Textbook of Pharmacology for Dental and Allied Health Sciences

SECOND EDITION

Padmaja Udaykumar Professor and Head Department of Pharmacology Fr. Muller Medical College, Mangalore Karnataka India

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD. New Delhi Published by Jitendar P Vij Jaypee Brothers Medical Publishers (P) Ltd B-3 EMCA House, 23/23B Ansari Road, Daryaganj, New Delhi 110 002, India Phones: +91-11-23272143, +91-11-23272703, +91-11-23282021, +91-11-23245672, Rel: 32558559 Fax: +91-11-23276490, +91-11-23245683 e-mail: [email protected] Visit our website: www.jaypeebrothers.com Branches  2/B, Akruti Society, Jodhpur Gam Road Satellite Ahmedabad 380 015, Phones: +91-079-26926233, Rel: +91-079-32988717, Fax: +91-079-26927094 e-mail: [email protected]  202 Batavia Chambers, 8 Kumara Krupa Road, Kumara Park East Bengaluru 560 001, Phones: +91-80-22285971, +91-80-22382956, Rel: +91-80-32714073 Fax:+91-80-22281761, e-mail: [email protected]  282 IIIrd Floor, Khaleel Shirazi Estate, Fountain Plaza, Pantheon Road Chennai 600 008, Phones: +91-44-28193265, +91-44-28194897, Rel: +91-44-32972089 Fax: +91-44-28193231, e-mail: [email protected]  4-2-1067/1-3, 1st Floor, Balaji Building, Ramkote Cross Road Hyderabad 500 095, Phones: +91-40-66610020, +91-40-24758498, Rel:+91-40-32940929 Fax:+91-40-24758499, e-mail: [email protected]  No. 41/3098, B & B1, Kuruvi Building, St. Vincent Road Kochi 682 018, Kerala, Phones: 0484-4036109, +91-0484-2395739, +91-0484-2395740 e-mail: [email protected]  1-A Indian Mirror Street, Wellington Square Kolkata 700 013, Phones: +91-33-22651926, +91-33-22276404, +91-33-22276415 Rel: +91-33-32901926, Fax: +91-33-22656075, e-mail: [email protected]  106 Amit Industrial Estate, 61 Dr SS Rao Road, Near MGM Hospital, Parel Mumbai 400 012, Phones: +91-22-24124863, +91-22-24104532, Rel: +91-22-32926896 Fax: +91-22-24160828, e-mail: [email protected]  “KAMALPUSHPA” 38, Reshimbag, Opp. Mohota Science College, Umred Road Nagpur 440 009 (MS), Phones: Rel: 3245220, Fax: 0712-2704275, e-mail: [email protected] Textbook of Pharmacology for Dental and Allied Health Sciences © 2007, Padmaja Udaykumar All rights reserved. No part of this publication should be reproduced, stored in a retrieval system, or transmitted in any form or by any means: electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the author and the publisher. This book has been published in good faith that the material provided by author is original. Every effort is made to ensure accuracy of material, but the publisher, printer and author will not be held responsible for any inadvertent error(s). In case of any dispute, all legal matters are to be settled under Delhi jurisdiction only.

First Edition: 2002 Reprint: 2003, 2006 Second Edition: 2007 ISBN 81-8448-149-7 Typeset at JPBMP typesetting unit Printed at Paras Press Dedicated to My beloved mother Mrs. Lalitha Narayan

Foreword

It is a daunting challenge to a studious student of a subject to write a textbook. This is particularly so in case of pharmacology, a subject having tremendous potential for expansion. Medicine is said to be the most dynamic amongst biological disciplines; pharmacology can be said to be so amongst health science disciplines. It has stupendously grown in its own right and on its own wicket. In addition, it has been quick in responding to advances in other disciplines. Ramification of pharmacology into various other disciplines has resulted in mutual sharing of knowledge and impetuous for further study. This has resulted in the continuing growth of both factual and conceptual knowledge-base, too rapid and huge to comprehend. These facts weigh on the mind of a studious student. A textbook for undergraduate students has to be clear, lucid, comprehensive and concise. This requires a critical and shrewd sifting and sieving of the vast data, to pick-up those that are necessary and relevant in a given context. Such a job demands grit, knowledge, ability and prudence. Dr (Mrs) Padmaja Udaykumar, a young pharmacologist has gratifyingly demonstrated these in her venture of writing a textbook in pharmacology for students of dental, physiotherapy and allied branches of health sciences. Most textbooks on this subject contain data and information that suit medical students. But many student-groups of other streams of health sciences require knowledgeability in the subject pharmacology in a way that is meaningful and relevant to their respective field. Indeed pharmacology is one of the core-subjects in these courses. This point in view, the author has made a commendable attempt in this direction. Need for condensation of the vast data inevitably makes the text and approach more catalogic and less thematic. Yet there is enough factual data as well as sufficient thematic message synchronized, a very important point in a text for undergraduates. Dr Padmaja Udaykumar has brought out a concise book in pharmacology with clear and comprehensive coverage of the topics in a systematically organized manner and presented in a simple— ‘easy to read and grasp’ style. This book though primarily meant for dental, physiotherapy and nursing students, it contains enough material to be useful even for medical students, particularly for quick revision. Teacher, like parent, gets proud pleasure at the progress and deserving achievements of the next generation. I did derive such pleasure while going through the text of this nice book by Dr Padmaja Udaykumar and say a few words about it.

Prof DR Kulkarni Head of the Department of Medical Education BM Patil Medical College, Bijapur Former Principal, DY Patil Medical College, Kollapur Former President, Indian Association of Pharmacologists

Preface to the Second Edition

Pharmacology is a subject that has been rapidly growing. To keep pace with it, books in pharmacology need to be updated frequently. The book has been thoroughly revised with appropriate additions, deletions and tailored to the needs of a dental student. In response to the feedback received, wherever applicable, the relevance of the topic to a dentist has been highlighted. More figures, charts and tables have been added and the book is brought out in multiple colours, all of which make it more student-friendly. Many universities have introduced ‘Compare and Contrast’, between related drugs in the question papers. There- fore a series of ‘Compare and Contrast’ have been given in all relevant chapters. Keeping in mind the burden on students, efforts have been made to include only the necessary things and prune the unwanted ones. A chapter on emergencies in dental practice has been included as required by some universities. The First edition of the book was titled ‘Short Textbook of Pharmacology for Dental and Allied Health Sciences’ and has been renamed in the second edition as Textbook of Pharmacology for Dental and Allied Health Sciences. I hope the book makes learning pharmacology a pleasurable experience.

Please send your feedback to [email protected].

Padmaja Udaykumar

Preface to the First Edition

Pharmacology is a science that forms the basis for modern medicine. It is a rapidly changing field with new drugs being constantly introduced. The knowledge of pharmacology is important for all those who deal with drugs apart from medical practitioners. But the depth could vary. The need was felt for a short textbook for Dental, Nursing, Physiotherapy and other health science students. Hence this book was brought out, keeping in mind the size of the book and information required. General pharmacology has been discussed in detail as it forms the basis for understanding pharmacology. Similarly chemotherapy, particularly general chemotherapy, analgesics, anaesthetics and corticosteroids are dealt with in adequate depth. Mechanisms of action have been discussed in brief. In each chapter, the prototype drug has been discussed in detail while the differing features of others are then mentioned. Simple figures have been used wherever necessary. Common drug interactions are given in the Appendices. Accepted abbreviations have been used. References for further reading are mentioned at the end of the text. The chapter on Dental Pharmacology is included. Adequate importance has been given to essential drugs. I hope this book serves to make pharmacology easy for the students of Health Sciences.

Padmaja Udaykumar Acknowledgements

I wish to express my sincere thanks to Prof. D.R. Kulkarni for writing Foreword to this book and for his valuable guidance. I place on record my heartfelt gratitude to Dr. Lakshmikant Chatra, Professor of Oral Medicine, Yenepoya Dental College, for his help and suggestions. I wish to thank Profes- sors of Pharmacology Prof. Nataraj K.V., Prof. Vijayaraghavan, Prof. Parvathi Bhat, Prof. K.S.Karanth, Prof. M.C. Alwar, Prof. Ahalya Devi, Prof. Vasanth Kumar, Prof. K.L. Bairy, Prof. Holla R., Prof. M.R.S.M.Pai, Prof. Venkatadri and Prof. Tara Shanbogue. I also thank my colleagues Dr.Vijayalakshmi M., Dr. Princy, Dr. Prasannalakshmi, Dr. Manohar Revonkar and Miss Deepa for their support. I am extremely thankful to the management of Fr. Muller Medical College—Director Fr. Baptist Menezes, Administrators Fr. Lawrence C D’Souza, Fr. Dennis D’Sa and Dean Dr. Sanjeev Rai for their encouragement. I wish to thank Dr. Prasanna Kumar J. Asst. Professor in oral medicine for his help. I owe a special note of thanks to my husband Prof. Udaykumar K. for his constant encouragement, valuable suggestions and support in this endeavor. I thank Jaypee Brothers Medical Publishers, New Delhi for bringing out this colourful book. Contents

SECTION 1 General Pharmacology

1. Introduction and Sources of Drugs ...... 1 2. Routes of Drug Administration ...... 3 3. Pharmacokinetics ...... 10 4. Pharmacodynamics ...... 24 5. Adverse Drug Reactions and Drug Interactions, Drug Nomenclature and Essential Drugs Concept ...... 36 SECTION 2 Autonomic Nervous System

6. Introduction to Autonomic Pharmacology ...... 42 7. Cholinergic System ...... 46 8. Anticholinergic Drugs ...... 56 9. Skeletal Muscle Relaxants ...... 60 10. Adrenergic System ...... 66 11. Adrenergic Drugs (Sympathomimetics) ...... 69 12. Adrenergic Antagonists ...... 76 SECTION 3 Drugs Acting on the Kidney

13. Diuretics and Antidiuretics ...... 82 SECTION 4 Cardiovascular System

14. Cardiac Glycosides and Treatment of Cardiac Failure ...... 90 15. Calcium Channel Blockers...... 96 16. Antiarrhythmic Drugs ...... 99 17. Drugs Used in Angina Pectoris and Myocardial Infarction ...... 104 18. Antihypertensive Drugs ...... 110 19. Plasma Expanders and Pharmacotherapy of Shock ...... 120 xiv Textbook of Pharmacology for Dental and Allied Health Sciences

SECTION 5 Central Nervous System

20. General Anaesthetics...... 122 21. Local Anaesthetics ...... 130 22. Sedative Hypnotics ...... 137 23. Alcohols ...... 143 24. Antiepileptics ...... 146 25. Drugs Used in Parkinsonism ...... 155 26. Opioid Analgesics ...... 158 27. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) ...... 172 28. Drugs Used in Rheumatoid Arthritis and Gout ...... 185 29. Drugs Used in Psychiatric Disorders ...... 190

30. CNS StimulantS ...... 201

SECTION 6 Autacoids

31. Autacoids • Histamine ...... 203 • 5-Hydroxytryptamine ...... 207 • Ergot Alkaloids ...... 208 • Eicosanoids ...... 210 • Other Autacoids ...... 212

SECTION 7 Respiratory System

32. Drugs Acting on Respiratory System • Drugs Used in the Treatment of Bronchial Asthma ...... 214 • Drugs Used in the Treatment of Cough ...... 220 Contents xv

SECTION 8 Blood 33. Haematopoietic System • Haematinics ...... 222 • Drugs Used in the Disorders of Coagulation ...... 226 • Hypolipidaemic Drugs ...... 235

SECTION 9 Gastrointestinal Tract

34. Drugs Used in Gastrointestinal Disorders • Drugs Used in Peptic Ulcer ...... 237 • Prokinetic Agents ...... 243 • Emetics and Antiemetics ...... 244 • Drugs for Constipation and Diarrhoea ...... 247

SECTION 10 Chemotherapy I

35. General Considerations ...... 252 36. Sulfonamides, Cotrimoxazole and Quinolones...... 262 37. Beta-lactam Antibiotics...... 267 38. Broad Spectrum Antibiotics ...... 276 39. Aminoglycosides ...... 280 40. Macrolides, Other Antibacterial Agents and Chemotherapy of Urinary Tract Infections ...... 284

SECTION 11 Chemotherapy II

41. Chemotherapy of Tuberculosis and Leprosy...... 291 42. Antifungal Drugs ...... 299 43. Antiviral Drugs ...... 305 44. Chemotherapy of Malaria ...... 312 45. Drugs Used in Amoebiasis, Leishmaniasis and Trypanosomiasis ...... 319 46. Anthelmintics ...... 324 47. Cancer Chemotherapy ...... 328 xvi Textbook of Pharmacology for Dental and Allied Health Sciences

SECTION 12 Hormones

48. Hypothalamus and Anterior Pituitary Hormones ...... 337 49. Thyroid Hormones and Antithyroid Drugs ...... 342 50. Corticosteroids ...... 347 51. Oestrogens, Progestins and Hormonal Contraceptives ...... 355 52. Androgens and Anabolic Steroids ...... 362 53. Insulin and Oral Hypoglycaemics ...... 364 54. Agents Affecting Bone Mineral Turnover ...... 372

SECTION 13 Miscellaneous Drugs

55. Miscellaneous Drugs • Immunopharmacology ...... 376 • Antiseptics and Disinfectants ...... 378 • Chelating Agents ...... 382 • Vitamins ...... 383 • Gene Therapy ...... 387

SECTION 14 Dental Pharmacology

56 Dental Pharmacology...... 389

Appendix 1- Important Drug Interactions ...... 405 Apendix 2-Prescription Writing ...... 408 Further Reading ...... 411 Index ...... 413 Section 1 General Pharmacology 1 Introduction and Sources of Drugs

HISTORICAL ASPECTS Various other traditional systems of medicine were practiced in different parts of Pharmacology is the science that deals with the world – like Homeopathy, Unani, Siddha the study of drugs and their interaction with system and Allopathy. the living systems. The useful and toxic effects of many plant Allopathy means ‘the other suffering’. This and animal products were known to man in word still being used for the modern system ancient times. The earliest writings on drugs of medicine, is a misnomer. Homoeopathy are the Egyptian Medical Papyrus (1600 BC). meaning ‘similar suffering’ was introduced The largest of them, Ebers Papyrus lists some by Hanneman. The principles of this system 800 preparations. include ‘like cures like’ and ‘dilution enhances In early days there was a close relationship the potency of drugs’. between religion and treatment of diseases. Thus several systems of medicine were The knowledge of the use of drugs often introduced, of which only a few survived. rested with the priest or holyman. Drugs The basic reason for the failure of many were thought to be magical in their actions. systems is that man’s concepts about diseases Several cultures like the Chinese, Greek, were incorrect and baseless in those days. Indian, Roman, Persian, European and many By the end of the 17th century the importance others contributed a great deal to the of experimentation, observation and development of medicine in early times. The scientific methods of study became clear. drug prescriptions included preparations Francois Magendie and Claude Bernard from herbs, plants, animals and minerals. In popularised the use of animal experiments the middle ages many herbal gardens were to understand the effects of drugs. cultivated particularly by monasteries. Simultaneous development of other branches Though medicine developed simulta- of science viz, botany, zoology, chemistry neously in several countries, the spread of and physiology helped in the better knowledge was limited because of poorly understanding of pharmacology. developed communication across the world. The last century has seen a rapid growth India’s earliest pharmacological writings of the subject with several new drugs, new are from the ‘Vedas’. An ancient Indian concepts and techniques being introduced. physician Charaka and then, Sushruta and We now know much more about receptors Vagbhata, described many herbal and molecular mechanisms of action of many preparations included in ‘Ayurveda’ drugs. Several diseases, which were (meaning ‘the science of life’). Indians considered incurable and fatal, can now be practiced vaccination as early as 550 BC. completely cured with just a few tablets. 2 Textbook of Pharmacology for Dental and Allied Health Sciences

DEFINITIONS preparations approved for use, their formulae and other information needed to prepare a The word pharmacology is derived from drug; their physical properties, tests for their the Greek word—Pharmacon meaning an identity, purity and potency. Each country active principle and logos meaning a study may follow its own pharmacopoeia to guide (discourse). its physicians and pharmacists. We thus have Drug (Drogue—a dry herb in French) is a the Indian Pharmacopoeia (IP), the British substance used in the diagnosis, prevention Pharmacopoeia (BP) and the United States or treatment of a disease. WHO definition— Pharmacopoeia (USP). The list is revised at “A drug is any substance or product that is regular periods to delete obsolete drugs and used or intended to be used to modify or to include newly introduced ones. explore physiological systems or pathological Pharmacy is the science of identification, states for the benefit of the recipient.” compounding and dispensing of drugs. It also Pharmacodynamics is the study of the effects includes collection, isolation, purification, of the drugs on the body and their synthesis and standardisation of medicinal mechanisms of action, i.e. what the drug does substances. to the body. SOURCES OF DRUGS Pharmacokinetics is the study of the absorption, distribution, metabolism and excretion of The sources of drugs could be natural or drugs, i.e. what the body does to the drug synthetic. Natural sources Drugs can be obtained from: (in Greek Kinesis = movement). 1. Plants, e.g. atropine, morphine, quinine, Therapeutics deals with the use of drugs in the and digoxin. prevention and treatment of disease. 2. Animals, e.g. insulin, heparin, gonad- Pharmacoeconomics deals with the cost, i.e. otrophins and antitoxic sera. economic aspects of drugs used therapeutically. 3. Minerals, e.g. magnesium sulphate, Pharmacogenomics is a branch of pharmaco- aluminium hydroxide, iron, sulphur and genetics which deals with the use of genetic radioactive isotopes. information in selecting drugs for a person. 4. Microorganisms—antibacterial agents are Pharmacoepidemiology is the study of both the obtained from some bacteria and fungi. We useful and adverse effects of drugs on large thus have penicillin, cephalosporins, numbers of people. Pharmacovigilance is a tetracyclines and other antibiotics. branch of pharmacoepidemiology which deals 5. Human—some drugs are obtained from with the epidemiologic study of adverse drug human beings, e.g. immunoglobulins from effects. blood, growth hormone from anterior Toxicology deals with the adverse effects of pituitary and chorionic gonadotrophins from the urine of pregnant women. drugs and also the study of poisons, i.e Synthetic Most drugs used now are synthetic, detection, prevention and treatment of poiso- e.g. quinolones, omeprazole, neostigmine, nings (Toxicon=poison in Greek). sulfonamides. Chemotherapy is the use of chemicals for the Many drugs are obtained by cell cultures, e.g. treatment of infections. The term now also urokinase from cultured human kidney cells. includes the use of chemical compounds to Some are now produced by recombinant DNA treat malignancies. technology, e.g. human insulin, tissue plasminogen Pharmacopoeia (in Greek Pharmacon = drug; activator, haematopoietic growth factors like poeia=to make) is the official publication erythropoietin and some others by hybridoma containing a list of drugs and medicinal technique eg. monoclonal antibiodies. 2 Routes of Drug Administration

Drugs may be administered by various 2. Irritant and unpalatable drugs cannot be routes. The choice of the route in a given administered. patient depends on the properties of the drug 3. Some drugs may not be absorbed due to and the patient’s requirements. A knowledge certain physical and chemical characte- of the advantages and disadvantages of the ristics, e.g. streptomycin is not effective different routes of administration is essential. orally. The routes can be broadly divided into: 4. Irritation to the gastrointestinal tract may • Enteral lead to vomiting. • Parenteral 5. There may be irregularities in absorption. • Local. 6. Some drugs may be destroyed by gastric juices, e.g. insulin. ENTERAL ROUTE (ORAL INGESTION) 7. Oral preparations cannot be given to Enteral route is the most commonly used, unconscious and uncooperative patients. oldest and safest route of drug adminis- 8. Some drugs may undergo extensive first tration. The large surface area of the pass metabolism in the liver. gastrointestinal tract, the mixing of its To overcome some of the disadvantages, contents and the differences in pH at irritants are given in capsules, while bitter different parts of the gut facilitate effective drugs are given as sugar coated tablets. absorption of the drugs given orally. Sometimes drugs are coated with substances However, the acid and enzymes secreted in like synthetic resins, gums, sugar, colouring the gut and the biochemical activity of the and flavouring agents making them more bacterial flora of the gut can destroy some acceptable. drugs before they are absorbed. Enteric Coated Tablets Advantages Some tablets are coated with substances like 1. Safest route cellulose-acetate, phthalate, gluten, etc. which 2. Most convenient are not digested by the gastric acid but get 3. Most economical disintegrated in the alkaline juices of the 4. Drugs can be self-administered intestine. This will: 5. Non-invasive route. • prevent gastric irritation. Disadvantages • avoid destruction of the drug by the stomach. 1. Onset of action is slower as absorption • provide higher concentration of the drug needs time. in the small intestine. 4 Textbook of Pharmacology for Dental and Allied Health Sciences

• retard the absorption, and thereby Though enteral route mainly includes oral prolong the duration of action. ingestion, sublingual and rectal adminis- But if the coating is inappropriate, the tration may also be considered as enteral tablet may be expelled without being route. absorbed at all. Similarly controlled-release or sustained-release preparations are PARENTERAL ROUTE designed to prolong the rate of absorption Routes of administration other than the and thereby the duration of action of drugs. enteral (intestinal) route are known as This is useful for short-acting drugs. In newer parenteral routes. Here the drugs are directly controlled release formulations, the tablet is delivered into tissue fluids or blood. coated with a semipermeable membrane through which water enters and displaces the Advantages drug out. • Action is more rapid and predictable than Advantages oral administration. • These routes can be employed in an • Frequency of administration may be unconscious or uncooperative patient. reduced. • Gastric irritants can be given parenterally • Therapeutic concentration may be and therefore irritation to the gastroin- maintained specially when nocturnal testinal tract can be avoided. symptoms are to be treated. • It can be used in patients with vomiting or those unable to swallow. Disadvantages • Digestion by the gastric and intestinal • There may be ‘failure of the preparation’ juices and the first pass metabolism are resulting in release of the entire amount avoided. of the drug in a short time, leading to Therefore, in emergencies parenteral toxicity. routes are very useful routes of drug • Enteric coated tablets are more administration as the action is rapid and expensive. predictable and are useful even in Certain precautions are to be taken during unconscious patients. oral administration of drugs—capsules and Disadvantages tablets should be swallowed with a glass of water with the patient in upright posture • Asepsis must be maintained. either sitting or standing. This facilitates • Injections may be painful. passage of the tablet into the stomach and • More expensive, less safe and its rapid dissolution. It also minimises inconvenient. chances of the drug getting into the larynx • Injury to nerves and other tissues may or behind the epiglottis. Recumbent patient occur. should not be given drugs orally as some Parenteral routes include : drugs may remain in the esophagus due to the absence of gravitational force facilitating 1. Injections the passage of the drug into the stomach. Such 2. Inhalation drugs can damage the esophageal mucosa, 3. Transdermal route e.g. iron salts, tetracyclines. 4. Transmucosal route. Routes of Drug Administration 5

INJECTIONS The drug is slowly released for weeks or Intradermal months to provide constant blood levels, e.g. testosterone, DOCA. The drug is injected into the layers of the 3. Sialistic implants The drug is packed in skin raising a bleb, (e.g. BCG vaccine, tests sialistic tubes and implanted sub- for allergy) or by multiple punctures of the cutaneously. The drug gets absorbed over epidermis through a drop of the drug, e.g. months to provide constant blood levels, smallpox vaccine. Only a small quantity can e.g. hormones and contraceptives. The be administered by this route and it may be empty non-biodegradable implant has to painful. be removed.

Subcutaneous (SC) Injection Intramuscular (IM) Here the drug is deposited in the SC tissue, Aqueous solution of the drug is injected into e.g. insulin, heparin. As this tissue is less one of the large skeletal muscles—deltoid, vascular, absorption is slow and largely triceps, gluteus or rectus femoris. Absorption uniform making the drug long-acting. It is into the plasma occurs by simple diffusion. reliable and patients can be trained for self- Larger molecules enter through the administration. Absorption can be enhanced lymphatic channels. As the muscles are by the addition of the enzyme hyaluronidase. vascular, absorption is rapid and quite uniform. Drugs are absorbed faster from the Disadvantages deltoid region than gluteal region especially • As SC tissue is richly supplied by nerves, in women. The volume of injection should irritant drugs cannot be injected because not exceed 10 ml. For infants, rectus femoris they can cause severe pain. is used instead of gluteus because gluteus is • In shock, absorption is not dependable not well-developed till the child starts because of vasoconstriction. walking. If the drug is injected as an oily • Repeated injections at the same site can solution or suspension, absorption is slow cause lipoatrophy resulting in erratic and steady. absorption. Hypodermoclysis is the SC administration of Advantages large volumes of saline employed in paediatric practice. • Intramuscular route is reliable. Drugs can also be administered sub- • Absorption is rapid. cutaneously as: • Soluble substances, mild irritants, depot 1. Dermojet In this method, a high velocity preparations, suspensions and colloids can jet of drug solution is projected from a be injected by this route. fine orifice using a gun. The solution gets Disadvantages deposited in the SC tissue from where it is absorbed. As needle is not required, • Intramuscular injection may be painful and this method is painless. It is suitable for may even result in an abscess. vaccines. • Irritant solutions can damage the nerve 2. Pellet implantation Small pellets packed if injected near a nerve. Nerve injury with drugs are implanted subcutaneously. should be avoided. 6 Textbook of Pharmacology for Dental and Allied Health Sciences

Intravenous (IV) • Only aqueous solutions can be given IV but not suspensions, oily solutions and Here, the drug is injected into one of the superficial veins so that it directly reaches depot preparations. the circulation and is immediately available • Self medication is difficult. for action. Intraperitoneal Peritoneum offers a large Drugs can be given IV as: surface area for absorption. Fluids are 1. A bolus—where an initial large dose is injected intraperitoneally in infants. This route given, e.g. heparin. The drug is dissolved is also used for peritoneal dialysis. in a suitable amount of the vehicle and Intrathecal Drugs can be injected into the injected slowly. subarachnoid space for action on the CNS, 2. Slow injection—over 15-20 minutes, e.g. e.g. spinal anaesthetics. Some antibiotics and aminophylline. corticosteroids are also injected by this route 3. Slow infusion—when constant plasma to produce high local concentrations. Strict concentrations are required, e.g. oxytocin aseptic precautions are a must. in labour or when large volumes have to Drugs are also given extradurally. be given, e.g. dextrose, saline. Generally Morphine can be given epidurally to about one litre of solution is infused over produce analgesia. Direct intraventricular 3 to 4 hours. However, the patient's administration of drugs may be employed in condition and the drug factors like the brain tumors. onset and duration of action of the drug Intra-articular Drugs are injected directly dictates the rate of infusion. into a joint for the treatment of arthritis and Advantages other diseases of the joints, e.g. hydrocortisone is injected into the affected • Most useful route in emergencies because joint in rheumatoid arthritis. Strict aseptic the drug is immediately available for precautions are required. action. Intra-arterial Here drug is injected directly • Provides predictable blood concentrations into the arteries. It is used only in the with 100% bioavailability. treatment of • Large volumes of solutions can be given. (i) peripheral vascular diseases, • Irritants can be given by this route as they (ii) local malignancies get quickly diluted in blood. (iii) diagnostic studies like angiograms. • Rapid dose adjustments are possible—if Intramedullary Injection into a bone marrow— unwanted effects occur, infusion can be stopped; if higher levels are required, now rarely used. infusion rate can be increased—specially INHALATION for short-acting drugs. Volatile liquids and gases are given by Disadvantages inhalation, e.g. general anaesthetics. In • Once injected, the drug cannot be addition, drugs can be administered as solid withdrawn. particles, i.e. solutions of drugs can be • Irritation of the veins may cause atomised and the fine droplets are inhaled thrombophlebitis. as aerosol, e.g. salbutamol. These inhaled • Extravasation of some drugs may cause drugs and vapours may act on the pulmonary severe irritation and sloughing. epithelium and mucous membranes of the Routes of Drug Administration 7 respiratory tract and are also absorbed area of application. The drug is held in a through these membranes. reservoir between an outer layer and a porous membrane. This membrane is Advantages smeared with an adhesive to hold on to the area of application. The drug slowly diffuses • Almost instantaneous absorption of the through the membrane and percutaneous drug is achieved because of the large absorption takes place. The rate of surface area of the lungs. absorption is constant and predictable. • In pulmonary diseases, it serves almost Highly potent drugs (because small quantity as a local route as the drug is delivered is sufficient) and short acting drugs (because at the desired site making it more effect terminates quickly after the system is effective and less harmful. removed) are suitable for use in such • Hepatic first pass metabolism is avoided. systems. • Blood levels of volatile anaesthetics can Sites of application are chest, abdomen, be conveniently controlled as their upper arm, back mastoid region, and absorption and excretion through the scrotum. Examples are hyoscine, nitro- lungs are governed by the laws of gases. glycerine, testosterone, estrogen and fentanyl transdermal patches. Disadvantage Advantages • Irritant gases may enhance pulmonary • Duration of action is prolonged secretions—should be avoided. • Provide constant plasma drug levels This is an important route of entry of • Patient compliance is good. certain drugs of abuse. Inunction The route where a drug rubbed Transdermal on to the skin gets absorbed to produce systemic effects is called inunction. Highly lipid soluble drugs can be applied Iontophoresis In this procedure, galvanic over the skin for slow and prolonged current is used for bringing about penetr- absorption, e.g. nitroglycerine ointment in ation of lipid insoluble drugs into the deeper angina pectoris. Adhesive units, inunction, tissues where its action is required, e.g. iontophoresis and jet injection are some salicylates. Fluoride iontophoresis is used in forms of transdermal drug delivery. the treatment of dental hypersensitivity. Adhesive units (transdermal therapeutic Jet injection As absorption of the drug occurs systems) are adhesive patches (Fig. 2.1) of across the layers of the skin, dermojet different sizes and shapes made to suit the may also be considered as a form of transdermal drug administration (description in page 5). Transmucosal Drugs are absorbed across the mucous membranes. Transmucosal administration includes sublingual, nasal and rectal routes. Sublingual Here, the tablet or pellet containing the drug is placed under the Fig. 2.1: Transdermal adhesive unit tongue. As the drug dissolves, it is absorbed 8 Textbook of Pharmacology for Dental and Allied Health Sciences across the sublingual mucosa. The for- Disadvantages mulation should be lipid soluble, e.g. • Irritation of the rectum can occur. nitroglycerine, nifedipine, buprenorphine. • Absorption may be irregular and Advantages unpredictable. • Absorption is rapid—within minutes the Drugs may also be given by rectal route drug reaches the circulation. as enema. • First pass metabolism is avoided. Enema is the administration of a drug in a • After the desired effect is obtained, the liquid form into the rectum. Enema may be drug can be spat out to avoid the evacuant or retention enema. unwanted effects. Evacuant enema In order to empty the bowel, about 600 ml of soap water is administered Disadvantages per rectum. Water distends and thus • Buccal ulceration can occur. stimulates the rectum while soap lubricates. • Lipid insoluble drugs cannot be given. Enema is given prior to surgeries, obstetric Nasal Drugs can be administered through procedures and radiological examination of nasal route either for systemic absorption or the gut. for local effects. Retention enema The drug is administered with E.g. about 100 ml of fluids and is retained in the (a) for systemic absorption — oxytocin spray rectum for local action, e.g. prednisolone (b) for local effect—decongestant nasal enema in ulcerative colitis. drops, e.g. oxymetazoline; budesonide nasal spray for allergic rhinitis. TOPICAL Rectal Rectum has a rich blood supply and Drugs may be applied on the skin for local drugs can cross the rectal mucosa to be action as ointment, cream, gel, powder, paste, absorbed for systemic effects. Drugs etc. Drugs may also be applied on the mucous absorbed from the upper part of the rectum membrane as in the eyes, ears and nose as are carried by the superior haemorrhoidal ointment, drops and sprays. Drugs may be veins to the portal circulation (can undergo administered as suppository for rectum, bougie first pass metabolism), while that absorbed for urethra and pessary and douche for vagina. from the lower part of the rectum is carried Pessaries are oval shaped tablets to be placed by the middle and inferior haemorrhoidal veins to the systemic circulation. Drugs like in the vagina to provide high local indomethacin, chlorpromazine, diazepam and concentrations of the drug at the site, e.g. paraldehyde can be given rectally. antifungal pessaries in vaginal candidiasis. Some irritant drugs are given rectally as suppositories because they cannot be given orally. SPECIAL DRUG DELIVERY SYSTEMS In order to improve drug delivery, to Advantages prolong the duration of action and thereby • Gastric irritation is avoided. improve patient compliance, special drug • Can be administered by unskilled delivery systems are being tried. Drug persons. targeting, i.e. to deliver drugs at the site • Useful in geriatric patients; patients with where it is required to act is also being aimed vomiting and those unable to swallow. at, especially for anticancer drugs. Some such Routes of Drug Administration 9 systems are ocuserts, progestaserts, pH, e.g. aspirin is converted to salicylic acid transdermal adhesive units, prodrugs, which is the active drug and aspirin is better osmotic pumps, computerised pumps and tolerated than salicylic acid. methods using monoclonal antibodies and Osmotic pumps– are small tablet shaped units liposomes as carriers. containing the drug and an osmotic substance Ocusert Ocusert systems are thin elliptical in two different chambers. The tablet is units that contain the drug in a reservoir coated with a semipermeable membrane in which slowly releases the drug through a which a minute laser-drilled hole is made. membrane by diffusion at a steady rate, e.g. When the tablet is swallowed and reaches pilocarpine ocusert used in glaucoma is the gut, water enters into the tablet through placed under the lid and can deliver the semipermeable membrane. The osmotic pilocarpine for 7 days. layer swells and pushes the drug slowly out Progestasert is inserted into the uterus where of the laser-drilled orifice. This allows slow it delivers progesterone constantly for over and constant delivery of the drug over a long one year. period of time. It is also called Transdermal adhesive units See page 7. Gastrointestinal Therapeutic System (GITS). Prodrug is an inactive form of a drug which Some drugs available in this formulation are gets metabolised to the active derivative in iron and prazosin. the body. A prodrug may overcome some Computerised miniature pumps These are of the disadvantages of the conventional programmed to release drugs at a definite forms of drug administration, e.g. dopamine rate either continuously as in case of insulin does not cross the BBB; levodopa, a prodrug or intermittently in pulses as in case of crosses the BBB and is then converted to GnRH. dopamine in the CNS. Prodrugs may also be Various methods of drug targeting are used to achieve longer duration of action, tried especially for anticancer drugs to e.g. Bacampicillin (a prodrug of ampicillin) reduce toxicity. is longer acting than ampicillin. Monoclonal antibodies against the tumor Cyclophosphamide - an anticancer drug - specific antigens are used to deliver gets converted to its active metabolite anticancer drugs to specific tumor cells. aldophosphamide in the liver. This allows Liposomes are phospholipids suspended oral administration of cyclophosphamide in aqueous vehicles to form minute vesicles. without causing much gastrointestinal Drugs encapsulated in liposomes are taken up toxicity. Zidovudine is taken up by virus mainly by the reticuloendothelial cells of the infected cells and gets activated in these cells. liver and are also concentrated in malignant This results in selective toxicity to infected tumors. Thus site-specific delivery of drugs cells. A prodrug may be more stable at gastric may be possible with the help of liposomes. 10 Textbook of Pharmacology for Dental and Allied Health Sciences 3 Pharmacokinetics

Pharmacokinetics is the study of the molecules can pass. Movement of some absorption, distribution, metabolism and specific substances is regulated by special excretion of drugs, i.e. the movement of the carrier proteins. The passage of drugs across drugs into, within and out of the body. For a biological membranes involves processes like drug to produce its specific response, it passive (filtration, diffusion) and active should be present in adequate concentrations transport. at the site of action. This depends on various factors apart from the dose. Once the drug is Mechanisms of Transport of Drugs administered, it is absorbed, i.e. enters the Across Biological Membranes blood, is distributed to different parts of the body, reaches the site of action, is Passive transfer metabolised and excreted (Fig. 3.1). All these • Simple diffusion processes involve passage of the drug • Filtration molecules across various barriers—like the Carrier-mediated transport intestinal epithelium, cell membrane, renal • Active transport filtering membrane, capillary barrier and so • Facilitated diffusion on. To cross these barriers the drug has to Endocytosis cross the cell membrane or pass in-between the epithelial or endothelial cells. Passive Transfer The cell membrane/biological membrane is made up of two layers of phospholipids The drug moves across a membrane without with intermingled protein molecules any need for energy. (Fig. 3.2). All lipid soluble substances get Simple diffusion is the transfer of a drug across dissolved in the cell membrane and readily the membrane in the direction of its permeate into the cells. The junctions between concentration gradient. Lipid soluble drugs adjacent epithelial or endothelial cells have are transferred across membranes by simple pores through which small water-soluble diffusion—after dissolving in the lipids of the cell membrane. Filtration is the passage of drugs through aqueous pores in the membrane. Water- soluble drugs with molecular size smaller than the diameter of the pores cross the biological Fig. 3.1: Schematic representation of movement of drug in the body membranes by filtration. Pharmacokinetics 11

Fig. 3.2: Movement of drugs across biological membrane

Carrier-mediated Transport substance, e.g. uptake of glucose by cells, vitamin B from intestines. Active transport is the transfer of drugs 12 against a concentration gradient and needs Endocytosis energy. It is carried by a specific carrier protein. Only drugs related to natural Endocytosis is the process where small metabolites are transported by this process, droplets are engulfed by the cell. Some e.g. levodopa, iron, amino acids. The proteins are taken up by this process (like compound binds to a specific carrier on one pinocytosis in amoeba). This process is side of the membrane and moves across the currently being tried for delivery of some cell. At the other side of the cell, the complex anticancer drugs to the tissues. The reverse dissociates and the carrier moves back to process— exocytosis is responsible for transport another molecule. Other substances secretion of many substances from cells, e.g. competing for the same mechanism for neurotransmitters stored in nerve endings. transport may interfere with drug movement as this process is saturable, e.g. penicillin and ABSORPTION probenecid - duration of action of penicillin Absorption is defined as the passage of the is prolonged because both of them compete drug from the site of administration into the for renal tubular secretion. circulation. For a drug to reach its site of Facilitated diffusion is a unique form of carrier action, it must pass through various transport which differs from active transport membranes depending on the route of in that it is not energy dependent and the administration. Absorption occurs by one of movement occurs in the direction of the the processes described above, i.e. passive concentration gradient. The carrier facilitates diffusion or carrier-mediated transport. Thus diffusion and is highly specific for the except for intravenous route, absorption is 12 Textbook of Pharmacology for Dental and Allied Health Sciences important for all other routes of the drug molecules have to dissolve in administration. Several factors influence the the tissue fluids. Liquids are absorbed rate and extent of absorption of a drug faster than solids. Delay in disintegration (Fig. 3.3). They are: and dissolution as with poorly water- 1. Disintegration and dissolution time The drug soluble drugs like aspirin, results in taken orally should break up into delayed absorption. individual particles (disintegrate) to be 2. Formulation Pharmaceutical preparations absorbed. It then has to dissolve in the are formulated to produce desired gastrointestinal fluids. In case of drugs absorption. Inert substances used with given subcutaneously or intramuscularly, drugs as diluents like starch and lactose

Fig. 3.3: Factors affecting absorption of drugs Pharmacokinetics 13

may sometimes interfere with absorption. Intestinal motility—when highly 3. Particle size Small particle size is important increased as in diarrhoeas, drug for better absorption of drugs. Drugs like absorption is reduced. corticosteroids, griseofulvin, digoxin, 8. Presence of food delays gastric emptying, aspirin and tolbutamide are better dilutes the drug and delays absorption. absorbed when given as small particles. Drugs may form complexes with food On the other hand, when a drug has to constituents and such complexes are act on the gut and its absorption is not poorly absorbed, e.g. tetracyclines chelate calcium present in the food because of desired, then particle size should be kept which their bioavailability is decreased. large, e.g. anthelmintics like bephenium Moreover, certain drugs like ampicillin, hydroxynaphthoate. roxithromycin and rifampicin are well 4. Lipid solubility Lipid soluble drugs are absorbed only on empty stomach. absorbed faster and better by dissolving 9. Metabolism Some drugs may be degraded in the phospholipids of the cell membrane. in the GI tract, e.g. nitroglycerine, insulin. 5. pH and ionisation Ionised drugs are poorly Such drugs should be given in higher absorbed while unionised drugs are lipid doses or by alternative routes. soluble and are well absorbed. Most 10.Diseases of the gut like malabsorption and drugs are weak electrolytes and exist in achlorhydria result in reduced absorption both ionized and unionized forms. But the of drugs. degree of ionisation depends on the pH. First pass metabolism is the metabolism of a Thus acidic drugs remain unionised in the drug during its passage from the site of acidic medium of the stomach and are absorption to the systemic circulation. It is rapidly absorbed from the stomach, e.g. also called presystemic metabolism or first aspirin, barbiturates. Basic drugs are pass effect and is an important feature of oral unionised when they reach the alkaline route of administration. Drugs given orally medium of the intestine from where they may be metabolised in the gut wall and in are rapidly absorbed, e.g. pethidine, the liver before reaching the systemic ephedrine. circulation. The extent of first pass Strong acids and bases are highly metabolism differs from drug to drug and ionised and therefore poorly absorbed, among individuals from partial to total e.g. heparin, streptomycin. 6. Area and vascularity of the absorbing surface The larger the area of absorbing surface and more the vascularity—better is the absorption. Thus most drugs are absorbed from the small intestine. 7. Gastrointestinal motility Gastric emptying time—if gastric emptying is faster, the passage of the drug Fig. 3.4: Study of bioequivalence. Three different to the intestines is quicker and hence oral formulations-P,Q & R of the same drug yield different absorption is faster. bioavailability values 14 Textbook of Pharmacology for Dental and Allied Health Sciences inactivation. When it is partial, it can be the bioavailability. Large bioavailability compensated by giving higher dose of the variations of a drug particularly when it is particular drug, e.g. nitroglycerine, unpredictable can result in toxicity or propranolol, salbutamol. But for drugs that therapeutic failure as in case of halofantrine. undergo complete first pass metabolism, the route of administration has to be changed, Bioequivalence e.g. isoprenaline, hydrocortisone, insulin. Comparison of bioavailability of different Bioavailability of many drugs is increased in formulations of the same drug is the study patients with liver disease due to reduction of bioequivalence. Often oral formulations in hepatic metabolism. containing the same amount of a drug from different manufacturers may result in First Pass Metabolism different plasma concentrations, i.e. there is • is metabolism of a drug during its first no bioequivalence among them (Fig. 3.4.) passage through gut wall and liver Such differences occur with poorly soluble, • reduces bioavailability slowly absorbed drugs mainly due to • extent of metabolism depends on the differences in the rate of disintegration and drug and individuals dissolution. Variations in bioavailability • measures to compensate first pass (nonequivalence) can result in toxicity or effect therapeutic failure in drugs that have low — dose has to be increased for some safety margin like digoxin and drugs that drugs like propranolol need precise dose adjustment like — route has to be changed for some anticoagulants and corticosteroids. For such others like hydrocortisone drugs, in a given patient, the preparations • Examples: morphine, chlorpromazine, from a single manufacturer should be used. nitroglycerine, verapamil, testosterone, insulin, lignocaine. DISTRIBUTION After a drug reaches the systemic circulation, Bioavailability it gets distributed to other tissues. It should Bioavailability is the fraction of the drug that cross several barriers before reaching the site reaches the systemic circulation following of action. Like absorption, distribution also administration by any route. Thus for a drug involves the same processes, i.e. filtration, given intravenously, the bioavailability is diffusion and specialised transport. Various 100%. On IM/SC injection, drugs are almost factors determine the rate and extent of completely absorbed while by oral route, distribution, viz lipid solubility, ionisation, bioavailability may be low due to incomplete blood flow and binding to plasma proteins absorption and first pass metabolism. For and cellular proteins. Unionised lipid soluble example bioavailability of chlortetracycline drugs are widely distributed throughout the is 30%, carbamazepine 70%, chloroquine body. 80%, minocycline and diazepam 100%. Transdermal preparations are absorbed Plasma Protein Binding systemically and may have 80-100% On reaching the circulation most drugs bind bioavailability. Infact all the ten factors which to plasma proteins; acidic drugs bind mainly influence the absorption of a drug also alter albumin and basic drugs to alpha-acid Pharmacokinetics 15

Table 3.1: Some highly protein bound drugs Tissue binding Some drugs get bound to certain tissue constituents because of special Warfarin Tolbutamide Phenytoin affinity for them. Tissue binding delays Frusemide Clofibrate Sulfonamides elimination and thus prolongs the duration Diazepam Salicylates Phenylbutazone of action of the drug. For example, lipid Indomethacin soluble drugs are bound to adipose tissue. Tissue binding also serves as a reservoir of glycoprotein. The free or unbound fraction the drug. of the drug is the only form available for action, metabolism and excretion while the Tissue Binding drugs protein bound form serves as a reservoir. The Adipose tissue Thiopentone sodium, extent of protein binding varies with each benzodiazepines drug, e.g. warfarin is 99% and morphine is Muscles Emetine 35% protein bound while binding of Bone Tetracyclines, Lead ethosuximide and lithium is 0%, i.e. they are Retina Chloroquine Thyroid Iodine totally free (Table 3.1). Redistribution When some highly lipid soluble Clinical Significance of Plasma Protein Binding drugs are given intravenously or by 1. Only free fraction is available for action, inhalation, they get rapidly distributed into metabolism and excretion. When the free highly perfused tissues like brain, heart and drug levels in the plasma fall, bound drug kidney. But soon they get redistributed into is released. less vascular tissues like the muscle and fat 2. Protein binding serves as a store resulting in termination of the action of these (reservoir) of the drug and the drug is drugs. The best example is the intravenous released when free drug levels fall. anaesthetic thiopental sodium which induces 3. Protein binding prolongs the duration of anaesthesia in 10-20 seconds but the effect action of the drug. ceases in 5-15 minutes due to redistribution. 4. Many drugs may compete for the same binding sites. Thus one drug may Blood-brain barrier (BBB) The endothelial cells displace another from the binding sites of the brain capillaries lack intercellular pores and result in displacement interactions, and instead have tight junctions. Moreover, e.g. warfarin is 99% protein bound (i.e. glial cells envelop the capillaries and together free fraction is 1%). If another drug like these form the BBB. Only lipid soluble, indomethacin reduces its binding to 95%, unionised drugs can cross this BBB. During the free form then becomes 5% which inflammation of the meninges, the barrier means, there is a 5-fold increase in free becomes more permeable to drugs, e.g. warfarin levels which could result in penicillin readily penetrates during toxicity. Fortunately the body largely meningitis. The barrier is weak at some areas compensates by enhancing metabolism like the CTZ, posterior pituitary and parts and excretion. of hypothalamus and allows some 5. Chronic renal failure and chronic liver compounds to diffuse. disease result in hypoalbuminaemia with reduced protein binding of drugs. Highly Placental barrier Lipid soluble, unionised drugs protein bound drugs should be carefully readily cross the placenta while lipid used in such patients. insoluble drugs cross to a much lesser extent. 16 Textbook of Pharmacology for Dental and Allied Health Sciences

Thus drugs taken by the mother can cause •Vd may vary with changes in tissue several unwanted effects in the foetus permeability and protein binding as seen (Table 3.5) in some diseases. • Drugs extensively bound to plasma proteins Volume of Distribution (V ) d have a low Vd - e.g. phenylbutazone. For the purpose of pharmacokinetic studies, BIOTRANSFORMATION (METABOLISM) body can be considered as a single compartment into which drugs are Biotransformation is the process of distributed uniformly. Each drug actually biochemical alteration of the drug in the follows its own pattern of distribution from body. Body treats most drugs as foreign plasma to other body fluids and tissues. substances and tries to inactivate and Apparent volume of distribution is defined as eliminate them by various biochemical the volume necessary to accommodate the reactions. These processes convert the drugs entire amount of the drug administered, if into more polar, water-soluble compounds the concentration throughout the body were so that they are easily excreted through the equal to that in plasma. It relates the amount kidneys. Some drugs may be excreted largely of the drug in the body to the concentration unchanged in the urine, e.g. frusemide, of the drug in plasma. It is calculated as atenolol. Amount of drug in the body Site The most important organ of biotrans-

Vd = formation is the liver. But drugs are also Plasma concentration metabolised by the kidney, gut, mucosa, For example, if the dose of a drug given is lungs, blood and skin. 500 mg and it attains a uniform concentration Consequences of biotransformation Though of 10 mg/litre of the plasma, its Vd = 50 litres. biotransformation generally inactivates the Important facts about Vd are: drug, some drugs may be converted to • If a drug is retained mostly in the plasma, metabolites which are also active or more its Vd is small (e.g. aspirin, amino- active than the parent drug. Bio- glycosides) while if it is distributed transformation may also activate an inactive widely in other tissues then its V is large d drug (Table 3.2). When the metabolite is (e.g. pethidine) active, the duration of action gets prolonged • The knowledge of V of drugs is clinically d (Table 3.3). Prodrug is an inactive drug which important in the treatment of poisoning. gets converted into an active form in the Drugs with large V like pethidine are not d body. In case of some drugs, the active easily removed by haemodialysis because metabolite may be toxic. For example: such drugs are widely distributed in the paracetamol is converted to n-acetyl-p-benzo- body. Table 3.2: Consequences of biotransformation Active drug to Active drug to active Inactive drug to active inactive metabolite metabolite (prodrug) metabolite e.g. Morphine e.g. Primidone Phenobarbitone e.g. Levodopa Dopamine Chloramphenicol Digitoxin Digoxin Prednisone Prednisolone Diazepam Oxazepam Enalapril Enalaprilat Pharmacokinetics 17

Table 3.3: Biotransformation

quinoneimine which causes hepatotoxicity; Phase I reactions convert the drug to a more cyclophosphamide is converted to acrolein polar metabolite by oxidation, reduction or which causes bladder toxicity. hydrolysis. Oxidation reactions are the most Enzymes in biotransformation The biotrans- important metabolising reactions, mostly formation reactions are catalysed by specific catalysed by mono-oxygenases present in the enzymes located either in the liver liver (Table 3.4). If the metabolite is not microsomes (microsomal enzymes) or in the sufficiently polar to be excreted, it undergoes cytoplasm and mitochondria of the liver cells phase II reactions. and also in the plasma and other tissues (non- Phase II reactions In phase II reactions, microsomal enzymes). endogenous water-soluble substances like The chemical reactions of biotransfor- glucuronic acid, sulfuric acid, glutathione or mation can take place in two phases (Fig. 3.5). an amino acid combine with the drug or its 1. Phase I (Non-synthetic reactions) phase I metabolite to form a highly polar 2. Phase II (Synthetic reactions). conjugate which is inactive and gets readily excreted by the kidneys. Large molecules are excreted through the bile. Conjugation results invariably in inactivation of the drug. Some products of conjugation are glucuronides, ethereal sulfates and amino acid conjugates. Glucuronide conjugation is the most common type of metabolic reaction. Endogenous substances like bilirubin and steroid hormones also undergo conjugation. Drugs like sulfonamides and isoniazid undergo conjugation with acetylcoenzyme A (acetylation) while some like adrenaline undergo methylation. Glu- tathione conjugation inactivates highly Fig. 3.5: Phases in metabolism of drugs. A drug may be reactive intermediates formed during the excreted as phase I metabolite or as phase II metabolite. Some drugs may be excreted as such metabolism of drugs like paracetamol. 18 Textbook of Pharmacology for Dental and Allied Health Sciences

Table 3.4: Important drug biotransformation reactions Reactions Examples of drugs Oxidation Phenytoin, Diazepam, Ibuprofen, Amphetamine, Chlorpromazine, Dapsone Reduction Chloramphenicol, Halothane Hydrolysis Pethidine, Procaine Conjugation reactions Glucuronide conjugation Chloramphenicol, Morphine Acetylation Sulfonamides, Isoniazid Methylation Adrenaline, Histamine Glutathione conjugation Paracetamol

ENZYME INDUCTION toxic intermediate metabolite of paracetamol is formed due to enzyme Microsomal enzymes are located in the induction. microsomes that line the smooth endoplasmic 2. Tolerance to drugs may develop as in case of reticulum of the liver cells. The synthesis of carbamazepine since it induces its own these enzymes, mainly cytochrome P450 can metabolism called autoinduction. be enhanced by certain drugs and enviro- 3. Result in disease—antiepileptics enhance the nmental pollutants. This is called enzyme breakdown of vitamin D resulting in induction and this process speeds up the osteomalacia on long-term adminis- biotransformation of the inducing drug itself tration. and other drugs metabolised by the 4. Variable response In chronic smokers and microsomal enzymes, e.g. phenobarbitone, alcoholics, enzyme induction may result rifampicin, alcohol, cigarette smoke, DDT, in failure to achieve the expected response griseofulvin, carbamazepine and phenytoin to some drugs metabolised by the same are some enzyme inducers. enzymes. Clinical relevance of microsomal enzyme 5. Therapeutic application of enzyme induction induction: Neonates are deficient in both microsomal 1. Drug interactions and non-microsomal enzymes. Hence their a. Therapeutic failure - By speeding up capacity to conjugate bilirubin is low which metabolism, enzyme induction may results in jaundice. Administration of reduce the duration of action of some phenobarbitone - an enzyme inducer, other drugs which can result in helps in rapid clearance of the jaundice in therapeutic failure, e.g. failure of oral them by enhancing bilirubin conjugation. contraceptives in patients taking rifam- Enzyme inhibition Some drugs inhibit picin. b. Toxicity - Enzyme induction may result cytochrome P450 enzyme activity. Drugs like in toxicity due to production of higher cimetidine and ketoconazole bind to amounts of the toxic intermediate cytochrome P450 and thus competitively metabolites, e.g. a patient undergoing inhibit the metabolism of endogenous treatment with rifampicin is likely to substances like testosterone and other drugs develop hepatotoxicity with paraceta- given concurrently. Enzyme inhibition by mol because a higher amount of the drugs is the basis of several drug interactions. Pharmacokinetics 19

Chloramphenicol, erythromycin, ketoco- penicillin, salicylic acid, probenecid, nazole, cimetidine, ciprofloxacin and frusemide and bases like amphetamine and verapamil are some enzyme inhibitors. histamine are so excreted. Drugs may compete for the same transport system Factors that Influence Biotransformation resulting in prolongation of action of each other, e.g. penicillin and probenecid. Genetic variation results in altered metabolism of drugs, e.g. succinylcholine is metabolised Passive tubular reabsorption Passive diffusion very slowly in people with defective of drug molecules can occur in either pseudocholinesterase resulting in prolonged direction in the renal tubules depending on apnoea. the drug concentration, lipid solubility and Environmental pollutants like cigarette smoke pH. As highly lipid soluble drugs are largely cause enzyme induction. reabsorbed, their excretion is slow. Acidic drugs get ionised in alkaline urine and are Age At extremes of age, the activity of easily excreted while bases are excreted metabolic enzymes in the liver is low and faster in acidic urine. This property is useful hence there is increased risk of toxicity with in the treatment of poisoning. In poisoning drugs. with acidic drugs like salicylates and Diseases of the liver markedly affect barbiturates, forced alkaline diuresis metabolism of drugs. (Diuretic + sodium bicarbonate + IV fluids) Drugs are excreted from the body after is employed to hasten drug excretion. being converted to water-soluble metabolites Similarly, elimination of basic drugs like while some are directly eliminated without quinine and amphetamine is enhanced by metabolism. The major organs of excretion forced acid diuresis. are the kidneys, the intestine, the biliary system and the lungs. Drugs are also Faecal and Biliary Excretion excreted in small amounts in the saliva, sweat and milk. Unabsorbed portion of the orally administered drugs are eliminated through the EXCRETION faeces. Liver transfers acids, bases and unionised molecules into bile by specific acid Renal Excretion transport processes. Large water-soluble Kidney is the most important organ of drug conjugates are excreted in the bile. Some excretion. The three processes involved in drugs may get reabsorbed in the lower the elimination of drugs through kidneys are portion of the gut and are carried back to glomerular filtration, active tubular secretion the liver. Such recycling is called enterohepatic and passive tubular reabsorption. circulation and it prolongs the duration of Glomerular filtration The rate of filtration action of the drug; examples are chloram- through the glomerulus depends on GFR, phenicol, tetracycline, oral contraceptives and concentration of free drug in the plasma and erythromycin. its molecular weight. Ionised drugs of low Pulmonary Excretion molecular weight (< 10,000) are easily filtered through the glomerular membrane. The lungs are the main route of elimination Active tubular secretion Cells of the proximal for gases and volatile liquids viz. general tubules actively secrete acids and bases by anaesthetics and alcohol. This also has legal two transport systems. Thus acids like implications in medicolegal practice. 20 Textbook of Pharmacology for Dental and Allied Health Sciences

Other Routes of Excretion Table 3.5: Example of drugs that could be toxic to the suckling infant when taken by the mother Small amounts of some drugs are eliminated through the sweat and saliva. Excretion in Sulphasalazine Doxepin Theophylline Amiodarone saliva may result in a unique taste with some Anticancer drugs Primidone drugs like phenytoin, clarithromycin; Salicylates Ethosuximide metallic taste with metronidazole, Chloramphenicol Phenobarbitone metoclopramide and disulfiram. Drugs like Nalidixic acid Phenothiazines iodide, rifampicin and heavy metals are Nitrofurantoin β-blockers excreted through sweat. 1. First-order kinetics In first order kinetics, a The excretion of drugs in the milk is in constant fraction of the drug is small amounts and is of no significance to metabolised/eliminated per unit the mother. But, for the suckling infant, it time. Most drugs follow first order may be sometimes important especially kinetics and the rate of metabolism/ because of the infant’s immature metabolic excretion is dependent on their and excretory mechanisms. Though most concentration (exponential) in the body drugs can be taken by the mother without (Fig. 3.6). It also holds good for significant toxicity to the child, there are a absorption of drugs. few exceptions (Table 3.5). 2. Zero order kinetics (Saturation kinetics) Here amount CLINICAL PHARMACOKINETICS a constant of the drug present in the body is metabolised/eliminated per unit The knowledge of pharmacokinetics is time. The metabolic enzymes get saturated clinically useful for several purposes and hence with increase in dose, the plasma including selection and adjustment of the drug level increases disproportionately dosage regimen, and to obtain optimum resulting in toxicity. effects from a drug. The three most Some drugs like phenytoin and warfarin important pharmacokinetic parameters are are eliminated by both processes, i.e. by first bioavailability (page 14), volume of order initially and by zero order at higher distribution (page 16) and clearance. concentrations. Clearance (CL) is the volume of plasma freed Example of drugs that follow zero order completely of the drug in unit time. It can be kinetics: calculated by the ratio of the rate of • Alcohol elimination to the plasma concentration. • Phenytoin Rate of elimination • Aspirin Thus, CL = • Heparin Plasma concentration • Phenylbutazone. Clearance is expressed as ml/litre/unit time. Plasma Half-life and Steady Clearance is the most important factor State Concentration determining drug concentration and should Plasma half-life (t½) is the time taken for the be considered when any drug is intended for plasma concentration of a drug to be reduced long-term administration. to half it’s value (Fig. 3.7). Four to five half- Drugs are metabolised/eliminated from lives are required for the complete the body by: elimination of a drug. Each drug has its own Pharmacokinetics 21

Fig. 3.6: First order kinetics-As the plasma concentration rises, metabolism and excretion proportionately increase. Zero order kinetics-In higher doses, the drug accumulates and the plasma concentration rises resulting in toxicity t½ and is an important pharmacokinetic Biological effect half-life is the time required parameter that guides the dosing regimen. for the biological effect of the drug to reduce It helps in calculating loading and to half. With some drugs like propranolol maintenance doses of a drug. It also indicates the pharmacological effect of the drug may the duration of action of a drug. last much longer, i.e. even after its plasma Biological half-life is the time required for total levels fall. In such drugs, biological effect amount of the drug in the body to be reduced half life gives an idea of the duration of to half. action of the drug.

Fig. 3.7: Plasma half life 22 Textbook of Pharmacology for Dental and Allied Health Sciences

If a drug is administered repeatedly at the beginning of the treatment. A loading short intervals before complete elimination, dose is a single large dose or a series of the drug accumulates in the body and reaches quickly repeated doses given to rapidly a ‘state’ at which the rate of elimination equals attain target concentration, e.g. heparin given the rate of administration. This is known as as 5000 IU bolus dose. Once the target level the ‘Steady-state’ or plateau level (Fig. 3.8). After is reached, a maintenance dose is sufficient to attaining this level, the plasma concentration ‘maintain the drug level’ and to balance the fluctuates around an average steady level. It elimination. takes 4-5 half-lives for the plasma concentration The disadvantage with the loading dose to reach the plateau level. is that the patient is rapidly exposed to high concentrations of the drug which may result DRUG DOSAGE in toxicity. Depending on the patient’s requirements and Therapeutic drug monitoring The response to the characteristics of the drug, drug dosage a drug depends on the plasma concentration can be of the following kinds - attained in the patient. This in turn depends Fixed dose In case of reasonably safe drugs, a on the bioavailability, volume of fixed dose of the drug is suitable for most distribution and clearance. As these patients, e.g. analgesics like paracetamol—500 parameters vary among individuals, there mg to 1000 mg 6 hourly is the usual adult dose. is a wide variation in the plasma concentration attained from patient to Individualised dose For some drugs especially patient. Hence in some situations it may be the ones with low safety margin, the dose has necessary to monitor treatment by to be ‘tailored’ to the needs of each patient, measuring plasma drug concentrations. e.g. anticonvulsants, antiarrhythmic drugs. Such situations are: Loading dose In situations when target plasma 1. while using drugs with low safety concentrations have to be attained rapidly, a margin—to avoid therapeutic failure, e.g. loading/bolus dose of the drug is given at digoxin, theophylline, lithium.

Fig. 3.8: Drug accumulation and attainment of steady state concentration on oral administration Pharmacokinetics 23

2. to reduce the risk of toxicity, e.g. Methods of Prolonging Drug Action aminoglycosides. (Table 3.6) 3. when there are no reliable methods to In several situations it may be desirable to assess benefit, e.g. antidepressants. use long-acting drugs. But when such drugs 4. to treat poisoning. are not available, the duration of action of the 5. when there is unexplainable therapeutic available drugs may be prolonged. failure—to check patient compliance. The duration of action of drugs can be But, for drugs whose response can be prolonged by interfering with the easily measured, e.g. blood pressure for anti- pharmacokinetic processes, i.e. by hypertensives and for ‘hit and run’ 1. slowing absorption. drugs whose effects persist for a long 2. using a more plasma protein bound time even after the drug is eliminated, derivative. monitoring of plasma drug concentration is 3. inhibiting metabolism. not required. 4. delaying excretion.

Table 3.6: Methods of prolonging duration of action of drugs

Processes Methods Examples Absorption Oral Sustained release preparation, Iron, deriphylline coating with resins, etc. Parenteral 1. Reducing solubility Procaine + Penicillin — Oily suspension Depot progestins 2. Altering particle size-given as Insulin zinc suspension large crystals that are slowly absorbed 3. Pellet implantation DOCA — Sialistic capsules Testosterone 4. Reduction in vascularity Adrenaline + lignocaine of the absorbing surface (vasoconstrictor) 5. Combining with protein Protamine + zinc + insulin 6. Chemical alteration — Esterification Oestrogen Testosterone Dermal Transdermal adhesive patches, Scopolamine Ointments Nitroglycerin Ocuserts (Transmucosal) —used in eye Pilocarpine Distribution Choosing more protein bound Sulfonamides-like member of the group sulfamethoxypyridazine Metabolism Inhibiting the metabolising Physostigmine prolongs enzyme cholinesterase the action of acetylcholine By inhibiting enzyme peptidase Cilastatin—prolongs the in renal tubular cells action of imipenem Excretion Competition for same transport system Probenecid prolongs the — for renal tubular secretion action of penicillin and ampicillin 24 Textbook of Pharmacology for Dental and Allied Health Sciences

4 Pharmacodynamics

Pharmacodynamics is the study of actions of or nutrients, e.g. insulin in diabetes mellitus, the drugs on the body and their mechanisms iron in anaemia, vitamin C in scurvy. of action, i.e. to know what drugs do and Anti-infective and cytotoxic action: Drugs may how they do it. act by specifically destroying infective Drugs produce their effects by interacting organisms, e.g. penicillins, or by cytotoxic with the physiological systems of the effect on cancer cells, e.g. anticancer drugs. organisms. By such interaction, drugs merely Modification of immune status: Vaccines and modify the rate of functions of the various sera act by improving our immunity while systems. But they cannot bring about immunosuppressants act by depressing qualitative changes, i.e. they cannot change immunity, e.g. glucocorticoids. the basic functions of any physiological MECHANISMS OF DRUG ACTION system. Thus drugs act by: 1. Stimulation Most drugs produce their effects by binding to 2. Depression specific target proteins like receptors, enzymes 3. Irritation and ion channels. Drugs may act on the cell 4. Replacement membrane, inside or outside the cell to produce 5. Anti-infective or cytotoxic action their effect. Drugs may act by one or more 6. Modification of the immune status. complex mechanisms of action. Some of them Stimulation is the increase in activity of the are yet to be understood. But the fundamental specialised cells, e.g. adrenaline stimulates the mechanisms of drug action may be: heart. • through receptors • through enzymes and pumps Depression is the decrease in activity of the • through ion channels specialised cells, e.g. quinidine depresses the • by physical action heart; barbiturates depress the central • by chemical interaction nervous system. Some drugs may stimulate • by altering metabolic processes. one system and depress another, e.g. morphine depresses the CNS but stimulates Through Receptors the vagus. Irritation: This can occur on all types of tissues Drugs may act by interacting with specific in the body and may result in inflammation, receptors in the body (see below). corrosion and necrosis of cells. Through Enzymes and Pumps Replacement: Drugs may be used for replacement when there is deficiency of Drugs may act by inhibition of various natural substances like hormones, metabolites enzymes, thus altering the enzyme-mediated Pharmacodynamics 25 reactions, e.g. allopurinol inhibits the enzyme Chelating agents – bind heavy metals xanthine oxidase; acetazolamide inhibits making them carbonic anhydrase, enalapril inhibits nontoxic. angiotensin converting enzyme, aspirin inhibits cyclo-oxygenase, neostigmine inhibits Altering Metabolic Processes acetylcholinesterase. Drugs like antimicrobials alter the metabolic + + Membrane pumps like H K ATPase and pathway in the microorganisms resulting in Na+ K+ ATPase may be inhibited by drugs destruction of the microorganism, e.g. like omeprazole and digoxin respectively. sulfonamides interfere with bacterial folic acid synthesis. Through Ion Channels RECEPTOR Drugs may interfere with the movement of ions across specific channels, e.g. calcium The works of Langley and Ehrlich put forth channel blockers, sodium channel blockers, the concept of a ‘receptor substance.’ In the potassium channel openers and GABA gated late 19th century, Langley noted that curare chloride channel modulators. could oppose contraction of skeletal muscles caused by nicotine but did not block Physical Action contraction due to electrical stimulation. Paul Ehrlich observed that some organic chemicals The action of a drug could result from its had antiparasitic activity while others with physical properties like: slightly different structures did not have such Adsorption – Activated charcoal activity. Clark put forward a theory to in poisoning explain the drug action based on the drug- Mass of the drug – Bulk laxatives like receptor occupation. psyllium, bran Last three decades have seen an explosion Osmotic property – Osmotic diuretics - in our knowledge of the receptors. Various Mannitol receptors have been identified, isolated and – Osmotic extensively studied. purgatives- Definition A receptor is a macromolecular site Magnesium on the cell with which an agonist binds to sulphate bring about a change. Radioactivity – 131I Affinity is the ability of a drug to bind to a Radio-opacity – Barium sulphate receptor. contrast media. Intrinsic activity or efficacy is the ability of a drug to elicit a response after binding to the Chemical Interaction receptor. Agonist An agonist is a substance that binds to Drugs may act by chemical reaction. the receptor and produces a response. It has Antacids – neutralise gastric affinity and intrinsic activity. E.g. adrenaline is acids an agonist at adrenergic receptors. Oxidising agents – like potassium Antagonist An antagonist is a substance that permanganate is binds to the receptor and prevents the action germicidal of the agonist on the receptor. It has affinity 26 Textbook of Pharmacology for Dental and Allied Health Sciences but no intrinsic activity. E.g. Tubocurarine is i. A ligand binding domain—the site to bind an antagonist at nicotinic receptors. the drug molecule. Partial agonist binds to the receptor but has ii. An effector domain—which undergoes a low intrinsic activity. Pentazocine is a partial change to propagate the message. agonist at μ opioid receptors. Several theories have been proposed to Inverse agonist Some drugs, after binding to explain drug receptor interaction. Drug- the receptors produce actions opposite to receptor interaction has been considered to those produced by a pure agonist. They are be similar to ‘lock and key’ relationship where known as inverse agonists, e.g. Diazepam the drug specifically fits into the particular acting on benzodiazepine receptors produces receptor (lock) like a key. The rate theory sedation, anxiolysis, muscle relaxation and proposes that the magnitude of response controls convulsions, while inverse agonists depends on the rate of agonist–receptor β-carbolines bind to the same receptors to association and dissociation. The rate of cause arousal, anxiety, increased muscle tone receptors binding is more initially but after and convulsions. it reaches the peak there is a decrease. Ligand is a molecule which binds selectively to a specific receptor. The occupation theory suggests that the Spare receptors Some experiments showed that magnitude of drug response depends on the high concentration of an agonist can still proportion of the receptors occupied by the produce maximal response in presence of an drug. Interaction of the agonist with the irreversible antagonist and this was because receptor brings about changes in the receptor of the presence of ‘spare’ or reserve receptors. which in turn conveys the signal to the Thus it is possible to stimulate the effector system. The final response is brought myocardium even when 90% of the cardiac β about by the effector system through second adrenergic receptors are blocked by an messengers. The agonist itself is the first irreversible β blocker. messenger. The entire process involves a Silent receptors are receptors to which an chain of events triggered by drug receptor agonist binds but does not produce a interaction. response. Presence of such silent receptors may explain the phenomenon of tolerance. Receptor Families Site The receptors may be present in the cell On stimulation of a receptor, the time membrane, in the cytoplasm or on the required to elicit the response varies largely nucleus. from a fraction of a second in some receptors Nature of receptors Receptors are proteins. to hours and days in others. This difference Synthesis and lifespan Receptor proteins are is because of the variation in mechanisms synthesized by the cells. They have a definite involved in linking the receptor and the lifespan after which the receptors are effector systems (transduction mechanisms). degraded by the cell and new receptors are synthesized. Based on this, four types or super families of Functions of receptors The two functions of receptors are identified. They are best receptors are - understood with the help of Figure 4.1. The • Recognition and binding of the ligand. receptor types are: • Propagation of the message. 1. Ion channels (inotropic receptor) For the above functions, the receptor has 2. G-protein coupled receptors (metabo- two functional domains (areas): tropic receptor) Pharmacodynamics 27

Fig. 4.1: (1) Binding of the agonist directly regulates the opening of the ion channel. (2) Agonist binding activates the receptor that is linked to an effector system by a G protein. (3) Agonist binding to extracellular domain activates enzymatic activity of its catalytic domain. (4) Agonist binds to the intracellular receptor, the complex moves to the nucleus and directs protein synthesis

3. Enzymatic receptors (kinase linked plasma membrane. The G-proteins consist of receptor) three subunits viz., α, β and γ. When a ligand 4. Transcription factors (receptors that binds to the G-protein coupled receptor, the regulate gene transcription or nuclear associated G-protein gets activated. These G- receptors). proteins acting through second messengers, Receptor families and their transduction bring about a chain of intracellular changes. mechanisms: These second messenger systems are called 1. Ion channels or receptor channels are effector pathways. Thus G-proteins act as proteins present on the cell surface. Binding links or mediators between the receptors and of the agonist opens the channel allowing ions the effector systems. They are called G- to cross the membrane. These are called proteins because of their interaction with the ligand-gated ion channels. Depending on the guanine nucleotides, GTP and GDP. G- ion and the channel, depolarisation/ proteins are of different classes like Gs Gi, Go hyperpolarisation occurs, e.g. nicotinic and Gq—GS is stimulatory and Gi is inhibitory. cholinergic receptor channel permits passage The second messengers include cyclic AMP + of Na ions resulting in depolarisation. (cAMP), inosital triphosphate (IP3), diacylgly- 2. G-protein coupled receptors are proteins cerol (DAG), calcium and cyclic GMP (cGMP). spanning the plasma membrane. The G- Adrenergic receptors and muscarinic proteins are bound to the inner face of the cholinergic receptors are examples of 28 Textbook of Pharmacology for Dental and Allied Health Sciences

G-protein coupled receptors. c. Ion channel regulation The activated G- Effector pathways through which the proteins can directly (without the help of G-protein coupled receptors work are: second messengers) convey the signal to a. Adenylylcyclase/cAMP pathway some ion channels causing opening or closing of the channels. The resulting b. Phospholipase C/IP3-DAG pathway c. Ion channel regulation. responses include depolarisation/hyper- a. Adenylylcyclase pathway (Fig. 4.2) Stimu- polarisation. lation of adenylylcyclase results in the 3. Enzymatic Receptors formation and accumulation of cAMP These are transmembrane proteins with an within the cell. This cAMP acts through extracellular domain (site) for ligand binding protein kinases which phosphorylate and intracellular domain to carry out the various proteins to regulate the cell catalytic activity and the two domains are function. The response may be linked by a single peptide chain. They are contraction, relaxation, lipolysis or protein kinases and hence are also known as hormone synthesis. kinase linked receptors. Binding of the agonist to the ligand binding domain results b. Phospholipase C/IP3-DAG pathway (Fig. 4.3) Activation of phospholipase C results in in autophosphorylation of the intracellular domain. This in turn triggers phosphorylation the formation of second messengers IP3 and DAG from the membrane phos- of various intracellular proteins resulting in pholipids phosphoinositol pyrophosphate the characteristic responses, Examples- receptors of insulin, leptin and growth factors (PIP2). IP3 mobilises calcium from intracellular depots and this calcium including epidermal growth factors and mediates responses like secretion, platelet derived growth factors. contraction, metabolism and hyperpolari- 4. Receptors that Regulate Gene Transcription sation. DAG activates protein kinase These receptors are also called C which regulates cell function. transcription factors or nuclear receptors. They are intracellular proteins which are in an inactive state. Binding of the agonist activates the receptor. The agonist-receptor complex moves to the nucleus where it interacts with DNA, regulates gene transcription and thereby directs the synthesis of specific proteins to regulate the activity of target cells. Examples are receptors for steroidal hormones, thyroid hormones, vitamin D and retinoids.

Receptor Regulation The number of receptors (density) and their sensitivity can be altered in many situations.

Fig. 4.2: G-protein coupled receptor - transduction through Denervation or prolonged deprivation of the adenylylcyclase pathway with cAMP as second agonist or constant action of the antagonist messenger. R = Receptor, Gs = G Protein (Stimulatory) all result in an increase in the number and Pharmacodynamics 29

Fig 4.3: G-protein coupled receptor acting through the second messengers IP3 and DAG sensitivity of the receptors. This phenomenon dose till the maximum response is reached. is called ‘up regulation’. The dose response curve has the shape of a Prolonged use of a β adrenergic antagonist rectangular hyperbola (Fig. 4.4). After the like propranolol results in up regulation of β maximum effect has been obtained, further adrenergic receptors. increase in doses does not increase the On the other hand, continued stimulation response. If the dose is plotted on a of the receptors causes desensitisation and a logarithmic scale, the curve becomes sigmoid decrease in the number of receptors—known (Fig. 4.5). The slope of DRC (Fig. 4.6) has as ‘down regulation’ of the receptors. clinical significance. A steep slope indicates Clinical consequences and implications of receptor that a small increase in dose produces a large regulation After prolonged administration, a increase in response, e.g. loop diuretics. Such receptor antagonist should always be tapered. drugs are more likely to cause toxicity and For example, if propranolol, a β adrenoceptor blocker is suddenly withdrawn after long- term use, it precipitates angina. Constant use of β adrenergic agonists in bronchial asthma results in reduced therapeutic response due to down regulation β of 2 receptors.

Dose Response Relationship The clinical response to the increasing dose of the drug is defined by the shape of the dose response curve (DRC). Initially the extent of response increases with increase in Fig. 4.4: Dose response curve 30 Textbook of Pharmacology for Dental and Allied Health Sciences

Fig. 4.5: Log dose response curve Fig. 4.7: Dose response curves of four drugs showing different potencies and maximal efficacies. Drug A is more therefore, individualisation of dose is potent but less efficacious than B and C. Drug D is less required. A relatively flat DRC indicates that potent and less efficacious than drugs B and C with an increase in dose, there is little increase in the response, e.g. thiazide than drugs C and D, drug A being the most diuretics. For such drugs standard doses can potent and drug D—the least potent. Hence be given to most patients. higher doses of drugs C and D are to be administered as compared to drugs A and Drug Potency and Maximal Efficacy B. Generally potency is of little clinical significance unless very large doses of the The amount of drug required to produce a drug needs to be given due to low potency. response indicates the potency. For example, Maximal efficacy Efficacy indicates the 1 mg of bumetanide produces the same maximum response that can be produced by diuresis as 50 mg of frusemide. Thus a drug, e.g. frusemide produces powerful bumetanide is more potent than frusemide. diuresis, not produced by any dose of In Figure 4.7, drugs A and B are more potent amiloride. In Figure 4.7, drugs B and C are more efficacious than drugs A and D. Drug A is more potent but less efficacious than drugs B and C. Such differences in efficacy are of great clinical importance.

Therapeutic Index The dose response curves for different actions of a drug could be different. Thus salbutamol may have one DRC for bronchodilation and another for tachycardia. The distance between beneficial effect DRC and unwanted effect DRC indicates the safety margin of the drug (Fig. 4.8).

Median lethal dose (LD50) is the dose which is Fig.4.6: Steep and flat dose response curves lethal to 50% of the population. Pharmacodynamics 31

Drug Synergism and Antagonism When two or more drugs are given concurrently, the effect may be additive, synergistic or antagonistic. Additive effect The effect of two or more drugs gets added up and the total effect is equal to the sum of their individual actions. Examples are ephedrine with theophylline in bronchial asthma; nitrous oxide and ether as general anaesthetics. Synergism When the action of one drug is enhanced or facilitated by another drug, the Fig. 4.8: The distance between curves A and B indicates combination is synergistic. In Greek, ergon = safety margin of the drug. The greater the distance, more work; syn = with. Here, the total effect of selective is the drug. the combination is greater than the sum of their independent effects. It is often called Median effective dose (ED ) is the dose that 50 ‘potentiation’ or ‘supra-additive’ effect. produces a desired effect in 50% of the test Examples of synergistic combination are — population. • acetylcholine + physostigmine Therapeutic index (TI) is the ratio of the median • levodopa + carbidopa. lethal dose to the median effective dose. Antagonism One drug opposing or inhibiting LD Therapeutic index = ______50 the action of another is antagonism. Based ED 50 on the mechanism, antagonism can be Therapeutic index gives an idea about the • Chemical antagonism safety of the drug. • Physiological antagonism • The higher the TI, the safer is the drug • Antagonism at the receptor level • TI varies from species to species – Reversible (Competitive) • For a drug to be considered reasonably – Irreversible safe, its TI must be > 1 • Non-competitive antagonism. • Penicillin has a high TI while lithium and Chemical antagonism Two substances interact digoxin have low TI. chemically to result in inactivation of the • TI may be different for each action of a drug. effect, e.g. chelating agents inactivate heavy For example TI of aspirin used for headache metals like lead and mercury to form inactive is different from its TI for inflammation. complexes; antacids like aluminium hydroxide Therapeutic window is the plasma concentration neutralize gastric acid. range below which the drug is ineffective and Physiological antagonism Two drugs act at above which toxicity appears. Hence it is different sites to produce opposing effects. For example, histamine acts on H desirable to have the plasma concentration 1 receptors of drugs within this therapeutic range. Some to produce bronchospasm and hypotension drugs like those with a low therapeutic index while adrenaline reverses these effects by have a narrow therapeutic window. e.g. acting on adrenergic receptors. Clonidine 0.2-2.ng/ml. Doses of such drugs Insulin and glucagon have opposite effects should be carefully titrated. on the blood sugar level. 32 Textbook of Pharmacology for Dental and Allied Health Sciences

Antagonism at the receptor level The antagonist inhibits the binding of the agonist to the receptor. Such antagonism may be reversible or irreversible. Reversible or competitive antagonism The agonist and antagonist compete for the same receptor. By increasing the concentration of the agonist, the antagonism can be overcome. It is thus reversible antagonism. Acetylcholine and atropine compete at muscarinic receptors. The antagonism can be overcome by increasing the concentration of acetylcholine at the receptor. d-tubocurarine and Fig. 4.10: Dose response curves of an agonist: A in the acetylcholine compete for the nicotinic absence of antagonist. B, C, and D in the presence of receptors at the neuromuscular junction. The increasing doses of an irreversible antagonist. dose response curve shifts to the right (Fig. 4.9) in presence of competitive There is progressive flattening of the dose antagonists. response curve (Fig. 4.10). Irreversible antagonism The antagonist binds so Noncompetitive antagonism The antagonist firmly by covalent bonds to the receptor that blocks at the level of receptor-effector it dissociates very slowly or not at all. Thus linkage, i.e. at a different site, beyond the it blocks the action of the agonist and the receptor and not on the receptor. There is blockade cannot be overcome by increasing flattening as well as some rightward shift of the dose of the agonist and hence it is the dose response curve (Fig. 4.11). For irreversible antagonism, e.g. adrenaline and example verapamil blocks the cardiac calcium phenoxybenzamine at alpha adrenergic channels and inhibits the entry of Ca++ during receptors. This antagonism is also called non- depolarisation. It thereby antagonises the equilibrium type of antagonism. effect of cardiac stimulants like isoprenaline and adrenaline.

Fig. 4.9: Dose response curves of an agonist: A in the absence of competitive antagonist; B, C and D in the Fig. 4.11: Non-competitive antagonism— there is presence of increasing doses of a competitive antagonist flattening as well as right ward shift of DRC Pharmacodynamics 33

FACTORS THAT MODIFY THE EFFECTS effects. Hence lower doses are recom- OF DRUGS mended, e.g. elderly are at a higher risk of ototoxicity and nephrotoxicity by The same dose of a drug can produce different streptomycin. degrees of response in different patients and 3. Sex The hormonal effects and smaller body even in the same patient under different size may influence drug response in situations. Various factors modify the women. Special care is necessary while response to a drug. They are: prescribing for pregnant and lactating 1. Body weight The recommended dose is women and during menstruation. calculated for medium built persons. For 4. Species and race Response to drugs may the obese and underweight persons, the vary with species and race. For example, dose has to be calculated individually. rabbits are resistant to atropine. Such Though body surface area is a better variation makes it difficult to extrapolate parameter for more accurate calculation the results of animal experiments. Blacks of the dose, it is inconvenient and hence need higher doses of atropine to produce not generally used. mydriasis. Formula 5. Diet and environment Food interferes with Body weight (kg) the absorption of many drugs. For ______Dose= × average adult dose example, tetracyclines form complexes 70 with calcium present in the food and are 2. Age The pharmacokinetics of many drugs poorly absorbed. change with age resulting in altered Polycyclic hydrocarbons present in the response in extremes of age. In the cigarette smoke may induce microsomal newborn, the liver and kidneys are not enzymes resulting in enhanced fully mature to handle the drugs, e.g. metabolism of some drugs. chloramphenicol can produce grey baby 6. Route of administration Occasionally route syndrome. The blood-brain barrier is not of administration may modify the well-formed and drugs can easily reach pharmacodynamic response, e.g. the brain. The gastric acidity is low, magnesium sulfate given orally is a intestinal motility is slow, skin is delicate purgative. But given IV it causes CNS and permeable to drugs applied topically. depression and has anticonvulsant effects. Hence calculation of the appropriate dose Applied topically (poultice), it reduces based on the body weight is important to local edema. Hypertonic magnesium avoid toxicity. Also pharmacodynamic sulfate retention enema reduces differences could exist, e.g. barbiturates intracranial tension. which produce sedation in adults may 7. Genetic factors Variations in an individual’s produce excitation in children. response to drugs could be genetically Formula for calculation of dose for children mediated. Pharmacogenetics is concerned Young’s formula with the genetically mediated variations Age (years) in drug responses. The differences in Child’s dose= ______× Adult dose response is most commonly due to Age + 12 variations in the amount of drug In the elderly, the capacity of the liver and metabolising enzymes since the kidney to handle the drug is reduced and production of these enzymes is genetically they are more susceptible to adverse controlled. 34 Textbook of Pharmacology for Dental and Allied Health Sciences

Examples enhances muscle power in therapeutic doses, but in high doses it causes muscle a. Acetylation of drugs The rate of drug paralysis, (ii) physiological doses of acetylation differs among individuals who vitamin D promotes calcification while may be fast or slow acetylators, e.g. INH, hypervitaminosis D leads to decalcifi- sulfonamides and hydralazine are cation. acetylated. Slow acetylators treated with 9. Diseases Presence of certain diseases can hydralazine are more likely to develop influence drug responses, e.g. lupus erythematosus. • Malabsorption Drugs are poorly b. Atypical pseudocholinesterase Succinylcholine absorbed. is metabolised by the enzyme pseudo- • Liver diseases Rate of drug metabolism cholinesterase. Some people inherit an is reduced due to dysfunction of atypical pseudocholinesterase which hepatocytes. Also protein binding is cannot quickly metabolise succinylcholine. reduced due to low serum albumin. When succinylcholine is given to such • Cardiac diseases In CCF, there is edema people they develop a prolonged apnoea of the gut mucosa and decreased due to persistant action of succinyl- perfusion of liver and kidneys. These choline. may result in cumulation and toxicity G PD deficiency c. 6 Primaquine, sulphones and of drugs like propranolol and quinolones can cause hemolysis in such lignocaine. people. • Renal dysfunction Drugs mainly d. Malignant hyperthermia Halothane and excreted through kidneys are likely to succinylcholine can trigger malignant accumulate and cause toxicity, e.g. hyperthermia in some genetically Streptomycin, amphotericin B—doses predisposed individuals. (page 124) of such drugs need to be reduced. e. Hepatic porphyrias Some people lack an 10. Repeated dosing can result in enzyme required for haeme synthesis, and • cumulation this results in accumulation of porphyrin- • tolerance containing haeme precursors. Some drugs • tachyphylaxis. like barbiturates, griseofulvin and Cumulation Drugs like digoxin which are carbamazepine induce the enzyme slowly eliminated may cumulate resulting in required for porphyrin synthesis resulting toxicity. in accumulation of porphyrins. In both the Tolerance Tolerance is the requirement of above cases neurological, gastrointestinal higher doses of a drug to produce a given and behavioural abnormalities can occur response. Tolerance may be natural or due to excess porphyrins. acquired. 8. Dose It is fascinating that the response to • Natural tolerance The species/race shows a drug may be modified by the dose less sensitivity to the drug, e.g. rabbits show administered. Generally as the dose is tolerance to atropine; Black race are tolerant increased, the magnitude of the response to mydriatics. also increases proportionately till the • Acquired tolerance develops on repeated ‘maximum’ is reached. Further increases administration of a drug. The patient who in doses may with some drugs produce was initially responsive becomes tolerant, e.g. effects opposite to their lower-dose effect, barbiturates, opioids and nitrites produce e.g. (i) in myasthenia gravis, neostigmine tolerance. Pharmacodynamics 35

Tolerance may develop to some actions of renaline from the sympathetic nerve the drug and not to others, e.g. morphine— endings. Other mechanisms involved tolerance develops to analgesic and euphoric may be slow dissociation of the drug from effects of morphine but not to its constipating the receptor thereby blocking the receptor. and miotic effects. Barbiturates—tolerance Thus ephedrine given repeatedly in develops to sedative but not antiepileptic bronchial asthma may not give the desired effects of barbiturates. response. Mechanisms The mechanisms of development 11. Psychological factor-The doctor-patient of tolerance could be: relationship influences the response to a Pharmacokinetic Changes in absorption, drug often to a large extent by acting on distribution, metabolism and excretion of the patient’s psychology. The patients drugs may result in reduced concentration confidence in the doctor may itself be of the drug at the site of action and is also sufficient to relieve a suffering, particularly known as dispositional tolerance, e.g. the psychosomatic disorders. This can be barbiturates induce microsomal enzymes and substantiated by the fact that large number enhance their own metabolism. of patients respond to placebo. Placebo is Pharmacodynamic Changes in the target tissue, the inert dosage form with no specific may make it less responsive to the drug. It is biological activity but only resembles the actual preparation in appearance (dummy also called functional tolerance. It could be medication). Placebo means ‘I shall be due to down regulation of receptors as in pleasing’ (in Latin). opioids or due to compensatory mechanisms Placebo medicines are used in - of the body, e.g. blunting of response to some 1. clinical trials as a control to compare and antihypertensives due to salt and water assess whether the new compound is retention. significantly better than the placebo. Cross tolerance is the development of tolerance 2. to benefit or please a patient to pharmacologically related drugs, i.e. to psychologically when he does not drugs belonging to a particular group. Thus actually require an active drug as in chronic alcoholics also show tolerance to mild psychosomatic disorders and in barbiturates and general anaesthetics. chronic incurable diseases. Tachyphylaxis is the rapid development of In fact all forms of treatment including tolerance. When some drugs are administered physiotherapy and surgery have some repeatedly at short intervals, tolerance placebo effect. Substances used as placebo develops rapidly and is known as include lactose, some vitamins, minerals and tachyphylaxis or acute tolerance, e.g. distilled water injections. ephedrine, amphetamine, tyramine and 5- 12. Presence of other drugs The concurrent use hydroxytryptamine. This is thought to be due of two or more drugs can influence the to depletion of noradrenaline stores as the response of each other (see Drug above drugs act by displacing norad- Interactions Chapter No 5). 36 Textbook of Pharmacology for Dental and Allied Health Sciences

Adverse Drug Reactions, 5 Drug Interactions, Drug Nomenclature and Essential Drugs Concept

ADVERSE DRUG REACTIONS dysfunction after a single dose of streptomycin may be seen in some patients. All drugs can produce unwanted effects. Intolerance could also be qualitative, e.g. WHO has defined an adverse drug reaction idiosyncrasy and allergic reactions. as “any response to a drug that is noxious and unintended and that occurs at doses used Idiosyncrasy is a genetically determined in man for prophylaxis, diagnosis or abnormal reaction to a drug, e.g. primaquine therapy.” and sulfonamides induce haemolysis in All drugs can cause adverse effects. Some patients with G6PD deficiency; some patients patients are more likely to exhibit adverse show excitement with barbiturates. In effects to drugs. Pharmacovigilance deals with addition, some responses like chloram- the epidemiologic study of adverse drug phenicol-induced agranulocytosis, where no effects. definite genetic background is known, are 1. Side Effects also included under idiosyncrasy. In some Side effects are unwanted effects of a drug cases the person may be highly sensitive even that are extension of pharmacological effects to low doses of a drug (e.g. a single dose of and are seen with the therapeutic dose of the quinine can produce cinchonism in some) or drug. They are predictable, common and can highly insensitive even to high doses of the occur in all people, e.g. hypoglycaemia due drug. to insulin; hypokalaemia following Allergic reactions to drugs are immuno- frusemide. logically-mediated reactions which are not 2. Toxic Effects related to the therapeutic effects of the Toxic effects are seen with higher doses of drug. The drug or its metabolite acts as an the drug and can be serious, e.g. morphine antigen to induce antibody formation. causes respiratory depression in overdosage. Subsequent exposure to the drug may 3. Intolerance result in allergic reactions. The Drug intolerance is the inability of a person manifestations of allergy are seen mainly to tolerate a drug and is unpredictable. on the target organs viz. skin, respiratory Patients show exaggerated response to even tract, gastrointestinal tract, blood and small doses of the drug, e.g. vestibular blood vessels. Adverse Drug Reactions, Drug Interactions, Drug Nomenclature and Essential 37

Types of Allergic Reactions and their Johnson syndrome are some of the Mechanisms manifestations of arthus type reactions. Serum sickness is characterized by fever, Drugs can induce both types of allergic arthritis, nephritis, oedema and skin rashes. reactions viz humoral and cell-mediated Penicillins, sulfonamides, phenytoin, immunity. Mechanisms involved in type I, II streptomycin and heparin can cause serum and III are humoral while type IV is by cell- sickness. Stevens-Johnson syndrome (SJS) is mediated immunity. characterized by severe bullous erythema Type I (Anaphylactic) reaction The drug multiformae particularly in the mucous induces the synthesis of IgE antibodies membranes with fever and malaise. Toxic which are fixed to the mast cells. On Epidermal Necrolysis (TEN) is the most subsequent exposure, the antigen-antibody serious form of drug allergy with cutaneous complexes cause degranulation of mast cells reactions that can be fatal. Aminopenicillins, releasing the mediators of inflammation like sulphonamides, phenytoin, barbiturates, histamine, leukotrienes, prostaglandins and carbamazepine and phenylbutazone are the platelet-activating factor. These are drugs associated with SJS and TEN. responsible for the characteristic signs and Type IV (Delayed hypersensitivity) reactions symptoms of anaphylaxis like bronchospasm, are laryngeal edema and hypotension which mediated by T-lymphocytes and macro- could be fatal. Allergy develops within phages. The antigen reacts with receptors on minutes and is called immediate T-lymphocytes which produce lymphokines hypersensitivity reaction, e.g. penicillins. leading to a local allergic reaction, e.g. Skin tests may predict this type of reactions. contact dermatitis in nurses and doctors Penicillins, cephalosporins, lignocaine, handling penicillins and local anaesthetics. procaine, iron dextran and streptomycin are 4. Iatrogenic Diseases (Physician Induced) some drugs known to cause anaphylaxis. These are drug induced diseases. Even after the drug is withdrawn, toxic effects can Type II (Cytolytic) reactions The drug binds to persist, e.g. isoniazid induced hepatitis; a protein and together they act as antigens chloroquine induced retinopathy. Drugs like and induce the formation of antibodies. The chlorpromazine, haloperidol and other antigen antibody complexes activate the phenothiazines and metoclopramide and complement system resulting in cytolysis reserpine can induce parkinsonism. causing thrombocytopenia, agranulocytosis 5. Drug Dependence and aplastic anaemia. Examples are carba- Drugs that influence the behaviour and mood mazepine, phenytoin, sulphonamides and are often misused to obtain pleasurable phenylbutazone. Mismatched blood effects. Repeated use of such drugs result in transfusion reactions are also cytolytic dependence. Several words like drug abuse, reactions. addiction and dependence are used Type III (Arthus) reactions The antigen binds confusingly. Drug dependence is a state of to circulating antibodies and the complexes compulsive use of drugs in spite of the are deposited on the vessel wall where it knowledge of the risks associated with its initiates the inflammatory response resulting use. It is also referred to as drug addiction. in vasculitis. Rashes, fever, arthralgia, lym- Dependence could be ‘psychologic’ or phadenopathy, serum sickness and Stevens- ‘physical’ dependence. Psychologic 38 Textbook of Pharmacology for Dental and Allied Health Sciences dependence is compulsive drug-seeking morning sickness resulted in thousands of behaviour to obtain its pleasurable effects, babies being born with phocomelia (seal e.g. cigarette smoking. limbs). This thalidomide disaster (1958-61) Physical dependence is said to be present opened the eyes of drug licensing authorities when withdrawal of the drug produces and various nations made it mandatory to adverse symptoms. The body undergoes conduct strict teratogenicity tests before a physiological changes to adapt itself to the new drug is approved for use. continued presence of the drug in the body. Depending on the stage of pregnancy Stopping the drug results in ‘withdrawal during which the teratogen is administered, syndrome.’ The symptoms of withdrawal it can produce various abnormalities. syndrome are disturbing and the person then craves for the drug, e.g. alcohol, opioids and (i) Conception to 16 days—Usually resistant barbiturates. to teratogenic effects. If affected, Mild degree of physical dependence is seen abortion occurs. in people who drink too much of coffee. (ii) Period of organogenesis— (17 to 55 days 6. Teratogenicity of gestation) - Most vulnerable period; Teratogenicity is the ability of a drug to cause major physical abnormalities occur. foetal abnormalities when administered to a (iii) Foetal period—56 days onwards is the pregnant woman. Teratos in Greek means period of growth and development— monster. The sedative thalidomide taken hence developmental and functional during early pregnancy for relief from abnormalities result. Table 5.1: Examples of drugs affecting various organ systems

Organ system affected Examples

1. Hepatotoxicity Isoniazid, pyrazinamide, paracetamol, chlorpromazine, 6-Mercaptopurine, halothane, ethanol, phenylbutazone 2. Nephrotoxicity Analgesics, aminoglycosides, cyclosporine, cisplatin, cephelexin, penicillamine, gold salts 3. Ototoxicity Aminoglycosides, frusemide 4. Ocular toxicity Chloroquine, ethambutol 5. Gastrointestinal system Opioids, broad spectrum antibiotics 6. Cardiovascular system Digoxin, doxorubicin 7. Respiratory system Aspirin, bleomycin, busulfan, amiodarone, methotrexate 8. Musculoskeletal system Corticosteroids, heparin 9. Behavioural toxicity Corticosteroids, reserpine 10. Neurological system INH, haloperidol, ethambutol, quinine, doxorubicin vincristine 11. Dermatological toxicity Doxycycline, sulfonamides, gold, d-penicillamine 12. Electrolyte disturbances Diuretics, mineralocorticoids 13. Haematological toxicity Chloramphenicol, sulfonamides 14. Endocrine disorders Methyldopa, oral contraceptives Adverse Drug Reactions, Drug Interactions, Drug Nomenclature and Essential 39

Therefore, in general, drugs should be (ii) In vivo, i.e. in the body after avoided during pregnancy specially in the administration. first trimester. The type of malformation Pharmacological basis of drug interactions The also depends on the drug, e.g. thalidomide two major mechanisms of drug interactions causes phocomelia; tetracyclines cause include pharmacokinetic and pharmaco- deformed teeth; sodium valproate causes dynamic interactions. spina bifida-See Table 5.1 for the organ Pharmacokinetic mechanisms Alteration in the systems affected. extent or duration of response may be 7. Carcinogenicity and Mutagenicity produced by influencing absorption, Some drugs can cause cancers and genetic distribution, metabolism or excretion of one abnormalities. For example anticancer drugs drug by another. can themselves be carcinogenic; other Absorption of drugs from the gut may be examples are radioactive isotopes and some affected by: hormones. (i) Binding—Tetracyclines chelate iron and 8. Other Adverse Drug Reactions antacids resulting in reduced absorption. Drugs can also damage various organ Cholestyramine is a bile acid binding systems. resin which also binds many drugs. (ii) Altering gastric pH-Antacids raise DRUG INTERACTIONS gastric pH and interfere with the Definition Drug interaction is the alteration absorption of drugs like iron and in the duration or magnitude of the anticoagulants. pharmacological effects of one drug by (iii) Altering GI motility. Atropine and another drug. morphine slow gastric emptying and When two or more drugs are given delay the absorption of drugs. concurrently, the response may be greater Purgatives reduce the absorption of or lesser than the sum of their individual riboflavin. effects. Such responses may be beneficial or Distribution Competition for plasma protein harmful. For example a combination of drugs or tissue binding results in displacement is used in hypertension—hydralazine + interactions, e.g. warfarin is displaced by propranolol for their beneficial interaction. phenylbutazone from protein binding sites. But unwanted drug interactions may result Metabolism Enzyme induction and inhibition in severe toxicity. Such interactions can be of metabolism can both result in drug avoided by adequate knowledge of their interactions (page 18), e.g. phenytoin, mechanisms and by judicious use of drugs. phenobarbitone, carbamazepine and Some important drug interactions are rifampicin are enzyme inducers while mentioned in Appendix-1. chloramphenicol and cimetidine are some Site Drug interactions can occur: enzyme inhibitors. (i) In vitro in the syringe before Excretion When drugs compete for the same administration—mixing of drugs in renal tubular transport system, they prolong syringes can cause chemical or physical each other’s duration of action, e.g. penicillin interactions—such drug combinations and probenecid. are incompatible in solution, e.g. Pharmacodynamic mechanisms Drugs acting penicillin and gentamicin should never on the same receptors or physiological be mixed in the same syringe. systems result in additive, synergistic or 40 Textbook of Pharmacology for Dental and Allied Health Sciences antagonistic effects. Many clinically blockers. It is convenient and the drug is important drug interactions have this basis. sometimes cheaper when prescribed by Examples are- generic name. The nonproprietary name of • Atropine opposes the effects of the above example given under chemical name physostigmine. is imipramine. • Naloxone antagonises morphine. Proprietary name is the brand name given by • Antihypertensive effects of β blockers are the manufacturer. Hence each drug may have reduced by ephedrine or other many brand names, e.g. Crocin, Metacin, vasoconstrictors present in cold remedies. Pacemol, Calpol are different brand names • Many diuretics produce hypokalaemia of paracetamol. The main advantage in using which potentiate digitalis toxicity. brand name is the consistency of the product • Organic nitrates (used in angina) act by especially bioavailability. Hence, for drugs increasing cGMP activity. Sildenafil with low therapeutic index like digoxin and inhibits phosphodiesterase which antiepileptics, prescribing the same brand inactivates cGMP and thereby potentiates name is beneficial. the effects of nitrates. Hence the combination can cause severe hypotension Essential Drugs Concept and even deaths have been reported. WHO has compiled a list of drugs that are • Aspirin inhibits platelet aggregation and required to meet the primary health care enhances the risk of bleeding due to oral needs of majority of the population and are anticoagulants like warfarin. called essential drugs. Essential drugs have • Many antihistamines produce sedation been defined by WHO as those that satisfy which may be enhanced by alcohol intake. the health care needs of majority of the population and should therefore be available Drug Nomenclature at all times in adequate amounts and in the A drug can have three names. appropriate dosage forms. The original list 1. Chemical name has undergone revisions and updating from 2. Nonproprietary (generic) name time to time to meet the changing require- 3. Proprietary (brand) name. ments. Based on the WHO guidelines for The chemical name gives the chemical selection of essential drugs and by referring description of the drug, e.g. 3, (10, 11- its model list, each country puts forth its dihydro-5H-dibenz (b,f) -azepin-5-yl) national list of essential drugs. propyldimethylamine. This is lengthy, • Adoption of the list has resulted in greater complex and unsuitable for prescribing. coordination in health care development. The nonproprietary name is given by an official • The list serves as a guideline for indenting agency like WHO and is internationally and stocking essential drugs. accepted, i.e. the drug has the same generic • The concept has also helped in the name all over the world. It gives a clue to development of national formularies. the class of the drug, because they sound • A short list is compiled for community similar as they end with the same letters, e.g. health workers to aid in providing primary propranolol, atenolol, esmolol, metoprolol— health care. all are β-blockers and cimetidine, ranitidine, • The use of Essential Drug List has also famotidine and roxatidine are all H2 receptor emphasised the need for drug research and Adverse Drug Reactions, Drug Interactions, Drug Nomenclature and Essential 41

development, e.g. safety and efficacy of a consisting of about 300 drugs was formulated new drug should be established for it to in 1996. The revised tenth model list brought be included in the essential drugs list. out by WHO is given in Appendix-2 of the India’s first National Essential Drugs List first edition of this book.

SOME EXAMPLES

Drugs that are almost completely absorbed on Drugs with very short t ½ (2-10 min) oral ingestion • Dobutamine • 5–Fluorouracil • Diazepam • Indomethacin • Sodium nitroprusside • Adenosine • Digitoxin • Lithium • Dopamine • Alteplase • Phenylbutazone • Phenobarbitone • Esmolol • Minocycline • Salicylic acid • Doxycycline • Valproic acid • Chlordiazepoxide Drugs with long t½ Drug t½ in days • Chloroquine 10-24 Prodrugs • Etanercept 3-4 Drug Active metabolite • Phenylbutazone 3-4 • Mefloquine 16-24 → • Levodopa Dopamine • Gold salts 7 • Prednisone → Prednisolone • Enalapril → Enalaprilat • Bacampicillin → Ampicillin Drugs with low safety margin • Cortisone → Hydrocortisone • Azathioprine → Mercaptopurine • Digoxin • Theophylline • Cyclophosphamide → Aldophosphamide • Lithium • Quinidine • Zidovudine → Zidovudine triphosphate Teratogenic drugs

• Thalidomide • Glucocorticoids Drugs which need tapering (after long-term use) • Tetracyclines • Androgens • Sodium valproate • Estrogens • β blockers • Sedatives • Phenytoin • Progestins • Glucocorticoids • Antidepressants • Carbamazepine • Antithyroid drugs • Antiepileptics • Antipsychotics • Phenobarbitone • Anticancer drugs • Clonidine • Lithium 42 Textbook of PharmacologySection for Dental 2 and Allied Health Sciences Autonomic Nervous System

6 Introduction to Autonomic Pharmacology

The nervous system is divided into central sympathetic and parasympathetic inner- and peripheral nervous systems (Fig. 6.1). vation. The two divisions have opposing The peripheral nervous system consists of effects and normally their effects are in a autonomic and somatic nervous systems. The state of equilibrium. The prime function of autonomic nervous system (ANS) is not under the sympathetic system is to help a person voluntary control and therefore was so named to adjust to stress and prepare the body for by Langley (Autos = self, nomos = governing— fight or flight reactions, while the in Greek). The ANS innervates the heart, the parasympathetic mainly participates in smooth muscles, the glands and the viscera tissue building reactions. Man can still and controls the functions of these organs survive without sympathetic system (if ( Fig. 6.2). maintained stress-free) but not without The centres for autonomic reflexes are parasympathetic. present in the hypothalamus, medulla and spinal cord. Hypothalamus coordinates the Autonomic Innervation autonomic activity. The autonomic afferents are carried in The ANS consists of 2 major divisions— visceral nerves through nonmyelinated the sympathetic and the parasympathetic fibres. For example, the parasympathetic (Fig. 6.4). Most of the viscera have both afferents are carried by the 9th and 10th

Fig. 6.1: Nervous system Introduction to Autonomic Pharmacology 43

Fig. 6.2: Structures under the control of autonomic nervous system cranial nerves. The autonomic efferent The parasympathetic efferents are carried innervation (Fig. 6.3) consists of a myelinated through the craniosacral outflow. The pre-ganglionic fibre which synapses with the parasympathetic ganglia are located close to axon of a nonmyelinated postganglionic the innervated structures and therefore their fibre. The postganglionic fibre in turn forms postganglionic fibres are short. The a junction with the receptors of the organs sympathetic efferents extend from 1st supplied by it. The junction between the pre- thoracic to 2nd or 3rd lumbar segments and postganglionic fibres is called a ganglion (T1-L3) of the spinal cord. The sympathetic and that between the postganglionic fibres ganglia are found at 3 sites—paravertebral, and the receptors is the neuroeffector junction. prevertebral and terminal. Postganglionic The travelling of an impulse along the nerve fibres arising from sympathetic ganglia are fibre is known as conduction while its long and they innervate the head, neck and passage across a synapse is known as the viscera of the thorax and abdomen. transmission. Adrenal medulla is also considered as a The autonomic efferent is divided into sympathetic ganglion and differs from sympathetic and parasympathetic divisions. other sympathetic ganglia in that the 44 Textbook of Pharmacology for Dental and Allied Health Sciences

Fig. 6.3: Autonomic innervation principal catecholamine that is released is the synaptic cleft. In the ANS, the neuro- adrenaline. transmitters released are acetylcholine, Neurotransmitters For the transmission of noradrenaline, dopamine and in adrenal an impulse across a synapse, a neurohum- medulla, it is adrenaline and nor- oural transmitter substance is released into adrenaline. Introduction to Autonomic Pharmacology 45 Drugs acting on sympathetic and parasympathetic nervous system Fig. 6.4: 46 Textbook of Pharmacology for Dental and Allied Health Sciences

7 Cholinergic System

Acetylcholine (ACh) an ester of choline, is catalysed by the enzyme choline acetyl- the neurotransmitter of the parasympathetic transferase. This ACh is stored in small oval system. The nerves that synthesize, store and vesicles in the cholinergic nerve terminals. release ACh are called ‘cholinergic.’ Transmission of an impulse When an action The sites of release of acetylcholine are potential reaches the presynaptic membrane, (Fig. 7.1): ACh is released into the synaptic cleft 1. Ganglia—All the preganglionic fibres of (Fig. 7.2). This ACh binds to and activates ANS, i.e. at both the sympathetic and the cholinergic receptor on the postsynaptic parasympathetic ganglia. membrane leading to the depolarisation of 2. The postganglionic parasympathetic nerve endings. this membrane. Thus the impulse is 3. Sweat glands—The sympathetic post- transmitted across the synapse. ganglionic nerve endings supplying the ACh released into the synaptic cleft is sweat glands. rapidly destroyed by the enzyme acetyl- 4. Skeletal muscles—somatic nerve endings cholinesterase (AChE). Then the post- supplying skeletal muscles. synaptic membrane is repolarised. 5. Adrenal medulla. Cholinesterases Acetylcholine is hydrolysed to 6. CNS—brain and spinal cord. choline and acetic acid by the enzymes Synthesis of Acetylcholine Acetylcholine is cholinesterases. Two types of AChE are synthesized from acetyl-CoA and choline, present: 1. True cholinesterase – at neurons, ganglia and neuromuscular junction. 2. Pseudocholinesterase (butyrylcho- linesterase) – in plasma, liver and other organs. Cholinergic receptors There are two classes of cholinergic receptors – muscarinic and nicotinic. Muscarinic receptors are present in the heart, smooth muscles, glands, eyes and CNS. Muscarinic receptors are G protein coupled receptors. Five subtypes of mus- Fig. 7.1: Sites of release of neurotransmitters— acetylcholine and noradrenaline in the peripheral nervous carinic receptors, M1-M5 are recognised system (Table 7.1). Cholinergic System 47

Fig. 7.2: Cholinergic transmission—schematic representation

Nicotinic receptors are present in the muscle end plate and NN receptors at the neuromuscular junction, autonomic ganglia autonomic ganglia and adrenal medulla. and adrenal medulla. Nicotinic receptors are ion channels made of five subunits (2α+1β+ CHOLINERGIC DRUGS 1γ+1δ) (Fig. 7.3). Binding of acetylcholine to Cholinergic drugs are chemicals that act at α subunits opens the channel allowing the the same site as acetylcholine and thereby entry of Na+ into the cell. Two subtypes of mimic its actions. They are therefore nicotinic receptors are identified (Table 7.1)- called parasympathomimetics or cholino-

NM receptors are present at the skeletal mimetics.

Table 7.1: Subtypes and location of cholinergic receptors

Subtypes Location

Muscarinic M1 Autonomic ganglia, gastric glands, CNS

M2 Heart, nerves, smooth muscles

M3 Glands, smooth muscles

M4 CNS

M5 CNS

Nicotinic NM Neuromuscular junction

NN Autonomic ganglia Adrenal medulla, CNS 48 Textbook of Pharmacology for Dental and Allied Health Sciences

Cholinergic drugs may be classified as: rooms. These actions result from the 1. Esters of choline stimulation of the muscarinic receptors by Acetylcholine acetylcholine. Methacholine 1. Heart The action of ACh is similar to that Carbachol of vagal stimulation. It depresses the SA Bethanechol node and thereby reduces the heart rate 2. Cholinomimetic alkaloids and force of contraction. In larger doses, Pilocarpine AV conduction is depressed. Muscarine 2. Blood vessels ACh relaxes the vascular 3. Anticholinesterases smooth muscles and dilates the blood Reversible - Neostigmine vessels of the skin and mucous membrane. The BP falls due to a fall in total peripheral Physostigmine resistance. Pyridostigmine 3. Smooth muscle ACh increases the tone of Ambenonium all other (non-vascular) smooth muscles. Edrophonium. Gastrointestinal tract–tone and peristalsis Irreversible Organophosphorus is enhanced, sphincters are relaxed, compounds. resulting in rapid forward propulsion of intestinal contents. ACTIONS OF ACETYLCHOLINE Urinary bladder–detrusor contracts and Acetylcholine is taken as the prototype of trigonal sphincter relaxes–promotes parasympathomimetic drugs. voiding of urine. Bronchial smooth muscle–contracts resulting Muscarinic Actions in bronchospasm. 4. Secretory glands Acetylcholine enhances the Muscarinic actions resemble the actions of the secretions of all glands; salivary, lacrimal, alkaloid muscarine found in some mush- nasopharyngeal, tracheobronchial, gastric and intestinal secretions are increased. Sweating is also increased. Enhanced bronchial secretions and bronchospasm result in severe dyspnoea. 5. Eye Acetylchetine brings about constriction of pupil (miosis) by contracting the circular muscles of the iris (Fig. 7.4). Stimulation of muscarinic receptors present in the sphincter pupillae results in miosis. Drainage of aqueous humor is facilitated and intraocular pressure falls. Ciliary muscle contracts resulting in spasm of accommodation. Nicotinic Actions These effects resemble the actions of the Fig. 7.3: Nicotinic receptor: Nicotinic receptor con- alkaloid nicotine and are brought about by tains 5 subunits—2α+β+γ+δ. Acetylcholine binds to the sites on α subunits resulting in opening of the stimulation of the nicotinic receptors by channel acetylcholine. Cholinergic System 49

1. NMJ Acetylcholine brings about Adverse effects include diarrhoea, flushing, contraction of skeletal muscles by salivation, sweating, bradycardia, hypo-

stimulating NM receptors present in the tension, syncope and bronchospasm. neuromuscular junction. Large doses cause persistent depolarisation of skeletal CHOLINOMIMETIC ALKALOIDS muscles resulting in paralysis. 2. Autonomic ganglia Acetylcholine stimulates Pilocarpine is an alkaloid obtained from the the sympathetic and parasympathetic leaves of Pilocarpus microphyllus. Like ACh it ganglia and the adrenal medulla. stimulates cholinergic receptors, but its 3. CNS Acetylcholine is a neurotransmitter muscarinic actions are prominent. at several sites in the CNS. Its actions on the eye are important–when The important actions of acetylcholine are applied to the eye it causes miosis, spasm of summarised in Table 7.2. accommodation and a fall in intraocular Uses Acetylcholine is destroyed in the gut tension. It also increases sweat (diaphoretic) when given orally. On intravenous and salivary secretions (sialogogue). administration, it is rapidly metabolised by Adverse effects When used as eyedrops, pseudocholinesterases in the plasma and by burning sensation and painful spasm of true cholinesterase at the site of action. accommodation, browache and corneal Therefore it is not used therapeutically except edema can occur. Long term use can cause occasionally as 1% eyedrops to produce retinal detachment. miosis during some eye surgeries. Esters of choline are effective orally; carbachol Uses and bethanechol are resistant to both 1. Pilocarpine is used in glaucoma (see cholinesterases and have a longer duration below). Pilocarpine ocusert is available of action. Their muscarinic actions are and can deliver pilocarpine constantly for prominent with a sustained effect on g.i. 7 days. smooth muscles and urinary bladder. 2. Pilocarpine is also used alternately with Methacholine is rarely used. Carbachol is mydriatics like homatropine to break the used in glaucoma. Bethanechol may be used adhesions between the iris and the lens. in hypotonia of bladder and g.i. smooth 3. It is used to counter dryness of mouth that muscles and in some cases of postoperative is seen following radiation of head and paralytic ileus and urinary retention; It may neck. also be used in xerostomia as an alternative Glaucoma is an eye disease characterised by to pilocarpine. increased intraocular pressure. Aqueous Table 7.2: Actions of acetylcholine humor is secreted by the ciliary body and it drains through the canal of Schlemn. Rise in CVS — ↓HR ↓BP intraocular pressure (above 30 mm of Hg) Non-vascular — contraction, ↑gut peristalsis, can damage the optic nerve. If untreated, promotes urine voiding irreversible damage can occur - optic nerve Smooth muscle — bronchospasm Glands — ↑secretion degenerates leading to permanent blindness. Eye — miosis, spasm of Glaucoma is one of the common causes of accommodation, ↓IOP blindness. Hypertension, myopia and family NMJ — muscle contraction history of glaucoma are risk factors. Ganglia — stimulation Glaucoma is of two types : 50 Textbook of Pharmacology for Dental and Allied Health Sciences

1. Acute congestive/narrow angle/closed browache because they do not cause angle glaucoma—in this, iris blocks the miosis. Even when used as eye drops, drainage of aqueous humor at the canal β blockers may be absorbed systemically. β of Schlemn leading to increased Hence 1 selective agents are preferred intraocular pressure (Fig. 7.4). It needs particularly in asthmatics - even these immediate treatment. should be used carefully. 2. Chronic simple/wide angle/open angle • Epinephrine, dipivefrine and glucoma–onset is slow; needs long term apraclonidine may act on the ciliary body treatment. Surgery is the preferred option. to reduce aqueous humor formation. Two categories of drugs may be used in the Apraclonidine is an analog of clonidine treatment of glaucoma. They are - which has higher topical than systemic 1. Drugs that decrease the formation of activity. aqueous humor– • Production of aqueous humor requires Timolol betaxolol levobunolol active transport of bicarbonate ions. carteolol apraclonidine brimonidine Inhibition of carbonic anhydrase by dipivefrine adrenaline acetazolamide acetazolamide decreases aqueous humor dorzolamide formation by enhancing bicarbonate loss. 2. Drugs that increase the drainage of Acetazolamide and methazolamide are aqueous humor- given orally but are poorly tolerated. Carbachol, pilocarpine, physostigmine, Topical agents like dorzolamide eyedrops echothiophate, latanoprost are now available. These can also be Drugs used in glaucoma are summarised in combined with β blockers and miotics. Table 7.3. • Miotics improve drainage of aqueous • β blockers are the first line drugs. They humor by constricting the pupil and reduce aqueous humor formation by opening the iridocorneal angle. blocking the β receptors in the ciliary • Latanoprost is a prostaglandin analog

body. They do not cause headache or (a prodrug of PGF2α). It increases the

Fig. 7.4: Schematic diagram showing pathway for the drainage of aqueous humor Cholinergic System 51

outflow of aqueous humor probably by Acetylcholine relaxing the ciliary muscle. It can be used as an adjuvant to other drugs. Cholinesterase

ANTICHOLINESTERASES Choline + Acetic acid Anticholinesterases (antiChEs) or choline- Thus ACh is not hydrolysed and it sterase inhibitors are drugs which inhibit the accumulates. The actions of all these drugs enzyme cholinesterase. As their structure are due to this accumulated ACh. Hence the resembles that of ACh, they bind to actions are similar to cholinergic agonists. acetylcholinesterases and inactivate them. The structure of AChE contains an anionic Table 7.3: Drugs used in glaucoma

Drugs Adverse effects Comments

β blockers Timolol, betaxolol Conjunctival irritation, • first line carteolol, levobunolol redness and discomfort drugs • No miosis-hence no headache or browache Cholinergics • Pilocarpine, carbachol Corneal edema, spasm of Used with accommodation, browache, β blockers myopia

• Physostigmine, Browache, cataract, retinal echothiophate detachment

Adrenergic agonists Dipivefrine, adrenaline Conjunctival redness, 2nd line drugs—may photosensitivity be combined allergic reactions with β blockers α 2 adrenergic agonists Apraclonidine Conjunctival redness, Higher topical brimonidine photosensitivity activity than clonidine Carbonic anhydrase inhibitors Acetazolamide, Hypokalaemia, anorexia, 2nd line drugs—given orally; methazolamide, drowsiness slow release acetazolamide dorzolamide is better tolerated; topical dorzolamide is now available - has fewer side effects 52 Textbook of Pharmacology for Dental and Allied Health Sciences site and an esteratic site (Fig. 7.5). Reversible bind only to the esteratic site but the enzyme anticholinesterases except edrophonium is phosphorylated (by covalent bonds) and bind to both anionic and esteratic sites. the binding is stable. With some OPs the Edrophonium binds only to anionic site and binding takes many days to be reversed the binding is quickly reversible—hence it while with others it is not fully reversible is very short acting. Organophosphates (OP) at all.

