
and post-exposure prophylaxis

Acute stage and carrier stage, along

4. Diphtheria
with antitoxin (life-saving)

5. Streptococcal infections Pharyngitis, tonsillitis, scarlet fever

6. Staphylococcal infections Now resistant

As alternative in
penicillin- 7. Syphilis and gonorrhea Alternative to penicillin
allergic patients
8. Campylobacter gastroenteritis Alternative to fluoroquinolone

9. Tetanus Eradicates carrier state

10. Anthrax Alternative to penicillin

11. Topical Boils, acne vulgaris

Prokinetic for postoperative/diabetic gastroparesis

12. Miscellaneous
Rheumatoid arthritis and chronic sinusitis Due to anti-inflammatory
actions 533
534 Pharmacology mind maps for medical students and allied health professionals

61.2 INDIVIDUAL MACROLIDES AND COMPARISON

Acid-stable, but given 30 min before food

Long-acting

More potent

Roxithromycin Better absorption

Better tissue penetration

No enzyme inhibition
Legionella infections
Use
Alternative to
erythromycin
Acid-stable, better absorbed, long-acting
More effective against H. influenzae,
Legionella, atypical mycobacteria, H. pylori
and some Protozoa, M. leprae, T. gondii

Enzyme inhibitor
Clarithromycin
Hence reduce dose in
Excreted in urine
renal dysfunction

i. H. pylori infections Component of triple regimen

Use
ii. Atypical mycobacterial
Prevention and treatment
infection in AIDS patients
Similar to clarithromycin

Effective against Mycobacterium avium

complex (MAC), T. gondii, and H. influenzae
Acid-stable, rapid absorption, good tissue
penetration
Hence once daily
Long-lasting, t½ 3 days
administration

Well-tolerated
Azithromycin

No enzyme inhibition; no drug interactions

Dose Loading dose of 500 mg 250 mg next 4 days

i. Atypical mycobacterial
Prophylaxis and treatment
infections in AIDS patients

ii. Legionnaires’ pneumonia

Use
iii. Chlamydial infections

iv. Other respiratory,

genital, and skin infections
Semisynthetic derivative
of erythromycin
Modified macrolides, similar
Effective against macrolide-resistant pneumonia
to newer macrolides
S. aureus, S. pyogenes, S. pneumoniae,
Spectrum H. influenzae, H. pylori, M. catarrhalis, Mycoplasma,
Chlamydia, Legionella, T. gondii, B. fragilis

Similar to macrolides
Mechanism of action
However, no resistance seen

Bioavailability – 60%, t½ - 9–10 h

Good oral absorption
Ketolides Telithromycin Hence given once daily

Nausea, vomiting, diarrhea, pseudomembranous colitis

Elevated liver enzymes, hepatic failure

ADR
Hence can lead to
QTc prolongation
arrhythmias
Hence drug
Microsomal enzyme inhibition
interactions

Mild to moderate infections

Use Sinusitis, pharyngitis

Community-acquired pneumonia (bacterial)

 62
Broad-spectrum antibiotics – Tetracyclines
and chloramphenicol

62.1 TETRACYCLINES – INTRODUCTION, CLASSIFICATION, AND MECHANISM

OF ACTION

4 cyclic rings in
the structure

Soil actinomycetes –
Introduction Source
Streptomyces aureofaciens

Inhibit Gm +ve, Rickettsiae,

Hence are called broad-
Chlamydiae, Mycoplasma
spectrum AMAs
and some Protozoa

Short-acting (t½–6 h) Tetracycline, oxytetracycline

Intermediate-acting
Classification Demeclocycline
(t½ –12 h)

Intermediate-and long-
acting preparations are Long-acting (t½ –18 h) Doxycycline, minocycline
semisynthetic
Broad-spectrum
antibiotics – tetracyclines
Enter susceptible micro-
organisms by active
transport

Mammalian cells lack active

transport and have different
ribosomes

Bacterial ribosomes have

50S and 30S subunit

Tetracyclines bind to 30S

ribosomal subunit

Ribosomes have 3 binding

Mechanism of action
sites i.e., A, P, and E sites

Tetracyclines bind to “A” site

and prevent binding of
tRNA to this site

tRNA carries amino acid for

protein synthesis

Amino acids cannot be Hence they inhibit protein

added synthesis

Hence they are

bacteriostatic

535
536 Pharmacology mind maps for medical students and allied health professionals

62.2 SPECTRUM OF ACTIVITY AND RESISTANCE

Broad-spectrum

Gm +ve, Gm –ve, Rickettsiae,

Chlamydiae, Actinomyces,
Spectrum of activity
Plasmodia, E. histolytica,
Mycoplasma

Streptococci, Staphylococci,
Gonococci, Meningcocci,
Clostridia, Bacillus anthracis,
Listeria, Corynebacteria,
Propionibacterium acnes,
H. influenzae, Vibrio
cholerae, Yersinia pestis,
H. ducreyi, Campylobacter,
Brucella, Bordetella, Pasteurella,
Spirochetes

Hence ↓ their utility

Many organisms have now

developed resistance
Resistance due to
↓ uptake or ↑ efflux
Displacing tetracyclines
from target ribosomes

Resistance

Inactivating enzymes

Cross-resistance among
different tetracyclines seen
 Broad-spectrum antibiotics – Tetracyclines and chloramphenicol 537

62.3 PHARMACOKINETICS AND ADMINISTRATION

Older tetracyclines
incompletely absorbed

Food interferes with Except doxycycline

absorption and minocycline

Hence they should not be

Calcium and other metals given with milk, milk products,
chelate tetracyclines antacids, iron preparations,
or zinc supplements

Accumulate in liver, spleen,

Pharmacokinetics Widely distributed bone, teeth, CSF, synovial
fluid, urine, prostate

Secreted in milk

Crosses placenta

Except doxycycline and

minocycline

Excreted in kidneys
Hence doxycycline and
minocycline are safe in
renal dysfunction
Oral, parenteral, topical

May be administered with

food to reduce GI irritation

Milk, dairy products,

∴ Avoid their
antacids, iron, and aluminium
coadministration
↓ GI absorption
Administration
Cholestyramine and
cholestipol reduce
absorption

Poor, unreliable, and

IM absorption
causes irritation

Except doxycycline
IV Thrombophlebitis
and minocycline
538 Pharmacology mind maps for medical students and allied health professionals

62.4 ADVERSE EFFECTS

Tetracyclines chelate
∴
calcium

Calcium tetracycline orthophosphate

Hence leads to their
complex gets deposited in
deformities
developing teeth and bone
1. Teeth and bone
Onycholysis and nail pigmentation
also occur

Hence are teratogenic

Suppression of GI flora

2. Superinfections

Most common AMAs to cause

Epigastric burning

3. GI irritation Esophageal ulcers, nausea, vomiting

Given with food

Large doses

4. Hepatotoxicity
Acute hepatic necrosis in pregnant
Adverse effects
women
Polyuria
Due to antianabolic effects,
↑ nitrogen
5. Nephrotoxicity Proteinuria
Fanconi syndrome (because of
outdated tetracyclines)
Glycosuria
6. Phototoxicity Common with doxycycline and
minocycline
Acidosis
↑ Intracranial pressure
in infants
7. Pseudotumor cerebri

Bulging of anterior fontanelle

Occur with large doses for

8. Antianabolic effects
prolonged duration

Hence used in SIADH

9. Nephrogenic Demeclolcycline inhibits action of (syndrome of
diabetes insipidus ADH on kidneys inappropriate ADH)

IM – pain, irritation

10. Local
Except doxycycline
IV – thrombophlebitis
and micocycline
 Broad-spectrum antibiotics – Tetracyclines and chloramphenicol 539

62.5 USES

Use has ↓ due to

emergence of resistance and
availability of safer AMAs

Tick typhus, Q fever, Rocky

Drug of choice
Mountain spotted fever

Lymphogranuloma
venereum

Trachoma

Inclusion conjunctivitis

2. Chlamydial infections

Urethritis/cervicitis

3. Mycoplasma pneumoniae

Pneumonia

Psittacosis

Caused by
4. Granuloma inguinale Calymmatobacterium
granulomatis

Rx of dehydration is
Uses 5. Cholera
life-saving

6. Brucellosis Along with rifampicin

Combined with
7. Plague
aminoglycoside

1. Traveler’s diarrhea

2. Sexually transmitted
Syphilis, gonorrhea, chancroid
diseases

3. Acne Low dose for long time

Other infections

4. Tularemia Along with aminoglycoside

Lyme disease, relapsing fever,

5. Miscellaneous leptospirosis, post-exposure
prophylaxis of anthrax
Chronic intestinal amoebiasis,
6. Protozoal infections multidrug-resistant malaria
(doxycycline + quinine)

SIADH Demeclocycline
540 Pharmacology mind maps for medical students and allied health professionals

62.6 CONTRAINDICATIONS AND ADVANTAGES/FEATURES OF DOXYCYLINE

AND MINOCYCLINE

Deformities of teeth
and bone

1. Pregnancy, lactation, Acute hepatic necrosis

children <8 yrs in pregnant women

Contraindications

Pseudotumor cerebri
2. Renal/hepatic impairment
in infants

1. 95%–100% bioavailability

2. Food does not interfere

with absorption

3. Highly lipid-soluble

4. Long t½, hence once daily

Advantages/features of
doxycyline and minocycline
5. Excreted in GIT, hence
safe in renal dysfunction

6. Given both orally and

parenterally

7. Minocycline used as
alternative to rifampicin in
eradicating meningococcal carrier
state, i.e., from nasopharynx

8. Doxycycline preferred for

post-exposure prophylaxis
of anthrax
 Broad-spectrum antibiotics – Tetracyclines and chloramphenicol 541

62.7 COMPARE/CONTRAST – TETRACYCLINE vs. DOXYCYCLINE

Tetracycline Doxycycline

1. Source Semisynthetic Semisynthetic

2. GI absorption Incomplete Complete

3. Bioavailability 75% 95%

4. t½ 8–10 h 18–24 h

5. Lipid solubility Low High

6. Dosing QID OD

7. Excretion Kidney GIT

8. Safety in renal impairment Not safe Safe

9. GI flora High suppression Low suppression

10. Phototoxicity Low High

542 Pharmacology mind maps for medical students and allied health professionals

62.8 CHLORAMPHENICOL – MECHANISM OF ACTION, SPECTRUM OF ACTIVITY,

MECHANISM OF RESISTANCE, AND PHARMACOKINETICS

Broad-spectrum
antibiotic

Obtained from Streptomyces venezuelae

Bacteriostatic

Mechanism of action Binds to 50S ribosomal subunit

Inhibits transpeptidation Hence inhibits

reaction protein synthesis

Gm –ve, some Gm +ve, anaerobes,

Rickettsiae, Mycoplasma

H. influenzae, Salmonella, Shigella,

Bordetella, Brucella, Gonococci,
Spectrum of activity
Meningococci, Streptococci, Staphylococci,
Chloramphenicol Clostridium, E. coli, and Klebsiella

Bactericidal to N. meningitidis,
H. influenzae

By drug-inactivating enzymes

Mechanism of resistance Reduced permeability to drug

↓ Sensitivity of target
ribosome

Good oral absorption

Excellent tissue penetration

Pharmacokinetics

High CSF concentration

Microsomal enzyme inhibitor

 Broad-spectrum antibiotics – Tetracyclines and chloramphenicol 543

62.9 ADVERSE EFFECTS, DRUG INTERACTIONS, AND USES

Caused due to inhibition of

mammalian cell protein synthesis

Anemia, leukopenia,
Dose-dependent
thrombocytopenia

These are reversible

1. Bone marrow
depression
Caused due to a toxic metabolite

Aplastic anemia, which could

Idiosyncratic
be fatal

Newborn babies given

This has reduced its use
high dose

Vomiting, refusal to feed, hypotonia,

Signs/symptoms hypothermia, abdominal distension,
metabolic acidosis, ashen gray cyanosis
2. Gray baby
Adverse effects syndrome
Can be fatal

Due to inability to Due to inadequate hepatic

metabolize glucuronidation

As it is a broad–spectrum
3. Superinfection
antibiotic

4. GI toxicity Nausea, vomiting, diarrhea

5. Hypersensitivity Uncommon

Due to enzyme Toxicity of phenytoin,

Drug interactions
inhibition warfarin, tolbutamide

1. Typhoid fever Earlier it was a drug of choice

As an alternative to penicillin
2. Bacterial meningitis
↓ Due to risk and cephalosporins
of bone marrow
depression As an alternative to metronidazole
Uses
and clindamycin
Specific uses 3. Anaerobic infections
Combined with aminoglycoside
and penicillin

As alternative to
4. Rickettsial infections
tetracyclines

∴
It has good aqueous
5. Eye/ear infection
humor concentration
544 Pharmacology mind maps for medical students and allied health professionals

62.10 TIGECYCLINE

Glycylcycline, a derivative
of minocycline

Wide antibacterial spectrum

Effective against methicillin and vancomycin-resistant

Staphylococci, Streptococci, multidrug-resistant
Enterococci, S. pneumoniae, anaerobes, Enterobacter,
Mycobacteria, Rickettsiae, Chlamydiae, and Legionella

Long t½–36 h

Tigecycline Good tissue penetration

Hence no dosage reduction in

Excreted from GIT
renal impairment

Well-tolerated Only nausea, vomiting

Life-threatening infections due

to resistant organisms

Use Nosocomial infection

Intra-abdominal infections
 63
Aminoglycosides

63.1 INTRODUCTION AND COMMON PROPERTIES

AMAs with amino sugars joined

by glycoside linkages
Soil actinomycetes of genus
Source Streptomyces and
Micromonospora

Introduction Semisynthetic in nature Amikacin and netilmicin

Streptomycin, kanamycin,
Streptomyces
tobramycin, neomycin

Micromonospora Gentamicin, netilmicin

1. Polycationic carbohydrates, containing

Aminoglycosides amino sugars joined with glycosides

2. Highly water-soluble polar compounds

3. Not absorbed orally, given parenterally

4. Remain extracellular, poor CSF concentration

5. Not metabolized, excreted

unchanged by kidneys
Common properties

6. More active at alkaline pH

7. Bactericidal

8. Inhibit bacterial protein synthesis

9. Spectrum mostly Gm –ve organisms

10. Ototoxicity and nephrotoxicity

545
546 Pharmacology mind maps for medical students and allied health professionals

63.2 SPECTRUM, MECHANISM OF ACTION, AND MECHANISM OF RESISTANCE

Narrow spectrum

Spectrum of activity Acts mainly against Gm –ve organisms

E. coli, Salmonella, Shigella, Proteus,

Klebsiella, Pseudomonas, V. cholerae,
Y. pestis, Nocardia, Brucella

Penetrate bacterial cell membrane by

aqueous pores

Transported
- by O2-dependent active
transport process

Bind to 30S ribosomal subunit

Hence forms abnormal protein

Blocks initiation of protein synthesis
synthesis

Also causes termination of protein

Mechanism of action Addition of incorrect amino acids
synthesis

Follows dose-dependent killing Hence has bactericidal action

Hence given once daily, in spite of

Residual post-antibiotic effect
short t½

Acidic pH and anaerobic environment

reduce efficacy

Penicillins inhibit cell wall synthesis,

Hence their combination is synergistic
assist aminoglycoside penetration

1. Inactivating enzymes

2. ↓ Affinity for ribosomes

Mechanism of resistance

3. Reduced penetration

Partial cross-resistance Among different aminoglycosides

 Aminoglycosides 547

63.3 PHARMACOKINETICS AND ADRs

Not orally absorbed

Absorbed if applied over

large wounds/body cavities

Not bound to plasma

proteins

Pharmacokinetics

Remains extracellularly, in
vasculature

Not metabolized

Excreted unchanged by Hence reduce dose in renal

kidneys impairment

Most important

Dose-and duration-dependent

Concentrates in labyrinthine
fluid

Damages cochlear hair cells

and vestibular sensory cells

Degeneration of auditory
Adverse effects 1. Ototoxicity
nerve

Tinnitus, then deafness

Cochlear cells cannot
∴
regenerate, there is progressive
permanent deafness Headache, nausea, vomiting,
dizziness, vertigo, nystagmus,
and ataxia
Manifestations
Most symptoms
↓ after 1–2 wks of
stopping drug
Elderly patients are
more prone
However, ataxia persists
for 1–2 yrs
Risk ↑ if given with
loop diuretics, vancomycin
548 Pharmacology mind maps for medical students and allied health professionals

63.4 ADRs AND PRECAUTIONS

As it is concentrated in renal cortex,

it damages tubules

Reduces urine concentration ability,

↓ GFR, albuminuria

2. Nephrotoxicity Effects are reversible

↑ Risk in elderly and patients

with preexisting renal disease

Concurrent administration of other Amphotericin B, vancomycin,

nephrotoxic agents viz cisplatin, cyclosporin ↑ risk

Curare-like effects

Due to ↓ release of
3. Neuromuscular blockade
acetylcholine from nerve endings

Myasthenic patients are more

susceptible

1. Concurrent use of other ototoxic

agents – loop diuretics

2. Concurrent use of other nephrotoxic

agents – amphotericin B,
cisplatin, vancomycin

3. Concurrent use of other

curarimimetic agents

4. Concurrent use of skeletal muscle

Precautions
relaxants

5. Elderly patients

6. Pregnancy, due to the risk of fetal

ototoxicity

7. Do not mix aminoglycosides with

any other drug in syringe
 Aminoglycosides 549

63.5 USES OF GENTAMICIN

With penicillin/
3rd-generation cephalosporin

UTI with pyelonephritis

Pneumonia

Meningitis
1. Severe Gm –ve aerobic
bacillary infections
Septicemia

Peritonitis

Osteomyelitis

Causative organisms –
Infected burns Pseudomonas, Klebsiella,
E. coli, Proteus, etc.

Penicillin G + gentamicin S. viridans

2. Bacterial endocarditis due

Ampicillin + gentamicin Enterococcus
to S. viridans, Enterococcus
Uses of gentamicin
Enterococcus (in patients
Vancomycin + gentamicin allergic to β-lactam
antibiotics)

Streptomycin, kanamycin,
3. Tuberculosis
amikacin

Streptomycin/gentamicin +
Plague
tetracyclines

Streptomycin/gentamicin +
Brucellosis
doxycycline
4. Other Gm –ve infections

5. Skin, eye, ear infections
due to Gm –ve organisms
Streptomycin/gentamicin
is drug of choice
Tularemia
Alternative is fluoroquinolone/
tetracyclines
Topical gentamicin/
neomycin/framycetin, etc.
550 Pharmacology mind maps for medical students and allied health professionals

63.6 OTHER AMINOGLYCOSIDES

1. Infections of
Ulcers, wounds, burns
∴
It is highly skin/mucous membrane
nephrotoxic,
not used systemically
Uses of neomycin Along with bacitracin/
2. Infections of ear/eye
polymyxin B
Used topically

1. Preparation of bowel Neomycin sulfate +

Initial treatment of before abdominal surgery erythromycin
Uses of amikacin serious nosocomial Gm –ve
and netilmicin bacillary infections resistant to
gentamicin/tobramycin Orally Reduces blood ammonia
level by destroying colonic
bacteria
2. Hepatic encephalopathy
It is highly
∴
Not used systemically
nephrotoxic ∴
Neomycin is
Oral lactulose is preferred
Uses of framycetin highly toxic
(Soframycin)
Used topically Skin, eye, ear infections

Tuberculosis 2nd-line drug

Subacute bacterial
With penicillin
endocarditis

Uses of streptomycin Plague

Tularemia With tetracylines

Brucellosis
 64
Miscellaneous antibiotics

64.1 LINCOSAMIDES, GLYCOPEPTIDES, AND TEICOPLANIN

Derivative of lincomycin
Like erythromycin, inhibits
protein synthesis by binding
to 50S ribosomal subunit
Streptococci, Staphylococci,
Spectrum Pneumococci, anaerobes, T. gondii,
P. jirovecii
Lincomycin (not used now) Good oral absorption
and clindamycin
90% plasma protein bound
Clindamycin
Good tissue penetration

Pseudomembranous colitis,
ADR
neuromuscular blockade
Abdominal, pelvic, bone, With aminoglycoside/
1. Anaerobic infections
and joint abscess cephalosporin
2. P. jirovecii infections in AIDS
With primaquine
patients
Use 3. T. gondii infection With pyrimethamine
4. Streptococcal and
staphylococcal infections Including MRSA infections

5. Prophylaxis – in valvular As an alternative to penicillin

heart disease patients and erythromycin
Source Streptococcus orientalis

Gm +ve bacteria esp.

Spectrum
Staphylococci, including MRSA
Inhibits cell wall synthesis
(like penicillin)
Mechanism of action
Also weakens cell membrane

Alteration of target protein

Vancomycin-resistant enterococci
Mechanism of resistance (VRE) cause several nosocomial
infections
Lincosamides
Vancomycin-resistant S. aureus
has also emerged (VRSA)
Vancomycin, teicoplanin,
telavancin Not absorbed orally, administered IV
Glycopeptides
Vancomycin
Pharmacokinetics Wide distribution

Hence reduce dosage

Excreted through kidneys
in renal impairment
Skin rashes, thrombophlebitis

Ototoxicity, nephrotoxicity
Adverse effects
Avoid concurrent ototoxic/
nephrotoxic drugs
Histamine release
1. MRSA infections
2. Enterococcal endocarditis
Uses
3. Pseudomembranous colitis
Source Actinoplanes teichomyeticus
4. Penicillin-resistant
Mechanism and Similar to vancomycin
spectrum pneumococcal meningitis
Hence maculopapular rash
over head, neck, and back Hence called “red
along with fever and chills man syndrome”
Osteomyelitis, endocarditis,
soft-tissue abscesses
As an alternative to
With gentamicin
penicillin
Due to Clostridium As an alternative to
difficile metronidazole
With cephalosporin

Administered IM Unlike IV vancomycin

Less toxic
Teicoplanin
Vancomycin 6–24 h, given
t½-70 h Hence given once daily
4 times a day
ADR Allergy, ototoxicity

MRSA infections
Use
MR enterococcal infections

551
552 Pharmacology mind maps for medical students and allied health professionals

64.2 POLYPEPTIDE ANTIBIOTICS

High systemic toxicity

Used only topically

Sourced from
Polymyxin
Bacillus polymyxa

Sourced from
Colistin
Bacillus colistinus
Polymyxin and
colistin
Effective against
Gm –ve organisms
Hence there is leakage
of cell contents
Alters cell membrane
Mechanism
permeability
Thus they are
bactericidal
Skin, eye, ear,
Use
infections

Oral colistin for Gm –ve

diarrhea in children

Source Bacillus subtilis

Spectrum Gm +ve bacteria

Bacitracin Inhibits cell wall

Hence is bactericidal
synthesis

Skin infections, surgical wounds,

Only topical use
ulcers, ocular infections
Polypeptide
antibiotics
Neosporin powder Bacitracin + neomycin

Source Fusidium coccineum

Gm +ve organisms,
Spectrum
esp. Staphylococci

Sodium fusidate Bactericidal

Mainly used topically

May be given orally for

resistant staphylococcal
infections

Source Pseudomonas fluorescens

Bacterial – Gm +ve
and some Gm –ve
Mupirocin organisms, MRSA
(pseudomonic acid)
Inhibits enzyme tRNA
synthetase
Due to Streptococci
Minor skin infections
and Staphylococci
Use
To eradicate
Also used intranasally staphylococcal
carrier state
 Miscellaneous antibiotics 553

64.3 FOSFOMYCIN, STREPTOGRAMINS, OXAZOLIDINONES, AND DAPTOMYCIN

Analog of phosphoenolpyruvate

Spectrum Gm +ve and Gm –ve organisms

This enzyme is required for the first

Fosfomycin step in cell wall synthesis
Inhibits enzyme endopyruvate transferase
Hence it inhibits bacterial cell wall synthesis
Administered both orally and parenterally
Uncomplicated UTI in women Achieves high concentration in urine
∴
Use
Used as single 3 g dose

Source Streptomyces pristinaspiralis

Combination of quinupristin
(streptogramin B) and dalfopristin
(streptogramin A) in ratio 30:70

Bactericidal Gm +ve cocci, MRSA

Binds 50S ribosomal subunit,

Mechanism
hence inhibits protein synthesis

Extensive first-pass metabolism Hence not given orally

Hence no dose adjustment in renal impairment

Pharmacokinetics
Primarily fecal excretion
Streptogramins
But ↓ dose in hepatic dysfunction
Microsomal enzyme inhibitors

Myalgia, arthralgia

Adverse effects Nausea, vomiting, diarrhea

Pain at injection site

Streptococcal infections

Use MRSA infections

Vancomycin-resistant E. faecium

Spectrum Gm +ve bacteria, MRSA, Gm +ve anaerobes

Binds to 23S ribosomal RNA of 50S subunit and

Mechanism Prevents initiation of protein synthesis

100% bioavailability Hence inhibits protein synthesis

Linezolid
No food interaction

Wide tissue distribution

Oral/IV administration

In dialysis patients, give after dialysis It is excreted in dialysis

∴
Oxazolidinones
Nausea, vomiting, dizziness
Reversible bone marrow suppression
( >2 wks use)
Peripheral neuropathy

Lactic acidosis
ADR Cheese reaction
Linezolid is MAO inhibitor hence
it can cause Serotonin syndrome (with SSRIs, tyramine-
rich foods)
Due to Staphylococci,
1. Nosocomial pneumonia
MRSA
2. Community-acquired pneumonia Due to S. pneumoniae
Lipopeptide Use
3. Vancomycin-resistant E. faecium infections
Source Streptomyces roseosporus
Due to Streptococci
4. Skin and soft tissue infections
Bactericidal and Staphylococci
Most susceptible organisms are aerobic Gm +ve
Daptomycin including MRSA and VRSA and anaerobes
Spectrum
Multidrug-resistant Staphylococci

Not exactly known

Mechanism But probably unique

Hence there is efflux of potassium ions
Myopathy Binds to cell membrane and causes
ADR
depolarization
This causes rapid cell death
Complicated skin and soft tissue infections;
alternative to vancomycin
Use
Lung surfactants antagonize
∴
Not used in pneumonia
effects of daptomycin
 65
Chemotherapy of tuberculosis (TB)

65.1 INTRODUCTION AND CLASSIFICATION

TB is a chronic
granulomatous disease

Cause – Mycobacterium
tuberculosis

Introduction

Incidence has ↑
due to spread of AIDS

Mycobacterium avium
complex (MAC) is
more common

Isoniazid (H), rifampicin (R),

1. First-line (standard) More effective, less toxic pyrazinamide (Z) ethambutol (E),
streptomycin (S)

Ethionamide, thiacetazone,
para-aminosalicylic acid (PAS),
2. Second-line (reserve) Less effective, more toxic
amikacin, capreomycin,
cycloserine

Ciprofloxacin, rifabutin,
Classification of anti-
3. Newer rifapentine, clarithromycin,
TB drugs
azithromycin

Isoniazid, rifampicin,
pyrazinamide, streptomycin,
Tuberculocidal
ciprofloxacin, capreomycin,
kanamycin

Ethambutol, PAS,
Tuberculostatic thiacetazone, cycloserine,
ethionamide

554
 Chemotherapy of tuberculosis (TB) 555

65.2 FIRST-LINE DRUGS – ISONIAZID

Most effective and

cheapest

Effective in both acidic

and alkaline pH

Tuberculocidal for
rapidly multiplying bacilli

Tuberculostatic for
Isoniazid
resting bacilli

Kills intracellular bacilli, INH, a prodrug, enters

i.e., in macrophages Mycobacteria
Converted by enzyme
Kills extracellular bacilli, catalase-peroxidase (katG)
i.e., in walls of cavities to active form
Active form covalently binds
Mechanism
to enzymes responsible

Mutation of InhA and Mycolic acid important constituent

katG enzymes of mycobacterial cell wall
Mechanism of
resistance Hence weakens cell wall,
Overproduction of Also interacts with and Hence inhibits mycolic
causing death, so
enzymes inhibited by INH inhibits InhA gene acid synthesis
is tuberculocidal cell

Good oral absorption Hence there are slow

or fast acetylators
Penetrates all tissues,
Pharmacokinetics tuberculous cavities, necrotic Slow acetylators t½: 3–5 h
tissues, caseous material,
ascitic fluid, and CSF
Fast acetylators t½: 1 h
Metabolized by genetically
determined acetylation
Peripheral
Slow acetylators side effect
neuropathy

Fast acetylators side effect Hepatotoxicity

Once-weekly regimen
inadequate in fast acetylators
∴
It interferes with utilization and
excretion of pyridoxine (vitamin B6)

Prevented by prophylactic
1. Peripheral neuropathy
10–50 mg pyridoxine

Common with high doses, but

uncommon with standard doses

Common in alcoholics and elderly

2. Hepatitis If mild, INH continued

Adverse effects
If severe hepatic necrosis,
INH withdrawn

Psychosis, seizures
3. CNS toxicity
Common in epileptics
4. Hemolysis in patients
with G6PD deficiency
556 Pharmacology mind maps for medical students and allied health professionals

65.3 RIFAMPICIN (RIFAMPIN)

Semisynthetic derivative of
rifamycin

Source Streptomyces mediterranei

Other rifamycins Rifabutin, rifapentine

M. tuberculosis, M. leprae, atypical mycobacteria,

Bactericidal spectrum Gm +ve and Gm –ve organisms like S. aureus,
N. meningitidis, E. coli, Proteus, Pseudomonas, Legionella
Acts on both intracellular and
extracellular organisms

Only drug that act on persisters

Effective against tubercle

bacilli resistant to other drugs

Called “sterilizing agent” Binds to β subunit of DNA-dependent RNA polymerase

Mechanism of action Inhibits bacterial RNA synthesis

No effect on human RNA polymerase

at therapeutic concentration

Mechanism of resistance Reduced binding to target RNA polymerase

Well absorbed

Good tissue penetration

Present in caseous material, cavities, macrophages, CSF

Pharmacokinetics Also present in saliva, tears, and sweat

Microsomal enzyme inducer

Hence many drug interactions

Undergoes enterohepatic circulation

Common in alcoholics, patients with preexisting
1. Hepatotoxicity liver dysfunction, and patients taking concurrent
hepatotoxic drugs
2. Flu-like syndrome Fever, chills, body ache

Epigastric distress, nausea, vomiting,

Adverse effects 3. GI syndrome diarrhea, abdominal cramps

4. CNS syndrome Headache, drowsiness, dizziness, ataxia,

Rifampicin confusion, peripheral neuritis
(Rifampin) Hence patients should
be informed
5. Orange-red secretions Saliva, tears, sweat, urine
However it is
Oral contraceptives, anticoagulants, corticosteroids, harmless
anticonvulsants, protease inhibitors, NNRTIs
↑ Metabolism and ↓ efficacy of
Hence advise patients to use
Drug interactions alternative methods of contraception

Aminosalicylic acid reduces absorption of rifampicin Hence there should be 8–12 h of gap between them

600 mg daily with other anti-TB drugs

1. Tuberculosis 600 mg biweekly

Prophylaxis, as alternative to INH

2. Atypical mycobacteria 600 mg twice weekly

3. Leprosy 600 mg once a month, supervised

4. Prophylaxis of H. influenzae and meningococcal

Uses
meningitis in close contacts, esp. children

5. Resistant staphylococcal infections With β-lactam antibiotic or vancomycin

6. Brucellosis With doxycycline, which is a drug of choice

7. Pneumococcal meningitis With ceftriaxone (if penicillin resistant)

8. Eradicate carrier state Nasal carriers of S. aureus, H. influenzae, N. meningitidis

Similar to rifampin

Milder enzyme induction

More active against atypical mycobacteria

Rifabutin
AIDS patients receiving protease inhibitors (PI)
Used
and NNRTIs (to ↓ drug interactions)

ADR Myalgia, anterior uveitis

Use: TB, atypical mycobacterial infections for prophylaxis

Similar to rifampicin
Rifapentine
600 mg once weekly in TB
 Chemotherapy of tuberculosis (TB) 557

65.4 PYRAZINAMIDE, ETHAMBUTOL, AND STREPTOMYCIN

Tuberculocidal

Requires acidic pH for activity (seen

Analog of nicotinamide
in phagosomes of macrophages)

Mechanism of action Not exactly known

Converted to pyrazinoic acid by

Pyrazinamide pyrazinamidase in Mycobacteria

Pyrazinoic acid inhibits mycolic

acid synthesis

Hepatotoxicity, most common,

dose-dependent
ADR
Hyperuricemia Hence gouty arthritis
Tuberculostatic

Acts on fast-multiplying
bacilli in cavities

Acts on atypical
mycobacteria
Inhibits
arabinosyltransferases
Mechanism
Inhibits mycolic acid
synthesis
Good oral absorption
(80% bioavailability)

