(Thakur) PHARMACOLOGY-II.pdf

* * PHARMACOLOGY-II B.Pharm, Semester-V According to the syllabus based on ‘Pharmacy Council of India’ Dr. Pankaj Mishra M.Pharm, Ph.D Principal, Keshlata College of Pharmacy, Bareilly International University, Bareilly Dr. Pragnesh Patani M.Pharm. (Pharmacology), Ph.D., DIM. Professor & Princi...

* * PHARMACOLOGY-II B.Pharm, Semester-V According to the syllabus based on ‘Pharmacy Council of India’ Dr. Pankaj Mishra M.Pharm, Ph.D Principal, Keshlata College of Pharmacy, Bareilly International University, Bareilly Dr. Pragnesh Patani M.Pharm. (Pharmacology), Ph.D., DIM. Professor & Principal, A-One Pharmacy College, SNME Campus, Naroda, Ahmedabad Dr. K. V. Otari M.pharm, Ph.D (Pharmacology) Professor & Principal, Navsahyadri Institute of Pharmacy, Naigon, Dist. Pune Books are Available for Online Purchase at: tppl.org.in THAKUR PUBLICATION PVT. LTD., LUCKNOW  Meerut  Bhopal  Nagpur  Bhubaneswar  Jaipur  Jalandhar  Kolkata   Chennai  Bengaluru  Ahmedabad  Pune  Hyderabad  Rohtak  Kerala* * * * * Pharmacology-II Edition 2019 Copyright © All Rights Reserved This book is sole subject to the condition that it shall not, by way of trade or otherwise, be lent, resold, hired out, or otherwise circulated without the publisher’s prior written consent, in any form of binding or cover, other than that in which it is published and without including a similar condition. This condition being imposed on the subsequent purchaser and without limiting the rights under copyright reserved above, no part of this publication may be reproduc ed, stored in or transmitted in any form or by any means (electronic, mechanical, photocopying, recording or otherwise), without the prior written permission of both the copyright owner and the below mentioned publisher of this book. Published by : Thakur Publication Pvt. Ltd. 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Post, Bengaluru-560029. Mob. 9341835403, 9379798011, 9343859590, 8880441707. 13. Thakur Publishers, H.No.34, Ward No. 6, Behind Verma Petrol Pump, Bhiwani Chungi, Rohtak 124001. Mob. 7876991824, 7876991825, 9068601142, 9729004576. 14. Thakur Publication Pvt. Ltd, H.No.-1312, Purba Sinthee Road, Fakir Ghosh Lane, Dumdum, Kolkota-700030. Mob. 9337585809, * * * * “Dedicated to my Beloved Parents, Shri P. C. Mishra and Mrs. Geeta Mishra” -Dr.Pankaj Mishra “Dedicated to My Loving Parents Mr. V.M.Patani & Mrs. Amitaben Patani & Aaditya, Vishvam, Khushi, Purva, Nishtha, Kavya & Prisha” -Dr. Pragnesh Patani “Dedicated to my Family and Friends” -Dr. Kishor Vasant Otari * * * * Preface It gives us immense pleasure to place before the B.Pharm Fifth Semester pharmacy students the book on “Pharmacology-II”. This book has been written strictly in accordance wi th the current syllabus prescribed by Pharmacy Council of India, for B.Pharm students. Keeping in view the requirements of students and teachers, this book has been written to cover all the topics in an easy -to-comprehend manner within desired limits of th e prescribed syllabus, and it provides the students fundamentals of pharmacology of drugs used in cardiovascular, urinary, and endocrine systems, which are required by them during their pharmaceutical career. All efforts have been made to keep the text e rror-free and to present the subject in a student friendly and easy to understand. However, any suggestions and constructive comments would be highly appreciated and incorporated in the future edition. Please e-mail us at, Website, * [email protected] www.tppl.org.in * * * Acknowledgement It gives me an immense pleasure to express my thankful gratitude to Professor (Dr.) K.K. Maheswari, Professor (Dr.) S. D. Singh , MJP Rohilkhand University Bareilly and Dr. Pushpendra Kanno jia, Principal BIU College of Pharmacy, Bareilly International University, Bareilly for their constant motivation and encouragement. I also express my thanks toMr. Gaurav Tripathi and Ms. Neha Singh, Faculty of Pharmacy, Keshlata College of Pharmacy Bareilly for their assistance and support. I am also thankful to all staff members of Thakur Publication Pvt. Ltd. especially, Ms. Tuhina Banerjee (Copy Editor) and Mr. Sharad Kushwaha (Marketing Coordinator), for providing me an opportunity to be a part ofhis t book. Finally my greatest debt of gratitude is to my family members for being supportive in times of stress and assisting with the tasks of manuscript preparation. Dr.Pankaj Mishra I bow in front of Lord Ganesha for all blessings he has conferred upon me. I am always thankful for his words “for every loss God will give you something if you look for it and work for it”. These words strengthen me throughout in writing of this book. I express my special thanks to Honorable Shri Narendrasinh Zala Sir (Ex.MLA), Chairman, and Honorable Shree Dhavalsinh Zala (MLA, Bayad -Malpur) Trustee of Divaba Education Trust, for providing me excellent infrastructural and constant encouragement during completion of this book. At the outset, I take this opportunity to e xpress my sincere gratitude to Dr. B. N. Suhagia Sir, Director, Faculty of Pharmacy, Dharamsinh Desai University, Nadiad, Dr. J. K. Patel , Dean, Sakalchand Patel University and Dr. A. K. Seth , Dean, Suandeep Vidyapeeth University, for their valuable guidance, which made me to overcome the implications through proper planning and execution. This boosted my confidence, enabled me to complete my working, and morally supported me. His continuous encouragement, imposing new ideas, keen interest served as a sou rce of constant inspiration during entire tenure of my professional carrier. I am honored to express my profound and deep sense of gratitude towards whole Pharma fraternity especially associated with Gujarat Technological University, Dr. N. R. Sheth (VC, GTU), Dr. C. N. Patel (Dean & BOG, GTU) for their creative suggestion, helpful discussion and unfailing advice during writing this book. * * * * Finally I wish to acknowledge the assistance given by the editorial and publication team. I especially thank Thakur P ublication Pvt Ltd. and whole team for offering us complete freedom to express my knowledge and thoughts through this book. -Dr. Pragnesh Patani It is a moment of pleasure & pride to look back with a sense of contentment during the course of book writing. Behind every success there are many efforts & efforts are fruitful due to the hands making the passage smooth. I wish to thank each one of them with all my heart, as the list is everlasting I attempted to include most of them, if someone missed, I request to consider my innocence & understand the limitations. The way to accomplish my ambitions was shown by Dr. C. D. Upasani , Professor & Principle SNJB’s College of Pharmacy, Chandwad. His time-to-time encouragement, excellent guidance & valuable suggestion s made me capable to bring this book at excellence. I am thankful to Dr. K. R. Mahadik , Dr. R. V. Shete, Dr. K. S. Jain, Dr. Thakurdesai P. A., Dr. R. J. Patil, Dr. K. S. Charak, Prof. Mrs. Sarita Gaikwad for their constant encouragement, valuable guidance and support. I thank to the Management of Navsahyadri Education Society’s Navsahyadri Institute of Pharmacy, Naigaon (Nasrapur), Pune for facilitating this book completion. I express my profound appreciation towards my students, colleagues, teaching & non-teaching staff. -Dr. K.V. Otari * * –7– Syllabus Module 01 10 Hours Pharmacology of Drugs Acting on Cardio Vascular System  Introduction to hemodynamic and electrophysiology of heart.  