Fig. 7.5: Acetylcholine and reversible anticholinesterases bind to both anionic and esteratic sites of the acetylcholinesterase (AChE) enzyme. Edrophonium binds only the anionic site and is short acting as the binding is rapidly reversible. OP compounds bind only esteratic site but exception is echothiophate which binds both anionic and esteratic sites Cholinergic System 53

Anticholinesterases are either esters of Neostigmine is a synthetic quaternary carbamic acid (carbamates) or phosphorus ammonium compound—poorly absorbed compounds. They may be: from the gut; it does not cross the BBB. It is 1. Reversible used in myasthenia gravis, (see below) post- Physostigmine operative paralytic ileus and atony of the Neostigmine urinary bladder. Pyridostigmine Edrophonium is rapid and short-acting. It is Rivastigmine used in myasthenia gravis, and intravenously Donepezil in snake bite and in curare poisoning. Edrophonium 2. Irreversible Uses of Reversible Anticholinesterases Organophosphates — 1. As a miotic Physostigmine causes miosis, Echothiophate spasm of accommodation and a ↓ IOP. It Malathion is used in: Sumithion a. Glaucoma—can be used with Toxic nerve gases - Sarin, Tabun pilocarpine for better effect Carbamates — b. Alternately with a mydriatic to break Carbaryl (SEVIN) adhesions between the iris and the Propoxure (BAYGON) lens. Aldicarb (TEMIK) 2. Myasthenia gravis is a chronic autoimmune Physostigmine is an alkaloid obtained from the disease characterised by progressive plant Physostigma venenosum (Table 7.4). It is weakness with rapid and easy fatiguability a tertiary ammonium compound—hence has of skeletal muscles. Antibodies to nicotinic better penetration into tissues and also receptors are formed, resulting in a crosses the BBB. It is available as IV injection, decrease in the number of these receptors as 0.1-1% eye drops and in combination with at NMJ. Neostigmine (15 mg tab 6 hrly) pilocarpine nitrate 2%. It is used in glaucoma or pyridostigmine or a combination of and in atropine poisoning. Its use as eyedrops these may be given. Edrophonium is used can cause browache and on long-term use, IV for the diagnosis. In addition to its retinal detachment and cataract. antiChE activity, neostigmine directly Table 7.4 : Compare and contrast physostigmine and neostigmine

Features Physostigmine Neostigmine

Source Natural Synthetic (Physostigma venenosum) Chemistry Tertiary ammonium compound Quaternary ammonium compound Absorption Absorbed orally Not absorbed Tissue penetration Good Poor BBB Cross BBB - has CNS effect Does not cross BBB - No CNS effects Primary use In glaucoma In Myasthenia gravis Use in poisoning Used in atropine poisoning Used in curare poisoning Similarities mode Cholinesterase inhibitor Cholinesterase inhibitor of action 54 Textbook of Pharmacology for Dental and Allied Health Sciences

stimulates the nicotinic receptors and 4. Curare poisoning Skeletal muscle paralysis increases the amount of ACh released caused by curare can be antagonised during each nerve impulse. AntiChEs by AntiChEs. Though edrophonium has enhance ACh levels at NMJ by preventing fast action, it is less effective than its destruction. They thus increase the force neostigmine. of contraction and improve muscle power 5. Postoperative paralytic ileus and urinary by more frequent activation of the existing retention Neostigmine may be useful. nicotinic receptors. In advanced disease 6. Cobra bite Cobra venom, a neurotoxin antiChEs are not effective because the causes skeletal muscle paralysis. Specific available nicotinic receptors are very few. treatment is antivenom. Intravenous Factors like infection, surgery and edrophonium prevents respiratory stress can result in severe muscle paralysis. weakness called-myasthenic crisis. But 7. Alzheimer's disease - To overcome the severe weakness may also result from an deficient cholinergic neurotransmission, excess dose of an anticholinesterase drug rivastigmine and donepezil are tried in (flaccid paralysis due to more of Alzheimer's disease. Tacrine is another acetylcholine) called-cholinergic crisis. reversible anticholinesterase tried in this These two crises can be differentiated by disease but tacrine is not preferred administering edrophonium 2 mg because it causes hepatotoxicity. intravenously. The patient immediately improves if it is myasthenic crisis but the Irreversible Anticholinesterases weakness worsens if it is cholinergic crisis. Treatment of cholinergic crisis is with Organophosphorus (OP) compounds are atropine while myasthenic crisis requires powerful inhibitors of AChE enzyme; a higher dose of or an alternative binding with the enzyme is stable–by anticholinergic drug. covalent bonds. They bind only the esteratic Other drugs used in myasthenia gravis are site and the enzyme is phosphorylated. • Glucocorticoids–inhibit the production of Effects are similar to that of cholinergic antibodies to the nicotinic receptors. stimulation as ACh accumulates in the tissues. These are used when anticholinesterases Organophosphates are highly lipid soluble alone are not adequate. and hence are absorbed from all routes • Immunosuppressants–Azathioprine and including intact skin. This makes OP cyclosporine can be used as alternatives poisoning possible even while insecticides are to prednisolone in advanced myasthe- used for spraying. nia gravis. They inhibit the production of antinicotinic receptor antibodies. Uses 3. Poisoning due to anticholinergic drugs Glaucoma—echothiophate eyedrops are Physostigmine is used in atropine poisoning sometimes used in glaucoma. and in toxicity due to other drugs with anticholinergic activity like phenothiazines, Organophosphorus Poisoning tricyclic antidepressants and antihis- Acute Toxicity tamines. Because physostigmine crosses the BBB, it reverses all the symptoms of As organophosphates are used as atropine poisoning including CNS effects. agricultural and domestic insecticides, Cholinergic System 55 poisoning by them is quite common. immediately, because the complex Poisoning may be occupational—as while undergoes ‘ageing’ and the enzyme spraying insecticides, accidental or suicidal. cannot be released. The complex becomes Symptoms result from muscarinic, nicotinic more stable by loss of a chemical group and central effects; vomiting, abdominal and this is responsible for ‘ageing’. cramps, diarrhoea, miosis, sweating, Cholinesterase reactivators are not useful increased salivary, tracheobronchial and in poisoning due to carbamate com- gastric secretions and bronchospasm; pounds because these compounds do not hypotension, muscular twitchings, have a free site for the binding of oximes. weakness, convulsions and coma. Death is Moreover, pralidoxime itself has weak due to respiratory paralysis. anticholinesterase activity particularly at higher doses. In severe poisoning 1-2 g Treatment of IV pralidoxime given within five minutes of poisoning gives best results. 1. If poisoning is through skin–remove But in practice it is rather uncommon for clothing and wash the skin with soap and a patient to get such quick treatment water; if consumed by oral route–gastric within minutes particularly in the rural lavage is given. setup and cholinesterase reactivators are 2. Maintain BP and patent airway. tried upto a few hours (maximum 24 3. Drug of choice is atropine IV 2 mg every hours) after poisoning. 10 minutes till pupil dilates. Maximum dose can be anything from 50 to 100 mg Chronic Organophosphate Toxicity or more depending on the severity of the poisoning. Treatment should be carefully Some OP compounds can produce neuro- monitored because of the risk of toxicity (polyneuropathy) several days after reappearance of symptoms due to delayed exposure to the compound. This toxicity came absorption of the OP compounds. to light when thousands of people developed 4. Cholinesterase reactivators–pralidoxime, paralysis in America after consuming obidoxime, diacetylmonoxime. These oxime "Jamaica ginger" which contained small compounds combine with cholinesterase amounts of an OP compound (triortho- organophosphate complex, release the cresylphosphate). The symptoms include binding and set free AChE enzyme. Thus weakness, fatigue, ataxia, sensory they reactivate the cholinesterase disturbances, muscle twitching and in severe enzyme. They should be given within cases flaccid paralysis - which may last for minutes after poisoning preferably several years. 56 Textbook of Pharmacology for Dental and Allied Health Sciences 8 Anticholinergic Drugs

Anticholinergic drugs are agents which block Actions the effects of acetylcholine on cholinergic The actions of atropine and scopolamine are receptors but conventionally antimuscarinic similar except that atropine is a CNS drugs are referred to as anticholinergic stimulant while scopolamine is a CNS drugs. They are also called cholinergic depressant and causes sedation. blocking or parasympatholytic drugs. Drugs 1. CVS—Atropine increases heart rate. In that block the nicotinic receptors are ganglion large doses, vasodilation and hypo- blockers and neuromuscular blockers. tension occurs. Anticholinergic drugs include atropine and 2. Secretions—Atropine reduces all related drugs—atropine is the prototype. secretions except milk. Lacrimal, salivary, Atropine is obtained from the plant Atropa nasopharyngeal, tracheobronchial and belladonna. Atropine and scopolamine gastric secretions are decreased. (hyoscine) are the belladonna alkaloids. They Decreased salivation results in dry mouth compete with acetylcholine for muscarinic and difficulty in swallowing—it is an receptors and block these receptors—they are antisialogogue. Sweating is also reduced. muscarinic antagonists. 3. Smooth muscle • GIT – ↓ tone and motility and relieves Classification spasm →may result in constipation. 1. Natural alkaloids • Biliary tract – smooth muscles are relaxed; Atropine, hyoscine (scopolamine) biliary spasm is relieved. 2. Semisynthetic derivatives • Bronchi – atropine causes bronchodilatation. Homatropine, ipratropium bromide, • Urinary bladder – relaxes ureter and tiotroprium bromide urinary bladder and may cause urinary 3. Synthetic substitutes retention particularly in the elderly men • Mydriatics because they may be having prostatic Eucatropine, cyclopentolate, tropicamide hypertrophy. • Antispasmodic-antisecretory agents 4. Eye—On local instillation, atropine Propantheline, dicyclomine, produces mydriasis by blocking the oxyphenonium, glycopyrrolate, muscarinic receptors in the sphincter telenzepine, tolterodine, propiverine pupillae. The ciliary muscle is paralysed • Antiparkinsonian agents resulting in cycloplegia or paralysis of Benzhexol, benztropine, trihexyphenidyl. accommodation. Because of mydriasis, Anticholinergic Drugs 57

Compare and contrast between atropine and scopolamine

Features Atropine Scopolamine

1. Source Both are Belladonna alkaloids 2. Chemistry Both are tertiary ammonium compounds 3. Mechanism of action Both block the muscarinic receptor 4. Source Atropa belladonna Hyoscyamus nigra 5. BBB Does not readily cross Readily crosses - even Higher doses are needed to reach CNS low doses produce CNS effects 6. Principle effect on CNS CNS stimulation CNS depression 7. Prominent actions Confusion, excitement, hallucinations, Sedation, drowsiness, on CNS ataxia, amnesia 8. Use in motion Sickness Not used Used. 9. Duration of action Longer Shorter 10. Use as cardiac vagolytic Can be used Not used

the iris may block the drainage of aqueous psychosis, convulsions and coma. Poisoning humor—IOP increases and may is treated with IV physostigmine. precipitate glaucoma in some patients. Uses of Belladonna Alkaloids 5. CNS—In higher doses atropine stimulates the CNS resulting in restlessness, diso- 1. As antispasmodic rientation, hallucinations and delirium. In • In diarrhoea and dysentery, atropine contrast, scopolamine produces sedation relieves colic and abdominal pain. and drowsiness. • In renal and biliary colic—atropine is Pharmacokinetics Atropine and hyoscine are used with morphine because atropine well-absorbed, cross the BBB and are partly overcomes spasm of the sphincter of Oddi. metabolised in the liver. • Nocturnal enuresis in children and in Adverse effects are common but not serious and paraplegia atropine reduces urinary include blurring of vision, dry mouth, frequency. dysphagia, dry skin, fever, constipation and 2. As mydriatric and cycloplegic urinary retention. Skin rashes may appear. • Diagnostic for testing error of refraction High doses cause palpitation, flushing, and fundoscopic examination of the restlessness, delirium, hallucinations, eye.

Drugs that can cause dryness of mouth due to anticholinergic property • Antihistamines – e.g. Diphenhydramine • Antipsychotics – e.g. Chlorpromazine • Tricyclic antidepressants – e.g. Imipramine • Atropine derivatives – e.g. glycopyrrolate 58 Textbook of Pharmacology for Dental and Allied Health Sciences

• Therapeutic To provide rest to the iris 7. Hyoscine can also be used during labour in iritis, iridocyclitis, keratitis and after to produce sedation and amnesia. partial iridectomy. Drug interactions When anticholinergics are Mydriatics are used alternately with given with other drugs that also have miotics to break adhesions between the anticholinergic property like antihistaminics, iris and the lens - both for the treatment phenothiazines, tricyclic antidepressants— and prevention of adhesion formation. side effects get added up. 3. As pre-anaesthetic medication When administered 30 min before anaesthesia, ATROPINE SUBSTITUTES atropine reduces salivary and respiratory secretions. This will prevent the deve- Belladonna alkaloids produce a wide range lopment of laryngospasm. It also prevents of effects, most of which are of therapeutic bradycardia during surgery. Its bron- value. But these can also result in various side chodilator action is of additional value. effects since they lack selectivity. Hence Glycopyrrolate an atropine substitute, is several semisynthetic and synthetic deriva- most commonly used for this purpose. tives have been introduced some of which 4. In organophosphorus poisoning Atropine is have selective actions (Table 8.1). life saving in OP poisoning and is also • Mydriasis and cycloplegia produced by useful in mushroom poisoning. atropine last for 7–10 days. The 5. In bronchial asthma, peptic ulcer and derivatives have shorter action (6–24 hrs), parkinsonism Atropine derivatives are tropicamide being the shortest acting. preferred over atropine—see below. Some can selectively produce either 6. Motion sickness Hyoscine given 30 minutes prominent mydriasis or cycloplegia. before the journey prevents travelling • Antispasmodics or spasmolytics are used sickness. Transdermal hyoscine patches to relieve spasms of the gastrointestinal are available to be applied behind the ear tract, biliary tract, ureter and uterus. They for a prolonged action. are also found to be useful in irritable

Table 8.1: Atropine substitutes

Indications Derivatives

1. On the eye - mydriatics Homatropine, eucatropine and cycloplegics cyclopentolate, tropicamide 2. As antispasmodics Propantheline, methantheline, dicyclomine, flavoxate hydrochloride, oxybutynin chloride, oxyphenonium, glycopyrrolate, clidinium 3. Peptic Ulcer Pirenzepine, telenzepine 4. Bronchial asthma Ipratropium, tiotropium 5. Preanaesthetic medication Glycopyrrolate 6. Urinary disorders Oxybutynin, tolterodine, propiverine, dicyclomine 7. Antiparkinsonian drugs Benzhexol, benztropine, trihexyphenidyl. Anticholinergic Drugs 59

bowel syndrome. Some of them in • Glycopyrrolate is an antisialogogue addition, reduce gastrointestinal motility. (reduces salivary secretions). It is a • Pirenzepine and telenzepine are selective quaternary amine – does not cross the BBB M1 blockers which inhibit gastric secretion – therefore no effects on the CNS. It is at doses that do not affect other functions. given IM as preanaesthetic medication and Pirenzepine also does not cross the BBB – in dental practice when it is necessary to hence has no CNS effects. They are tried reduce salivary secretions. in peptic ulcer. • When used in bronchial asthma, atropine • Benztropine, benzhexol and trihexy- thickens the bronchial secretions and phenidyl are the derivatives used in drug interferes with the movement of cilia, thus induced parkinsonism. favouring formation of mucus plugs. • Urinary disorders – atropine substitutes Ipratropium bromide is a bronchodilator are used to reduce urinary urgency and that does not affect mucociliary activity. frequency to relieve bladder spasm and When given as inhalation it acts only on improve bladder capacity in urinary the airways and does not produce any disorders and following urologic significant systemic effects because it is surgeries. They are also tried in nocturnal poorly absorbed. enuresis in children. 60 Textbook of Pharmacology for Dental and Allied Health Sciences

9 Skeletal Muscle Relaxants

Skeletal muscle relaxants (SMR) are drugs PERIPHERALLY ACTING SKELETAL that reduce the muscle tone either by acting MUSCLE RELAXANTS peripherally at the neuromuscular junction Neuromuscular Blockers (NMB) (neuromuscular blockers) or centrally in the Competitive Blockers cerebrospinal axis or directly on the contractile mechanism. They reduce the Curare was used by the South American spasticity in a variety of neurological Indians as an arrow poison for hunting wild conditions and are also useful in surgeries. animals because curare paralysed the animals. On extensive research, the active CLASSIFICATION principle from curare, tubocurarine was identified. Skeletal muscle relaxants may be classified d-tubocurarine (d-Tc) is the dextro- as follows: rotatory quaternary ammonium alkaloid 1. Drugs acting peripherally at the NMJ obtained from the plant Chondrodendron Competitive blockers tomentosum and plants of the Strychnos (Nondepolarising agents)– species (l-tubocurarine is less potent). Several d-Tubocurarine, synthetic agents have been developed. All pancuronium, these are quaternary ammonium compounds alcuronium, because of which they are not well absorbed and are quickly excreted. atracurium, Mechanism of action Non-depolarising mivacurium, blockers bind to nicotinic receptors on the rocuronium, motor end plate and block the actions of doxacurium, acetylcholine by competitive blockade pipecuronium, (Fig. 9.1). These compounds slowly vecuronium, dissociate from the receptors and trans- rapacuronium, mission is gradually restored. Thus the gallamine action of d-Tc is reversible. Depolarising blockers–Succinylcholine, Tubocurarine decamethonium 2. Drugs acting centrally-Diazepam, baclofen, Pharmacological Actions mephenesin, Skeletal muscle On parenteral adminis- tizanidine. tration, tubocurarine initially causes muscular 3. Drugs acting directly on the muscle– weakness followed by flaccid paralysis. Dantrolene. Small muscles of the eyes and fingers are Skeletal Muscle Relaxants 61 the first to be affected, followed by those Treatment of toxicity - Neostigmine (Table 9.2) of the limbs, neck and trunk. Later the may be used to reverse the skeletal muscle intercostal muscles and finally the paralysis and it is the antidote in curare diaphragm are paralysed and respiration poisoning. Antihistamines should be given stops. Consciousness is not affected to counter the effects of histamine. throughout. Recovery occurs in the reverse order, i.e. the diaphragm is the first to Synthetic Competitive Blockers recover. The effect lasts for 30-60 minutes Pancuronium, atracurium, vecuronium, (Table 9.1). gallamine, doxacurium, mivacurium, Autonomic ganglia In high doses tub- pipecuronium, rapacuronium, rocuronium are ocurarine can block autonomic ganglia and (Table 9.1) synthetic NMBs. They have the adrenal medulla resulting in hypotension. following advantages over tubocurarine - Histamine release Tubocurarine can cause • Less/no histamine release. histamine release from the mast cells leading • Do not block autonomic ganglia hence to bronchospasm, increased tracheo- cause less hypotension. bronchial and gastric secretions and this • Spontaneous recovery takes place with histamine release also contributes to most of these drugs. hypotension. • Some are more potent than tubocurarine. Pharmacokinetics d-Tc is a quaternary • The newer agents rapacuronium and ammonium compound—hence not absorbed rocuronium have a rapid onset of action. orally. It is given either IM or IV. Hence they can be used as alternatives to succinylcholine for muscle relaxation Adverse Reactions before endotracheal intubation. 1. Respiratory paralysis and prolonged • Rocuronium does not cause hypotension, apnoea—Patient should be given artificial tachycardia and is fast acting. ventilation. Neostigmine may be used to • Atracurium can be safely used in reverse the skeletal muscle paralysis. patients with renal impairment because 2. Hypotension is due to ganglion blockade it is degraded by plasma esterases and and histamine release. does not depend on the kidney for 3. Flushing and bronchospasm due to elimination. Atracurium is metabolised histamine release by tubocurarine–this is to a derivative which causes CNS not seen with newer agents. stimulation, seizures and increases the

Fig. 9.1: d-Tc molecules bind to nicotinic receptors and prevent the binding of ACh on these receptors 62 Textbook of Pharmacology for Dental and Allied Health Sciences

Table 9.1: Duration of action of competitive it is not used now. The synthetic neuromuscular blockers compounds are preferred.

Drug Duration (min) Depolarising Blockers Tubocurarine 35-60 Succinylcholine (SCh, Suxamethonium) is a Gallamine 35-60 quaternary ammonium compound with the Pancuronium 35-80 structure resembling two molecules of Doxacurium 90-120 acetylcholine joined together. Atracurium 20-35 Vecuronium 20-35 Mechanism of action The neuromuscular effects Mivacurium 12-18 of SCh are like those of ACh. SCh reacts with Pipecuronium 80-100 the nicotinic receptors (Fig. 9.2) and Rapacuronium 15-30 depolarises the skeletal muscle membrane. Rocuronium 30-60 But, unlike ACh, it is destroyed very slowly by pseudocholinesterase. Thus continued presence of the drug causes persistent dose of the anaesthetic needed. depolarisation resulting in flaccid paralysis. Cisatracurium does not form this This is phase I block. In high doses SCh derivative and also causes less histamine produces a dual block—initial depolarising release when compared to atracurium. block followed by nondepolarising block. The Therefore cisatracurium is now a membrane gets slowly repolarised but cannot preferred skeletal muscle relaxant. be depolarised again. The mechanism is not • Tubocurarine, doxacurium and gallamine clearly known. have a slow onset but longer duration of action (about 5 minutes). Pancuronium, Pharmacological Actions vecuronium, atracurium have inter- Skeletal muscle On intravenous administration mediate onset (2-4 minutes) while onset of action is very rapid—within 1 minute. rapacuronium and rocuronium have fast Initial transient muscular fasciculations and onset of action (1-2 minutes). twitchings, mostly in the chest and abdominal • Tubocurarine causes histamine release, regions are followed by skeletal muscle ganglion blockade (resulting in hypo- paralysis. The fasciculations are maximum in tension) and its muscle relaxant effect 2 minutes and subside in 5 minutes. It is due needs to be reversed with drugs. Hence to stimulation of the muscle fibres by the

Table 9.2 : Comparison and constrast d-Tubocurarine and succinylcholine

Tubocurarine Succinylcholine Mechanism of action Competitive blockade Persistant depolarization Type of blockade Nondepolarising Depolarising Phases of blockade Single Dual block Anticholinesterases Reverse blockade Do not reverse Initial fasciculations Nil Present Metabolism Only partly metabolized By pseudocholinesterase in the liver Onset of action Slow Fast Duration of action Long (30-60 min) Short (5-10 min) Treatment of toxicity Neostigmine Fresh blood transfusion Action Skeletal muscle relaxant Skeletal muscle relaxant Skeletal Muscle Relaxants 63

Fig. 9.2: Mechanism of action of succinylcholine discharge of action potentials in them. SCh is to muscle fibers that occurs during initial a short acting muscle relaxant and the effect fasciculations. lasts for 5-10 minutes. Hence it has to be given Hyperkalaemia–Depolarising blockers can continuously as an infusion for longer effect. cause hyperkalaemia due to sudden release of K+ from the intracellular sites. This can be CVS Initially hypotension and bradycardia dangerous particularly in patients with CCF. may result from stimulation of vagal ganglia. It may result in cardiac arrest in patients with This is followed by hypertension and burns and nerve injuries. tachycardia due to stimulation of sympathetic Cardiac arrhythmias– SCh can cause cardiac ganglia. Higher doses can cause cardiac arrhythmias. arrhythmias. SCh can also cause histamine Malignant hyperthermia– is a rare genetically release if injected rapidly. determined condition where there is a Pharmacokinetics SCh is rapidly hydrolysed by sudden increase in the body temperature and pseudocholinesterase–hence it is short- severe muscle spasm due to release of acting-about 5 minutes. Some people (1 in intracellular Ca++ from the sarcoplasmic 2000) have an abnormal pseudocholinesterase reticulum. Certain drugs like halothane, enzyme due to a hereditary defect. In such isoflurane and succinylcholine can trigger the people, SCh does not get metabolised and process which can be fatal. Combination of even the usual dose results in prolonged halothane and SCh is the most common apnoea and paralysis which may last for triggering factor. Intravenous dantrolene is several hours. Artificial ventilation and fresh life-saving in malignant hyperthermia. blood transfusion are needed to supply Oxygen inhalation and immediate cooling of pseudocholinesterase. the body also help.

Adverse Reactions Drug Interactions Postoperative muscle pain is a common adverse 1. General anaesthetics augment the action effect of SCh. It may be due to the damage of SMRs. 64 Textbook of Pharmacology for Dental and Allied Health Sciences

2. Anticholinesterases like neostigmine agonist. It depresses the monosynaptic and reverse the action of competitive blockers. polysynaptic reflexes in the spinal cord. It 3. Aminoglycosides and calcium channel relieves painful spasms including flexor and blockers potentiate the action of SMRs. extensor spasms and may also improve bladder and bowel functions in patients with Uses of Peripherally Acting Skeletal spinal lesions. Normal tendon reflexes are Muscle Relaxants not affected. Baclofen is generally given orally. It should Inappropriate use of peripherally acting SMRs be gradually withdrawn after prolonged use can be fatal. Hence they should be given only because abrupt withdrawal can cause anxiety, by qualified anaesthetists or adequately palpitations and hallucinations. trained doctors. Side effects are drowsiness, weakness and 1. Adjuvant to anaesthesia Adequate muscle ataxia. relaxation is essential during surgeries. Mephenesin is not preferred due to its side Skeletal muscle relaxants are used as effects. A number of related drugs like adjuvants to general anaesthesia. Short carisoprodol, methocarbamol, chlorzoxazone are acting SMRs like succinylcholine are used used in acute muscle spasm caused by local during endotracheal intubation. SMRs are trauma. All of them also cause sedation. also useful in laryngoscopy, bronc- Tizanidine is a congener of clonidine. It is a hoscopy, esophagoscopy and in central α agonist like clonidine. It increases orthopaedic procedures like reduction of 2 presynaptic inhibition of motor neurons and fractures and dislocations. reduces muscle spasms. Adverse effects 2. In electroconvulsive therapy SMRs protect the include drowsiness, weakness, hypotension patient from convulsions and trauma and dry mouth. Tizanidine is used in the during ECT. treatment of spasticity due to stroke, multiple 3. In spastic disorders SMRs are used to sclerosis and amyotropic lateral sclerosis. overcome the spasm of tetanus, athetosis Other centrally acting spasmolytic agents and status epilepticus. include riluzole, gabapentin and progabide. CENTRALLY ACTING MUSCLE RELAXANTS Riluzole has both presynaptic and postsynaptic effects. It inhibits glutamate release These drugs act on higher centres and cause in the CNS. It is well tolerated with minor muscle relaxation without loss of conscious- adverse effects like nausea and diarrhoea. It ness. They also have sedative properties. is used to reduce spasticity in amyotropic lateral sclerosis. Mechanism of Action Uses of Centrally Acting Muscle Centrally acting muscle relaxants depress the Relaxants spinal polysynaptic reflexes. These reflexes maintain the muscle tone. By depressing these 1. Musculoskeletal disorders like muscle strains, spinal reflexes, centrally acting muscle sprains, myalgias, cervical root relaxants reduce the muscle tone. syndromes, herniated disc syndromes, Diazepam has useful antispastic activity. It can low backache, dislocations, arthritis, be used in relieving muscle spasm of almost fibrositis and bursitis all cause painful any origin including local muscle trauma muscle spasms. Muscle relaxants are used (see Page 140). with analgesics in these conditions. Baclofen is an analog of the inhibitory 2. Spastic neurological disorders like cerebral neurotransmitter GABA. It is a GABAB palsy, multiple sclerosis, poliomyelitis, Skeletal Muscle Relaxants 65

hemiplegia and quadriplegia are treated • All these drugs act by depressing spinal with diazepam or baclofen. polysynaptic reflexes. 3. Tetanus Diazepam is given IV. • Common adverse reactions include 4. ECT Diazepam is given along with drowsiness and dizziness. peripherally acting SMRs. • Cyclobenzaprine has anticholinergic 5. Orthopaedic procedures like fracture effects and can therefore cause dryness reduction may be done after of mouth, drowsiness and dizziness. administering diazepam. • Many of them are available in DIRECTLY ACTING MUSCLE RELAXANTS combination with NSAIDs. • NSAIDs are equally or more effective in Dantrolene directly affects the skeletal muscle relieving muscle spasms. contractile mechanism. It inhibits the muscle Botulinum toxin is produced by the anaerobic contraction by preventing the calcium release bacterium Clostridium botulinum. The toxin from the sarcoplasmic reticulum. inhibits the release of acetylcholine at the Adverse effects include drowsiness, cholinergic synapses resulting in flaccid dizziness, fatigue, diarrhoea, muscle paralysis of skeletal muscles. weakness and rarely hepatotoxicity. Liver Botulinum toxin is useful (local injection) function tests should be done to look for in the treatment of dystonias, including hepatotoxicity. sports or writer’s cramps, muscle spasms, Uses Dantrolene is used in spastic disorders tremors, cerebral palsy and in rigidity seen like hemiplegia, paraplegia, spinal injuries, in extrapyramidal disorders. It is commonly multiple sclerosis and cerebral palsy. used to relieve blepharospasm (spasm of the Dantrolene is the drug of choice in malignant orbicularis oculi muscle of the eyes). hyperthermia which is due to excessive Botulinum toxin is also gaining popularity in release of calcium from the sarcoplasmic reticulum. Dantrolene blocks the release of cosmetic therapy to remove facial lines by Ca++ from the sarcoplasmic reticulum and local injection. relieves muscle spasm in malignant Skeletal muscle relaxants in dentistry hyperthermia. 1. Spasm SMRs like mephenesin, diazepam and others along with analgesics are used DRUGS USED IN THE TREATMENT OF to relieve the spasm of the masticatory LOCAL MUSCLE SPASM muscles. Such spasm can cause pain around Several agents are used for the treatment of temporomandibular joint. local muscle spasms which may result from 2. Dislocation–Sometimes in temporo- injury or strain. Cyclobenzaprine, metax- mandibular joint dislocation, just relaxing alone, carisoprodol, chlorzoxazone, mep- the related muscles with SMRs may be robamate and methocarbamol are some of sufficient to set right the dislocation. them. They have the following common 3. Fractures–SMRs may also be used to features- reduce fractures of the mandible. 66 Textbook of Pharmacology for Dental and Allied Health Sciences 10 Adrenergic System

The prime function of the adrenergic or sympathetic nervous system is to help the human being to adjust to stress and prepare the body for fight or flight reactions. When exposed to stress, the heart rate and stroke volume increase with the resultant increase in cardiac output. The blood is shifted from the skin, gut, kidney and glands to the heart, skeletal muscles, brain and lungs, as these organs need more blood during stress. Pupils and bronchi are dilated and sweating is increased. Blood glucose increases by glycogenolysis. Fig. 10.1: Biosynthesis of catecholamines Neurotransmitters of the sympathetic system nerve terminals by an active transport process are noradrenaline (NA, norepinephrine) and termed uptake 1, which is responsible for dopamine (DA). Adrenaline (epinephrine) is termination of action of NA. Of this portion the major hormone secreted by the adrenal which is taken up, a fraction is metabolised medulla (Table 10.2). by MAO and the remaining NA is then Synthesis of catecholamines The three transferred to the storage vesicles. Some part catecholamines–noradrenaline, adrenaline of NA released into the synaptic cleft and dopamine are synthesized from the penetrates into the effector cells and is known amino acid tyrosine (Fig. 10.1). as uptake 2. The sympathetic postganglionic nerve Adrenergic receptors Ahlquist classified fibres that synthesize, store and release NA adrenergic receptors into 2 types—α and β. are called adrenergic. Noradrenaline is stored With the availability of newer, synthetic, in small vesicles in the adrenergic nerve selective drugs, these are further classified terminals (Fig. 10.2) In response to nerve α α β into subdivisions. We now know 1, 2, 1, impulse, NA is released into the synaptic cleft β β 2 and 3 adrenergic receptors. by a process called exocytosis. This NA binds The stimulation of α receptors mainly to adrenergic receptors located on the produces excitatory effects (exception-GIT); postsynaptic membrane to produce the β stimulation causes mainly inhibitory effects response. A small portion of NA is (exception- heart). The characteristics of α metabolised by the enzyme COMT but a large these receptors are given in Table 10.1. 2 portion (nearly 80%) is taken back into the receptors are located on the presynaptic Adrenergic System 67

Fig. 10.2: Synthesis, storage, release and metabolism of noradrenaline

DA–Dopamine, NA-Noradrenaline, U-1-Uptake 1, U-2–Uptake 2, MAO-Monoamine oxidase, COMT-Catechol-O-methyltransferase membrane (Fig. 10.3). Stimulation of receptors are also present postsynaptically in α presynaptic 2 receptors inhibits the further pancreatic islets, platelets and brain. release of NA. Thus α receptors exert a Mechanism of action Both α and β adrenergic 2 α negative feed back on NA release. 2 receptors are G-protein coupled receptors

Table 10.1: Characteristics of adrenergic receptors

Receptor Selective Selective Location Response type agonist antagonist

α 1 Phenylephrine Prazosin Vascular smooth muscle Contraction Mephenteramine Terozosin Gut Relaxation Methoxamine Genitourinary smooth muscle Contraction Liver Glycogenolysis α β 2 Clonidine Yohimbine Pancreatic cells  Insulin release Platelets Aggregation Nerve terminals  NE release β ↑ 1 Dobutamine Metoprolol Heart Force of Atenolol contraction, ↑ heart rate, AV conduction velocity β 2 Salbutamol Butoxamine Smooth muscle–vascular, Relaxation bronchial, gut and genitourinary β 3 — — Adipose tissue Lipolysis 68 Textbook of Pharmacology for Dental and Allied Health Sciences

α α α Fig. 10.3: 1 and 2 receptor stimulation: NA binds to 1 receptors and stimulates it to produce response α like vasoconstriction. Presynaptic 2 receptor stimulation inhibits the further release of NA from the storage vesicles

(See page 27). Stimulation of alpha receptors Stimulation of beta receptors activates an activates phospholipase C in the cell enzyme adenylylcyclase resulting in membrane which acts through generation of increased intracellular cyclic AMP levels. This second messengers inositol triphosphate and second messenger acts through various diacylglycerol and increase intracellular intracellular proteins to bring about the calcium. response.

Table 10.2: Compare and contrast adrenaline and noradrenaline

Feature Adrenaline Noradrenaline

Chemistry Catecholamine Catecholamine On adrenergic Agonist Agonist receptors Receptor selectivity Both α and β Predominently α agonist Effect on BP • Biphasic • Monophasic • ↑ in systolic, •↑ in systolic, diastolic ↓ in diastolic and mean BP Dales vasomotor reversal Yes No Clinical uses Many Rarely used Major indications • Anaphylactic shock, • Rarely used • Cardiac arrest, in hypotension • Local haemostatic 11 Adrenergic Drugs (Sympathomimetics)

Sympathomimetics are drugs whose actions III. Therapeutic or clinical classification mimic that of sympathetic stimulation. 1. Vasopressors Noradrenaline, Catecholamines and sympathomimetics or dopamine, methoxamine, adrenergic drugs may be classified in various metaraminol ways depending on the presence/absence of 2. Cardiac stimulants Adrenaline, dopamine, catechol nucleus, mode of action and dobutamine, therapeutic indications as follows: isoprenaline, ephedrine 3. CNS stimulants CLASSIFICATION Amphetamine, I. Chemical classification—based on the ephedrine presence/absence of catechol nucleus 4. Bronchodilators 1. Catecholamines Adrenaline, isoprenaline, salbutamol, terbutaline, Noradrenaline (NA), salmeterol, perbuterol, Adrenaline, fenoterol, formoterol Dopamine (DA), 5. Nasal decongestants Isoprenaline (Synthetic) Ephedrine, 2. Non-catecholamines pseudoephedrine, Ephedrine, phenylpropanolamine, Amphetamine phenylephrine, II. Depending on the mode of action oxymetazoline, 1. Directly acting sympathomimetics xylometazoline (by interacting with adrenergic 6. Appetite suppressants receptors) (anorectics) Fenfluramine, Noradrenaline, adrenaline, dexfenfluramine dopamine, isoprenaline 7. Uterine relaxants 2. Indirectly acting sympathomimetics Salbutamol, terbutaline, (by releasing NA from nerve isosxuprine, ritodrine terminals) Amphetamine, tyramine Actions 3. Mixed action amines 1. Cardiovascular System (both direct and indirect actions) Heart Adrenaline is a powerful cardiac Ephedrine, methoxamine β stimulant. Acting through 1 receptors, it 70 Textbook of Pharmacology for Dental and Allied Health Sciences increases the heart rate, force of contraction, • Pilomotor muscles of the hair follicle cardiac output and conduction velocity. The contract. work done by the heart and the resultant • Bladder Detrusor is relaxed (β receptors) oxygen consumption are increased. while trigone is contracted thereby Blood vessels and BP Blood vessels of the skin increasing the urine holding capacity of α and mucous membrane are constricted ( 1) the bladder. and that of the skeletal muscles are dilated 3. Eye β ( 2) by adrenaline. Since injection of adrena- Adrenaline causes mydriasis due to line causes local vasoconstriction, it is used contraction of the radial muscles of the to prolong the duration of action of local α iris ( 1); it also reduces intraocular anaesthetics. pressure. Moderate doses given IV produce a rapid 4. Metabolic Effects increase in BP followed by a fall— a biphasic Adrenaline increases the blood sugar level α response. The pressor effect is due to 1 by enhancing hepatic glycogenolysis. It β mediated vasoconstriction. Action on also inhibits insulin release. By enhancing receptors is more persistent and as the action β breakdown of triglycerides in the adipose on alpha receptors wears off, the action on tissue, more free fatty acids are made receptors gets unmasked resulting in a fall β available in the plasma by action on 3 in BP. Sir Henry Dale demonstrated that receptors in adipocytes. when α receptors are blocked (with ergot α 5. Skeletal Muscles alkaloids which are blockers), adrenaline Catecholamines facilitate neuromuscular produces only a fall in BP and this is named transmission by action on both α and β after him as Dale’s vasomotor reversal (or Dale’s receptors—they enhance the amount of phenomenon). ACh released. Noradrenaline is mainly an alpha agonist Pharmacokinetics As catecholamines are and brings about a rise in BP. rapidly inactivated in the gut and the liver Other vascular beds Adrenaline causes renal they are not given orally. Adrenaline and NA vasoconstriction resulting in a fall in renal are metabolised by COMT and MAO. blood flow; it also causes pulmonary and mesenteric vasoconstriction. Adverse reactions Anxiety, palpitation, Cerebral and coronary blood flow is weakness, tremors, pallor, dizziness, rest- enhanced. lessness and throbbing headache may follow 2. Smooth Muscles adrenaline/NA administration. In patients • Bronchi Adrenaline is a powerful with ischaemic heart disease, both adrenaline bronchodilator and a weak respiratory stimulant. Pulmonary vasoconstriction relieves bronchial congestion. All these result in an increase in vital capacity. • Uterus Nonpregnant uterus—contracts Last month of pregnancy—relaxes. • Gut Smooth muscle is relaxed—but weak and transient action. • Splenic capsule contracts resulting in the release of RBCs into the circulation. Adrenergic Drugs (Sympathomimetics) 71 and NA can precipitate anginal pain. Rapid metabolised. 1: 10,000 to 1: 2,00,000 IV injection can cause sudden sharp rise in adrenaline is used for this purpose. BP which may precipitate arrhythmias, 5. Acute bronchial asthma Adrenaline subarachnoid haemorrhage or hemiplegia. produces bronchodilation. It may be given Preparations Adrenaline 1:1000, 1: 10,000 and SC/inhalation, but is not preferred as more 1:1,00,000 solutions are available for injection. selective drugs are available (See page Adrenaline is given SC/IM; intracardiac in 216). emergencies. Adrenaline aerosol for 6. Glaucoma (see page 49) Adrenaline ↓ IOP inhalation and 2% ophthalmic solution are and can be used in glaucoma. But it has also available. the disadvantages of being - (1) poorly absorbed, (2) short acting as it is quickly Uses of Adrenaline metabolised in the eye. Dipivefrin is a prodrug which gets converted to 1. Anaphylactic shock Adrenaline is the drug adrenaline in the eye by the action of of choice (0.3-0.5 ml of 1:1000 solution). It corneal esterases. Dipivefrin has good promptly reverses hypotension, laryngeal penetrability due to high lipid solubility oedema and bronchospasm and is life and it is used in glaucoma. saving in presence of anaphylactic shock. IM route is preferred as absorption by SC Contraindications route is not reliable in presence of shock. Dentists should be well versed with the Adrenaline is contraindicated in patients with use of adrenaline for this purpose because angina pectoris, hypertension and in patients anaphylaxis can occur following the use on β blockers. of any drug even in dental practice. Noradrenaline can be used in shock to increase 2. Cardiac arrest Sudden cardiac arrest (Table BP—but it is very rarely used. 11.2) due to drowning, electrocution, etc. Isoprenaline (Isoproterenol, Isopropyl are treated with intracardiac adrenaline arterenol) is a synthetic catecholamine with (into 4th or 5th intercostal space, 2-3 predominantly β receptor stimulant action inches from the sternum); before injecting, and negligible α actions. It has cardiac ensure that the tip of the needle is in the stimulant and smooth muscle relaxant heart–when the piston is withdrawn, properties. Due to vasodilation BP falls; it is blood should enter the syringe. a potent bronchodilator. Adverse effects 3. Control of haemorrhage Cotton or gauze include palpitation, angina, headache and soaked in adrenaline–1: 10,000 to 1 : 20,000 flushing. concentration is used as a topical Isoprenaline is used in heart block and haemostatic to control bleeding. Bleeding shock for its cardiac stimulant actions. It can stops due to vasoconstriction. Adrenaline be used in bronchial asthma (page 216). packs are used to control bleeding after Dopamine is the precursor of NA. It acts on tooth extraction and in epistaxis. dopaminergic and adrenergic receptors. It is 4. With local anaesthetics (see page 130) a central neurotransmitter. Low doses

Injected with LA, adrenaline produces stimulate vascular D1 receptors in renal, vasoconstriction and reduces the rate of mesenteric and coronary beds causing absorption of the LA. By this it prolongs vasodilatation in these vessels. Hence renal the action of the LA. It also reduces blood flow and GFR increase. Higher doses systemic toxicity of LA because as and cause cardiac stimulation through β receptors α 1 when the LA is getting absorbed, it gets and in high doses 1 receptors are activated 72 Textbook of Pharmacology for Dental and Allied Health Sciences resulting in vasoconstriction and increased arteries. It is used as an IV infusion in severe BP. Dopamine does not cross the BBB - hence hypertension to rapidly reduce the BP. it has no CNS effects. It is given IV (2-5 μg/ Kg/min). It is short acting and the infusion NONCATECHOLAMINES rate can be adjusted to get the appropriate Noncatecholamines are devoid of catechol effect by monitoring BP. Dopamine is nucleus, they act both by direct stimulation metabolised by COMT and MAO. Epinine of the adrenergic receptors and indirectly by (Ibopamine) is an ester of methyldopamine releasing NA. In contrast to catecholamines, which acts like dopamine. they are effective orally (Table 11.1), Adverse effects Nausea, vomiting, palpitation, relatively resistant to MAO and therefore are headache, angina, sudden rise in BP may longer-acting; they cross the blood-brain occur. barrier and have CNS effects. Uses Dopamine is used in the treatment of Ephedrine is an alkaloid obtained from the shock—cardiogenic, hypovolaemic and septic plants of the genus Ephedra. Ephedrine acts α β shock for the following reasons: by direct stimulation of and receptors • Dopamine increases renal blood flow and and indirectly through release of NA. Repeated administration at short intervals thereby GFR. result in tachyphylaxis. Ephedrine raises BP • DA stimulates the heart-increases force of by peripheral vasoconstriction and by contraction, cardiac output and B.P. increasing the cardiac output. Like adrenaline Hence it is of special value when shock is it relaxes smooth muscles; it is a CNS associated with renal dysfunction and low stimulant and produces insomnia, cardiac output. restlessness, anxiety, tremors and increased • Because DA is short acting, the response mental activity. can be easily controlled by modifying the Adverse effects include gastric upset, insomnia, infusion rate. tremors and difficulty in micturition. Dopexamine is a synthetic analog of dopamine Uses β 1. Bronchial asthma Ephedrine is useful in acting on D1 D2 and 2 receptors. It is found to have beneficial effects in CCF. mild chronic bronchial asthma (See Dobutamine a derivative of dopamine, is a page 218) but it is not preferred. β 2. Nasal decongestion Ephedrine nasal drops relatively selective 1 agonist. Though it also activates α receptors, in therapeutic doses are used. Pseudoephedrine—an isomer of 1 ephedrine is used orally for decongestion. the only dominant action is an increase in the It causes vasoconstriction in the skin and force of contraction of the heart without a mucous membrane but its effects on the significant increase in the heart rate. Hence CNS and the heart are milder. the increase in myocardial oxygen demand 3. Mydriasis Ephedrine eyedrops are used is milder when compared to dopamine and to produce mydriasis without cycloplegia. is therefore more useful than dopamine in 4. Hypotension For prevention and treat- cardiogenic shock. Dobutamine is used in ment of hypotension during spinal an- patients with CCF or acute myocardial aesthesia—IM ephedrine is used. infarction or following cardiac surgery when 5. Narcolepsy is a condition with an there may be pump failure. irresistible desire and tendency to sleep. As ephedrine is a CNS stimulant, it is Fenoldopam is a selective D1 agonist which dilates coronary, renal and mesenteric useful in narcolepsy. Adrenergic Drugs (Sympathomimetics) 73

Table 11.1: Compare and contrast noradrenaline and ephedrine

Features Noradrenaline Ephedrine 1. Source Endogenous Exogenous (From plants of genus Ephedra) 2. Chemistry Monoamine Non-catecholamine 3. Structure Has catechol nucleus No catechol nucleus 4. Mode of action Directly stimulates Acts both adrenergic receptors (1) directly on adrenergic receptors (2) Indirectly – through release of NA. 5. BBB Does not easily cross Easily crosses. 6. Action on CNS Only in very high doses CNS stimulation in therapeutic doses 7. Role in CNS Central neurotransmitter Not formed in the body. 8. Oral use Not effective orally Effective orally, parenterally and topically. 9. Action on Predominantly α agoinst Stimulates both α and β receptors. adrenoceptors 10. t½ Short (minutes) Long (hrs) 11. Topical use Not used Used as eyedrops - Mydriasis Nasal drops - decongestion

6. Nocturnal enuresis (Bed wetting) in children Amphetamine also has weak anticon- may be treated with ephedrine as it vulsant property. increases the holding capacity of the Adverse effects include restlessness, tremors, bladder. Drugs should be used only when insomnia, palpitation, anxiety, confusion and non-pharmacological measures have hallucinations. Prolonged use may precipitate failed. psychosis. High doses cause angina, delirium, 7. Stokes Adam's syndrome As an alternative arrhythmias, hypertension, acute psychosis, to isoprenaline. coma and death due to convulsions. Amphetamine is a synthetic compound with Dependence Amphetamine causes psychologic actions similar to ephedrine; tachyphylaxis dependence. can occur on repeated use. Amphetamine is Uses a potent CNS stimulant; it produces increased 1. Attention deficit hyperactivity disorder mental and physical activity, alertness, (ADHD) in children is characterised by increased concentration and attention span, decreased ability to concentrate and hold elation, euphoria and increased capacity to attention, aggressive behaviour and work. It also increases initiative and self hyperactivity; Amphetamine increases confidence, postpones fatigue and improves attention span in such children and physical performance (temporarily) as seen improves performance in school. in athletes. All these properties make 2. Narcolepsy Amphetamine is preferred over amphetamine a drug of dependence and ephedrine. Other drugs used in abuse. Higher doses produce confusion, narcolepsy include methylphenidate and delirium and hallucinations. modafinil. Methylphenidate is an indirectly α Respiration Amphetamine stimulates respi- acting sympathomimetic like amphet - ration—it is an analeptic. mine. Modafinil is a centrally acting CNS Depression of appetite Acting on the feeding stimulant which may act by stimulating α centre in the hypothalamus, amphetamine 1 adrenoceptors. It is better tolerated reduces hunger and suppresses appetite. with fewer adverse effects. 74 Textbook of Pharmacology for Dental and Allied Health Sciences

3. Obesity Though appetite is suppressed, mucosa, resulting in its shrinkage and they due to risk of dependence and other side decrease the volume of the mucosa. Thus they effects, amphetamine should not be used relieve nasal congestion and decrease for this purpose. resistance to airflow through the nose.They 4. Epilepsy Amphetamine can be used as also reduce nasal secretion. The nasal adjuvant and to counter the sedation due decongestants thus provide symptomatic to antiepileptics. relief in rhinitis due to allergy and upper Methamphetamine has more prominent central respiratory infections. Mechanism of action - Nasal decongestants act than peripheral actions. Methylphenidate, by stimulating the α receptors present in the phenmetrazin and pemoline are other 1 blood vessels of the nasal mucosa. amphetamine-like drugs with actions and They bring about vasoconstriction of the abuse potential similar to amphetamine. nasal mucosa resulting in its shrinkage. Thus they relieve nasal congestion. VASOPRESSORS They may be used: α 1. Orally Ephedrine These are 1 agonists and include metaraminol, mephenteramine, pheny- Pseudoephedrine lephrine and methoxamine. They increase the 2. Topically (as nasal drops) BP by increasing total peripheral resistance Oxymetazoline, (TPR) or cardiac output (CO) or both. They Xylometazoline are given parenterally with constant Naphazoline, monitoring of BP. Tachyphylaxis may Phenylephrine develop. Mephenteramine Metaraminol Uses Vasopressors are used to raise the BP in hypotension as seen in cardiogenic or Adverse effects neurogenic shock and during spinal anaesthesia. When used orally ephedrine and pseudo- Metaraminol is an alpha stimulant and also acts ephedrine can cause insomnia, tremors and indirectly by NA release. CO is increased. It irritability. On topical use, nasal irritation can is also a nasal decongestant. occur. Mephenteramine acts on both α and β receptors Most disadvantages result from long term to increase TPR and CO and thereby raises use - prolonged use of topical agents can BP. It is orally effective. Pressor effect is cause- accompanied by bradycardia. • atrophy of the nasal mucosa due to intense vasoconstriction. Phenylephrine is a selective α stimulant; it is 1 • recongestion or 'after congestion' may also a nasal decongestant. Reflex bradycardia result when the drug is stopped (due to is prominent. It produces mydriasis without vasodilatation). cycloplegia. • loss of efficacy or tolerance due to Methoxamine has actions similar to desensitization of the receptors. phenylephrine. Nasal decongestants should be used carefully in patients with hypertension. The NASAL DECONGESTANTS use of phenylpropanolamine is associated α with an increased risk of haemorrhagic Nasal decongestants are 1 agonists. They bring about vasoconstriction of the nasal stroke and is therefore banned. Adrenergic Drugs (Sympathomimetics) 75

Uses Isosxuprine is a selective β receptor stimulant • Rhinitis in upper respiratory infections. used as uterine relaxant in premature labour, • Allergic and vasomotor rhinitis, sinusitis. threatened abortion and dysmenorrhoea. • Blocked eustachian tubes. Nasal decongestants afford symptomatic ANORECTIC AGENTS (ANOREXIANTS) relief in the above conditions. Though amphetamine suppresses appetite, βββ SELECTIVE 2 STIMULANTS it is not recommended for the treatment β of obesity due to its central stimulant Selective 2 stimulants include orciprenaline, salbutamol, terbutaline and the newer ones effects. Many amphetamine like drugs include salmeterol, perbuterol, bitolterol, which suppress appetite but lack significant fenoterol and formoterol. These are smooth CNS stimulant effects are now available. muscle relaxants which produce broncho- They are fenfluramine, dexfenfluramine, dilatation, vasodilation and uterine relaxation mazindol, phenylpropanolamine (now banned), without significant cardiac stimulation. penmetrazine and others. Adverse effects include β Salbutamol and other 2 stimulants can be risk of abuse, drowsiness and depression given by inhalation. because of which they are only used for short Side effects include muscle tremors, palpitation periods as adjuncts to other measures. and arrhythmias. Sibutramine suppresses appetite and has been tried in obesity. It inhibits the uptake Uses of NA and 5-HT but causes many serious i. Bronchial asthma (chap 32) adverse effects including insomnia, anxiety, ii. As uterine relaxants to delay premature mood changes, hypertension and cardio- labour. vascular deaths.

Table 11.2 : Uses of adrenergic agonists

Indication Sympathomimetics used 1. Cardiac arrest – Adrenaline 2. Hypotension – Methoxamine, mephenteramine α 3. Hypertension – Clonidine ( 2 agonist) 4. Anaphylactic shock – Adrenaline 5. Severe allergic reactions – Adrenaline (bee sting, food & drug allergy) 6. To arrest local bleeding – Adrenaline 7. To prolong local anaesthesia – Adrenaline 8. Bronchial asthma – Salbutamol, terbutaline, salmeterol, ibuterol 9. Narcolepsy – Amphetamine, ephedrine 10. Glaucoma – Adrenaline, dipivefrine 11. Weight reduction – Fenfluramine, dexfenfluramine, mazindol, amphetamine 12. Nasal decongestion – Oxymetazoline, xylometazoline, 13. Mydriasis for fundoscopy – Phenylephrine 14. Attention deficit hyperactivity disorder – Amphetamine, methylphenidate 76 Textbook of Pharmacology for Dental and Allied Health Sciences 12 Adrenergic Antagonists

α ↑ Adrenergic blockers bind to the adrenergic Selective 2-blockade— NA release receptors and prevent the action of resulting in hypertension. adrenergic drugs. They may block alpha or α-blockade also results in miosis and nasal beta receptors or both. stuffiness. α-blockade in the bladder and prostate leads to decreased resistance to the ALPHA ADRENERGIC BLOCKING AGENTS flow of urine. α Alpha receptor antagonists block the Adverse effects of -blockers—Postural adrenergic responses mediated through hypotension, palpitation, nasal stuffiness, miosis, impaired ejaculation and impotence. alpha adrenergic receptors. Some of them α have selectivity for α or α receptors. blockers are classified as follows— 1 2 1. Non-selective Actions a. Non-competitive blocker Phenoxybenzamine α The important effects of receptor b. Competitive blockers stimulation are α mediated vasoconstriction 1 Ergot alkaloids (ergotamine), tolazo- and α - (presynaptic) receptor mediated 2 line, phentolamine, chlorpromazine inhibition of NA release. The result of alpha 2. Selective blockade by α-antagonists (Fig 10.3, Page 68) α a. 1-blockers are: Prazosin, terazosin, doxazosin, α -blockade—inhibits vasoconstriction -- 1 tamsulosin, alfuzosin leading to vasodilation and thereby ↓ BP. α b. 2-blocker This fall in BP is opposed by the baroreceptor Yohimbine reflexes which tend to ↑ heart rate and Phenoxybenzamine binds covalently to alpha cardiac output. receptors causing irreversible blockade. α -blockade—enhances release of NA 2 Given IV, blood pressure gradually falls and which stimulates β receptors (α are already is associated with tachycardia and increased blocked) - β stimulation in heart results in 1 CO. The action lasts for 3-4 days. It also tachycardia and increased cardiac output. Thus the predominant effects of non- blocks histamine, 5-HT and cholinergic selective α-blockade is hypotension with receptors. Phenoxybenzamine can be used α orally in the treatment of pheochromocy - tachycardia. This is because 2 receptors are blocked and there is no increase in NA toma (Table 12.1). release. Ergot alkaloids (Page 208) Ergotamine, α ergotoxine and their derivatives are Selective 1-blockade—results in hypotension without significant tachycardia. competitive antagonists and the blockade is Adrenergic Antagonists 77 of short duration. Some of them have a direct • They also relax the urinary bladder neck stimulant effect on smooth muscles—cause and the prostatic capsule because of which contraction of the uterus and ↑ BP due to they are useful in prostatic hypertrophy. vasoconstriction. Prolonged use of these can Prazosin is orally effective, extensively cause gangrene of the toes and fingers. bound to plasma proteins and is metabolised Phentolamine and tolazoline are competitive α- in the liver. Its duration of action is 8-10 hrs. blockers. In addition they also block 5-HT Adverse effects First dose phenomenon– one receptors, stimulate gut motility and ↑ gastric hour after the initial dose, marked postural secretion. Hence they can cause vomiting and hypotension occurs which may lead to diarrhoea in addition to the effects of α- fainting. To avoid this, prazosin should be blockade. started with a low dose and taken at bed time. Other side effects include headache and ααα Selective 1 Blockers dizziness. Tamsulosin can cause abnormal ejaculation. Prazosin is a potent, highly selective, α - 1 Congeners of Prazosin-include terazosin, blocker with 1000 times greater affinity for α doxazosin, alfuzosin and tamsulosin. Others 1 receptors. Arterioles and venules are dilated resulting in decreased peripheral are indoramin and urapidil. vascular resistance and cardiac output (CO • These congeners are longer acting and can falls because of venodilation→→→ decreased be given once daily. α preload). There is no significant tachycardia • highly selective for 1 receptors. α ↑ • Postural hypotension is milder than with (as 2 receptors are spared there is no in NA release). In addition it may decrease prazosin. central sympathetic outflow. Prazosin also • No significant effect on cardiac function. ↓ ↑ inhibits phosphodiesterase, the enzyme that • LDL and HDL cholesterol ↑ α degrades cAMP resulting in cAMP which • Tamsulosin has selective activity on 1A also contributes to vasodilation. receptors in the bladder and prostate while α Other actions: hypotension (mediated by 1B) is mild. • Prazosin and its congeners are found to Therefore tamsulosin relieves the ↓ LDL and triglycerides and ↑ HDL symptoms of benign prostatic hypertrophy cholesterol. (BPH) and is used in BPH.

Table 12.1 Compare and contrast phenoxybenzamine and prazosin

Features Phenoxybenzamine Prazosin

Chemistry β haloalkylamine Quinazoline Receptors blocked α adrenergic α adrenergic α α α Receptor Subtype Selectivity Both 1 and 2 1 selective Type of blockade Non equilibrium Equilibrium α ↑ Effects of 2 blockade NA release Does not increase Reflex tachycardia Significant Negligible Postural hypotension Significant Less Primary use Pheochromocytoma Hypertension 78 Textbook of Pharmacology for Dental and Allied Health Sciences

• Alfuzosin is also useful in BPH. BETA ADRENERGIC BLOCKING AGENTS • Terazosin and doxazosin are used in β-blockers are drugs that block the actions hypertension. of catecholamines mediated through the α β • Urapidil has 1 and 1 (weak) blocking β receptors. properties. It is used in hypertension and BPH. Classification α Yohimbine is a relatively selective 2-blocker ↑ 1. Non-selective: which increases BP and heart rate due to NA Propranolol, nadolol release. It causes congestion of genitals timolol, sotalol because of which it is used to treat β 2. Cardioselective ( 1) psychogenic impotence. It is also claimed to Metoprolol, atenolol, be an aphrodisiac though the effect is only acebutolol, esmolol psychological. 3. Partial agonists Pindolol, oxprenolol, Uses of α-blockers carteolol, bopindolol, penbutotol 1. Hypertension Selective α -blockers like 1 4. With additional alpha blocking property prazosin are used in the treatment of Labetalol, carvedilol hypertension (Page 116). Phenoxybenz- β β 5. 1 blocker 2 agonist amine or phentolamine can be used in Celiprolol. hypertensive crisis. 2. Pheochromocytoma is an adrenal medullary Pharmacological Actions tumour which secretes large amounts of 1. CVS β-blockers decrease heart rate, force catecholamines resulting in hypertension. of contraction and cardiac output. Blood The tumour has to be removed surgically. pressure falls. The effect is more Phenoxybenzamine and phentolamine are pronounced in presence of increased used for the preoperative management of sympathetic tone than in a normal situation. the patient and during the operation. AV conduction is delayed. Myocardial Inoperable cases are put on long-term oxygen requirement is reduced due to treatment with phenoxybenzamine. reduced cardiac work. They also improve 3. Peripheral vascular diseases like Raynaud’s exercise tolerance in angina patients. β- phenomenon may be benefited by α- blockers prevent the exercise-induced blockers which afford symptomatic relief. increase in heart rate and force of 4. Congestive cardiac failure Because of its contraction. vasodilator action, prazosin is useful in High doses cause direct depression of the heart. CCF. But ACE inhibitors are preferred. 2. Respiratory tract Blockade of β receptors 5. Benign prostatic hypertrophy (BPH) Blockade 2 in the bronchial smooth muscle causes of α receptors in the bladder, prostate and 1 increase in airway resistance—may urethra reduce resistance to urine outflow. precipitate acute attack in asthmatics. Prazosin, tamsulosin and alfuzosin are 3. Eye Many β-blockers reduce intraocular useful in patients who cannot be operated pressure by decreased secretion of aqueous upon. humor. Adrenergic Antagonists 79

4. Metabolic β-antagonists block lipolysis and especially in patients with peripheral β vascular disease. glycogenolysis ( 2 mediated) induced by sympathetic stimulation. Hence non- 4. β-blockers can precipitate acute asthmatic selective β blockers may interfere with attack in asthmatics and is contraindicated recovery from hypoglycaemia in diabetics. in them. Plasma triglycerides may increase and 5. CNS Insomnia, depression and rarely β HDL levels decrease in some patients. hallucinations can follow the use of - blockers. Pharmacokinetics 6. Fatigue due to decreased blood flow to the muscles during exercise and reduced Though well absorbed on oral administration, cardiac output. some β-blockers like propranolol undergo 7. Metabolic effects Weakness, ↓ exercise extensive first pass metabolism. Most of them capacity may be seen due to its metabolic have short t½ and are metabolised in the effects. liver. Dose Table 12.3 8. Abrupt withdrawal of β-blockers after prolonged use can cause rebound hyper- Adverse Reactions tension and precipitate anginal attacks. This is due to up-regulation of β receptors. 1. Bradycardia is common. Patients with AV Hence β-blockers should be gradually conduction defects may develop tapered. arrhythmias and heart block with β- 9. β blockers can also cause dizziness. blockers. 2. CCF In patients with impaired myocardial Contraindications function, sympathetic activity supports the heart. β-blockade eliminates this and may Beta blockers are contraindicated in precipitate CCF and acute pulmonary bradycardia, heart block, asthmatics and edema. chronic obstructive pulmonary disease 3. Cold extremities may be experienced (COPD).

Table 12.2: Compare and contrast propranolol and atenolol

Features Propranolol Atenolol

β β β 1. Receptors blocked Both 1 and 2 1 selective 2. Lipid solubility High Low 3. First pass metabolism High Not significant 4. Protein binding Extensive (>90%) Poor (<5%) 5. BBB Crosses Does not cross 6. Effects on CNS Significant No significant effects 7. Excretion through kidneys Negligible (0.5%) Major route (85%) 8. Plasma t½ 3 – 6 hrs 6 – 8 hrs 9. Duration of action Short (6-12 hrs) Long (12 – 24 hrs) 10. In asthmatic and chronic Contraindicated Not contraindicated - bronchitis patients used with caution 11. In diabetics and peripheral Avoided Can be used with caution vascular diseases 12. Local anaesthetic Yes No action 80 Textbook of Pharmacology for Dental and Allied Health Sciences

Some Important Drug Interactions Some Individual βββ-antagonists 1. Propranolol + insulin—when diabetics on Atenolol (see Table 12.2) insulin also receive propranolol: • Selective β -blocker β 1 i. -blockade masks tachycardia which is • Longer acting-given once daily the first warning signal of hypo- • Less lipid soluble-does not cross BBB- glycaemia. hence no CNS side effects β ii. -blockade delays the recovery from • No side effects on lipid profile. hypoglycaemia by preventing Hence very commonly used (25-100 mg glycogenolysis induced by sympathetic daily) β stimulation (acting through 2 receptors). This may be avoided by Esmolol using a β selective blocker. 1 • Selective β -blocker 2. Propranolol + verapamil—Because both 1 • Ultra short-acting– t½–8 minutes. these cause myocardiac depression, • Used IV profound depression may result if both are • Safer in critically ill patients and in used together. Hence the combination emergencies when immediate β-blockade should be avoided. is needed. 3. β-blockers + catecholamines—in patients β on nonselective -blockers, blockade of Metoprolol vascular β receptors results in up regulation β of the receptors and intense vasocons- • Selective 1 blocker triction is possible from even small doses • Well absorbed but undergoes significant of adrenaline that is used with LAs. Hence first-pass metabolism it is safer to use plain local anaesthesia in • Given twice daily (50-200 mg) such patients. • Used in hypertension and angina pectoris Cardioselective β-blockers e.g. Atenolol, Acebutolol metoprolol, esmolol. These drugs: • β selective with some partial agonistic β β 1 • Selectively block 1 receptors; 2-blockade effects is weak • May be used in hypertension and • Bronchospasm is less/negligible arrhythmias. • Inhibition of glycogenolysis is lower— hence safer in diabetics Celiprolol • Exercise performance is impaired to a β β • 1 blocker and 2 agonistic effects lesser degree • Safer in asthmatics • Lesser chances of peripheral vascular • Used in hypertension. disease. Partial agonists—Pindolol, oxprenolol. Timolol These have some sympathomimetic activity due to their partial β-agonistic property. As • Nonselective, short-acting • Used in glaucoma—as eyedrops. a result, bradycardia and myocardiac depression are less marked. They are Uses of βββ-blockers therefore preferred in patients who are likely 1. Hypertension β-blockers are useful in the to have severe bradycardia. treatment of mild to moderate hyper- Adrenergic Antagonists 81

Table 12.3: Doses of some β-blockers Drug (Trade name) Total daily dose (mg) Frequency

Propranolol (INDERAL) 40-240 6-12 hr Metoprolol (MEFOCARD) 50-200 12-24 hr Atenolol (ATEN) 25-100 once daily Pindolol (PINADOL) 10-45 6 hr Acebutolol (SECTRAL) 200-400 12-24 hr

tension. A β-blocker can be used alone or 8. Thyrotoxicosis Propranolol controls with other antihypertensives (Page 116). palpitation, tremors and affords 2. Angina pectoris β-blockers are useful in the symptomatic relief in thyrotoxicosis; it is prophylaxis of exertional angina. Both used as an adjuvant. It is also useful in the severity and frequency are reduced thyrotoxic crisis. (page 106). They reduce both cardiac 9. Glaucoma Timolol is used topically in open β work and O2 demand. angle glaucoma. Newer -blockers are 3. Cardiac arrhythmias β-blockers are useful now developed. in the treatment of both ventricular and 10. Prophylaxis of migraine Propranolol reduces supraventricular arrhythmias. Sotalol the frequency and severity of migraine has additional antiarrhythmic effects headache; used for prophylaxis. (Page 102). 11. Anxiety Propranolol prevents the acute 4. Myocardial infarction IV β-blockers in acute panic symptoms seen in public speaking, MI may limit the size of the infarct. In examination and other such anxiety- patients who have recovered from MI, provoking situations. Performance in β long-term treatment with -blockers musicians can be improved. Tremors, prolongs survival (page 108). tachycardia and other symptoms of 5. Congestive cardiac failure Earlier experience sympathetic overactivity are alleviated. has shown that β-blockers can worsen CCF because of their negative inotropic Alpha and Beta-adrenergic Blockers effect (page 95). But several recent α β β β studies have shown that when judiciously Labetalol blocks both 1 and ( 1 and 2) used in selected patients, β blockers can receptors. It is a competitive antagonist. be beneficial in CCF. They reduce the risk Heart rate, contractility, AV conduction and α β of sudden death and prolong survival on BP fall. Vasodilation ( 1 and blockade) and long term use. The exact mechanism is reduced CO contribute to antihypertensive not known. Sympathetic system is effect. Blood flow to the limbs increases. stimulated in CCF which may infact be Side effects include postural hypotension, GI deleterious to the heart in many ways disturbances and other effects of alpha and and even contribute to cardiac remo- beta blockade. delling. Blocking the β receptors may help Uses Labetalol is used in hypertensive to improve cardiac function and prevent emergencies and pheochromocytoma. cardiac remodelling. Carvedilol and medroxalol also are alpha and β- β α β β 6. Obstructive cardiomyopathy -blockers are antagonists. Carvedilol blocks 1, 1 and 2 found to be beneficial. receptors. In addition it has antioxidant 7. Pheochromocytoma Propranolol is given property. It is used in the treatment of with α-blockers before surgery to control hypertension and congestive cardiac hypertension. failure. 82 Textbook of PharmacologySection for Dental 3 and Allied Health Sciences Drugs Acting on the Kidney 13 Diuretics and Antidiuretics

Kidney, the excretory organ of our body serves the important functions of excretion of waste products, regulation of fluid volume and electrolyte content of the extracellular fluid.

PHYSIOLOGY OF URINE FORMATION Normally about 180 litres of fluid is filtered everyday, of which 99% gets reabsorbed and about 1.5 litres of urine is formed. For simplification, the nephron can be divided into four sites (Fig. 13.1). Proximal tubule Sodium bicarbonate, sodium chloride, amino acids and glucose are reabsorbed in the proximal tubule along with Fig. 13.1: Simplified diagram of a nephron showing sites water by specific transport mechanisms. of action of diuretics (1) Proximal tubule—osmotic diuretics, Osmotic diuretics act here. mannitol, (2) Ascending limb of Henle’s loop—loop diuretics, (3) Early distal tubule—thiazides, (4) Distal tubule Henle’s loop In the thin descending limb of and collecting duct—K+ sparing diuretics the loop of Henle, water is reabsorbed by osmotic forces. Hence osmotic diuretics are + + acting here too. The thick ascending limb in exchange for K and H to maintain the actively reabsorbs sodium chloride from the ionic balance regulated by aldosterone. lumen (but is impermeable to water) by Na+/ Absorption of water is under the control of K+/2Cl– co-transporter. ‘Loop diuretics’ antidiuretic hormone (ADH). selectively block this transporter. Diuretic is an agent which increases urine and Distal convoluted tubule In the early distal solute excretion. Diuretics may be classified tubule, sodium chloride is reabsorbed by an as follows- electrically neutral Na+ and Cl– transporter. CLASSIFICATION This transporter is blocked by thiazide diuretics. 1. High efficacy diuretics Collecting tubule In the late distal tubule and Furosemide, bumetanide, piretanide, collecting duct, NaCl– is actively reabsorbed, ethacrynic acid, torsemide, azosemide Diuretics and Antidiuretics 83

2. Moderate efficacy diuretics Thiazides Benzothiadiazines–Chlorothiazide, hydrochlorothiazide, polythiazide, bendroflumethiazide, Cyclopenthiazide Thiazide related agents Chlorthalidone, clopamide, indapamide, metolazone, xipamide 3. Low efficacy diuretics Potassium sparing diuretics Triamterene, amiloride, spironolactone Carbonic anhydrase inhibitors Acetazolamide, methazolamide Fig 13.2: Mechanism of action of loop diuretics dorzolamide Osmotic diuretics Other actions Loop diuretics also enhance the Mannitol, urea, glycerol excretion of K+, Ca++ and Mg++ (but Ca++ is Methylxanthines reabsorbed in the distal tubule—hence no Theophylline hypocalcaemia). They increase reabsorption HIGH EFFICACY, HIGH CEILING OR LOOP of uric acid in the proximal tubule. On long DIURETICS term use, they also alter renal haemo- dynamics to reduce fluid and electrolyte Loop diuretics act on the ascending limb of reabsorption in the proximal tubule. the loop of Henle. They are highly efficatious Frusemide is also a weak carbonic enhydrase as diuretics. Frusemide is the most commonly inhibitor hence it increases the excretion of used loop diuretic. – HCO3 and phosphate. Loop diuretics Frusemide (Furosemide) is a sulfonamide enhance renin release. derivative. It is a powerful diuretic. Given intravenously frusemide acts in 2-5 minutes, while following oral use, it takes Mechanism of Action 20-40 minutes; duration of action is 3-6 hours. Frusemide acts by inhibiting NaCl– Intravenous frusemide causes veno- reabsorption in the thick ascending limb of dilation and reduces left ventricular filling the Henle’s loop (Fig. 13.2). It blocks the Na+ pressure. It thus relieves pulmonary K+ 2Cl– symporter in the thick ascending limb congestion in congestive heart failure and in of the Henle's loop because of which it is pulmonary edema even before the onset of called is a loop diuretic. It greatly increases diuresis. the excretion of Na+ and Cl– in the urine. As a Pharmacokinetics Furosemide is rapidly large amount of NaCl– is absorbed in this absorbed orally, (Table 13.3) highly bound segment, loop diuretics are highly efficacious. to plasma proteins, metabolised in the liver Diuretic response increases with dose and and excreted by kidneys. Plasma t½ is 1½ over-enthusiastic treatment can cause hours and duration of action is 4 to 6 hours. dehydration (high ceiling of effect) (Table 13.1). Loop diuretics reach the ascending limb of 84 Textbook of Pharmacology for Dental and Allied Health Sciences

Henle's loop as they are secreted by the Uses organic acid transport system. 1. Edema Loop diuretics are highly effective Bumetanide is a sulfonamide like frusemide for the relief of edema of all origins like but is 40 times more potent than frusemide. cardiac, hepatic or renal edema. In Bioavailability is 80% and is better tolerated. chronic congestive cardiac failure loop Ethacrynic acid is more likely to cause adverse effects and hence is not commonly used. diuretics reduce venous and pulmonary Torsemide is a recently introduced loop congestion. diuretic. It is longer acting and therefore can 2. Acute pulmonary edema is quickly relieved be given once a day. by IV frusemide due to its immediate vasodilator effect and then by diuretic Adverse Effects of Loop Diuretics action. 3. Cerebral edema- frusemide is used as an 1. Hypokalaemia and metabolic alkalosis (due to alternative to osmotic diuretics. loss of H+ ) is dose dependent and can be 4. Forced diuresis In poisoning due to drugs corrected by K+ replacement and like barbiturates and salicylates, correction of hypovolaemia. frusemide is used with IV fluids. 2. Hyponatraemia, dehydration hypovolaemia and 5. Hypertension with renal impairment may hypotension should be treated with saline be treated with loop diuretics. infusion. 6. Hypercalcaemia and hyperkalaemia Loop 3. Hyperuricaemia may precipitate acute diuretics enhance excretion of Ca++ and attacks of gout. K+. But Na+ and Cl– should be replaced to 4. Hypocalcaemia and hypomagnesaemia - After avoid hyponatraemia and hypo- prolonged use this may result in chloraemia. osteoporosis. 5. Ototoxicity Loop diuretics cause hearing THIAZIDES AND THIAZIDE-LIKE loss by a toxic effect on the hair cells in DIURETICS the internal ear. Associated tinnitus and vertigo may also occur. Ototoxicity is more Chlorothiazide was the first thiazide to be common with ethacrynic acid. It is dose- synthesized. All thiazides have a sulfonamide related, more common on IV adminis- group. tration and generally reversible. Con- current use of other ototoxic drugs should Actions and Mechanism of Action be avoided. Thiazides act on the early distal tubule. 6. Hyperglycaemia and hyperlipidaemia are mild Thiazides have a moderate efficacy because in therapeutic doses. 90% of the filtered sodium is already 7. GIT disturbances like nausea, vomiting and reabsorbed before reaching the distal tubule. diarrhoea are common with ethacrynic This group of drugs block Na+/Cl– co- acid. transport system (Fig. 13.3) in the early distal 8. Allergic reactions like skin rashes are tubule (site 3). They also inhibit carbonic more common with sulfonamide anhydrase activity and increase bicarbonate derivatives. loss. Thiazides also enhance excretion of Mg+ Diuretics and Antidiuretics 85

Adverse Effects Hypokalaemia, metabolic alkalosis, hyperuricaemia, hypovolaemia, hypotension, dehydration, hyponatraemia, hypomagnesaemia, hypochloraemia, hypercalcaemia, and hyperlipidaemia are similar to that seen with loop diuretics. Hyperglycaemia induced by thiazides may precipitate diabetes mellitus probably by inhibition of insulin secretion. It is more common when long- acting thiazides are used for a long time. Thiazides can cause impotence in men. Weakness, fatigue, anorexia, gastrointestinal Fig. 13.3: Mechanism of action of thiazide diuretics disturbances and allergic reactions like rashes and photosensitivity can be seen. and K+ (in distal segments, Na+ in the lumen Uses is exchanged for K+ which is then excreted). But they inhibit urinary excretion of Ca++ and 1. Hypertension Thiazides are the first line uric acid resulting in hypercalcaemia and drugs (see page 111). hyperuricaemia. 2. Congestive heart failure Thiazides are useful in the management of edema due to mild Pharmacokinetics to moderate CHF. Thiazides are well absorbed orally and 3. Edema Thiazides may be tried in hepatic are rapid acting. Duration varies from 6-48 (cirrhosis) or renal edema. Renal edema hr (Table 13.2). They are excreted by the may be due to nephrotic syndrome, acute kidney. glomerulonephritis or chronic renal

Table 13.1: Compare and contrast hydrochlorothiazide and frusemide

Features Hydrochlorothiazide Frusemide Efficacy Low High Site of action Early distal tubule Ascending limb of loop of Henle Mechanism of action Inhibits Na+Cl– symport Inhibits Na+K+2Cl– cotransport Onset of action After 1 hour In minutes (20-40) Duration action Long (8-12 hrs) Short (3-6 hrs) Response to increasing dose No significant increase Increases (Dose dependent) Hyperuricemia Higher incidence Low Blood glucose May increase – No significant effect Contraindicated in Diabetics Not contraindicated Ototoxicity Not known to cause Can cause Primary use Hypertension Edema 86 Textbook of Pharmacology for Dental and Allied Health Sciences

Table 13.2: Dose and duration of action of commonly used diuretics

Diuretic Daily dose (mg) Duration (hrs) Brand name

Furosemide 20-80 mg 3-6 LASIX Bumetanide 0.5-2 mg 3-6 BUMET Hydrochlorothiazide 25-100 8-12 ESIDREX Polythiazide 1-3 24-48 NEPHRIL Chlorthalidone 50-100 48-72 HYTHALTON Xipamide 20-60 24-36 XIPAMID Metolazone 5-10 18-24 ZAROXYLIN Spironolactone 50-100 6-12 ALDACTONE Triamterene 50-100 4-6 DYTIDE (with benzthiazide) Amiloride 5-10 20-24 LASIRIDE (with frusemide)

failure. Metolazone may be combined with It enhances the excretion of calcium by a loop diuretics in severe refractory edema. direct action on the renal tubules. 4. Renal stones Hypercalciuria with renal Adverse effects include gynaecomastia, stones can be treated with thiazides which drowsiness, hyperkalaemia especially in renal reduce calcium excretion. insufficiency; metabolic acidosis and skin 5. Diabetes insipidus Thiazides reduce plasma rashes. volume and GFR - a paradoxical effect - Amiloride and triamterene are directly acting + and benefit such patients. agents which enhance Na excretion and Indapamide is particularly suitable in hypertension because it is claimed to lower blood pressure in subdiuretic doses and in such doses adverse effects are milder. It is well absorbed orally and has a long duration of action to permit once a day dosing.

POTASSIUM SPARING DIURETICS Aldosterone enhances the Na+ reabsorption through Na+ channels in the collecting tubule and enhances K+ secretion. It binds aldosterone receptors on distal tubule and collecting duct and competitively inhibits the action of Fig 13.4: Mechanism of action of potassium sparing aldosterone. Spironolactone is an aldosterone diuretics. Spironolactone antagonises the action of antagonist (Fig. 13.4). As major amount of Na+ aldosterone while amiloride and triamterene directly inhibit is already reabsorbed in the proximal parts, the Na+ channels. (ADH promotes reabsorption of water through aqueous channels - it also increases the number spironolactone has low efficacy. Spironolactone of these channels). also reduces K+ loss due to other diuretics. Diuretics and Antidiuretics 87

Table 13.3: Compare and contrast frusemide and spironolactone

Features Frusemide Spironolactone Chemistry Sulfonamide Synthetic steroid Sites of action Ascending limb of loop of Distal tubule and collecting duct Henle Mechanism of Blocks Na+/K+/2 Cl Aldosterone antagonist action cotransport Efficacy High Low Onset of action Quick - 2-5 minutes Slow – May take several days Effect on K+ ↑Excretion – Hypokalaemia ↓ excretion – Hyperkalaemia Unique adverse Ototoxicity Gynaecomastia, Hirsuitism effects Primary use * CCF, edema, ascitis * Hyperaldosteronism * Pulmonary edema * As adjuvant to other diuretics to reduce K+ loss. Contraindications Allergy to sulfonamides Peptic ulcer reduce K+ loss by acting on ion channels in Carbonic anhydrase inhibitors block sodium the distal tubule and collecting duct. They bicarbonate reabsorption and cause HCO – + 3 block the Na transport through ion-channels diuresis. Carbonic anhydrase is present in the + in the luminal membrane. Since K secretion nephron, eyes, gastric mucosa, pancreas and is dependent on Na+ entry, these drugs + other sites. reduce K excretion. Acetazolamide, a sulfonamide derivative is a Adverse effects are gastrointestinal disturba- carbonic anhydrase inhibitor and enhances nces, hyperkalaemia and metabolic acidosis. excretion of sodium, potassium, bicarbonate Uses of K+ Sparing Diuretics and water. The loss of bicarbonate leads to metabolic acidosis. 1. With thiazides and loop diuretics to prevent potassium loss. Other Actions 2. Edema In cirrhosis and renal edema where aldosterone levels may be high. 1. Eye The ciliary body of the eye secretes 3. Hypertension Along with thiazides to avoid bicarbonate into the aqueous humor. hypokalaemia and for additive effect. Carbonic anhydrase inhibition results in 4. Primary or secondary aldosteronism decreased formation of aqueous humor Spironolactone is used. and thereby reduces intraocular pressure. 2. Brain Bicarbonate is secreted into CSF and CARBONIC ANHYDRASE INHIBITORS carbonic anhydrase inhibition reduces the Carbonic anhydrase is an enzyme that formation of CSF. catalyses the formation of carbonic acid which spontaneously ionises to H+ and Adverse Effects – – + – HCO3 . This HCO3 combines with Na and is 1. Metabolic acidosis due to HCO3 loss. reabsorbed. ++ – 2. Renal stones–Ca is lost with HCO3 resulting in hypercalciuria. This excess H2O + CO2 H2CO3 Ca++ may precipitate resulting in the + – formation of renal stones. H2CO3 H + HCO3 88 Textbook of Pharmacology for Dental and Allied Health Sciences

3. Hypokalaemia, drowsiness and allergic 2. To reduce intracranial and intraocular reactions can occur. pressure–following head injury and glaucoma respectively. Uses Glycerol is effective orally. It reduces 1. Glaucoma–(see page 49) Intraocular intraocular and intracranial pressure. pressure is decreased by acetazolamide; Methylxanthines like theophylline have mild it is given orally. Newer ones–methazo- diuretic effect. lamide and dorzolamide are better tolerated and are available as eye drops. Drug Interactions with Diuretics 2. Alkalinization of urine–as required 1. Frusemide and ethacrynic acid are highly in overdosage of acidic drugs. Also, uric protein bound and may compete with acid and cysteine excretion can be drugs like warfarin and clofibrate for enhanced as these are soluble in alkaline protein binding sites. urine. 2. Other ototoxic drugs like aminoglycosides 3. Metabolic alkalosis–acetazolamide – should not be used with loop diuretics to enhances HCO3 excretion. 4. Mountain sickness–In mountain climbers avoid enhanced toxicity. who rapidly ascend great heights, severe 3. Hypokalaemia induced by diuretics pulmonary edema or cerebral edema may enhance digitalis toxicity. occur. Acetazolamide may relieve 4. NSAIDs blunt the effect of diuretics as symptoms by reducing the formation and they cause salt and water retention to pH of CSF-it can also be used for avoid enhanced toxicity. prophylaxis. 5. Diuretics enhance lithium toxicity by 5. Epilepsy–acetazolamide is used as an reducing renal excretion of lithium. adjuvant as it increases the seizure 6. Other drugs that cause hyperkalaemia + threshold. (ACE inhibitors) and oral K supplements should be avoided with K+ sparing OSMOTIC DIURETICS diuretics because, given together they can cause severe hyperkalaemia. Mannitol is a pharmacologically inert substance. When given IV (orally not DIURETICS AND DENTISTRY absorbed), mannitol gets filtered by the glomerulus but not reabsorbed. It causes 1. When a patient is on concurrent medication water to be retained in the proximal tubule with anticoagulants like warfarin and and descending limb of Henle’s loop by diuretics like frusemideprofound anti- osmotic effect resulting in water diuresis. coagulant activity would be present. Minor There is also some loss of sodium. dental procedures including dental Adverse effects are dehydration, ECF extraction can cause severe bleeding. volume expansion, headache and allergic 2. When a patient is already receiving reactions. frusemide or other loop diuretics, avoid using aminoglycoside antibiotics as the Uses ototoxicity can get added up. 3. It is necessary to be cautious when it is 1. To maintain urine volume and prevent required to give any of the NSAIDs to a oliguria in conditions like massive haemolysis and shock. patient who is already receiving diuretics Diuretics and Antidiuretics 89

because NSAIDs blunt the diuretic effect. Adverse Effects However one or two doses of analgesics When used intranasally ADH can cause nasal does not matter much. irritation, allergy, rhinitis and atrophy of nasal mucosa. Other effects include nausea, ANTIDIURETICS abdominal cramps and backache (due to Antidiuretics are drugs that reduce urine contractions of the uterus). volume. These include 1. Antidiuretic hormone (Vasopressin) Uses 2. Thiazide diuretics 1. Diabetes insipidus of pituitary origin– 3. Miscellaneous Desmopressin is the preparation used. It – Chlorpropamide should be used life long. – Carbamazepine. 2. Bleeding oesophageal varices–ADH Antidiuretic hormone (ADH) is secreted by the constricts mesenteric blood vessels (V1 anterior pituitary along with oxytocin. It is receptors) and may help. Analogs like synthesized in the supraoptic and desmopressin, terlipressin and lypressin paraventricular nuclei of the hypothalamus, can be used. transported along the hypothalamo- 3. Before abdominal radiography—expels hypophyseal tract to the posterior pituitary gases from the bowel. and is stored there. 4. Haemophilia and Von Willebrand’s ADH is released in response to two stimuli – disease - ADH may release factor VIII and dehydration and rise in plasma osmolarity. prevent bleeding.

Vasopressin Receptors Vasopressin Analogs

ADH acts on V1 and V2 receptors. V1 receptors Desmopressin is selective for V2 receptors and are present in vascular and other smooth is longer acting. It is given as nasal spray. muscles, kidneys and anterior pituitary while Terlipressin is longer acting while felypressin

V2 receptors are present in collecting duct in is short acting. Felypressin is used with local the kidneys. (See Fig 13.4). anaesthetics to prolong the duration of action because of its vasoconstrictor properties. Actions Lypressin is another analog used in place of ADH. ADH enhances water reabsorption by acting on the collecting duct. ADH activates the V 2 Miscellaneous receptors present on the cell membrane of the collecting duct and increases the water Thiazides Paradoxically thiazides reduce urine permeability of these cells. ADH causes volume in diabetes insipidus of both vasoconstriction and raises BP mediated by pituitary and renal origin by an unknown mechanism. V1 receptors. It also acts on other smooth muscles to increase peristalsis in the gut and Chlorpropamide an oral hypoglycaemic, contracts the uterus. sensitizes the kidney to ADH action. Vasopressin is given parenterally as Carbamazepine an antiepileptic, stimulates ADH injection- SC/IM/IV. secretion. 90 Textbook of PharmacologySection for Dental 4 and Allied Health Sciences Cardiovascular System Cardiac Glycosides 14 and Treatment of Cardiac Failure

The cardiac muscle is a specialised tissue with unique properties like excitability, contractility and automaticity. The myocardium has two types of cells—the contracting cells and the conducting cells. The contracting cells participate in the pumping action of the heart. Parts of the conducting tissue have the characteristic property of automaticity. Automaticity is the ability of the cell to generate electrical impulses spontaneously. SA node, AV node and His- Purkinje system comprise the conducting tissue of the heart. Normally the SA node acts as the pace maker. Excitability is the ability of the cell to undergo depolarization in response to a stimulus. Contractility is the Fig. 14.1: Cardiac action potential phases 0-4: Phase 0— indicates rapid depolarisation, Phases 1-3—indicate ability of the myocardium to adequately repolarisation, Phase 4—gradual depolarisation during contract and pump the blood out of the heart. diastole Cardiac action potential When a stimulus reaches the cardiac cell, specific ions move Phase 2 is a prolonged plateau phase due to into and out of the cell eliciting an action slow entry of calcium ions into the cell potential. Such movement of ions across the through the calcium channels. Cardiac cell cardiac cell may be divided into phases differs from other cells in having this phase (Fig. 14.1). of action potential. Phase 0 is rapid depolarisation of the cell Phase 3 is a second period of rapid membrane during which there is fast entry repolarisation with potassium ions moving of sodium ions into the cell through the out of the cell. sodium channels. This is followed by Phase 4 is the resting phase during which repolarisation. potassium ions return into the cell while Phase 1 is a short, initial, rapid repolarisation sodium and calcium ions move out of it and due to efflux of potassium ions. the resting membrane potential is restored. Cardiac Glycosides and Treatment of Cardiac Failure 91

During phases 1 and 2, the cell does not Low output failure could result from depolarise in response to another impulse, ischaemic heart disease, hypertension, i.e. it is in absolute refractory period. But valvular and congenital heart diseases. High during phases 3 and 4, the cell is in relative output failure results from anaemia, refractory period and may depolarise in thyrotoxicosis, beriberi and certain congenital response to a powerful impulse. heart diseases. The cardiac output is determined by heart The drugs used in CCF include diuretics, rate and stroke volume. The stroke volume vasodilators and cardiac glycosides. The in turn depends on the preload, afterload and pharmacology of cardiac glycosides has been contractility. Preload is the load on the heart discussed first, followed by the role of other due to the volume of blood reaching the left drugs in CCF. ventricle. It depends on the venous return. Afterload is the resistance to the left CARDIAC GLYCOSIDES ventricular ejection, i.e. the total peripheral Cardiac glycosides are obtained from the resistance. plants of the foxglove family. Though these Congestive cardiac failure (CCF) is one of the plants were known to Egyptians 3000 years common causes of morbidity and mortality. ago, they were irrationally used. William In congestive cardiac failure, the heart is Withering, an English physician first unable to provide adequate blood supply to described the clinical effects of digitalis in meet the body’s oxygen demand. The CCF in 1785. pumping ability of the heart is reduced and Source Digitoxin is obtained from the leaves the cardiac output decreases. The ventricles of Digitalis purpurea. From the leaves of are not completely emptied resulting in Digitalis lanata, digitoxin and digoxin are increased venous pressure in the pulmonary derived and the seeds of Strophanthus gratus and systemic circulation. This causes contain ouabain. They are all called cardiac pulmonary oedema, dyspnoea, liver glycosides but digoxin is the most commonly enlargement and peripheral oedema. As a used of them because of its favourable compensatory mechanism, there is pharmacokinetic properties. The word stimulation of the sympathetic system, renin digitalis is used to mean cardiac glycosides. angiotensin system and release of atrial Chemistry The glycosides consist of an aglycon natriuretic peptides which help in attached to sugars. The aglycon has maintaining the cardiac output. Atria, pharmacodynamic activity while sugars ventricles and vascular endothelium store influence pharmacokinetic properties. natriuretic peptides and release them in volume overload. These peptides increase Pharmacological Actions renal excretion of salt and water and dilate 1. Cardiac actions vascular smooth muscles. The myocardium • Positive inotropic effect Cardiac glycosides also undergoes structural alterations like are cardiotonic drugs - they increase the ventricular hypertrophy and remodelling to force of contraction of the heart - the adapt itself to the stressful situation. These stroke volume increases and thereby the compensatory changes maintain the cardiac cardiac output. The systole is shortened output for sometime. and the diastole is prolonged which Depending on the cardiac output, cardiac allows more rest to the heart. The failure may be of two types-low output ventricles are more completely emptied failure and high output failure. because of more forceful contractions. 92 Textbook of Pharmacology for Dental and Allied Health Sciences

• The heart rate is reduced due to: Mechanism of action Cardiac glycosides inhibit a. increased vagal tone the enzyme Na+K+ ATPase—also called the b. decreased sympathetic overactivity ‘sodium pump’ present on the cardiac myocytes due to improved circulation (Fig. 14.2 and Fig. 14.3). Inhibition of this c. by a direct action on SA and AV nodes. pump results in an increase in the intracellular The effects on electrophysiological properties Na+ and Ca++. Thus more calcium is available of the heart varies with dose and in different for contraction, resulting in increased force parts of the heart. Digitalis shortens and velocity of contraction. This happens as ventricular refractory period, depresses AV follows– conduction and enhances automaticity of the Inhibition of the ‘sodium pump’ increases ventricles and the Purkinje cells. Digitalis also intracellular sodium because sodium gets ++ produces the characteristic ECG changes. accumulated. This prevents Ca extrusion + ++ • Blood pressure No significant effects in CCF from the cardiac cell (through Na –Ca patients. Pulse pressure may increase. exchanger) and also drives more calcium into the cell during depolarisation through • Coronary circulation improves due to voltage-sensitive calcium channels. This increased cardiac output and prolonged excess calcium gets stored in the sarcoplasmic diastole during which the coronaries get reticulum. As a result more calcium is filled better. available for contraction and thus an 2. Extracardiac actions increased amount of calcium is released • Kidney—Diuresis occurs which relieves during each action potential resulting in an edema in CCF patients. increased force and velocity of contraction. • CNS—High doses stimulate CTZ resulting in nausea and vomiting.

Cardiac glycosides ↓ ↓Na+ pump ↓ Accumulation of intracellular Na+

Prevents ↑Ca++ entry extrusion of Ca++ through Ca++ (by Na+ Channels Ca++ exchanger)

↑intracellular Ca++ ↓ More Ca++ Stored in sarcoplasmic reticulum ↓ More Ca++ released during each depolarisation ↓ Fig. 14.3: Mechanism of action of cardiac glycosides. + + ↑force and velocity of contraction Cardiac glycosides inhibit the Na K ATPase pump and ↑intracellular Na+ which in turn prevents Ca++ extrusion. Thus more calcium is available for contraction. SR–Sarcoplasmic Fig. 14.2: Mechanism of action of cardiac glycosides reticulum Cardiac Glycosides and Treatment of Cardiac Failure 93

Pharmacokinetics Digoxin is well-absorbed Extracardiac Anorexia, nausea, vomiting and (Table 14.1). Presence of food in the stomach diarrhoea are the first symptoms to appear. delays absorption. Bioavailability varies with Cardiac glycosides directly stimulate the different manufacturers and because the CTZ. Weakness, confusion, hallucinations, safety margin is low, in any given patient, blurred vision and gynaecomastia can occur. the preparations from the same manufacturer Cardiac toxicity Arrhythmias of any type should be used. Glycosides are cumulative including extrasystoles, bradycardia, pulses drugs. bigeminy and AV block (ventricular Digitalization Response to digitalis develops tachycardia and fibrillation) can be caused over 5-7 days with the maintenance dose as by cardiac glycosides. Hypokalaemia enhances digitalis toxicity (Table 14.2). given in mild to moderate cases of CCF. But when rapid response is required, rapid Treatment of Toxicity digitalization can be done by more frequent • Stop digitalis dosing with constant monitoring. • Oral or parenteral K+ supplements are Adverse effects Cardiac glycosides have a low given safety margin and adverse effects are • Ventricular arrhythmias are treated with + + common. They inhibit Na /K -ATPase in all IV lignocaine excitable tissues - including neurons and • Bradycardia is treated with atropine and smooth muscle cells where spontaneous supraventricular arrhythmias with activity is increased - responsible for toxicity. propranolol

Table 14.1: Compare and contrast digoxin and digitoxin

Properties Digoxin Digitoxin

1. Source Digitalis lanata Digitalis purpurea and lanata 2. Pharmacokinetics • Route of administration Oral, IV Oral • Absorption 40-60% 90-100% • Plasma protein binding 25% 95% • Onset of action 15-30 min 30-120 min • t½ 24-48 hr 5-7 days • Time for digitalization (without loading dose) 5-7 days 25-30 days 3. Dose • Daily dose (slow loading or maintenance) 0.125-0.5 mg 0.05-0.2 mg • Rapid digitalising dose 0.5-0.75 mg every 0.2-0.4 mg every 8 hours 3 doses 12 hours 3 doses • Route of elimination Renal excretion Hepatic metabolism

4. Used for • Most used among • Less often used cardiac glycosides • Used for initiation and • Used only for maintenance maintenance therapy therapy 94 Textbook of Pharmacology for Dental and Allied Health Sciences

• In severe toxicity–antidigoxin immuno- DRUGS USED IN CONGESTIVE therapy (antidigoxin antibodies) is now CARDIAC FAILURE available. It can be life saving in severe In congestive cardiac failure, the heart is digoxin overdosage. unable to provide adequate blood supply to Uses meet the demand. The aim of treatment is to reduce morbidity and mortality by restoring 1. Congestive cardiac failure (see below) cardiac output and relieving congestion. 2. Cardiac arrhythmias The drugs used in CCF include: • Atrial fibrillation and atrial flutter— 1. Diuretics digoxin reduces the ventricular rate 2. Vasodilators • Paroxysmal supraventricular tachy- 3. Positive inotropic agents - cardia (PSVT)—digoxin is an alter- • Digitalis native to verapamil. • β adrenergic agonists Precautions and contraindications to • Phosphodiesterase (PDE) inhibitors digitalis therapy • Others • Hypokalaemia—enhances toxicity 1. Diuretics High ceiling diuretics like • MI, thyrotoxicosis patients and elderly— frusemide are used. They increase salt and more prone to arrhythmias water excretion and reduce blood volume. • Acid base imbalance—prone to toxicity. By this they reduce preload and venous Other Positive-inotropic Drugs pressure, improve cardiac performance and relieve oedema. Phosphodiesterase inhibitors–Amrinone 2. Vasodilators reduce the mortality in patients (inamrinone) and milrinone-These drugs inhibit with cardiac failure. Vasodilators may be the enzyme phosphodiesterase (which arteriolar or venular dilators or both. ↑ degrades cAMP) resulting in cAMP levels. • Arteriolar dilators (↓ after load) — They increase the force of contraction and hydralazine-relax arterial smooth also cause vasodilatation. But because of the muscles, thus reducing peripheral adverse effects and increased mortality seen vascular resistance (↓ afterload). As a with the use of these drugs, they are result, the work load on the heart is generally not preferred. However, they may reduced. be used for short periods in severe heart • Venodilators (↓ preload) — nitrates - failure. Milrinone has shorter t½ and fewer reduce the venous return to the heart side effects. (↓ preload) thus reducing the stretching Table 14.2: Drug interactions of the ventricular walls and myocardial oxygen requirements. Drugs that enhance digoxin toxicity Organic nitrates: Nitroglycerine and • Diuretics (due to hypokalaemia), calcium isosorbide dinitrate are good • Quinidine, verapamil, methyldopa– vasodilators with a rapid and short ↑digoxin levels action. They can be used for short Drugs that reduce digoxin levels periods to decrease the ventricular • Antacids, neomycin, metoclopramide– filling pressure in acute heart failure. ↓ absorption • Rifampicin, phenobarbitone–hasten meta- Nitroglycerine can be used IV in acute bolism due to enzyme induction CCF. Nitrates may be given in combination with hydralazine. Cardiac Glycosides and Treatment of Cardiac Failure 95

• Both arteriolar and venular dilators— patients in whom other vasodilators are ACE inhibitors, sodium nitroprusside, contraindicated. prazosin, calcium channel blockers - 3. Positive inotropic agents these reduce both preload and Digitalis: Mild to moderate cases of low afterload. output failure are treated with diuretics and Angiotensin converting enzyme inhibitors vasodilators (ACE-inhibitors preferred). (ACE-I) (Page 111) like captopril, enalapril, When patients are not controlled by these, lisinopril and ramipril act by - they may be given digoxin. Digoxin improves i. reduction of afterload Angiotensin II is a cardiac performance in the dilated, failing heart. If there is associated atrial fibrillation, powerful vasoconstrictor present in the digoxin is the preferred drug in such plasma in high concentrations in cardiac patients. failure. ACE-I prevent the conversion of β adrenergic agonists: Dobutamine is a positive angiotensin I to angiotensin II and thereby β inotropic agent. It stimulates the cardiac 1 reduce the after load. receptors and enhances the force of ii. reduction of preload Aldosterone causes salt contraction of the cardiac muscle. It increases and water retention and increases plasma the cardiac output without significant volume. ACE-I prevent the formation of tachycardia. It also produces some aldosterone (by reducing Ang-II) and β vasodilation by stimulating the 2 receptors. thereby reduce the preload. They also Dopamine may be used in patients with prevent bradykinin degradation and associated renal impairment because increase bradykinin levels which also dopamine increases renal perfusion in addition causes vasodilatation. to increased cardiac output. iii. reversing compensatory changes Angiotensin PDE Inhibitors: Amrinone or milrinone may II formed locally in the myocardium is be used for short periods to enhance the responsible for various undesirable cardiac output in severe heart failure. compensatory changes like ventricular 4. Others β β hypertrophy and ventricular remodelling Adrenergic blockers : Though blockers are seen in CCF. ACE-I reverse these changes. negative inotropic agents, several recent studies have shown that when used carefully ACE inhibitors are the most preferred drugs along with other drugs, β blockers can in chronic congestive cardiac failure. improve long-term survival (Page 80). Sodium nitroprusside is a powerful vasodilator. Since it dilates both arterioles and venules, Cardiac Failure and Dentistry it reduces both ventricular filling pressure 1. The antibiotic neomycin can reduce and peripheral arterial resistance. It is given digoxin absorption and could worsen IV, has a rapid (30-60 sec) and short action (3 CCF. Alternative antibiotic may be used minutes). Hence it is useful in acute severe if its long-term use is required. heart failure. 2. Use of NSAIDs especially long-term use α Prazosin an 1 antagonist, is a vasodilator. It can cause salt and water retention and can be used in acute heart failure for longer worsen CCF. periods than nitrates. 3. A knowledge of CCF is necessary as a Calcium channel blockers are not routinely used. dentist has to be careful while carrying Amlodipine or felodipine may be tried in on surgical procedures in such patients. 96 Textbook of Pharmacology for Dental and Allied Health Sciences

15 Calcium Channel Blockers

The discovery of the calcium channels in the calcium channels - L, N and T types). This cardiac cells helped in understanding the decreases calcium current and calcium entry mechanisms involved in smooth muscle into cardiac and vascular smooth muscle cells contraction. Verapamil was the first agent resulting in the following effects— found to have calcium channel blocking 1. Vascular smooth muscle Relaxation of the properties and now we have many more. arteriolar smooth muscles results in reduced peripheral vascular resistance Dihydropyridines and blood pressure. The effect on venous Nifedipine Nicardipine beds is not significant. Reflex tachycardia Nimodipine Nitrendipine may occur with some CCBs like Nisoldipine Felodipine nifedipine. Dihydropyridine CCBs have Amlodipine Isradipine prominent effects on the blood vessels, i.e. they are vascular selective. Others 2. Heart CCBs depress myocardial Verapamil Diltiazem contractility, reduce heart rate and in Bepridil higher doses they slow AV conduction. The depolarisation of the cardiac and They reduce cardiac work and thereby vascular smooth muscle cells depend on the myocardial oxygen consumption. entry of extracellular calcium into the cell Verapamil, bepridil and diltiazem have through the calcium channels. Intracellular prominent cardiac effects. calcium is also increased by receptor- 3. Coronary circulation CCBs dilate the mediated action – i.e. agonist induced calcium coronary vessels, increasing the coronary release. This calcium triggers the release of blood flow. Hence they are useful in intracellular calcium from the sarcoplasmic variant angina. reticulum. All these calcium ions bring about 4. Other effects contraction of the cardiac and vascular • Nimodipine is highly lipid soluble, smooth muscle cells. crosses the BBB and relaxes the Calcium channel antagonists inhibit the cerebral blood vessels. entry of calcium by blocking the L-type • CCBs relax the uterus and may be of calcium channels. (There are 3 types of useful in premature labour. Calcium Channel Blockers 97

Pharmacokinetics CCBs are well-absorbed but some pharmacokinetic variations. They undergo extensive first pass metabolism. have higher vascular selectivity. They are all highly plasma protein bound and • Amlodipine, felodipine, nitrendipine and are metabolized in the liver. nisoldipine are longer acting and can be Verapamil has prominent myocardiac given once daily. depressant actions. AV conduction is • Nimodipine selectively relaxes cerebral depressed and usually bradycardia is seen. vasculature as it crosses the BBB because Hence it should not be combined with β- it is highly lipid soluble. blockers. Fall in BP is mild as the vasodilator Therapeutic Uses of CCBs effect of verapamil is less potent. Diltiazem has less potent vasodilator effects but is a 1. Angina pectoris – CCBs are useful in the myocardiac depressant. the prophylaxis of patients with exertional Adverse effects of verapamil and diltiazem angina as they decrease myocardial include constipation, bradycardia, heart oxygen demand and bring about coronary block, hypotension and skin rashes. They vasodilatation. CCBs are also useful in may precipitate CCF in patients with diseased variant angina as they bring about heart. coronary vasodilation. 2. Hypertension – Long acting CCBs or Dihydropyridine CCBs sustained release preparations may be used in chronic hypertension. In Nifedipine is a potent vasodilator and causes hypertensive crisis nifedipine is used a significant fall in BP and evokes reflex sublingually or the capsule is bitten and tachycardia. Myocardiac depressant effect is swallowed. weak (table 15.1). It can be given sublingually. 3. Arrhythmias – Verapamil, diltiazem and Adverse effects of nifedipine are headache, bepridil have antiarrhythmic properties. flushing, palpitation, dizziness, fatigue, Verapamil is used in PSVT and to control hypotension, leg cramps and ankle oedema. ventricular rate in atrial flutter or Long term use can cause gum hypertrophy. fibrillation. 4. Peripheral vascular disease – Nifedipine, Other Dihydropyridines Like felodipine and diltiazem can be used in • Amlodipine, felodipine, nitrendipine and Raynaud’s disease for their vasodilator nicardipine are similar to nifedipine with effects. Table 15.1: Compare and contrast verapamil and nifedipine

Verapamil Nifedipine

1. Bioavailability Poor (20-35%) Good (50-70%) 2. Sublingual form Not available Available 3. t½ 6 hrs 4 hrs 4. Effects on heart Prominent Weak 5. Effects on vasculature Mild Prominent 6. Reflex tachycardia Negligible Prominent 7. Use in arrhythmias Used Not used 98 Textbook of Pharmacology for Dental and Allied Health Sciences

5. Other uses (iv) Preterm labour – Nifedipine inhibits (i) Hypertrophic cardiomyopathy - uterine contractions and is found to Verapamil can be beneficial due to its be useful in delaying labour in negative inotropic effects on the heart. premature uterine contractions. (ii) Migraine – Verapamil is useful in the prophylaxis of migraine Drug Interactions (iii) Subarachnoid haemorrhage – Vasospasm that follows subarachnoid • Verapamil and diltiazem should be avoided haemorrhage is believed to be in patients receiving beta-adrenergic responsible for neurological defects. blockers because the myocardiac dep- As nimodipine brings about cerebral ressant effects get added up. vasodilatation, it is used to treat • Verapamil can precipitate digoxin toxicity neurological deficits in patients with by increasing digoxin levels (verapamil cerebral vasospasm. reduces digoxin excretion). Antiarrhythmic Drugs 99

16 Antiarrhythmic Drugs

Arrhythmia is an abnormality of the rate, Class II. β-adrenergic blockers rhythm or site of origin of the cardiac (reduce sympathetic tone) impulse or an abnormality in the impulse - Propranolol, acebutolol, conduction. The word dysrhythmia is also esmolol, etc. used by some. Cardiac arrhythmias may be Class III. K+ channel blockers due to abnormal generation or conduction (Prolong repolarization) of impulses. Factors like myocardial hypoxia, - Amiodarone, bretylium, sotalol, myocardial ischaemia, electrolyte distur- dofetilide, ibutilide bances, trauma, drugs and autonomic Class IV. Ca++ channel blockers influences can cause arrhythmias. (Prolong conduction and Arrhythmias may be tachyarrhythmias, refractoriness specially in SA bradyarrhythmias or digitalis-induced and AV nodes) arrhythmias. Based on the site of impulse - Verapamil, diltiazem origin, they may be grouped as supra- Sodium Channel Blockers ventricular (SA node, AV node, atria) or ventricular arrhythmias (in ventricles). Mechanism of action All drugs in Class I block Ventricular arrhythmias are a common cause the sodium channels and prevent the inward of death, particularly sudden death. movement of Na+ ions. The sodium channels exist in three states—resting, open and CLASSIFICATION inactivated (refractory) state. Sodium + Based on the cardiac cycle, Vaughan Williams channel blockers preferrentially bind Na classified antiarrhythmics as follows: channels in the open and inactivated state Class I. Sodium channel blockers and thus interfere with depolarisation. + A. Prolong repolarization Class IA drugs block Na channels and - Quinidine, procainamide, depress phase-0 depolarisation. They also + disopyramide, moricizine prolong repolarisation by blocking K B. Shorten repolarization channels. (Fig. 16.1) - Lignocaine, mexiletine, Quinidine phenytoin C. Little effect on repolarization Quinidine is the D-isomer of quinine - Encainide, flecainide, obtained from the cinchona bark. By blocking propafenone Na+ channels, it depresses all cardiac 100 Textbook of Pharmacology for Dental and Allied Health Sciences

Non-cardiac - Diarrhoea, nausea, vomiting and hypersensitivity reactions including thrombocytopenia and rarely bone marrow depression, hepatitis and idiosyncratic reactions can occur. Higher doses can cause cinchonism like quinine.

Drug Interactions • Quinidine is a microsomal enzyme inhibitor. It raises the plasma levels of propafenone and reduces the conversion of codiene to morphine thereby decreasing its analgesic efficacy. • Microsomal enzyme inducers like phenytoin and phenobarbitone enhance Fig. 16.1: Cardiac action potential: Phase 0-rapid depolarisation, phase 1-initial rapid repolarisation, phase metabolism of quinidine resulting in 2-prolonged plateau phase, phase 3-second rapid therapeutic failure. repolarisation, phase 4-resting phase • Quinidine reduces the clearance of digoxin thereby precipitating digoxin properties—automaticity, excitability, toxicity. conduction velocity and prolongs Procainamide a derivative of the local repolarization - quinidine thus has anaesthetic procaine has the advantages over membrane-stabilizing activity, i.e. it inhibits quinidine that it has weak vagolytic the propagation of the action potential. properties and is not an α-blocker. It is better Quinidine also has vagolytic and α- tolerated than quinidine and can cause blocking properties. It is also a skeletal muscle nausea, vomiting and hypersensitivity relaxant. reactions including lupus syndrome. Higher Pharmacokinetics Given orally quinidine is doses can cause hypotension, heart block and rapidly absorbed, 90% bound to plasma torsades de pointes. proteins, metabolised in the liver and Disopyramide has significant anticholinergic excreted in the urine. properties which is responsible for adverse Adverse effects Quinidine is not well-tolerated effects like dry mouth, blurred vision, due to adverse effects and may need to be constipation and urinary retention. It can also stopped. cause torsades de pointes. Cardiac Quinidine itself can cause arrhythmias Uses Class IA drugs are useful in almost all and heart block. It can also cause hypotension, types of arrhythmias (Table 16.1). They are prolongation of QT interval and torsades de used in atrial fibrillation and atrial flutter for pointes. Torsades de pointes refers to maintenance of sinus rhythm and in polymorphic ventricular tachycardia and is ventricular arrhythmias to prevent so called because of the pattern of EEG recurrence. Because of the adverse effects, changes - in French, it means twisting of quinidine and procainamide are not preferred points. All drugs which prolong QT interval by most practitioners in arrhythmias but can also cause this. Hence treatment should quinidine can be used in malaria in place of be monitored. quinine. Antiarrhythmic Drugs 101

Class IB Drugs ventricular arrhythmias, especially that caused by acute myocardial infarction or Class IB drugs block the sodium channels and open heart surgery. Lignocaine is not useful also shorten repolarization. in atrial arrhythmias and the reason for this Lignocaine suppresses the electrical activity is not clear. It could be because the atrial of the arrhythmogenic tissues while the action potentials are so short that the sodium normal tissues are not much affected. It is a channels are in an inactivated state for a very local anaesthetic. Given orally lignocaine short period and lignocaine is unable to block undergoes high first pass metabolism and has them. a short t½—hence used parenterally. It may Phenytoin is an antiepileptic also useful in cause drowsiness, hypotension, blurred ventricular arrhythmias (not preferred due vision, confusion and convulsions. to toxicity) and digitalis induced Lignocaine is used in the treatment of arrhythmias.