Ethambutol
Good tissue penetration
Hence reduced visual acuity
Hence ↓ dose in
Excreted in kidneys
renal dysfunction
Hence there is inability to
differentiate red from green
ADR Optic neuritis
Hence color vision monitoring
during treatment

Hence contraindicated in
children <6 yrs

↓ Renal excretion Hence ↑ plasma

Drug interactions
of uric acid urate levels

Tuberculocidal

Acts only against extracellular

organisms; poor penetration
Streptomycin
ADR Ototoxicity, nephrotoxicity

Least preferred
558 Pharmacology mind maps for medical students and allied health professionals

65.5 SECOND-LINE DRUGS

Related to sulfonamides

Tuberculostatic
1. Para-aminosalicylic
acid (PAS)
Poorly tolerated

Nausea, anorexia,
ADR
epigastric pain, diarrhea

Tuberculostatic

2. Thiacetazone Low efficacy

ADRs Hepatitis, dermatitis

Tuberculostatic

Acts on both intra- and

extracellular organisms
3. Ethionamide
Acts on atypical
mycobacteria as well Nausea, anorexia,
metallic taste
ADR
Hepatitis, peripheral
Administered neuritis
parenterally
Ototoxic and
4. Amikacin, kanamycin, nephrotoxic
Second-line capreomycin Also effective against
drugs atypical mycobacteria

Used in multidrug-resistant TB

Tuberculostatic

Inhibits cell wall synthesis

5. Cycloserine
Effective against some
Gm +ve organisms
Headache, tremors,
ADR CNS toxicity
psychosis, seizures
e.g., Ciprofloxacin, ofloxacin,
moxifloxacin, gatifloxacin,
levofloxacin, sparfloxacin
Inhibits tubercle bacilli,
atypical mycobacteria, Gm +ve
and Gm –ve organisms
6. Fluoroquinolones
Kills intracellular mycobacteria

Used in combination regimens

in TB resistant to 1st-line drugs

Use as 2nd-line drug

Good penetration
7. Linezolid
Kills intracellular bacilli

Single daily dose of 600 mg

 Chemotherapy of tuberculosis (TB) 559

65.6 TREATMENT OF TUBERCULOSIS – OBJECTIVES AND REGIMENS

1. Make patients Achieved by rapidly killing

noninfectious as early as dividing bacilli with 3–4
WHO recommends MDT possible bactericidal drugs
(multidrug therapy) for
all cases of TB
Treatment of
2. Prevent resistance
tuberculosis
Objective of MDT

3. Prevent relapse By killing persisters

4. Reduce total duration

of effective therapy

INH with 1–2

tuberculostatic drugs

Duration – 18 months
a. Long-course regimens
(conventional regimen)
Not recommended now

Due to poor compliance

and high failure rate

6–9 months duration

b. Short-course
Convenient
chemotherapy (SCC)

Treatment regimens
Highly effective and
less toxic

3–4 tuberculocidal drugs

daily/thrice weekly for
2–3 months
1. Intensive phase
Objective to render patient
noncontagious

2–3 drugs, usually INH

and rifampin, daily/thrice
weekly for 4–6 months

Objective eliminate
2. Continuation phase
persisters

Prevent relapse
560 Pharmacology mind maps for medical students and allied health professionals

65.7 DOSES OF COMMONLY USED ANTI-TB DRUGS

Recommended Daily Thrice weekly

50 kg 50 kg
dosage mg/kg mg/kg

1. Isoniazid (H) 5 (4–6) 300 mg 10 (8–12) 600 mg

2. Rifampicin (R) 10 (8–12) 600 mg 10 (8–12) 600 mg

3. Pyrazinamide (Z) 25 (20–30) 1500 mg 35 (35–40) 2000 mg

4. Ethambutol (E) 15 (15–20) 1000 mg 30 (20–30) 1000 mg

5. Streptomycin (S) 15 (12–18) 1000 mg 15 (12–18) 1000 mg

 Chemotherapy of tuberculosis (TB) 561

65.8 WHO GUIDELINES FOR TB TREATMENT

Depends on diagnostic
category

Revised National Tuberculosis

Control Program (RNTCP)
launched in India in 1997

DOTS (directly observed

treatment short course) was
implemented under RNTCP
WHO guidelines for
TB treatment
Of the WHO regimens,
thrice-weekly regimen is
followed in DOTS Patients administered drug
under supervision of health
worker/trained person
DOTS is backbone of RNTCP

Ensures actual consumption

of drug

DOTS
Rx must be supervised and
monitored by bacteriological
examination

Ensures compliance;
prevents resistance
 DOTS, TB TREATMENT REGIMENS

TB Diagnostic
Category

Category I Category II Category III Category IV

Chronic or
TB TB TB
Type of Total Type of Type of Total Suspected
Treatment Treatment Treatment
Patient Duration Patient Patient Duration Multidrug-
Regimens Regimens Regimens
Resistant TB

New Sputum
Sputum positive
positive pulmonary TB, Sputum negative;
relapse, sputum TB
Seriously ill sputum Intensive Continuation 6 months Intensive Continuation Total not seriously ill; Intensive Continuation 6 months
positive failure, Treatment
negative pulmonary TB, phase phase phase phase Duration extrapulmonary phase phase
sputum positive Regimens
Seiously ill not seriously ill
after default
extrapulmonary TB
65.9 DOTS, TB TREATMENT REGIMENS

Daily
2(HRZES)
Daily 2HRZE; Daily 2HRZE; Specially
3,1HRZE;
Thrice 6 months 5(HRE)3; 8 months Thrice 4HR; 4 6 months designed
4HR 4(HR)3 Thrice
weekly 5(HRE) weekly (HR)3 individualized
weekly 2
2(HRZE)3 2(HRZE)3 regimens
(HRZES)3,
1(HRZE)3

8 months
562 Pharmacology mind maps for medical students and allied health professionals

• Prefix before number indicates months of treatment

• Subscript after regimen indicates number of doses per week
• No subscript means regimen is given daily
• H - isoniazid, R - rifampicin, Z - pyrazinamide, E - ethambutol, S - streptomycin
• HRZ are given orally
• S is given IM
 Chemotherapy of tuberculosis (TB) 563

65.10 MULTIDRUG-RESISTANT TUBERCULOSIS (MDR-TB), TB IN HIV PATIENTS, TB

IN PREGNANCY, CHEMOPROPHYLAXIS OF TB, ROLE OF GLUCOCORTICOIDS
IN TB, AND DRUGS FOR MYCOBACTERIUM AVIUM COMPLEX (MAC)

Inadequate Rx
If sputum remains positive even
after 6 months of Rx
Irregular drug supply
Cause
Poor compliance
Resistance to both INH and rifampicin
Impaired host defense, like AIDS
With or without resistance to
Multidrug-resistant any other anti-TB drugs
tuberculosis (MDR-TB) Susceptibility testing is recommended
(if facility is available)
Rx by either specially designed
standardized or individualized regimens Rx with 5–6 drugs, including 2–3 anti-TB
drugs which the patient has
not received in the past

Rx given daily and supervised

Drugs Rx continued for at least 24 months

Same diagnostic categories WHO is implementing DOTS-Plus

DOTS-Plus uses second-line

Same treatment
anti-TB drugs
SCC started immediately Recommended where DOTS
TB in HIV patients
upon TB diagnosis is fully in place
INH, rifampicin, ethambutol Rifabutin used in place
are safe in pregnancy of rifampicin
Hence there are no drug interactions
with protease inhibitors

Prevents active TB in at-risk patients 1. Newborn of a mother with active TB

INH most ideal it is orally 2. Children <6 yrs with positive

Chemoprophylaxis of TB
TB is a relative contraindication
Role of glucocorticoids
in TB
∴
effective, less toxic, and cheap tuberculin test
3. Household contacts of
Indications
patients with TB
4. Patients with positive TB Like diabetes mellitus, AIDS,
test with additional risk factors malignancy, silicosis, etc.
5. Patients with old active disease
not adequately treated
TB of serous membranes, to e.g., Pleura, peritoneum,
for use of glucocorticoids prevent fibrosis and its sequelae meninges, pericardium
Certain situations where
Rx of hypersensitivity to anti-TB drugs
corticosteroids are used in TB
TB of eye, larynx, genitourinary tract
Prednisolone preferred
to prevent fibrosis and scarring

When patient’s general condition

improves, steroids should be gradually
tapered to avoid HPA-axis suppression

MAC is more common and severe

in AIDS patients
Rifabutin, clarithromycin, azithromycin,
Effective drugs are fluoroquinolones, ethambutol,
clofazimine, amikacin, ethionamide
Regimen–clarithromycin/azithromycin +
Macrolides – drugs of choice
Drugs for Mycobacterium ethambutol
avium complex (MAC)
Needs lifelong Rx

Ciprofloxacin + clarithromycin +
Four-drug regimen is used
rifabutin + amikacin

Prophylaxis Rifabutin/clarithromycin/azithromycin
 66
Chemotherapy of leprosy

66.1 DRUGS USED IN LEPROSY

Diaminodiphenyl sulfone
(DDS) or dapsone

Rifampicin

Clofazimine

Drugs used in leprosy Ethionamide

Ofloxacin

Minocycline

Clarithromycin

564
 Chemotherapy of leprosy 565

66.2 DAPSONE (DDS), RIFAMPICIN, CLOFAZIMINE, ETHIONAMIDE, AND NEWER AGENTS

A sulfone

Oldest, cheapest Hence widely used

Chemically related to sulfonamides Hence same mechanism

M. Leprae utilize PABA for

synthesis of folic acid

Folic acid is necessary for its growth

Mechanism of action
and multiplication
Dapsone is structurally similar to
PABA

1. Dapsone (DDS) It competitively inhibits folate Hence it prevents formation of

Thus, dapsone is leprostatic
synthetase tetrahydrofolic acid (THFA)

Complete oral absorption

Widely distributed, especially in

infected skin, muscle, liver, kidney
Pharmacokinetics
Undergoes enterohepatic
circulation

Metabolized by acetylation

Dose-related hemolytic anemia and

methemoglobinemia in patients
with G6PD deficiency
Fever, dermatitis, pruritus,
Adverse effects Sulfone syndrome i.e., Exacerbations of lesions lymphadenopathy, hepatitis, anemia,
methemoglobinemia

Most effective Allergic dermatitis, itching,

Others
peripheral neuropathy
Bactericidal for rapidly multiplying
2. Rifampicin M. Leprae

WHO recommends it for all types of

multidrug regimens

Phenazine dye

Weak bactericidal

Hence useful for type 2 lepra

Has additional anti-inflammatory effect
reaction
Binds to mycobacterial DNA to
inhibit template function

3. Clofazimine Acts against dapsone-resistant bacilli

Given orally Food ↑ absorption

Not metabolized
Red–brown discoloration of
exposed skin
Excreted in feces, via bile
Conjunctival and corneal
pigmentation
ADR
Discoloration of hair, tears, sweat,
2nd-line anti-TB, effective against urine, etc.
M. Leprae Nausea, vomiting, diarrhea,
abdominal pain
4. Ethionamide Alternative to clofazimine

ADR Hepatotoxicity

Clarithromycin (C) 500 mg daily for 28 days

Only tetracycline effective against

M. Leprae
Minocycline (M)
5. Newer agents Used in combination regimens

Bactericidal

Ofloxacin (O) Use in multidrug regimen

O 400 mg + 600 mg rifampicin for

28 days
566 Pharmacology mind maps for medical students and allied health professionals
66.3 TREATMENT OF LEPROSY AND LEPRA REACTIONS
Render patient noncontagious
WHO recommends MDT for all
leprosy cases
Objectives of MDT
Shorten duration of treatment
Treatment of leprosy
Treatment schedule: All
drugs are given orally
Immunologically mediated
Occurs during course of disease
Lepra reactions Cause not known
Precipitated by infection,
trauma, stress, etc.
Two types
2. Type 2 (erythema nodosum
By killing rapidly multiplying bacilli
at earliest
Prevent resistance
Prevent relapse By destroying persisters
Rifamprin 600 mg once monthly – Supervised
Clofazimine 300 mg once monthly Supervised
Dapsone 100 mg daily Unsupervised (self-administered)
1. For multibacillary leprosy
Clofazimine 50 mg daily Unsupervised (self-administered)
(LL, BL, and BB)
Treatment duration 2 yrs
Follow-up At least 5 yrs
Use ethionamide 250 mg
If clofazimine unacceptable
daily, unsupervised
Rifampicin 600 mg once monthly Supervised
2. For paucibacillary
leprosy (TT, BT, and I)
Dapsone 100 mg daily Unsupervised
Clofazimine 50 mg + any two newer
drugs (C/M/O) daily for 6 months
Followed by
3. Alternative regimens
Clofazimine 50 mg + any one Rifampicin 600 mg
newer drug for another 18 months
For single-lesion PBL Ofloxacin 400 mg as a single dose
Delayed-type hypersensitivity Minocycline 100 mg
Seen in borderline leprosy cases
Neuropathy, painful tender lesions
1. Type 1 (reversal reaction) Characterized by
Cutaneous ulcerations
When they occur after
initiation of treatment, called
reversal reaction
Rx by oral prednisolone
Type III hypersensitivity
Commonly seen in
lepromatous leprosy
Tender, inflammed subcutaneous
More severe than type 1
nodules
Associated fever, lymphadenopathy,
Characterized by arthritis, nerve pain, orchitis,
leprosum–[ENL])
iridocyclitis, etc.
Due to release of antigen from
dying M. Leprae
Rx with thalidomide Contraindicated in pregnancy
Clofazimine, chloroquine,
Other drugs
corticosteroids (prednisolone), aspirin
 67
Chemotherapy of malaria

67.1 CLASSIFICATION OF ANTIMALARIALS

Primaquine, pyrimethamine
1. Causal prophylactics
Primary tissue schizontocides,
destroy parasites in liver cells,
prevent RBC invasion

Chloroquine, quinine,
mefloquine, halofantrine,
atovaquone

2. Blood schizontocides Pyrimethamine, artemisinin

derivatives
Clinical suppressives, destroy
RBC parasites, terminate
clinical attack
A. Therapeutic classification
Primaquine
3. Tissue schizontocides
Hypnozoitocidal, prevent relapse

Blood schizontocides +
hypnozoitocidals (2+3)
4. Radical curatives
Eradicate all forms of P. vivax
and P. ovale from body

Primaquine, chloroquine, quinine

Classification 5. Gametocidals
Destroy gametes and
prevent transmission

1. 4-Aminoquinolines Chloroquine

2. 8-Aminoquinoline Primaquine

3. Quinolone methanols Quinine, quinidine, mefloquine

Artemisinin, artesunate,
B. Chemical classification 4. Sesquiterpene lactones
artemether, arteether

Sulfadoxine, pyrimethamine,
5. Folate antagonists
proguanil

6. Phenanthrene methanol Halofantrine, lumefantrine

7. Naphthoquinone Atovaquone

567
568 Pharmacology mind maps for medical students and allied health professionals

67.2 CHLOROQUINE – MECHANISM OF ACTION AND RESISTANCE

Highly effective blood schizontocide

Activity against all 5 species Enters parasite-infected RBC

Enters acidic food vacuoles

Rapidly acting – patients afebrile in 24–48 h
( chloroquine is base)
∴

Parasites digest host hemoglobin

Gametocidal for P. vivax, P. ovale, and P. malariae
(source of its amino acid)

No effect on hypnozoites in liver Transport it to acidic food vacuole

Safe in pregnancy Toxic heme is formed in process

Mechanism of action Detoxified to hemozoin by heme

polymerase

Chloroquine, quinine, and mefloquine

inhibit heme polymerase

Accumulation of toxic heme in parasite

Death of parasite

Chloroquine
Chloroquine also prevents digestion of
hemoglobin by parasite

Disrupts parasites, amino acid supply

Chloroquine-resistant P. falciparum
very common

Mutant gene that encodes for

chloroquine transporter

Hence chloroquine transported

out of food vacuoles
Mechanism of resistance
In P. vivax, resistance modulated by
P-glycoprotein and other transporters

Resistance may be prevented by verapamil,

desipramine, and chlorpheniramine
(benefits need to be confirmed)

These drugs prevent chloroquine efflux

from parasite

Effective against Giardia lamblia and

Entamoeba histolytica

Other actions Concentrated in liver, hence useful in

hepatic amebiasis

Anti-inflammatory property, hence useful

in rheumatoid arthritis and lepra reactions
 Chemotherapy of malaria 569

67.3 PHARMACOKINETICS AND ADVERSE EFFECTS

Given both orally and parenterally

Toxic concentration is reached

following rapid parenteral administration

Hence given as slow infusion, in divided doses

Rapid oral absorption

Pharmacokinetics

Wide tissue distribution

Large volume of distribution Vd > 100 L/kg

High affinity for melanin-rich

tissues and nuclear chromatine

Hence accumulates in retina

(leads to retinopathy on long-term use)

Reasonably safe

Nausea, vomiting very severe

Hence give antiemetic 30 min

before

Pruritus, dizziness, visual disturbances,

insomnia
Adverse effects
IV chloroquine – hypotension,
widening of QRS complex, arrhythmics

Hence avoid parenteral use

High dose: Cardiomyopathy, peripheral

neuropathy, ototoxicity, convulsions

Long-term use: Blurring of vision, bleaching of

hair, myopathy, irreversible retinopathy,
reversible corneal deposits
570 Pharmacology mind maps for medical students and allied health professionals

67.4 USES

1 g (600 mg) –
4 tablets – at 0 h
Highly effective in
treatment of sensitive
strains of all 4 species
0.5 g (300 mg) – 2 tablets –
at 6 h

Chloroquine phosphate 250

mg (150 mg base)

0.5 g (300 mg) 2 tablets –

at 24 h

0.5 g (300 mg) 2 tablets –

1. Malaria
at 48 h

1 g (600 mg) – 4 tablets –

at 0 h

1 g (600 mg) – 4 tablets –

at 24 h

WHO regimen

0.5 g (300 mg) – 2 tablets –

at 48 h
As it is completely absorbed
2. Extraintestinal (hepatic)
from small intestine and
amebiasis
concentrated in liver
Prophylaxis – 300 mg base –
2 tablets/wk
Uses
3. Rheumatoid arthritis

4. Lepra reactions

Due to anti-inflammatory
5. Photogenic reactions
actions

6. Infectious mononucleosis

7. Discoid lupus
erythematosus
 Chemotherapy of malaria 571

67.5 PRECAUTIONS AND CONTRAINDICATIONS

Avoid parenteral administration Slow infusion if required

∴
There is competition for
accumulation in parasite
Avoid concurrent quinine, mefloquine

Hence therapeutic failure

Chloroquine + mefloquine avoid

Due to ↑ risk of seizures

Chloroquine + halofantrine avoid Due to ↑ risk of arrhythmias

Precautions and contraindications

Chloroquine + gold/
Due to ↑ risk of dermatitis
penicillamine avoid

Retinal disease

Myopathy

Avoid in patients with Porphyria

Antacids reduce absorption,

Neurological disorders
hence avoid

Hepatic disorders
572 Pharmacology mind maps for medical students and allied health professionals

67.6 MEFLOQUINE AND HALOFANTRINE

Quinolone methanol

Highly effective against

erythrocytic forms

Also effective against

MDR P. falciparum

Mechanism – similar to chloroquine

Good oral absorption

Extensive enterohepatic circulation

CNS effects: Visual and auditory

t½ 20–30 days impairment, ataxia, disorientation,
seizures, encephalopathy, psychosis,
sleep disturbances
Mefloquine ADR
CVS: Myocardial depressant,
bradycardia, arrhythmias

Arrhythmias

Conduction block

Contraindications Epileptics

Psychiatric patients

Concomitant quinine/halofantrine
20 mg/kg single dose
1. MDR P. falciparum
Combined with artesunate
Uses

2. Prophylaxis in travelers 250 mg/wk

(areas with chloroquine resistance)

Mechanism – similar to chloroquine

GI disturbances: Nausea,
Schizonticidal against erythrocytic vomiting, pain
Erratic absorption, fatty
forms of all species, including
meal/food ↑ absorption Cardiotoxicity, QTc
MDR P. falciparum
prolongation, arrhythmias
Adverse effects
Avoid concurrent arrhythmogenic
drugs, e.g., mefloquine
Erratic absorption, hence toxicity
or therapeutic failure
Drawbacks Contraindicated during pregnancy
Cannot be given parenterally,
especially during emergencies

As alternative in MDR
P. falciparum malaria
Halofantrine Uses
1500 mg in three divided doses

A congener of halofantrine

Unpredictable absorption

Less cardiotoxicity

Given with artemisinin/mefloquine

Lumefantrine
for MDR P. falciparum

99% plasma protein binding

Well tolerated

Minimal, GI disturbances,
ADR
headache, dizziness
 Chemotherapy of malaria 573

67.7 PRIMAQUINE

Effective against all forms of

malaria parasite

Not effective against

erythrocytic forms

Kills hepatic parasites and

prevents RBC invasion

Casual prophylactic, but

not used for this

Kills hepatic hypnozoites

(exoerythrocytic forms) hence
prevents relapse of P. vivax and P. ovale

Gametocidal for all 4 species Good oral absorption

Mechanism not known Wide tissue distribution

Pharmacokinetics Well tolerated

Primaquine

Metabolite causes hemolysis in

G6PD-deficient patients

G6PD protects RBCs from oxidative

Along with blood schizontocide
damage

1. Radical cure of P. vivax and

Kills gametocytes of vivax and ovale
P. ovale malaria

15 mg/day × 14 days
(30 mg in areas of resistance)

For P. falciparum

2. Gametocidal

45 mg single dose

Not routinely recommended

Uses

3. Chemoprophylaxis As it has to be given daily 30 mg

Used as alternative to
mefloquine/doxycycline

After visiting endemic area, with

regular chloroquine prophylaxis

4. Terminal prophylaxis

15–30 mg × 14 days

With clindamycin, as an
5. Pneumocystis jiroveci
alternative to cotrimoxazole
574 Pharmacology mind maps for medical students and allied health professionals

67.8 QUININE

Kills erythrocytic forms of

parasite like chloroquine

Alkaloid from bark of

Clinical suppressive
cinchona tree

Actions Rapidly acting

Effective even in
chloroquine-resistant
strains of P. falciparum
Gametocidal for all 3 species
except P. falciparum

Mild analgesic and

antipyretic

Myocardial depressant
(like quinidine)

Skeletal muscle relaxant

Other actions
Stimulates uterus, hence
abortifacient

Local anesthetic
properties

Hypotension on IV
administration

Good oral absorption

Wide tissue distribution

Pharmacokinetics
Metabolized in liver

Excreted in urine

Hence causes nausea, vomiting,

1. Highly bitter and gastric
epigastric distress, thus poorly
irritant tolerated
Due to stimulation of pancreatic
Quinine 2. Hypoglycemia beta cells and parasite utilizes
host glucose

Tinnitus, high-tone deafness,

3. Cinchonism
visual impairment, and vertigo

Hypotension On rapid IV injection

Adverse effects Widening of QRS complex

4. CVS
AV block

Hence frequent monitoring of

Arrhythmias
CV functions is a must

5. CNS Neurotoxicity Hence leads to convulsions

Acute hemolytic anemia,

6. Allergic Blackwater fever hemoglobinuria, fever with
renal failure
Given orally preferably; if IV
injection, slow infusion

Precautions and
Hypoglycemia
contraindications

Avoid concurrent mefloquine Even if mefloquine is given

due to risk of cardiotoxicity 20–30 days before
Chloroquine-resistant
a. Uncomplicated Falciparum
malaria
Quinine 600 mg orally TDS ×
3–7 days

IV quinine 20 mg/kg
1. Malaria Slow infusion
over 4 h

Diluted in 500 mL of 5%
Followed by 15mg/kg over
dextrose until patient
4 h thrice daily
b. Complicated Falciparum takes orally
malaria and cerebral malaria
Then oral quinine 600 mg TDS
Uses to complete 7 days Rx
With clindamycin,
2. Babesiosis
drug of choice
Monitor BP, blood sugar,
and ECG
3. Nocturnal muscle cramps Low dose 200–300 mg at night

4. Myotonia congenita
 Chemotherapy of malaria 575

67.9 FOLATE ANTAGONIST – PYRIMETHAMINE

Related to trimethoprim

Effective against erythrocytic

forms of all 4 species

Slow acting if given alone

Hence when combined with

sulfadoxine, it acts faster
Dihydrofolate reductase (DHFR)
inhibitor
Long t½ 3–4 days, hence once a
wk administration
2000 times more selective for
Hence prevents conversion of
plasmodial DHFR than
PABA to dihydrofolic acid
mammalian DHFR
Mechanism of action
Hence there is sequential
Sulfadoxine inhibits folic acid
blockade
synthetase (FAS)
of nucleic acid synthesis

Can also be combined with Hence there is synergistic Thus slow development of
dapsone combination resistance

Folate antagonist–
pyrimethamine
Is widespread, due to mutation
Resistance
of DHFR/FAS

Well tolerated

Alternative in uncomplicated
chloroquine–resistant Falciparum
malaria
Megaloblastic anemia
ADR
(high dose)

a. Treatment As an adjunct to quinine

Stevens–Johnson syndrome
(sulfadoxine)
3 tablets single dose
(pyrimethamine 25 mg +
sulfadoxine 500 mg –1 tablet)
1. Malaria

MDR Falciparum malaria

b. Prophylaxis 1–2 tablets/wk

Drug of choice Usually not preferred

Uses

200 mg pyrimethamine bolus

2. Toxoplasmosis followed by 50 mg daily
for 4–6 wks + sulfadoxine 4 g/day

Leucovorin (folinic acid) 10 mg

daily to prevent severe folate
deficiency

3. Pneumocystosis As an alternative to cotrimoxazole

576 Pharmacology mind maps for medical students and allied health professionals

67.10 PROGUANIL (CHLOROGUANIDE) AND ATOVAQUONE

Is a biguanide, a prodrug

Erythrocytic schizontocide

Also a causal prophylactic, i.e.,

against pre-erythrocytic form

Slow onset

Proguanil (Chloroguanide)
Combined with atovaquone, as there
is resistance to monotherapy

Converted to achive cycloguanil,

Mechanism
this inhibits plasmodial DHFR

1. With atovaquone for MDR

Falciparum malaria treatment

Use 2. Causal prophylaxis of

Falciparum malaria

Alternative to pyrimethamine +
Naphthoquinone derivative 3. Prophylaxis of MDR Falciparum malaria
sulfadoxine

Effective against erythrocytic forms

Also effective against T. gondii

and P. jiroveci

Resistance develops with Hence synergistically combined

monotherapy with proguanil

Inhibits mitochondrial electron

transport

Collapse of mitochondrial
membrane potential in parasite
Mechanism of action
This action is potentiated by
proguanil

Also inhibits pyrimidine and ATP

Atovaquone
synthesis in parasite (dependent on
electron transport)

Low oral absorption,

↑ by fatty food

Pharmacokinetics High plasma protein binding

Long t½ of 2–3 days

Vomiting, headache, diarrhea,

ADR MDR Falciparum malaria
abdominal pain, rashes, insomnia

Atovaquone 250 mg + proguanil

Contraindicated in pregnancy 1. Atovaquone + proguanil
100 mg – 4 tablets daily for 3 days

Chemoprophylaxis of Falciparum
malaria – 1 tablet daily
Use

P. jiroveci infections

2. Atovaquone alone Alternative to cotrimoxazole

750 mg BD with food × 3 wks

 Chemotherapy of malaria 577

67.11 ARTEMISININ AND DERIVATIVES

Artemisinin–sesquiterpene
lactone

Source – Artemisia annua plant

Used in China as “Quinghaosu”

for 2000 yrs

Semisynthetic derivatives – better Artesunate, artemether, arteether,

efficacy and pharmacokinetics dihydroartemisinin

Interacts with heme

Generation of free radicals

Mechanism of action
Free radicals damage macromolecules
and parasite membrane

Also inhibits calcium ATPase

However, reports of resistance Hence, avoid monotherapy

Resistance develops less readily
emerging

Potent, rapid acting

Erythrocytic schizontocide
effective against all 4 species
Artemisinin and derivatives
Also effective against
MDR P. falciparum

Also effective against

gametocytes (not liver stage)
Actions
Also effective against
cerebral malaria

Hence recrudescence (resumption of

t½ short symptoms after period of remission)
common

Avoided by combining
with mefloquine

Also effective against T. gondii,

leishmania, and schistosomes

Artemisinin Poor water and oil solubility

Artesunate Water soluble, hence given orally,

rectally, IM, IV

Artemether Lipid soluble, hence given orally,

rectally, IM

Arteether Long-acting, hence given IM

Pharmacokinetics Dihydroartemisinin Water soluble, hence given orally

Oral bioavailability of
artemisinin is poor

Artemisinin and artemether

are prodrugs

Converted to active
dihydroartemisinin

Microsomal enzyme inducers

(Continued)
578 Pharmacology mind maps for medical students and allied health professionals

67.11 ARTEMISININ AND DERIVATIVES (Continued)

Well tolerated

Mild GI symptoms, itching,

bradycardia

Adverse effects Raised liver enzymes

Bone marrow toxicity, hence

anemia, neutropenia,
↓ reticulocyte count

Use with caution during

As it is embryotoxic in animals
pregnancy

Complicated and severe

infections
1. MDR Falciparum malaria

Cerebral malaria
2. Severe malaria during
↑ Efficacy
pregnancy
Rx of chloroquine/MDR
Falciparum malaria
↓ Resistance

Combination (ACT)

Uses ↓ Side effects

↓ Duration of Rx

Uncomplicated MDR
Oral Rx
Falciparum malaria

3. Artemisinin-based
Complicated, severe MDR
combination therapy (ACT) – Parenteral Rx
Falciparum malaria
WHO recommended

Short t½ of artemisinin Compensated by second drug

1. Artesunate + mefloquine

2. Artesunate + sulfadoxine +
pyrimethamine

3. Artesunate + lumefantrine

Regimens

4. Artesunate + amodiaquine

5. Artesunate + pyronaridine

6. Dihydroartemisinin and
piperaquine
 Chemotherapy of malaria 579

67.12 REGIMENS FOR MALARIA CHEMOPROPHYLAXIS

Start 1 wk before
entering endemic area

Chloroquine phosphate
1. Chloroquine-sensitive
500 mg (300 mg base) Continue during stay
areas
orally once weekly

Until 4 wks after leaving

area

Start 1 wk before
entering endemic area

Mefloquine 250 mg salt

(228 mg base) orally once Continue during stay
A. Regimens for malaria weekly
chemoprophylaxis

4 wks after leaving

Or
area

Contraindicated in
pregnancy and children

Start 1 day before entering

endemic area
2. Chloroquine-resistant Doxycycline hyclate
areas 100 mg orally daily

Continue during stay

Or

4 wks after leaving

area

Start 1 day before entering

endemic area

Atovaquone 250 mg +
proguanil 100mg FDC Continue during stay
tablet

Until 1 wk after leaving area

580 Pharmacology mind maps for medical students and allied health professionals
67.13 REGIMENS FOR MALARIA TREATMENT
a. Acute attack of P. vivax,
P. ovale, P. malariae, and
chloroquine-sensitive
P. falciparum
b. For radical cure of P. vivax
and P. ovale
1. Treatment of
uncomplicated malaria
c. For chloroquine-resistant
P. falciparum
d. Multidrug-resistant
P. falciparum
B. Regimens for malaria
treatment
Quinine
2. Severe or complicated
P. falciparum
malaria (cerebral malaria)
Supportive Rx
Quinine-resistant
P. falciparum
Chloroquine 600-mg base
(10 mg/kg) stat 0 h
300-mg base (5mg/kg) at
6 h –1st day
Oral chloroquine Drug of choice
300-mg base 2nd day
Chloroquine (as above)
300-mg base 3rd day
+
Primaquine 15 mg base orally ×
from day 4 daily for 14 days
Quinine sulfate 600 mg orally
TDS x 3–7 days + doxycycline
100 mg BD × 7 days
Or
Clindamycin 600 mg
BD × 7 days
Or
Pyrimethamine 25 mg +
sulfadoxine 500 mg FDC
3 tablets as single oral dose
Mefloquine HCI 750 mg orally
stat, followed 12 h later by
second dose of 500 mg
Artemisinin
Alternatives
Atovaquone + proguanil
Drug of choice 20 mg/kg
Quinine dihydrochloride diluted
in 500 mL of 5% dextrose
Infuse slowly over 3–4 h
Then 10 mg/kg repeated every
8 h until patient takes orally
Then oral quinine sulfate 600 mg
TDS should be substituted
to complete 1 wk therapy
Frequently monitor BP,
blood sugar, ECG
Use either
doxycycline/clindamycin/
Along with quinine orally sulfadoxine +
pyrimethamine (see
above for doses)
Tepid sponging for fever
NaHCO3 for acidosis correction
IV diazepam, if convulsions
10% dextrose to control
hypoglycemia
Blood transfusion to
correct anemia
Artesunate 2 mg/kg IM/IV stat,
followed by 1 mg/kg, then
1 mg/kg for next 4 days
 68
Drugs for amebiasis/pneumocystosis/
leishmaniasis/trypanosomiasis

