Medicinal Chemistry II PDF Textbook

* * MEDICINAL CHEMISTRY-II B.Pharm, Semester-V According to the syllabus based on ‘Pharmacy Council of India’ Dr. Selvakumar. S M.Pharm, Ph.D...

* * MEDICINAL CHEMISTRY-II B.Pharm, Semester-V According to the syllabus based on ‘Pharmacy Council of India’ Dr. Selvakumar. S M.Pharm, Ph.D Professor & HOD, Cherraan’s College of Pharmacy, Coimbatore Dr. Sachin J. Dighade M.Pharm, Ph.D Principal, VYWS, Amravati’s Institute of Pharmacy, Maharashtra Dr. R. Srinivasan M.Pharm, Ph.D (Pharmaceutical Chemistry) Principal & Professor, Pallavan College of Pharmacy 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* * * * * Medicinal Chemistry-II Edition 2019 Copyright © All Rights Reserved This book is sole subje ct 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 in cluding 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 reproduced, stored in or transmitted in any form or by any means (elect ronic, 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 Pe trol 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 Students” -Dr.Selvakumar.S “Dedicated to my Beloved Parents” -Dr. Sachin J. Dighade “Dedicated to my Family, Teachers, Colleagues & Beloved Students” -Dr. R. Srinivasan * * * * Preface It gives us immense pleasure to place before the B.Pharm Fifth Semester pharmacy students the book on “Medicinal Chemistry-II”. This book has been written strictly in accordance with 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 the prescribed syllabus, and it provides the students fundamentals of differ ent categories of drugs like anti -anginal, anti -hypertensives, anti -hyperlipidemics, anticoagulants, antineoplastic agents, anti -diabetics, local anaesthetics, gastric PPIs, etc. which are required by them during their pharmaceutical career. All efforts have been made to keep the text error -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, [email protected] Website, www.tppl.org.in * * * * Acknowledgement I am taking deep pleasure to put on my heartiest gratitude to Dr. S. Ravichandran, M.Pharmacy., Ph.D, Principal, PSV College of Pharmacy, Dharmapuri and Dr. K.Prabhu , Principal, Cherraan’s C ollege of Pharmacy, Coimbatore. M.Pharmacy, Ph.D for their encouragement and suggestions by them during all stages of this entire text book work. I express my deep sense of gratitude and indebtedness to my friends Dr. P. Kumarnallasivan, M.Pharmacy, Ph.D., Dr. Kathiravan M.Pharmacy, Ph.D and Dr. A. Arunachalam, M.Pharmacy, Ph.D for their affection, active cooperation and moral support. Families are always listed last by some strange custom even though they are the most i mportant people to acknowledge. I would like to extend my heart -felt gratitude to my parents, Mr. K. Sivananacha Perumal and Mrs. N. S. Roja. -Dr. Selvakumar. S First and foremost, I would like to thank Almighty God. In the process of putting this book together in front of you, I realized how precious gift God has given to me by giving me the capability and the power to believe in my passion and pursue my dreams. “I could never have done this without the faith, which I have in you.” I would also like to thank the Management of VYWS, Amravati’s Institute of Pharmacy And Research Amravati, for their constant motivation and support. Finally, I thank Thakur Publication Pvt. Ltd., especially, Ms. Tuhina Banerjee (Copy Editor) and Mr. S harad Kushwaha (Marketing Coordinator), for providing me an opportunity to be a part of this book. -Dr. Sachin J. Dighade I owe great thanks to Great People, who are working and contributing their findings in the pharmacy profession I extend my heartful thanks to Managing Director of Thakur Publication Pvt Ltd., Dr. Saroj Kumar (Director), Ms. Tuhina Banerjee (Copy Editor) & Mr. Sharad Kushwaha (Marketing Coordinator), for giving this wonderful opportunity. -Dr. R. Srinivasan * *  –6– Syllabus Study of the development of the following classes of drugs, Classification, mechanism of action, uses of drugs mentioned in the course, Structure activity relationship of selective class of drugs as specified in the course and synthesis of drugs superscripted (*) Module 01 10 Hours Antihistaminic Agents  Histamine, receptors and their distribution in the human body.  H1–Antagonists: Diphenhydramine hydrochloride*, Dimenhydrinate, Doxylaminescuccinate, Clemastine fumarate, Diphenylphyraline hydroc hloride, Tripelenamine hydrochloride, Chlorcyclizine hydrochloride, Meclizine hydrochloride, Buclizine hydrochloride, Chlorpheniramine maleate, Triprolidine hydrochloride*, Phenidamine tartarate, Promethazine hydrochloride*, Trimeprazine tartrate, Cyprohep tadine hydrochloride, Azatidine maleate, Astemizole, Loratadine, Cetirizine, Levocetrazine Cromolyn sodium.  H2-Antagonists: Cimetidine*, Famotidine, Ranitidin. Gastric Proton Pump Inhibitors  Omeprazole, Lansoprazole, Rabeprazole, Pantoprazole. Anti-Neoplastic Agents  Alkylating Agents: Meclorethamine*, Cyclophosphamide, Melphalan, Chlorambucil, Busulfan, Thiotepa.  Antimetabolites: Mercaptopurine*, Thioguanine, Fluorouracil, Floxuridine, Cytarabine, Methotrexate*, Azathioprine.  Antibiotics: Dactinomycin, Daunorubicin, Doxorubicin, Bleomycin.  Plant products: Etoposide, Vinblastin sulphate, Vincristin sulphate  Miscellaneous: Cisplatin, Mitotane. Module 02 10Hours Anti-Anginal  Vasodilators: Amyl nitrite, Nitroglycerin*, Pentaerythritol tetranitrate, Isosorbide dinitrite*, Dipyridamole.  Calcium Channel Blockers :Verapamil, Bepridil hydrochloride, Diltiazem hydrochloride, Nifedipine, Amlodipine, Felodipine, Nicardipine, Nimodipine. Diuretics  Carbonic anhydrase inhibitors: Acetazolamide*, Methazolamide, Dichlorphenamide.  Thiazides: Chlorthiazide*, Hydrochlorothiazide, Hydroflumethiazide, Cyclothiazide.  Loop diuretics: Furosemide*, Bumetanide, Ethacrynic acid.  Potassium sparing Diuretics: Spironolactone, Triamterene, Amiloride.  Osmotic Diuretics: Mannitol. Anti-Hypertensive Agents  Timolol, Captopril, Lisinopril, Enalapril, Benazepril hydrochloride, Quinapril hydrochloride, Methyldopate hydrochloride,* Clonidine hydrochloride, Guanethidine monosulphate, Guanabenz acetate, Sodium nitroprusside, * Diazoxide, Minoxidil, Reserpine, Hydralazine hydrochloride. *  –7– Module 03 10 Hours Anti-Arrhythmic Drugs  Quinidine sulphate, Procainamide hydrochloride, Disopyramide phosphate*, Phenytoin sodium, Lidocaine hydrochloride, Tocainide hydrochloride, Mexiletine hydrochloride, Lorcainide hydrochloride, Amiodarone, Sotalol. Anti-Hyperlipidemic Agents  Clofibrate, Lovastatin, Cholesteramine and Cholestipol. Coagulant and Anticoagulants  Menadione, Acetomenadione, Warfarin*, Anisindione, clopidogrel. Drugs used in Congestive Heart Failure  Digoxin, Digitoxin, Nesiritide, Bosentan, Tezosentan. Module 04 08 Hours Drugs acting on Endocrine System  Nomenclature, Stereochemistry and metabolism of steroids. Sex Hormones  Testosterone, Nandralone, Progestrones, Oestriol, Oestradiol, Oestrione, Diethyl stilbestrol. Drugs for Erectile Dysfunction  Sildenafil, Tadalafil. Oral Contraceptives  Mifepristone, Norgestril, Levonorgestrol Corticosteroids  Cortisone, Hydrocortisone, Prednisolone, Betamethasone, Dexamethasone Thyroid and Anti-Thyroid Drugs  L-Thyroxine, L-Thyronine, Propylthiouracil, Methimazole. Module 05 07 Hours Antidiabetic Agents  Insulin and its preparations.  Sulfonyl ureas: Tolbutamide*, Chlorpropamide, Glipizide, Glimepiride. Biguanides: Metformin.  Thiazolidinediones: Pioglitazone, Rosiglitazone. Meglitinides: Repaglinide, Nateglinide. Glucosidase inhibitors: Acrabose, Voglibose. Local Anaesthetics  SAR of local anaesthetics.  Benzoic Acid derivatives: Cocaine, Hexylcaine, Meprylcaine, Cyclomethycaine, Piperocaine.  Amino Benzoic acid derivatives: Benzocaine*, Butamben, Procaine*, Butacaine, Propoxycaine, Tetracaine, Benoxinate.  Lidocaine/Anilide derivatives: Lignocaine, Mepivacaine, Prilocaine, Etidocaine.  Miscellaneous: Phenacaine, Diperodon, Dibucaine.