Drugs used in congestive heart failure  Anti-hypertensive drugs.  Anti-anginal drugs.  Anti-arrhythmic drugs.  Anti-hyperlipidemic drugs. Module 02 Pharmacology of Drugs Acting on Cardio Vascular System  Drug used in the therapy of shock.  Hematinics, coagulants and anticoagulants.  Fibrinolytics and anti-platelet drugs.  Plasma volume expanders. 10Hours Pharmacology of Drugs Acting on Urinary System  Diuretics.  Anti-diuretics. Module 03 10 Hours Autocoids and Related Drugs  Introduction to autacoids and classification.  Histamine, 5-HT and their antagonists.  Prostaglandins, Thromboxanes and Leukotrienes.  Angiotensin, Bradykinin and Substance P.  Non-steroidal anti-inflammatory agents.  Anti-gout drugs.  Antirheumatic drugs. Module 04 08 Hours Pharmacology of Drugs Acting on Endocrine System  Basic concepts in endocrine pharmacology.  Anterior Pituitary hormones- analogues and their inhibitors.  Thyroid hormones- analogues and their inhibitors.  Hormones regulating plasma calcium level - Parathormone, Calcitonin and Vitamin -D.  Insulin, Oral Hypogl ycemic agents and glucagon.  ACTH and corticosteroids. Module 05 Pharmacology of Drugs Acting on Endocrine System  Androgens and Anabolic steroids.  Estrogens, progesterone and oral contraceptives.  Drugs acting on the uterus. 07 Hours Bioassay  Principles and applications of bioassay.  Types of bioassay  Bioassay of insulin, oxytocin, vasopressin, ACTH, d -tubocurarine, digitalis, histamine and 5-HT. * * –8– Contents 1.3.4. Module 1 Chapter 1: Pharmacology of Drugs Acting on CVS 1.1. 1.1.1. 1.1.2. 1.1.3. 1.2. 1.2.1. 1.2.2. 1.2.3. 1.2.3.1. 1.2.3.2. 1.2.3.3. 1.2.3.4. 1.2.3.5. 1.2.3.6. 1.2.3.7. 1.2.3.8. 1.2.4. 1.2.4.1. 1.2.4.2. 1.2.4.3. 1.2.5. 1.2.5.1. 1.2.5.2. 1.2.5.3. 1.2.6. 1.2.6.1. 1.2.6.2. 1.2.6.3. 1.2.7. 1.2.7.1. 1.2.7.2. 1.2.7.3. 1.2.7.4. 1.2.8. 1.2.9. 1.3. 1.3.1. 1.3.2. 1.3.3. 1.3.3.1. 1.3.3.2. 1.3.3.3. 1.3.3.4. * Cardiovascular System Introduction Hemodynamics Electrophysiology of Heart Drugs Used in Congestive Heart Failure Introduction Classification Cardiac Glycosides Mechanism of Action Pharmacokinetics Pharmacological Actions Therapeutic Uses Adverse Effects Drug Interactions Contraindications Treatment of Digitalis Toxicity Bipyridines Mechanism of Action Therapeutic Uses Adverse Effects β-Adrenergic Agonists Mechanism of Action Therapeutic Uses Adverse Effects Diuretics Mechanism of Action Therapeutic Uses Adverse Effects Angiotensin Antagonists Mechanism of Action Pharmacological Actions Therapeutic Uses Adverse Effects β-Adrenoceptor Antagonists Vasodilators Anti-Hypertensive Drugs Introduction Classification Diuretics Mechanism of Action Therapeutic Uses Adverse Effects Individual Drugs 15 15 15 16 17 17 17 17 18 18 19 20 20 20 21 21 22 22 22 22 22 22 23 23 23 23 23 23 24 24 24 24 24 24 24 25 25 25 26 26 27 27 27 1.3.4.1. 1.3.4.2. 1.3.4.3. 1.3.4.4. 1.3.5. 1.3.5.1. 1.3.5.2. 1.3.5.3. 1.3.5.4. 1.3.6. 1.3.6.1. 1.3.6.2. 1.3.6.3. 1.3.7. 1.3.7.1. 1.3.7.2. 1.3.7.3. 1.3.8. 1.3.8.1. 1.3.8.2. 1.3.8.3. 1.3.8.4. 1.3.8.5. 1.3.9. 1.3.9.1. 1.3.9.2. 1.3.9.3. 1.3.9.4. 1.4. 1.4.1. 1.4.2. 1.4.3. 1.4.3.1. 1.4.3.2. 1.4.3.3. 1.4.3.4. 1.4.4. 1.4.4.1. 1.4.4.2. 1.4.4.3. 1.4.4.4. 1.4.5. 1.4.5.1. Angiotensin Converting Enzyme (ACE) Inhibitors Mechanism of Action Therapeutic Uses Adverse Effects Individual Drugs Angiotensin II Receptor Antagonists Mechanism of Action Therapeutic Uses Adverse Effects Individual Drug - Losartan Ganglion Blockers Mechanism of Action Therapeutic Uses Adverse Effects Adrenergic Drugs Centrally Acting Sympatholytic Drugs Adrenergic Neuron Blockers Sympatholytics (Adrenergic Receptor Blockers) Calcium Channel Blockers Classification Mechanism of Action Therapeutic Uses Adverse Effects Individual Drugs Vasodilators Mechanism of Action Therapeutic Uses Adverse Effects Individual Drugs Anti-Anginal Drugs Introduction Classification Organic Nitrites & Nitrates Mechanism of Action Therapeutic Uses Adverse Effects Individual Drugs Calcium Channel Blockers Mechanism of Action Therapeutic Uses Adverse Effects Individual Drugs Potassium Channel Openers Mechanism of Action 28 28 28 29 29 30 30 30 31 31 31 31 31 31 32 32 33 34 37 37 37 37 38 38 38 38 39 39 39 40 40 41 41 41 42 42 42 43 43 43 43 43 44 44 * –9– 1.4.5.2. Therapeutic Uses 44 1.4.5.3. Adverse Effects 45 1.4.5.4. Individual Drug - 45 Nicorandil 1.4.6. β-Adrenoceptor 45 Antagonists 1.4.6.1. Mechanism of Action 45 1.4.6.2. Therapeutic Uses 45 1.4.6.3. Adverse Effects 45 1.4.6.4. Individual Drug - Atenolol 45 1.4.7. Metabolic Modifiers 46 1.5. Anti-Arrhythmic Drugs 47 1.5.1. Introduction 47 1.5.2. Classification 47 1.5.3. Sodium Channel Blockers 48 (Class I) 1.5.3.1. Mechanism of Action 48 1.5.3.2. Therapeutic Uses 48 1.5.3.3. Adverse Effects 48 1.5.3.4. Individual Drugs 48 1.5.4. 51 -Blockers (Class II) 1.5.4.1. Mechanism of Action 51 1.5.4.2. Therapeutic Uses 51 1.5.4.3. Adverse Effects 51 1.5.4.4. Individual Drugs 52 1.5.5. Potassium Channel 52 Blockers (Class III) 1.5.5.1. Mechanism of Action 53 1.5.5.2. Therapeutic Uses 53 1.5.5.3. Adverse Effects 53 1.5.5.4. Individual Drugs 53 1.5.6. Calcium Channel Blockers 54 (Class IV) 1.5.6.1. Mechanism of Action 54 1.5.6.2. Therapeutic Uses 54 1.5.6.3. Adverse Effects 54 1.5.6.4. Individual Drug - 54 Verapamil 1.6. Anti-Hyperlipidemic Drugs 55 1.6.1. Introduction 55 1.6.2. Classification 55 1.6.3. HMG-CoA Reductase 55 Inhibitors (Statins) 1.6.3.1. Mechanism of Action 56 1.6.3.2. Therapeutic Uses 56 1.6.3.3. Adverse Effects 56 1.6.3.4. Individual Drugs 56 1.6.4. Bile Acid Sequ estrants 57 (Resins) 1.6.4.1. Mechanism of Action 58 1.6.4.2. Therapeutic Uses 58 1.6.4.3. Adverse Effects 58 * 1.6.4.4. Individual Drug - 58 Cholestyramine 1.6.5. Fibric Acid Derivatives 59 (Fibrates) 1.6.5.1. Mechanism of Action 59 1.6.5.2. Therapeutic Uses 59 1.6.5.3. Adverse Effects 59 1.6.5.4. Individual Drug - 60 Clofibrate 1.6.6. Triglyceride Synthesis and 60 Lipolysis Inhibitors 1.6.7. Other Drugs 61 1.7. Summary 62 1.8. Exercise 63 Module 2 Chapter 2: Pharmacology of Drugs Acting on CVS and Haemopoietic System 2.1. 2.1.1. 2.1.2. 2.1.2.1. 2.1.2.2. 2.1.2.3. 2.1.2.4. 2.1.2.5. 2.1.2.6. 2.1.2.7. 2.2. 2.2.1. 2.2.2. 2.2.2.1. 2.2.2.2. 2.2.2.3. 2.2.3. 2.2.3.1. 2.2.3.2. 2.2.3.3. 2.2.4. 2.2.4.1. 2.2.4.2. 2.2.4.3. 2.2.4.4. 2.2.4.5. Drugs Used In The 66 Therapy of Shock Introduction 66 Treatment for 66 Cardiovascular Shock Sympathomimetic Amines 66 α-Adrenoceptor Blocking 68 Agents Corticosteroids 69 Oxygen 69 Cardiac Glycosides 70 Glucagon 70 Dextrans 70 Drugs Acting on 71 Haemopoietic System Introduction 71 Hematinics 71 Iron 71 Folic Acid 74 Vitamin B 12 76 (Cyanocobalamin) Coagulants 78 Classification 78 Vitamin K 78 Other Drugs 79 Anticoagulants 80 Classification 80 Injectable Anticoagulants - 80 Heparin Oral Anticoagulants 82 Coumarin Derivatives 82 Indandione Derivative - 84 Phenindione * – 10 – 2.2.5. 2.2.5.1. 2.2.5.2. 2.2.5.3. 2.2.5.4. 2.2.6. 