68.1 INTRODUCTION AND DRUGS – CLASSIFICATION

Amebiasis caused
due to Entamoeba
histolytica

Spreads by fecal
contamination of
food and water

Primary site of
Colon
infection

Secondary site
Introduction Liver, lungs, and brain
of infection

Bloody mucoid stools

Acute amebiasis
and abdominal pain

Anorexia, abdominal
pain, intermittent
Chronic amebiasis
diarrhea, and
constipation

Cyst passers/
Asymptomatic
carriers
Antiamebic
drugs Attain high tissue
concentration following
oral/parenteral
administration
Metronidazole,
tinidazole,
a. Nitroimidazoles
secnidazole,
1. Tissue ornidazole
amebicides
Emetine,
b. Emetine group
dehydroemetine (DHE)

Only extraintestinal
Classification c. 4-aminoquinoline Chloroquine
amebiasis
of antiamebic
drugs
Poorly absorbed after
oral administration

2. Luminal Attain high

a. Amide Diloxanide furoate
amebicides concentration in bowel

Acts on mucosal
b. Halogenated Iodoquinol,
cysts and
hydroxyquinolines iodochlorhydroxyquin
trophozoites

Tetracyclines,
c. Antibiotics paramomycin,
erythromycin

581
582 Pharmacology mind maps for medical students and allied health professionals

68.2 METRONIDAZOLE (MTZ)

Nitroimidazole
E. histolytica, Giardia lamblia, Trichomanas
Highly effective against vaginalis, Balatindum coli
most anaerobic bacteria Also effective against
Dracunculus medinensis

Metronidazole (prodrug)

Enters susceptible microorganisms

Nitro group is reduced by nitroreductase

Mechanism of action Active cytotoxic metabolite formed

Breaks and damages microbial DNA

Kills organism (bactericidal)

Aerobic bacteria lacks

nitroreductase, hence not sensitive
Available for oral, parenteral,
and topical administration

Good oral absorption

Poor protein binding

Pharmacokinetics
Attains therapeutic concentration in Saliva, semen, vaginal secretions,
various body fluids bile, breast, milk, CSF

Metabolized by glucuronide conjugation

Excreted in urine

Rarely severe
Metronidazole
(MTZ) Anorexia, nausea, metallic taste,
Gastrointestinal
epigastric distress, abdominal cramps
ADRs
Allergic Rashes, urticaria, itching, flushing

Dizziness, vertigo, confusion, irritability,

CNS headache, rarely convulsion,
polyneuropathy on long–term use
Nausea, vomiting, abdominal
cramps, headache, flushing
1. Disulfiram-like reaction
Hence avoid alcohol
With alcohol
during Rx
Drug interaction 2. ↑ Effect of warfarin,
Hence ↑ prothrombin time
as it inhibits metabolism

3. ↑ Lithium toxicity As it reduces renal clearance

Drug of choice

1. Amebiasis 400–800 mg TDS × 7–10 days

Does not eradicate cysts

Drug of choice
2. Giardiasis
200 mg TDS × 7 days

Drug of choice

3. Trichomonas vaginalis 200 mg TDS × 7 days

Or 2 g single dose

Intra-abdominal infections
Uses
Pelvic inflammatory disease
Long-acting, better
4. Anaerobic infections
tolerated
Lung abscess
2 g OD × 3 days for
Tinidazole
amebiasis
With 3rd generation cephalosporins
Single dose for other
indications
5. H. pylori infection With clarithromycin + PPI
Secnidazole, Long-acting, 2 g
ornidazole single dose
6. Pseudomembranous colitis Caused by Clostridium difficile

7. Acute ulcerative gingivitis

Alternative to penicillin G
(Vincent’s angina)

8. Dracunculosis Facilitates extraction of guinea worm

9. Acne/skin infections Topical 1% gel

 Drugs for amebiasis/pneumocystosis/leishmaniasis/trypanosomiasis 583

68.3 EMETINE AND DEHYDROEMETINE, DILOXANIDE FUROATE (DF)

Emetine – derived from alkaloid

from lpecac (brazil root)

Dehydroemetine –
semisynthetic

Directly affects
trophozoites, but not cysts

Improper oral absorption Pain at site of injection

Emetine and
Given SC/IM, but not IV Thrombophlebitis
dehydroemetine

ADR Nausea, vomiting, diarrhea

Cardiotoxicity, arrhythmia,
hypotension, cardiac failure

Lesser with DHE

Severe amebiasis, where

Uses
MTZ cannot be used

Direct luminal amebicidal

Split in intestine to
diloxanide and furoic acid

Flatulence, nausea,
ADR
Diloxanide furoate (DF) abdominal cramps

Alone in asymptomatic
cyst passers

Mild intestinal amebiasis

Use
With MTZ to cure
amebiasis

500 mg orally TDS × 10 days

584 Pharmacology mind maps for medical students and allied health professionals

68.4 NITAZOXANIDE, IODOQUINOL, AND QUINIODOCHLOR

Congener of niclosamide
(anthelminthic)

Effective against E. histolytica,

T. vaginalis, G. lamblia

Also effective against

intestinal helminthes like
ascaris and H. nana
Nitazoxanide and its active
metabolite interferes with PFOR
Mechanism
enzyme-dependent electron
transfer in anaerobic metabolism

Good oral absorption

Nitazoxanide

High plasma protein

Pharmacokinetics
bound (99%)

Converted to tizoxamide

ADR Rare, greenish tinge to urine

Giardiasis

Use
Diarrhea due to cryptospora,
C. parvum, H. nana, Ascaris,
T. trichura, and E. vermiculoris
8-hydroxyquinoline

Directly acting luminal

amebicides

Mechanism – not known

Iodine present in these agents
Iodoquinol and
results in thyroid enlargement,
quiniodochlor
pruritus, skin rashes
ADR
Long-term use can cause
neurotoxicity like subacute Irreversible loss of vision
myelo-optic neuropathy (SMON)

Asymptomatic amebiasis

Use
Hence DF (Rx for 10 days)
Requires 20 days treatment
safe and preferred
 Drugs for amebiasis/pneumocystosis/leishmaniasis/trypanosomiasis 585

68.5 PAROMOMYCIN, TETRACYCLINE, AND CHLOROQUINE

Aminoglycoside, given orally

Paromomycin Poorly absorbed from gut

Acts as intestinal/
luminal amebicide

Older agents like

chlortetracycline used

Not absorbed well as it

inhibits intestinal flora
Tetracycline
Breaks symbiosis between
intestinal flora and amebae

Used as adjuvants in
chronic cases

Completely absorbed from

small intestine

Highly concentrated in liver

Chloroquine Direct toxicity to trophozoites

Used in hepatic
amebiasis
Not effective against colonic
amebae
Alternative to MTZ

Use

300 mg × 21 days

Combined with luminal

amebicide (DF)
586 Pharmacology mind maps for medical students and allied health professionals

68.6 TREATMENT OF AMEBIASIS, TREATMENT OF PNEUMOCYSTOSIS

Luminal amebicide
(or) Tetracycline
is used
1. Asymptomatic
carriers
Diloxanide furoate
(or) Iodoquinol
50 mg TDS × 10 days

(or) Paromomycin
Metronidazole/
tinidazole + luminal
agent
Or tinidazole 2 g
OD × 3 days
Treatment of
2. Intestinal Metronidazole 400–800
amebiasis
amebiasis mg TDS × 7–10 days
Or secnidazole 2 g
single dose
+ Diloxanide furoate
500 mg TDS × 7–10 days

+ Dehydroemetine if
Rx Similar to intestinal
patient not
amebiasis
responding to MTZ
3. Severe intestinal and
+ Chloroquine
extraintestinal amebiasis Similar to severe
phosphate orally
intestinal amebiasis
500 mg BD x 2 days,
4. Hepatic amebiasis
Later 500 mg OD ×
3 wks
Features of both
Pneumocystis jiroveci
protozoa and fungi

Pneumocystosis in
Caused by P. jiroveci
humans

Pneumocystosis in
Treatment of Caused by P. carinii
animals
pneumocystosis
High oral dose
Causes opportunistic
infections like pneumonia 1. Cotrimoxazole
in patients of AIDS
Trimethoprim 20 mg/kg +
sulfomethaxazole 100 mg/kg daily

Treatment
4 mg/kg daily for 14 days
2. Pentamidine
parenterally

3. Atovaqone Alternative to cotrimoxazole

 Drugs for amebiasis/pneumocystosis/leishmaniasis/trypanosomiasis 587

68.7 TREATMENT OF LEISHMANIASIS

Caused due to Leishmonia

Kala-azar/visceral leishmaniasis
donovani

Oriental sore L. tropica

Treatment of Mucocutaneous leishmaniasis L. braziliensis

leishmaniasis Sodium stibogluconate
Infection transmitted by bite
1. Antimony compounds
of female sandfly phlebotomus
Meglumine antimonite
Drugs used
2. Diamidines Pentamidine
Sodium stibogluconate Amphotericin B,
3. Miscellaneous ketoconazole, miltefosine,
Pentavalent antimonial allopurinol, paromomycin

Most effective in kala–azar

1. Antimony Also effective in mucocutaneous

compounds and cutaneous leishmaniasis Metallic taste, nausea,
vomiting, diarrhea
Mechanism unknown
Myalgia, arthralgia, headache
Dose – 4% solution 10–20
mg/kg IM/IV x 20 days
Pain at site of injection
ADR
Hematuria, jaundice

Sudden death due to shock

Arrhythmias, hence requires

ECG monitoring
Aromatic diamidine
Liberates histamine
Effective against L. donovani, trypanosomes,
P. jiroveci, and some fungi Flushing, pruritus, rashes,
hypotension, tachycardia,
Given IM vomiting, diarrhea
Hepatotoxicity
ADR
Renal impairment
2. Pentamidine
ECG changes

Diabetes mellitus
Alternative to sodium
1. Visceral leishmaniasis
stibogluconate

Sleeping sickness
(or) Combined
Uses 2. Trypanosomiasis
with suramin
Alternative to suramin
Chemoprophylaxis
As alternative to
3. Pneumocystosis
cotrimoxazole
Tried where antimonials
Amphotericin B
are ineffective
Effective in cutaneous ∴
It inhibits ergosterol
Ketoconazole
leishmaniasis synthesis in leishmania
Its metabolite inhibits
leishmania protein synthesis
Allopurinol
Used with antimonials

Miscellaneous Aminoglycoside for all

forms of leishmaniasis
Paromomycin
Used alone or with antimonials

First oral drug for leishmaniasis

Highly effective against visceral
and cutaneous leishmaniasis
Effective against leishmaniasis
Miltefosine
resistant to stibogluconate
Vomiting, diarrhea, elevated
ADR
liver enzymes and creatinine
Contraindicated in pregnancy
588 Pharmacology mind maps for medical students and allied health professionals

68.8 DRUGS FOR DERMAL LEISHMANIASIS (ORIENTAL SORE),

TREATMENT OF TRYPANOSOMIASIS

Sodium stibogluconate
injected around sore

Drugs for dermal

2 mL solution containing
leishmaniasis
200 mg infiltered
(Oriental sore)

Alternative – paramomycin
ointment topically

Caused by protozoa of
genus Trypanosoma

T. gambiense, African trypanosomiasis

T. rhodesiense (sleeping sickness)

South American
T. cruzi
trypanosomiasis

Suramin, pentamidine,
Drugs used melarsoprol, eflornithine,
nifurtimox, benznidazole

Drug of choice for

early stages

Does not cross BBB, not

used in later stages
Treatment of
trypanosomiasis
Given IV, has high plasma
Suramin sodium protein binding, hence present
in plasma for nearly 3 months

Also effective in eradicating

adult forms of onchocerca
volvulus

High incidence, causes vomiting,

shock, loss of consciousness,
ADR
neuropathy, hemolytic anemia,
agranulocytosis

Used as alternative in CNS

Eflornithine
trypanosomiasis

Preferred in later stages of

Melarsoprol trypanosomiasis associated with
meningitis and encephalitis

Nifurtimox and Useful in Chagas disease

benznidazole (American trypanosomiasis)
 69
Antiviral drugs

69.1 ANTIVIRAL DRUGS – CLASSIFICATION

Acyclovir, ganciclovir,
1. Antiherpes drugs valacyclovir, foscarnet,
idoxuridine, vidarabine

Lamivudine, interferon,
2. Antihepatitis drugs
ribavirin, tenofovir

Amantadine,
3. Anti-influenza drugs rimantadine,
oseltamavir, zanamavir
Classification of
Antiviral drugs
antiviral drugs
a. Nucleoside reverse Zidovudine (AZT),
transcriptase stavudine, lamivudine,
–
inhibitors (NRTI) didanosine, zalcitabine

b. Non-nucleoside
Nevirapine, efavirenz,
reverse transcriptase
delavirdine
inhibitors (NNRTI)

Saquinavir, ritonavir,
4. Antiretroviral drugs c. Protease inhibitors (PI) indinavir, lopinavir

d. Fusion inhibitors Enfuvirtide, maraviroc

e. Integrase inhibitors Raltegravir

589
590 Pharmacology mind maps for medical students and allied health professionals

69.2 ANTIHERPES AGENT – ACYCLOVIR

Diseases associated with herpes

infections

a. HSV-1 Herpes labialis, herpes esophagitis

b. HSV-2 Genital herpes, herpes encephalitis

Antiherpes agents
c. VZV Chicken pox, varicella zoster

d. Epstein–Barr virus (EBV) Infectious mononucleosis

Retinitis, pneumonia, encephalitis,

e. Cytomegalovirus (CMV)
gastroenteritis

Synthetic purine nucleoside analog

Prodrug
Effective against HSV-1, HSV–2,
and less against VZV Selectively taken up by
herpes virus-infected cells
Mechanism of action
Converted to active triphosphate

Inhibits DNA synthesis and viral

replication

Production of viral kinases

Mechanism of resistance
Altered viral DNA polymerases

Poor oral absorption

Bioavailability 10%–15%

Good tissue distribution

Pharmacokinetics
Good concentration in CSF and
Acyclovir
aqueous humor

Excreted by kidneys

Administered orally, IV, topical

Well tolerated

Nausea, vomiting, diarrhea,

headache
Adverse effects
Tremors, confusion,
High-dose
disorientation, convulsions

Topically Burning and irritation

Oral acyclovir for primary infections,

1. Genital herpes
recurrent infections (high-dose)

2. Herpetic encephalitis IV acyclovir is drug of choice

3. Herpes simplex keratitis Topical

Uses
4. Mucocutaneous HSV In immunocompromised patients

5. Herpetic whitloe (nail–bed

Orally for prevention and Rx
infection)

6. Chicken pox and herpes zoster Orally, IV in immunocompromised

 Antiviral drugs 591

69.3 OTHER ANTIHERPES DRUGS

Prodrug of acyclovir

Valacyclovir Converted to acyclovir

Better bioavailability

Prodrug of penciclovir
Famciclovir
Used orally

Active metabolite of famciclovir

Used topically for recurrent

Penciclovir
herpes labialis and VZV infections

Also administered IV

Guanosine analog

More effective in CMV infections

than acyclovir

More toxic than acyclovir Severe CMV infection Retinitis, pneumonia, etc. in
Ganciclovir immunocompromised patients
Reserved for treatment of Also used for prevention of CMV
disease in organ transplantation

ADR Myelosuppression, gonadal toxicity

Thymidine analog

Acts against DNA viruses

Inhibits their viral replication

Idoxuridine
Used Topically for HSV keratoconjunctivitis

ADR Too toxic for systemic use

Local irritation, itching, pain,

Topical
eyelid, edema
Trifluridine Used Topically in HSV eye infections
Suppresses viral replication by
preventing viral entry in cell
Docosanol
Used Topically for orolabial herpes

Pyrophosphate analog

Directly inhibits viral DNA

polymerase, RNA polymerase,
reverse transcriptase
CMV retinitis as alternative to
Given IV
ganciclovir
Foscarnet
Use CMV colitis and esophagitis

Acyclovir-resistant herpes infections

ADR Nephrotoxicity

Injected intravitreally in severe

Fomivirsen
CMV retinitis

Cytidine analog
Cidofovir
EBV, HPV (human herpes virus, VZV,
Use
CMV, papilloma virus), adenovirus
592 Pharmacology mind maps for medical students and allied health professionals

69.4 ANTIINFLUENZA VIRUS AGENTS

Inhibit replication of
influenza A virus

Inhibit uncoating of viral

RNA

Good oral absorption

Good concentration in
nasal secretions

Amantadine and
Well tolerated Nausea, vomiting, diarrhea
rimantadine

Dizziness, insomnia,
ADR
difficulty in concentration

Rimantadine more active

and longer acting than Ankle edema
amantadine

i. Treatment of influenza A

Uses ii. Prophylaxis influenza A

Antiinfluenza virus
agents
Inhibit viral neuraminidase
It ↑ the
∴
essential for release iii. Parkinsonism
release of dopamine
of daughter virions

Inhibit viral replication

Effective against both

influenza A and B

Should be administered
within a few hours of
onset of symptoms
Oseltamavir and
zanamavir
Given orally, well absorbed

Nausea, vomiting, diarrhea,

abdominal discomfort –
ADR
should not be given in
children <1 yr

Zanamavir also May cause respiratory

administered by inhalation distress

Prevention and treatment Avian influenza

of influenza A (bird flu)
Use
Prevention and treatment
of influenza B
 Antiviral drugs 593

69.5 ANTIHEPATITIS DRUGS

Adefovir dipivoxil is a prodrug

Converted to adefovir by blood and intestinal esterase

Adefovir converted to adefovir diphosphate by viral kinases This inhibits viral DNA polymerase
It is incorporated in viral DNA,
1. Adefovir
hence causing DNA chain termination
Remains in cells for 18 h, hence given once daily

ADR Headache, diarrhea, abdominal pain, nephrotoxicity

Orally in treatment of chronic HBV
Use
infection, lamivudine-resistant HBV patients
Guanosine analog

Inhibits DNA polymerase

2. Entecavir
Given on empty stomach

Use Chronic HBV infection

Broad-spectrum antiviral
Influenza A, influenza B, respiratory syncytial
Spectrum
virus (RSV) and many other DNA and RNA viruses
3. Ribavirin
As aerosol for RSV bronchiolitis in children

Use Severe influenza – in immunocompromised patients

Are cytokines produced by host
Measles
cells in response to viral infections
Immunomodulators and antiproliferative

Types – α, β, and γ

α and β - produced in response to viral infections

Antihepatitis drugs

γ produced by T lymphocytes in response

to antigens and some cytokines
Given IM/IV/SC

Prevents replication of many DNA and RNA viruses

Binds to receptors and activates JAK-STAT pathway
4. Interferons (IFN) Mechanism of action
Hence stimulates synthesis of certain protein
synthesis which inhibit viral protein synthesis
Myelosuppression, hypotension, arrhythmias

ADR Alopecia, headache, arthralgia

Confusion, sedation,
Neurotoxicity
rarely seizures
May be combined
1. Chronic hepatitis B and C
with ribavirin
2. Kaposi sarcoma in AIDS patients

3. Genital warts due to papilloma virus Injected into lesion

Use
4. Hairy cell leukemia
In immunocompromised
5. HSV, CMV, herpes zoster infections
patients
6. Rhinovirus cold Intranasally

Adenosine analog
Tenofovir
Given for chronic hepatitis resistant to lamivudine

Thymidine analog
Telbivudine
Inhibits DNA polymerase in hepatitis B
5. Others
Palivizumab Monoclonal antibody for RSV in children

Stimulates cytokines, interferon α , TNF α and interleukins

Imiquimod Applied topically thrice a week for 16 wks

Immunomodulator for
Used as an condyloma acuminata,
actinic keratoses
594 Pharmacology mind maps for medical students and allied health professionals

69.6 ANTIRETROVIRAL DRUGS – INTRODUCTION AND CLASSIFICATION

Acquired immunodeficiency
syndrome (AIDS) results from
human immunodeficiency
virus (HIV), a retrovirus

Two types HIV-1 and HIV-2

Suppress HIV replication,

Goal of treatment improve prognosis,
prolong survival

Combination of drugs used Highly active antiretroviral

in HAART i.e., therapy

Reduces HIV replication

Introduction
↓ HIV plasma
HAART advantages
RNA levels

Improves survival

Adverse effects

HAART drawbacks Relapse

Antiretroviral drugs
Resistance occurs easily as
Resistance
HIV has high mutation rate

a. Nucleoside reverse Zidovudine (AZT), stavudine,

transcriptase inhibitors lamivudine, didanosine,
(NRTI) zalcitabine

b. Non-nucleoside reverse
Nevirapine, efavirenz,
transcriptase inhibitors
delavirdine
(NNRTI)

Classification of Saquinavir, ritonavir,

Antiretroviral drugs c. Protease inhibitors (PI)
anti-retroviral drugs indinavir, lopinavir

d. Fusion inhibitors Enfuvirtide, maraviroc

e. Integrase inhibitors Raltegravir

 Antiviral drugs 595

69.7 NUCLEOSIDE REVERSE TRANSCRIPTION INHIBITORS (NRTIs)

Zidovudine, Lamivudine, Stavudine,

Didonosine, Zalcitabine

Enter HIV-infected cells

Converted to active triphosphate

forms by cellular kinase

Competitively inhibit HIV reverse

transcriptase (RT)

Gets incorporated in growing viral

DNA

Causes premature DNA chain

Anemia, granulocytopenia,
termination, hence synthesis
myopathy, peripheral neuropathy,
and pancreatitis
Common ADRs
Lactic acidosis and hepatic
steatosis are rare but fatal

First antiretroviral drug for Rx of

HIV infection

Nucleoside reverse transcription Prototype drug

inhibitors (NRTIs)
Effective against HIV-1 and
HIV-2

Thymidine analog

Protects uninfected cells, no

effect on HIV infected cells

Good oral absorption

Metabolized by glucuronidation

Crosses placenta and BBB

Bone marrow suppression
Secreted in milk also
Anemia Rx with erythropretin
ADR
Granulocytopenia Rx with
G-CSF/GM-CSF
Zidovudine (azidothymidine, AZT)
Neurotoxicity (with high Both metabolized by
doses), insomnia, myopathy glucuronidation

Paracetamol competes and interferes

1. AZT with paracetamol –
with glucuronide conjugation of AZT

Hence ↑ AZT
concentration and toxicity

2. Zalcitabine + lamivudine – Antagonize each other

Drug interactions
Azoles inhibit microsomal enzymes,
3. Azoles + AZT
hence ↑ AZT toxicity

Not combined together, they

∴
4. AZT + stavudine compete for intracellular–
phosphorylation

– ↑ Pancreatitis and
5. Zalcitabine + didanosine
peripheral neuropathy

↑ Survival

↓ Opportunistic infection
1. Drug of choice in AIDS
↑ Weight

Uses Delays disease progression

(in early cases)

2. Given during pregnancy, Reduces risk of vertical transmission,

continued in newborn for 6 wks but nevirapine preferred
596 Pharmacology mind maps for medical students and allied health professionals

69.8 OTHER NRTIs

Adenosine analog

Hence given on empty

Didanosine Destroyed by gastric acid
stomach

Food ↓ absorption

Cytosine analog

Bioavailability 90%

Zalcitabine
t½ 8 h, given thrice
daily

ADR Peripheral neuropathy

Cytidine analog

Also effective against HBV

Lamivudine

Good oral absorption

Insomnia, fever, headache,

ADR
diarrhea

Cytosine analog of
lamivudine

Good bioavailability (90%)

Emtricitabine

Intracellular t½ >24 h Hence once daily dosing

Rarely pigmentation of
ADR
palms and soles

Adenosine analog

Converted to tenofovir
diphosphate
Tenofovir
Hence causes chain
Incorporated into RT
termination

Alternative in combination
Used as
with other anti-HIV drugs

69.9 PROTEASE INHIBITORS (PIs)
e.g., Indinavir, ritonavir,
saquinavir, nelfinavir
Saquinavir first agent in this
group to be used in Rx
Mechanism of action
Pharmacokinetics
Protease inhibitors (PIs)
Adverse effects
Uses
Nausea, headache
Nephrolithiasis,
Indinavir
hyperbilirubinemia
Good hydration reduces
nephrolithiasis
Diarrhea is common,
Nelfinavir
↑ blood sugar, lipid levels
Ritonavir Enzyme inhibitor
Antiviral drugs 597
Competitively block enzyme
HIV protease Hence PIs prevent assembly and
maturation of virus before their
HIV protease is essential for release from infected cells
production of mature virions
and for viral infectivity
Hence, immature, non-infectious
virus particles are formed
Well absorbed orally (except
saquinavir)
High plasma protein binding
Potent microsomal enzyme
inhibitor, hence many drug
interactions
Redistribution of fat in back
and abdominal regions
Skeletal muscle wasting
Perioral paresthesia
Hyperlipidemia
GI disturbances
Insulin wasting
Taste perversion
In combination with other
antiretrovirals
Hence ↑ bioavailability
of other PIs
Hence reduce the dose of
other PIs (when combined)
598 Pharmacology mind maps for medical students and allied health professionals

69.10 NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs)

e.g., Nevirapine, efavirenz,

Binds directly and inhibits RT
delavirdine

Does not get converted to

Mechanism of action
triphosphates

Effective only against HIV-1, but

not HIV-2

GI disturbances

Adverse effects Skin rashes, fever, pruritus

Headache, confusion, insomnia,

CNS disturbances
bad dreams, amnesia

>90% bioavailability

High CSF concentrations

Long t½

Fatty meal ↑ absorption,

hence toxicity
Nevirapine
Hence taken on empty stomach Allergic reactions ranging from skin
rashes to Stevens–Johnson syndrome,
toxic epidermal necrolysis (TEN),
ADR fulminant hepatitis
Non-nucleoside reverse
transcriptase inhibitors (NNRTIs)
HIV-1 infection, in combination
with other drugs

Uses During labor and in new born to

vertical transmission

2 mg/kg single dose within 3 days

High plasma protein binding
of birth of newborn

Microsomal enzyme inhibitor

Delavirdine
ADR Skin rash is most common

Rx of HIV-1 infection as
Use
combination drug

99% plasma protein binding

Long-acting, hence once daily dose

Efavirenz
Teratogenic in animals, hence it is
contraindicated in pregnancy

with other antiretrovirals for HIV-1

Used
infection

Hence ↓ efficacy of oral

Nevirapine is enzyme inducer
contraceptive

Hence ↑ plasma levels of

Drug interactions Delavirdine is enzyme inhibitor
PI like indinavir

Efavirenz is enzyme inducer Induces its own metabolism

 Antiviral drugs 599

69.11 ENTRY INHIBITOR

Recent introduction

Hence inhibits binding of virus

Binds to glycoprotein on virus
to host cell membrane

Thus, prevents entry of virus

Hence reduces transmission
into cell

1. Fusion inhibitor – enfuvirtide Route – SC twice daily

Metabolized by hydrolysis,
microsomes not involved

Local reaction, pneumonia,

ADR
lymphadenopathy

In patients not responding to

Use
standard antiretroviral drugs

CCR5 is coreceptor

Involved in fusion and entry of

virus in CD4 cells

Maraviroc selectively binds to Hence blocks entry of virus

CCR5 into cell
Entry inhibitor
2. CCR5 receptor antagonist –
Effective orally, metabolized by
maraviroc
microsomal enzymes, and
excreted by GIT
Diarrhea, sleep disturbances

ADR
Cough, myalgia, arthralgia,
respiratory infections,
raised liver enzymes

In patients not responding

Use
to standard HAART drugs

Integrase is an enzyme
necessary for replication of HIV-1
and 2 viruses

Raltegravir binds to integrase and

prevents integration of HIV-DNA
into chromosomes of host cells

Integrase inhibitors – Effective orally, metabolized by

raltegravir non-CYP450 system

Nausea, diarrhea, dizziness,

ADR
headache

HIV-1 resistant to other

Use
drugs
 70
Antifungal drugs

70.1 CLASSIFICATION OF ANTIFUNGAL DRUGS

Polyene Amphotericin B,
antibiotics nystatin
1. Antifungal
antibiotics
Others Griseofulvin

2. Antimetabolites Flucytosine (5-FU)

Clotrimazole,
Imidazoles miconazole,
ketoconazole
3. Azoles
Fluconazole,
Triazoles
itraconazole

Antifungal Classification of
drugs antifungal drugs
Terbinafine

4. Miscellaneous
Echinocandins Caspofungin,
(pneumocandins) micafungin

Tolnaftate, benzoic acid,

5. Topical salicylic acid, selenium
sulfide, ciclopirox olamine

600
 Antifungal drugs 601

70.2 ANTIFUNGAL ANTIBIOTICS – AMPHOTERICIN B (AMB)

Source Streptomyces nodosus

Polyene antibiotic containing

Wide
many double bonds
Inhibits Candida albicans, Histoplasma capsulatum,
Spectrum Cryptococcus neoformans, Coccidioides,
Aspergillus, Blastomyces dermatidis, Leishmania
Fungistatic at low and fungicidal at
high concentration
Binds to ergosterol in fungal cell
membrane

Forms pores in cell membrane

Mechanism of action
Hence there is leakage of cell contents
and cell death

High selectivity for fungal ergosterol

than human cholesterol

Not absorbed orally, insoluble in

water, given IV

90% plasma protein binding

Long t½–15 days

Dispensed as colloidal suspension

Pharmacokinetics
for IV use

Lipid formulation less likely to bind to

1. Amphotericin B (AMB)
human cells, hence less toxic
∴
Lipid acts on reservoir for amphotericin
and avoids its binding with human cells

Formulation is expensive

Oral paracetamol and IV

Fever, chills, muscle spasms, vomiting, dyspnea, hydrocortisone given as
headache, and hypotension following IV infusion prophylaxis, can reduce the
intensity of side effects

Injected slowly to avoid arrhythmias Common

Associated with renal

tubular acidosis
Adverse effects
Renal impairment (nephrotoxicity) K+ and Mg+ loss

Anemia as it inhibits Dose and duration

erythropoietin production dependent

Avoid concurrent
Bone marrow depression
nephrotoxic drugs

Drug of choice

1. Life-threatening fungal infections Aspergillosis, blastomycosis,

cryptococcosis, coccidioid-
omycosis, histoplasmosis,
mucormycosis, paracoccidio-
idomycosis, sporotrichosis

Bladder irrigation with

2. Candida cystitis
amphotericin B
3. Prevent relapse of cryptococcosis
Uses
and histoplasmosis in AIDS patients

4. Fungal infections of GIT Given orally

5. Topically in candidiasis 3% lotion, cream, ointment

Kala-azar, mucocutaneous
6. Leishmaniasis
leishmaniasis
602 Pharmacology mind maps for medical students and allied health professionals

70.3 NYSTATIN, GRISEOFULVIN

Source Streptomyces noursei

Similar to amphotericin B
Nystatin
However, too toxic for
Hence used topically
systemic use
5 mL oral suspension
Oral thrush, vaginal swished in mouth and
Use
candidiasis then swallowed to treat
candida of esophagus
Source Penicillin griseofulvum

Fungistatic

Effective against superficial

dermatophytosis Binds to microtubular protein
Trichophyton, microsporum, in nucleus
epidermophyton
Disrupts mitotic spindle
Administered orally
Inhibits mitosis
Mechanism of action
Deposited in newly formed
skin

Binds to keratin

Protects skin from getting

newly infected

Poorly water soluble

Griseofulvin Low bioavailability

Pharmacokinetics
Micronization and fatty
food ↑ bioavailability

Microsomal enzyme inducer

Allergic reaction, hepatitis,

Adverse effects
neurotoxicity
Phenobarbitone reduces Hence there is therapeutic
absorption failure
↑ Warfarin
Drug interactions
metabolism

Alcohol intolerance

Orally in superficial
dematophytosis
Preferred for larger area
infection

1 g daily
Uses
Duration depends on site
of infection

Varies from 3 wks to 1 yr

Nail infections 6–12 months

treatment
 Antifungal drugs 603

70.4 ANTIMETABOLITES

Fluorinated
pyrimidine

Effective against
Cryptococcus
neoformans and some
stains of candida

Prodrug, converted
to 5-fluorouracil
(5-FU)