Table 16.1: Major causes and choice of drugs in cardiac arrhythmias

Arrhythmia Cause Treatment

Sinus tachycardia ↑ sympathetic tone, • Treat the cause fever, thyrotoxicosis • If severe →propranolol Atrial extrasystoles Excess caffeine, nicotine, • Treat the cause alcohol • Reassurance • If severe→propranolol / disopyramide Atrial flutter/fibrillation Rheumatic heart disease, • Cardioversion cardiomyopathy, • Propranolol / quinidine/ hypertension disopyramide / digitalis

PSVT • Vagal manouvers like carotid massage • Verapamil/adenosine • β-blockers Ventricular ectopics Normal heart—benign; • β-blockers also in cardiomyopathy, • Lignocaine ischaemia, digitalis induced Ventricular tachycardia Organic heart disease, • Cardioversion ventricular dysfunction, • Lignocaine drug-induced Ventricular fibrillation Acute MI, organic heart • Cardioversion disease, surgical trauma, • Lignocaine drug-induced • Class I A drugs for prevention Digitalis induced Digitalis toxicity • Lignocaine tachyarrhythmias • Potassium • Phenytoin Sinus bradycardia • Atropine 102 Textbook of Pharmacology for Dental and Allied Health Sciences

Mexiletine can be used orally; causes dose Amiodarone can cause various adverse related neurologic adverse effects including effects like heart block, cardiac failure, tremors and blurred vision. Nausea is hypotension, bluish discolouration of the common. It is used as an alternative to skin, hypothyroidism, gastrointestinal lignocaine in ventricular arrhythmias. disturbances and hepatotoxicity. It can cause pulmonary fibrosis that can be fatal. Class IC Drugs Amiodarone is used only in resistant cases Class IC drugs are the most potent sodium of chronic ventricular arrhythmias and to channel blockers. Because of the risk of prevent recurrence of atrial fibrillation and cardiac arrest, sudden death and other flutter. adverse effects, they are not commonly used. Bretylium is an adrenergic neurone blocker They may be used in severe ventricular used in resistant ventricular arrhythmias. arrhythmias and to maintain sinus rhythm in Sotalol a β-blocker also prolongs the action atrial fibrillation. potential duration and is classified under class III antiarrhythmic drugs and is often Class II Drugs preferred when a β-blocker is needed. β-blockers (Chapter 12) like propranolol exert antiarrhythmic effect due to blockade of Class IV Drugs β cardiac receptors. They depress myocardial Calcium channel blockers (Page 96) inhibit contractility, automaticity and conduction the inward movement of calcium resulting velocity. In higher doses they also have in reduced contractility, automaticity and AV membrane stabilising activity like class I nodal conduction. Verapamil, diltiazem, and drugs. β bepridil have prominent cardiac effects, Propranolol and cardioselective blockers like because they block the calcium channels in atenolol and metoprolol are used in the the cardiac cells in therapeutic doses. treatment and prevention of supraventricular Verapamil is used to terminate paroxysmal arrhythmias especially those associated with supraventricular tachycardia (PSVT). It is also exercise, emotion or hyperthyroidism. used to control ventricular rate in atrial Esmolol given intravenously is rapid and flutter or fibrillation because it depresses the short-acting and can be used to treat arrhythmias during surgeries, following AV nodal conduction. Diltiazam can be used myocardial infarction and other emergencies. in place of verapamil. Dofetilide is a newly introduced and selective Class III Drugs K+ channel blocker. It has no other actions as + These drugs prolong the action potential it is a pure K channel blocker and prolongs duration and refractory period by blocking APD. It is used orally in atrial fibrillation to the potassium channels. convert and to maintain sinus rhythm. The Amiodarone an analog of thyroid hormone is only adverse effect known is torsades de pointes a powerful antiarrhythmic. It acts by multiple in 1% patients. mechanisms. Ibutilide is a K+ channel blocker used as – prolongs APD by blocking K+ channels. intravenous infusion to quickly convert atrial – blocks sodium channels. flutter/fibrillation to sinus rhythm. It can – blocks β adrenergic receptors. cause torsades de pointes. Antiarrhythmic Drugs 103

Drug Interactions of choice for acute termination of paroxysmal supraventricular tachycardias (PSVT). Verapamil displaces digoxin from tissue Adverse effects are nausea, dyspnoea, binding sites and also reduces its renal flushing, dizziness and headache but are of clearance resulting in digoxin toxicity - dose short duration. Theophylline blocks ade- of digoxin should be reduced. nosine receptors and inhibits the action of Other Antiarrhythmics adenosine. Atropine is used in sinus bradycardia. It acts Adenosine, atropine, digoxin and magnesium by blocking M2 muscarinic receptors. sulphate also have antiarrhythmic properties Digitalis depresses AV conduction, reduces but are not included in Vaughan Willams heart rate and increases the force of classification. contraction of the myocardium. Digoxin is Adenosine is a purine nucleotide having rapid used in atrial fibrillation to control the and short antiarrhythmic action. Given IV it ventricular rate. suppresses automaticity, AV conduction and Magnesium sulphate is used IV to treat digitalis dilates the coronaries. Adenosine is the drug induced arrhythmias and torsades de pointes. 104 Textbook of Pharmacology for Dental and Allied Health Sciences

Drugs Used in 17 Angina Pectoris and Myocardial Infarction

Angina pectoris is the chief symptom of myocardium (coronary dilation) or by ischaemic heart disease (IHD) characterised reducing the oxygen demand (reducing by sudden, severe, substernal discomfort or preload/afterload/heart rate or all of these). pain which may radiate to the left shoulder Drugs used in the treatment of angina are as and along the flexor surface of the left arm. follows: Myocardial oxygen consumption depends on preload (determined by venous return and Classification stretching of the heart), afterload (deter- 1. Nitrates mined by peripheral arterial resistance) and Nitroglycerine, isosorbide dinitrate, heart rate. When the oxygen supply to the isosorbide mononitrate, penta erythritol myocardium is insufficient for its needs, tetranitrate. myocardial ischaemia develops. Pain is due 2. Calcium channel blockers to accumulation of metabolites in the cardiac Verapamil, diltiazem, amlodipine, muscle. nifedipine. 3. β-blockers Two Forms of Angina are Propranolol, atenolol, etc. 1. Classical angina (stable angina, angina of 4. Potassium channel openers effort, exertional angina) Pain is induced by Nicorandil exercise or emotion, both of which increase 5. Miscellaneous myocardial oxygen demand. In such Dipyridamole, aspirin, trimetazidine patients there is narrowing of the coronary arteries due to atherosclerosis Nitrates and therefore the coronaries cannot dilate Mechanism of action Nitrates are vasodilators to increase the blood supply during (Fig. 17.1). They are converted to nitric oxide exercise. Hence there is an imbalance which activates vascular guanylyl cyclase between oxygen supply and demand. which in turn increases the synthesis of 2. Variant or Prinzmetal’s angina occurs at rest cGMP. This cGMP catalyses the phosp- and is caused by spasm of the coronary horylation of protein kinases causing artery. relaxation of the smooth muscles. Drugs are used to improve the balance Pharmacological actions Nitrates are between oxygen supply and demand either predominantly venodilators. Venodilation by increasing oxygen supply to the reduces venous return to the heart thereby Drugs Used in Angina Pectoris and Myocardial infarction 105

Fig. 17.1: Mechanism of action of nitrates reducing preload. Arteriolar dilation reduces continuous high plasma nitrate levels are vascular resistance thus decreasing afterload. present. By adopting proper dosing schedule, As both preload and afterload are reduced, tolerance can be avoided. The patient must workload of the heart is decreased thereby be free of nitrates for at least 8 hours of the reducing oxygen requirement of the heart. day to prevent the development of tolerance. In variant angina, nitrates relieve Tolerance can also be minimized by twice/ vasospasm due to coronary vasodilation. thrice daily dosing schedule. Nitrates also cause dilation of blood vessels in the skin—resulting in flushing; dilatation Uses of the meningeal vessels results in headache. Bronchial smooth muscles are also relaxed. 1. Angina Sublingual nitroglycerine is the Pharmacokinetics Nitrates are well absorbed drug of choice for acute anginal attacks. orally but they undergo extensive first pass It relieves pain in 3 minutes. If the pain is metabolism. Nitroglycerine, isosorbide not relieved, the dose may be repeated dinitrate, (Table 17.1) isosorbide mononitrate (up to 3 tablets in 15 minutes). and pentaerythrital tetranitrate are the Nitrates are also used orally for the nitrates used in angina. Amyl nitrate is used prophylaxis of angina. Longer acting in cyanide piosoning. nitrates are preferred for this. Nitrates are available for oral, sublingual, Nitroglycerine ointment may be applied parenteral use and as ointment and over the chest. transdermal patches for topical use. Topical 2. Cardiac failure Nitrates are useful due to preparations are used for the prevention of their vasodilator property (see page 95). nocturnal episodes of angina. But there is an 3. Myocardial infarction IV nitroglycerine is increased risk of development of tolerance used by many physicians to reduce with topical and slow release preparations. cardiac work. Adverse effects Headache is common; flushing, 4. Cyanide poisoning Cyanide rapidly binds sweating, palpitation, weakness, postural to cytochrome oxidase and other vital hypotension and rashes can occur. Tolerance enzymes resulting in inhibition of cellular to vascular effects of nitrates develops on respiration and blocks the utilization of repeated long term use particularly when oxygen. It requires immediate treatment. 106 Textbook of Pharmacology for Dental and Allied Health Sciences

Table 17.1: Some nitrates used in angina pectoris Drug Dose and route Duration of action Nitroglycerine (GTN) 0.5 mg SL 15-40 min (ANGISED) 5 mg oral 4-8 hr 2% Skin ointment applied 1-2 inches on the precardial region 4-6 hr Isosorbide dinitrate 5-10 mg SL 20-40 min (SORBITRATE) 10-20 mg oral 2-3 hr Isosorbide mononitrate (ISMO) 10-20 mg oral 6-8 hr

Amylnitrite is given by inhalation and tachycardia can occur particularly with sodium nitrite by IV injection (10 ml of dihydropyridines. But CCBs also depress the 3% solution). Sodium thiosulphate is given myocardial contractility thereby reducing the IV (50ml of 25% solution). It reacts with heart rate and force of contraction. This cyanmethaemoglobin to form thiocyanate results in reduced cardiac workload and which is easily excreted by the kidneys. oxygen consumption. CCBs also dilate the Nitrates convert haemoglobin to coronaries thereby increasing the coronary methaemoglobin which has a high affinity blood flow. for cyanide and binds to cyanide forming CCBs are used for the prophylaxis of cyanmethaemoglobin. It thus protects the exertional angina. They can be combined important enzymes from binding to (except verapamil) with beta blockers like cyanide. Amyl nitrite is preferred. Early propranolol. CCBs are also useful in treatment is very important. vasospastic angina since they dilate the Calcium Channel Blockers (Chapter 15) coronaries and relieve vasospasm. Infact they CCBs relax the arterioles leading to a are preferred over nitrates in vasospastic decrease in the peripheral vascular resistance angina. and a reduction in the afterload. Some reflex βββ-blockers β-blockers reduce the frequency and severity of attacks of exertional angina and are useful in the prevention of angina. Exercise, emotion and similar situations increase sympathetic activity leading to increased heart rate, force

of contraction and BP, thereby increasing O2 consumption by the heart. β-blockers prevent angina by blocking all these actions (Chap. 12). They are used for the long-term prophylaxis of classical angina and may be combined with nitrates. β-blockers should always be tapered after prolonged use. They are not useful in variant angina. Drugs Used in Angina Pectoris and Myocardial infarction 107

Potassium Channel Openers Chronic prophylaxis Long-acting nitrates or β- blockers (preferred) or calcium channel Nicorandil is an arterial and venous dilator. blockers can be used. All are given orally. Opening of the ATP-sensitive K+ channels If one drug is not effective, a combination results in efflux of K+ leading to of drugs may be used. hyperpolarization and therefore relaxation of the vascular smooth muscles. In addition it Vasospastic Angina also acts through NO like nitrates. It is tried in angina when other drugs do not afford Nitroglycerine and nifedipine given significant benefit. It is expensive. Dose sublingually are effective in preventing and 10-20mg twice daily. treating vasospastic episodes. Adverse effects are headache, flushing, palpitation, dizziness and hypotension. Combinations of Drugs in Angina Pinacidil is similar to nicorandil. It is useful 1. Nitrates + β-blockers—Very effective in in angina and hypertension. exertional angina. Reflex tachycardia due to nitrates is countered by β-blockers. Miscellaneous Ventricular dilatation due to β-blockers Dipyridamole is a coronary vasodilator but it is opposed by nitrates. diverts the blood from ischaemic zone and is 2. Nifedipine + β-blockers—The antianginal therefore not beneficial. It inhibits platelet effects are additive. Reflex tachycardia aggregation for which it is used in post MI due to nifedipine is countered by β- and post-stroke patients for prevention of blockers. coronary and cerebral thrombosis. 3. Nitrates + CCBs—Nitrates decrease Aspirin Long-term administration of low dose preload, CCBs reduce afterload and the aspirin is recommended to prevent combination reduces cardiac workload. myocardial infarction. 4. CCBs + β-blockers + Nitrates—If the Trimetazidine is a calcium channel blocker angina is not controlled by 2 drug claimed to have a protective effect on the combinations, 3 drugs can be used. ischaemic myocardium and to maintain left Nitrates reduce preload, CCBs reduce ventricular function. It is tried in exertional afterload while β-blockers decrease heart angina - 20 mg t.d.s. rate. This combination is useful in severe angina. Pharmacotherapy of Angina Exertional Angina UNSTABLE ANGINA Acute attack Sublingual nitroglycerine 0.5 mg Unstable angina includes: is the drug of choice. If the pain does not – patients with exertional angina developing subside in 5 minutes, repeat the dose. After angina at rest the relief of pain, the tablet should be – severe, prolonged anginal attacks without discarded. If the pain does not subside with ECG evidence of MI 3 tablets, physician should be consulted as – angina developing after myocardial the pain may be of myocardial infarction. infarction. Acute prophylaxis Sublingual nitroglycerine Such patients with unstable angina are at given 15 minutes before an exertion (e.g. a high risk of developing MI or sudden death walking uphill) can prevent the attack. The and need hospitalisation and rigorous prophylactic effect lasts for 30 minutes. treatment for its prevention. 108 Textbook of Pharmacology for Dental and Allied Health Sciences

Drugs used in unstable angina are- 1. Aspirin – Platelet aggregation can occlude narrowed coronary arteries and can also release potent vasoconstrictors. Aspirin (75-300 mg daily) prevents platelet aggregation and thereby could prevent myocardial infarction. 2. Heparin–In high risk patients IV/SC heparin reduces pain. 3. Nitrates–Intravenous nitroglycerine relieves pain. 4. Other drugs–β adrenergic blockers like atenolol (50-100 mg daily) may be given; if they are to be avoided for some reason, calcium channel blockers like verapamil may be given. Glycoprotein receptor antagonists (abciximab, integrilin and tirofiban) inhibit the final steps of platelet aggregation and are being tried in 2. Thrombolytics – Streptokinase 1.5 million unstable angina. units infusion is given over 1 hour. Alternatively alteplase or other throm- DRUGS USED IN MYOCARDIAL bolytics may be given. Thrombolytics INFARCTION should be started at the earliest possible Coronary heart disease is the most important (within 6 - 12 hours) as they can limit cause of premature death, particularly in the the extent of damage and reduce developed countries. mortality. Rupture of an atheromatous plaque in the 3. Aspirin – 300 mg of soluble aspirin given coronary artery results in an occlusive orally reduces mortality and improves the thrombus leading to acute myocardial effect of thrombolysis. It should be infarction. The process of infarction gradually continued (75-150 mg/day) even after the develops (unless it is severe) over 6-8 hours after which there is cell death in the infarcted patient recovers. area. But timely intervention can reduce the 4. Oxygen – High flow oxygen should be extent of damage. The immediate objective given by inhalation. of treatment is to limit the myocardial 5. Other drugs ischemia and the consequent cell death. (i) β – adrenergic antagonists– IV atenolol (5–10 mg over 5 minutes) reduces Immediate Treatment short-term mortality and lowers the 1. Analgesia - Morphine 10 mg or pethidine incidence of arrhythmias. 50 mg is given intravenously through an (ii) Antiemetics– an antiemetic may be IV cannula. They relieve pain and thereby given IV. reduce anxiety. Hence the demerits of (iii) Antiarrhythmics– Arrhythmias are sympathetic overactivity are reduced. common in patients in acute MI; Diazepam may also be given to reduce suitable antiarrhythmics should be anxiety and produce sedation. used depending on the arrhythmia. Drugs Used in Angina Pectoris and Myocardial infarction 109

Long-term Treatment Dental implications: A majority of dental procedures can evoke anxiety in the patient. Once the patient is stabilized, certain This could precipitate an attack of angina or drugs are recommended for prevention of rarely even myocardial infarction. Utmost further ischaemic events. Long-term importance is given to keep the patient stress- administration of low dose aspirin, a β– free. Adequate antianxiety agents, analgesics adrenergic blocker and an ACE inhibitor are and anaesthetics are used to avoid pain and useful in reducing long-term mortality. ACE anxiety. Patient is taken for the procedure as inhibitors prevent ventricular remodelling the first case in the morning because waiting and cardiac failure. in anxiety could be harmful to such patients. Adrenaline is avoided in such patients. The Risk Factor Management dentist should know to handle the emergency • Smoking should be stopped. if the need arises and then shift the patient • Hyperlipidaemia if any should be to the physician’s care at the earliest. For an controlled. acute episode of angina, nitroglycerine 0.5 • Body weight should be reduced if needed. mg is given sublingually immediately. The • Regular moderate exercises should be pain should subside in 3-5 minutes (See Page advised. 107). If MI is suspected, injection pethidine •Adequate control of diabetes and 50 mg should be given immediately even hypertension if any. before shifting the patient to the physician. 110 Textbook of Pharmacology for Dental and Allied Health Sciences 18 Antihypertensive Drugs

Hypertension is an elevation of systolic and/ Antihypertensives may be classified as or diastolic BP above 140/90 mm of Hg. It is follows : a common cardiovascular entity. Hyper- tension (HT) may be primary (essential) CLASSIFICATION hypertension—where the cause is not known 1. Diuretics or secondary—when it is secondary to other • Thiazides conditions like renal, endocrine or vascular Hydrochlorothiazide, disorders. chlorthalidone, indapamide Based on the degree of severity, • Loop diuretics hypertension can be graded as: Frusemide, bumetanide, torsemide • Mild—diastole up to 104 • K+ Sparing diuretics • Moderate—105-114 Spironolactone, amiloride, triamterene. • Severe— more than 115. 2. Angiotensin converting enzyme inhibitors Blood pressure is determined by cardiac Captopril, enalapril, lisinopril, output (CO) and total peripheral vascular ramipril, perindopril, fosinopril, resistance (PVR). Blood pressure is controlled trandolapril, quinapril, benazepril. by baroreceptor reflexes acting through autonomic nervous system along with the 3. Angiotensin II receptor antagonists renin-angiotensin-aldosterone system. Losartan, candesartan, valsartan, Prolonged hypertension damages the eprosartan, irbesartan. blood vessels of the heart, brain and the 4. Sympatholytics kidneys and may result in several • Centrally acting drugs complications like stroke, coronary artery Clonidine, methyldopa, guanabenz, disease or renal failure. Hence hypertension guanfacine needs to be treated even though as such it • Ganglion blockers does not generally produce obvious Trimethaphan troublesome symptoms. • Adrenergic neuron blockers Antihypertensives act by influencing the Guanithidine, reserpine BP regulatory systems viz. the autonomic • Adrenergic receptor blockers: system, renin-angiotensin system, calcium – α blockers channels or sodium and water balance Prazosin, terazosin, doxazin (plasma volume). phenoxybenzamine, Phentolamine Antihypertensive Drugs 111

– β blockers subdiuretic doses. Moreover it causes milder Propranolol, atenolol, esmolol, electrolyte disturbances. metoprolol. Loop diuretics - Although loop diuretics like – α and β blockers frusemide are powerful diuretics, their Labetalol, carvedilol antihypertensive efficacy is low. They are 5. Ca++ channel blockers used only in hypertension with chronic renal Verapamil, nifedipine, nicardipine failure or congestive heart failure. nimodipine, amlodipine, felodipine. 6. Vasodilators Angiotensin Converting Enzyme (ACE) • Arteriolar dilators Inhibitors Hydralazine, minoxidil, diazoxide Angiotensin II is a powerful vasoconstrictor. • Arteriolar and venular dilators Sodium nitroprusside. Aldosterone also raises the BP by increasing the plasma volume (Fig. 18.2). ACE inhibitors Diuretics (see Chap. 13) The antihypertensive prevent the formation of angiotensin II and effect of diuretics is mild—BP falls by 15-20 (indirectly) aldosterone. There is vaso- mm of Hg over 2-4 weeks. Diuretics act as dilation and decrease in PVR resulting in a antihypertensives as follows. fall in BP. As ACE also degrades bradykinin, Diuretics enhance the excretion of sodium ACE inhibitors raise the bradykinin levels and water resulting in which is a potent vasodilator. This also 1. ↓ Plasma volume → ↓ cardiac output → contributes to the fall in BP. ↓ BP The blood flow to the kidneys, brain and 2. ↓ Body sodium → relaxation of vascular heart increases due to selective vasodilation smooth muscles (due to Na+ depletion in and thus maintains adequate blood supply the vascular smooth muscle) - ↓ PVR → to these vital organs. ↓ BP. Pharmacokinetics ACE inhibitors are generally Restriction of dietary salt intake will well-absorbed. Except captopril and lisinopril reduce the dose of the diuretic needed. all others are prodrugs. They differ in their Thiazides are the first-line antihypertensives potency and pharmacokinetic properties and are inexpensive. An initial dose of 12.5 (Table 18.1) like bioavailability, distribution, 1 mg daily hydrochlorothiazide/chlorth- plasma t /2 and excretion. Most ACE alidone is given. If the response is not inhibitors are excreted through the kidney adequate the dose may be increased to a → dose should be reduced in renal dys- maximum of 25 mg daily. They may be function. combined with a K+ sparing diuretic which is Adverse effects ACE inhibitors are well- the best way to avoid hypokalaemia-1.25 mg tolerated. Adverse effects include: amiloride with 12.5 mg hydrochlo-rothiazide. 1. Persistent dry cough due to ↑ bradykinin Thiazides may be used in combination with levels is more common in women. It may other antihypertensives particularly with require withdrawal of the ACE inhibitors. those that cause salt and water retention as An angiotension II receptor antagonist a side effect. may be used in such patients (Page 114) Indapamide is particularly useful in 2. Hypotension–On initiation of therapy, ACE hypertension because it lowers BP in inhibitors may cause significant hypo- 112 Textbook of Pharmacology for Dental and Allied Health Sciences

Fig. 18.1 : Sites of action of antihypertensive drugs

tension called first dose phenomenon. immediately withdrawn at the first Hence, treatment should be started with sign of angioedema. Severe cases small doses and if patients are already on may need adrenaline and glucocorticoids. diuretics - temporarily diuretics should be 6. Skin rashes–ACE inhibitors can occasionally stopped. cause skin rashes which are self-limiting. 3. Hyperkalaemia–ACE inhibitors may cause 7. Teratogenicity–Given during second and third hyperkalaemia particularly in patients trimester of pregnancy, ACE inhibitors can on K+ sparing diuretics or on K+ cause various foetal malformations including supplements. foetal growth retardation, malformed lungs 4. Dysguisia–An altered taste sensation is and even death→ ACE inhibitors are more common with captopril-it is contraindicated in pregnancy. however reversible. 8. Other effects–They can cause headache, 5. Angioneurotic edema–ACE inhibitors nausea, abdominal pain, proteinuria and can rarely cause (0.1% incidence) angio- rarely neutropenia. edema with swelling in the lips, nose, Neutropenia is more common in patients with larynx and airway obstruction. It may be collagen diseases and should be watched for. due to increased bradykinin levels and ACE inhibitors can precipitate acute renal can be fatal. ACE inhibitors should be failure in patients with renal artery stenosis. Antihypertensive Drugs 113

Fig 18.2: Renin-angiotensin system

Uses • In severe hypertension, they may be combined with other antihypertensives 1. Hypertension β • ACE inhibitors are presently the first like blockers, CCBs or diuretics. line antihypertensives. 2. CCF-ACE inhibitors are the first line • ACE inhibitors are useful in the drugs (see page 111). treatment of hypertension of all grades 3. Myocardial infarction ACE inhibitors due to all causes. started within 24 hours and given for several weeks prevent the development • Addition of a diuretic potentiates their of CCF and reduce mortality. antihypertensive efficacy. They are 4. Coronary artery disease-In patients who are generally combined with thiazides at a high risk of ischaemic cardiovascular without a K+ sparing diuretic because conditions like MI and stroke, ACE there can be significant hyperkalaemia. inhibitors afford significant benefit by • They are specially indicated as reducing the risk of MI, stroke and antihypertensives in: sudden death. a. hypertension with left ventricular 5. Chronic renal failure-In patients with hypertrophy — hypertrophy is diabetic nephropathy and chronic renal gradually reversed by ACE failure, ACE inhibitors delay the inhibitors. progression of renal disease. b. patients with diabetes because 6. Scleroderma renal crisis-ACE inhibitors may ACE-I slow the development of be life saving in these patients. nephropathy. c. renal diseases with hypertension— Precautions and Contraindications ACE inhibitors slow the • ACE inhibitors are contraindicated in progression of chronic renal pregnancy diseases like glomerulosclerosis. • ACE inhibitors should not be combined d. patients with co-existing IHD with K+ sparing diuretics. including post-MI patients. • At the first sign of angioedema, ACE • ACE inhibitors are well tolerated inhibitors should be stopped. 114 Textbook of Pharmacology for Dental and Allied Health Sciences

• They are contraindicated in patients with all extensively protein bound and excreted renal artery stenosis as they can cause by kidneys. renal failure in them. Adverse effects ARBs are well tolerated. They • ACE inhibitors may enhance plasma levels can cause hypotension and hyperkalaemia like of digoxin. ACE inhibitors. Angioedema is rare. ARBs are contraindicated in pregnancy because of Angiotensin II Receptor Blockers (ARBs) their teratogenic potential. Uses Losartan was the first orally effective AT1 receptor antagonist to be developed. There 1. Hypertension–ARBs are used in the are 2 subtypes of angiotensin II receptors— treatment of hypertension in similar AT1 and AT2. AT1 receptors are present in indications as that of ACE inhibitors as vascular and myocardial tissue, brain, kidney alternatives to ACE inhibitors. They can and adrenal glomerular cells. Losartan has be considered as the first line drugs in high affinity for AT1 receptors when hypertension. Losartan, candesartan and compared to AT2 receptors. By blocking AT1 irbesartan are available in India. ARBs can receptors, losartan blocks the effect of be usefully combined with diuretics angiotensin II. It thus relaxes vascular smooth (Table 18.2) muscles, promotes salt and water excretion 2. Cardiac failure–ARBs may be used as and reduces plasma volume. alternatives to ACE inhibitors in cardiac The main advantage of ARBs over ACE failure. i.e., in patients who poorly tolerate inhibitors is that there is no increase in ACE inhibitors. bradykinin levels and its associated adverse SYMPATHOLYTICS effects like dry cough and angioedema because angiotensin converting enzyme is not I. Drugs Acting Centrally inhibited. Clonidine an imidazoline derivative is a Many other ARBs have now been α α selective 2 agonist. Stimulation of 2 synthesized including candesartan, receptors in the CNS (in the vasomotor centre irbesartan, valsartan, telmisartan and and hypothalamus), decreases central eprosartan. sympathetic outflow, blocks the release of ARBs are all given orally. Their noradrenaline from the nerve terminals bioavailability is generally <50%. They are leading to a fall in BP and bradycardia.

Table 18.1: Dose and duration of action of some commonly used ACE inhibitors

Drug Duration of action (in hrs) Daily dose in hypertension (mg)

Captopril 6-12 12.5-50 mg BD Enalapril 24 2.5-20 mg OD Lisinopril >24 5-40 mg OD Ramipril 8-48 1.25-10 mg OD Fosinopril 12-24 10-60 mg Benazepril 12-24 10-40 mg Perindopril 24 2-8 mg Antihypertensive Drugs 115

Table 18.2: Dose and route of administration of some commonly used antihypertensives

Antihypertensives Daily doses Routes

Hydrochlorothiazide + Amiloride 12.5-25 mg + 1.25-2.5 mg daily Oral Losartan 50 mg OD Oral Clonidine 100-300 μg Oral Methyldopa 250-500 mg q 6-12 hr Oral Atenolol 25-100 mg OD Oral Prazosin 2-20 mg daily Oral Hydralazine 25-50 mg q 8-24 hr Oral Diazoxide 50-100 mg every 5-10 min IV Sodium nitroprusside 0.2-0.3 mg/min IV Nifedipine 10 mg SL 5-20 mg q 8-12 hr Oral

For ACE inhibitors see Table 18.1

Adverse effects include drowsiness, α-methyl dopa—an analog of dopa, is a dryness of mouth, nose and eyes; parotid prodrug. It is metabolised in the body to α- α gland swelling and pain, fluid retention, methylnorepinephrine which is an 2 agonist constipation and impotence. Sudden and acts like clonidine. Renin levels also fall. withdrawal of clonidine will lead to rebound Left ventricular hypertrophy is reversed in hypertension, headache, tremors, sweating about 12 weeks of treatment. and tachycardia. Hence the dose should be Adverse effects are sedation, dryness of tapered. mouth and nose, headache, postural hypotension, fluid retention and impotence. Uses Uses 1. Mild to moderate hypertension. α -methyl dopa is used in mild to moderate Other Uses hypertension along with a diuretic. It is safe 2. In Opioid withdrawal Most withdrawal in hypertension during pregnancy and is the symptoms in opioid addicts are of preferred antihypertensive in such patients. sympathetic overactivity and can be Started with 250 mg twice daily, the dose may benefited by treatment with clonidine. be increased to a maximum of 750 mg BD. 3. Diabetic neuropathy Clonidine controls Ganglion Blockers diarrhoea by improving absorption of sodium chloride and water in the gut by Trimethaphan stimulation of α receptors in the 2 These drugs block both sympathetic and intestines. parasympathetic ganglia resulting in dec- 4. With anaesthetics Clonidine given reased sympathetic tone and a fall in BP. preoperatively reduces the dose of the But they produce several side effects as general anaesthetic needed due to its they block both sympathetic and analgesic effects. parasympathetic ganglia and are not used 116 Textbook of Pharmacology for Dental and Allied Health Sciences now. Trimethaphan is the only ganglion combination with other antihypertensives blocker in use. It is used intravenously to particularly with drugs that cause tachycardia produce controlled hypotension during as their side effect (e.g. vasodilators). They certain surgeries for its rapid and short are thus the first line antihypertensive drugs action (15 minutes). in mild to moderate hypertension. Atenolol is the preferred β-blocker because of the Adrenergic Neuron Blockers advantages like once a day dosing, absence of CNS side effects and β selectivity. Guanethidine depletes the stores of 1 β-blockers should always be tapered while noradrenaline in the adrenergic neurons and withdrawing. also blocks its release. Because of the adverse α-blockers (see Chapter 12) Nonselective α effects like postural hypotension, diarrhoea blockers like phenoxybenzamine and and sexual dysfunction, it is not used. phentolamine are used in the treatment of Reserpine is an alkaloid obtained from hypertension due to pheochromocytoma. Rauwolfia serpentina (Sarpagandhi) that grows Selective α blockers like prazosin, terazosin in India. In the adrenergic neurons, it binds 1 and doxazosin dilate both arterioles and to the vesicles that store monoamines like venules. Peripheral vascular resistance is noradrenaline, dopamine and 5-HT and decreased leading to a fall in BP with only destroys these vesicles. It thus depletes the mild tachycardia. stores of these monoamines and reduces BP. ‘First dose phenomenon’ can be avoided Reserpine also has antipsychotic effects for by starting with a low dose prazosin (0.5 mg) which it is used in psychosis. Reserpine causes given at bed time. Dose is gradually various side effects like drowsiness, α increased. 1 blockers are used in mild to depression, parkinsonism, postural hypo- moderate hypertension; they may be tension, edema and sexual dysfunction. combined with diuretics and β-blockers. Though it is generally not preferred. It has α and β-blockers Labetalol and carvedilol block the advantages of being inexpensive, α β 1 and receptors. It is used IV in the effective, long acting (once daily dose) and treatment of hypertension in pheochro- generally well tolerated when given with a mocytoma and in hypertensive emergencies. diuretic. Calcium Channel Blockers Adrenergic Receptor Blockers Calcium channel blockers (see chap 15) are β -blockers (see Chapter 12) are mild another important group of antihyper- β antihypertensives. Blockade of cardiac 1 tensives. They dilate the arterioles resulting receptors results in decreased myocardial in reduced peripheral vascular resistance. contractility and cardiac output. Thus they Nifedipine produces some reflex tachycardia reduce the BP due to a fall in the cardiac while this is not seen with verapamil and output. They also lower plasma renin activity diltiazem as they are cardiac depressants. and have an additional central antihy- Fluid retention is negligible unlike other pertensive action. arteriolar dilators. Calcium channel blockers β blockers are effective and well-tolerated were earlier considered first line antihyper- and are of special value in patients who also tensives and were extensively used. But have arrhythmias or angina. They may be several recent large scale studies have shown used alone but are also suitable for them to have many disadvantages. They are Antihypertensive Drugs 117 not preferred in patients who also have left retention and reflex tachycardia are common ventricular hypertrophy and previous with vasodilators. myocardial infarction. Short acting DHPs Hydralazine is a directly acting arteriolar produce frequent changes in BP and dilator. The fall in BP is associated with sympathetic activity and hence should be tachycardia, renin release and fluid retention. avoided in hypertension. Coronary, cerebral and renal blood flow are increased. Use in Hypertension Hydralazine is metabolised by acetylation • CCBs are well-tolerated, and effective. in the liver (like INH) and the rate of • CCBs are particularly effective in elderly acetylation is genetically determined - people patients. may be fast or slow acetylalors. • CCBs may be used as monotherapy or in Adverse effects are headache, dizziness, moderate to severe HT along with other flushing, palpitation, nausea, hypotension antihypertensives. and salt and water retention. It may • It has now been shown that sublingual precipitate angina in some patients because nifedipine does not actually achieve of increased O2 demand due to reflex plasma concentration quicker than oral tachycardia and decreased myocardial blood formulation. Thus in hypertensive supply due to peripheral vasodilatation. emergencies, short acting DHPs can be Hypersensitivity reactions like serum used parenterally. sickness and lupus erythematosus (arthralgia, • There is a growing concern that use of fever, pleuritis, pericarditis) may occur and CCBs, especially short acting ones, is is more common in slow acetylators. associated with increased mortality and Uses Hydralazine is used with a β-blocker risk of sudden death. and/or a diuretic in moderate to severe • Sustained release preparations or long hypertension not controlled by the first line acting dihydropyridine CCBs may be drugs. It can be given in hypertension during used for smoother control of BP. pregnancy (2nd and 3rd trimester). Minoxidil is a directly acting arteriolar dilator Vasodilators used in severe hypertension not responding Vasodilators relax the vascular smooth to other drugs. It acts by opening K+ channels muscles thus reducing BP due to decreased in the smooth muscles. Opening of the K+ peripheral vascular resistance. Salt and water channels causes efflux of K+ resulting in hyperpolarisation and smooth muscle relaxation. Minoxidil is used along with a diuretic - as a reserve drug in patients with severe hypertension who do not respond to other drugs. Minoxidil stimulates the growth of hair on prolonged use (hypertrichosis). Hence it is used topically (2% solution) in alopecia. Young men with relative alopecia are more likely to respond. Minoxidil can cause fluid retention, tachycardia and anginal 118 Textbook of Pharmacology for Dental and Allied Health Sciences episodes. Growth of hair on the face, arms, exposure to light the infusion bottle and tubing legs and back make it unacceptable in women. should therefore be covered with opaque foil. Diazoxide is related to thiazide diuretics and Adverse reactions are palpitation, sweating, is a potent arteriolar dilator. It’s mechanism weakness, nausea, vomiting and hypo- of action is like minoxidil. Diazoxide can tension. In higher doses nitroprusside gets cause hyperglycaemia because it inhibits the converted to cyanide and thiocyanate which insulin secretion from pancreas. Other side can result in toxicity. Symptoms of toxicity effects include salt and water retention, include nausea, anorexia, weakness, disor- palpitation and myocardial ischaemia. It is ientation and psychosis. Administration of used intravenously in hypertensive emer- sodium thiosulphate along with nitroprusside gencies where monitoring of infusion is not prevents the accumulation of cyanide. possible. Diazoxide has a long duration of action (24 hours) and is suitable in such Uses situations. 1. Nitroprusside is the drug of choice in Sodium nitroprusside is a rapidly acting hypertensive emergencies. vasodilator and it relaxes both arterioles and 2. It is used in situations where short-term venules. Both peripheral resistance and reduction of myocardial work load is cardiac output are reduced resulting in lower required as in myocardial infarction. myocardial oxygen consumption. Drug Interactions 1. Sympathomimetics and tricyclic antidepressants can antagonise the effects of sympatholytics. 2. Antihistamines add to sedation produced by clonidine and methyldopa. 3. NSAIDs tend to cause salt and water retention and may blunt the effect of antihypertensives.

Treatment of Hypertension Mild hypertension Treatment is started with low dose of a single drug—a thiazide diuretic or a β-blocker. If the patient does not adequately respond in 3-4 weeks, an ACE Nitroprusside acts through the release of inhibitor or a calcium channel blocker should nitric oxide which activates guanylyl cyclase, be tried. If BP is not controlled by one drug, resulting in the formation of cGMP which another should be added. relaxes the vascular smooth muscles. On IV Moderate hypertension A combination of a administration, it is rapid (acts within 30 diuretic with a sympatholytic may be given. seconds) and short-acting (duration 3 minutes) If response is inadequate add a third drug. allowing titration of the dose. This makes it Severe hypertension may be associated with suitable for use in hypertensive emergencies cardiac or renal disorder. A vasodilator with with close monitoring. It decomposes on a diuretic and a β-blocker is useful. Antihypertensive Drugs 119

Hypertensive emergencies Conditions like Vasodilators like nifedipine and hypertensive encephalopathy and acute hydralazine evoke reflex tachycardia. This cardiac failure due to hypertension require can be countered by β-blockers, while immediate reduction of BP. Parenteral drugs propranolol may cause initial rise in PVR are preferred. IV sodium nitroprusside under which is countered by vasodilators. close monitoring is the drug of choice (in Combination of ACE inhibitors and some conditions BP should be lowered diuretics is synergistic. gradually to avoid ischaemia to vital organs). Non-pharmacological measures Low salt diet, IV esmolol, diazoxide and sublingual weight reduction and transidental meditation- nifedipine are alternatives. BP should be all go a long way in controlling the blood constantly monitored because drugs like pressure. Smoking and alcohol should be sodium nitroprusside can bring down BP given up. These measures also help in reducing suddenly which results in hypoperfusion of the dose of the antihypertensive needed. vital organs. As soon as possible switch over to oral drugs. Hypertension and Dentistry Hypertension in pregnancy The drugs found safe are—methyldopa orally for maintenance A dentist may have to carry on surgeries and and hydralazine (parenteral) for reduction other procedures on a hypertensive patient of BP in emergency. However they should and needs caution. It may not matter much be used only after the first trimester. Cardio- in minor procedures but in major procedures, selective β-blockers (atenolol) can also be good control of BP should be ensured before, used. during and after the procedure. BP is Combination of antihypertensives When it is not maintained below 150/100 mm of Hg. To possible to achieve adequate control of BP control postoperative bleeding ethamsylate with a single drug, a combination may be is given. When local anaesthetic is required, used. Antihypertensives may also be for minor procedures plain lignocaine is used combined to overcome the side effects of one and adrenaline avoided. Procedures are done another. This also allows use of lower doses in multiple sittings. For example if multiple of each drug. teeth are to be pulled out, 1-2 teeth are Sympatholytics and vasodilators cause extracted at a time. If the bleeding is more, fluid retention which can be overcome by botropase or gel foam application is used and adding a diuretic. not adrenaline packs. 120 Textbook of Dental Pharmacology 19 Plasma Expanders and Pharmacotherapy of Shock

PLASMA EXPANDERS Dextrans have a long shelf-life (10 years) and can be easily sterilized. Dextrans are the Plasma expanders are high molecular weight substances which when infused IV exert commonly used plasma expanders. osmotic pressure and remain in the body for Gelatin products have a mol. wt. of 30,000 and a long time to increase the volume of a duration of action of 12 hours. Gelatin circulating fluid. polymers can remain stable for almost 3 years An ideal plasma expander should exert at a pH of 7.2-7.3. They do not interfere with oncotic pressure comparable to plasma, be coagulation, blood grouping and cross long-acting, non-antigenic and pharma- matching. They can rarely cause urticaria, cologically inert. allergic reactions and bronchospasm. The plasma expanders used are dextrans, Hydroxyethyl starch (Hetastarch) maintains gelatin polymer, hydroxyethyl starches and blood volume for a long period. Allergic polyvinyl pyrrolidone - all colloidal reactions are rare and it does not interfere compounds. Human albumin obtained from with coagulation. pooled human plasma is also useful. Polyvinyl pyrrolidone (PVP) is a synthetic Dextrans (Dextran 70 - mol. wt. 70,000 and polymer. It is not preferred due to various dextran 40 - mol. wt. 40,000) are disadvantages like - it provokes histamine polysaccharides obtained from sugar beet. release and interferes with blood grouping. Their osmotic pressure is similar to that of Human albumin is obtained from pooled plasma proteins. Dextran 70 effectively human blood. It is given as 5% or 20% expands the plasma volume and remains so solution. It is nonantigenic, does not interfere for 24 hours. It interferes with coagulation, with coagulation, blood grouping or cross blood grouping and cross matching. matching. Dextran 40 is faster but shorter acting. It Human albumin is used in oedema, burns, can improve microcirculation in shock by hypovolaemic shock, hypoproteinaemia, preventing rouleax formation of RBCs and acute liver failure and in dialysis. have an antisludging effect. It can clog renal Allergic reactions and fever can occur tubules resulting in renal failure - though rare though rarely. should be watched for. Allergic reactions are Uses of plasma expanders These are used as common as dextrans are antigenic. plasma substitutes in hypovolaemic shock, Plasma Expanders and Pharmacotherapy of Shock 121 burns and in extensive fluid loss—as an 4. Anaphylactic shock Type I hypersensitivity emergency measure to restore plasma reaction causing release of massive volume. amounts of histamine which is triggered by antigen-antibody reaction. Adrenaline PHARMACOTHERAPY OF SHOCK 0.3–0.5 ml of 1:1000 solution given Shock is acute circulatory failure with intramuscularly is the drug of choice (see underperfusion of tissues. Symptoms of page 71) sympathetic overactivity are generally seen— 5. Neurogenic shock is due to venous pooling like pallor, sweating, cold extremities and as following spinal anaesthesia, tachycardia. Shock may be: abdominal or testicular trauma. Shock of any type needs immediate 1. Hypovolaemic shock Decreased fluid volume treatment: due to sudden loss of plasma or blood as in haemorrhage, burns or dehydration— General Measures results in hypovolaemic shock.Fluid and a. The cause should be identified and treated electrolytes (See page 401) should be b. Maintain BP and plasma volume replaced and BP monitored. c. Correct the acid base and electrolyte 2. Septic shock is precipitated by severe disturbances bacterial infection. It may be due to d. Ensure adequate urine output. release of bacterial toxins — should be To restore the intravascular volume, the treated with appropriate antibiotics apart component that is lost should ideally be from general measures. replaced-like plasma in burns and blood after 3. Cardiogenic shock is due to failure of heart haemorrhage. But in emergency, immediate as a pump as in myocardial infarction. IV volume replacement is important. In such morphine is the drug of choice to relieve situations plasma expanders and intravenous pain and anxiety (see page 108). fluids are used. 122 Textbook of PharmacologySection for Dental 5 and Allied Health Sciences Central Nervous System 20 General Anaesthetics

General Anaesthetics are agents that bring depression → cessation of breathing, about reversible loss of sensation and circulatory failure and death may follow. consciousness. Before 1846, alcohol, opium, Ideal anaesthetic should be pleasant, non- packing a limb with ice and concussion, i.e. irritating, provide adequate analgesia, making the patient unconscious by a blow immobility and muscle relaxation; should be on the head were used to relieve surgical non-inflammable and administration should be pain. Dr Horace Wells a dentist, tried to easy and controllable and have a wide margin demonstrate the effect of nitrous oxide as an of safety. Induction and recovery should be anaesthetic in 1844 but was unsuccessful as smooth and should not affect cardiovascular he removed the gas bag too early. Dr William functions. It should be inexpensive. Morton who was present at the demonstration, worked on it and in 1846 Mechanism of Action of General Anaesthetics demonstrated ether anaesthesia successfully. The exact mechanism of action of general Since then several anaesthetics have been anaesthetics is not known. The most accepted synthesized over the decades. mechanisms of action are as follows. 1. Inhaled and some intravenous Stages of General Anaesthesia anaesthetics bind to specific sites on 1. Stage of analgesia is from the beginning of GABA receptor chloride channels and inhalation of the anaesthetic to loss of activate these receptors. By this they consciousness. increase the inhibitory neurotransmission and depress the CNS. 2. Stage of delirium This stage is from loss of 2. Inhalational anaesthetics also enhance the consciousness to beginning of surgical sensitivity of glycine-gated chloride anaesthesia. It may be associated with channels to glycine. These glycine excitement—shouting, crying and violent receptors bring about inhibitory behaviour. neurotransmission in the brainstem. 3. Stage of surgical anaesthesia This has 4 3. Some anaesthetics like ketamine and planes. As anaesthesia passes to deeper nitrous oxide bind to and inhibit the N- planes, respiratory depression is seen. methyl D – aspartate (NMDA) receptors. There is gradual loss of reflexes and 4. Inhalational and intravenous agents act at relaxation of skeletal muscles. multiple sites in the nervous system and 4. Stage of medullary paralysis is seen only with depress the neuronal activity at many overdose. It is the stage of medullary sites in the brain. General Anaesthetics 123

General anaesthetics are as follows- for elimination and therefore recovery is slower. CLASSIFICATION Minimum alveolar concentration (MAC) is I. Inhalational the concentration that immobilizes 50% of A. Gases subjects in response to a surgical skin incision. – Nitrous oxide, cyclopropane MAC is used to describe the potencies of B. Liquids different volatile anaesthetics. – Ether, halothane, enflurane, Nitrous oxide is a gas with a slightly sweetish isoflurane, methoxyflurane, odour. It produces light anaesthesia without desflurane, sevoflurane significant depression of respiration or II. Intravenous vasomotor centre (Table 20.1). A. Inducing agents Advantages –Thiopentone sodium, methohexitone, propofol, 1. Strong analgesic etomidate 2. Induction is rapid and smooth B. Dissociative anaesthesia 3. It is non-irritating and non-inflammable – Ketamine 4. Recovery is rapid C. Neuroleptanalgesia 5. Postoperative nausea is not significant – Fentanyl + droperidol 6. Has little effect on respiration and D. Benzodiazepines cardiovascular functions, hence ideal for – Diazepam, lorazepam, combination midazolam 7. It is non-toxic to liver, kidney and brain and is quickly removed from lungs. Inhalational anaesthetics are either gases or volatile liquids. Given by inhalation they are Disadvantages absorbed by the pulmonary circulation. On 1. It is less potent and should be used with attaining adequate concentration in the brain, other agents. they produce general anaesthesia. 2. Poor muscle relaxant. Pharmacokinetics Inhalational anaesthetics are 3. N2O displaces nitrogen from the air-filled administered at a specific concentration. cavities and while doing so, it enters the Since the brain is a highly perfused organ, cavities faster, i.e. even before nitrogen steady state can be achieved quickly. When escapes. This results in expansion of such the steady state is reached, the partial cavities like in patients with pneumothorax pressure of the anaesthetic in the lung and and air embolus. Hence N2O should be the brain are equal and this makes it possible avoided in such patients. to monitor the anaesthesia. But, for 4. Repeated use can depress the bone anaesthetics with high solubility in blood and marrow. tissues, rise in alveolar partial pressure (and 5. Long-term exposure (like in staff of thereby induction) is slower. Such operation theatre) to low doses can impair anaesthetics need to be administered at DNA synthesis which may result in foetal higher pressures. abnormalities on conception. Inhaled anaesthetics are largely eliminated Status in anaesthesia Nitrous oxide is used as unchanged by the lungs. Agents which are an adjuvant to other anaesthetics. It is used soluble in fat and tissues require longer time along with oxygen (30%). 124 Textbook of Pharmacology for Dental and Allied Health Sciences

Ether is a colourless volatile liquid. It is highly 2. Induction is smooth and rapid—in 2-5 min inflammable; vapours are irritating. surgical anaesthesia can be produced. 3. Non-irritant—therefore does not Advantages augment salivary or bronchial secretions. 1. Potent and reliable anaesthetic. 4. Recovery is rapid (Table 20.2). 2. Good analgesic. 5. Postoperative nausea and vomiting are of 3. Effect on cardiovascular and respiratory low incidence. functions are not significant in therapeutic doses; reflexes are well-maintained. Disadvantages 4. It is a bronchodilator. 1. Neither a good analgesic nor a muscle 5. Provides full muscle relaxation in deep relaxant. anaesthesia. 2. Halothane is a direct myocardiac 6. Does not sensitize the heart to adrenaline. depressant. Cardiac output and BP start 7. Easy to administer as complicated falling and heart rate may decrease. It equipment is not necessary. sensitizes the heart to the arrhythmogenic 8. Inexpensive. action of adrenaline. 3. It also causes some respiratory Disadvantages depression. 1. It is inflammable—hence diathermy is 4. Severe hepatitis which may be fatal occurs contraindicated. in 1: 50,000 patients. A metabolite may be 2. Highly soluble in body tissues—induction responsible for this toxicity. is slow and unpleasant. 5. Malignant hyperthermia—a genetically 3. It is irritating and therefore enhances determined reaction occurs rarely. respiratory secretions. Premedication Succinylcholine accentuates this effect of with atropine is essential—laryngeal halothane. It is due to intracellular release spasm may occur during induction. of calcium from the sarcoplasmic 4. Postoperative nausea and vomiting are reticulum which causes muscle contraction frequent. and increased heat production. It is treated 5. Recovery is slow. with dantrolene. Status in anaesthesia Ether is now not 6. Expensive when compared to ether. preferred because of flammability and Status in anaesthesia Halothane is one of the irritant property. But it is still used in most popular anaesthetics. Analgesics and developing countries like India because it is muscle relaxants are used as adjuvants. Non- cheap, easy to administer (by open drop flammability, non-irritant property, rapid method) and relatively safe. induction and recovery has made it an Halothane is a colourless volatile liquid with important and preferred anaesthetic—most a sweet odour. It is non-irritant and non- widely used. inflammable. Enflurane is similar to halothane except that: 1. it is metabolised to a lesser extent than Advantages halothane—therefore safer regarding the 1. Potent, non-inflammable anaesthetic. liver toxicity. General Anaesthetics 125

2. does not sensitize the heart to adrenaline. formed in the liver also may cause renal But enflurane may precipitate seizures in damage. If these disadvantages of epileptics and should be avoided in them. sevoflurane could be overcome, we may Isoflurane is an isomer of enflurane and is have found an ideal anaesthetic. similar to halothane. It differs as follows: Oxygen in anaesthesia Oxygen should be 1. more potent than halothane. added routinely to inhalational agents to 2. does not sensitize the heart to adrenaline. protect against hypoxia (especially when 3. metabolism is negligible—therefore safer halothane is used). When O2 is not available, regarding the liver toxicity. ether is the safest agent for maintenance of 4. it does not provoke seizures. anaesthesia. Isoflurane is extensively used now. It is INTRAVENOUS ANAESTHETICS expensive and can cause hypotension. Desflurane and sevoflurane are newer Intravenous anaesthetics allow an extremely agents which allow very rapid induction and rapid induction because the blood recovery because of low solubility in blood. concentration can be raised rapidly—in one But they too have some disadvantages. arm-brain circulation (~ 11 sec) there is loss Desflurane is pungent—may induce of consciousness. But when we administer coughing and sometimes laryngospasm. anaesthetics intravenously, there is no Because of low volatility, a special channel for quick elimination like the lungs. vapouriser is required for administration. Moreover, elimination of inhaled anaesthetics Sevoflurane is chemically unstable and may can be hastened by inducing hyperventilation, get degraded to a compound that is while this is not possible with intravenous nephrotoxic. A metabolite of sevoflurane anaesthetics. Hence IV anaesthetics are used

Table 20.1: Compare and contrast nitrous oxide , ether and halothane

Features Nitrous oxide Ether Halothane

State Gas Liquid Liquid Potency Low Good Good Flammability No Inflammable No Irritant property No Yes No Analgesia Good Good Poor Effect on CV function Not significant Not significant Significant and respiration (Depressant) Muscle relaxation Poor Good Very poor Risk of hepatitis No No Yes Induction and recovery Smooth and rapid Unpleasant Smooth and and slow rapid Use in Used as adjuvant Rarely used Commonly used anaesthesia along with oxygen 126 Textbook of Pharmacology for Dental and Allied Health Sciences

Table 20.2: Compare and contrast halothane and thiopentone sodium

Features Halothane Thiopentone

1. Chemistry Fluorinated compound Barbiturate 2. State liquid liquid 3. Route of administration Inhalation Intravenous 4. Onset of action In minutes In seconds 5. Recovery Medium Fast (8-10 min) 6. Cardiac effect Sensitizes heart to the effect No such effects of adrenaline 7. Equipment for Special equipment required Not required administration 8. Risk of malignant Present Nil hyperthermia 9. Use in anaesthesia For maintenance For induction 10. Contraindication Previous halothane hepatitis Acute intermittent porphyria for induction because of the rapid onset of respiratory depression. Artificial action (Table 20.3) and anaesthesia is ventilation has to be given. maintained by an inhalational agent. • Severe hypotension, hiccoughs may occur. Hypotension should be treated with INDUCING AGENTS plasma expanders, head low position and Thiopentone sodium is an ultrashort-acting pressor agents. barbiturate which when administered IV, rapidly induces hypnosis and anaesthesia Uses without analgesia. It is highly water soluble. Thiopentone sodium is used for induction of Extravasation of the solution produces anaesthesia prior to administration of intense pain, necrosis and gangrene. inhalational anaesthetics On IV inj (3-5 mg/kg as a 2.5% solution) it Precautions Equipment for resuscitation produces unconsciousness in 20-30 sec. should be ready. Duration of action is 4-7 minutes. It is highly lipid soluble and gets rapidly redistributed Methohexitone is similar to thiopentone but in the body tissues. is more potent. It is not preferred due to Advantages toxicity. Quick onset of action; induction is smooth, Propofol is an oily liquid; quick induction rapid and pleasant. (30 sec) and recovery (4 min) is possible from Disadvantages a single dose. It is used for induction and maintenance for short procedures of up to 1 • Not a good analgesic and not a muscle hour duration. The effect of a single dose is relaxant. • It cannot be used alone as the dose terminated by distribution. It can be used for required results in delayed recovery, total IV anaesthesia as continuous infusion respiratory and circulatory depression. or intermittent injection. It is particularly • A short period of apnoea occurs. preferred for ‘day-cases’ when the patient Overdosage results in profound has to be discharged the same day. General Anaesthetics 127

Etomidate is similar to thiopental but it dissociative anaesthesia characterised by intense differs in that - analgesia, immobility, amnesia and a feeling • It is rapidly metabolised—as a result of dissociation from ones own body and recovery is fast. surroundings with or without actual loss of • Less cardiovascular and respiratory consciousness. depression. Mechanism of action–Ketamine acts by But it may cause - blocking the NMDA receptor which is an • involuntary movements and excitatory excitatory amino acid receptor. effects during induction. • pain at the injection site. Ketamine is highly lipid soluble and gets • adrenocortical suppression on long term rapidly distributed into highly perfused use. organs and then redistributed to less Etomidate is preferred for induction in vascular structures. Ketamine hydrochloride patients with cardiovascular problems. given 1-2 mg/kg slow IV or 10 mg/kg IM produces dissociative anaesthesia within 3- DISSOCIATIVE ANAESTHESIA 5 min which lasts for 10-15 min after a single Ketamine In anaesthetic doses ketamine injection. Amnesia lasts for 1-2 hr. produces a trans-like state known as Premedication with atropine is needed.

Table 20.3: Prominent features and use of intravenous anaesthetics

Drug Prominent features Uses Thiopental • Fast onset of action For induction • CV* and respiratory depression Propofol • Fast onset and recovery Short procedures • Pain at injection site • CV and respiratory depression Etomidate • Fast onset and recovery For induction particularly • Less CV and respiratory depression in patients with low • Involuntary movements cardiovascular reserve during induction • Suppresses adrenal steroidogenesis • Pain at injection site Ketamine • Slow onset Short procedures • Good analgesia and amnesia particularly in • No respiratory depression, children no hypotension • ↑ BP • Hallucinations and involuntary movements during recovery Midazolam • Slow onset and recovery Short procedures • Less CV and respiratory like endoscopy, depression fracture reduction Fentanyl + • Slow onset and recovery Short procedures Droperidol • Profound analgesia *CV Cardiovascular 128 Textbook of Pharmacology for Dental and Allied Health Sciences

Return to ‘consciousness’ is gradual. When the combination is given IV, a state Delirium with vivid dreams may be of neuroleptanalgesia is produced. This is accompanied. If diazepam is administered characterised by quiescence, psychic pre- and postoperatively, delirium can be indifference and intense analgesia without avoided. Heart rate, Cardiac output and BP loss of consciousness. It lasts for 30-40 min. are increased due to sympathetic stimulation. Fentanyl 0.05 mg + droperidol 2.5 mg/ml – 4 to 6 ml of the solution is infused IV over 10 Advantages min. Patient is drowsy but cooperative. Respiratory depression is present. There is a • Provides profound analgesia and amnesia; slight fall in BP and HR (vagal stimulation). can be used as the sole agent for minor During recovery extra pyramidal symptoms procedures may be seen—due to droperidol. It is • Respiration is not depressed, does not employed for endoscopies, burn dressing, induce hypotension angiographies and other diagnostic and minor • Less likely to induce vomiting surgical procedures. • Pharyngeal and laryngeal reflexes are only Neuroleptanaesthesia Addition of 65% N2O + slightly affected 35% O2 to the above combination produces • It is of particular value in children and neuroleptanaesthesia. poor-risk patients and also in asthmatic BENZODIAZEPINES patients since it does not induce bronchospasm. Benzodiazepines like diazepam, lorazepam and midazolam are used to induce or Disadvantages supplement anaesthesia. They cause sedation, amnesia and reduce anxiety which are • Hallucinations and involuntary move- beneficial in such patients. BZDs may be ments may occur during recovery if used employed alone in procedures like as a sole agent. endoscopies, reduction of fractures, cardiac • May be dangerous in hypertensives as it catheterisation and cardioversion. IV raises the BP. midazolam is particularly preferred as it is • Ketamine increases cerebral blood flow faster and shorter-acting, more potent, does and intracranial pressure. not cause significant respiratory and Contraindications Hypertension, CCF, cerebral cardiovascular depression and does not cause haemorrhage, increased intracranial tension, pain or irritation at the injection sites. BZDs psychiatric disorders and pregnancy before are also used as preanaesthetic medication. term. Dentistry and general anaesthesia–Though Precautions Pulse and BP should be closely several dental procedures require general monitored; during recovery patients must be anaesthesia, they are usually administered by undisturbed and under observation. an anaesthetist. NEUROLEPTANALGESIA PREANAESTHETIC MEDICATION A combination of a neuroleptic (droperidol) Prior to anaesthesia, certain drugs are with an analgesic (fentanyl) is used. administered in order to make anaesthesia Fentanyl is a short-acting (30-50 min) and safer and more pleasant and is known as potent opioid analgesic (See Page 166). preanaesthetic medication. It is given in order Droperidol is a rapidly acting, potent to: neuroleptic related to haloperidol. 1. decrease anxiety General Anaesthetics 129

2. provide amnesia for the preoperative • prevent laryngospasm which is due to period excessive secretions. 3. relieve preoperative pain if present Scopolamine produces more sedation. 4. make anaesthesia safer Glycopyrrolate—as compared to atropine, 5. reduce side effects of anaesthetics glycopyrrolate is longer acting, is a better 6. reduce gastric acidity. antisialogogue and is less likely to cause To achieve the above purpose, more than significant tachycardia. It also produces less sedation than scopolamine. one drug is required. An informative, supportive, preoperative visit by the Drugs that reduce acidity General anaesthetics anaesthesiologist is very much essential. may induce vomiting. This is associated with an increased risk of aspiration into the Sedative hypnotics Antianxiety agents like respiratory tract because normal protective benzodiazepines are used extensively as airway reflexes are blunted by anaesthetics. preanaesthetic medication. They reduce Aspiration of the acidic gastric contents into anxiety and produce sedation. Diazepam 5- the lungs cause damage to the lungs. H2 10 mg is given orally. It also produces blockers like ranitidine decrease gastric acid amnesia. Barbiturates are not preferred due secretion and are given on the night before to the disadvantages like respiratory surgery. Decrease in gastric secretions depression. reduces the damage to lungs if aspiration Antihistamines have sedative, antiemetic and occurs while on anaesthesia. anticholinergic properties and are useful, e.g. Gastrokinetic agents metoclopramide is a promethazine. dopamine antagonist that promotes Antiemetics Metoclopromide, domperidone gastrointestinal motility and increases the or ondansetron may be used. Antihistamines tone of oesophageal end of the stomach. This with antiemetic properties may also be used. speeds gastric emptying. The combination of H blocker + metoclopramide provides best Anticholinergic drugs Some irritant anaesthetics 2 protection against aspiration. like ether increase the salivary and Opioids like morphine and pethidine reduce respiratory secretions. The secretions from anxiety and apprehension, provide analgesia the oral cavity and trachea may creep into and reduce the dose of the anaesthetic the larynx inducing laryngospasm. They may required. But they depress respiration and enter into the lungs causing aspiration may cause hypotension, postoperative pneumonia. This indicated the need for drugs constipation, and urinary retention; that reduce secretions. Fortunately we now precipitate asthma and delay recovery. have less irritant anaesthetics and secretions are less of a problem. Atropine 0.6 mg IM or Balanced Anaesthesia scopolamine 0.6 mg IM or glycopyrrolate — Since it is not possible to achieve ideal can be used. anaesthesia with a single drug, multiple drugs are employed to attain this—preanaesthetic They medication, IV anaesthetics for induction, • reduce the secretions inhalational agents for maintenance, oxygen, • prevent bradycardia due to vagal skeletal muscle relaxants and analgesics. This stimulation is termed balanced anaesthesia. 130 Textbook of Pharmacology for Dental and Allied Health Sciences 21 Local Anaesthetics

Local anaesthetics are drugs that block nerve II. Surface anaesthetics conduction when applied locally to nerve Lignocaine, cocaine, tissue in appropriate concentrations. Their tetracaine, benzocaine, action is completely reversible. They act on oxethazaine. every type of nerve fibre and can cause both sensory and motor paralysis in the Chemistry innervated area. They act on axons, cell body, dendrites, synapses and other excitable Local anaesthetics are bases and consist of a membranes that utilize sodium channels as hydrophilic amino group on one side and a the primary means of action potential lipophilic aromatic residue on the other, generation. joined by an intermediate chain through an Cocaine was the first agent to be isolated ester or amide linkage. Since ester links are by Niemann in 1860. In spite of its addiction more prone to hydrolysis than amide links, potential, cocaine was used for 30 years as a generally esters have a shorter duration of surface anaesthetic. In an effort made to action. Depending on the linkage, LAs can improve the properties of cocaine, procaine be classified as: was synthesized in 1905. It ruled the field • Ester Linked for the next 50 years. In 1943, lignocaine was – Cocaine, procaine, tetracaine, synthesized and it continues to dominate the benzocaine, chloroprocaine field till today. • Amide Linked Classification of local anaesthetics (LAs) – Lignocaine (Lidocaine), mepivacaine, based on the route of administration and bupivacaine, etidocaine, prilocaine, duration of action is as follows. ropivacaine CLASSIFICATION Since local anaesthetics are weak bases and the infected tissues have a low extracellular I. Injectable pH, LA ionise in such medium and a very 1. Short-acting low fraction of non-ionised LA is available Procaine, chloroprocaine for diffusion into the cell. Therefore LAs are 2. Intermediate-acting much less effective in infected tissues. Lignocaine, prilocaine 3. Long-acting Mechanism of Action Tetracaine (amethocaine), bupivacaine, dibucaine, Local anaesthetics prevent the generation and ropivacaine, etidocaine. the conduction of nerve impulses (Fig. 21.1). Local Anaesthetics 131

The primary mechanism of action is blockade CNS local anaesthetics depress the cortical of voltage-gated sodium channels. inhibitory pathway thereby allowing Local anaesthetics diffuse through the cell unopposed activity of excitatory components. membrane and bind to the voltage-sensitive This loss of inhibition is manifested as sodium channels from the inner side of the restlessness, tremors and may proceed to cell membrane. They prevent the increase in convulsions. This central stimulation is permeability to Na+ and gradually raise the followed by generalised CNS depression and threshold for excitation. With increasing death may result from respiratory failure. concentration, impulse conduction slows, rate CVS The primary site of action is the of rise of action potential (AP) declines, AP myocardium. Lignocaine decreases excit- amplitude decreases and finally the ability ability, conduction rate and force of to generate an AP is abolished. These result contraction (quinidine like effects). They also from binding of LA to more and more cause arteriolar dilatation. Since procaine is short-acting, procainamide is used as an sodium channels. Thus they prevent the antiarrhythmic. Bupivacaine is more generation of an AP and its conduction. cardiotoxic than other LAs. Small nerve fibres are more susceptible as Smooth muscle LAs depress contractions in the they present a greater surface area per unit intact bowel. They also relax vascular and volume. Thus smaller fibres are blocked bronchial smooth muscles. first–autonomic fibres are blocked first followed by sensory fibres conducting pain, Pharmacokinetics temperature sense, then touch, pressure and vibration sensations in the same order. This Local anaesthetics are rapidly absorbed from is called differential blockade. Sensory and the mucous membranes and abraded skin. motor fibres are equally sensitive. Non- Rate of absorption is dependent on the myelinated fibres are blocked more readily vascularity of the area. Thus vasoconstriction than the myelinated. decreases the absorption. Toxicity depends Addition of a vasoconstrictor like on the balance between absorption and adrenaline (1:1,00,000 to 1: 2,00,000) or metabolism, i.e. if it gets metabolised as it phenylephrine (1:20,000): gets absorbed, then toxicity is less. Binding 1. prolongs the duration of action of LAs by to tissues decreases the concentration in slowing the rate of absorption from the systemic circulation and thereby toxicity. site of administration. Esterlinked LAs are rapidly hydrolysed by 2. reduces systemic toxicity of LAs since the absorption rate is reduced and as it gets absorbed, it gets metabolised.

ACTIONS Systemic Actions Depending on the concentration attained in the plasma, any LA can produce systemic effects. LAs interfere with the functions of all organs in which conduction or Fig 21.1: Mechanism of action of local anaesthetics. In the transmission of impulses occur. Thus CNS, open state the Na+ moves in and within milliseconds the autonomic ganglia, NMJ and all muscles are channel is inactivated due to closure of the inactivating affected. gate. LA block the sodium channels. 132 Textbook of Pharmacology for Dental and Allied Health Sciences plasma pseudocholinesterase and in the liver. Individual Compounds Amide-linked LAs are metabolised by the A. Injectable (Table 21.2) liver microsomes by dealkylation and hydrolysis and are not effective orally (as 1. Lignocaine is the most widely used LA. It antiarrhythmics). They undergo extensive is fast and long-acting. It is useful for all first pass metabolism. types of blocks. Maximum anaesthetic effect is seen in 2-5 minutes and lasts for Adverse Effects (Table 21.1) 30-45 minutes. In contrast to other LAs, lignocaine causes drowsiness and mental 1. Hypersensitivity reactions– include skin clouding. Though it is a good corneal rashes, dermatitis, asthma or rarely anaesthetic, it is not generally preferred anaphylaxis. These reactions are more because it causes irritation. common with ester type of drugs. Ester Lignocaine (XYLOCAINE) is available as type LA are metabolised to PABA 4% topical solution, 2% jelly, 5% ointment, derivatives. These are responsible for 1% and 2% injection, 5% for spinal allergic reactions while with amides, allergy anaesthesia and 10% spray. Though is rare. Intradermal sensitivity test should lignocaine can be used on the eye for be done before using these drugs. Drugs surface anaesthesia, it is not preferred needed to manage such reactions should because it causes some irritation. be kept ready. Moreover, allergy is most 2. Bupivacaine HCl–widely used. However, often due to the preservative methyl- it can cause more cardiotoxicity than paraben. Preparations that do not contain others. Injection 0.25-0.5% with or this preservative are now available. without adrenaline. Levobupivacaine 2. CNS–Dizziness, auditory and visual hydrochoride is a derivative of disturbances, mental confusion, dis- bupivacaine that seems to be less orientation, anxiety, muscle tremors, neurotoxic and less cardiotoxic than convulsions and respiratory failure can bupivacaine. result from large doses. Intravenous 3. Ropivacaine–is similar to bupivacaine diazepam controls convulsions. Infact, except that it is less cardiotoxic. these can be prevented by preanaesthetic 4. Chloroprocaine HCl–potency is twice that administration of diazepam (1-2 mg/kg), especially if large doses are to be used. of procaine and its toxicity is lower 3. CVS–Hypotension, bradycardia and because of its more rapid metabolism. arrhythmias may be encountered. Rarely 5. Etidocaine HCl–its analgesic action lasts 2- cardiac arrest can occur. 3 times longer. It is used for epidural and 4. Local irritation–can be seen with bupivacaine. all types of infiltration and regional Wound healing may be delayed. anaesthesia.

Table 21.1: Adverse effects of local anaesthetics

CNS : Dizziness, confusion, anxiety, tremors, occasionally convulsions and respiratory depression CVS : Hypotension, bradycardia, arrhythmias Hypersensitivity : Rashes, dermatitis, asthma, rarely anaphylaxis reactions Local Anaesthetics 133

Table 21.2: Preparations and uses of some local anaesthetics Drug Preparation Uses 1. Tetracaine 1-2% ointment, eyedrops, Topical, spinal anaesthesia cream, powder, 0.25, 0.5% inj 2. Lignocaine 2-4% drops, spray, jelly, Topical, infiltration, nerve block, spinal, ointment, cream, 1-10% inj epidural and IV regional anaesthesia 3. Benzocaine 1-2% dusting powder, Topical anaesthesia 5% suppository, cream, gels, ointments, 20% spray 4. Oxethazaine 0.2% suspension Topical anaesthesia (used in peptic ulcer) 5. Prilocaine 5% cream, 4% inj Topical, nerve block anaesthesia 6. Dibucaine 0.5-1% cream Topical anaesthesia 7. Mepivacaine 1-3% inj Nerve block, epidural anaesthesia 8. Bupivacaine 0.25-0.75% inj Infiltration, nerve block, spinal, epidural anaesthesia 9. Ropivacaine 2-10% inj Infiltration, nerve block, spinal, epidural anaesthesia 10. Etidocaine 1% inj Epidural anaesthesia

6. Mepivacaine–action is more rapid in onset constriction of conjunctival vessels, and more prolonged than that of clouding and sometimes corneal lignocaine. sloughing and is therefore not preferred 7. Prilocaine HCl–onset of action and on the eye. Cocaine is used topically for duration are longer. Because of it’s anaesthesia of upper respiratory tract. It toxicity, its use is restricted to dental has the advantage of being a vasocon- procedures. strictor and a local anaesthetic— both in 8. Cocaine–(Table 21.3) produces euphoria one. and is a drug of dependence and abuse. 9. Procaine–was widely used once. But is now It is a surface anaesthetic. It is a replaced by other agents (Table 21.4). It protoplasmic poison and hence cannot be is hydrolysed to PABA which interferes injected. Cocaine was used for ocular with antimicrobial activity of sul- anaesthesia earlier. But it causes fonamides. It is rapidly absorbed

Table 21.3: Compare and contrast procaine and cocaine

Features Procaine Cocaine

1. Source Synthetic Natural–Erythroxylon coca 2. Chemistry Both are esters 3. Euphoria Nil Produces 4. Abuse potential Nil Abused since centuries 5. C.V. effects ↓cardiac contraction→ ↓ BP Vasoconstriction→hypertension, arrhythmias 6. Surface anaesthesia Does not produce Surface anaesthetic 7. Ocular anaesthesia Not useful Useful-was used earlier 8. IV use Injected IV Protoplasmic poison– cannot be injected IV 134 Textbook of Pharmacology for Dental and Allied Health Sciences

Table 21.4: Compare and contrast procaine and lignocaine

Features Procaine Lignocaine

1. Chemistry Ester Amide 2. Distribution Not good; rapidly excreted. Widely distributed 3. Metabolism Metabolised rapidly in blood Metabolised in liver 4. In liver disease Can be used Toxicity likely 5. Allergic reaction Ester type – allergy more likely Amide – allergy less common 6. Penetrability Poor Good 7. Surface anaesthesia Not a surface anaesthetic Surface anaesthetic 8. Use Not preferred Most commonly used

following parenteral administration. It is D. Poorly soluble anaesthetics ineffective when applied topically–thus These are too slowly absorbed to be toxic. not useful as a surface anaesthetic. They can be applied to wounds directly and 10.Tetracaine–is a PABA derivative and is 10 ulcerated surfaces as they produce sustained times more toxic and more active than anaesthetic effect, e.g. benzocaine. procaine. It is used on the eye as 0.5% Benzocaine is a PABA derivative. It is poorly drops, ointment 0.5% and cream 1% for soluble in water because of which it remains topical use. 0.25 to 0.5% injection is used at the site for a longer time and toxicity is for spinal anaesthesia. low because absorption is poor. It is used B. Local anaesthetics used only on the eye topically to anaesthetise the skin and mucous membrane. Benoxinate HCl–within 60 seconds of administration it produces corneal USES OF LOCAL ANAESTHETICS anaesthesia enough to perform tonometry. Local anaesthesia is the loss of sensation Proparacaine HCl–produces little or no initial without the loss of consciousness or irritation–0.5% ophthalmic solution is used. impairment of central control of vital C. Local anaesthetics used on the skin and functions. Depending on the site and mucous membranes technique of administration, LA can be: Surface Anaesthesia LAs used on the skin and mucous membranes are dibucaine, dyclonine hydrochloride and Anaesthesia of mucous membrane of the eye, pramoxine hydrochloride. These drugs are nose, mouth, tracheobronchial tree, effective when used topically in the oesophagus and genitourinary tract can be symptomatic relief of anal and genital produced by direct application of the pruritus, poison ivy rashes, acute and chronic anaesthetic solution. Tetracaine 2%, dermatoses. Dibucaine is the most potent, lignocaine 2-10% are most often used. most toxic and longest-acting LA. It is Phenylephrine (but not adrenaline because available as cream and ointment. its penetration is poor) produces vasoconstriction on topical application and prolongs Corneal anaesthetics used clinically duration of action. Tetracaine Benoxinate Anaesthesia is entirely superficial and does Lignocaine Proparacaine not extend to submucosal structures. But LAs are absorbed from mucous membranes and Local Anaesthetics 135 may result in systemic toxicity. Patient should Field Block be cautioned to expectorate the excess Subcutaneous injection of a LA solution solution to avoid excess absorption. Local proximal to the site to be anaesthetised, anaesthetics can also be used on abraded interrupts nerve transmission in the region skin. Surface anaesthesia is useful. distal to the injection. Sites such as forearm, 1. On the eye scalp, anterior abdominal wall and lower (a) for tonometry, surgery extremity are used for field block. Knowledge (b) to remove foreign bodies from the of the relevant neuroanatomy is essential. cornea and conjunctiva Advantage Lesser dose can be used to provide (c) for preoperative preparation a greater area of anaesthesia. 2. Others Nasal lesions, stomatitis, sore throat, Nerve Block tonsillectomy, endoscopies, intubation, gastric ulcer, burns and proctoscopy. Injection of a solution of a LA about/around An eutectic mixture containing 2.5% each of individual peripheral nerves or nerve lignocaine and prilocaine at room temperature plexuses produces larger areas of anaesthesia has a lower melting point than either of the with a smaller amount of the drug than the drugs. This is emulsified and applied as a above techniques. Anaesthesia starts a few cream to anaesthetise the intact skin. The centimeters distal to the injection. cream should be applied on the skin under Nerve block anaesthesia is useful for: an occlusive dressing and can produce 1. blocks of brachial plexus for procedures anaesthesia upto a depth of 5 mm. It can be on the arm (distal to deltoid). used for procedures like venipuncture and 2. intercostal nerve blocks to anaesthetise skin graft harvesting. anterior abdominal wall. 3. cervical plexus block for surgery of the Infiltration Anaesthesia neck. 4. sciatic and femoral nerve blocks for Injection of a local anaesthetic solution surgeries distal to the knee. directly into the tissue can be (i) superficial– 5. blocks of nerves at wrist and ankle. only into the skin, or (ii) into deeper 6. radial and ulnar nerve block at the elbow. structures including intra-abdominal organs. 7. sensory cranial nerves block. Duration can be doubled by adrenaline 8. facial and lingual nerves block. (1:2,00,000). Adrenaline should not be used 9. inferior alveolar nerve block for extraction (i) around end arteries to avoid necrosis, and of lower jaw teeth. (ii) intracutaneously to avoid sloughing. Onset of action is within 3 minutes with Drugs used are lignocaine, procaine, lignocaine. Duration depends on lipid bupivacaine. solubility and protein binding. Anaesthesia Advantage By using infiltration anaesthesia, lasts longer than by field block or infiltration it is possible to provide anaesthesia without techniques. Nerve blocks are done for tooth disruption of normal bodily functions. extraction, operations on the eye, limbs and Disadvantage In major surgeries–systemic in neuralgias. toxicity due to local anaesthetic is likely as large amounts of the anaesthetic is required Spinal Anaesthesia (SA) for such procedures. Uses For minor procedures like incisions, Local anaesthetic solution is injected into the drainage of an abscess, excision, etc. subarachnoid space between L2-3 or L3-4 136 Textbook of Pharmacology for Dental and Allied Health Sciences below the lower end of the spinal cord. The 4. Cauda equina syndrome is uncommon– drug acts on nerve roots. Lower abdomen control over bladder and bowel sphincters and lower limbs are anaesthetised and is lost because of damage to nerve roots. paralysed. The level of anaesthesia can be 5. Sepsis–resulting in meningitis altered by the volume of injection, specific 6. Nausea and vomiting–premedication can be gravity of the solution and posture of the given to prevent this. patient. Generally a hyperbaric solution (in 10% glucose) is injected. Isobaric and Epidural Anaesthesia hypobaric solutions can also be given. Level LA is injected into the spinal extradural space. of sympathetic block produced is two It acts on nerve roots while small amounts segments higher and motor paralysis two diffuse into subarachnoid space. It is segments lower than sensory or cutaneous technically more difficult and comparatively anaesthesia. Duration depends on the larger volumes of the anaesthetic are needed. concentration, dose and the drug itself. After repeated injections tachyphylaxis may Lignocaine, tetracaine, bupivacaine and develop. ropivacaine are used for spinal anaesthesia. Advantages Advantages 1. Sensory blockade is 4-5 segments higher Safer, affords good analgesia and muscle than motor blockade. This difference is relaxation and there is no loss of useful for obstetric analgesia, as the consciousness. In cardiac, pulmonary and mother has painless labour and can still renal diseases, SA may be preferred over cooperate in the process of labour and is general anaesthesia whenever possible. conscious throughout. Uses 2. As there is no risk of injecting into subarachnoid space, there are no chances Surgical procedures on the lower limb, pelvis, of infection. lower abdomen, obstetric procedures, caesarean section and other operations are Intravenous Regional Anaesthesia done on spinal anaesthesia. This type of anaesthesia is useful for rapid Complications of SA anaesthetization of an extremity. A rubber bandage is used to force the blood out of 1. Hypotension and bradycardia–sympathetic the limb (veins) and a tourniquet is applied blockade results in venous pooling of the to prevent the re-entry of the blood. A dilute blood leading to decreased venous return, solution of the local anaesthetic is then decreased cardiac output and hypo- injected intravenously. It diffuses into tension. extravascular tissues. Onset of anaesthesia is 2. Respiratory paralysis–hypotension and in 2 minutes. Because of the pain produced ischaemia of the respiratory centre results by the tourniquet, this type of anaesthesia in respiratory failure. Due to paralysis of is used for procedures lasting less than one the abdominal muscles, cough reflex is less hour. About 25% of the drug enters into the effective resulting in stasis of respiratory systemic circulation. This type of anaes- secretions leading to respiratory infections. thesia is commonly used on the upper limbs 3. Headache due to seepage of CSF can be though it can also be used on the legs and the treated with analgesics. thighs. Sedative Hypnotics 137 22 Sedative Hypnotics

Sedative is a drug that produces a calming or Oxazepam quietening effect and reduces excitement. It Nitrazepam may induce drowsiness. Hypnotic is a drug Alprazolam that induces sleep resembling natural sleep. Halazepam. Both sedation and hypnosis may be • Ultra short acting (< 6 hours) considered as different grades of CNS Triazolam, depression. Midazolam All human beings need sleep. Insomnia is 2. Newer agents Zolpidem sleeplessness. Approximately 1/3rd of our Zopiclone life is spent in sleep. Since centuries man has Zaleplon sought the help of drugs and other remedies 3. Barbiturates Phenobarbitone for insomnia. Mephobarbitone Secobarbitone Sleep can be classified into two types Pentobarbitone depending on the physiological characte- Thiopentone ristics - Hexobarbitone 1. Non-rapid eye movement (NREM)-sleep 4. Miscellaneous Paraldehyde 2. Rapid eye movement sleep (REM). Chloral hydrate Throughout the night, NREM and REM Glutethimide sleep cycles repeat alternately for brief Meprobamate periods. BENZODIAZEPINES (BZD) CLASSIFICATION Chlordiazepoxide was the first BZD to be 1. Benzodiazepines introduced into clinical medicine in 1961 and • Long-acting (24-48 hours) since then thousands of BZDs have been Diazepam synthesized of which about 35 are now in Chlordiazepoxide clinical use. Clonazepam Pharmacological actions The most important Flurazepam actions of BZDs are on the CNS and include: Chlorazepate 1. Sedation and hypnosis Clobazam 2. Reduction in anxiety • Short-acting (12-24 hours) 3. Muscle relaxation Temazepam 4. Anticonvulsant effects Lorazepam 5. Amnesia. 138 Textbook of Pharmacology for Dental and Allied Health Sciences

Sedation and hypnosis BZDs hasten the onset after the administration of BZDs. This of sleep and increase the duration of sleep. property is an advantage when BZDs are used The quality of sleep resembles natural sleep in surgical procedures as the patient does not more closely when compared to other remember the unpleasant events. hypnotics. Tolerance develops to this effect Other actions In higher doses BZDs decrease gradually. BP and increase heart rate. Diazepam Anxiolytic or antianxiety effects BZDs reduce decreases nocturnal gastric acid secretion. anxiety and aggression and thus produce a calming effect. Alprazolam has additional Mechanism of Action antidepressant properties. Benzodiazepines bind to the GABA receptor Muscle relaxant action BZDs reduce muscle A (Fig. 22.1) at a site which is different from tone by a central action. Generally anxiety is associated with an increased muscle tone and the GABA-binding site. They enhance the may be responsible for aches and pains in affinity of GABA for the receptor and these patients. The muscle relaxation by BZDs modulate the effects of GABA. BZDs bind to adds to its beneficial effects in such patients the receptor and increase the frequency of (See page 64). chloride channel opening. This in turn leads Anticonvulsant effects BZDs increase the to increased flow of chloride ions into the seizure threshold and act as anticonvulsants. neurons, resulting in hyperpolarization. Diazepam is used intravenously for the BZDs as hypnotics – when compared to treatment of status epilepticus. Other BZDs barbiturates: like clonazepam are used in the treatment of 1. BZDs induce sleep which more closely absence seizures and myoclonic seizures in resembles natural sleep and has less children (See page 151). hangover. Amnesia BZDs produce anterograde amnesia, 2. In hypnotic doses they do not affect i.e.loss of memory for the events happening respiration or cardiovascular functions.

α β γ Fig. 22.1: GABAA receptor is a pentamer made of 5 subunits (2 , 2 and 1 ). BZDs, GABA, barbiturates and newer non- - BZD agents bind to different sites on the GABAA receptor to facilitate the opening of the Cl channel. Binding of agonists opens the Cl- ion channels. β carbolines bind to the BZD receptors and produce opposite effects (inverse agonists). Sedative Hypnotics 139

3. BZDs have a higher safety margin and are effects. For doses and duration of action see safer than barbiturates even in overdoses. Table 22.1. The respiratory depression in overdoses Adverse effects BZDs are generally well is milder. tolerated. The common side effects include 4. In case of BZD overdosage, a specific BZD drowsiness, confusion, amnesia, lethargy, antagonist–flumazenil can be used to weakness, headache, blurred vision, ataxia, reverse the symptoms. day time sedation and impaired motor 5. BZDs do not cause microsomal enzyme coordination such as driving skills–therefore, induction and therefore do not alter the while on BZDs driving should be avoided. blood levels of other drugs. In some patients it may cause paradoxical 6. BZDs have lower abuse liability. irritability and anxiety. Because of the above reasons, BZDs are Tolerance and dependence Both tolerance and the most preferred sedative hypnotics. dependence liability are less with BZDs as Pharmacokinetics There are significant compared to barbiturates. Patients develop pharmacokinetic differences among BZDs tolerance to the sedative effects very slowly. due to their difference in lipid solubility. The withdrawal symptoms are milder and BZDs are completely absorbed on oral slower in onset because of the longer plasma administration. Intramuscular absorption is half-life of most BZDs, but they may be slow - hence oral route is preferred. They abrupt and more intensive with short-acting are extensively bound to plasma proteins, agents. Withdrawal symptoms include metabolised in the liver by glucuronide anxiety, nervousness, tremors, dizziness and conjugation. Many BZDs particularly long anorexia. When given to a pregnant mother acting ones are converted to metabolites during labour, BZDs cause hypotonia and which are active - thereby prolonging their respiratory depression in the neonate.

Table 22.1: Dose and duration of action of some commonly used hypnotics

Hypnotic Hypnotic Duration dose of action (mg) (hrs)

Long acting Diazepam 5-10 24-48 Chlordiazepoxide 10-20 24-48 Nitrazepam 5-10 24 Alprazolam 0.25-0.5 24

Short acting Triazolam 0.125-0.25 <6 Midazolam 7.5-10 <6 Lorazepam 1-2 12-18 Temazepam 10-20 12-18

Newer agents Zolpidem 5-10 <4 Zaleplon 5-20 <4 Zopiclone 7.5-10 <4 140 Textbook of Pharmacology for Dental and Allied Health Sciences

Acute overdosage–BZD overdosage induces NEWER AGENTS sleep but the respiratory depression is mild. Newer agents include zolpidem, zopiclone Hence BZDs are safe and the availability of a and zaleplon. specific antagonist- flumazenil- makes it safer to use BZDs because poisoning can be treated. • They are not BZDs but produce their effects by binding to benzodiazepine site

Uses of BZDs on the GABAA receptors and facilitate the inhibitory actions of GABA. 1. Insomnia When drugs are to be used to treat • They are all rapid and short acting agents insomnia, BZDs are the agents of choice. and produce minimum hangover. Lorazepam, oxazepam, temazepam, • Their actions are blocked by flumazenil. nitrazepam or triazolam may be used. • They are used for short periods when 2. In anxiety states BZDs are the most short acting hypnotics are needed. commonly used anxiolytics for the Zolpidem is a good hypnotic but has weak treatment of anxiety states and anxiety anticonvulsant and muscle relaxant effects. neuroses (see Page 194). Any of the BZDs It is short acting (t½ - 2 hours) but the effects except the ultra short acting ones may be on sleep continue for a long time even after used. stopping zolpidem. 3. As anticonvulsants IV diazepam is the drug of choice in the treatment of status It is well absorbed from the gut and epilepticus. Clonazepam or clobazam are metabolized in the liver. Dose should be used as adjuncts with other anti-epileptic reduced in hepatic dysfunction. drugs (Page 151). Zaleplon is rapidly absorbed from the gut and 4. Muscle relaxant BZDs are centrally acting has a short t½ of about 1 hour. It is muscle relaxants used in chronic muscle metabolised in the liver. It has the advantages spasm and spasticity. that no withdrawal symptoms are reported 5. As preanaesthetic medication–for their after stopping it and no tolerance develops. sedation and anxiolytic effects BZDs are It has rapid onset and short duration of useful (Page 128). action. No side effects are reported. 6. During alcohol withdrawal–BZDs are useful Zopiclone is another newly introduced in patients during withdrawal of alcohol hypnotic. Its actions resemble those of BZDs. or other sedative-hypnotics. BARBITURATES BENZODIAZEPINE ANTAGONIST Barbiturates are derivatives of barbituric acid Flumazenil is a BZD receptor antagonist which and were the largest group of hypnotics in competes with BZDs for the receptor. Given clinical use until the 1960s. intravenously flumazenil is rapid and short acting. It may rarely induce seizures. Classification Barbiturates can be classified based on their Uses duration of action as: 1. To reverse BZD sedation/anaesthesia • Long-acting 2. In BZD overdosage. Phenobarbitone, Mephobarbitone Sedative Hypnotics 141

• Short-acting 2. Respiratory system Barbiturates depress the Pentobarbitone, Butobarbitone respiration. High doses bring about a direct • Ultrashort-acting paralysis of the medullary respiratory centre Thiopentone, Hexobarbitone, and can be fatal. Methohexitone 3. Cardiovascular system Hypnotic doses of barbiturates produce a slight reduction in Mechanism of Action blood pressure and heart rate as seen during natural sleep. Barbiturates bind to a specific site on the Toxic doses of barbiturates produce a GABA receptor Cl– channel complex. They significant fall in BP due to direct decrease facilitate inhibitory neurotransmission by in myocardial contractility and vasomotor opening chloride ion channels and centre depression. hyperpolarise the neural membrane. 4. Skeletal muscles Higher doses of barbi- Pharmacological Actions turates depress the excitability of the neuromuscular junction. 1. CNS Barbiturates cause depression of all excitable tissues of which CNS is the most Pharmacokinetics sensitive. Barbiturates are well-absorbed and widely Sedation and hypnosis In hypnotic doses, distributed in the body. The highly lipid barbiturates induce sleep and prolong the soluble barbiturates like thiopentone have a duration of sleep. The REM-NREM sleep fast onset of action and duration is short due cycle is altered with decreased duration of to redistribution into adipose tissues. REM and prolonged NREM sleep. On Barbiturates are metabolised in the liver. waking up there is hangover with headache They are hepatic microsomal enzyme and residual sedation. inducers. The metabolites are excreted in Barbiturates reduce anxiety, impair short- urine. term memory and judgement. They can produce euphoria and are drugs of addiction Adverse Reactions while some people may experience dysphoria. Barbiturates produce hyperalgesia Hangover–due to residual depression of the (increased sensitivity to pain). Therefore CNS may be accompanied by nausea, barbiturates, when given as hypnotics for a vomiting, vertigo and diarrhoea. Distortions patient in pain may be more troublesome of mood, impaired judgement and fine motor than being of any benefit. skills may be evident. Barbiturates may cause Anaesthesia In higher doses barbiturates excitement and irritability in some patients produce general anaesthesia. The ultrashort- particularly children. acting barbiturates are used intravenously for Barbiturates cause respiratory depression this effect. and in the presence of respiratory disorders Anticonvulsant effects All barbiturates have even the hypnotic doses of barbiturates can anticonvulsant actions. Phenobarbitone and cause serious respiratory depression. mephobarbitone have specific anticonvulsant Hypersensitivity reactions like skin rashes, activity in subhypnotic doses and are used swelling of the eyelids and lips and rarely in the treatment of epilepsy. exfoliative dermatitis may be seen. 142 Textbook of Pharmacology for Dental and Allied Health Sciences

Barbiturates are contraindicated in 2. Antiepileptic Phenobarbitone is used as porphyrias because they increase porphyrin an antiepileptic (page 149). synthesis. 3. Neonatal jaundice Phenobarbitone is a Tolerance and dependence On repeated microsomal enzyme inducer and thereby administration, tolerance develops to the enhances the production of glucuronyl effects of barbiturates. transferase—the enzyme required for Development of both psychological and metabolism and excretion of bilirubin. It physical dependence to barbiturates make therefore helps in the clearance of jaundice them one of the drugs with abuse liability. in the neonates. Withdrawal symptoms include anxiety, 4. Sedation and hypnosis Benzodiazepines are restlessness, abdominal cramps, hallucin- preferred to barbiturates as sedative ations, delirium and convulsions. hypnotics. Acute barbiturate poisoning The fatal dose of 5. Preanesthetic medication Barbiturates were phenobarbitone is 6-10 gm. Manifestations used earlier for the sedative-hypnotic include respiratory depression with slow and property, but are not preferred now. shallow breathing, hypotension, skin eruptions, cardiovascular collapse and renal MISCELLANEOUS failure. Chloral hydrate is used as an alternative to Treatment There is no specific antidote. The BZD. It has a bad taste and is an irritant- measures include: causes nausea and vomiting. It produces 1. Gastric lavage followed by administration hypnosis without affecting respiratory and of activated charcoal to prevent further cardiovascular functions. absorption of barbiturates. Meprobamate has sedative and antianxiety 2. General supportive measures like properties but is now not recommended. It maintenance of BP, patent airway, produces respiratory depression, ataxia and adequate ventilation and oxygen is a drug of abuse. administration. Paraldehyde is a colourless, transparent, 3. Forced alkaline diuresis with sodium pungent, inflammable liquid. It is an irritant bicarbonate, a diuretic and IV fluids will and can dissolve plastic—cannot be given by hasten the excretion of long-acting a plastic syringe. It is a good hypnotic causing barbiturates through the kidneys since little hangover. It can be given rectally, they are acidic drugs. intramuscularly or orally. 4. Haemodialysis should be done especially It also has anticonvulsant properties. if there is renal failure. Uses Because of respiratory depression and Uses abuse liability, barbiturates are generally not preferred. 1. As anticonvulsant in status epilepticus 1. Anaesthesia Thiopentone sodium is used particularly in children; tetanus and IV for the induction of general anaes- eclampsia. thesia. 2. Hypnotic–rarely used. Alcohols 143 23 Alcohols

ETHYL ALCOHOL (ETHANOL) depression of myocardium and vasomotor centre. Ethyl alcohol is a monohydroxy alcohol 4. GIT and liver Alcohol is an irritant– manufactured by fermentation of sugars. It increases gastric secretion and produces is a colourless, volatile, inflammable liquid. The ethanol content of various alcoholic vasodilation and warmth. It is an appetizer. beverages ranges from 4-55%. Chronic alcoholism results in peptic ulcer. Chronic consumption of moderate Actions amounts of alcohol results in accumulation of fat in the liver, enlargement of the liver, 1. Local On topical application, ethanol followed by fatty degeneration and cirrhosis. evaporates quickly and has a cooling effect. Alcohol induces microsomal enzymes. It is an astringent–precipitates surface 5. Other effects Though alcohol is called an proteins and hardens the skin. 40-50% alcohol aphrodisiac, this effect could be due to loss is rubefacient and counter irritant. Alcohol of inhibition. Low doses taken over a long is also an antiseptic. At 70%, it has maximum time increases HDL and lowers LDL antiseptic properties which decrease above cholesterol. Alcohol is a diuretic (↓ADH that. It is not effective against spores. secretion). It interferes with folate 2. CNS Alcohol is a CNS depressant. Small metabolism and may cause megaloblastic doses cause euphoria, relief of anxiety and anaemia. Though alcohol causes a feeling of loss of social inhibitions. Moderate doses warmth, heat loss is increased due to impair muscular coordination and visual vasodilation and should not be used for acuity making driving dangerous. With ‘warming up’ in cold surroundings. Food higher doses mental clouding, impaired value is 7 calories/gram. judgement, drowsiness and loss of self control result. High doses cause stupor and Mechanism of Action coma. Death is due to respiratory depression. Alcohol may precipitate convulsions in Ethanol acts by - epileptics. Tolerance develops on long-term 1. inhibiting central neuronal nicotinic use. acetylcholine receptors. 3. CVS The actions are dose dependent. 2. inhibiting excitatory NMDA (N-methyl-D- Small doses cause cutaneous vasodilation asparate receptors mediate excitatory resulting in flushing and feeling of warmth. responses in the CNS and kainate receptor Large doses cause hypotension due to functions. 144 Textbook of Pharmacology for Dental and Allied Health Sciences

3. promoting the function of 5 HT3 6. In methanol poisoning (See below) receptors. Acute alcoholic intoxication causes severe 4. ethanol also influences many ion channels gastritis, hypotension, hypoglycaemia, + including K channels. respiratory depression, coma and death. Treatment measures include gastric lavage, Pharmacokinetics airway maintenance, positive pressure Alcohol is rapidly absorbed from the stomach ventilation and maintenance of fluid and and is metabolised in the liver by alcohol and electrolyte balance. Haemodialysis is needed aldehyde dehydrogenase. in severe intoxication. Metabolism follows zero order kinetics–a Chronic alcoholism causes dependence. constant amount is metabolised per unit time, Wernicke’s encephalopathy, Korsakoff’s i.e. about 10 ml absolute alcohol is psychosis, tremors, cirrhosis of liver, metabolised per hour. It is excreted through hypertension and cardiomyopathy can occur. kidneys and lungs. In addition, nutritional deficiencies such as

Drug Interactions polyneuritis, anaemia and pellagra can occur. In pregnant women, alcohol is teratogenic. 1. Alcohol potentiates other CNS Even moderate drinking during pregnancy depressants including hypnotics, opioids can produce ‘fetal alcohol syndrome’ with and antipsychotics. manifestations like low IQ, microcephaly, 2. Sulfonylureas, metronidazole and growth retardation and facial anomalies in griseofulvin have disulfiram like effects the foetus. It can also cause stillbirths and on alcohol consumption. abortions. 3. Alcohol is an enzyme inducer. Chronic alcoholics have poor dental hygiene resulting in a higher rate of Uses associated dental ailments like periodontitis, 1. Antiseptic–70% alcohol is applied topically. gingivitis and dental plaque. 2. Bedsores–When rubbed onto the skin, alcohol hardens the skin and prevents bed- Treatment of alcohol dependence sores. Disulfiram 3. Fever Alcoholic sponges are used for Disulfiram inhibits the enzyme aldehyde reduction of body temperature in fevers. dehydrogenase. If alcohol is consumed after 4. Appetite stimulant–About 50 ml of 6-10% taking disulfiram, acetaldehyde accumulates alcohol given before meals is an appetite and within few minutes it can produce stimulant. flushing, throbbing headache, nausea, 5. Neuralgias–In severe neuralgias like vomiting, sweating, hypotension and trigeminal neuralgia, injection of alcohol confusion - called the antabuse reaction, due to around the nerve causes permanent loss accumulation of acetaldehyde. The effect lasts of transmission and relieves pain. for 7-14 days after stopping disulfiram. The Alcohols 145 reactions can sometimes be very severe and hypotension, delirium, acidosis and coma. therefore treatment should be given in a Formic acid has affinity for optic nerve and hospital. causes retinal damage resulting in blindness. Other drugs that cause antabuse reaction There are reports of even 15 ml of methanol are metronidazole, chlorpropamide, tol- causing blindness. Death is due to respiratory butamide, griseofulvin, cephalosporins and failure. phenylbutazone. Contraindications Patients with liver disease, patients physically dependent on alcohol. Other drugs-Several drugs are being tried in the pharmacotherapy of alcohol dependence. Orally effective opioid antagonists Treatment naltrexone and nalmefene reduce the urge 1. Correction of acidosis As acidosis hastens and craving to drink and are recommended retinal damage, immediate correction of as adjuvants to other measures. They also acidosis with IV sodium bicarbonate reduce the chances of relapse of heavy infusion helps in preventing blindness. drinking. Ondansetron, a 5HT3 antagonist antiemetic has been shown to reduce alcohol 2. Protect eyes Patient should be kept in a dark consumption and is being evaluated for use room to protect the eyes. in alcohol withdrawal. Benzodiazepines 3. Gastric lavage should be given. reduce the symptoms of alcohol withdrawal 4. BP and ventilation should be maintained. α 5. Ethyl alcohol should be given imme- like anxiety and insomnia. Clonidine an 2 agonist also reduces symptoms of sympa- diately. It competes with methanol for thetic overactivity like tremors and alcohol dehydrogenase, because of its tachycardia. Acamprosate an antagonist of higher affinity for alcohol dehydro- NMDA receptor is also found to prevent genase. It thus slows the metabolism of relapse of heavy drinking. methanol and prevents the formation of toxic metabolites. A loading dose of 0.6 METHYL ALCOHOL (METHANOL, WOOD g/Kg is followed by an infusion of 10 g/ ALCOHOL) hour. Methanol is used to denature ethyl alcohol. 6. Antidote Fomepizole specifically inhibits It is of no therapeutic value. Ingestion results the enzyme alcohol dehydrogenase in methanol poisoning. Methanol is and thereby prevents the formation of converted to formaldehyde - catalysed by toxic metabolites—formaldehyde and alcohol dehydrogenase; formaldehyde is formic acid. Fomepizole thus acts as an converted to formic acid by the action of antidote in methanol poisoning. It has an aldehyde dehydrogenase. Toxic effects are advantage over ethyl alcohol that it does due to formic acid. not cause any intoxication by itself. Manifestations of toxicity are vomiting, 7. Haemodialysis should be started at the headache, vertigo, severe abdominal pain, earliest possible. 146 Textbook of Pharmacology for Dental and Allied Health Sciences 24 Antiepileptics

Epilepsy is a common neurological abnor- thumb. If the sensory area representing the mality that affects about 0.5-1% of the left palm is involved, there is numbness or population. Epilepsy is a chronic disorder paraesthesia of the left palm. This type of characterised by recurrent seizures often seizures lasts for 20-60 seconds. accompanied by episodes of unconsciousness Complex partial seizures are the most common and/or amnesia. It is a disorder of brain types of epilepsy.They are characterised by function. purposeless movements like lipsmaking, hand Seizure indicates a transient alteration in wringing or swallowing that lasts for 30 sec behaviour because of disordered firing of to 2 minutes. Consciousness is impaired and groups of brain neurons. Such discharges may may be preceded by an aura. spread to other parts of the brain to different Partial with secondarily generalised seizures extents. In most of the cases, the cause is not Simple or complex partial seizure may evolve known. It may be due to various reasons into a generalised seizure. including trauma during birth process, head Generalised seizures Account for 40% of all epilepsies and is usually of genetic aetiology. injury, childhood fevers, brain tumours, Generalised seizures affect the whole brain. meningitis or drug induced. They may be: Seizures have been classified into partial Absence seizures (petit mal) In this, there is a and generalised seizures. sudden onset of impaired consciousness Partial seizures account for about 60% of all associated with staring. The person stops all epilepsies and begin focally in the cortex, i.e. on-going activities and the episode lasts for they involve focal brain regions. It is classified a brief period usually less than 30 sec. as simple partial in which there is no Myoclonic seizures involve a sudden, brief, impairment of consciousness and complex shock like contraction of muscles. It may be partial seizures with impairment of limited to a part of the body or may affect consciousness. When reticular formation is the whole body. affected unconsciousness results. Atonic seizures (Drop attacks) are characterised Simple partial seizures There is no impairment by sudden loss of postural tone and the head of consciousness. The manifestation depends may drop for a few seconds or the person on the site in the cortex that is activated by may drop to the ground for no obvious the seizure, e.g. if the motor cortex reasons. representing the right thumb is involved, Tonic-clonic seizures (Grand mal epilepsy) is there is recurrent contractions of the right characterised by sudden loss of consciousness Antiepileptics 147 followed by sustained contraction of muscles – by inhibiting GABA metabolism, e.g. throughout the body (known as tonic phase), valproic acid, vigabatrin. lasting for 1 minute and then, a series of jerks, – by blocking exitatory glutamate rece- i.e. periods of muscle contraction alternating ptors, e.g. topiramate and some drugs with periods of relaxation (clonic phase) under investigation. lasting for 2-4 minutes follow. CNS depression then occurs and the person goes CLASSIFICATION into sleep. Injury may occur during the Hydantoins Phenytoin, mephenytoin convulsive episode. Barbiturates Phenobarbitone, Status epilepticus is continuous or recurrent mephobarbitone seizures of any variety without recovery of Deoxybarbiturate Primidone consciousness between the attacks. Iminostilbene Carbamazepine Succinimide Ethosuximide Mechanism of Action of Antiepileptics GABA transaminase Antiepileptics act by one or more of the inhibitors Valproic acid, vigabatrin following mechanisms (Fig. 24.1): Benzodiazepines Diazepam, clonazepam, • Blockade of Na+ channels and prolong- lorazepam, clorazepate ation of their inactive state delaying their Newer agents recovery, e.g. phenytoin, carbamazapine, GABA analogues Gabapentin,vigabatrin, lamotrigine. tiagabine. • Blockade of low threshold Ca++ current Others Lamotrigine, (T-type) in the thalamic neurons - controls levetiracetam, felbamate, absence seizures, e.g. ethosuximide. topiramate, zonisamide. • Enhancing GABA mediated inhibition Phenytoin (Diphenylhydantoin) was synth- – by acting on GABA receptors, e.g. esized in 1908, but its anticonvulsant property benzodiazepines was discovered only in 1938.

Fig 24.1: Mechanisms of action of antiepileptics. Antiepileptics may act by blockade of Na+ channels, by facilitating GABA activity or by blockade of Ca++ current. 148 Textbook of Pharmacology for Dental and Allied Health Sciences

Pharmacological Actions 2. Nystagmus, diplopia, ataxia are common. 3. Gingival hyperplasia–Long-term adminis- CNS Phenytoin has good antiseizure activity tration of phenytoin can result in gingival and is one of the most effective drugs against generalised tonic-clonic seizures and partial hyperplasia particularly in children with seizures. It brings about its effects without poor oral hygiene. Maintaining good oral causing general depression of the CNS. hygiene can prevent this. However, it is generally reversible though it takes 1-2 Mechanism of Action years after the discontinuation of phenytoin. Phenytoin causes blockade of the voltage 4. Peripheral neuropathy. dependent sodium channels and stabilizes the 5. Endocrine neuronal membrane. It inhibits the generation i. Hirsutism, acne, coarsening of facial of repetitive action potentials. features. Voltage dependent Na+channels enter an ii. Hyperglycaemia – as phenytoin inactive stage after each action potential. inhibits insulin release. Phenytoin blocks the Na+ channels which are iii. ↓ release of ADH. in an inactivated state and delay the recovery of these channels from inactivation. It iv. Osteomalacia, hypocalcaemia due to decreases the number of channels which are altered metabolism of vitamin D and available for the generation of action inhibition of intestinal absorption of ++ potentials and it inhibits the membrane Ca . Phenytoin also reduces target excitability of these voltage-dependent Na+ tissue sensitivity to vitamin D. channels. Phenytoin preferentially blocks 6. Hypersensitivity–rashes, hepatic necrosis, high frequency firing (neurons in normal state lym-phadenopathy and neutropenia. have low frequency firing while in seizures, Idiosyncratic reactions including hepatic high-frequency firing occurs). necrosis and systemic lupus erythe- matosis, have been reported. Pharmacokinetics 7. Megaloblastic anaemia–because phenytoin decreases absorption and increases Phenytoin is poorly water-soluble–hence excretion of folates. absorption is slow. Phenytoin is 90% bound to plasma proteins. Valproic acid competes 8. Teratogenicity–when taken by the with phenytoin for plasma protein binding pregnant lady, phenytoin produces foetal sites and may result in phenytoin toxicity. It hydantoin syndrome characterised by is metabolised in the liver initially by first hypoplastic phalanges, cleft palate, harelip order and later by zero order kinetics as the and microcephaly in the offspring. dose increases. Therefore monitoring of Toxic doses–cerebellar and vestibular effects plasma concentration is useful. Phenytoin is are prominent; drowsiness, delirium, an enzyme inducer. Dose table 24.1. confusion, hallucinations, altered behaviour and coma follow. Adverse Effects Uses Adverse effects depend on the dose, duration and route of administration. 1. Generalised tonic-clonic seizures and 1. Nausea, vomiting, epigastric pain, partial seizures (not useful in absence anorexia. seizures). Antiepileptics 149

2. Status epilepticus–phenytoin is used by PHENYTOIN slow IV injection. + 3. Trigeminal neuralgia–as an alternative to • Blocks voltage dependent Na channels. • Preferably blocks high frequency firing that carbamazepine. is seen in seizures. 4. Cardiac arrhythmias–Phenytoin is useful • Blocks Na+ channels in an inactivated state in digitalis induced arrhythmias (see page and delays their recovery. 101). • Main adverse effects include vestibular effects, G.I. disturbances; long term use Drug Interactions results in gum hyperplasia, hirsutism and • Phenytoin is an enzyme inducer. Given megaloblastc anaemia. with phenobarbitone, both increase each • It is teratogenic. other's metabolism. Also phenobarbitone • Used in partial and generalised tonic- competitively inhibits phenytoin clonic seizures. metabolism. anticonvulsant effects, the dose required • Carbamazepine and phenytoin enhance produces significant sedation. each other’s metabolism. Mechanism of action Barbiturates enhance the • Valproate displaces protein bound inhibitory neurotransmission in the CNS by phenytoin and may result in phenytoin enhancing the activation of GABAA receptors toxicity. and thus facilitating the GABA-mediated • Cimetidine and chloramphenicol inhibit opening of chloride ion channels. the metabolism of phenytoin resulting in Pharmacokinetics Oral absorption of pheno- toxicity. barbitone is slow but complete. About 50% ↓ • Antacids absorption of phenytoin. is bound to plasma proteins. It is a microsomal Mephenytoin, ethatoin and phenacemide enzyme inducer and can result in many drug are congeners of phenytoin. Ethatoin can interactions. be used as an alternative in patients Adverse effects Sedation is the most common allergic to phenytoin. Adverse effects of side effect.Tolerance develops to some extent ethatoin are milder. Phenacemide is used to sedation after prolonged use. Pheno- in patients with refractory partial seizures barbitone can also cause nystagmus, ataxia, when other drugs fail. It is a highly toxic megaloblastic anaemia and osteomalacia like drug. phenytoin. Skin rashes and other hypersensitivity reactions can occur. PHENOBARBITONE (See Chap 22) Uses Phenobarbitone is still widely used Phenobarbitone was the first effective because of its efficacy and low cost. However, antiepileptic drug to be introduced in 1912. carbamazepine and phenytoin are often It still remains one of the widely used drugs. preferred. Phenobarbitone can be used in: Antiepileptic actions Phenobarbitone has 1. Generalised tonic-clonic seizures. specific antiepileptic activity and raises the 2. Partial seizures. seizure threshold. Primidone which is rarely CARBAMAZEPINE used now is metabolised to phenobarbitone. Phenobarbitone is effective in tonic-clonic Carbamazepine is a tricyclic compound closely seizures and is ineffective in absence seizures. related to imipramine. It is one of the most Though other barbiturates also have commonly used antiepileptic drugs. 150 Textbook of Pharmacology for Dental and Allied Health Sciences

Antiseizure activity Carbamazepine has good advantages over carbamazepine - fewer anti-seizure activity. It’s mechanism of action hypersensitivity reactions, milder induction and antiepileptic actions are similar to of microsomal enzymes - hence fewer drug phenytoin, i.e. it blocks sodium channels. interactions. It has been tried as an alternative Carbamazepine is also useful in the to carbamazepine in partial seizures. treatment of trigeminal neuralgia (severe pain along the distribution of the trigeminal ETHOSUXIMIDE nerve) and glossopharyngeal neuralgia. It is also found to be beneficial in mood disorders. Ethosuximide is a succinimide. It raises the Carbamazepine has mild antidiuretic effects. seizure threshold. Pharmacokinetics Absorption is slow and Mechanism of action Ethosuximide reduces the erratic; has a t½ of 10-30 hours. Carbamaze- low threshold calcium currents (T-currents) pine is a powerful microsomal enzyme in the thalamic neurons. These T currents are inducer. Therefore, after repeated adminis- thought to be responsible for absence tration, its t½ reduces to 15 hours due to seizures. autoinduction. Pharmacokinetics Absorption is complete on Adverse effects Drowsiness, vertigo, ataxia, administration of oral dosage forms. It is diplopia, blurring of vision, nausea, vomiting metabolised in the liver. and dizziness are common. Driving is Adverse effects The most common adverse therefore dangerous for patients on effects are nausea, vomiting, epigastric pain, carbamazepine. It also causes water retention gastric irritation and anorexia. These can be due to antidiuretic effects. Hypersensitivity avoided by starting with a low dose and reactions–like skin rashes may occur. gradually increasing it. CNS effects like Haematological toxicity includes leukopenia, drowsiness, fatigue, lethargy, euphoria, thrombocytopenia and rarely agranulocytosis dizziness, headache and hiccough are dose- and aplastic anaemia. It is a teratogen. Its related effects. Hypersensitivity reactions like t½ reduces to 15 hrs due to autoinduction. rashes, urticaria, leukopenia, thrombocytopenia or pancytopenia have been Uses reported. 1. Generalised tonic-clonic seizures (grand Uses Ethosuximide is the drug of choice for mal epilepsy). absence seizures. 2. Simple and complex partial seizures– especially temporal lobe epilepsy. VALPROIC ACID 3. Trigeminal neuralgia and glosso- → pharyngeal neuralgia–carbamazepine is Valproic acid (salt sodium valproate) is a the drug of choice for these neuralgias and very effective antiepileptic drug useful in has to be given for several months. many types of epilepsies including absence 4. Carbamazepine is also found to be useful seizures, partial and generalised tonic-clonic in chronic neuropathic pain and in tabetic seizures. pain. Divalproex sodium is a combination of 5. Bipolar mood disorder–carbamazepine is valproic acid and sodium valproate. The used as an alternative to lithium as a mood combination is said to have a better stabilizer (see Page 200). bioavailability and is better tolerated. Oxcarbazepine– is similar to carbamazepine in Mechanism of action Valproic acid acts by action and uses. It has the following multiple mechanisms. Antiepileptics 151

1. It enhances the level of GABA by: in absence seizures. In patients with both i. increasing the synthesis of GABA–by absence seizures and generalised tonic-clonic increased activity of GABA synthetase attacks, valproate is the drug of choice. enzyme. Valproate is also useful as a mood ii. decreasing the metabolism of GABA– stabilizer in bipolar mood disorder. by inhibiting GABA transaminase enzyme. BENZODIAZEPINES 2. Like phenytoin, valproic acid blocks the Benzodiazepines have useful anticonvulsant sodium channels. properties. Diazepam is the drug of choice in 3. Like ethosuximide valproate decreases status epilepticus. Clonazepam is a potent low threshold Ca++ (T-currents) current antiepileptic useful in absence and myoclonic in the thalamus. seizures. But tolerance develops to its Adverse effects Gastrointestinal symptoms like antiepileptic effects. Clobazam causes less nausea, vomiting, epigastric distress occur sedation and is effective in most types of initially. Tremors, sedation, ataxia, rashes epilepsies-used as an adjuvant to other and alopecia are rare. An idiosyncratic antiepileptic drugs. response causing fulminant hepatitis–though rare can be fatal. Hence careful monitoring NEWER ANTIEPILEPTICS (Table 24.1) of liver functions is mandatory. Valproic acid Gabapentin is a highly lipid soluble analogue is teratogenic, it can cause neural tube defects of GABA which was designed to cross the including spina bifida. BBB. It is effective in tonic-clonic seizures. Uses Useful in partial and generalised Its exact mechanism of action is not known, seizures. Valproic acid is particularly useful but it does not act on GABA receptors. Table 24.1: Therapeutic dose of antiepileptic drugs

Drug Dose Trade name Phenytoin 100 mg BD EPILEPTIN EPTOIN Children 5-8 mg/kg/day Carbamazepine 200-400 mg TDS TEGRETOL, Children 15-30 mg/kg/day CARBATOL Phenobarbitone 60 mg OD - TDS GARDINAL Children 3-6 mg/kg/day Ethosuximide 20-30 mg/kg/day ZARONTIN Valproic acid 200-500 mg TDS VALPARIN Children 15-30 mg/kg/day Clonazepam 0.5 - 5 mg TDS CLONOTRIL Children 0.01 - 0.2 mg/kg/day Clobazam 10-20 mg HS FRISIUM Max 60 mg HS Lamotrigine 50-300 mg/day LAMITOR Gabapentin 300 mg OD - TDS NEURONTIN 152 Textbook of Pharmacology for Dental and Allied Health Sciences

Newer antiepileptics: Levetiracetam is effective against partial and secondarily generalized seizures. Its • Gabapentin, vigabatrin, tiagabine, mechanism of action is not known. It is not lamotrigine, levetiracetam, topira- an enzyme inducer-no related drug mate, felbamate, zonisamide. interactions. Levetiracetam can be used as an • All are generally well tolerated except add-on drug in refractory partial seizures. that felbamate can rarely cause aplastic Tiagabine a GABA analogue, inhibits the anaemia and hepatitis. reuptake of GABA into neurons and thereby • Presently they are recommended as enhances extracellular GABA levels. It may add-on drugs in refractory partial cause drowsiness and dizziness. Tiagabine seizures. can be used as an add-on drug for refractory partial seizures. Topiramate a monosaccharide, acts by multiple Advantages Absorption of gabapentin mechanisms. It blocks the sodium channels, depends on a carrier protein and does not enhances GABAA receptor currents, blocks increase with increase in dose - hence it is AMPA receptors (glutamate receptor). It is safe. It is well tolerated. It does not influence effective in partial and generalized seizures. the plasma concentrations of other Topiramate can be used as add-on therapy antiepileptics. in refractory epilepsy. Adverse effects include ataxia, fatigue, Felbamate an analogue of meprobamate is drowsiness and dizziness. Tolerance found to have good antiepileptic action. It develops to these effects in 1-2 weeks. blocks the NMDA receptors in addition to Gabapentin is used in combination with other weak sodium channel blocking effect. But antiepileptic drugs, as an add-on drug in felbamate can sometimes cause serious partial seizures. It is also used in migraine, adverse effects like aplastic anaemia and neuropathic pain and in bipolar mood hepatitis because of which it is employed disorder. only in refractory epilepsy. Progabalin is a prodrug, which is more potent Zonisamide a sulfonamide derivative acts by than gabapentin. ++ Lamotrigine inhibiting T type Ca currents and also by has a broad spectrum of + antiepileptic activity. It inhibits the sodium blocking Na channels. It is well tolerated channels and also inhibits the release of the and is indicated in refractory partial excitatory amino acids like glutamate. It is seizures. completely absorbed from the gut. TREATMENT OF EPILEPSIES Lamotrigine may cause skin rashes, nausea, ataxia and dizziness. It is used either alone An attempt should be made to detect the or with other drugs in partial and cause. When drugs are found to be generalized seizures. necessary, the goal of therapy is to keep Vigabatrin is a GABA analogue which acts by the patient free of seizures (Table 24.2) irreversibly inhibiting the enzyme GABA without interfering with normal daily transaminase thereby raising brain GABA activity. Treatment should be started with levels. It can cause depression in some a single drug at a low dose; dosage is patients. Vigabatrin is useful in patients not increased gradually, preferably by responding to other antiepileptics. monitoring the drug levels in plasma. Antiepileptics 153

Table 24.2: Choice of antiseizure drugs

Types of seizures Preferred drugs

1. Simple partial seizures Carbamazepine, Phenytoin Valproic acid 2. Complex partial seizures Carbamazepine, Phenytoin, Valproic acid 3. Partial with secondarily generalised Carbamazepine, Phenytoin, tonic-clonic seizures Valproic acid 4. Absence seizures Ethosuximide, Valproate 5. Tonic-clonic seizures Carbamazepine, Phenytoin Valproic acid 6. Tonic-clonic + absence seizures Valproic acid 7. Myoclonic seizures Diazepam, Valproic acid 8. Status epilepticus Diazepam, Phenytoin, General anaesthesia 9. Febrile convulsions Diazepam

Good compliance is very important for of choice or phenytoin IV can be given. A success. Regarding the duration–decision loading dose 500-1000 mg phenytoin (max should be made on an individual basis and 1000 mg in 24 hr) takes 15-20 min to act. Some dose should be very gradually reduced over prefer to combine diazepam and phenytoin months to avoid status epilepticus. (60 mg/min). If seizures continue-general Febrile convulsions Two to four per cent of anaesthesia is the last resort. Airway children experience convulsions during fever; maintenance is important. After the control of them 2-3% become epileptics. Treatment of seizures, long-term antiepileptic therapy is controversial. Children <18 months is needed. developing febrile convulsions, those with In pregnancy–antiepileptics should be neurological abnormalities and those with continued because abrupt discontinuation seizures lasting for > 15 minutes, complex increases the risk of status epilepticus which seizures–all these have greater risk of is hazardous to the foetus. recurrence. Diazepam (0.5 mg/kg) given orally or rectally at the onset of fever Epilepsy and Dentistry prevents convulsions. Timely use of paracetamol and tepid sponging prevent high 1. When patients on antiepileptics are fever. If convulsions occur, diazepam admitted for dental procedures, (rectally or intravenously) can be used. antiepileptic drugs should be continued Status epilepticus is a neurological emergency and not stopped. which may be fatal. Diazepam IV 5-10 mg 2. Long-term administration of phenytoin every 10-15 minutes up to 30 mg is the drug can induce gingival hyperplasia. This is 154 Textbook of Pharmacology for Dental and Allied Health Sciences

more common in children with poor oral to protect the tongue from getting bitten. hygiene. It is thought to be an exaggerated The head should be turned to a side so drug induced response of gingival tissues that the tongue does not obstruct the to the oral plaque. airway. If the convulsions continue, 3. Though uncommon, some patients might diazepam 10 mg may be given intravenously have convulsions while undergoing a over 1-2 minutes. Physicians' help should dental procedure (See page 400). The be sought at the earliest possible. procedure should be immediately stopped. 4. Long-term administration of some All instruments and dentures should be antiepileptics like sodium valproate can removed from the oral cavity. Gentle increase the bleeding tendency. Appro- passive restraints should be used to prevent priate precautions should be taken to physical injury. A padded tongue control bleeding during dental pro- depressor should be placed in the mouth cedures. 25 Drugs Used in Parkinsonism

Parkinsonism is a chronic, progressive, motor iii. Dopaminergic agonists disorder characterised by rigidity, tremors Bromocryptine and bradykinesia. Other symptoms include Lisuride excessive salivation, abnormalities of posture Ropinirole and gait, seborrhoea and mood changes. It Pramipexole was described by James Parkinson in 1817 iv. Inhibit dopamine metabolism and is therefore named after him. • MAO inhibitors The incidence is about 1 per cent of Selegiline population above 65 years of age. It is usually • COMT inhibitors idiopathic in origin but can also be drug Tolcapone induced. In idiopathic parkinsonism, there is Entacapone degeneration of nigrostriatal neurons in the 2. Drugs influencing cholinergic system basal ganglia resulting in dopamine i. Central anticholinergics deficiency. The balance between inhibitory dopaminergic neurons and excitatory Benztropine cholinergic neurons is disturbed. Benzhexol Antiparkinsonian drugs can only help to Biperidine alleviate the symptoms and improve the Trihexyphenidyl quality of life. The two strategies in the ii. Antihistamines treatment are- Diphenhydramine (i) to enhance dopamine activity Orphenadrine (ii) to depress cholinergic overactivity. Promethazine Often combination of drugs are used to influence both functions. DOPAMINE PRECURSOR Levodopa CLASSIFICATION Drugs used in parkinsonism can be classified Though parkinsonism is due to dopamine as - deficiency, dopamine is of no therapeutic 1. Drugs that increase dopamine levels value because it does not cross the blood- i. DA precursor brain barrier. Levodopa is a prodrug which Levodopa is converted to dopamine in the body. It ii. Drugs that release dopamine crosses the BBB and is taken up by the Amantadine surviving nigrostriatal neurons. 156 Textbook of Pharmacology for Dental and Allied Health Sciences