2.2.6.1. 2.2.6.2. 2.2.6.3. 2.2.6.4. 2.2.6.5. 2.2.6.6. 2.2.6.7. 2.2.6.8. 2.2.7. 2.2.7.1. 2.2.7.2. 2.2.7.3. 2.2.7.4. 2.2.7.5. 2.2.7.6. 2.2.7.7. 2.3. 2.4. Fibrinolytics 84 Mechanism of Action 84 Therapeutic Uses 85 Adverse Effects 85 Individual Drugs 86 Anti-Platelet Drugs 87 Classification 87 Prostaglandin Synthesis 87 (PG) Inhibitors Phosphodiesterase 88 Inhibitors ADP-Induced Platelet 88 Aggregation Inhibitors Glycoprotein II b/IIIa 88 Receptor Inhibitors Mechanism of Action 89 Therapeutic Uses 89 Adverse Effects 90 Plasma Volume Expanders 90 Classification 90 Human Albumin 90 Dextran-40 91 Dextran-70 91 Polyvinylpyrrolidone 91 Hetastarch (Hydroxyethyl 91 Starch) Degraded Gelatin Polymer 91 Summary 92 Exercise 92 3.1.4.6. Contraindications 99 3.1.5. Weak or Adjunctiv e 100 Diuretics 3.1.5.1. Mechanism of Action 100 3.1.5.2. Pharmacokinetics 102 3.1.5.3. Therapeutic Uses 103 3.1.5.4. Adverse Effects 103 3.1.5.5. Drug Interactions 104 3.1.5.6. Contraindications 104 3.2. Anti-Diuretics 105 3.2.1. Introduction 105 3.2.2. Classification 105 3.2.3. Antidiuretic Hormone 105 3.2.3.1. ADH (Vasopressin) 106 Receptor 3.2.3.2. Vasopressin Analogues 106 3.2.3.3. Mechanism of Action 107 3.2.3.4. Pharmacokinetics 108 3.2.3.5. Pharmacological Actions 108 3.2.3.6. Therapeutic Uses 109 3.2.3.7. Adverse Effects 109 3.2.3.8. Drug Interactions 109 3.2.3.9. Contraindications 110 3.2.4. Thiazide Diuretics 110 3.2.4.1. Mechanism of Action 110 3.2.4.2. Therapeutic Uses 110 3.2.4.3. Adverse Effects 110 3.2.4.4. Contraindications 111 3.3. Summary 111 3.4. Exercise 111 Chapter 3: Pharmacology of Drugs Acting on Urinary System 3.1. 3.1.1. 3.1.2. 3.1.3. 3.1.3.1. 3.1.3.1. 3.1.3.2. 3.1.3.3. 3.1.3.4. 3.1.3.5. 3.1.4. 3.1.4.1. 3.1.4.2. 3.1.4.3. 3.1.4.4. 3.1.4.5. * Diuretics 94 Introduction 94 Classification 94 High Efficacy D iuretics 94 (High Ceiling or Loop Diuretics) Mechanism of Action 95 Pharmacokinetics 95 Therapeutic Uses 95 Adverse Effects 96 Drug Interactions 96 Contraindications 97 Medium Efficacy Diu retics 97 (Thiazides and Thiazide Like Drugs) Mechanism of Action 97 Pharmacokinetics 98 Therapeutic Uses 98 Adverse Effects 99 Drug Interactions 99 Module 3 Chapter 4: Autocoids 4.1. 4.1.1. 4.1.2. 4.1.3. 4.1.3.1. 4.1.3.2. 4.1.3.3. 4.1.3.4. 4.1.3.5. 4.1.3.6. 4.1.4. 4.1.4.1. 4.1.4.2. 4.1.4.3. 4.1.4.4. 4.1.5. 4.1.5.1. Autocoids Introduction Classification Histamine Biosynthesis Histamine Receptor Subtypes Mechanism of Action Pharmacological Actions Pathophysiological Actions Histamine Agonists Histamine Antagonists (Antihistamines) H1-Antagonists H2-Antagonists H3 Antagonists H4 Antagonists 5-HT (Serotonin) Biosynthesis & Metabolism 113 113 113 113 114 115 115 116 118 119 119 120 122 123 123 124 124 * – 11 – 4.1.5.2. 4.1.5.3. 4.1.5.4. 4.1.5.5. 4.1.6. 4.1.7. 4.1.7.1. 4.1.7.2. 4.1.7.3. 4.1.7.4. 4.1.7.5. 4.1.7.6. 4.1.8. 4.1.8.1. 4.1.8.2. 4.1.8.3. 4.1.9. 4.1.9.1. 4.1.9.2. 4.1.9.3. 4.1.9.4. 4.1.10. 4.1.10.1. 4.1.10.2. 4.1.10.3. 4.1.10.4. 4.1.10.5. 4.1.10.6. 4.1.11. 4.1.11.1. 4.1.11.2. 4.1.11.3. 4.1.11.4. 4.1.12. 4.1.12.1. 4.1.12.2. 4.1.12.3. 4.2. 4.3. 5-HT Receptor Subtypes 125 Mechanism of Action 127 Pharmacological Actions 127 5-HT Agonists 128 5-HT Antagonists 129 Prostaglandins (PGs) 130 Synthesis 131 Pharmacological Actions 131 Therapeutic Uses 132 Adverse Effects 132 Prostaglandin Agonists 132 Prostaglandin Antagonists 134 Thromboxanes 134 Synthesis 134 Mechanism of Action 135 Therapeutic Uses 135 Leukotrienes (LTs) 135 Types 135 Synthesis 135 Pharmacological Actions 136 Pathophysiological Actions 137 Angiotensin (AT) 137 Angiotensin Receptors 137 (ATRs) Synthesis and Metabolism 138 Pharmacological Actions of 138 Angiotensin-II Inhibition of Renin - 139 Angiotensin System Angiotensin Converting 139 Enzyme (ACE) Inhibitor Angiotensin Receptor 140 Antagonists Bradykinin 140 Synthesis and Metabolism 140 Receptors 141 Pharmacological Actions 141 Therapeutic Uses 141 Substance P 142 Pharmacological Actions 142 Therapeutic Uses 142 Substance P Antagonist 142 Summary 143 Exercise 143 5.1.1. 5.1.2. * Non-Steroidal Anti Inflammatory Drugs (NSAIDs) Introduction Mechanism of Action 5.1.6.1. 5.1.6.2. 5.1.6.3. 5.1.6.4. 5.1.7. 5.1.7.1. 5.1.7.2. 5.1.7.3. 5.1.7.4. 5.1.8. 5.1.8.1. 5.1.8.2. 5.1.8.3. 5.1.8.4. 5.1.9. 5.1.9.1. 5.1.9.2. 5.1.9.3. 5.1.9.4. 5.1.10. 5.1.10.1. 5.1.10.2. 5.1.10.3. 5.1.10.4. 5.1.11. 5.1.12. - 145 5.1.12.1. 5.1.12.2. 5.1.12.3. 5.1.13. 145 145 5.1.13.1. 5.1.13.2. 5.1.13.3. Chapter 5: Non-Steroidal AntiInflammatory Agents 5.1. 5.1.3. 5.1.4. 5.1.4.1. 5.1.4.2. 5.1.4.3. 5.1.4.4. 5.1.4.5. 5.1.4.6. 5.1.4.7. 5.1.5. 5.1.6. Classification 147 Salicylates - Aspirin 147 Mechanism of Action 147 Pharmacokinetics 147 Pharmacological Actions 148 Therapeutic Uses 149 Adverse Effects 149 Drug Interactions 150 Contraindications 150 Pyrazolone Derivatives 151 Indole Derivatives - 151 Indomethacin Mechanism of Action 151 Pharmacokinetics 152 Therapeutic Uses 152 Adverse Effects 152 Propionic Acid Derivatives 152 - Ibuprofen Mechanism of Action 153 Pharmacokinetics 153 Therapeutic Uses 153 Adverse Effects 154 Anthranilic Acid Derivatives 154 – Mefenamic Acid Mechanism of Action 154 Pharmacokinetics 154 Therapeutic Uses 154 Adverse Effects 154 Aryl Acetic Acid Derivatives154 - Diclofenac Mechanism of Action 155 Pharmacokinetics 155 Therapeutic Uses 155 Adverse Effects 155 Oxicam Derivatives - 155 Piroxicam Mechanism of Action 155 Pharmacokinetics 155 Therapeutic Uses 156 Adverse Effects 156 Pyrrolo-Pyrrole Derivatives 156 - Ketorolac Preferential COX -2 156 Inhibitors - Nimesulide Mechanism of Action 156 Therapeutic Uses 156 Adverse Effects 156 Selective COX -2 Inhibitors 157 - Celecoxib Mechanism of Action 157 Therapeutic Uses 157 Adverse Effects 157 * – 12 – 5.1.14. 5.1.14.1. 5.1.14.2. 5.1.14.3. 5.1.14.4. 5.1.15. 5.1.16. 5.2. 5.3. Para-Aminophenol 157 Derivatives - Paracetamol Mechanism of Action 157 Pharmacokinetics 157 Therapeutic Uses 157 Adverse Effects 158 Pyrazolone Derivatives - 158 Metamizol (Dipyrone) Benzoxazocine Derivatives 158 - Nefopam Summary 159 Exercise 159 Chapter 6: Anti-Gout and Antirheumatic Drugs 6.1. 6.1.1. 6.1.2. 6.1.3. 6.1.4. 6.1.5. 6.1.6. 6.1.6.1. 6.1.6.2. 6.1.6.3. 6.1.6.4. 6.1.6.5. 6.2. 6.2.1. 6.2.2. 6.2.3. 6.2.3.1. 6.2.3.2. 6.2.3.3. 6.2.3.4. 6.2.3.5. 6.2.3.6. 6.2.3.7. 6.2.4. 6.2.5. 6.3. 6.4. Anti-Gout Drugs Introduction Classification Mechanism of Action Therapeutic Uses Adverse Effects Individual Drugs Probenecid Colchicine NSAIDs Allopurinol Sulfinpyrazone Antirheumatic Drugs Introduction Classification Disease Modifying Anti Rheumatic Drugs (DMARDs) Methotrexate (MTX) Azathioprine Sulfasalazine Chloroquine Leflunomide Gold Salts Penicillamine Biologic DMARDs Corticosteroids Summary Exercise 161 161 161 161 162 162 162 162 163 164 164 165 165 165 166 - 166 166 167 167 167 167 168 168 169 169 170 170 Module 4 Chapter 7: Pharmacology of Drugs Acting on Endocrine System - I 7.1. * Pharmacology of Drugs Acting on Endocrine System 172 7.1.1. 7.1.2. 7.1.3. 7.2. 7.2.1. 7.2.2. 7.2.2.1. 7.2.2.2. 7.2.2.3. 7.2.2.4. 7.2.2.5. 7.2.3. 7.2.3.1. 7.2.3.2. 7.2.3.3. 7.2.3.4. 7.2.4. 7.2.4.1. 7.2.4.2. 7.2.4.3. 7.2.4.4. 7.2.5. 7.2.5.1. 7.2.5.2. 7.2.5.3. 7.2.5.4. 7.2.5.5. 7.2.5.6. 7.3. 7.3.1. 7.3.2. 7.3.2.1. 7.3.2.2. 