5-FU inhibits DNA Human cells cannot Hence toxic only

synthesis activate flucytosine to fungal cells

∴
Amphotericin
B damages fungal
Flucytosine + cell membrane
amphotericin B/
2. Antimetabolites Flucytosine azoles – synergistic Hence it assists
penetration of
Good oral absorption, flucytosine
wide tissue distribution
including CSF

Excreted by kidneys

Bone marrow
ADR depression, GI
disturbances

Cryptococcal meningitis
along with
amphotericin B

Systemic candidiasis
Uses along with
amphotericin B

Chromoblastomycosis
with itraconazole
604 Pharmacology mind maps for medical students and allied health professionals

70.5 AZOLES

Effective orally and

less toxic

Triazoles are more selective

on fungal sterol synthesis
than imidazoles

Triazoles are longer acting

Ketoconazole (oral and topical),

Imidazoles clotrimazole (topical),
miconazole (topical)

Triazoles Fluconazole, itraconazole

Broad spectrum

Spectrum
Blastomyces dermatidis, candida,
Cryptococcus neoformans,
Histoplasma capsulatum,
Imidozoles coccidoides, other deep mycoses
3. Azoles
and triazoles
Inhibits fungal
cytochrome P450 enzyme
lanosine 14 demethylase

Converts
lanasterol to ergosterol

Inhibits ergosterol and

Mechanisms of action important constituents of
fungal cell membrane

Inhibits fungal
replication

Also interferes with some

other fungal enzymes

Common in AIDS
patients
Resistance
Due to altered enzyme
14α demethylase
 Antifungal drugs 605

70.6 KETOCONAZOLE

Food and acidic

pH ↑ absorption

Gynecomastia, infertility, ∴
It inhibits
First oral azole Potent enzyme ↓ libido,
adrenal and
available inhibitor azoospermia, menstrual
gonadal synthesis
irregularities, hypertension

ADR Rarely fatal hepatotoxicity

Antacids, H2 blockers, Nausea, vomiting, headache,

PPIs ↓ absorption allergic reactions

Rifampicin and phenytoin

Ketoconazole Drug interactions ↑ its metabolism,
hence ↓ its efficacy

↑ Arrhythmogenic
potential of terfanadine,
astemizole by inhibiting
their metabolism

Mucocutaneous candidiasis,
dermatophytosis

∴
It inhibits steroid
Uses Cushing’s syndrome
synthesis

But not preferred due to

Deep mycoses
toxicity
606 Pharmacology mind maps for medical students and allied health professionals

70.7 FLUCONAZOLE

Fluorinated
triazole

Water soluble

Good absorption,
wide tissue distribution
including CSF

t½ 25 h

Given orally/
parenterally
Fluconazole
GI disturbances,
headache, rashes

ADR
Less drug interaction,
∴
mild enzyme
inhibition

1. Cryptococcal After
meningitis amphotericin B

2. Coccididal Drug of choice,

meningitis in AIDS also for prophylaxis

Oropharyngeal,
esophageal candidiasis,
Uses 3. Candidiasis Given IV
mucocutaneous candidiasis
candidemia in ICU patients

But due to high cost,

4. Tinea infections
not preferred

Itraconazole preferred as it
5. Histoplasmosis
has better efficacy
 Antifungal drugs 607

70.8 ITRACONAZOLE

Most potent azole

Given orally, food

↑ its absorption,
can be given as IV

No effect on
microsomal enzymes

No effect on steroid Hence preferred

synthesis over ketoconazole

99% plasma protein

binding

t½ 30–36 h
Itraconazole

Headache, dizziness,
Does not reach CSF
GI upset, allergy

ADR Hepatitis

Hypokalemia

1. Systemic mycoses Without meningitis

Use
Oral solution swished
2. Orophangeal,
in mouth before
esophageal
swallowing on empty
candidiasis
Contraindicated in stomach
pregnancy
608 Pharmacology mind maps for medical students and allied health professionals

70.9 TOPICAL AZOLES

e.g., Clotrimazole,
miconazole

They have a poor skin

absorption

Used topically in dermotophytic

infections (ringworm) and
Topical azoles
mucocutaneous candidiasis
(clotrimazole troche)

Miconazole better
efficacy

Terconazole,
Others econazole, sertaconazole,
oxiconazole

70.10 MISCELLANEOUS – TERBINAFINE

Synthetic antifungal

Effective against
dermatophytes and
candida

Orally effective fungicidal

Concentrated in skin
4. Miscellaneous Terbinafine
like griseofulvin

Inhibits enzyme squalene

epoxidase

This enzyme essential for

synthesis of ergosterol

GI disturbances,
ADR
headache, rashes
 Antifungal drugs 609

70.11 ECHINOCANDINS OR PNEUMOCANDINS

Recently introduced

Fungicidal agents

e.g., Caspofungin,
micafungin, amidulafungin

Effective against candida,

aspergillus, and strains
resistant to azoles

Caspofungin also effective

against Pneumocytis
jiroveci Inhibits synthesis of glucose
polymer β glucan, an essential
component of fungal cell wall
Mechanism
Echinocandins or
pneumocandins
Hence causes fungal cell lysis

∴
Route of administration IV, not absorbed orally

t½ – caspofungin 13 h,
amidulafungin 24–48 h
Histamine release on
rapid infusion
ADR

Thrombophlebitis

1. Prophylaxis and treatment

of candida infections
Use
2. Invasive aspergillosis not
responding to amphotericin B
610 Pharmacology mind maps for medical students and allied health professionals

70.12 TOPICAL ANTIFUNGALS AND NEWER AGENTS

Salicylic acid, benzoic acid,

tolnaftate, selenium sulfide,
ciclopirox olamine, naftifine,
and others (nystatin, clotrimazole,
miconazole, and terbinafine)

Effective against candida,

5. Topical antifungals Ciclopirox olamine dermatophytes,
Malassezia furfur

Used for tinea versicolor

Selenium sulfide caused due to
M. furfur, dandruff

Nikkomycins Inhibit chitin synthesis

6. Newer agents
Inhibit protein synthesis by
blocking elongation factor 2

Sordarins

Effective against candida,

Pneumocystis jiroveci

70.13 DRUGS USED IN SUPERFICIAL MYCOSES

Topical Azole/terbinafine

1. Ringworm

Oral Terbinafine/itraconazole/
griseofulvin

Topical Amphotericin B/azole/

nystatin/ciclopirox
2. Cutaneous

Oral Fluconazole
Drugs used in
superficial mycoses
Topical Azole/nystatin/
amphotericin B
3. Oropharyngeal

Oral Itraconazole

Topical Azole/nystatin

4. Vaginal

Oral Fluconcozole
 Antifungal drugs 611

70.14 DRUGS FOR SYSTEMIC FUNGAL INFECTIONS

1. Aspergillosis (invasive) Voriconazole

Amphotericin B/
2. Blastomycosis
itraconazole

Fluconazole/
3. Candidiasis
voriconazole

Amphotericin B ±
4. Coccidioidomycosis
flucytosine
Drugs for systemic
fungal infections
Intraconazole/
5. Histoplasmosis
amphotericin B

Amphotericin B/
6. Mucormycosis
flucytosine

7. Paracoccidioidomycosis Itraconazole

8. Sporotrichosis Itraconazole
 71
Anthelmintics

71.1 MEBENDAZOLE

Broad-spectrum
anthelmintic

Cures roundworm,
hookworm, pinworm
Common in developing and Strongyloides
countries

Eggs and larvae also

People with poor destroyed
hygiene – common

Introduction Bind to B-tubulin and

Dead parasites slowly
inhibit synthesis of
expelled from gut
Vermicidal-kills worms microtubules

Microtubules essential for

Mechanism of action several metabolic
Vermifuge-promotes processes
worm expulsion

Also inhibit glucose

e.g., Mebendazole, uptake
albendazole,
thiabendazole (toxic)
Benzimidazoles
Poorly absorbed from
gut (20%)
Mebendazole
Pharmacokinetics

Fatty food absorption

Well tolerated

Abdominal pain, diarrhea

ADR
Dizziness, alopecia,
granulocytopenia
(high-dose)

Migration of roundworms,
tapeworm, trichuriasis,
hydatid disease

Roundworm, hookworm,
tapeworm, trichuriasis,
hydatid cyst
Use

Special value in multiple

worm infestation

612
 Anthelmintics 613

71.2 ALBENDAZOLE, PYRANTEL PAMOATE, PIPERAZINE CITRATE

Congener of mebendazole Better tolerated

Actions similar to mebendazole Effective in single dose

but with certain advantages for most infestations

Superior to mebendazole in
Advantages hookworm, threadworm, hydatid
disease, and neurocysticercosis

Also effective against T. vaginalis,

G. lamblia, and W. bancrofti

Active metabolite 100 times

concentration than mebendazole

Rapid absorption, fatty

food ↑ absorption

Hence given on empty

stomach for intestinal worms
Pharmacokinetics
But given with fatty food
for tissue parasites
Albendazole
Penetrates well in tissues,
including hydatid cyst

Minor, well tolerated, nausea, diarrhea,

abdominal pain, allergic reactions
Adverse effects
Jaundice, fever, weakness, alopecia,
granulocytopenia (high dose)
Contraindicated in
pregnancy Repeat dose after 2 wks in
1. Drug of choice for roundworm,
hookworm, pinworm, trichuriasis 400 mg single dose pinworm infestation to prevent
reinfection from ova

2. Trichinosis, tapeworm, and 400 mg daily × 3 days

strongyloidosis

Drug of choice

Depends on number
3. Neurocysticercosis 400 mg BD × 8–30 days
of cysts

Uses Prophylactic steroids to

prevent immunological
reactions of dead parasite

Drug of choice
4. Hydatid disease
400 mg BD x 4 wks Repeat after 2 weeks

Albendazole
400 mg + DEC (6mg/kg)
5. Filariasis
Or ivermectin Then continued once
(0.3 mg/kg) As single dose a year for 5–6 yrs

(Continued)
614 Pharmacology mind maps for medical students and allied health professionals

71.2 ALBENDAZOLE, PYRANTEL PAMOATE, PIPERAZINE CITRATE (Continued)

Effective against roundworms,

hookworms, pinworms
Hence persistent
depolarization and
Stimulates nicotinic
receptors in worm
Spastic paralysis
Expulsion of paralyzed
Pyrantel pamoate
worms

Well tolerated

Single dose of 250 mg

curative

Effective against
roundworm and pinworm

Competitively blocks Hence there is flaccid

action of Ach contractions paralysis and expulsion

Piperazine citrate Also a GABA agonist

Safe in pregnancy

ADR–mild

71.3 PRAZIQUANTEL

Effective against
schistosomes of all species

Most other trematodes and

cestodes including
cysticercosis

Praziquantel Effective as single oral dose

1. Schistosomiasis Drug of choice

↑ Cell permeability to
calcium, leads to its contraction,
paralysis, and expulsion
Single (10 mg/kg) dose is
effective in all tapeworms

Uses 2. Tapeworm
In T. solium, it has
Hence avoids
advantage that it kills
visceral cysticercosis
larvae

3. Neurocysticercosis Alternative to albendazole

 Anthelmintics 615

71.4 LEVAMISOLE AND NICLOSAMIDE

Effective against roundworm

and hookworm

Used as alternative

Paralyzes the worm

and expels it live

Levamisole

Roundworm 150 mg single dose

Then after 12 h
Hookworm First 150 mg
again 150 mg

Also acts as an
immunomodulator

Effective against most

tapeworms where

T. solium, T. saginata,
Drug of choice
H. nana, D. latum

Niclosamide Segments of dead tapeworms

are partly digested
In case of T. solium, ova are
released from these segments,
may develop into larvae
resulting in visceral cysticercosis
Hence purge after 2 h of
therapy to wash off worms
and avoid cysticercosis
Scolex in stools detected
ensures eradication

Alternative drug in intestinal

fluke infestation
616 Pharmacology mind maps for medical students and allied health professionals

71.5 DIETHYLCARBAMAZINE (DEC)

Filariasis, W. bancrofti,
Drug of choice
B. malayi, and B. timori

Hence their displacement

Immobilizes microfilariae
from tissues

Hence they become more

Alters surface structure
susceptible to host defense

Microfilariae rapidly disappear

from blood, except those
present in hydrocele and nodules

Destroys adult worms

of loa loa

Prolonged treatment kills

adult worms of B. malayi and
Diethylcarbamazine (DEC) W. bancrofti Allergic reactions like itching,
fever, rashes due to liberation Allergic reactions by ↓
of protein and antigens antihistaminics/steroids

Alkalinizing urine from dead worms

↑ duration of action

Safe during pregnancy

ADR

Reduce dose in renal

dysfunction

Contraindicated in It can cause severe

∴
onchocerciasis allergic reactions

1. Filariasis Drug of choice 2 mg/kg TDS × 21 days

Uses 2. Tropical eosinophilia 2 mg/kg TDS × 7 days

Followed by 150 mg
3. Loa loa 50 mg/day as test
TDS × 2–3 wks
 Anthelmintics 617

71.6 IVERMECTIN

Semisynthetic derivative of
avermectin B sourced from
Streptomyces avermitilis

Effective against many nematodes,

arthropods, and filariae

Very effective against microfilariae

of Onchocerca volvulus

Microficidal and blocks release

of microfilariae from uterus of
adult worms
Binds to glutamate-gated chloride
channel

Mechanism

Hence there is hyperpolarization

Also enhances GABA
and paralysis
Effective against W. bancrofti,
B. malayi, Strongylodis stercoralis,
Ascaris lumbricoides, cutaneous
Ivermectin larva migrans, Sarcoptes scabiei, and lice
Allergic reactions due to dying
parasites (Mazzoti reaction)

Avoid concomitant GABA- Benzodiazepines,

ADR
activity drugs valproic acid, etc.

Avoid in patients with meningitis

and sleeping sickness

Single dose 150 mcg/kg orally

1. Onchocerciasis
once/twice a year

Single dose of 400 mcg/kg + 400 mg

2. Lymphatic filariasis albendazole once a year for mass
chemotherapy

Single dose of 200 mcg/kg is

Uses
curative

3. Strongyloidiasis

Repeat dose after 2 wks

4. Ascariasis, scabies, lice,

Single dose of 200 mcg/kg
cutaneous larva migrans
618 Pharmacology mind maps for medical students and allied health professionals

71.7 MISCELLANEOUS

Effective for W. bancrofti and

Onchocerca volvulus

Doxycycline

Kills bacterium Wolbachia which

exists in symbiosis with filaria

A prodrug, converted to dichlorovas,

an organophosphorus insecticide

Used as alternative to praziquantel

to treat Schistosoma hematobium
infections
Miscellaneous
Metrifonate

Anticholinesterase activity paralyzes

worm, which move to lungs and are
killed by host defense

However eggs are not destroyed

Drug of choice for Fasciola hepatica

Bithionol
infections
 Anthelmintics 619

71.8 PREFERRED DRUGS FOR HELMINTIC INFESTATIONS

Worm Drugs of choice Alternative

1. Ascaris lumbricoides Mebendazole (M)/albendazole (A) Pyrantel (P)

(roundworm) piperazine (Pp)

2. Ankylostoma duodenale M/A Pyrantel (P)

(hookworm) Necator americanus

3. Enterobius vermicularis M/A/P Pp

(pinworm)

4. Trichuris trichura M A
(whipworm)

5. Strongyloides stercoralis A Thiabendazole

6. Dracunculus medinensis Metronidazole M

(guineaworm)

7. Neurocysticercosis Niclosamide/praziquantel Praziquantel

(tapeworms) A A

8. Hydatid disease A M

9. Filaria DEC + A Ivermectin + A

10. Schistosomes Praziquantel –

11. Onchocerca volvulus Ivermectin –

12. Fasciola hepatica Bithionol –

(sheep liver fluke)
620 Pharmacology mind maps for medical students and allied health professionals

71.9 DRUGS FOR SCABIES AND TREATMENT OF PEDICULOSIS

Applied throughout body below

chin, including soles of feet
25% emulsion applied Repeat application after 12 h
after hot scrub bath

1. Benzyl benzoate After next 12 h hot

scrub bath is repeated

ADR Irritation

Synthetic pyrethroid, insecticide

effective against scabies and lice Applied below chin
throughout body
5% cream
Washed after 12 h
Insects are paralyzed
2. Permethrin
Single application is 100% curative

Preferred over benzyl benzoate for

treatment of scabies and pediculosis
Kept for 10 min
For pediculosis 1%
cream applied over scalp
Then washed off

Applied over body

1% lindane mixed in vegetable oil
Repeat after 2–3 days
Scabies caused due to Sarcoptes Effective for scabies and pediculosis
scabiei or Ascarus scabiei (itch mite)
Common in people with
poor hygiene Milder irritation

Drugs for Transmitted by close body 3. Lindane or gamma benzene

hexachloride (gammexane, BHC) Resistance common
scabies contact with infected person
Spreads easily in overcrowded Combined with benzyl benzoate
houses

Drugs to treat scabies ADR Lindane is lipid soluble Hence absorbed

via skin

Systemic toxicity Arrhythmias, seizures,

aplastic anemia
10% cream 2–3
times/day for scabies and lice
Crotamiton
Preferred in children No irritation
∴

An anthelmintic,
effective in scabies and lice
Only orally effective Rest are topical
drug preparations
Ivermectin
Single dose 200 mg/kg
highly effective
4. Miscellaneous
Avoid during
pregnancy, lactation, and in children

10% ointment, used earlier

Sulfur
Not preferred because of unpleasant
smell and repeated applications

2% lotion paralyzes insects

DDT
Not preferred now

Monosulfiram Related to disulfiram

5% solution applied TDS in

24 h for scabies

Tetmosol Effective sarcopticide

Permethrin 1% (left for Avoid concurrent alcohol

Caused by louse 10 min) is preferred consumption
Pediculus humanus
DDT 2% lotion Not used in children <5 yrs
Treatment of Infects scalp,
pediculosis body, or pubic region
Lindane 2% shampoo
Treatment
Malathion 0.5% lotion

Benzyl benzoate (not

preferred as it is weak ovicidal)
Ivermectin orally
single dose 200 mcg/kg
 72
Antiseptics and disinfectants

72.1 DEFINITION AND CLASSIFICATION

Sterilization: Destruction of all

microorganisms including spores

Germicide: Kills microorganisms

but not spores; includes
disinfectants and antiseptics
Definition
Disinfectants: Eliminate microorganisms
from inanimate objects

Antiseptics: Eliminate microorganisms

from living tissues

Chemically stable

Cheap

Cidal and not merely static

Active against all pathogens

Ideal antiseptic/
disinfectant
Active in presence of
blood, pus, etc.

Antiseptics and Disinfectants should

disinfectants not corrode/rust instruments

Non-irritating to tissues

Should not interfere

with healing

Biguanide Chlorhexidine

Phenol derivatives Phenol, cresol, etc.

Halogens Iodine, iodophores,

chlorine

Alcohols Ethanol

SuRface active agents Cetrimide, benzalkonium

chloride
Classification
(B PHARMA GOD)
Metallic salts Zinc sulfate, calamine,
zinc oxide

Formaldehyde,
Aldehydes glutaraldehyde acids:
Boric acid, acetic acid

Gases Ethylene oxide

Oxidizing agents KMnO4, H202, benzyl

peroxide

Dyes Gentian violet, Acriflavine

621
622 Pharmacology mind maps for medical students and allied health professionals

72.2 BIGUANIDES

Alter the properties of

Mechanism
bacterial cell wall

Highly effective against Gm +ve

bacteria (bacteriocidal)

Chlorhexidine

Gm –ve, M. tuberculosis, fungi, spores

are resistant

“Savlon” (chlorhexidine gluconate

Preparations
1.5% + cetrimide 3%)

Widely used as sanitizers, antiseptic,

and disinfectant for surgical
Biguanides instruments, surgical scrub, neonatal
bath, mouthwash, obstetrics, and
general skin antiseptic

Most widely used antiseptic in

Uses dentistry in form of oral rinse,
toothpaste

Most effective antiplaque and

antigingivitis agent
(ANUG) for prevention and
treatment

Brownish discoloration of teeth

and tongue

Unpleasant aftertaste, alteration

Major disadvantage
of taste perception and rarely

Oral ulcers
 Antiseptics and disinfectants 623

72.3 PHENOLS

Denaturing bacterial
Mechanism
proteins

Earliest and standard

Weak agent and poor

sporicidal

High concentration causes

Phenol
skin burns and is caustic

Mild local anesthetic

action

Disinfects urine, feces,

Uses
pus, sputum, etc.

More active, less toxic

Phenols
Cresol

Disinfect utensils, excreta,

and washing hands

Soapy emulsion of cresol

Lysol
Widely used as
disinfectant in hospital
and domestic practice

Phenol substitute having

efficacy equal to phenol

Chloroxylenol (Dettol)
Used for surgical
antisepsis, obstetric
cream, mouthwash
Triclosan – non-irritating, non
staining, low sensitization,
LlSTERINE mouthwash used for
halitosis, plaque, and gingivitis
624 Pharmacology mind maps for medical students and allied health professionals

72.4 HALOGENS

Mechanism: Iodinating Rapidly acting and most

Advantages
and oxidizing protoplasm broad spectrum

Coloring of skin and

Iodine
materials

Odor, painful on
Disadvantages
open wounds

Iodine or triiodide
complexed with polymers Organic matter retards
lodophores
(polyvinyl pyrrolidone)- germicidal action
povidone

Tincture iodine, Mandl’s

paint, iodex, betadine, etc.
Preparations
Halogens 1% povidone iodine
oral rinse for gingivitis

Kills most pathogens

except M. tuberculosis

Most commonly used

to disinfect water

Salts of hypochlorite in
Chlorophores
the form of chloride lime

Chlorophores Slow HOCI releasers

Chlorine
Chlorinated lime Disinfectant of water

Chlorinated lime
(1.25%) + boric acid
“EUSOL”
(1.25%) clean infected
wounds

Loosens and dissolves

dead tooth pulp
Na hypochlorite
solution 2%
In addition to exerting
rapid antisepsis; hence
used in RCT
 Antiseptics and disinfectants 625

72.5 ALCOHOLS

Denature and precipitate

Mechanism
bacterial proteins

Ethanol Concentration used 70%–90%

Poor disinfectant
and poor sporicidal

Hence not applied on

Irritant mucous membrane, ulcers,
open wounds, scrotum
Alcohols
Broad-spectrum
activity
Antiseptic before Cotton swab soaked
hypodermic injections in 70% alcohol
Use
Sanitize working surface
in dentistry

More potent

Isopropanol
Used to disinfect
thermometers

72.6 SURFACE ACTIVE AGENTS

Detergent action (cationic

Mechanism
surface active agents)

Highly effective against

Gm +ve bacteria

Gm –ve, M. tuberculosis,
Benzalkonium chloride
fungi, spores
and cetrimide
are resistant

1:1000–1:10,000 solution
of benzalkonium chloride
Surface active agents and 1%–3% of cetrimide is
used for preservative
and antiseptic purpose

Good cleansing agent and

often combined with other
Advantage
agents to serve as broad-
spectrum disinfectant

Activity is greatly reduced

Disadvantage in presence of
organic materials

Sanitizers, disinfectants
Use for surgical instruments,
gloves
626 Pharmacology mind maps for medical students and allied health professionals

72.7 METALLIC SALTS

Antiseptic, astringent

Used topically for conjunctivitis,

ulcers, and acne

Zinc sulfate

Hence used in
Reduces sweating
deodorants

Zn salts component
of calamine lotion

Metallic salts 1% eye drops for

conjunctivitis (Ophthalmia
neonatorum)
Silver nitrate
Antiseptic on burns, removal
of warts and oral ulcers,
hypertrophied tonsillitis

Hence used topically

Very effective against
Silver sulfadiazine for prevention of infection
Pseudomonas
in burns patients
 Antiseptics and disinfectants 627

72.8 ALDEHYDES

Mechanism Denaturing bacterial proteins

Broad-spectrum
germicidal agents

Formaldehyde Pungent gas, used for fumigation

Used for preserving dead tissues

Aldehydes
Volatile, irritating, and causes
Formalin (37% aqueous sol)
sensitization

Occasionally used to disinfect

instruments and excreta

Less volatile, less pungent,

less irritating

Used to disinfect surgical

instruments, glassware,
endoscopes, etc.

2% Glutaraldehyde

Used in dentistry as an immersion

agent for instruments that
cannot be autoclaved

Should not be used to disinfect

working surfaces, as repeated
inhalation can cause asthma
628 Pharmacology mind maps for medical students and allied health professionals

72.9 ACIDS

Fungistatic and
bacteriostatic

2%–4% solution as
Antibacterial activity
mouthwash

Boric acid and sodium 30% paint for

borate (borax) stomatitis and glossitis

10% ointment for cuts

and abrasions

Acids
Component of prickly
heat powder

Boroglycerine Used for stomatitis

paint and glossitis

Antibacterial and
antifungal

Benzoic acid
Whitfield’s ointment
Used for ringworm
6% benzoic acid +
infections
3% salicylic acid
 Antiseptics and disinfectants 629

72.10 GASES

Mode of action Alkylating agent

Cyclic molecule

Colorless liquid at room

temperature
Properties
Has a sweet ethereal odor

Readily polymerizes and

is flammable

Highly effective chemisterilant

Capable of killing spores rapidly

∴
It is highly flammable, it is
Application usually combined with CO2 (10% CO2
+ 90% EO) or dichlorodifluoromethane

Requires presence of humidity

Good penetration and is well

absorbed by porous material

Gases Ethylene oxide To sterilize heat-labile articles such as

bedding, textiles, rubber, plastics,
syringes, disposable petri dishes
Uses
Complex apparatus like
heart-lung machine

Respiratory and dental equipments

Highly toxic

Irritating to eyes, skin

Disadvantages
Highly flammable

Mutagenic and carcinogenic

630 Pharmacology mind maps for medical students and allied health professionals

72.11 OXIDIZING AGENTS

Releases hydroxyl radicals

Mechanism
and nascent O2

3% antisepsis and

10%–30% sporicidal

Removes slough from

tissues (earwax) and
Hydrogen peroxide

Effective against anaerobes

Oxidizing agents
∴
Used in ANUG,
predominance
of anaerobic bacteria

Mouthwash used for

periodontal disease

Crystal form, highly water soluble,

slow onset of action and effective
even with organic matter

Condy’s lotion (1:4000 to

Preparation
1:10,000)
Potassium permanganate
Gargling, irrigating cavities, urethra,
wounds, disinfect water (wells and
Uses
ponds), and stomach wash
in alkaloidal poisoning

Irritant, blistering, promotes

Disadvantages of KMnO4 rusting of surgical equipment,
staining tissue, etc.

72.12 DYES

Gentian violet, brilliant

green

Used in gingivitis, oral

thrush, bed sores,
chronic ulcers and burns

Dyes Stain skin

Used topically as
antiseptic

Methylene blue used

in cyanide poisoning
 73
Cancer chemotherapy

73.1 INTRODUCTION AND PHASES OF CELL CYCLES

Cancer is one of the major causes of death

In developed countries –1 in
3 is diagnosed as cancer
↑ Life expectancy has
↑ its incidence
Cancer is characterized by progressive,
persistent, perverted (abnormal),
purposeless, and uncontrolled
proliferation of tissues
i.e., Uncontrolled proliferation,
Special characteristics of cancer cells invasiveness, metastasis, and
dedifferentiation
Cancer cells multiply faster than host cells

Introduction Cancer cells are own cells, unlike microbes

Hence anticancer drugs which

destroy cancer cells also kill host cells
Host defenses do not attack
cancer cell, they are also host cells
Additionally cancer cells enter a resting
phase, only to multiply and recur later
Anticancer agents do not act during
resting phase

Hence making treatment difficult

4 phases of cell cycle G1, S, G2, and M

G1 Presynthetic phase, variable duration

S Synthesis phase, DNA synthesis occurs Duration 12–18 h

Cancer G2 Postsynthetic phase Duration 1– 8 h

chemotherapy
M Mitosis phase Duration 1–2 h
Phases of
cell cycle Daughter cells divide or remain dormant
(G0 phase)
Knowledge of cell cycle is used for
staging and treatment schedule
∴
Different drugs act on
different phases (cell cycle-specific)
Mainly acts on dividing cells
Some drugs are cell cycle non-specific Antimetabolites,
S phase doxorubicin,
epipodophyllotoxins
Cell cycle-specific drugs
G2 and M phase Bleomycin

Taxanes, vinca
M phase
alkaloids

Alkylating agents

Anticancer antibiotics
Cell–cycle Mainly act on dividing
non-specific drugs and resting cells Cisplatin

Procarbazine

Camptothecins

631
632 Pharmacology mind maps for medical students and allied health professionals

73.2 COMMON ADVERSE EFFECTS OF ANTICANCER AGENTS AND MEASURES

TO PREVENT ADVERSE EFFECTS

Most anticancer agents

Both cancer cells and
act on rapidly
normal cells
multiplying cells
Bone marrow, gonads,
epithelial cells of skin
and mucous membrane
Leukopenia, anemia,
1. Bone marrow
thrombocytopenia,
depression
infections, and bleeding
Stomatitis, glossitis,
Common adverse 2. GIT esophagitis, proctitis,
effects of anticancer diarrhea, and ulcers
agents
Partial/total, but
3. Alopecia
reversible

4. Reduces
Very common due to
spermatogenesis in men,
Hence normal CTZ stimulation
amenorrhea in women
multiplying cells
are affected 5. Immediate side Starts after 4–6 h,
Nausea and vomiting
Some unique adverse effects lasts 1–2 days
effects are discussed
individually Due to rapid tumor cell
Hence prophylactic
lysis there is ↑ in antiemetic is must
plasma uric acid
6. Hyperuricemia
Hence there is tumor
lysis syndrome
and renal failure
Hence they are
7. Teratogenicity contraindicated in
pregnancy
e.g., Leukemia following
8. Carcinogenicity –
treatment of Hodgkin’s
secondary cancers
lymphoma
Antiemetics e.g.,
1. Nausea, vomiting ondansetron,
metoclopramide

2. Hyperuricemia Allopurinol

3. Methotrexate
Folinic acid
toxicity

IV mesna, N-acetyl
4. Cyclophosphamide
cysteine bladder wash,
cystitis
plenty of oral fluids

Measures to prevent
Anemia Erythropoietin
adverse effects

5. Myelosuppression Leukopenia G-CSF, GM-CSF

Thrombocytopenia Thrombopoietin

6. Cisplatin
Amifostin
nephrotoxicity

7. Xerostomia due to
Amifostin
radiation
 Cancer chemotherapy 633

73.3 CLASSIFICATION OF ANTICANCER AGENTS

Mechlorethamine,
a. Nitrogen mustards cyclophosphamide, ifosfamide,
chlorambucil, melphalan

b. Alkyl sulfonate Busulfan

1. Alkylating agents
Carmustine, streptozocin,
c. Nitrasoureas
lomustine

Containing compounds –
d. Platinum
cisplatin, carboplatin

a. Folate antagonist Methotrexate

2. Antimetabolites 6-Mercaptopurine
b. Purine antagonist
6-thioguanine

c. Pyrimidine
5-Fluorouracil cytarabine
antagonist

Vincristine,
i. Vinca alkaloids
vinblastine

Paclitaxel,
ii. Taxanes
docetaxel
3. Natural products a. Plant products
iii. Epipodophyllotoxins Etoposide

Actinomycin D, bleomycin,
mitomycin C, mithramycin, Topotecan,
iv. Camptothecins
doxorubicin, daunorubicin irinotecan
b. Antibiotics
c. Enzymes L-asparginase

Classification of
anticancer agents Ethinyl estradiol, fosfestrol
i. Estrogens

ii. Antiestrogens Tamoxifen

Hydroxyprogesterone caproate,
iii. Progestins
medroxyprogesterone acetate

iv. Androgens Testosterone propionate

4. Hormones and
antagonists
v. Antiandrogens Flutamide

vi. 5-α reductase inhibitors Finasteride

vii. GnRH analog Buserelin, goserelin, naferelin

viii. Corticosteroids Prednisolone and others

i. Interferon α, interleukin 2,
5. Biological response
amifostine, hematopoietic
modifiers
growth factors
Hydroxyurea, imatinib,
6. Miscellaneous thalidomide, monoclonal
antibodies
634 Pharmacology mind maps for medical students and allied health professionals

73.4 ALKYLATING AGENTS AND NITROGEN MUSTARDS

Mechlorethamine,
a. Nitrogen mustards cyclophosphamide, ifosfamide,
chlorambucil, melphalan

b. Alkyl sulfonate Busulfan

Carmustine, streptozocin,
c. Nitrasoureas
lomustine
Containing compounds –
d. Platinum
cisplatin, carboplatin