Dopa Fluctuation in response to levodopa can occur decarboxylase after 2-5 years of use—known as ‘on-off’ Levodopa ______→ Dopamine phenomenon—where the patient swings Antiparkinsonian effect On administration of alternately from periods of good response levodopa, there is an overall improvement to severe disabling disease. in the patient as all the symptoms subside. Uses Levodopa is the most effective drug in Other actions Large amounts of levodopa are idiopathic parkinsonism but is not useful in converted to dopamine in the periphery drug induced parkinsonism. which brings about other actions. Drug interactions • CTZ—Dopamine stimulates the CTZ to 1. Pyridoxine enhances peripheral decarbo- induce vomiting. xylation of levodopa and thus reduces its • CVS— It causes postural hypotension, availability to the CNS. tachycardia and arrhythmias. Dopamine 2. Phenothiazines and metoclopramide are is a catecholamine. DA antagonists. They reverse the effects • Endocrine—Dopamine suppresses the of levodopa. prolactin secretion. Carbidopa and Benserazide Pharmacokinetics Carbidopa and benserazide are peripheral Levodopa is rapidly absorbed from the small dopa decarboxylase inhibitors. When intestine. Presence of food delays absorption. carbidopa or benserazide are given with Some amino acids in the food compete with levodopa, they prevent the formation of levodopa for absorption and transport to the dopamine in the periphery. They do not cross brain. It undergoes first pass metabolism in the BBB and hence allow levodopa to reach the gut and the liver. Its t½ is 1-2 hours. the CNS. The combination is synergistic and therefore levodopa is always given with Adverse Reactions carbidopa/benserazide. Advantages of the combination As 95% of levodopa is converted to dopamine 1. Dose of L-dopa can be reduced by 75%. in the periphery, several adverse effects are 2. Response to L-dopa appears earlier. expected. Nausea, vomiting, anorexia, 3. Side effects like vomiting and tachycardia postural hypotension, palpitation and are largely reduced. occasionally arrhythmias can occur. Tolerance 4. Pyridoxine does not interfere with develops to these effects after some time. treatment. These peripheral effects can be prevented by concurrent administration of domperidone DRUGS THAT RELEASE DOPAMINE which is a peripheral dopamine antagonist. Behavioural effects like anxiety, depression, Amantadine is an antiviral drug. It enhances hallucinations and sometimes psychosis can the release of DA in the brain and diminishes occur. the re-uptake of DA. The response starts early Abnormal involuntary movements like facial tics, and its adverse effects are minor. Large doses grimacing, choreoathetoid movements of the produce insomnia, dizziness, vomiting, limbs may develop after a few months of use postural hypotension, hallucinations and and require reduction in the dose of levodopa. ankle oedema. Drugs Used in Parkinsonism 157

Amantadine is used in mild cases of COMT Inhibitors parkinsonism. It can also be used along with Tolcapone and entacapone inhibit the peripheral levodopa as an adjunct. metabolism of levodopa thereby increasing DOPAMINE RECEPTOR AGONISTS its bioavailability. Tolcapone crosses the BBB and enhances the availability of levodopa Bromocriptine and pergolide are ergot in the brain. derivatives having dopamine agonistic Adverse effects are nausea, orthostatic activity at D2 receptors. Bromocriptine is also hypotension, confusion and hallucinations. a partial agonist while pergolide is an agonist Tolcapone can also cause hepatotoxicity. at D 1 receptors. The newer agents ropinirole COMT inhibitors are used as add-on and pramipexole are selective D2 agonists, drugs in parkinsonism. are better tolerated, quickly attain therapeutic levels and adverse effects are milder except ANTICHOLINERGICS that they may cause some sleep disorders. Dopamine agonists are all longer acting The cholinergic overactivity is overcome by because of which they are useful in the anticholinergics. Tremors, seborrhoea and treatment of ‘on-off’ phenomenon. sialorrhoea are reduced more than rigidity. Adverse effects include nausea, vomiting, Atropine derivatives like benzhexol, hallucinations and skin eruptions. Ergot benztropine, trihexyphenidyl are used. derivatives can cause postural hypotension Antihistamines owe their beneficial effects or hypertension initially and first dose in parkinsonism to their anticholinergic phenomenon–sudden cardiovascular collapse. properties. Atropine-like side effects such DA agonists are used: as dry mouth, constipation, urinary 1. in the treatment of ‘on-off’ phenomenon retention and blurred vision may be 2. as alternatives in the initial treatment of encountered. parkinsonism (particularly newer agents). Uses Anticholinergics are used as (i) adjunct Lisuride is similar to bromocriptine. to levodopa, (ii) drugs of choice in drug- induced parkinsonism. DRUGS THAT INHIBIT DA METABOLISM Drug induced parkinsonism Drugs like MAO Inhibitor reserpine, metoclopramide and pheno- Selegiline (Deprenyl) is a selective MAO-B thiazines can induce parkinsonism. Reserpine inhibitor. MAO-B is present in DA containing depletes catecholamine stores, while regions of the CNS. Selegiline prolongs the metoclopramide and phenothiazines are action of levodopa by preventing its dopamine antagonists. degradation. Selegiline may delay the Treatment Withdrawal of the drug usually progression of parkinsonism. reverses the symptoms. When drugs are Adverse effects include nausea, postural needed, one of the anticholinergics are hypotension, confusion and hallucinations. effective. Levodopa or other dopamine Uses Mild cases of parkinsonism are started agonists are not effective because DA on selegiline. It is also used as an adjunct to receptors are blocked by drugs like levodopa. metoclopramide and phenothiazines. 158 Textbook of Pharmacology for Dental and Allied Health Sciences 26 Opioid Analgesics

Pain or algesia is an unpleasant subjective presence of anxiety. A person who is already sensation. It cannot be easily defined. Pain is in stress can poorly tolerate pain. a warning signal and indicates that there is Pain may be acute or chronic. Acute pain an impairment of structural and functional may result from wounds, irritants, burns or integrity of the body. It is the most important from ischaemia. The cause is usually well symptom that brings the patient to the doctor defined. In chronic pain the origin may not and demands immediate relief. Prompt relief be well defined. Example: Pain due to of pain instills enormous confidence in the arthritis, cancers and neuropathic pain. patient regarding the doctor's treating ability. Analgesic Pain arising from the skin and Analgesic is a drug which relieves pain integumental structures, muscles, bones and without loss of consciousness. Analgesics joints is known as somatic pain. It is usually only afford symptomatic relief from pain caused by inflammation and is well-defined without affecting the cause. or sharp pain. Analgesics are of 2 classes. Pain arising from the viscera is vague, dull- aching type, difficult to pinpoint to a site and • Opioid or morphine type of analgesics is known as visceral pain. It may be • Non-opioid or aspirin type of analgesics. accompanied by autonomic responses like sweating, nausea and hypotension. It may be OPIOID ANALGESICS due to spasm, ischaemia or inflammation. Opioid analgesics are one of the oldest When pain is referred to a cutaneous area remedies for relief of pain. which receives nerve supply from the same Opium is the dark brown gummy exudate spinal segment as that of the affected viscera, obtained from the poppy capsule (Papaver it is known as referred pain, e.g. cardiac pain somniferum). On incising the unripe seed referred to the left arm. capsule, a milky juice emerges which turns Pain consists of 2 components - the original brown on drying and this is crude opium. ‘sensation’ and the ‘reaction’ to it. The original The word opium is derived from Greek in sensation is carried by the afferent nerve which ‘opos’ means juice. Opium has been in fibres and is the same in all. The reaction use since 4000 BC. It was used both for component differs widely from one person to medicinal and recreational purposes. By 18th another. Perception of pain is increased in century, opium smoking had become quite Opioid Analgesics 159 popular in Europe. It was Serturner who Morphine isolated a pure opium alkaloid in 1806. He Morphine is the most important alkaloid of named it Morphine after Morpheus, the Greek opium. Many new opioids with actions similar God of dreams. As the research progressed, opium was found to contain 20 alkaloids. By to morphine have been synthesized. But none around 19th century, the pure opium of them are superior to morphine as an alkaloids were available for therapeutic use analgesic. Morphine is discussed as the - but because they were equally abused, prototype of the group. efforts were made to isolate their analgesic property, i.e. to obtain an opioid that is only Mechanism of Action an analgesic and has no euphoric effects. In Morphine and other opioids produce their the process, various agonists, antagonists and effects by acting on specific opioid receptors. partial agonists were synthesized. ‘Opioid’ is (Fig. 26.1) These receptors are abundant in the term used for drugs with morphine-like the CNS and other tissues. The opioid actions. They were earlier called narcotic receptors are mu (μ), kappa (k) and delta (δ). It analgesics. is found that there are 3 families of CLASSIFICATION endogenous opioid peptides released in the body is response to pain viz the enkephalins, Based on receptor occupation the endorphins and the dynorphins. This 1. Agonists indicates that we have a natural system in Natural opium alkaloids the body that releases various opioid Morphine, codeine peptides in response to pain. These opioid Synthetic opioids peptides act on opioid receptors and relieve Pethidine, methadone pain. Most pharmacological effects of opioids 2. Antagonists including analgesia, sedation, euphoria, Naloxone, naltrexone respiratory depression, miosis and 3. Mixed agonist-antagonists constipation are mediated through μ Pentazocine, nalbuphine, receptors. ‘Endomorphins’ are endogenous butorphanol, buprenorphine, nalorphine ligands for μ receptors but other endogenous Chemically the opium alkaloids can be peptides also bind to μ receptors. Dynorphins grouped into: are endogenous ligands for k receptors while 1. The Phenanthrene group δ Morphine, codeine, thebaine enkephalins bind receptors. Various 2. The Benzylisoquinoline group subtypes of these receptors are now known. Papaverine, noscapine, narcine. A fourth type of opioid receptor was recently identified. It is called nociceptin (N) / Opioids can also be classified depending on orphanin FQ receptor. their source as 1. Natural opium alkaloids All opioid receptors are G-protein-coupled Morphine, codeine, noscapine receptors. Stimulation of these receptors 2. Semisynthetic derivatives inhibits adenylyl cyclase resulting in Heroin, oxymorphone, pholcodeine decreased intracellular cAMP formation. They 3. Synthetic opioids also facilitate the opening of K+ channels Pethidine, fentanyl, diphenoxylate, leading to hyperpolarisation and inhibit the loperamide, dextropropoxyphene, entry of calcium into the cell. In addition to methadone, tramadol, ethoheptazine. this they inhibit the opening of calcium 160 Textbook of Pharmacology for Dental and Allied Health Sciences

Fig . 26.1: Mechanisms of action of opioids. Opioid receptors are G-Protein coupled receptors. Stimulation of these receptors cAMP formation, K+ efflux causing hyperpolarisation and also inhibit Ca++ entry through voltage gated Ca++ channels. AC=Adenylyl cyclase cAMP=cyclic AMP. channels. All these result in a decrease in the to tolerate pain. Further, it alters the intracellular calcium which, in turn, decrease emotional reaction to pain. the release of neurotransmitters. Various Euphoria and sedation also contribute to neurotransmitters including dopamine, its analgesic effects. glutamate, GABA, NA, 5HT and substance 2. Euphoria, sedation and hypnosis Morphine P are involved in transmission of pain produces a feeling of well-being termed impulses. euphoria. It is this effect which makes it an Opioids also directly inhibit the important drug of abuse. Rapid transmission in the dorsal horn ascending intravenous injection of morphine pathway. Opioids stimulate the descending produces a warm flushing of the skin and pain control pathway - from the midbrain an immensely pleasurable sensation in the and brainstem to the dorsal horn of the spinal lower abdomen lasting for about 45 cord. Opioid receptors are abundant in these seconds which is known as ‘high’, ‘rush’ areas including the peri-aqueductal grey or ‘kick’. The person loses rational (PAG) area, substantia gelatinosa and the thinking and is lost in colourful day spinal cord. dreams. It also produces drowsiness, a calming effect, inability to concentrate, Pharmacological Actions feeling of detachment and indifference to surroundings. Central Nervous System The effects of morphine may not be 1. Analgesia Morphine is a potent analgesic pleasurable in all. A person has to learn and relieves pain without loss of to perceive its pleasurable effects. It may consciousness. Dull aching visceral pain produce dysphoria in some. is relieved better than sharp pricking pain 3. Respiration Morphine produces significant (Table 26.1). But in higher doses it relieves respiratory depression. It directly even the severe pain as that of biliary colic. depresses the respiratory centre in the Morphine alters both the perception and brainstem. This action is dose dependent. reaction to pain. It raises the pain It depresses all phases of respiratory threshold and thus increases the capacity activity - rate and tidal volume. It may Opioid Analgesics 161

also alter the rhythm to produce irregular • direct peripheral vasodilatation and periodic breathing. Death from • inhibition of baroreceptor reflexes morphine poisoning is almost always due In higher doses it causes depression of the to respiratory arrest. vasomotor centre and histamine release both Morphine suppresses neurogenic (ori- contributing to a fall in BP. Postural ginating in RAS), chemical (hyper- hypotension and fainting may occur. capnoeic) and hypoxic drive in the order. The respiratory centre is insensitive to GIT increased plasma CO concentration. With 2 Opioids decrease the motility of the gut. toxic doses, breathing is maintained by Stomach Gastric motility is decreased hypoxic drive. resulting in increased gastric emptying time. Sedation and indifference to surroundings Oesophageal reflux may increase. Gastric acid add to the depression. secretion is reduced. Opioids increase the 4. Cough centre It directly depresses the cough centre and thereby suppresses tone of the antrum and first part of the cough. duodenum which also contribute to delayed 5. Nausea and emesis Morphine directly emptying by almost 12 hours and this can stimulates the CTZ in the medulla causing retard the absorption of orally given drugs. nausea and vomiting. In higher doses it Intestines Morphine diminishes all intestinal depresses the vomiting centre and hence secretions, delays digestion of food in the there is no vomiting in poisoning. small intestine; resting tone is increased. Therefore, emetics should not even be There can be spasms of the intestine. The tried in morphine poisoning. tone of the sphincters is increased leading to 6. Pupils Morphine produces miosis spasm. The intestinal motility (propulsive) is resulting in a characteristic pinpoint pupil markedly diminished. The resulting delay in in high doses. This is due to stimulation the passage of the intestinal contents in the of (EW) nucleus of the third cranial nerve. large intestine, together with reduced Thus by a central effect it produces miosis. secretions and inattention to the sensory Hence morphine used as eyedrops does stimuli for defecation reflex - all contribute not produce miosis. to produce marked constipation. The effects 7. Vagus Morphine stimulates vagal centre of morphine on the gut are by stimulation of causing bradycardia. μ and δ receptors in the gut. 8. Heat regulation Opioids shift the equilibrium point of heat-regulating Other Smooth Muscles centre so that body temperature falls Biliary tract Morphine causes spasm of the slightly. sphincter of Oddi. Intrabiliary pressure rises 9. Excitatory effect In high doses opioids and may cause biliary colic. Atropine partly produce convulsions. They may increase antagonises this while opioid antagonists the excitability of the spinal cord. relieve it. Urinary bladder and ureter Tone and amplitude Cardiovascular System of contractions of the ureter is increased; In therapeutic doses, morphine produces tone of external sphincter and volume of the hypotension by: bladder are increased. Opioids inhibit 162 Textbook of Pharmacology for Dental and Allied Health Sciences urinary voiding reflex. All these result in Allergic reactions including skin rashes, urinary retention especially in the elderly pruritus and wheal at the site of injection of male with prostatic hypertrophy. morphine may be seen. Morphine is a Uterus No significant effect. May prolong histamine liberator and this action is labour in high doses. responsible for the allergic effects. Rarely Bronchi Morphine causes release of histamine intravenous injection can cause anaphylaxis from the mast cells leading to broncho- due to the same reason. It is a drug of constriction. This can be dangerous in dependence. asthmatics. Tolerance Neuroendocrine Effects Repeated administration of morphine results Morphine acts in the hypothalamus to inhibit in the development of tolerance to some of the release of gonadotrophin-releasing its effects including respiratory depression, hormone and CRF, thus decreasing blood analgesia, sedation and euphoriant effects levels of FSH, LH, ACTH and β-endorphins. and other CNS depressant effects. Consti- Tolerance develops after long-term use. pation and miosis show no tolerance. Though These effects are reversible on cessation of lethal dose of morphine is about 250 mg, therapy. addicts can tolerate morphine in grams. Patients in pain can also tolerate a higher dose Pharmacokinetics of morphine. Cross-tolerance is seen among Given orally, absorption of morphine is slow different opioids. and incomplete. Morphine undergoes Tolerance is mainly pharmacodynamic, extensive first pass metabolism. Bioa- where the cells adapt to the effect of opioids - vailability is 20 to 40%. Some opioids are also at the receptor level, though pharmacokinetic given as rectal suppositories while highly mechanisms like increased metabolism also lipid soluble opioids are available as contribute. An addict needs progressively transdermal preparation. Dose - Table 26.3. higher doses to get his ‘kick’ or ‘rush’. Given subcutaneously, onset of action is in 15-20 min, peak effect - in 1 hr, duration Dependence of action is - 3-5 hr. Morphine is metabolised Opium has been a drug of addiction for many in the liver by glucuronide conjugation. The centuries. Its ability to produce euphoria active metabolite morphine-6-glucuronide, is makes it a drug of addiction. Opioids produce more potent than morphine and is excreted both psychological and physical dependence. through the kidneys. Morphine undergoes Sudden cessation of opioids or adminis- enterohepatic circulation. tration of opioid antagonists produce significant withdrawal symptoms in such Adverse Effects dependent individuals. Manifestations are Morphine can produce a wide range of lacrimation, sweating, yawning, anxiety, adverse effects like nausea, vomiting, apprehension, restlessness, rhinorrhoea and dizziness, mental clouding, respiratory tremors - seen 8-12 hr after the last dose. The depression, constipation, dysphoria, urinary person craves for the drug. As the syndrome retention and hypotension. progresses, fever, insomnia, abdominal colic, Opioid Analgesics 163 severe sneezing, violent yawning, diarrhoea, fists, diarrhoea, sneezing, yawning, vomiting blurring of vision due to mydriasis, and fever. Tincture of opium 0.2 ml /kg/3-4 hypertension, severe dehydration, ‘goose- hr is started at birth and gradually flesh’, palpitation, prostration and cardio- withdrawn. vascular collapse can occur. There is profound weakness, depression and irritability. Management of Addiction ‘Gooseflesh’ is due to pilomotor activity; Morphine is slowly withdrawn over several skin resembles that of a plucked turkey. days and substituted by oral methadone. Hence the word ‘cold turkey’ is used for symptoms due to abrupt withdrawal. Advantages of methadone administration are Abdominal cramps, pain in the bones and muscles of the back and limbs are also 1. Methadone is effective orally and by this characteristic. route no ‘kick’ is experienced. 2. It is more potent, long - acting and In spite of all these disturbing symptoms, prevents withdrawal symptoms because withdrawal symptoms are generally not life- it is slowly released from the tissues. threatening. Administration of a suitable The dose is adjusted as per the degree of opioid, dramatically and completely reverses dependence - 1 mg methadone for every 4 the symptoms of withdrawal. Without mg of morphine (once a day). Methadone is treatment, symptoms disappear in 7-10 days. then gradually withdrawn. Withdrawal in the Newborn Most addicts can be completely withdrawn from opioids in about 10 days though mild Babies born to mothers who were addicts tolerable withdrawal symptoms persist. prior to delivery - will also be dependent. Symptoms like insomnia, malaise, restless- Withdrawal symptoms seen are irritability, ness, irritability, fatigue and GI hyperactivity excessive crying, tremors, frantic suckling of may last up to several months.

Table 26.1: Compare and contrast aspirin and morphine

Features Aspirin Morphine

Chemistry Acid Alkaloid (Acetyl Salicylic Acid) Natural Source Bark of willow tree Papaver Somniferum Anti inflammatory action Yes No Antipyretic, and Yes No uricosuric effects Euphoria, Sedation No Yes Abuse Potential No Yes Effect on Respiration Stimulant Depressant (in therapeutic doses) Mechanism of action PG synthesis Opioid receptor inhibition stimulation Effect on pupil Not significant Miotic Effect on stomach ↑ HCl secretion ↓Decrease secretions → Ulcerogenic Major action Analgesic Analgesic 164 Textbook of Pharmacology for Dental and Allied Health Sciences α Clonidine a central 2 agonist can suppress (iii) vomiting, miosis and mental clouding some of the autonomic withdrawal symp- seen with morphine interfere with toms like anxiety, nausea, vomiting and diagnosis and assessment of progress diarrhoea. It is given for 7 - 10 days and in head injuries. withdrawn over 3 - 4 days. Night time 5. In hypovolaemic shock, morphine further sedation with a hypnotic like diazepam is decreases the BP. helpful. 6. Opioids potentiate CNS depressants. 7. Undiagnosed acute abdomen - Morphine Acute Morphine Poisoning relieves pain and may interfere with the diagnosis. It induces vomiting and its Acute morphine poisoning may be accidental, spasmogenic effect may add to its suicidal or homicidal. Lethal dose in non - drawbacks. Hence it can be administered addicts is about 250 mg but addicts can only after the diagnosis is established - if tolerate grams of morphine. Signs and necessary. symptoms include respiratory depression with shallow breathing, pin point pupils, Other Opioids hypotension, shock, cyanosis, flaccidity, Heroin or diamorphine or diacetyl morphine is stupor, hypothermia, coma and death due to converted to morphine in the body. It has respiratory failure and pulmonary oedema. higher lipid solubility because of which euphoric effects are faster and greater Treatment resulting in higher abuse potential. It has a strong smell of vinegar. Though it can be 1. Positive pressure respiration. used as an analgesic, it is banned in most 2. Maintenance of BP. countries. 3. Gastric lavage with potassium per- Levorphanol is similar to morphine but it is manganate to remove unabsorbed drug. longer acting. 4. Specific antidote is naloxone - 0.4 - 0.8 mg Codeine is a naturally occurring opium IV repeated every 10-15 min. alkaloid. Codeine depresses the cough centre in subanalgesic doses. It is effective orally Precautions and Contraindications and is well-absorbed. 1. Avoid opioids in patients with respiratory It is less potent (one-sixth) than morphine insufficiency - COPD. as an analgesic (60 mg codeine = 10 mg morphine). 2. An attack of bronchial asthma can be It produces less respiratory depression and precipitated by morphine. is less constipating. Codeine has less addiction 3. In extremes of age - more susceptible to liability and tolerance is uncommon. respiratory depression. Hence codeine is used as an antitussive. It 4. Head injury - morphine is contraindicated is well-absorbed when given orally com- in head injury because: pared to morphine. Duration of action is 4-6 (i) morphine increases CSF pressure by hours. 10 to 30 mg is the antitussive dose.

retaining CO2 and thereby increases About 10% of codeine is converted to the intracranial tension. morphine. Constipation is the most common (ii) causes marked respiratory depression. side effect. Opioid Analgesics 165

Uses Codeine is a commonly used antitussive. It should be avoided in patients on MAO It is also available in combination with inhibitors because tramadol inhibits paracetamol for analgesia. It is to be given at serotonin uptake. bed time (CODOPLUS - Codeine 30 mg + Tramadol is used in acute and chronic pain, Paracetamol 500 mg). like postoperative pain and neuralgias.

Papaverine is devoid of opioid and analgesic Pethidine (Meperidine) activity. Noscapine is a naturally occurring opium Pethidine is a phenylpiperidine derivative of alkaloid. In therapeutic doses, it has no morphine. Many of its actions resemble that significant actions on the CNS except for of morphine Table 26.2. When compared to antitussive effects. Hence it has no morphine: disadvantages of opioids. In large doses it • pethidine is 110th as potent as morphine may cause bronchoconstriction due to the (100 mg pethidine = 10 mg morphine). release of histamine. Dose: 15-30 mg, 3-4 However, efficacy as an analgesic is equal times a day. Noscapine is highly effective to morphine and safe. The only adverse effect is nausea. • the onset of action is more rapid and It is used as a cough suppressant. duration of action is shorter Several other centrally acting antitussives • it produces corneal anaesthesia have been synthesized including, • it is not a good antitussive pholcodeine, and dextromethorphan. • it is less constipating Pholcodeine though structurally related to • in some patients, it may cause dysphoria opioids, has no other opioid-like actions. It • it also has anticholinergic effects which is as effective as codeine as an antitussive; can cause dry mouth, and blurring of has a long half-life and therefore can be given vision. once a day. • in toxic doses, pethidine sometimes Dextromethorphan has no analgesic or produces CNS stimulation with tremors, addictive properties. It acts centrally to restlessness and convulsions instead of elevate the threshold for coughing for which sedation. This is because of the toxic it is as effective as codeine. Toxicity is very metabolite - norpethidine. low; extremely high doses cause CNS Adverse effects are similar to morphine except depression. Antitussive dose: 10 - 30 mg, 3 - that constipation and urinary retention are 4 times a day. less common. Tramadol is a recently developed synthetic codeine analog. It is an effective analgesic but Uses its mechanism of action is not clear. It is a Dose 25-100 mg IM/SC is the analgesic dose. weak opioid agonist. In addition it inhibits In pain Pethidine is used as an analgesic in the reuptake of noradrenaline and serotonin visceral pain and also for other indications in the CNS. of morphine. Because of its better oral Adverse effects include drowsiness, efficacy and less spasmogenic effect, dryness of mouth, sedation and nausea. pethidine is preferred to morphine. Respiratory depression is mild. It is a drug During labour Given during labour, pethidine of dependence. It may precipitate seizures. produces less respiratory depression in the 166 Textbook of Pharmacology for Dental and Allied Health Sciences newborn when compared to morphine. Because of the above advantages fentanyl is Moreover it does not interfere with uterine a commonly used opioid analgesic. contractions and labour and is therefore For neuroleptanalgesia the combination is preferred to morphine for obstetric anal- given IV to produce sedation and intense gesia. analgesia without loss of consciousness. This Preanaesthetic medication – Pethidine can also state is maintained for 30-40 minutes as both be used as preanaesthetic medication. have rapid and short-action (See page 128). A fixed dose combination is available with DERIVATIVES OF PETHIDINE 0.05 mg fentanyl + 2.5 mg droperidol per Fentanyl ml. 5 ml is the dose used IV over 10 minutes. Patient is drowsy but responds to Fentanyl is a pethidine congener. commands.

Advantages Uses • It is about 100 times more potent than 1. Neuroleptanalgesia is used for short morphine as an analgesic. surgical procedures especially in ‘poor • Fentanyl is highly lipid soluble and fast risk’ patients. acting (maximum effect within 5 minutes.) 2. Epidural fentanyl is used for posto- • Fentanyl has mild effects on the cardio- perative and obstetric analgesia. For this vascular system. It slightly reduces HR and morphine/fentanyl may be combined with BP. Hence it is found to be safer than other local anaesthetics so that lower doses of opioids in cardiovascular surgeries. both drugs are sufficient. • Transdermal patches of fentanyl are 3. Fentanyl can also be used in chronic pain available which acts for 48 hours. where opioid use is permissible. • Unlike morphine, fentanyl does not increase the intracranial pressure. Adverse Effects • Fentanyl is not a histamine liberator. Bolus doses of fentanyl cause muscle rigidity. • It can be used in combination with This can be reduced by avoiding bolus doses. droperidol, a neuroleptic agent to produce Other adverse effects include nausea, neuroleptanalgesia. vomiting and respiratory depression. Table 26.2: Compare and contrast morphine and pethidine

Features Morphine Pethidine

Source Natural opium alkaloid Synthetic Potency More potent Less potent (1/10th of mophine) Corneal anaesthesia No effect Corneal anaesthetic Higher doses Profound CNS depression CNS stimulation (due to norpethidine) Antitussive property Good Poor or nil Constipation effect Marked Less Analgesic dose 10 mg 100 mg Anticholinergic effect Absent Present Use during labour Significant respiratory Less neonatal respiratory depression - depression in the neonate hence preferred over morphine Opioid Analgesics 167

Congeners of fentanyl are sufentanil, alfentanil 3. Methadone can also be used as an analgesic. and remifentanil. Alfentanil and remifentanil LAAM (L - alpha - acetyl - methadol) is a are faster acting (act within one minute) and derivative of methadone. L- alpha- acetyl- recovery is rapid. They are used for short methadol is found to have longer duration surgical procedures. of action than methadone so that it can be Methadone given three times a week. It is used to prevent withdrawal symptoms in addicts. Methadone a synthetic opioid, has actions similar to morphine. Its outstanding features Dextropropoxyphene are: Dextropropoxyphene is a congener of • It is an effective analgesic methadone. It binds to the opioid receptors • It is effective by oral route and produces effects similar to morphine. It • It has a long duration of action ( t½ 24 - is less constipating, longer acting and has 36 hours) and therefore effectively good oral efficacy. But dextropropoxyphene suppresses withdrawal symptoms in is an irritant when given parenterally. Large addicts. doses cause CNS stimulation. It also has abuse Methadone is about 90% bound to plasma potential. proteins; it is firmly bound to proteins in various tissues, including brain. After Uses repeated administration, it gradually accumulates in tissues. When administration Used in mild to moderate pain. It is marketed is discontinued, the drug is slowly released in combination with aspirin. from these binding sites. This probably Dextropropoxyphene 32 mg+aspirin 600 mg. accounts for its milder withdrawal symptoms. As euphoric effects are less intense, abuse Ethoheptazine potential is less. Tolerance develops more Ethoheptazine is related to pethidine and has slowly. Even in addicts, withdrawal symp- mild analgesic effects with low addiction toms are gradual in onset, less intense, but potential. It is used orally are combination prolonged. with NSAIDs for relief of pain. Preparation 10 mg inj, (2 mg/5 ml syrup) Dose - 10 mg oral or IM. Uses of Morphine and Its Congeners Dose Morphine 10 to 20 mg IM/SC; 20 mg Uses tablets of ethylmorphine are now available 1. Substitution therapy In opioid dependence, for oral use. 1 mg oral methadone is given for every 4 1. Analgesic Morphine is one of the most mg morphine. potent analgesics available. It affords 2. Opioid maintenance: Gradually increasing symptomatic relief of pain without affecting doses of methadone is given orally to the underlying disease. It is an excellent produce a high degree of tolerance. Such analgesic for severely painful conditions subjects do not experience the pleasurable such as acute myocardial infarction, effects of IV morphine, i.e. opioids are not fractures, burns, pulmonary embolism, pleasurable in them and they give up the terminal stages of cancer, acute peri- habit. carditis, spontaneous pneumothorax and 168 Textbook of Pharmacology for Dental and Allied Health Sciences

postoperative pain. In excruciating pain, of the opioid is pushed through an morphine can be given IV. intravenous device. Careful monitoring is In myocardial infarction, morphine relieves needed to avoid over-dosage. pain and thereby apprehension. As a result 2. As preanaesthetic medication Morphine and reflex sympathetic stimulation is reduced pethidine are commonly used as and shock is minimized. preanaesthetic medication. They reduce • Morphine is given with atropine to anxiety, provide analgesia, allow relieve renal and biliary colic. Atropine smoother induction and reduce the dose relieves spasm of the sphincter of oddi. of the anaesthetic required. But they have Morphine relieves pain in biliary colic certain disadvantages: but may cause spasm of the sphincter • Opioids depress respiration of Oddi which in turn raises intra- • Morphine precipitates bronchospasm biliary pressure. Hence atropine is and is dangerous in patients with poor given to relieve the spasm of the respiratory reserve sphincter of Oddi. • They cause vasomotor depression • Since opiate receptors are present in • They may induce vomiting the spinal cord, epidural morphine can • They may interfere with pupillary be used to produce epidural analgesia. response to anaesthesia because they Such analgesia is segmental in cause miosis. distribution and there is no • Postoperative urinary retention and interference with motor function or constipation may be troublesome. autonomic changes and no systemic 3. Acute left ventricular failure Morphine is adverse effects. Small doses of used to alleviate the dyspnoea of LVF and morphine can produce profound pulmonary oedema in which the response analgesia for 12-24 hours. • Obstetric analgesia Pethidine is preferred to IV morphine may be dramatic. The to morphine for this condition. mechanism is not clear. The relief may be • Opioids can be liberally given to due to: control pain of terminal illness like (i) alteration in the patient’s reaction to cancers. impaired respiratory function. • But opioids should not be freely used (ii) reduction in the work of the heart in case of other chronic pain due to due to decreased fear and appre- their addiction liability. hension. Reduced anxiety decreases Various alternative routes of sympathetic stimulation which in administration are tried for opioids - in turn decreases cardiac work. order to reduce their systemic effects and (iii) cardiovascular effects like decreased provide longer duration of analgesia PVR leading to shifting of blood from particularly for patients with chronic pain. pulmonary to peripheral circulation, Morphine and other opioids are being thereby reducing cardiac work tried as intraspinal infusion, rectal, load. transmucosal, transdermal administration Morphine is contraindicated in bronchial and by inhalation. In patient controlled asthma and pulmonary oedema due to analgesia (PCA) with opioids, the patients respiratory irritants. decide their own need for the analgesic. 4. Diarrhoea Opioids are effective for the By the press of a button, a specific dose symptomatic treatment of diarrhoea. Opioid Analgesics 169

Table 26.3: Dose, duration of action and preparations of opioid analgesics

Name Dose Duration Preparations* Trade name (mg) of analgesia (hours)

Morphine 20-40 4-5 10, 30 mg CR-Tabs Morcontin Continus Ethyl morphine 16-32 6-8 16 mg tab Dionindon Methadone 10 4-6 ------Pethidine 50-100 2-4 50 mg, 100 mg inj. Pethidine Fentanyl 0.05-0.2 1-2 50 mcg inj. Trofentyl TD Patch-release 25-75 mcg/hr. Sufentanil 0.02 1-2 ------Codeine 30-60 3-5 Codeine Codoplus 30 mg+Paracetamol 500 mg tab Dextropropoxyphene 60 q 4-6 60 mg caps Parvodex Pentazocine 30-60 3-4 30 mg inj. Pentawin IM/SC 30 IV q 4-6 hr Nalbuphine 10-15 3-6 ------Buprenorphine 0.3-0.6 4-8 0.3 mg inj., 0.2 mg Pentorel IM/Slow SL tab IV q 6 - 8 hr Butorphanol 2 3-4 1,2 mg inj. Butrum Ethoheptazine 75 3-4 75 mg tab with Equagesic aspirin 325 mg Tramadol 50-100 4-6 50,100 mg inj. Urgendol IM q 4-6 hr

* Preparations available in India . IM–Intramuscular IV–Intravenous SC–Subcutaneous TD–Transdermal CR–Controlled release SL–Sublingual

Synthetic opioids - diphenoxylate and • Morphine can be used epidurally for loperamide are preferred as antidiarr- the relief of postoperative and chronic hoeals. pain. 5. Cough Though morphine is an effective 7. Sedative Morphine relieves anxiety in antitussive, codeine is the preferred threatened abortion without affecting opioid for this purpose. But now many uterine motility. It is an useful sedative in nonaddictive antitussives are available. the presence of pain. 6. Special anaesthesia • High doses of morphine can be used MIXED AGONISTS AND ANTAGONISTS IV to produce general anaesthesia. • Neuroleptanalgesia - fentanyl with They include - pentazocine, cyclazocine droperidol can be used to produce nalbuphine, buprenorphine, butorphanol and neuroleptanalgesia. nalorphine. 170 Textbook of Pharmacology for Dental and Allied Health Sciences

Pentazocine Nalbuphine In an attempt to develop an analgesic with Nalbuphine is an agonist - antagonist - more less addiction liability and low adverse potent than pentazocine. It is a good effects, pentazocine was developed. Penta- analgesic. Though it produces respiratory zocine it is a k receptor agonist. depression like morphine, it has a ceiling • CNS effects of pentazocine are similar to effect at 30 mg, i.e. an increase in dose beyond morphine. 20 mg pentazocine = 10 mg 30 mg does not increase respiratory morphine. Euphoria is seen only in low depression further. Higher doses produce dysphoria. doses. With higher doses - above 60 mg Uses As analgesic - 10-20 mg IM. dysphoria can occur due to k receptor stimulation. Buprenorphine • Sedation and respiratory depression are less marked. Buprenorphine is a highly lipid soluble μ • It has weak antagonistic properties at μ synthetic thebaine congener. It is a partial receptors. agonist, 25 times as potent as morphine. • Tolerance and dependence develop on Though onset of action is slow, duration of analgesia is long. Other CNS effects are repeated use. similar to morphine while respiratory • CVS - In contrast to morphine, pentazocine depression is less marked. Patients exhibit increases BP and heart rate and thereby lower degree of tolerance and dependence increases cardiac work. It is therefore not liability. Withdrawal syndrome appears late suitable in MI. and is mild. • Biliary spasm and constipation are less Dose 0.3-0.6 mg SC, IM or sublingual (oral severe. not available). Preparations Pentazocine can be given both Uses Chronic pain like in terminal cancer orally and parenterally. It undergoes first patients. Buprenorphine can also be used as pass metabolism. a maintenance drug in opioid addicts as the Dose 50-100 mg oral; 30-60 mg IM withdrawal symptoms are mild. (FORTWIN). Butorphanol is similar to pentazocine. Adverse effects Sedation, sweating, dizziness, nausea, dysphoria with anxiety, nightmares Nalorphine and hallucinations which are unpleasant are Nalorphine is also an agonist - antagonist. seen above 60 mg. As it is an irritant, IM At low doses, it is a good analgesic. But with injection can be painful and cause sterile increase in dose there is no increase in abscesses. analgesia. It causes dysphoria (k agonist) and Uses respiratory depression even in low doses. Hence it cannot be used as an analgesic. At Pentazocine is a commonly used opioid high doses it acts as an antagonist and analgesic especially in postoperative and counters all the actions of opioids. chronic pain - abuse liability is less than Uses Nalorphine may be used in acute opioid morphine. poisoning. It can also be used for the Cyclazocine is similar to pentazocine. diagnosis of opioid addiction. Opioid Analgesics 171

Newer Agonist-Antagonists Uses Meptazinol 1. Naloxone is the drug of choice for morphine overdosage. Meptazinol is a short acting agonist - 2. It is also used to reverse neonatal asphyxia antagonist with additional anticholinergic due to opioids used in labour. effects. It produces short duration analgesia 3. Naloxone can also be used for the with less respiratory depression and is diagnosis of opioid dependence - it therefore suitable for obstetric analgesia. precipitates withdrawal symptoms. 4. Hypotension seen during shock could be Dezocine due to endogenous opioids released Dezocine is a partial agonist at μ receptors. during such stress. Naloxone has been Its analgesic actions are similar to morphine found to be beneficial in reversing but respiratory depression does not increase hypotension. with an increase in dose (ceiling effect). Naltrexone OPIOID ANTAGONISTS Naltrexone is another pure opioid antagonist. Naloxone It is • more potent than naloxone Naloxone acts as a competitive antagonist to • orally effective all types of opioid receptors. It is a pure • has a longer duration of action of 1-2 days. antagonist. In normal individuals, it does not produce any significant actions. But in opium Uses addicts, given IV, it promptly antagonises all the actions of morphine including respiratory 1. Naltrexone is used for ‘opioid blockade’ depression and sedation and precipitates therapy in post addicts (50-100 mg/ day withdrawal syndrome. It also blocks the orally) so that even if the addicts take an action of endogenous opioid peptides - opioid, they do not experience the endorphins, enkephalins and dynorphins. It pleasurable effects and therefore lose the blocks the analgesia produced by placebo and craving. acupuncture. This suggests that endogenous 2. Alcohol craving is also reduced by opioid peptides are responsible for analgesia naltrexone and is used to prevent relapse by these techniques. of heavy drinking (See page 145). Given orally it undergoes first pass Nalmefene metabolism and is metabolised by the liver. Hence it is given intravenously. Duration of Nalmefene is orally effective and longer action is 3-4 hours. acting. It has better bioavailability and is not Dose 0.4 mg IV. hepatotoxic. It is used in opioid overdosage. 172 Textbook of Pharmacology for Dental and Allied Health Sciences

27 Nonsteroidal Anti- inflammatory Drugs (NSAIDs)

Nonsteroidal anti-inflammatory drugs are 5. Arylacetic acid derivatives aspirin-type or non-opioid analgesics. In Diclofenac, ketorolac, tolmetin addition, they have anti-inflammatory , 6. Propionic acid derivatives antipyretic and uricosuric properties - Ibuprofen, fenoprofen, without addiction liability. carprofen, naproxen, The medicinal effects of the bark of the ketoprofen, flurbiprofen Willow tree have been known since centuries. oxaprozin The active principle ‘salicin’ was isolated from 7. Anthranilic acids (Fenamates) the Willow bark. This salicin is converted to Flufenamic acid glucose and salicylic acid in the body. In 1875, mefenamic acid sodium salicylate was first used in the enfenamic acid treatment of rheumatic fever. After its anti- meclofenamic acid inflammatory and uricosuric properties were 8. Oxicams established, efforts were made to synthesize Piroxicam, tenoxicam meloxicam derivatives which were less expensive. Now 9. Alkanones they have replaced the natural ones in the Nabumetone market. B. Selective COX-2 Inhibitors CLASSIFICATION Nimesulide, celecoxib, A. Nonselective COX Inhibitors rofecoxib, valdecoxib, etodolac 1. Salicylic acid derivatives Aspirin, sodium salicylate MECHANISM OF ACTION diflunisal During inflammation, arachidonic acid 2. Para-aminophenol derivatives liberated from membrane phospholipids is Paracetamol converted to prostaglandins (PGs), catalysed 3. Pyrazolone derivatives by the enzyme cyclo-oxygenase (COX). These Phenylbutazone prostaglandins produce hyperalgesia - they azapropazone sensitize the nerve endings to pain caused 4. Indole acetic acid derivatives by other mediators of inflammation like Indomethacin, sulindac bradykinin and histamine. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) 173

relieved. But in vague visceral pain, aspirin is relatively ineffective. The pain is relieved without euphoria and hypnosis. Hence there is no development of tolerance and dependence. But aspirin is a weak analgesic when compared to morphine. (Table 27.3) 2. Antipyretic action In presence of fever, salicylates bring down NSAIDs inhibit the PG synthesis by the temperature to normal level. But, in inhibiting the enzyme cyclo-oxygenase. normal individuals, there is no change in Aspirin is an irreversible inhibitor of COX temperature. (by acetylation) while the others are In fever, pyrogen - a protein, circulates in reversible competitive COX inhibitors. There the body and this increases the synthesis of are two forms of cyclo-oxygenase viz., COX- PGs in the hypothalamus, thereby raising its temperature set point. The thermostatic 1 and COX-2 (see page 210). COX-1 is found in most of the normal cells (constitutive) and mechanism in the hypothalamus is thus is involved in maintaining tissue homeostasis. disturbed. Aspirin inhibits PG synthesis in COX-2 is induced in the inflammatory cells the hypothalamus and resets the thermostat by cytokines and other mediators of at the normal level bringing down the inflammation. This COX-2 catalyses the temperature. synthesis of prostanoids which are the Enhanced sweating and cutaneous vasodi- mediators of inflammation. Most NSAIDs latation promote heat loss and assist in the inhibit both COX-1 and COX-2 while some antipyretic action. newer agents like celecoxib and rofecoxib 3. Anti-inflammatory action selectively inhibit only COX-2. At higher doses of 4-6 gm/day, aspirin acts as an anti-inflammatory agent. Signs of SALICYLATES inflammation like tenderness, swelling, erythema and pain are all reduced or Salicylates are salts of salicylic acid, e.g. suppressed. But, the progression of the methyl salicylate, sodium salicylate, acetyl disease in rheumatoid arthritis, rheumatic salicylic acid (aspirin). Aspirin is taken as the fever or osteoarthritis is not affected. prototype. Once again the mechanism involved is PG synthesis inhibition-PGs present in Pharmacological Actions inflammatory tissues are responsible for 1. Analgesia oedema, erythema and pain. In addition, Aspirin is a good analgesic and relieves pain aspirin also interferes with the formation of of inflammatory origin. This is because PGs chemical mediators of the kallikrein system. are formed during inflammation and they As a result, it decreases the adherence of sensitize the tissues to pain and aspirin granulocyte to the damaged vasculature, inhibits PG synthesis and thereby acts as an stabilizes lysosomes and decreases the analgesic. Pain originating from the migration of the polymorphonuclear integumental structures like muscles, bones, leukocytes and macrophages into the site of joints, and pain in connective tissues is inflammation. 174 Textbook of Pharmacology for Dental and Allied Health Sciences

4. Respiration • increased sweating In therapeutic doses of 4-6 gm/day - • water lost during hyperventilation. salicylates increase consumption of oxygen Thus there is severe dehydration with by skeletal muscles. As a result there is acidosis. increased CO2 production. This increased 6. Metabolic effects

CO2 stimulates respiratory centre. Salicylates Salicylates enhance the cellular metabolism also directly stimulate the medullary due to uncoupling of oxidative respiratory centre. Both these actions increase phosphorylation. More of O2 is used and the rate and depth of respiration. These more CO2 is produced, especially in skeletal effects are dose dependent. muscles, leading to increased heat As a result of this stimulation of production. respiration, plasma CO2 is washed out In toxic doses, hyperpyrexia, increased leading to respiratory alkalosis. With toxic protein catabolism with resultant doses, the respiratory centre is depressed aminoaciduria and negative nitrogen balance leading to respiratory failure. are seen. Enhanced utilization of glucose leads 5. Acid-base and electrolyte balance to mild hypoglycaemia. But in toxic doses, In anti-inflammatory doses, salicylates hyperglycaemia occurs due to central produce significant respiratory stimulation - sympathetic stimulation which increases

CO2 is washed out resulting in respiratory adrenaline levels. alkalosis; pH becomes alkaline. This is 7. Gastrointestinal tract compensated by increased excretion of Aspirin is a gastric irritant. Irritation of the – + + HCO3 in urine accompanied by Na , K and gastric mucosa leads to epigastric distress, water. pH then returns to normal. This stage nausea and vomiting. Aspirin also stimulates is known as compensated respiratory the CTZ to produce vomiting. alkalosis. Erosive gastritis, mucosal congestion, With toxic doses, salicylates depress the gastric ulceration and GI bleeding resulting respiratory centre directly. As a result, CO2 in malaena and occasionally haematemesis accumulates because more CO2 is produced can occur particularly in higher doses. than is exhaled. Thus plasma CO2 rises and pH decreases. Since the concentration of Mechanism of Action HCO – is already low due to enhanced renal 3 (i) In the acidic pH of the stomach, salicylates excretion, the change results in remain unionised. These drug particles uncompensated respiratory acidosis. This is adhere to the mucosa producing irritation. superimposed by metabolic acidosis caused These particles also promote local back by accumulation of acids. diffusion of acid. Toxic doses also depress vasomotor centre. (ii) Aspirin decreases prostaglandin syn- This vasomotor depression impairs renal thesis. PGs inhibit gastric acid secretion, function resulting in accumulation of strong increase mucus production and act as acids of metabolic origin like lactic, pyruvic cytoprotectives in gastric mucosa. This and acetoacetic acids. defense mechanism is lost due to PG The above effects are accompanied by inhibition. dehydration due to: – + The above actions make aspirin ulcero- • water lost in urine with HCO3 , Na and K+ genic. In addition, it decreases platelet Nonsteroidal Anti-inflammatory Drugs (NSAIDs) 175 aggregation which also increases the aspirin is adequate for its antiplatelet tendency to bleed. aggregatory effect. With soluble aspirin, gastric irritation is 12. Local effects less. The selective COX-2 inhibitors cause less Salicylic acid when applied locally is a gastric irritation. keratolytic. It also has mild antiseptic and 8. CVS fungistatic properties. Salicylic acid is also an In therapeutic doses no significant irritant for the broken skin. cardiovascular effects are seen. In toxic doses it depresses the VMC and thus depresses the Pharmacokinetics circulation. Salicylates being acidic drugs are absorbed 9. Immunological effects from the stomach and the upper small In higher doses, salicylates suppress several intestine. But aspirin as such is poorly soluble, antigen-antibody reactions including hence not well-absorbed. When administered inhibition of antibody production, Ag-Ab as microfine particles, absorption increases. aggregation and antigen induced release of Thus particle size, pH of the GIT, solubility histamine. These effects might also contribute of the preparation and presence of food in to the beneficial effects in rheumatic fever. the stomach influence the absorption. 10. Uric acid excretion Salicylic acid and methylsalicylate are Uric acid is excreted by secretion from the absorbed from the intact skin. They are distal tubules. In a dose of 1-2 gm/day, extensively bound to plasma proteins. aspirin increases plasma urate levels by urate Aspirin is deacetylated in the liver, plasma retention because it interferes with urate and other tissues to release salicylic acid secretion by the distal tubules. which is the active form. Plasma t½ of aspirin Large doses of > 5 gm/day increase urate is 3-5 hours. Elimination is dose dependent. excretion because it inhibits reabsorption of It follows first order kinetics in small doses urate by proximal tubule causing uricosuria. and zero order kinetics in higher doses. But, its uricosuric effect cannot be used Therefore in anti-inflammatory doses, t½ therapeutically because high doses are increases to 12 hr. Salicylates are excreted in required and such doses result in prominent urine. adverse effects. 11. Blood Adverse Effects Even in small doses aspirin irreversibly Analgesic doses are generally well tolerated inhibits platelet cyclooxygenase and thereby but anti-inflammatory doses are usually TXA2 synthesis by the platelets. It therefore associated with adverse effects especially interferes with platelet aggregation and when used over a long period. prolongs the bleeding time. Even a single • GI tract Nausea, epigastric distress, dose can irreversibly inhibit TXA2 synthesis vomiting, erosive gastritis, peptic ulcer, which is for the life of the platelets (8-11days). increased occult blood loss in stools are As platelets cannot synthesize proteins which common. means COX cannot be regenerated, fresh • Allergic reactions are not common and may platelets have to be formed to restore TXA2 be manifested as rashes, urticaria, photo activity. Moreover aspirin inhibits platelet sensitivity, rhinorrhoea, angio-oedema COX in the portal circulation itself and and asthma especially in those with a therefore even small doses (40 mg daily) of history of allergies. 176 Textbook of Pharmacology for Dental and Allied Health Sciences

As aspirin inhibits only cyclo-oxygenase mental confusion, diarrhoea, sweating, pathway, arachidonic acid is available for difficulty in hearing, thirst and conversion by lipoxygenase pathway into dehydration. These symptoms are leukotrienes. Leukotrienes are powerful reversible on withdrawal of salicylates. bronchoconstrictors. Hence aspirin can Acute salicylate intoxication Poisoning may be precipitate bronchial asthma in some accidental or suicidal. It is more common in individuals. Of the currently available children, 15-30 grams is the fatal dose of aspirin. NSAIDs, diclofenac and indomethacin inhibit the synthesis of both PGs and LTs. Symptoms and Signs • Haemolysis: Salicylates can cause Dehydration, hyperpyrexia, GI irritation, haemolysis in patients with G6PD deficiency. vomiting, sometimes haematemesis, acid-base • Nephrotoxicity: Almost all NSAIDs can imbalance, restlessness, delirium, cause nephrotoxicity after long-term use. hallucinations, metabolic acidosis, tremors, Salt and water retention and impaired convulsions, coma and death due to renal function can occur. respiratory failure and CV collapse. • Hepatotoxicity can also occur when high Treatment is Symptomatic and Includes: doses of NSAIDs are used over a long period. Plasma levels of liver enzymes are 1. Gastric lavage to eliminate unabsorbed raised. drugs. • Reye’s syndrome seen in children is a form 2. IV fluids to correct acid-base imbalance of hepatic encephalopathy which may be and dehydration. fatal. It develops a few days after a viral 3. Temperature is brought down by external infection especially influenza and varicella. cooling with alcohol or cold water An increased incidence of this syndrome sponges. has been noted when aspirin is used to 4. If haemorrhagic complications are seen, treat fever. Hence aspirin is blood transfusion and vitamin K are contraindicated in children with viral needed. fever. 5. The IV fluids should contain Na+, K+, • Pregnancy and infancy Aspirin when taken – HCO3 and glucose (to treat hypokalaemia at term delays the onset of labour due to and acidosis). Blood pH should be inhibition of PG synthesis (PGs play an monitored. important role in the initiation of labour). 6. In severe cases, forced alkaline diuresis Premature closure of ductus arteriosus with sodium bicarbonate and a diuretic may occur in the foetus resulting in portal like frusemide is given along with IV hypertension. It can also increase fluids. Sodium bicarbonate ionizes postpartum bleeding due to inhibition of salicylates making them water soluble and platelet aggregation. enhances their excretion through kidneys. • Salicylism Higher doses given for a long time as in treatment of rheumatoid Precautions and Contraindications arthritis may cause chronic salicylate intoxication termed ‘Salicylism’. The Peptic ulcer, liver diseases, bleeding syndrome is characterised by headache, tendencies and viral fever in children vertigo, dizziness, tinnitus, vomiting, contraindicate the use of aspirin/salicylates Nonsteroidal Anti-inflammatory Drugs (NSAIDs) 177

Pregnancy - Aspirin should be avoided in 3. For inflammatory conditions pregnancy because it can cause premature Aspirin is effective in a number of closure of the ductus arteriosus in the foetus. inflammatory conditions such as arthritis and Treatment with NSAIDs should be stopped fibromyositis. one week before any surgery because of the 4. Acute rheumatic fever risk of bleeding due to antiplatelet effect. In a dose of 4-6 gm/day (100 mg/kg/day) in 4-6 divided doses, aspirin brings about a Preparations dramatic relief of signs and symptoms in 24 to 48 hr. The dose is reduced after 4-7 days Preparations and dosage of salicylates (Table and maintenance doses of 50 mg/kg/day are 27.1 and 27.2). given for 2-3 weeks. Uses 5. Rheumatoid arthritis Aspirin relieves pain, reduces swelling and 1. As analgesic redness of joints in rheumatoid arthritis. For headache, backache, myalgias, arthralgias, Joint mobility improves, fever subsides and neuralgias, toothache and dysmenorrhoea. In there is a reduction in morning stiffness. But headache PGs may be responsible for cerebral NSAIDs do not alter the progress of the vasodilation. NSAIDs inhibit PG synthesis disease. The relief is only symptomatic. and relieve headache. - PG synthesis is Dose: 4-6 gm/day in 4-6 divided doses. responsible for dysmenorrhoea - aspirin 6. Osteoarthritis effectively relieves pain. The NSAIDs are NSAIDs provide symptomatic relief in osteo- beneficial in a variety of painful conditions arthritis. of integumental origin and all these are 7. Postmyocardial infarction and post-stroke associated with increase prostaglandin Aspirin inhibits platelet aggregation and this synthesis. may lower the incidence of reinfarction in a 2. Fever low dose of 50 to 300 mg/day. It also NSAIDs are useful for the symptomatic relief decreases the incidence of transient ischaemic of fever. attacks (TIA) and stroke in such patients.

Table 27.1: Preparations and dosage of salicylates

Drug Preparation Dose

Aspirin 300, 350 tab (ASABUF); Analgesic - 300-600 mg every 6-8 hr DISPRIN (Aspirin 350 mg and Anti-inflammatory - 4-6 gm/day Calcium carbonate 105 mg) Antiplatelet effects - 75-300 mg/day Sodium salicylate 325, 650 mg tablets 325-650 mg every 4-8 hr Salicylic acid 2% ointment; For topical use Whitfield’s ointment- - Salicylic acid 3% - Benzoic acid 6% Methylsalicylate Ointment/liniment for As counter irritant (Oil of wintergreen) topical use Diflunisal 250, 500 mg tab (DOLOBID) 250 mg every 8-12 hr 178 Textbook of Pharmacology for Dental and Allied Health Sciences

Low dose aspirin is also given to patients syndrome characterised by raised with angina pectoris with the hope of plasma renin and aldosterone with preventing MI in such patients. hypokalemia. NSAIDs are useful in It is also given in deep vein thrombosis to such patients. prevent recurrence. (v) Aspirin 60-100 mg daily is recommen- 8. Miscellaneous uses ded in pregnant women with ‘high (i) To delay labour–Since PGs are risk’ of hypertension. PGs are involved in the initiation of labour, involved in the genesis of eclampsia aspirin delays labour due to PG and hypertension. Hence NSAIDs are synthesis inhibition. But such use is useful in lowering BP in such patients. associated with the risk of increased 9. Local bleeding and premature closure of the Salicylic acid is used as a keratolytic, ductus arteriosus. fungistatic and mild antiseptic. Methyl- (ii) Some studies suggest that long-term salicylate is a counter-irritant used in use of aspirin at low doses is myalgias. Mesalamine is used in infla- associated with a lower incidence of mmatory bowel disease. colon cancer. (iii) Patent ductus arteriosus (PDA): Drug Interactions Aspirin may be given to bring about closure of PDA in the newborn. • Salicylates compete for protein binding (iv) Excess production of renal PGs is sites and displace drug molecules resulting thought to be responsible for Bartter's in toxicity with warfarin, heparin,

Table 27.2: Topical preparations of NSAIDs

NSAID Preparation Brand Name

Salicylic acid 6 % W/W oint KERALIN with hydrocortisone acetate and benzoic acid 3 % oint MYCODERM with benzoic acid and menthol 2.2 % eardrops METHAZIL with 6% methanol Diclofenac diethyl ammonium 1.16 % gel VOVERAN emulgel, RELAXYL gel, INAC gel Piroxicam 0.5 % gel DOLONEX gel, PIROX gel Ibuprofen 50 mg gel ACKS gel with mephenisin, methyl salicylate and menthol Flurbiprofen 0.03% W/V eyedrops OCUFLUR Indomethacin 1% W/V eyedrops INDOCAP ophthalmic drops Naproxen 10% gel XENOLID gel Ketorolac tromethamine 0.5% W/V Eyedrops KETANOV eyedrops KETLUR Nimesulide 10 mg gel NIZU gel with menthol 50 mg and Methyl salicylate 100 mg Rofecoxib 1% gel ROFIZ gel, ROFECOXIB 1%. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) 179

naproxen, phenytoin and sulfonylureas. system and platelet function; it is not a Inhibition of platelet aggregation may uricosuric agent and gastric irritation is mild. increase the risk of bleeding with oral anticoagulants. Pharmacokinetics • In low doses salicylates can counter the Paracetamol is well-absorbed orally and 30% uricosuric actions of probenecid by protein bound; it is metabolised by the decreasing uric acid excretion. hepatic microsomal enzymes: by glucuronide Diflunisal conjugation (60%) and glutathione conjugation (20%). Diflunisal is a difluorophenyl derivative of salicylic acid. Diflunisal is 3-4 times more Adverse Effects potent than aspirin as an anti-inflammatory agent but is a poor antipyretic due to poor In antipyretic doses, paracetamol is safe and penetration into CNS. Gastrointestinal and well-tolerated. Nausea and rashes may occur. antiplatelet effects are less intense than But when large doses are taken, acute aspirin. Side effects are fewer. paracetamol poisoning results. Children are more susceptible because their ability to Uses Osteoarthritis, strain and sprains initial conjugate by glucuronidation is poor. 10-15 dose 500-1000 mg followed by 250 bd/tid. grams in adults cause serious toxicity. Symptoms are - nausea, vomiting, anorexia PARA-AMINOPHENOL DERIVATIVES and abdominal pain during first 24 hours. Paracetamol (acetaminophen) Paracetamol is hepatotoxic and causes severe Phenacetin was the first drug used in this hepatic damage. Manifestations are seen group. But, due to severe adverse effects it within 2-4 days and include increased serum is now banned. transaminases, jaundice, liver tenderness and Paracetamol, a metabolite of phenacetin is prolonged prothrombin time which may found to be safer and effective. progress to liver failure in some patients. Hepatic lesions are reversible when promptly Actions treated. Nephrotoxicity may result in acute renal Paracetamol has analgesic, good antipyretic failure in some. and weak anti-inflammatory properties. Due to weak PG inhibitory activity in the Mechanism periphery, it has poor anti-inflammatory actions. A small portion of paracetamol is metabolised Paracetamol is active on cyclo-oxygenase to a highly reactive intermediate - N-acetyl- in the brain which accounts for its antipyretic benzoquinone-imine which is detoxified action. In the presence of peroxides which generally by conjugation with glutathione. are present at the site of inflammation, But when large doses of paracetamol are paracetamol has a poor ability to inhibit taken, hepatic glutathione is depleted and the cyclo-oxygenase. It does not stimulate toxic metabolite binds to sulphydryl groups respiration, has no actions on acid-base in hepatic proteins resulting in hepatic balance, cellular metabolism, cardiovascular necrosis. 180 Textbook of Pharmacology for Dental and Allied Health Sciences

Chronic alcoholics and infants are more Dose 100-200 mg, BD. Small doses may be prone to hepatotoxicity. given 3-4 times a day to avoid gastric irritation. Treatment Adverse Effects Stomach wash is given. Activated charcoal prevents further absorption. Antidote is-N- • Phenylbutazone is more toxic than aspirin acetylcysteine (150 mg/kg IV infusion over and is poorly tolerated - dyspepsia, 15 min repeated as required; oral loading epigastric distress, nausea and vomiting dose - 140 mg/kg followed by 70 mg/kg are common. Peptic ulceration and every 4 hr - 17 doses) - more effective when diarrhoea may occur. Oedema is a limiting given early. N-acetylcysteine partly factor and may precipitate CCF. replenishes the glutathione stores of the liver • Hypersensitivity reactions like rashes, and prevents binding of toxic metabolites to serum sickness, stomatitis, hepatitis, the cellular constituents. nephritis, dermatitis and jaundice can occur. Phenylbutazone may cause serious Uses haematological complications such as bone • Paracetamol is used as an analgesic in marrow depression, aplastic anaemia, painful conditions like toothache, agranulocytosis and thrombocytopenia. headache and myalgia • It may inhibit iodine uptake by thyroid, • As an antipyretic resulting in hypothyroidism and goitre on • Chronic pulpitis, periodontal abscess, long-term use. post-extraction - paracetamol is used with • CNS effects like insomnia, vertigo, optic ibuprofen. neuritis, blurring of vision and convulsions may be encountered. PYRAZOLONE DERIVATIVES Because of its toxicity, phenylbutazone is withdrawn from the market in many western Phenylbutazone countries. Phenylbutazone has good anti-inflammatory activity, is more potent, but has poorer Uses analgesic and antipyretic effects. It is a 1. Rheumatoid arthritis uricosuric agent. 2. Ankylosing spondylitis + Phenylbutazone causes retention of Na 3. Osteoarthritis and water. Thus after 1-2 weeks of use 4. Gout - phenylbutazone produces satis- oedema results. It can also precipitate factory relief from pain and inflammation congestive cardiac failure. in acute attacks 5. Other musculoskeletal disorders. Pharmacokinetics Azapropazone is structurally related to Phenylbutazone is completely absorbed phenylbutazone but is less likely to cause orally; IM injection is not recommended agranulocytosis; t½ is 12-16 hours. because its absorption is slow as it binds to Metamizol is a potent analgesic and local tissue proteins and also causes local antipyretic, but poor anti-inflammatory agent tissue damage. It is 98% bound to plasma and has no uricosuric properties (ANALGIN, NOVALGIN) Dose: 500 mg 3-4 times a day. proteins; t½ is 60 hr. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) 181

It offers no advantages over aspirin. Not is good and attains good concentration in recommended in children upto 6 years. synovial fluid which is maintained for a long Propiphenazone is similar to metamizol. time. Adverse effects are mild. Dose 300-600 mg 3-4 times a day (SARIDON). Dose 50 mg bd-tds. Gel is available for topical application (INAC GEL). Ophthalmic prepar- INDOLE ACETIC ACID DERIVATIVES ation is available for use in postoperative pain. Indomethacin is a potent anti-inflammatory Uses agent, antipyretic and good analgesic. It is 1. Treatment of chronic inflammatory well-absorbed, 90% bound to plasma conditions like rheumatoid arthritis and proteins; t½ - 4-6 hr. osteoarthritis. Dose 25-50 mg b.d-t.d.s. 2. Acute musculoskeletal pain, painful dental Adverse effects are high; gastrointestinal lesions. irritation with nausea, GI bleeding, vomiting, 3. Postoperatively for relief of pain and diarrhoea and peptic ulcers can occur. inflammation. CNS effects include headache, dizziness, Ketorolac is another PG synthesis inhibitor ataxia, confusion, hallucinations, depression having good analgesic and anti-inflammatory and psychosis. properties. It is used for its analgesic Hypersensitivity reactions like skin rashes, properties to relieve postoperative pain. It is leukopenia, and asthma in aspirin sensitive mostly used parenterally though it can also individuals. It can also cause bleeding due be given orally. to decreased platelet aggregation and PROPIONIC ACID DERIVATIVES oedema due to salt and water retention. Ibuprofen is better tolerated than aspirin. Drug interactions Indomethacin blunts the Analgesic, antipyretic and anti-inflammatory diuretic action of furosemide and the efficacy is slightly lower than aspirin. It is antihypertensive action of thiazides, β 99% bound to plasma proteins. furosemide, -blockers and ACE inhibitors Adverse effects are milder when compared to by causing salt and water retention. other NSAIDs and the incidence is low. Uses (Table 27.3) Nausea, vomiting, gastric discomfort, CNS effects, hypersensitivity reactions, fluid • Rheumatoid arthritis retention are all similar but less severe than • Gout phenylbutazone or indomethacin. • Ankylosing spondylitis Dose Ibuprofen - 400-800 mg TDS (BRUFEN) • Psoriatic arthritis ibuprofen + paracetamol (COMBIFLAM) • For closure of patent ductus arteriosus. Uses Sulindac has weaker analgesic, antipyretic and anti-inflammatory actions but is less toxic. 1. As an analgesic in painful conditions. Does not antagonize the diuretic and 2. In fever. antihypertensive actions of thiazides. It may 3. Soft tissue injuries, fractures, following tooth extraction, to relieve postoperative be used as an alternative drug for pain, dysmenorrhoea and osteoarthritis. inflammatory conditions. 4. Gout. 5. Surgical removal of impacted tooth-a ARYLACETIC ACID DERIVATIVES combination of ibuprofen with a skeletal Diclofenac is an analgesic, antipyretic and anti- muscle relaxant like chlorzoxazone is inflammatory agent. Its tissue penetrability recommended. 182 Textbook of Pharmacology for Dental and Allied Health Sciences

Table 27.3: Properties of some commonly used NSAIDs

NSAID Properties Advantages Uses

Aspirin Good analgesic, • Antiplatelet As analgesic-headache antipyretic, anti- activity even backache, neuralgias, inflammatory and in low doses dysmenorrhoea; pyrexia, uricosuric agent • Powerful antirheumatic fever, rheumatic, inflammatory psoriatic and osteoarthritis, activity for antiplatelet activity in poststroke and post- MI; closure of PDA; to delay labour Paracetamol Good analgesic, antipyretic • Less gastric As analgesic in fever but poor anti-inflammatory irritation Diclofenac Analgesic, antipyretic, • Good concentra- Chronic inflammatory anti-inflammatory tion in synovial conditions; fluid; rheumatoid arthritis, • Adverse effects osteoarthritis, acute mild musculoskeletal pain and postoperative pain; acute pulpitis and acute periapical abscess Piroxicam Analgesic, antipyretic, • Long-acting Arthritis, musculoskeletal anti-inflammatory (given once a day) pain, postoperative pain • Less ulcerogenic • Better tolerated Phenylbutazone Good anti-inflammatory; • Powerful Rheumatoid and poor analgesic, antipyretic; anti-inflammatory osteoarthritis; gout, salt and water retention agent ankylosing spondylitis causes oedema; more toxic than aspirin Indomethacin Good analgesic, • Potent anti- Rheumatoid, psoriatic and anti-inflammatory inflammatory osteoarthritis, gout, anky- and antipyretic but and analgesic losing spondylitis, closure toxicity is high of PDA Ibuprofen Analgesic, • Adverse effects As analgesic in painful anti-inflammatory, milder therefore conditions, antipyretic, soft antipyretic all actions better tolerated tissue injuries, fractures, milder than aspirin postoperative pain, arthritis and gout; chronic pulpitis, peridontal abscess, gingival abscess Nonsteroidal Anti-inflammatory Drugs (NSAIDs) 183

ANTHRANILIC ACID DERIVATIVES SELECTIVE COX-2 INHIBITORS Fenamates are analgesic, antipyretic, anti- Celecoxib, rofecoxib and valdecoxib are diaryl inflammatory drugs with less efficacy, and substituted compounds. They are highly are more toxic; contraindicated in children. selective COX-2 inhibitors. They have good They should not be used for more than one anti-inflammatory, analgesic and antipyretic week. They are not generally preferred. properties but do not affect platelet aggregation (Table 27.4). Adverse effects GI side effects are similar to They are better tolerated because of milder aspirin but GI bleeding is less. Diarrhoea is gastric irritation (due to COX-2 selectivity) - common. but more long term studies are needed. Uses Analgesic in myalgias, dysmenorrhoea, (250-500 mg TDS). Disadvantages

OXICAMS The coxibs can cause hypertension and oedema which can be troublesome in patients Piroxicam is an oxicam derivative. It is long- with cardiovascular problems. Studies have acting, has good anti-inflammatory, analgesic shown that use of coxibs can increase the risk and antipyretic activity. No clinically of myocardial infarction and stroke. The exact significant drug interactions are seen; better cause is not known but could be because of tolerated as it is less ulcerogenic. It is a inhibition of PGI2 production without reversible COX inhibitor. Dose 20 mg OD. It inhibiting TXA2. This results in a pro- is long-acting. Piroxicam is used for rheu- thrombotic effect leading to myocardial matoid arthritis, osteoarthritis, ankylosing infarction and stroke. Because they are derivatives of sulphonamides, allergic spondylitis, acute musculoskeletal pain and reactions including Stevens–Johnson postoperative pain and painful dental lesions. syndrome have been reported. Hence most Meloxicam is similar to piroxicam but in lower coxibs have been with-drawn from the doses it causes less gastric irritation than market. Celecoxib has been approved for use piroxicam. It is therefore better tolerated. in osteoarthritis and rheumatoid arthritis in Dose 7.5-15 mg once daily. the lowest effective dose and for the shortest Many other oxicams are being developed period possible. with the idea of obtaining one which is nonulcerogenic. But most of them are Dose: prodrugs of piroxicam and in lower doses Celecoxib - anti-inflammatory - 100-200 mg some of them are selective COX-2 inhibitors. once or twice daily. Rofecoxib - 12.5-25 mg daily. ALKANONES Valdecoxib-20 mg twice daily. Other coxibs include etoricoxib, lumira- Nabumetone is an anti-inflammatory agent coxib and paracoxib. They have properties with significant efficacy in rheumatoid similar to other coxibs. arthritis and osteoarthritis. It shows a Nimesulide a sulfonamide compound is a relatively low incidence of side effects, it is sulfonanilide derivative. It is a weak inhibitor comparatively less ulcerogenic. It is a prodrug of PG synthesis with a higher affinity for and also selectively inhibits COX-2 - both COX-2 than COX-1. It inhibits leukocyte account for the low ulcerogenic potential. function, prevents the release of mediators It is used in rheumatoid and osteoarthritis. and in addition has antihistaminic and 184 Textbook of Pharmacology for Dental and Allied Health Sciences

Table 27.4: Compare and contrast aspirin and celecoxib

Features Aspirin Celecoxib

1. Chemistry Salicylic acid derivative Sulfonamide derivative 2. COX inhibition Nonselective (COX-1, COX-2) Selective COX-2 inhibitor 3. Ulcerogenic effect on +++ (Significant) + Mild gastric mucosa 4. t½ 2-3 hours (short) 6-12 hours (Long) 5. Effect on platelet function Inhibits platelet aggregation Does not 6. Risk of Reye’s syndrome Present Nil in children 7. Risk of thrombosis, Nil Present atherogenesis 8. Cardiovascular toxicity No significant effect Risk of MI 9. Cerebrovascular toxicity No significant effect Risk of stroke 10. Use in post MI patients Recommended Contraindicated 11. Prominent action Analgesic, antipyretic Analgesic, antipyretic anti-inflammatory anti-inflammatory 12. P G synthesis Inhibited Inhibited antiallergic properties. Nimesulide has and arthritis. It is beneficial in patients who analgesic, antipyretic and anti-inflammatory develop bronchospasm with other NSAIDs. actions like other NSAIDs. But because of the risk of hepatotoxicity, Nimesulide is well-absorbed orally, nimesulide is now banned. extensively bound to plasma proteins and has a t½ of 3 hours. It is excreted by the kidney. ANTAGONISTS OF LEUKOTRIENE Dose 50-100 mg BD SYNTHESIS AND LEUKOTRIENE Adverse effects are mild; they are nausea, RECEPTORS epigastric pain, rashes, drowsiness and dizziness. It is claimed to be better tolerated. Zileuton, montelukast, pranlukast, docebenone, Long-term use can cause hepatotoxicity. piriprost - Some of them inhibit 5-lipoxygenase preventing the synthesis of leukotrienes, Uses while others act as competitive antagonists Nimesulide is used as an analgesic, antipyretic of LT receptor. They are useful in asthma and and anti-inflammatory agent for short other inflammatory conditions. periods as in headache, toothache, myalgia, Adverse effects Dyspepsia, diarrhoea and dysmenorrhoea, sinusitis, postoperative pain headache. Drugs Used in Rheumatoid Arthritis and Gout 185

Drugs Used 28 in Rheumatoid Arthritis and Gout

RHEUMATOID ARTHRITIS Disease modifying drugs (DMDs) are also called disease modifying anti-rheumatic drugs Rheumatoid arthritis (RA) is a chronic, (DMARDs). These are the second line drugs progressive, autoimmune, inflammatory and are reserved for patients with disease, mainly affecting the joints and the progressive disease who do not obtain periarticular tissues. The antigen-antibody satisfactory relief from NSAIDs. They are complexes trigger the pathological process. capable of arresting the progress of the Mediators of inflammation released in the joints initiate the inflammatory process. The disease and inducing remission in these earliest lesion is vasculitis, followed by patients. The effects of these drugs may take synovial oedema and infiltration with 6 weeks to 6 months to become evident and inflammatory cells. There is local synthesis are therefore called slow-acting anti- of prostaglandins and leukotrienes. rheumatic drugs (SAARDs). Prostaglandins cause vasodilation and pain. Gold salts were introduced for the treatment The inflammatory cells release lysosomal of RA in 1920s. They are considered to be enzymes which cause damage to bones and the most effective agents for arresting the cartilage. disease process. Drugs used in the treatment of rheumatoid arthritis On treatment, a gradual reduction of the 1. NSAIDs signs and symptoms are seen. It brings about 2. Disease modifying agents a decrease in the rheumatoid factor and Gold, d-penicillamine, chloroquine and immunoglobulins. hydroxychloroquine, sulphasalazine, TNF Mechanism of action is not exactly known - but blocking drugs gold depresses cell-mediated immunity 3. Immunosuppressants (CMI). Gold salts concentrate in tissues rich Methotrexate, cyclophosphamide, in mononuclear phagocytes, selectively azathioprine, leflunomide accumulate in the lysosomes of synovial cells 4. Adjuvants and other macrophages in the inflamed Glucocorticoids synovium. They alter the structure and Nonsteroidal anti-inflammatory drugs are the functions of the macrophages, depress their first line drugs in RA. NSAIDs afford migration and phagocytic activity. They also symptomatic relief but do not modify the inhibit lysosomal enzyme activity. Thus gold course of the disease. salts depress CMI. 186 Textbook of Pharmacology for Dental and Allied Health Sciences

Preparations Aurothiomalate sodium and preferred. It is used as an alternative to gold auronofin are given orally. Aurothioglucose in early, mild and non-erosive disease. is given parenterally. Adverse effects include drug fever, skin rashes, Adverse effects Treatment with gold is proteinuria, leucopenia, thrombocytopenia, associated with several adverse effects and aplastic anaemia, a variety of autoimmune only 60% of patients remain on treatment at diseases including lupus erythematosus, the end of 2 years. thyroiditis and haemolytic anaemia. Anorexia, Adverse effects include: nausea, vomiting, loss of taste perception and 1. On skin and mucous membrane Dermatitis, alopecia may also be seen. pruritus, stomatitis, pharyngitis, glossitis, Chloroquine and hydroxychloroquine These gastritis, colitis and vaginitis. A grey blue antimalarial drugs are found to be useful in pigmentation on exposed parts of the skin mild non-erosive rheumatoid arthritis. They may be seen. induce remission in 50% of patients. They are 2. Renal toxicity Haematuria, glomerulo- less effective but are better tolerated than gold. nephritis. Mechanism of action is not exactly 3. Nervous system Encephalitis, peripheral understood but they are known to depress neuritis. cell-mediated immunity. 4. Liver Hepatitis, cholestatic jaundice. Toxicity Chloroquine and hydroxy- 5. Blood Thrombocytopenia, leukopenia, chloroquine accumulate in tissues leading to agranulocytosis, aplastic anaemia. 6. CVS Postural hypotension. toxicity. The most significant side effect is 7. Lungs Pulmonary fibrosis. the retinal damage on long-term use. This toxicity is less common and reversible with Contraindications Kidney, liver and skin hydroxychloroquine which is therefore diseases; pregnancy and blood dyscrasias. preferred over chloroquine in rheumatoid Uses arthritis. Every 3 months eyes should be tested. Other adverse effects include 1. Rheumatoid arthritis–gold is used in active myopathy, neuropathy and irritable bowel arthritis that progresses despite an syndrome. adequate course of NSAIDs, rest and Sulphasalazine is a compound of sulpha- physiotherapy. In most patients gold salts pyridine and 5-amino salicylic acid. In arrest the progression of the disease, the colon, sulphasalazine is split by the improve grip strength, reduce morning bacterial action and sulphapyridine gets stiffness and prevent involvement of absorbed. This has anti-inflammatory actions unaffected joints. though the mechanism is not known. Adverse Gold is also beneficial in: effects include gastrointestinal upset and skin 2. Juvenile rheumatoid arthritis rashes. 3. Psoriatic arthritis 4. Pemphigus TNF Blocking Agents 5. Lupus erythematosus. d-penicillamine is an analog of the amino acid Cytokines, particularly tumour necrosis cysteine and a metabolite of penicillin. It is a factor (TNF) play an important role in the chelating agent that chelates copper. Its process of inflammation. TNF produced by actions and toxicities are similar to gold but macrophages and activated T cells, acts is less effective than gold. Hence it is not through TNF receptors to stimulate the Drugs Used in Rheumatoid Arthritis and Gout 187 release of other cytokines. TNF blocking progress of the disease. However, long-term drugs are found to be useful in rheumatoid use of these drugs leads to several adverse arthritis. effects. Moreover, on withdrawal of gluco- Infliximab is a monoclonal antibody which corticoids, there may be an exacerbation of specifically binds to human TNF. When given the disease. Therefore glucocorticoids are in combination with methotrexate, it slows used as adjuvants. They may be used to treat the progression of rheumatoid arthritis. exacerbations. Low dose long-term treatment Adverse effects of the combination include with prednisolone is used in some patients increased susceptibility to upper respiratory (5-10 mg/day). infections, nausea, headache, cough, sinusitis Intra-articular corticosteroids are helpful and skin rashes. to relieve pain in severely inflamed joints. Etanercept is a recombinant fusion protein that binds to TNF molecules. It is found to slow Diet and Inflammation the progression of the disease in rheumatoid Clinical studies have shown that when arthritis patients. It is also found to be useful patients of rheumatoid arthritis are given a in psoriatic and juvenile arthritis. Etanercept diet rich in unsaturated fatty acids (such as is also given with methotrexate and the marine fish), there is a decrease in morning combination has a higher efficacy. It can stiffness, pain and swelling of the joints. cause pain, itching and allergic reactions at Unsaturated fatty acids compete with the site of injection. arachidonic acid for uptake and metabolism. Immunosuppressants are reserved for patients Many products of arachidonic acid meta- with seriously crippling disease with bolism are mediators of inflammation. reversible lesions after conventional therapy Adequate consumption of marine fish should has failed. Among the immunosuppressants, be recommended. For people who do not eat methotrexate (see page 330) is the best fish, eicosapentaenoic acid 1-4 gm/day may tolerated. Weekly regimens of low oral doses be given as tablets. It serves as an adjuvant. are given. Leflunomide is a prodrug. The active Relevance in Dentistry metabolite inhibits autoimmune T cell 1. Treatment with gold can cause glossitis. proliferation and production of auto- 2. Gold, d-penicillamine, immunosupp- antibodies by B cells. Leflunomide is orally ressants and glucocorticoids depress effective, and has a long t½ of 5-40 days. immunity. Treatment of dental infection Adverse effects include diarrhoea and raised requires powerful antibiotics in such hepatic enzymes. patients. Leflunomide is used with methotrexate in rheumatoid arthritis patients who do not PHARMACOTHERAPY OF GOUT respond to methotrexate alone. Gout is a familial metabolic disorder chara- Corticosteroids cterised by recurrent episodes of acute arthritis due to deposits of monosodium urate Glucocorticoids (chap-55) have anti- in the joints and cartilage. There is an inflammatory and immunosuppressant inherent abnormality of purine metabolism activity. They produce prompt and dramatic resulting in over production of uric acid—a relief of symptoms but do not arrest the major end product of purine metabolism. As 188 Textbook of Pharmacology for Dental and Allied Health Sciences uric acid is poorly water soluble, it gets Adverse effects are dose related. Nausea, precipitated—especially at low pH and is vomiting, diarrhoea and abdominal pain are deposited in the cartilages of joints and ears, the earliest side effects and may be avoided subcutaneous tissues, bursae and sometimes by giving colchicine intravenously. Anaemia, in kidneys. An acute attack of gout occurs as leukopenia and alopecia may be seen. In high an inflammatory reaction to crystals of doses haemorrhagic gastroenteritis, sodium urate deposited in the joint tissue. nephrotoxicity, CNS depression, muscular There is infiltration of granulocytes which paralysis and respiratory failure can occur. phagocytize the urate crystals and release a glycoprotein that causes joint destruction. Uses The joint becomes red, swollen, tender and 1. Acute gout—colchicine 1 mg orally initially extremely painful. followed by 0.5 mg every 2-3 hours Secondary hyperuricaemia may be drug relieves pain and swelling within 12 hours. induced or may occur in lymphomas and But diarrhoea limits its use. leukaemias. Gout may also be due to 2. Prophylaxis—Colchicine may also be used decreased excretion of uric acid. for the prophylaxis of recurrent episodes Strategies in the treatment of gout is either of gouty arthritis. to decrease the biosynthesis of uric acid or enhance the excretion of uric acid. NSAIDs afford symptomatic relief in the treatment of gout. Indomethacin is the most Drugs Used in Gout commonly used agent in acute gout. Piroxicam, naproxen and other newer In acute gout: NSAIDs are also used. They relieve an acute Colchicine, NSAIDs. attack in 12-24 hours and are better tolerated In chronic gout: than colchicine. But NSAIDs are not Uric acid synthesis inhibitor recommended for long-term use due to their Allopurinol toxicity. Uricosuric drugs Allopurinol is an analog of hypoxanthine and Probenecid, sulphinpyrazone, inhibits the biosynthesis of uric acid. benzbromarone. Mechanism of action Purine nucleotides are Colchicine is an alkaloid of Colchicum degraded to hypoxanthine. Uric acid is autumnale. It is a unique anti-inflammatory produced as shown in Figure 28.1. agent effective only against gouty arthritis. Allopurinol and its metabolite alloxanthine It is not an analgesic. both inhibit the enzyme xanthine oxidase and Actions In gout, colchicine is highly effective thereby prevent the synthesis of uric acid. The in acute attacks and it dramatically relieves plasma concentration of uric acid is reduced. pain within a few hours. It increases gut Pharmacokinetics Allopurinol is 80% absorbed motility by neurogenic stimulation. orally; t½ of allopurinol is 2-3 hr; t½ of Mechanism of action Colchicine inhibits the alloxanthine is 24 hours. migration of granulocytes into the inflamed Adverse effects are mild. Hypersensitivity area and the release of glycoprotein by them. reactions include fever and rashes. Colchicine binds to micro-tubules and arrests Gastrointestinal irritation, headache, nausea cell division in metaphase. and dizziness may occur. Pharmacokinetics Colchicine is rapidly Attacks of acute gouty arthritis may be seen absorbed orally, metabolised in the liver and frequently during the initial months of undergoes enterohepatic circulation. treatment with allopurinol. Drugs Used in Rheumatoid Arthritis and Gout 189

Fig. 28.1: Biosynthesis of uric acid

Drug interactions The anticancer drugs—6- secretion of penicillin in order to prolong its mercaptopurine and azathioprine are action. metabolised by xanthine oxidase. Hence Probenecid blocks tubular reabsorption of when allopurinol is used concurrently, the uric acid and thereby promotes its excretion. dose of these anticancer drugs should be It is well-absorbed and well-tolerated. reduced. Adverse effects include gastrointestinal Uses Allopurinol is used in chronic gout and irritation and skin rashes. Large amounts of secondary hyperuricaemia. Initial dose is water should be given to prevent the 100 mg/day and may be gradually increased formation of renal stones. to 300 mg/day depending on the response. Probenecid is indicated in chronic gout and Colchicine or an NSAID should be given secondary hyperuricaemia. Probenecid may also precipitate acute attacks of gout due to during the first few weeks of allopurinol fluctuating urate levels. therapy to prevent the acute attacks of gouty Sulphinpyrazone a pyrazolone derivative is arthritis. On treatment with allopurinol, tophi another uricosuric drug which has actions and are gradually resorbed and the formation of adverse effects similar to probenecid. It is renal stones are prevented. In patients with used in chronic gout. large tophaceous deposits, both allopurinol Benzbromarone is a potent uricosuric drug and uricosuric drugs can be given. which acts by inhibiting renal tubular Uricosuric Drugs reabsorption of uric acid. It is used as an alternative in patients allergic to other drugs. Probenecid is an organic acid which was Benzbromarone can also be used in developed to inhibit the renal tubular combination with allopurinol. 190 Textbook of Pharmacology for Dental and Allied Health Sciences

29 Drugs Used in Psychiatric Disorders

ANTIPSYCHOTICS (ii) Functional or idiopathic disorders–where there is no definable cause like in Since ages man has sought the help of drugs schizophrenia, paranoia and affective to modify behaviour, mood and emotion. disorders. Psychoactive drugs were used both for Schizophrenia (split mind) affects about 1% of recreational purposes and for the treatment population, starts at an early age and is highly of mental illnesses (Psyche = mind). incapacitating. It has a strong heriditary In 1931 Sen and Bose showed that Rawolfia tendency and is characterised by delusions, serpentina is useful in the treatment of hallucinations, irrational conclusions, insanity. Electroconvulsive therapy (ECT) interpretations and withdrawal from social was introduced in 1937 for the treatment of contacts. Symptoms are grouped as positive depression. In 1950 chlorpromazine was and negative.Positive symptoms include synthesized in France and its usefulness in delusions, hallucinations and disorders of psychiatric patients was demonstrated in thought while negative symptoms include poor 1952. During the second half of the twentieth concentration, social withdrawal, poverty of century, extensive research has been carried speech and lack of initiative and energy. out in psychopharmacology and we now have Negative symptoms generally indicate poor prognosis and these symptoms do not several useful drugs in this branch of respond to antipsychotic drugs. Patients with pharmacology. chronic schizophrenia have progressive Psychiatric conditions are broadly divided shrinkage of the brain. into psychoses, neuroses and personality The pathology is not exactly understood but disorders. available evidence suggest overactivity of the Psychoses are the more severe psychiatric neurotransmitters—mainly dopamine and disorders of the three and involve a marked probably others including glutamate and 5-HT. impairment of behaviour, inability to think Neuroses are the milder forms of psychiatric coherently, and to comprehend reality. disorders and include anxiety, mood Patients have no ‘insight’ into these changes, panic disorders, obsessions, abnormalities. irrational fears and reactive depression as Psychoses could be due to: seen following tragedies. (i) An organic cause, i.e. there is a definable Personality disorders include paranoid, toxic, metabolic or pathological change– schizoid, histrionic, avoidant, antisocial and as following head injury. obsessive compulsive personality types. Drugs Used in Psychiatric Disorders 191

Drugs used in psychiatric illnesses may be grouped CNS (Fig. 29.1). Since dopaminergic as: overactivity, mainly in the limbic area, is 1. Antipsychotics or neuroleptics – used in thought to be responsible for schizophrenia, psychoses. DA receptor blockade helps. Some of them Antidepressant drugs 2. – used in affective like phenothiazines also block D1, D3, and D4 disorders. receptors. (There are 5 subtypes of dopamine 3. Antianxiety drugs receptors D1 to D5). Dopamine receptor Psychotropic drugs are drugs used in mental blockade also is responsible for the classical illnesses - they are drugs capable of affecting side effects of these agents. the mind, emotions and behaviour. Neuroleptic is a drug that reduces initiative, Pharmacological Actions brings about emotional quietening and induces drowsiness. Tranquilliser is a drug that brings CNS Behavioural effects–in normal subjects about tranquillity by calming, soothing and CPZ reduces motor activity, produces quietening effects. This is the older terminology. drowsiness and indifference to surroundings. Neuroleptics or antipsychotics were called In psychotic agitated patients, it reduces ‘major tranquillisers’ and antianxiety drugs were aggression, initiative and motor activity, called ‘minor tranquillisers’. These terminologies relieves anxiety and brings about emotional are no longer used. quietening and drowsiness. It normalises the sleep disturbances characteristic of psychoses. ANTIPSYCHOTICS (NEUROLEPTICS) Other CNS Actions Classification 1. Cortex CPZ lowers seizure threshold and 1. Classical/typical neuroleptics can precipitate convulsions in untreated a. Phenothiazines– epileptics. Chlorpromazine, triflupromazine, 2. Hypothalamus CPZ decreases gonado- thioridazine, mesoridazine, trophin secretion and may result in trifluoperazine, fluphenazine. amenorrhoea in women. It increases the b. Butyrophenones– secretion of prolactin resulting in Haloperidol, droperidol, galactorrhoea and gynaecomastia. trifluperidol, penfluridol. 3. Basal ganglia CPZ acts as a dopamine c. Thioxanthenes– antagonist and therefore results in Thiothixene, chlorprothixene, extrapyramidal motor symptoms (drug flupenthixol induced parkinsonism). 2. Atypical neuroleptics– 4. Brainstem Vasomotor reflexes are Clozapine, olanzapine, depressed leading to a fall in BP. risperidone, quetiapine, 5. CTZ Neuroleptics block the dopamine ziprasidone, amisulpride, (DA) receptors in the CTZ and thereby remoxipride. act as antiemetics. 3. Miscellaneous– Autonomic nervous system The actions on the Reserpine, loxapine, ANS are complex. CPZ is an alpha blocker. pimozide. The alpha blocking potency varies with each neuroleptic. CPZ also has anticholinergic Chlorpromazine (CPZ) properties which leads to side effects like Mechanism of action– Typical neuroleptics act dryness of mouth, blurred vision, reduced by blocking the dopamine D2 receptors in the sweating, decreased gastric motility, 192 Textbook of Pharmacology for Dental and Allied Health Sciences

Fig. 29.1: Mechanism of action of neuroleptics. Neuroleptics block the dopamine D2 receptors and act as antipsychotics constipation and urinary retention. The dry mouth, constipation, nasal stuffiness degree of anticholinergic activity also varies and urinary retention result from blockade with each drug. of α adrenergic and muscarinic receptors. CVS Neuroleptics produce orthostatic 2. CNS effects–drowsiness and mental hypotension due to alpha blockade action and confusion are common, several reflex tachycardia. CPZ also has a direct neurological syndromes involving the myocardiac depressant effect like quinidine. extrapyramidal system are troublesome Local anaesthetic CPZ has local anaesthetic side effects. properties–but is not used for the purpose They are - since it is an irritant. Extrapyramidal Symptoms Kidney CPZ depresses ADH secretion and has (i) Acute dystonias - Facial grimacing, tics, weak diuretic effects. muscle spasms, protruding tongue and Tolerance develops to the sedative and similar involuntary movements can hypotensive actions while no tolerance is seen occur in the first few days of starting to the antipsychotic actions. antipsychotics especially the high potency ones like haloperidol. They Pharmacokinetics respond to anticholinergics. (ii) Parkinsonism - Bradykinesia, tremors CPZ is incompletely absorbed following oral and rigidity including the typical administration and also undergoes significant parkinsonian face' may be noticed in the first pass metabolism (bioavailability is 30%). first few weeks. It responds to It is highly protein bound; has a t½ of 20 to anticholinergic antiparkinsonian drugs. 24 hr and is therefore given once a day. (iii) Perioral tremors - also called ‘rabbit syndrome’ may occur after several Adverse Reactions months of antipsychotic therapy, Antipsychotics have a high therapeutic index Anticholinergics are useful. and are fairly safe drugs. (iv) Akathesia–is a feeling of intense 1. Cardiovascular and autonomic effects–postural discomfort which compels the person hypotension, palpitation, blurred vision, to be continuously moving, like - Drugs Used in Psychiatric Disorders 193

constant walking. It necessitates a syndromes like delirium and dementia all reduction in antipsychotic dosage and respond to antipsychotics. treatment with propranolol or other 2. Nausea, vomiting CPZ is a good antiemetic antianxiety drugs. and is used in vomiting due to radiation (v) Tardive dyskinesia–appears after months sickness and drug induced vomiting. or years of therapy and is characterised 3. Hiccough CPZ can control intractable by involuntary movements of the face, hiccough though the mechanism of action tongue, eyelids, trunk and limbs. It can is not known. be disabling. Atypical antipsychotics 4. Other neuropsychiatric syndromes Neuro- like clozapine may be beneficial in such leptics are useful in the treatment of patients. several syndromes with psychiatric (vi) Malignant neuroleptic syndrome is features like psychoses associated with characterised by immobility, tremors chronic alcoholism, Huntington’s disease and fever with autonomic effects like and Gilles de La Tourette’s syndrome. fluctuating blood pressure and heart Haloperidol is a potent antipsychotic with rate. It can be fatal and requires actions similar to chlorpromazine. It differs immediate stopping of the neuroleptic. from chlorpromazine in that it has lesser Dantrolene and bromocriptine may be incidence of autonomic side effects and is useful. therefore preferred in older patients. 3. Endocrine disturbances–gynaecomastia, Haloperidol is useful in acute schizo- amenorrhoea and galactorrhoea due to phrenia, and is the drug of choice in Gilles DA receptor blockade. de la Tourette’s syndrome and Huntington's 4. Hypersensitivity reactions–jaundice, disease. agranulocytosis and skin rashes. Atypical Antipsychotics Drug Interactions The newer atypical antipsychotics like Neuroleptics enhance the sedative effects of clozapine and others have the advantages of CNS depressants, alpha blockers and of 1. Causing fewer side effects like less anticholinergic drugs. When combined with sedation these groups of drugs, the effects may be 2. Being effective in suppressing both additive. positive and negative symptoms of Neuroleptics antagonise the actions of schizophrenia dopamine agonists and levodopa. 3. Effective in resistant cases of psychoses. Clozapine is an effective antipsychotic. It Uses blocks the dopamine D1 and D4 receptors but

Neuroleptics are given orally. (Table 29.1). has low affinity for D2 receptors. Hence it In acute psychosis they may be given has very low incidence of extrapyramidal side α intramuscularly and response is seen in 24 hr effects (EPS). Clozapine also blocks 5-HT2, while in chronic psychosis it takes 2-3 weeks adrenergic and muscarinic receptors. of treatment to demonstrate the beginning Clozapine has the following advantages over of obvious response. conventional antipsychotics: 1. Psychiatric conditions Psychoses including 1. Very low incidence of EPS schizophrenia and organic brain 2. Sedation is low. 194 Textbook of Pharmacology for Dental and Allied Health Sciences

3. No endocrine side effects no galac- Advantages torrhoea and gynaecomastia. 1. At low doses no EPS dysfunction. 4. It is effective in patients not responding 2. Low sedation. to conventional antipsychotics. Ziprasidone is an effective antipsychotic with Adverse effects: The most important actions and mechanism of action similar to disadvantage with clozapine is that it may risperidone. cause agranulocytosis in some patients, which Amisulpride is a potent D2 and D3 antagonist. can be fatal. Hence its use should be restricted Its actions and advantages are similar to to patients not responding to other risperidone. conventional drugs. Moreover, regular WBC Riserpine acts by depleting monoamines, i.e. counts are a must. NA and DA. It causes serious side effects Clozapine can also cause sedation, weight including depression because of which it is gain and hypotension. now not preferred as an antipsychotic. Olanzapine is similar to clozapine in actions and advantages except that, olanzapine does ANTIANXIETY DRUGS (ANXIOLYTICS) not cause agranulocytosis. Anxiety is tension or apprehension which is Quetiapine is an effective antipsychotic, a normal response to certain situations in life. similar in actions to clozapine. Drowsiness It is a universal human emotion. But when it and postural hypotension are seen. becomes excessive and disproportionate to Risperidone blocks serotonin (5HT2A) and the situation, it becomes disabling and needs dopamine (D2) receptors. It is effective against treatment. both positive and negative symptoms of Antianxiety Drugs Include schizophrenia. Benzodiazepines Diazepam, chlordiazepoxide, lorazepam, alprazolam. Table 29.1: Therapeutic dosage of commonly 5-HT agonist-antagonists used antipsychotics Buspirone, gepirone, ipsapirone. Drug Antipsychotic β-blockers dose in mg/day Propranolol. Others Chlorpromazine 100-800 Triflupromazine 50-200 Meprobamate, hydroxyzine. Thioridazine 100-400 Benzodiazepines (Chap 22) have good Trifluoperazine 2-20 antianxiety actions and are the most Fluphenazine 1-10 commonly used drugs for anxiety. They are Haloperidol 2-20 CNS depressants. Alprazolam in addition has Trifluperidol 1-8 antidepressant properties. Flupenthixol 3-15 Buspirone is an azapirone with good anxiolytic Loxapine 20-100 properties. It is a selective 5-HT1A partial Clozapine 50-300 agonist. 5-HT receptors are inhibitory Olanzapine 2.5-10 1A autoreceptors and binding of buspirone Risperidone 2-12 Pimozide 2-6 inhibits the release of 5HT. Buspirone is also Sertindol 4-24 a weak D2 antagonist. It is useful in mild to moderate anxiety. Antianxiety effect Drugs Used in Psychiatric Disorders 195 develops slowly over 2 weeks. Unlike Endogenous depression is major depression and diazepam, it is not a muscle relaxant, not an results from a biochemical abnormality in the anticonvulsant, does not produce significant brain. Deficiency of monoamine (NA, 5HT) sedation, tolerance or dependence and is not activity in the CNS is thought to be useful in panic attacks. responsible for endogenous depression. Buspirone is rapidly absorbed and Symptoms are metabolised in the liver. • Emotional symptoms - sadness, misery, Dose 5-15 mg OD or TDS. hopelessness, low self esteem, loss of Side effects are mild including headache, interest and suicidal thoughts. dizziness, nausea and rarely restlessness. • Biological symptoms - fatigue, apathy, loss Uses Buspirone is used in mild to moderate anxiety and is particularly beneficial when of libido, loss of appetite, lack of sedation is to be avoided. Ipsapirone and concentration and sleep disturbances. gepirone are similar to buspirone. Bipolar depression is characterised by alternate β-blockers (Chap 12) In patients with mania and depression. It is less common and prominent autonomic symptoms of anxiety is associated with a hereditary tendency. like tremors, palpitation and hypertension, Mania can be considered opposite of propranolol may be useful. β-blockers are depression with elation, over-enthusiasm, also useful in anxiety inducing states like over-confidence, often associated with public speaking and stage performance. irritation and aggression. They can be used as adjuvants to benzodiazepines. Drugs Used in Affective Disorders are

Others Classification Meprobamate has anxiolytic property but is not 1. Tricyclic antidepressants (TCA)– preferred now as it is less effective and Imipramine, desipramine, causes high sedation. clomipramine, amitriptyline, Hydroxyzine is an antihistaminic with nortriptyline, doxepin anxiolytic actions. But due to high sedation 2. Selective serotonin reuptake inhibitors (SSRI)– it is not preferred. Fluoxetine, fluoxamine, paroxetine, citalopram, sertraline, ANTIDEPRESSANTS 3. Monoamine oxidase (MAO) inhibitors – Affective disorders are a group of psychoses Phenelzine, tranylcypromine, associated with changes of mood, i.e. isocarboxazid, moclobemide. depression and mania. 4. Atypical antidepressants Depression is a common psychiatric disorder Trazodone, nefazodone, but the aetiology of it is not clear. venlafaxine, bupropion, mianserine, Depression could be mirtazapine, reboxetine. 1. Unipolar • Reactive Tricyclic Antidepressants • Endogenous Pharmacological Actions 2. Bipolar mood disorder or manic depressive illness. 1. CNS In normal subjects, TCA cause Reactive depression is due to stressful and dizziness, drowsiness, confusion and distressing circumstances in life. difficulty in thinking. In depressed 196 Textbook of Pharmacology for Dental and Allied Health Sciences

patients, after 2-3 weeks of treatment, Adverse Effects elevation of mood occurs; the patient Sedation, postural hypotension, tachycardia, shows more interest in the surroundings sweating and anticholinergic side effects like and the sleep pattern becomes normal. dry mouth, constipation, blurred vision and 2. CVS Postural hypotension and tachy- urinary retention are relatively common. cardia (due to blockade of α adrenergic 1 TCA may precipitate convulsions in and muscarinic receptors) can be severe epileptics; may cause hallucinations and mania in overdosage. in some patients. Many TCAs may also cause 3. ANS TCAs have anticholinergic properties weight gain due to increased appetite. and cause dry mouth, blurred vision, Acute toxicity is manifested by (mimic constipation and urinary retention. symptoms of atropine poisoning) delirium, Mechanism of Action excitement, hypotension, convulsions, fever, arrhythmias, respiratory depression and TCAs block the reuptake of amines (norad- coma. renaline or 5-HT) into the presynaptic Treatment Physostigmine is given to overcome terminal and thereby prolong their action on atropine-like effects; sodium bicarbonate for the receptors (Fig. 29.2). Thus they potentiate acidosis, phenytoin for seizures and amine neurotransmission in the CNS. arrhythmias - with other supportive measures. Pharmacokinetics Tolerance and dependence–tolerance develops TCAs are rapidly absorbed, extensively gradually to the sedative and anticholinergic protein bound and metabolised in the liver. effects over 2-3 weeks. Starting with a low They have a long t½ and can be given once dose and gradually increasing the dose daily. On prolonged administration accumu- minimises the side effects. lation can occur resulting in cumulative Following long-term treatment, TCAs toxicity. should be gradually withdrawn, because

Fig. 29.2: Mechanism of action of tricyclic antidepressants. 80% of noradrenaline released into the synaptic cleft enters into the synaptic neuron by reuptake. This reuptake is blocked by TCA Drugs Used in Psychiatric Disorders 197 withdrawal symptoms like headache, anxiety • Low cardiovascular side effects. and chills can occur due to physical • Anticholinergic side effects are negligible. dependence. • Less sedation. • Preferred in elderly because of low Drug Interactions anticholinergic effects (anticholinergic 1. Tricyclics potentiate sympathomimetics– effects like constipation and urinary even small amounts of adrenaline used retention may be troublesome in the with local anaesthetics can cause serious elderly). hypertension. • Safer in overdose (this is particularly 2. Highly protein bound drugs like advantageous in patients with depression phenytoin, aspirin and phenylbutazone who may have suicidal tendencies). displace TCAs from binding sites resulting • Due to low side effect profile, SSRIs are in toxicity. generally well accepted by patients. 3. TCAs potentiate the effects of alcohol and Adverse effects to SSRIs include nausea, other CNS depressants. vomiting, insomnia, anxiety and sexual dysfunction. Selective Serotonin Reuptake Among the SSRIs, fluoxetine is the most Inhibitors (SSRI) commonly used.

Include fluoxetine, fluoxamine, paroxetine MAO Inhibitors citalopram, and sertraline. Antidepressant actions and efficacy of SSRIs are similar to Monoamine oxidase (MAO) is an enzyme TCAs. which metabolizes NA, 5-HT and DA. Drugs Mechanism of action–SSRIs block the reuptake which inhibit this enzyme enhance the of serotonin into the serotonergic nerve neuronal levels of NA, DA and 5HT. MAO endings. Hence they enhance serotonin levels exists as two isozymes - MAOA and MAOB. in these synapses (Fig. 29.3). MAOA is selective for 5-HT. Reversible and

SSRIs have the following advantages over MAOA selective inibitors like moclobemide TCAs. are now developed. Nonselective and

Fig. 29.3: Mechanism of action of SSRIs. They block the reuptake of serotonin and improve serotonergic transmission. 198 Textbook of Pharmacology for Dental and Allied Health Sciences irreversible MAO inhibitors- phenelzine and Moclobemide is used in mild to moderate tranylcypromine are associated with several depression as an alternative to TCA. side effects and risk of many food-drug interactions. Atypical Antidepressants Tranylcypromine and Phenelzine: • Irreversibly inhibit the enzyme MAO and Atypical antidepressants include trazodone, enhance neuronal levels of noradrenaline, bupropion, mianserin, nefazodone and dopamine and 5-HT. mirtazapine. • Antidepressant actions develop slowly over weeks of treatment. Advantages • Most of them are long acting and require • Fewer side effects–particularly sedation 1-2 weeks for recovery of MAO activity and anticholinergic effects after stopping the drug. • Safer in overdose • Side effects are hypotension, weight gain, restlessness, insomnia (due to CNS • Effective in patients not responding to stimulation), anticholinergic effects and TCA. rarely liver dysfunction. Trazodone is a weak serotonin reuptake • They interact with many drugs and food. inhibitor. It is short acting (t ½ - 6 hr) and • Patients on MAO inhibitors taking lacks anticholinergic activity. It is well tyramine containing foods like cheese, tolerated and safe in overdosage. It can cause beer, wine, yeast, buttermilk and fish– postural hypotension and priapism due to its α develop severe hypertension and is 1 blocking effects. known as ‘cheese reaction.’ Tyramine is Nefazodone blocks serotonin reuptake and is normally metabolised by MAO in the gut an effective antidepressant. It is well wall. On inhibition of MAO by drugs, tolerated-causes sedation and mild postural tyramine escapes metabolism and hypotension. Nefazodone is used in the displaces NA from nerve endings leading prophylaxis of recurrent depression. to hypertension. Venlafaxine is considered by some as atypial • Similar interaction with SSRIs can result antidepressant because it inhibits the in severe hypertension (serotonin syndrome). reuptake of noradrenaline in addition to 5 • Because of the side effects and drug HT (Serotonin and noradrenaline reuptake interactions, MAO inhibitors are not the inhibitor - SNRI). It is thought to be faster preferred antidepressants. acting and may be useful in patients not responding to other antidepressants. Moclobemide is a reversible, competitive, Mirtazapine blocks 5HT , 5HT and α selective MAO inhibitor. It is short acting 2 3 2 A receptors and enhances the release of NA and and MAO activity recovers within 1-2 days 5HT. It is faster acting - action starts by one after stopping the drug. It is found to be an effective antidepressant and has the week of treatment. It causes sedation but advantages that it is not a sedative, does not other side effects are negligible. produce cardiovascular and anticholinergic Bupropion is a weak DA reuptake inhibitor side effects. Hence it is well tolerated. No and has CNS stimulant effects. It is used in significant drug interactions are seen. depression with anxiety. Bupropion is also Adverse effects include nausea, insomnia, used to help stop smoking (along with headache and dizziness. nicotine patch). Drugs Used in Psychiatric Disorders 199 α Mianserin acts by blocking presynaptic 2 Lithium is a monovalent cation. On receptors but toxicity including blood prophylactic use in bipolar mood disorder dyscrasias, seizures and liver damage has (manic-depressive illness), lithium acts as a limited its use. mood stabilizer. It prevents swings of mood and thus reduces both the depressive and Uses of Antidepressants manic phases of the illness. Given in acute mania, it gradually suppresses the episode 1. Endogenous depression Antidepressants are over weeks. used over a long period. The response Mechanism of action of lithium is complex and appears after 2-3 weeks of treatment. The not fully understood. It is thought that choice of drug depends on the side effects lithium blocks the formation of inositol from and patient factors like age. In severe IP and thereby inhibits the regeneration of depression with suicidal tendencies, 3 phosphotidyl inositol (PI) Depletion of electroconvulsive therapy (ECT) is given. membrane phosphotidyl inositol results in 2. Panic attacks, Post-traumatic stress disorders inhibition of receptor mediated effects and other anxiety disorders–all respond through IP3 and DAG. This is the accepted to antidepressants (acute episodes of mechanism of action. anxiety are known as panic attacks). Pharmacokinetics Lithium is a small ion and 3. Obsessive compulsive disorders SSRIs and mimics the role of sodium in excitable tissues. clomipramine are effective. Given orally it is well-absorbed. It is filtered 4. Nocturnal enuresis in children may be at the glomerulus but reabsorbed like treated with antidepressants only when sodium. Steady state concentration is reached other measures fail and drugs are in 5-6 days. Lithium is secreted in sweat, indicated. saliva and breast milk. Since safety margin is 5. Psychosomatic disorders Newer antide- narrow, plasma lithium concentration needs to pressants are tried in fibromyalgia, be monitored (0.5-1 mEq/lit is the therapeutic irritable bowel syndrome, chronic fatigue, plasma concentration). 3-5 mEq/lit can cause tics, migraine and sleep apnoea. fatal toxicity. 6. Other indications Attention deficit Adverse effects Lithium is a drug of low hyperactivity disorder, chronic pain and therapeutic index and side effects are chronic alcoholism–may result in common. Nausea, vomiting, mild diarrhoea, depression–antidepressants are tried. thirst and polyuria occur initially in most MOOD STABILIZERS patients. Weight gain can also occur. As the plasma concentration rises, hypothyroidism, Mood stabilzers control the mood swings CNS effects like coarse tremors, drowsiness, that are seen in bipolar mood disorders. giddiness, confusion, ataxia, blurred vision Mood stablizers include– and nystagmus are seen. In severe Lithium overdosage, delirium, muscle twitchings, Sodium valproate convulsions, arrhythmias and renal failure Carbamazepine develop. Lamotrigine Gabapentin Precautions Lithium has been used for several decades but several antiepileptics like carbamazepine, 1. Minimum effective dose should be used. valproic acid and gabapentin are now being 2. Patients should always use the same tried. formulation. 200 Textbook of Pharmacology for Dental and Allied Health Sciences

3. Patients should be made aware of the first 4. Other uses – Lithium is tried in recurrent symptom of toxicity. neuropsychiatric disorders, childhood 4. Lithium is contraindicated in pregnancy. mood disorders, hyperthyroidism and inappropriate ADH secretion syndrome. Drug Interactions Other Mood Stabilizers 1. Diuretics enhance sodium loss and lithium absorption from the kidney. This Because of difficulty in using lithium, other increases plasma lithium levels resulting drugs are being tried. The antiepileptics in toxicity. carbamazepine, sodium valproate and 2. NSAIDs reduce lithium elimination and gabapentin are found to be useful, less toxic alternatives (see Chap 24). enhance toxicity. Carbamazepine is found to be effective in preventing the relapses of bipolor mood Uses disorder and in the treatment of acute 1. Prophylaxis of bipolar mood disorder– mania. It can be combined with lithium for episodes of mania and depression and better therapeutic effects but lithium can their severity are reduced. enhance the toxicity of carbamazepine. 2. Acute mania – since the response to lithium Sodium valproate can be tried alone in mild to moderate cases or along with lithium in is slow, neuroleptics are preferred. refractory cases. 3. Depression – Lithium is tried along with Lamotrigine, gabapentin and other newer other antidepressants as an add-on drug antiepileptics are being tried in the in the treatment of severe recurrent prophylaxis of bipolar mood disorder as depression. alternatives to lithium. CNS Stimulants 200 30 CNS Stimulants

Drugs that have a predominantly stimulant Psychomotor stimulants Amphetamine and effect on the CNS may be broadly divided dextroamphetamine are sympathomimetic into: drugs (Chapter 11). 1. Respiratory stimulants Cocaine is a CNS stimulant, produces euphoria Doxapram, nikethamide and is a drug of abuse (Page 133). 2. Psychomotor stimulants Methylxanthines Caffeine, theophylline and Amphetamine, cocaine theobromine are the naturally occurring methylxanthines xanthine alkaloids. The beverages—coffee 3. Convulsants contains caffeine; tea contains theophylline Leptazol, strychnine. and caffeine; cocoa has caffeine and Respiratory stimulants are also called analeptics. theobromine. These drugs stimulate respiration and are sometimes used to treat respiratory failure. Actions Though they may bring about temporary improvement in respiration, the mortality is CNS Caffeine and theophylline are CNS not reduced. They have a low safety margin stimulants. They bring about an increase in and may produce convulsions. mental alertness, a reduction of fatigue, Doxapram appears to act mainly on the produce a sense of well being and improve brainstem and spinal cord and increase the motor activity and performance with a clearer activity of respiratory and vasomotor flow of thought. Caffeine stimulates the centres. respiratory centre. Higher doses produce Adverse effects are nausea, cough, irritability, nervousness, restlessness, restlessness, hypertension, tachycardia, insomnia, excitement and headache. High arrhythmias and convulsions. doses can result in convulsions. CVS Methylxanthines increase the force of Uses contraction of the myocardium and increase 1. Doxapram is occasionally used IV as an the heart rate and therefore increase the analeptic in acute respiratory failure. cardiac output. But, they also produce 2. Apnoea in premature infants not peripheral vasodilatation which tends to responding to theophylline. decrease the BP. The changes in BP are Nikethamide is not used because of the risk of therefore not consistent. Caffeine causes convulsions. vasoconstriction of cerebral blood vessels. 202 Textbook of Pharmacology for Dental and Allied Health Sciences

Kidneys The xanthines have a diuretic effect with ergotamine for the relief of migraine and thereby increase the urine output. headache. Caffeine is also combined with Smooth muscle Xanthines cause relaxation of aspirin/paracetamol for the treatment of smooth muscles especially the bronchial headache. smooth muscle (Page 218). (ii) Bronchial asthma Theophylline is used in Skeletal muscle Xanthines enhance the power the treatment of bronchial asthma. of muscle contraction and thereby increase the capacity to do muscular work by both a NOOTROPICS central stimulant effect and the peripheral Nootropics are drugs that improve memory actions. and cognition. They are also called cognition GI tract Xanthines increase the secretion of enhancers. acid and pepsin in the stomach and are gastric Piracetam – described as a ‘nootropic agent’ irritants. is thought to protect cerebral cortex from Adverse effects include nervousness, insomnia, hypoxia and improve learning and memory. tremors, tachycardia, hypotension, arrhy- In higher doses it also inhibits platelet thmias, headache, gastritis, nausea, vomiting, aggregation. Adverse effects include inso- epigastric pain and diuresis. High doses mnia, weight-gain, nervousness, depression produce convulsions. Tolerance develops and gastrointestinal disturbances. after sometime. Habituation to caffeine is Piracetam has been tried in dementia, common. myoclonus, stroke and other cerebrovascular accidents; alcoholism, behavioural disorders Uses and learning problems in children and in (i) Headache Because of the effect of caffeine vertigo. The beneficial effects in all these are on cerebral blood vessels, it is combined not proved. Section 6 Autacoids 31 Autacoids

Autacoids are substances formed in various serves as a neurotransmitter. Degranulation tissues, have complex physiologic and of the mast cells release histamine which is pathologic actions and act locally at the site quickly degraded by deamination and of synthesis. They have a brief action and methylation. are destroyed locally. Hence they are called ‘local hormones’ and differ from true Mechanism of Action hormones which are produced by specific Histamine produces its effects by acting on cells and reach their target tissues through the histamine receptors. Three subtypes are circulation. The word autacoid is derived known. from Greek: autos = self akos = remedy. •H1—present in lungs, gut, blood vessels, nerve endings and brain. Autacoids Include (Fig. 31.1) •H2—stomach (gastric glands), heart, blood Histamine, 5-hydroxytryptamine vessels and brain. Angiotensin, kinins, •H3—CNS. Prostaglandins, leukotrienes, platelet activating factor. Actions 1. CVS Histamine dilates small blood vessels HISTAMINE resulting in hypotension accompanied by reflex Histamine or tissue amine (Histos = tissue) is tachycardia. Cerebral blood vessels dilate a biogenic amine formed in many tissues. It which causes severe throbbing headache. is also found in the venoms of bees, wasps Triple response Intradermal injection of his- and other stinging secretions. tamine elicits triple response comprising of: (i) red spot at the site (flush) - due to local Synthesis, Storage, Distribution and capillary dilation. Degradation (ii) flare - redness surrounding the ‘flush’ due to arteriolar dilatation. In humans, histamine is formed by the (iii) wheal - local oedema due to the escape decarboxylation of the amino acid histidine. of fluid from the capillaries. Large amounts are found in the lungs, skin This response is accompanied by pain and and intestines. It is stored in the granules of itching. the mast cells and basophils in an inactive 2. Smooth muscle Histamine causes contr- form. Non-mast cell histamine found in brain, action of the nonvascular smooth muscles. 204 Textbook of Pharmacology for Dental and Allied Health Sciences

Fig. 31.1: Some autacoids with examples of agonists and antagonists, Receptor types are given in brackets

Thus bronchospasm and increased intestinal 1. Testing gastric acid secretion To test the acid motility are produced. secreting ability of the stomach. But now Actions on other visceral smooth muscles pentagastrin is preferred for this purpose. like uterus are insignificant in humans. 2. Diagnosis of pheochromocytoma Histamine 3. Glands Histamine is a powerful stimulant releases catecholamines and rises BP— of the gastric acid secretion-acts through H2 now not used. receptors (see page 239). It also stimulates 3. Pulmonary function To test for bronchial pepsin and intrinsic factor secretion. hyperreactivity. 4. CNS Histamine functions as a neurotransmitter in the CNS. Histamine Substitutes 5. Nerve endings Histamine stimulates sensory nerve endings causing pain and itching. Betazole is a H2 agonist and can be used in

Adverse reactions include hypotension, gastric function tests. Betahistine is a H1 flushing, tachycardia, headache, wheal, agonist used to control vertigo in Meniere’s bronchospasm and diarrhoea. disease.