7.3.2.3. 7.3.2.4. 7.4. 7.4.1. 7.4.2. 7.4.3. Introduction and Basic 172 Concepts in Endocrine Pharmacology Hormones 173 Classification 173 Anterior Pituitary 173 Hormones Introduction 173 Growth Hormone 175 (Somatotropin) Regulation of Secretion 175 Physiological Actions 176 Growth Hormone 176 Analogues Growth Hormone Inhibitors 176 Growth Hormone 177 Abnormalities Prolactin (Prl) 177 Regulation of Secretion 177 Physiological Actions 178 Prolactin Inhibitors - 178 Bromocriptine Prolactin Abnormalities 179 Thyroid Stimulating 180 Hormone (TSH, Thyrotropin) Regulation of Secretion 180 Physiological Actions 180 Use 181 TSH Abnormalities 181 Gonadotropins 181 Regulation of Secretion 182 Physiological Actions 182 Uses 183 Gonadotropin Analogues 183 Gonadotropin Inhibitors 184 Gonadotropin 184 Abnormalities Posterior Pituitary 184 Hormones Introduction 184 Vasopressin (Anti -Diuretic 185 Hormone, ADH) Regulation of Secretion 185 Physiological Actions 185 Uses 186 Vasopressin Abnormalities 186 Thyroid Hormones 187 Introduction 187 Synthesis, Storage, 187 Release, and Metabolism Regulation of Secretion 188 * – 13 – 7.4.4. 7.4.5. 7.4.6. 7.4.7. 7.4.7.1. 7.4.7.2. 7.4.7.3. 7.4.7.4. 7.5. 7.5.1. 7.5.2. 7.5.2.1. 7.5.2.2. 7.5.2.3. 7.5.2.4. 7.5.2.5. 7.5.2.6. 7.5.3. 7.5.3.1. 7.5.3.2. 7.5.3.3. 7.5.3.4. 7.5.3.5. 7.5.3.6. 7.5.4. 7.5.4.1. 7.5.4.2. 7.5.4.3. 7.5.4.4. 7.5.4.5. 7.5.4.6. 7.5.4.7. 7.5.4.8. 7.5.4.9. 7.6. 7.6.1. 7.6.2. 7.6.2.1. 7.6.2.2. 7.6.2.3. 7.6.2.4. 7.6.2.5. 7.6.2.6. 7.6.2.7. * Physiological Actions 189 Uses 190 Thyroid Hormone 191 Abnormalities Thyroid Hormone 191 Inhibitors Anti-Thyroid Drugs - 192 Propylthiouracil Ionic Inhibitors 192 Iodine and Iodides 192 Radioactive Iodine (RAI) 193 Hormones Regulating 194 Plasma Calcium Level Introduction 194 Parathormone (Parathyroid 194 Hormone, PTH) Synthesis 195 Regulation of Secretion 195 Mechanism of Action 195 Physiological Actions 195 Uses 196 PTH Abnormalities 196 Calcitonin 197 (Thyrocalcitonin) Synthesis 197 Regulation of Secretion 197 Mechanism of Action 198 Physiological Actions 199 Uses 199 Calcitonin Abnormalities 199 Vitamin D (Calcitriol) 199 Synthesis 200 Regulation of Synthesis 200 Mechanism of Action 201 Pharmacokinetics 201 Physiological Actions 201 Uses 202 Drug Interactions 202 Vitamin D Abnormalities 202 Vitamin D Toxicity 202 Insulin, Oral 202 Hypoglycaemic Agents and Glucagon Introduction 202 Insulin 203 Insulin Preparations 203 Synthesis 203 Regulation of Secretion 204 Mechanism of Action 205 Physiological Actions 206 Uses 206 Drug Interactions 207 7.6.2.8. Insulin Analogues 7.6.2.9. Insulin Abnormalities 7.6.3. Oral Hypoglycaemic Agents 7.6.3.1. Classification 7.6.3.2. Sulfonylureas 7.6.3.3. Biguanides 7.6.3.4. Meglitinide Analogues 7.6.3.5. Thiazolidinediones 7.6.3.6. -Glucosidase Inhibitors 7.6.4. Glucagon 7.6.4.1. Synthesis 7.6.4.2. Regulation of Secretion 7.6.4.3. Mechanism of Action 7.6.4.4. Physiological Actions 7.6.4.5. Uses 7.6.4.6. Glucagon Abnormalities 7.7. ACTH (Corticotropin or Adrenocorticotropic Hormone) 7.7.1. Introduction 7.7.2. Regulation of Secretion 7.7.3. Physiological Actions 7.7.4. Uses 7.7.5. ACTH Abnormalities 7.8. Corticosteroids 7.8.1. Introduction 7.8.2. Biosynthesis 7.8.3. Glucocorticoids (GCs) 7.8.3.1. Regulation of Synthesis 7.8.3.2. Mechanism of Action 7.8.3.3. Pharmacokinetics 7.8.3.4. Physiological Actions 7.8.3.5. Uses 7.8.3.6. Adverse Effects 7.8.3.7. Contraindications 7.8.4. Mineralocorticoids 7.8.4.1. Regulation of Synthesis 7.8.4.2. Mechanism of Action 7.8.4.3. Pharmacokinetics 7.8.4.4. Physiological Actions 7.8.4.5. Uses 7.8.4.6. Adverse Effects 7.8.5. Corticosteroid Inhibitors 7.9. Summary 7.10. Exercise 207 208 208 209 209 210 211 211 212 213 213 213 213 214 214 215 215 215 215 216 216 216 217 217 217 219 219 219 220 220 221 222 222 223 223 224 224 224 225 225 225 226 227 Module 5 Chapter 8: Pharmacology of Drugs Acting on Endorcine System - II 8.1. 8.1.1. Male Sex Hormones Introduction 229 229 * – 14 – 8.1.2. 8.1.2.1. 8.1.2.2. 8.1.2.3. 8.1.2.4. 8.1.2.5. 8.1.2.6. 8.1.2.7. 8.1.2.8. 8.1.3. 8.1.3.1. 8.1.3.2. 8.1.3.3. 8.2. 8.2.1. 8.2.2. 8.2.2.1. 8.2.2.2. 8.2.2.3. 8.2.2.4. 8.2.2.5. 8.2.2.6. 8.2.2.7. 8.2.2.8. 8.2.2.9. 8.2.2.10. 8.2.3. 8.2.3.1. 8.2.3.2. 8.2.3.3. 8.2.3.4. 8.2.3.5. 8.2.3.6. 8.2.3.7. 8.2.3.8. 8.2.4. 8.2.4.1. 8.2.4.2. 8.2.4.3. 8.2.4.4. 8.2.4.5. * Androgens Classification Synthesis Regulation of Secretion Mechanism of Action Pharmacokinetics Physiological Actions Uses Androgen Abnormalities Anabolic Steroids Physiological Actions Uses Adverse Effects Female Sex Hormones Introduction Estrogens Classification Synthesis Regulation of Secretion Mechanism of Action Pharmacokinetics Physiological Actions Uses Drug Interactions Contraindications Estrogen Abnormalities Progesterone Classification Synthesis Regulation of Secretion Mechanism of Action Pharmacokinetics Physiological Actions Uses Progesterone Abnormalities Oral Contraceptives Classification Contraception Methods Mechanism of Action Physiological Actions Uses 229 230 230 230 231 231 231 231 232 232 233 233 233 234 234 234 234 234 235 236 236 236 237 237 237 237 237 238 238 238 238 239 239 239 240 240 240 241 242 243 243 8.2.4.6. 8.2.4.7. 8.2.4.8. 8.3. 8.3.1. 8.3.2. 8.3.3. 8.3.3.1. 8.3.3.2. 8.3.3.3. 8.3.4. 8.3.4.1. 8.3.4.2. 8.3.4.3. 8.3.4.4. 8.3.4.5. 8.4. 8.5. Adverse Effects Drug Interactions Contraindications Drugs Acting on the Uterus Introduction Classification Uterine Stimulants (Oxytocics, Abortifacients) Oxytocin Ergometrine Prostaglandins Uterine Relaxants (Tocolytics) Adrenergic Agonists Calcium Channel Blockers Magnesium Sulphate Oxytocin Antagonist Miscellaneous Drugs Summary Exercises 243 244 244 244 244 244 245 245 248 250 252 253 253 254 254 254 254 255 Chapter 9: Bioassay 9.1. 9.1.1. 9.1.2. 9.1.3. 9.1.4. 9.1.5. 9.1.5.1. 9.1.5.2. 9.1.5.3. 9.1.5.4. 9.1.5.5. 9.1.5.6. 9.1.5.7. 9.1.5.8. 9.2. 9.3. Bioassay Introduction Principles Applications Types of Bioassay Bioassay of Individual Drugs Insulin Oxytocin Vasopressin ACTH d-Tubocurarine Digitalis Histamine 5-HT Summary Exercises 257 257 257 258 259 262 262 265 267 269 270 271 272 273 276 277 * Pharmacology of Drugs Acting on CVS (Chapter 1) CHAPTER 1 15 Pharmacology of Drugs Acting on CVS 1.1. CARDIOVASCULAR SYSTEM 1.1.1. Introduction Cardiovascular system comprises of the heart and an extensively branched structure of blood vessels that transports oxygen, nutrients , heat, and other substances throughout the body. Cardiac or heart muscles are involuntary striated muscles found in the heart and its walls, especially in the myocardium (the muscle tissue forming a thick middle layer amid the outer epicardium and the inner endocardium ). For delivering oxygen and nutr ients, and removing waste products such as carbon dioxide, the cardiac muscle cells depend on the available blood and e lectrical supply. The myocardial tissue is made up of contracting cells and conducting cells . The pumping action of the heart involves the contracting cells. The conducting tissues of the heart include SA node (acts as the pacemaker), AV node, and His -Purkinje system. Various parts of the conducting tissue exhibit automaticity. Cardiac muscles being specialised tissues have distinct properties of: 1) Excitability: It is the ability of cardiac cells to depolarise in response to a stimulus. 