* * *  -8- Contents Module 1 Chapter 1: Antihistaminic Agents 1.1. Antihistaminic Agents 15 1.1.1. Introduction 15 1.1.2. Histamine 15 1.1.3. Histamine Receptors and their Distribution in the Human Body 16 1.1.4. Classification of Antihistaminic Agents 16 1.1.5. Mechanism of Action 21 1.1.6. Uses 21 1.1.7. Structure-Activity Relationship 21 1.1.8. Recent Developments 23 1.2. H1-Antagonists 24 1.2.1. Introduction 24 1.2.2. Study of Individual Drugs 24 1.3. H2-Antagonists 39 1.3.1. Introduction 39 1.3.2. Study of Individual Drugs 39 1.3.2.1. Cimetidine 39 1.3.2.2. Famotidine 41 1.3.2.3. Ranitidine 41 1.4. Summary 42 1.5. Exercise 43 Chapter 2: Gastric Proton Pump Inhibitors 2.1. Gastric Proton Pump Inhibitors 45 2.1.1. Introduction 45 2.1.2. Classification 45 2.1.3. Mechanism of Action 45 2.1.4. Uses 46 2.1.5. Study of Individual Drugs 46 2.2. Summary 49 2.3. Exercise 50 Chapter 3: Antineoplastic Agents 3.1. Anti-Neoplastic Agents 51 3.1.1. Introduction 51 3.1.2. Classification 51 3.1.3. Mechanism of Action 52 3.1.4. Recent Developments 53 3.2. Alkylating Agents 53 3.2.1. Introduction 53 3.2.2. Mechanism of Action 54 3.2.3. Classification 54 3.2.4. Study of Individual Drugs 54 3.3. Antimetabolites 59 3.3.1. Introduction 59 3.3.2. Mechanism of Action 59 3.3.3. Classification 59 3.3.4. Study of Individual Drugs 59 3.4. Antibiotics 65 * *  -9- 3.4.1. Introduction 65 3.4.2. Study of Individual Drugs 65 3.5. Plant Products 68 3.5.1. Introduction 68 3.5.2. Mechanism of Action 69 3.5.3. Study of Individual Drugs 69 3.6. Miscellaneous Agents 72 3.6.1. Study of Individual Drugs 72 3.6.2. Cisplatin 72 3.6.3. Mitotane 72 3.7. Summary 73 3.8. Exercise 75 Module 2 Chapter 4: Anti-Anginal 4.1. Anti-Anginal 76 4.1.1. Introduction 76 4.1.2. Classification 76 4.1.3. Uses 77 4.1.4. Structure-Activity Relationship 77 4.1.5. Recent Developments 79 4.2. Vasodilators (Organic Nitrites and Nitrates) 80 4.2.1. Introduction 80 4.2.2. Mechanism of Action 81 4.2.3. Study of Individual Drugs 82 4.3. Calcium Channel Blockers 85 4.3.1. Introduction 85 4.3.2. Mechanism of Action 85 4.3.3. Study of Individual Drugs 86 4.4. Summary 91 4.5. Exercise 92 Chapter 5: Diuretics 5.1. Diuretics 94 5.1.1. Introduction 94 5.1.2. Classification 94 5.1.3. Uses 95 5.1.1. Structure-Activity Relationship 95 5.1.2. Recent Developments 98 5.2. Carbonic Anhydrase Inhibitors 99 5.2.1. Introduction 99 5.2.2. Mechanism of Action 99 5.2.3. Study of Individual Drugs 100 5.3. Thiazides 102 5.3.1. Introduction 102 5.3.2. Mechanism of Action 102 5.3.3. Study of Individual Drugs 103 5.4. Loop Diuretics 106 5.4.1. Introduction 106 5.4.2. Mechanism of Action 106 5.4.3. Study of Individual Drugs 107 5.5. Potassium Sparing Diuretics 109 5.5.1. * Introduction * 109  - 10 - 5.5.2. Mechanism of Action 109 5.5.3. Study of Individual Drugs 110 5.6. Osmotic Diuretics 112 5.6.1. Introduction 112 5.6.2. Mechanism of Action 112 5.6.3. Mannitol 112 5.7. Summary 113 5.8. Exercise 114 Chapter 6: Anti-Hypertenive Agents 6.1. Anti-Hypertensive Agents 116 6.1.1. Introduction 116 6.1.2. Classification 116 6.1.3. Mechanism of Action 117 6.1.4. Uses 119 6.1.5. Structure-Activity Relationship 121 6.1.6. Recent Developments 124 6.1.7. Study of Individual Drugs 126 6.2. Summary 136 6.3. Exercise 138 Module 3 Chapter 7: Anti-Arrhythmic Drugs 7.1. Anti-Arrhythmic Drugs 140 7.1.1. Introduction 140 7.1.2. Classification 140 7.1.3. Mechanism of Action 141 7.1.4. Uses 142 7.1.5. Structure-Activity Relationship 143 7.1.6. Recent Developments 144 7.1.7. Study of Individual Drugs 145 7.2. Summary 152 7.3. Exercise 153 Chapter 8: Anti-Hyperlipidimic Agents 8.1. Anti-Hyperlipidemic Agents 155 8.1.1. Introduction 155 8.1.2. Classification 155 8.1.3. Mechanism of Action 155 8.1.4. Uses 156 8.1.5. Structure-Activity Relationship 157 8.1.6. Recent Developments 159 8.1.7. Study of Individual Drugs 160 8.2. Summary 162 8.3. Exercise 163 Chapter 9: Coagulant and Anticoagulants 9.1. Coagulants 164 9.1.1. Introduction 164 9.1.2. Classification 164 9.1.3. Mechanism of Action 164 9.1.4. Uses 165 9.1.5. Study of Individual Drugs 165 9.2. Anticoagulants 166 * *  - 11 - 9.2.1. Introduction 166 9.2.2. Classification 167 9.2.3. Mechanism of Action 168 9.2.4. Uses 168 9.2.5. Recent Developments 169 9.2.6. Study of Individual Drugs 169 9.3. Summary 171 9.4. Exercise 172 Chapter 10: Drugs Used in Congestive Heart Failure 10.1. Drugs Used in Congestive Heart Failure 174 10.1.1. Introduction 174 10.1.2. Classification 174 10.1.3. Cardiac Glycosides 174 10.1.4. Bipyridines 180 10.1.5. β-Adrenergic Agonists 180 10.1.6. Diuretics 181 10.1.7. Angiotensin Antagonists 181 10.1.8. β-Adrenoceptor Antagonists 181 10.1.9. Vasodilators 182 10.1.10. Study of Individual Drugs 182 10.2. Summary 185 10.3. Exercise 186 Module 4 Chapter 11: Drugs Acting on Endocrine System 11.1. Drugs Acting on Endocrine System 188 11.1.1. Introduction 188 11.1.2. Hormones 188 11.1.3. Major Hormones Secreted by the Endocrine Glands 189 11.2. Steroids 190 11.2.1. Introduction 190 11.2.2. Nomenclature of Steroids 190 11.2.3. Stereochemistry of Steroids 194 11.2.4. Biosynthesis of Steroids 196 11.2.5. Metabolism of Steroids 197 11.2.6. Classification 198 11.2.7. Mechanism of Action 198 11.2.8. Recent Developments 199 11.3. Sex Hormones 200 11.3.1. Introduction 200 11.3.2. Classification 200 11.3.3. Study of Individual Steroidal Drugs 201 11.3.3.1. Testosterone 201 11.3.3.2. Nandrolone 202 11.3.3.3. Progesterone 203 11.3.3.4. Oestriol 204 11.3.3.5. Oestradiol 204 11.3.3.6. Oestrone 205 11.3.3.7. Diethylstilbestrol 206 11.4. Summary 206 11.5. Exercises 207 * *  - 12 - Chapter 12: Drugs for Erectile Dysfunction 12.1. Drugs for Erectile Dysfunction 209 12.1.1. Introduction 209 12.1.2. Drugs Used 209 12.1.3. Study of Individual Drugs 210 12.1.3.1. Sildenafil 210 12.1.3.2. Tadalafil 211 12.2. Summary 211 12.3. Exercises 212 Chapter 13: Oral Contraceptives 13.1. Oral Contraceptives 213 13.1.1. Introduction 213 13.1.2. Classification 213 13.1.3. Mechanism of Action 214 13.1.4. Uses 214 13.1.5. Study of Individual Drugs 215 13.1.5.1. Mifepristone 215 13.1.5.2. Norgestrel 215 13.1.5.3. Levonorgestrel 216 13.2. Summary 217 13.3. Exercise 217 Chapter 14: Corticosteroids 14.1. Corticosteroids 219 14.1.1. Introduction 219 14.1.2. Classification 219 14.1.3. Mechanism of Action 219 14.1.4. Uses 220 14.1.5. Study of Individual Drugs 220 14.1.5.1. Cortisone 221 14.1.5.2. Hydrocortisone 221 14.1.5.3. Prednisolone 222 14.1.5.4. Betamethasone 223 14.1.5.5. Dexamethasone 223 14.2. Summary 224 14.3. Exercises 225 Chapter 15: Thyroid and Anti-Thyroid Drugs 15.1. Thyroid Hormones 226 15.1.1. Introduction 226 15.1.2. Synthesis, Storage, Release, and Metabolism 226 15.1.3. Mechanism of Action 227 15.1.4. Uses 228 15.1.5. Study of Individual Thyroid Hormone 228 15.1.5.1. L- Thyroxine 228 15.1.5.2. L-Thyronine 229 15.2. Anti-Thyroid Drugs 230 15.2.1. Introduction 230 15.2.2. Classification 230 15.2.3. Mechanism of Action 230 15.2.4. Structure-Activity Relationship 230 15.2.5. Uses 231 * *  - 13 - 15.2.6. Study of Individual Drugs 231 15.2.6.1. Propylthiouracil 231 15.2.6.2. Methimazole 232 15.3. Summary 232 15.4. Exercises 233 Module 5 Chapter 16: Antidiabetic Agents 16.1. Antidiabetic Agents 234 16.1.1. Introduction 234 16.1.2. Insulin 234 16.1.2.1. Synthesis 235 16.1.2.2. Mechanism of Action 236 16.1.2.3. Uses 236 16.1.2.4. Insulin Preparations 236 16.2. Oral Hypoglycaemic Drugs 238 16.2.1. Introduction 238 16.2.2. Classification 238 16.2.3. Sulphonylureas 239 16.2.3.1. Mechanism of Action 240 16.2.3.2. Structure-Activity Relationship 240 16.2.3.3. Study of Individual Drugs 241 16.2.3.4. Tolbutamide 241 16.2.3.5. Chlorpropamide 242 16.2.3.6. Glipizide 242 16.2.3.7. Glimepiride 243 16.2.4. Biguanides 244 16.2.4.1. Mechanism of Action 244 16.2.4.2. Study of Individual Drug - Metformin 244 16.2.5. Thiazolidinediones 244 16.2.5.1. Mechanism of Action 245 16.2.5.2. Uses 245 16.2.5.3. Study of Individual Drugs 245 16.2.5.4. Pioglitazone 245 16.2.5.5. Rosiglitazone 246 16.2.6. Meglitinides 246 16.2.6.1. Mechanism of Action 247 16.2.6.2. Study of Individual Drugs 247 16.2.6.3. Repaglinide 247 16.2.6.4. Nateglinide 248 16.2.7. -Glucosidase Inhibitors 249 16.2.7.1. Mechanism of Action 249 16.2.7.2. Study of Individual Drugs 249 16.2.8. Acarbose 249 16.2.9. Voglibose 250 16.3. Summary 251 16.4. Exercises 252 Chater 17: Local Anaesthetics 17.1. Local Anaesthetics 254 17.1.1. Introduction 254 17.1.2. Classification 254 * *  - 14 - 17.1.3. Mechanism of Action 257 17.1.4. Uses 257 17.1.5. SAR of Local Anaesthetics 258 17.1.6. Recent Developments 260 17.2. Benzoic Acid Derivatives 260 17.2.1. Introduction 260 17.2.2. Study of Individual Drugs 261 17.2.2.1. Cocaine 261 17.2.2.2. Hexylcaine 261 17.2.2.3. Meprylcaine 262 17.2.2.4. Cyclomethycaine 263 17.2.2.5. Piperocaine 263 17.3. Amino Benzoic Acid Derivatives 263 17.3.1. Introduction 263 17.3.2. Study of Individual Drugs 263 17.3.2.1. Benzocaine 264 17.3.2.2. Butamben 264 17.3.2.3. Procaine 265 17.3.2.4. Butacaine 266 17.3.2.5. Propoxycaine 267 17.3.2.6. Tetracaine 267 17.3.2.7. Benoxinate 268 17.4. Lidocaine/Anilide Derivatives 268 17.4.1. Introduction 268 17.4.2. Study of Individual Drugs 268 17.4.2.1. Lignocaine 269 17.4.2.2. Mepivacaine 269 17.4.2.3. Prilocaine 270 17.4.2.4. Etidocaine 270 17.5. Miscellaneous 271 17.5.1. Phenacaine 271 17.5.2. Diperodon 271 17.5.3. Dibucaine 272 17.6. Summary 273 17.7. Exercises 274 * * Antihistaminic Agents (Chapter 1) 15 CHAPTER Antihistaminic Agents 1 1.1. ANTIHISTAMINIC AGENTS 1.1.1. Introduction Histamine, a biologically active substance potentiates the inflammatory and immune responses of the body. It also regulates the physiological functions in the gut, and behaves as neurotransmitter. Anti-histaminic agents (or histamine antagonists) are the drugs that antagonise the action of histamine. On the basis of the type of H receptor targeted, antihistamines are divided into: 1) H1-Antihistamines: They are used for treating allergic reactions and disorders mediated by mast cells. H1-antihistamines are sub- divided into two generations. The first generation H1-antihistamines have a central effect so are used as sedatives. The second generation H1- antihistamines have low central effects so are used as anti-allergenic drugs. 