Alkylating agents All have alkyl group(s)

Capable of introducing “alkyl”

groups into nucleophilic sites of
DNA bases with covalent bonds Form highly reactive
These are cell-cycle carbonium ion
non-specific drugs Transfers “alkyl” group(s)
Also have radiomimetic on DNA bases
actions Cross-linking of DNA
(inhibiting DNA replication)
Mechanism of action
Abnormal base pairing
(hence abnormal protein synthesis)
DNA strand breakage
cell proliferation
Also damage of RNA
and proteins
Most commonly used
alkylating agent
Prodrug converted to phosphoramide
mustard and acrolein

Phosphoramide mustard Has cytotoxic effects

Acrolein Causes hemorrhagic cystitis

Route of administration – Hemorrhagic cystitis (due to

orally, IM, IV acrolein)

Causes dysuria and hematuria

A. Nitrogen mustard Cyclophosphamide Adverse effects (besides

Dose-limiting toxicity
general toxicity)
Managed by good hydration
and IV mesna
Mesna is excreted by urine,
hence inactivates acrolein

Hodgkin’s disease

Burkitt’s lymphoma

Lymphatic leukemia
Uses – in combination with
other anticancer agents
Rheumatoid arthritis

Nephrotic syndrome

Graft versus host rejection

during transplantation due
to immunosuppressant action
 Cancer chemotherapy 635

73.5 OTHER ALKYLATING AGENTS, ALKYL SULFONES, AND NITROSUREAS

Spontaneously converted
to highly reactive cytotoxic
Prodrug at product
physiological pH One of the components of MOPP
regimen for Hodgkin’s disease
nitrogen mustard, oncovin,
Mechlorethamine
prednisone, and procarbazine
Hence care during IV
Highly irritant administration
(avoid extravasation)

Slow-acting, least toxic

nitrogen mustard

Marked lympholytic effect

Chlorambucil
(leukeran)
Non-irritant hence
given orally

Standard treatment of chronic

lymphatic leukemia (CLL)
Selective action on
myeloid series
Highly effective in multiple
Melphalan
myeloma (in combination)
Causes bone marrow
suppression
B. Alkyl Sulfonates Busulphan (Myleran)
Preferred for chronic
myeloid leukemia (CML)

Skin pigmentation,
ADR pulmonary fibrosis,
hyperuricemia

Hence high concentration

in brain and CSF
C. Nitrosoureas Carmustine, lomustine Highly lipid soluble
Hence mainly used in brain
tumor, Hodgkin’s disease,
Effective orally in Hodgkin’s disease meningeal leukemias
(MOPP regimen), non-Hodgkin's
lymphoma, brain tumors
Procarbazine
One of metabolites is MAO Hence leads to food/
inhibitor drug interactions

An antibiotic used in
pancreatic islet cell tumors

ADR Nephrotoxicity
Streptozocin

Malignant melanoma,
soft tissue sarcomas,
Use
neuroblastoma, and
Hodgkin’s disease
Dacarbazine

Given IV Pain on extravasation

636 Pharmacology mind maps for medical students and allied health professionals

73.6 PLATINUM-CONTAINING COMPOUNDS

Heavy metal
complex

Cell cycle non-

specific drug

Given IV, has high

protein binding

Concentrated in On entering cell, forms

kidney, liver, highly reactive platinum
intestine, and testes complexes

Does not
These react with DNA
cross BBB

Mechanism Hence there is intrastrand

D. Platinum-
Cisplatin, of action and interstrand cross-linking
containing
carboplatin
compounds
This causes DNA
damage, hence inhibits
cell proliferation

Testicular, ovarian, endometrial

Use and bladder cancers, lung,
gastric, and esophageal cancer

Most emetogenic drug

Hence prior 5-HT3

e.g., Ondansetron is necessary
antagonist

Reduced by good hydration

Nephrotoxicity
and diuresis
ADR

Ototoxicity Severe with repeated use

Electrolyte
K+, Ca+2, Mg+2
imbalance

Mutagenic,
carcinogenic, teratogenic
 Cancer chemotherapy 637

73.7 ANTIMETABOLITES – FOLATE ANTAGONISTS – METHOTREXATE (MTX)

Most commonly
used

Hence prevents conversion

Cell cycle-specific drug, MTX structurally of dihydrofolic acid (DHFA)
acts during S phase resembles folic acid to tetrahydrofolic acid
(THFA) thus ↓ THFA
Antineoplastic, Competitively inhibits THFA is essential for
immunosuppressant and dihydrofolate synthesis of purines,
anti-inflammatory effects reductase (DHFR) pyrimidines, and DNA

Also inhibits RNA and

Mechanism of action
protein synthesis

Route of
Oral, IM, IV, intrathecal
administration

∴
Bound to plasma
Does not cross BBB
protein

1. Choriocarcinoma Drug of choice

2. Acute leukemia

3. Burkitt’s lymphoma

A. Folate Methotrexate
2. Antimetabolites 4. Breast cancer
antagonists (MTX)
Use
Low dose i.e., 7.5–30 mg
5. Rheumatoid arthritis
once weekly

6. Organ
transplantation

7. Psoriasis

8. Inflammatory
bowel disease

Megaloblastic anemia,
ADR pancytopenia, hepatic
fibrosis, osteoporosis
Salicylates, sulfonamides,
As they displace it
tetracyclines
from protein binding sites
↑ MTX toxicity
Drug interactions
∴
NSAIDs, sulfonamides – They reduce its
↑ MTX toxicity excretion

Hence use of very high

↓ Toxic effects
doses (mega pulse therapy)
on normal cells
of MTX possible

Folinic acid rescue/ Folinic acid is active

leucovorin rescue co-enzyme form

Bypasses block
produced
by MTX toxicity
638 Pharmacology mind maps for medical students and allied health professionals

73.8 PURINE – ANTAGONISTS AND PYRIMIDINE ANTAGONIST

This inhibits purine ring

6-MP is activated to its
biosynthesis and
ribonucleotide
nucleotide interconversion

Cell cycle-specific
drug, acts on S phase

Also has
immunosuppressant effects

Given orally, does not

6-Mercaptopurine cross BBB
(6-MP)

Metabolized by xanthine
oxidase, excreted in urine
Hence interferes with its
metabolism, thus ↑
the effects of 6-MP
Allopurinol, inhibits
xanthine oxidase
Hence, allopurinol is combined
to reduce the dose of 6-MP
and prevent hyperuricemia
B. Purine antagonists
Acute lymphoblastic
Use
leukemia, choriocarcinoma

Analog of vidarabine
(antiviral agent)

Converted to
active triphosphate derivatives
Fludarabine
Causes DNA chain breakage
Inhibits DNA polymerase
and termination

Chronic lymphocytic leukemia

Use
(CLL), non-Hodgkin's lymphoma

Prodrug activated to
deoxyuridine
monophosphate

This interferes with DNA

Fluorouracil (FU) synthesis by inhibiting
thymidylate synthetase enzyme

Mainly in GI cancers, breast,

Use ovary, skin carcinomas,
C. Pyrimidine antagonist premalignant keratosis (topically)

Recently developed
analog of cytarabine
Gemcitabine
Pancreatic, lung, cervical,
Use bladder, ovarian,
breast cancer
 Cancer chemotherapy 639

73.9 NATURAL PRODUCTS – PLANT PRODUCTS: VINCA ALKALOIDS

Vincristine and
vinblastine derived
from periwinkle plant
Cell cycle specific
i. Vinca alkaloids drugs, act during Same for both
M phase

Mechanism of action Bind to β-tubulin, forms

drug–tubulin complex
Hence chromosomes fail to
move apart during mitosis
Vincristine Disruption of mitotic
Vinblastine spindle
Hence metaphase arrest,
and inhibition of cell division
Childhood leukemias
Hodgkin’s disease

Childhood tumors i.e.,

breast carcinoma
Uses
Wilms' tumor
testicular tumors

Neuroblastoma

Hodgkin’s disease

Peripheral neuritis,
anorexia, nausea

Constipation,
ADR vomiting, diarrhea

Bone marrow
sparing bone
marrow suppression
3. Natural A. Plant
products products
Paclitaxel, derived from
bark of western yew tree
Binds to β–tubulin
Docetaxel is a newer
taxane
Stabilizes polymerized tubulin
Mechanism of action
Formation of abnormal
ii. Taxanes microtubules (spindle poison)
Route–IV infusion
Inhibition of mitosis

Advanced breast and ovarian

Use cancers; lung, esophageal
and bladder cancers
Bone marrow suppression,
ADR peripheral neuritis, arthralgia,
myalgia, hypersensitivity reactions
Binds and stabilizes
DNA topoisomerase Hence inhibits
1 complex resealing function

Strand breaking Hence there is cell death

action is not affected
iii. Camptothecins
Advanced ovarian, lung,
Use colon, cervical cancers

ADR Bone marrow suppression

and GI disturbances

Etoposide, teniposide

Acts in S–G2 phase

Forms complex with

DNA–topoisomerase II
iv. Epipodophyllotoxins
Leads to DNA damage Hence cell death
and strand breakage

Testicular and lung cancer, non-

Use Hodgkin’s lymphoma, breast cancer,
AIDS-related kaposis sarcoma
Bone marrow suppression,
ADR GI side effects, hepatotoxicity
(high doses)
640 Pharmacology mind maps for medical students and allied health professionals

73.10 ANTICANCER ANTIBIOTICS

All are cell cycle non-

specific agents except Direct action
bleomycin

Cause intercalation
between adjoining
Mechanism of action
nucleotide pairs on
same strand of DNA

Interferes with
cell division

Wilms’ tumor, Ewing’s

Used in sarcoma, methotrexate-
resistant choriocarcinoma
i. Actinomycin D
Bone marrow
ADR suppression,
GI disturbances

GI tumors, cervix and

Use
bladder cancer

ii. Mitomycin C
Bone marrow suppression,
ADR GI disturbances,
nephrotoxicity

B. Anticancer
antibiotics Cell cycle-
specific drug

Testicular and ovarian

iii. Bleomycin Use tumors, squamous cell
carcinoma of skin

Skin hyperpigmentation,
ADR pulmonary fibrosis, no
bone marrow suppression

Most commonly
used

Acute leukemias,
iv. Doxorubicin Use
Hodgkin’s lymphoma

Bone marrow suppression, Hence can cause CCF,

ADR GI disturbances, hypotension,
cardiomyopathy arrhythmias

↓ Blood
calcium by inhibiting
osteoclasts
v. Mithramcin

Hypercalcemia with
Use
bone metastasis
 Cancer chemotherapy 641

73.11 ENZYMES

Isolated from bacteria

Aspargine is an amino
acid essential for
protein synthesis

Normal cells can synthesize

∴
aspargine, they contain
enzyme aspargine synthetase

Hence depend on
Cancer cells lack this
external source, i.e.,
enzyme
extracellular fluid

L-Asparginase converts
aspargine to aspartic acid
C. Enzymes L-Asparginase
Its inhibition reduces the
source of aspargine, hence
inhibits protein synthesis

Acute lymphocytic
Use
leukemia

Hypersensitivity
∴
reactions it is an
enzyme, it is allergic

Hemorrhage due to
inhibition of synthesis of
clotting factors

Hyperglycemia, due to
ADR
insulin deficiency

Headache

Hallucinations and
coma
642 Pharmacology mind maps for medical students and allied health professionals

73.12 HORMONAL AGENTS

Hence used in acute

Marked lympholytic effect leukemias and
lymphomas

Anti-inflammatory

↑ Effect of
i. Glucocorticoids antiemetics

Nonspecific
antipyretic effect
Reduces hypersensitivity
reactions due to certain
Other beneficial anticancer agents
actions
Controls bleeding

Controls hypercalcemia

Improves appetite

Physiologic antagonists
Produces euphoria
of androgens

Androgen-dependent
ii. Estrogens Used in
prostatic tumors

Fosfeterol, a prodrug, Achieves a high

Hence used in
activated to stilbesterol concentration in
prostate carcinoma
prostate

Antiestrogen
4. Hormonal agents- iii. Tamoxifen
only palliative effects Palliative treatment of
Used in hormone-dependent
breast carcinoma

iv. Progestins Used in Endometrial carcinoma

Flutamide is a
nonsteroidal agent

Blocks androgen at
v. Antiandrogens
receptor level
Palliative treatment of
Used for advanced prostate
carcinoma
Blocks conversion of testosterone
to dihydrotestosterone by
blocking 5α reductase
Palliative treatment of
Both flutamide and
vi. Finasteride advanced prostate
finasteride are used for
carcinoma

Finasteride Also useful for BPH

Pulsatile administration of buserelin,

goserelin, leuprolide, FSH, and LH
Continuous administration suppresses
vii. GnRH agonists pituitary gonadotropins (FSH and LH)
by down regulating GnRH receptors
Palliative treatment of
Used in advanced prostate
and breast cancer
 Cancer chemotherapy 643

73.13 BIOLOGICAL RESPONSE MODIFIERS

Erythropoietin

Myeloid growth factors

like G-CSF, M-CSF, GM-CSF
a. Hematopoietic
growth factors
Thrombopoietin

Bone marrow
Used to treat
suppression

Interferon α

b. Interferons
Hairy cell leukemia,
Use Kaposis sarcoma,
condylomata acuminata

Aldesleukin

↑ Cytotoxic activity
of T-cells

Induces effects of natural

killer cells
c. Interleukin 2
5. Biological response
modifiers Induces interferon
production

Induces remission of renal

Use
cell carcinoma

ADR Hypotension

Induces differentiation
in leukemic cells

Leukemic promyelocytes
d. Tretinoin
lose their ability
(all transretinoic acid)
to proliferate

To induce remission in
Use acute promyelocytic
leukemia

Provides selective
cytoprotection to
normal tissues

Activates an enzyme in
normal tissues which can
e. Amifostine
inactivate the active form
of cisplatin and radiation

May stimulate bone marrow

644 Pharmacology mind maps for medical students and allied health professionals

73.14 MISCELLANEOUS

Analog of urea

Inhibits enzyme
Hence inhibits DNA
ribonucleotide
synthesis
reductase

Acts on S phase
a. Hydroxyurea
Orally effective

ADR Skin pigmentation

Chronic myeloid
Use
leukemia (CML)

Selective inhibitor of
tyrosine kinase

These enzymes
take part in signal
transduction
Also involved in
Hence a drug of
pathogenesis of chronic
choice in CML
myeloid leukemia

GI tumors that expresses

Also used in
tyrosine kinase
6. Miscellaneous
b. Protein tyrosine Used in imatinib-
Imatinib Dasatinib, nilotinib
kinase inhibitors resistant cases

Inhibit epidermal growth

factor receptor (EGFR)
tyrosine kinase

EGFR is overexpressed in
Gefitinib
several malignancies

Hence used in non-small

cell lung cancer not
responding to first-line drugs

Banned for many Used in renal cell

Sunitinib
years, now used again carcinoma

Used in Multiple myeloma

Exact mechanism
unknown
c. Thalidomide
May act by stimulating
T cells and NK cells

Inhibits angiogenesis,
tumor cell proliferation,
and modulation of
hematopoietic stem
cell differentiation
Sedation, constipation,
ADR peripheral neuropathy,
carpal tunnel syndrome
 Cancer chemotherapy 645

73.15 MONOCLONAL ANTIBODIES AND RADIOACTIVE ISOTOPES

∴
Cancer cells express
several antigens, these
antigens are targeted by
monoclonal antibodies

Lymphomas and
Used for
solid tumors
B-cell lymphoma and CLL
Targets CD20 antigen
on B cell
Maintenance therapy
Rituximab
to delay progression
Used in
Synergistic effect
with chemotherapy
d. Monoclonal antibodies
Rituximab sensitizes lymphoma
Binds to CD52 antigen on
cells susceptible to apoptotic
B and T cells
effects of chemotherapy
Alemtuzumab

Used in l Lymphomas and CLL

Humanized antibody
against HER2 receptors

HER2 receptor belongs to

family of EGF receptors
Trastuzumab
HER2 receptor overexpressed
in breast cancer cells and are
involved in resistance
to chemotherapy

Along with or following

Used chemotherapy in breast
cancers (HER-2+)

Used in polycythemia vera

t½ 14 days, taken
Radiophosphorus P32
up by bone

Emits β rays
from bones

Emits β rays
from bones
c. Radioactive isotopes

Strontium chloride Has a longer t½

↓ Pain in painful
bony metastases

Radioactive iodine 131I Used in thyroid cancers

646 Pharmacology mind maps for medical students and allied health professionals

73.16 RESISTANCE TO ANTICANCER DRUGS AND GENERAL PRINCIPLES

OF CANCER TREATMENT

Non-responsiveness from
Primary
first exposure

Secondary Acquired during treatment

1. Reduced drug uptake

Resistance to anticancer drugs
2. Drugs expelled from cells by
transport proteins like P-glycoprotein
Hence appropriate treatment of
cancers is important for success
3. ↓ Activation of
prodrug (MP, FU)

Mechanisms 4. ↑ Inactivation (cytarabine)

5. Production of target enzymes

6. Use of alternate
metabolic pathway

7. Altered target protein (e.g.,

modified topoisomerase II)

Chemotherapy is generally
Except curable ones
palliative and suppressive
∴
Cancers recur, avoid this by
killing all the cells or as many cells Called “total cell kill”
as possible during treatment

Other modalities are surgery

Besides chemotherapy
and radiotherapy

Used for synergism

Combination of drugs Reduce adverse effects

General principles of Avoid drugs with overlapping

Prevent resistance
cancer treatment adverse effects

Maintain good nutrition

Treat anemia

Protect against infection

Adequate control of pain

and anxiety

Helps in the management of this

Good emotional support
disease successfully
 XI
Part    

Miscellaneous
 74
Chelating agents

74.1 CHELATING AGENTS

Tissue enzymes contain ligands or

functional groups Hence it interferes with normal
Heavy metals bind and inactivate tissue functioning
these ligands
Heavy metals are not metabolized
Chelating agents are heavy metal
antagonists

They bind to heavy metals and

makes them nontoxic
Chelating agents Introduction
This process of complex formation
is called chelation

Calcium disodium edetate Complex is water soluble Hence excreted by kidneys

More effective as prophylactic Hence earlier therapy is

Chelates divalent, trivalent metals
than treatment preferable

e.g., Calcium disodium edetate (EDTA),

EDTA Zinc, manganese, iron, lead dimercaprol, D-penicillamine,
desferrioxamine

Lead poisoning, sodium edetate in

Use
severe hypercalcemia

ADRs Nephrotoxicity, dermatitis

Also called British anti-Lewisite

(BAL)

Colorless, oily liquid developed by

the British during World War II
Dimercaprol
Lewisite – arsenical war gas

Chelation of arsenic, mercury,

Use
and lead

Degradation product of penicillin

No antibacterial property
Wilson’s disease (hepatolentricular
D-penicillamine
Chelates copper, mercury, lead, degeneration)
and zinc
Rheumatoid arthritis
Use
As it enhances excretion of
Cystinuria
cysteine by forming complexes
Isolated from Streptomyces pilosus
Cu, Hg, Zn, Pb poisoning
High affinity for iron

Chelates iron from hemosiderin and

Dexferrioxamine
ferritin

Does not chelate iron from

hemoglobin and cytochromes Acute iron poisoning, drug of
choice
Uses
Chronic iron poisoning in patients
receiving repeated blood
transfusion, e.g., thalassemia

648
 75
Immunosuppressants and immunostimulants

75.1 CLASSIFICATION OF IMMUNOSUPPRESSANTS – CALCINEURIN INHIBITORS/

T-CELL INHIBITORS

1. Calcineurin inhibitors/ Cyclosporine

T-cell inhibitors
Tacrolimus

Sirolimus
2. Antiproliferative agents
Mycophenolate mofetil

Azathioprine

Methotrexate
3. Cytotoxic drugs
Cyclophosphamide
Immuno- Classification of
immuno- Leflunomide
suppressants suppressants
Prednisolone
4. Glucocorticoids
Methylprednisolone

Antithymocyte antibodies (ATG)

Antilymphocyte globulin (ALG)

Anti-Rh (d) immune globulin

5. Immunosuppressive
antibodies Muromonab CD3

Infliximab
1. Cyclosporine Cyclic peptide antibiotic
Etanercept Suppresses
Obtained from fungus Forms Complex Inhibits
Introduction antigen
Beauveria nivea Binds to cyclosporine– inhibits Reduces IL2 cell-
Enters target cells activation
cyclophilin cyclophilin calcineurin synthesis mediated
Mechanism of
complex phosphatase immunity
Given orally/parenterally (IV) T-cells
Prophylaxis and treatment of
graft rejection in organ Kidney, liver, bone marrow, etc.
transplantation
Rheumatoid arthritis

Uses Atopic dermatitis

Myasthenia gravis

Autoimmune diseases Nephrotic syndrome

Hepatotoxicity Inflammatory bowel disease (IBD)

Calcineurin Hypertrophy of gums Uveitis
inhibitors/T-cell
inhibitors Hypertension
Systemic lupus erythematosus
ADRs (all start Hyperglycemia
with “H”)
Hyperlipidemia

Hirsuitism

Higher risk of infections

Aminoglycosides/
↑ Nephrotoxicity
amphotericin B
Drug
interactions K+ sparing diuretics Leads to hyperkalemia

Similar to cyclosporine,
obtained from Streptomyces
tsukubaensis
But binds to different
2. Tacrolimus immunophilin
More potent
Also used topically for
atopic dermatitis, psoriasis

649
650 Pharmacology mind maps for medical students and allied health professionals

75.2 ANTIPROLIFERATIVE AGENTS

Is a macrocyclic
lactone

Streptomyces
Source
hygroscopicus
Mechanism
mTOR involved in Inhibits activation
Complexes with Inhibits protein
cell proliferation and and multiplication
immunophilin kinase (mTOR)
growth of T cells

t½ 60 h

As monotherapy or in
Prevention of organ
combination with other
transplantation rejection
immunosuppressants

1. Sirolimus Coronary stents Reduces local cell

incorporated into drug- – proliferation and
eluting stents restenosis
Use

Psoriasis Topical sirolimus

Choreoretinitis

Hyperlipidemia,
ADRs
infections, lymphomas

Antiproliferative
agents Prodrug, activated to
mycophenolic acid
Organ transplant
rejection prophylaxis
Active drug inhibits
guanine
nucleotide synthesis Alternative to calcineurin
inhibitors and in
Inhibits proliferation combination
and function of B and
T lymphocyte
Rheumatoid arthritis

Use

2. Mycophenolate IBD
mofetil (MMF)

Lupus nephritis

Psoriasis

Hypertension

Bone marrow
ADRs
suppression

CMV infection
 Immunosuppressants and immunostimulants 651

75.3 CYTOTOXIC AGENTS AND GLUCOCORTICOIDS

e.g., Azathioprine,
cyclophosphamide, methotrexate

Inhibit cell-mediated immunity

Cytotoxic agents
Cyclophosphamide inhibits
humoral immunity

Used in organ transplantation

rejection and autoimmune disease Prevention of organ transpant
rejection
Prodrug of mercaptopurine
Rheumatoid arthritis
Mercaptopurine is purine analog
Crohn’s disease
Inhibits cell-mediated and
humoral immunity
SLE
Uses
Autoimmune hemolytic anemia

1. Azathioprine
Glomerulonephritis

Multiple sclerosis

Idiopathic thrombocytopenic
purpura (ITP)

Alopecia

ADRs Bone marrow suppression

Hepatotoxicity

Hence suppresses humoral

Greater effect on B cells
immunity
2. Cyclophosphamide
Multiple sclerosis
Use
Autoimmune hemolytic anemia
Folate antagonist

Immunosuppressant and
anti-inflammatory

3. Methotrexate Inhibits cell-mediated immunity

Reduces cytokine synthesis Rheumatoid arthritis

Use Psoriasis

Prednisolone, methylprednisolone Pemphigus, etc.

Anti-inflammatory and
immunosuppressant
Glucocorticoids Hence inhibits cell-mediated
Suppress T-cell multiplication
immunity

Organ transplantation
rejection prevention and treatment
Use
Autoimmune disorders
652 Pharmacology mind maps for medical students and allied health professionals

75.4 IMMUNOSUPPRESSIVE ANTIBODIES

Destroys T cells To induce immunosuppression in solid

organ transplantation and bone marrow
transplantation
Use
1. Antilymphocyte and anti-
In combination with cyclosporine
thymbocyte globulin (ALG, ATG)

Anaphylaxis

ADRs

Serum sickness

Human IgG

Antibodies against Rh(d) antigen

on RBCs

Given IM to Rh (–) mother within

2. Anti-Rh(d) immunoglobulin
24–72 h of childbirth or abortion

Anti-Rh (D) Ig binds to antigens on

RBCs of baby which have entered
mother’s circulation

Prevent Rh incompatibility and

occurrence of hemolytic
complications in subsequent fetuses

Immunosuppressive antibodies
Monoclonal antibody against CD3
molecule on T lymphocytes

Blocks T-cell function

3. Muromonab CD3 T cells disappear from circulation

In combination with other

Use immunosuppressant in transplant
rejection reaction

Fever, arthralgia, pulmonary

ADRs
edema

Monoclonal antibody

Etanercept is a protein

Bind and blocks tumor necrosis

4. Infliximab
factor α (TNF α )
Rheumatoid arthritis
TNF α mediated inflammation
is suppressed
Crohn's disease

Use

Ulcerative colitis

Psoriatic arthritis
 Immunosuppressants and immunostimulants 653

75.5 IMMUNOSTIMULANTS

↑ Immune response e.g., AIDS, cancers,

in immunodeficiency patients chronic illness, etc.

Used in tuberculosis

1. BCG vaccine
Tried in situ carcinoma
of urinary bladder

Tried as adjuvant in colon

2. Levamisole (anthelmintic)
cancer

Anti-inflammatory,
immunosuppressant

Enhances cell-mediated immunity

and interleukin synthesis

Lepra reaction (Erythema

Suppresses TNF-α
nodosum leprosum; i.e., ENL)

Inhibits angiogenesis Multiple myeloma

3. Thalidomide
Uses Crohn's disease

SLE
Immunostimulants

Transplantation rejection
reactions

Peripheral neuropathy

ADRs

Teratogenicity
Cytokines with antiviral,
immunomodulatory effects

Recombinant interferon
α, β, and are used clinically

↑ Immune activity
4. Interferons
and host defense
Hairy cell leukemia
↑ Number and function
of helper and cytotoxic T cells
AIDS-related kaposis sarcoma

Use

Malignant melanoma
Synthesized and purified from
bovine/human thymus
Condylomata acuminata
Stimulates precursor T-cell
5. Thymosin
maturation

Use -tried in hepatitis B/C

Index

A ADHD, see Attention deficit nasal decongestants, 118

hyperactivity disorder neurotransmitters, 102
AA, see Arachidonic acid
Adjuvants, 334; see also Antirheumatic noncatecholamines, 114
Abatacept, 332; see also Antirheumatic
drugs noradrenaline, 110
drugs
ADME (absorption, distribution, noradrenaline release, 102
AC, see Adenylyl cyclase
metabolism, and excretion), 13 preparations, 108
ACE, see Angiotensin-converting
ADP antigonists, 380; see also pulmonary vasoconstriction, 107
enzyme
Antiplatelet agents selective β2-stimulants, 119
Aceclofenac, 321
Adrenaline, 109; see also Adrenergic smooth muscles, 107
ACEIs, see Angiotensin-converting
system and drugs sympathetic nervous system, 102
enzyme inhibitors
Adrenal medulla, 67, 68 therapeutic classification, 105
Acetylcholine (ACh), 69; see also
Adrenergic agonists in glaucoma, 78; see vasopressors, 117
Cholinergic system and drugs
also Cholinergic system and Adrenocorticotropic hormone (ACTH),
actions of, 73
drugs 434, 436, 470; see also
metabolism of, 70
Adrenergic neuron blockers, 143; see also Hypothalamic and pituitary
uses of, 74
Sympatholytics hormones
Acetylcholinesterase(AChE), 70; see also
Adrenergic receptors, 44, 104; see also ADRs, see Adverse drug reactions
Cholinergic system and drugs
Adrenergic system and drugs Adsorbants, 427; see also Diarrhea
Acetyl salicylic acid (ASA), 302
α receptor stimulation, 104 treatment drugs
ACh, see Acetylcholine
β receptor stimulation, 104 Adverse drug reactions (ADRs), 56
AChE, see Acetylcholinesterase
classification, 104, 105 ACEIs and, 139
Acidic drugs, 20
directly acting drug, 105 actinomycin D, 640
Acids, 628; see also Antiseptics
indirectly acting, 105 adefovir, 593
Acquired immunodeficiency syndrome
mixed acting, 105 alkyl sulfones, 635
(AIDS), 594
pharmacological actions, 106 aloesetron, 422
ACT, see Artemisinin-based combination
uses, 116 alpha-adrenergic blocking agents, 121
therapy
Adrenergic system and drugs, 102; alpha-glucosidase inhibitor, 488
ACTH, see Adrenocorticotropic
see also Adrenaline use; aminoglycosides, 547–548
hormone
Adrenergic receptors; ampicillin, 516
Actinomycin D, 640
Amphetamine; Catecholamine antacids, 397
Active transport, 14; see also Drug
pharmacological actions; anthranilic acid derivatives, 318
transport
Dopamine; Ephedrine; antihistaminics, 286
Active tubular secretion, 31; see also
Isoprenaline antimony compounds, 587
Drug excretion
adrenaline pharmacological actions, antipsychotics, 233–234
Acute myocardial infarction
106 aspirin, 379
(AMI), 113
adverse reactions, 108 atovaquone, 576
Acyclovir, 590; see also Antiviral drugs
anorectics, 119 azathioprine, 651
AD, see Alzheimer’s disease
blockade of receptors, 106 barbiturates, 214
Adalimumab, 331; see also Antirheumatic
bronchodilation, 107 β blockers, 130
drugs
catecholamines biosynthesis, 103 biguanides, 487
Adefovir, 593
classification, 105 bile acid-binding resins, 389
Adenosine A1 receptors antagonists, 191;
contraindications, 108 bisacodyl, 418
see also Diuretics
Dale’s vasomotor reversal, 106 bleomycin, 640
Adenosine triphosphate (ATP), 68
dobutamine, 113 bromocriptine, 438
Adenylyl cyclase (AC), 44
fenoldopam, 113 BZDs, 210