2) Contractility: It is the ability of myocardium to contract and pump blood out of the heart. 3) Automaticity: It is the ability of cardiac cells to generate electrical impulses spontaneously. 1.1.2. Hemodynamics The study of the dynamic behaviour of blood is termed hemodynamics. Pressures are generated in the various parts of heart (cardiovascular pressures) when blood flows from one chamber to another, when valves open and close, and when the myocardium contracts and relaxes. Catheters are used to measure and monitor these pressures by placing their tips in the atria, pulmonary artery , or systemic arteries; these are called the hemodynamic lines. Hemodynamic lines have multiple uses: 1) They allow the sampling of venous and arterial blood without having to stick a patient frequently. 2) They help in monitoring different patient’s status. * waveforms, thus providing evidences to * 16 Pharmacology-II 3) The cardiac output can be calculated arterial, and systemic arterial lines. with the combination of pulmonary, 4) They allow direct monitoring of various cardiac pressures, and a nalysis of these pressures helps in planning and assessing therapy in shock, cardiac failure, fluid overload or deficit, and other conditions. 1.1.3. Electrophysiology of Heart The cardiac cell is a polarised membrane . It has a resting membrane potential of –80 to –90mV, and a high Na+ ion concentration outside the membrane and K + ion concentration inside the membrane. Upon excitation, depolarisation occurs as the cell membrane permeability to Na + ions increases, the negativity of resting potential is lost, and a positive current is gen erated inside the cell. The characteristics of action potential rely on the type of the cell -myocardial contractile cell, or pacemaker, or potential pacemaker cell. There are five phases of the action potential of cardiac cells (figure 1.1): 1) Phase 0: In t his phase, rapid +20 1 depolarisation of the cell membrane +10 2 is observed as the sodium ions 0 rapidly enter the cell through sodium –10 ERP channels. This phase is followed by –20 re-polarisation. –30 3 0 –40 2) Phase 1: In this short and initial phase, rapid re-polarisation is –50 observed as the potassium ions move –60 –70 out of the cell. –80 4 3) Phase 2: This prolonged plateau –90 –100 phase is observed as the calcium Figure 1.1: Phases of Cardiac Action Potential. ions enter the cell slowly through the Phase 0 Indicates Rapid Depolarisation, Phases calcium channels . This phase of 1-3 Indicate Repolarisation, Phase 4 Indicates Gradual Depolarisation during Diastole. action potential is present only in the cardiac cells. 4) Phase 3: This phase is th e second period of rapid re -polarisation as the potassium ions move out of the cell. 5) Phase 4: This is the resting phase as the resting membrane potential is re established when the potassium ions return into the cell and sodium and calcium ions move out of it. The cell s do not depolarise in response to another impulse during the phases 1 and 2; and this is called the absolute refractory period. The cells depolarise in response to a powerful impulse d uring the phases 3 and 4 ; and this is called the relative refractory period. The heart rate and stroke volume are used for determining the cardiac output. The stroke volume depends on the preload (which itself depends on venous return) , afterload, and contractility. The load on the heart due to the blood volume reaching the left ventricle is called preload; while the resistance to the left ventricular ejection, i.e., the total peripheral resistance is called afterload. * * Pharmacology of Drugs Acting on CVS (Chapter 1) 17 1.2. DRUGS USED IN CONGESTIVE HEART FAILURE 1.2.1. Introduction When a heart fails to pump blood in a quantity sufficient to fulfil the body requirements, a condition of Congestive Heart Failure (CHF) occurs, which is also known as a Heart Failure (HF). CHF is caused due to: 1) Narrowing of the arteries supplying blood to the heart muscles, 2) Any congenital heart defects, 3) Endocarditis (infection in heart valves) or myocarditis (infection of heart muscles), 4) Cardiomyopathy (disease of the heart muscles), 5) Any long -term heart valve disease (due to past rheumatic fever or other causes) and high blood pressure, and 6) Past history of the patient who has suffered from myocardial infar ction or heart attack and the injured tissue obstructs the normal functioning of heart. Some common symptoms of CHF are: 1) Fatigue, 3) Shortness of breath, and 1.2.2. 2) Swelling or oedema, 4) Increased urination. Classification The following drugs are employed in the treatment of CHF: 1) Drugs with Positive Inotropic Effects i) Cardiac Glycosides: Digoxin, Digitoxin, and Ouabain. ii) Bipyridines/Phosphodiesterase Inhibitors: Amrinone and Milrinone. iii) β-Adrenergic Agonists: Dobutamine and Dopamine. 2) Drugs without Positive Inotropic Effects i) Diuretics: Thiazides, Furosemide, and Spironolactone. ii) Angiotensin Antagonists: ACE inhibitors and Losartan. iii) β-Adrenergic Antagonists: Bisoprolol, Carvedilol, and Metoprolol. iv) Vasodilators: Nitrates and Hydralazine. 1.2.3. Cardiac Glycosides Cardiac glycosides are derived from plant derivatives and are steroidal in nature . A glycoside is a sugar-containing compound in which one of the hydroxyl groups of the sugar molecule is replaced with another compound. Digoxin, digitoxin, and ouabain are the commonly used cardiac glycosides. Often, the term digitalis refers to the complete group of cardiac glycosides as all the drugs in this group exert the same effects on the heart. They differ only in lipid solubility, rapidity, degree of absorption, protein binding, metabolic pathway, and excretion. * * 18 1.2.3.1. Pharmacology-II Mechanism of Action The mechanism of action of digitalis can be explained as follows (figure 1.2): 1) Digitalis exerts a positive inotropic effect due to its ability to potentiate the excitation-contraction coupling. This is possible since digitalis increases the concentration of free intracellular Ca2+ ions. a Na+ b K+ K+ Na+ * Na+- K+ATPase c Ca2+ Na+ exchange Myocardial cell Ca2+ Na+ e Ca2+ SR d Ca + Troponin Actin + Myosin Actomyosin Myocardial contraction * Digitalis acts on the enzyme Na+/K+-ATPase Figure 1.2: Cellular Mechanism of Digitalis Action. a) Tendency of Na+ to flow in and K+ to flow out along the concentration gradient; b) Na+/K+-ATPase pushing the Na+ out and drawing the K+ in; c) Na+/Ca2+ exchange mechanism; d) Release of Ca2+ from Sarcoplasmic Reticulum (SR); e) Ca2+ + troponin initiating myocardial contraction. 2) It inhibits the membrane bound Na +/K+-ATPase transport system (sodium pump), resulting in increase of intracellular Na + ions and loss of intracellular K+ ions. 3) As Na + ions accumulate inside the cell, it activates a Na +/Ca2+ carrier system (a non -enzymatic protein carrier) within the membrane. The activation of Na+/Ca2+carrier system results in an increase in the influx of Ca 2+ ions. Three Na+ ions are exchanged for each Ca2+ ion, thereby generating an electrogenic potential by this exchanger. 