2) H2-Antihistamines: They can reduce the production of stomach acid by reversibly blocking the H2-histamine receptors found in the parietal cells of gastric mucosa; thus, they are used in gastric reflux diseases. The pregnant women and children should avoid using most H1- and H2- antihistamines. First-generation H1-antihistamines are contraindicated in patients having angle-closure glaucoma and pyloric stenosis. 1.1.2. Histamine Histamines are nitrogen containing organic compounds belonging to the group of amines. Histamines are produced in almost all the cells (present in an animal) during a local immune response. They regulate various physiological functions of the gut. In addition, histamines have also be en known to play a role in neurotransmission. Release of histamines is the initiating factor of any inflammatory response. Histamines are synthesised and released by basophils and mast cells (found in the nearby connective tissues) on stimulation (as a part of an immune response against foreign pathogens). They cause increased vascular (capillary) permeability for WBCs and other proteins to facilitate adequate invasion of foreign bodies within the tissues. * * 16 Medicinal Chemistry - II 1.1.3. Histamine Receptors and their Distribution in the Human Body The biological effects produced by histamine are mediated through histaminergic receptors (H1, H2 and H3 types). Histamine was identified and anti-histamines (H1 blockers) were synthesised in the beginning of this century. Since then i t was known that these anti-histamines cannot block all the histamine actions. H4 receptors are linked to the pathology of allergy and asthma; and regulate the changes in cellular shape, chemotaxis, and up -regulation of adhesi on molecules (CD11b/CD18 and ICAM, P -selectin). H 4-receptors present on haematopoietic cells (neutrophils and eosinophils) have been recognised lately. Table 1.1: Histamine Receptor Sub-Types, their Location, Mechanisms of Action, and Effects Types of Location Mechanism of Effects Receptor Action H1 Throughout the G-protein linked to Increased vascular body, especially in intercellular G q permeability induced by smooth muscles, on that activates histamine at inflammation vascular endothelial phospholipase C. sites; bronchoconstriction; cells, in heart , and increased gut motility; CNS. triple response and oedema formation; stimulation of sensory nerve endings. H2 Gastric parietal cells, G-protein coupled; Increase in gastric acid vascular smooth linked to secretion; vasodilatation. muscles, neutrophils, intercellular G s that CNS, heart , and stimulates uterus. adenylcyclase and increases cAMP. H3 Mostly in the CNS G-protein coupled; Inhibition of synthesis and with high levels in linked to release of histamine acting thalamus, caudate intercellular G 1 that on the presynaptic sites in nucleus and cortex; inhibits CNS; modulates the release also in intestine, adenylcyclase and of 5 -HT, dopamine, NAD, testis and pros tate to decreases cAMP. ACh and GABA in CNS a small extent. by acting as heteroreceptor. H4 Expressed in various G-protein coupled; Immunomodulation. cells of immune decrease in cAMP. system and mast cells and mediate chemotaxis of eosinophils and mast cells. 1.1.4. Classification of Antihistaminic Agents Following are the three types of histamine receptor antagonists: 1) H1-Antagonists: These are classical antihistamines blocking the physiological effects of histamine and used in allergic disorders. * * Antihistaminic Agents (Chapter 1) 17 2) H2-Antagonists: Cimetidine, Ranitidine, and Famotidine are H 2-antagonists reducing gastric HCl secretion and used in peptic ulcer diseases. 3) H3-Antagonists: Thioperamide is an H 3-antagonist regulating histamine release from histaminergic neurons of CNS by presynap tic auto -regulatory mechanism. It is not recommended to be used therapeutically. Given below is the classification of antihistaminic agents: 1) H1-Receptor Antagonists: They are grouped into: i) Ethylenediamines Drugs Ar Ar1 Tripelennamine Pyrilamine Methapyrilene Thonzylamine Zolamine ii) Amino Alkyl Ethers Drugs Ar1 Ar2 R Diphenhydramine C6H5 C6H5 H Bromodiphenhydramine C6H5 H * * 18 Medicinal Chemistry - II Doxylamine C6H5 CH3 Carbinoxamine H Medrylamine H iii) Mono Amino Propyl Analogues a) Saturated Analogues Drugs Ar Ar1 Pheniramine Chlorpheniramine Bromopheniramine b) Unsaturated Analogues Drugs Ar Ar1 Pyrrobutamine Triprolidine iv) Tricyclic Ring Systems or Phenothiazine Derivatives * * Antihistaminic Agents (Chapter 1) 19 Drugs R Promethazine hydrochloride Trimeprazine Methdilazine v) Cyclic Basic Chain Analogues or Piperazine Derivatives Drugs R1 R2 Cyclizine H CH3 Chlorcyclizine Cl CH3 Meclizine Cl Buclizine Cl vi) Dibenzocycloheptenes * * 20 Medicinal Chemistry - II vii) Miscellaneous viii) Newer Agents 2) H2-Receptor Antagonists: Ranitidine and Cimetidine 3) H3-Receptor Antagonists: Thioperamide and Impromidine 4) H4-Receptor Antagonists: Thioperamide Thioperamide is a potent H 4-antagonist and selective H 3-antagonist. It can cross the blood brain barrier. * * Antihistaminic Agents (Chapter 1) 21 1.1.5. Mechanism of Action Histamine binds with the histaminergic receptors (H 1, H 2, and H 3) after being released by the mast cells. This binding stimulates a series of events that facilitate the characteristic responses by second messenger systems. The histaminergic receptors are G -protein coupled type. Thus, the H1-receptors are coupled to phospholipase-C and on activation they form inositol phosphate (Ip 3) and diacylglycerol (DAG) from the cell membrane phospholipids. Ca2+ ions are rapidly released from endoplasmic reticulum under the influence of Ip3. Protein kinase C is activated by DAG. Thus, the turnover of Ca 2+ ions and protein kinase C stimulates the Ca2+/calmodulin dependent protein kinase and phospholipase A 2. The anti -histaminergic (H 1-antagonist) binds to the H 1- receptors and decreases the production of phospholipase-C and their activation to form IP3 and DAG. Therefore, it inhibits the characteristic response of histamine. Histamine forms cAMP-dependent protein kinase (also known as cyclic AMP or 3-5-cyclic adenosine monophosphate) on H 2-receptors for producing a response in the GIT. The H 2-antagonist and the H 2-receptors bind reversibly and this decreases cAMP formation. Subsequently, the proton pump is activated and the formation of gastric acid in the GIT decreases. H3-receptors are a lso G -protein coupled receptors. They decrease the Ca2+ ions influx. H 3-receptors act as feedback inhibitors for histamine a nd other neurotransmitters as they reduce calcium influx in the cells in CNS, decrease gastrin secretion in the GIT, and down -stimulates histamine by auto-regulatory effects. These effects are antagonised by blocking the H3-receptors, whereas the clinical extendibility is narrow for H3. 1.1.6. Uses Following are the therapeutic uses of antihistaminic agents: 1) They have same efficacy when used in suitable doses. 2) The H2-blockers are used for reducing gastric acid secretion. 3) Sometimes other types of therapy are similarly effective, still the H2-blockers are chosen due to suitability and good patient acceptability. 1.1.7. Structure-Activity Relationship H1-Receptor Antagonists 1) Aryl Groups: Diaryl substitution is required for H 1 affinity, and is found in first-generation and second -generation antihistamines. The co -planarity of two aryl substitutions influences the optimal antihistaminic activity. Active aryl substitutions are as follows: i) Ar is phenyl and hetero aryl group (like 2-pyridyl). * ii) Ar1 is aryl or aryl methyl group. * 22 Medicinal Chemistry - II 2) Nature of X: Antihistamines with X = carbon (pheniramine series ) signifies the stereo selective receptor binding to the receptors because of its chirality. The active substitutions of X are as follows: i) X = Oxygen (amino alkyl ether analogue) ii) X = Nitrogen (ethylene-diamine derivative) iii) X = Carbon (mono amino propyl analogue) 3) Alkyl Chain: Mostly antihistamines have ethylene chain, t he b ranching of which forms a less active compound. This general chain is present in all the antihistamines. 4) Terminal Nitrogen Atom: The nitrogen atom at the terminal should be a tertiary amine for maximum activity. The terminal nitrogen can be the part of heterocyclic ring, for example , antazoline and chlorcyclizine have a high antihistaminic activity. The am ino moiety on interaction with H 1-receptor shows protonation due to basicity with pka 8.5-10. H2-Receptor Antagonists H2-blockers are not like H 1-blockers that are typically lipophilic amines. Instead, they are very polar in nature ( e.g., cimetidine). H 2-blockers also have longer uncharged side chains non -related to the protonated dialkylaminoalkyl side chains present in H 1-blockers. The imidazole ring in H 2-blocker structure is important for the identification of the receptor. 