655
656 Index

Adverse drug reactions (ADRs) idoxuridine, 591 proton pump inhibitors, 398
(Continued) imipenem, 522 pyrazinamide, 557
calcium channel blockers, 152 insulin, 484 quiniodochlor, 584
camptothecins, 639 interferons, 593 racecadrotil, 428
carcinogenicity and mutagenicity, 58 interleukins, 364, 643 raltegravir, 599
cephalosporins, 521 iodine and iodides, 445 side effects, 56
cholinomimetics, 74 iodoquinol, 584 sirolimus, 650
clavulanic acid, 519 iron, 359 sparfloxacin, 532
clindamycin, 551 itraconazole, 607 streptomycin, 557
clofazimine, 565 ivermectin, 617 streptozocin, 635
clomiphene citrate, 452 ketoconazole, 605 sulfonylureas, 486
clonidine, 428 lamivudine, 596 suramin sodium, 588
colchicine, 335 L-asparginase, 641 taxanes, 639
cycloserine, 558 levodopa, 241 tegaserod, 422
dehydroemetine, 583 liquid paraffin, 417 teicoplanin, 551
delavirdine, 598 local anesthetics, 256 temocillin, 517
depolarizing blockers, 97 lumefantrine, 572 teratogenicity, 59
diethylcarbamazine, 616 maraviroc, 599 terbinafine, 608
diloxanide furoate, 583 mebendazole, 612 thalidomide, 644, 653
diuretics, 184 mebeverine, 422 thiacetazone, 558
domperidone, 411 mefloquine, 572 thiazide diuretics, 187
dopamine receptor agonists, 243 meglitinide analogs, 487 thiazolidinediones, 488
doxorubicin, 640 methanamine mandelate, 528 thioamides, 442
dronabinol, 413 methotrexate, 637 thrombolytics, 384
drotaverine, 429 methylxanthines, 276, 342 toxic effects, 56
drug dependence, 57 metoclopramide, 410 types of, 56–59
echinocandins, 609 metronidazole, 582 vinca alkaloids, 639
EDTA, 648 mifepristone, 456 warfarin, 375
eicosanoids, 298 mitomycin C, 640 zalcitabine, 596
emetine, 583 mood stabilizers, 228 Aerosols in asthma, 350; see also
emtricitabine, 596 moxifloxacin, 532 Bronchial asthma
enfuvirtide, 599 mycophenolatemofetil, 650 AHG, see Antihemophilic globulin
epipodophyllotoxins, 639 nephrotoxic reactions, 58 AIDS, see Acquired immunodeficiency
ergot alkaloids, 293 neurokinin receptor antagonists, 413 syndrome
erythropoietin, 363 nevirapine, 598 Albendazole, 613; see also Anthelmintics
estrogens, 451 niacin, 390 Alcohol, 200, 625; see also Antiseptics
ethambutol, 557 nitazoxanide, 584 disulfiram, 203
ethionamide, 558, 565 of nitrates, 156 drugs for dependence, 203
fluconazole, 606 nitrofurantoin, 528 ethyl alcohol, 201
flucytosine, 603 nonsystemic antacids, 397 methyl alcohol, 204
folate antagonist, 575 nootropics, 277 pharmacokinetics, 202
foscarnet, 591 ocular reactions, 58 Aldehydes, 627; see also Antiseptics
ganciclovir, 591 opioid analgesics, 264 ALG, see Antilymphocyte globulin
gatifloxacin, 532 ototoxic reactions, 58 Alkalones, 320; see also Nonsteroidal
glycoprotein IIB/IIIA receptor oxazolidinones, 553 anti-inflammatory
antagonists, 381 para-aminosalicylic acid, 558 drugs
gold salts, 333 paracetamol, 324 Alkylating agents, 634, 635; see also
heparin, 371 pentamidine, 587 Cancer chemotherapy
hepatotoxic reactions, 58 peripheral skeletal muscle relaxant, 93 Alkyl sulfones, 635; see also Cancer
histamine, 284 pharmacovigilance, 61 chemotherapy
HMG-CoA reductase inhibitors, 387 phenolphthalein, 418 Allopurinol, 336, 587
5-HT3RA, 408 photosensitivity reactions, 58 Aloesetron, 422
hydroxyurea, 644 platinum-containing compounds, 636 Alpha-adrenergic blocking agents
hyoscine, 412 postcoital pill, 461 (α blockers), 120; see also
hypersensitivityreactions, 56 principles of treatment of poisoning, 60 Non selective α blockers;
iatrogenic diseases, 58 probenecid, 337 Selective α1 blockers;
idiosyncrasy, 57 progestins, 455 Selective α2 blockers
 Index 657

adverse drug reactions, 121 Anakinra, 332; see also Antirheumatic bithionol, 612
classification, 120 drugs diethylcarbamazine, 616
pharmacological actions, 121 Analeptics, see Respiratory stimulants doxycycline, 618
uses of, 124–125 Analgesics, 260; see also Nonsteroidal ivermectin, 617
α blockers, see Alpha-adrenergic anti-inflammatory drugs; levamisole, 615
blocking agents Opioid analgesics mebendazole, 612
Alpha-glucosidase inhibitor, 485, 488; see aspirin-type vs. opioid-type, 300 metrifonate, 612
also Oral antidiabetic agents Androgens, 452, 465 niclosamide, 615
Alteplase, 383 action mechanism, 465 pediculosis treatment, 620
Alzheimer’s disease (AD), 240; see also adverse effects, 466 piperazine citrate, 614
Dopamine anabolic steroids, 467 praziquantel, 614
benserazide, 242 antiandrogens, 468 pyrantel pamoate, 614
carbidopa, 242 classification, 465 for scabies, 620
central anticholinergics, 244 male contraceptives, 469 Anthranilic acid derivatives, 318;
drugs for, 245 for male sexual dysfunction, 469 see also Nonsteroidal anti-
AMAs, see Antimicrobials agents physiology, 465 inflammatory drugs
Amebiasis, 581; see also Antiamebic precautions and contraindications, Anthraquinones, 418
drugs 466 Antiamebic drugs, 581
treatment of, 586 therapeutics, 466 chloroquine, 585
AMI, see Acute myocardial infarction Anesthesia, balanced, 253; see also classification of, 581
Amidinopenicillins, 518; see also General anesthetics dehydroemetine, 583
Penicillins Anesthetic partial pressure in brain, diloxanide furoate, 583
Amifostine, 643 factors of, 247 emetine, 583
Amikacin, 550, 558; see also Angina pectoris, 153 iodoquinol, 584
Aminoglycosides; antianginals, 154 metronidazole, 582
Chemotherapy of tuberculosis pharmacotherapy, 159 nitazoxanide, 584
Aminoglycosides, 545 treatment, 161 ornidazole, 582
action mechanism, 546 Angiotensin-converting enzyme (ACE), paromomycin, 585
ADRs, 547–548 139 quiniodochlor, 584
amikacin, 550 Angiotensin-converting enzyme secnidazole, 582
framycetin, 550 inhibitors (ACEIs), 137 tetracycline, 585
gentamicin, 549 adverse dtrug reactions, 139 tinidazole, 582
neomycin, 550 uses and contraindications, 140 Antiandrogens, 468, 642; see also
netilmicin, 550 Angiotensin II receptor blockers (ARBs), Androgens
pharmacokinetics, 547 137, 141 Antianginals, 154; see also Angina
precautions, 548 Anion inhibitors, 444; see also pectoris
properties, 545 Antithyroid drugs combination of, 160
resistance mechanism, 546 Anisoylated plasminogen streptokinase Antiarrhythmics, 173
spectrum, 546 activator complex (APSAC), arrythmias, 173
streptomycin, 550 383 class IB drugs, 177
Aminopenicillin, 516; see also Anistreplase, 383 class IC drugs and class II drugs, 178
Penicillins ANP, see Atrial natiuretic peptide classification of, 174
Aminosalicylates, 423 ANS, see Autonomic nervous system class III drugs and amiodarone, 179
Amiodarone, 179 Antabuse reaction, 203 class IV drugs and miscellaneous
Amoxicillin, 516; see also Beta-lactam Antacids; see also Peptic ulcer treatment agents, 180
antibiotics drugs disopyramide, 176
Amphetamine, 115; see also Adrenergic adverse dtrug reactions, 397 procainamide, 176
system and drugs nonsystemic, 396 quinidine, 175
Amphotericin B (AMB), 587; see also systemic, 395 sodium channel blockers, 175, 176
Antifungal drugs Antagonism, 50; see also uses of class 1A drugs, 176
antifungal drugs, 601 Pharmacodynamics Antibiotics, 551; see also Broad-spectrum
Ampicillin, 516; see also Beta-lactam Anterior pituitary hormones, 434; antibiotics
antibiotics see also Hypothalamic and bacitracin, 552
Amylin analogs, 490; see also Diabetes pituitary hormones clindamycin, 551
mellitus drug Anthelmintics, 612, 619 colistin, 552
Anabolic steroids, 467; see also albendazole, 613 daptomycin, 553
Androgens benzimidazoles, 612 fosfomycin, 553
658 Index
Antibiotics (Continued)
glycopeptides, 551
lincosamides, 551
mupirocin, 552
oxazolidinones, 553
polymyxin, 552
polypeptide antibiotics, 552
sodium fusidate, 552
streptogramins, 553
teicoplanin, 551
Anti-B lymphocyte antibody, 332; see
also Antirheumatic drugs
Anticancer agents; see also Cancer
chemotherapy
adverse effects of, 632
antibiotics, 640
classification of, 633
resistance to, 646
Anticholinergics, 86, 340, 343, 412; see
also Antiemetics; Bronchial
asthma
actions, 87
adverse effects, 88
classification, 86
uses, 89–90
Anticholinesterases (AntiChE), 72, 79,
411; see also Anticholinergics
classification of, 79
irreversible, 83
uses of reversible, 81–82
Anticoagulants, 369
classification, 369
heparin adverse reactions, 371
heparin antagonist and LMW
heparin, 372
heparinoids, 373
heparin synthetic derivatives, 373
heparin vs. dicumarol/warfarin, 378
heparin vs. LMW heparin, 378
oral anticoagulants, 374
oral direct thrombin inhibitors, 377
parenteral anticoagulants, 370
parenteral direct thrombin inhibitors,
373
protamine sulfate, 372
warfarin adverse reactions, 375
warfarin interactions, 376
Anticonvulsant, 115; see also
Antiepileptics; Barbiturates
Antidepressants, 222
atypical antidepressants, 224
classification, 222
5-HT2 antagonists, 224
moclobemide, 225
monoamine oxidase inhibitors, 225
selective serotonin norepinephrine
reuptake inhibitors, 224
selective serotonin reuptake used in superficial mycoses, 610
inhibitors, 222 Antihemophilic globulin (AHG), 367
tricyclic antidepressants, 223 Antihepatitis drugs, 589, 593; see also
uses of, 226 Antiviral drugs
Antidiuretics, 193; see also Diuretics Antiherpes drugs, 589, 590, 591; see also
Antiemetics; see also Emetics Antiviral drugs
adjuvants, 414 Antihistamines, 351
anticholinergics, 412 adverse effects, 286
anticholinesterases, 411 pharmacological actions, 285
antihistaminics, 412 uses, 287
cannabinoids, 413 Antihistaminics, 244, 412; see also
cholinomimetics, 411 Antiemetics
classifications of, 407 Anti-H pylori agents, 403; see also Peptic
domperidone, 411 ulcer treatment drugs
dopamine D2 receptor antagonists, Antihypertensives, 136
409 adverse reactions, 139
5-HT3 receptor antagonists, 408 angiotensin-converting enzyme
metoclopramide, 410 inhibitors, 139, 140
motilin receptor agonists, 411 angiotensin II receptor blockers, 141
neurokinin receptor antagonists, 413 calcium channel blockers, 144
neuroleptic, 413 classification, 137
preferred antiemetics, 414 combination of, 147
Antiepileptics, 215, 227; see also Mood diuretics, 138
stabilizers drug interactions with, 147
benzodiazepines, 220 HT in pregnancy, 147
carbamazepine, 218 hypertensive crisis, 147
classification and action mechanism, management of HT, 146
215 sympatholytics, 142–143
ethosuximide, 218 vasodilators, 145
newer antiepileptics, 221 Anti-IgE antibody, 340, 347; see also
phenobarbitone, 217 Bronchial asthma
phenytoin, 216 Anti-inflammatory drugs, 340; see also
valproic acid, 219 Bronchial asthma
Antiestrogens, 452; see also Estrogens action mechanism, 344
Antifibrinolytics, 385; see also inhalation steroids, 345
Thrombolytics uses, 345
Antifoaming agents, 402; see also Peptic Anti-influenza drugs, 589
ulcer treatment drugs Antiinfluenza virus agents, 592; see also
Antifungal drugs, 600 Antiviral drugs
amphotericin B, 601 Antilymphocyte globulin (ALG),
antibiotics, 601 649, 652; see also
antimetabolites, 603 Immunosuppressants
azoles, 604 Antimalarials, 567; see also
ciclopirox olamine, 610 Chemotherapy of malaria
classification of, 600 Antimanic drugs, see Mood stabilizers
echinocandins, 609 Antimetabolites, 603, 637; see also
fluconazole, 606 Antifungal drugs; Cancer
flucytosine, 603 chemotherapy
griseofulvin, 602 Antimicrobial resistance, 506, 507;
itraconazole, 607 see also Antimicrobials agents
ketoconazole, 605 Antimicrobials agents (AMAs), 504;
nikkomycins, 610 see also Chemotherapy
nystatin, 602 classifications, 504, 505
selenium sulfide, 610 combinations, 510
sordarins, 610 resistance, 506, 507
for systemic infections, 611 selection of, 508–509
terbinafine, 608 superinfection, 512
 Index 659

Antimony compounds, 587 etanercept, 331 anti-TNF, see Anti-tumor necrosis

Antimotility agents, 427; see also gold salts, 333 factors
Diarrhea treatment drugs hydroxychloroquine, 334 Anti-tumor necrosis factors (anti-TNF),
Antimuscarinic agents, 400; see also IL-1 antagonist, 332 424
Peptic ulcer treatment drugs immunoadsorption apheresis, 334 Antitussives, 351; see also Cough
Antimuscarinics, see Anticholinergics immunosuppressants, 329 treatment
Antiparkinsonian drugs, 240; see also inhibitors of T-cell activation, 332 Antiviral drugs, 589
Parkinsonism treatment NSAIDs, 329 acyclovir, 590
Antiplatelet agents, 379 pencillamine, 334 antihepatitis drugs, 593
aspirin, 379 rituximab, 332 antiherpes agent, 590, 591
cilostazol, 381 sulfasalazine, 334 antiinfluenza virus agents, 592
classification, 379 TNFα blocking agents, 330 antiretroviral drugs, 594
glycoprotein IIB/IIIA receptor Antisecretory agents, 427, 428; see also classification, 589
antagonists, 381 Diarrhea treatment entry inhibitor, 599
phosphodiesterase inhibitors, 380 drugs non-nucleoside reverse transcriptase
prostacyclin, 381 Antiseptics, 621 inhibitors, 598
purinergic receptor antagonists, 380 acids, 628 nucleoside reverse transcription
uses of, 382 alcohols, 625 inhibtors, 595, 596
Antiprogestins, 456; see also Progestins aldehydes, 627 protease inhibitors, 597
Antiproliferative agents, 650; see also biguanides, 622 Anxiolytics (nonbenzodiazepines), 239;
Immunosuppressants chloroxylenol, 623 see also Antipsychotics
Antipseudomonal penicillins, 517; classification, 621 Apparent vd (Avd), 21
see also Penicillins cresol, 623 Appetite suppressants, 105
Antipsychotics, 227, 230; see also Mood dyes, 630 Applied pharmacokinetics, 33; see also
stabilizers ethylene oxide, 629 Pharmacokinetics
adverse effects, 233–234 gases, 629 Apraclonidine, 78
anxiolytics, 239 halogens, 624 APSAC, see Anisoylated plasminogen
aripiprazole, 237 hydrogen peroxide, 630 streptokinase activator
atypical, 237 lysol, 623 complex
butyrophenones, 236 metallic salts, 626 Arachidonic acid (AA), 302
chlorpromazine, 231–232 oxidizing agents, 630 Arginine antagonists (AVP), 191
classification, 230 phenols, 623 Aripiprazole, 237; see also Antipsychotics
clozapine, 237 potassium permanganate, 630 Arrythmias, 173; see also
drug interactions and uses, 235 silver nitrate, 626 Antiarrhythmics
individual, 236 silver sulfadiazine, 626 Artemisinin, 577–578; see also
loxapine, 238 surface active agents, 625 Chemotherapy of malaria
olanzapine, 237 triclosan, 623 Artemisinin-based combination
phenothiazines, 236 zinc sulfate, 626 therapy (ACT), 578; see also
pimozide, 238 Antispasmodics, 422, 429; see also Chemotherapy of malaria
quetiapine, 237 Diarrhea treatment drugs Aryl-actetic acid derivatives, 321;
reserpine, 238 Anti-TB drugs, 58; see also see also Nonsteroidal anti-
risperidone, 237 Chemotherapy of tuberculosis inflammatory drugs
thioxanthines, 236 classification of, 554 ASA, see Acetyl salicylic acid
Antiretroviral drugs, 589, 594; see also doses, 560 Aspirin, 379; see also Acetyl salicylic
Antiviral drugs Antithymocyte antibodies (ATG), acid; Antiplatelet agents;
Anti-Rh(d) immunoglobulin, 652; see 649, 652; see also Nonsteroidal anti-
also Immunosuppressants Immunosuppressants inflammatory drugs;
Antirheumatic drugs, 328, 334 Antithyroid drugs, 439; see also Thyroid Salicylates
abatacept, 332 hormones drug interactions, 314
adalimumab, 331 anion inhibitors, 444 pharmacokinetic, 308
adjuvants, 334 classification of, 441 restriction of, 314
anakinra, 332 iodine and iodides, 445 -type of analgesics, 300
anti-B lymphocyte antibody, 332 management of thyrotoxic ATG, see Antithymocyte antibodies
antirheumatic drugs, 334 crisis, 447 Atovaquone, 576; see also Chemotherapy
biological agents, 330–331 propylthiouracil vs. methimazole, 448 of malaria
chloroquine, 334 radioactive iodine, 446 ATP, see Adenosine triphosphate
classification, 328 thioamides, 442–443 Atrial natiuretic peptide (ANP), 164
660 Index

Atropine derivatives, 244 Beta-adrenergic blockers (β blockers), agents, 330–331

Attention deficit hyperactivity disorder 126, 172; see also Cholinergic membranes, 13
(ADHD), 115, 116, 226 system and drugs response modifiers, 424, 643
Atypical antidepressants, 224; see also adverse reactions, 130 Biotransformation, 24
Antidepressants as antianginals, 158 Bisacodyl, 418
Autacoids, 282 cardioselective, 132 Bisphosphonates, 495; see also Calcium
Autonomic afferents, 67 classification, 126 balance, agents affecting
Autonomic nervous system (ANS), 66 contraindications, 131 Bithionol, 612; see also Anthelmintics
adrenal medulla, 67, 68 drug interactions, 131 Bleomycin, 640
autonomic afferents, 67 in glaucoma, 77 Blockade therapy, 57
innervations of, 67 individual, 133 Blood–brain barrier (BBB), 22; see also
neurotransmitters, 68 partial agonists, 132 Pharmacokinetics
Avd, see Apparent vd pharmacokinetics, 128 Bound drug, 20
Aversion therapy, 57 pharmacological actions, 127 Brain, anesthetic partial pressure
AVP, see Arginine antagonists uses, 128–129 in, 247
Azathioprine, 651; see also β blockers, see Beta-adrenergic blockers British anti-Lewisite (BAL), 648
Immunosuppressants Beta-lactam antibiotics, 513 Broad-spectrum antibiotics, 535
Azithromycin, 534; see also Macrolides amidinopenicillins, 518 chloramphenicol, 542–543
Azoles, 604; see also Antifungal drugs aminopenicillin, 516 doxycycline, 540
imidozoles, 604 amoxicillin, 516 minocycline, 540
topical azoles, 608 ampicillin, 516 tetracyclines, 535–540
triazoles, 604 antipseudomonal penicillins, 517 tetracycline vs. doxycycline, 541
AZT, see Zidovudine bacampicillin, 516 tigecycline, 544
β-lactamase inhibitors, 519 Bromocriptine, 438, 490; see also
carbacephems, 524 Diabetes mellitus drugs
B
carbapenems, 522–523 Bronchial asthma
BA, see Bioavailability carbenicillin, 517 aerosols in, 350
BAB resins, see Bile acid binding resins carboxypenicillins, 517 anticholinergics, 340, 343
Bacampicillin, 516; see also Beta-lactam cephalosporins, 520–521 anti-IgE antibody, 340, 347
antibiotics clavulanic acid, 519 anti-inflammatory drugs, 340, 344,
Bacitracin, 552; see also Antibiotics ertapenem, 523 345
BAL, see British anti-Lewisite imipenem, 522 bronchodilators, 340
Balanced anesthesia, 253; see also mecillinam, 518 drug classification, 340
General anesthetics meropenem, 523 inhalation technique, 350
Barbiturates; see also Antiepileptics monobactams, 524 LT receptor antagonists, 340
action mechanism, 213 natural penicillins, 514 mast cell stabilizers, 340, 346
advantages of BZDs over, 209 penicillins, 513 methylxanthines, 340, 342
classification, 213 pivmecillinam, 518 sympathomimetics, 340, 341
pharmacokinetics, 214 semisynthetic penicillins, 515 treatment of, 348
pharmacological action, 213 temocillin, 517 Bronchodilators, 105, 340; see also
phenobarbitone, 214 ticarcillin, 517 Bronchial asthma
Basic drugs, 20 ureidopenicillins, 518 Bulk laxatives, 416; see also Constipation
BBB, see Blood–brain barrier β-lactamase inhibitors, 519; see also treatment drugs
BCG vaccine, 653 Beta-lactam antibiotics Bupivacaine, 257
Benoxinate, 257 Biers’ block, 259 Buprenorphine, 272; see also Opioid
Benserazide, 242 Biguanides, 485, 487, 622; see also analgesics
Benzbromarone, 337 Antiseptics; Oral antidiabetic Bupropion, 280; see also Central nervous
Benzimidazoles, 612; see also agents system stimulants
Anthelmintics Bile acid binding resins (BAB resins), Butyrophenones, 236; see also
Benznidazole, 588 389, 490; see also Diabetes Antipsychotics
Benzocaine, 257 mellitus drugs; Hypolipidemic BZDs, see Benzodiazepines
Benzodiazepines (BZDs), 220, 252, 414; drugs
see also Antiepileptics; General Bile for drug excretion, 32
C
anesthetics Bioavailability (BA), 18
advantages, 209 Bioequivalence, 18; see also CA, see Carbonic anhydrase
uses and BZD antagonist, 211 Pharmacokinetics Caffeine, 278; see also Central nervous
Benzonatate, 351 Biological; see also Antirheumatic drugs; system stimulants
β adrenergic agonists, 172 Cancer chemotherapy CAIs, see Carbonic anhydrase inhibitors

Calcineurin inhibitors, 649; see also
Immunosuppressants
Calcitonin, 493; see also Calcium
balance, agents affecting
Calcitonin–gene related protein (CGRP),
294
Calcium balance, agents affecting, 491
bisphosphonates, 495
calcitonin, 493
calcium preparations and uses, 491
drug abuse in sports, 496
osteoporosis prevention and
treatment, 496
parathyroid hormone, 492
vitamin D, 494
Calcium channel blockers (CCBs), 137,
144, 148, 500
as antianginals, 158
classification and action mechanism,
149
indications, 151
interactions and ADRs, 152
pharmacokinetics, 150
Calcium channels, 148
Calcium preparations and uses, 491;
see also Calcium balance,
agents affecting
Camptothecins, 639; see also Cancer
chemotherapy
Cancer chemotherapy, 631
adverse effect prevention, 632
adverse effects, 632
alkylating agents, 634, 635
alkyl sulfones, 635
anticancer antibiotics, 640
antimetabolites, 637
biological response modifiers, 643
camptothecins, 639
cell–cycle non-specific drugs, 631, 634
cell cycle phases, 631
chlorambucil, 635
classification, 633
cyclophosphamide, 634
enzymes, 641
epipodophyllotoxins, 639
folate antagonists, 637
hormonal agents, 642
hydroxyurea, 644
mechlorethamine, 635
melphalan, 635
methotrexate, 637
monoclonal antibodies, 645
natural products, 639
nitrogen mustards, 634
nitrosureas, 635
plant products, 639
platinum-containing compounds, 636
procarbazine, 635
protein tyrosine kinase inhibitors, 644
purine antagonists, 638
pyrimidine antagonist, 638
radioactive isotopes, 645
resistance to anticancer drugs, 646
streptozocin, 635
taxanes, 639
thalidomide, 644
treatment principles, 646
vinca alkaloids, 639
Cannabinoid (CB), 280, 413; see also
Antiemetics; Central nervous
system stimulants
Capreomycin, 558; see also
Chemotherapy of tuberculosis
Carbacephems, 524; see also Beta-lactam
antibiotics
Carbamazepine, 218, 229; see also
Antiepileptics; Mood
stabilizers
Carbapenems, 522–523; see also Beta-
lactam antibiotics
Carbenicillin, 517; see also Beta-lactam
antibiotics
Carbenoxolone, 402; see also Peptic ulcer
treatment drugs
Carbidopa, 242
Carbimazole, see Methimazole
Carbonic anhydrase (CA), 189; see also
Diuretics
Carbonic anhydrase inhibitors (CAIs),
78, 189; see also Cholinergic
system and drugs; Diuretics
Carboplatin, 636
Carboxypenicillins, 517; see also Beta-
lactam antibiotics
Carcinogenicity and mutagenicity, 58; see
also Adverse drug reactions
Cardiac glycosides, 165; see also
Congestive cardiac failure
adverse effects, 168
and cardiac failure treatment, 163
drug interactions, 169
pharmacokinetics, 166, 167
Cardiac output (CO), 136
Cardiac stimulant, 105, 111
Cardioselective β blockers, 132; see also
Beta-adrenergic blockers
Castor oil, 418
CAT, see Choline acetyltranferase
Catecholamine pharmacological actions,
106; see also Adrenergic system
and drugs
cardiac stimulant, 106
eye, 107
metabolic effects, 107
pharmacokinetics, 104
skeletal muscles, 107
Index 661
smooth muscles, 107
Catecholamines, endogenous, 103
CB, see Cannabinoid
CBG, see Corticosteroid binding globulin
CBS, see Colloidal bismuth subcitrate
CCBs, see Calcium channel blockers
CCK, see Cholecystokinin
CCR5 receptor antagonist, 599
CDER, see Center of Drug Evaluation
and Research
CDSCO, see Central Drugs Standard
Control Organization
Cell cycles; see also Cancer chemotherapy
non-specific drugs, 631, 634
phases of, 631
Centchroman, 464; see also Hormonal
contraceptives
Center of Drug Evaluation and Research
(CDER), 62
Central anticholinergics, 244
Central cough suppressants, 351; see also
Cough treatment
Central Drugs Standard Control
Organization (CDSCO), 61
Centrally acting agents, 142; see also
Sympatholytics
Central nervous system (CNS), 200
depressants, 278
Central nervous system stimulants, 105,
274, 278
cannabinoids, 280
classification, 274
drugs for tobacco withdrawal, 280
hallucinogens, 279
methylxanthines, 276
nootropics, 277
opioids and CNS depressants, 278
psychomotor stimulants, 275
respiratory stimulants, 274
Cephalosporins (CP), 520; see also Beta-
lactam antibiotics
ADRs and use, 521
CGRP, see Calcitonin–gene related
protein
Chelating agents, 648
Chemical
drug name, 3
pharmacology, 2
Chemoprophylaxis, 511; see also
Chemotherapy; Chemotherapy
of tuberculosis
for malaria, 579
of TB, 563
Chemoreceptor Trigger Zone (CTZ), 22
Chemotherapy, 2, 504; see also
Antimicrobials agents
chemoprophylaxis, 511
classification, 506
662 Index
Chemotherapy (Continued)
factors influencing, 506
notable scientists, 504
of sexually transmitted diseases, 530
urinary analgesics, 529
of UTI, 528
Chemotherapy of malaria, 567
antimalarials classification, 567
artemisinin and derivatives, 577–578
atovaquone, 576
chemoprophylaxis regimens, 579
chloroquine, 568–571
folate antagonist, 575
halofantrine, 572
mefloquine, 572
primaquine, 573
proguanil, 576
quinine, 574
treatment regimens, 580
Chemotherapy of tuberculosis, 554
chemoprophylaxis, 563
doses of drugs, 560
DOTS, 562
drug classification, 554
ethambutol, 557
first-line drugs, 555
multidrug-resistant tuberculosis, 563
for Mycobacterium avium complex,
563
pyrazinamide, 557
rifampicin, 556
role of glucocorticoids in TB, 563
second-line drugs, 558
streptomycin, 557
TB in HIV patients, 563
TB in pregnancy, 563
treatment regimens, 562
WHO treatment guidelines, 561
Chlorambucil, 635; see also Cancer
chemotherapy
Chloramphenicol; see also Broad-
spectrum antibiotics
action mechanism, 542
adverse effects, 543
pharmacokinetics, 542
resistance, 542
uses, 543
Chloride channel activator, 420; see also
Constipation treatment drugs
Chloroguanide, 576; see also
Chemotherapy of malaria
Chloroquine, 334, 585; see also
Antiamebic drugs;
Antirheumatic drugs;
Chemotherapy of malaria
action mechanism, 568
contraindications, 571
pharmacokinetics, 569
uses, 570
Chloroxylenol (Dettol), 623; see also
Antiseptics
Chlorpromazine (CPZ), 227, 231; see
also Antipsychotics; Mood
stabilizers
action mechanism, 231
pharmacological actions, 232
Chlorthalidone, 187; see also Diuretics
Cholecystokinin (CCK), 68
Choline acetyltranferase (CAT), 70
Choline esters, 72
Cholinergic blocking drugs, see
Anticholinergics
Cholinergic receptors, 71
Cholinergic system and drugs, 69, 72
ACh and cholinomimetics, 74
ACh metabolism, 70
actions of ACh, 73
adrenergic agonists in glaucoma, 78
adverse reactions of cholinomimetics,
74
anticholinesterases, 79
β blockers in glaucoma, 77
carbonic anhydrase inhibitors, 78
cholinergic receptors, 71
cholinesterases, 70
cholinomimetic alkaloids, 75
donepezil, 81
edrophonium, 81
galantamine, 81
glaucoma, 76
irreversible AntiChE, 83
miotics in glaucoma, 78
neostigmine, 80
organophosphorus poisoning, 84
physostigmine, 80, 85
prostaglandin analogs in glaucoma,
78
reversible AntiChE uses, 81–82
rivastigmine, 81
tacrine, 81
Cholinesterases, 70; see also Cholinergic
system and drugs
inhibitors, 245
Cholinomimetics, 411; see also
Antiemetics; Cholinergic
system and drugs
adverse reactions of, 74
alkaloids, 72, 75
uses of, 74
Chronic lymphatic leukemia (CLL), 635
Chronic myeloid leukemia (CML), 635
Chronic obstructive pulmonary disease
(COPD), 87, 349; see also
Bronchial asthma
Ciclopirox olamine, 610; see also
Antifungal drugs
Cidofovir, 591
Cilostazol, 381; see also Antiplatelet
agents
Cimetidine, 399
Ciprofloxacin, 532; see also Quinolones
Cisplatin, 636
CL, see Clearance
Clarithromycin, 534; see also Macrolides
Class IA drugs, 175, 176
Class IB drugs, 177
Class IC drugs, 178
Class II drugs, 178
Class III drugs, 179
Class IV drugs, 180
Clavulanic acid, 519; see also Beta-lactam
antibiotics
Clearance (CL), 33
Clindamycin, 551; see also Antibiotics
Clinical trial phases, 62; see also New
drug approval process
human microdosing studies, 63
Phase 0,1 and 2, 63
Phase 3 and 4, 64
CLL, see Chronic lymphatic leukemia
Clofazimine, 565; see also Leprosy
chemotherapy
Clomiphene citrate, 452
Clonidine, 100, 428; see also Diarrhea
treatment drugs; Tizanidine
Clotting factors, 366–367; see also
Hemostatic agents
Clozapine, 237, 292; see also
Antipsychotics
CML, see Chronic myeloid leukemia
CMV, see Cytomegalovirus
CNS, see Central nervous system
CO, see Cardiac output
Cocaine, 275, 278; see also Central
nervous system stimulants
Codeine, 267, 351; see also Opioid
analgesics
Colchicine, 335
Colistin, 552; see also Antibiotics
Colloidal bismuth subcitrate (CBS), 394
Congeners, 249; see also General
anesthetics
Congestive cardiac failure (CCF), 23, 113,
129, 164; see also Adrenergic
system and drugs; Cardiac
glycosides
diuretics, 170, 182
drug interactions, 169
drugs for, 170
positive inotropic agents, 172
vasodilators, 171