4) Normally, the concentration of Ca2+ ions around the myofilaments is lowered by the Ca2+ ion pump in the Sarcoplasmic Reticulum (SR). The energy for driving + this pump is obtained by ATP hydrolysis carried out by Na /K+-ATPase. However, digitalis inhibits this enzyme and hence less energy is available for driving the Ca2+ ion pump. Thus, the supply of Ca 2+ ions from SR around the myofilaments increases, which in turn activates the contractile machinery. 5) The binding of digitalis to sodiu m pump is inhibited by the K+ ions present in the serum. Hence, conditions of hypokalaemia facilitate the action of digitalis. On the other hand, conditions of hyperkalaemia can decrea se cardiac toxicity. Arrhythmia induced by digitalis, is increased by co nditions of hypercalcaemia or hypomagnesaemia. 1.2.3.2. Pharmacokinetics Route of administration of digitalis is either oral or intravenous. It is not suitable for administration by subcutaneous or intramuscular routes as its absorption from these sites is not re liable and may bring about local irritation, tenderness, swelling, and abscess. * * Pharmacology of Drugs Acting on CVS (Chapter 1) 19 Digitalis does not bind selectively to the myocardium when administered through these sites. Digitalis is a cumulative drug. It has a prolonged half -life and the duration of its action ranges from days to weeks . The prolonged plasma half life of digitoxin is due to its enterohepatic circulation. 1.2.3.3. Pharmacological Actions Cardiac glycosides have the capability of increasing the myocardial contraction force, which is the most sig nificant property of these drugs. Other than this, they have several extra-cardiac effects on vascular smooth muscle s, kidneys, gut and theCNS: 1) Actions on Heart i) Administration in small doses causes an increase in the vagal tone by sensitisation of baroreceptors and/or activity of the afferent nerves. As a result, sinus activity decreases which le ads to decrease in conductivity, prolongation of refractory period of the AV node, decre ase in atrial refractory period, and bradycardia. ii) Contractility of the myo cardium increases by a direct positive inotropic action of digitalis on the heart. Thus, the failing heart contracts even more forcefully, which results in increased cardiac output, complete ventricular emptying, and decreased diastolic pressure and ventricular size. Systole lasts for a shorter duration, giving more time for ventricular filling and rest to the heart. iii) With the increase in contractility of heart, the oxygen consumption in the myocardium increases. On the other hand, decrease in the heart rate and ventricular size decreases oxygen requirements of the heart. Hence, the general effect of digitalis is an improved ventricular performance of the failing heart without any significant increase in energy requirement. iv) When administered in comparatively small therapeutic doses, digitalis improves the ability of excitation of the myocardium and the conduction velocity. However, its administration in high doses causes an increased automaticity and decreases the refractory period of the atria and the ventri cles, resulting in extra -systoles, pulsus bigeminus , and ventricular fibrillation. v) Digitalis slows the conduction velocity in the AV node and His-Purkinje system, regardless of the dose administered. This is achieved by an increase in the refractory period by both vagal as well as the extra -vagal actions of digitalis. Low doses are characterised by a predominance of vagal effects . As the dose is increased, direct depressant action on the AV node is seen. vi) Digitalis does not act directly to influence the coronary flow. The enhanced coronary circulation is a secondary effect of the increased cardiac output and extended diastole. vii) Changes evident in an ECG after administration of digitalis includes prolongation of the PR interval (due to delayed conduction) and shortening of QT interval (shorter ventricular systole). Other changes are that the ST segment sags below the isoelectric line , and the T-wave appear smaller, inverted or disappears. * * 20 Pharmacology-II 2) Extra-Cardiac Effects of Digitalis i) On Blood Vessels: Digitalis exerts a minor direct constrictor action on the smooth muscles of arteries and veins. ii) On Kidneys: Digitalis improves circulation and decreases sympathetic activity, thereby increasing the blood flow to kidneys. This increases the urinary output and relieves oedema ni patients with cardiac oedema. iii) On Gastrointestinal Tract: Digitalis stimulates the Chemoreceptor Trigger Zone(CTZ) in the medulla, thus resulting in nausea and vomiting. iv) On CNS: Digitalis may produce symptoms of visual disturbances such as blurring of vi sion, photophobia, a dark spot in centre of vision , and disturbances of coloured vision with yellow and green. In some patients, psychic symptoms and confusion may also be seen. 1.2.3.4. Therapeutic Uses Cardiac glycosides have the following therapeutic benefits: 1) Patients with congestive heart failure characterised by a dilated, failing heart with low cardiac output (impaired systolic function) are benefited by administration of digitalis. 2) Treatment of low output cardiac failure with digitalis, in patients where t he myocardium is not principally damaged, shows the best results. Examples of such conditions include atrial fibrillation, valvular defects, and hypertension. 3) The management of cardiac arrhythmias (supraventricular tachyarrhythmias), like atrial flutter and atrial fibrillation, occurring either with or without CCF, employs the use of digitalis. 1.2.3.5. Adverse Effects Digitalis is highly toxic. It has a low margin of safety with a therapeutic index ranging from 1.5 -3. Patients with stead y-state plasma digoxin le vels report a higher cardiac mortality during maintenance therapy. Nearly 25% of the patients show either of the toxic symptoms, which include: 1) Extra-Cardiac Effects: These adverse effects are seen initially and include anorexia, nausea, vomiting, and abdo minal pain. These effects appear due to gastric irritation, mesenteric vasoconstriction, and CTZ stimulation. The other adverse effects include fatigue, absence of a desire to walk or lift an arm, malaise, headache, mental confusion, restlessness, hyperpno ea, disorientation, psychosis, and visual disturbances . Rare adverse effects include diarrhoea, skin rashes, and gynaecomastia. 2) Cardiac Effects: Digitalis produces almost every type of arrhythmia, including pulsus bigeminus, nodal and ventricular extrasyst oles, ventricular tachycardia, and terminally fibrillation. 1.2.3.6. Drug Interactions Cardiac glycosides undergo the following drug interactions: 1) Administration of digitalis with a diuretic results in hypokalaemia, which can precipitate digitalis arrhythmias. * * Pharmacology of Drugs Acting on CVS (Chapter 1) 21 2) Administration of digitalis with calcium synergises the actions of digitalis, thereby precipitating toxicity. 3) Quinidine decreases the binding of digoxin to tissue proteins. 4) Administration of digitalis with adrenergic drugs induces arrhythmias and increases ectopic automaticity. 