1) Imidazole Ring Substitutions : The imidazole ring is found in two tautomeric forms as shown below. The first form (I) is important for maximal H2-antagonistic activity. Mostly, the activity is potentiated when R is a –CH3 group. * * Antihistaminic Agents (Chapter 1) 23 2) Chain: Four carbon atoms chain is best for the activity of H 2-blockers. The antagonist activity is extremely reduced in case of a shorter chain. The chain should have an electron withdrawing substituent. An isosteric thioether (─S─) link at the place of methylene group (─CH2─) gives more active compounds. 3) Terminal Nitrogen Group: To achieve maximal antagonist activity t he terminal N -group should be a polar, non -basic substituent. A positively charged group binds more firmly to the receptor and this exerts an agonist activity (and not an antagonist activity). 1.1.8. Recent Developments The effect of first generation sedating H 1-antihistamines i n humans has never been investigated. But, most of the second -generation non -sedating H 1- antihistamines are well investigated. The H1-antihistamines are widely used in the treatment of allergic rhinitis, allergic conjunctivitis, and chronic urticaria. The second generation H1-antihistamines produce comparatively less CNS and cardiac toxicity if taken in standard doses and even in overdose. Screening and structural modification of the pre -existing second generation H 1 antihistamines have led to the identification of many new medications of the same class. For example, cetirizine is a metabolite of hydroxyzine, levocetirizine is the active R -enantiomer of cetirizine, desloratadine is a metabolite of loratadine, and fexofenadine is a metabolite of terfenadine. New H 1-antihistamines continue to be developed and introduced for clinical use; however, they should be inspected carefully as they may or may n ot exhibit clinically important features as compared to the existing second generation H1- antihistamines. Till date, no second generation H1-antihistamine is found to have efficacy superior to the others, though some are safer. The terms third generation , new generation , or next generation are used to market certain new H 1-antihistamines. But, clinically advantageous H 1- antihistamines should be designated by these terms. Some of these medications also have the intrinsic ab ility to down -regulate histamine a t H 2-, H 3-, or H 4- receptors or to down-regulate leukotrienes or cytokines. Without the discussion of histamine -globulin injection , any discussion on histamine is incomplete. There are no double-blind placebo-controlled, published studies on this formulati on, however , it is generally prescribed in India. This combination should be banned. * * 24 Medicinal Chemistry - II 1.2. H1-ANTAGONISTS 1.2.1. Introduction Until the discovery of H 1-receptors, no other histamine receptors had been identified. The H1-antagonists, termed as antihistamines cause a co mpetitive inhibition of only H 1-receptors (they do not block any other histamine receptors). Adrenaline is a physio logical antagonist of histamine. It acts via adrenergic receptors and reverses the bronchodila tion and vasoconstriction effects of histamine. Cromolyn sodium and corticosteroids block h istamine release from mast cells. The H1-receptor antagonists are employed in the treatment of allergic disorders. The action of histamines on H 1-receptors is blocked by antihistamines (H 1- blockers) categorised into first and second generations. The first generation antihistamines bind to the central and peripheral H 1-receptors, while the second generation antihistamines bind to the peripheral H1-receptors. Though the sedative effects of second generation antih istamines are lesser as compared to the first generation antihistamines, still they are beneficial for the treatment of allergies. 1.2.2. Study of Individual Drugs The following H1-antagonists are discussed below: 1) Diphenhydramine hydrochloride, 2) Dimenhydrinate, 3) Doxylamine succinate, 4) Clemastine fumarate, 5) Diphenylpyraline hydrochloride, 6) Tripelennamine hydrochloride, 7) Chlorcyclizine hydrochloride, 8) Meclizine hydrochloride, 9) Buclizine hydrochloride, 10) Chlorpheniramine maleate, 11) Triprolidine hydrochloride, 12) Phenindamine tartrate, 13) Promethazine hydrochloride, 14) Trimeprazine tartrate, 15) Cyproheptadine hydrochloride, 16) Azatadine maleate, 17) Astemizole, 18) Loratadine, 19) Cetirizine, 20) Levocetirizine, and 21) Cromolyn sodium. * * Antihistaminic Agents (Chapter 1) 25 1.2.2.1. Diphenhydramine Hydrochloride Diphenhydramine is a first generation antihistamine which is mainly used for treating seasonal allergies. But it also exhibits antiemetic, anti -Parkinson, antitussive, and hypnotic properties. Synthesis Firstly, diphenylmethane undergoes bromination in the presence of light to form diphenylbromomethane. Then, diphenylbromomethane, -dimethyl-amino- ethanol, and sodium carbonate are heated in the presence of toluene to obtain diphenhydramine base. The purified diphenhydramine after distilling-off toluene converts into its hydrochloride form with hydrogen chloride. Mechanism of Action Diphenhydramine works through the antagonism of H 1-receptors found on the respiratory smooth muscles, vascular endothelial cells, GIT, cardiac tissue, immune cells, uterus, and CNS neurons. On stimulating the H 1-receptors in these tissues, they increase vascular permeability, stimulate vasodilation that leads to flushing, decrease the conduction time of atrioventricular (AV) node , stimulate the sensory nerves of a irways that leads to coughing, contract the smooth muscles of bronchi and GIT, and cause eosinophilic chemotaxis that enhances the allergic immune response. Diphenhydramine functions as an inverse agonist at H1-receptors, and then it converses the histamine effects on capillaries, and decreases the symptoms of allergic reaction. * * 26 Medicinal Chemistry - II Uses 1) It is used for preventing and curing nausea, vomiting and dizziness caused by motion sickness. 2) It is used to relax and fall asleep. 3) It is used for relieving the symptoms of a llergy, hay fever, common cold, rashes, itching, watery eyes, itchy eyes/nose/throat, cough, runny nose, and sneezing. 1.2.2.2. Dimenhydrinate Dimenhydrinate is a combination drug as it comprises of diphenhydramine (53- 55.5%) and 8-chlorotheophylline (not less than 44-47%) in a salt form, calculated on the dried basis. Mechanism of Action Mechanism of some antihistamines producing antiemetic, anti -motion sickness and anti-vertigo effects is not known ; however, it can be related to their central anticholinergic actions. They reduce the vestibular stimulation and lower the labyrinthine function. The antiemetic effect may also be the result of a n action on the medullary chemoreceptive trigger zone. Dimenhydrinate is a competitive an tagonist of H1- receptors found in the human brain. It produces anti-emetic effect because of H1- antagonism in the vestibular system in the brain. Uses 1) It is used for preventing motion sickness, nausea, and vomiting. 2) It helps in the treatment of ear congestion. 3) It is used for relieving vertigo and vestibular disorder. 1.2.2.3. Doxylamine Succinate Doxylamine succinate is a pyridine derivate H 1-antagonist having sedative properties. It competitively blocks the H1-receptor and controls t he allergic and anaphylactic responses, such as bronchoconstriction, vasodilation, increased capillary permeability, and spasmodic contraction of gastrointestinal smooth muscles caused by histamine actions on bronchial and gastrointestinal smooth muscles. Doxylamine succinate also prevents pain and itching of the skin and mucous membranes induced by histamine. * * Antihistaminic Agents (Chapter 1) 27 Mechanism of Action Doxylamine shows antihistaminic and sedative effects because it acts as an antagonist of the H 1-receptors. It also slightly antagonises the muscarinic acetylcholine receptors. Uses 1) It relieves the symptoms of allergy, hay fever, and common cold. 2) It relieves sneezing, runny nose, watery eyes, hives, and skin rash. 3) It is used for treating insomnia. 4) It is used for preventing morning sickness in pregnant women in combination with vitamin B6 (pyridoxine). 