Constipation causing drugs, 421
Constipation treatment drugs, 415
bulk laxatives, 416
chloride channel activator, 420
classification of drugs, 415
glycerine, 419
5-HT4 receptor agonist, 420
lactilol, 419
lactulose, 419
laxative abuse, 421
nonpharmacological measures, 421
opioid antagonists, 420
osmotic purgatives, 419
purgatives, 420
sorbitol, 419
stimulant purgatives, 418
stool softeners, 417
Continuous subcutaneous insulin
infusion (CSII), 483
COPD, see Chronic obstructive
pulmonary disease
Corticosteroid binding globulin (CBG),
471
Corticosteroids, 414, 470
action mechanism and
pharmacokinetics, 471
adverse effects, 475–476
contraindications, 477
glucocorticoid actions, 472
preparations and classifications, 478
structure synthesis and release, 470
therapeutic uses, 473–474
Corticotropin, 436; see also
Hypothalamic and pituitary
hormones
Corticotropin-releasing factor (CRF),
433, 470; see also Hypothalamic
and pituitary hormones
Cotrimoxazole, 527; see also
Sulfonamides
Cough inducing drugs, 353
Cough treatment, 351
antitussives, 351
central cough suppressants, 351
expectorants, 352
mucolytics, 353
pharyngeal demulcents, 352
Coupling, 42; see also Drug receptor
interaction theories
COX, see Cyclooxygenase
COX-2 inhibitors; see also Nonsteroidal
anti-inflammatory drugs
preferrential, 322
selective, 326
CP, see Cephalosporins
CPP, see Cyclopenta(a) phenanthrenes
Cresol, 623; see also Antiseptics
Index 663
CRF, see Corticotropin-releasing factor amylin analogs, 490
CSII, see Continuous subcutaneous bile acid-binding resins, 490
insulin infusion bromocriptine, 490
CTZ, see Chemoreceptor Trigger Zone incretins, 489
Cyanocobalamin, see Vitamin B12 sodium-glucosecotransporter-2
Cyclooxygenase (COX), 295, 302 inhibitors, 490
Cyclopenta(a) phenanthrenes(CPP), 470 Diacylglycerol (DAG), 44, 104, 227
Cyclophosphamide, 634, 651; see also Diaminodiphenyl sulfone (DDS), 564,
Cancer chemotherapy; 565
Immunosuppressants Diarrhea treatment drugs, 425
Cycloplegia, 87 antimotility and antisecretory agents,
Cycloserine, 558; see also Chemotherapy 427
of tuberculosis antispasmodics, 429
Cyclosporine, 649; see also ORS, 425
Immunosuppressants probiotics, 428
Cyproheptadine, 292 specific therapy, 426
Cyproterone acetate, 468 Dibucaine, 257
Cytomegalovirus (CMV), 590 DIC, see Disseminated intravascular
Cytotoxic agents, 651; see also coagulation
Immunosuppressants Diclofenac, 321
Dicyclomine, 412
Didanosine, 596; see also Nucleoside
D
reverse transcriptase inhibitors
DA, see Dopamine Dietary cholesterol absorption inhibitor,
DAB12, see Deoxyadenosylcobalamin 391; see also Hypolipidemic
Dale’s vasomotor reversal (Dale’s drugs
phenomena), 106 Diethylcarbamazine (DEC), 616; see also
Dapsone, see Diaminodiphenyl sulfone Anthelmintics
Daptomycin, 553; see also Antibiotics Differential blockade, 255
DDS, see Diaminodiphenyl sulfone Diffusion, facilitated, 14; see also Drug
DEC, see Diethylcarbamazine transport
Decongestants of nose, 105 Digitalis, 172
Deep vein thrombosis (DVT), 375 Dihydrofolate reductase (DHFR), 527,
Dehydroemetine (DHE), 581, 583; see 637
also Antiamebic drugs Dihydrofolic acid (DHFA), 637
Delavirdine, 598 Dihydropyridine(DHPs), 148, 149
Deoxyadenosylcobalamin (DAB12), 360 adverse effects of, 152
Depolarizing blockers adverse reactions, Diiodotyrosine (DIT), 439
97 Diloxanide furoate (DF), 583; see also
Dermal leishmaniasis (Oriental sore), 588 Antiamebic drugs
Desflurane, 249; see also General Dimercaprol, 648
anesthetics DINV, see Drug-induced nausea and
Dexferrioxamine, 648 vomiting
Dextrans, 194, 195; see also Dioctyl sodium sulfo succinate (DOSS),
Pharmacotherapy of shock 417
Dextromethorphan, 267, 351; see also Diphenylhydantoin, see Phenytoin
Opioid analgesics Dipivefrine, 78
Dextropropoxyphene, 269; see also Directly observed treatment short course
Opioid analgesics (DOTS),
DF, see Diloxanide furoate 561, 562
DHE, see Dehydroemetine Disease modifying antirheumatic drugs
DHFA, see Dihydrofolic acid (DMARDs), 328
DHFR, see Dihydrofolate reductase Disinfectants, 621; see also Antiseptics
DHPs, see Dihydropyridine Disopyramide, 176
Diabetes mellitus drugs, 489; see also Dispositional tolerance, 53
Insulin; Oral antidiabetic Disseminated intravascular coagulation
agents (DIC), 375
664 Index

Dissociative anesthesia, 251; see also Doxycyline, 540; see also Broad- genetic engineered, 3
General anesthetics spectrum antibiotics for glaucoma, 76
Disulfiram, 203 tetracycline vs., 541 for gout, 335
DIT, see Diiodotyrosine Doxylamine, 412 for helmintic infestations, 619
Diuretics, 138, 170, 181; see also D-penicillamine, 648 -induced parkinsonism, 244
Antidiuretics DRC, see Dose–response curve inhibiting acid secretion, 398
adenosine A1 receptors Dronabinol, 413 interactions, 55
antagonists, 191 Drotaverine, 429; see also Diarrhea involved in vomiting, 405
adverse reactions, 184 treatment drugs for male sexual dysfunction, 469
carbonic anhydrase inhibitors, 189 Drug, 2; see also Adverse drug reactions; metabolism, 24
chlorthalidone, 187 Antirheumatic drugs; from microorganisms, 3
classification, 181 Bronchial asthma; Calcium minerals as, 3
differences in, 192 balance, agents affecting; for Mycobacterium avium complex,
drug interactions, 185 Central nervous system 563
ethacrynic acid, 183 stimulants; Constipation name, 3
furosemide vs. spironolactone, 192 treatment drugs; Diarrhea natural, 3
high-efficacy, 182 treatment drugs; Drug non-proprietary, 3
indapamide, 187 receptor; Peptic ulcer treatment oral, 17, 37
loop diuretics, 183 drugs; Pharmacokinetics orphan, 2
metolazone, 187 absorption, 15–16 parenteral, 37
newer, 191 abuse in sports, 496 peripherally acting, 91
osmotic, 190 acidic, 20 from plant, 3
potassium-sparing, 188 action prolonging methods, 37 potency, 47
thiazide, 187 for acute muscle spasm, 100 proprietary, 3
thiazides and thiazide-like, 186 for alcohol dependence, 203 for scabies, 620
thiazide vs. furosemide, 192 allergy, see Hypersensitivity reactions source of, 3
torsemide, 183 for Alzheimer’s disease, 245 synthetic, 3
vasopressin antagonists, 191 from animals, 3 for systemic fungal infections, 611
DMARDs, see Disease modifying antiparkinsonian, 240 for tobacco withdrawal, 280
antirheumatic drugs anti-TB, 58 transport, 14
DOC, see Drug of choice antithyroid, 439 treatment for migraine, 294
Docosanol, 591 basic, 20 unconventional, 227
Domperidone, 411; see also Antiemetics bound, 20 used in superficial mycoses, 610
Donepezil, 81; see also Cholinergic causing constipation, 421 for vertigo, 288
system and drugs causing cough, 353 Drug action; see also Pharmacodynamics
Dopamine (DA), 102, 112, 172, 241, 438; CCF, 170 mechanisms, 39
see also Adrenergic system and centrally acting, 91 principles of, 38
drugs; Alzheimer’s disease; chemical, 3 Drug administration routes, 4; see also
Antiemetics; Hypothalamic class 1A, 176 Specialized drug delivery;
and pituitary hormones class IB, 177 Systemic drug administration
metabolism inhibitors, 243 class IC, 178 Drug effect modifying factors, 51
NA Precursor, 112 class II, 178 age, 51
neurotransmitter, 112 class III, 179 body weight, 51
precursor, 241 class IV, 180 diet and environment, 51
receptor agonists, 243, 409, 438 conventional, 227 diseases, 53
releasers, 242 dependence, 57 dose, 52
Dose–response curve (DRC), 47 for dermal leishmaniasis, 588 genetic factors, 52
Dose–response relationship, 47; see also for diabetes mellitus, 489–490 presence of other drugs, 54
Pharmacodynamics directly acting, 91 psychological factors, 54
DOSS, see Dioctyl sodium sulfo distribution, 19 repeated dosing, 53
succinate dosing factors, 34 route and time of administration, 52
DOTS, see Directly observed treatment drug synergism and antagonism, 50 sex, 51
short course effect modifying factors, 51 species and race, 51
Downregulation, 46 efficacy, 48 Drug excretion, 30; see also
Doxorubicin, 640 essential, 2 Pharmacokinetics
Doxycycline, 618; see also excretion, 30, 31 active tubular secretion, 31
Anthelmintics free, 20 glomerular filtration, 31
 Index 665

through milk, 32 d-Tc, see d-Tubocurarine ER, see Estrogen receptors

other routes of, 32 d-Tubocurarine (d-Tc), 22 Erectile dysfunction, 469
passive tubular reabsorption, 31 DUB, see Dysfunctional uterine bleeding Ergometrine, 501
through saliva, 32 DVT, see Deep vein thrombosis Ergot; see also Non selective α blockers;
Drug-induced nausea and vomiting Dyes, 630; see also Antiseptics Uterine stimulants
(DINV), 235 Dysfunctional uterine bleeding alkaloids, 122, 293
Drug interactions, 55; see also (DUB), 455 derivatives, 498
Pharmacodynamics Ertapenem, 523; see also Beta-lactam
alcohol, 202 antibiotics
E
antacids, 397 Erythema nodosum leprosum (ENL), 566
antihistaminics, 286 EBV, see Epstein–Barr virus Erythropoietin, 363; see also Hematinics
with antihypertensives, 147 Echinocandins, 609; see also Antifungal Essential drugs, 2
antipsychotics, 235 drugs Estrogen receptors (ER), 449
bile acid-binding resins, 389 Edrophonium, 81; see also Cholinergic Estrogens, 468, 642; see also Hormonal
calcium channel blockers, 152 system and drugs contraceptives; Progestins
cardiac glycosides, 169 EDTA, 648 adverse reactions, 451
diuretics, 185 EE, see Ethinyl estradiol antiestrogens, 452
HMG-CoA reductase inhibitors, 387 Efavirenz, 598 pharmacokinetics, 450
insulin, 484 Effector pathways, see Second messengers and progestin preparations, 459
levodopa, 241 Eflornithine, 588 receptor modulators, 453
of nitrates, 156 Eicosanoids, 295 synthesis inhibitors, 453
sulfonylureas, 486 action mechanism, 296–297 types, 449
of warfarin, 376 ADR, 298 Etanercept, 331; see also Antirheumatic
Drug of choice (DOC), 90 synthesis, 295 drugs
Drug receptor, 40; see also uses, 298 Ethacrynic acid, 183; see also Diuretics
Pharmacodynamics EMEA, see European Medicines Agency, Ethambutol, 557; see also Chemotherapy
agonist, 40 the of tuberculosis
antagonist, 40 Emergency contraception, see Postcoital Ethanol, 278; see also Central nervous
enzymatic receptors, 45 pill system stimulants
families, 43 Emetics, 406; see also Antiemetics Ethinyl estradiol (EE), 459
functions, 41 drugs involved in, 405 Ethionamide, 558, 565; see also Leprosy
interaction theories, 42 Emetine, 583; see also Antiamebic drugs chemotherapy; Chemotherapy
inverse agonist, 40 Emtricitabine, 596; see also Nucleoside of tuberculosis
nature, 41 reverse transcriptase inhibitors Ethoheptazine, 269; see also Opioid
nuclear receptor, 46 Enflurane, 249; see also General analgesics
partial agonist, 40 anesthetics Ethosuximide, 218; see also
regulation, 46 Enfuvirtide, 599 Antiepileptics
silent receptors, 41 ENL, see Erythema nodosum leprosum Ethyl alcohol, 201
sites, 41 Enolic acid derivatives, 319; see Ethylene oxide, 629; see also Antiseptics
spare receptor, 41 also Nonsteroidal anti- Etidocaine, 257
substance, 40 inflammatory drugs Etomidate, 250; see also General
transduction mechanisms, 43 Entamoeba histolytica, 581 anesthetics
Drug receptor interaction theories, 42; Entecavir, 593 European Medicines Agency, the
see also Pharmacodynamics Entry inhibitor, 599; see also Antiviral (EMEA), 61
coupling, 42 drugs Excitatory neurotransmitters, 200
lock-and-key relationship, 42 Enzymatic receptors, 45; see also Exemestane, 468
occupation theory, 42 Pharmacodynamics Expectorants, 352; see also Cough
rate theory, 42 Enzymes, 641; see also Cancer treatment
two-state model, 42 chemotherapy;
Drugs acting on uterus, 497 Pharmacokinetics
F
oxytocin vs. ergometrine, 501 induction, 28
uterine relaxants, 500 for metabolism, 27 FA, see Folic acid
uterine stimulants, 497–499 Ephedrine, 114; see also Adrenergic Facilitated diffusion, 14; see also Drug
Drug synergism, 50; see also system and drugs transport
Pharmacodynamics Epipodophyllotoxins, 639; see also Famciclovir, 591
Drug transport, 14; see also Cancer chemotherapy FAS, see Folic acid synthetase
Pharmacokinetics Epstein–Barr virus (EBV), 590 FDA, see Food and Drug Administration
666 Index
FDC, see Fixed-dose combination
Febuxostat, 336
Feces for drug excretion, 32
Fentanyl, 268; see also Opioid analgesics
Fetal hydantion syndrome, 216
Fibrates, see Fibric acids
Fibric acids (Fibrates), 388; see also
Hypolipidemic drugs
Fibrinolytics, see Thrombolytics
Filtration, 14; see also Drug transport
Finasteride, 468, 642
First-dose phenomena, 139
First-order kinetics, 33
First-pass metabolism (presystemic
metabolism), 17; see also
Pharmacokinetics
Fixed-dose combination (FDC), 36
Fluconazole, 606; see also Antifungal
drugs
Flucytosine, 603; see also Antifungal
drugs
Fludarabine, 638
Fluoroquinolones (FQs), 531, 558; see also
Chemotherapy of tuberculosis;
Quinolones
5-Fluorouracil (5-FU), 503, 638
Flutamide, 468
Folate antagonist, 575, 637; see also
Cancer chemotherapy;
Chemotherapy of malaria
Folic acid (FA), 362; see also Hematinics
Folic acid synthetase (FAS), 527
Follicle-stimulating hormone (FSH),
436; see also Hypothalamic and
pituitary hormones
Fomivirsen, 591
Food and Drug Administration (FDA),
61, 62
Foscarnet, 591
Fosfomycin, 553; see also Antibiotics
FQs, see Fluoroquinolones
Framycetin, 550; see also
Aminoglycosides
Free drug, 20
FSH, see Follicle-stimulating hormone
5-FU, see 5-Fluorouracil
Furosemide, 192; see also Diuretics
Fusion inhibitor, 599
G
G6PD, see Glucose 6 Phosphate
Dehydrogenase
GA, see General anesthesia; General
anesthetics
GABA, see Gamma aminobutyric acid
Galantamine, 81; see also Cholinergic
system and drugs
Gamma aminobutyric acid (GABA), 68
Ganciclovir, 591
Ganglion blockers, 143; see also
Sympatholytics
Gases, 629; see also Antiseptics
Gastric emptying time (GET), 16
Gastro esophageal reflux disease
(GERD), 398; see also Peptic
ulcer treatment drugs
management, 404
Gatifloxacin, 532; see also Quinolones
G-CSF, see Granulocyte colony
stimulating factor
Gelatin products, 196; see also
Pharmacotherapy of shock
Gemcitabine, 638
General anesthesia (GA), 208
balanced anesthesia, 253
dissociative anesthesia, 251
inducing agents, 250
General anesthetics (GA), 246
action mechanism, 246
benzodiazepines, 252
concentration effect, 247
congeners, 249
desflurane, 249
elimination, 247
enflurane, 249
factors in anesthetic PP in
brain, 247
halothane, 249
inhalational anesthetics, 247
intravenous anesthetics, 250
isoflurane, 249
minimum alvelolar concentration,
247
neuroleptanalgesia, 252
nitrous oxide, 248
preanesthetic medication, 253
secondary gas effect, 247
sevoflurane, 249
Genetic engineered drug, 3
Gentamicin, 549; see also
Aminoglycosides
GERD, see Gastro esophageal reflux
disease
Germicide, 621; see also Antiseptics
GET, see Gastric emptying time
GH, see Growth hormone
GHRH, see Growth hormone releasing
hormone
Glaucoma, 76; see also Cholinergic
system and drugs
adrenergic agonists in, 78
β blockers in, 77
drugs for, 76
miotics in, 78
prostaglandin analogs in, 78
Glitazones, see Thiazolidinediones
Glomerular filtration, 31; see also Drug
excretion
Glucocorticoid, 424, 642, 651; see also
Immunosuppressants
role in TB, 563
Glucose 6 Phosphate Dehydrogenase
(G6PD), 29
Glucose transporters (GLUT), 479
GLUT, see Glucose transporters
Glycerine, 419; see also Constipation
treatment drugs
Glycopeptides, 551; see also Antibiotics
Glycoprotein IIB/IIIA receptor
antagonists, 381; see also
Antiplatelet agents
GM-CSF, see Granulocyte macrophage
colony stimulating factor
GnRH, see Gonadotrophin–releasing
hormone
GnRH agonists, 642
Gold salts, 333; see also Antirheumatic
drugs
Gonadotrophin–releasing hormone
(GnRH), 433; see also
Hypothalamic and pituitary
hormones
Gonadotropins, 436; see also
Hypothalamic and pituitary
hormones
Gossypol, 469
Gout treatment drugs, 335
allopurinol, 336
colchicine, 335
febuxostat, 336
NSAIDs, 336
G-protein coupled receptor(GPCR), 43,
44; see also Pharmacodynamics
G-proteins, 44
Graft-versus-host disease (GVHD), 474
Granulocyte colony stimulating factor
(G-CSF), 364
Granulocyte macrophage colony
stimulating factor
(GM-CSF), 364
Gray baby syndrome, 543
Griseofulvin, 602; see also Antifungal
drugs
Growth hormone (GH), 434, 435; see also
Hypothalamic and pituitary
hormo
Growth hormone releasing hormone
(GHRH), 433; see also
Hypothalamic and pituitary
hormones
Gugulipid, 391; see also Hypolipidemic
drugs
GVHD, see Graft-versus-host disease
 Index 667

H action mechanism, 283 Hyoscine, 412

uses, and ADRs, 284 Hyperprolactemia, 438; see also
H1 blockers, 412
HIT, see Heparin-induced Hypothalamic and pituitary
H2-receptor blockers, 399; see also Peptic
thrombocytopenia hormones
ulcer treatment drugs
HIV, see Human immunodeficiency Hypersensitivity reactions (Drug
HAART, see Highly active antiretroviral
virus allergy), 56; see also Adverse
therapy
HMG-CoA reductase inhibitors (Statins), drug reactions
Hallucinogens, 279; see also Central
387; see also Hypolipidemic Hypertension (HT); see also Vasodilators
nervous system stimulants
drugs management of, 146
Halofantrine, 572; see also
Hormonal agents, 642; see also Cancer in pregnancy, 147
Chemotherapy of malaria
chemotherapy Hypertensive crisis, 147
Halogens, 624; see also Antiseptics
Hormonal contraceptives; see also Hyperthyroidism, 441; see also Thyroid
Haloperidol, 227; see also Mood
Estrogens; Progestins hormones
stabilizers
action mechanism, 463 Hypertonic fluids, 198; see also
Halothane, 249; see also General
adverse effects, 464 Pharmacotherapy of shock
anesthetics
benefits of, 460 Hypolipidemic drugs, 386
Helmintic infestations, drugs for, 619; see
centchroman, 464 bile acid binding resins, 389
also Anthelmintics
drug interactions, 464 classification of, 386
Hematinics, 356
parenteral contraceptives, 462 dietary cholesterol absorption
erythropoietin, 363
postcoital pill, 461 inhibitor, 391
folic acid, 362
single preparations, 461 fibric acids, 388
interleukins, 364
types of, 458 gugulipid, 391
iron metabolism, 356, 357
Hormone, 432; see also Hypothalamic HMG-CoA reductase inhibitors, 387
iron preparations, 358
and pituitary hormones niacin, 390
maturation factors, 360
HPA axis, see Hypothalamo–pituitary– omega-3 fatty acids, 391
megakaryocyte growth factors, 364
adrenal axis Hypothalamic and pituitary hormones,
myeloid growth factors, 364
5-HT, see 5-hydroxytryptamine 432
uses, 361
5-HT3RA, see 5-hydroxytryptamine 3 action mechanism, 432
uses of iron and ADRs, 359
receptor antagonists anterior pituitary hormones, 434
vitamin B12, 360
Human albumin, 194, 197; see also corticotropin, 436
Hematopoietic growth factor, 363, 643;
Pharmacotherapy of shock dopamine receptor agonists, 438
see also Hematinics
Human immunodeficiency virus (HIV), gonadotropins, 436
Hemostatic agents, 365
594 growth hormone, 435
local agents, 365
Hydrogen peroxide, 630; see also hyperprolactemia, 438
sclerosing agents, 368
Antiseptics hypothalamic hormones, 433
synthesis of clotting factors,
Hydrolysis, 26; see also Non-synthetic prolactin, 437
366–367
reactions thyroid-stimulating hormone, 436
systemic agents, 366–367
Hydroxychloroquine, 334; see also Hypothalamic hormones, 433; see also
Heparin, 370; see also Anticoagulants
Antirheumatic drugs Hypothalamic and pituitary
ADRs and contraindications of, 371
Hydroxyethyl starch, 196; see also hormones
antagonist and LMW heparin, 372
Pharmacotherapy of shock Hypothalamo–pituitary–adrenal axis
vs. dicumarol/warfarin, 378
5-hydroxytryptamine (5-HT), 289; (HPA axis), 476
heparinoids, 373
see also Antidepressants; Hypotonic fluids, 198; see also
vs. LMW heparin, 378
Antiemetics; Constipation Pharmacotherapy of shock
parenteral direct thrombin inhibitors,
treatment drugs
373
clozapine, 292
synthetic heparin derivatives, 373 I
cyproheptadine, 292
Heparin-induced thrombocytopenia
5-HT agonists, 291, 420 I, see Radioactive iodine
131
(HIT), 371
5-HT antagonists, 224, 292 Iatrogenic diseases, 58; see also Adverse
Heparinoids, 373; see also Heparin
5-HT receptors, 290 drug reactions
Hepatotoxic reactions, 58; see also
ketanserin, 292 IBD, see Inflammatory bowel diseases
Adverse drug reactions
ondansetron, 292 IBS, see Irritable bowel syndrome
Heroin, 267; see also Opioid analgesics
sumatriptan, 291 ICSH, see Interstitial cell-stimulating
High-efficacy/high-ceiling/loop
5-hydroxytryptamine 3 receptor hormone
diuretics, 182
antagonists (5-HT3RA), 408; ICT, see Intracranial tension
Highly active antiretroviral therapy
see also Antiemetics Idiosyncrasy, 57; see also Adverse drug
(HAART), 594
Hydroxyurea, 644; see also Cancer reactions
Histamine, 282
chemotherapy Idoxuridine, 591
668 Index
IFN, see Interferons
IGF, see Insulin-like growth factors
IHD, see Ischemic heart disease
Imipenem, 522; see also Beta-lactam
antibiotics
Immunoadsorption apheresis, 334; see
also Antirheumatic drugs
Immunostimulants, 653; see also
Immunosuppressants
Immunosuppressants, 329, 424, 649; see
also Immunostimulants
antilymphocyte globulin, 652
antiproliferative agents, 650
anti-Rh(d) immunoglobulin, 652
antithymocyte antibodies, 652
azathioprine, 651
calcineurin inhibitors, 649
classification of, 649
cyclophosphamide, 651
cyclosporine, 649
cytotoxic agents, 651
glucocorticoids, 651
immunosuppressive antibodies, 652
infliximab, 652
methotrexate, 651
muromonab CD3, 652
mycophenolatemofetil, 650
sirolimus, 650
tacrolimus, 649
Incretins, 489; see also Diabetes mellitus
drugs
IND, see Investigation and newdrug
applications
Indapamide, 187; see also Diuretics
Indinavir, 597
Indole acetic acid derivatives, 316;
see also Nonsteroidal anti-
inflammatory drugs
Inducing agents, 250; see also General
anesthetics
Inflammatory bowel diseases (IBD), 313,
423, 649; see also Constipation
treatment drugs
aminosalicylates, 423
biological response modifiers, 424
glucocorticoid, 424
immunosuppressants, 424
treatment, 423–424
Infliximab, 652; see also
Immunosuppressants
Inhalation, 9; see also Bronchial asthma
steroids, 345
Inhalational anesthetics, 247; see also
General anesthetics
Inhibitory neurotransmitters, 200
Injection, 10; see also Systemic drug
administration
Inositol triphosphate (IP3), 104, 227
Insulin, 479; see also Diabetes mellitus
drugs; Oral antidiabetic
agents
action mechanism, 480
devices and use, 483
dosage, 482
drug interactions, 484
human insulins, 482
insulin analogs, 482
pharmacokinetics, 481
regulation and glucose transporters,
479
Insulin-like growth factors (IGF), 425
Integrase inhibitors, 599
Interferons (IFN), 593, 643, 653
Interleukins, 364; see also Antirheumatic
drugs; Hematinics
IL-1 antagonist, 332
IL-2, 643
Interstitial cell-stimulating hormone
(ICSH), 465
Intra-arterial drug administration, 12
Intracranial tension (ICT), 190
Intradermal injection, 10
Intramuscular injection, 10
Intrathecal drug administration, 12
Intrauterine contraceptive devices
(IUCD), 455
Intrauterine device (IUD), 458
Intravenous anesthetics, 250; see also
General anesthetics
Intravenous drug administration, 11
Intravenous fluids, 198; see also
Pharmacotherapy of shock
Investigation and newdrug applications
(IND), 62
Iodides, 445; see also Antithyroid drugs
Iodoquinol, 584; see also Antiamebic
drugs
Ion channels, 43
IP3, see Inositol triphosphate
Iron; see also Hematinics
absorption, 356
metabolism and requirements, 357
preparations, 358
uses and ADRs, 359
Irreversible AntiChE, 83; see also
Cholinergic system and drugs
Irritable bowel syndrome (IBS), 422; see
also Constipation treatment
drugs
Ischemic heart disease (IHD), 153
Isoflurane, 249; see also General
anesthetics
Isoniazid, 555; see also Chemotherapy of
tuberculosis
Isoprenaline, 111; see also Adrenergic
system and drugs
Isotonic fluids, 198; see also
Pharmacotherapy of shock
Itraconazole, 607; see also Antifungal
drugs
IUCD, see Intrauterine contraceptive
devices
IUD, see Intrauterine device
Ivermectin, 617; see also Anthelmintics
J
JAK, see Janus kinase
Janus kinase (JAK), 45
K
Kanamycin, 558; see also Chemotherapy
of tuberculosis
Ketamine, 251; see also General
anesthetics
Ketanserin, 292
Ketoconazole, 468, 587, 605; see also
Antifungal drugs
Ketolides, 534; see also Macrolides
Ketorolac, 321
Kinase-linked receptors, 45
L
LAAM, see L-α–acetyl–methadone
Lactilol, 419; see also Constipation
treatment drugs
Lactogenic hormone, see Peptide
hormone
Lactulose, 419; see also Constipation
treatment drugs
L-α–acetyl–methadone (LAAM), 269
Lamivudine, 596; see also Nucleoside
reverse transcriptase
inhibitors
L-Asparginase, 641
Laxatives, 416; see also Constipation
treatment drugs
abuse, 421
bulk, 416
Leishmaniasis
drugs for dermal, 588
treatment, 587
Lepra reactions, 566; see also Leprosy
chemotherapy
Leprosy chemotherapy, 564, 566
clofazimine, 565
dapsone, 565
drugs used in leprosy, 564
ethionamide, 565

lepra reactions, 566
minocycline, 565
ofloxacin, 565
rifampicin, 565
LES, see Lower esophageal sphincter
Leukeran, see Chlorambucil
Leukotriene, 299; see also Eicosanoids
Leukotriene receptor antagonists (LRA),
347; see also Bronchial asthma
Levamisole, 615, 653; see also
Anthelmintics
Levofloxacin, 532; see also Quinolones
Levonorgestrel (LNG), 458
LH, see Luteinizing hormone
Ligand, 41
-gated ion channels, 43
Lignocaine, 177, 257
Lincosamides, 551; see also Antibiotics
Linezolid, 558; see also Chemotherapy of
tuberculosis
Liposomal drug delivery, 12
Lipoxygenase (LOX), 295
Lithium, 227; see also Mood stabilizers
LMWH, see Low-molecular-weight
heparins
LNG, see Levonorgestrel
Local agents, 365; see also Hemostatic
agents
Local anesthetics (LA), 37, 254
action mechanism, 255
classification, 254
individual agents, 257
pharmacokinetics, 256
uses of, 258–259
Local drug administration, 5; see also
Drug administration routes
Local hormones, see Autacoids
Lock-and-key relationship, 42; see also
Drug receptor interaction
theories
Lomefloxacin, 532; see also Quinolones
Loop diuretics; see also Diuretics
high-efficacy diuretics, 182
uses, 183
Lower esophageal sphincter (LES), 410
Low-molecular-weight heparins
(LMWH), 369
heparin and, 378
and heparin antagonist, 372
LOX, see Lipoxygenase
Loxapine, 238; see also Antipsychotics
LRA, see Leukotriene receptor
antagonists
LSD, see Lysergic acid diethylamide
LT receptor antagonists, 340; see also
Bronchial asthma
Lungs, routes of drug excretion, 32
Luteinizing hormone (LH), 436; see also
Hypothalamic and pituitary
hormones
Lysergic acid diethylamide (LSD), 279,
293
Lysol, 623; see also Antiseptics
M
MAC, see Minimum alvelolar
concentration; Mycobacterium
avium complex
Macrolides, 533, 534
Malaria; see also Chemotherapy of
malaria
chemoprophylaxis, 579
treatment regimens, 580
Male contraceptives, 469; see also
Androgens
Male sexual dysfunction drugs, 469
Maraviroc, 599
Mast cell stabilizers, 340, 346; see also
Bronchial asthma
M-CSF, see Monocyte colony stimulating
factor
MDR-TB, see Multidrug-resistant
tuberculosis
Mebendazole, 612; see also Anthelmintics
Mebeverine, 422
Mechlorethamine, 635; see also Cancer
chemotherapy
Mecillinam, 518; see also Beta-lactam
antibiotics
Median effective dose, 48; see also
Therapeutic index
Median lethal dose, 48; see also
Therapeutic index
Mefloquine, 572; see also Chemotherapy
of malaria
Megakaryocyte growth factors, 364;
see also Hematinics
Meglitinide analogs, 485, 487; see also
Oral antidiabetic agents
Melanocyte-stimulating hormone
(MSH), 434; see also
Hypothalamic and pituitary
hormones
Melarsoprol, 588
Melphalan, 635; see also Cancer
chemotherapy
Memantine, 245
Menopausal symptoms treatment drug,
457; see also Estrogens
Menotropins, 436
Meptazinol, 272; see also Opioid
analgesics
6-Mercaptopurine (6-MP), 424, 638
Index 669
Meropenem, 523; see also Beta-lactam
antibiotics
Metabolism; see also Pharmacokinetics
of ACh, 70
drug metabolism, 24
enzymes for, 27
factors modifying, 29
pathways of, 25
Metallic salts, 626; see also Antiseptics
Methadone, 269; see also Opioid
analgesics
Methanol, see Methyl alcohol
Methimazole, 448; see also Antithyroid
drugs
Methotrexate (MTX), 637, 651; see also
Cancer chemotherapy;
Immunosuppressants
Methyl alcohol (methanol), 204
Methyl B12, see Methylcobalamin
Methylcobalamin (Methyl B12), 360
Methylphenidate, 278; see also Central
nervous system stimulants
Methylpolysiloxane (MPS), 402
Methylxanthines, 275, 340, 342; see also
Bronchial asthma; Central
nervous system stimulants
actions, 275
pharmacokinetics, 276
Metoclopramide, 410; see also
Antiemetics
Metolazone, 187; see also Diuretics
Metrifonate, 612; see also Anthelmintics
Metronidazole, 582; see also Antiamebic
drugs
Mexiletine, 177
MHLW, see Ministry of Health, Labour
and Welfare, Japan
Michelis-Menten kinetics, see Mixed-
order kinetics
Microsomal enzymes, 27
Migraine treatment drug, 294
Miltefosine, 587
Minerals as drug, 3
Minimum alvelolar concentration
(MAC), 247
Ministry of Health, Labour and Welfare,
Japan (MHLW), 61
Minocycline, 540, 565; see also Broad-
spectrum antibiotics; Leprosy
chemotherapy
Miotics in glaucoma, 78; see also
Cholinergic system and drugs
MIT, see Monoiodotyrosine
Mithramcin, 640
Mitomycin C, 640
Mixed-order kinetics (Michelis-Menten
kinetics), 33
670 Index
MMF, see Mycophenolatemofetil
Moclobemide, 225; see also
Antidepressants
Monoamine oxidase (MAO), 143, 222;
see also Antidepressants
inhibitors, 225
Monobactams, 524; see also Beta-lactam
antibiotics
Monoclonal antibody, 645; see also
Cancer chemotherapy
drug delivery, 12
Monocyte colony stimulating factor
(M-CSF), 364
Monoiodotyrosine (MIT), 439
Mood stabilizers, 227
ADRs, 228
conventional drugs, 227
nonconventional, 229
pharmacokinetics, 228
riluzole, 229
unconventional drugs, 227
uses, 228
Morphine, 270–271; see also Opioid
analgesics
Motilin receptor agonists, 411; see also
Antiemetics
Moxifloxacin, 532; see also Quinolones
MPS, see Methylpolysiloxane
MSH, see Melanocyte-stimulating
hormone
MTX, see Methotrexate
Mucolytics, 353; see also Cough
treatment
Multidrug-resistant tuberculosis
(MDR-TB), 563; see also
Chemotherapy of tuberculosis
Mupirocin, 552; see also Antibiotics
Muromonab CD3, 652; see also
Immunosuppressants
Muscarinic receptors, 44, 71
actions, 73
Mycobacterium avium complex (MAC),
563
Mycophenolatemofetil (MMF), 650; see
also Immunosuppressants
Myeloid growth factors, 364; see also
Hematinics
Myocardial infarction (MI), 148, 161, 375
treatment of, 162
N
NA, see Noradrenaline
N-acetyl-p-benzoquinoneimine
(NAPQI), 24
Nalbuphine, 272; see also Opioid analgesics
Nalidixic acid, 531; see also Quinolones
Nalmefane, 273
Nalorphine, 272
Naloxone, 273
Naltrexone, 273
NAPQI, see
N-acetyl-p-benzoquinoneimine
Natural drug, 3
NDA, see New Drug Application
Nelfinavir, 597
Neomycin, 550; see also Aminoglycosides
Neostigmine, 80, 85; see also Cholinergic
system and drugs
Nephrotoxic reactions, 58; see also
Adverse drug reactions
Nervous system (NS), 66
NET, see Norepinephrine transporter
Netilmicin, 550; see also
Aminoglycosides
Neurokinin receptor 1(NK1), 413; see
also Antiemetics
Neuroleptanalgesia, 252; see also General
anesthetics
Neuroleptics, 413; see also Antiemetics;
Antipsychotics
Neuromuscular junction (NMJ), 69
Neuroprotective agent, 229; see also
Mood stabilizers
Neurotransmitters, 102
excitatory, 200
involved in vomiting, 405
Nevirapine, 598
New Drug Application (NDA), 62
New drug approval process, 62; see also
Clinical trial phases
Niacin, 390; see also Hypolipidemic
drugs
Niclosamide, 615; see also Anthelmintics
Nicotine, 278, 280; see also Central
nervous system stimulants
Nicotinic acid, see Niacin
Nicotinic receptors, 71
actions, 73
Nifedipine, 149
Nifurtimox, 588
Nikkomycins, 610; see also Antifungal
drugs
Nitazoxanide, 584; see also Antiamebic
drugs
Nitrates
beta blockers as antianginals, 158
calcium channel blockers as
antianginals, 158
pharmacokinetics, 156
pharmacological actions, 155
potassium channel openers as
antianginals, 158
uses of, 157
Nitric oxide (NO), 68
Nitrogen mustards, 634; see also Cancer
chemotherapy
Nitroglycerin (NTG), 16
Nitrosureas, 635; see also Cancer
chemotherapy
Nitrous oxide, 248; see also General
anesthetics
NK1, see Neurokinin receptor 1
NMJ, see Neuromuscular junction
NO, see Nitric oxide
Nonbenzodiazepines, see Anxiolytics
Non-microsomal enzymes, 27
Non-nucleoside reverse transcriptase
inhibitors (NNRTIs), 589, 598;
see also Antiviral drugs
Non-proprietary drug name, 3
Non-rapid eye movement (NREM), 205
Non selective α blockers, 120, 122; see
also Alpha-adrenergic blocking
agents
Nonselective β–agonist, 111
Nonsteroidal anti-inflammatory drugs
(NSAIDs), 300, 329, 336
action mechanism, 302
adverse effects, 309–310, 324
alkalones, 320
analgesics, 300
anthranilic acid derivatives, 318
aryl-actetic acid derivatives, 321
aspirin doses, 308
aspirin drug interactions, 314
aspirin-type vs. opioid-type of
analgesics, 300
choice of, 327
classification, 301
COX-2 inhibitors, 322, 326
enolic acid derivatives, 319
indications, 312–313
indole acetic acid derivatives, 316
para-aminophenol derivatives, 323
paracetamol, 323
pharmacokinetic aspects, 308, 323
pharmacological actions, 304–307
precautions and contraindications, 311
propionic acid derivatives, 317
pyrazolone derivatives, 315
restriction of aspirin, 314
salicylates, 303
uses, 325
Non-synthetic reactions, 25, 26; see also
Pharmacokinetics
Nootropic agents, 245, 277; see also
Central nervous system
stimulants
Noradrenaline (NA), 102
Norepinephrine transporter (NET), 223