Uses ANTIHISTAMINES Histamine is of no therapeutic value. It is Histamine antagonists can be H1 receptor occasionally used in some diagnostic tests like. blockers and H2 receptor blockers. Autacoids 205

Drugs that competitively block H1 5. Anticholinergic actions Many of the H1 histamine receptors are conventionally called blockers have anticholinergic property. the ‘antihistamines’. H2 blockers are used in This accounts for both useful and adverse the treatment of peptic ulcer Table 34.2 (Page effects. Such antihistamines have 240). antisecretory, antiemetic and antiparkinsonian effects. Classification 6. Other actions Antihistamines also have local Sedative anaesthetic effects in high doses. Some of α Diphenhydramine, dimenhydrinate, them also block 1 adrenergic and 5-HT promethazine receptors. Less sedative Pharmacokinetics Antihistamines are well- Pheniramine, chlorpheniramine, cyclizine, absorbed, widely distributed in the body, meclizine, buclizine, mepyramine, metabolised in the liver and are excreted in tripelennamine. the urine. Dose and route of administration Newer non-sedative (II generation agents) are given in Table 31.1. Terfenadine, astemizole, loratadine, Adverse reactions are mild and on continued cetirizine, fexofenadine, acrivastine, use tolerance develops. azelastine, mizolastine, levocabastine, Sedation, dizziness, motor incoordination mequitazine and inability to concentrate make driving dangerous while on antihistamines. Actions Anticholinergic effects like dryness of mouth, blurred vision, constipation and urinary 1. Blockade of actions of histamine H1 receptor antagonists block the actions of histamine retention may be troublesome. Epigastric distress, allergic reactions and headache can on H1 receptors. They block the histamine induced effects on smooth muscles of the also occur. Many of them are teratogenic. gut, bronchi, blood vessels and triple Newer non-sedative antihistamines also called II response. generation antihistamines have the following 2. Sedation Antihistamines cause CNS advantages (Table 31.2) over classical depression; sedation, dizziness, inability antihistamines: to concentrate and disturbances of • No sedation because they poorly cross the coordination are common. Alcohol and blood-brain barrier. other CNS depressants potentiate this action. Some patients may experience CNS • No anticholinergic side effects as they are pure H blockers and do not block stimulation resulting in tremors, 1 restlessness and insomnia. cholinergic receptors. 3. Antimotion sickness effects Several • Some of them like astemizole are long- antihistamines prevent motion sickness acting. and vomiting due to other labyrinthine However, the therapeutic indications of these disturbances. Some of them also control agents are limited to allergic disorders like vomiting of pregnancy. allergic rhinitis and chronic urticaria. They 4. Antiparkinsonian effects Some of them are more expensive. Terfenadine and suppress tremors, rigidity and sialorrhoea astemizole can sometimes cause torsades de probably due to their anticholinergic pointes and fatal ventricular arrhythmias; properties. erythromycin, ketoconazole and itraconazole 206 Textbook of Pharmacology for Dental and Allied Health Sciences

Table 31.1: Dose and preparations of some antihistamines

Antihistamine Dose and route Trade name

Diphenhydramine HCl 25-50 mg oral IM 10 mg BENADRYL Cap, Syr Dimenhydrinate 25-50 mg oral, IM DRAMAMINE Tab, Syr Inj Promethazine 25-50 mg oral, IM PHENERGAN Tab, Syr, Inj Promethazine chlortheophyllinate 25-75 mg oral AVOMINE Tab Pheniramine maleate 25-50 mg oral, IM AVIL Tab, Syr, Inj Chlorpheniramine 4-20 mg oral, IM ZEET Tab, Syr, Inj Cyclizine HCl 50 mg oral MAREZINE Tab Meclizine HCl 25-50 mg oral ANCOLAN Tab Buclizine 25-50 mg oral LONGIFENE Tab, Syr Cinnarizine 25-50 mg oral STUGERON Tab Nonsedative antihistamines Loratadine 10 mg oral LORFAST, Tab, Syr Cetirizine 10 mg oral ALERID, Tab, Syr Azelastine 8 mg oral SEMPRAX, Tab potentiate this cardiotoxicity. Terfenadine Though they prevent bronchospasm and astemizole are therefore withdrawn now. induced by histamine, antihistamines are Loratadine and fexofenadine appear to be not useful in bronchial asthma because free from the cardiotoxic effect. Though many other mediators are also involved considered nonsedative, cetirizine can cause in the pathogenesis of bronchial asthma. some sedation when compared to other Moreover antihistamines render the second generation agents. respiratory secretions thicker making it difficult to cough it out. Other Drugs 2. Common cold Antihistamines reduce rhinorrhoea and afford symptomatic Doxepine-A tricyclic antidepressant also relief in common cold. blocks H receptors. Hydroxyzine is a good 1 3. Motion sickness Given 30-60 minutes before antipruritic and has a long duration of action- journey, antihistamines prevent motion it is used in skin allergies- but it causes sickness - promethazine, dimenhydrinate, significant sedation. Cyproheptadine blocks meclizine and cyclizine are useful. They both H histamine and 5HT serotonin 1 2 are also useful in treating vertigo of receptors. Meniere’s disease and other vestibular Uses disturbances- dimenhydrinate, meclizine and cinnarizine are preferred. 1. Allergic reactions Antihistamines are useful 4. Antiemetic Promethazine is used to for the prevention and treatment of prevent drug induced and postoperative symptoms of allergic reactions. They are vomiting. It has also been used in effective in allergic rhinitis, conjunctivitis, ‘morning sickness.’ hayfever, urticaria, pruritus, some allergic 5. Preanaesthetic medication For the sedative, skin rashes and pollinosis. anticholinergic and antiemetic properties, Autacoids 207

promethazine has been used as pre- while arterioles dilate. A characteristic anaesthetic medication. triphasic response is seen on blood 6. Hypnotic The sedative antihistamines are pressure following IV injection. sometimes used to induce sleep. • Initial fall in BP is due to increased vagal Hydroxyzine has been used as an activity anxiolytic. • Rise in BP—due to vasoconstriction of 7. Parkinsonism Some of them are useful in large vessels, followed by drug induced parkinsonism due to their • fall in BP—due to arteriolar dilation. anticholinergic action. 2. GI tract Increases GI motility and 8. Cough due to postnasal drip can be contraction resulting in diarrhoea. controlled by antihistamines like 3. Other actions Weak bronchoconstriction, diphenhydramine. platelet aggregation; stimulation of sensory nerve endings — causes pain if 5-HYDROXYTRYPTAMINE injected into the skin. 5-HT is a 5-Hydroxytryptamine (serotonin, 5-HT) was neurotransmitter in the CNS. isolated in 1948 and has been of great Physiological and pathophysiological role 5-HT is pharmacological interest. It is found in postulated to be having a role in peristalsis, various plant and animal tissues. vomiting, platelet aggregation, homeostasis In human body, 5-HT is present in the and inflammation. It is also thought to initiate intestines, platelets and brain. It is the vasoconstriction in migraine. synthesized from the amino acid tryptophan Drugs acting on 5-HT receptors Serotonin has and is stored in granules. It is degraded no therapeutic uses. However its receptor mainly by MAO. agonists and antagonists have been used in 5-HT receptors The actions of serotonin are various conditions (Table 31.3). mediated through its receptors. Seven types Serotonin Agonists of 5-HT receptors (5-HT1-7) with further subtypes of 5-HT1, 5-HT2 and 5-HT5 receptors Sumatriptan– a 5-HT1D agonist is effective in are presently known. Many receptor- the treatment of acute migraine and cluster selective agonists and antagonists are being headache. Given orally/SC at the onset of an developed. attack, sumatriptan relieves headache and Actions also suppresses nausea and vomiting of migraine. It is short-acting. 1. CVS The action on blood vessels is Adverse effects include dizziness, altered complex. Large vessels are constricted sensations, weakness, chest discomfort and Table 31.2: Compare and contrast diphenydramine and loratadine

Features Diphenhydramine Loratadine

1. Receptors blocked H1 histamine, M1 muscarinic H1 selective 2. t½ 4–6 hrs 16–18 hrs 3. Ability to cross BBB Present Absent 4. Sedation Yes No 5. Anticholinergic effects Yes No 6. In rhinorrhoea Useful Not useful 7. Route of administration Oral and Parenteral Oral 208 Textbook of Pharmacology for Dental and Allied Health Sciences neck pain. It is contraindicated in coronary are complex. Some of them are powerful artery disease. hallucinogens, e.g. lysergic acid diethylamide (LSD). They cause stimulation of smooth Other Agonists muscles—some stimulate mainly vascular smooth muscles and others mainly uterine • Buspirone (Page 194) is a 5-HT1A agonist- antagonist used as an antianxiety agent. smooth muscles. The vasoconstrictor effect • Dexfenfluramine (Page 75) is used as an is responsible for gangrene. appetite suppressant. Adverse effects like nausea, vomiting and diarrhoea are common. Prolonged use results Serotonin Antagonists in gangrene due to persistent vasospasm.

• Cyproheptadine blocks 5-HT2, H1 histamine and cholinergic receptors. It increases Uses appetite and is used to promote weight 1. Migraine gain especially in children. It is also used 2. Postpartum haemorrhage—ergometrine is in carcinoid tumours. used for prevention and treatment • Ketanserin blocks 5-HT2 receptors and antagonises vasoconstriction and platelet Drugs Used in the Treatment of Migraine aggregation promoted by 5-HT. It is used in hypertension. Migraine is a common disorder characterised

• Ondansetron is a 5-HT3 antagonist (see by severe, throbbing, unilateral, headache page 245) used in the prevention and often associated with nausea, vomiting and treatment of vomiting. fatigue lasting for several hours. In the Many other drugs including some classical migraine, a brief ‘aura’ of visual antihistamines also block serotonin receptors. disturbances occurs prior to the headache. An attack is triggered by factors like stress, Ergot Alkaloids anxiety, excitement, food (like chocolate and Ergot alkaloids are produced by Claviceps cheese) and hormonal changes. These purpurea, a fungus that infects rye, millet and triggering factors stimulate the release of other grains. Consumption of such grains vasoactive substances from nerve endings results in ‘ergotism’ manifested as gangrene which are responsible for the events that of the hands and feet, hallucinations and follow. However the exact pathophysiology other CNS effects. Barger and Dale isolated is not understood and several hypotheses ergot alkaloids in 1906. have been put forward. Natural ergot alkaloids include ergometrine, ergotamine and ergotoxine. The Drugs Used in Acute Attacks semisynthetic derivatives are also available. Drugs should be taken at the initiation of attack. Actions • Aspirin, paracetamol or other NSAIDs are Ergot alkaloids have agonist, partial agonist effective. and antagonistic actions at 5-HT and alpha • Metoclopramide can be combined with adrenergic receptors and agonistic actions at aspirin as it is an antiemetic and also CNS dopamine receptors. Thus their actions speeds up absorption of aspirin. Autacoids 209

Table 31.3: Serotonin agonists, antagonists and their therapeutic uses

Receptor Uses Comments

Agonists

Sumatriptan 5-HT1D • Acute migraine Short-acting; may • Cluster headache need repetition of dose

Buspirone 5-HT1A (Agonist-antagonist) Anxiolytic —

Dexfenfluramine 5-HT Appetite Patients should be carefully suppressant monitored for risk of pulmonary hypertension Antagonists

Cyproheptadine 5-HT2; H1-histamine and • Appetite stimulant — muscarinic receptors • Carcinoid tumours

Ketanserin 5-HT1 and 5-HT2 Hypertension Also antagonises platelet aggregation promoted by 5-HT

Ondansetron 5-HT3 Antiemetic — Ergot alkaloids

Ergotamine 5-HT1 partial agonist/ Acute attack antagonist of migraine —

Ergometrine 5-HT1 partial agonist/ Postpartum antagonist haemorrhage —

Methysergide 5-HT2 partial agonist/ Prophylaxis of Not preferred due to antagonist migraine risk of retroperitoneal and mediastinal fibrosis

• Ergotamine given orally (or sublingual/ mg twice daily. The mechanism of action rectal when vomiting is present) is an is not exactly known. effective alternative. • Ca++ channel blockers Flunarizine may be • Sumatriptan is very effective but short- useful. It has weak Ca+ channel blocking acting. properties and is thought to be selective for the CNS. Adverse effects include Prophylaxis hypotension, flushing, drymouth, When the attacks are frequent and severe, constipation and sedation. prophylaxis is needed. Drugs used for the • Pizotifen and cyproheptadine block 5-HT and prophylaxis are: H1 histamine receptors; may be used as • β-adrenergic blockers Propranolol reduces alternatives. frequency and severity of attacks. The • Tricyclic antidepressants Amytriptyline may initial dose is 40 mg twice daily and is be tried but it is associated with many gradually increased to a maximum of 160 adverse effects, (see page. 195) 210 Textbook of Pharmacology for Dental and Allied Health Sciences

• Methysergide blocks 5-HT receptors but involved in inflammatory and pathological due to adverse effects like retroperitoneal changes. All products of COX pathway are fibrosis, it is not preferred. metabolised by oxidation and excreted in urine. EICOSANOIDS PROSTAGLANDINS AND THROMBOXANES Eicosanoids are 20-carbon (eicosa referring to the 20-carbon atoms) unsaturated fatty In 1930s it was found that human semen contains a substance that contracts uterine acids derived mainly from arachidonic acid smooth muscle. As this substance was in the cell walls. The principal eicosanoids thought to originate in the prostate, they are the prostaglandins (PG), the throm- called it ‘Prostaglandin’ but it was later boxanes (TX), and the leukotrienes (LT). found to be produced in many tissues. Biosynthesis Prostanoid receptors Eicosanoids are synthesized locally The prostanoids bring about their effects by in most tissues from arachidonic acid. acting on prostanoid receptors, which are G- The pathway for synthesis is shown in protein coupled receptors. There are five Figure. 31.2. classes of prostanoid receptors. They are- The cyclo-oxygenase (COX) pathway • DP (for PGD2) generates PGs and TXs while lipoxygenase • EP (for PGE2) (LOX) pathway generates LTs. There are 2 • FP (for PGF α) cyclo-oxygenase isozymes viz. COX-1 and 2 • IP (for PGI2) COX-2. COX-1 is present in almost all cells • TP (for TXA ) and prostanoids (PGs and TXs) obtained 2 from COX-1 mainly take part in Actions physiological functions. COX-2 is induced by inflammation in the inflammatory cells The prostanoids act on many tissues to bring and the prostanoids produced by COX-2 are about the following effects. 1. CVS Prostacyclin causes vasodilation

while TXA2 causes vasoconstriction. PGE2

and PGF2α are weak cardiac stimulants. 2. GIT Most PGs and TXs stimulate gastrointestinal smooth muscle resulting

in colic and watery diarrhoea. PGE2 inhibits gastric acid secretion and enhances mucous production. Thus they have a protective effect on gastric mucosa.

3. Airways PGE2 and PGI2 relax bronchial

smooth muscles while TXA2 and PGF2α contract them. They may have a role in the pathophysiology of bronchial asthma.

4. Platelets TXA2 induces platelet aggregation

while PGI2 inhibits platelet aggregation.

5. Uterus PGE2 and PGF2α contract human Fig. 31.2: Biosynthesis of eicosanoids uterus which is more sensitive to PGs Autacoids 211

fever, hypotension and pain due to uterine Prostaglandins contractions are common. • 20-carbon unsaturated fatty acids PG analogs used therapeutically synthesized from arachidonic acid Misoprostol PGE through cyclo-oxygenase pathway 1 Gemeprost PGE1 Rioprostil PGE • Prostacycline (PGI2) causes vasodilation 1 Alprostadil PGE while TXA causes vasoconstriction 1 2 Enprostil PGE • PGs contract g.i. and bronchial (TXA , 2 2 Dinoprostone PGE2

PGE2) smooth muscles. TXA2 induces Carboprost 15-Methyl PGF2α Latanoprost PGF α platelet aggregation (PGI2 inhibits); 2 Dinoprost PGF α PGE and PGF α contract uterus. PGs 2 2 2 Epoprostenol PGI stimulate bone turnover and sensitize 2 the nerve endings to pain Uses • Uses Abortion, facilitation of labour, cervical priming, to control post-partum 1. Gynaecological and obstetrical haemorrhage, to maintain the patency a. Abortion For I and II trimester of ductus arteriosus, for prevention of abortion and ripening of cervix during

platelet aggregation, open angle abortion, PGE2 and PGF2α are used. glaucoma and peptic ulcer. They are also used with mifepristone to ensure complete expulsion of the during pregnancy. They also soften the products of conception. cervix. Thus PGs may be involved in the b. Facilitation of labour As alternative to initiation and progression of labour. PGs oxytocics in patients with renal failure. are produced by foetal tissues during c. Cervical priming Intravaginal PGE2 is labour. PGs present in the semen may used. facilitate movement of sperms and d. Postpartum haemorrhage Intramuscular fertilization by coordinating the PGF is used as an alternative to movement of the uterus. They also play a 2α ergometrine. role in dysmenorrhoea and menorrhagia. 2. Gastrointestinal 6. Kidneys PGE and PGI cause renal 2 2 Peptic ulcer PGE (misoprostol) and PGE vasodilation and have a diuretic effect. 1 2 7. CNS PGs increase body temperature when (enprostil) are used for the prevention of administered into cerebral ventricles. peptic ulcer in patients on high dose They also induce sleep. NSAIDs. 8. Nerves PGs sensitize sensory nerve 3. Cardiovascular endings to pain and on intradermal a. Patent ductus arteriosus Patency of foetal injection cause pain. They have a role in ductus arteriosus depends on local PG the genesis of inflammation. synthesis. In neonates with some 9. Bone PGs stimulate bone resorption and congenital heart diseases, patency of formation-increase bone turnover. the ductus arteriosus is maintained 10. Some PGs lower intraocular pressure. with PGs until surgery is done. Adverse effects depend on the type of PG, dose b. To prevent platelet aggregation during and route. Diarrhoea, nausea, vomiting, haemodialysis. 212 Textbook of Pharmacology for Dental and Allied Health Sciences

4. Other uses PGs are used in pulmonary as adjuvants in bronchial asthma. They are hypertension and some peripheral all effective orally. vascular diseases. They can also be used in open angle glaucoma to lower PLATELET ACTIVATING FACTOR (PAF) intraocular pressure. PAF is an important mediator in acute and OTHER AUTACOIDS chronic, allergic and inflammatory pheno- mena. PAF is released from inflammatory cells LEUKOTRIENES on stimulation and acts on specific receptors. Leukotrienes (LT) are products of arachi- It causes local vasodilatation resulting in donic acid metabolism synthesized by the oedema, hyperalgesia and wheal formation. lipoxygenase pathway and are found in the It is a potent chemotaxin for leucocytes and a lungs, platelets, mast cells and white blood spasmogen on bronchial and intestinal smooth cells (‘Leuko’—because they are found in muscles. It is a mediator of inflammation. white cells; ‘trienes’—they contain triene system of double bonds). LTA4 is the ANGIOTENSIN precursor from which LTB , LTC , LTD , LTE 4 4 4 4 Angiotensins are peptides synthesized from and LTF4 are derived. LTC4, LTD4 and LTE4 are together known as slow reacting the precursor angiotensinogen. Angio- substances (SRS-A) of anaphylaxis. The LTs tensinogen, a circulating protein synthesized produce their effects through specific in the liver is converted sequentially to receptors. angiotensin I, angiotensin II and angiotensin III (Fig. 31.2). Angiotensin converting enzyme Actions is widely distributed in the body. It is present Leukotrienes cause vasoconstriction, increase in blood vessels, kidneys, heart, brain, lungs, vascular permeability leading to oedema, adrenals and other tissues. Angiotensin II, increase airway mucous secretion and are the most potent angiotensin acts through potent bronchiolar spasmogens. Given angiotensin receptors (AT1 and AT2) present subcutaneously they cause wheal and flare. on the tissues. Leukotrienes have a role in inflammation including rheumatoid arthritis, psoriasis and ulcerative colitis. They also contribute to bronchial hyper-responsiveness in bronchial asthma. Drugs like zileuton that inhibit lipoxygenase and thereby block the synthesis of leukotrienes are useful in the treatment of bronchial asthma and allergic rhinitis.

Leukotriene Receptor Antagonists Montelukast, zafirlukast and pranlukast block the actions of LTC4 and LTD4 on the bronchial and vascular smooth muscles. They are useful Fig. 31.3: Synthesis and metabolism of angiotensins Autacoids 213

Actions Actions Angiotensin II causes vasoconstriction Kinins are potent vasodilators and cause a resulting in increased blood pressure. It brief fall in BP. They stimulate contraction stimulates the synthesis of aldosterone by of other smooth muscles — thus they induce the adrenal cortex, increases sodium reabs- bronchospasm in asthmatics, slow contr- orption by the kidneys and increases the action of intestines (Brady= slow) and uterus. secretion of vasopressin. Angiotensin II also Kinins mediate inflammation, and stimulate the pain nerve endings. Kinins produce their promotes the growth of vascular and cardiac actions by acting through B and B muscle cells and may play a role in the 1 2 receptors. development of cardiac hypertrophy as in Drugs affecting the kallikrein-kinin hypertension. By these actions, renin- system—B1 and B2 antagonists are now being angiotensin system regulates the fluid and developed. electrolyte balance as well as blood pressure. CYTOKINES Inhibitors of ACE and blockers of Cytokines are also considered as autacoids. angiotensin II receptors are now used in They are peptides released from the the treatment of hypertension, congestive inflammatory cells. They are classified into 5 heart failure and other conditions that are due families. to excess of angiotensin II activity (see • Interleukins Section 4). • Colony stimulating factors • Chemokines KININS • Growth factor and tumour necrosis factors Kinins are vasodilator peptides formed from • Interferons the precursor kininogen by the action of the Cytokines stimulate specific receptors to bring about their effects. IL-1 and TNF - α enzymes called kallikreins. Kallikreins are are involved in inflammation - they are pro- present in the plasma, kidneys, pancreas, inflammatory cytokines while IL-4, IL-10 and intestines, salivary glands and other tissues. IL-13 inhibit inflammatory activity - they are Bradykinin is the chief kinin. anti-inflammatory cytokines. The interferons Kinins are rapidly degraded by kininase α and β have antiviral activity while II which is same as ACE and has a very short interferon γ has immunoregulatory activity t½ (< 15 seconds). and is used in multiple sclerosis. 214 Textbook of PharmacologySection for Dental 7 and Allied Health Sciences Respiratory System

32 Drugs Acting on Respiratory System

DRUGS USED IN THE TREATMENT OF CLASSIFICATION BRONCHIAL ASTHMA 1. Bronchodilators Bronchial asthma is characterised by a. Sympathomimetics dyspnoea and wheeze due to increased β i. Selective 2 agonists resistance to the flow of air through the Short acting- bronchi. Bronchospasm, mucosal congestion – Salbutamol, terbutaline. and oedema result in increased resistance. The tracheobronchial smooth muscle is Longer acting - hyper-responsive to various stimuli like – Salmeterol, fenoterol, formoterol, dust, allergens, cold air, infection and pirbuterol, Ibuterol drugs. These trigger-factors trigger an ii. Nonselective agents acute attack. – Adrenaline, isoprenaline, Antigen-antibody interaction on the surface ephedrine. of mast cells cause (Fig. 32.1): b. Methylxanthines - (i) degranulation of mast cells releasing Theophylline, aminophylline. stored mediators of inflammation c. Anticholinergics - (ii) synthesis of other inflammatory mediators which are responsible for Ipratropium bromide, atropine. bronchospasm, mucosal congestion and 2. Anti-inflammatory agents oedema. a. Systemic - Glucocorticoids Inflammation is the primary pathology. Hydrocortisone, Prednisolone. Clinically 2 types of asthma are identified. b. Inhalational - (a) Extrinsic asthma Starts at an early age, Beclomethasone, Budesonide, occurs in episodes; the patient has a Flunisolide, Triamcinolone family history of allergies. 3. Mast cell stabilizers - (b) Intrinsic asthma Starts in the middle age Disodium cromoglycate, Nedocromil, and assumes chronic form. There is no family history of allergies. Ketotifen. Drugs used in the bronchial asthma may be grouped 4. Leukotriene receptor antagonists - as follows. Montelukast, zafirlukast. Drugs Acting on Respiratory System 215

Fig. 32.1: Immediate and late responses of mast cell activation by antigen

β SYMPATHOMIMETIC DRUGS Selective 2 agonists are the most commonly used bronchodilators as they are the Sympathomimetics (see Chapter 11) are most effective, fast-acting, convenient and potent bronchodilators and are the most relatively safe bronchodilators. They are useful drugs to relieve bronchospasm. available as metered dose inhalers, nebu- Mechanism of action Adrenergic agonists lizers, injections and also tablets for oral use. stimulate β receptors in the bronchial smooth 2 The proper technique in using the inhaler muscles which in turn cause activation of should be taught. ‘Spacers’ (Fig. 32.3) can be adenylyl cyclase resulting in increased cAMP levels (Fig. 32.2). This increased cAMP leads used in children and adults who cannot to bronchodilatation. The increased cAMP in follow the right technique of inhalation. β agonists have higher adverse mast cells inhibits the release of inflammatory Oral 2 mediators. They also reduce bronchial effects than inhaled ones and are used only secretions and congestion (by acting on α in small children who cannot use inhalers receptors). and have occasional wheezing (1-4 mg 6 Short Acting β Agonists like salbutamol hourly). 2 β (albuterol) and terbutaline are given by Longer Acting 2 Agonists like salmeterol have inhalation, they are fastest acting broncho- a slow onset of action (hence not useful in dilators with peak effect in 10 minutes. The acute attacks) but the effect remains for 12 β action lasts for 6 hours. Adverse effects to 2 hours. Salmeterol is therefore used for long- agonists include muscle tremors, palpitation term maintenance and for prevention of and nervousness. nocturnal asthmatic attacks. 216 Textbook of Pharmacology for Dental and Allied Health Sciences

β Fig 32.2: Mechanism of action of 2 agonists in bronchial asthma

Other longer acting agents are also Methylxanthines inhibit PDE and thereby available for use - they are formoterol, fenoterol, enhance cAMP levels which brings about bambuterol and pirbuterol. bronchodilation. cAMP also inhibits the β release of mediators of inflammation. The long term use of 2 agonists may result in reduced response due to development of tolerance. Management of acute broncho- cAMP ←

spasm becomes a problem in such patients. PDE Methylxanthines Others include adrenaline, ephedrine and 5’AMP isoprenaline. Though these produce prompt Aminophylline is given intravenously, bronchodilation, they are not preferred due slowly, in acute attacks of asthma not to the risk of adverse effects. responding to β agonists. In an acute attack, Bronchodilation by ephedrine is slow in 2 onset. Because of low efficacy, side effects drugs given by inhalation may sometimes fail and availability of better drugs, ephedrine to reach the bronchioles because of severe is not preferred. bronchospasm. Intravenous aminophylline may then be tried. 250 mg aminophylline should be injected slow IV over 15-20 minutes. Rapid IV injection may cause collapse and death due to hypotension and arrhythmias. Convulsions can also occur and should be carefully watched for. Adverse effects Theophylline is a drug of low therapeutic index. Gastric irritation, vomiting, insomnia, tremors, diuresis, palpitation, and Fig 32.3: Spacer hypotension are quite common. Higher doses cause restlessness, delirium, convulsions and METHYLXANTHINES (Page 203) arrhythmias. Children may develop Theophylline and its derivatives like behavioural abnormalities on prolonged aminophylline are good bronchodilators. use—should be avoided. Mechanism of action Phosphodiesterase (PDE) Status in bronchial asthma Theophylline is a is the enzyme that degrades cyclic AMP. second line drug in bronchial asthma. Drugs Acting on Respiratory System 217

1. Chronic asthma Oral theophylline can be receptors in the cytoplasm, drug receptor used to control mild to moderate asthma. complex moves to the nucleus, binds to DNA Etophylline + 80% theophylline (Deri- and induces the synthesis of specific mRNA. phylline) injections (IM) are used to This in turn results in the synthesis of specific relieve acute attacks. When used over a proteins to bring about the following effects long-term, plasma levels should be (Fig. 54.2, Page 349) monitored. 1. they decrease the formation of cytokines. ↓ 2. Acute severe asthma (status asthmaticus) 2. PG synthesis. Intravenous aminophylline is tried when 3. inhibit the production of leukotrienes and sympathomimetics fail to relieve broncho- platelet activating factor. spasm—but is found to be less effective. 4. reduce the influx of eosinophils into the lungs and thus reduce the release of ANTICHOLINERGICS mediators from them. 5. ↓ synthesis of interleukins. Anticholinergics (See chap. 8) relax bronchial β 6. restore response to 2 agonist -(if tolerance smooth muscles but response is slower than β has developed)-by upregulating 2 sympathomimetics. Ipratropium bromide is receptors. given by inhalation and its actions are largely Glucocorticoids may be given systemically confined to the respiratory tract. It is more in acute episodes. Oral prednisolone is effective in chronic bronchitis including commonly used (dose 30-60 mg/day).The chronic obstructive pulmonary disease onset of response requires about 12 hours. (COPD). It is safe and well-tolerated. Unlike Chronic asthma requires prophylaxis with atropine it does not dry up the secretions and inhaled steroids. hence does not inhibit mucociliary motility. Inhaled steroids The use of inhalational steroids Infact it may increase mucociliary clearance. largely minimizes the adverse effects of steroids because of the small dose required, Uses but they are not effective in acute attacks and are only of prophylactic value. They prevent 1. As an adjunct to β agonists particularly 2 episodes of acute asthma, reduce bronchial in severe acute episodes. hyperreactivity and effectively control 2. As a bronchodilator in some cases of symptoms. The effect gradually develops chronic bronchitis and COPD. after 1 week of treatment. Side effects of inhaled steroids include ANTI-INFLAMMATORY DRUGS hoarseness of voice - (by a direct effect on Glucocorticoids Since inflammation is the vocal cords), sore throat and oropharyngeal primary pathology in bronchial asthma, candidiasis. Rinsing the mouth and throat antiinflammatory agents afford significant with water after each use can reduce the benefit (See chap. 54). incidence of candidiasis and sore throat. HPA Mechanism of action Steroids are not axis suppression is generally not seen in the bronchodilators. They suppress the recommended doses. But, the drug that is inflammatory response to antigen-antibody swallowed may be systemically absorbed. reaction and thereby reduce mucosal oedema Large doses given for a long time may and hyperirritability. They bind to steroid occasionally result in systemic effects of 218 Textbook of Pharmacology for Dental and Allied Health Sciences steroids particularly in children. The use of We know that cromolyn prevents a ‘spacer’ reduces this risk and the adverse bronchospasm and inflammation following effects are also less common when a spacer exposure to allergen and decreases bronchial is used (Fig. 32.3). hyper-reactivity. It is therefore used for Beclomethasone dipropionate, budesonide, prophylaxis. It is not a bronchodilator - hence triamcinolone and fluticasone are used as not useful in acute episodes. inhalers. Cromolyn sodium is used as an inhaler; it Beclomethasone dipropionate is available as takes 2-4 weeks of treatment for the beneficial metered dose inhaler and rotacaps. It is also effects to develop. All patients do not available in combination with salbutamol. respond but it should be tried in all suitable Budesonide has the advantage of having high patients. Children are more likely to topical activity and the absorbed portion is respond. rapidly metabolised (Flunisolide is available Adverse effects are rare. Throat irritation, as nasal spray for allergic rhinitis.) cough and sometimes bronchospasm can Fluticasone is poorly absorbed from the gut occur on inhalation due to deposition of the and also undergoes high first pass fine powder. Allergic reactions are rare. metabolism. Hence even when swallowed, systemic adverse effects are unlikely with Uses fluticasone. 1. Prophylaxis of bronchial asthma—cromolyn Status of Glucocorticoids in Asthma sodium used over a long period—2 puffs—3-4 times daily reduces episodes 1. Acute exacerbation A short course (5-7 days) of acute asthma. Young patients with of oral prednisolone 30-60 mg/day for 7 extrinsic asthma are more likely to be days is given in addition to β agonists. 2 benefitted. Cromolyn can also be used for 2. Chronic asthma Steroid inhalation (2-4 prophylaxis before exposure to a known times a day) for a long period as allergen. prophylaxis. Allergic rhinitis 3. Status asthmaticus Intravenous hydro- 2. —Prophylactic nasal spray cortisone hemisuccinate (100-200 mg) is used. followed by oral prednisolone. 3. Allergic conjunctivitis—Eyedrops are used prophylactically- 1-2 drops, 3-4 times a MAST CELL STABILIZERS day. Preparations: FINTAL inhaler (1 mg), Cromolyn sodium (disodium cromoglycate) eyedrops 2%, nasal spray 2%, CROMAL was synthesized in 1965. inhaler 200 mg, eyedrops, nasal spray. Nedocromil is similar to cromolyn sodium in Mechanism of Action its actions and uses. It is given twice daily. • Cromolyn inhibits the degranulation of Ketotifen is an antihistaminic with actions like mast cells and thereby inhibits the release cromolyn sodium. It inhibits airway of mediators of inflammation, particularly inflammation but it is not a bronchodilator. histamine. It is given orally. Beneficial effects are seen • It also inhibits the release of cytokines. after 6-12 weeks of use. It is used for the • It may depress the neuronal reflexes prophylaxis of bronchial asthma and other which are exaggerated. But the exact allergic disorders like allergic rhinitis, atopic mechanism of action is not known. dermatitis, urticaria and conjunctivitis. Drugs Acting on Respiratory System 219

Drowsiness and dry mouth are common side c. Oral steroids may be considered effects. It can also cause dizziness and weight d. Additional inhaled ipratropium bromide gain. or oral theophylline may be given. Acute severe asthma or status asthmaticus is an LEUKOTRIENE RECEPTOR ANTAGONISTS acute exacerbation. It is a medical emergency; Leukotrienes are one of the important may be triggered by an acute respiratory mediators of inflammation. They bring about infection, abrupt withdrawal of steroids after bronchospasm, mucosal oedema, increase the prolonged use, by drugs, allergens or influx of inflammatory cells and mucous emotional stress. production, by their actions on leukotriene receptors. Zafirlukast, montelukast and Treatment pranlukast are highly selective and β 1. Nebulization of 2 agonist and competitive antagonists of leukotriene ipratropium alternately—every 30 receptors. They block the effects of minutes. Additional salbutamol 0.4 mg leukotrienes and thereby reduce mucosal IM/SC may be given. Severe tachycardia oedema and relieve bronchospasm. They should be watched for. decrease the response to allergens. They 2. Hydrocortisone hemisuccinate IV 100 mg inhibit exercise-induced and aspirin - induced stat followed by 100 mg every 8 hours bronchospasm. Adverse effects are rare - infusion followed by a course of oral headache, rashes and gastrointestinal prednisolone. disturbances. 3. Oxygen inhalation. Montelukast and zafirlukast can be used in 4. Antibiotics - if infection is present. the prophylaxis of mild to moderate asthma 5. IV fluids to correct dehydration and as alternatives or as add-on drugs. They also acidosis. reduce the dose of the steroid required. β 6. Aminophylline 250 mg slow IV over 15- Bronchodilator effect is additive with 2 agonists. Their place in asthma is yet to be 20 minutes has been used by some clearly known. physicians should be given carefully— Zileuton inhibits leukotriene synthesis by watching for adverse effects but is now inhibiting the enzyme lipoxygenase. But it not preferred. causes a rise in liver enzymes. Hence not 7. Artificial ventilation may be required in preferred. extreme cases.

Treatment of Asthma Bronchial Asthma and Dentistry β 1. A small amount of water or dental Mild asthma–Rapidly acting, inhaled 2 stimulants like salbutamol. materials used in dental procedures may Moderate asthma– Regular prophylaxis with aspirate into the respiratory passage cromoglycate. If the patient does not respond and trigger an acute attack of bronchial to cromolyn—inhaled steroids are given for asthma. Salbutamol inhalation should prophylaxis. Acute episodes are managed be given immediately. The dental β procedure may be continued after the with inhaled 2 agonists. Severe asthma patient recovers. a. Regular inhaled steroids 2. Analgesics (NSAIDs) prescribed for relief β of pain may trigger acute episodes of b. Inhaled 2 agonists 3-4 times a day 220 Textbook of Pharmacology for Dental and Allied Health Sciences

asthma. This should be kept in mind. Codeine is a good antitussive with less Depending on the severity of asthma and addiction liability. However, nausea, the dose of the NSAID required, constipation and drowsiness are common. appropriate drug should be prescribed. Dose 10-15 mg every 6 hours (See page 164). If the patient has severe asthma and Noscapine is a natural opium alkaloid which requires an antiinflammatory drug for his dental problem prednisolone should be is a potent antitussive. No other CNS effects considered. are prominent in therapeutic doses (See page 3. If the patient has been receiving steroid 164). Nausea is the only occasional side inhalation for prophylaxis of bronchial effect. Dose 15-30 mg every 6 hours. asthma for a long period, the oral Dextromethorphan and pholcodeine are synthetic microflora could be altered. This opioid derivatives with antitussive actions predisposes the oral mucosa to infection with microorganisms like candida and like codeine but with lesser side effects. certain bacteria. Appropriate care should Pholcodeine is longer-acting - given twice be taken. daily. DRUGS USED IN THE TREATMENT OF Benzonatate is chemically related to the local COUGH anaesthetic procaine. It acts on the cough receptors in the lungs and also has a central Cough is a protective reflex that removes the effect. It is given orally - 100 mg thrice daily. irritant matter and secretions from the respiratory tract. It could be due to infection, Antihistamines are useful in cough due to allergy, pleural diseases and malignancy. allergy except that due to bronchial asthma. Since it is a protective mechanism, undue They thicken the secretions which may be suppression of cough can cause more harm difficult to cough out. An antihistamine is than benefit. In some conditions, as in dry generally one of the components of cough annoying cough, it may serve no useful purpose. In such situations, antitussives or syrups. Their sedative property may be of cough suppressants may be used. additional value in suppressing cough. Antitussives only provide symptomatic relief Other centrally acting antitussives include and do not alter the cause. carbetapentane, chlophedianol and Antitussives caramiphen. More extensive studies are required to prove their efficacy. 1. Central cough suppressants Codeine, pholcodeine, noscapine, Pharyngeal Demulcents dextromethorphan, antihistamines, benzonatate. Pharyngeal demulcents (demulcere = to 2. Pharyngeal demulcents caress soothingly - in LATIN) increase the Lozenges, cough drops, linctuses flow of saliva which produces a soothing 3. Expectorants effect on the pharyngeal mucosa and reduce Potassium iodide, Guaiphenesin, afferent impulses arising from the irritated ammonium chloride, ipecacuanha mucosa. Dry cough due to irritation of the Central Cough Suppressants pharyngeal mucosa is relieved. Candy sugar Central cough suppressants act by inhibiting or a few drops of lemon also serve this cough centre in the medulla. purpose. Drugs Acting on Respiratory System 221

Expectorants plasma proteins present in the exudate and the secretions become thick and viscid. Expectorants (Latin - expectorare = to drive Mucolytics liquefy the sputum making it less from the chest) increase the production of viscid so that it can be easily expectorated. respiratory tract secretions which cover the The following are mucolytics - irritated mucosa. As the secretions become Bromhexine, a semisynthetic compound thin and less viscid, they can be easily related to vasicine (an alkaloid from the plant coughed out. Expectorants may increase the Adhatoda vasica) is a good mucolytic. It secretions directly or reflexly. depolymerises the mucopolysaccharides in • Direct stimulants Volatile oils like the mucus. It is given orally (8-16 mg thrice eucalyptus oil; creosotes, alcohol, cidar daily). Side effects are minor - may cause wood oil - when administered by rhinorrhoea. inhalation with steam can increase Ambroxol is a metabolite of bromhexine with respiratory secretions. actions similar to it. Ambroxol may be given • Reflex expectorants are given orally, they orally or by inhalation. It can be used as an are gastric irritants and reflexly increase alternative to bromhexine. respiratory secretions. Acetylcysteine opens disulfide bonds in Potassium iodide acts both directly and mucoproteins of the sputum reducing its reflexly. viscosity. It is given by aerosol. Side effects Ipecacuanha is an emetic. In sub-emetic doses are common and hence not preferred. it is used as an expectorant. Carbocysteine Carbocysteine is similar to acetylcysteine and is used orally. Bronchodilators Pancreatic dornase Deoxyribonucleoprotein is Bronchodilators like salbutamol and a major component of the purulent respiratory tract secretions. Pancreatic terbutaline relieve cough that results from dornase is a deoxyribonuclease obtained bronchospasm. from the beef pancreas. It breaks the The antitussive preparations generally have deoxyribonucleic acid (DNA) into smaller a combination of a central cough suppressant, parts thus making the secretions thin and less an expectorant, an antihistaminic and viscid. It is administered by inhalation. sometimes a bronchodilator and a mucolytic Pancreatic dornase can cause allergic agent. reactions. Steam inhalation offers an effective and Mucolytics inexpensive alternative to drugs. It humidifies Normally the respiratory mucous is watery. the sputum as well as respiratory mucosa. The glycoproteins in the mucous are linked This helps in reducing the irritation and for by disulphide bonds to form polymers easier expectoration of the sputum. In making it slimy. In respiratory diseases, the presence of dehydration, just rehydrating the glycoproteins form larger polymers with patient is found to be beneficial. 222 Textbook of PharmacologySection for Dental 8 and Allied Health Sciences Blood

33 Haematopoietic System

HAEMATINICS Absorption Haematinics are compounds required in the The average Indian diet provides about 10- formation of blood and are employed in the 20 mg of iron. 10 percent of this iron is treatment of anaemias. Haematinics include absorbed. Dietary iron may be present as iron, vitamin B12 and folic acid. Haema- haeme or as inorganic iron. It is mostly topoietic growth factors are also discussed absorbed from the upper gut in the ferrous here. form. During deficiency, absorption is better. Haeme iron is better absorbed than inorganic Iron iron.

Iron, vitamin B12 and folic acid are essential Factors that Influence Iron Absorption for normal erythropoiesis. ↑ Iron is essential for haemoglobin Ascorbic acid, amino acids, meat, gastric, production. Total body iron is about 2.5 to 5 acidity – Increase absorption. grams, two-thirds of which is present in Antacids, phosphates, phytates, tetracyclines haemoglobin. Each molecule of haemoglobin presence of food in the stomach–Decrease has 4 iron containing residues. It is also absorption. present in myoglobin, the cytochromes and Transport and Distribution other enzymes. Iron is transported with the help of a Distribution of Iron in the Body glycoprotein transferrin and stored as ferritin and haemosiderin, in liver, spleen and bone Haemoglobin 66% marrow. Ferritin, haemosiderin 25% Myoglobin (in muscles) 03% Excretion Enzymes (cytochromes, etc.) 06% Daily 0.5-1 mg of iron is excreted. A large Daily Requirement of Iron part is lost in shedding of intestinal mucosal cells and small amounts in the bile, Adult male 0.5-1 mg desquamated skin and urine. In females, iron Adult female 1-2 mg is also lost in menstruation. Pregnancy and lactation 3-5 mg Preparations of Iron Dietary sources of iron Food items that are rich in iron are liver, egg yolk, meat, fish, chicken, Iron is generally given orally–but can be spinach, dry fruits, wheat and apple. given parenterally. Haematopoietic System 223

Oral Iron Preparations Preparations 1. Ferrous sulphate–200 mg tab 1. Iron dextran has 50 mg elemental iron/ml 2. Ferrous fumarate–200 mg tab (2 ml ampoule) - it is the only preparation 3. Ferrous gluconate–300 mg tab that can be given intravenously. It can also be given IM. 4. Ferrous succinate–100 mg 2. Iron-sorbitol - citric acid complex –contains 5. Iron calcium complex–5% iron 50 mg elemental iron/ml; given only IM. 6. Ferric ammonium citrate–45 mg. This preparation should not be given IV • Ferrous salts are better absorbed than because it quickly saturates the transferrin ferric salts and are cheaper. stores. As a result free iron levels in the • The last three preparations given above plasma rises and can cause toxicity. are claimed to be better tolerated but Dose is to be calculated using a formula. are more expensive. Iron requirement=4.4×body weight ×Hb deficit • Expensive preparations of iron with (mg) (kg) (g/dl) vitamins, liver extract, amino acids, etc. are available but offer no obvious This also includes iron needed for benefits. replenishment of stores. • Dose Ferrous sulphate 200 mg - 3-4 Adverse Effects tablets daily. The elemental iron content of different salts varies. Local Pain at the site of injection, pigmentation of the skin and sterile abscess. Adverse Effects of Oral Iron Systemic Fever, headache, joints pain, Epigastric pain, nausea, vomiting, gastritis, palpitation, difficulty in breathing, lymph metallic taste, constipation (due to astringent node enlargement and rarely anaphylaxis. effect) or diarrhoea (irritant effect) are the Acute iron poisoning is common in infants usual adverse effects. Liquid preparations of and children in whom about 10 tablets (1-2 iron cause staining of the teeth. g) can be lethal. Manifestations include vomiting, abdominal pain, haematemesis, Parenteral Iron bloody diarrhoea, shock, drowsiness, Intramuscular injection of iron is given deep cyanosis, acidosis, dehydration, cardio- IM in the gluteal region using ‘Z’ technique vascular collapse and coma. Immediate to avoid staining of the skin. Intravenous diagnosis and treatment are important as iron is given slowly over 5-10 minutes or as death may occur in 6-12 hr. infusion after a test dose. Treatment Indications • Gastric lavage with sodium bicarbonate 1. When oral iron is not tolerated solution. 2. Failure of absorption–as in malabsorption, • Desferrioxamine is the antidote. It is chronic bowel disease instilled into the stomach after lavage, to 3. Noncompliance prevent iron absorption; injected IV/IM. 4. Severe deficiency with bleeding. • Correction of acidosis and shock. 224 Textbook of Pharmacology for Dental and Allied Health Sciences

Table 33.1: Daily requirement of vitamin B12 and folic acid

Adults Pregnancy and lactation μ μ Vitamin B12 1-3 g 3-5 g Folic acid 50-100 μg 200-400 μg

As 50% of ingested drug is lost, double the amount is recommended for daily dietary intake

Indications for Iron secreted by the stomach. It is carried in the plasma by B –binding proteins called Iron deficiency anaemia–both for the 12 transcobalamin and is stored in the liver. prophylaxis and treatment. The cause for iron deficiency should be identified. Treatment Functions should be continued depending on the response for 3-6 months to replenish iron Vitamin B12 and folic acid act as coenzymes stores. Prophylactically iron is given in for several vital metabolic reactions and are conditions with increased iron requirement essential for DNA synthesis. as in pregnancy, infancy and professional Daily requirement– (Table 33.1). blood donors. Deficiency

VITAMIN B12 AND FOLIC ACID B12 deficiency may be due to:

Vitamin B12 and folic acid are water soluble 1. Addisonian pernicious anaemia Thomas vitamins, belonging to the B-complex group. Addison first described cases of anaemia They are essential for normal DNA synthesis. not responding to iron. There is deficiency Their deficiency leads to impaired DNA of intrinsic factor due to destruction of synthesis and abnormal maturation of RBCs parietal cells resulting in failure of B12 and other rapidly dividing cells. This results absorption. in megaloblastic anaemia, characterised by 2. Other causes Gastrectomy, chronic the presence of red cell precursors in the gastritis, malabsorption and fish blood and bone marrow. Vitamin B12 and tapeworm infestation (fish tapeworm folic acid are therefore called maturation consumes B12). factors. Other manifestations of deficiency include glossitis, stomatitis and mala- Preparations bsorption; neurological manifestations can • Cyanocobalamin–100 μg/ml injection may also result. be given IM or deep SC - hypersensitivity reactions can occur. Vitamin B 12 • Hydroxocobalamin–100, 500, 1000 μg/ml

Vitamin B12 (Cyanocobalamin) is synthesized injection-has longer lasting effect but by microorganisms. Liver, fish, egg yolk, hydroxocobalamin administration can meat, cheese and pulses are the dietary result in the formation of antibodies. sources of B12. • Multivitamin preparations contain

Vitamin B12 or extrinsic factor is absorbed variable amounts of vitamin B12 with or with the help of intrinsic factor, a protein without intrinsic factor for oral use. Haematopoietic System 225

Uses Uses

1. B12 deficiency Prophylaxis and treatment of 1. Megaloblastic anaemia due to folate as well

megaloblastic anaemia due to B12 as B12 deficiency–folic acid 2-5 mg/day is

deficiency of any cause. If B12 deficiency given orally along with vitamin B12. In folic is due to lack of intrinsic factor, it is given acid deficiency due to malabsorption IM or SC. Pernicious anaemia needs life syndromes, folic acid is given IM. 2. Prophylactically in pregnancy, lactation, long treatment with B12. Oral folic acid infancy and other situations with should be added because B12 induced brisk haemopoiesis may also increase the increased requirement of folic acid - 500 μ demand for folic acid. Prophylactic dose g daily orally. μ of vitamin B12 is 3-10 g daily. Folinic acid (citrovorum factor, leucovorin)

2. B12 neuropathies like subacute combined is N-formyl tetrahydrofolic acid and is the

degeneration respond to vitamin B12. active coenzyme form which overcomes methotrexate toxicity (Page 330). Folic Acid HAEMATOPOIETIC GROWTH FACTORS Folic acid is pteroylglutamic acid. It was first isolated from spinach and therefore named Haematopoietic growth factors are hormones as folic acid (from leaf). that regulate erythropoiesis. Many of these Dietary source Green vegetables, liver, yeast, glycoproteins have now been produced for egg, milk and some fruits. Prolonged cooking clinical use by recombinant DNA technology. with spices destroys folic acid. Frequent blood counts are needed to monitor Absorption takes place in the duodenum and therapy with these growth factors. jejunum and is transported in the blood by Haemotopoietic Growth Factors Include: active and passive transport, widely • Erythropoietin distributed in the body and is stored in the • Myeloid growth factors liver. GM-CSF Functions Folic acid is converted to G-CSF M-CSF dihydrofolic acid and then to tetrahydrofolic • Megakaryocyte growth factors acid which serves as a coenzyme for many Thrombopoietin vital (one-carbon transfer) reactions Interleukin-II necessary for DNA synthesis. Erythropoietin is produced by the kidney in Deficiency Folate deficiency may be due to response to hypoxia and anaemia. It binds to dietary folate deficiency, malabsorption and erythropoietin receptors on red cell other diseases of the small intestine or drug progenitors and stimulates red cell induced. Phenytoin, phenobarbitone, oral production. contraceptives, methotrexate and trime- It can cause hypertension, thrombosis and thoprim can induce folate deficiency. allergic reactions. Parenteral iron may be Increased requirement as in growing needed to prevent iron deficiency that is children, pregnancy and lactation can also precipitated by rapid erythropoiesis. cause deficiency. Manifestations include Uses - Erythropoietin is useful in the treatment megaloblastic anaemia, glossitis, diarrhoea of anaemia seen in chronic renal failure, bone and weakness. marrow disorders, malignancies, chronic 226 Textbook of Pharmacology for Dental and Allied Health Sciences inflammation and anaemia associated with AIDS. Myeloid growth factors include granulocyte - macrophage colony stimulating factor (GM- CSF), Granulocyte colony stimulating factor (G-CSF) and Monocyte colony stimulating factor (M-CSF). Recombinant human GM-CSF is sargramostim and G-CSF is filgrastim. They bind to specific receptors on the myeloid progenitor cells and stimulate the proliferation and differentiation of neutrophils Fig. 33.1: Major reactions of blood coagulation and monocytes. Adverse effects include bone pain, fever, Anticoagulants are drugs that reduce the arthralgia, myalgia and dyspnoea. coagulability of the blood. Myeloid growth factors are used in bone marrow transplantation, following cancer Classification chemotherapy, aplastic anaemia, congenital 1. Anticoagulants used in vivo neutropenia, myelodysplasia and in AIDS A. Fast acting patients with neutropenia. • Heparin Megakaryocyte Growth Factors • Low mol. wt. heparins • Heparinoids - Thrombopoietin increases the production of - Heparan sulphate platelets. It is being tried in severe thrombo- - Dextran sulphate cytopaenia as that seen following cancer - Danaparoid chemotherapy. - Lepirudin B. Slow acting DRUGS USED IN THE DISORDERS OF (oral anticoagulants) COAGULATION • Coumarin derivatives: Haemostasis is the spontaneous arrest of - Bishydroxycoumarin bleeding from the damaged blood vessels. - Warfarin sodium In the process, complex interactions take - Nicoumalone place between the injured vessel wall, • Indandione derivatives: platelets and clotting factors. - Phenindione Following injury, there is local vaso- - Diphenadione constriction and platelet adhesion–forming 2. Anticoagulants used in vitro a plug which temporarily stops bleeding. This - Heparin is reinforced by fibrin for long-term - Citrates, Oxalates haemostasis. - Sodium edetate. Clotting factors are proteins synthesized by the liver. Two systems–the extrinsic and HEPARIN AND HEPARINOIDS the intrinsic system are involved in the process of coagulation. Several proteins Heparin was discovered by McLean, a medical interact in a cascading series to form the clot student in 1916. It was named ‘heparin’ as it (Fig. 33.1). was first extracted from the liver. It is a Haematopoietic System 227 mucopolysaccharide found in the mast cells of the liver, lungs and intestinal mucosa. Heparin is the strongest acid in the body. It is a glycosaminoglycan. Actions Heparin is a powerful anticoagulant that acts instantaneously both in vivo and in vitro. Fig. 33.3: Mechanism of action of heparin Mechanism of Action: Antithrombin III is a peptide that is synthesized in the liver and Pharmacokinetics Heparin is not effective orally. It is given IV or SC. It should not be given IM circulates in the plasma. Heparin activates because it may cause haematomas, due to local plasma antithrombin III (Fig. 33.3). bleeding, absorption is erratic and also causes Antithrombin III binds to and inhibits the irritation. Given intravenously the onset of activated thrombin and coagulation factors action is immediate, reaches peak in 5-10 (Xa and IXa). This is a physiological reaction, minutes and clotting time returns to normal but heparin accelerates it by 1000 times. in 2-4 hours. Treatment is monitored by aPTT Clotting time is prolonged. The heparin- (preferable) or clotting time. Heparin is antithrombin III complex inhibits activated metabolised by heparinase in the liver. Heparin is given as a bolus dose of 5000 factor X and thrombin, while low molecular units followed by a maintenance dose of 1000 weight (LMW) heparin only inhibits factor X units/hour as infusion. and not thrombin (Table 33.2). Other actions Heparin activates lipoprotein lipase Adverse Reactions which hydrolyses triglycerides present in the 1. Bleeding is the most common, major adverse plasma and thus clears the plasma of lipids. effect of heparin. Careful monitoring and

Fig. 33.2: Drugs used in the disorders of coagulation 228 Textbook of Pharmacology for Dental and Allied Health Sciences

Table 33.2: Compare and contrast standard heparin and LMW heparin

Features Standard Heparin LMW Heparin

Mol. Weight 10,000-20,000 4,000-7,000 Source Natural Semisynthetic (Chemical treatment of std. herpain) Thrombin activity in Inhibited Not inhibited therapeutic doses Effect on tests of clotting Significant Not significant Lab. monitoring Required Not required SC Bioavailability Short (20-30%) (70-90%) Duration of action Short (2-4 hrs) Long (18-24 hrs) Frequency of administration Every 4-6 hrs Once a day Thrombocytopenia Can occur Lesser Chances Risk of bleeding Present Lower

dose control will prevent this to a great Low molecular weight (LMW) heparins, e.g. extent. enoxaparin, dalteparin, tinzaparin, ardeparin 2. Hypersensitivity reactions For commercial and reviparin have a mol. wt. of 4000-7000. use heparin is obtained from bovine lung LMW heparins are obtained by chemical/ or porcine intestine. Because of its animal enzymatic treatment of standard heparin. origin allergic reactions are quite common. LMW heparins inhibit factor Xa like 3. Thrombocytopenia Heparin induced platelet conventional heparin but differ from it as aggregation and formation of antiplatelet follows - in therapeutic doses LMW heparins antibodies both result in throm- do not inhibit thrombin activity (because they bocytopenia. The antigen antibody are too short). In thorapeutic doses, LMW complexes may damage the vessel wall heparins do not have significant effect on the triggering thrombosis and disseminated tests of clotting. Therefore lab monitoring is not required. Apart from being equally intravascular coagulation. This paradoxical efficacious, LMW heparins have a favourable complication of heparin therapy is rare but pharmacokinetic profile and have the can be serious. Heparin should be stopped following advantages over standard immediately at the first sign of heparins- thrombocytopenia. • Better bioavailability following SC 4. Alopecia is reversible. injection. 5. Osteoporosis - on long-term use - the cause • Longer action is unknown. • Lower risk of bleeding (because of less 6. Hypoaldosteronism - Heparin can inhibit the interaction with platelets) synthesis of aldosterone and may result • Lower risk of osteoporosis in hyperkalemia. • Lower incidence of thrombocytopenia Contraindications to heparin therapy (because less antigenic) and thrombosis Bleeding disorders, thrombocytopenia, • Routine lab monitoring not required. haemophilia, severe hypertension, intr- Uses - LMW heparins are used in– acranial haemorrhage, cirrhosis, ulcers in the • The prevention and treatment of venous gut, renal failure and neurosurgery. thrombosis and pulmonary embolism Haematopoietic System 229

• In unstable angina North America in 1924. This turned out to be • To maintain the patency of tubes in due to bishydroxycoumarin, an anticoagulant dialysis patients. in the spoiled sweet clover. Many related Heparin antagonist Mild heparin overdosage compounds were then developed and are also can be treated by just stopping heparin being used as rat poison. because heparin is short acting. In severe Mechanism of action Warfarin and its heparin overdose, an antagonist may be congeners act as anticoagulants only in vivo needed to arrest its anticoagulant effects. because they act by interfering with the Protamine sulphate is a protein obtained from synthesis of vitamin K dependent clotting the sperm of certain fish. Given intra- factors in the liver. They block the γ venously, it neutralises heparin (1 mg for carboxylation of glutamate residues in every 100 units of heparin). In the absence of prothrombin, factors VII, IX and X. γ heparin, protamine sulphate can itself act as carboxylation is necessary for these factors a weak anticoagulant. Hence overdose to participate in coagulation. should be avoided. Protamine sulphate is a The onset of action is slow; anticoagulant strongly basic protein which binds with the effect develops over 1-3 days because oral strongly acidic groups of heparin forming a anticoagulants do not destroy the already stable complex which is devoid of circulating clotting factors. Prothrombin time anticoagulant activity–this is the pharma- (PT) is measured to monitor the treatment. cological basis for using protamine sulphate It takes 5-7 days for PT to return to normal in heparin overdosage. after stopping oral anticoagulants. Whole blood transfusion may be needed. Pharmacokinetics Warfarin is completely absorbed orally and is 99% bound to plasma Heparinoids proteins. Heparan sulfate present in some tissues is similar to heparin. It is believed to be Adverse Effects responsible for antithrombotic activity on the 1. Haemorrhage is the main hazard. Bleeding vascular endothelium. in the intestines or brain can be trou- Hirudin is the anticoagulant found in the blesome. Minor episodes of epistaxis and salivary glands of leeches. It is a powerful bleeding gums are common. Lepirudin thrombin inhibitor. is produced by Treatment–depends on the severity: recombinant DNA technology and can be a. Stop the anticoagulant. used in patients allergic to heparin but it has b. Fresh blood transfusion is given to no antagonist yet. supply clotting factors. Danaparoid is a mixture of heparinoids and c. Antidote The specific antidote is vitamin acts by inhibiting factor Xa. It does not K oxide. It allows synthesis of clotting prolong aPTT and is longer acting. It is used 1 factors. But even on IV administration, subcutaneously in the treatment of deep vein the response to vitamin K oxide needs thrombosis and in other conditions as an 1 several hours. Hence in emergency, alternative to heparin. fresh whole blood is necessary to counter ORAL ANTICOAGULANTS the effects of oral anticoagulants. 2. Other adverse effects include allergic Cattle that were fed on spoiled sweet clover reactions, gastrointestinal disturbances hay, developed a haemorrhagic disease in and teratogenicity. 230 Textbook of Pharmacology for Dental and Allied Health Sciences

Factors influencing oral anticoagulant activity

Factors enhancing activity Factors reducing activity Poor diet, bowel disease, Pregnancy—there is increased synthesis liver disease and chronic of clotting factors alcoholism—result in vitamin K Hypothyroidism—there is reduced deficiency degradation of clotting factors.

Drug Interactions Uses of Anticoagulants Many drugs potentiate warfarin action Anticoagulants can prevent the extension of 1. Drugs that inhibit platelet function– thrombus but cannot destroy the existing NSAIDs like aspirin increase the risk of clots. Heparin has rapid and short action bleeding. which makes it suitable for initiating 2. Drugs that inhibit hepatic drug treatment (Table 33.3) while warfarin is metabolism like cimetidine, chloram- suitable for long-term maintenance due to its phenicol and metronidazole enhance slow and prolonged action and convenience plasma levels of warfarin. of oral use. Some drugs reduce the effect of oral 1. Venous thrombosis and pulmonary embolism– anticoagulants. anticoagulants prevent extension of 1. Drugs that enhance the metabolism of oral thrombus and recurrence of embolism. anticoagulants–microsomal enzyme 2. Postoperative, post-stroke patients; bedridden inducers like barbiturates, rifampicin, patients due to leg fractures and other griseofulvin enhance the metabolism of causes–who cannot be ambulant for oral anticoagulants. When these drugs are several months – anticoagulants prevent suddenly withdrawn, excess anticoagulant venous thrombosis and pulmonary activity may result in haemorrhages. embolism in such patients. 2. Drugs that increase the synthesis of 3. Rheumatic valvular disease–anticoagulants clotting factors – oral contraceptives. prevent embolism.

Table 33.3: Differentiating features between Heparin and Dicoumarol/Warfarin

Features Heparin Dicoumarol/warfrain

1. Source Natural Synthetic 2. Chemistry Mucopolysaccharide Coumarin derivative 3. Site of action Parenteral Oral 4. Route of administration In vivo and In vitro In vivo only 5. Onset of action Immediate Slow (1-3 days) 6. Duration of action Short (2-4 hours) Long (4 –7 days) 7. Mechanism Activates antithrombin III Inhibits synthesis of which inhibits thrombin and clotting factors Xa and IX a (II, VII, IX, X) 8. Antagonist Protamine sulfate Vit. K1 oxide 9. Monitoring with aPTT/clotting time Prothrombin time 10. Used for Initiation of therapy Maintenance therapy Haematopoietic System 231

4. Unstable angina–heparin reduces the risk Anistreplase of myocardial infarction in patients with unstable angina. Anistreplase (Anisoylated plasminogen 5. Vascular surgery, artificial heart valves and streptokinase activator complex) is a form of haemodialysis–anticoagulants prevent streptokinase which is long acting and can thromboembolism. be injected in a single IV bolus. Hence it is Contraindications to anticoagulant therapy more convenient to use. • Bleeding disorders including thrombocytopenia Urokinase • Severe hypertension Urokinase is an enzyme prepared from • Malignancies cultures of human kidney cells (it was first • Bacterial endocarditis isolated from human urine–hence the name). • Liver and kidney diseases. It activates plasminogen. It is more expensive • Recent surgery (in the last 10-15 days) than streptokinase. • History of cerebrovascular accident Tissue Plasminogen Activator THROMBOLYTICS (FIBRINOLYTICS) Tissue plasminogen activator (tPA) pre- Thrombolytics lyse the clot or thrombi by ferentially activates plasminogen that is activating the natural fibrinolytic system. bound to fibrin (clot) which means circulating Plasminogen circulates in the plasma and plasminogen is largely spared. also some of it is bound to fibrin. Tissue plasminogen activator (tPA) activates Alteplase, Duteplase plasminogen which is converted to plasmin. Plasmin degrades fibrin thereby dissolving Alteplase, duteplase are tPA produced by the clot. Thrombolytic agents are streptokinase, recombinant DNA technology. They are very urokinase, alteplase and reteplase. All are expensive. expensive drugs. Streptokinase obtained from β-haemolytic Reteplase streptococci activates plasminogen. Anti- Reteplase is modified human tPA obtained streptococcal antibodies present in the blood by genetic engineering .It is claimed to have due to previous streptococcal infections inactivate a large amount of streptokinase. the following advantages over tPA Streptokinase is antigenic and can cause • faster reperfusion allergy. The antibodies formed may persist • bleeding tendency is negligible. for five years. Hence if thrombolytics are Tenecteplase required during that period, others like tPA or urokinase should be used. Streptokinase Tenecteplase is longer acting and can be also causes hypotension. given as an IV bolus injection. Its ability to bind fibrin is better than that of alteplase.

Adverse Effects of Thrombolytics Bleeding is the major toxicity of all thrombolytics. Hypotension and fever can occur. Allergic reactions are common with streptokinase. 232 Textbook of Pharmacology for Dental and Allied Health Sciences

Uses 1. PG synthesis inhibitors - Aspirin 1. Acute myocardial infarction–Intravenous 2. Phosphodiesterase inhibitor - thrombolytics given immediately reduce Dipyridamol the mortality rate in acute MI. They should 3. ADP antagonists - be given within 12 hours but preferably Ticlopidine immediately because early treatment Clopidogrel largely reduces mortality. 4. Glycoprotein IIb/IIIa receptor antagonists - 2. Deep vein thrombosis and large Abciximab pulmonary emboli are also treated with Eptifibatide fibrinolytics. Tirofiban

Contraindications to thrombolytic therapy 5. Others- PGI2

• Recent surgery, injury, gastrointestinal Aspirin (see chap 27) Thromboxane A2 bleeding, stroke. promotes platelet aggregation. Aspirin • Severe hypertension. inactivates cyclo-oxygenase (COX) and • Bleeding disorders. thereby inhibits the synthesis of throm-

boxane A2 even in low doses (75 mg/day). ANTIFIBRINOLYTICS The COX inhibition is irreversible and the effect lasts for 7 to 10 days–till fresh platelets Antifibrinolytics inhibit plasminogen are formed. Aspirin is the most commonly activation and thus prevent fibrinolysis. used antiplatelet drug. Epsilon aminocaproic acid (EACA) and its Dipyridamole is a phosphodiesterase inhibitor analogue tranexaemic acid are antifibrinolytics. which interferes with platelet function by They bind to plasminogen and plasmin and increasing platelet cyclic AMP levels. It is used prevent the binding of fibrin to these along with aspirin for the prophylaxis of proteins. Aprotinin is another fibrinolytic thromboemboli in patients with prosthetic drug which acts by inhibiting proteolytic heart valves. enzymes. Antifibrinolytics are used in overdose of fibrinolytics and to reduce ADP Antagonists bleeding after prostatic surgery and some Ticlopidine ADP binds to receptors on patients undergoing cardiac surgeries or platelets to bring about platelet aggregation. after tooth extraction in haemophiliacs–but Ticlopidine is a prodrug. Its active metabolite the beneficial effect is uncertain. blocks ADP receptors and prevents platelet ANTIPLATELET DRUGS aggregation. Onset of action is slow (7-11 days) and the antiplatelet effect remains Platelets form the initial haemostatic plug at for some days even after stopping the drug. the site of vascular injury and are also Dose: 250 mg twice daily. Adverse effects involved in the formation of atherosclerosis. include dyspepsia, diarrhoea, bleeding and By inhibiting the platelet function, throm- leukopenia. It is used in patients who cannot bosis and atherosclerotic vascular disease can tolerate aspirin. be largely prevented. Clopidogrel has structural similarity to Antiplatelet drugs or drugs interfering with ticlopidine with similar mechanism of action. platelet function include - Like ticlopidine it is a prodrug and the active Haematopoietic System 233 metabolite blocks ADP receptors. Its actions pass surgery–long-term use of low dose are additive with aspirin as the mechanisms aspirin is recommended. are different. Toxicity is milder with lesser 4. Cerebral thrombosis and TIA In patients with incidence of leukopenia and throm- transient ischaemic attacks aspirin reduces bocytopenia. the incidence of stroke and mortality. In Clopidogrel is used as an alternative when cerebral thrombosis aspirin prevents aspirin cannot be used. It can also be used recurrence. with aspirin for additive effects. 5. Atrial fibrillation If oral anticoagulants can Glycoprotein IIb/IIIA receptor antagonists not be given, aspirin is useful. Fibrinogen and von Willebrand factor bind to glycoprotein IIb/IIIA receptors on the COAGULANTS platelets and mediate platelet aggregation by Coagulants are drugs that promote platelet agonists like thrombin, collagen and coagulation (procoagulants) and control TXA . Drugs that block these receptors inhibit 2 bleeding. They are also called haemostatics. platelet aggregation induced by all platelet They may be used locally or systemically. agonists. Local haemostatics are called styptics. Physical Abciximab is a monoclonal antibody which methods like local application of pressure, binds GP IIb/IIIA receptors and inhibits tourniquet or ice can control bleeding. platelet aggregation. It can cause bleeding and Styptics are local haemostatics that are used allergic reactions. It is used in patients on bleeding sites like tooth socket and undergoing coronary angioplasty. wounds. Eptifibatide and tirofiban are peptides given as They are: IV infusion. They are short acting and are 1. Adrenaline Sterile cotton soaked in 1:10,000 tried in unstable angina and myocardial solution of adrenaline is commonly used infarction. in tooth sockets and as nasal packs for Others epistaxis. Adrenaline arrests bleeding by vasoconstriction. Epoprostenol (PGI2) can be used during 2. Thrombin powder is dusted over the haemodialysis to prevent platelet aggregation bleeding surface following skin grafting. as an alternative to heparin. It is obtained from bovine plasma. 3. Fibrin obtained from human plasma is Uses of Antiplatelet Drugs available as sheets. It is used for covering 1. Myocardial infarction Aspirin with throm- or packing bleeding surfaces. bolytics improves survival in acute MI. 4. Gelatin foam is porous spongy gelatin used Long-term treatment with aspirin reduces with thrombin to control bleeding from reinfarction in post MI patients. wounds. It gets completely absorbed in 4 2. Unstable angina and stable angina pectoris- to 6 weeks and can be left in place after Aspirin reduces the risk of acute MI. suturing of the wound. Clopidogrel may be added to aspirin in 5. Thromboplastin powder is used in surgery unstable angina. as a styptic. 3. In patients with prosthetic heart valves, 6. Astringents like tannic acid are used on valvular heart disease, coronary artery by- bleeding gums. 234 Textbook of Pharmacology for Dental and Allied Health Sciences

Coagulants Used Systemically are OTHER COAGULANTS • Vitamin K • Fresh plasma or whole blood is useful in • Fibrinogen most coagulation disorders as it contains • Specific deficient factor–factors, II, VII, all the clotting factors. VIII, IX, X • Concentrated plasma fractions like • Ethamsylate fibrinogen, factors VIII, II, VII, IX and X are available for the treatment of specific Vitamin K deficiencies. • Snake venom Some venoms like Russels Vitamin K is a fat-soluble vitamin essential viper venom stimulate thrombokinase and for the biosynthesis of clotting factors. There promote coagulation. are three compounds: • Ethamsylate is used orally to arrest

• Vitamin K1– present in food from plant bleeding. The exact mode of action is not source known but it is thought that it acts by

• Vitamin K2– produced in the gut by inhibiting the synthesis of prostacycline bacteria. (PGI2) and correct the abnormal platelet function. It may also stabilize the wall of • Vitamin K3– a synthetic compound used therapeutically. the capillaries and reduce capillary Actions Vitamin K is essential for the bleeding. Ethamsylate is given orally to biosynthesis of clotting factors–prothrombin control bleeding in– and factors VII, IX and X by the liver. 1. Dental extraction and other procedures Human requirement-Not clearly known- in patients with coagulation disorders. 2. Menorrhagia recommended intake in adults is 50-70 mg/ 3. Post-partum haemorrhage. day 4. Haematemesis and malena Deficiency—Vitamin K deficiency results from liver diseases, malabsorption, long-term Dentistry and Drugs Affecting Coagulation antibiotic therapy and rarely by dietary deficiency. It is manifested as bleeding Most dental procedures including minor ones tendencies. like scaling and tooth extraction involves Adverse reactions are seen on parenteral some amount of bleeding. In patients with administration of vitamin K–allergic normal haemostasis, this is not much of a reactions and jaundice can occur. problem as bleeding stops by itself. However, even minor dental procedures may result in Uses continuous bleeding from the site in the following patients– 1. Vitamin K deficiency • Patients receiving drugs that inhibit 2. Newborn babies lack intestinal flora and coagulation. have low levels of prothrombin and other • Thrombocytopenic purpura clotting factors. Routine administration of • Vitamin C deficiency vitamin K–1 mg IM prevents haemo- • Haemophiliacs rrhagic disease of the newborn. • Long-term glucocorticoid therapy. 3. Oral anticoagulant toxicity. For management of bleeding-See page 399 Haematopoietic System 235

HYPOLIPIDAEMIC DRUGS 5. Miscellaneous — Nicotinic acid Lipids and proteins form complexes called Neomycin lipoproteins and circulate in the blood Gugulipid vessels. There are four types of lipoproteins- • Low density lipoproteins (LDL) HMG CoA Reductase Inhibitors (Statins) • High density lipoproteins (HDL) Hydroxymethylglutaryl-CoA (HMG-CoA) is • Very low density lipoproteins (VLDL) the rate-controlling enzyme in the bio- • Chylomicrons. synthesis of cholesterol. Lovastatin and its LDL is the primary carrier of cholesterol congeners are competitive inhibitors of the while VLDL carry triglycerides. Hyperli- enzyme HMG-CoA. They lower plasma LDL poproteinaemias (HPL) are conditions in cholesterol and triglycerides. The con- which the concentration of cholesterol or centration of HDL-cholesterol (the protective triglyceride (TG) carrying lipoproteins in the lipoprotein) increases by 10%. plasma is elevated above normal (Table 33.4) Pharmacokinetics Statins are well absorbed Increase in lipoproteins can hasten the when given orally but may undergo extensive development of atherosclerosis and is a risk first pass metabolism in the liver. Food factor for myocardial infarction. Therefore, enhances their absorption. Simvastatin is a along with reduction of body weight and low prodrug converted to its active metabolite cholesterol diet, significant hyperlip- in the liver. oproteinaemias should be treated with Adverse effects include GI disturbances, hypolipidaemic drugs. It should be noted that headache, insomnia, rashes, and rarely angio- HDL is known to have antiatherogenic oedema. Statins can rarely cause muscle effects. Low levels of HDL can increase the tenderness and myopathy with inflammation risk of atherosclerosis. It is therefore of the skeletal muscles causing muscle pain desirable to have higher HDL levels with low and weakness. LDL and TG levels. Uses

HYPOLIPIDAEMICS 1. Several large scale studies have shown statins to be useful in lowering morbidity 1. HMG CoA reductase inhibitors — and mortality in patients with coronary Lovastatin heart disease. Hence they are used in Simvastatin patients with MI, angina, stroke and Pravastatin transient ischemic attacks to lower Atorvastatin cholesterol levels. 2. Fibric acids — 2. HMG CoA reductase inhibitors are the Gemfibrozil first line drugs for hyperlipidaemias Clofibrate (Table 33.5) both for familial and Fenofibrate secondary hyperlipidaemias as in diabetes Bezafibrate mellitus. Ciprofibrate Fibric Acids (Fibrates) 3. Bile acid binding resins— Cholestyramine Fibric acids enhance activity of the enzyme Colestipol lipoprotein lipase which degrades VLDL 4. Antioxidant — resulting in lowering of triglycerides. They Probucol also increase HDL levels. 236 Textbook of Pharmacology for Dental and Allied Health Sciences

Table 33.4: Plasma lipid levels (mg/dl)

Grade Total cholesterol LDL Triglycerides HDL

Normal < 200 < 130 < 150 > 40 Borderline 200-240 130-160 150-199 – High > 240 > 160 > 200 > 60

Fibrates also inhibit coagulation and warfarin, chlorothiazide digoxin in the promote thrombolysis which also account for intestines thereby reducing their absorption. their beneficial effects. Gemfibrozil 600 mg Bile acid binding resins can be used in BD is the drug of choice in patients with patients with raised LDL levels; they can be increased TG levels and in type III, type IV used along with lovastatin or nicotinic acid. and type V hyperlipoproteinaemias. Antioxidant Adverse effects GI upset, skin rashes, headache, myositis, muscle cramps and blurred vision. Probucol lowers LDL and HDL cholesterol Fibrates can cause rhabdomyolysis and has antioxidant properties. It is generally particularly in patients with renal failure. not preferred. Bezafibrate is similar to gemfibrozil and has greater LDL lowering effects. Miscellaneous Nicotinic acid-a B group vitamin, in large Bile Acid Binding Resins doses inhibits triglyceride synthesis in the Bile acid binding resins—are not absorbed liver and VLDL production resulting in a decrease in LDL and increase in HDL but they bind bile acids in the intestine and cholesterol. Adverse effects include flushing, increase their excretion. Bile acids are dyspepsia, dryness and pigmentation of the required for intestinal absorption of skin. cholesterol. Plasma cholesterol and LDL Niacin is used in hypertriglyceridaemia levels fall. Bile acid binding resins are with low HDL levels. unpleasant to take; they may cause GI upset, Gugulipid obtained from ‘gum guggul’ lowers constipation and piles. They also bind fat plasma cholesterol and triglycerides. It is well soluble vitamins and many drugs like tolerated but can cause diarrhoea.

Table 33.5: Choice of hypolipidaemics G↑ T Gemfibrozil ↑ LDL Lovastatin* + cholestyramine/nicotinic acid ↑ TG+ ↑ LDL Lovastatin* + Gemfibrozil * or any other statin Section 9 Gastrointestinal Tract

34 Drugs Used in Gastrointestinal Disorders

DRUGS USED IN PEPTIC ULCER with Cl– (drawn from plasma) and HCl is secreted. Acetylcholine and gastrin act both Acid-peptic disease is common in the present directly on the parietal cells and indirectly by days that are full of tension and anxiety. Peptic ulcer is thought to result from an releasing histamine from the enterochromaffin cells. Histamine acts through H receptors on imbalance between acid-pepsin secretion and 2 parietal cells while acetylcholine through M mucosal defense factors. The stomach 1 secretes about 2.5 litres of gastric juice daily. muscarinic and gastrin through G receptors. The chief cells secrete pepsinogen while the The factors that protect the mucosa are its parietal cells secrete HCl and intrinsic factor. ability to secrete mucous, bicarbonate and Gastric acid secretion is regulated by three prostaglandins. The mucous and bicarbonate pathways–vagus (through acetylcholine), form a layer which protects the gastric gastrin and local release of histamine–each mucosa from gastric acid. Prostaglandins acting through its own receptors (Fig. 34.1). (PGE2&I2) stimulate the secretion of mucus These activate H+ K+ ATPase (proton pump) and bicarbonate, bring about vasodilation and on the parietal cells resulting in the secretion also inhibit acid secretion. They act on the PG of H+ into the gastric lumen where it combines receptors present on the parietal cell.

CLASSIFICATION Drugs used in peptic ulcer may be classified as follows:

1. Drugs that neutralise gastric acid - Antacids - Magnesium hydroxide, aluminium hydroxide, calcium carbonate, sodium bicarbonate 2. Drugs that reduce gastric acid secretion

a. H2 receptor blockers - Cimetidine, ranitidine, famotidine, roxatidine, nizatidine b. Proton pump inhibitors - Omeprazole, lansoprazole, esomeprazole, pantoprazole, rabeprazole c. Muscarinic antagonists - Pirenzepine, telenzepine 3. Ulcer protectives - Sucralfate, bismuth compounds 4. Other drugs - Carbenoxolone, cisapride, prostaglandins. 238 Textbook of Pharmacology for Dental and Allied Health Sciences

Fig. 34.1: Regulation of gastric secretion: ECL–Enterochromaffin cell; M–Muscarinic receptor

(chiefly M1); G–Gastrin receptors; H2–Histamine H2 receptor

The exact aetiopathogenesis of peptic ulcer intestines leading to systemic alkalosis. There is not known. Infection of the stomach mucosa is ‘rebound’ hyperacidity as gastrin levels with Helicobacter pylori is now known to be increase due to raised gastric pH. Sodium associated with chronic gastritis, peptic ulcers load may increase. It is not preferred for long- and their recurrence. term use because of the above disadvantages. Sodium bicarbonate is used with other ANTACIDS antacids in peptic ulcer. Other uses are to alkalinise the urine in poisoning due to certain Antacids are basic substances. Given orally dgurs and to treat metabolic acidosis. they neutralize the gastric acid and raise the pH of gastric contents. Peptic activity is also Non-systemic Antacids reduced, as pepsin is active only below pH 4. Antacids are of 2 types: Non-systemic antacids are insoluble 1. Systemic Sodium bicarbonate compounds that react in the stomach with HCl to form a chloride salt and water. They 2. Non-systemic are not absorbed. Aluminium hydroxide, Aluminium hydroxide is slow acting. Food further Magnesium trisilicate, slows it’s neutralizing capacity. It is also an Magnesium hydroxide, astringent and demulcent–forms a protective Calcium carbonate. coating over the ulcers. The aluminium ions relax the smooth muscles resulting in delayed Systemic Antacids gastric emptying and constipation. Aluminium Sodium bicarbonate is rapid but short-acting. hydroxide binds phosphate and prevents its absorption resulting in hypophosphataemia on CO2 that is released in the stomach escapes as eructation. It gets absorbed from the prolonged use. Drugs Used in Gastrointestinal Disorders 239

Magnesium salts The action is quick and Drug Interactions prolonged. Rebound acidity is mild. Antacids form complexes with iron, Magnesium salts are osmotic purgatives and tetracyclines, digoxin, ranitidine, fluor- the dose used as antacids may cause mild diarrhoea. oquinolones, sulfonamides and antimus- Calcium carbonate acts quickly and has carinic drugs. To avoid these, antacids should be taken 2 hours before or 2 hours after other prolonged action but liberates CO2 which may cause discomfort. It may also cause drugs. constipation and hypercalcaemia.

Antacid combinations are given to obtain H2 RECEPTOR BLOCKERS maximum effects with least adverse effects Cimetidine, ranitidine, famotidine, roxatidine. as follows (Table 34.1)- nizatidine. 1. Quick and prolonged effect–Fast-acting These drugs competitively inhibit the action [Mg(OH)2] and slow as well as long acting of histamine on H2 receptors (Table 34.2) and [Al(OH)3] compounds are combined 2. Neutralising side effects–Magnesium salts thereby reduce gastric secretion. Both volume have a laxative effect while aluminium and acidity of basal, nocturnal and food salts are constipating–combination induced secretion are reduced. They can neutralises each others side effects. cause 90% reduction in gastric secretion by a 3. Gastric emptying–Magnesium salts hasten single dose. Gastrin induced HCl secretion while aluminium salts delay gastric and pepsin is also reduced. These actions, emptying. particularly their ability to suppress nocturnal 4. Additive effect–The acid neutralising acid secretion, hasten the healing of peptic effects of both salts get added up. ulcers. All antacid tablets should be chewed and Pharmacokinetics H2 blockers are rapidly and swallowed as they do not disintegrate well well-absorbed. Cimetidine acts for 5-8 hours, in the stomach. Gels are more effective than ranitidine and famotidine for 12 hours. They tablets. One dose given 1 hr after food are partly metabolised in the liver and neutralises the acid for 2 hours. excreted by the kidneys. Dose - Table 34.3. Adverse effects The H blockers are well- Uses 2 tolerated with minor side effects like Antacids are used as adjuvants in hyperacidity, diarrhoea, dizziness, muscle pain and peptic ulcer and reflux oesophagitis. headache.

Table 34.1: Some antacid combination preparations

Brand name Combination

1. GELUSIL liquid Aluminium hydroxide gel 312 mg + Magnesium trisilicate 625 mg in every 5 ml 2. GELUSIL tablet Aluminium hydroxide gel 250 mg + Magnesium trisilicate 500 mg 3. DIGENE gel Magnesium hydroxide 185 mg + Aluminium hydroxide gel 830 mg + Carboxymethyl cellulose sodium 100 mg + Methylpolysiloxane 25 mg–in every 10 ml 4. DIGENE tablet Dried aluminium hydroxide gel 30 mg + Magnesium silicate 50 mg + Magnesium hydroxide 25 mg+Methylpolysiloxane 10 mg 240 Textbook of Pharmacology for Dental and Allied Health Sciences

Table 34.2: Compare and contrast promethazine (H1 blocker) and ranitidine (H2 blocker)

Features Promethazine Ranitidine

Antagonist of Histamine Histamine

Subtype of receptor blocked H1 H2

Other receptors blocked M1 Muscarinic Nil Effect on sleep Sedative No sedation Anticholinergic effects Present Absent Gastric HCl secretion Not affected Decreased Antiemetic property Present Absent Primary use Allergic disorders Acid peptic disease CNS effects of alcohol Potentiated No effect

Cimetidine has antiandrogenic actions, it aspiration occurs during surgery (See increases plasma prolactin levels and inhibits Page 139). Ranitidine is the most preferred. oestrogen metabolism in the liver. On It is given for 4-8 weeks in peptic ulcers. It prolonged use it may result in gynaecomastia, may be continued for 6 months to prevent decreased sperm count, impotence and loss recurrence. of libido in men. CNS effects include confusion, delirium and hallucinations in the PROTON PUMP INHIBITORS elderly. Headache, dizziness, rashes and Proton pump (PP) inhibitors are the most diarrhoea can result. Cimetidine inhibits efficacious inhibitors of the gastric acid microsomal enzymes (cytochrome P450) and secretion. Omeprazole was the first to be interferes with the metabolism of many drugs. developed but we now have lansoprazole,

Ranitidine is the preferred H2 blocker as it pantoprazole and rabeprazole with minor has several advantages over cimetidine. pharmacokinetic variations. Ranitidine is more potent, longer acting, has Omeprazole is the most commonly used PP no antiandrogenic effects, no CNS effects as inhibitor. it does not cross the BBB and does not inhibit microsomal enzymes significantly. Only Mechanism of Action adverse effects are headache and dizziness. Famotidine is similar to but more potent than ranitidine. Headache and rashes can occur. Roxatidine is similar to ranitidine but is more potent and longer-acting.

Uses of H2 Blockers

H2 blockers are used in the treatment of peptic ulcer, gastritis, reflux oesophagitis (GERD) and as preanaesthetic medication–to prevent damage to the respiratory mucosa if Drugs Used in Gastrointestinal Disorders 241

Table 34.3: Dosage and frequency of administration of drugs used in peptic ulcer

Drug Dose and frequency

Ranitidine (RANTAC) 150 mg BD/300 mg HS Famotidine (FAMOTIN) 20 mg BD/40 mg HS Roxatidine (ROTANE) 75 mg BD/150 mg HS Cimetidine (CIMET) 400 mg BD/800 mg HS Omeprazole (OMEZ, LOMAC) 20-40 mg OD Lansoprazole (LANZOL) 15-30 mg OD Rabeprazole (VELOZ) 20 mg OD Sucralfate (SUCRACE) 1 g 1 hr before each meal Colloidal bismuth subcitrate (PYLOCID) 120 mg 1 hr before meals and at bed time Carbenoxolone (GASTRIULCER) 50-100 mg TDS Misoprostol 200 mg BD-QID

The parietal cells of the stomach secrete H+ PP inhibitors are microsomal enzyme with the help of an enzyme H+K+ ATPase inhibitors and can result in many drug (proton pump) present in the plasma interactions-they may enhance the plasma membrane. This is the final step in gastric levels of drugs like benzodiazepines, acid secretion due to all stimuli. Proton pump warfarin and phenytoin–precipitating inhibitors accumulate in the parietal cells toxicity. where they specifically and irreversibly Adverse effects Omeprazole is well-tolerated. inhibit H+K+ATPase and thereby inhibit Prolonged acid suppression may allow gastric secretion. Omeprazole and other bacterial over growth in the stomach. proton pump inhibitors are prodrugs, get Dizziness, headache, diarrhoea, abdominal activated in the acidic environment of the stomach to sulfenamide which binds pain, nausea, arthralgia and rashes are rare. covalently with (SH groups on) H+K+ ATPase. Long-term administration may result in- The binding is irreversible. A single dose can • Vitamin B12 deficiency due to its reduced almost totally (95%) inhibit gastric secretion. absorption. Acid secretion starts only after new • ↑Gastrin levels. H+K+ATPase enzyme is synthesized. Ulcer • Atrophic changes in the stomach have been heals rapidly even in resistant cases. noticed after 3-4 years of use. Pharmacokinetics PP inhibitors are given as enteric coated granules to avoid degradation Drug Interactions by the acid in the stomach. Omeprazole is rapidly absorbed and reaches the parietal • Antacids, H2 receptor blockers and other cells; it is highly protein bound and is drugs which reduce gastric acidity reduce metabolised in the liver by the microsomal the efficacy of proton pump inhibitors. enzymes (cytochrome P450). Though the t½ of omeprazole is 1-2 hours, the effect of a • PP inhibitors inhibit the microsomal single dose remains for 2-3 days because of enzyme activity which can result in many its accumulation in the parietal cell canaliculi. drug interactions. 242 Textbook of Pharmacology for Dental and Allied Health Sciences

Lansoprazole is similar to omeprazole but is 1 gram BD is continued for 6 months to longer-acting. prevent recurrence. Pantoprazole is more acid stable and an Side effects are rare and include intravenous formulation is also available for constipation and dryness of mouth. use. It does not inhibit microsomal enzymes. All other features are similar to omeprazole. Drug Interactions Rabeprazole is shorter acting. • Sucralfate needs acidic pH for activation. Hence antacids should not be given with Uses of PP Inhibitors it. • Proton pump inhibitors are used in peptic • Sucralfate absorbs and interferes with the ulcers and in severe gastroesophageal absorption of tetracyclines, digoxin, reflux disease that does not respond to phenytoin and cimetidine. Bismuth salts Colloidal bismuth subcitrate on H2 blockers. Ulcers heal fast and pain is relieved. They are given for 4-8 weeks. oral administration chelates proteins in the • They also form a component in H. pylori ulcer base and forms a protective coating treatment regimen. over the gastric mucosa. It also inhibits the • PP inhibitors are useful in Zollinger growth of H. pylori on gastric mucosa and Ellison syndrome associated with gastrin stimulates the mucus production and PG secreting tumours. synthesis. By these actions it promotes ulcer healing in 4-8 weeks. It may cause Anticholinergics Though atropine reduces constipation and black stools. gastric secretion, the dose needed results in several adverse effects. A derivative of Other Drugs atropine–pirenzepine selectively blocks Carbenoxolone is a steroid like compound gastric M1 receptors and inhibits gastric secretion by 40-50% without significant side obtained from glycyrrhizic acid found in the effects. It also inhibits the secretion of gastrin, root of liquorice. On ingestion, it alters the mucous and bicarbonate. It is used as an composition of mucus so that it is more viscid adjuvant. and adheres to gastric mucosa and protects the ulcer base. It also inhibits pepsin activity Ulcer Protectives and prolongs the life of PGs. Because of its steroid like effects, it causes salt and water Sucralfate In acidic medium (pH < 4), retention. It is therefore not preferred. sucralfate polymerises to form a sticky, viscid Prostaglandins PGE2 and PGI2 synthesized by gel which firmly adheres to the base of the the gastric mucosa inhibits gastric secretion, ulcers. It remains there for over 6 hours acting enhances mucus production as well as mucosal as a physical barrier and prevents contact blood flow and exert a cytoprotective effect. with acid and pepsin. It also stimulates the They act by binding to the PG receptor (EP3) PG synthesis in gastric mucosa. It thus present on the parietal cells and inhibit cAMP promotes healing by protecting the ulcer. production. Misoprotol is a synthetic PGE1 Sucralfate is not absorbed and is well- analog given orally. It is of special value in tolerated. preventing NSAID induced gastric ulceration One tablet is given 1 hr before each meal because NSAIDs are PG synthesis inhibitors. and one at bed time for 4-8 weeks and then Diarrhoea and muscle cramps are common. Drugs Used in Gastrointestinal Disorders 243

Treatment of H. pylori Infection prokinetic agents. Metoclopramide, domperidone and cisapride are some prokinetic The gram-negative bacterium H. pylori is adapted to living in the stomach. Infection agents. with H. pylori is associated with gastro- Metoclopramide duodenal disease including gastritis and peptic ulcer. It is also thought to be responsible for Actions recurrence of peptic ulcer disease and is considered as a major risk factor for stomach GIT–Metoclopramide promotes forward cancer. Eradication of H. pylori along with movement of contents of the upper GI tract. drugs that reduce acid secretion has shown It raises lower esophageal sphincter pressure, to reduce the relapse rate. speeds up gastric emptying, prevents reflux Various combination regimens are tried esophagitis and also slightly enhances with clarithromycin, amoxicillin or intestinal peristalsis. tetracycline; metronidazole and omeprazole CNS– Metoclopramide acts as an antiemetic by its actions on CTZ and by speeding up or a H2 receptor blocker for 1-2 weeks. Use of a PP inhibitor in the regimen improves the gastric emptying. efficacy of the antibiotics in eradicating H. Pylori by raising gastric pH and enhancing Mechanism of Action antibiotic stability - activity of amoxicillin and Prokinetics act: clarithromycin are pH dependent. Some (i) by blocking D dopamine receptors. regimens are: 2 Antiemetic action is due to blockade of 1. Clarithromycin 250 mg BD + metro- D receptors in the CTZ. nidazole 400 mg BD + omeprazole 20 mg 2 BD–for one week. (ii) by enhancing acetylcholine release from 2. Clarithromycin 500 mg TDS/amoxicillin the cholinergic neurons in the gut. 750 mg TDS + omeprazole 20 mg BD–for Adverse effects are sedation, dystonia and two weeks. diarrhoea; gynaecomastia, galactorrhoea and parkinsonism (extrapyramidal symptoms) can Relevance in Dentistry occur on long-term use.

Many drugs used by dentists particularly Uses NSAIDs, can cause gastric irritation of varying degree. Dentists should be careful 1. Reflux oesophagitis–‘heart burn’ due to in using NSAIDs and other gastric irritant reflux of acid into the oesophagus is drugs including some antibiotics like benefited by prokinetic agents. doxycycline, ciprofloxacin, etc. in patients 2. As antiemetics – in postoperative period suffering from acid peptic disease. Though and vomiting due to anticancer drugs. prophylactic ranitidine/omeprazole has been 3. As preanaesthetic medication to promote commonly prescribed with ulcerogenic drugs, gastric emptying before induction of routine use of such drugs is not reco- general anaesthesia in emergency. mmended. 4. In endoscopy–to assist passage of tubes into the duodenum. PROKINETIC AGENTS Domperidone is a D2 dopamine receptor blocker Drugs that enhance gastroduodenal motility like metoclopramide. It does not cross the and hasten gastric emptying are called blood-brain barrier and hence extrapyramidal 244 Textbook of Pharmacology for Dental and Allied Health Sciences side effects are rare. As CTZ is outside the BBB, it acts as an antiemetic. Side effects are rare and include headache, dryness of mouth, diarrhoea and rashes. Domperidone can be used in place of metoclopramide. Cisapride enhances gastric motility by promoting the release of acetylcholine in the gut wall. It does not block dopamine receptors–hence is not an antiemetic and there are no antidopaminergic side effects. It also promotes colonic motility which may result in diarrhoea. It was used in reflux oesophagitis.Cisapride is now banned because it can cause serious cardiac adverse effects. Cardiac arrhythmias including Fig. 34.2 : The stimuli, pathways and centres mediating ventricular tachycardia, and atrial fibrillation emetic reflex can occur- particularly when used with microsomal enzyme inhibitors like EMETICS AND ANTIEMETICS erythromycin, fluconazole, ketoconazole, Stimulation of the vomiting centre in the indinavir and ritonavir. medulla oblongata results in vomiting. The

Tegaserod is a 5HT4 partial agonist which vomiting centre receives afferents from the promotes gastric emptying. It is free of the chemoreceptor trigger zone (CTZ), vestibular drug interactions and cardiotoxicity seen apparatus, GI tract and centres in the brain with cisapride. (Fig. 34.2). CTZ is not protected by the blood- Gastroesophageal reflux disease (GERD) brain barrier and is stimulated by various Reflux of acidic gastric contents into the drugs, chemicals and radiation. oesophagus results in ‘heart burn’ due to Emetics are drugs that produce vomiting. When a noxious substance is ingested, oesophagitis. Chronic oesophagitis can result vomiting has to be induced. Mustard powder in changes in the esophageal mucosa which (1 teaspoon) with water or hypertonic salt could be a premalignant condition. Based on solution can evoke vomiting. severity, GERD may be treated with antacids, Apomorphine is a derivative of morphine. metoclopramide or drugs that reduce acid Given SC/IM, it produces vomiting in 5-10 secretion. Uncomplicated, mild GERD may minutes. It acts by stimulating the CTZ. be relieved with antacids, H2 receptor Ipecacuanha contains an alkaloid emetine. blockers or prokinetic agents. In moderate Given as a syrup (15- 20 ml), it produces to severe cases, proton pump inhibitors like vomiting in 15 minutes. It is safe even in omeprazole are the drugs of choice. They children. effectively relieve symptoms and promote the healing of oesophagitis in 4-8 weeks. Antiemetics Avoiding–heavy meals, late night dinner, Vomiting is a protective mechanism aimed smoking and alcohol–all help. at eliminating the unwanted harmful Drugs Used in Gastrointestinal Disorders 245 material from the stomach. But in some in the gut, NTS and area postrema. situations, vomiting may not serve any Ondansetron blocks 5-HT3 receptors in the useful purpose and may only be GI tract, CTZ and nucleus tractus solitarius troublesome. It can cause dehydration, and prevents vomiting. It is a powerful weakness and electrolyte imbalance. In such antiemetic and can be given orally or circumstances, vomiting needs to be intravenously (4-8 mg). suppressed with drugs.

5-HT3 antagonists CLASSIFICATION • Block 5-HT3 receptors in the gut, CTZ and NTS. 1. Dopamine D2 antagonists–prokinetics - Metoclopramide, domperidone • Efficient antiemetics. • Some are effective both orally and 2. 5HT3 antagonists Ondansetron, granisetron parenterally. dolasetron, tropisetron • Largely safe – no sedation or other 3. Antimuscarinics CNS/autonomic side effects. Hyoscine • Adverse effects negligible – headache, cyclizine gastrointestinal disturbances. H anti- • Drugs of choice in postoperative and promethazine 1 histamines anticancer drug-induced vomiting. diphenhydramine. { 4. Neuroleptics Granisetron is more potent than ondansetron Chlorpromazine, as an antiemetic. Though granisetron, prochlorperazine, haloperidol dolasetron and tropisetron have longer t½, their 5. Other agents biological effect half-life remains the same Cisapride, corticosteroids. and they can all be given once daily.

5HT3 antagonists are well absorbed from Dopamine D2 Antagonists the gut and are metabolised by the liver. Metoclopramide and domperidone (page 243) They can be given both orally, IM and IV. All 5HT3 antagonists are well tolerated act centrally by blocking dopamine D2 receptors in the CTZ. They enhance the tone with minor adverse effects like headache and of the lower oesophageal sphincter and also constipation. enhance gastric peristalsis. They are used in Uses nausea and vomiting due to gastrointestinal disorders, migraine, in postoperative period 5HT3 antagonists are used to control and vomiting due to cytotoxic drugs and vomiting induced by anticancer drugs or radiotherapy. radiotherapy. They are also useful in postoperative vomiting and other drug 5-HT Antagonists 3 induced vomiting (Table 34.4). Ondansetron 5-hydroxytryptamine released in the gut is an important transmitter of emesis. Antimuscarinics It is believed that anticancer drugs induce Hyoscine (see Chap. 8) is a labyrinthine the release of 5-HT in the gut which initiates sedative very effective in motion sickness. emetic reflex through 5-HT3 receptors present Motion sickness or travelling sickness is due 246 Textbook of Pharmacology for Dental and Allied Health Sciences to over stimulation of the vestibular Other Antiemetics apparatus along with psychological and Corticosteroids are used in combination with environmental factors. Hyoscine also relaxes other antiemetics like ondansetron or the gastrointestinal smooth muscle. Taken 30 metoclopramide. Corticosteroids control minutes before journey, hyoscine (0.4-0.6 mg delayed vomiting following anticancer drug oral) acts for 6 hours and the dose should be therapy. repeated if the journey is longer than that. A Pyridoxine is used in the prevention of transdermal patch delivers hyoscine vomiting in pregnancy without any known constantly over 3 days and is to be applied pharmacological basis behind the ear. Sedation and dry mouth are Sedative hypnotics–Barbiturates and common side effects. benzodiazepines may raise the threshold for Dicyclomine is used to control vomiting in vomiting by depressing the CNS. Their morning sickness and motion sickness (Table anxiolytic and sedative properties also help. 34.3). Sedative hypnotics are used as adjuvants to H antihistamines (see Chap. 31) like 1 other antiemetics in treating anticancer drug promethazine, diphenhydramine, cyclizine -induced vomiting. and cinnarizine have anticholinergic Cannabinoids–Dronabinol, a cannabinoid has properties. Antihistamines block H receptors 1 antiemetic properties. It may act by the in the area postrema as well as muscarinic receptors in the CNS. They probably also act stimulation of the cannabinoid receptors (CB ) in the vomiting centre. It also increases on the GI tract. Some of them are useful in 1 motion sickness and postoperative vomiting. appetite. Dronabinol can cause behavioural abnormalities and dependence. It can be used Neuroleptics (Chap. 29) also block D2- receptors in the CTZ and are useful in as an alternative in the prevention of vomiting due to most causes except motion vomiting when other drugs are ineffective. sickness. Sedation and extrapyramidal Antiemetic Combinations symptoms are the common side effects. Prochlorperazine is mainly used as an Severe retching and vomiting like that antiemetic in vomiting and is also effective induced by anticancer drugs are treated with in vertigo associated with vomiting. a combination of antiemetics including

Table 34.4: Preferred drugs for vomiting due to various causes

Conditions Drugs

Motion sickness Hyoscine, Cyclizine, Promethazine, Cinnarizine Vomiting due to cytotoxic drugs 1. Ondansetron + Dexamethasone 2. Metoclopramide + dexamethasone + diphenhydramine+ lorazepam Vomiting due to other drugs Chlorpromazine, Metoclopramide Postoperative vomiting Ondansetron, Metoclopramide Vomiting in pregnancy Dicyclomine, Pyridoxine, Cyclizine, Meclizine, Metoclopramide Drugs Used in Gastrointestinal Disorders 247 ondansetron, metoclopramide, glucocorti- Bran is the residue left when flour is made coids and sedative-hypnotics. from cereals and contains 40% fibre–but is Later cycles of anticancer drug regimens unpalatable and can cause flatulence. can cause ‘anticipatory’ vomiting i.e.vomiting Ispaghula and plantago seeds contain natural at the sight/thought of receiving anticancer mucilage which absorbs water to form a drugs. This can be avoided by using gelatinous mass and are more palatable than appropriate antiemetics from the initial cycles bran. Methylcellulose is a semisynthetic of anticancer therapy. derivative of cellulose. Adequate water intake should be stressed. DRUGS USED IN THE TREATMENT OF CONSTIPATION Faecal Softeners Purgatives are drugs that promote defecation. Docusate sodium (dioctyl sodium sulpho- They are also called laxatives or cathartics. succinate) softens faeces by lowering the Laxatives have milder action while cathartics surface tension of the intestinal contents or purgatives are more powerful evacuants. which allows more water to be retained in Purgatives may be classified as- the faeces. Liquid paraffin is a chemically inert mineral CLASSIFICATION oil that is not digested. It lubricates and softens faeces. It is unpalatable; aspiration 1. Bulk laxatives may cause lipoid pneumonia; small amounts Bran, plantago seeds, agar, methyl- absorbed in intestines may cause paraf- cellulose, ispaghula husk finomas; it may leak out of the anus causing 2. Faecal softeners discomfort. Long-term use can result in Docusate sodium, liquid paraffin deficiency of fat - soluble vitamins due to (emollients) impaired absorption. Hence not preferred. 3. Osmotic purgatives Magnesium sulphate, Magnesium Osmotic Purgatives hydroxide, Sodium phosphate, Sodium sulphate, Magnesium citrate, Osmotic purgatives are solutes that are not Lactulose, Sorbitol, Polyethylene absorbed in the intestine, osmotically retain glycol water and increase the bulk of intestinal 4. Stimulant purgatives contents. They increase peristalsis to evacuate Phenolphthalein, bisacodyl, castor oil, a fluid stool. They produce soft liquid stools Anthraquinones - cascara sagrada, in 1-3 hours. Osmotic purgatives include senna • nonabsorbable salts (saline purgatives) Bulk laxatives include indigestible vegetable • nonabsorbable sugars - Lactulose fibre and hydrophilic colloids that increase • polyethylene glycol the volume and lower the viscosity of Nonabsorbable salts Magnesium hydroxide, intestinal contents forming a large, soft, solid magnesium sulphate, sodium potassium stool. Dietary fibre consists of cell walls and tartrate (Rochelle’s salt), sodium sulphate and other parts of fruits and vegetables that are phosphate are some inorganic salts used as unabsorbable. Adding fibre to the diet is a osmotic or saline purgatives. They are used to safe and natural way of treating constipation prepare the bowel before surgery and in in persons on low-fibre diet. food poisoning. 248 Textbook of Pharmacology for Dental and Allied Health Sciences

Nonabsorbable sugars Lactulose is a synthetic coloured skin erruptions, other severe forms disaccharide that is not absorbed, holds of allergy and risk of cardiac toxicity and colic water and acts as an osmotic purgative. limit it’s use. Flatulence and cramps may be accompanied. Bisacodyl related to phenolphthalein is In the colon, lactulose is fermented to lactic converted to active metabolite in the and acetic acids which inhibit the growth of intestines. It can be given orally (5 mg) but colonic ammonia - producing bacteria. It also usually is used as rectal suppositories (10 mg) inhibits the absorption of ammonia by which results in defecation in 15-30 minutes. lowering pH and lowers blood ammonia It is safe except that prolonged use may cause levels. It is used in hepatic coma for this effect local inflammation. (hepatic coma is worsened by ammonia). Castor oil is hydrolysed in the upper small Sorbitol is similar to lactulose intestine to ricinoleic acid, a local irritant that Polyethylene glycol (PEG) is a nonabsorbable increases intestinal motility. It is a powerful sugar. Balanced isotonic solution containing and one of the oldest purgatives. Stool is PEG with sodium sulphate, sodium chloride, semiliquid and is accompanied by gripping. sodium bicarbonate and potassium chloride It is not preferred. is given orally. The solution is balanced in Enema Enema produces defecation by such a way that it avoids electrolyte softening stools and distending the bowel. imbalance or fluid shift into the gut. Large Evacuant enema is used to prepare the gut volumes are rapidly ingested→ 3-4 litres over for surgery, endoscopy and radiological 2 hours - for cleaning the bowel. PEG powder examination (see Page 8). may be taken with water for chronic Use of laxatives in constipation Fibre rich diet, constipation. It has the advantage that there adequate fluid intake and physical activity is no associated flatulence or abdominal are the best measures to prevent and treat cramps. constipation in the otherwise normal subjects. If these measures are inadequate, a laxative Stimulant Purgatives may be given (Table 34.5). Drug induced constipation Drugs like Stimulant purgatives increase intestinal anticholinergics, NSAIDs, opioids, clonidine, motility and increase secretion of water and iron, calcium channel blockers; antihistamines electrolytes by the mucosa. They may cause and tricyclic antidepressants (due to abdominal cramps. anticholinergic effect) can cause constipation. When anthraquinones like cascara sagrada When withdrawal of the causative agent is and senna (source: plants) are given orally, not possible, a laxative may be used. active anthraquinones are liberated in the Laxative abuse Habitual use of laxatives, intestines and stimulate the myenteric plexes especially stimulant laxatives may lead to in the colon. Evacuation takes 6-8 hr. Long- various gastrointestinal disturbances like term use causes melanotic pigmentation of irritable bowel syndrome, loss of electrolytes, the colon. loss of calcium in the stool and Phenolphthalein an indicator, acts on the colon malabsorption. Misconceptions regarding after 6 to 8 hours to produce soft, semiliquid bowel habits should be cleared. The patient stools with some gripping. It undergoes should be convinced that normal bowel enterohepatic circulation which prolongs its habits may vary between 3 motions daily and actions. Allergic reactions including pink 2 motions per week. Drugs Used in Gastrointestinal Disorders 249

Table 34.5: Choice of purgatives

Conditions Preferred laxative 1. Functional constipation Increasing dietary fibre and adequate fluid intake 2. Elderly patients Increasing dietary fibre and adequate fluid intake 3. Pregnancy Dietary fibre 4. To avoid straining at stools—as in hernia, Bulk laxatives or faecal softeners piles, fissure, cardiovascular diseases like myocardial infarction 5. Irritable bowel syndrome—chronic Bulk laxatives constipation 6. Food or drug poisoning Osmotic purgatives 7. Bowel preparation before surgery, endos- Bisacodyl, osmotic purgatives copy and radiological examination

DRUGS USED IN THE TREATMENT Table 34.6: Composition of oral rehydration OF DIARRHOEA salt/solution (ORS)

Diarrhoea is the frequent passage of liquid Sodium chloride — 3.5 gm stools. It can be due to a variety of causes Potassium chloride — 1.5 gm like infection, toxins, anxiety and drugs. Sodium citrate — 2.9 gm Acute diarrhoea is one of the major causes of Glucose — 20 gm death in infants specially in the developing To be dissolved in 1 litre of boiled and countries. cooled water In diarrhoea, there is an increase in motility and secretions in the gut with better and stool output is lower. If the ORS decreased absorption of water and powder is not available, a mixture of 5 g table electrolytes. Hence the approaches in the salt with 20 g sugar dissolved in one litre of treatment of diarrhoea include: boiled and cooled water may be used till 1. replacement of fluid and electrolytes regular ORS is available. In severe degrees 2. treatment of the cause of dehydration, prompt intravenous 3. antidiarrhoeal agents. rehydration is vital. Correction of fluid and electrolyte disturbances can Treatment of the cause Acute diarrhoea could be life saving in most cases especially infants. Oral rehydration with sodium chloride, often be due to viral, bacterial or protozoal glucose and water is useful. In the ileum, infection. The pathogen should be identified glucose and sodium citrate enhance sodium whenever possible and treated accordingly. absorption and water follows. Oral Gastroenteritis is often due to virus and does rehydration powders are available (Table not require antibiotics. Mild bacterial gastro- 34.6) to be mixed with water for mild to enteritis is also self-limiting but some moderate cases. ORS with sodium bi- infections like typhoid, cholera and amoebic carbonate and with sodium citrate are dysentry need chemotherapy. available. Trisodium citrate is used in place Antidiarrhoeal drugs afford symptomatic of bicarbonate because use of citrate makes relief and include adsorbents and antimotility ORS more stable, absorption of glucose is drugs. 250 Textbook of Pharmacology for Dental and Allied Health Sciences

Adsorbents include kaolin, pectin, chalk and Pathogens commonly causing diarrhoea activated charcoal. Kaolin is a natural Virus Bacteria compound containing hydrated magnesium, Others aluminium silicate while pectin is the sugar Rotavirus E. coli E. histolytica obtained from apples. These adsorb Astrovirus Salmonella Giardia lamblia intestinal toxins and microorganisms by Adenovirus Shigella Intestinal worms Coronavirus coating them. They are not absorbed and V. cholerae Enterovirus have no prominent side effects. They bind C. jejuni to and interfere with the absorption of other drugs because of which a 2-hour Antimotility drugs are used for symptomatic interval is required after administration of treatment of non-infective diarrhoeas and other drugs. traveller’s diarrhoea (as adjuvant).

Antimotility Drugs Other Drugs Codeine an opium alkaloid, stimulates the Lactobacillus acidophilus is available as opioid receptors on the gastrointestinal powders and tablets and is useful in some smooth muscles to reduce peristalsis. This diarrhoeas. It promotes the growth of delays passage of intestinal contents and saccharolytic flora and alters the gut pH so facilitates absorption of water. Nausea and that growth of pathogenic organisms is vomiting may occur. inhibited. Diphenoxylate is an opioid related to Antispasmodics Atropine derivatives like pethidine. It is given with a small dose of propantheline and dicyclomine relax atropine in order to discourage abuse. In gastrointestinal smooth muscles and relieve therapeutic doses CNS effects are not abdominal colics. prominent and is used only in diarrhoeas. Octreotide is a synthetic analog of somatostatin. Nausea, drowsiness and abdominal pain may Somatostatin has the following actions: occur (Table 34.7). • reduces GI motility and fluid secretion. Loperamide is an opiate. It has selective action • inhibits the secretion of various hormones on GI tract with additional antisecretory like gastrin, secretin, cholecystokinin, action. CNS effects are negligible. It is less growth hormone, insulin, glucagon, 5-HT, sedating, less addicting and is the most pancreatic polypeptide and vasoactive commonly used antimotility drug. It’s low intestinal peptide. solubility in water discourages abuse by Octreotide is a longer acting analog and can injection. Loperamide may cause nausea, be given subcutaneously. It is used in vomiting and abdominal cramps. diarrhoea caused by gastrointestinal secretory

Table 34.7: Antimotility drugs—some preparations and dosage

Drugs Trade names Doses

Diphenoxylate 2.5 mg LOMOTIL 2-4 tablets stat; 1 every 6 hr + Atropine 0.025 mg Loperamide LOPESTAL 4 mg stat; 2 mg every 6 hr Drugs Used in Gastrointestinal Disorders 251 tumours and in diarrhoea due to vagotomy, Diarrhoea or constipation with abdominal dumping syndrome and AIDS. pain are seen. Causes could be stress, lack of dietary fibre, food allergy or emotional Traveller’s diarrhoea disturbances. When constipation is Infection is the most common cause of prominent, soluble dietary fiber like traveller’s diarrhoea and should be treated ispaghula is recommended and loperamide with suitable antimicrobials like doxycycline is preferred for diarrhoea. Benzodiazepines or ciprofloxacin. Oral rehydration salts and are given for the treatment of anxiety and loperamide may also be used. other appropriate measures are taken depending on the symptoms and probable IRRITABLE BOWEL SYNDROME cause. Irritable bowel syndrome (IBS) is a common Newer drugs like alosetron and tegaserod condition characterised by abnormal bowel which act on 5-HT receptors have been functions with no specific organic cause. found to be useful in IBS. 252 Textbook of PharmacologySection for Dental 10 and Allied Health Sciences Chemotherapy I 35 General Considerations

INTRODUCTION CLASSIFICATION Chemotherapy can be defined as the use of Based on their mechanisms of action, anti- chemicals in infectious diseases to destroy microbials are classified (Fig. 35.1) as follows. microorganisms without damaging the host tissues. Antibiotics are substances produced Drugs that: by microorganisms which suppress the 1. Inhibit cell wall synthesis- growth of or destroy other microorganisms. Penicillins, cephalosporins, vancomycin, Pasteur and Joubert were the first to bacitracin, cycloserine. identify that microorganisms could destroy 2. Damage cell membranes- other microorganisms. Paul Ehrlich ‘The father -causing leakage of cell contents - of Modern Chemotherapy’ coined the term ‘chemotherapy’. He showed that certain dyes Polymyxins, colistin, amphotericin B, can destroy microbes and demonstrated that nystatin. methylene blue can be used in malaria. He 3. Bind to ribosomes and inhibit protein also synthesised some arsenical compounds synthesis - for the treatment of syphilis and sleeping Chloramphenicol, tetracyclines, erythro- sickness. Domagk in 1936 demonstrated that mycin, aminoglycosides, clindamycin, prontosil, a sulfonamide dye is effective in linezolid, streptogramins. some infections. The production of penicillin 4. Inhibit DNA gyrase- for clinical use in 1941 marked the beginning Fluoroquinolones like ciprofloxacin, of the ‘golden era’ of antibiotics. In the last norfloxacin 5. Inhibit DNA function- 60 years, several powerful antibiotics and (DNA dependent RNA polymerase) their semisynthetic derivatives have been Rifampicin produced. 6. Interfere with metabolic steps- Many infectious diseases which were -Antimetabolite action- sulfonamides, earlier incurable can now be treated with sulfones, trimethoprim, pyrimethamine just a few doses of antimicrobial drugs. Thus the development of antimicrobial Antimicrobials may also be Classified as- drugs is one of the important advances of modern medicine. Infact antimicrobials are 1. Bacteriostatic - agents that suppress the one of the most commonly prescribed drugs growth of bacteria. but are often the most over used or For example, Sulfonamides, tetracyclines, misused drugs. linezolid chloramphenicol, clindamycin. 252

General Considerations 253

Fig. 35.1: Classification of antimicrobials based on their mechanisms of action

2. Bactericidal - agents that kill the bacteria. used to include all antimicrobials with a wide For example, Penicillins, cephalosporins, spectrum of activity i.e. those effective against aminoglycosides, fluoroquinolones, both gram-positive and gram-negative rifampicin, metronidazole, vancomycin. organisms e.g. ampicillin. However, some drugs may be bacter- Factors that influence the successful iostatic at low doses and bactericidal at higher chemotherapy of an infection are: doses. For example erythromycin; also, some • Site The drug should reach the site of drugs may be bacteriostatic to some infection. microorganisms and ‘cidal’ to others. For • Concentration It should attain adequate example chloramphenicol is bactericidal to H. concentration at the site. influenzae, S. pneumoniae and N. menigitidis, • Host defence Active host defences reduce while it is bacteriostatic to other micro- the antibiotic requirement. organisms. • Sensitivity The microorganism should be Antibacterial spectrum An antimicrobial may sensitive to the antimicrobial agent. have a narrow or broad spectrum of activity. Narrow spectrum - RESISTANCE TO ANTIMICROBIAL AGENTS For example: Penicillin G - gram-positive Aminoglycosides - gram-negative Resistance is the unresponsiveness of a Broad spectrum - Tetracyclines, microorganism to the antimicrobial agent. - Chloramphenicol The resistance may be natural or acquired. Broad spectrum antibiotics are so called In natural resistance, the organisms have never because, in addition to suppression of gram- responded to the antimicrobial–may be due positive and gram-negative bacteria, they to the absence of the particular enzyme or also inhibit the growth of other micro- target site affected by the drug, e.g. gram- organisms like Rickettsiae, Chlamydiae, negative bacilli are not sensitive to Pencillin Mycoplasma and some protozoa.But in G. But this type of resistance is clinically not practice the term' broad spectrum' is often a problem as alternative drugs are available. 254 Textbook of Pharmacology for Dental and Allied Health Sciences

Acquired resistance Here, the microbes which 2. Transformation Resistant bacteria may were previously sensitive to the antimicrobial release genetic material into the medium agents become resistant to it. Clinically this which is taken up by other bacteria. poses a problem. 3. Conjugation is the most important mode Bacteria acquire resistance by a change in of spread of resistance. The R-factor is their DNA. Such DNA changes may occur transferred from cell to cell by direct by: (i) mutation or (ii) transfer of genes. contact through a sex pilus or bridge and Mutation is a genetic change that occurs the process is known as conjugation. spontaneously. In any population of bacteria, The resistance acquired by the bacteria may a few resistant mutants may be present. When be exhibited in the following ways: the sensitive organisms are destroyed by the • Production of enzymes that inactivate the antibiotic, the resistant mutants freely multiply. drug, e.g. β-lactamase by staphylococci; Mutation may take place in a single step (e.g aminoglycoside inactivating enzymes by Staphlococcus aureus to rifampicin) or multiple E.coli. steps where several gene modifications are • Decreased accumulation of the drug in the made, e.g. gonococci to penicillin G. bacterium, e.g. resistance to tetracyclines Transfer of genetic material Many bacteria by gram-positive and gram-negative contain extrachromosomal genetic material bacteria. called plasmids in the cytoplasm. These carry • Altered target for the drug – the binding genes coding for resistance (called R-factors). site may be altered, e.g. binding sites for These R-factors are transferred to other aminoglycosides on the ribosomes may be bacteria and spread resistance (Fig. 35.2). altered. This may take place by: • Altered metabolic pathway–bacteria may 1. Transduction Plasmid DNA is transferred produce folic acid by an alternative through bacteriophage, i.e. virus which pathway. infects bacteria. Cross resistance is the resistance seen among chemically related drugs. When a microorganism develops resistance to one drug, it

Fig. 35.2: Mechanisms of transfer of resistance 254

General Considerations 255 is also resistant to other drugs of the same infections, selection of an antibiotic is group, even when not exposed to it, e.g. empirical. For acute dental infections the resistance to one tetracycline means antibiotic should have a spectrum that resistance to all other tetracyclines. includes streptococcal species and anaerobic bacteria. When samples can be taken without Prevention of Resistance to contamination or when empiric therapy fails, Antimicrobials antibiotic selection should be based on culture report. Drug toxicity and cost should Development of resistance to drugs can be be borne in mind. With proper clinical avoided to some extent by the following judgement–considering the above factors, measures: most infections can be successfully treated • antibiotics should be used only when (Table 35.1). necessary • selection of the appropriate antibiotic is DOSE OF THE ANTIMICROBIALS absolutely important The dose of the antimicrobial should be • correct dose and duration of treatment adequate enough for the drug to attain plasma should be followed concentrations above the minimum inhibitory • combination of drugs should be used as concentration (MIC). MIC is the lowest in tuberculosis to delay the development concentration of the antimicrobial agent that of resistance. prevents visible growth of the microorganism after 18 to 24 hours of incubation. The Selection of an Antibacterial Agent bactericidal effect with many drugs is dose- Antibiotics are used in 2 ways: dependent i.e. higher the concentration, 1. Empiric therapy The antibiotic must cover greater is the bactericidal effect, e.g. all the likely pathogens. A combination aminoglycosides. or a broad spectrum agent may be used. Postantibiotic effect - Some antibiotics have a This therapy should be employed only in postantibiotic effect i.e., they continue to some specific situations. suppress the bacterial multiplication even 2. Definitive therapy When the organism is after their plasma concentration falls below identified, specific antibacterial agents the MIC. Aminoglycosides and fluoro- should be given. quinolones have such effect against gram- Various factors should be considered in negative bacteria. selection of an antibiotic like, the patient COMBINATION OF ANTIMICROBIALS factors, the microbe factors, the properties of the drug and the clinical assessment. Site Use of a combination of antimicrobials may of infection is the prime factor that guides have synergistic, antagonistic or indiffe- the choice of the drug and its route of rent (no change) effects. Hence appropriate administration. Age of the patient, host drugs should be used for combination. defence status, renal and hepatic functions Two bactericidal drugs given together (e.g: should be considered. Whenever possible, Penicillin + aminoglycosides) are generally bacteriological culture report should guide synergistic. the drug selection. When not available, Combination of a bacteriostatic with a empirical therapy should be started to cover bactericidal drug is not useful because all the likely organisms. Infact for most dental bacteriostatic drugs inhibit the multiplication 256 Textbook of Pharmacology for Dental and Allied Health Sciences

Table 35.1: Choice of antibiotics recommended in the treatment of some common infections

Microorganisms Diagnosis Drug of first choice Alternative drugs

Gram-positive organisms Group A Pharyngitis, Penicillin or Erythromycin, Streptococcus Otitis media, Sinusitis, amoxicillin A first generation Cellulitis, Erysipelas, cephalosporin Impetigo, Bacteraemia Group B Bacteraemia Ampicillin or A first generation Streptococcus Endocarditis penicillin + cephalosporin Meningitis an aminoglycoside Staphylococcus Furuncle, Cellulitis, aureus Bacteraemia, Osteo- myelitis, Pneumonia • Methicillin Cloxacillin or A first generation sensitive dicloxacillin cephalosporin or vancomycin • Methicillin Vancomycin Ciprofloxacin + rifampicin resistant Quinupristine- dalfopristine, Linezolid Pneumococcus Pneumonia, Penicillin A first generation Sinusitis, Otitis, Amoxicillin cephalosporin Endocarditis Meningitis Penicillin – Ceftriaxone Clindamycin resistant Cefotaxime Cotrimoxazole Vancomycin Enterococcus Endocarditis Penicillin G Vancomycin + gentamicin + gentamicin Gonococcus Gonorrhoea, Pelvic Ceftriaxone Ampicillin inflammatory disease Amoxicillin Doxycycline Erythromycin Meningococcus Meningitis Ceftriaxone Penicillin G Cefotaxime Chloramphenicol Carrier state Rifampicin Minocycline Corynebacterium Diphtheria Erythromycin A first generation diphtheriae cephalosporin Clindamycin Clostridium tetani Tetanus Penicillin G Clindamycin Doxycycline

Clostridium difficile Pseudomembranous colitis Metronidazole Vancomycin Clostridium Gas gangrene Penicillin G Ceftizoxime perfringens Cefoxitine Chloramphenicol Doxycycline Contd... 256

General Considerations 257

Contd...