1.2.2.4. Clemastine Fumarate Clemastine fumarate is the fumaric acid salt of clemastine. It is an antihistamine having antimuscarinic and moderate sedative properties. It is used for the symptomatic relief of allergic conditions l ike rhinitis, urticaria, conjunctivitis, and pruritic (severe itching) skin conditions. It is an H 1-receptor antagonist, an anti-allergic agent, a muscarinic antagonist, and an antipruritic drug. Mechanism of Action Clemastine is a se lective H 1-antagonist. It binds to the H1-receptors and blocks the action of histamine, thus temporary relieving the negative symptoms caused due to histamine. Uses 1) It is used for relieving the symptoms of allergic rhinitis like sneezing, rhinorrhea, pruritus, and acrimation. 2) It is used for the management of mild, uncomplicated allergic skin conditions of urticaria and angioedema. 3) It is u sed as a self-medication for temporary relief of symptoms related to common cold. * * 28 Medicinal Chemistry - II 1.2.2.5. Diphenylpyraline Hydrochloride Diphenylpyraline is an antihistamine used for treating allergy by competing with histamine to bind to the H1-receptor sites found on the effector cells. Mechanism of Action Diphenylpyraline is used for treating allergy as it competes with histamine for binding on the H1-receptors on effector cells. After binding it suppresses the histamine effects, thus causing temporary relief of the allergic symptoms. Uses 1) It is used for treating allergic rhinitis. 2) It is used for treating hay fever. 3) It is used for treating allergic skin orders. 1.2.2.6. Tripelennamine Hydrochloride Tripelennamine is an ethylenediamine derivative having anti -histaminergic property. Tripelennamine hydrochloride is the hydroc hloride salt of tripelennamine. Mechanism of Action Tripelennamine binds to the H1-receptor and blocks the action of endogenous histamine, thus temporarily relieving the negative symptoms caused by histamine. * * Antihistaminic Agents (Chapter 1) 29 Uses 1) It treats the conditions of upper respiratory tract caused due to illnesses and hay fever. 2) It relieves sneezing, runny nose, itching, watery eyes, hives, rashes, and other symptoms of allergies and common cold. 1.2.2.7. Chlorcyclizine Hydrochloride Chlorcyclizine is a first generation antihistamine belonging to phenylpiperazine class. It is used for treating urticaria, rhinitis, pruritus, and other allergy symptoms. It also has some local anaesthetic, anticholinergic, antiemetic, and antiserotonergic properties. Mechanism of Action Antihistamines are pharmacological antagonists of histamine acting at mo st of the histamine receptor sites, but they do not inhibit histamine release. Since chlorcyclizine exhibit hepatic microsomal enzyme-inducing properties, it reduces the duration of action of certain barbiturates due to enzyme induction. Uses 1) It is used for the treatment of allergic symptoms like rhinitis, urticaria, and pruritus. 2) It is also used for treating hepatitis C. 1.2.2.8. Meclizine Hydrochloride Meclizine hydrochloride is the hydrochloride salt form of meclizine, which is a synthetic piperazine having anti-emetic, sedative and H1-antagonistic properties. * * 30 Medicinal Chemistry - II Mechanism of Action Meclizine hydrochloride inhibits the H 1-receptors. It prevents histamine actions on capillaries, bronchial and gastrointestinal smooth muscles, such as vasodilation, increased capillary permeability, bronchoconstriction, and spasmodic contraction of gastrointestinal smooth muscles. It produces antiemetic effects through its anticholinergic actions or by direct effect on the medullary chemoreceptive trigger zone. Uses 1) It is used for treating motion sickness. 2) It is safely used in the treatment of nausea in pregnancy. 3) It helps in relieving vertigo. 1.2.2.9. Buclizine Hydrochloride Buclizine hydrochloride is the hydrochloride salt form of buclizine, which is a piperazine H1-receptor antagonist having antiemetic and anti-vertigo properties. Mechanism of Action Emesis (vomiting) is a protective mechanism as it removes irritant or harmful substances from the upper GIT. Emesis is regulated by the vomiting centre in the medulla region of brain. The vomiting centre has neurons which possess many muscarinic cholinergic and histamine-containing synapses. These neurons are involved in transmission from the vestibular apparatus to the vomiting centre. Motion sickness includes overstimulation of these pathways because of various sensory stimuli. Hence , buclizine blocks the histamine r eceptors in the vomiting centres and decreases the activity along these pathways. Buclizine also has anti- cholinergic properties and blocks the muscarinic receptors. * * Antihistaminic Agents (Chapter 1) 31 Uses 1) It is used as an anti-vertigo or antiemetic agent. 2) It is used in the management of vertigo in diseases affecting the vestibular apparatus. 3) It is used for treating nausea, vomiting and dizziness related to motion sickness. 1.2.2.10. Chlorpheniramine Maleate Chlorpheniramine maleate is a H 1-recpetor antagonist. It is used in allergic reactions, hay fever, rhinitis, urticaria, and asthma. It is also used in veterinary applications. Mechanism of Action Chloropheniramine binds to H 1-receptors and inhibits the action of histamine, thus temporarily relieving the negative symptoms produced by histamine. Uses Chlorpheniramine is used for relieving the symptoms of allergy, hay fever, common cold, rashes, watery eyes, itchy eyes/nose/throat/skin, cough, runny nose, and sneezing. 1.2.2.11. Triprolidine Hydrochloride Triprolidine hydrochloride is obtained by the reaction between equimolar amounts of triprolidine and hydrogen chloride. Its monohy drate form is used for symptomatic relief of urticaria, rhinitis, and many pruritic skin disorders. It is also a H1-receptor antagonist. * * 32 Medicinal Chemistry - II Synthesis Mechanism of Action Triprolidine hydrochloride binds to the H1-receptors and inhibits the action of histamine, thus temporarily relieving the negative symptoms of histamine. Uses 1) It is used for the symptomatic relief of seasonal or perennial allergic rhinitis or non -allergic rhinitis; allergic conjunctivitis; and mild, uncomplicated allergic skin conditions of urticaria and angioedema. 2) It is used in combination with other agents for the symptomatic relief of symptoms related to common cold. 1.2.2.12. Phenindamine Tartrate Phenindamine tartrate is a phenylalkylamine sympathomimetic amine. It exhibits appetite depressant property. It inhibits the effects of the naturally occurring histamine in the body. * * Antihistaminic Agents (Chapter 1) 33 Mechanism of Action Phenindamine competes with histamine for H1-receptor sites on effector ce lls. It antagonises those pharmacological effects of histamine that are induced by the activation of H 1-receptor sites. Hence, it decreases the intensity of allergic reactions and tissue injury response that causes histamine release. Uses It is used for relieving sneezing, runny nose, itching, watery eyes, hives, rashes, itching, and other symptoms of allergies and common cold. 1.2.2.13. Promethazine Hydrochloride Promethazine hydrochloride is the hydrochloride salt form of promethazine, which is a phenothiazine derivative having antihistaminic, sedative and antiemetic properties. Synthesis Promethazine is form ed by the alkylation of phenothiazine with 1 - dimethylamino-2-chloropropane in the presence of sodium amide. Mechanism of Action Promethazine hydrochloride selectively inhibits the peripheral H 1-receptors, thus reduces the histamine effects on effector cells. It also inhibits the central histaminergic receptors, thus depresses the reticular system that causes sedative and hypnotic effects. It also exhibits centrally acting anticholinergic properties. It may control nausea and vomiting by acting on the medullary chemoreceptive trigger zone. * * 34 Medicinal Chemistry - II Uses 1) It is used for preventing and curin g vertigo and motion sickness. However, it shows marked and long antihistaminic activity. 2) Due to its antiemetic properties, it is added in postoperative nausea and vomiting tablets, elixirs, syrups, suppositories, and injections. 3) It is also used for anaest hetic premedication through intramuscular injection with atropine and meperidine. 1.2.2.14. Trimeprazine Tartrate Trimeprazine t artrate (or alimemazine) is a tartrate salt and a phenothiazine derivative, which is used as an antiprurit ic agent (prevents itching caused due to eczema or poison ivy). It also acts as a sedative, hypnotic, and antiemetic. Mechanism of Action Trimeprazine acts by competing with free histamine f or binding at HA -receptor sites. This antagonis es histamine effects on HA -receptors, thus reducing the negative symptoms caused by binding of histamine to HA-receptors. Uses 1) It is used alone or along with corticosteroids in controlling inflammatory and allergic problems. 2) It is used for preventing and relie ving the allergic conditions that cause pruritus (itching) and urticaria (some allergic skin reactions). 