Norfloxacin, 532; see also Quinolones
Noscapine, 267, 351; see also Opioid
analgesics
NREM, see Non-rapid eye movement
NRTI, see Nucleoside reverse
transcriptase inhibitors
NS, see Nervous system
NSAIDs, see Nonsteroidal anti-
inflammatory drugs
NTG, see Nitroglycerin
Nuclear receptor, 46; see also
Pharmacodynamics
Nucleoside reverse transcriptase
inhibitors (NRTI), 589, 595,
596; see also Antiviral drugs
Nystatin, 602; see also Antifungal
drugs
O
Occupation theory, 42; see also
Drug receptor interaction
theories
Octreotide, 428; see also Diarrhea
treatment drugs
Ocular reactions, 58; see also Adverse
drug reactions
Ocusert, 12
Ofloxacin, 532, 565; see also Leprosy
chemotherapy; Quinolones
Olanzapine, 237; see also Antipsychotics
Omega-3 fatty acids, 391; see also
Hypolipidemic drugs
Ondansetron, 292
Opioid, 278; see also Central nervous
system stimulants;
Constipation treatment
drugs; Nonsteroidal anti-
inflammatory drugs
antagonists, 272, 273, 420
Opioid analgesics, 260, 300
analgesics, 260
classification, 260
codeine, 267
dependence, 265
dextromethorphan, 267
dextropropoxyphene, 269
ethoheptazine, 269
heroin, 267
methadone, 269
mixed agonists and antagonists, 272
morphine and action mechanism, 261
noscapine, 267
opioid antagonists, 273
opium, 260
pethidine, 267, 268
pharmacokinetics, 264
pharmacological actions, 262–263
pholcodeine, 267
precautions and contraindications,
266
tramadol, 267
uses of morphine and congeners,
270–271
Opium, 260; see also Opioid analgesics
Oral; see also Anticoagulants
anticoagulants, 374
direct thrombin inhibitors, 377
drugs, 17, 37
Oral antidiabetic agents; see also Diabetes
mellitus drugs; Insulin
alpha-glucosidase inhibitor, 485, 488
biguanides, 485, 487
classification, 485
meglitinide analogs, 485, 487
sulfonylureas, 485, 486
thiazolidinediones, 485, 488
Oral rehydration solution(ORS), 425; see
also Diarrhea treatment drugs
Organophosphorus compounds, 84; see
also Cholinergic system and
drugs
poisoning, 83, 84, 86
uses, 90
Oriental sore, see Dermal leishmaniasis
Ornidazole, 582; see also Antiamebic
drugs
Orphan drug, 2
ORS, see Oral rehydration solution
Osmotic diuretics, 190; see also Diuretics
Osmotic purgatives, 419; see also
Constipation treatment drugs
Osteoporosis, 496; see also Calcium
balance, agents affecting
Ototoxic reactions, 58; see also Adverse
drug reactions
Oxazolidinones, 553; see also Antibiotics
Oxidation, 26; see also Non-synthetic
reactions
Oxidizing agents, 630; see also
Antiseptics
Oxytocin, 497; see also Uterine
stimulants
vs. ergometrine, 501
P
PAF, see Platelet activating factor
Para-aminophenol derivatives, 323;
see also Nonsteroidal anti-
inflammatory drugs
Para-aminosalicylic acid (PAS), 554,
558; see also Chemotherapy of
tuberculosis
Index 671
Paracetamol, 323; see also Nonsteroidal
anti-inflammatory drugs
adverse effects, 324
uses, 325
Parasympathetic NS (PSNS), 66
Parasympatholytics, see Anticholinergics
Parathyroid hormone (PTH), 492; see
also Calcium balance, agents
affecting
Parenteral; see also Anticoagulants;
Drug administration routes;
Hormonal contraceptives
anticoagulants, 370
contraceptives, 462
direct thrombin inhibitors, 373
drugs, 8, 37
Parenteral route absorption, 17; see also
Pharmacokinetics
Parkinsonism treatment, 240
antiparkinsonian drugs, 240
benserazide, 242
carbidopa, 242
central anticholinergics, 244
dopamine metabolism inhibitors, 243
dopamine precursor, 241
dopamine receptor agonists, 243
dopamine releasers, 242
drug-induced parkinsonism, 244
Paromomycin, 585, 587; see also
Antiamebic drugs
Paroxysmal supraventricular tachycardia
(PSVT)
PAS, see Para-aminosalicylic acid
Passive; see also Drug excretion; Drug
transport
diffusion, 14
tubular reabsorption, 31
Patient controlled analgesia (PCA), 270
PBP, see Penicillin-binding protein
PCA, see Patient controlled analgesia
PCP, see Phencyclidine
PDE, see Phosphodiesterase
PE, see Pulmonary embolism
Pediculosis treatment, 620; see also
Anthelmintics
Pefloxacin, 532; see also Quinolones
PEG, see Polyethylene glycol
Penciclovir, 591
Pencillamine, 334; see also
Antirheumatic drugs
Penicillin-binding protein (PBP), 507
Penicillins, 513; see also Beta-lactam
antibiotics
amidinopenicillins, 518
aminopenicillin, 516
antipseudomonal, 517
carboxypenicillins, 517
672 Index

Penicillins (Continued) barbiturates, 214 Pharmacology, 2

natural, 514
semisynthetic, 515
ureidopenicillins, 518
Pentamidine, 587
Pentazocine, 272; see also Opioid
analgesics
Peptic ulcer treatment drugs, 394
antacids, 395
antifoaming agents, 402
anti-H pylori agents, 403
antimuscarinic agents, 400
carbenoxolone, 402
classification of drugs, 394
drugs inhibiting acid secretion, 398
H2-receptor blockers, 399
nonsystemic antacids, 396, 397
prostaglandin analogs, 400
proton pump inhibitors, 398
ulcer protectives, 401
Peptide hormone, 437; see also
Hypothalamic and pituitary
hormones
Peripheral skeletal muscle relaxant,
adverse reactions of, 93
Peripheral vascular disease (PVD), 293
Peroxisome proliferator-activated
receptor α (PPAR-α), 388
Pethidine, 267; see also Opioid analgesics
derivatives, 268
PGIs, see Prostacyclin
PGs, see Prostaglandins
Pharmacodynamics, 2, 38; see also Drug
receptor
action mechanisms, 38, 39
dose–response relationship, 47
enzymatic receptors, 45
factors modifying drug effects, 51
G-protein coupled receptors, 44
nuclear receptor, 46
therapeutic index, 48
therapeutic window, 49
Pharmacokinetic parameters, 33
clearance, 33
first-order kinetics, 33
mixed-order kinetics, 33
plasma half-life, 33
zero-order kinetics, 33
Pharmacokinetics (PK), 2, 13
ADME, 13
albendazole, 613
alcohol, 202
aminoglycosides, 547
amphotericin B, 601
applied pharmacokinetics, 33
artemisinin and derivatives, 577
atovaquone, 576
bioavailability and bioequivalence, 18
blood–brain barrier, 22
BZDs, 210
cardiac glycosides, 167
chloramphenicol, 542
chloroquine, 569
cotrimoxazole, 527
dapsone, 565
drug absorption, 15–16
drug action prolonging methods, 37
drug distribution, 19
drug dosing factors, 34
drug excretion, 30, 31
drug metabolism, 24
enzyme induction, 28
enzyme inhibition, 29
estrogens, 450
etymology, 13
factors determining distribution, 23
factors modifying metabolism, 29
first-pass metabolism, 17
fixed-dose combination, 36
griseofulvin, 602
iodoquinol, 584
isoniazid, 555
levodopa, 241
local anesthetics, 256
mebendazole, 612
metabolic enzymes, 27
methylxanthines, 276
metronidazole, 582
mood stabilizers, 228
nitazoxanide, 584
of nitrates, 156
non-synthetic reactions, 25
opioid analgesics, 264
other routes of drug excretion, 32
parenteral route absorption, 17
pathways of metabolism, 25
placental barrier, 22
plasma protein binding, 20
primaquine, 573
prodrug, 30
progestins, 454
protease inhibitors, 597
quinine, 574
quiniodochlor, 584
redistribution, 22
sulfonamides, 526
synthetic reactions, 26
tetracyclines, 537
therapeutic drug monitoring, 35
thioamides, 442
tissue binding, 22
transport of drugs, 14
volume of distribution, 21
Pharmacotherapy of angina, 159
Pharmacotherapy of shock, 194
dextrans, 194, 195
gelatin products, 196
human albumin, 194, 197
hydroxyethyl starch, 196
hypertonic fluids, 198
hypotonic fluids, 198
intravenous fluids, 198
isotonic fluids, 198
plasma expanders, 194, 197
polyvinylpyrrolidone, 197
Pharmacovigilance, 61; see also Adverse
drug reactions
Pharmacy, 2
Pharyngeal demulcents, 352; see also
Cough treatment
Phencyclidine (PCP), 279
Phenobarbitone, 214, 217; see also
Antiepileptics
Phenolphthalein, 418
Phenols, 623; see also Antiseptics
Phenothiazines, 236; see also
Antipsychotics
Phenoxybenzamine, 122; see also Non
selective α blockers
Phentolamine andtolazoline, 122; see also
Non selective α blockers
Phenytoin, 177, 216; see also
Antiepileptics
Pholcodeine, 267, 351; see also Opioid
analgesics
Phosphodiesterase (PDE), 172,
378, 380, 380; see also
Antiplatelet agents
antispasmodics inhibiting, 429
cAMP degradeation, 342
INHIBITORS, 380, 381
Phosphoinositol (PI), 227
Photosensitivity reactions, 58; see also
Adverse drug reactions
Physostigmine, 80; see also Cholinergic
system and drugs
PI, see Phosphoinositol; Protease
inhibitors
Pilocarpine, 75
Pimozide, 238; see also Antipsychotics
Pinocytosis, 14; see also Drug transport
Piperazine citrate, 614; see also
Anthelmintics
Pivmecillinam, 518; see also Beta-lactam
antibiotics
PK, see Pharmacokinetics
Placebo, 54
Placental barrier, 22; see also
Pharmacokinetics
 Index 673

Plasma expanders, 194, 197; see also
Pharmacotherapy of shock
Plasma half-life (t½), 33
Plasma protein binding (PPB), 20; see
also Pharmacokinetics
Platelet activating factor (PAF), 282
Platinum-containing compounds, 636;
see also Cancer chemotherapy
Pneumocandins, 609; see also Antifungal
drugs
Pneumocystosis treatment, 586
Poisoning, treatment principles of, 60
Polyethylene glycol (PEG), 415, 419
Polymyxin, 552; see also Antibiotics
Polypeptide antibiotics, 552; see also
Antibiotics
Polyvinylpyrrolidone, 197; see also
Pharmacotherapy of shock
Positive inotropic agents, 172
Postcoital pill, 461; see also Hormonal
contraceptives
Postpartum hemorrhage (PPH), 293
Post-traumatic stress disorder (PTSD),
226
Potassium channel openers as
antianginals, 158
Potassium permanganate, 630; see also
Antiseptics
Potassium-sparing diuretics, 188; see also
Diuretics
PPAR-α, see Peroxisome proliferator-
activated receptor α
PPB, see Plasma protein binding
PPH, see Postpartum hemorrhage
PPIs, see Proton pump inhibitors
Pramoxine, 257
Praziquantel, 614; see also Anthelmintics
Prazosin, 123; see also Selective α1
blockers
Preanesthetic medication, 253; see also
General anesthetics
Prilocaine, 257
Primaquine, 573; see also Chemotherapy
of malaria
PRL, see Prolactin
Probenecid, 337
Probiotics, 428; see also Diarrhea
treatment drugs
Procainamide, 176
Procaine, 257
Procarbazine, 635; see also Cancer
chemotherapy
Prodrug, 30; see also Pharmacokinetics
Progestasert, 12
Progestins, 642; see also Estrogens;
Hormonal contraceptives
antiprogestins, 456
combined estrogen and, 459 Pyrazolone derivatives, 315; see
for menopausal symptoms, 457 also Nonsteroidal anti-
pharmacokinetics, 454 inflammatory drugs
uses and ADRs of, 455 Pyrimethamine, 575; see also
Proguanil, 576; see also Chemotherapy of Chemotherapy of malaria
malaria Pyrimidine antagonist, 638; see also
Prokinetics, 409; see also Antiemetics Cancer chemotherapy
Prolactin (PRL), 434, 437; see also
Hypothalamic and pituitary
Q
hormones
Prolonging drug action, 37; see also Quetiapine, 237; see also Antipsychotics
Pharmacokinetics Quinidine, 175
Proparacaine, 257 Quinine, 574; see also Chemotherapy of
Propionic acid derivatives, 317; see malaria
also Nonsteroidal anti- Quiniodochlor, 584; see also Antiamebic
inflammatory drugs drugs
Propofol, 250; see also General Quinolones, 531
anesthetics ciprofloxacin, 532
Proprietary drug name, 3 fluoroquinolones, 531
Propylthiouracil, 448; see also gatifloxacin, 532
Antithyroid drugs individual agents, 532
Prostacyclin (PGIs), 295, 381; see also levofloxacin, 532
Antiplatelet agents lomefloxacin, 532
Prostaglandins (PGs), 295, 302, 498; see moxifloxacin, 532
also Cholinergic system and nalidixic acid, 531
drugs; Eicosanoids; Peptic norfloxacin, 532
ulcer treatment drugs; Uterine ofloxacin, 532
stimulants pefloxacin, 532
action mechanism, 296–297 sparfloxacin, 532
analogs, 400
in glaucoma, 78
R
Protamine sulfate, 372
Protease inhibitors (PI), 589, 597; see also Racecadrotil, 428; see also Diarrhea
Antiviral drugs treatment drugs
Protein tyrosine kinase inhibitors, 644; Radiation induced nausea and vomiting
see also Cancer chemotherapy (RINV), 235
Proton pump inhibitors (PPIs), 394, 398; Radioactive iodine (131I), 446
see also Peptic ulcer treatment Radioactive isotopes, 645; see also
drugs Cancer chemotherapy
PSNS, see Parasympathetic NS Raloxifene, 453
Psychomotor stimulants, 275; see also Raltegravir, 599
Central nervous system Ranitidine, 399
stimulants Rapid eye movement (REM), 205
PTH, see Parathyroid hormone Rate theory, 42; see also Drug receptor
PTSD, see Post-traumatic stress interaction theories
disorder Redistribution, 22; see also
Pulmonary embolism (PE), 375 Pharmacokinetics
Purgatives, 420; see also Constipation Reduction, 26; see also Non-synthetic
treatment drugs reactions
Purine antagonists, 638; see also Cancer REM, see Rapid eye movement
chemotherapy Renin-angiotensin aldosterone system
Purinergic receptor antagonists, 380 (RAAS), 136, 164, 470
PVD, see Peripheral vascular disease Reserpine, 238; see also
Pyrantel pamoate, 614; see also Antipsychotics
Anthelmintics Respiratory stimulants, 274; see also
Pyrazinamide, 557; see also Central nervous system
Chemotherapy of tuberculosis stimulants
674 Index
Reteplase, 383
Reverse transcriptase (RT), 595
Reversible AntiChE, 81–82; see also
Cholinergic system and drugs
Reversible dysguisia, 139
Revised National Tuberculosis Control
Program (RNTCP), 561
Ribavirin, 593
Rifampicin, 556, 565; see also
Chemotherapy of tuberculosis;
Leprosy chemotherapy
Rifampin, see Rifampicin
Riluzole, 229; see also Mood stabilizers
Rimonabant, 280; see also Central
nervous system stimulants
RINV, see Radiation induced nausea and
vomiting
Risperidone, 237; see also Antipsychotics
Ritonavir, 597
Rituximab, 332; see also Antirheumatic
drugs
Rivastigmine, 81; see also Cholinergic
system and drugs
RNTCP, see Revised National
Tuberculosis Control Program
Ropivacaine, 257
Roxithromycin, 534; see also Macrolides
RT, see Reverse transcriptase
S
Salicylates, 303; see also Nonsteroidal
anti-inflammatory drugs
adverse effects, 309–310
indications, 312–313
pharmacokinetics, 308
pharmacological actions, 304–307
precautions and contraindications, 311
Saliva for drug excretion, 32
SC, see Subcutaneous
Scabies, drugs for, 620; see also
Anthelmintics
SCC, see Short-course chemotherapy
SCh, see Succinylcholine
Sclerosing agents, 368; see also
Hemostatic agents
Scopolamine, 87
Secnidazole, 582; see also Antiamebic
drugs
Second messengers, 44
Sedative hypnotics, 205, 278; see also
Central nervous system
stimulants
action mechanism, 207
advantages of BZDs, 209
barbiturates, 213
BZDs as antagonist, 211
classification, 206
newer agents, 212
pharmacokinetics, 210, 214
pharmacological actions, 208
Selective central cholinesterase
inhibitors, 245
Selective estrogen receptor modulators
(SERMs), 453; see also
Estrogens
Selective Serotonin Norepinephrine
Reuptake Inhibitors
(SNRIs), 222, 224; see also
Antidepressants
Selective serotonin reuptake inhibitors
(SSRIs), 222, 291; see also
Antidepressants
Selective α1 blockers, 120, 123; see also
Alpha-adrenergic blocking
agents
Selective α2 blockers, 124
Selenium sulfide, 610; see also Antifungal
drugs
SERMs, see Selective estrogen receptor
modulators
Serotonin, see 5-hydroxytryptamine
Serotonin transport (SERT), 222
SERT, see Serotonin transport
Sevoflurane, 249; see also General
anesthetics
SGLT-2, see Sodium-glucose
cotransporter-2
Short-course chemotherapy (SCC), 559;
see also Chemotherapy of
tuberculosis
SIADH, see Syndrome of inappropriate
ADH secretion
Side effects, 56; see also Adverse drug
reactions
Signal transducer and activation
transcription (STAT), 45
Sildenafil, 469
Silver nitrate, 626; see also Antiseptics
Silver sulfadiazine, 626; see also
Antiseptics
Sirolimus, 650; see also
Immunosuppressants
Skeletal muscle relaxant, 91; see also
Depolarizing blockers adverse
reactions; Peripheral skeletal
muscle relaxant, adverse
reactions of
for acute muscle spasm, 100
on autonomic ganglia, 93
centrally acting drugs, 91
central SMRs, 99
classification, 91
depolarizing blockers, 91, 95
directly acting drugs, 91
directly acting SMRs, 101
drug interactions, 97
on histamine release, 93
muscle tone, 91
non-depolarizing blockers, 91, 92
peripherally acting drugs, 91
peripheral skeletal muscle relaxant, 92
pharmacological actions of
depolarizing blockers, 96
presynaptic inhibition of motor
neurons by tizanidine, 100
sedation drugs, 100
on skeletal muscle, 93
spasticity, 91
synthetic competitive blockers, 94
tizanidine, 100
uses of SMRs, 98
Skin for drug excretion, 32
SLUDGE (Salivation, Lacrimation,
Urination, Diarrhea, GI/GU
cramps, Emesis), 84
SNRIs, see Selective Serotonin
Norepinephrine Reuptake
Inhibitors
SNS, see Sympathetic nervous system
Sodium; see also Antibiotics; Mood
stabilizers
channel blockers, 175
fusidate, 552
picosulfate, 418
SGLT-2 inhibitors, 490
valproate, 229
Sodium-glucose cotransporter-2 (SGLT-
2), 490; see also Diabetes
mellitus drugs
Soframycin, see Framycetin
Somatotrophin, see Growth hormone
Sorbitol, 419; see also Constipation
treatment drugs
Sordarins, 610; see also Antifungal drugs
Sparfloxacin, 532; see also Quinolones
Specialized drug delivery, 12; see also
Drug administration routes
Spironolactone, 192, 468; see also
Diuretics
SSRIs, see Selective serotonin reuptake
inhibitors
STAT, see Signal transducer and
activation transcription
Statins, see HMG-CoA reductase
inhibitors
Sterilization, 621; see also Antiseptics
Stimulant purgatives, 418; see also
Constipation treatment drugs
Stool softeners, 417; see also Constipation
treatment drugs

Streptogramins, 553; see also Antibiotics
Streptokinase, 383
Streptomycin, 550, 557; see also
Aminoglycosides;
Chemotherapy of tuberculosis
Streptozocin, 635; see also Cancer
chemotherapy
Subcutaneous (SC), 481
injection, 10
Substitution therapy, 57
Succinylcholine (SCh), 29, 95
Sulfasalazine, 334; see also
Antirheumatic drugs
Sulfinpyrazone, 337
Sulfonamides, 525
action mechanism, 525
adverse effects, 526
classification, 525
cotrimoxazole, 527
pharmacokinetics, 526
resistance, 525
spectrum, 525
uses, 526
Sulfonylureas, 485, 486; see also Oral
antidiabetic agents
Sumatriptan, 291
Superficial mycoses, 610; see also
Antifungal drugs
Superinfection, 512; see also
Antimicrobials agents
Suprainfection, see Superinfection
Suramin sodium, 588
Surface active agents, 625; see also
Antiseptics
Sympathetic nervous system (SNS), 66,
102, 164
Sympatholytics, 142–143
adrenergic neuron blockers, 143
centrally acting agents, 142
ganglion blockers, 143
Sympathomimetics, 340; see also
Adrenergic system and drugs;
Bronchial asthma
action mechanism, 341
Syndrome of inappropriate ADH
secretion (SIADH), 191, 228
Synthetic drug, 3
heparin derivatives, 373
Synthetic reactions, 26; see also
Pharmacokinetics
Syringe and needle drug administration,
5 vs. doxycycline, 541
Systemic agents, 366–367; see also
Hemostatic agents
Systemic drug administration, 6; see also
Drug administration routes
inhalation, 9
Index 675
intra-arterial, 12 Tetrahydrocannabinoid (THC), 280
intra-articular, 12 Tetrahydrofolic acid(THFA), 637
intradermal injection, 10 Thalidomide, 644, 653; see also Adverse
intramuscular injection, 10 drug reactions; Cancer
intrathecal, 12 chemotherapy
intravenous route, 11 tragedy, 61
oral route, 6 THC, see Tetrahydrocannabinoid
rectal route, 7 Therapeutic drug monitoring (TDM), 35,
subcutaneous injection, 10 167; see also Pharmacokinetics
sublingual route, 7 Therapeutic index (TI), 48; see also
transdermal route, 9 Pharmacodynamics
Systemic fungal infections, drugs for, implications of, 49
611; see also Antifungal drugs limitations, 49
median effective dose, 48
median lethal dose, 48
T
Therapeutics, 2
t½, see Plasma half-life Therapeutic window, 49; see also
Tacrine, 81, 245; see also Cholinergic Pharmacodynamics
system and drugs THFA, see Tetrahydrofolic acid
Tacrolimus, 649; see also Thiacetazone, 558; see also
Immunosuppressants Chemotherapy of tuberculosis
Tamoxifen, 453, 642 Thiazide; see also Diuretics
Taxanes, 639; see also Cancer diuretics and ADRs, 187
chemotherapy vs. furosemide, 192
TB, see Tuberculosis and thiazide-like diuretics, 186
TCAs, see Tricyclic antidepressants Thiazolidinediones (TZD), 485, 488; see
T-cell activation inhibitors, 332; see also also Oral antidiabetic agents
Antirheumatic drugs Thioamides, 442; see also Antithyroid
T-cell inhibitors, 649; see also drugs
Immunosuppressants action mechanism, 442
TDM, see Therapeutic drug monitoring adverse effects, 442
Tegaserod, 422 pharmacokinetics, 442
Teicoplanin, 551; see also Antibiotics uses, 443
Temocillin, 517; see also Beta-lactam Thiopentone sodium, 250; see also
antibiotics General anesthetics
Tenecteplase, 383 Thiourea derivatives, see Thioamides
Tenofovir, 596; see also Nucleoside Thioxanthines, 236; see also
reverse transcriptase inhibitors Antipsychotics
Teratogenicity, 59; see also Adverse drug Thrombolytics, 383; see also
reactions Antifibrinolytics
Terbinafine, 608; see also Antifungal adverse reactions, 384
drugs classification, 383
Tetracaine, 257 Thromboxanes (TX), 295; see also
Tetracycline, 585; see also Antiamebic Eicosanoids
drugs; Broad-spectrum action mechanism, 296–297
antibiotics Thymosin, 653
adverse effects, 538 Thyroid hormones, 439; see also
classification and action mechanism, Antithyroid drugs
535 action mechanism, 440
contraindications and advantages, hyperthyroidism, 441
540 regulation and synthesis, 439
Thyroid-stimulating hormone (TSH),
pharmacokinetics and 433, 434, 436; see also
administration, 537 Hypothalamic and pituitary
spectrum of activity and resistance, hormones
536 Thyroid storm, see Thyrotoxic crisis
uses, 539 Thyrotoxic crisis, 447
676 Index
Thyrotrophin, 436; see also
Hypothalamic and pituitary
hormones
Thyrotropin-releasing hormone (TRH),
433; see also Hypothalamic and
pituitary hormones
TI, see Therapeutic index
TIAs, see Transient ischemic attacks
Ticarcillin, 517; see also Beta-lactam
antibiotics
Tigecycline, 544; see also Broad-
spectrum antibiotics
Tinidazole, 582; see also Antiamebic
drugs
Tissue binding, 22; see also
Pharmacokinetics
Tizanidine, 100
TNFα, see Tumor necrosis factor α
Tocolytics, see Uterine relaxants
Topical antifungals, 610; see also
Antifungal drugs
Topical azoles, 608; see also Antifungal
drugs
Topical drug administration, 5
Torsemide, 183; see also Diuretics
Total peripheral resistance(TPR), 136
Toxic effects, 56; see also Adverse drug
reactions
Toxicology, 2
TPR, see Total peripheral resistance
Tramadol, 267; see also Opioid analgesics
Transdermal drug administration, 9
Transient ischemic attacks (TIAs), 382
Tretinoin, 643
TRH, see Thyrotropin-releasing
hormone
Triclosan, 623; see also Antiseptics
Tricyclic antidepressants (TCAs), 222,
223; see also Antidepressants
Trifluridine, 591
Trypanosomiasis treatment, 588
TSH, see Thyroid-stimulating hormone
Tuberculosis (TB), 554; see also Valproic acid, 219; see also Antiepileptics
Chemotherapy of tuberculosis Varenidine, 280; see also Central nervous
chemoprophylaxis of, 563 system stimulants
in HIV patients, 563 Vasoactive intestinalpeptide (VIP), 68
multidrug-resistant, 563 Vasodilators, 145, 171; see also
in pregnancy, 563 Hypertension
role of glucocorticoids in, 563 Vasopressin antagonists, 191; see also
treatment, 559 Diuretics
Tumor necrosis factor α (TNFα), Vaughan Williams classification, 174
330, 652; see also Verapamil, adverse effects of, 152
Antirheumatic drugs Vertigo treatment drugs, 288
Two-state model, 42; see also Drug Vinca alkaloids, 639; see also Cancer
receptor interaction chemotherapy
theories VIP, see Vasoactive intestinalpeptide
TX, see Thromboxanes Vitamin B, see Niacin
TZD, see Thiazolidinediones Vitamin B12, 360; see also Hematinics
deficiency, 361
Vitamin D, 494; see also Calcium
U
balance, agents affecting
UFH, see Unfractionated heparin Volume of distribution, 21; see also
Ulcer protectives, 401; see also Peptic Pharmacokinetics
ulcer treatment drugs
Unfractionated heparin (UFH), 369
W
Uppasala Monitoring Centre, 61
Upregulation, 46 Warfarin, 374; see also Anticoagulants
Ureidopenicillins, 518; see also adverse reaction, 375
Penicillins drug interactions of, 376
Uricosuric drugs, 337 heparin vs., 378
Urinary analgesics, 529 Withdrawal syndrome, 57
Urokinase, 383
Uterine relaxants, 105, 500
Y
Uterine stimulants, 497
ergot derivatives, 498 Yohimbine, 124; see also Selective α2
oxytocin, 497 blockers
preparations, 499
prostaglandins, 498
Z
side effects, 499
uses, 499 Zalcitabine, 596; see also Nucleoside
reverse transcriptase inhibitors
Zero-order kinetics, 33
V
Zidovudine (AZT), 589
Valacyclovir, 591 Zinc sulfate, 626; see also Antiseptics