Microorganisms Diagnosis Drug of first choice Alternative drugs Bacillus Malignant Penicillin G Erythromycin anthracis pustule, pneumonia Doxycycline A first generation cephalosporin Gram-negative organisms Escherichia coli Urinary tract Norfloxacin Ampicillin + gentamicin; infection Ciprofloxacin Amoxicillin + clavulinic Cotrimoxazole acid; Aztreonam Proteus mirabilis Urinary Ampicillin or Cephalosporin - I or IIG Ciprofloxacin tract infection Bacteraemia Amoxicillin A cephalosporin and other infections Gentamicin Pseudomonas Urinary tract A broad spectrum Gentamicin aeruginosa infection pencillin + Ceftazidime Ciprofloxacin A cephalosporin Imipenem Aztreonam Klebsiella Urinary tract A cephalosporin Mezlocillin/ pneumoniae infection Piperacillin Pneumonia An aminoglycoside A cephalosporin Mezlocillin/ + Piperacillin gentamicin Aztreonam Amoxicillin + clavulinic acid Salmonella Typhoid fever Ciprofloxacin Chloramphenicol Bacteraemia Ceftriaxone Ampicillin Cotrimoxazole Shigella Gastroenteritis Ciprofloxacin Cotrimoxazole or norfloxacin Ampicillin Haemophillus Sinusitis Amoxicillin + Amoxicillin influenzae Pneumonia clavulinic acid Ciprofloxacin Otitis media Cotrimoxazole Azithromycin A cephalosporin Meningitis Ceftriaxone Chloramphenicol Ampicillin + sulbactam Haemophillus Chancroid Ceftriaxone Ciprofloxacin ducreyi Cotrimoxazole Erythromycin Doxycycline Brucella Brucellosis Doxycycline + Cotrimoxazole rifampicin Gentamicin Yersenia pestis Plague A tetracycline + Doxycycline streptomycin Chloramphenicol Ciprofloxacin Contd... 258 Textbook of Pharmacology for Dental and Allied Health Sciences

Contd...

Microorganisms Diagnosis Drug of first choice Alternative drugs

Vibrio cholerae Cholera Doxycycline Cotrimoxazole Ciprofloxacin Chloramphenicol Campylobacter jejuni Enteritis Ciprofloxacin Erythromycin Treponema pallidum Syphilis Penicillin G Ceftriaxone Doxycycline Leptospira Weil’s disease Penicillin G Doxycycline Meningitis Helicobacter Peptic ulcer Metronidazole + Omeprazole+ pylori amoxicillin + amoxicillin+ Bismuth/omeprazole clarithromycin

Legionella Pneumonia Azithromycin + Erythromycin rifampicin Clarithromycin Doxycycline Ciprofloxacin + rifampicin Other agents Mycoplasma Atypical Erythromycin Azithromycin pneumoniae pneumonia Doxycycline Rickettsiae Typhus fever, Doxycycline Chloramphenicol Q fever Rocky mountain spotted fever Chlamydia Lymphogranuloma Doxycycline Erythromycin trachomatis venereum Azithromycin Trachoma Inclusion conjunctivitis Urethritis Chlamydia psittaci Psittacosis Doxycycline Chloramphenicol Chlamydia Pneumonia Doxycycline Erythromycin pneumoniae Azithromycin Pneumocystis jiroveci Pneumonia Cotrimoxazole Trimethoprim and P. carinii Atovaquone + proguanil Dapsone of bacteria and thereby antagonize the effect 1. To obtain synergism Combination of of bactericidal drugs (as bactericidal drugs antibiotics to attain synergism is recomm- act on actively multiplying bacteria). Hence ended in - such combinations should be avoided. • Bacterial endocarditis– A combination of antimicrobial agents is Penicillin + streptomycin/genta- indicated in certain specific situations. The micin is synergistic. combination serves one of the following • Pseudomonas infections– purposes. Carbenicillin + gentamicin 258

General Considerations 259

• Pneumocystis carinii pneumonia– Vancomycin + aminoglycoside →→→ more Trimethoprim + sulfamethoxazole severe renal toxicity • β-lactamase producing organisms like 2. Selection of resistant strains–The few H. influenzae - resistant mutants that remain may Amoxicillin + clavulinic acid multiply unchecked. • Tuberculosis – INH + rifampicin. 3. Emergence of organisms resistant to 2. Treatment of mixed infections Orodental, multiple drugs. intra-abdominal infections, brain 4. Increased cost of therapy. abscesses, genitourinary infections and traumatic wound infections are often CHEMOPROPHYLAXIS mixed infections. Aerobic and anaerobic Chemoprophylaxis is the use of antimicrobial organisms may be involved. Two or more agents to prevent infection. antimicrobials can be used depending on In dentistry– Prophylactic use of antibiotics the culture and sensitivity report. Dentists may not be required in routine dental generally use a combination of a treatment if the patient's immune function is penicillin/cephalosporin/macrolide with normal. Certain dental procedures, including metronidazole. deep scaling, tooth extraction, periodontal 3. Initial treatment of severe infections Drugs procedures, oral and maxillofacial surgeries covering both gram-positive and gram- can produce transient bacteremia. In patients negative pathogens may be used initially at special risk including those with depressed till the culture report is available, e.g. immunity, insertion of prosthesis, implants penicillin + aminoglycoside; cephalosporin and prolonged surgeries would require + aminoglycoside. If anaerobes are likely antibiotic prophylaxis (Table 35.2). In general to be present, metronidazole may be chemoprophylaxis is recommended in the added. Samples for culture should following situations: however be taken before starting the 1. To protect healthy persons antibiotics. • Penicillin G is given for prevention of 4. To prevent the emergence of resistance In the gonorrhoea or syphilis in patients after treatment of tuberculosis and leprosy, contact with infected persons - combination of drugs is used to prevent postexposure prophylaxis. the development of resistance. • For preventing meningococcal infection 5. To reduce the adverse effects The doses in healthy children during an needed may be lower when a combination epidemic–rifampicin or sulfonamides is used. This may reduce the incidence and may be used. severity of adverse effects, e.g. Ampho- • Malaria- In healthy individuals visiting tericin B + flucytosine in cryptococcal an endemic area. meningitis. 2. To prevent infection in high risk patients • In neutropenic patients- like patients Disadvantages of Antimicrobial Combination receiving anticancer drugs, immuno- 1. Risk of toxicity from each agent–especially suppressive agents and patients with if toxicity is overlapping–may get added AIDS, a penicillin or fluoroquinolones up e.g. many antitubercular drugs are or cotrimoxazole may reduce the hepatotoxic. incidence of bacterial infection. Toxicity of one drug may be enhanced by • In patients with valvular heart diseases another e.g., prosthetic heart valves, and previous 260 Textbook of Pharmacology for Dental and Allied Health Sciences

Table 35.2: Antibiotics used in dentistry for chemoprophylaxis

Antibiotic Dose* Route

1. Cefazolin 1 g IV 2. Clindamycin + 600 mg IV gentamicin 1.5 mg/kg 3. Amoxicillin 2 g Oral 4. Cephalexin 2 g Oral 5. Erythromycin 1 g Oral For contaminated, traumatic, orofacial wounds 6. Amoxicillin + 750 BD for 5 days Oral Clavulanic acid 125 mg }

* all single dose except no. 6. history of bacterial andocarditis even 4. In close contacts- minor procedures like dental extra- Chemoprophylaxis is recommended ction, tonsillectomy or endo-scopies particularly in children when infectious may result in bacterial endocarditis (open) cases of leprosy (dapsone) or (damage to mucosa results in tuberculosis (INH, rifampicin) are in close bacteremia leading to endocarditis). contact. Penicillin is used for prophylaxis. SUPERINFECTION • In patients with contaminated or exposed wounds as in road traffic Superinfection/suprainfection is the accidents. appearance of a new infection resulting from • Catheterisation of urinary tract - the use of antimicrobials. Antibacterials alter norfloxacin is used. the normal microbial flora of the intestinal, • In burns - to prevent colonisation by respiratory and genitourinary tracts. The bacteria. normal flora contribute to host defence 3. Surgical prophylaxis Certain guidelines are mechanisms as follows—they inhibit colo- to be followed: nisation of pathogenic organisms by • Adequate antibacterial activity should producing antibacterial substances called bacteriocins and by competing for nutrients. be present during surgery. Hence the When the normal flora are destroyed by drug should be started 30-60 minutes antibacterials, there can be dangerous before surgery. infections due to various organisms especially • The drug should not be continued the normal commensals. The broader the beyond 24 hours after surgery (risk of antibacterial spectrum of a drug, the more are resistance development). the chances of superinfection, as the alteration • The drug should be effective against of the normal flora is greater (Table 35.3). all organisms that are likely to Sites involved–intestinal, respiratory and contaminate the wound. genitourinary tracts. • A single dose of 1 gm IV cefazolin injection is the most commonly used. MISUSE OF ANTIBIOTICS In patients allergic to it, clindamycin Antibiotics are one of the most overused or 600 mg IV+ gentamicin 1.5 mg/kg IV misused drugs. Faulty practices like the use may be given. of antibacterials in viral infections which are 260

General Considerations 261

Table 35.3: Common microorganisms causing superinfection

Microorganisms Manifestations Treatment

Candida albicans Oral thrush, diarrhoea, vaginitis Clotrimazole Staphylococci Enteritis Cloxacillin Clostridium difficile Pseudomembranous colitis Metronidazole, Vancomycin E.coli UTI Norfloxacin Pseudomonas UTI Carbenicillin aeruginosa self-limiting, using too low doses or tered orally to alter the intestinal microflora. unnecessarily prolonged treatment, using Lactobacillus, Bifido bacterium, Streptococcus antibiotics in all fever cases–are all irrational salivarius, some enterococci and Saccharomyces and can do more harm than any benefit. boulardii are some of the presently tried probiotics. Studies have shown them to be PROBIOTICS useful in acute infectious diarrhoea and antibiotic induced diarrhoea. Probiotics have Probiotics are products containing viable, also been tried in ulcerative colitis and non-pathogenic micro-organisms adminis- irritable bowel syndrome. 262 Textbook of Pharmacology for Dental and Allied Health Sciences

36 Sulfonamides, Cotrimoxazole and Quinolones

SULFONAMIDES Resistance Bacteria acquire resistance to sulfonamides by: Sulfonamides were the first effective 1. Mutations–resulting in over production of antibacterial agents to be used systemically PABA. in man. They are synthetic agents that contain 2. Using alternative metabolic pathway for a sulfonamide group. folic acid synthesis. Antibacterial spectrum Sulfonamides inhibit 3. Low permeability to sulfonamides. gram-positive and some gram-negative bacteria, nocardia, chlamydiae, Plasmodium Classification falciparum and Toxoplasma gondii. 1. Short-acting Mechanism of Action Sulfisoxazole, sulfadiazine 2. Intermediate-acting PABA Sulfamethoxazole ↓ Folic acid synthetase ←←← Sulfonamides 3. Long-acting Dihydrofolic Acid Sulfamethoxypyridazine, Bacteria synthesize their own folic acid from Sulfadoxine p-amino benzoic acid (PABA) with the help 4. Poorly absorbed of the enzyme folic acid synthetase. Sulfasalazine 5. Topical Sulfonamides are structurally similar to Sulfacetamide, mefenide PABA and competitively inhibit the enzyme Silver sulfadiazine. folic acid synthetase. This results in folic acid Pharmacokinetics Sulfonamides are well- deficiency and injury to the bacterial cell. absorbed, extensively bound to plasma Human cells are not affected because proteins and are well distributed to all they require preformed folic acid supplied tissues. They are metabolized in the liver by from the diet and cannot synthesize folic acetylation. acid by themselves. Sulfonamides are bacteriostatic. Adverse Effects Presence of pus, blood and tissue breakdown products make sulfonamides 1. Renal irritation, haematuria, albuminuria ineffective as these are rich in PABA. and crystalluria–due to precipitation of the Sulfonamides, Cotrimoxazole and Quinolones 263

drug in acidic urine. This can be avoided COTRIMOXAZOLE by intake of large volumes of fluids and by alkalinising the urine. The combination of trimethoprim and 2. Hypersensitivity reactions like rashes, sulfamethoxazole is cotrimoxazole. Trime- fever, Stevens Johnsons syndrome and thoprim is effective against several gram- rarely exfoliative dermatitis. positive and gram-negative organisms. But 3. Anorexia, nausea and abdominal pain. when used as a sole agent, resistance develops rapidly. 4. Haemolytic anaemia in patients with G6PD deficiency. Mechanism of action Sulfonamides inhibit the 5. Kernicterus–sulfonamides displace conversion of PABA to dihydrofolic acid bilirubin from the binding sites which (DHF) (Fig. 36.1) and trimethoprim inhibits crosses the BBB and may cause kernicterus dihydrofolate reductase (DHFR) and thus in the newborn. Hence sulfonamides are prevents the reduction of DHF to contraindicated in pregnancy and in tetrahydrofolic acid (THF). The two drugs infants. thus block sequential steps in folic acid synthesis and the combination in bactericidal. Uses The ratio of ‘trimethoprim : sulf- Because of the development of resistance and amethoxazole’ used is 1:5 to attain the right availability of better antimicrobials, plasma concentration. Among sulfonamides, sulfonamides are not commonly used now sulfamethoxazole is chosen because its except in a few cases. pharmacokinetic properties closely match 1. Urinary tract infections Sulfonamides may be with that of trimethoprim. used in areas where resistance is not high. Antibacterial spectrum Cotrimoxazole is 2. Nocardiosis High doses of sulfonamides can effective against several gram-positive and be used. gram-negative organisms like Staph. aureus, 3. Toxoplasmosis Sulfonamides with streptococci, meningococci, C. diphtheriae, E. pyrimethamine is the treatment of choice. coli, Proteus, H. influenzae, Salmonella and 4. Trachoma and inclusion conjunctivitis Shigella. Tetracylines are the drugs of choice; Resistance Development of resistance to the sulfonamides are used as alternatives. combination is slower when compared to 5. Lymphogranuloma venereum and chancroid either drugs given alone. Bacteria may Sulfonamides are used as alternatives to acquire resistance by mutation or by tetracyclines. acquisition of a plasmid coding for an altered 6. Malaria Sulfadoxine is used with DHFR. pyrimethamine in chloroquine resistant malaria. 7. Prophylactic use In patients allergic to penicillins, sulfonamides may be used for prophylaxis of streptococcal pharyngitis in rheumatic fever. 8. Topical Sulfacetamide eye drops are used in bacterial conjunctivitis; mafenide and silver sulfadiazine are used in burns to prevent infection. 9. Ulcerative colitis Sulfasalazine is useful in ulcerative colitis and rheumatoid arthritis. Fig. 36.1: Sequential blockade in folic acid synthesis 264 Textbook of Pharmacology for Dental and Allied Health Sciences

Adverse Effects AIDS patients. It also protects against infection with other gram-negative • Nausea, vomiting, headache, glossitis, bacteria. stomatitis and allergic skin rashes are 6. Chancroid Cotrimoxazole (DS, BD for 7 relatively common. In fact all the adverse days) is the drug of choice. effects to sulphonamides can also be seen 7. Orodental infections–Cotrimoxazole may be with cotrimoxazole because it contains used the treatment of mild infections as sulfamethoxazole. an alternative to penicillin. • In patients with folate deficiency, cotrimoxazole may precipitate megalo- QUINOLONES blastic anaemia. • Haematological reactions like anaemia The quinolones are a group of synthetic and granulocytopenia are rare. antimicrobial agents. Nalidixic acid is the • AIDS patients are more prone to adverse older agent in the group. Oxalinic acid and effects to cotrimoxazole. cinoxacin are other quinolones. • Patients with renal disease may develop uraemia. Nalidixic Acid Nalidixic acid is bactericidal against various Preparations gram-negative organisms like E. coli, Shigella, Trimethoprim Sulfamethoxazole (SEPTRAN, Proteus and Klebsiella. Its mechanism of action CIPLIN) is same as that of fluoroquinolones (see 80 mg 400 mg below). Nalidixic acid is well absorbed 160 mg 800 mg–double strength (DS) orally. However, the plasma concentration of the drug is inadequate to have systemic Uses effects but it attains high concentrations in the urine. 1. Urinary tract infection Uncomplicated acute Adverse effects Haemolytic anaemia, allergic UTI is treated for 7-10 days (DS, twice a reactions and CNS effects like headache, day) with cotrimoxazole. myalgia and drowsiness may be encoun- Chronic and recurrent UTI–small doses tered. are given for prophylaxis. Bacterial prostatitis–Trimethoprim attains Uses high concentration in prostatic fluid. Nalidixic acid is used in uncomplicated UTI 2. Respiratory tract infections Upper and and diarrhoea due to E.coli, Shigella and lower respiratory infections including Proteus (GRAMONEG 0.5-1g 3-4 times a day). bronchitis, sinusitis and otitis media respond. Oxalinic acid and cinoxacin have properties and 3. Bacterial gastroenteritis due to Shigella and uses similar to nalidixic acid. E. coli respond to cotrimoxazole. FLUOROQUINOLONES 4. Typhoid Cotrimoxazole is used as an alternative to fluoroquinolones. The quinolones were fluorinated to obtain 5. Pneumocystis carinii infection (now compounds with a wider spectrum of activity, identified as Pneumocystis jiroveci) fewer side effects, lesser chance of resistance Cotrimoxazole is used for prophylaxis and and better tissue penetration when compared high doses for treatment of Pneumocystis to quinolones. The fluoroqui-nolones (FQs) carinii pneumonia in neutropenic and include norfloxacin, ciprofloxacin, pefloxacin, Sulfonamides, Cotrimoxazole and Quinolones 265 ofloxacin, lomefloxacin and sparfloxacin—many Adverse reactions Fluoroquinolones are well- more are being added. The newer agents tolerated. Nausea, vomiting, abdominal include trovafloxacin, gatifloxacin, moxifloxacin, discomfort, diarrhoea and rashes may be and clinafloxacin. seen. Tendinitis with associated risk of tendon rupture has been reported. Mechanism of Action Fluoroquinolones damage the growing cartilage resulting in arthropathy and are Fluoroquinolones are bactericidal. They therefore contraindicated upto 18 years of inhibit the bacterial enzyme DNA gyrase age. CNS effects include headache and (topoisomerase II) which is required for DNA dizziness. In patients receiving NSAIDs and replication and transcription. other epileptogenic drugs like theophylline, During DNA replication there is positive fluoroquinolones can sometimes precipitate supercoiling of the DNA. This is corrected seizures. Grepafloxacin was found to cause by the enzyme DNA gyrase by introducing cardiac arrhythemias due to which it has negative supercoils and therefore this enzyme already been withdrawn from the market. is necessary for DNA replication. By inhibiting the enzyme DNA gyrase, Uses fluoroquinolones inhibit DNA replication. 1. Urinary tract infections Very effective in UTI Resistance is comparatively not very frequent even when caused by multi-drug resistant due to the unique mechanism of action. bacteria—norfloxacin is generally used (400 Resistance is due to mutations in the target mg—BD for 5-10 days). enzyme or a change in the permeability of 2. Typhoid Ciprofloxacin is the drug of the organism. Several strains of E.coli, choice (500 mg BD—10 days)— it also Staphylococci, Pseudomonas and Serratia have eradicates carrier state. now developed resistance. 3. Diarrhoea due to Shigella, E.coli and Antibacterial spectrum Gram-negative Campylobacter respond. organisms like gonococci, meningococci, H. 4. Gonorrhoea Single dose 250 mg cipro- influenzae, E. coli, Salmonella, Shigella, floxacin is curative. Ciprofloxacin is used enterobacteria; H. pylorii and gram-positive for 3 days. organisms like staphylococci; chlamydiae, 5. Chancroid As an alternative to cotri- mycoplasma and myobacterium are susceptible. moxazole-ciprofloxacin is used for 3 Some of the newer fluoroquinolones are effective against some anaerobic organisms and Streptococcus pneumoniae. Pharmacokinetics On oral administration, fluoroquinolones are well-absorbed and widely distributed. Food and antacids interfere with absorption; Pefloxacin and ofloxacin cross the BBB. All FQs are metabolised by hepatic microsomal enzymes and FQs are microsomal enzyme inhibitors – can result in related drug interactions. These drugs are excreted by the kidneys. Hence dose should be reduced in renal failure.

Plasma t½ varies from 3 hrs (norfloxacin), 10 hrs (pefloxacin) to 18-20 hrs (sparfloxacin given once daily) (Table 36.1). Fig. 36.2: Schematic diagram of DNA 266 Textbook of Pharmacology for Dental and Allied Health Sciences

days. Chlamydial urethritis, cervicitis, atypical mycobacterial infections. ciprofloxacin or sparfloxacin can be used 9. Bacterial prostatitis and cervicitis-FQs as alternatives to tetracyclines. are useful. 6. Respiratory tract infections—due to H. 10. Eye infections-Ciprofloxacin and influenzae, Legionella and Mycoplasma can ofloxacin may be used topically in the be treated with fluoroquinolones. treatment of eye infections. 7. Bone, joint, soft tissue and intra abdominal 11. Anthrax - also responds to fluoro- infections — osteomyelitis and joint quinolones. infections require prolonged treatment. 12. Orodental infections–Levofloxacin, Soft tissue infections due to sensitive ofloxacin, gatifloxacin and moxifloxacin bacteria can be treated with fluor- are all long acting, orally effective and oquinolones. have moderate efficacy against some 8. Tuberculosis Ciprofloxacin is one of the anaerobes. They can be used in the drugs in multi-drug regimens used for prevention and treatment of orodental resistant tuberculosis. It is also useful in infections.

Table 36.1: Dose and route of administration of some fluoroquinolones

Drug Dose and route Remarks

Norfloxacin Oral: 400 mg BD Preferred in urinary and genital (NORFLOX) infections Ciprofloxacin Oral: 250-750 mg BD Most widely used fluoroquinolone (CIPLOX) IV: 100-200 mg 12 h Pefloxacin Oral: 400 mg BD Penetration into CSF is good (PEFLOX) IV: 400 mg q 12 h Ofloxacin Oral: 200-400 mg OD Indicated in urinary and (TARIVID) IV: 200-400 mg respiratory tract infections and q 12-24 h gonorrhoea; Effective in chlamydial infections Levofloxacin Oral: 500 mg OD Better activity against gram-positive organisms and atypical pneumonia pathogens; excreted mainly through kidneys Lomefloxacin Oral: 400 mg OD Has a long t½ (LOMEF) Sparfloxacin Oral: 200-400 mg OD Enhanced activity against gram positive (SPARLOX) organisms and in atypical pneumonia; also useful in chlamydial infections. Gatifloxacin Oral : 400 mg OD Better activity against gram positive organisms and atypical pneumonia pathogens. Trovafloxacin Oral : 200 mg Excreted by non-renal mechanisms. Moxifloxacin Oral : 400 mg OD High activity against gram positive bacteria and some anaerobes. To be avoided in patients with risk of seizures. Beta-lactam Antibiotics 267 37 Beta-lactam Antibiotics

The β-lactam antibiotics have a β-lactam ring. Classification Penicillins, cephalosporins, monobactams and A. Natural— Penicillin G β carbapenems are -lactam antibiotics. B. Semisynthetic 1. Acid resistant—Penicillin V PENICILLINS 2. Penicillinase resistant— Methicillin, Oxacillin, Sir Alexander Fleming discovered penicillin Cloxacillin, Nafcillin in 1928. Penicillins are one of the most 3. Aminopenicillins— important groups of antibiotics. Penicillin is Ampicillin, Bacampicillin, now obtained from the fungus Penicillium Amoxicillin chrysogenum. 4. Antipseudomonal penicillins • Carboxypenicillins— Mechanism of Action Carbenicillin, Ticarcillin β • Ureidopenicillins— The -lactam antibiotics act by inhibiting the Azlocillin, Mezlocillin, cell wall synthesis in the bacteria. Piperacillin. The rigid cell wall of the bacteria protects it from lysis. Peptidoglycan—a complex NATURAL PENICILLINS polymer, is an important component of the Penicillin G (Benzyl Penicillin) cell wall. It consists of glycan chains which are cross-linked by peptide chains. The Antibacterial spectrum Penicillin G (PnG) has a synthesis of this peptidoglycan requires narrow antibacterial spectrum (Table 37.2) and is effective against gram-positive cocci enzymes called transpeptidases. β-lactam and bacilli and a few gram-negative cocci. antibiotics inhibit these transpeptidases and Thus streptococci, pneumococci, gonococci, thus inhibit the synthesis of the meningococci, B. anthracis, C. diphtheriae, peptidoglycan, resulting in the formation of clostridia, listeria and spirochetes are highly cell wall deficient bacteria. Such bacteria sensitive. undergo lysis. Thus penicillins are Resistance Many organisms like staphylococci bactericidal. produce a penicillinase which is a beta- 268 Textbook of Pharmacology for Dental and Allied Health Sciences lactamase—which opens the β-lactam ring potassium PnG is also available. Oral and inactivates penicillins. Altered target penicillin is used only in minor infections. proteins on the bacterial cell which reduces Since benzyl penicillin is short-acting, affinity for penicillins also lead to resistance. repository forms like procaine penicillin and Pharmacokinetics PnG is destroyed by gastric benzathine penicillin, which are longer-acting juice; food interferes with its absorption — are made available. Given deep IM they hence it is to be given 2 hr after food. It has release penicillin slowly from the site. a short t½ of 30 min. Though it does not Procaine penicillin is given 12-24 hourly while readily cross the BBB, in presence of a single injection of benzathine penicillin is inflammation of the meninges, therapeutic effective for 3-4 weeks. For preparation and concentration is attained in the CSF. It is dose see Table 37.1. excreted by the kidneys. Probenecid blocks the renal tubular secretion of penicillin and Adverse Effects thereby prolongs its duration of action. Preparations and dose PnG is mainly given Hypersensitivity PnG is the most common parenterally though orally effective form— cause of drug allergy. Manifestations range Table 37.1: Preparations, dose and route of administration of penicillins

Drug Dose Route Trade name

NATURAL PENICILLINS Sodium penicillin G 0.5-5 MU q 4-6 hr IM/IV CRYSTAPEN (Crystalline penicillin) Procaine penicillin G 0.5-1 MU q 12-24 hr IM PROCAINE PENICILLIN G

Benzathine penicillin G 1.2-2.4 MU Deep IM PENIDURE LA every 3-4 weeks SEMISYNTHETIC PENICILLINS Penicillin V 250-500 mg QID Oral CRYSTAPEN-V Cloxacillin 250-500 mg QID Oral KLOX Dicloxacillin 250-500 mg QID Oral BIOCLOX Nafcillin 1-2 gm q 4-6 hr IV UNIPEN Ampicillin 250 mg to 1 gm QID Oral AMPICILLIN IM/IV ROSCILLIN Ampicillin + sulbactum 1 gm Ampi + IV SULBACIN 0.5 gm sulb q 6-8 hr Amoxicillin 250-500 mg TID Oral NOVAMOX SYNAMOX Amoxicillin + clavulanic acid 250 mg Amox + Oral AUGMENTIN 125 mg Clav TID Piperacillin 3-4 gm q 4-6 hr IV PIPRAPEN Piperacillin+tazobactum 4g Pip+0.5g IV ZOSYN tazo q 8 hr Ticarcillin 3 gm q 4-6 hr IV TICAR q4-6hr — every 4 to 6 hours. MU-Mega Unit Beta-lactam Antibiotics 269 from skin rashes, urticaria, fever, anaerobic microorganisms and therefore very bronchospasm, serum sickness and rarely useful in most orodental infections. However exfoliative dermatitis and anaphylaxis. the disadvantages of parenteral adminis- Though all forms of penicillins can cause tration and hypersensitivity reactions have allergy, anaphylaxis is more common limited its use. Procaine Penicillin can be used following parenteral than oral preparations. IM. The highest incidence is with procaine (B) Other infections penicillin where allergy is most often due to 1. Pneumococcal infections For infections like the procaine component. There is cross- pneumonia, meningitis and osteomyelitis sensitivity among different penicillins. due to penicillin-sensitive pneumococci, Topical penicillins are highly sensitizing and PnG is the drug of choice. their use is banned. 2. Streptococcal infections Pharyngitis, sinusitis, History of allergy to penicillins should be pneumonia, meningitis and endocarditis taken before prescribing; incidence of allergy are all treated with penicillin. Infective is higher among atopic individuals. A scratch endocarditis due to Strep. viridans is test or intradermal sensitivity test with 2-10 treated with high dose PnG ± an units should be done. Even if this is negative, aminoglycoside. it does not completely rule out allergy. 3. Meningococcal infections PnG is the drug Penicillin should be given cautiously and a of choice for all meningococcal infections. 4. Staphylococcal infections Since most syringe loaded with adrenaline to treat staphylococci produce penicillinase, a anaphylaxis should be kept ready. penicillinase resistant penicillin should be Other Adverse Effects used. 5. Syphilis is treated with procaine penicillin Local Pain at the site of injection, for 10 days or with benzathine penicillin. thrombophlebitis on IV injection. 6. Diphtheria Antitoxin is the only effective CNS Large doses of PnG may produce treatment. PnG eliminates carrier state - confusion, muscle twitchings, convulsions PP6 given for 10-12 days. and coma. 7. Anaerobic infections Pulmonary, per- Suprainfections are rare due to its narrow iodontal and brain abscesses due to spectrum of activity. anaerobes respond to PnG. Jarisch-Herxheimer reaction When penicillin is 8. Actinomycosis PnG is the drug of choice injected in a patient with syphilis, there is for all forms of actinomycosis. 12 to 20 sudden destruction of spirochetes and release MU should be given for 6 weeks. of its lytic products. This triggers a reaction 9. Tetanus and gas gangrene Antitoxin is the with fever, myalgia, shivering, exacerbation treatment for tetanus—but PnG has of syphilitic lesions and vascular collapse. adjuvant value. Gas gangrene— PnG is the drug of choice. Uses 10.Other infections PnG is the agent of choice for infections like anthrax, trench mouth, Penicillin G is the antibiotic of choice for rat bite fever and listeria infections. several infections unless the patient is allergic 11.Prophylactic uses: to it. • Rheumatic fever Benzathine penicillin 1.2 (A) Orodental infections—Penicillin G is MU every month prevents colonisation effective against a variety of aerobic and by streptococci and thereby decreases 270 Textbook of Pharmacology for Dental and Allied Health Sciences

the recurrences of rheumatic fever. It Uses is to be continued for several years. Penicillinase resistant penicillins are the drugs • Gonorrhoea and syphilis Sexual contacts of choice for infections with penicillinase are effectively protected against these producing staphylococci. Methicillin resistant diseases when treated with penicillin strains have now emerged and are treated within 12 hours of exposure. with vancomycin. • Valvular heart diseases—25% cases of bacterial endocarditis are seen Extended Spectrum Penicillins following dental extractions. Patients Aminopenicillins These agents cover a wider with valvular heart diseases under- antibacterial spectrum including many gram- going dental extractions, endoscopies negative bacilli. They are orally effective but and other minor surgical procedures are sensitive to betalactamases. that may cause bacteraemia should be Antibacterial spectrum Both gram-positive and given penicillin prophylaxis. gram-negative organisms including stre- Disadvantages of natural penicillins are: ptococci, meningococci, pneumococci, H. 1. they are not effective orally. influenzae, E. coli, Proteus, Salmonella, Shigella 2. have a narrow spectrum of activity. and Klebsiella are sensitive. Many strains are 3. are susceptible to β lactamase. now resistant. 4. can cause hypersensitivity. Ampicillin is well-absorbed orally; food To overcome the above disadvantages, interferes with absorption. It is excreted semisynthetic penicillins have been intro- mainly through kidneys. duced. Adverse effects Diarrhoea due to irritation of the gut by the unabsorbed drug is the most SEMISYNTHETIC PENICILLINS common adverse effect with ampicillin. Skin rashes are also fairly frequent. Acid resistant penicillins Penicillin V (Phenoxymethyl penicillin) is acid stable and Uses can be given orally. It is used only in mild 1. Respiratory tract infections like bronchitis, streptococcal pharyngitis, sinusitis and trench sinusitis and otitis media respond to mouth. ampicillin. Dose 250-500 mg 6 hourly. 2. Urinary tract infections Though ampicillin Penicillinase resistant penicillins are resistant was the drug of choice earlier, many to hydrolysis by penicillinase produced by organisms have now become resistant. bacteria. However, against other micro- 3. Meningitis Ampicillin is given with a organisms—they are less effective than PnG. cephalosporin. Methicillin is destroyed by gastric juice— 4. Typhoid Ampicillin is an alternative to hence given parenterally. Cloxacillin is given ciprofloxacin. orally. Nafcillin is highly resistant to 5. Septicaemia due to gram-negative organisms. penicillinase and also has useful activity Intravenous ampicillin may be used, with against nonpenicillinase producing organ aminoglycoside. anisms. It requires parenteral administration 6. Dental infections–Ampicillin is useful in the because of its unreliable absorption from the treatment of most orodental infections. gut. However, diarrhoea has limited its use. Beta-lactam Antibiotics 271

Bacampicillin is an ester of ampicillin. It is a is given parenterally while carbenicillin prodrug that is better absorbed (hence indanyl is effective orally. Ticarcillin has diarrhoea is less common) and longer-acting better activity against P. aeruginosa. All three than ampicillin. are susceptible to penicillinase. Amoxicillin differs from ampicillin in the Adverse effects Carbenicillin is used as a sodium following: salt and in higher doses this excess sodium 1. Amoxicillin is better absorbed orally may cause oedema and CCF; may also cause 2. Food does not interfere with its absorption bleeding due to abnormal platelet 3. Diarrhoea is rare (because it is well aggregation. absorbed). 4. Given thrice daily (Table 37.2). Ureidopenicillins Amoxicillin is used in similar infections as Ureidopenicillins have a wider antibacterial ampicillin like respiratory infections, spectrum and are effective against prevention and treatment of infections in Pseudomonas and Klebsiella infections. dental practice, Salmonella gastroenteritis Moreover, their sodium content is low. Hence and urinary tract infections. Amoxicillin is a they have almost replaced carboxypenicillins. component of the various regimens to Azlocillin, mezlocillin and piperacillin are all eradicate H. pylori. Amoxicillin is preferred administered intravenously. When combined over ampicillin because of its advantages with a beta lactamase inhibitor, piperacillin mentioned above. can be considered to have the broadest antibacterial spectrum among the penicillins. ANTIPSEUDOMONAL PENICILLINS Carboxypenicillins Beta-Lactamase Inhibitors Carbenicillin is effective in Pseudomonas β-lactamases are enzymes produced by aeruginosa and Proteus infections. Carbenicillin bacteria that open up the β-lactam ring and

Table 37.2: Compare and contrast penicillin G and amoxicillin

Feature Penicillin G Amoxicillin

Source Natural Semisynthetic (Penicillium chrysogenum) Acid stability Acid labile Acid stable Antibacterial spectrum Narrow Wide (Mostly Gm+ve) (Gm+ve and Gm –ve)* Route of administration Parenteral only Oral and parenteral Duration of action Short Longer Plasma t½ 30 minutes 2 hrs Frequency of administration QID TID Prominent adverse effect Allergy Diarrhoea Structure Has β lactam ring Has β lactam ring Penicillinase susceptibility Yes Yes

* Gm +ve - Gram positive Gm –ve – Gram negative 272 Textbook of Pharmacology for Dental and Allied Health Sciences inactivate the β-lactam antibiotics. Resistance As in the case of penicillins, beta- β-lactamase inhibitors bind to and inactivate lactamases and altered target proteins β-lactamases preventing the destruction of determine resistance to cephalosporins. the β-lactam antibiotics.The antibacterial Cephalosporins are classified into 4 spectrum depends on the penicillin used. generations as follows: β-lactamase inhibitors are clavulanic acid, sulbactam and tazobactam. CLASSIFICATION Clavulanic acid inhibits β-lactamases and is combined with amoxicillin for both oral Parenteral Oral and parenteral administration. It extends the First generation Cephalothin Cephalexin antibacterial spectrum of amoxicillin and the Cefazolin Cefadroxil combination inhibits organisms like betalactamase producing staphylococci, Second generation Cefamandole Cefachlor gonococci, E.coli and H. influenzae. The Cefuroxime Cefuroxime Cefotetan, axetil combination is used for mixed aerobic- Cefoxitin anaerobic infections including orodental infections, gonorrhoea and nosocomial Third generation Cefotaxime Cefixime infections. Clavulanic acid is also combined Ceftrioxone Cefpodoxime with ticarcillin. Cefoperazone proxetil Ceftizoxime Cefdinir Sulbactam is combined with ampicillin. It Ceftazidime Ceftibuten is given parenterally for mixed aerobic- anaerobic infections including orodental, Fourth generation Cefepime intra-abdominal, gynaecological, surgical, Cefpirome pelvic and other infections. Tazobactam is combined with piperacillin First Generation Cephalosporins for parenteral administration. They are available in fixed combinations. First generation cephalosporins are very effective against gram-positive organisms. Drugs Route Cephalothin is resistant to penicillinase, Clavulanic acid + amoxicillin Oral hence can be used in staphylococcal Clavulanic acid + ticarcillin IV 1 infections. Cefazolin has a longer t /2 and its Sulbactam + ampicillin IV tissue penetrability is good—Therefore used Tazobactam + piperacillin IV for surgical prophylaxis. Streptococci, staphylococci, E.coli and Klebsiella are CEPHALOSPORINS inhibited. Cephalexin is used orally for minor Cephalosporins are semisynthetic antibiotics infections like abscesses or cellulitis. with a beta-lactam ring related to penicillins. For preparations, dose and routes see Table 37.3. They are derived from cephalosporin-C and have a wider spectrum of activity than Second Generation Cephalosporins penicillins. Mechanism of action Cephalosporins inhibit Second generation cephalosporins are more the bacterial cell wall synthesis similar to active against some gram-negative organisms penicillins (see page 270). compared to first generation ones. H. Beta-lactam Antibiotics 273

Table 37.3: Preparations, doses and routes of administration of some cephalosporins

Drugs Doses Routes Cephalothin (KAFLIN) 1-2 gm q 6 h IV Cefazolin (ALCIZON) 0.5-1 gm q 6 h IM/IV Cephalexin (SPORIDEX) 0.25-1 gm qid Oral Cefadroxil (DROXYL) 0.5-1 gm bid Oral Cefamandole (KEFADOL) 0.5-2 gm q 4-8 h IM/IV Cefuroxime (SUPACEF) 0.75-1.5 gm q 8 h IM/IV Cefuroxime axetil (CEFTUM) 0.25 -0.5 gm bid Oral Cefachlor (KEFLOR) 0.25-0.5 gm q 8 h Oral Cefotaxime (OMNATAX) 1-2 gm q 8 h IM/IV Ceftriaxone (OFRAMAX) 1-2 gm q 12-24 h IM/IV Cefoperazone (CEFOBID) 1-2 gm q 8-12 h IM/IV Cefixime (CEFSPAN) 0.2-0.4 gm q 12 h Oral Cefpodoxime proxetil (CEPODEM) 200-400 mg q 12 h Oral Cefpirome (CEFROM) 1-2 gm q 12 h IV influenzae, E. coli, Proteus and Klebsiella are Fourth Generation Cephalosporins inhibited. Cefuroxime is resistant to β- Fourth generation cephalosporins - cefepime lactamases; attains good CSF concentration and cefpirome are active against a variety of and is useful in meningitis. Cefoxitin and gram positive and gram negative organisms cefotitan are effective against B. fragilis and including streptococci, staphylococci, are used in mixed infections like in meningococci, gonococci, some enterococci, intraabdominal infections. enterobacteriaceae, H.influenzae and Pseudomonas aeruginosa. They are more Third Generation Cephalosporins resistant to β lactamases. Both cefepime and Third generation cephalosporins are highly cefpirome are administered parenterally. resistant to β-lactamases; have good activity Cefepime attains good CSF levels while against gram-negative organisms including cefpirome has good tissue penetrability. Both Citrobacter, Serratia, Enterobacteriaceae, are excreted almost completely through the Pseudomonas aeruginosa, N.gonorrhoeae and kidneys. betalactamase producing H.influenzae; but these The fourth generation agents are used in have weak activity against gram positive septicaemia, nosocomial and other serious cocci. Many cross BBB and are useful in infections of the skin, respiratory and urinary meningitis. Ceftrioxone has a long t½ and can tract as well as infections in immuno- be given once daily. It is excreted mainly compromised patients. through biliary tract and no dosage Adverse Reactions adjustment is needed in renal insufficiency. Ceftazidime is effective against P.aeruginosa. Cephalosporins are generally well-tolerated. 274 Textbook of Pharmacology for Dental and Allied Health Sciences

1. Hypersensitivity reactions like skin rashes, 8. Orodental infections–Orally effective fever, serum sickness and rarely cephalosporins like cephalexin, cefaclor, anaphylaxis are seen. 20% of patients cefuroxime axetil are used for the allergic to penicillin show cross-reactivity treatment of orodental infections. The to cephalosporins. There are no reliable latter two also have good activity against skin tests for testing allergy. anaerobes which make them the preferred 2. Nephrotoxicity Mild nephrotoxicity is cephalosporins in dentistry. Cefazolin and noted with some cephalosporins. cefotaxime are used for surgical Combination with other nephrotoxic prophylaxis in dental surgeries. drugs should be avoided. 3. Diarrhoea can result from some of the CARBAPENEMS cephalosporins. β 4. Bleeding is due to hypoprothrombinaemia Carbapenems contain a -lactam ring fused which is more common in malnourished with a five-membered penem ring. Carba- patients. penems include imipenem, meropenem and 5. Low WBC count may be seen though ertapenem. rarely. Antibacterial spectrum – Carbapenems have a 6. Pain at the injection site may occur. wide antibacterial spectrum and inhibit 7. Disulfiram-like reaction with alcohol is various gram-positive, gram-negative reported with some cephalosporins. organisms and anaerobes including streptococci, staphylococci, enterococci, Listeria, Uses of Cephalosporins enterobacteriaceae, Pseudomonas and B.fragilis. 1. Gram-negative infections Urinary, Mechanism of Action respiratory and soft tissue infections due to gram-negative organisms respond–a Carbapenems inhibit bacterial cell wall third generation agent is used. synthesis similar to penicillins (see page 270). 2. Surgical prophylaxis Cefazolin is preferred Imipenem-is not absorbed orally and is 1 due to its longer t /2 and better tissue administered intravenously (250-500 mg penetrability for surgical prophylaxis every 6-8 hours); it has good tissue including dental surgeries. penetrability. Imipenem is inactivated quickly 3. Gonorrhoea Ceftriaxone (single dose 250 by a dehydropeptidase in the renal tubules. mg) is the drug of choice. Hence it is always combined with cilastatin, 4. Meningitis due to H. influenzae, an inhibitor of dehydropeptidase in order to N. meningitidis and S. pneumoniae—third prolong its plasma half life. generation agents are useful - cefotaxime Adverse effects to imipenem include nausea, or ceftrioxone may be used. Pseudomonas vomiting, diarrhoea and allergic reactions meningitis - ceftazidime + an amino- especially in patients allergic to other →→→ glycoside very effective. β-lactam antibiotics. High doses can 5. Mixed aerobic-anaerobic infections–common occasionally cause seizures. following pelvic surgeries–a third generation agent is used. Uses 6. Typhoid-As an alternative to ciprofloxacin. 7. Nosocomial infections can be treated with Imipenem-cilastatin is used in UTI, third generation cephalosporins. respiratory, skin, bone, soft tissue, intra- Beta-lactam Antibiotics 275 abdominal and gynaecological infections due MONOBACTAMS to susceptible microorganisms. It is parti- Monobactams are monocyclic beta-lactams, cularly useful in enterobacter, penicillin- i.e they contain a single ring–the beta-lactam resistant pneumococci and other nosocomial ring. infections resistant to other antibiotics. It is Aztreonam is the monobactam available. It is used with an aminoglycoside in pseu- active against gram - negative bacilli including domonas infections. Pseudomonas aeruginosa but is not effective Meropenem has the following advantages over against gram-positive organisms and imipenem- anaerobes. Aztreonam acts by inhibiting cell wall synthesis like penicillins. It is given • It is not destroyed by renal dipeptidase parenterally (IM/IV 1-2 G every 6-8 hrs). and therefore does not require to be Aztreonam can be used in patients allergic combined with cilastatin. to penicillins because there is no cross • Risk of seizures less than with imipenem. allergenicity with other β-lactams. The only Indications of meropenem are similar to reported adverse effects are occasional skin imipenem. rashes. Aztreonam is used in pseudomonas Ertapenem is similar to meropenem except that infections especially nosocomial and in other it is not useful against P. aeruginosa. gram-negative infections. 276 Textbook of Pharmacology for Dental and Allied Health Sciences 38 Broad Spectrum Antibiotics

TETRACYCLINES Tetracyclines are antibiotics with four cyclic rings (hence the name) obtained from the soil actinomycetes. In addition to gram-positive and gram-negative bacteria, tetracyclines also inhibit the growth of other microorganisms like Rickettsiae, Chlamydiae, Mycoplasma and some protozoa. Therefore they are called broad spectrum antibiotics. The tetracyclines include- Tetracyclines Semisynthetic derivatives Chlortetracycline Demeclocycline Tetracycline Methacycline Fig. 38.1 : Mechanism of action of tetracyclines Oxytetracycline Doxycycline and chloramphenicol Minocycline plasmodia. Many organisms have now become Mechanism of action Tetracyclines are taken up resistant. by the susceptible microorganisms by active Pharmacokinetics Older tetracyclines are transport. The bacterial ribosome (Fig. 38.1) incompletely absorbed from the gut; food consists of 50S and 30S subunits. The tRNA carries amino acids to the ribosome for protein interferes with their absorption. Doxycycline synthesis. The ribosome has three binding sites - 95% and minocycline is 100% absorbed and viz. A, P and E sites. Tetracyclines bind to 'A' food does not affect the absorption of these site and prevent the binding of tRNA to this two agents. Tetracyclines chelate calcium and site. Thus they prevent protein synthesis and other metals which reduce their absorption. are bacteriostatic. Hence tetracyclines should not be given with Antibacterial spectrum is broad including gram- milk, iron preparations and antacids. positive and gram-negative organisms like Tetracyclines except doxycycline and Streptococci, Staphylococci, Gonococci, minocycline are excreted through kidneys. Meningococci, H. influenza, Brucella, V. cholerae, Doxycycline and minocycline are excreted Campylobacter, Y.pestis and many anaerobes. through the gut and are therefore safe in renal They also inhibit rickettsiae, chlamydiae, insufficiency. For dosage of tetracyclines see mycoplasma, actinomyces, E. histolytica and Table 38.1. Broad Spectrum Antibiotics 277

Table 38.1: Dosage of some tetracyclines

Tetracyclines Doses

Chlortetracycline (AUREOMYCIN) 250-500 mg QID Tetracycline (HOSTACYCLINE) 250-500 mg QID Doxycycline (DOXYCAPS) 200 mg initially then 100 mg OD Minocycline (CYANOMYCIN) 200 mg initially then 100 mg OD

Adverse Effects 6. Suprainfections Since the intestinal flora are extensively suppressed by tetracyclines, 1. GIT Gastrointestinal irritation, nausea, these are the most common antibiotics to vomiting and diarrhoea—tetracyclines are to be given with food to minimise these cause suprainfections. effects. 7. Hypersensitivity reactions are not very 2. Hepatotoxicity may result in jaundice. Acute common. hepatic necrosis may occur in pregnant Uses women but is rare. 3. Renal toxicity Renal failure may be A. Tetracyclines are the drugs of choice in aggravated. Outdated tetracyclines cause 1. Rickettsial infections All rickettsial infections a syndrome like Fanconi’s syndrome with respond to tetracyclines. vomiting, polyuria, proteinuria, glycosuria 2. Chlamydial infections: and acidosis due to the metabolites of — lymphogranuloma venereum—tetra- outdated tetracyclines. cyclines given for 2 weeks 4. Phototoxicity Skin reactions and dermatitis — trachoma—both topical and oral on exposure to sun are more likely with tetracyclines are needed doxycycline and demeclocycline. — inclusion conjunctivitis. 5. Effect on teeth and bones Tetracyclines chelate 3. Atypical pneumonia due to Mycoplasma calcium. The calcium - tetracycline - ortho- pneumoniae. phosphate complexes get deposited in the 4. Cholera Tetracyclines reduce the duration developing teeth and bones. The defor- of illness and are of adjuvant value. mities depend on the time of tetracycline 5. Brucellosis Doxycycline 200 mg + administration as given below (Table 38.2) Rifampicin 600 mg daily for 6 weeks is Tetracyclines are thus teratogenic. the treatment of choice.

Table 38.2: Terotogenic effects of tetracyclines

Period Structure affected Deformity • Mid pregnancy Brownish discolouration, ill to 5 months Deciduous teeth formed and are more of postnatal life susceptible to caries

• 2 months Permanent teeth Pigmentation, to 5 years of age discolouration • Pregnancy Skeleton Depressed and childhood bone growth up to 8 years of age 278 Textbook of Pharmacology for Dental and Allied Health Sciences

6. Plague Tetracyclines may be combined 4. Acne—The propioni bacteria in the with an aminoglycoside. sebaceous follicles metabolise lipids into B. Tetracyclines are useful in other infections like irritating free fatty acids which trigger the 1. Periodontitis–In chronic periodontitis that development of acne. Tetracyclines inhibit does not respond to usual line of these bacteria. Low doses are given for a treatment, many modalities of treatment long time (250 mg BD for 4 weeks). including surgery are used in order to 5. Protozoal infections: reduce the number of microorganisms • Amoebiasis—Tetracyclines are useful in infecting the periodontium. Low dose chronic intestinal amoebiasis (page 321) tetracyclines (250mg q.i.d.) are used as • Malaria—Doxycycline is given with adjuvants. 20 mg doxycycline given twice quinine in multi-drug resistant malaria. daily for 2-4 weeks is thought to act by C. Inappropriate secretion of ADH Demeclo- inhibiting crevicular bacterial collage- cycline is used because it inhibits the nases. These enzymes are thought to be action of ADH in the kidney. responsible for the inflammation and Contraindications Tetracyclines are contrain- injury to the periodontium - collagenases dicated in pregnancy, lactation and in are dependent on calcium. By chelating children up to 8 years of age. Ca++, tetracyclines suppress the collagenase activity and thereby suppress Doxycycline (Table 38.3) and minocycline are inflammation. Doxycycline polymer gel is semisynthetic tetracyclines. now available in some countries - to be • given orally they are 95 and 100% placed into the periodontial pocket so that absorbed respectively the drug gets slowly absorbed. • food does not interfere with their For systemic antibacterial activity absorption tetracyclines may be combined with • have long t½—can be given once daily metronidazole or ciprofloxacin. • excreted through gut hence can be given 2. Traveller’s diarrhoea—Doxycycline reduces in usual dose even in the presence of renal the incidence of traveller’s diarrhoea. impairment 3. Sexually transmitted diseases like syphilis, • minocycline causes vestibular toxicity gonorrhea and chancroid also respond to characterised by vertigo, dizziness, ataxia, tetracyclines—but are not preferred. nausea and vomiting. Table 38.3: Compare and contrast tetracyline and doxycycline

Feature Tetracycline Doxycycline

1. Source Semisynthetic Semisynthetic 2. Intestinal absorption Incomplete Complete 3. Bioavailability 75% 95% 4. Lipid solubility Low High 5. Plasma t½ 8-10 hrs 18-24 hrs 6. Dose and frequency 500mg QID 200mg stat, 100 mg O.D. from of administration day 2 7. Route of excretion Kidney Gut 8. Safety in renal Not safe Safe impairment 9. Inhibition of intestinal Significant Low flora 10. Phototoxicity Low high Broad Spectrum Antibiotics 279

CHLORAMPHENICOL 3. Gray baby syndrome Newborn babies given Chloramphenicol is a broad spectrum high doses of chloramphenicol may antibiotic first obtained from Streptomyces develop vomiting, refusal of feeds, venezuelae in 1947. hypotonia, hypothermia, abdominal Mechanism of action Chloramphenicol is distension, metabolic acidosis and ashen bacteriostatic but to some organisms it is gray cyanosis—described as gray baby bactericidal. It binds to 50S ribosomal subunit syndrome. It may be fatal. As the and inhibits protein synthesis - by inhibiting newborn cannot metabolize (due to transpeptidation reaction (Fig. 38.1). inadequate hepatic glucuronidation) and Antibacterial spectrum is broad and includes excrete chloramphenicol adequately, gram-negative organisms, some gram- toxicity results. positive organisms, anaerobic bacteria, 4. Hypersensitivity reactions like rashes and Rickettsiae, Chlamydiae and Mycoplasma. fever are uncommon. Thus H. influenzae, Salmonella, Shigella, 5. Superinfection can occur. Bordatella, Brucella, gonococci, meningococci, streptococci, staphylococci, Clostri- Drug Interactions dium, E.coli and Klebsiella—are inhibited apart from Rickettsiae, Chlamydiae and Chloramphenicol inhibits hepatic microsomal Mycoplasma. enzymes and thereby prolongs the half-life Resistance is plasmid mediated and may be of drugs metabolised by this system. This may due to: result in enhanced toxicity of some drugs like 1. Inactivating enzymes phenytoin, tolbutamide and dicumarol. 2. ↓ permeability of the microorganisms 3. Ribosomal insensitivity. Uses Pharmacokinetics Chloramphenicol is rapidly Because of the risk of bone marrow toxicity absorbed from the gut; penetration into tissues and availability of safer drugs, chloram- is excellent; attains high concentration in CSF. phenicol is not generally preferred either in It is metabolised in the liver by conjugation. dentistry or general medicine. The Adverse Reactions indications are: 1. Typhoid fever Very effective in typhoid; 1. Gastrointestinal disturbances Nausea, given for 14 days (500 mg QID till fever vomiting, diarrhoea. subsides then 250 mg QID up to 14th day). Bone marrow depression 2. Chloramphenicol 2. Bacterial meningitis In meningococcal and may cause bone marrow depression in H. influenzae meningitis—chloramphenicol two ways: is an alternative to penicillin. (i) dose dependent anaemia, leukopenia and thrombocytopenia due to 3. Anaerobic infections Chloramphenicol + inhibition of protein synthesis. It is penicillin + an aminoglycoside can be used reversible. in severe anaerobic infections as an (ii) idiosyncratic response—resulting in alternative to metronidazole and aplastic anaemia which may be fatal. clindamycin. It may be due to a toxic metabolite. 4. Rickettsial infections As an alternative when Incidence is 1 in 30,000 patients and tetracyclines are contraindicated. occurs in genetically predisposed 5. Eye infections Chloramphenicol is used individuals. This toxicity has limited topically because of the good penetration the use of chloramphenicol. into aqueous humour. 280 Textbook of Pharmacology for Dental and Allied Health Sciences

39 Aminoglycosides

Aminoglycosides are antibiotics with amino there they are taken up by an active transport sugars in glycosidic linkages. They are process. Inside the cell, (Fig. 39.1) amino- derived from the soil actinomycetes of the glycosides bind to 30S ribosomes and inhibit genus streptomyces (streptomycin, kana- bacterial protein synthesis - block initiation mycin, tobramycin, neomycin) and the genus of protein synthesis, cause termination of micromonospora (gentamicin and netilmicin) protein synthesis and cause addition of - hence the difference in spelling. Amikacin incorrect amino acids resulting in the and netilmicin are semisynthetic products. synthesis of abnormal proteins. Amino- glycosides are bactericidal. Higher the Common Properties of Aminoglycosides concentration, greater is the bactericidal 1. Aminoglycosides are not absorbed orally effect. A residual bactericidal effect— (as they ionize in solution) therefore they postantibiotic effect—remains even after the are given parenterally. plasma levels of aminoglycosides fall. Hence, 2. They remain extracellularly and pene- even though they have a short t½, they can tration into CSF is very poor. be given once a day (Table 39.1). 3. They are excreted unchanged by the Resistance to aminoglycosides is acquired by kidneys. 1. Aminoglycoside inactivating enzymes. 4. They are all bactericidal. 2. Low affinity of ribosomes - acquired by 5. They act by inhibiting bacterial protein mutation. synthesis. 3. Decrease in permeability to the antibiotic. 6. They are mainly effective against gram- There is partial cross-resistance among negative organisms. various aminoglycosides. 7. They produce variable degrees of ototoxicity and nephrotoxicity as adverse Pharmacokinetics effects. Antibacterial spectrum Aminoglycosides have Aminoglycosides are not absorbed from the a narrow spectrum and are effective mainly gut but when instilled into body cavities or against aerobic gram-negative bacilli like E. applied over large wounds, they may get coli, Proteus, Pseudomonas, Brucella, Salmonella, rapidly absorbed. Following IM injection Shigella and Klebsiella. peak levels are seen in 60 minutes. They are Mechanism of action Aminoglycosides, being not bound to plasma proteins and do not water-soluble penetrate the bacterial cell enter cells or cross barriers - mostly remain membrane through aqueous pores and from in the vasculature. In patients with severe Aminoglycosides 281

Stopping the drug can prevent further damage. Vestibular dysfunction is manifested by headache, nausea, vomiting, dizziness, vertigo, nystagmus and ataxia. Most symptoms subside in two weeks except ataxia which may persist for 1-2 years. 2. Nephrotoxicity Aminoglycosides attain high concentration in the renal cortex and cause damage to the renal tubules. This results in loss of urine concentrating capacity, low GFR and albuminuria. These Fig. 39.1: Mechanism of action of aminoglycosides effects are reversible. Most symptoms subside in 2 weeks except ataxia which infection, plasma concentration of amino- may persist for 1-2 years. glycosides should be determined to guide the 3. Neuromuscular blockade Aminoglycosides treatment. have curare-like effects and block neuromuscular transmission. Adverse Effects Precautions in Using Aminoglycosides 1. Ototoxicity is the most important toxicity. 1. Avoid concurrent use of other ototoxic Both vestibular and auditory dysfunction drugs like loop diuretics. can occur depending on the dose and 2. Avoid concurrent use of other nephrotoxic duration. The aminoglycosides get drugs like amphotericin B, cephalothin and concentrated in the labyrinthine fluid of cisplatin. the inner ear and damage both cochlear 3. Avoid concurrent use of curarimimetic hair cells and vestibular sensory cells. As drugs. the cochlear cells cannot regenerate, there 4. To be used cautiously in elderly, in renal is progressive, permanent deafness. The damage and in combination with skeletal auditory nerve degenerates. Tinnitus muscle relaxants. appears first, followed by deafness; 5. Contraindicated in pregnancy because of elderly people are more susceptible. risk of deafness in the child.

Table 39.1: Dose and routes of administration of aminoglycosides

Aminoglycosides Doses Routes

Streptomycin (STREPTONEX) 1-2 g/day IM Gentamicin (GARAMYCIN) 3-5 mg/kg/day in 3 divided doses IM/IV Tobramycin (TOBRANEG) 3-5 mg/kg/day in 3 divided doses IM/IV Amikacin (AMICIN) 15 mg/kg/day in 2-3 divided doses IM/IV Netilmicin (NETROMYCIN) 4-6 mg/kg/day in 2-3 divided doses IM/IV 282 Textbook of Pharmacology for Dental and Allied Health Sciences

6. Do not mix aminoglycosides with any Uses other drug in the same syringe. 1. UTI Gentamicin is effective in uncompli- 7. Determination of plasma levels of amino- cated UTI as it is released for a long time glycosides may be needed in severe infections from the renal cortex. and in patients with renal dysfunction. 2. Pneumonia due to gram-negative orga- Streptomycin obtained from Streptomyces griseus nisms may be treated with gentamicin + is mainly effective against aerobic gram- penicillin. negative bacilli. When used alone, bacteria, 3. Osteomyelitis, peritonitis, septicaemia caused especially the tubercle bacillus rapidly by gram-negative organisms can be develops resistance to it. Streptomycin is the treated with gentamicin. least nephrotoxic among aminoglycosides. 4. Meningitis due to gram-negative bacilli— gentamicin is used with a III generation Uses cephalosporin. 5. Gentamicin may be used in place of 1. Tuberculosis streptomycin in SBE. 2. Subacute bacterial endocarditis (SBE)— 6. Topical Combination of streptomycin and • Gentamicin cream is used topically in penicillin is synergistic in this condition. burns and other infected wounds. 3. Plague, tularaemia and Brucellosis— • Gentamicin eye drops are used in the Streptomycin is given with a tetracycline. prevention and treatment of bacterial Gentamicin obtained from Micromonospora conjunctivitis. purpurea (Table 39.2) is more potent and has a broader spectrum of action compared to Tobramycin has better activity against streptomycin. Development of resistance has Pseudomonas and is used with an antips- limited its use. eudomonal penicillin in such infections.

Table 39.2: Compare and contrast amoxillin and gentamicin

Features Amoxicillin Gentamicin

Chemistry β lactam antibiotic Aminoglycoside Source Semisynthetic Natural from Micromonospora purpurea Antibacterial spectrum Wide - Gm+ve and Gm-ve Narrow – mostly microorganisms Gm-ve microorganisms. Mechanism of action Inhibits cell wall synthesis Inhibits protein synthesis. Intestinal absorption Well absorbed Not absorbed Route of administration Oral Parenteral Volume of distribution Large Small Therapeutic index High Low Prominent adverse effects Diarrhoea, allergy Ototoxicity, Nephrotoxicity Major action • Antibiotic • Antibiotic • Bactericidal • Bactericidal

Gm+ve-gram positive Gm–ve– gram negative Aminoglycosides 283

Antibiotics that inhibit protein synthesis bind to Neomycin has a wide antibacterial spectrum. ribosomes As it is highly ototoxic, it is not given 50S 30S systemically. It is used topically as ointments, creams and powder. Erythromycin Tetracyclines Adverse effects Neomycin can cause Chloramphenicol Aminoglycosides Clindamycin skin rashes on topical use. Oral use can Streptogramins cause diarrhoea, steatorrhoea and Linezolid malabsorption due to damage to the intestinal villi. Superinfection with Candida Kanamycin Due to its toxicity, its use is can also occur. limited to multi-drug resistant tuberculosis. Amikacin has widest antibacterial spectrum Uses among the aminoglycosides. It is resistant 1. Neomycin is used topically in skin to aminoglycoside inactivating enzymes. infections, burns, ulcers and wounds; eye and ear infections. Uses 2. Orally—neomycin is not absorbed when 1. Nosocomial infections due to gram- given orally. It is used to prepare the negative organisms bowel for surgery, i.e. for preoperative 2. Tuberculosis—Amikacin is useful in gut sterilization. multidrug resistant tuberculosis in 3. Hepatic coma—ammonia produced by combination with other drugs. It is also colonic bacteria is absorbed and used in infections due to atypical converted to urea by the liver. In severe mycobacteria in patients with AIDS. hepatic failure, as liver is unable to Netilmicin Like amikacin, netilmicin is handle this NH3, blood NH3 levels rise resistant to aminoglycoside inactivating resulting in encephalopathy. As enzymes. It is used in serious infections due neomycin inhibits intestinal flora, NH3 to gram-negative bacilli. production falls. Neomycin is given Sisomicin has actions, toxicity and uses orally for this purpose. similar to gentamicin. 284 Textbook of Pharmacology for Dental and Allied Health Sciences

40 Macrolides, Other Antibacterial Agents and Chemotherapy of Urinary Tract Infections

Macrolides are antibiotics with a macrocyclic Resistance Resistance to macrolides is acquired lactone ring to which sugars are attached. through plasmids. The mechanism involved Erythomycin and its semisynthetic deri- may be: vatives roxithromycin, clarithromycin and • Low permeability of the bacteria to the azithromycin are macrolides. antibiotic • Production of inactivating enzymes ERYTHROMYCIN • Low affinity of ribosomes to macrolides. Erythromycin is obtained from Streptomyces Pharmacokinetics Erythromycin is destroyed erythreus. by gastric acid and is therefore given as Antibacterial spectrum Erythromycin has a enteric coated tablets. Good concentration is narrow spectrum and is effective against attained in most fluids except brain and CSF. aerobic gram-positive bacteria and a few It is mainly excreted through bile; dose gram-negative organisms. adjustment is not needed in renal failure. For Streptococci, pneumococci, staphylococci, dose and duration of treatment with gonococci, C. diphtheriae, C. jejuni, Mycoplasma, macrolide antibiotics see Table 40.1. Chlamydiae and some atypical mycobacteria are sensitive. Adverse Effects Mechanism of Action 1. Hepatitis with cholestatic jaundice starts after 2-3 weeks of treatment and is more Erythromycin is bacteriostatic at low and common with the estolate salt. The cidal at high concentrations. It binds to 50S ribosomes (Fig. 40.1) and inhibits bacterial symptoms—nausea, vomiting and abdo- protein synthesis. Chloramphenicol and minal cramps, mimic acute cholecystitis clindamycin also bind to 50 S ribosomes and may be wrongly treated. These are and the three may inhibit each others followed by jaundice and fever. It may activity. Hence the combination should be be an allergic response to the estolate salt. avoided. The patient recovers on stopping the drug. Macrolides, Other Antibacterial Agents and Chemotherapy of UTI 285

thereby raise the plasma levels of carbamazepine, terfenadine, theophylline, valproate, digoxin and warfarin resulting in toxicity due to these drugs.

Uses Erythromycin can be used as an alternative to penicillin in patients allergic to penicillin. 1. Orodental infections–Erythromycin is quite commonly used in the prevention and Fig. 40.1: Mechanism of action of macrolide antibiotics treatment of orodental infections including post-extraction infections, 2. Epigastric distress, nausea, vomiting and periapical abscesses and other infected diarrhoea are often reported. Eryth- periodontal lesions. It is also the romycin is a motilin receptor agonist due preferred antibiotic in patients allergic to to which it causes increased intestinal penicillins. motility. 2. Atypical pneumonia may be caused by 3. Allergic reactions including fever and skin agents like Mycoplasma, Chlamydia and rashes can occur. Legionella. Atypical pneumonia due to 4. Cardiac arrhythmias are reported in Mycoplasma pneumoniae —erythromycin patients with cardiac diseases or on other is the drug of choice- 500 mg 6 hrly oral arrhythmogenic drugs. or IV. 5. Erythromycin can also cause reversible 3. Legionnaire’s pneumonia—is treated for 10- hearing impairment in some patients. 14 days with erythromycin. IV erythro- Drug Interactions Erythromycin and clarithromycin is preferred. Azithromycin is now mycin inhibit the hepatic metabolism and considered the drug of choice.

Table 40.1: Adult dose and duration of treatment with macrolide antibiotics

Drug Dose (oral) and duration

Erythromycin stearate 250-500 mg QID (ERYTHROCIN) 7-14 days Erythromycin estolate 250-500 mg QID (ALTHROCIN) 7-14 days Erythromycin gluceptate 500-1000 mg 6 hrly for 10-14 days Roxithromycin 150 mg BD (ROXID) (to be taken 30 minutes before food) Clarithromycin 250-500 mg BD (CLARIBID) 7-14 days Azithromycin Ist day 500 mg OD (AZITHRAL) 250 mg OD for next 3-4 days (to be taken 1 hr before or 2 hrs after food) 286 Textbook of Pharmacology for Dental and Allied Health Sciences

4. Whooping cough—erythromycin is the 8. Syphilis and gonorrhoea—erythromycin is drug of choice for the treatment and post- used as an alternative to pinicillins. exposure prophylaxis of close contacts. 9. Campylobacter gastroenteritis—as an Clarithromycin and azithromycin may alternative to fluoroquinolones. also be used. 10. Tetanus—erythromycin eradicates carrier 5. Streptococcal infections—pharyngitis, state. tonsillitis and scarlet fever respond to 11. Anthrax—erythromycin is an alternative erythromycin. to penicillin. 6. Staphylococcal infections—minor infections 12. Topical—erythromycin ointment is used may be treated. But now resistant strains for skin infections and boils. Lotion is are common (Table 40.2). used for acne vulgaris. 7. Diphtheria—erythromycin is very effective Roxithromycin is longer-acting, acid stable, in acute stage though antitoxin is life more potent, better absorbed and has better saving. Erythromycin also eradicates tissue penetrability compared to erythro- carrier state. mycin. It does not inhibit the metabolism of

Table 40.2: Preferred drugs in some infections

Drugs used in MRSA* Pseudomonas aeruginosa

• Vancomycin • Antipseudomonal penicillin + tobramycin • Teicoplanin • Ceftazidime or cefepime • Quinupristin-dalfopristin • Antipseudomonal penicillin + ciprofloxacin • Linezolid • Imipenem/meropem+tobramycin • Rifampicin • Aztreonam + tobramycin

* Methicillin - Resistant Staphylococcus aureus

Anaerobic infections

• Metronidazole • Clindamycin • Chloramphenicol • Cefotaxime, ceftizoxime, cefotetan • Imipenem • Ampicillin + Sulbactam • Piperacillin + Tazobactam

Atypical mycobacteria Toxoplasma gondii

• Clarithromycin + ethambutol • Pyrimethamine + Sulfadiazine + folinic acid • Rifabutin + ethambutol + ciprofloxacin • Spiramycin • Amikacin • Pyrimethamine + clindamycin Macrolides, Other Antibacterial Agents and Chemotherapy of UTI 287 other drugs—hence drug interactions are MISCELLANEOUS ANTIBIOTICS avoided. It should be taken 30 min before Spectinomycin is related to aminoglycosides food. and is effective against gram-negative It can be used as an alternative to bacteria. It is used only in gonorrhoea (2 gm erythromycin but is more expensive. IM) in patients allergic to penicillin and Roxithromycin is quite a popular antibiotic quinolones. because of its advantages over erythromycin. It is used in orodental infections apart from Lincosamides other indications of erythromycin. Lincomycin and clindamycin are (Table 40.3) Clarithromycin Compared to erythromycin, lincosamides. Lincomycin is no longer used clarithromycin is longer-acting, acid stable clinically. and better absorbed; it is more effective Clindamycin is a congener of lincomycin. It against atypical mycobacteria, H. pylori and binds to 50S ribosomal subunit and some protozoa. Clarithromycin is structurally suppresses protein synthesis. Streptococci, similar to erythromycin and therefore its staphylococci, pneumococci and many drug interactions are also similar to anaerobes are inhibited by clindamycin. erythromycin. Clindamycin is well-absorbed on oral Clarithromycin is used: administration. It attains good concentration 1. As a component of triple regimen for H. in the bone and many other tissues. It is pylori infections in peptic ulcer patients. metabolised in the liver. 2. Atypical mycobacterial infections. Adverse effects include diarrhoea due to Though clarithromycin is effective in other pseudomembranous colitis, skin rashes and indications of erythromycin, its higher cost neuromuscular blockade. Intravenous use can makes it less preferable. cause thrombophlebitis. Azithromycin an azalide, is a derivative of Uses Anaerobic infections—abdominal, pelvic, erythromycin with activity similar to bone and joints infections due to anaerobes clarithromycin. It is acid stable, rapidly are treated with clindamycin. It may be absorbed, has better tissue penetrability, is combined with an aminoglycoside or a longer acting and better tolerated than cephalosporin. erythromycin. It is given as a single loading Clindamycin is also useful in Pneumocystis dose of 500 mg followed by 250 mg for the carinii pneumonia and toxoplasmosis in AIDS next 4 days. Azithromycin is free of drug patients. interactions as it does not suppress hepatic metabolism of other drugs. GLYCOPEPTIDES It is used in the prophylaxis and treatment Vancomycin and teicoplanin are glycopeptides. of atypical mycobacterial infections in AIDS (Table 40.2) Vancomycin produced by patients. Like erythromycin it can also be Streptococcus orientalis is active against gram- used in respiratory, genital and skin positive bacteria particularly staphylococci infections and in pneumonias. including those resistant to methicillin. It acts KETOLIDES are modified macrolides that by inhibiting cell wall synthesis and is are similar to newer macrolides except that bactericidal. Vancomycin is not absorbed they are effective against macrolide - resistant orally—given IV. It is widely distributed and pneumococci. Telithromycin is a ketolide. excreted through kidneys. 288 Textbook of Pharmacology for Dental and Allied Health Sciences

Adverse effects are skin rashes, pain at the site Uses of injection, thrombophlebitis, ototoxicity and 1. Used topically for skin infections, ear and nephrotoxicity. Concurrent use of other eye infections. ototoxic and nephrotoxic drugs should be 2. Oral colistin is used in children for avoided; dose should be adjusted in renal diarrhoea due to gram-negative bacilli. dysfunction. OTHER ANTIMICROBIAL AGENTS Uses Bacitracin produced by Bacillus subtilis is 1. Pseudomembranous colitis—oral vanco- effective against gram-positive bacteria. It mycin is used. inhibits the cell wall synthesis and is 2. Methicillin resistant staphylococci— bactericidal. It is too toxic to be given vancomycin is given IV for serious systemically, not absorbed orally and is infections like osteomyelitis, endocarditis therefore used only for topical application— and soft-tissue abscesses. in skin infections, surgical wounds, ulcers and 3. Enterococcal endocarditis—as an alter- ocular infections (NEOSPORIN powder is native to penicillin. bacitracin + neomycin). 4. Penicillin resistant pneumococcal in- Sodium Fusidate (Fusidic acid) obtained from fections—vancomycin is recommended Fusidium coccineum is effective against gram- with a cephalosporin. positive organisms particularly staphylococci. Teicoplanin has mechanism of action and It is bactericidal. It is mainly used topically antibacterial spectrum similar to vancomycin, as a 2% ointment (FUCIDIN). It may be given but teicoplanin can be safely given intra- orally for resistant staphylococcal infections. muscularly. It is also less toxic. Occasionally Mupirocin or pseudomonic acid is obtained causes allergic reactions. It is used in from Pseudomonas fluorescens. It is bactericidal osteomyelitis and endocarditis due to against gram-positive and some gram- methicillin resistant staphylococci and negative organisms including methicillin enterococci. TARGOCID 200-400 mg/day. resistant Staphylococcus aureus. Mupirocin acts by inhibiting the enzyme tRNA synthetase. POLYPEPTIDE ANTIBIOTICS It is used as a 2% ointment (BACTROBAN) for minor skin infections particularly due to Polymyxin and Colistin are too toxic to be given staphylococci and streptococci. It is also used systemically. They are used topically. intranasally as spray to eradicate stap- Polymyxin obtained from Bacillus polymyxa hylococcal carrier state. and colistin from Bacillus colistinus are Fosfomycin is an analog of phosphoenol effective against gram-negative bacteria. pyruvate. Fosfomycin is effective against both Mechanism of action Polymyxin and colistin gram-positive and gram-negative organisms. alter the permeability of the cell membrane It acts by inhibiting the enzyme endo- resulting in leakage of the cell contents. They pyruvate transferase. This enzyme is required are bactericidal. for the first step in bacterial cell wall Polypeptide antibiotics are not absorbed synthesis. Thus it inhibits bacterial cell wall orally; applied topically, they may rarely synthesis. The salt used is fosfomycin cause skin rashes. tetrametol which is available for both oral Macrolides, Other Antibacterial Agents and Chemotherapy of UTI 289 and parenteral use. It is excreted by the nausea, diarrhoea, dizziness and throm- kidneys and attains high concentration in the bocytopenia. It can be given orally or IV. urine. Fosfomycin is approved for use in Linezolid is useful in the treatment of uncomplicated lower UTI in women - single nosocomial infections resistant to other 3G dose is effective. drugs. Cycloserine obtained from Streptomyces orchidaceus inhibits many gram-positive and Nitroimidazoles gram-negative organisms including Nitroimidazoles include metronidazole, M. tuberculosis. It acts by inhibiting protein tinidazole, secnidazole, ornidazole and synthesis and is used as a second line drug satranidazole. They are very effective in the in tuberculosis (see page 294). treatment of anaerobic microorganisms apart Newer Agents from amoebiasis. They are discussed under antiamoebic drugs (see page 321). Streptogramins quinupristin and dalfopristin are obtained from Streptomyces pristinaspiralis. CHEMOTHERAPY OF URINARY TRACT A combination of quinupristin and dalfopristin INFECTION in the ratio 30:70 is bactericidal against gram- positive cocci including methicillin-resistant Infection of the urinary tract is quite common staphylococci. and may be acute or chronic. Urinary Mechanism of action Streptogramins bind to antiseptics are drugs which exert antibacterial 50S ribosomal subunit and inhibit protein activity only in the urinary tract (and no synthesis. systemic activity). They include nitro- Given intravenously, streptogramins are furantoin and methenamine mandelate. rapidly metabolised and excreted largely Nitrofurantoin is bacteriostatic, but at higher through faeces. Hence adjustment of dose is concentrations it may be bactericidal. It is a not required in renal insufficiency. Adverse synthetic compound, effective against many effects include arthralgia, myalgia, nausea, gram-positive and gram-negative bacteria. vomiting, diarrhoea and pain at the site of Mechanism of action is not known.It is injection. The combination is used rapidly and completely absorbed from the intravenously in the treatment of infections gut. It attains high concentration in urine and due to streptococci, methicillin-resistant is used in acute UTI, long-term suppression staphylococci and enterococci. Strepto- of chronic UTI (single dose 100 mg at bed gramins are not effective orally as they are time) and for prophylaxis of UTI. It may cause rapidly metabolised in the liver - undergo nausea,vomiting, diarrhoea and allergic extensive first pass metabolism. reactions. Development of resistance is rare. Dose 50 - 100 mg 6 hrly (FURADANTIN). Oxazolidinones Methenamine mandelate—a salt of mandelic Linezolid is an oxazolidinone effective acid and methenamine, releases formal- against gram-positive bacteria including dehyde in acidic urine below pH 5.5. methicillin resistant staphylococci and Formaldehyde is bactericidal and resistance gram-positive anaerobic organisms. It acts does not develop to it. by inhibiting protein synthesis on binding High doses can cause nausea, epigastric to 50S ribosomes. Adverse effects include distress, haematuria and painful micturition. 290 Textbook of Pharmacology for Dental and Allied Health Sciences

Table 40.3: Antimicrobial agents

β-lactam antibiotics Quinolones Sulphanomides Macrolides • Penicillins Benzyl penicillin Nalidixic acid Sulfisoxazole Erythromycin Ampicillin Cinoxacin Sulfadiazine Roxithromycin Amoxicillin Oxalinic acid Sulfadoxine Azithromycin Methicillin Fluoroquinolones Sulfacetamide Clarithromycin Cloxacillin Ciprofloxacin Sulfasalazine Ketolides Nafcillin Norfloxacin Telithromycin Carbenicillin Ofloxacin Ticarcillin Sparfloxacin Cotrimoxazole Aminoglycosides Azlocillin Trovafloxacin Trimethaprim Gentamycin Piperacillin + Streptomycin • Cephalosporins: Sulfamethoxazole Neomycin Cephalexin Newer agents Amikacin Cephazolin • Streptogramins Netilmicin Cefuroxime Quinupristin Miscellaneous Sisomycin Cefachlor + • Glycopeptides Ceftrioxone Dalfopristin - Vancomycin Broad spectrum Ceftazidime • Oxazolidinones - Teicoplanin Antibiotics Cefpirome - Linezolid • Lincosamides Chloramphenicol Cefepime - Clindamycin Tetracycline • Polypeptides Oxytetracycline - Polymyxin Demeclocycline • Carbapenems - colistin Doxycycline Imipenem • Others Minocycline Meropenem - Bacitracin Ertapenem - Sodium usidate • Carbacephem - Mupirocin Loracarbef • Monobactams Aztreonam

Drug Interactions Other drugs used in UTI are sulfonamides, Methenamine binds sulfonamides and cotrimoxazole, nalidixic acid, fluoroquino- neutralises their action. Also, sulfonamides lones, ampicillin, cloxacillin, carbenicillin, are precipated in the acidic urine. Hence the aminoglycosides, tetracyclines and combination should be avoided. cephalosporins. Urinary analgesic—phenazopyridine has Uses analgesic actions on the urinary tract and Methenamine mandelate is used orally in relieves burning symptoms of dysuria and chronic UTI that is resistant to other drugs. urgency. Section 11 Chemotherapy II 41 Chemotherapy of Tuberculosis and Leprosy

Tuberculosis is a chronic granulomatous tuberculocidal for rapidly multiplying bacilli disease caused by Mycobacterium tuberculosis. but static for resting bacilli. INH destroys: In developing countries, it is a major public (i) intracellular bacilli as it penetrates into health problem; 5 lakh people die in India the cells, i.e. tubercle bacilli in every year due to this disease. After the macrophages, and spread of AIDS, the problem has become (ii) bacilli multiplying in the walls of the more complex, as tuberculosis and cavities. Thus it is effective against both Mycobacterium avium complex (MAC) intra and extracellular organisms (Fig. 41.1, Table 41.2). If used alone, infections are more common and rapidly mycobacteria develop resistance to it. progress in these patients. Hence it should be used in combination Drugs Used in Tuberculosis with other drugs. Mechanism of action INH inhibits the synthesis • First line drugs Isoniazid, rifampicin, of mycolic acids which are the important pyrazinamide, ethambutol, streptomycin. components of the mycobacterial cell wall. INH enters the mycobacteria where it is • Second line drugs Ethionamide, thia- converted to an active metabolite. This cetazone, para aminosalicylic acid (PAS), metabolitie binds the enzymes necessary for amikacin, ciprofloxacin, capreomycin, mycolic acid synthesis. Thus the synthesis of cycloserine, rifabutin, kanamycin. mycolic acid is inhibited. Based on antitubercular activity, drugs may be grouped as: Pharmacokinetics INH is completely absorbed • Tuberculocidal agents–Isoniazid, rifam- orally, penetrates all tissues, tubercular cavities, necrotic tissues and CSF. It is picin, streptomycin, pyrazinamide, metabolised by acetylation. Patients can be capreomycin, kanamycin, ciprofloxacin. fast or slow acetylators depending on the • Tuberculostatic agents–Ethambutol, ethio- genetic inheritance - slow acetylators respond namide, thiacetazone, cycloserine PAS. better. The t½ in slow acetylators is 3-5 hours First Line Drugs while in fast acetylators it is 1 hour. Peripheral neuropathy is more common in slow Isoniazid acetylators while hepatotoxicity is more Isoniazid (INH) is the most effective and likely in fast acetylators. Metabolites of INH cheapest primary antitubercular drug. It is are excreted in urine. 292 Textbook of Pharmacology for Dental and Allied Health Sciences

Antitubercular action Rifampicin is highly effective, tuberculocidal and is the only drug that acts on persisters; acts on both intra-and extracellular organisms and is effective against tubercle bacilli resistant to other drugs. If used alone resistance develops. Mechanism of action Rifampicin binds to DNA dependent RNA polymerase and inhibits RNA synthesis in the bacteria. Pharmacokinetics Rifampicin is well-absorbed and has good tissue penetrability—reaches caseous material, cavities and CSF; It also appears in saliva, tears and sweat. It is a microsomal enzyme inducer-hence can result in many drug interactions. See - Table 41.1 Fig 41.1 : Sites of action of antitubercular drugs for doses of antitubercular drugs. Adverse effects 1. Hepatotoxicity–Rifampicin can cause Adverse effects Peripheral neuritis (due to hepatitis. Patients receiving other hepato- interference with utilization and increased toxic drugs or those with any liver excretion of pyridoxine) can be avoided by dysfunction should be carefully monitored giving prophylactic pyridoxine (10-50 mg) deaths have been reported in such patients. with INH. Hepatitis is another major adverse 2. Gastrointestinal disturbances–Epigastric effect, more common in alcoholics. It can distress, nausea, vomiting, abdominal cause CNS toxicity including psychosis and cramps and diarrhoea can occur. seizures but are less common - epileptics are 3. Flu-like syndrome-characterised by fever, more prone to this effect. Other minor effects bodyache, chills and haemolytic anaemia like anorexia, gastrointestinal discomfort, is more common in intermittent dosing fever and allergic reactions can occur. regimen.

Haemolysis can occur in patients with G6PD 4. CNS symptoms–Including headache, deficiency. drowsiness, dizziness, ataxia, confusion and peripheral neuropathy with pain and Rifampicin numbness in the extremities and muscle Rifampicin (rifampin) is a semisynthetic weakness have been reported. derivative of rifamycin, an antibiotic obtained Table 41.1: Recommended doses of from Streptomyces mediterranei. The other antitubercular drugs rifamycins are rifabutin and rifapentine. Drugs Doses Rifampicin is bactericidal to M. tuberculosis, Isoniazid (INH) 300-400 mg M. leprae and atypical mycobacteria. It also Ethambutol (E) 800-1000 mg inhibits most gram-positive and gram- Rifampicin (R) 450-600 mg negative bacteria like Staph. aureus, N. Streptomycin (S) 750-1000 mg meningitidis, E. coli, Proteus, Pseudomonas and Pyrazinamide (Z) 1200-1500 mg Legionella. Thiacetazone (T) 150 mg Chemotherapy of Tuberculosis and Leprosy 293

5. Hypersensitivity reactions–With fever, 5. Brucellosis - Rifampicin 600-900 mg + skin rashes and urticaria, rarely renal doxycycline 200 mg daily for 6 weeks - manifestations with nephritis, hemolysis, drug of choice. haematuria and renal insufficiency can 6. To eradicate carrier state - rifampicin occur. eradicates the nasal carrier state of N. 6. Staining of secretions–Rifampicin stains the meningitidis, H. influenzae and S. aureus - 600 mg BD for 2 days. secretions including tears, saliva and Rifabutin is similar to rifampicin except that sweat-an orange red colour and the patient it causes milder enzyme induction and is should be informed about this. more active against atypical mycobacteria. Rifabutin may be used in place of rifampicin Uses in tuberculosis patients with AIDS who are 1. Tuberculosis and atypical mycobacterial receiving antiretroviral drugs. These infections. antiviral drugs are also metabolised by microsomal enzymes and rifampicin being a 2. Leprosy (see page 296). powerful enzyme inducer, can result in many 3. Prophylaxis of H. influenzae and drug interactions. meningococcal meningitis in close contacts Rifapentine is an analog of rifampicin and is particularly children - 20 mg/kg/day for similar to it. 4 days. 4. Resistant staphylococcal infections - Pyrazinamide rifampicin may be given in combination Pyrazinamide is tuberculocidal, being more with a β lactam antibiotic or vancomycin. active in acidic pH. Mechanism of action is

Table 41.2: Antitubercular actions and characteristic adverse effects of some antitubercular drugs

Drug Antitubercular action Serious toxicity

Isoniazid Tuberculocidal; acts on intra- and Peripheral neuritis, extracellular organisms seizures, psychosis Rifampicin Tuberculocidal; Acts on intra- and Hepatotoxicity, flu-like extracellular organisms, persisters syndrome, nephritis; urine and drug resistant organisms and secretions are coloured orange-red Pyrazinamide Tuberculocidal, kills intracellular Hepatotoxicity, arthralgia, organisms; more active in acidic pH hyperuricaemia Streptomycin Tuberculocidal, acts on extracellular Ototoxicity, organisms nephrotoxicity Ethambutol Tuberculostatic; inhibits tubercle Optic neuritis with bacilli in the walls of cavities ↓ visual acuity and red-green colour blindness Thiacetazone Tuberculostatic; low efficacy; Hepatotoxicity, delays development of resistance dermatitis to other drugs 294 Textbook of Pharmacology for Dental and Allied Health Sciences not known. It is effective against intracellular organisms. It is also effective in atypical bacilli. If used alone resistance develops. It mycobacteria. is well-absorbed (achieves good con- Anorexia, nausea, vomiting and metallic centration in CSF). Hepatotoxicity is the most taste in the mouth are the most common common adverse effect. Hyperuricaemia adverse effects. It can also cause hepatitis, (due to ↓ excretion of uric acid may result in skin rashes and peripheral neuritis (needs gouty arthritis), arthralgia, anorexia, vomit- prophylactic pyridoxine). ing and rashes may be seen. Ethionamide is a secondary agent used only when primary drugs are ineffective. Streptomycin Para-aminosalicylic acid (PAS) related to Streptomycin (page 282) is tuberculocidal, sulfonamides is tuberculostatic. Gastro- acts only against extracellular organisms due intestinal effects like nausea, anorexia, to poor penetrating power. It has to be given epigastric pain and diarrhoea make it a IM. When used alone resistance develops. poorly tolerated drug. Allergic reactions and Because of these disadvantages and its hepatitis are also seen. It is rarely used. toxicity (ototoxicity and nephrotoxicity), streptomycin is the least preferred of the first Other Second Line Drugs line drugs. Amikacin, kanamycin and capreomycin are Second Line Drugs second line drugs that need parenteral administration. They are ototoxic and Ethambutol is tuberculostatic and acts on fast nephrotoxic and are used only in resistant multiplying bacilli in the cavities. It is also cases. Amikacin is also effective against effective against atypical mycobacteria. It atypical mycobacteria. inhibits the incorporation of mycolic acids Cycloserine is an antibiotic that inhibits cell wall into the mycobacterial cell wall. synthesis, is tuberculostatic and is also effective ↓ Optic neuritis resulting in visual acuity against some gram-positive organisms. It and inability to differentiate red from green causes CNS toxicity including headache, is an important adverse effect which needs tremors, psychosis and sometimes seizures. withdrawal of the drug. Colour vision should It is used only in resistant tuberculosis. be monitored during treatment. Ethambutol Fluoroquinolones Ciprofloxacin, ofloxacin and is to be avoided in children because their sparfloxacin inhibit tubercle bacilli and ability to differentiate red from green cannot be reliably tested. Other adverse effects atypical mycobacteria. They are useful in include nausea, anorexia, headache, fever and multi-drug resistant tuberculosis in allergic reactions. combination with other drugs. Thiacetazone is tuberculostatic with low efficacy; it delays the development of Treatment of Tuberculosis resistance to other drugs and its low cost Tuberculosis is one of the most difficult makes it a suitable drug in combination infections to cure. The properties of the regimens. Hepatotoxicity, dermatitis, allergic mycobacteria like slow division, deve- reactions and GI side effects may occur. lopment of resistance, ability to remain as Ethionamide This tuberculostatic drug is persisters for years and intracellular location effective against both intra- and extracellular of the bacilli have enhanced the problem. Chemotherapy of Tuberculosis and Leprosy 295

Moreover, the caseous material makes it Failure rates are high and compliance is difficult for the drugs to reach. The need for poor. long-term treatment, drug toxicity, cost and Though many effective antitubercular drugs thereby poor patient compliance have all are available, the success of chemotherapy added to further complicate the problem. But depends on regular intake of appropriate with the availability of effective drugs, most drugs by the patients. Directly Observed patients can now be treated as outpatients. Treatment, Short course chemotherapy The aim of treatment is to kill the dividing (DOTS) is a strategy that is found to be bacilli thus making the patient sputum effective and is recommended throughout the negative and to destroy the persisters in world. In India, it is implemented by the order to prevent relapse and ensure complete Revised National Tuberculosis Control cure. Programme (RNTCP) which was launched in A combination of drugs is used in 1997. It involves providing most effective tuberculosis to - medicine and confirming that it is taken - a 1. delay the development of resistance 2. reduce toxicity health worker ensures that the drug is taken 3. shorten the course of treatment. by the patient. Patients are grouped into 3 Majority of cases are sensitive to first line categories for treatment (Table 41.3). drugs. Initial treatment should be intensive Resistant tuberculosis If sputum remains and include drugs that have maximum effect. positive even after 6 months of treatment, Good patient compliance and cost of therapy organisms are likely to be resistant. Such should also be considered. patients should be treated with 4-5 drugs, of Chemotherapy is given in two phases- which 3 are first line drugs and treatment is • First phase - initial, intensive phase of 1-3 continued for at least 1 year after the sputum months duration aimed at killing as many becomes negative. Fluoroquinolones and bacilli as possible. amikacin may be considered for multidrug • Second phase - continuation phase to resistant strains. destroy the dormant or persisters- Role of glucocorticoids As steroids depress host duration 6-9 months. defense mechanisms, they should be used only in conditions like tubercular meningitis, Short-term Regimens miliary tuberculosis, pleural effusion, renal 1. INH + R + Z + E/S daily for 2 months tuberculosis and rapidly progressing followed by INH + R daily for 4 months. pulmonary tuberculosis. Steroids suppress 2. INH + R + Z daily for 2 months followed inflammatory reaction which can lead to by INH + R daily for 7 months. extensive fibrosis and damage. Chemoprophylaxis is given only in: Advantages (i) Contacts of open cases especially children Short-term therapy has rapid response, lower (ii) Patients with old inactive disease who failure rates, lesser chances of resistance and have not been adequately treated. INH better patient compliance. is used daily (5 mg/kg) for 6-12 months. (iii) HIV infected patients exposed to multi Conventional Regimen drug resistant tuberculosis rifampicin • INH + S + T daily for 2 months and pyrazinamide are given daily for 2 • INH + T daily for 10 months months. 296 Textbook of Pharmacology for Dental and Allied Health Sciences

Table 41.3 : Treatment categories of DOTS chemotherapy in India

Category Patients Initial phase Continuation Total daily/ 3 per phase duration week (months)

I • New sputum smear - positive HRZE HR daily 6 • Sputum negative with extensive for 2 m for 4 m or pulmonary Tb. HE twice • Severe extrapulmonary Tb. weekly for 6 m 8 II Sputum +ve relapse HRZES HRE 8 Sputum +ve failure 2 m 5 m Sputum +ve interrupted HRZE Sputum +ve treatment 1 m III Sputum negative HRZ HR 6 extrapulmonary 2 m 4 m H - INH R = rifampin, Z = pyrazinamide, E = ethambutol, S = streptomycin, m =months

Tuberculosis in AIDS patients Due to depressed LEPROSY immunity, AIDS patients are at a higher risk Leprosy caused by Mycobacterium leprae is a (25-30 times). AIDS patients are likely to have chronic infectious disease affecting skin, more severe and rapidly progressing mucous membranes and nerves. Hansen tuberculosis. Adverse effects to anti- discovered lepra bacillus in 1873. As lepra tubercular drugs are more common in them. bacillus does not grow on artificial media and They should be given more vigorous and cannot be transmitted to all animals, it is supervised chemotherapy as the guidelines difficult to culture this organism and study of DOTS. INH + R + S + Z for 2 months the effect of drugs. followed by INH + R for 7 months. In India leprosy (kusta roga) is a major Drugs for Mycobacterium avium complex (MAC) public health problem affecting millions of Infection with MAC is more common and people. more severe in HIV patients. With the use of prophylactic regimens, the incidence of MAC Drugs Used in Leprosy infections has greatly decreased. In non-HIV • Sulfones: Dapsone patients MAC infection causes milder disease • Rifampicin with chronic productive cough. The drugs • Clofazimine effective are rifabutin, clarithromycin, • Ethionamide and Protionamide azithromycin, fluoroquinolones, ethambutol, clofazimine, amikacin and ethionamide. The Dapsone macrolides clarithromycin and azithromycin Dapsone is diaminodiphenylsulfone (DDS) are highly effective - and are the first choice and is related to sulfonamides. drugs in MAC therapy. Clarithromycin/ Mechanism of action Like sulfonamides, it azithromycin with ethambutol is the inhibits the incorporation of PABA into folic preferred regimen (rifabutin may be added) acid. for MAC infection and needs life long Actions Dapsone is leprostatic. Though it treatment. Rifabutin, clarithromycin or inhibits growth of many other bacteria, the azithromycin are used for prophylaxis. dose needed is high and is therefore not used. Chemotherapy of Tuberculosis and Leprosy 297

The lepra bacillus develops resistance to suppressing lepra reactions. It is used orally dapsone on prolonged use. in multi-drug regimens. Dapsone is completely absorbed on oral Clofazimine imparts a reddish-black administration and reaches high con- discolouration to the skin specially on the centrations in skin. It is metabolised in the exposed parts which remains for several liver and excreted in bile. months. It can also cause dryness of skin, Adverse effects Dapsone is well-tolerated— itching and phototoxicity. anorexia, nausea and vomiting are common. Fever, pruritus, rashes and dermatitis can Ethionamide occur. Haemolytic anaemia is the most Ethionamide is bactericidal to lepra bacilli but important dose-related toxicity (more is more expensive and more toxic than common in patients with G PD deficiency). 6 dapsone. It can cause gastric irritation, Iron preparations should be given to prevent peripheral neuritis and hepatotoxicity. anaemia. Hepatitis and agranulocytosis are Ethionamide can be used in multidrug seen. Patients with lepromatous leprosy may regimen in patients who cannot tolerate develop lepra reactions. clofazimine. Protionamide is similar to Rifampicin ethionamide. Rifampicin is rapidly bactericidal to M. leprae Other Drugs and is highly effective - a single dose of 1500 Fluoroquinolones Ofloxacin is lepricidal and is mg can kill 99% of the lepra bacilli. It can be suitable for use in multidrug regimens in conveniently given once monthly. Used in leprosy along with rifampicin. combination with dapsone, it shortens the Minocycline a tetracycline has been found to duration of treatment. Given alone— have useful activity against M. leprae and is resistance develops. being tried in combination regimens to shorten the duration of treatment. Clofazimine Clarithromycin a macrolide antibiotic has Clofazimine a dye, has weak bactericidal bactericidal activity against M. leprae. Given actions against M. leprae. It also has anti- 500 mg daily for 28 days can kill 99% of viable inflammatory properties which is useful in bacilli.

Table 41.4: Multi-drug regimen for leprosy

Drugs Multibacillary leprosy (for 24 months) Paucibacillary leprosy (for 6 months)

Rifampicin 600 mg once monthly supervised 600 mg once monthly supervised Dapsone 100 mg daily self-administered 100 mg daily self-administered Clofazimine 300 mg once monthly supervised — 50 mg daily self-administered — Single-lesion paucibacillary leprosy Rifampicin 600 mg Ofloxacin 400 mg given as a Minocycline 100 mg } single dose. All drugs are given orally 298 Textbook of Pharmacology for Dental and Allied Health Sciences

Treatment of Leprosy with corticosteroids or clofazimine while in mild cases aspirin suffices. For the sake of treatment, leprosy is divided Type II reactions are seen in lepromatous into paucibacillary (non-infectious) and leprosy (are known as erythema nodosum multibacillary (infectious) leprosy. (Table leprosum or ENL). New lesions appear and 41.4). Several atlernative and short term the existing lesions become worse. Fever, regimens including drugs like ofloxacin, lymphadenitis, myositis. and neuralgia may minocycline and clarithromycin are under occur. It is a hypersensitivity reaction to the evaluation. antigens of M. leprae - an arthus type reaction. WHO has recommended a combination of Type II reactions can be treated with drugs in leprosy in order to: clofazimine which is effective due to its anti- 1. eliminate persisters inflammatory properties. Chloroquine, 2. prevent drug resistance corticosteroids or thalidomide are also 3. reduce the duration of therapy. effective. Aspirin is effective in mild cases. Dapsone should be continued throughout. Lepra reactions are the acute exacerbations Chemoprophylaxis Only about 1% of contacts that occur in leprosy. They are triggered by develop clinical disease. Dapsone 100 mg acute infections, stress, anxiety and treatment daily and rifampicin 600 mg once a month with dapsone. for 6 months or till the contact case becomes Type I reactions seen in tuberculoid noninfectious are recommended for child leprosy are cell mediated, delayed hyper- contacts. Acedapsone is found to be sensitivity reactions to the antigens of M. advantageous for chemoprophylaxis leprae. Cutaneous ulcerations occur and as a single IM injection every 10 weeks. existing lesions show more erythema; nerves All contacts should be examined every 6 may be painful and tender. They are treated months. 42 Antifungal Drugs

Fungal infections may be systemic or 2. Antimetabolites superficial. There has been an increase in the Flucytosine (5-FC) incidence and severity of fungal infections 3. Azoles in the recent years. Several unusual and drug- Imidazoles resistant organisms have emerged. This may Clotrimazole, econazole, be consequent to the use of broad spectrum miconazole, ketoconazole, antibiotics, anticancer drugs and HIV butaconazole, oxiconazole, infections all of which impair host defense sulconazole, isoconazole. mechanisms. Antifungal drugs may be Triazoles classified into: Fluconazole, itraconazole, terconazole. CLASSIFICATION 4. Miscellaneous Terbinafine, pneumocandins 1. Antifungal antibiotics 5. Other topical agents Polyene antibiotics - Tolnaftate, undecylenic acid, Amphotericin B, nystatin, benzoic acid, salicylic acid, hamycin, natamycin selenium sulfide, ciclopirox Others-Griseofulvin olamine.

Fig. 42.1 : Sites of action of antifungal drugs 300 Textbook of Pharmacology for Dental and Allied Health Sciences

Sites of action Antifungal drugs may act (Fig. Adverse effects Fever, chills, muscle spasms, 42.1) on the fungal cell wall (pneumocandins), vomiting, dyspnoea, headache and cell membrane (polyenes, azoles) or on the hypotension can be encountered on IV nucleus (griseofulvin, flucytosine). infusion. Amphotericin should be injected slow IV, cautiously - to avoid arrhythmias. Antifungal Antibiotics Pain and thrombophlebitis at the site of Amphotericin B obtained from Streptomyces injection are common. Dose should be nodosus is a polyene antibiotic containing gradually increased. Renal impairment, many double bonds. neurotoxicity and anaemia due to decreased Antifungal spectrum Amphotericin B has a production of erythropoietin and bone wide antifungal spectrum. It inhibits the marrow depression can also occur. growth of Candida albicans, Histoplasma Concurrent administration of other capsulatum, Cryptococcus neoformans, nephrotoxic drugs should be avoided. Coccidioides, Aspergillus and Blastomyces dermatitidis. It is fungistatic at low and Uses fungicidal at high concentrations. • Amphotericin B is the drug of choice for Amphoterecin B also has activity against all life-threatening mycotic infections. 0.5 Leishmania. mg/Kg in 5% dextrose infused over 4 hours is the usual therapeutic dose. Mechanism of Action Amphotericin B is given intravenously in the treatment of mucormycosis, invasive aspergillosis, cryptococcosis, sporotrichosis, trichosporanosis, blastomycosis, histoplasmosis, coccidioidomycosis and paracoccidioidomycosis. • In cystitis due to candida, amphotericin B is used to irrigate the bladder. • Amphotericin B is also used to prevent relapse of cryptococcosis and histoplasmosis in patients with AIDS. • Amphotericin B can be given orally in fungal infections of the gut. • It is used topically in candidiasis (3% Amphotericin B binds to ergosterol present lotion, cream, ointment). in fungal cell membrane and forms pores in • Leishmaniasis: In kala-azar and muco- the cell membrane. Through these pores, cell cutaneous leishmaniasis, amphotericin is contents leak out resulting in cell death. Since used as an alternative. amphotericin has greater affinity for the Nystatin obtained from Streptomyces noursei fungal membrane sterol (ergosterol), action has actions similar to amphotericin B. But as is selective for the fungi. it is too toxic for systemic use, it is used Pharmacokinetics Amphotericin is not topically. It is used for local candidial absorbed orally. It is insoluble in water. infections like oral thrush and vaginal Given IV, it is widely distributed in the body candidiasis. 5 ml oral nystatin suspension and has a long t½ of 15 days. should be swished in the mouth and then Antifungal Drugs 301 swallowed 4 times a day to treat the candida suitable. Duration of treatment varies from in the esophagus. 3 weeks to 1 year depending on the site of Hamycin is similar to nystatin. It is used infection. Nail infections require 6-12 months topically for cutaneous candidiasis and of treatment. otomycosis. Antimetabolites Griseofulvin is a fungistatic derived from Penicillium griseofulvum. It is effective in Flucytosine is a fluorinated pyrimidine superficial dermatophytosis (caused effective against Cryptococcus neoformans and by Trichophyton, Microsporum and some strains of Candida. It is taken up by the Epidermophyton). Griseofulvin is the fungal cells and converted to 5-fluorouracil antifungal given orally for superficial which inhibits DNA synthesis. dermatophytosis. Bone marrow depression and gastro- Mechanism of action Griseofulvin binds to intestinal disturbances are the most common microtubular protein in the nucleus, adverse effects. It is used with amphotericin disrupts the mitotic spindle and inhibits B (used alone, resistance develops rapidly) mitosis in the fungus. It gets deposited in in cryptococcal meningitis and systemic the newly forming skin, binds to keratin candidiasis. and protects the skin from getting newly infected. Azoles Pharmacokinetics Griseofulvin is poorly water Imidazoles and Triazoles soluble with poor bioavailability. Absorption can be enhanced by using microfined drug The older antifungals need to be given intravenously and are quite toxic. Azoles are particles and by giving it with fatty food. newer synthetic antifungals that are effective Griseofulvin is a microsomal enzyme inducer. orally and are less toxic. Imidazoles and Adverse effects include allergic reactions, triazoles are azoles; the triazoles have hepatitis and neurotoxicity. more selective effect on fungal sterol Drug Interactions synthesis than imidazoles.Triazoles are also longer acting. • Phenobarbitone reduces the absorption of Antifungal spectrum Azoles have a broad griseofulvin - may result in therapeutic spectrum antifungal activity. They inhibit failure dermatophytes, candida, Cryptococcus neoformans, • Griseofulvin enhances warfarin H.capsulatum and other deep mycoses. metabolism by inducing microsomal enzymes. Mechanism of Action • Alcohol should be avoided because griseofulvin can cause intolerance to alcohol.

Uses Griseofulvin is used orally in superficial dermatophytosis. Dose : 1 g daily. It is Azoles inhibit the synthesis of ergosterol, an particularly preferred when a larger area is important component of the fungal cell involved when topical antifungals are not membrane. Azoles inhibit the fungal 302 Textbook of Pharmacology for Dental and Allied Health Sciences cytochrome P450 enzyme lanosine 14α - Preparations FUNGICIDE, NIZRAL–oint- demethylase which catalyses the convertion ment, shampoo, 20 mg tablets are avai- of lanosterol to ergosterol. Thus it results in lable. ergosterol deficiency which alters the enzyme activity and fungal replication. They also Drug Interactions interfere with the function of some fungal • Antacids, H2 receptor blockers, and enzymes and inhibit the growth of the fungi. proton pump inhibitors reduce the Of the azoles, clotrimazole and miconazole bioavailability of KTZ because acidic are used only topically. medium is necessary for KTZ dissolution. Ketoconazole (KTZ) is the first oral azole to be • Rifampicin and phenytoin induce KTZ available. It is well-absorbed from the gut. metabolism and decrease its efficacy. Food and low gastric pH enhance absorption. Uses (Table 42.1) Adverse reactions include gastric irritation, nausea, vomiting, headache, • Mucocutaneous candidiasis and allergic reactions, and rarely fatal dermatophytosis can be treated with hepatotoxicity. In large doses KTZ inhibits ketoconazole. the biosynthesis of adrenal and gonadal • It is also useful in Cushing’s syndrome. steroids in humans–resulting in gynae- • Though KTZ is useful in deep mycoses, it comastia, infertility, decreased libido, is not preferred in them because of slow azoospermia, menstrual irregularities and response, toxicity and long duration of hypertension. treatment (6 to 12 months) required.

Table 42.1: Drugs used in fungal infections

Fungal infection Drug of Choice Alternative Drugs

Systemic Invasive aspergillosis Amphotericin Itraconazole Blastomycosis Amphotericin Itraconazole Ketoconazole Candidiasis Fluconazole Amphotericin Flucytosine Coccidioidomycosis Amphotericin Ketoconazole Itraconazole Fluconazole Cryptococcosis Amphotericin Itraconazole + Flucytosine Fluconazole Histoplasmosis Amphotericin Flucanazole Itraconazole Mucormycosis Amphotericin Itraconazole Flucytosine Paracoccidioidomycosis Fluconazole Amphotericin Itraconazole Sporotrichosis Amphotericin Itraconazole Antifungal Drugs 303

Clotrimazole and miconazole are used topically has very little effect on hepatic microsomal in dermatophytic infections (ringworm) and enzymes, drug interactions are less common. mucocutaneous candidiasis (Table 42.2). Miconazole penetrates the cutaneous layer - Uses stratum corneum and remains at this site for Fluconazole is used in cryptococcal 3-4 days. It has better efficacy than meningitis after initial treatment with clotrimazole. Clotrimazole troche is available amphotericin B and is the drug of choice in for oral thrush. Both can cause mild irritation coccidioidal meningitis. It is also useful in at the site of application - particularly on systemic candidiasis and other systemic mucous membrane. Skin preparations can fungal infections. Though it is also effective rarely cause rashes, oedema and pruritus. in tinea infections and mucocutaneous Preparations candidiasis, its higher cost makes it less preferable. • Clotrimazole (CANDID, CLODERM) Itraconazole is the most potent azole. Given Lotion, cream, vaginal pessary 100 mg orally, its absorption is increased by food and inserted into the vagina at bed time for 7 gastric acid. Its effect on hepatic microsomal days or 200 mg daily for 3 days or 500 mg enzyme inhibition is less; does not affect single dose. steroid synthesis. Thus it is preferred over • Miconazole (DAKTARIN, ZOLE) 2-4% ketoconazole. It has a t½ of 36 hours. It is ointment, gel, cream, lotion and vaginal available both for oral and IV use. Adverse suppository (100, 200 mg). effects include headache, dizziness, GI Fluconazole is water soluble, well-absorbed disturbances and allergic reactions. It can orally and attains good CSF concentration. rarely cause hepatitis and hypokalemia. Hence it is useful even in fungal meningitis. Itraconazole is the drug of choice in most Fluconazole is available for oral and IV use. systemic mycoses (without meningitis) 100 Adverse effects are mild gastrointestinal mg BD with food. It can be given IV in severe disturbances, headache and rashes. Since it infections. Table 42.2: Drugs used in superficial mycosis It can also be used in onychomycosis, Topical Oral candidiasis and dermatophytoses but is expensive. (ITASPOR, SPORANOX 100 mg Ringworm An azole Terbinafine cap). Itraconazole Candidiasis Econazole, terconazole, tioconazole, butaconazole, • Cutaneous Amphotericin oxiconazole and sulconazole are all azoles An azole available for topical use as creams and lotions Ciclopirox for use in dermatophytoses and muco- Nystatin cutaneous candidiasis. • Oropharyn- Amphotericin Itraconazole geal An azole Terbinafine is a synthetic antifungal that is Nystatin effective against dermatophytes and Candida. Fluconazole It is orally effective and is fungicidal. It gets • Vaginal An azole concentrated in the keratin like griseofulvin. Nystatin Fluconazole It inhibits an enzyme needed for biosynthesis of ergosterol by fungi. 304 Textbook of Pharmacology for Dental and Allied Health Sciences

Adverse effects are rare – gastrointestinal Echinocandins include caspofungin, micafungin disturbances, rashes and headache can occur. and amorolfine. Caspofungin has activity in Terbinafine is used in dermatophytosis, candidiasis, aspergillosis and in Pneumocystis pityriasis, onychomycosis and candidiasis. It carinii infections. Micofungin is effective against is particularly preferred in onychomycosis - candida and aspergillus while amorolfine is useful in fungal infections of the nail. 250 mg OD for 12 weeks - where it is superior to azoles and griseofulvin. Other Topical Antifungal Agents Dose 250 mg once daily; (SEBIFIN) 1% cream Apart from nystatin, clotrimazole, is also available. miconazole and terbinafine, some drugs like salicylic acid, benzoic acid, tolnaftate and Pneumocandins or Echinocandins cyclopirox olamine are used topically for dermatophytosis and pityriasis versicolor. Pneumocandins inhibit the formation of the Selenium sulfide is useful in tinea versicolor fungal cell wall. They inhibit the synthesis of caused by Malassezia furfur, and also in an important component of the fungal cell dandruff. SELSUN is 2.5% suspension of wall - a glucose polymer as a result of which selenium sulfide in a shampoo base. It is irritant the fungal cell lysis occurs. to the eyes and the odour is unpleasant. 43 Antiviral Drugs

Viruses are intracellular parasites and There are two types of viruses- DNA and depend on the host cells for their food, RNA viruses and there are minor differences growth and multiplication. The virus attaches in their replicative cycles. The DNA virus (Fig. 43.1) itself to the host cell membrane depends on host cell enzymes (mRNA and penetrates it (entry), DNA/RNA is polymerase) to synthesize mRNA while RNA released in the host cell (uncoating) where it viruses use their own enzymes for mRNA is duplicated. The viral components are synthesis. assembled (assembly) and the mature viral Retroviruses–a type of RNA viruses are particle is then released from the host cell known to cause AIDS. In retroviruses a viral (budding and release). Chemotherapy can enzyme reverse transcriptase is involved in interfere with any of these steps (Table 43.1). replication. Two groups of antiviral drugs But drugs that interfere with viral replication inhibit this enzyme. The immature virion may also interfere with host cell function. formed undergoes maturation with the help Currently, efforts are being made to develop of the enzyme protease. Inhibitors of this drugs that selectively inhibit the virus enzyme protease prevent maturation of the without affecting the host cell function. virions.

Fig. 43.1: Sites of action of antiviral drugs Antiviral drugs may act on any of the stages of viral replication 306 Textbook of Pharmacology for Dental and Allied Health Sciences

Antiviral drugs may be classified as follows occur occasionally. Topical acyclovir can cause burning and irritation. Given IV, it may cause CLASSIFICATION renal and neurotoxicity but are uncommon. 1. Anti-herpes virus agents Acyclovir, ganciclovir, famciclovir, Uses penciclovir, valaciclovir, idoxuridine, 1. HSV infections Infection with HSV-1 causes trifluridine, vidarabine, foscarnet, diseases of the mouth, face, skin, fomivirsen, cidofovir oesophagus or brain. HSV-2 usually causes 2. Anti-influenza virus agents infections of the genitals, rectum, skin, Amantadine, rimantadine, oseltamivir, zanamivir, hands or meninges (Table 43.2). 3. Others • Oral acyclovir is effective in primary Ribavirin, interferons, lamivudine. and recurrent genital and labial herpes. 4. Anti-retroviral agents In mild cases, topical acyclovir can be • Nucleoside Reverse Transcriptase inhibitors tried. In recurring genital herpes–oral (NRTI) acyclovir is given for 1 year. Zidovudine, didanosine, stavudine, • HSV encephalitis and other severe HSV zalcitabine, lamivudine, abacavir infections–IV acyclovir is the drug of • Nonnuclease Reverse Transcriptase choice. inhibitors (NNRTI) • HSV keratoconjunctivitis Acyclovir eye Nevirapine, efavirenz, delavirdine drops are effective. • Protease inhibitors (PI) 2. Herpes zoster Acyclovir shortens the Saquinavir, indinavir, ritonavir, duration of illness. In immunodeficient nelfinavir, amprenavir, lopinavir patients–IV acyclovir is used. • Nucleotide reverse transcriptase inhibitors. (NTRTI), Tenofovir

ANTI-HERPES VIRUS AGENTS Acyclovir is effective against Herpes simplex virus (HSV) type 1 and type 2, Varicella zoster virus (VZV) and Epstein-Barr virus (EBV). Mechanism of action Acyclovir (Fig. 43.2) is taken up by the virus infected cell, converted to acyclovir triphosphate and this inhibits viral DNA synthesis by inhibiting viral DNA polymerases and causing DNA chain termination. Oral absorption of acyclovir is poor; it is well distributed–attains good concentration in the CSF and aqueous humour. Adverse effects Acyclovir is well-tolerated; nausea, diarrhoea, headache and rashes may Fig. 43.2: Mechanism of action of acyclovir Antiviral Drugs 307

3. Chickenpox In adults and in immun- given intravenously to prevent the odeficient patients, acyclovir reduces progression of CMV retinitis in AIDS patients. duration and severity of illness. In It can also be used topically in HPV skin children, routine use is not recommended. infections. Valacyclovir is a prodrug of acyclovir. Famciclovir is a prodrug of penciclovir–used ANTI-INFLUENZA VIRUS AGENTS in HSV and VZV infections. Amantadine and Rimantadine inhibit the Ganciclovir is effective against herpes viruses replication of influenza A viruses. They are especially Cytomegalovirus (CMV). Toxicity generally well-tolerated; nausea, vomiting, includes myelosuppression and gonadal diarrhoea, dizziness, insomnia and ankle toxicity. It is used in immunocompromised oedema are reported. Rimantadine is longer- patients with CMV retinitis. acting and has fewer adverse effects. Idoxuridine is effective in DNA viruses. It acts by inhibiting viral DNA synthesis. Idoxuridin Uses (Table 43.2) is used topically in HSV keratitis (it is too toxic for systemic use). Eyelid edema, itching, 1. Treatment of influenza A during an allergic reactions may occur. epidemic- they reduce the duration and Trifluridine is used topically in HSV eye severity; dose: 200 mg/day for 5 days. infections. 2. Prophylaxis of influenza A during an Foscarnet is given intravenously to treat CMV epidemic especially in high-risk patients. retinitis as an alternative to ganciclovir. Also for seasonal prophylaxis in high-risk Vidarabine was used earlier for HSV and VZV patients. infections but is now replaced by acyclovir. 3. Parkinsonism–amantadine enhances the Fomivirsen is effective against cytomegalo- release of dopamine and is beneficial in virus. It is given by intravitreal injection in parkinsonism. severe cases of CMV retinitis which do not Oseltamivir and Zanamivir–inhibit viral respond to other drugs. replication. They act by inhibiting the Cidofovir is a cytidine analog effective against neuraminidase activity which is essential for herpes viruses, VZV, CMV, EBV, Human the release of daughter virions. Oseltamivir papilloma virus (HPV) and adenoviruses – is given orally, can cause nausea and vomiting has a broad spectrum of activity. Cidofovir while zanamivir is given by inhalation which acts by inhibiting viral DNA synthesis. It is can occasionally cause respiratory distress.