1.2.2.15. Cyproheptadine Hydrochloride Cyproheptadine is a first generation antihistamine which is used as an appetite stimulant and for treating allergic rhinitis and urticaria. * * Antihistaminic Agents (Chapter 1) 35 Mechanism of Action Cyproheptadine acts by competing with free histamine for binding at HA - receptor sites. This antagonises histamine effects on HA -receptors, thus reducing the negative sy mptoms caused by binding of histamine to HA - receptors. It also competes with serotonin for binding to receptor sites in smooth muscle s in intestines and other locations. Antagonism of serotonin on the appetite centre of hypothalamus is responsible for cypr oheptadine’s ability to stimulate appetite. Uses It is used for treating perennial and seasonal allergic rhinitis, vasomotor rhinitis, allergic conjunctivitis, mild uncomplicated allergic skin manifestations of urticarial and angioedema, amelioration of a llergic reactions to blood or plasma, dermatographism, cold urticaria, and as a treatment for anaphylactic reactions adjuvant to epinephrine. 1.2.2.16. Azatadine Maleate Azatadine maleate is a first -generation antihistamine. It is the dima leate salt of azatadine. It acts as a H1-receptor antagonist and an anti-allergic agent. Mechanism of Action Azatadine competes with histamine for H 1-receptor sites on effector cells. It antagonises those pharmacological effects of histamine that are induced by the activation of H 1-receptor sites. Hence, it decreases the intensity of allergic reactions and tissue injury response that causes histamine release. Uses 1) It is used for treating the symptoms of upper respiratory mucosal congestion in perennial and allergic rhinitis. 2) It is also used for treating nasal congestion and eustachian tube congestion. 1.2.2.17. Astemizole Astemizole is a long -acting, non -sedating second generation antihistamine. It is used for treating the allergic symptoms. At higher doses, it causes arrhythmias due to which it was withdrawn from the market by the manufacturer in 1999. * * 36 Medicinal Chemistry - II Mechanism of Action Astemizole acts by competing with histamine for binding reversibly to H1- receptor sites in the GIT, uterus, large blood vessels, and bronchial muscles. This reversible binding suppresses oedema, flare, and pruritus caused by histaminic activity. Since astemizole does not cross the blood-brain barrier easily, it binds to the peripheral H1-receptors (and not with those found in the brain); thus, it causes minimal CNS depression. Astemizole also act on H 3-receptors, but produces adverse effects. Uses It is used for treating the allergic symptoms such as rhinitis and conjunctivitis. 1.2.2.18. Loratadine Loratadine is an azatadine derivative and a second generation H 1-receptor antagonist. It is used for relieving the symptoms of allergic rhinitis and urticaria. * * Antihistaminic Agents (Chapter 1) 37 Mechanism of Action Loratadine competes with free histamine. It shows specific and selective peripheral H 1-antagonistic activity, thus inhibits the action of histamine and temporarily relieves nasal congestion and watery eyes caused by histamine. It has a low affinity for cholinergic receptors and does not show any ap preciable in- vitro α-adrenergic blocking activity. The clinic al use of loratadine is unknown, but it s uppresses histamine and leukotrienes release from animal mast cells, and leukotrienes release from human lung fragments. Uses 1) It is a self-medication and is used alone or along with pseudoephedrine sulphate for the symptomatic treatment of seasonal allergic rhinitis. 2) It is also used for the symptomatic relief of pruritus, erythema, and urticaria related to chronic idiopathic urticaria (it is not used in children below 6 years of age if not directed by a clinician). 1.2.2.19. Cetirizine Cetirizine (or zyrtec) is an orally active second generation H1-antagonist. It is used for treating the various allergic symptoms like sneezing, coughing, nasal congestion, hives, etc. Mechanism of Action Cetirizine is an antihistamine drug and a hydroxyzine metabolite. It mainly acts by the selective inhibition of peripheral H 1-receptors. Its antihistamine activity is given in a variety of animal and human models. In vivo and ex vivo animal models have shown insignificant anticholinergic and anti -serotonergic effects. However during clinical studies, dry mouth occurred frequently with cetirizine than with a placebo. In vitro receptor binding studies explain that no detec table affinity of cetirizine exists for histamine receptors other than the H1-receptors. In studies with radiolabeled cetirizine in rats, it was seen that cetirizine insignificantly penetrates into the brain. Ex vivo studies in mouse have shown that cetirizine on systemic administration does not occupy the cerebral H1-receptors. Uses 1) Seasonal Allergic Rhinitis: It is used for treating symptoms related to seasonal allergic rhinitis caused by allergens (like ragweed, grass , and tree pollens) in adults and children of 2 years of age and above. Cetirizine is also used for treating sneezing, rhinorrhoea, nasal pruritus, ocular pruritus, * tearing, and redness of eyes. * 38 Medicinal Chemistry - II 2) Perennial Allergic Rhinitis: It is used for treating the symptoms related to perennial allergic rhinitis caused by dust mites, animal dander, and molds in adults and children of 6 months of age and above. Cetirizine is also used for treating sneezing, rhinorrhoea, postnasal discharge, nasal pruritus, ocular pruritus, and tearing. 3) Chronic Urticaria: It is used for treating uncomplicated skin conditions of chronic idiopathic urticaria in adults and children of 6 months of age and above. Mainly, cetirizine decreases the occurrence, severity, and duration of hives and pruritus. 1.2.2.20. Levocetirizine Levocetirizine is a third generation non -sedative antihistamine. It is used for treating the symptoms related to seasonal and perennial allergic rhinitis and uncomplicated skin conditions of chronic idiopathic urticaria. Mechanism of Action Levocetirizine is the active enantiomer of cetirizine. It produces its major effects by selective inhibiti on of H 1-receptors. The antihistaminic act ivity of levocetirizine has been studied in many animal and human models. Its affinity for human H 1-receptor is twice than that of cetirizine (Ki=3 nmol/L and 6 nmol/L, respectively) , and this has been revealed in the in vitro binding studies. However clinical importance of this increased affinity is indefinite. Uses 1) It is used for treating the symptoms related to seasonal and perennial allergic rhinitis in adults and children of 6 years of age and above. 2) It is used for treating the allergic symptoms like watery eyes, runny nose, itching eyes/nose, and sneezing. 3) It is also used to treat itching and hives. 1.2.2.21. Cromolyn Sodium Cromolyn sodium is the sodium salt form of cromolyn, which is a mast cell stabiliser having anti-inflammatory activity. It may inhibit the antigen -stimulated calcium transport across the mast cell membrane. Hence , it inhibits the release of histamine, leukotrienes, and other substances that causes hypersensitivity reactions from the mast cells. * * Antihistaminic Agents (Chapter 1) 39 Mechanism of Action Cromolyn sodium prevents the degranulation of mast cells, and thus prevents the release of h istamine and Slow-Reacting Substance of Anaphylaxis (SRS -A, mediators of type I allergic reactions ). It may also suppress the release of inflammatory leukotrienes. It acts by inhibiting calcium influx. Uses 1) It used for the management of bronchial asthma. 2) It is used for treating vernal keratoconjunctivitis, vernal conjunctivitis, and vernal keratitis. 3) It is used in the prophylactic treatment of asthma induced by allergy and exercise. 4) On inhalation it prevents bronchial asthma attacks in adults and childre n of 2 years of age. 1.3. H2-ANTAGONISTS 1.3.1. Introduction Cimetidine was the first agent to be clinically used as an H 2-blocker. The H 2- receptors present on parietal cells are blocked by cimetidine. The activation of H+- K+-ATPase proton pump is prevented by the antagonistic activity against these receptors. Thus, a decrease in the secretion of H+ ions into the lumen is seen,which in turn decreases the detrimental effects of the acid on mucosal lining. 1.3.2. Study of Individual Drugs The following H2-antagonists are discussed below: 1) Cimetidine, 2) Famotidine, and 3) Ranitidine. 1.3.2.1. Cimetidine Cimetidine is a histamine congener and competitively inhibits the binding of histamine to histamine H2-receptors. It prevents gastric acid secretion, pepsin and gastrin output. * * 40 Medicinal Chemistry - II Synthesis (3 mistakes in the reaction) Ethyl-2-chloroacetoacetate on reacting with two moles of formamide forms 4 - carbethoxy-5-methylimidazole. This carbethoxy group is reduced with lithium aluminium hydride to form 4-hydroxymethyl-5methylimidazol. T he hydrochloride of the resulting alcohol and 2-mercaptoethylamine hydrochloride reacts to form 4-(2-aminomethyl)-thiomethyl-5-methylimidazole dihydrochloride. This compound is reacted with N-cyanimido-S,S-dimethyl dithiocarbonate to form a thiou rea derivative, which on reacting with methylamine forms cimetidine. Mechanism of Action Cimetidine blocks the histamine effects by binding to the H2-receptors found on the baso lateral membra ne of gastric parietal cell. Reduction in gast ric acid secretion, gastric volume and acidity are the results of this competitive inhibition. Uses 1) It is used for treating certain types of ulcer. 