5) Metoclopramide (gastrointestinal hurrying), sucralfate, neomycin, sulphasalazine, and antacids decrease the absorption of digoxin by adsorbing it. 6) Atropinic drugs including tricyclic antidepressants increase the absorption of digoxin by delaying its gastric emptying. 7) Erythromycin, omeprazole, and tetracycline increase the bioavailability of digoxin. 8) Propranolol, verapamil, diltiazem, and disopyramide oppose the positive inotropic action of digitalis and may add to the depression of A -V conduction. 9) Phenobarbitone accelerates the m etabolism of digitoxin , thus , reducing its plasma half-life. 10) Administration of succinylcholine by the patients on digitalis therapy causes arrhythmias. 1.2.3.7. Contraindications Cardiac glycosides are contraindicated in the following conditions: 1) Digitalis is contraindicated in hypokalaemia as its binding to Na+K+-ATPase is increased, thus increasing digitalis toxicity. 2) It is contraindicated in elderly and in patients having severe renal or hepatic disease. 3) It is con traindicated in myocardial infarction as s evere arrhythmias may develop. 4) It is contraindicated in thyrotoxicosis as the patient’s responsiveness decreases, and arrhythmias may also develop. 5) It is contraindicated in ventricular tachycardia as it may precip itate ventricular fibrillation. 6) It is contraindicated in Wolff-Parkinson-White Syndrome as it may result in ventricular failure. 7) Administration of digitalis in patients with a partial A-V block may convert it into a complete A-V block. 8) Digoxin is contrain dicated in myxoedema as its elimination rate decreases, thus, cumulative toxicity of digitalis may be seen. 1.2.3.8. Treatment of Digitalis Toxicity The cases of digitalis toxicity can be treated in the following ways: 1) Withdrawal: Administration of digitalis should either be stopped or the dose should be reduced based on the severity of toxicity. Use of potassium depleting diuretics should be discontinued. 2) Potassium Repletion: KCl is administered by oral route (or by slow IV drip) in a dosage of 2gm in every 4 hour s. During this time, ECG of the patient should be continuously monitored. However, in case of a severe AV block, KCl should not be given. * * 22 Pharmacology-II 3) Antiarrhythmic Drugs: Ventricular tachyarrhythmias can be suppressed by phenytoin and lignocaine since they have eith er little or no effect on conduction. Phenytoin is administered in a dose of 100mg via IV infusion in every 5 minutes till arrhythmia is treated. Supraventricular and ventricular tachycardia, without AV block, can be treated by administering propranolol in dosages of 20-80mg/day. Sinus bradycardia and various degrees of AV block can be controlled with atropine. 4) Advanced Cases of Life Threatening Digitalis Intoxication:Such conditions can be reversed by inserting a temporary cardiac pacemaker catheter,long a with purified digoxin-specific antibody (digitalis immune fab) fragments. 1.2.4. Bipyridines Bipyridine derivatives ( e.g., amrinone and milrinone) show phosphodieste rase (PDE) inhibiting activity. These drugs are selective inhibitors of PDE-isoenzyme III, found in the cardiac and smooth muscles. 1.2.4.1. Mechanism of Action Bipyridines increase the production of cAMP in the heart and blood vessels , and thus exert a positive inotropic action along with vas odilator activities. Increased 2+ levels of intracellular cAMP enable the availability of more intracellular Ca ions, thus, a more positive inotropism may result. 1.2.4.2. Therapeutic Uses Cardiac output is increased. The peripheral vascular resistance and the after-load are decreased with no significant change in heart rate and blood pressure. Bipyridines are used only for the treatment of heart failure or exacerbation of CCF. 1.2.4.3. Adverse Effects Given below are the adverse effects of bipyridine derivatives: 1) Amrinone causes nausea, vomiting, liver enzyme changes, and occasionally thrombocytopenia. 2) Milrinone may cause cardiac arrhythmia, bone marrow depression, and liver toxicity. Due to these adverse effects, these agents are used for short-term therapy only. 1.2.5. β-Adrenergic Agonists 1.2.5.1. Mechanism of Action The discovery of 1-agonists has sufficed the search for a positive inotropic agonist with minimal positive chronotropic and arrhythmogenic potential, with dobutamine being the most potential one amongst these agents. The β-adrenergic agonists increase the cardiac output, and decrease the ventricular filling pressure and pre -load. Some degree of tachycardia is also seen with the use of these drugs. They increase the consumption of oxygen. * * Pharmacology of Drugs Acting on CVS (Chapter 1) 1.2.5.2. 23 Therapeutic Uses The β-adrenergic agonists have been limited to the management of acute heart failure. They may occasionally be employed in the treatment of refractory CCF. 1.2.5.3. Adverse Effects The β-adrenergic agonists may cause tachyphylaxis. 1.2.6. Diuretics Diuretics are commonly used in the management of CHF. Since the last 50 years, these agents are favoured for CHF treatment. 1.2.6.1. Mechanism of Action Diuretics increase the excretion of salt and water. This in turn decreases the ventricular pre -load and the cardiac size, improves pump function , and helps relieve oedema. In CHF patients, aldosterone promotes fibrosis in the heart and blood vessels. This effect of aldosterone is antagonised by spironolactone (an aldosterone antagonist). 1.2.6.2. Therapeutic Uses Diuretics are used in the management of all stages of CHF. Furosemide is a very efficient diuretic in treating acute left ventricular failure (cardiac asthma). 1.2.6.3. Adverse Effects The adverse effects of various classes of diuretics are: 1) Loop Diuretics : Hypokalae mia is a common adverse effect. Patients on long-term diuretics require potassium supplements and regular monitoring. At high doses, hyponatraemia may occur, whi ch needs careful supervision in heart failure patients. Ototoxicity characterised with tinnitus, vertigo and deafness also occurs at high doses of loop diuretics. Therefore, intravenous administration of furosemide should not be faster than 4mg/min. 2) Thiazide Diuretics: Due to potassium and sodium loss, the adverse effects of thiazide diuretics are similar to those of loop diuretics. However, the potassium loss is reduced when ACE inhibitors are simultaneously prescribed. Diabetic patients need monitoring as diabetes may occur with thiazide diuretics. Impotence as well as sensitivity may also develop due to the presence of sulphonamide in the drugs. 3) Aldosterone Antagonists : Adverse effects include fibrosis, hypertrophy , arrhythmogenesis, and hyperkalaemia, wh ich require regular monitoring because of its potentially lethal effects in CHF patients due to renal failure. Hyponatraemia and feminisation such as gynaecomastia are other adverse effects. In patients having severe symptomatic systolic heart failure, spironolactone is recommended along with ACE inhibitors. * * 24 1.2.7. Pharmacology-II Angiotensin Antagonists The ACE inhibitors and angiotensin receptor blockers are included in this group. 