Table 43.1: Drugs acting on viral replication steps

Viral replication steps Drugs effective

Uncoating Amantadine, Rimantadine Transcription Interferons Translation of viral proteins Fomivirsen, interferons DNA and RNA replication Acyclovir, cidofovir, famciclovir, ganciclovir, foscarnet, idoxuridin, ribavirin, sorivudine Assembly Interferons Budding and release Zanamivir, oseltamivir 308 Textbook of Pharmacology for Dental and Allied Health Sciences

Oseltamivir and zanamivir are indicated in Adverse effects include myelosuppression, the prevention and treatment of influenza. hypotension, arrhythmias, alopecia, headache and arthralgia. It can also cause neurotoxicity Docosanol suppresses viral replication by inhibiting the viral entry into the cell. It is resulting in confusion, sedation and rarely seizures. used topically in the treatment of orolabial herpes. It should be used early at the onset Uses of lesion. 1. Chronic hepatitis B and C. OTHER ANTIVIRAL AGENTS 2. Kaposi’s sarcoma in AIDS patients. 3. Genital warts caused by Papilloma virus– Ribavirin has broad spectrum antiviral activity. It is effective against influenza A and interferons are injected into the lesion. 4. Hairy cell leukaemia. B, respiratory syncytial virus (RSV) and many DNA and RNA viruses. It is used as an 5. HSV, herpes zoster and CMV infections in immunocompromised patients. aerosol in RSV bronchiolitis in children. Also α it can be used in severe influenza and measles 6. Rhinovirus cold–interferon is given intranasally for prophylaxis. in immunocompromised patients. Interferons are cytokines produced by host ANTI-RETROVIRAL DRUGS cells in response to viral infections. There are three types - α, β and γ interferons in man. Acquired immunodeficiency syndrome They also have immunomodulating and (AIDS) results from infection with Human antiproliferative properties. They inhibit the immunodeficiency virus (HIV) - a retrovirus. multiplication of many DNA and RNA The spread of HIV infection is alarmingly viruses. high with around 20 million deaths reported.

Table 43.2: Routes of administration and indications of some antiviral drugs

Drugs Routes Indications

Acyclovir Topical Herpes genitalis, HSV eye infections Oral Herpes genitalis, mucocutaneous HSV, chickenpox IV HSV encephalitis, severe herpes genitalis, chickenpox/herpes zoster in immunocompromised patients Idoxuridine Topical HSV keratitis Trifluridine } Ganciclovir IV/oral CMV infections Foscarnet IV CMV retinitis, acyclovir resistant HSV infections Amantadine Oral Influenza A Rimantadine } Ribavirin Aerosol RSV bronchiolitis oral/IV Severe influenza and measles Interferon α IV Chronic hepatitis B and C, genital warts, Kaposi’s sarcoma Antiviral Drugs 309

Two types of HIV have been identified - HIV- Nucleoside Reverse Transcriptase 1 and HIV-2. Inhibitors (NRTI) Drugs used in the treatment of AIDS are Zidovudine is the first drug to be used in of two groups - the reverse transcriptase inhibitors and protease inhibitors. A the treatment of HIV infection. Others combination of drugs is used in AIDS to including didanosine, stavudine, zalcitabine, improve prognosis - known as Highly lamivudine and abacavir were developed Active Antiretroviral Therapy (HAART). A later. HAART regimen includes two NRT Mechanism of action NRT inhibitors are inhibitors with either NNRT or protease converted to their corresponding inhibitors. Using a HAART regimen triphosphate derivatives which have a high supresses HIV replication, plasma HIV RNA affinity for reverse transcriptase, an enzyme levels are greatly reduced and prolongs specific to HIV and required for DNA patient survival. HAART also has some synthesis. The NRT inhibitors are nucleoside disadvantages of being difficult to follow analogs. They competitively inhibit reverse and is associated with adverse effects from transcriptase and terminate DNA chain drugs and with relapse. elongation. HIV has a high mutation rate and therefore Pharmacokinetics The NRT inhibitors are well easily develops resistance to the drugs. Multi- absorbed when given orally. Their plasma drug resistant strains have emerged and t½ varies from 1–4 hours. All NRT inhibitors they further complicate treatment. (except abacavir) are excreted in the urine. Zidovudine (Azidothymidine, AZT) is a Table 43.3: Adverse effects of nucleoside reverse thymidine analog, active against HIV transcriptase inhibitors infections and other retroviruses. Drug Adverse effects Adverse effects Bone marrow suppression is the most prominent adverse effect (Table 43.3) Zidovudine Myelosuppression of zido-vudine. It is more common in patients headache, nausea, with advanced AIDS. Anaemia can be treated insomnia with erythropoietin while neutropenia needs Didanosine Pancreatitis, peripheral G-CSF or GM-CSF. Headache, nausea, neuropathy, myalgia, fatigue and insomnia can occur. High diarrhoea, doses cause myopathy and neurotoxicity. hyperuricaemia Stavudine Peripheral Uses neuropathy, stomatitis AZT is the drug of choice in AIDS. Treatment Zalcitabine Peripheral with AZT results in prolonged survival, neuropathy, decreased opportunistic infections, weight stomatitis, pancreatitis gain and in early cases it delays disease Lamivudine Headache, nausea progression. Abacavir Hypersensitivity Given during pregnancy and continued in syndrome new borns for 6 weeks, AZT reduces the risk 310 Textbook of Pharmacology for Dental and Allied Health Sciences of transmission to the baby. But it has no and is contraindicated in pregnant women. prophylactic value in those who are Nevirapine can occasionally cause fulminant accidentally exposed to HIV infection (e.g. hepatitis. following blood transfusion). Combination therapy of AZT with other antiretroviral Uses drugs gives better results. NNRTIs are used in the treatment of HIV Didanosine, Zalcitabine, Stavudine Lamivudine infections in combination with other drugs. and Abacavir are other reverse transcriptase Nevirapine can be tried in pregnant women inhibitors effective against AZT resistant HIV during labour and in newborn to prevent infections. They are used as alternatives to vertical transmission to the newborn. AZT or with AZT in patients with advanced HIV who are intolerant to AZT or are not Protease Inhibitors (PI) responding to AZT. Lamivudine is well tolerated with no Saquinavir is the first agent in this group to significant adverse effects in therapeutic be used. doses other than headache and nausea: Mechanism of action HIV protease activity is essential for the activation of viral enzymes Abacavir can cause a hypersensitivity and HIV replication. It is needed for the syndrome with fever, rash and bronchitis production of mature virion and for viral which can be fatal. Hence abacavir should be infectivity. The protease inhibitors bind withdrawn at the onset of such symptoms. competitively to HIV protease and block viral Peripheral neuropathy, pancreatitis, rash, maturation. This makes the daughter viral fever and headache can occur with particles immature and noninfectious. didanosine, stavudine and zalcitabine. Pharmacokinetics–Saquinavir has poor oral Nonnucleoside Reverse Transcriptase bioavailability (4-10%) while others are well Inhibitors (NNRTIs) absorbed. All PIs are extensively bound to plasma proteins. They are all metabolised by The NNRT inhibitors nevirapine, delavirdine hepatic microsomal enzymes and are also and efavirenz are synthetic compounds. Mechanism of action – The NNRT inhibitors NNRT inhibitors bind to reverse transcriptase (are not converted to triphosphate derivatives) and • Nevirapine, delavirdine, efavirenz. bring about a change in the enzyme thereby • Bind reverse transcriptase of HIV – 1 inactivating the enzyme. NNRT inhibitors are and inactivate it. effective only against HIV -1(not against • Given orally, they are well absorbed and extensively bound to plasma proteins. HIV-2 and other retroviruses) • Metabolised by microsomal enzymes. Adverse effects Allergic reactions ranging from Nevirapine and efavirenz are enzyme skin rashes, pruritus to Stevens Johnson inducers; delavirdine is an enzyme syndrome and toxic epidermal necrolysis can inhibitor – drug interactions are occur. Other effects include headache, common. dizziness, drowsiness, nightmares, con- • Used in HIV–1 infections in combination fusion, vomiting, diarrhoea and skin rashes. with other antiretroviral drugs. Efavirenz has teratogenic effects in monkeys Antiviral Drugs 311

Protease inhibitors Uses • Bind HIV protease and prevent Protease inhibitors are used in combination viral maturation with other antiretroviral drugs in the • All except saquinavir all well absorbed treatment of HIV infections. Ritonavir • All are metabolised by microsomal inhibits microsomal enzymes and thereby enzymes and inhibit these enzymes – prolongs the plasma half-life of other drug interactions are common. protease inhibitors. This beneficial drug • Gastrointestinal disturbances are the interaction, permits the use of lower doses common side effects of other PIs with ritonavir. • Used in combination with other antiretroviral drugs in HIV infections. Other Drugs microsomal enzyme inhibitors. Hence many Enfuvirtide is a recent introduction for use in drug interactions can occur. AIDS. It inhibits the binding of the virus to Adverse effects–Protease inhibitors are well the host cell membrane and thereby blocks tolerated. Gastrointestinal symptoms like the entry of the virus. It is tried as an add- nausea, vomiting and diarrhoea can occur. For other adverse effects see Table 43.4. on drug in patients not responding to other antiretroviral drugs in HIV-1 infected Table 43.4: Adverse effects of protease inhibitors patients. Drug Adverse effects Many new antiretroviral agents are under evaluation. Saquinavir Gastrointestinal disturbances, Ritonavir Gastrointestinal disturbances, Drug interactions of antiretroviral drugs taste perversion, perioral • Since AZT causes myelosuppression, it and peripheral paresthesias, should not be combined with other myelo- ↑ ↑ Serum cholesterol, TG suppressants. Indinavir Crystalluria, nephrolithiasis (advise lot of fluid intake) • Plasma levels of abacavir are increased by ↑serum bilirubin, alopecia, dry alcohol. skin, gastrointestinal • Nevirapine and efavirenz are microsomal disturbances enzyme inducers— concurrent adminis- Nelfinavir Diarrhoea ↑ Blood glucose ↑ Serum lipids tration of rifampicin and ketoconazole Amprenavir Gastrointestinal disturbances, should be avoided. Oral contraceptives can rash, ↑ blood glucose, avoid fail, hence alternative methods of ↓ high fat meals contraception should be followed. Lopinavir Gastrointestinal disturbances ↑ Serum lipids • Delavirdine is a microsomal enzyme inhibitor. 312 Textbook of Pharmacology for Dental and Allied Health Sciences

44 Chemotherapy of Malaria

Malaria is caused by protozoa of the genus The 4 species of the malarial parasite include: Plasmodium, transmitted through the bite of • P. falciparum–causes most severe form of a female Anopheles mosquito. It is a major malaria (malignant tertian) which can be public health problem in most of the fatal. But relapses do not occur because it developing countries including India. Every has no exoerythrocytic stage in its life year about 200-500 million cases of malaria cycle. occur throughout the world with about 2 • P. vivax causes less severe malaria (benign million deaths. tertian) with a low mortality rate. Relapses Life cycle of the malaria parasite. The bite of an can occur because of the exoerythrocytic infected female anopheles mosquito forms or hypnozoites. introduces sporozoites into the blood stream • P.ovale is mostly seen in Africa, causes of man (Fig 44.1). These sporozoites enter milder type similar to P.vivax - but the liver cells where they develop and relapses can occur. multiply and the cells rupture to release • P. malariae is also of milder type similar merozoites (pre-erythrocytic stage). The to P.vivax (benign quartan) with no merozoites enter red blood cells to develop exoerythrocytic cycle. and mature (erythrocytic stage/erythrocytic schizogony) and the RBCs rupture releasing Chemical Classification merozoites which invade fresh RBCs and 4-aminoquinolines continue to multiply. The rupture of RBCs Chloroquine, amodiaquine releases the products of the parasite which 8 – aminoquinolines induce chills and fever. In P. vivax and P. ovale Primaquine, bulaquine species, some sporozoites in the liver cells Quinoline methanols enter a dormant stage (hypnozoites or Quinine, quinidine, mefloquine sleeping forms) which can multiply later Acridine (even after several months) resulting in Mepacrine relapse (exoerythrocytic stage). Some Folate antagonists merozoites entering the RBCs, differentiate Proguanil, sulfadoxine, pyrimethamine into male and female sexual forms or Phenanthrene methanol gametocytes. These forms enter the mosquito Halofantrine, atovaquone when they suck the blood and undergo sexual Sesquiterpine lactones cycle in the mosquito. Artesunate, artemether, arteether Chemotherapy of Malaria 313

Therapeutic Classification

1. Causal Prophylactics (primary tissue schizontocides) −−− Primaquine, pyrimethamine (destroy parasite in liver cells and prevent invasion of erythrocytes) 2. Blood schizontocides (suppressives) Chloroquine, quinine, (destroy parasites in the RBCs and mefloquine, halofantrine, terminate clinical attacks of malaria.) pyrimethamine, chloroguanide, artemisinin. 3. Tissue schizontocides used to prevent relapse Primaquine (hypnozoitocidal drugs)— (act on hypnozoites of P. vivax and P. ovale that produce relapses). Radical curatives- Blood schizontocides+ (Eradicate P.vivax and P.ovale) hypnozoitocidal drugs 4. Gametocidal drugs Primaquine, chloroquine, quinine. (destroy gametocytes and prevent transmission).

Fig 44.1: Stages of life cycle of the malaria parasite and drugs acting on these stages 314 Textbook of Pharmacology for Dental and Allied Health Sciences

Chloroquine Chloroquine resistant strains of P. falciparum are now common throughout Chloroquine is a synthetic 4-aminoquinoline. the world. Chloroquine is rapidly transported Antimalarial actions Chloroquine is a highly out of the food vacuole by the resistant effective blood schizontocide with activity strains. Chloroquine resistant P. vivax strains against all 4 species of plasmodia. It are also increasing and posing a problem in completely cures falciparum malaria. It is controlling malaria. Several studies have rapidly acting - patients become afebrile in shown that resistance to chloroquine can be 24-48 hr. Chloroquine also destroys reversed by using drugs like verapamil, gametocytes of P. vivax, P. ovale and P. chlorpheniramine and desipramine. But the malariae. Chloroquine is safe in pregnancy. It benefits of their clinical application need to also has anti-inflammatory properties and is be established. used in rheumatoid arthritis as a disease- Pharmacokinetics Chloroquine is rapidly and modifying antirheumatic drug. It has activity well absorbed from the gut. It has a high against Giardia lamblia and Entamoeba affinity for melanin rich tissues and nuclear histolytica. chromatin. It is metabolized by hepatic Mechanism of action is not clear. Chloroquine microsomal enzymes and is largely excreted is a base. It concentrates in acidic food in the urine. vacuoles of the parasite. Malarial parasites Adverse effects Doses used for the treatment digest the host haemoglobin and transport it of malaria are often poorly tolerated as into their acidic food vacuoles (which is their compared to prophylactic doses. Nausea and source of aminoacids). In this process a toxic vomiting may be quite severe. Prior product ‘haeme’ is formed. treatment with an antiemetic 30 minutes before chloroquine is generally practiced. Pruritus, headache, visual disturbances, insomnia and skin rashes may occur. IV chloroquine may cause hypotension, widening of QRS complex and arrhythmias. High doses can also cause cardiomyopathy, peripheral neuropathy and psychiatric problems. Long-term suppressive therapy can cause blurring of vision, confusion, bleaching of hair and rarely blood dyscrasias. Prolonged treatment with high doses can This haeme is converted to nontoxic cause irreversible retinopathy ‘haemazoin’ a malarial pigment, by the enzyme haeme polymerase. Chloroquine, Uses (Table 44.1) quinine and mefloquine inhibit the enzyme 1. Malaria Chloroquine is highly effective in haemepolymerase resulting in accumulation the treatment of malaria due to sensitive of haeme which causes lysis of the parasite strains of all 4 species - Chloroquine membrane and thereby death of the phosphate 250 mg tab (contains 150 mg parasite. Chloroquine also prevents the base) Dose 600 mg (base) stat, 300 mg digestion of haemoglobin by the parasite after 6 hours and 300 mg for the next 2 thereby depriving the parasite's aminoacid days. It is also used for the prophylaxis– supply. 300 mg base per week. Chemotherapy of Malaria 315

2. Extraintestinal Other Actions amoebiasis (Page 321) • Quinine also has mild analgesic and 3. Rheumatoid arthritis Effective antipyretic activity. 4. Photogenic reactions because of anti • Like quinidine it is also a myocardiac 5. Lepra reactions inflammatory } property. depressant. IV administration can cause (Page 298) significant hypotension. Precautions and Contraindications • It acts as local anaesthetic and has skeletal muscle relaxant properties. • Chloroquine should be avoided or used • Quinine stimulates the uterus and is an carefully in patients with myopathy and abortifacient. hepatic, gastrointestinal or neurological Pharmacokinetics Quinine is well absorbed disorders. orally, widely distributed in the body, • Concurrent use of gold or d-penicillamine metabolized in the liver and excreted in the with chloroquine can cause more severe urine. dermatitis. • Chloroquine, quinine and mefloquine Adverse Effects are high should not be given concurrently because • Quinine is highly bitter and is a gastric they compete for accumulation in the irritant-causes nausea, vomiting and parasite and may result in therapeutic epigastric pain-hence poorly tolerated. →→→ failure. Also, chloroquine + mefloquine • Hypoglycaemia can be quite profound to increased risk of seizures. →→→ result in coma. Hypoglycaemia may be • Chloroquine + halofantrine increased because - i. quinine stimulates the insulin risk of arrhythmias. Hence a gap of at least release. ii. parasite consumes glucose. 12 hours should be given if patients • Cinchonism with ringing in the ears, have to be switched over from chloro- headache, nausea, visual disturbances and quine to quinine/mefloquine/halof- vertigo may be encountered. antrine. • In more severe poisoning, hypoglycaemia, • Chloroquine should be avoided in patients with retinal diseases. When chloroquine fever, delirium, confusion, hypotension, is given in high doses for a long time, cardiac arrhythmias and coma may regular neurological and eye examination develop. Death is due to respiratory should be done. arrest. • Black water fever - quinine can precipitate Quinine acute haemolytic anaemia with renal failure, haemoglobinuria and fever, which Quinine is an alkaloid obtained from the bark can be fatal. Fortunately this complication of the cinchona tree. It destroys erythrocytic is uncommon. forms of the parasite similar to chloroquine and is useful as a suppressive. It is also Uses gametocidal for three species of the malarial parasite except for P. falciparum. Mechanism • Quinine is used in the treatment of of action is unknown. It may act like resistant falciparum malaria and cerebral chloroquine by inhibiting the enzyme haeme malaria. Dose - Table 44.1. polymerase. • Nocturnal muscle cramps. 316 Textbook of Pharmacology for Dental and Allied Health Sciences

Mefloquine Nausea, vomiting, dizziness, confusion, abdominal pain and bradycardia are common. Mefloquine in a single dose is highly effective CNS effects like ataxia, disorientation, against erythrocytic forms of the malaria seizures, encephalopathy and psychotic parasite including– the multi-drug resistant manifestations are rare and reversible. (MDR) strains of P. falciparum. Mefloquine gets concentrated in the acidic Uses vacuoles of the parasite. Mechanism of action Mefloquine is indicated only in MDR strains is not exactly known but it is thought to act of falciparum malaria - 20 mg/ kg, single dose like chloroquine by inhibiting haeme or in two divided doses. Mefloquine can also polymerase in the parasite. Some strains of be used in the prophylaxis of multidrug P.falciparum have developed resistance to resistant malaria in travellers (250 mg/week). mefloquine in parts of Asia. It is well absorbed orally and has a long Halofantrine t½ of nearly 20-30 days–as it undergoes Halofantrine is schizonticidal against extensive enterohepatic circulation. erythrocytic forms of all Plasmodium species

Table 44.1: Preferred antimalarials in the treatment and prophylaxis of malaria

Malaria Drug therapy

Chloroquine sensitive strains Treatment Chloroquine Oral - 600 mg base stat, 300 mg after 6 hr, 300 mg/ day for next 2 days or 600 mg (4 tabs) stat. 600 mg (4 tabs) after 24 hr, 300 mg (2 tabs) after 48 hr. Prophylaxis Chloroquine 2 tabs/week; start 1 week before and continue for 4 weeks after leaving the endemic area Chloroquine resistant and MDR strains Treatment Choices are: 1. Quinine Oral - 600 mg TDS for 3 days Severe cases IV 10 mg/kg 8 hourly followed by one of the following • Doxycycline 100 mg BD for 7 days or • Pyrimethamine + sulfadoxine 3 tabs as a single dose on the last day of quinine therapy.

2. Mefloquine 15 mg/kg single dose (Max 1000 mg) 3. Artemisinin 100 mg BD on first day, 50 mg BD for next 5 days 4. Atovaquone + proguanil 250 mg daily for 3 days 100 mg daily for 3 days Prophylaxis 1. Mefloquine 250 mg weekly; start 1 week before and continue for 4 weeks after leaving the area 2. Doxycycline 100 mg daily; start 2 days before and continue for 4 weeks after leaving the area Chemotherapy of Malaria 317 including MDR strains of P. falciparum. extensive clinical trials are required to prove Actions are similar to mefloquine but the its clinical benefits. disadvantages are that Etaquine and tafenoquine are other longer • The response to oral dosage is unpredictable acting analogs of primaquine under trial. due to variable absorption toxicity due to FOLATE ANTAGONISTS good absorption or therapeutic failure due to poor absorption may result. Pyrimethamine is effective against the • It is used as an alternative in MDR strains erythrocytic forms of all 4 species of of falciparum malaria. plasmodia but it is slow acting. • Cannot be given parenterally. • It can cause cardiotoxicity apart from GI Mechanism of Action Pyrimethamine is a disturbances. dihydrofolate reductase inhibitor (Fig 44.2). When given with sulfadoxine (a sulfonamide), the combination is synergistic and Primaquine the development of resistance is slower. Primaquine is effective against all forms of Pyrimethamine can also be combined with the malarial parasite except erythrocytic dapsone. forms. • It destroys the parasite in the liver cells and prevents the invasion of erythrocytes – causal prophylactic. But it is generally not used for this purpose. • Primaquine destroys the hypnozoites (exoerythrocytic form) in the liver and thereby prevents relapse of P. vivax and P. ovale malaria. • It is also effective against the gametocytes of all four species of the malarial parasite. Fig. 44.2: Sequential blockade in folic acid synthesis • It has weak and insignificant activity against the erythrocytic forms. Pyrimethamine is quite safe, the combi- Its mechanism of action is not known. nation may cause nausea, rashes and in high Primaquine is completely absorbed orally. It doses megaloblastic anaemia. Sulfadoxine may is well tolerated in therapeutic doses. cause serious allergic reactions including Epigastric distress can occur. It may cause Stevens Johnson syndrome. haemolysis in patients with G6PD deficiency. Primaquine is used for radical cure along Uses with a blood schizontocide in P. vivax and 1. Malaria ovale 15 mg /day for 14 days and as a • Acute attacks – Pyrimethamine + gametocidal agent in P. falciparum malaria - sulfadoxine combination is used as an 45 mg single dose. alternative in uncomplicated, Bulaquine is an analog of primaquine chloroquine resistant falciparum developed in India (CDRI, Lucknow). It is malaria. It is also used as an adjunct to claimed that patients require fewer days quinine in acute attacks of malaria. (5 days) of antirelapse therapy when • Prophylaxis–1-2 tablets once weekly for compared to primaquine. But further prophylaxis against MDR falciparum 318 Textbook of Pharmacology for Dental and Allied Health Sciences

malaria–when a person is visiting an Artimisinin and Derivatives endemic area. Artemisinin is a sesquiterpine lactone obtained 2. Toxoplasmosis–Pyrimethamine + sulfa- from the plant Artemisia annua which has been doxine combination is the treatment of used in chinese traditional medicine choice for Toxoplasma gondi infection. ‘Quinghaosu’ for almost 2000 years. Pyrimethamine is given as 200 mg bolus Mechanism of action–Artemisinin interacts dose followed by 50 mg daily for 4 to 6 with heme resulting in the generation of free weeks along with sulfadoxine 4 g/day. radicals that bind to the membrane protein Leucovorin (folinic acid) should be given and damages the parasite membrane. 10 mg daily to prevent severe folate Artemisinin is a potent, rapidly acting, deficiency. blood schizontocide effective against all the Chloroguanide (Proguanil) is a schizontocide 4 plasmodial species, including MDR P. with causal prophylactic activity against the falciparum. It is also effective against pre-erythrocytic forms of the malaria gametocytes. It is useful in cerebral malaria. parasite. It is used - No resistant strains are known so far. • with atovaquane in the treatment of MDR Recrudescence (the disease becomes active falciparum malaria. again after a period of remission) is common • for causal prophylaxis of falciparum due to its short t½. Combining with malaria mefloquine avoids this. It has been shown • as an alternative to pyrimethamine- that it can be safely used in pregnancy. sulfadoxine for prophylaxis of MDR Artesunate (oral, IM, IV, rectal) and falciparum malaria. artemether (IM, oral) artemisinin(oral) and Atovaquone – is a naphthaquinone, effective arteether (IM) are the compounds used . against the erythrocytic forms of plasmodia. Arteether is longer acting - given 150 mg (IM) When combined with proguanil, the activity for 3 days. is synergistic and development of resistance Artemisinin and derivatives are the best is less common. tolerated antimalarials–mild GI symptoms, Mechanism of action– Atovaquone inhibits the fever, itching and bradycardia are reported. mitochondrial electron transport and Uses Acute attacks of MDR falciparum malaria collapses the mitochondrial membrane in the and cerebral malaria. Artemisinin can be used malarial parasite. Proguanil potentiates this even in pregnancy. action. Dose Artemisinin - Orally 100 mg BD on first Atovaquone is also effective against day, 50 mg BD for the next 4 days and in T. gondii and P. carinii (P.jiroveci) infections. more severe cases, artesunate IV 120 mg on the first day, 60 mg daily for the next 4 days; Adverse effects include vomiting, mefloquine (25 mg/kg)is given on the second headache and abdominal pain. It is day. contraindicated in pregnancy. Uses Atovaquone + Proguanil can be used in Newer Antimalarials Lumefantrine and the treatment of chloroquine resistant and pyronaridine were synthesized in China. multi drug–resistant falciparum malaria Both are effective against erythrocytic forms Atovaquone 250 mg + proguanil 100 mg daily of the malaria parasite. Both have poor oral for three days. Atovaquone may also be used bioavailability. Lumefantrine is combined in P. carinii infection as an alternative to with artemisinin/mefloquine in the treatment cotrimoxazole. of MDR falciparum malaria. 45 Drugs Used in Amoebiasis, Leishmaniasis and Trypanosomiasis

ANTIAMOEBIC DRUGS Metronidazole Amoebiasis caused by the protozoan Metronidazole a nitroimidazole, is a powerful Entamoeba histolytia is a tropical disease amoebicide. Apart from this it also inhibits common in developing countries. It spreads Trichomonas vaginalis, Giardia lamblia and by faecal contamination of food and water. Balantidium coli. Anaerobic bacteria are also Though it primarily affects colon, other sensitive. organs like liver, lungs and brain are the Mechanism of action Metronidazole is a secondary sites. Acute amoebiasis is prodrug. Susceptible microorganisms reduce characterised by bloody mucoid stools and the nitro group of metronidazole by a abdominal pain. Chronic amoebiasis nitroreductase and convert it to a cytotoxic manifests as anorexia, abdominal pain, derivative which binds to DNA and inhibits intermittent diarrhoea and constipation. Cyst protein synthesis.Aerobic bacteria lack this passers or carriers are symptom free. nitroreductase and are therefore not Classification susceptible to metronidazole. Pharmacokinetics Metronidazole is well- 1. Drugs effective in both intestinal and absorbed and reaches adequate conc- extraintestinal amoebiasis entrations in the CSF; has a plasma t½ - 8 hr. Metronidazole, Tinidazole, It is metabolised in the liver by oxidation and Secnidazole, Ornidazole, glucuronide conjugation. Satranidazole, Emetine Dehydroemetine. Adverse effects Gastrointestinal effects like 2. Drugs effective only in intestinal amoebiasis nausea, anorexia, abdominal pain and (Luminal amoebicides) metallic taste in the mouth are the most Diloxanide furoate, Quiniodochlor, frequent. Headache, stomatitis, glossitis, Iodoquinol, Tetracylines. furry tongue; dizziness, insomnia, ataxia, 3. Drugs effective only in extraintestinal vertigo and rarely peripheral neuropathy can amoebiasis occur. Pruritus, urticaria and skin rashes can Chloroquine also occur. High doses can cause convulsions. 320 Textbook of Pharmacology for Dental and Allied Health Sciences

Hence metronidazole should be cautiously being effective against gram-positive and used in patients with neurological diseases anaerobic bacteria is an alternative. and severe hepatic dysfunction. It is (b) Anaerobic infections at other sites- contraindicated in pregnancy. Intravenous Intra-abdominal infections, brain injection can cause thrombophlebitis. This can abscesses, genitourinary infections are be avoided by adequate dilution of the drug often mixed infections with aerobes and solution. anaerobes. Metro-nidazole is used in combination with other antimicrobials. Drug Interactions Metronidazole is given intravenously for serious anaerobic infections. It is also • Metronidazole can produce a disulfiram - useful for surgical prophylaxis of like reaction in patients taking alcohol. Hence patients should be advised to avoid abdominal and pelvic infections. alcohol while on metronidazole. 2. Amoebiasis–Metronidazole is the drug of • Drugs like cimetidine which are choice in all forms of amoebiasis in the microsomal enzyme inhibitors, enhance dose of 400-800 mg TDS for 7-10 days. plasma levels of metronidazole resulting But it does not eradicate the cysts. in toxicity. 3. Trichomonas vaginitis–Metronidazole 200 mg TDS for 7 days is the drug of choice. Preparations 4. Giardiasis–Metronidazole given 200 mg TDS for 7 days is the treatment of choice. Metronidazole is available as 200, 400 mg 5. H. pylori infections in peptic ulcer patients tablets; 200 mg /5 ml suspension; 500 mg / can be treated with a combination of 100 ml inj and 1% gel and ointment. metronidazole, clarithromycin and omeprazole/ranitidine. Uses 6. Pseudomembranous colitis due to Clostridium 1. Anaerobic infections difficile–responds to metronidazole. (a) Ordental infections–Metronidozole and 7. Dracunculosis Metronidazole facilitates it congeners are one of the most extraction of the guinea worm. commonly used antimicrobial agents in 8. Topical preparations - like gel and ointment dentistry because anaerobes are an are used in skin infections and acne. important component of the oral flora. Tinidazole is longer-acting and is better Hence most acute odontogenic infections tolerated than metronidazole due to fewer are caused by a combination of aerobic side effects. It can be given 2 g once daily for and anaerobic bacteria. Metronidazole is 3 days in amoebiasis and as a single dose for the drug of choice for most odontogenic most other indications of metronidazole. infections especially those not controlled Secnidazole is longer-acting (t½ 18-30 hrs) and by penicillins. Odontogenic infections like can be given as a single 2 g dose for most acute periapical abscess, periodontitis, indications of metronidazole. acute ulcerative gingivitis, pericoronitis Ornidazole–is similar to tinidazole and is and other oral infections and salivary gland longer acting. infections are treated with metronidazole Satranidazole – More potent and longer acting (200-400 mg TDS) in combination with an than metronidazole. It is claimed to be better antibiotic effective against aerobes like a tolerated particularly because it does not penicillin or a macrolide. Clindamycin cause nausea or metallic taste. Drugs Used in Amoebiasis, Leishmaniasis and Trypanosomiasis 321

Emetine and Dehydroemetine Tetracylines The older tetracylines are not well-absorbed and large amounts reach the Emetine and dehydroemetine derived from colon–hence these are useful in intestinal Ipecac (Brazil root) directly affect the amoebiasis. They inhibit the intestinal flora trophozoites but not the cysts. As oral and break the symbiosis between them and absorption is improper, they are given the amoebae. Tetracyclines are used as parenterally. They can be used only in severe adjuvants in chronic cases. amoebiasis but are not preferred due to toxicity. Adverse effects include pain at the Treatment of Different Forms of injection site, thrombophlebitis, nausea, Amoebiasis vomiting, diarrhoea and cardiotoxicity. 1. Acute intestinal amoebiasis–one of the following can be given. Diloxanide Furoate • Metronidazole 400-800 mg TDS for 5- Diloxanide furoate is directly amoebicidal. 7 days (METROGYL, FLAGYL) Flatulence, nausea and occasionally or abdominal cramps and rashes can occur. It is • Metronidazole 2.4 g OD for 3 days used alone in asymptomatic cyst passers, mild or intestinal amoebiasis and along with a • Tinidazole 2 g OD for 3 days (TINIBA) nitroimidazole–for the cure of amoebiasis, or because diloxanide eradicates cysts. It is • Secnidazole 2 g single dose (SECZOL, given orally–500 mg TDS for 10 days. It is SECNIL) This should be followed by diloxanide also available in combination with furoate 500 mg TDS for 10 days to eradicate metronidazole (DYRADE-M). the cysts. Chloroquine 2. Chronic amoebiasis Diloxanide furoate 500 mg TDS for 10 days or tetracycline 250 Chloroquine attains high concentration in mg qid for 10 days. the liver, is directly toxic against 3. Hepatic amoebiasis requires intensive trophozoites and is therefore useful in treatment for the complete eradication of hepatic amoebiasis. As chloroquine is the parasite from the liver in order to avoid completely absorbed from the small relapses. A course of metronidazole or intestines, it is not effective against tinidazole are the first line drugs. In addition amoebae in the colon. It is used (300 mg/ chloroquine may be given to ensure day for 2-3 weeks) as an alternative to complete destruction of the liver forms. A metronidazole in hepatic amoebiasis. A course of diloxanide furoate should follow luminal amoebicide should also be given. in order to eradicate the cysts. TREATMENT OF PNEUMOCYSTOSIS Iodoquinol and Quiniodochlor Pneumocystis carinii is a micro-organism Iodoquinol and quiniodochlor (8-hydro- having features of both protozoa and fungi xyquinolines) are directly acting luminal though now considered by most to be a amoebicides. They were used for eradication fungus. Recent studies have shown that of cysts but are not preferred now due to pneumocystosis in human beings is caused their toxicity like subacute myelo-optic by Pneumocystis jiroveci while P.carinii causes neuropathy. pneumocystosis in animals. 322 Textbook of Pharmacology for Dental and Allied Health Sciences

It is now known to cause opportunistic Though sodium stibogluconate is quite infections particularly pneumonia in patients effective, resistance has been encountered in with AIDS which can often be fatal. endemic areas like Bihar. Drugs used in the treatment of pneumo- Meglumine antimonate and ethyl stibamine can cystosis include also be used in all forms of leishmaniasis. • Cotrimoxazole - high oral dose of Pentamidine is an aromatic diamidine effective Trimethoprim 20 mg/kg + sulphame- against Leishmania donovani, trypanosomes, thoxazole 100 mg/kg daily. Pneumocystis carinii and some fungi. Given • Pentamidine - 4 mg/kg daily for 14 days intramuscularly the drug is rapidly absorbed parenterally. but very little reaches the CNS. Dose 4 mg/ • Atovaquone - as an alternative to cotrimoxazole. kg deep IM/slow IV on alternate days for 5- 25 weeks. LEISHMANIASIS Adverse effects Pentamidine liberates histamine which is responsible for vomiting, Leishmaniasis is caused by protozoa of the diarrhoea, flushing, pruritis, rashes, genus Leishmania. Kala-azar or visceral tachycardia and hypotension apart from pain leishmaniasis is caused by Leishmania donovani; at the injection site. Other effects include oriental sore by L. tropica and mucocutaneous hepatotoxicity, renal impairment, ECG leishmaniasis by L. braziliensis. The infection changes and in some patients diabetes is transmitted by the bite of the female sandfly phlebotomus. It is endemic in Bihar. mellitus may be precipitated. Drugs used in leishmaniasis include: Antimony compounds Sodium stibogluconate Uses Meglumine antimonate 1. Leishmaniasis Pentamidine can be used in Diamidines Pentamidine visceral leishmaniasis as an alternative to Other drugs Amphotericin B, Ketoconazle, sodium stibogluconate. Allopurinol, Paramomycin 2. Trypanosomiasis Pentamidine can be used as an alternative to suramin or along with Antimony Compounds suramin in trypanosomiasis. It can also be Sodium stibogluconate, a pentavalent used for chemoprophylaxis against African antimonial is the most effective drug in kala- trypanosomiasis. azar. It is also effective in mucocutaneous and 3. Pneumocystosis Pentamidine is an cutaneous leishmaniasis. It is given as a 4% alternative in Pneumocystis jiroveci solution in the dose of 10-20 mg/kg IM infections in patients unable to tolerate (gluteal region) or IV for 20 days. Mechanism cotrimoxazole. of action is unknown. Adverse effects include a metallic taste in Other Drugs the mouth, nausea, vomiting, diarrhoea, headache, myalgia, arthralgia, pain at the Amphotericin B (page 300) has been tried in injection site, bradycardia, skin rashes, leishmaniasis in the endemic areas where haematuria and jaundice. Some cases of antimonials may be ineffective. sudden death due to shock have occurred. Ketoconazole inhibits ergosterol synthesis in ECG should be monitored as arrhythmias can the leishmania and is effective in cutaneous occur during the later days of therapy. leishmaniasis. Drugs Used in Amoebiasis, Leishmaniasis and Trypanosomiasis 323

Allopurinol (page 188) In leishmania, is the drug of choice for early stage of allopurinol is converted to a metabolite trypanosomiasis but it does not cross the BBB which inhibits protein synthesis. It may be and therefore cannot be used in later stages used along with antimonials. of the disease. It is also useful for the Dose: 300 mg 3-4 times a day for 2-4 weeks. prophylaxis but pentamidine is preferable. Paramomycin (aminosidine) is an amoebicidal Suramin is given IV; it is extensively bound drug which is also found to be effective in to plasma proteins and may be traced for leishmaniasis. It is useful in all forms of nearly 3 months in the plasma. Suramin is leishmaniasis. It can be used alone or in also effective in eradicating adult forms of combination with antimonials. Onchocerca volvulus. Toxicity is high; vomiting, shock and loss TRYPANOSOMIASIS of consciousness may follow IV injections. Rash, neuropathies, haemolytic anaemia and Trypanosomiasis is caused by protozoa of the agranulocytosis may also occur. genus Trypanosoma. African trypanosomiasis Melarsoprol is the preferred drug in later or sleeping sickness is caused by T. gambiense stages of trypanosomiasis which is associated and T. rhodesiense while South American with encephalitis and meningitis. trypanosomiasis is caused by T. Cruzi. Drugs Eflornithine is used as an alternative in CNS used in trypanosomiasis are suramin, trypanosomiasis. Nifurtimox and benznida- pentamidine, melarsoprol, eflornithine, zole are useful in Chaga’s disease (American nifurtimox and benznidazole. Suramin sodium trypanosomiasis). 324 Textbook of Pharmacology for Dental and Allied Health Sciences 46 Anthelmintics

Worm infestations are more common in the Adverse effects Mebendazole is well-tolerated; developing countries. It is seen in people nausea, abdominal pain and diarrhoea are with poor hygiene. Anthelmintics are seen in heavy infestations. Large doses may deworming agents. A vermicidal kills while a rarely cause headache, dizziness, loss of hair vermifuge promotes expulsion of worms. and granulocytopenia. It may rarely provoke abnormal migration of the roundworms Benzimidazoles which may come out through the mouth or Benzimidazoles include thiabendazole, nose. mebendazole and albendazole. Thiaben- Uses Mebendazole is used in the treatment dazole the first agent of this group was of roundworm, hookworm, pinworm, discovered in 1961 but now the newer ones, tapeworm, trichuriasis and hydatid disease. mebendazole and albendazole are more It is of special value in multiple worm commonly used due to lesser toxicity. infestations. (Table 46.1)

Mebendazole Albendazole Mebendazole a broad spectrum anthelmintic Albendazole is a congener of mebendazole cures roundworm, hookworm, pinworm and with actions and mechanism of action similar strongyloides infestations. The eggs and to mebendazole but it has several advantages larvae are also destroyed. The dead parasites over it. are slowly expelled from the gut over several days. Advantages over Mebendazole Mechanism of action Benzimidazoles bind to β-tubulin with high affinity and inhibit • Albendazole is better tolerated glucose uptake in the parasite. • Effective in single dose Pharmacokinetics Mebendazole is poorly • Superior to mebendazole in hook worm absorbed from the gut and also undergoes and thread worm infections, hydatid first pass metabolism - bioavailability disease and neurocysticercosis around 20%. Fatty food enhances • Albendazole also has some activity against absorption. Mebendazole is extensively Trichomonas vaginalis, Giardia lamblia and bound to plasma proteins and is metabolised Wuchareria.bancrofti. by the liver. • The active metabolite of albendazole Mebendazole is given orally 100 mg twice a achieves a higher concentration (100 times day for 3 days. more) than mebendazole. Anthelmintics 325

Table 46.1: Preferred drugs for helminthiases

Worms Drugs of choice Alternative drugs

1. Roundworm Mebendazole/albendazole/ Piperazine (Ascaris lumbricoides) pyrantel 2. Hookworms Mebendazole/ Pyrantel (Ancylostoma duodenale, albendazole Necator americanus) 3. Pinworm (Enterobius vermicularis) Mebendazole/albendazole/ Piperazine pyrantel 4. Whipworm (Trichuris trichura) Mebendazole Albendazole 5. Strongyloides stercoralis Albendazole Thiabendazole 6. Guineaworm Metronidazole Mebendazole (Dracunculous medinensis) 7. Tapeworms Niclosamide/ Albendazole (Taenia saginata, Taenia solium, praziquantel H. nana, D. latum) Neurocysticercosis Albendazole Praziquantel 8. Hydatid disease Albendazole Mebendazole (E. granulosus, E. multilocularis) 9. Filaria Diethylcarbamazine Ivermection (Wuchareria bancrofti, Brugia malayi) + albendazole albendazole 10. Schistosomes Praziquantel — 11. Onchocerca volvulus Ivermectin — 12. Fasciola hepatica Bithionol — (Sheep liver fluke)

Pharmacokinetics-Albendazole is rapidly reinfection from ova that have matured absorbed from the gut and fatty food later. enhances its absorption. It penetrates well 2. Trichinosis, tapeworms and stron- into tissues including hydatid cyst. It is gyloidosis require 400 mg daily for 3 days. rapidly metabolised in the liver and excreted 3. Neurocysticercosis–Albendazole is the in urine. drug of choice in a dose of 400 mg twice Adverse effects - are minor similar to daily but the duration depends on the mebendazole. Nausea, diarrhoea, abdominal number of cysts and may vary from 3 to pain, headache and dizziness can occur. High 28 days. Glucocorticoids should be given doses used over a long time can cause before starting albendazole to prevent jaundice, fever, weakness, alopecia and immunological reactions to the dead graunlocytopenia. Albendazole is teratogenic parasite. in animals and therefore should not be given 4. Hydatid disease–Albendazole is the drug in pregnancy. of choice; 400 mg twice daily is given for 4 weeks. If needed, the course may be Uses repeated after 2 weeks. When the cysts 1. Albendazole is the drug of choice in are removed by surgery, albendazole is roundworm, hookworm, pinworm, more effective in providing cure. trichuriasis infestations in a single 400 mg 5. Filariasis–Combination of albendazole dose. Dose should be repeated after 2 (400 mg) with diethylcarbamazine (6 mg/ weeks in pinworm infestation to prevent kg) or ivermectin (0.3 mg/kg) given as a 326 Textbook of Pharmacology for Dental and Allied Health Sciences

single dose is found to be effective in W. Levamisole bancrofti in suppressing microfilariae for Levamisole is effective against roundworms one year. This also prevents the spread and hookworms and can be used as an of filariasis and may be continued once a alternative drug in these infestations. It is year for 5-6 years. well-tolerated and is effective in a single dose. Thiabendazole It is also an immunomodulator.

Thiabendazole a benzimidazole, acts like Niclosamide mebendazole. But due to frequent side effects, it is not preferred. Dizziness, Niclosamide is effective against most anorexia, vomiting, diarrhoea, drowsiness, tapeworms. The segments of the dead paraesthesia, bradycardia, hypotension, tapeworms are partly digested and in case convulsions and liver damage can occur. It is of T. solium, the ova released from these used as an alternative to albendazole in segments may develop into larvae and reach strongyloidosis and cutaneous larva migrans. various organs resulting in visceral cysticercosis. Purge may be given 2 hours Pyrantel Pamoate after niclosamide to wash off the worms and Pyrantel pamoate is effective against avoid cysticercosis. The scolex detected in the roundworm, hookworm and pinworms. It stool ensures eradication. stimulates the nicotinic cholinergic receptor Niclosamide is well-tolerated. Abdominal in the worm leading to persistent discomfort and rarely pruritus and rashes depolarisation and spastic paralysis may occur. (depolarising neuromuscular blocker). The Uses Niclosamide is the drug of choice in paralysed worms are expelled. infestations by tapeworms like T. solium, It is well-tolerated; occasional abdominal T. saginata, H. nana and D. latum. It is also an pain, headache, rashes, weakness and alternative drug in intestinal fluke infestation. dizziness may occur. Dose: 10-15 mg/kg single dose. Praziquantel Uses Pyrantel pamoate is used in the Praziquantel is effective against schistosomes treatment of roundworm, hookworm and of all species, most other trematodes and pinworm infestations. Oxantel pamoate an analog of pyrantel cestodes including cysticercosis. It is effective pamoate is effective in the treatment of as a single oral dose in most infestations. It trichuriasis infection. increases cell membrane permeability to calcium resulting in contraction followed by Piperazine Citrate paralysis and the worms are expelled. Adverse effects are mild and include GI Piperazine citrate is effective in roundworm disturbances, headache, dizziness, drow- and pinworm infestations. It competitively siness, rashes and myalgia. blocks the actions of acetylcholine and thereby contractions in the worms. Flaccid Uses paralysis results and the worms are expelled. Adverse effects are mild–gastrointestinal 1. Schistosomiasis Praziquantel is the drug of symptoms, headache and dizziness are seen choice in all forms of schistosomiasis. occasionally. Piperazine citrate is indicated 2. Tapeworms Single dose (10 mg/kg) of for roundworm and pinworm infestations. praziquantel is effective in all tapeworm It is also safe in pregnancy. infestations. In T. solium it has the Anthelmintics 327

advantage that it kills the larvae and Ivermectin is believed to act by paralysing therefore visceral cysticercosis is avoided. the worms by binding to GABA–gated 3. Neurocysticercosis Praziquantel is an chloride channels and enhancing GABA alternative to albendazole. activity. Ivermectin is as effective as DEC against W. Diethylcarbamazine bancrofti and B.malayi. It is also effective against Strongyloidis stercoralis, Ascaris Diethylcarbamazine (DEC) is the drug of lumbricoides, and cutaneous larva migrans. choice in filariasis. It immobilizes the Adverse effects–Ivermectin is well tolerated. microfilariae resulting in their displacement Apart from nausea and vomiting, allergic in the tissues and also alters their surface reactions can result due to hypersensitivity structure making them more susceptible to to the dying microfilarial proteins (mazotti the host defense mechanisms. Microfilariae reaction). rapidly disappear from the blood except Ivermectin should not be used with other those present in hydrocele and nodules. drugs that influence GABA activity (e.g. Adverse effects are mild; anorexia, nausea, benzodiazepines, valproic acid) in patients vomiting, dizziness and headache; allergic with meningitis and sleeping sickness as these reactions with itching, rashes and fever due conditions impair the blood brain barrier. to release of antigens from the dying worms may occur. Antihistamines are given with Uses DEC to minimize these reactions. DEC can be given during pregnancy. 1. Ivermectin is the preferred drug in the treatment of onchocerciasis. Uses 2. Ivermectin is also useful in the treatment of lymphatic filariasis. • Filariasis DEC is the drug of choice (2 mg/ 3. A single dose of 400 mg/kg ivermectin kg TDS for 21 days). In 7 days patients with 400 mg albendazole is given once a are rendered non-infective to mosquitoes year for mass chemotherapy of lymphatic as microfilariae rapidly disappear. But filariasis. adult worms may need repeated courses. 4. Strongyloidiasis – A single dose of 200 • Tropical eosinophilia (2 mg/kg TDS for 7 mg/kg is curative in strongyloidiasis. days). Symptoms rapidly disappear. However the dose is to be repeated on the second day. Ivermectin 5. Ivermectin is also useful in cutaneous larva Ivermectin is a semisynthetic analog of migrans, ascariasis and in scabies. avermectin B obtained from streptomyces Metrifonate is a prodrug that is converted avermitilis. Ivermectin is effective against to dichlorovas–an organophosphorus insec- many nematodes, arthropods and filariae that ticide. Metrifonate is used as an alternative infect animals and human beings. Ivermectin to praziquantel in the treatment of is very effective against the microfilaria of Schistosoma haematobium infections. Onchocerca volvulus. It is microfilaricidal and Oxamniquine is effective against S.mansoni also blocks the release of microfilariae from and is used as an alternative to praziquantel the uterus of adult worms. There is a rapid in the treatment of S. mansoni infections. decrease in the microfilarial count in the skin Bithionol is the drug of choice in the and eyes. treatment of Fasciola hepatica infections. 328 Textbook of Pharmacology for Dental and Allied Health Sciences 47 Cancer Chemotherapy

Cancer is one of the major causes of death. because different drugs act at different stages The treatment of cancers is still unsatisfactory of the cell cycle. However, some drugs are due to certain characteristics of the cancer cell cycle non-specific (Table 47.1). cells–like capacity for uncontrolled proliferation, invasiveness and metastasis. Common Adverse Effects to Moreover the cancer cells are our own cells Anticancer Drugs unlike microbes, which means that, drugs Since most anticancer drugs act on the rapidly which destroy these cells also can affect multiplying cells, they are also toxic to the normal cells. The host defence mechanisms normal rapidly multiplying cells in the bone which help us in infections is not doing so in marrow, epithelial cells of the skin and cancers as these cancer cells are also host cells. mucous membranes, lymphoid organs and Moreover, the cancer cells can be in a resting gonads. Thus the common adverse effects phase during which they are not sensitive to are: anticancer drugs but can start multiplying 1. Bone marrow depression resulting in later–resulting in recurrence. These features leukopenia, anaemia, thrombocytopenia have made cancer chemotherapy more and in higher doses–aplastic anaemia. In difficult. such patients, infections and bleeding are Phases of cell cycle-Four phases of cell cycle common. are G1, S, G2, and M (Fig 49.1). G1 is the presynthetic phase and the duration is variable. During the S phase the synthesis of DNA occurs and hence the activity of replicating enzymes like DNA and RNA polymerases, topoisomerases, thymidine kinases and dihydrofolate reductases are maximum at this phase of 12 to 18 hours duration. G2 is the postsynthetic phase (1 to 8 hrs) and in the M phase (1 to 2 hrs) the mitosis takes place. The daughter cells may start dividing or may enter into a dorment phase called G0. The knowledge of cell cycle may be used for staging and scheduling treatment Fig 47.1: Phases of cell cycle Cancer Chemotherapy 329

Drugs used in cancers may be classified as follows:

CLASSIFICATION

1. Alkylating agents Nitrogen mustards Mechlorethamine, cyclophosphamide, ifosfamide, chlorambucil, melphalan Ethylenimines Thio-TEPA Alkyl sulfonate Busulfan Nitrosoureas Carmustine, streptazocin Triazine Dacarbazine 2. Antimetabolites Folate antagonist Methotrexate Purine antagonist 6-Mercaptopurine thioguanine, azathioprine pentostatin, fludarabin, cladribin. Pyrimidine antagonist 5-Fluorouracil, floxuridine, cytarabine (cytosine arabinoside) gemcitabine 3. Antibiotics Actinomycin-D (Dactinomycin), daunorubicin, doxorubicin, bleomycin, mitomycin-C, mithramycin 4. Epipodophyllotoxins Etoposide, teniposide 5. Camptothecins Topotecan, irinotecan 6. Taxanes Paclitaxel, docetaxel 7. Vinca alkaloids Vincristine, vinblastine, vinorelbine 8. Miscellaneous Procarbazine, mitotane, l-asparaginase, cisplatin, interferon alpha, imatinib 9. Hormones and their Glucocorticoids, androgens, antiandrogens, estrogens, antagonists antiestrogens, progestins, aromatase inhibitors

2. Other proliferating cells • GIT–esophagits and proctitis can be • Oral lesions including stomatitis and painful. Diarrhoea and ulcers through- glossitis can be painful and bleeding out the gut are common following the from oral lesions are common following use of anticancer drugs. the use of anticancer drugs. Since they • Alopecia (loss of hair) - partial to total also depress the bone marrow, even alopecia is seen following treatment minor dental procedures can cause with most anticancer drugs but it is severe bleeding because platelet count reversible and the hair grows after the gets reduced. Good oral hygiene should chemotherapy is completed. be maintained. Antiseptic mouth • Reduced spermatogenesis in men and washes may be given till the bone amenorrhoea in women (due to damage marrow recovers. to the germinal epithelium) can occur. 330 Textbook of Pharmacology for Dental and Allied Health Sciences

3. Immediate adverse effects Nausea and Mechlorethamine is given IV as it is a highly vomiting are very common with most irritant compound. It is used in Hodgkin’s cytotoxic drugs. They result from the (MOPP regime) and other lymphomas. stimulation of the vomiting centre and Cyclophosphamide is converted to its active CTZ and starts about 4 to 6 hours after metabolite aldophosphamide in the body. It treatment and may continue for 1 to 2 can be given orally. Cyclophosphamide days. Prior treatment with powerful causes cystitis due to a metabolite acrolein. antiemetics is required. This can be prevented by giving IV Mesna, 4. Teratogenicity All cytotoxic drugs are irrigating the bladder with acetylcysteine, teratogenic and are therefore contra- and by taking in large amounts of fluids. indicated in pregnancy. Mesna (sodium-2 mercaptoethane sul- 5. Carcinogenicity Cytotoxic drugs them- phonate) and acetylcysteine contain SH selves may cause secondary cancers, e.g. groups which bind the toxic metabolites and leukaemias are common after treatment inactivate them. of Hodgkin’s lymphoma. Apart from the above, the adverse effects Cyclophosphamide is used in Hodgkin’s unique to some drugs are discussed under lymphoma, leukaemias in children and as an individual drugs listed in Table 47.2. immunosuppressive agent. Ifosfamide has actions and toxicities similar to ALKYLATING AGENTS cyclophosphamide except that it is longer acting. Actions Alkylating agents exert cytotoxic, Chlorambucil (LEUKERAN) is very effective immunosuppressant and radiomimetic effects against lymphoid series. It is the drug of (similar to radiotherapy). Mechanism of action These drugs form highly choice in chronic lymphocytic leukaemia. reactive derivatives which transfer alkyl Melphalan is given orally in multiple myeloma groups to various cellular constituents and Its actions and toxicities are similar to other bind them with covalent bonds. Thus such nitrogen mustards. constituents are not available for normal Busulfan (MYLERAN) has selective activity metabolic reactions. Moreover, alkylation against cells of the myeloid series and is the of DNA results in breakage of the DNA drug of choice in chronic myeloid leukaemia. strand. Nitrosoureas Carmustine is effective in Table 47.1: Cell cycle specific and non- meningeal leukaemias and brain tumours specific drugs because it crosses the blood-brain barrier. It is also used in lymphomas and malignant Cell cycle specific drugs Cell cycle non specific drugs melanoma. Streptozocin is an antibiotic. It is S phase- Alkylating agents used in pancreatic islet cell tumours. Antimetabolites, Anticancer antibiotics Dacarbazine is useful in malignant melanoma. Doxorubicin, Cisplatin Epipodophyllotoxins, Procarbazine Vinca alkaloids. ANTIMETABOLITES Folate Antagonist G2 and M Phases - Bleomycin Methotrexate is a folic acid antagonist. It binds M phase - Taxanes, to dihydrofolate reductase (DHFR) and Vinca alkaloids. prevents the formation of tetrahydrofolate Cancer Chemotherapy 331

Table 47.2: Specific adverse effects of some anticancer drugs

Drugs Specific adverse effects Other prominent adverse effects

Cyclo- Cystitis, stomatitis Bone marrow depression, alopecia, phosphamide vomiting, amenorrhoea, teratogenicity Busulfan Pulmonary fibrosis, stomatitis Bone marrow depression, alopecia, vomiting, amenorrhoea, teratogenicity Cisplatin Ototoxicity Renal dysfunction Bleomycin Pulmonary fibrosis, Stomatitis, alopecia oedema of hands Daunorubicin Cardiotoxicity, red coloured urine Bone marrow depression, alopecia Doxorubicin Cardiotoxicity Bone marrow depression, alopecia Mithramycin Hepatotoxicity Thrombocytopenia (Plicamycin) Vincristine Neurotoxicity, Peripheral neuritis Muscle weakness, alopecia mental depression Asparaginase Pancreatitis, hepatotoxicity, Allergic reactions Mitotane Dermatitis, mental depression Diarrhoea

(THF). This THF is a coenzyme essential in Uses Methotrexate is curative in choriocarci- several reactions in protein synthesis. The noma and is useful in acute leukaemias, breast deficiency results in inhibition of protein cancer and soft tissue sarcomas. It is also used synthesis. Thus rapidly multiplying cells are in rheumatoid arthritis and psoriasis. the most affected. Purine Antagonists 6 Mercaptopurine, thioguanine, azathioprine, fludarabine, pentostatin and cladribine are purine antagonists. Mechanism of action Purine antagonists enter the cells and get converted to active metabolites (triphosphates in most Actions Cytotoxic actions–methotrexate compounds) which are incorporated into DNA. They cause breakages in DNA strands mainly affects the bone marrow, skin and and inhibit protein synthesis. gastrointestinal mucosa and other rapidly Mercaptopurine (6-MP) undergoes extensive dividing cells. first pass metabolism. It is metabolised by It also has immunosuppressant and some xanthine oxidase. Adverse effects include anti-inflammatory properties. bone marrow depression, anorexia, nausea, Methotrexate toxicity can be largely vomiting, stomatitis, jaundice and dermatitis. prevented by administering folinic acid. This Drug interaction 6-Mercaptopurine is folinic acid (also called leucovorin or metabolised by xanthine oxidase. Allopurinol citrovorum factor) gets converted to a form inhibits xanthine oxidase and thus prolongs of THF that can be utilised by the cells. the action of 6-MP. 332 Textbook of Pharmacology for Dental and Allied Health Sciences

bone marrow suppression, nausea, vomiting, weakness and skin rashes.

PYRIMIDINE ANTAGONISTS Pyrimidine antagonists are converted to active metabolites which resemble natural nucleotides. They compete with natural nucleotides, are incorporated into DNA in place of natural nucleotides and inhibit DNA synthesis. 5-Fluorouracil is a pyrimidine analog. It inhibits the enzyme thymidylate synthetase due to which it inhibits the synthesis of Mechanism of action of purine antagonists thymine and thereby inhibits DNA synthesis. It is used in carcinoma of the stomach, colon, Uses 6-MP is used in acute leukaemias in rectum, breast and ovaries. children, choriocarcinoma and some solid Cytosine arabinoside or cytarabine is the most tumours. effective agent in acute myelocytic leukaemia. Thioguanine is effective orally and is used in It causes nausea, vomiting and bone marrow acute leukemias particularly acute depression. granulocytic leukaemia. Cytarabine is useful in acute leukaemias Fludarabine is converted to an active particularly myeloid leukaemia and in triphosphate derivative which inhibits DNA relapsed cases of acute lymphocytic leukaemia. synthesis. It is also incorporated into DNA Gemcitabine is a recently developed analog and causes breakage and termination of the DNA chain. Adverse effects include nausea, of cytarabine with mechanism of action vomiting, anorexia, bone marrow depression, similar to cytarabine. Adverse effects are and neurotoxicity. Fludarabine is used in the treatment of Purine Antagonists chronic lymphocytic leukaemia (CLL) and • Purine antagonists get incorporated Hodgkin’s lymphomas. into DNA and inhibit protein Pentostatin obtained from Streptomyces antibioticus inhibits the enzyme adenosine synthesis. deaminase and inhibits DNA synthesis. • Mercaptopurine, thioguanine are Pentostatin can cause nausea, vomiting, used in acute leukaemias, fludarabine diarrhoea, skin rashes and bone marrow and pentostatin in CLL and non- suppression. Hodgkin’s lymphomas; cladribin is the Pentostatin is used intravenously in the drug of choice in hairy cell leukaemia. treatment of hairy cell leukaemia and other • Purine antagonists share the common chronic leukaemias and non-Hodgkin’s adverse effects of anticancer drugs. lymphomas. Fludarabine and pentostatin Cladribine is the drug of choice in hairly cell combination can cause fatal lung leukaemia. It is also useful in CLL, AML and toxicity. some lymphomas. Cladribine causes mild Cancer Chemotherapy 333 milder with flu-like syndrome and mild bone Bleomycin is used in solid tumours– marrow depression. It is used in pancreatic, testicular tumours, squamous cell carcinoma lung, cervical, ovarian and breast cancers. of the head, neck and oesophagus. It’s most serious toxicity includes ANTIBIOTICS pulmonary fibrosis and cutaneous toxicity but does not cause significant bone marrow Actinomycin D (Dactinomycin) acts by depression. inhibiting DNA-dependent RNA synthesis. Mithramycin (Plicamycin) is highly toxic, used It is one of the most potent anticancer drugs in disseminated testicular tumours and in and is used in Wilms’ tumour, rhabdo- severe hypercalcaemia due to bone cancers. myosarcoma, choriocarcinoma and some soft It reduces plasma calcium levels by its action tissue sarcomas. on the osteoclasts. Daunorubicin and doxorubicin are anth- racyclines. They act by inhibiting DNA EPIPODOPHYLLOTOXINS synthesis. Cardiotoxicity with hypotension, Etoposide and teniposide are plant extracts arrhythmias and CCF, is unique to both these obtained from the mandrake plant. They bind drugs. They also cause vomiting, stomatitis, to topoisomerase II as well as DNA resulting alopecia and bone marrow depression. in DNA strand breakages. They are used in Daunorubicin is used in acute leukaemias testicular and lung cancers. while doxorubicin is useful in solid tumours and in acute leukaemias. TAXANES Epirubicin and mitoxantrone are analogs of Paclitaxel was obtained from the bark of the doxorubicin which are less cardiotoxic. western yew tree. It binds to β-tubulin of Mitomycin C is converted to an alkylating microtubules and arrests mitosis. Paclitaxel agent in the body. It is used in cancers of the is given intravenously; it is metabolised by stomach, lungs and cervix. the liver microsomal enzymes. Adverse Bleomycin is obtained from Streptomyces effects include myelosuppression, myalgia verticillus. It binds with iron and forms free and peripheral neuropathy. Docetaxel is more radicals and causes breakage in DNA strand. potent and orally effective. It has the advantage of the unique mechanism Taxanes are useful in breast cancers and of action and is less toxic to the bone ovarian cancers. They are also found to be marrow–this is advantageous in combination effective in the cancers of the head and neck, regimens. oesophagus and lungs.

Drugs which cause least/no Curable cancers Tumours resistant to treatment bone marrow depression

• Hormones • Hodgkin’s disease • Carcinoma colon • Vincristine • Choriocarcinoma • Carcinoma rectum • Bleomycin • Burkitt’s lymphoma • Melanomas • L-asparaginase • Testicular tumours • Pancreatic tumours • Cisplatin • Wilms’ tumour • Renal cancers • Acute leukaemias in children • Some lung cancers • Ewing’s sarcoma 334 Textbook of Pharmacology for Dental and Allied Health Sciences

CAMPTOTHECINS Cisplatin gets converted to its active form in Camptothecin the first anticancer agent in the cell, inhibits DNA synthesis and causes this group was found to be too toxic. Its cytotoxicity. It causes ototoxicity, nephro- analogs, topotican and irinotecan are less toxic toxicity, peripheral neuropathy, nausea, and useful. They inhibit topoisomerase I vomiting and anaemia. Anaphylactoid resulting in DNA strand breakages leading reactions can follow its use. It is relatively to cell death. They act on the S phase of the less toxic to bone marrow. Cisplatin is used cell cycle. Both are given intravenously. in ovarian and testicular tumours and cancers Toxicity is milder and includes diarrhoea of the head and neck. and reversible bone marrow suppression, Carboplatin is a less toxic derivative of nausea, weakness and skin rash. Irinotecan cisplatin and is better tolerated than cisplatin inhibits the enzyme acetylcholinesterase as adverse effects are milder but it causes resulting in accumulation of acetylcholine myelosuppression. causing excessive salivation, abdominal Oxaliplatin is effective in advanced colorectal cramps, miosis, bradycardia and sweating cancer and in other cancers like ovarian and which respond to treatment with atropine. cervical cancers. VINCA ALKALOIDS L-asparaginase The amino acid asparagine is synthesized by normal cells but malignant Vincristine and vinblastine are obtained from cells are unable to synthesize asparagine and Vinca rosea, the periwinkle plant. They bind depend on the host for the supply. As- to microtubules in the mitotic apparatus and paraginase is an enzyme that converts arrest cell division in metaphase. They are asparagine to aspartic acid and deprives the spindle poisons. The alkaloids differ in malignant cells of asparagine supplies toxicity. resulting in inhibition of protein synthesis. Vincristine (Oncovin) is neurotoxic while bone It is used in acute leukaemias. It causes marrow depression is less. It is used in nausea, vomiting and CNS depression. Bone leukaemias, Hodgkin’s lymphoma, Wilms’ marrow suppression is mild. tumour and brain tumour. Imatinib is a recent introduction in cancer Vinblastine causes bone marrow depression, chemotherapy. It acts by inhibiting some alopecia and vomiting. It is used with selective tyrosine kinases which are bleomycin and cisplatin (VBC) in testicular considered to be involved in the pathogenesis tumours; it is also useful in Hodgkin’s of chronic myeloid leukaemia. lymphoma. Imatinib is almost completely absorbed Vinorelbine is a semisynthetic vinca alkaloid when given orally. It can cause skin rashes used intravenously in lung cancers. It can and elevated serum transaminases. Imatinib cause granulocytopenia, nausea, vomiting and is used in chronic myeloid leukaemia. paraesthesias. HORMONES IN CANCER MISCELLANEOUS CHEMOTHERAPY Procarbazine is effective orally in Hodgkin’s Glucocorticoids Due to their lympholytic lymphoma (MOPP regime component). It action, glucocorticoids are used in acute damages DNA. This may make it leukaemias and lymphomas. Rapid clinical carcinogenic. improvement is seen but duration can vary Cancer Chemotherapy 335 from 2 weeks to 9 months. They are used for GnRH analogs Long-term administration of initiation of therapy due to their rapid action. leuprolide, goserelin and buserelin are useful Glucocorticoids are also of value in the in prostatic and breast cancers. They may be following: combined with tamoxifen in breast cancers. 1. with radiation therapy to reduce Antiandrogen Flutamide is used in prostatic radiation oedema cancer. 2. in intracranial tumours to reduce cerebral oedema RADIOACTIVE ISOTOPES 3. for symptomatic relief in critically ill Some radioactive isotopes can be used in the patients. treatment of certain specific cancers. Prednisolone or dexamethasone are Radiophosphorus P32 is used in polycythemia commonly used. vera. It is taken up by the bone where it emits Oestrogens are useful in (i) prostatic carcinoma β rays and has a half-life of about 14 days. as it is an androgen dependent tumour, (ii) Strontium chloride emits β rays and has a breast cancer in males and in postmenopausal longer t½ in the bony metastases. It is used women–oestrogens are used in advanced to alleviate pain in painful bony metastases. cases where surgery or radiotherapy cannot Radio active iodine I131 is used in the treatment be employed. of thyroid cancers (See Page 344). Progestins are useful in the palliative management of endometrial carcinoma. OTHER AGENTS Androgens are used in the palliative treatment Several agents are used to beneficially of breast cancer in postmenopausal women influence the patients’ response to treatment along with oophorectomy. and to overcome some adverse effects. These Hormone Antagonists have also been termed biological response modifiers. They are as follows: Aromatase inhibitors The enzyme aromatase 1. Haematopoietic growth factors like catalyzes the convertion of androgens to erythropoietin and myeloid growth oestrogens. Inhibitors of aromatase have factors like GM-CSF, G-CSF, M-CSF and been found to be effective in breast cancers. thrombopoietin (see Page 225) are used Formestane, exemestane, anastrozole, to treat bone marrow suppression. vorozole and letrozole are the aromatase 2. Interferons (see Page 308) like interferon inhibitors used. α are used in hairy cell leukaemia, Kaposi’s Aminoglutethemide and trilastane inhibit the sarcoma and condylomata acuminata. convertion of cholesterol to pregnenolone 3. Monoclonal antibodies are immu- (the first step in corticosteroid synthesis) and noglobulins that react specifically with thereby inhibit the synthesis of adreno- antigens present on the cancer cells. corticoids. Aminoglutethemide is useful in Allergic reactions are common. advanced breast cancers when cancer cells Trastuzumab also enhances host immune contain oestrogen receptors. responses and is useful in breast cancers. Antioestrogens Tamoxifen is an oestrogen Rituximab attaches to antigens on the B receptor antagonist used in estrogen receptor cells causing lysis of these cells. It is used containing breast cancer (page 356). in B cell lymphomas. 336 Textbook of Pharmacology for Dental and Allied Health Sciences

General Principles in the Treatment of not depress bone marrow are useful in Cancers (Table 47.3) combination regimens to avoid overlapping Chemotherapy in cancers is generally of adverse effects. With appropriate palliative and suppressive. Chemotherapy is treatment, cure can now be achieved in a few just one of the modes in the treatment of cancers. Maintenance of good nutrition, cancer. Other modes like radiotherapy and treatment of anaemia, protection against surgery are also employed. Combination of infections, adequate relief of pain and anxiety drugs is preferred for synergistic effect, to and good emotional support–all go a long reduce adverse effects and to prevent rapid way in the appropriate management of this development of resistance. Drugs which do dreaded disease.

Table 47.3: Choice of drugs in some malignancies

Malignancy Preferred drugs

Acute lymphatic leukaemia Vincristine + prednisolone Maintenance - Mercaptopurine/Methotrexate, Cyclophosphamide Acute myeloid leukaemia Cytosine arabinoside + daunorubicin Chronic lymphatic leukaemia Chlorambucil + Prednisolone Chronic myeloid leukaemia Busulfan Imatinib; interferons Hodgkin’s disease M-Mechlorethamine Vinblastin O-Oncovin (Vincristine) Doxorubicin OR P-Procarbazine Dacarbazine P-Prednisolone - MOPP Bleomycin Non-Hodgkin’s lymphoma Cyclophosphamide + doxorubicin + vincristine + prednisolone Carcinoma of stomach Fluorouracil + cisplatin Carcinoma of colon Fluorouracil + irinotecan Multiple myeloma Melphalan + Prednisolone Choriocarcinoma Methotrexate Carcinoma of testis Etoposide + bleomycin + cisplatin Osteogenic sarcoma Methotrexate or doxorubicin, vincristine Wilms’ tumour Vincristine + actinomycin-D after surgery Carcinoma of the head and neck Fluorouracil + cisplatin Carcinoma of lung Cisplatin + paclitaxel Hypothalamus and SectionAnterior Pituitary 12 Hormones 337 Hormones

48 Hypothalamus and Anterior Pituitary Hormones

The pituitary gland, under the influence of is a synthetic analog of TSH used in the the hypothalamus secretes many hormones diagnosis of thyroid disorders. which either control the secretion of other Corticotrophin releasing factor (CRF) releases glands or directly act on the target tissues. ACTH and β-endorphins from the anterior These are peptides and act by binding to pituitary. It is used in diagnostic tests in specific receptors present on the target cells Cushing’s disease. (Table 48.1). Gonadotrophin-releasing hormone (GnRH, LHRH, Gonadorelin)–secreted in a pulsatile manner, Hypothalamic Hormones regulates the secretion of gonadotrophins– Growth hormone releasing hormone (GHRH), FSH and LH. It is used in diagnostic tests in (sermorelin) stimulates anterior pituitary to hypogonadism. Therapeutically pulsatile secrete growth hormone. Sermorelin (Table administration is used in infertility and 48.2) is an analog of GHRH used in diagnostic delayed puberty. Continuous administration tests of growth hormone deficiency (Table inhibits gonadotrophin secretion and is used 48.3). in prostatic cancers. GnRH analogue leuprolide Somatostatin is growth hormone release- is more potent and is used for inhibiting hormone present in the pharmacological orchiectomy/oophorectomy hypothalamus, parts of the CNS, pancreas in prostatic cancer and some gynaecological and in gastrointestinal tract. It inhibits the conditions like uterine fibroids and secretion of growth hormone, TSH, prolactin, endometriosis. insulin, glucagon and gastro the intestinal secretions. But it is very short-acting. ANTERIOR PITUITARY HORMONES Octreotide is the synthetic analog of somatostatin which is longer-acting and Growth hormone (GH) a peptide, stimulates useful in acromegaly, some hormone the growth of all organs except brain and eye. secreting tumours and in bleeding It increases the uptake of amino acids by the oesophageal varices. tissues, promotes protein synthesis and Thyrotrophin releasing hormone (TRH) secreted positive nitrogen balance. It causes lipolysis by the hypothalamus stimulates the release and reduces glucose uptake by skeletal of TSH from the anterior pituitary. Protirelin muscles. It brings about linear growth. These 338 Textbook of Pharmacology for Dental and Allied Health Sciences

Table 48.1: Hormones secreted by the hypothalamus and anterior pituitary and their chief functions

Hypothalamic hormone Anterior pituitary hormone Chief actions

1. a. Growth hormone releasing Growth hormone Regulates growth hormone (GHRH) (GH) b. Growth hormone release- inhibiting hormone (soma- Inhibits GH release tostatin) (GHRIH) 2. Corticotropin releasing Corticotrophin Stimulates adrenal cortex to secrete factor (CRF) (ACTH) glucocorticoids, mineralocorticoids and androgens

3. Thyrotropin–releasing Thyroid-stimulating Stimulates release of T3 and T4 hormone (TRH) hormone (TSH) (Thyrotrophin) 4. Gonadotrophin releasing • Follicle stimulating Stimulates growth of ovum and hormone (GnRH, somatorelin) hormone (FSH) grafian follicle in the female and gametogenesis in the male • Luteinising hormone Stimulates ovulation in females and (LH) or (ICSH) regulates testosterone secretion in males 5. Prolactin–releasing factor Prolactin (PRL) Development of breast and lactation 6. Prolactin-release inhibiting factor — Inhibits prolactin-release 7. Melanocyte stimulating Melanocyte stimulating Promotes melanine synthesis causing hormone - releasing factor hormone darkening of skin; regulates feeding

Table 48.2: Analogs of hypothalamic and anabolic actions are mediated by somatomedins anterior pituitary hormones or insulin-like growth factors (IGF) produced Hormones Analogs in the liver. GHRH Sermorelin The secretion of growth hormone is regulated by GHRH and somatostatin Somatostatin Octreotide (GHRIH). Thyrotrophin (TSH) Protirelin GH deficiency in children results in GnRH Buserelin dwarfism while excessive production results Leuprorelin in gigantism in children and acromegaly in Goserelin adults. Nafarelin ADH Desmopressin Uses (Table 48.4) Terlipressin • GH deficiency Replacement therapy with Felypressin GH in deficient children brings about Hypothalamus and Anterior Pituitary Hormones 339

Table 48.3: Uses of Hypothalamic hormones Hypothalamic hormone Uses

1. Sermorelin Diagnosis of GH deficiency 2. Octreotide Acromegaly, hormone secreting tumours, bleeding oesophageal varices. 3. TRH Diagnosis of thyroid disorders 4. CRF Diagnostic tests in Cushing's disease, tests of hypothalamic and pituitary function 5. GnRH (gonadorelin) Diagnostic tests of hypogonadism 6. Leuprolide Prostatic cancer, uterine fibroids

normal growth. It can also be used in GH Gonadotrophins Follicle stimulating hormone deficient adults. (FSH) and luteinising hormone (LH)– • Other conditions GH has been tried in produced by the anterior pituitary regulate chronic renal failure and in catabolic gonadal function. They stimulate follicular states – like severe burns and AIDS. It is development in women and also stimulate liable for abuse in athletes to promote ovarian steroidogenesis (oestrogens and growth. progesterone synthesis). In men they Corticotrophin (Adrenocorticotrophic hormone, promote spermatogenesis. ACTH) controls the synthesis and release of Uses Menotropins is the combination of FSH- glucocorticoids, mineralo-corticoids, and androgens from the adrenal cortex (Fig. 50.1). LH obtained from the urine of It is used in the diagnosis of adrenocortical postmenopausal women. It is used in: insufficiency. 1. Gonadotrophin deficiency in males. Thyroid-stimulating hormone (TSH, Thyro- 2. Undescended testes. trophin) Thyrotrophin stimulates the 3. Amenorrhoea and infertility. production and secretion of thyroid 4. In vitro fertilization - to time the ovulation. hormones and thus regulates thyroid Prolactin This peptide hormone promotes the function. It is used to test thyriod function growth and development of breast during and to increase the uptake of radioactive pregnancy. It stimulates milk production iodine in thyroid carcinoma. along with other hormones like oestrogens

Table 48.4 : Uses of anterior pituitary hormones

Anterior pituitary hormones Uses

1. Growth hormone GH deficiency, Chronic renal failure, burns, Diagnosis of GH deficiency 2. Corticotrophin Diagnosis of adrenocortical insufficiency 3. Thyrotrophin To test thyroid function 4. Gonadotrophins FSH-LH deficiency, undescended testes, amenorrhoea, infertility 340 Textbook of Pharmacology for Dental and Allied Health Sciences

Few examples have been given for each group Hypothalamus and Anterior Pituitary Hormones 341 and progestins. Deficiency results in lactation birth) and following abortion. Bromo- failure while excess prolactin results in criptine stimulates the dopamine receptors galactorrhoea. in the pituitary to inhibit the release of Regulation of secretion–suckling is the principal prolactin. stimulus for prolactin secretion. Suckling 2. In galactorrhoea–due to excess prolactin. stimulates the release of prolactin-releasing 3. Prolactin secreting tumours or factor from hypothalamus. Oestrogens and prolactinomas. dopamine antagonists also stimulate 4. Parkinsonism–bromocriptine is used with prolactin-release. Prolactin is not used levodopa. clinically. 5. Acromegaly–In normal subjects, dopamine Dopamine agonists like bromocriptine agonists stimulate the release of growth inhibit prolactin-release. hormone by the pituitary but in patients Bromocriptine is an ergot derivative with with acromegaly, they suppress growth dopamine agonistic properties. hormone release by a paradoxical effect. Bromocriptine is used Bromocriptine is therefore used in 1. To suppress lactation and breast acromegaly. It also reduces prolactin engorgement after delivery (like in still release. 342 Textbook of Pharmacology for Dental and Allied Health Sciences

49 Thyroid Hormones and Antithyroid Drugs

THYROID HORMONES Normally about 70-90 mcg of T4 and 15-30 mcg of T are secreted daily. In the peripheral Thyroxine (T ) and triiodothyronine (T ) are 3 4 3 tissues, most of the secreted T is converted iodothyronine hormones secreted by the 4 to T which is the active hormone. Both T thyroid gland. The other hormone, calcitonin 3 4 and T are extensively bound to plasma is secreted by the parafallicular cells (see page 3 proteins. The free hormone is metabolised 375). T is a less active precursor of T . 4 3 in the liver and excreted in the bile. The t½ Synthesis, Storage and Secretion The thyroid of T is 6-7 days and that of T is 1-2 days. T hormones are synthesized and stored in the 4 3 3 is 3-5 times more potent than T and acts thyroid follicles. The principle source of 4 faster. iodine is diet. The main steps involved in the Actions Thyroid hormones are essential for synthesis of thyroid hormones are as follows: normal growth, development, function and (Fig. 49.1) 1. Uptake of plasma iodide by thyroid cells by an active transport process with the help of sodium - iodide symporter. 2. Oxidation of iodide to I+ (iodinium ions) by a thyroperoxidase enzyme with the help of hydrogen peroxide. These combine with tyrosine residues of thyroglobulin (TG) to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). 3. Coupling Pairs of MIT and DIT are coupled

to form T3 (MIT+DIT) and T4 (DIT+DIT) catalysed by the same peroxidase enzyme. 4. Storage TG containing iodinated tyrosine residues are stored in the follicles.

5. Release the hormones T4 and T3 are released into the circulation. Regulation-The thyroid secretion is regulated by TSH secreted by the anterior pituitary and TRH from the hypothalamus (Fig. 49.2). Fig. 49.1: Steps in thyroid hormone synthesis Thyroid Hormones and Antithyroid Drugs 343

1. Replacement therapy • Cretinism, may be sporadic or endemic. Congenital absence of thyroid or defective thyroid hormone synthesis cause sporadic cretinism. Extreme deficiency of iodine can also result in endemic cretinism. Treatment should be started immediately to avoid mental retardation. Early detection and treatment produce dramatic results with normal physical and mental development. Levothyroxine (10-15 mcg/kg/day orally) is started and treatment monitored. Replacement should be continued lifelong. • Hypothyroidism in adults results from decreased thyroid activity and can be Fig. 49.2: Regulation of thyroid hormone secretion reversed by appropriate treatment. Treatment is started with levothy- maintenance of all body tissues. Congenital roxine 50 mcg daily and increased deficiency results in cretinism. Thyroid gradually every 2-3 weeks, depending hormones have important metabolic functions on the plasma TSH levels. – they increase metabolic rate, enhance • Myxoedema coma is a medical carbohydrate and protein metabolism and emergency. IV thyroxine 500 mcg or stimulate lipolysis. They facilitate liothyronine 100 mcg should be given erythropoiesis, are essential for normal with prophylactic corticosteroids to functioning of the CNS (mental retardation avoid adrenal insufficiency. is seen in cretinism), skeletal muscles, 2. Non-toxic goitre T4 suppresses TSH cardiovascular system, reproductive system production and the goitre regresses. and gastrointestinal system (hypothyroid 3. Thyroid carcinoma T4 induces temporary patients are constipated while hyperthyroid remission. It is used after surgery. have diarrhoea). 4. Miscellaneous Thyroxine is tried in Mechanism of action Thyroid hormones act on refractory anaemias, infertility and non- specific receptors. Thyroid receptors are healing ulcers. nuclear receptors like the steroid receptors. HYPERTHYROIDISM AND ANTITHYROID T enters into the cells, bind to the receptor 3 DRUGS and the T3 - receptor complex moves to the nucleus where it binds to DNA, activates Hyperthyroidism is due to an excess of gene transcription and regulates protein circulating thyroid hormones and could be synthesis (see Fig. 50.2 Page 349). due to various causes. Graves’ disease, an Uses Both thyroxine and triiodothyronine are autoimmune disorder, is the most common available. Levothyroxine is synthetic T4 and cause. It is characterised by hyperthyroidism, leothyronine is synthetic T3 and are given diffuse goitre and IgG antibodies that orally. activate TSH receptors. Antithyroid drugs 344 Textbook of Pharmacology for Dental and Allied Health Sciences may act by interfering with the synthesis, carbimazole is longer acting. Carbimazole is release or actions of thyroid hormones. a prodrug of methimazole. Pharmacokinetics Thioureylenes are effective Drugs Used in Hyperthyroidism orally; about 75% propylthiouracil is firmly bound to plasma proteins - hence very little 1. Antithyroid drugs Thioureylenes - crosses the placenta and a negligible fraction reaches the milk; but carbimazole and Propylthiouracil, methimazole cross the the placenta and are Methimazole, secreted in the milk (Table 49.1). Carbimazole. Thioureylenes are concentrated in the 2. Iodine, Iodides, thyroid. They are metabolised in the liver. Radioactive iodine. Adverse effects are allergic reactions, jaundice Thioureylenes are thionamides and include and headache. Agranulocytosis is a rare but propylthiouracil, methimazole and serious adverse effect which occurs in about carbimazole. 0.1% of patients. It is reversible on stopping Actions Thioureylenes reduce the synthesis the antithyroid drug but patient should be of thyroid hormones by inhibiting iodination monitored with frequent WBC counts. of tyrosine residues and coupling of iodotyrosine residues. They bring about Uses these effects by inhibiting the peroxidase enzyme. Propylthiouracil also inhibits Hyperthyroidism - antithyroid drugs are used peripheral conversion of T4 to T3. T3 and T4 in hyperthyroidism. levels fall. Large doses may stimulate release a. Graves’ disease or diffuse toxic goitre needs of TSH resulting in thyroid enlargement. long-term (1-15 yr) treatment with Over 3-4 weeks of treatment, the signs and antithyroid drugs. Patients are usually symptoms of hyperthyroidism subside. euthyroid after 8-12 weeks of treatment. Propylthiouracil is faster acting while Smaller maintenance doses (Table 49.2) are then sufficient.

Table 49.1: Compare and contrast propylthiouracil and methimazole carbimazole

Features Propylthiouracil Methimazole

Onset of action Faster acting Slower acting t½ 1-2 hours 6 hours →→→ Additional action Prevents peripheral convertion of T4 T3 No such effect Protein binding 75%, Firmly protein bound Nil Placental transfer Negligible Significant Secretion in milk Negligible Significant Pregnancy Preferred Not Preferred Lactating mothers Drug of choice Not used Dose frequency t.i.d.- q.i.d. o.d.- b.i.d.

(Carbimazole is a prodrug, converted to methimazole in the body) Thyroid Hormones and Antithyroid Drugs 345 b. Toxic nodular goitre Antithyroid drugs are Lugol's iodine is 5% iodine in 10% potassium used as alternatives when surgery cannot iodide. Iodine is converted into iodides in be done as in the elderly patients. the intestine which is then absorbed. c. Preoperatively – hyperthyroid patients are Adverse effects include allergic reactions like made euthyroid with antithyroid drugs skin rashes, conjunctivitis, swelling of the lips and then operated. and salivary glands, fever and lympha- d. Hyperthyroidism in pregnancy - is rare denopathy. Chronic overdose can cause but when severe, requires treatment. iodism with metallic taste, excessive salivation, Propylthiouracil is the preferred drug as lacrimation, burning sensation in the oral it poorly crosses the placental barrier. It cavity and throat, running nose, sore throat, is also preferred in thyrotoxicosis in cough, headache and rashes. lactating mothers as only a negligible amount of propylthiouracil is secreted in Uses the milk. e. Thyroid storm or thyrotoxic crisis is sudden, 1. Preoperative preparation for thyroidectomy severe exacerbation of thyrotoxicosis and Iodine is started just 10 days prior to can be life threatening. It is precipitated surgery to make the thyroid gland firm by factors like stress, infections, trauma, and less vascular. surgery, etc. Symptoms include fever, 2. Thyroid storm Iodides act rapidly to reduce tachycardia, nausea, vomiting, diarrhea, the release of thyroid hormones. confusion, restlessness and may lead on 3. Prophylaxis Iodide or iodate is added to to coma and death. Propylthiouracil, oral/ common salt to prevent endemic goitre. rectal potassium iodide, IV hydro- 4. Antiseptic see Page 378. cortisone, tepid sponging, sedation, IV 5. Expectorant Used in cough. 131 fluids and supportive therapy are needed Radioactive iodine I given orally as a solution immediately. Propranolol may be used to is rapidly absorbed and is concentrated by rapidly control the symptoms. It also the thyroid in the follicles. It emits both γ and β rays. The γ rays pass through the tissue impairs the conversion of T4 to T3 which may add to the benificial effect. while β particles penetrate only 0.5 to 2 mm Iodides inhibit the release of thyroid of the tissue due to which it destroys only hormones and when given in thyrotoxic the thyroid tissue without damaging the patients the symptoms subside in 1-2 days. The gland becomes firm, less vascular and Table 49.2 : Dosage of antithyroid drugs shrinks in size over a period of 10-14 days. Drug Daily dose These effects are transient and decrease after 15 days. Iodides are administered Carbimazole Start with 15-45 mg orally as Lugol's iodine or as potassium Maintenance 5-10 mg iodide solution - 3 drops 3 times a day. Methimazole Start 15- 30 mg Maintenance 5-15 mg Propylthiouracil Start 150-300 mg Drugs that influence thyroid function Maintenance 40-100 mg Amiodarone Phenytoin Lugol’s Iodine 5-15 drops Sulfonamides Carbamazepine (5% iodine in 10% Lithium Sodium nitroprusside potassium iodide solution) 346 Textbook of Pharmacology for Dental and Allied Health Sciences surrounding structures. Iodides also inhibit The patient should be followed up the synthesis of thyroid hormone for 1-2 days for the symptoms of hypo- (known as Wolff-Chaikoff effect). 131I has a thyroidism and replacement therapy half-life of 8 days but the radioactivity is with thyroid hormones should be present upto 2 months. It is given as a single promptly given. dose; clinically the effect is seen after 1-2 β-adrenergic blockers Many of the symptoms months. of hyperthyroidism are of sympathetic over- Radioactive Iodine (3–10 m curie) is used activity as there is increased tissue sensitivity in the treatment of hyperthyroidism and in to catecholamines in hyperthyroidism. β thyroid carcinoma. Small dose is used for adrenergic blockers like propranolol relieve diagnostic purpose in thyroid function tests. symptoms like palpitation, tremors, Advantages of 131I over thyroidectomy are nervousness, sweating and myopathy. They that only afford symptomatic relief and are used (i) administration is simple, as adjuvants in hyperthyroidism and (ii) convenient; thyrotoxic crisis. (iii) surgery and its associated risks can be Ionic inhibitors interfere with the avoided. concentration of iodine by the thyroid gland. (iv) less expensive when compared to Thiocyanate and perchlorate inhibit the surgery. organification of iodine but are not used now The disadvantages are: due to the adverse effects. Food items like (i) the long time (3 months) taken for cabbage; cigarette smoking and drugs like maximum response sodium nitroprusside, increase the (ii) the risk of hypothyroidism which may concentration of thiocyanate in the blood and develop after a few months or years. may result in hypothyroidism. Corticosteroids 347 50 Corticosteroids

Corticosteroids are hormones produced in They enhance protein breakdown and the cortex of the adrenal gland. They are nitrogen is excreted leading to negative glucocorticoids, mineralocorticoids and a nitrogen balance. Glucocorticoids are small amount of androgens. Cortisol is the catabolic hormones. major glucocorticoid while aldosterone is the Glucocorticoids promote lipolysis and major mineralocorticoid. The secretions of redistribution of fat takes place–fat is the adrenal cortex are under the control of mobilised from extremities and deposited ACTH secreted by the anterior pituitary and over the face, neck and shoulder and this fat deposition in excess glucocorticoid activity this is in turn regulated by CRF and plasma corticosterone levels (Fig. 50.1). This is termed hypothalamic-pituitary-adrenal axis.

STRUCTURE AND SYNTHESIS The corticosteroids have a cyclopentano- perhydrophenanthrene (steroid) ring. They are synthesized in the adrenal cortex from cholesterol under the influence of ACTH. Everyday about 10-20 mg of hydrocortisone (maximum in the early morning) and 0.125 mg of aldosterone are secreted. They are also released in response to stress.

ACTIONS Glucocorticoid Actions 1. Metabolic effects Carbohydrate, protein and fat metabolism– Glucocorticoids promote gluconeogenesis and glycogen deposition in the liver and inhibit peripheral utilization of glucose Fig. 50.1: Hypothalamo-pituitary-adrenal axis regulation resulting in increased blood glucose levels. of synthesis and secretion of adrenal corticosteroids 348 Textbook of Pharmacology for Dental and Allied Health Sciences is described as ‘moon face’, ‘fish mouth’ and • GIT–Glucocorticoids enhance the ‘buffalo hump’. secretion of gastric acid and pepsin in 2. Anti-inflammatory and immunosuppressive the stomach. effects Glucocorticoids suppress the • Calcium metabolism–Glucocorticoids development of inflammatory response to all inhibit absorption and enhance the types of stimuli like chemical, mechanical and renal excretion of calcium–they immunological stimuli. They inhibit both antagonise the effect of vitamin D on early and late manifestations of infla- calcium absorption. Bone resorption mmation. Inhibition of late response like takes place. capillary proliferation, collagen deposition, • Formed elements of blood– fibroblastic activity and scar formation may glucocorticoids have a lympholytic delay wound healing. They inhibit migration effect which is very prominent in and depress the function of the leucocytes lymphomas; but they increase the and macrophages and inhibit the release of number of platelets and RBCs. chemical mediators. The ability of these cells • They are essential for maintaining to respond to antigens is decreased. normal GFR. Glucocorticoids - even a single dose bring 4. Mineralocorticoid action Glucocorticoids about a decrease in the number of WBCs - also have a weak mineralocorticoid action– lymphocytes, monocytes, eosinophils and cause some salt and water retention and basophils decline. In addition glucocorticoids potassium excretion. Some synthetic also induce the synthesis of a protein - glucocorticoids are devoid of this activity. lipocortin, which inhibits phospholipase A2 thereby decreasing the production of Mechanism of Action prostaglandins and leukotrienes. Corticosteroids enter the cells by simple Glucocorticoids thus suppress cell- diffusion, bind to specific receptors in the mediated immunity, prevent manifestations cytoplasm (Fig. 50.2) and activate them. The of allergy and prevent homograft rejection. drug- receptor complex is then transported Large doses also inhibit antibody production. into the nucleus where it binds to specific sites 3. Other actions on DNA and induce the synthesis of specific • Glucocorticoids reduce capillary mRNA. By this they regulate the synthesis permeability, thereby reducing fluid of new proteins that bring about the hormone exudation and maintain the tone of effects. arterioles. They have a positive inotropic effect on the heart. Prolonged PHARMACOKINETICS use can cause hypertension. • They are essential for normal muscular Most glucocorticoids are well-absorbed activity. orally. Hydrocortisone undergoes high first • They are required for normal pass metabolism. It is 95% bound to plasma functioning of the central nervous proteins–corticosteroid binding globulin system. Deficiency results in apathy (CBG) or transcortin. Glucocorticoids are and depression while large doses metabolised in the liver by oxidation and result in restlessness, anxiety and reduction followed by conjugation. sometimes psychosis. Metabolites are excreted by the kidneys. The Corticosteroids 349

Preparations Glucocorticoids are given by many routes - orally, parenterally, topically, by inhalation and nasal spray. They may also be injected intra-articularly. The synthetic analogs are more potent than hydrocortisone and have less or no mineralocorticoid activity (Table 50.2). • Hydrocortisone, the chief natural glucocorticoid is used orally and parenterally; in emergencies it is used intravenously. • Prednisolone has potent glucocorticoid with mild mineralocorticoid activity. It is the most commonly used glucocorticoid. • Prednisone is a prodrug converted to prednisolone in the liver. • Methylprednisolone is similar to prednisolone and is used as retention enema Fig. 50.2: Mechanism of action of corticosteroids and for high dose pulse therapy. • Triamcinolone, dexamethasone, beta- t½ varies with each agent and we have short, methasone have no mineralocorticoid intermediate and long-acting agents (Table activity and have selective, potent 50.1). glucocorticoid effects.

Table 50.1: Relative potency of some corticosteroids

Drug Glucocorticoid Mineralocorticoid Equivalent activity activity dose

Short-acting (8-12 hr) Hydrocortisone 1 1 20 mg Cortisone 0.8 0.8 25 mg Intermediate-acting (18-36 hr) Prednisolone 4 0.8 5 mg Methylprednisolone 5 0.5 4 mg Triamcinolone 5 0 4 mg Fludrocortisone 10 125 2 mg Long-acting (36-54 hr) Paramethasone 10 0 2 mg Dexamethasone 25 0 0.75 mg Betamethasone 30 0 0.6 mg 350 Textbook of Pharmacology for Dental and Allied Health Sciences

Table 50.2: Preparations and dose of some commonly used glucocorticoids

Glucocorticoid Trade name Dosage form Daily dose

Hydrocortisone EFCORLIN 10 mg tablet 50 mg/ml inj IM, IV 30-100 mg hemisuccinate Also available for retention enema, IA inj and topical use Prednisolone WYSOLONE 5,10, 20 mg tab 20 mg/ml inj 5-60 mg pediatric and topical preparations oral 10-40 mg IM also available Methylprednisolone SOLVMEDROL 4 mg tab 20 mg/ml inj 4-32 mg acetate Retention enema Triamcinolone KENACORT 4 mg tab 10 mg/ml inj 4-20 mg 5- 40 mg inj IM/IA Dexamethasone DEXONA 0.5 mg tab 0.5-5 mg oral 4 mg/ml inj 4-20 mg IV/IM 0.1% ointment

Betamethasone BETNESOL 0.5 mg tab 0.5-5 mg oral 4 mg/ml inj 4-20 mg IM/IV 0.025% ointment

Topical : IM = intramuscular, IV = intravenous, IA = intra-articular

• Topical Preparations 1. Cushing’s syndrome with characteristic Several glucocorticoids like hydro- appearance of moon face, supraclavicular cortisone, dexamethasone and beta- hump (buffalo hump), truncal obesity, muscle methasone are available for topical use as wasting, thinning of the limbs and skin, easy creams, ointments, nasal and eye drops. bruising, purple striae and acne. Some of them also contain antibiotics. 2. Hyperglycaemia and sometimes diabetes • Beclomethasone, budesonide, fluticasone mellitus may be precipitated. are available for inhalation. 3. Susceptibility to infections is increased and the severity of any infection may be more Adverse Effects of Glucocorticoids because of immunosuppression. Oppor- Adverse effects of glucocorticoids (Fig. 50.4) tunistic infections may occur. Previously are dependent on dose, duration of therapy dormant tuberculosis may become active. and the relative potency of additional 4. Osteoporosis especially of the vertebrae is mineralocorticoid effects. Whenever possible, more common in the elderly. they should be used topically to avoid 5. Avascular necrosis of the bone due to systemic effects. Single doses are harmless restriction of blood flow through bone while short courses are well-tolerated. capillaries may cause joint pain, stiffness and Prolonged use is associated with toxicity. restriction of movement. Head of the femur, Adverse effects include: humerus and distal part of femur may be Corticosteroids 351 affected. Growth in children may be 9. Delayed wound healing Steroids may delay suppressed. wound healing. 6. Peptic ulceration may sometimes occur on 10. Other effects include raised intracranial prolonged therapy especially when other pressure, convulsions, hypercoagulability of ulcergenic drugs (e.g. NSAIDs) are used the blood and menstrual disorders. concurrently. 11. HPA axis suppression depends on the dose, 7. Mental disturbances Alterations in behaviour duration and time of administration. After can occur with high doses of steriods. prolonged steroid therapy, adrenal cortex Symptoms may range from insomnia, anxiety, gradually atrophies due to feedback nervousness, mood changes, euphoria, inhibition. If steroid administration is psychosis or depression. suddenly stopped, acute adrenal insufficiency 8. Cataract and glaucoma may follow long- results. Hence after prolonged adminis- term use of glucocorticoids even as eye tration, steroids should be tapered before drops. Patients receiving long-term steroids withdrawal to allow HPA axis to recover. should undergo eye examinations for these. Prior to surgery or general anaesthesia, it is

Fig. 50.3: Adverse effects of glucocorticoids 352 Textbook of Pharmacology for Dental and Allied Health Sciences advisable to elicit proper drug history. If the bolus followed by infusion is given patient has received long-term steroids immediately. within previous six months, it is prudent to B. Chronic adrenal insufficiency (Addison’s administer prophylactic hydrocortisone to disease). Oral hydrocortisone 20-40 mg daily avoid shock. Two weeks of use of > 20 mg is given. Some patients may need additional hydrocortisone/day needs tapering of the fludrocortisone (a mineralocorticoid). dose. C. Congenital adrenal hyperplasia is In order to minimize HPA axis characterised by impaired synthesis of suppression, lowest effective dose of a corticosteroids due to deficiency of some glucocorticoid for the shortest possible period enzymes involved in synthesis. As a result should be used. The drug should be given in ACTH levels rise resulting in adrenal a single morning dose. Administration on hyperplasia. Hydrocortisone and if required alternate days is found to be associated with mineralocorticoids are given daily. least/no HPA axis suppression and whenever II. Pharmacotherapy possible this measure should be followed, Glucocorticoids have been used in a variety especially when long-term steroids are of nonendocrine conditions where they are needed. used for symptomatic relief, but may even 12. Mineralocorticoid effects including salt and be life saving. water retention, oedema, hypokalaemia and 1. Rheumatoid arthritis In progressive disease hypertension are rare with selective steroids are given with NSAIDs. If glucocorticoids. 1-2 joints are involved, intra-articular injections are preferred. Uses 2. Osteoarthritis Steroids are given as intra- I. Replacement therapy articular injections with strict aseptic A. Acute adrenal insufficiency is an emergency precautions. A minimum of 3 months interval condition that could be precipitated by an should be given between two injections of infection or sudden withdrawal of steroids. steroids into the joint. Repeated injections can Symptoms include nausea, vomiting, result in joint destruction. weakness, hypotension, dehydration, 3. Rheumatic carditis Severely ill-patients with hyponatremia and hyperkalemia. Intra- fever and not responding adequately to venous hydrocortisone hemisuccinate 100 mg NSAIDs require glucocorticoids.

Table 50.3: Compare and contrast hydrocortisone and dexamethasone

Features Hydrocortisone Dexamethasone

Source Natural Synthetic Mineralocorticoid activity Present Absent Potency Less potent More potent Equivalent dose 20 mg 0.75 mg Plasma t½ 8-12 hrs 36-54 hrs Duration of action Short Long Production in the body Endogenous Not produced (Exogenous) Corticosteroids 353

4. Acute gout When treatment with NSAIDs 11. Gastrointestinal diseases Mild inflammatory have not been successful, prednisolone is used bowel diseases like ulcerative colitis are as an adjuvant. treated with steroid retention enema while 5. Allergic diseases like angioneurotic edema, severe cases need oral prednisolone. hay fever, serum sickness, contact dermatitis, 12. Liver diseases Steroids are useful in urticaria, drug reactions and anaphylaxis– conditions like autoimmune chronic active steroids are indicated. Steroids are slow hepatitis and alcoholic hepatitis. acting and in less severe cases, antihistamines 13. Haematologic disorders like purpura and should be preferred. haemolytic anaemia having immunological 6. Bronchial asthma aetiology respond to steroids. • Acute exacerbations – a short course 14. Cerebral oedema Large doses of dexa- of prednisolone methasone reduces cerebral oedema occurring • Status asthmaticus – intravenous in some malignancies. hydrocortisone hemisuccinate 100-200 15. Malignancies Because of their lympholytic mg repeated after 8 hrs 40-60 mg per effects, steroids are used in the treatment of day. acute lymphocytic leukaemia and lymphomas. • Chronic asthma–Inhalational steroids Steroids are also used for rapid symptomatic are used and in more severe cases low relief in other malignancies like breast cancer. dose oral prednisolone is indicated. 16. Lung diseases Apart from bronchial COPD– exacerbation may be treated asthma, steroids are used in other diseases with short course of prednisolone. like aspiration pneumonia and prevention of 7. Collagen diseases like polyarthritis nodosa, infant respiratory distress syndrome. lupus erythematosus, polymyositis, Wegener’s 17. Organ transplantation For prevention and granulomatosis and other rheumatoid treatment of graft rejection, high doses of disorders respond to glucocorticoids. Gluco- prednisolone are started at the time of corticoids are the first-line drugs. Predni- surgery with immunosuppressive agents. 18. Others - Glucocorticoids are useful in solone is given for 6 weeks and tapered over • Sarcoidosis to induce remission. another 6 weeks. • Pneumocystis carinii pneumonia is 8. Eye diseases Allergic conjunctivitis, uveitis, common in patients with AIDS - optic neuritis and other inflammatory Glucocorticoids reduce the risk of conditions are treated with steroid eye respiratory failure and decrease drops. Long-term steriods administration can mortality. increase IOP which should be monitored. In ocular infections, steroids are contra- Table 50.4: Contraindications to indicated. glucocorticoid therapy 9. Renal diseases like nephrotic syndrome are Steroids should be used with caution in: treated with steroids. Glucocorticoids are 1. Peptic ulcer 6. Osteoporosis the first line drugs. 2. Hypertension 7. Psychoses 10. Skin diseases Atopic dermatitis, seborrhoeic 3. Infections 8. Epilepsy dermatitis, inflammatory dermatoses and 4. Diabetes mellitus 9. CCF other local skin conditions are treated with 5. Ocular infections 10. Glaucoma topical steroids. Systemic steroids are life particularly viral 11. Renal failure saving in pemphigus. infections 354 Textbook of Pharmacology for Dental and Allied Health Sciences

• In haemolytic anaemia glucocorticoids Steroids and Dentistry reduce the autoimmune destruction of Glucocorticoids are one of the most widely erythrocytes. Contraindications–see table 50.4. used drugs. When a patient on glucocorticoids, especially on long-term steroids MINERALOCORTICOIDS requires a dental procedure, adequate precautions are to be taken. The most important natural mineralocorticoid (a) Patients on steroids are more susceptible is aldosterone synthesized in zona to infections. Antibiotic coverage may be glomerulosa of the adrenal cortex. Small needed depending on the procedure amounts of desoxycorticosterone is also (b) If the patient is on steroids, it should released. be continued because if steroids are Actions Mineralocorticoids promote sodium suddenly stopped, the patient may go into and water retention by distal renal tubules with loss of potassium. acute adrenal insufficiency (due to HPA axis Adverse effects include weight gain, oedema, suppression) particularly following major hypertension and hypokalaemia. procedures. Infact patients on long-term Fludrocortisone has predominantly glucocorticoids may require an additional mineralocorticoid properties and is used for dose of the steroid to manage the stress. replacement therapy in aldosterone (c) Long-term administration of glucocor- deficiency as in Addison’s disease. Although ticoids may delay wound healing. aldosterone is the principal natural (d) If a patient on glucocorticoids, undergoes mineralocorticoid, it is not used therap- a dental procedure and requires NSAIDs for eutically since it is not effective orally. analgesia, care should be taken to use the ones which do not produce much INHIBITORS OF ADRENAL STEROIDS gastric irritation - paracetamol (400-600 mg) SYNTHESIS or ibuprofen may be given. Both NSAIDs and Metyrapone, trilastane, aminoglutethimide and glucocorticoids can produce gastric irritation ketoconazole These drugs inhibit the synthesis and when given together it can be severe. of adrenal steroids by inhibiting certain (e) Therapeutic use of steroids in dental enzymes involved in steroid synthesis. They procedures is not very common. Severe are used in Cushing’s syndrome and some inflammation may rarely require steroids in prostatic and breast cancers. addition to NSAIDs. 51 Oestrogens, Progestins and Hormonal Contraceptives

OESTROGENS Actions Estrogens are required for– The oestrogens are produced by the ovaries, 1. the normal maturation of the female placenta and in small amounts by the adrenals reproductive tract. and testes. The major oestrogens are 2. development of secondary sexual oestradiol, oestrone and oestriol. oestradiol characters in the female. is converted to oestrone and oestriol by the 3. stimulation of preovulatory endome- liver and other tissues. trium. Natural oestrogens Oestrogens, oestradiol, 4. metabolic effects–oestrogens inhibit the oestrone, oestriol. resorption of bone and maintain the bone Synthetic oestrogens Ethinyl oestradiol, mass. They promote the fusion of stilboestrol, epiphyses. mestranol. 5. Estrogens are important for the Estrogen receptors are of two types–ERα and maintenance of normal structure of the β ER . skin and blood vessels in women. Distribution- 6. oestrogens decrease plasma LDL ERα–Female reproduction tract, breast, cholesterol and raise HDL cholesterol and blood vessels and hypothalamus. triglycerides. ERβ–Ovaries and prostate. 7. effect on blood coagulation–oestrogens enhance the coagulability of the blood. Pharmacokinetics Natural oestrogens are metabolised rapidly in the gut–hence are not effective orally; they have a short t½.. They are largely bound to plasma proteins. Synthetic oestrogens are orally effective and are long-acting. Adverse effects Nausea, breast tenderness, migraine headaches, hyperpigmentation, hypertension and cholestasis may be seen. In men gynaecomastia and feminization can Fig. 51.1: Regulation of secretion of gonadal hormones occur. 356 Textbook of Pharmacology for Dental and Allied Health Sciences

Cancers Increased incidence of endometrial 6. Dysfunctional uterine bleeding oestrogens and breast cancers are reported on long-term are used as adjuvants to progesterone. oestrogen therapy. 7. Carcinoma prostate is an androgen Teratogenic—When given to a pregnant lady dependent tumour. Oestrogens oestrogens may cause: antagonise the action of androgens, • In female child–increased risk of vaginal suppress androgen production and are and cervical cancers useful for palliative therapy. • In male child–genital abnormalities. Contraindications Oestrogen dependent tumours, liver disease, thromboembolic Uses disorders. 1. Replacement therapy (a) In primary hypogonadism–Oestrogen Selective oestrogen receptor started at 11-13 years of age modulators (SERMs) and anti- stimulates the development of oestrogens. secondary sexual characters and menstruation. Tamoxifen (b) Postmenopausal syndrome-Due to Tamoxifen was earlier considered to be an decreased oestrogen production at oestrogen antagonist. But now it is menopause, hot flushes, anxiety, understood that it acts as an agonist, fatigue, sweating, muscle and joints antagonist or partial agonist depending on pain are common (Post menopausal the site. Raloxifene and toremifene have actions syndrome). Other longer-lasting similar to tamoxifen and are all termed changes including osteoporosis, selective oestrogen receptor modulators genital atrophy, skin changes, (SERMs). SERMs have tissue-selective increased risk of cardiovascular oestrogenic activities. i.e., disease and psychological disturbances may be seen. Oestrogens given • they act as agonists at bone, lipid, brain in low doses as hormone replacement and liver. therapy (HRT) are highly effective in • antagonists at breast, pituitary and reversing most of the changes. endometrium; 2. Senile vaginitis is common in elderly • partial agonist at genitourinary women due to reduced oestrogen epithelium, in bone remodeling and synthesis by the ovary–ostrogen cream is cholesterol metabolism. used topically. Tamoxifen By its tissue selective activity on 3. Osteoporosis In postmenopausal osteo- the oestrogen receptor, tamoxifen: porosis, oestrogens restore calcium • inhibits the proliferation of tumour cells balance and need to be given for a long in the breast. time. • stimulates the proliferation of the 4. Oral contraceptives Oestrogens are used endometrium. (See Page 375) with progestins. • reduces bone resorption. 5. Dysmenorrhoea oestrogens combined with • decreases total cholesterol progestins suppress ovulation and such Side effects include hot flushes, nausea, anovulatory cycles are painless. vomiting, vaginal dryness, cataract and skin Oestrogens are used only in severe rashes. Tamoxifen increases the risk of dysmenorrhoea. endometrial cancer and thromboembolism Oestrogens, Progestins and Hormonal Contraceptives 357

Uses Breast cancer–Tamoxifen is used in the 2. In vitro fertilization Clomiphene induced palliation of advanced breast cancer in ovulation is also useful in in vitro postmenopausal women with oestrogen fertilization. receptor positive tumours. Raloxifene acts as an oestrogen receptor Oestrogen Synthesis Inhibitors agonist in the bone. In women with Aromatase inhibitors like formestane, postmenopausal osteoporosis, raloxifene has exemestane, anastrozole, letrozole and antiresorptive effects on the bone. It reduces vorazole block the production of oestrogens bone loss and may even help to gain bone and are used in the treatment of breast mass. Raloxifene also lowers LDL. It acts as cancer. an oestrogen antagonist in the breast due to which it reduces the incidence of breast PROGESTINS cancer. Raloxifene does not stimulate the uterine endometrial proliferation. Progesterone is the natural progestin Adverse effects include hot flushes, leg cramps synthesized in the ovary and placenta. It is and an increased risk of deep vein thrombosis also synthesized by the testis and adrenals and pulmonary embolism. where it acts as a precursor of various steroid Raloxifene is indicated for the prevention of hormones (see under corticosteroids). postmenopausal osteoporosis. Toremifene has actions similar to tamoxifen Progestins and is indicated in the treatment of metastatic Natural Progesterone breast cancer in postmenopausal women. Synthetic Medroxyprogesterone acetate Clomiphene Citrate Allylestrenol Clomiphene citrate binds to the oestrogen Megestrol receptors and acts as a competitive inhibitor Levonorgestrel of endogenous oestrogens. Like tamoxifen, Norethisterone acetate it is also a partial agonist. Clomiphene Lynestrenol opposes the negative feedback of endoge- Norgestimate nous oestrogens on the hypothalamo- pituitary axis resulting in increased gonadotrophin secretion and thereby induces Actions ovulation. 1. Uterus The secretory changes in the Side effects include ovarian hyperstimulation endometrium like increased tortuosity of resulting in multiple pregnancy, ovarian the glands are due to progesterone. In cysts, hot flushes, headache and skin rashes. pregnancy, decidual changes in the endometrium take place under the Uses influence of progesterone. Progesterone 1. Infertility Clomiphene citrate is used in is very important for the maintenance of infertility due to ovarian disorders. It is pregnancy (Progestin= favours pregnancy). given orally, 50 mg daily for 5 days 2. Cervix The watery cervical secretions are starting from 5th day of the cycle; course changed to a viscid scanty secretion by is repeated till ovulation occurs progesterone. 358 Textbook of Pharmacology for Dental and Allied Health Sciences

3. Vagina Vaginal epithelium changes to that 5. Endometrial carcinoma Progestins are used seen in pregnancy. as a palliative measure in cases with 4. Mammary gland Along with oestrogen, metastasis. progesterone is responsible for the development of the secretory apparatus ANTIPROGESTINS in the breast and prepares the gland for lactation. Mifepristone binds to the progesterone 5. Body temperature Increase in the body receptor and blocks the actions of temperature by 1°C during luteal phase progesterone. When given in early pregnancy– beginning at ovulation is due to abortion occurs. progesterone. Mechanism of action Mifepristone blocks the progesterone receptors in the uterus which Adverse effects Headache, breast engorgement, causes decidual breakdown; blastocyst gets rise in body temperature, edema, acne and detached, HCG and progesterone secretions mood swings may be seen. Progesterone is fall. This in turn increases prostaglandin levels teratogenic. and stimulate uterine contractions. It also softens the cervix and facilitates expulsion of Uses the blastocyst. 1. Contraception (see below). 2. Hormone replacement therapy (HRT) Uses Progestins are combined with oestrogens 1. Termination of pregnancy Early pregnancy in HRT of postmenopausal women (given up to 9 weeks can be terminated with a cyclically), oestrogen administration single oral dose–600 mg of mifepristone increases the risk of endometrial cancer– followed 48 hr later by a prostaglandin but supplementing it with a progestin to increase uterine contractions and counters this risk. facilitate expulsion of the blastocyst. 3. Ovarian suppression Progestins are used to Adverse effects include heavy bleeding, suppress ovulation in dysmenorrhoea, nausea and abdominal pain. endometriosis, dysfunctional uterine 2. Postcoital contraceptive Mifepristone bleeding (DUB) and premenstrual prevents implantation when given within syndrome. 72 hrs after coitus. Regular use of 4. Threatened or habitual abortion Efficacy in mifepristone once a month as a con- such patients is not proved. traceptive has been tried.