2) It is used for treating the conditions in which too much acid is secreted by the stomach. 3) It is also used for treating acid-reflux disorders ( like GERD), peptic ulcer disease, heartburn, and acid indigestion. * * Antihistaminic Agents (Chapter 1) 41 1.3.2.2. Famotidine Famotidine is a competitive H 2-receptor antagonist and its main pharmacodynamic effect is the inhibition of gastric secretion. Mechanism of Action Famotidine blocks the histamine effects by competitively binding to H2-receptors found on the basolateral membrane of gastric parietal cell. This competitive inhibition reduces basal and nocturnal gastric acid sec retion, gastric volume, acidity, and amount of gastric acid produced in response to stimuli including food, caffeine, insulin, betazole, or pentagastrin. Uses 1) It is used for treating and preventing stomach and intestinal ulcers. 2) It is used in Zollinger-Ellison syndrome (in which excess amounts of acid is produced by the stomach). 3) It is used for treating Peptic Ulcer Disease (PUD) and Gastroesophageal Reflux Disease (GERD). 1.3.2.3. Ranitidine Ranitidine is a non-imidazole blocker of those histamine receptors which mediate gastric secretion (H2-receptors). It is used for treating gastrointestinal ulcers. Mechanism of Action Ranitidine reduces the normal as well as the meal-stimulated secretion of acid by parietal cells by two mechanisms: 1) Histamine is released by the ECL cells in stomach is prevented from binding to the H2-receptors on parietal cells that stimulate acid secretion. 2) When H2-receptors are blocked, substances promoting acid secretion ( e.g., gastrin and acetylcholine) have a decreased effect on parietal cells. Uses 1) It is used for treating peptic ulcer disease and gastroesophageal refluxdisease. 2) It is used in gastric and duodenal u lcer and in conditions in which gastric juice secretion needs to be inhibited. 3) It is given in combination with fexofenadine a nd other antihistamines for treating skin conditions like hives. * * 42 Medicinal Chemistry - II 1.4. SUMMARY The details given in the chapter can be summarised as follows: 1) Histamine, a biologically active substance potentiates the inflammatory and immune responses of the body. 2) Anti-histaminic agents (or histamine antagonists ) are the drugs that antagonise the action of histamine. 3) The first generation H1-antihistamines have a central effect so are used as sedatives. 4) The second generation H1-antihistamines have low central effects so are used as anti-allergenic drugs. 5) Histamines are nitrogen containing organic co mpounds belonging to the group of amines. 6) Histamines are synthesised and released by basophils and mast cells on stimulation. 7) Diphenhydramine is a first generation antihistamine which is mainly used for treating seasonal allergies. 8) Dimenhydrinate is a comb ination drug as it comprises of diphenhydramine (53-55.5%) and 8-chlorotheophylline (not less than 44 - 47%) in a salt form, calculated on the dried basis. 9) Clemastine fumarate is the fumaric acid salt of clemastine. It is an antihistamine having antimuscarinic and moderate sedative properties. 10) Diphenylpyraline is an antihistamine used for treating allergy by competing with histamine to bind to the H1-receptor sites found on the effector cells. 11) Tripelennamine is an ethylenediamine derivative having anti -histaminergic property. 12) Chlorcyclizine is a first generation antihistamine belonging to phenylpiperazine class. 13) Meclizine hydrochloride is the hydrochloride salt form of meclizine, which is a synthetic piperazine having anti -emetic, sedative and H 1-antagonistic properties. 14) Buclizine hydrochloride is the hydrochloride salt form of buclizine, which is a piperazine H 1-receptor antagonist having antiemetic and anti -vertigo properties. 15) Chlorpheniramine maleate is a H1-recpetor antagonist. 16) Triprolidine hydrochloride is obtained by the reaction between equimolar amounts of triprolidine and hydrogen chloride. 17) Phenindamine tartrate is a phenylalkylamine sympathomimetic amine. 18) Promethazine hydrochloride is the hydrochloride salt form of promethazine, which is a phenothiazine derivative having antihistaminic, sedative and antiemetic properties. * * Antihistaminic Agents (Chapter 1) 43 19) Trimeprazine tartrate (or alimemazine) is a tartrate salt and a phenothiazine derivative, which is used as an antipruritic agent. 20) Cyproheptadine is a first generation antihistamine wh ich is used as an appetite stimulant and for treating allergic rhinitis and urticaria. 21) Azatadine maleate is a first-generation antihistamine. It is the dimaleate salt of azatadine. 22) Astemizole is a long-acting, non-sedating second generation antihistamine. 23) Loratadine is an azatadine derivative and a second generation H 1-receptor antagonist. 24) Cetirizine (or zyrtec) is an orally active second generation H1-antagonist. 25) Levocetirizine is a third generation non-sedative antihistamine. 26) Cromolyn sodium is the sodium salt form of cromolyn, which is a mast cell stabiliser having anti-inflammatory activity. 27) Cimetidine is a histamine congener and competitively inhibits the binding of histamine to histamine H2-receptors. 28) Famotidine is a competitive H 2-receptor antagonist and its main pharmacodynamic effect is the inhibition of gastric secretion. 29) Ranitidine is a non -imidazole blocker of those histamine receptors which mediate gastric secretion (H2-receptors). 1.5. EXERCISE 1.5.1. True or False 1) Histamine, a biologically active substa nce potentiates the inflammatory and immune responses of the body. 2) The first gene-antihistamines have a central effect so are used as hypnotics. 3) The second generation H1-antihistamines have low central effects so are used as sedatives. 4) Histamines are nit rogen containing organic compounds belonging to the group of amine 5) Diphenhydramine is a first generation antihistamine which is mainly used for treating seasonal allergies. 6) Chlorcyclizine is a second generation antihistamine belonging to phenylpiperazine class. 7) Buclizine hydrochloride is the hydrochloride salt form of buclizine, which is a piperazine H2-receptor antagonist. 8) Chlorpheniramine maleate is a H 1-recpetor antagonist. 9) Cimetidine is a histamine congener and competitively inhibits the binding of histamine to histamine H 2-receptors. 1.5.2. Fill in the Blanks 10) Anti-histaminic agents are the drugs that antagonise the action of ________. 11) Histamines are synthesised and released by _______ and __________ on stimulation. * * 44 Medicinal Chemistry - II 12) __________ is a first gene ration antihistamine which is mainly used for treating seasonal allergies. 13) ___________ is a H1-recpetor antagonist. 14) ___________ is a phenylalkylamine sympathomimetic amine. 15) __________ is a long-acting, non-sedating second generation antihistamine. is an azatadine derivative and a second generation H 1-receptor antagonist. 16) _________ is a non -imidazole blocker of those histamine receptors which mediate gastric secretion. 17) ___________ is a third generation non-sedative antihistamine. Answers 1) True 2) False 3) False 4) True 5) False 6) False 7) True 8) True 9) Histamine, 10) Basophils, Mast cells 11) Diphenhydramine 12) Chlorpheniramine maleate 13) Phenindamine tartrate 14) Astimazole 15) Losartan 16) Ranitidine 17) Levocetrizine. 1.5.3. Very Short Answer Type Questions 1) Give the structure of histamine 2) What are the types of histamine receptors? 3) Give the structure of diphenhydramine. 4) What is the mechanism of action of clemastine fumarate? 5) Enlist uses of doxylamine succinate. 6) Give the mechanism of action of levocetrizine. 1.5.4. Short Answer Type Questions 1) Write a short note on histamine. 2) Explain histamine receptors and their distribution in the body. 3) Write a note on recent development of antihistaminic agents. 4) Give the synthesis of cimetidine. 5) Write a short note on ranitidine. 