1.2.7.1. Mechanism of Action Drugs which inhibit the activity of RAS either interfere with the biosynthesis of angiotensin II [Angiotensin Converting Enzyme (ACE) inhibitors], or act as antagonists of angiotensin receptors [Angiotensin Receptor Blockers (ARBs)]. The production of an giotensin II from angiotensin I is inhibited by ACE inhibitors. These agents neutralise the raised peripheral vascular resistance and retention of sodium and water that resulted from angiotensin II and aldosterone. 1.2.7.2. Pharmacological Actions The pharmacological actions of angiotensin antagonists are: 1) Reduction in peripheral arterial resistance and after-load. 2) Reduction in aldosterone secretion, thus decreasing the retention of salt and water. This causes venodilatation and reduces pre-load. 3) Reduction in angiotensin concentration in the tissues, thus reducing angiotensin-induced tissue norepinephrine release. 4) Reduction in the long-term remodelling of heart and blood vessels. 1.2.7.3. Therapeutic Uses Angiotensin antagonists are indicated in all symptomatic and asympto matic patients with Left Ventricular (LV) dysfunction . ACE inhibitors ( e.g., enalapril, lisinopril, or ramipril) have a wide diversity of actions and are considered to be better drugs for the treatment of CHF. 1.2.7.4. Adverse Effects Angiotensin antagonists give rise to occasional adverse effects that include hypotension, hyperkalemia, angioedema, cough, and syncope. Several studies have suggested that the beneficial effects of ACE inhibitors are reduced when they are given along with aspirin. Actually, ACE inhibitors did not produced any different effects when were administered with or without aspirin. 1.2.8. β-Adrenoceptor Antagonists 1.2.9. Vasodilators The -blockers (most commonly propranolol and other agents having membranestabilising activity) were contraindicated in patients with CHF as they were found to precipitate acute decompensation. Yet, it has been found that some of these drugs may be useful in the treatment of diastolic dysfunction or cardiomyopathies in patients requiring bradycardia and in decreasing the contraction velocity. It has been found in the current stud ies that bisoprolol, carvedilol, and metoprolol may decrease mortality in patients with class II and III heart failure. Vasodilators have an indirect benef icial effect on the heart. Arteriolar dilatation (caused by hydralazine and nitrates) decreases the afterload. Venodilatation (caused by nitrates) decreases pre-load. These agents are useful adjunctive for the primary treatment. Use of hydralazine or isoso rbide on a long -term has been shown to decrease damage to the remodelling heart. * * Pharmacology of Drugs Acting on CVS (Chapter 1) 25 1.3. ANTI-HYPERTENSIVE DRUGS 1.3.1. Introduction A condition in which the blood pressure of systemic artery increases beyond the normal pressure is known as hypertension. Therefore to deliver blood to tissues, the heart works harder to overcome the increased systemic pressure. This increased systemic arterial pressure puts strain on the heart and other arteries, thus resulting in high blood pressure. Based on the degree of severity, hypertension can be graded as: 1) Mild: Diastole up to 104mmHg, 2) Moderate: Diastole105-114mmHg, and 3) Severe: Diastole more than 115mmHg. Symptoms of hypertension are: 1) Chest pain, 3) Ear noise or buzzing (tinnitus), 5) Nosebleed (epistaxis), 7) Vision changes. 2) Confusion, 4) Irregular heartbeat (arrhythmia), 6) Exhaustion (lethargy), and Therapy for hypertensive patients aims at reducing the increased blood pressure. This is accomplished by administration of drugs from different classes; t reatment is often given in the form of a combination of several agents. If left untreated, it would result in organ damage, thus an increased risk for MI and stroke. 1.3.2. Classification The antihypertensive agents are classified into the following classes: 1) Diuretics i) Thiazides: Hydrochlorothiazide, Chlorthalidone, and Indapamide. ii) Loop Diuretics: Furosemide, Bumetanide, and Torsemide. + iii) K Sparing Diuretics: Spironolactone, Amiloride, and Triamterene. 2) Angiotensin Converting Enzyme Inhibitors:Captopril, Enalapril, Lisinopril, Ramipril, Perindopril, Fosinopril, Trandolapril, Quinapril, and Benazepril. 3) Angiotensin II Receptor Antagonists: Losartan, Candesartan, Valsartan, Eprosartan, and Irbesartan. 4) Ganglion Blockers: Trimethaphan. 5) Adrenergic Drugs i) Centrally Acting D rugs: Clonidine, Methyldopa, Guanabenz, and Guanfacine. ii) Adrenergic Neuron Blockers: Guanethidine and Reserpine. iii) Sympatholytics (Adrenergic Receptor Blockers) a)  Blockers: Prazosin, Terazosin, Doxazosin, Phenoxybenzamine, and Phentolamine. b)  Blockers: Propranolol, Atenolol, Esmolol, and Metoprolol. c) + Blockers: Labetalol and Carvedilol. * * 26 Pharmacology-II 6) Calcium Channel Blockers: Verapamil, Nifedipine, Nicardipine, Nimodipine, Amlodipine, and Felodipine. 7) Vasodilators i) Arteriolar Dilators: Hydralazine, Minoxidil, and Diazoxide. ii) Arteriolar and Venular Dilators: Sodium nitroprusside. 1.3.3. Diuretics Drugs promoting urine output are known as diuretic s. They act directly on the kidneys and primarily increase the excretion of water and ions [so dium (Na +), chloride (Cl−) or bicarbonates ( HCO3 )] from the body. The antihypertensive action of diuretics is that they promote the excretion of sodium and water resulting in: 1) Decreased plasma volume   cardiac output   BP 2) Decreased body sodium  relaxation of vascular smooth m uscles (due to Na+ ion depletion in the vascular smooth muscle)   PVR   BP. The amount of diuretic required will be reduced if the intake of dietary salt is restricted. Some common drugs used as diuretics are: 1) Thiazides: These diuretics (e.g., hydrochlorothiazide and chlorthalidone) are the inexpensive first -line antihypertensive agents. They are commonly used in hypertension treatment. 2) Loop Diuretics: These diuretics ( e.g., furosemide, bumetanide, and torsemide) are powerful diuretics but have low an tihypertensive efficacy. They are used only in hyper tensive patients having chronic renal failure or congestive heart failure. They are included in the treatment of malignant hypertension and hypertension with hypervolemia ( e.g., renal insufficiency). 3) Potassium-Sparing Diuretics: These diuretics ( e.g., spironolactone, amiloride, and triamterene) have comparatively low efficacy; however, they correct the po tassium loss caused by thiazide and loop diuretics. They are used in combination with hydrochlorothiazide. 1.3.3.1. Mechanism of Action The three commonly used diuretics act as follows: 1) Thiazides and Thiazide-like Diuretics: Thiazide (e.g., hydrochlorothiazide) and thiazide-like diuretics (e.g., chlorthalidone, indapamide, and metolazone) increase the excretion of Na+ ions t hrough urine by inhibiting the sodium chloride pump in the early segment of the distal convoluted tubule. This initially reduces the plasma volume, which increases the plasma renin activity and aldosterone. Ultimately, vascular resistance decrea ses by some uncertain mechanisms because plasma volume approaches the pre -treatment levels. 2) Loop Diuretics: These diuretics act at the thick ascending loop of Henle to prevent the reabsorption of Cl− and Na+ ions