1.5.5. Long Answer Type Questions 1) Explain H 1-antagonists and give mechanism of action , uses a nd structure of following drugs: i) Doxylamine succinate ii) Clemastine fumarate iii) Meclizine hydrochloride iv) Chlorpheniramine v) Levocetrizine 2) Explain antihistaminic agents in detail and give its SAR. 3) Write about H 2-antagonists in d etails and mechanism of action of action, uses of following drugs: i) Cimetidine ii) Famotidine iii) Ranitidine * * Gastric Proton Pump Inhibitors (Chapter 2) 45 CHAPTER Gastric Proton Pump 2 Inhibitors 2.1. GASTRIC PROTON PUMP INHIBITORS 2.1.1. Introduction Proton Pump Inhibitors (PPIs) are irreversible inhibitors of gastric parietal cell proton pump. This enzyme promotes the exchange of H + or K + ions, which are required for mediating HCl secretion. PPIs induce 80 -90% inhibition of basal, nocturnal, and food stimulated acid levels after single administration. PPIs reduce the acid production by blocking the enzyme present in the stomach wall. Reduction in the production of acid by stomach prevents the occurrence of ulcers and also facilitates the healing of ulcers already existing in the oesophagus, stomach, and duodenum. 2.1.2. Classification Proton pump inhibitors are classified as follows: Drugs X R1 R2 R3 R4 Omeprazole CH OCH3 CH3 CH3 CH3 Esomeprazole CH OCH3 CH3 CH3 CH3 (S-enantiomer) Tenatoprazole N OCH3 CH3 CH3 CH3 Lansoprazole CH H CH3 CH2CF3 H Rabeprazole CH H CH3 (CH2)3OCH3 H Pantoprazole CH OCHF2 OCH3 CH3 H 2.1.3. Mechanism of Action The H+-K+-ATPase proton pump of the apical membrane of parietal cell is the mediator of acid secretion. The newer substituted benzimidazoles have been developed as specific inhibitors because the H+-K+-ATPase proton pump is unique to parietal cells. These benzimidazoles are used in peptic ulcer. * * 46 Medicinal Chemistry - II The PPIs have a sulphinyl group in a bridge between substituted benzimidazole and pyridine rings. These agents ar e chemically stable and lipid -soluble weak bases without inhibitory activity at neutral pH. These neutral weak bases reach the parietal cells from the blood and diffuse into the secretory canaliculi. Here the drugs become protonated and trapped. The protonated agent re-arranges for producing sulphuric acid and sulphonamide, which covalently interacts with sulphhydryl groups of cysteine at critical sites in the extra cellular domain of the H+- K+-ATPase. Thus, it irreversibly inhibits gastric acid secretion. 2.1.4. Uses Proton pump inhibitors are used for treatin g ulcers and haemorrhagic ulcers caused by Helicobacter pylori as they inhibit the growth of H. pylori. They also allow the continuous use of NSAIDs in a patient with known peptic ulcer. Proton pump inhib itors are also used for preventing recurrent haemorrhagic ulcers. Clot formation comprises of the processes that weaken in acidic environments, and the clot integrity is maintained in the ulcer bed by the suppression of gastric acid secretion by proton pump inhibitors. For example, an intravenous infusion o f omeprazole maintains the intragastric pH above 6, thus, it supports platelet aggregation and clot stability. Proton pump inhibitors are superior to H 2-receptor antagonists (like ranitidine) for heali ng gastric and duodenal ulcers in patients who continue the use of NSAIDs. This is because proton pump inhibitors can withstand a constant increase in gastric pH. 2.1.5. Study of Individual Drugs The following gastric PPIs are discussed below: 1) Omeprazole, 2) Lansoprazole, 3) Rabeprazole, and 4) Pantoprazole. 2.1.5.1. Omeprazole Omeprazole inhibits the proton pump and decreases the amount of acid produced in the stomach. * * Gastric Proton Pump Inhibitors (Chapter 2) 47 Mechanism of Action Omeprazole suppresses gastric acid secretion by inhibiting the H +-K+-ATPase in the gastric parietal cell. Thus, by acting specifically on the proton pump it blocks the final step in acid production, and reduces gastric acidity. Uses 1) It is used for t reating GERD and other conditions caused by excessive production of stomach acid. 2) It is used to promote the healing of erosive oesophagitis (damage caused to oesophagus by the stomach acid). 3) It is used to relieve heartburn, difficulty in swallowing, and persistent cough. 4) It is used to prevent oesophageal cancer. 5) It is used along with antibiotics to treat gastric ulcer caused by H. pylori. 2.1.5.2. Lansoprazole Lansoprazole i s a substituted benzimidazole prodrug having the selective and irreversible proton pump inhibitor activity. It prevents the production of acid in the stomach. Mechanism of Action Lansoprazole is an anti -secretory compound. It is a substituted benzimidazole that is devoid of anticholinergic or H2-receptor antagonist properties. However, it suppresses gastric acid secretion by inhibiting the H +-K+-ATPase enzyme system at the secretory surface of gastric parietal cell. Since this enzyme system i s the acid (proton) pump in the parietal cell, lansoprazole is considered the gastric acid-pump inhibitor which inhibits the final step of acid production. This effect is dose -dependent and inhibits the basal as well as stimulated gastric acid secretion irrespective of the stimulus. Uses 1) It is used for treating acid -reflux disorders ( like GERD) and peptic ulcer disease. 2) It is used for H. pylori eradication. 3) It is used in combination with NSAIDs for preventing gastrointestinal bleeding. * * 48 Medicinal Chemistry - II 2.1.5.3. Rabeprazole Rabeprazole is an antiulcer drug that blocks the H+-K+-ATPase of the coating gastric cells. It also inhibits the dose -dependent oppresses basal and stimulated gastric acid secretion. Mechanism of Action Rabeprazole is an anti -secretory compound. It is a substituted benzimidazole proton-pump inhibitor that suppresses gastric acid secretion by inhibiting the H +- K+-ATPase enzyme system at the secretory surface of gastric parietal cell. Since this enzyme system is the acid (proton) pump i n the parietal cell, rabeprazole is considered the gastric acid -pump inhibitor which inhibits the final step of acid production. Uses 1) It is used in the treatment of Gastroes ophageal reflux disease (GERD) and poorly responsive systemic GERD. 2) It is used in severe erosive esophagitis. 3) It is used in pathol ogic hypersecretory conditions, like Zollinger-Ellison syndrome, systemic mastocytosis, and multiple endocrine adenomas. 4) It is used for treating duodenal ulcers with or without anti -infectives for Helicobacter pylori. 5) It is also used for curing the daytime or night time heartburn. 2.1.5.4. Pantoprazole Pantoprazole is a first generation PPI. It is also used for treating other disorders wherein gastric acid secretion needs to be reduced. Pantoprazole is available in many forms , such as a delayed -release oral capsule, oral suspension, and intravenous injection. Mechanism of Action Pantoprazole is a substituted benzimidazole derivative and a weak base. It collects in the acidic space of the pa rietal cell and then converts into active sulfenamide derivatives in the acidic environment of the canaliculi of gastric * * Gastric Proton Pump Inhibitors (Chapter 2) 49 parietal cell. The active derivatives obtained inhibit the function of gastric acid pump by making disulfide bonds with important cyste ines on the pump. Pantoprazole binds to the sulfhydryl group of H +-K+-ATPase (an enzyme that accelerates the final step in acid secretion pathway ). This enzyme is inactivated and gastric acid secretion is inhibited. Uses 1) Pantoprazole injection is given t o patients having GERD and history of erosive esophagitis for short -term treatment (7 -10 days). It is given as an alternate to pantoprazole delayed-release tablets in patients who are not able to swallow the tablets. 2) It is used in the treatment of pathological hypersecretory conditions related to Zollinger-Ellison syndrome or other neoplastic conditions. 3) Pantoprazole delayed-release oral suspension is used for short-term treatment of erosive esophagitis related to GERD. 4) It is also used to promote the healing of erosive esophagitis and decrease the relapse rates of daytime and night time heartburn symptoms in adult patients of GERD. 2.2. SUMMARY The details given in the chapter are summarised as follows: 1) Proton Pump Inhibitors (PPIs) are irreversible inhibitor s of gastric parietal cell proton pump. 2) PPIs induce 80 -90% inhibition of basal, nocturnal, and food stimulated acid levels after single administration. 3) PPIs reduce the acid production by blocking the enzyme present in the stomach wall. 4) Proton pump inhibit ors are used for treating ulcers and haemorrhagic ulcers caused by Helicobacter pylori as they inhibit the growth of H. pylori. 5) Proton pump inhibitors are superior to H 2-receptor antagonists (like ranitidine) for healing gastric and duodenal ulcers in pati ents who continue the use of NSAIDs. 6) Omeprazole inhibits the proton pump and decreases the amount of acid produced in the stomach. 7) Lansoprazole is a substituted benzimidazole prodrug having the selective and irreversible proton pump inhibitor activity. 8) Rabeprazole is an antiulcer drug that blocks the H+-K+-ATPase of the coating gastric cells. It also inhibits the dose -dependent oppresses basal and stimulated gastric acid secretion. 9) Pantoprazole is a first generation PPI. It is also used for treating other disorders wherein gastric acid secretion