Table 51.1: Antagonists of sex hormones and their uses

Hormone Receptor antagonist Uses of antagonist

Oestrogen Tamoxifen Breast cancer Clomiphene citrate • Infertility • In vitro fertilization Progesterone Mifepristone Termination of pregnancy Androgen Flutamide Carcinoma prostate Cyproterone • Carcinoma prostate • Hypersexuality in men • Female hirsutism Oestrogens, Progestins and Hormonal Contraceptives 359

HORMONAL CONTRACEPTIVES teratogenic. However, recent studies have Millions of women around the world use found low doses of the hormones to be non hormonal contraceptives making them one teratogenic. of the most widely prescribed drugs. When 2. Mini-pill A low dose progestin is taken properly used, they are the most effective daily without a gap. Oestrogen and its spacing methods of contraception. Hormonal accompanied long-term adverse effects are contraceptives have greatly contributed to also eliminated. But efficacy is lower, the control of population throughout the menstrual cycles may be irregular and is world. therefore not popular. 3. Postcoital contraceptives Postcoital pills act Oral pills Depot preparations by preventing implantation. The earlier they • Combined-pill • Injectables are given the better. High dose of an • Mini-pill • Subcutaneous oestrogen was used earlier. Combination of implants • Postcoital pill • Transdermal oestrogen and progestins is now preferred patches due to lower doses needed and lesser side • Vaginal rings effects reported. The pill should be started within 72 hours of coitus and has an efficacy Oral Pill of 90-98%. 1. Combined pill contains low doses of an Benefits of combined pills oestrogen and a progestin. They are highly 1. Effective and convenient method of efficacious (success rate 98%). Ethinylo- contraception. estradiol or mestranol (in the dose of 30-50 2. Reduced risk of ovarian cancers (ovarian mcg) are the oestrogens used. Newer stimulation by gonadotropins) progestins like desogestrel and norgestimate 3 Reduced risk of endometrial cancers cause least side effects. The pill is started on (progesterone antagonises the endo- the 5th day of the menstrual cycle, taken daily metrial proliferation induced by for 21 days followed by a gap of 7 days oestrogens) during which bleeding occurs. This is 4. Reduced incidence of pelvic inflammatory monophasic regimen. disease and ectopic pregnancy. Oral contraceptives are also available as 5. Menstrual benefits—less menstrual blood biphasic or triphasic preparations (Table 51.2). loss, less iron-deficiency; premenstrual This reduces the amount of hormones needed tension and dysmenorrhoea are less and more closely mimics menstrual cycle. intense. If a woman misses a pill, she should take 2 They are advocated as an emergency pills the next day and continue the course. If method in situations following rape or more than 2 pills are missed, then that course contraceptive failure. should be withdrawn, should follow an Depot preparations are given as: alternative method of contraception for that 1. Progestin injections particular cycle and restart the course on the a. Intramuscular injections at 3-6 months 5th day of the next menstrual cycle. If the intervals, e.g. depot medroxyprogesterone woman has conceived, the pregnancy should acetate (DMPA 150-400 mg) or Nore- be terminated because these hormones are thisterone enanthate (NET EN 200 mg). 360 Textbook of Pharmacology for Dental and Allied Health Sciences

Table 51.2: Oral contraceptive preparations

Regimen Oestrogen Progestin Trade name

Monophasic E E 50 mcg Norgestrel 0.5 mcg OVRAL-G E E 30 mcg Levonorgestrel 0.15 mcg OVRAL-L Biphasic E E 35 mcg Norethindrone — 0.5 mcg (10 days) 1 mcg (11 days) Triphasic 6 days E E 30 mcg Levonorgestrel 50 mcg next 5 days E E 40 mcg Levonorgestrel 75 mcg TRIQUILAR next 10 days E E 30 mcg Levonorgestrel 125 mcg Mini-pill Nil Norgestrel 75 mcg OVRETTE Postcoital pill Diethyl stilboestrol — — (25 mg/day for 5 days) Or Combined pill (2 stat and 2 after 12 hr) OVRAL Or Levonorgestrel ECEE-2 (0.75mg –1 pill stat and 1 after 12 hr) EE-Ethinyl estradiol b. Implants–They are implanted under the Mechanism of action of oral contraceptives skin. Norplant capsules implanted subcuta- Combined pills act by multiple mechanisms. neously in the forearm or upper arm work 1. They prevent ovulation - By a negative for 5 years. feedback on the hypothalamus, progesterone Disadvantages (i) Amenorrhoea is frequent decreases GnRH pulses and thereby LH (ii) Permanent sterility may occur. release which is essential for ovulation. 2. Combined injectable contraceptives- 2. Oestrogens suppress FSH release by oestrogen and progestin injected at negative feedback on the pituitary. As a result monthly intervals are highly effective. the ovarian follicle fails to develop. 3. Progesterone also inhibits oestrogen- 3. Transdermal patch-containing a progestin induced mid-cycle LH surge. and an oestrogen is applied once a week 4. Progesterone renders the cervical mucous for 3 weeks and the next week withdrawal thick and unfavourable for sperm bleeding occurs. It is well accepted as it is penetration. more convenient. 5. OCs alter the uterine endometrium making 4. Vaginal rings–containing low dose it not favourable for implantation. of levonorgestrel is placed in the 6. OCs also adversely influence the vagina for 3 weeks of the cycle and then coordinated contractions of the cervix, uterus removed for one week. The hormone is and fallopian tubes which are required for absorbed gradually through the vaginal transport of ovum, sperm as well as mucosa. fertilisation and implantation. Oestrogens, Progestins and Hormonal Contraceptives 361

Adverse Effects Centchroman is a nonsteroidal oral contraceptive developed by CDRI, Lucknow. • Headache, migraine headache in some It has antioestrogenic and antiprogestogenic women, nausea, vomiting, oedema, breast activity and may act by preventing tenderness, amenorrhoea and irregular implantation. Onset of action is quick (< 60 menstrual cycles may be commonly seen. minutes) and duration of action is 7 days. • Weight gain, acne, mood swings and Dosage (SAHELI, CENTRON) 30 mg twice hirsutism may occur. a week for 3 months followed by once a week More severe side effects include - till contraception is desired (The tablet should • Cardiovascular effects - in women above be continued without withdrawing for 35 years, OCs may increase the risk of MI menstruation). Success rate claimed is 97-99% and venous thromboembolism. OCs may also and is devoid of the side effects of hormonal increase the coagulability of blood. But the contraceptives. It is well tolerated. newer low-dose preparations are found to be safer when used in healthy women with Drugs Acting on the Uterus no other risk factors for MI or thromboembolism. Uterine Stimulants (Ecbolics) • Hypertension-The high dose preparations Drugs which stimulate the uterine contractions may precipitate hypertension in some women. are oxytocin, ergometrine and prostaglandins. But the newer low dose preparations are They are used in obstetrics. Oxytocin is used safer. for induction of labour; ergometrine is used • Cancers OCs may increase the incidence to prevent and control postpartum bleeding. of cervical, breast and other cancers–but the Prostaglandins–PGE and PGF are used to risk is not significant. 2 2α induce mid trimester abortion and for cervical • Cholestatic jaundice and gallstones Incidence priming. may be higher in high dose preparations. • Glucose tolerance OCs may impair glucose Uterine Relaxants (Tocolytics) tolerance-but the newer low dose preparations do not carry such risk. Tocolytics are drugs that reduce uterine Contraindications to combined pill: motility. Beta adrenergic agonists like • Thromboembolic and cerebrovascular salbutamol, terbutaline and isoxuprine and disease other drugs like ethyl alcohol, calcium • breast cancers channel blockers, aspirin and magnesium • liver disease sulphate have tocolytic properties. They are • OCs should be used with caution in used to delay premature labour, in threatened diabetes, hypertension, convulsive abortion to inhibit uterine contractions and disorders, oedema and CCF. in dysmenorrhoea. 362 Textbook of Pharmacology for Dental and Allied Health Sciences 52 Androgens and Anabolic Steroids

Androgens are produced chiefly in the testes Uses and small amounts in the adrenal cortex. In 1. Testicular failure Androgen replacement the females, small amounts of androgens are therapy in primary and secondary produced in the ovary and adrenal cortex. testicular failure. Testosterone is the most important natural 2. Other uses Androgens may be used in androgen. In the adult male, 8-10 mg of senile osteoporosis and carcinoma of the testosterone is produced daily. Secretion is breast in premenopausal women. regulated by gonadotrophins and GnRH. Physiological actions In the male, testosterone ANABOLIC STEROIDS is essential for the development of secondary Anabolic steroids are synthetic androgens sexual characters and sex organs. It is with higher anabolic and low androgenic necessary for normal spermatogenesis and activity. These are believed to enhance is important for maintaining sexual function protein synthesis and increase muscle mass. in men. Testosterone promotes bone growth, But with higher doses, the relative anabolic enhances the muscle mass, protein synthesis activity is lost. Methandienone, nandrolone, and positive nitrogen balance—has anabolic oxandrolone and stanozolol are some actions. anabolic steroids available at present. Adverse Mechanism of action is similar to other steroids. effects are similar to those caused by Androgens bind to androgen receptors on androgens. the target cells, the complex moves to the nucleus where it stimulates protein synthesis. Uses Adverse effects Masculinization and acne in 1. Catabolic states Anabolic steroids may females, hepatotoxicity, increased libido and benefit patients following surgery, trauma, precocious puberty can occur in young boys. prolonged illness and debilitating conditions. With large doses, salt and water retention, Given during convalescence, the negative suppression of spermatogenesis resulting in nitrogen balance is corrected, appetite infertility can be seen. Feminizing effects like improves and there is a feeling of well being. gynaecomastia in men can occur as some 2. Senile osteoporosis seen in elderly males androgens are converted to oestrogens. respond by formation of new bone tissue. Androgens and Anabolic Steroids 363

3. Growth stimulation in children Anabolic It is used in endometriosis in women and steroids promote linear growth in prepubertal precautious puberty in boys. boys. They may be used only for short Finasteride inhibits the enzyme 5-alpha periods—but actual benefit on final height is reductase and thus inhibits the convertion of not established. testosterone to its active metabolite dihy- 4. Other uses Anabolic steroids are tried in drotestosterone which acts mainly in the male chronic renal failure to reduce nitrogen load urogenital tract. Finasteride is used in benign on the kidneys. They may benefit in prostatic hypertrophy to reduce the prostate refractory anaemias with bone marrow size. failure. DRUGS USED IN MALE SEXUAL Abuse in athletes Anabolic steroids enjoy a IMPOTENCE reputation for improving athletic performance. When combined with adequate Sexual impotence is the inability of a man to exercise, the muscle mass increases. But the have satisfactory sexual intercourse due to dose used by athletes is very high and is inability to have and maintain an erection. associated with serious adverse effects like Very often it is psychological while in some testicular atrophy, sterility and cases there could be an organic cause. Several gynaecomastia in men and virilizing effects drugs have been tried including testosterone, in women; increased aggressiveness, yohimbine, papaverine and antidepressants. psychotic symptoms and increased risk of The recent introduction—Sildenafil (Viagra) coronary heart disease in both sexes. has been a success in a large percentage of Moreover, there is no evidence that athletic them. performance improves. Hence the use of Sildenafil (Viagra) anabolic steroids by athletes has been banned and is medically not recommended. Sildenafil is the first agent to be effective orally for the treatment of erectile ANTIANDROGENS dysfunction. Sildenafil inhibits the enzyme phosphodiesterase in the penis and thus Cyproterone acetate—a derivative of prolongs the life of cyclic GMP. This causes progesterone competitively binds to relaxation of smooth muscle in the corpus androgen receptors and thus blocks the cavernosum and vasodilation—both actions of androgens. It also has proge- resulting in cavernosal engorgement and stational activity. Cyproterone is used to penile erection. treat severe hypersexuality in males, in Sildenafil is given orally (50-100 mg) 1 hour carcinoma prostate and in female hirsuitism. before sexual activity. Flutamide is a potent competitive antagonist Adverse effects and precautions Due to at androgen receptors. It is used with GnRH/ vasodilation—headache, dizziness and nasal leuprolide in the treatment of carcinoma stuffiness can occur. It potentiates the prostate. hypotensive action of nitrates and is Danazol–has weak androgenic, anabolic and contraindicated in patients on nitrates and in progestational activity. It suppresses patients with coronary artery disease. Elderly gonadotrophin secretion from the pituitary. men above 60 years need less dose (25 mg). 364 Textbook of Pharmacology for Dental and Allied Health Sciences

53 Insulin and Oral Hypoglycaemics

Diabetes mellitus is a chronic metabolic disorder 1922 the extract containing insulin was first characterised by hyperglycaemia and altered used on a 14 years old boy suffering from metabolism of carbohydrates, lipids and severe diabetes mellitus with excellent proteins. It is a common condition affecting response. Insulin was then purified in a few 1-2% of population with a strong hereditary years. tendency. Chemistry, synthesis and secretion Natural Diabetes mellitus can be of 2 types. insulin is a polypeptide synthesized from the Type I Insulin dependent diabetes mellitus precursor proinsulin. It has two peptide (IDDM) is an autoimmune disorder where chains - A chain (21 amino acids) and B chain β antibodies destroy the cells of the islets of (30 amino acids) linked by disulphide Langerhans. It usually occurs in the young bridges. Human insulin differs from bovine children and adolescents (hence called insulin by 3 amino acids and from porcine juvenile onset diabetes mellitus). insulin by 1 amino acid. Hence porcine insulin Type II Non-insulin dependent diabetes is closer to human insulin. mellitus (NIDDM) is of maturity onset. Most Insulin is stored in granules in the β islet patients are obese. There is both reduced cells of the pancreas. Normal pancreas sensitivity of tissues to insulin and impaired releases about 20-40 units of insulin regulation of insulin secretion. Prolonged hyperglycaemia results in everyday. The secretion is regulated by various complications including premature factors like food, hormones and autonomic atherosclerosis, retinopathy, nephropathy nervous system. Blood glucose concentration and gangrene of the limbs. This is thought to is the main factor. The islets of Langerhans β be due to reduced blood supply to these are composed of 4 types of cells– cells α δ structures - because of thickening of the secrete insulin, (A) cells glucagon, (D) capillary walls. Hence, it is necessary to cells somatostatin and P cells secrete maintain normal blood glucose levels though pancreatic polypeptide. diabetes mellitus as such does not cause Insulin is metabolised in the liver, kidney significant troublesome symptoms. Treatment and muscle. helps to prevent or delay the onset of complications of diabetes. Actions of Insulin 1. Carbohydrate metabolism Insulin stimulates INSULIN the uptake and metabolism of glucose in the In 1921 Banting and Best first obtained peripheral tissues especially skeletal muscles insulin in the form of pancreatic extract. In and adipose tissue. It inhibits glucose Insulin and Oral Hypoglycaemics 365 production in the liver by inhibiting cells. This binding stimulates tyrosine kinase gluconeogenesis and glycogenolysis. activity in the β subunit. This in turn activates By the above actions, insulin lowers the a cascade of phosphorylation and depho- blood glucose concentration. sphorylation reactions which stimulate or 2. Lipid metabolism Insulin inhibits lipolysis in inhibit the enzymes involved in the metabolic adipose tissue and promotes the synthesis of actions of insulin. triglycerides. In diabetes, large amounts of fat are broken down. The free fatty acids so Side Effects formed are converted by the liver to acetyl CoA and then ketone bodies. This results in 1. Hypoglycaemia is the most common ketonaemia and ketonuria. complication of insulin therapy. It may be due Insulin indirectly enhances lipoprotein to too large a dose, inappropriate time of lipase activity resulting in increased clearance administration, unusually small meal or of VLDL and chylomicrons. In insulin vigorous exercise. Symptoms include deficiency, there is hypertriglyceridaemia. sweating, palpitation, tremors, blurred vision, 3. Protein metabolism Insulin facilitates amino weakness, hunger, confusion, difficulty in acid uptake and protein synthesis and inhibits concentration and drowsiness. Severe protein break down–anabolic effect. hypoglycaemia may result in convulsions and In diabetes, there is increased catabolic coma. effect and negative nitrogen balance. Treatment Oral glucose or fruit juice like Mechanism of action Insulin acts by binding to orange juice or in severe cases IV glucose specific receptors.(Fig 53.1). Insulin receptor promptly reverse the symptoms. is made up of two α and two β subunits. 2. Allergy This is due to the contaminating Insulin receptors are present on almost all proteins. Urticaria, angioedema and rarely cells in the body. Insulin binds to these anaphylaxis can occur. It is rare with purified receptors present on the surface of target preparations and human insulin.

Fig. 53.1: Mechanism of action of insulin 366 Textbook of Pharmacology for Dental and Allied Health Sciences

3. Lipodystrophy Atrophy of the subcutaneous Table 53.1: Preparations of insulin fat at the site of injection may be due to Conventional Insulins immune response to contaminating proteins. Short and Rapid acting Regular Lipohypertrophy i.e. enlargement of Semilente subcutaneous tissue can also occur due to the Intermediate acting Lente local action of insulin. Insulin absorption may Isophane be irregular from such areas. This can be insulin prevented by frequently changing the sites (NPH) Long acting Ultralente of injection. Lipodystrophy is rare with Protamine zinc purified preparations. insulin 4. Oedema Some severe diabetics develop Highly Purified Insulins oedema which is self-limiting. Single peak insulin Regular Lente Preparations of Insulin (Table 53.1) Monocomponent insulins Regular Lente Insulin preparations differ in their source and Human Insulin Regular duration of action. Based on the source they Lente Isophane may be grouped as Bovine, Porcine and Insulin Analogs Insulin lispro Human insulins. Conventional preparations Insulin aspart are obtained from bovine and porcine Insulin glargine pancreas. They may be short, intermediate Insulin Mixtures Combinations or long-acting (Table 53.2). All preparations of 20-50% regular with are given SC. Only regular (plane) insulin can 80-50% NPH be given IV in emergencies. Insulins are Insulins destroyed when given orally. Doses are expressed as units of insulin and should be contaminating protein content is negligible. calculated in each patient by monitoring They are available in short and long acting blood glucose and glycosylated haemoglobin forms. levels. Mixtures of short and acting and Human insulins are produced by recombinant intermediate/long-acting preparations are DNA technology. Human insulin is available given for a rapid onset and long duration of as regular, NPH, lente and ultralente action. preparations - but they are all expensive. They are absorbed more rapidly; dose Disadvantages of the conventional needed is lesser (10%). preparations are that: Highly purified insulins and human insulin i. They are allergenic because of the have the following advantages over impurities (1%) and their animal source. conventional insulins- ii. They are not very stable. 1. they are less antigenic Hence highly purified preparations and 2. more stable human insulins are now made available. 3. lesser chances of resistance Highly purified insulins are mostly porcine 4. lesser chances of lipodystrophy. insulins purified by more developed Indications for highly purified/human insulins: purification techniques including gel filtration 1. Allergy to conventional preparations and ion exchange chromatography. The 2. Insulin resistance Insulin and Oral Hypoglycaemics 367

Table 53.2: Onset and duration of action of insulin preparations

Preparation Onset (hrs) Duration (hrs)

Short-acting Regular (plane, soluble) 0.5-1 8 Semilente 1 14 (Insulin zinc suspension/amorphous) Intermediate-acting Lente (Insulin zinc suspension) 2 24 NPH (Neutral protamine hagedorn 2 24 or Isophane insulin) Long-acting Ultra lente (Insulin zinc suspension/crystalline) 6 36 PZI (Protamine zinc insulin) 6 36

3. Lipodystrophy at the site of injection Use of Insulin in Diabetes Mellitus 4. Pregnancy Insulin is effective in all types of diabetes Insulin analogs with favourable phar- mellitus. The dose should be adjusted as per macokinetic properties have been the needs of each patient–guided by blood synthesized by genetic engineering. They are sugar levels. absorbed 3 times faster than human insulins– Insulin resistance is said to be present when can be given (subcutaneously) 10 minutes the insulin requirement is increased to > 200 before food; have lesser chances of U/day. It is due to the antibodies to insulin hypoglycaemia. Blood glucose control is which partly neutralise it. This is rare with better than with regular insulin. Currently purified preparations and human insulin. available analogs include insulin lispro, aspart Antibodies may also develop to contaminants and glargine. Insulin lispro and aspart are and other added constituents like protamine. rapid and short acting while glargine is the Hence in presence of resistance, it is necessary long acting analog. to change over to highly purified/human Insulin delivery devices like portable pen insulin. In some patients immunosuppression injectors and insulin pumps have been with corticosteroids like prednisolone may designed which make insulin administration help. more convenient. ORAL HYPOGLYCAEMIC DRUGS Drug Interactions The main disadvantage of insulin is the need β 1. adrenergic blockers mask tachycardia, for injection. The advent of oral hypo- the important warning symptom of hypoglycaemics came as a boon to millions of glycaemia. They also prolong hypoglycaemia NIDDM patients with early and mild by inhibiting compensatory mechanisms diabetes. Sulfonylureas were the first oral β acting through 2 receptors. antidiabetics (OAD) to be made available in 2. Salicylates precipitate hypoglycaemia by 1950s. We now have 5 groups of oral enhancing both insulin secretion and β cell hypoglycaemics and may be classified as sensitivity to glucose. follows- 368 Textbook of Pharmacology for Dental and Allied Health Sciences

CLASSIFICATION Chlorpropamide is long acting (t½ 32 hrs) and can cause prolonged hypoglycaemia 1. Sulfonylureas particularly in the elderly. Tolazamide has a I generation slow onset of action. Use of first generation Tolbutamide, agents can result in several drug interactions. chlorpropamide acetohexamide, tolazamide Second Generation Agents II generation Second generation agents are more potent, Glibenclamide, glipizide, have fewer side effects and drug interactions. gliclazide, glimepiride But they can cause hypoglycaemia because 2. Biguanides of which they should be used cautiously Phenformin, metformin particularly in the elderly. They are all 3. Meglitinides contraindicated in renal and hepatic Repaglinide, nateglinide impairment. 4. Thiazolidinediones Glibenclamide (Gliburide) is a commonly used Troglitazone, rosiglitazone, sulfonylurea. It is longer acting – can be given pioglitazone once a day. It can cause hypoglycaemia and 5. Alpha glucosidase inhibitors rarely flushing after alcohol consumption. Acarbose, miglitol Glipizide has a short t½; food delays its absorption, it is less likely to cause Sulfonylureas hypoglycaemia. A sulfonamide derivative used for its Glimepiride is longer acting and can be given antibacterial effects in typhoid patients produced as a single morning dose. hypoglycaemia. This observation led to the Pharmacokinetics Sulfonylureas are well- development of sulfonylureas. absorbed orally, extensively bound to plasma Mechanism of action Sulfonylureas reduce the proteins, metabolised in the liver and some blood glucose level by: are excreted in the urine. Hence they should 1. stimulating the release of insulin from the be avoided in patients with renal or liver pancreatic β cells. dysfunction. Dose - Table 53.3. 2. increasing the sensitivity of peripheral Adverse effects Second generation agents have tissues to insulin. fewer adverse effects. Hypoglycaemia is the 3. increasing the number of insulin receptors. most common adverse effect, least with 4. suppressing hepatic gluconeogenesis. tolbutamide due to its short t½ and low Sulfonylureas bind to receptors on potency. pancreatic β cells, and block the ATP - Nausea, vomiting, jaundice, and allergic sensitive K+ channels. This reduced K+ reactions can occur (Table 53.4). Patients on conductance causes depolarization and Ca++ sulfonylureas may have an increase in the influx leading to increased insulin secretion. rate of cardiovascular death. However this Thus some functional β cells are essential for is still controversial and sulfonylureas the action of sulfonyl ureas. continue to be used. Drug Interactions First Generation Agents I. Drugs that augment hypoglycaemic effect. Tolbutamide is short acting and is therefore • NSAIDs, warfarin, sulfonamides – associated with lesser risk of hypoglycaemia displace sulfonylureas from protein - hence it is safer in the elderly diabetics. binding sites. Insulin and Oral Hypoglycaemics 369

• Alcohol, chloramphenicol, cimetidine– Biguanides inhibit metabolism II. Drugs that decrease the action of sulfonylureas • Have insulin-like effects • Do not cause hypoglycaemia • Diuretics and corticosteroids – ↑blood • Weight reduction—due to anorexia glucose levels. • Nausea, diarrhoea, metallic taste are Biguanides transient Biguanides lower blood glucose level by • Preferred in obese diabetics either insulin-like effects on the tissues. Mechanism alone or with sulfonylureas • Contraindicated in renal, hepatic and of action is not clear. They cardiac diseases • Suppress hepatic gluconeogenesis. • Inhibit glucose absorption from the Thiazolidinediones (TZDs) intestines. • Stimulate peripheral uptake of glucose in Thiazolidinediones or glitazones are agonists tissues in the presence of insulin. at the PPAR γ receptors (gamma subtype of Phenformin is not used therapeutically as peroxisome – proliferator activated receptors.) it causes lactic acidosis. Metformin is safer TZDs activate the PPARγ receptors and induce with lower incidence of lactic acidosis. It does the synthesis of genes which enhance insulin not cause hypoglycaemia since it is an action. euglycaemic agent. • TZDs increase insulin–mediated glucose Adverse effects Nausea, diarrhoea, and metallic transport into muscle and adipose tissue. taste are self-limiting. Rarely lactic acidosis • reduce hepatic gluconeogenesis can occur. Anorexia is advantageous as it • once a day administration helps in reducing body weight. Long-term • low potential for hypoglycaemia • ↑ HDL cholesterol use may interfere with vitamin B 12 • no clinically significant drug interactions absorption. known so far. Meglitinides Disadvantages Repaglinide and nateglinide are insulin • 6-12 weeks of treatment is required to secretogogues. Like sulphonylureas, megli- establish maximum therapeutic effect. tinides enhance the release of insulin by • May cause weight gain and anaemia. • May cause oedema and precipitate or blocking the ATP dependent K+ channels in worsen CCF. the pancreatic β cells. • Liver function should be monitored Both repaglinide and nateglinide are rapidly regularly. absorbed from the gut; repaglinide has a t½ • Troglitazone causes severe hepatotoxicity of 1 hour. Both drugs can cause hyper- and therefore is not used now. sensitivity reactions and hypoglycaemia – but Uses-TZDs are used as adjuvants to the incidence is relatively lower with sulfonylureas or biguanides in Type II nateglinide. Gastrointestinal disturbances diabetes mellitus. Though they can also be are common with repaglinide. used as monotherapy in mild cases of type II Meglitinides can be used in type 2 diabetes diabetes, further studies are needed to prove mellitus either alone or with biguanides. their long term benefits. 370 Textbook of Pharmacology for Dental and Allied Health Sciences

ααα– Glucosidase Inhibitors reaching the colon and then getting fermented. Acarbose an oligosaccharide and miglitol α gulcosidase inhibitors can be used alone competitively inhibit the enzymes α – in patients with predominantly postprandial glucosidases present in the intestinal brush hyperglycaemia or in combination with other border and thereby prevent the absorption oral antidiabetics or insulin. of carbohydrates. Monosaccharides like glucose and fructose are absorbed from the TREATMENT OF DIABETES MELLITUS intestines while disaccharides and oligosaccharides are broken down into The aim of treatment is to keep the blood monosaccharides before being absorbed. This sugar within normal limits and prevent ‘breaking down’ is done by the enzymes α - complications of diabetes. For patients with glucosidases (e.g. sucrase, maltase, IDDM, insulin is the only treatment. glycoamylase) and α - amylase present in the Mild NIDDM may be controlled by diet, intestinal wall. α glucosidase inhibitors exercise and weight reduction. When not inhibit the hydrolysis of disaccharides and controlled, an oral hypoglycaemic should be decrease carbohydrate absorption. given. Most NIDDM patients may require • Alpha glucosidase inhibitors reduce the insulin sometime later in life. glucose absorption from upper intestines Status of Oral Antidiabetics thereby reducing post-prandial blood glucose levels. Uncomplicated NIDDM patients not • Alpha glucosidase inhibitors do not cause controlled by diet and exercise are given oral hypoglycaemia. But when used with other hypoglycaemics. Mild NIDDM patients with antidiabetics if hypoglycaemia occurs, recent onset diabetes, age above 40 years at glucose should be given and not sucrose the onset of diabetes, obese with fasting because sucrase is inhibited. blood sugar < 200 mg/dl are candidates for • They may cause gastrointestinal oral hypoglycaemics. They are convenient to disturbances including abdominal use. Sulfonylureas are preferred, but when distention, flatulence and diarrhoea not adequately controlled, metformin can be because of undigested carbohydrates added. Metformin has the advantages of Table 53.3: Dose and duration of action of oral hypoglycaemics

Drug Dose Duration of action Tolbutamide (RASTINON) 500 mg q 8-12 h 6-8 hr Chlorpropamide (DIABINESE) 250-500 mg OD 36-48 hr Glibenclamide (DAONIL, EUGLUCON) 5 mg q 12-24 h 18-24 hr Glipizide 5-15 mg OD-BD 12-18 hr Gliclazide 40-240 mg OD 12-24 hr Glimepiride 1-4 mg OD 12-24 hr Metformin (GLYCIPHAGE) 500 mg OD-BD 6-8 hr Repaglinide 0.5-4 mg BD-TID 4-5 hr Nateglinide 60-120 mg BD-TID 3-4 hr Pioglitazone 15-45 mg OD 12-24 hr Rosiglitazone 2-8 OD 24 hr Acarbose 25-100 mg before each meal – Miglitol 25-100 mg before each meal – Insulin and Oral Hypoglycaemics 371

Table 53.4: Mechanism of action and prominent adverse effects of oral antidiabetics

Oral antidiabetics Major mechanism Adverse effects

Sulfonylureas ↑ insulin release Hypoglycaemia, (e.g. Tolbutamide, from pancreas cholestatic jaundice glibenclamide) ↑tissue sensitivity to insulin Biguanides ↓hepatic gluconeogenesis Diarrhoea, metallic taste, (Metformin) ↑ tissue sensitivity to insulin rarely lactic acidosis Meglitinides ↑insulin release Hypoglycaemia (Repaglinide, nateglinide) from pancreas Thiazolidinediones PPAR γ agonist Weight gain, oedema, (Rosiglitazone, pioglitazone) ↑glucose transport into tissues may ppt CCF, ↓ hepatic gluconeogenesis Risk of hepatotoxicity α glucosidase inhibitors ↓ glucose absorption Flatulence, diarrhoea, (Acarbose, Miglitol) ↓ hydrolysis of disaccharides abdominal distension reducing appetite and being euglycaemic. In patient is on only OAD, he may have to be conditions like stress, surgery or switched over to insulin by the physician. complications of diabetes, insulin should be Adequate antibiotic coverage is a must. used. TZDs, meglitinides or α - glucosidase Dental procedures may often reduce food inhibitors may be used as monotherapy in intake and diabetics may go into hy- mild NIDDM patients or as adjuvants along poglycaemia. Patient should be warned with sulfonylureas or biguanides. If diabetes about it and insulin/OAD dose adjustment is not controlled, patient should be switched may rarely be required. over to insulin. In some patients, insulin may be supplemented with sulfonylureas as the GLUCAGON latter increase the tissue sensitivity to insulin. For treatment of diabetic ketoacidosis (see Glucagon is synthesized in the alpha (A) cells page 402)– of the pancreatic islets of Langerhans; like insulin, the secretion of glucagon is regulated Diabetes Mellitus and Dentistry. by nutrients–chiefly glucose, paracrine hormones and autonomic nervous system. Patients with diabetes need to maintain very Fasting stimulates glucagon secretion. It is good oral hygiene as they are prone for degraded in the liver, kidney and plasma. odontogenic, periodontal and other Actions Glucagon increases blood glucose infections including a higher incidence of caries. level by glycogenolysis and gluconeogenesis In well controlled diabetics, dental in the liver. It evokes insulin release. It procedures generally do not require any mobilises stored fat and carbohydrates. special precaution. However, antibiotic Glucagon increases the heart rate and force coverage may be required. of contraction. It also relaxes the intestinal In uncontrolled diabetics, infections and smooth muscles. Glucagon can be used in the wound healing may be a problem even after emergency treatment of severe hypo- minor procedures. If major dental procedures glycaemia due to insulin. It can also be used or surgery is to be undertaken, prior control in radiology of the bowel–as glucagon relaxes of diabetes by the physician is needed. If the intestines. 372 Textbook of Pharmacology for Dental and Allied Health Sciences 54 Agents Affecting Bone Mineral Turnover

Calcium and phosphorus are the most secretion from glands, myocardial contra- important minerals of the bone with 1-2 kg ctility and formation of bones and teeth. It of calcium and 1 kg of phosphorus stored in also maintains the integrity of mucous it. Calcium and phosphorus metabolism are membranes and cell membrane. Calcium is chiefly regulated by vitamin D and para- essential for normal blood coagulation. thormone. Other hormones that also influ- Calcium is absorbed from the small ence calcium and phosphorus metabolism are intestines by a carrier mediated active calcitonin, growth hormone, insulin, thyroid transport. Normally about 30% of the dietary ++ hormone, prolactin, glucocorticoids and sex calcium is absorbed, while in Ca deficiency, hormones. the absorption increases under the control of vitamin D (Fig. 54.1). The normal plasma CALCIUM calcium level is 9-11 mg/dl. It is excreted in faeces, urine and sweat. Calcium is essential for tissue excitability, Adverse effects Oral calcium can produce muscular excitation-contraction coupling, constipation.

Fig. 54.1: Regulation of plasma calcium level Agents Affecting Bone Mineral Turnover 373

Uses which in turn enhances calcium absorption from the intestines. PTH also promotes 1. To prevent and treat calcium deficiency. phosphate excretion. Calcium supplements are given orally in children, pregnant and lactating women Hypoparathyroidism is characterised by and in postmenopausal osteoporosis to low plasma calcium levels with its associated prevent calcium deficiency. manifestations. Hyperparathyroidism which Tetany: 5-10 ml IV calcium gluconate is most commonly due to parathyroid tumour followed by 50-100 ml slow IV infusion produces hypercalcaemia and deformities of promptly reverses the muscular spasm. the bone. The injection produces a sense of warmth. PTH is not therapeutically used. It is used This is followed by oral calcium 1.5 g for the diagnosis of pseudohypoparathy- daily for several weeks. roidism. 2. Vitamin D deficiency rickets—calcium is given along with vitamin D. VITAMIN D 3. As an antacid—calcium carbonate is used Vitamin D a fat-soluble vitamin, is a orally. prehormone produced in the skin from 7- 4. For placebo effect—IV calcium is used in dehydrocholesterol under the influence of weakness, pruritus and some dermatoses. ultraviolet rays. It is converted to active The feeling of warmth produced by the metabolites in the body which regulate plasma injection could afford psychological calcium levels and various functions of the benefit. cells. PHOSPHATE Hormones that influence bone metabolism • Vitamin D Phosphates play a vital role in various • Oestrogens enzymatic reactions, are important for the • Parathormone structure and function of the cells and are • Glucocorticoids important constituents of teeth and bones. Phosphorus is absorbed by the small intestine Source and excreted through kidneys under the influence of parathormone. • Diet - as ergocalciferol (vitamin D2) from Hypophosphataemia results in muscle plants. weakness and abnormal bone mineralization. • Fish, liver, fish liver oils - (cod, shark liver oil); milk. PARATHYROID HORMONE • Cholecalciferol (vitamin D3) is synthesized (Parathormone, PTH) in the skin from 7-dehydrocholesterol.

Parathormone is a peptide secreted by the Cholecalciferol (vitamin D3) is converted parathyroid gland. Secretion of PTH is to 25-OHD3 (calcifediol) in the liver regulated by plasma Ca++ concentration—low (Fig. 54.2) which is in turn converted to plasma Ca++ stimulates PTH release, while 1,25-dihydroxy-cholecalciferol (calcitriol) in high levels inhibit secretion. Parathormone the kidneys. Calcitriol is the active form of maintains plasma calcium concentration by vitamin D while calcifediol is the main mobilising calcium from the bone, promoting metabolite in circulation. Convertion of reabsorption of Ca++ from the kidneys and calcifediol to calcitriol is influenced by PTH by stimulating the synthesis of calcitriol and plasma phosphate concentration. 374 Textbook of Pharmacology for Dental and Allied Health Sciences

• Cholecalciferol granules—oral 60,000 IU in Ig; 3,00,000 IU/ml; 6,00,000 IU/ml inj. • Shark liver oil with vit D—1000 IU/ml, vit A—6000 IU/ml. • Calcifediol (25(OH)D ), alfa calcidiol (1- α 3 (OH)D3) and calcitriol (1,25(OH)2D3) are synthetic Vitamin D analogs available for use. Adverse reactions High doses of vitamin D used for long periods result in hypervitaminosis D manifesting as generalised decalcification of the bones, hypercalcaemia, hyperphosphataemia resulting in weakness, drowsiness, nausea, abdominal pain, thirst, renal stones and hypertension. Hyper- Fig. 54.2: Synthesis and functions of vitamin D vitaminosis D in children is most often due Actions The chief actions of calcitriol are: to unnecessary vitamin D supplementation • it stimulates calcium and phosphate by parents. absorption in the intestine Uses • mobilises calcium from bone by promoting osteoclastic activity 1. Prophylaxis—400 IU daily or 3,00,000 IU • increases reabsorption of Ca++ from every 3-6 months IM prevents vitamin D kidney tubules. deficiency. Adequate dietary calcium and Calcitriol is essential for normal bone phosphate intake is necessary. In the mineralization. It is essential for skeletal breastfed infants, from the first month muscles as well as cellular growth and onwards oral vitamin D supplements are differentiation. needed. In obstructive jaundice, Vitamin D deficiency results in low plasma prophylactic 6,00,000 units vit D given IM calcium and phosphate levels with abnormal prevents deficiency. mineralization of the bone; causes rickets in 2. Nutritional rickets and osteomalacia 6,00,000 children and osteomalacia in adults. units IM repeated after 4-6 weeks is needed in rickets and osteomalacia along Daily requirement—400 IU (10 mg). with calcium supplements. 3. Vitamin D resistant rickets is a hereditary Pharmacokinetics Given orally, vitamin D is disorder with abnormality in renal well-absorbed from the small intestines in the phosphate reabsorption. Phosphate with presence of bile salts. It is converted to 25- vitamin D is found to be useful. OHD in the liver and circulates in the plasma, 3 4. Vitamin D dependent rickets is due to bound to a protein and is stored in the calcitriol deficiency (inability to convert adipose tissue. Vitamin D is also degraded calcifediol to calcitriol) and is treated with in the liver and the metabolites are excreted calcitriol. in the bile. 5. Senile osteoporosis Oral vitamin D supplements with calcium may be tried. Preparations 6. Hypoparathyroidism Calcitriol with Ca++ • Calciferol capsules 25000; 50,000 IU. supplements are beneficial. Agents Affecting Bone Mineral Turnover 375

CALCITONIN to osteomalacia due to inhibition of bone mineralisation. Calcitonin is a peptide hormone secreted by Uses the parafollicular ‘C’ cells of the thyroid Bisphosphonates are used in Paget’s gland. Secretion is regulated by plasma Ca++ disease of the bone, hypercalcaemia and is concentration—high plasma Ca++ stimulates tried in postmenopausal osteoporosis. calcitonin release. 1. Paget's disease - Bisphosphonates relieve Actions The chief effects of calcitonin are to pain and induce remission. lower serum calcium and phosphate by its 2. Hypercalcaemia - Some malignancies are actions on the bone and kidney. It inhibits associated with hypercalcaemia. Intra- osteoclastic bone resorption and in the venous pamidronate is useful in reducing kidney, it reduces both calcium and plasma Ca++ levels. phosphate reabsorption. 3. Osteoporosis - Alendronate and residro- In general the effects are opposite to that nate are tried with calcium and vitamin D of PTH. Calcitonin is used to control for the prevention of postmenopausal hypercalcaemia, Paget’s disease, metastatic osteoporosis. bone cancer and osteoporosis and to increase Raloxifene is a SERM useful in women for the bone mineral density. prevention of postmenopausal osteoporosis. Other hormones that regulate bone turnover are Agents used in the prevention and treatment glucocorticoids and oestrogens. Gluco- of osteoporosis corticoids antagonise vitamin D stimulated Drugs may be used either to prevent bone intestinal calcium absorption and enhance ++ resorption or promote bone formation or a renal Ca excretion. Oestrogens reduce bone combination of both in the prevention and resorption by PTH and also enhance calcitriol treatment of osteoporosis. These agents levels. Oestrogen receptors are found in reduce the risk of fractures in patients with bone which suggests that they may also have osteoporosis. a direct effect on bone remodeling. I. Drugs that Prevent Bone Resorption DRUGS USED IN THE DISORDERS OF BONE • Calcium (↑ BMD*) • Vitamin D ( ↑ absorption of calcium) Drugs used in disorders of bone are: • Oestrogen (prevents osteoporosis) • Bisphosphonates - • Raloxifene – a SERM (↑ BMD) Alendronate etidronate • Calcitonin (prevents bone resorption, Pamidronate residronate ↑ BMD) • Raloxifene (selective oestrogen receptor • Bisphosphonates - ↓bone resorption, modulator) (↑ BMD) • Vitamin D BMD – Bone mineral density. Bisphosphonates-are analogs of pyrophosphate; they inhibit bone resorption. Bisphos- II. Drugs that Promote Bone Formation phonates get incorporated into bone matrix, are imbibed by osteoclasts and then • Fluoride (in small doses ↑ osteoblastic incapicitate the osteoclasts resulting in activity - ↑ bone mass - but generally not reduced bone resorption. They also slow the preferred). formation and dissolution of hydroxyapatite • Testosterone (in hypogonadal men) crystals. • Anabolic steroids (in postmenopausal Fever, oesophagitis, gastritis and hypo- women). calcaemia can occur. Long-term use can lead • PTH analogs (are being tried). 376 Textbook of PharmacologySection for Dental 13 and Allied Health Sciences Miscellaneous Drugs 55 Miscellaneous Drugs

IMMUNOPHARMACOLOGY inhibits the enzyme calcineurin phosphatase. Immunosuppressants This results in inhibition of T cell activation and IL-2 production. T cells do not respond Immunosuppressants are drugs which inhibit to specific antigenic stimulation. Cyclos- immunity. They may suppress cell mediated porine also suppresses the proliferation of or humoral immunity or both. They are: cytoxic T cells. Tacrolimus binds to another immunophilin and then the complex inhibits CLASSIFICATION calcineurin. 1. T-cell inhibitors Cyclosporine, tacrolimus sirolimus, mycophenolate mofetil 2. Cytotoxic drugs Azathioprine, methotrexate, cyclophosphamide, chlorambucil 3. Glucocorticoids 4. Antibody reagents Muromanab CD3, Antithymocyte globulin

T-Cell inhibitors Cyclosporine is a cyclic peptide produced by a fungus Beauveria nivea. Pharmacokinetics Cyclosporine is metabolised Actions Cyclosporine acts at an early stage, by microsomal enzymes in the liver. It can selectively inhibits T cell-proliferation and therefore interact with many drugs given suppresses cell mediated immunity. It can be concurrently. given orally and intravenously. Adverse effects include nephrotoxicity, hepatotoxicity, anorexia, gum hypertrophy Mechanism of Action and increased susceptibility to infections, Cyclosporine binds to cyclophilin (an hypertension, hyperglycaemia, hyper- immophilin) and this complex binds to and lipidaemia and hirsutism. Miscellaneous Drugs 377

Uses CYTOTOXIC DRUGS • In organ transplantation Cyclosporine is Cytotoxic drugs like azathioprine, cyclo- very effective for the prophylaxis and phosphamide and methotrexate inhibit cell treatment of graft rejection in organ mediated immunity (while cyclophosphamide transplantation surgeries–like kidney, predominantly suppresses humoral immunity). liver, bone marrow and other transplants. They are used in the prevention of graft • Autoimmune disorders Cyclosporine is also rejection and in autoimmune disorders. useful in some autoimmune disorders like Glucocorticoids rheumatoid arthritis as an alternative in patients who do not respond to Glucocorticoids have potent immuno- methotrexate. Cyclosporin is also tried in suppressant activity and are used in the severe psoriasis, atopic dermatitis, prevention of organ transplant rejection and inflammatory bowel disease and in autoimmune disorders. nephrotic syndrome. Antibody Reagents Tacrolimus is a macrolide antibiotic obtained Muromonab CD3 is a monoclonal antibody from Streptomyces tsukubaensis. Its mechanism to CD3 antigens on T lymphocytes. On of action is similar to cyclosporine. intravenous administration, T cells disappear Tacrolimus can be given both orally and from the circulation within minutes. It is used parenterally but absorption from the gut is with other immunosuppressants in organ incomplete. It is extensively bound to plasma transplantation. Fever, chills and pulmonary proteins. oedema may occur. Adverse effects include nephrotoxicity, Antithymocyte globulin (ATG) binds to T gastrointestinal disturbances, hypertension, lymphocytes and depletes them thereby hyperglycaemia, tremors and seizures. suppressing immune response. It is used in the management of organ transplantation. Sirolimus obtained from Streptomyces Infliximab is a monoclonal antibody and hygroscopicus acts by inhibiting calcineurin like etanercept is a protein that blocks TNFα. They cyclosporine. Sirolimus may be used in are useful in rheumatoid arthritis and Crohn’s combination with other drugs for the disease. prophylaxis of organ transplant rejection and in psoriasis and uveoretinitis. IMMUNOSTIMULANTS Toxicity includes hyperlipidaemia, Immunostimulating and immunomodulating gastrointestinal disturbances and an agents are drugs that modulate the immune increased risk of infections and lymphomas. response and can be used to increase the Mycophenolate mofetil a prodrug, is immune responsiveness of patients with immunodeficiency as in AIDS, chronic illness converted to mycophenolic acid, which and cancers. This is yet a developing field of inhibits guanine nucleotide synthesis and pharmacology. The drugs currently used for inhibits the proliferation and functions of this purpose are BCG and levamisole. BCG lymphocytes. has been tried in cancers. Levamisole used Mycophenolate mofetil is indicated as an in helminthiasis is also found to enhance cell- adjunct to other immunosuppressive drugs mediated immunity in humans. It has been in the prophylaxis of transplant rejection. tried in some cancers. 378 Textbook of Pharmacology for Dental and Allied Health Sciences

Interferons are cytokines with antiviral and CLASSIFICATION immunomodulatory properties. Recombinant 1. Acids Boric acid, Benzoic acid. interferons α, β and γ are available for clinical 2. Alcohols Ethanol, Isopropyl alcohol use. They bind to specific receptors and bring 3. Aldehydes Formaldehyde, about immune activation and increase host Glutaraldehyde. defences. There is an increase in the number 4. Surfactants Soaps, Benzalkonium, and activity of cytotoxic and helper T cells Cetrimide, and killer cells (See Page 308) α β Cetylpyridinium chloride, Interferons , and are mainly used for Dequalinium chloride. γ antiviral effects while interferon for its 5. Phenol Phenol, Cresol, Resorcinal, immunomodulating actions. derivatives Chlorhexidine, Interferons are indicated in several Chloroxylenol, tumours including malignant melanoma, Hexachlorophene. hairy cell leukaemia lymphomas, kasposi’s 6. Halogens Iodine, Iodophores, sarcoma, condylomata acuminata and in viral Chlorine, Chloramines. infections. 7. Oxidizing Hydrogen peroxide, agents Potassium permanganate, ANTISEPTICS AND DISINFECTANTS Benzoyl peroxide. Disinfection is destruction of all pathogenic 8. Dyes Gentian violet, Methylene organisms but not spores. If spores are also blue, Brilliant green, killed, it is called sterilization. A disinfectant is Acriflavin, Proflavine. 9. Metallic salts Mercurial compounds, used on inanimate objects. Silver nitrate, Zinc comp- Antiseptic is an agent that destroys micro- ounds. organisms and can be used on living tissues. The term germicide can be used for either drugs. Factors that influence the activity of germicidal Germicides are widely used in domestic agents products like soaps, tooth pastes and after- shave lotions. 1. Concentration of the drug and duration of Mechanism of action contact In general, higher the concen- Germicides may act by the following mecha- tration of the antiseptic, greater is its nisms– effect. But alcohol is an exception to this 1. Oxidation of bacterial protoplasm and at 70% concentration maximum 2. Denaturation of bacterial proteins antiseptic effect is seen. 3. Detergent like action 2. Susceptibility of the organism Spores and 4. Competition with essential substrates for viruses are resistant to many antiseptics. 3. Temperature A rise in temperature will the important enzymes in the bacterial cell. increase antiseptic activity. An ideal germicide should have a wide antibacterial spectrum, should be chemically Acids stable, should have rapid action, non- irritating to the tissues, not interfere with Boric acid and sodium borate (borax) have weak wound healing activity even in presence of bacteriostatic and fungistatic activity. pus, exudates and tissue degradation Aqueous solutions of boric acid are used for products; it should not be absorbed into irrigating eyes, bladder, vagina and large systemic circulation. wounds. Miscellaneous Drugs 379

Benzoic acid is an antibacterial (below pH 5) for disinfection of surgical instruments and and antifungal agent used as a preservative gloves; embalming and preservation of in laboratory. tissues. Fibre optic endoscopies, respiratory Salicylic acid has bacteriostatic, fungicidal and therapy equipment, haemodialysers and keratolytic properties. It is used as a dusting dental hand pieces which cannot withstand powder or 2% ointment for seborrhoeic high temperatures of stearn sterilisation are dermatitis, warts and corns. disinfected with formaldehyde. Automatic circulating baths are used which Alcohols increase penetration of aldehyde solution into the instruments and decrease operator Ethyl alcohol is employed as an antiseptic at exposure to the chemical. It’s rapidity of 60-90% concentration. The antiseptic activity action increases by making a solution in 70% decreases above 90%. It rapidly denatures propanol. the bacterial proteins (page 143). Glutaraldehyde is a dialdehyde used as a 2% Disadvantages solution. It is bactericidal, sporicidal, fungicidal and viricidal. pH should be 1. It has poor activity against spores, some between 7.4 and 8.5. It is less irritant than viruses and fungi formaldehyde; has greater sporicidal activity; 2. Irritant—causes burning when applied on does not damage lenses and cementing open wounds material in endoscopes. Glutaraldehyde is 3. Alcohols are flammable—should be superior to formaldehyde for sterilising allowed to evaporate before using cautery rubber, plastic and metal appliances. Two per or laser surgery. cent solution is used for local application in Uses Ethyl alcohol is used to clean the skin idiopathic hyperhidrosis of palms and soles. before injections and surgeries. Isopropyl alcohol is more potent and more toxic Surfactants than ethanol. It is used in 68-72% Surfactants are chemicals that lower the concentration as skin antiseptic. surface tension of solutions and are termed Aldehydes detergents. They may be anionic, cationic, ampholytic surfactants or polysorbates. Formaldehyde is a gas at room temperature Anionic surfactants e.g. soaps. used for fumigation; the 40% aqueous solution • They dissociate in aqueous solutions to is noncorrosive and has a broad antimicrobial form a large and complex anion which spectrum. It has a pungent odour and is an lowers the surface tension. irritant—highly irritating to respiratory • Effective for gram-positive and acid fast mucous membranes and eyes. Formaldehyde organisms. is also a carcinogen and OSHA has set • Microorganisms are enmeshed in the standards to limit exposure of health care lather and washed away on rinsing. workers to formaldehyde. • Anionic surfactants have a narrow Mechanism of action Aldehydes act by spectrum; precipitate in hard water; cause alkylation of chemical groups in proteins and drying of the skin. nucleic acids. Preparations Uses Formaldehyde gas is used for fumigation 1. Potassium hydroxide or sodium and for sterilizing instruments which cannot hydroxide + vegetable oil. be moistened with solution. Formaldehyde 2. Sodium lauryl sulphate-is effective in hard 40% solution (100% formalin) in water is used water. 380 Textbook of Pharmacology for Dental and Allied Health Sciences

Cationic surfactants-e.g. Benzalkonium chloride, Phenol is extremely irritant to exposed Cetrimide, Cetylpyridinium chloride, Dequa- tissues (corrosive)-when swallowed, it burns linium chloride. Cationic surfactants dissociate buccal, oesophageal and gastric mucous into large cations. membrane. They are: Uses Phenol is used to disinfect urine, faeces, • active against gram-positive and gram- sputum of patients and is sometimes used as negative organisms (less active against antipruritic because of its local anaesthetic spores, viruses and fungi) action. • most effective in neutral solution Cresol is methylphenol, which is as toxic as • non-irritating and safe phenol but is more active. It is used as a • incompatible with anionic surfactants disinfectant for utensils and excreta. • absorbed by cotton and rubber Lysol is cresol with soap solution. It has higher • one of the most commonly used antiseptic activity and is an useful disinfectant germicidal agents. for hospital and domestic use. Benzalkonium chloride (ZEPHlRAN) has an Chloroxylenol (DETTOL) is a less toxic aromatic odour and is soluble in water. chlorinated phenol, effective against gram- • 1: 1000 solution for cleansing skin positive and gram-negative organisms. • 1:2000 for mucous membranes and Surgical dettol contains 1.4% of chloroxylenol denuded skin for skin; 6.25% for instruments and 1 to 3% • 1:20,000 for irrigation of the bladder and in antiseptic cream. urethra Hexachlorophene This chlorinated phenol acts • It is also used for (1: 1000-4000) storing by inhibiting bacterial enzymes and causing sterilised surgical instruments. But instru- lysis. It is effective mainly against gram- ments should be thoroughly washed positive organisms and has weak action before use. against gram-negative organisms. It is Cetrimide (CETAVLON) 1% solution is used odourless and non-irritating to use on skin. like above. It is also used as a cream. It is It is used in soaps for surgical scrubbing, for very effective for cleaning wounds. In cleaning the skin in obstetrics, carbuncles and combination with chlorhexidine it is the most seborrhoeic dermatitis. It may cause allergic popular antiseptic. SAVLON is cetrimide 3% reactions. It also reduces body odour by +chlorhexidine. preventing bacterial decomposition of Dequalinium chloride is used in gum paints and organic material and therefore is used as a lozenges. deodorant. In USA, hexachlorophene was Cetylpyridinium chloride is used in used to wash newborn babies which resulted mouthwashes and lozenges. in brain damage in such babies and therefore use of > 3% hexachlorophene is banned. Phenol Derivatives Chlorhexidine (HIBITANE) is effective against Phenol is one of the oldest antiseptics gram-positive, gram-negative organisms and introduced by Lord Lister in 1867. It is fungi. It is rapid acting and non-irritating. bactericidal and fungicidal but has poor SAVLON is chlorhexidine + cetrimide. action against spores and viruses. It acts by Halogens denaturing the bacterial proteins. It also has a mild local anaesthetic action. Phenol rapidly Iodine is one of the oldest antiseptics. It has a penetrates even intact skin and mucous broad spectrum of activity, is a powerful membrane. It is a protoplasmic poison. bactericidal, sporicidal, fungicidal and Miscellaneous Drugs 381 viricidal agent. The activity is inhibited by 2. Chloramine is an organic chloride. The organic material but enhanced by alcohol. freshly prepared solution is used for Disadvantages It is irritating, painful, stains mouthwash, for irrigating the bladder the area, and may delay wound healing. and urethra. Rashes, fever and generalised skin eruptions 3. Eusol is a solution of chlorinated lime with may develop in some patients who are boric acid. sensitive to iodine. Prolonged systemic use Oxidizing Agents causes iodism. Hydrogen peroxide is a colourless and odourless Uses of iodine liquid. It liberates nascent oxygen when applied to tissues and then oxidizes bacteria 1. Tincture iodine (I in KI + alcohol)-used to 2 and necrotic tissue. On application, there is clean skin before surgery. Iodine crystals effervescence and this helps in removing are used to sterilize water for soaking tissue debris, ear wax, etc. Hydrogen vegetables and cleaning before use. peroxide has poor penetrability and the 2. Mandl’s paint (Compound Iodide paint) action is of short duration. On keeping, it is,used in the treatment of tonsillitis and loses its potency. It is also a deodorant. pharyngitis. ‘ Uses Hydrogen peroxide is used for cleansing 3. Iodine ointment-as fungicide in ringworm. wounds, abscesses and for irrigation. In Iodides have no antibacterial action. dentistry, it is used to clean septic sockets lodophors Iodophors are soluble complexes of and root canals and also as a mouthwash and iodine with surfactants like detergents. The deodorant gargle. It is used as ear drops detergents serve as carriers and slowly while removing ear wax. release iodine, e.g. Povidone iodine (BET Potassium permanganate is an oxidizing agent ADINE)-5% solution; Piodine-10% solution. and an astringent. The purple crystals are Advantages Iodophors are non-irritating, non- water-soluble. It acts by liberating oxygen staining, water-soluble, less toxic and non- which oxidizes bacterial protoplasm. Organic sensitizing to the skin. matter reduces its activity and the solution Uses Used for preoperative scrubbing, skin gets decolourised. It promotes rusting; preparation, disinfection of instruments, as concentrated solution is caustic and causes local antiseptic in boils, furunculosis, burns, burns and blistering. ulcers, ringworm and in oral/vaginal moniliasis. Uses Chlorine is a potent germicide and is bactericidal against several gram- • 1:4000-1: 10000 solution of potassium positive and gram-negative organisms in a permanganate is used for gargling, very low concentration (0.1 PPM in 30 irrigating cavities, urethra and wounds. seconds). It also destroys protozoa and • For stomach wash in alkaloidal poisoning viruses. The’antibacterial activity of chlorine (except atropine and cocaine because these is reduced in presence of organic matter since are not efficiently oxidized). they bind chlorine and therefore need higher • 1% solution in mycotic infections like concentration of free chlorine. Chloramines athletes foot. are compounds that release chlorine slowly. • 5% solution as a styptic. 1. Chlorinated lime (bleaching powder) is • Topically to oxidise venom in case of obtained by the action of chlorine on lime. snake and scorpion bite. It is used for disinfection of water in • To purify well water. swimming pools and water for drinking. • To disinfect vegetables and fruits. 382 Textbook of Pharmacology for Dental and Allied Health Sciences

Dyes Colloidal silver compounds slowly release silver. They are non-corrosive, non-irritant, non- Gentian violet (aniline dye, crystal violet or astringent and have better penetrability used medicinal gentian violet) is effective against as nasal and eyedrops. gram-positive organisms and fungi. Staining Zinc salts like zinc oxide has astringent and is the only disadvantage. It is a non-irritant mild antiseptic properties. It is used as an and potent antiseptic. 0.5-1% solution is used ointment or lotion in eczema, impetigo and topically on furunculosis, burns, boils, chronic psoriasis. ulcers, infected eczema, thrush, ringworm Mercury compounds act by inhibiting and mycotic infections of the skin and mucous sulphydryl enzymes of bacteria. They are membranes. bacteriostatic and are poor antiseptics-not Brilliant green Actions are similar to gentian commonly used. violet. Used as a 0.5-1% solution in the treatment of burns, impetigo and infected CHELATING AGENTS wounds like gentian violet. Heavy metals bind to and inactivate the Methylene blue is used systemically in cyanide functional groups (ligands) of essential tissue poisoning as it converts methaemoglobin to enzymes. By this they interfere with normal haemoglobin. cell functions which require these ligands. Acriflavine and proflavine are acridine dyes Heavy metals cannot be metabolised in the active against gram-positive bacteria and body. gonococci (proflavine is better). They are Chelating agents or heavy metal anta- non-irritant; efficacy is unaffected by organic gonists bind the heavy metal ions and make matter but is increased in alkaline medium; them non-toxic. The chemical complex formed 1: 1000 solution is used in infected wounds is called chelate (Chele = claw; in Greek). The process of complex formation is chelation. and burns, 2% pessary in vaginitis and The complex so formed is water-soluble and cervicitis. is eliminated by the kidneys. Triple dye lotion contains gentian violet 0.25% The clinically useful chelating agents are + brilliant green 0.25% + acriflavine or CaNa2 EDTA, dimercaprol, d-penicillamine proflavine 0.1 %-it is used in burns dressing. and desferrioxamine. Chelating agents are more effective in preventing the utilization Metals of ligands than in reactivating them—hence, Silver compounds have antiseptic, astringent the earlier they are given, the better. Calcium disodium edetate (CaNa EDTA) and caustic properties. Silver nitrate kills 2 chelates several divalent and trivalent metals microbes rapidly and the action is prolonged like zinc, manganese, iron and lead. It is used due to slow release of silver ions from silver in the treatment of lead poisoning. Given proteinate that is formed by an interaction parenterally, lead deposits in the bone are with tissue proteins. The reduced silver gets mobilised, chelated and excreted through deposited and stains the tissues black. kidneys. Silver nitrate is used for the prophylaxis of Adverse effects include nephrotoxicity, fatigue, ophthalmia neonatorum. fever, myalgia and dermatitis.

Silver sulfadiazine is active against Pseudomonas CaNa2EDTA is mainly used in lead and is used in burn wounds. poisoning. It can also be used in zinc, Miscellaneous Drugs 383 manganese and iron poisoning. Sodium in some. On long-term use renal, haemato- edetate is used in severe hypercalcaemia. logical, dermatological and other toxicities Dimercaprol is a colourless, oily liquid can occur. developed by the British during World war II as an antidote to lewisite—an arsenical war Uses gas. Hence it is also known as British Anti- 1. Treatment of copper, mercury and lead lewisite or BAL. Dimercaprol chelates poisoning. arsenic, mercury, lead and other heavy 2. Wilson’s disease (hepatolenticular metals. It is given IM; appropriate plasma degeneration)—copper is deposited in the concentrations should be maintained. liver and brain causing degeneration. Adverse effects are dose related and include 3. Rheumatoid arthritis (Page 186). hypertension, tachycardia, vomiting, swe- 4. Cystinuria—promotes excretion of ating, burning sensation in the lips and mouth cysteine by forming soluble complexes and headache. Dimercaprol is used in arsenic and and prevents formation of cysteine stones. mercury poisoning; also used in lead Desferrioxamine isolated from Streptomyces poisoning with CaNa EDTA. pilosus, chelates iron. It has a high affinity for 2 iron, forms stable complexes and removes Unithiol iron from haemosiderin and ferritin. It does not chelate the iron in haemoglobin and Unithiol is a water soluble analog of cytochromes. It is given parenterally dimercaprol that can be given both orally and (Page 223). parenterally. It enhances the excretion of Toxicity Allergic reactions range from rashes mercury, arsenic and lead. Adverse effects to anaphylaxis (rare), diarrhoea, muscle are mild and include allergic reactions. cramps and blurred vision. Unithiol may be used in mercury, lead and arsenic poisoning. Uses

Succimer 1. Acute iron poisoning—desferrioxamine is the drug of choice. Succimer is another water soluble analog of 2. Chronic iron poisoning—as in thalas- dimercaprol. It protects against acute arsenic saemia patients who receive repeated poisoning and it is also effective in lead and blood transfusion. mercury poisoning. It can be given both orally Deferiprone chelates iron and is orally effective. and intravenously. Succimer is used in the It is used in thalassemia major to chelate iron treatment of chronic lead poisoning and in as an alternative to desferrioxamine. mercury and arsenic poising. Anorexia, nausea, vomiting, diarrhoea and skin rashes VITAMINS can occur. d-Penicillamine is prepared by degradation Vitamins are organic compounds essential for of penicillin but has no antibacterial activity. normal metabolism in the body. They are It chelates copper, mercury, zinc and lead. It supplied by the diet. A balanced diet supplies is orally effective. adequate amounts of vitamins to fulfill the Toxicity Patients allergic to penicillin may daily requirement. The requirement is develop anaphylaxis; dermatitis may occur increased during periods of rapid growth, 384 Textbook of Pharmacology for Dental and Allied Health Sciences pregnancy and lactation. Vitamin deficiencies Hypervitaminosis A Since vitamin A is a fat- result in characteristic signs and symptoms. soluble vitamin, it accumulates in the body Vitamins are grouped into fat-soluble and on prolonged administration. The symptoms water-soluble vitamins (Table 55.1). are dry skin (hyperkeratosis), anorexia, fever, alopecia, anaemia, oedema, headache, FAT-SOLUBLE VITAMINS skin ulcers and tenderness over the bones. Vitamin A Vitamin D See Page 373 Vitamin K See Page 234 Vitamin E Vitamin A is present in the diet as retinol, Vitamin E or Alpha tocopherol is present in dehydroretinol or as carotenoids. Caro- wheat germ oil, rice germ oil and soya bean tenoids are pigments present in green yellow oil. vegetables and fruits and is converted in the Physiological role Vitamin E acts as an body to retinol. antioxidant. It prevents the damage due to Source Green leafy vegetables, carrots, free radicals in normal metabolic reactions. mango, papaya, eggs, milk, butter, cheese, Vitamin E is essential for normal structure liver and fish liver oils. Maximum content is in Halibut liver oil - 9,00,000 mg/100 gm. and function of the nervous system. It is also Physiological functions Vitamin A has an required to maintain the integrity of the important role in dark adaptation. It is biological membranes. Vitamin E deficiency essential for the synthesis of rhodopsin, the in animals results in reproductive and photosensitive pigment of rods. Vitamin A haemopoietic system abnormalities, dege- is also essential for maintenance of the nerative changes in the spinal cord and heart. integrity of epithelial cells, for growth and Daily requirement is 10-15 mg. cell-mediated immunity. Uses Clinically vitamin E deficiency in human Signs and symptoms of deficiency Xerophthalmia beings is not known. It has been tried in G- (dryness of eyes), Bitot’s spots in the 6-PD deficiency, sterility, menopausal conjunctiva, night blindness, diarrhoea, dry syndrome and other conditions with no and rough skin are seen in early stages. In definite evidence of obvious benefit. the later stages, keratomalacia, perforation of the cornea, necrosis and blindness can WATER-SOLUBLE VITAMINS occur. Vitamin B-complex Daily requirement–3000-5000 IU/day. B-complex group of vitamins includes Uses thiamine, riboflavin, nicotinic acid, pyrido- In the prophylaxis and treatment of vitamin xine, pantothenic acid, biotin and cyano- A deficiency. cobalamin. 1. Prophylaxis–3000-5000 IU/day in presence Thiamine (Vitamin B1, Aneurine) of increased requirement. 2. Treatment–50,000-1,00,000 IU intramus- Sources Pulses, outer layers of cereals, rice cularly or orally for 1-3 days followed by polishings, peas, nuts, green vegetables, egg oral supplementation. and meat. 3. Acne–Retinoic acid or synthetic analogs Physiological role Thiamine is converted to of vitamin A like tretinoin or isotretinoin thiamine pyrophosphate which acts as a are used. coenzyme in carbohydrate metabolism. Miscellaneous Drugs 385

Daily requirement 1-2 mg. Physiological functions Nicotinic acid is converted to nicotinamide. Nicotinamide Symptoms of deficiency Thiamine deficiency adenine dinucleotide (NAD) and it’s produces Beriberi. phosphate (NADP) are coenzymes involved Dry beriberi is characterised by peripheral neuritis and muscular atrophy. in several oxidation-reduction reactions. Wet beriberi The characteristic features are Nicotinic acid is also a lipid-lowering dependent oedema and high output cardiac agent. failure. Wernicke’s encephalopathy and Symptoms of deficiency Niacin deficiency Korsakoff’s psychosis are also thought to be results in Pellagra characterised by due to thiamine deficiency. dermatitis, diarrhoea and dementia. Other symptoms include: pigmentation of the skin, Uses stomatitis, glossitis, headache, insomnia, 1. Prophylactically in presence of increased hallucinations, confusion and megaloblastic demand as in pregnancy, lactation and anaemia. Chronic alcoholics, people living on infants. maize as the staple diet, patients with 2. Beriberi–50 mg daily parenterally. Once malabsorption and cirrhosis develop the patient recovers, maintenance dose of pellagra. 10 mg/day is given orally. Uses 3. Chronic alcoholics–50 mg daily. 4. Empirical use–thiamine is tried in several 1. Prophylaxis and treatment of pellagra (50- neurological and cardiovascular disorders 500 mg). and morning sickness. 2. Nicotinic acid is used in hyperlipo- proteinaemia (see Page 236). Riboflavin (Vitamin B2)

Sources Milk, egg, liver, meat, grains and Pyridoxine (Vitamin B6) green leafy vegetables. Sources Cereals, legumes, liver, milk, meat Physiological function Flavin mononucleotide and eggs. (FMN) and flavin adenine dinucleotide Physiological functions Pyridoxal phosphate is (FAD) containing the active form of a coenzyme involved in the synthesis of riboflavin are coenzymes in various several amino acids, biogenic amines and oxidation-reduction reactions. other compounds like GABA. Symptoms of deficiency Angular stomatitis, glossitis, seborrhoeic keratosis of the nose, Symptoms of deficiency Glossitis, peripheral ulcers in the mouth, dry skin, burning neuritis, anaemia, dermatitis and low seizure sensation in the plantar surface of the feet, threshold due to decreased GABA levels in vascularization of the cornea and alopecia. the brain. Uses Riboflavin is used for the prevention and Uses treatment (2-10 mg) of riboflavin deficiency. Nicotinic Acid and Nicotinamide 1. Prophylaxis and treatment of pyridoxine deficiency. (Vitamin B ) 3 2. INH induced peripheral neuritis– Nicotinic acid and nicotinamide are together pyridoxine is used both for prophylaxis known as niacin. and treatment. Sources Rice polishings, liver, fish, milk, eggs, 3. Convulsions in infants due to pyridoxine nuts and pulses. deficiency. 386 Textbook of Pharmacology for Dental and Allied Health Sciences

Table 55.1: Sources, recommended daily allowances and deficiency symptoms of various vitamins in the diet (for adults)

Vitamin Important dietary Daily allowance Deficiency symptoms sources

Fat soluble vitamins

Vitamin A Green leafy vegetables, carrots, mango, 3000-4000 IU Night blindness, xerophthalmia, papaya, eggs, milk, butter, cheese, liver hyperkeratosis of skin and fish liver oils and epithelial tissues

Vitamin D Liver, egg yolk, fish liver oils, 200-400 IU Rickets, osteomalacia milk, butter

Vitamin E Wheat germ, nuts, cereals, eggs, green 10-15 mg Not known leafy vegetables Vitamin K Green leafy vegetables, liver, meat, 50-100 mg Hypoprothrombinaemia, cheese, egg yolk and tomatoes haemorrhage Water soluble vitamins Vitamin B complex

Thiamine (B1) Cereals, rice polishing, liver, egg yolk 1.2-1.4 mg Beriberi, peripheral neuritis, anorexia

Riboflavin (B2) Milk, cereals, pulses, leafy 1.5-2 mg Stomatitis, glossitis, vegetables, eggs and meat cheilosis, vascularisation of cornea

Nicotinic acid Rice polishings, cereals, pulses, 20 mg Pellagra - diarrhoea, dermatitis,

(Niacin B3) groundnut, liver, meat, fish. dementia; glossitis, stomatitis, delusions, confusion

Pantothenic acid Rice polishings, whole grains, meat, 4-7 mg Weakness, fatigue, burning egg yolk sensation in the feet

Pyridoxine (B6) Whole grains, pulses, green 2 mg Peripheral neuritis vegetables, milk, liver, egg yolk glossitis, stomatitis

Biotin Liver, nuts, egg yolk 0.1-0.2 mg Not known Folic acid Leafy vegetables, milk, liver, meat, 100-200 mg Megaloblastic anaemia, cereals glossitis, GI disturbances μ Vitamin B12 Milk, egg yolk, liver, meat, fish 1-2 g Megaloblastic anaemia, demyelinating, neurological disorders of the spinal cord

Vitamin C Goose berry (amla), citrus fruits, 50 mg Scurvy - petichiae, bleeding gums, green vegetables and tomatoes easy bruising, delayed wound germinating pulses healing, anaemia, weakness Miscellaneous Drugs 387

4. ‘Morning sickness’ in pregnancy– subcutaneous tissues, petechiae, ecchymoses, pyridoxine may reduce vomiting by an impaired wound healing, tender bleeding unknown mechanism. gums, deformed teeth, brittle bones, anaemia and growth retardation. Pantothenic Acid Uses Sources Wheat, cereals, milk, peanuts, liver, egg yolk and vegetables. 1. Prevention of vitamin C deficiency–50-100 Physiological role Pantothenic acid is converted mg daily. to coenzyme A which is involved in several 2. Scurvy–500-1000 mg daily. metabolic reactions. Pantothenic acid 3. Common cold–large doses (0.5-1.5 gm) of deficiency in human beings is not known. vitamin C has been tried as prophylactic Experimentally induced deficiency results in against common cold with controversial fatigue and paraesthesia. Calcium panto- benefits. thenate is a component of multivitamin 4. To acidify urine. preparations. GENE THERAPY Biotin Gene therapy is the replacement of defective Biotin is an organic acid found in liver, nuts, gene by the insertion of a normal, functional egg yolk and other foods. Biotin deficiency gene. It is the genetic modification of cells in humans is not known. Experimentally for the prevention or treatment of a disease. induced deficiency results in dermatitis, Gene transfer may be done to replace a anorexia, alopecia and glossitis. Biotin is a missing or defective gene or provide extra- coenzyme in several metabolic reactions. It copies of a normally expressed gene. Gene is present in many multi-vitamin therapy is aimed at genetically correcting the preparations. Avidin, a protein present in egg defect in the affected part of the body. Unlike white prevents the absorption of biotin. all other drugs which only alter the rate of normal cell functions, gene therapy can confer new functions to the cell. VITAMIN B12, FOLIC ACID (see Page 225) VITAMIN C (ASCORBIC ACID) Vectors Sources Citrous fruits, tomatoes, goose berry, Gene transfer requires the use of vectors to green vegetables and potatoes are rich in deliver the DNA material. An ideal vector vitamin C. should be safe and effective in inserting the Physiological role Ascorbic acid is involved in therapeutic gene into the target cells. several metabolic reactions including Physical, chemical and biological vectors have oxidation reduction reactions and in cellular been tried. respiration. It is essential for the integrity of • Physical vectors - DNA is complexed with connective tissue, for the development of substances like lipids and administered. cartilage, bone and teeth and for wound • Chemical vectors - Liposomes are used to healing. carry genes into the cells. Symptoms of deficiency Vitamin C deficiency • Biological vectors - The most important results in scurvy characterised by connective biological vectors are viral vectors. tissue defects resulting in haemorrhages in Viruses invade cells and use the metabolic 388 Textbook of Pharmacology for Dental and Allied Health Sciences

processes of these host cell for replication. 2. Familial hypercholesterolaemia - LDL receptor This property of viruses helps to deliver gene is introduced into liver cells. the gene — adenoviruses and retroviruses 3. Cancer- are used for this purpose. a. introducing the gene which makes the malignant cells sensitive to drugs. Therapeutic Applications of b. inactivating the expression of oncogenes. Gene Therapy c. introducing genes that attaches to Gene therapy is at present a developing cancer cells and make them susceptible area. Though originally it was seen as a to host defense cells. remedy for inherited single gene defects, d. introducing genes to healthy cells to gene therapy has now been found to be protect them from cytotoxic drugs. useful in several acquired disorders. The 4. HIV infections principal applications are in single gene a. Introducing genes coding for CD4 cells defects like thalassaemia, cystic fibrosis and that could inactivate HIV before haemoglobinopathies and in the treatment of entering the cell itself. cancer, cardiovascular diseases, atheros- b. Introducing genes that enhance clerosis, immunodeficiency disorders– immunity against HIV. particularly AIDS; anaemia, Alzheimer’s 5. Diabetes mellitus - Introducing insulin disease and many infectious diseases. gene into the liver which can produce insulin. Some examples are- 6. Coronary atherosclerosis - Prevention of 1. Growth hormone deficiency - Growth restenosis and ischaemia in coronary hormone gene is transferred to myoblasts vessels by genes which inhibits the and these are implanted in patients. growth of vascular endothelial cells. SectionDental Pharmacology 14 389 Dental Pharmacology

56 Dental Pharmacology

DENTIFRICES 2. Detergents

Dentifrices are therapeutic aids meant for Detergents are cleansing agents which act by: cleaning the teeth with the help of a (i) lowering surface tension, i.e. they toothbrush. They are available in the form possess emulsifying properties. of powders, liquids and paste, e.g. (ii) dissolving fatty substances and mucus toothpastes and tooth powders. Though the plaques. prime purpose of a dentifrice is to assist the (iii) foaming—on scrubbing the teeth, brush in cleaning the teeth, addition of certain detergents foam and act as lubricants. substances like fluoride and antiseptics can (iv) loosening the debris adhering to the afford additional benefits. The ingredients teeth. are: (v) some of them also liberate oxygen and 1. Abrasive Agents have antiseptic properties. Thus detergents act as deodorants, e.g. Dental abrasives are fine powdered sodium lauryl sulphate and soaps. Sodium substances which assist the scouring action lauryl sulphate–a pale yellow powder is of the toothbrush. They are inorganic salts effective in both acid and alkaline medium of low solubility, e.g. prepared chalk, calcium and in hard water. It is also used as a skin phosphate, calcium and magnesium cleanser and in medicated shampoo. carbonates; magnesium oxide, ferric oxide, charcoal, silicates, powder pumice, kaolin 3. Antiseptics and stannic oxide. The abrasive powder The small amount of antiseptics used in should be fine to avoid scratching of the teeth dentifrices may not be sufficient to afford surfaces. Abrasives are also available as adequate antiseptic action. Antiseptics used pastes. Generally powders are more in dentistry are thymol, menthol, eugenol, powerful abrasives than pastes. benzoic acid, boric acid, myrrh, calcium and Uses magnesium peroxide. Thymol is a powerful antiseptic and a deodorant used in 1. Polishing the teeth and fillings. mouthwashes and gargles. Eugenol has the 2. Cleaning the teeth. odour of clove and is also a local anaesthetic 3. In toothpastes and tooth powders. commonly used for dental filling. 390 Textbook of Pharmacology for Dental and Allied Health Sciences

4. Sweetening Agents 7. Other Agents Sweetening agents are substances used to Other agents used in dentifrices include impart a sweet taste to a pharmaceutical (i) binding agents like mucilage of preparation. They are used to make the use tragacanth, gum acacia and bentonite; of dentifrice more pleasant and acceptable. They help to bind the liquid and solid Saccharine sodium is commonly used in tooth phases together in a paste. powders and is intensely sweet. It is an (ii) humectants like glycerine and sorbitol artificial sugar 500 times sweeter than sugar prevent drying up of the paste. and can be used as a dilute(1%) solution. (iii) Antacids like sodium bicarbonate- Saccharine has no caloric value and is neutralize acidity in the oral cavity. excreted unchanged with in 24 hours. It is A good dentifrice should be pleasant in stable and nontoxic. Saccharine is less likely taste, odour and consistency; should not damage the gums or the teeth. to encourage the development of caries when compared to other carbohydrates. It OBTUNDENTS enhances the palatability. Though sucrose can also be used, it causes fermentation and is Obtundents are agents that diminish dentine therefore not preferred. sensitivity. They are used to make the excavation painless. Obtundents act by one 5. Colouring Agents of the following mechanisms. 1. Paralysing the sensory nerves, e.g. phenol, Colouring agents are used to make the menthol, thymol, clove oil, camphor, preparation more attractive for commercial benzyl alcohol purpose. Bright colours like cherry red, blue 2. Precipitating proteins Astringents like silver and green are used. Liquor rubri imparts red nitrate, zinc oxide and zinc chloride. colour while methylene blue gives blue 3. Destruction of nervous tissue, e.g. Absolute colour and chlorophyll is employed for green alcohol (Table 56.1). colour. Most colours used commercially are But, the disadvantages with the use of synthetically produced, though some of them obtundents are: pulp may shrink and irritants may also be obtained from natural sources may stimulate the formation of secondary like plants, animals or minerals. Only dentine. After the advent of local anaesthetics, premitted colour can be used in dentifrices. the use of obtundents has declined.

6. Flavouring Agents ANTISEPTICS Flavouring agents are substances used to Antiseptics used in dentistry are phenol, impart a pleasant smell and taste to the cresol, chloroxylenol, hexachlorophene, preparation so that it is more palatable. chlorhexidine, sodium hypochlorite, iodine Though natural flavouring agents are and iodophors and oxidising agents like available, synthetic flavours are preferred hydrogen peroxide, and sodium perborate; because of their easy availablity. Generally alcohol and benzalkonium chloride. For fruity and spicy flavours are preferred. details see page 378. Peppermint, lemon, mint and pineapple are MUMMIFYING AGENTS some natural flavours; synthetic flavours include alcohols, aldehydes, esters and fatty Agents used to harden and dry the tissues acids. of the pulp are called mummifying agents. Dental Pharmacology 391

Table 56.1: Some obtundents, their mechanisms of action, advantages and disadvantages

Obtundent Mechanism of action Advantages Disadvantages

Phenol • Protoplasmic • Rapid action • Infected dentine poison—paralyses • Does not stain healthy is darkened nerves dentine • Poor penetrability • Initial irritation • Penetrability can be followed by increased by combining numbness with KOH and glycerine Thymol • Paralyse sensory • Combination of these • Clove oil may stain the Menthol nerves—initial oils has rapid action dentine yellow Clove oil irritation followed by Camphor] numbness Silver nitrate • Astringent—precipitates • Rapid action • Stains the dentine black superficial proteins • Penetrability is poor Zinc chloride • Similar to silver nitrate • Rapid action • Initial pain is sharp • Does not stain the teeth Parafor- • Acts by release of • Painless • Slow action maldehyde formaldehyde which • Non-staining • Formaldehyde may precipitates proteins penetrate pulp to cause inflammation

This hardening makes the tissues resistant like sodium peroxide and perhydrol, to infection. Astringents and antiseptics are reducing agents like sodium thiosulphate and used in combination as a paste for this other agents like chlorides, hydrogen purpose. Some mummifying agents are: peroxide and ultraviolet rays have been used 1. Liquid formaldehyde It is used with zinc as bleaching agents. Hypochlorites remove oxide and glycerine to harden the tissues. silver and iron stains; sodium thiosulphate 2. Paraform—acts by slow release of removes iodine stains while chlorinated lime formaldehyde and is used in combination is used to remove stains by aniline dyes. with zinc oxide and glycerine. 3. Iodoform—acts by liberation of iodine. It STYPTICS is made into a paste with eugenol, phenol, Styptics are local haemostatics. They are used tannic acid and glycerol for use in dental to arrest local bleeding following tooth practice. extraction and other dental procedures 4. Tannic acid—is an astringent, precipitates (Page 233) proteins and hardens the tissues. The tissues may also shrink. MOUTHWASHES

BLEACHING AGENTS Mouthwashes are solutions containing active ingredients meant for cleansing and Bleaching agents are used to remove deodorising the oral cavity. 15-30 ml of the pigmentation of the teeth. Oxidising agents diluted solution is used for gargling and 392 Textbook of Pharmacology for Dental and Allied Health Sciences

rinsing the mouth. Mouthwashes contain Types of Astringents astringents, antiseptics and/or obtundents, 1. Vegetable astringents—tannic acid, gall. flavouring and sweetening agents. Prolonged 2. Metallic astringents—salts of zinc, copper, use of concentrated solutions result in iron, aluminium and silver; also alum. staining. 3. Miscellaneous—alcohol, dilute acids. Uses Astringents are used as mouthwashes, Types of Mouthwashes paints, lotions and dentifrices in aphthous 1. Antiseptic and astringent mouthwash— ulcers, stomatitis, gingivitis and as local haemostatics. for soreness under dentures. They harden the mucous membrane. DISCLOSING AGENTS 2. Obtundent mouthwash—for sensitive oral lesions. Dental plaques are relatively invisible. 3. Detergent mouthwash—for cleansing and Certain agents (dyes) and iodine containing deodourising action. solutions may be used to make the supra- gingival plaques visible and such agents are Uses called disclosing agents. Dyes used as disclosing agents are as 1. Soreness under dentures. follows. 2. Sensitive oral lesions. 3. Postoperative and other bedridden 1. Erythrosin patients for deodourising the oral cavity Erythrosin tablets are dissolved into a and to maintain oral hygiene; solutions or chewed to dissolve in the mouth. mouthwashes are refreshing. It stains the plaque area red but also may 4. In halitosis. stain soft tissues. It is the most widely used 5. Stomatitis. disclosing agent. 6. Surgical impaction—after removal of impacted tooth. 2. Fluorescein Dye Chlorhexidine (CHLORHEX REXIDINE) On application, fluorescein dye stains the and Povidine iodine (BETADINE) are some plaque yellow. It does not stain the soft commonly used mouthwashes. tissues. But special light is required to see the stained plaque. It is more expensive. ASTRINGENTS Astringents are agents which precipitate 3. Two-tone Dyes superficial proteins when applied to the skin A solution containing a combination of two or mucous membrane. They form a dyes is used. Mature plaques are stained blue, protective coating and harden the surface. while new plaques are stained red. Astringents check minor haemorrhages— arrest capillary oozing as they promote Advantages clotting and precipitate proteins on the • Dyes used as disclosing agents help to bleeding surface. Astringents are therefore differentiate mature and immature used as obtundents, styptics and plaques. mummifying agents. • They do not stain the gingival tissues. Dental Pharmacology 393

4. Iodine Containing Solutions Uses 1. Sialocele–An antisialogogue is used to Iodine containing solutions have been used suppress glandular function during as disclosing agents but have the healing or to encourage spontaneous disadvantage of causing a high incidence of allergic reactions. They also have an resolution of the sialocele. Propanthelene unacceptable taste. Hence iodine solutions bromide (Pro-banthine) is given in the are not preferred. dose of 15 mg orally 4 times a day half an hour before food. Methods of application To stain the plaque, 2. Post surgical–An antisialogogue is used solutions of disclosing agents may be used for a short period following surgeries of as follows: the salivary glands and salivary ducts. (i) Painting the teeth with a cotton swab Temporary reduction in the flow of saliva (ii) Rinsing the mouth is thought to be helpful in faster wound (iii) As tablets/wafers to be chewed healing. dissolving it in the saliva. The mouth 3. In post-traumatic parotid fistulas and should then be rinsed with water. sialoceles. 4. Trauma to the salivary gland and salivary SIALOGOGUES AND ANTISIALOGOGUES ducts. Sialogogoues are agents which enhance ANTICARIES DRUGS salivary secretions. Pilocarpine is generally used as a sialogogue though other drugs like Caries is a degenerative condition charac- bethanechol, and anticholinesterases like terised by decay of hard and soft parts of neostigmine also reduce salivary secretions the teeth. Cevimeline a newly introduced drug Fermentation of carbohydrates in the oral enhances salivary secretion by directly cavity results in the production of acids like stimulating the muscarinic receptors. It is used lactic acid. These acids convert the insoluble to treat dry mouth in patients with Sjögren's calcium salts of the teeth into soluble salts syndrome. (decalcification) which are easily removed. (i) Sialogogues are used to treat acute The oral flora produce proteolytic enzymes symptoms of sialoadenitis that may be which digest the organic enamel matrix. Thus seen in sialolithiasis. Surgical excision both organic and inorganic matter of the is required in most cases. teeth are destroyed. As the process (ii) Xerostomia-often follows radio-therapy continues, the pulp is penetrated and the of the head and neck. It may be infection may gain access into the systemic troublesome because it causes difficulty circulation. in speaking and swallowing. It may be Fluorides Fluorine, a halogen, is the most treated with pilocarpine. electronegative of all elements and is (iii) Sjögren’s syndrome-cevimeline is used. therefore highly reactive. The efficacy of fluoride in the prophylaxis of dental caries Antisialogogue has been well-established. An antisialogogue is a substance that reduces Mechanism of action Fluorides alter the salivary secretion. Propantheline bromide an physicochemical properties of the teeth as atropine substitute is commonly used for this follows: purpose though atropine and many other 1. Fluorides inhibit bacterial enzymes which anticholinergic drugs also decrease salivary produce acids and therefore prevent secretion. decalcification of the teeth. 394 Textbook of Pharmacology for Dental and Allied Health Sciences

2. Fluorides convert the hydroxyapatite of Fluoride Toxicity enamel and dentine to fluorapatite which Chronic toxicity results in mottling of the is more resistant to destruction by acids. enamel, brownish-black discolouration of the Thus fluorides make the outer layers of teeth, joints pain and stiffness, osteosclerosis enamel harder and more resistant to of the spine and pelvis. Crippling fluorosis is demineralization. characterised by thickening of the cortex of 3. Fluorides also stimulate remineralization long bones and bony exostoses specially in of the enamel. the vertebrae. Fluoridation of water supplies Fluoridation of Acute toxicity could result from accidental or drinking water is the most effective measure suicidal overdose often due to ingestion of in preventing dental caries—if consumed fluoride-containing rat poisons. 2.5-5 gm is prior to eruption of the permanent teeth. the lethal dose in adults. Manifestations Several large-scale studies have established include nausea, vomiting, diarrhoea, the beneficial effects of optimum fluoridation hypotension, hypocalcaemia, hypoma- of communal water supplies in preventing gnesaemia, cardiac arrhythmias and acidosis. caries. The optimum level of fluoride is 0.5-1 ppm and is found to be safe and effective. Treatment More than 1-2 ppm result in toxicity—cause dental fluorosis. • Vomiting should be induced and gastric When communal water fluoridation is lavage should be given with fluids impracticable, table salt can be fluorinated. containing calcium. Topical fluoride Topical use of high doses of • Cardiac arrhythmias should be treated. fluorides effectively prevents caries, It may • Correction of acid base imbalance. be used as: • Alkaline diuresis to enhance fluoride Fluoride dentifrices Several commercial excretion. preparations containing fluoride salts are Prevention of caries Caries can be largely available. Sodium fluoride, sodium prevented by the following measures: monofluorophosphate or stannous fluoride are 1. Resistance of the host can be increased by the salts used in such dentifrices. Mouth should fluoride therapy. be thoroughly rinsed and dentifrice should not 2. Oral flora to be controlled by antiplaque be swallowed; children should be specially agents. warned—to avoid fluorosis. Used twice a day 3. Soluble carbohydrates present in ice- regularly, they effectively prevent caries. creams, sweets, chocolates, etc.—the Fluoride mouthrinses 0.2% sodium fluoride substrate for bacterial growth—should be solution containing 900 ppm of fluoride, avoided. retained in the mouth for one minute—to be 4. ‘In-between’ eating habits should be used twice a week is effective in preventing reduced. caries. 5. Public should be educated regarding the Topical application by a dentist of 2% sodium proper use of toothbrush, dentifrices and fluoride or 8% stannous fluoride once a week prevention of caries. for 4 weeks also prevents caries but is expensive. Special precaution should be taken DRUGS USED IN DENTAL PLAQUE to avoid swallowing. Topical application is the most effective if done just as the teeth Plaque is the soft, non-mineralised bacterial erupt. deposit formed on inadequately cleaned Dental Pharmacology 395 teeth. Proteins in saliva adhere to the surface Mechanism of action–Chlorhexidine is of the enamel. Microorganisms from oral bacteriastatic in low concentrations but cavity colonise on these to from a plaque. As bactericidal at higher concentrations. in caries, poor oral hygiene and carbohydrate Chlorhexidine binds to the bacterial cell wall rich food encourage plaque formation when and interferes with the uptake of sugars by a plaque gets mineralised, it is called a dental the bacteria. Higher doses cause precipitation calculus or tartar. of intracellular proteins leading to cell death. Treatment All plaque should be removed as Long-term use of chlorhexidine can cause quickly as possible. The virulent yellowish brown staining of the teeth, microorganisms of the plaque flora like Streptococcus mutans and Streptococcus sobrinus mucosal soreness, desquamation and are associated with the pathogenesis of caries occasionally altered taste sensation. How- and many periodontal diseases. These ever, systemic side effects are unlikely since organisms should be controlled either by a chlorhexidine is used topically. Alexidine can suitable antibacterial agent or altering tooth also be used. surface to prevent the bacterial attachment to the plaque. Scaling is done to remove the Uses plaque. a. Bisbiguanides are used as mouthrinses, Antibacterial Agents gels and in dentifrices for the control of plaque and gingivitis. Though penicillins, erythromycin and b. Chlorhexidine mouth wash is also used tetracyclines are effective in controlling to disinfect the oral cavity before dental plaque, antibiotics which are not absorbed procedures. from the oral mucosa should be preferred. c. Ulcerative gingivitis. Vancomycin, kanamycin, bacitracin and d. Following oral surgery and denture polymyxin-B are used as topical mouthrinses insertion. or gels. Controlled delivery systems e. Prophylactically in immunocompromised containing tetracyclines for intra pocket insertion, effectively suppresses periodontal patients like those with leukaemia, AIDS pathogens. However, long-term use of and agranulocytosis. antibiotics should be avoided because of the 2. Fluorides Stannous fluoride mouth rinses risk of toxicity. or gels are effective in plaque control and Other agents that can be used in plaque make the gums healthier. Fluorides inhibit control are: enzymatic reactions involved in glycolysis. 1. Bis-biguanides Chlorhexidine (page 380) is 3. Oxygenating agents like hydrogen peroxide the most effective anti-plaque and (page 381) and sodium perborate. These antigingivitis agent. Chlorhexidine gluconate compounds act by liberating nascent oxygen. 0.12–0.2% solution is used twice daily for rinsing–15 ml solution is retained for 30 4. Halogens Halogen releasing compounds seconds in the month and then spat out. For like chlorophors and iodophors are used in the next 30 minutes, eating, drinking and many antiseptic mouthwashes. Chlorine rinsing the mouth should be avoided. dioxide and povidone iodine have been Chlorhexidine binds to oral tissues and is widely used—but these are not popular slowly released for about 12 hours. because of their unpleasant taste. 396 Textbook of Pharmacology for Dental and Allied Health Sciences

5. Other compounds hypersensitivity is due either to loss of enamel • Other antiseptics like phenol and its or exposure of the root surface. Loss of derivatives hexylresorcinol and enamel may follow mechanical wear or thymol are used in many anti-plaque chemical erosion due to acidic food. The root mouthrinses. But their properties like surface gets exposed due to gingival disagreeable taste, rapid discolouration recession as seen in old age, incorrect and poor solubility make them less toothbrushing habits or chronic periodontal preferred. diseases. • A combination of oils including thymol An ideal desensitising agent should be non- (0.06%, eucalyptus oil (0.09%), irritant, non-toxic, painless, rapid acting, easy menthol (0.04) and methyl salicyte to use and have a long-lasting effect. At (0.06%) in an alcohol based vehicle is present no such single agent is available. found to be useful in inhibiting plaque. Hence multi-modal approach could be These oils act by inhibiting bacterial employed depending on the severity. enzymes and alcohol acts on the bacterial cell wall. The combination is Dental Desensitising Agents are useful in reducing plaque and gingivitis. 1. Agents occluding dentinal tubules: Potassium • Detergents like sodium lauryl sulphate nitrate, Potassium oxalate, Calcium have also been used in several hydroxide, Fluorides, Sodium citrate, mouthrinses. Formaldehyde • Nonionic bisphenols–Triclosan is a 2. Agents precipitating proteins: germicidal used in toothpaste and in a. Astringents other dental preparations. It has a wide Silver nitrate, Zinc chloride antibacterial spectrum including many b. Precipitating tubule proteins gram positive and gram negative causing occlusion bacteria. It causes leakage in the Strontium chloride, Formaldehyde bacterial cell membrane leading to 3. Tubule sealants: 4-Methacryloxyethyl bacterial cell lysis. It is retained in the trimellitate dental plaque for 8 hours. Triclosan also 4. Physical methods: Restorations—Glass inhibits gingivitis. When triclosan is ionomer cements, composites; Laser incorporated in a polyvinyl copolymer sealing of the tubule its antibacterial activity improves. Therefore triclosan is used along with 1. Agents Occluding Dentinal Tubules the copolymer in toothpaste and is found to be useful in controlling plaque Five per cent potassium nitrate used daily is and calculus formation. effective in 4 weeks as a desensitising agent. It acts by occluding the dentinal tubules DENTAL DESENSITISING AGENTS through crystallisation. Used as a toothpaste Dentin hypersensitivity is a common problem twice a day, potassium nitrate is a popular affecting millions of people all over the world. desensitising agent. Pain could be evoked by mechanical, chemical SENQUEL, SENQUEL AD, THERMO or thermal stimuli, i.e. the patient experiences SEAL, Potassium nitrate 5%. pain while eating hot and cold, sweet or sour Calcium hydroxide supplies calcium ions which food or even while brushing the teeth. The hasten remineralisation of the exposed Dental Pharmacology 397 dentin. But it has to be applied by a dentist 1. A rise in geriatric population and a and may require repeated application as the consequent increase in the number of effect is short lived. elderly patients seeking dental therapy. Fluorides High doses of fluorides used as 2. the tendency for longer dental appoint- dentifrices act by hardening the dentin ments. surface and is claimed to be effective in 3-4 3. an increase in the use of drugs in denti- weeks. Fluoride iontophoresis (using 2% stry. NaF) may be employed to occlude the Dentists therefore, must be equipped with dentinal tubule. The procedure is immediately adequate knowledge for appropriate effective but is expensive and may require management of such situations, because they repetition. can be life threatening. Treatment and 2. Agents Precipitating Proteins prevention of some of the common emergencies that may be encountered in Astringents—Silvernitrate and zinc chloride act dental practice are discussed below. by precipitating proteins and were used earlier. But they cause permanent staining of 1. Anaphylaxis the teeth, are toxic to the gingiva and pulp and are therefore not preferred. Anaphylaxis: is an immediate type of Strontium chloride and formaldehyde act by hypersensitivity reaction and can occur precipitating proteins within the tubules following the use of drugs, and allergens. occluding them. They have been used in the Anaphylaxis is more common following form of dentifrices in the past. parenteral administration of drugs. Though it can be induced by any or all drugs, some 3. Tubule Sealants drugs like lignocaine, penicillins, cepha- The newer agents including 4–methacry- losporin and sulfonamides are more likely loxyethyl trimellitate have been tried as to induce anaphylaxis. Antigen – antibody desensitizers. complexes bind to the mast cells leading to 4. Physical Methods the degranulation of these mast cells. This results in the release of massive amounts of Restorations to cover the dentinal tubules histamine and other inflammatory mediators using glass ionomer and composites are found which are responsible for the symptoms of to be effective in patients with eroded gingiva. anaphylaxis. Symptoms usually occur within A combination of glass ionomer and composite minutes of exposure to the offending agent. resins is more beneficial when compared to Signs and symptoms include— either agents used alone. In patients with • Cutaneous – itching at the site of injection gingival loss, soft tissue grafts cover the exposed dentin to relieve the sensitivity. and/or generalized itching, swelling of subcutaneous tissues, eyelids, lips and EMERGENCIES IN DENTAL PRACTICE tongue. • Respiratory–wheezing due to bronchos- A dentist can come across several life threatening emergencies in dental practice pasm, cough and laryngeal oedema. although not frequently. Several factors have • Cardiovascular – hypotension resulting in contributed to an increase in the rate of these dizziness and in more severe cases loss of emergencies like – consciousness. 398 Textbook of Pharmacology for Dental and Allied Health Sciences

When severe, it can be rapidly fatal. Hence, 1. Patients on antiplatelet drugs or those with every medical and dental practitioner must thrombocytopenia due to any cause. know to manage anaphylaxis. 2. Patients on anticoagulant therapy Treatment – should be immediate. 3. Haemophiliacs • Intramuscular injection of adrenaline 0.5ml 4. Vitamin C deficiency of 1:1000 solution is life saving. The dose 5. Long-term glucocorticoid therapy may be repeated every 10 minutes if They should be controlled as follows: required. If hypotension is not significant, • Reduction in the platelet count or adrenaline may be injected subcutane- impaired platelet function due to antiplatelet ously. If anaphylaxis is very severe, 0.5 drugs can result in severe bleeding. ml adrenaline may even be given Appropriate measures should be taken to intravenously slowly. Dose may be correct the above before taking the patient repeated if needed after 5 to 10 minutes. for surgery or other dental procedures • The patient should be put in reclining associated with bleeding. If the patient is on position. drugs that inhibit platelet aggregation, • Arrangement should be made to transfer consult the physician 1-2 weeks before an the patient to the nearest emergency ward. elective surgery and under his guidance such • High flow oxygen should be given. drugs may be withdrawn temporarily. • Vital signs should be carefully monitored. Duration of antiplatelet effects of clinically • Cardiopulmonary resuscitation may be used drugs like ticlopidine and clopidogrel done if required. is around 7 to 10 days. Therefore these drugs • Intravenous hydrocortisone hemisuc- should be withdrawn about 7-8 days before cinate 100-200 mg will be needed in the procedure and prothrombin time should severe cases particularly in asthmatics. be brought down to 1½ to 2 times the control • An antihistamine like chlorpheniramine 20 value. The antiplatelet drugs should be mg IM or diphenhydramine 50 mg IM may restarted after adequate healing has be given as an adjuvant. Antihistamines occurred. Even minor bleeding including should be continued orally for 2 to 3 days. petichiae and ecchymoses should be watched • Intravenous fluids should be started. for. Vasopressors like dopamine may be given • If thrombocytopenia is due to any if needed. other cause, platelet transfusion may be required before any surgical procedure is 2. Uncontrolled Bleeding undertaken in consultation with a physician. • If the patient is on anticoagulants, they Most dental procedures cause some bleeding. may be temporarily withdrawn or the dose It is mostly minor and local application of reduced in consultation with a physician. mild pressure for 10-20 seconds would • Drugs with antiplatelet effects like generally arrest bleeding. If bleeding NSAIDs should be used carefully. continues, a cotton swab dipped in 1% • Vitamin C deficiency as such may result adrenaline solution may be used as a pack. in bleeding from the gums and may enhance Ice pack for a few minutes may also be tried. bleeding from dental procedures and also Gel foam may be used in more severe impair wound healing. Local application of bleeding. adrenaline pack or pressure may be needed Uncontrolled bleeding following dental following minor dental procedures. Major procedures may be seen in one of the dental procedures should be done after the following- correction of vitamin C deficiency. Dental Pharmacology 399

• Glucocorticoid therapy—Patients on b. Hypoglycaemia – is to be expected in long-term glucocorticoid therapy may bleed patients with diabetes mellitus. Signs and more and wound healing may be impaired. symptoms include sweating, tachycardia, Wounds are also more susceptible to tremors, blurred vision, weakness, infections. Adequate local haemostatic hunger, confusion and drowsiness measures should be taken. leading on to unconsciousness. In mild • Haemophiliacs—are deficient in hypoglycaemia, oral administration of coagulation factor VIII and are therefore sugar or sugar containing fruit juices are likely to bleed more even from minor dental sufficient to overcome the symptoms. In procedures. Factor VIII should be unconscious patients, 50 ml of 50% supplemented before the dental procedure dextrose is given intravenously – usually and adequate local haemostatic measures patient recovers within a few minutes. should be taken. c. Seizures – see below. d. Arrhythmias – may be 3. Unconsciousness: • Bradyarrhythmias-transient loss of Patients with no response to stimuli need consciousness with slow irregular heart immediate attention. rate of <40 beats/minute. Unconsciousness in dental practice may be • Tachyarrhythmias-Heart rate >150/ due to one of the following causes- minute may be associated with fatigue, a. Vasovagal attack/syncope/fainting breathlessness and syncope Vasovagal attack is the transient loss of e. Cardiac arrest is stoppage of the heart, consciousness due to a painful or an also called cardiac standstill. If revived emotional stimulus. Pathophysiology on time the heart may recover. involves an autonomic imbalance. In response Clinical features – Loss of consciousness to the stimulus, the vagus is stimulated which – Absence of pulses in turn results in bradycardia, reduced – Gasping or absence of cardiac output and hypotension accompanied breathing. by peripheral vasodilation. Hypotension Management reduces the blood supply to the brain leading • Maintain airway – turn the patient’s head to cerebral hypoxia which in turn results in to a side, use mouth gag. unconsciousness. However, the patient • Raise the foot end. recovers in 1-2 minutes because the • Mouth to mouth respiration to be given- sympathetic system gets activated and take 4 quick, deep breaths and then exhale reverses the symptoms. into the patient’s mouth. This has to be repeated 12 times per minute. Treatment: • As an alternative, bag mask may be used • Loosen tight clothing to facilitate brea- with 100% oxygen. thing. • External cardiac massage to be given at • Elevate feet to increase venous return. 60 chest compressions per minute. • Give cold compress to promote peripheral • 0.5ml of 1:1000 solution of adrenaline vasoconstriction and increase venous should be injected intravenously or in return. more severe cases intracardiac adrenaline • Oxygen inhalation may be given. injection may be needed. 400 Textbook of Pharmacology for Dental and Allied Health Sciences

• Medical assistance should be taken at the 5. Ischemic Heart Disease earliest possible. Ischemic heart diseases include angina and myocardial infarction. 4. Seizures Angina pectoris is the principle symptom of Patients can develop symptoms ranging from ischemic heart disease and is characterised brief lapses of awareness to generalized by sudden severe substernal pain or convulsions usually lasting for less than 5 discomfort which may radiate to the left minutes. shoulder or medial aspect of the left arm. It (i) If tonic clonic seizures start during a dental is precipitated by stress and anxiety. Most procedure: dental procedures are painful and may evoke some anxiety. Therefore during a dental • Remove instruments or dentures if procedure, IHD patients may experience an any from the oral cavity. episode of exertional angina or very rarely • Place a gag or a padded tongue develop myocardial infarction. depressor in the mouth between the 1. IHD patients should be taken up for early teeth. appointments in the morning and not • Turn the head to a side this keeps the made to wait. airway clear and prevents the tongue 2. Patients with known IHD should be asked from falling back. to carry their rescue medication i.e • If seizures continue, 10 mg diazepam nitroglycerine tablets for sublingual use should be given intravenously. to the dental clinic. In patients with • Whenever possible dental procedure moderate to severe angina, prophylactic may be postponed. nitroglycerine ( 0.5mg tab sublingually) • If the patient continues to have may be used 5 minutes before starting the seizures despite treatment, physician dental procedure. should be called and managed as 3. If a patient gets an acute episode of angina status epilepticus. ( see page 153) during a dental procedure. (ii) Absence seizures—There is sudden • Stop the dental procedure for a few impairment of consciousness associated minutes with starring. The patient stops all on- • Administer tab nitroglycerine 0.5mg going activities but recovers within a sublingually. It relieves pain in 2-5 few seconds. The episode lasts for a minutes. brief period, generally less than 30 • Monitor pulse and BP. seconds. It only requires reassurance. • If pain is not relieved in 8-10 minutes, Patient should be advised to see a nitroglycerine dose may be repeated. physician later. (maximum of 3 tablets in 15-20 minutes). (iii) Atonic seizures—also called drop Even then, if the pain does not sub- attacks are characterised by sudden loss side,there are chances that the patient of postural tone and the head may drop may be going into myocardial for a few seconds or the person may infarction. Immediate medical attention drop to the ground for no obvious should be sought. reasons. The patient recovers usually Myocardial Infarction within a few seconds and only requires reassurance particularly if the patient is Signs and symptoms – Severe substernal pain, already on treatment by a physician. radiating to the left shoulder, with nausea, Dental Pharmacology 401 vomiting, palpitation, and sweating, patient do not alter the size of RBCs (neither shrink appears pale and apprehensive. Patient nor swell). One litre of isotonic solution should be shifted to emergency care at the expands ECF by 1 litre. But it quickly diffuses earliest possible. While such arrangements into the ECF compartment and therefore are being done, injection pethidine 50 mg or around 3 litres of isotonic fluid is needed to morphine 10 mg should given intramuscularly. replenish volume of one litre of lost blood. Patient should be made to swallow a tablet However patients with hypertension and of aspirin 300 mg. Oxygen inhalation should cardiac failure need careful monitoring to be given if possible. For treatment see page avoid fluid overload. Isotonic solutions 108. include normal saline and lactated ringer solution. 6. Shock Normal saline solution – 0.9 % sodium chloride Treatment of shock is discussed in page 121. It is used in hyponatraemia. It should be Intravenous fluids are given in almost all the avoided in heart failure, pulmonary oedema different types of shock. Therefore a and renal impairment. knowledge of the different IV fluids available Lactated ringer solution contains potassium, is important. calcium and sodium chloride. It is used to correct dehydration, hyponatraemia and to Intravenous Fluids replace gastrointestinal fluids. Many other similar solutions are available with minor Intravenous fluids are sterile solutions meant changes in the electrolyte content. for intravenous administration. The content and quantity of solute varies. Intravenous Hypotonic fluids Hypotonic fluids replace fluids are used for replacement of fluid, cellular fluid because they are hypotonic as electrolytes and nutrition. There are compared to plasma. Half normal saline different types of IV fluids to be given (0.45% sodium chloride solution) is the depending on the patient’s requirements. commonly used hypotonic solution but other electrolyte solutions are also available. Types of IV Solutions Hypotonic sodium solution is used in hypernatraemia and other hyperosmolar Intravenous solutions are of 3 types conditions. Overdosage can result in depending on osmolality - isotonic, hypotonic intravascular fluid depletion, hypotension, or hypertonic. Fluids having an osmolality cellular edema and later cell damage. nearly equal to that of extracellular fluid (ECF) or if the electrolyte content (cations + Hypertonic fluids Five percent dextrose in anions) is nearly equal to 310 mEq/L – they normal saline or lactated ringer’s solution or are considered isotonic. in hypotonic solution has osmolality more Isotonic-electrolyte content = 310 mEq/L than ECF 45 to 50%. Dextrose solution may Hypotonic-electrolyte content < 250 mEq/L be administered in hypoglycaemia or to Hypertonic-electrolyte content > 375 supplement calories. Since these solutions are mEq/L strongly hypertonic, they should be injected (Plasma osmolality is nearly equal to 300 into central veins for rapid dilution. m mol / L. Osmolality of 10% dextrose is Hypertonic saline solutions draw water from 505 m mol / L.) the cells and the cells shrink. They should be Isotonic Fluids As isotonic fluids have an injected slowly and carefully to avoid ECF osmolality nearly equal to that of ECF, they volume overload. 402 Textbook of Pharmacology for Dental and Allied Health Sciences

7. Diabetic Ketoacidosis phosphate is also low, potassium biphosphate may be given to supplement both potassium May be precipitated by infection, stress or and phosphorus. trauma. It is more common in patients with Hyperglycemic, hyperosmolar, nonketotic, coma – insulin – dependent diabetes mellitus. Severe hyperglycaemia and glycosuria result Diabetic ketoacidosis is a medical emergency in severe dehydration and increased plasma and can be life threatening. Insulin deficiency osmolarity leading to coma and has a high results in severe hyperglycaemia (600 - mortality rate. The treatment is similar to 800mg/dl) and excessive production of ketoacidosis with correction of fluid and ketone bodies. electrolyte balance and plane insulin. Clinical features include metabolic acidosis, dehydration with loss of sodium 8. Acute Addisonian Crisis and potassium in the urine causing electrolyte Acute Addisonian crisis is an emergency imbalance, impaired consciousness and condition that could be precipitated by an hyperventilation – may proceed to coma. infection or sudden withdrawal of steroids Diabetic ketoacidosis should be suspected after long-term administration. Proper drug when the patient has IDDM, diabetes is history is therefore very important. If the uncontrolled, patient is under stress, or has patient has been on glucocorticoids like infection and develops the above signs and (prednisolone) for more than 2 weeks, it symptoms. should be continued. The dentist should make sure that the patient receives his dose Treatment of glucocorticoid on the day of dental procedure particularly if it is a major • Correction of hyperglycaemia – procedure. Symptoms include nausea, intravenous regular (plane) insulin 0.1U/kg vomiting, weakness, hypotension, bolus followed by 0.1 U/kg/hour by dehydration, hyponatraemia and hyper- continuous IV infusion till the patient kalaemia. Intravenous hydrocortisone recovers. Once the patient has fully hemisuccinate 100 mg bolus followed by recovered, insulin should be administered infusion 100 mg every 4-6 hours is given subcutaneously 30 minutes before stopping immediately. The dose may be repeated the infusion. depending on the patient’s condition. Once • Correction of dehydration – Fluid and the patient recovers, switch over to oral electrolyte replacement are important. preparations. Immediate correction of fluid Normal saline infusion 1 litre in the first hour and electrolyte balance is important. When and then 1 litre over the next 4 hours and acute adrenal insufficiency is not confirmed, then the quantity can be titrated based on dexamethasone (4mg IV) should be used in the severity of dehydration. place of hydrocortisone because • Correction of acidosis – Sodium dexamethasone does not interfere in the bicarbonate may be needed in some patients estimation of hydrocortisone levels for with severe acidosis. diagnosis. • Potassium – Rapid correction of hyperglycaemia may result in the movement 9. Tetany of potassium into the cells resulting in Tetany is due to hypocalcaemia (Page 373): hypokalemia. 10-20 mEq/hour potassium Other features of hypocalcaemia include chloride is added to the drip. When serum muscle cramps, paraesthesias, laryngospasm Dental Pharmacology 403 and in more severe cases – convulsions. Slow selves, the stress or anxiety due to them or intravenous injection of 5-20ml of 10% calcium the drugs and materials used in such gluconate relieves tetany. Care should be procedures. A known asthmatic patient taken to inject calcium slowly because rapid should be told to attend the clinic with intravenous injection of calcium can cause bronchodilator inhaler which the patient has cardiac arrhythmias which can be fatal. been taking - preferably salbutamol. An acute attack should be treated with 1-2 puffs of 100- 10. Status Asthmatics 200 μg salbutamol (Page 215). An acute attack of bronchial asthma may be Acute severe asthma or status asthmatics precipitated by dental procedures them- needs immediate treatment (See Page 219). Appendices 405

Appendices

 APPENDIX-1—IMPORTANT DRUG INTERACTIONS  APPENDIX-2—PRESCRIPTION WRITING

APPENDIX-1

IMPORTANT DRUG INTERACTIONS

Interacting drugs Consequence Pharmacological basis 1. β-blockers + ↑↑↑ β blocking effect ↓↓↓ metabolism of hydralazine/frusemide propranolol 2. β-blockers + insulin i. β-blockers mask palpi- • Blockade of cardiac tation, the most important β receptors warning symptom of hypoglycaemia ii. They prolong recovery • Block hepatic glycogenolysis β from hypoglycaemia mediated by 2 receptors; homoeostatic mechanisms are blocked 3. Propranolol ↑↑↑ BP As β receptors are blocked, + ephedrine unopposed stimulation of α receptors by ephedrine elevates BP 4. Propranolol May cause heart block Both drugs depress conducting + verapamil resulting in cardiac arrest tissues of the heart and have negative inotropic effects 5. Calcium channel blockers ↓↓↓ effects of calcium Both increase metabolism + phenytoin/rifampicin channel blockers of calcium channel blockers by enzyme induction 6. Digoxin + Digoxin toxicity Thiazides cause hypokalaemia hydrochlorothiazide which in turn aggravates digoxin toxicity 7. Digoxin + quinidine Digoxin toxicity Quinidine displaces digoxin from tissue binding sites and inhibits digoxin excretion 8. Digoxin + antacids/ ↓↓↓ bioavailability Reduce absorption sucralfate/metoclopramide of digoxin of digoxin Contd... 406 Textbook of Pharmacology for Dental and Allied Health Sciences

Contd...

Interacting drugs Consequence Pharmacological basis 9. Bile acid-binding resins ↓↓↓ bioavailability Bind and prevent + Frusemide/ absorption of orally thiazides/thyroid hormones administered drugs 10. Anticoagulants Anticoagulant toxicity Inhibit anticoagulant + phenylbutazone metabolism 11. Warfarin + aspirin i. Anticoagulant toxicity • Aspirin displaces warfarin from binding sites ii. Bleeding from aspirin • Inhibition of platelet aggre- induced peptic ulcer gation by aspirin potentiates anticoagulant effect • Aspirin induced gastric erosion and ulcers may bleed more due to anticoagulant effects 12. Alcohol + disulfiram Antabuse reaction Disulfiram inhibits aldehyde Other drugs that produce dehydrogenase resulting in disulfiram like effects accumulation of acetaldehyde cephalosporins, metronidazole, sulfonylureas 13. Alcohol + CNS depressants Profound CNS depression CNS depressant effect like opioids/antidepressants gets added up /antihistamines/hypnotics 14. Carbamazepine + Decreased efficacy Carbamazepine is an haloperidol/oral contra- of interacting drugs enzyme inducer—enhances ceptives/corticosteroids metabolism of interacting drugs 15. Carbamazepine + Decreased carbamazepine Inhibition of drug metabolising cimetidine/erythromycin/ metabolism enzymes by interacting drugs INH/ketoconazole 16. Phenytoin Decreased effects Phenytoin and carbamazepine + carbamazepine of both increase each other’s metabolism 17. Phenytoin + chloramphe- Phenytoin toxicity The interacting drugs inhibit nicol/cimetidine/warfarin phenytoin metabolism 18. Phenytoin + steroids/ Phenytoin increases meta- Phenytoin is an enzyme inducer doxycycline/theophylline bolism of interacting drugs 19. Barbiturates + other Profound CNS depression CNS depression gets added up CNS depressants 20. Barbiturates + calcium Decreased efficacy Barbiturates are enzyme channel blockers/cortico- of interacting drugs inducers. They enhance the steroids/ketoconazole/ metabolism of interacting drugs oestrogen/chloramphenicol/ tricyclic antidepressants Contd... Appendices 407

Contd...

Interacting drugs Consequence Pharmacological basis 21. Tricyclic and related Increased metabolism Carbamazepine and rifampicin antidepressants + of antidepressants are enzyme inducers carbamazapine/rifampicin 22. Tricyclic antidepressants Decreased metabolism of SSRIs inhibit metabolising + SSRIs like fluoxetine and antidepressants enzymes paroxetine 23. Tricyclic antidepressants + Hypertensive crisis Uninhibited action of MAO inhibitors catecholamines due to inhibition of MAO 24. Levodopa + Decreased anti- Phenothiazines block phenothiazines parkinsonian effect dopamine receptors 25. Levodopa + Inhibits antiparkinsonian Pyridoxine enhances peripheral pyridoxine effect decarboxylation of levodopa 26. Lithium + diuretics Lithium toxicity Decreased excretion of lithium 27. NSAIDs + frusemide Blunting of diuretic effect PG inhibition may result in salt and water retention 28. Aspirin + warfarin/ Toxicity of co-administered Aspirin displaces these drugs phenytoin/ sulfonylureas drugs from protein binding sites 29. Quinolone antibiotics ↓↓↓ bioavailability Reduced gastrointestinal + sucralfate/antacids absorption of quinolones 30. Quinolones + Toxicity due to Quinolones inhibit the metabo- theophylline/caffeine theophylline/caffeine lism of theophylline/caffeine 31. Chloramphenicol + Toxicity due to Chloramphenicol decreases phenytoin/sulfonylureas phenytoin/sulfonylureas metabolism of these drugs 32. Rifampicin + oestrogens/ Therapeutic failure Rifampicin is an enzyme inducer corticosteroids/sulfonylureas/ and increases the metabolism theophylline of other drugs 33. Antacids + quinolones/ ↓↓↓ bioavailability Antacids may adsorb drugs and salicylates/tetracycline reduce their absorption 34. Antacids + sucralfate Therapeutic failure of Sucralfate acts in acidic pH sucralfate while antacids make the gastric pH alkaline 35. Allopurinol + 6-mercaptopurine Allopurinol inhibits xanthine 6-mercaptopurine toxicity oxidase which metabolises 6-mercaptopurine 36. Piperazine Therapeutic failure Piperazine causes hyperpolari- citrate + pyrantel zation while pyrantel causes pamoate depolarization. They antagonise each others effects 408 Textbook of Pharmacology for Dental and Allied Health Sciences

APPENDIX-2

PRESCRIPTION WRITING The Prescription is a written order by a physician to the pharmacist to prepare and/or dispense specific medication for a specific patient. A specific pattern should be followed in writing prescriptions, in order to avoid errors and to safeguard the interests of the patient. Moreover the fact that it is a medicolegal document makes it all the more important to be accurate and precise. The following points should be remembered in writing a prescription: 1. The writing should be legible. 2. Indelible ink should be used in writing. 3. Abbreviations should be avoided. 4. In writing quantities—decimals should be avoided; when inevitable, zero should be used— 0.1 for .1. 5. Less than 1 gm—should be written as milligrams, e.g. 200 mg and not 0.2 g. No abbreviation should be used for micrograms and units. 6. Blank space should be avoided between direction and the signature of the doctor. If blank space is present, it should be striked off to avoid misuse of the space to obtain drugs illegally.

PARTS OF THE PRESCRIPTION 1. Date of writing the prescription. 2. Address of the prescriber—preferrably prescriptions are written on the letter pad with doctor’s name and address printed at the top. 3. Name, age, sex and address of the patient. 4. Superscription—the symbol  meaning ‘take thou’ is also considered as an invocation to the Greek gods of healing—Jupitor and Horus. 5. Drug name and strength. This is the body of the prescription—also called inscription. Abbreviations should never be used. 6. Directions to the pharmacist (subscription)—consists of instructions for compounding if any and the quantity to be supplied. 7. Directions to the patient—should be clear and should indicate the quantity, frequency, time, route of administration and other information relevant to the preparation. If a drug is meant only for external application or needs to be shaken well or mixed before using—such instructions should be mentioned. 8. Signature of the prescriber—the prescriber should sign along with registration number.

TYPES OF PRESCRIPTIONS 1. Precompounded prescription orders for a drug manufactured by a pharmaceutical company, has a trade name and is available for use. 2. Compounded or extemporaneous prescription the physician directs the pharmacist to compound a preparation. The ingredients, their quantity and the form of preparation (like mixture, powder or ointment) is chosen by the physician and instructed accordingly. Appendices 409

MODEL PRESCRIPTION

Dr Vaidya July 10, 2007 Highland Mangalore Tel No.______

Ramu Male Age: 35 years No. 7, Kankanady Mangalore

 Tab Roxithromycin 150 mg Dispense 10 tablets Label—Take 1 tab orally twice a day, 30 minutes before food.

Signature

Regn. No. SOME COMMONLY USED LATIN ABBREVIATIONS IN PRESCRIPTIONS

Abbreviation Latin derivation Meaning in English o.d. onus in die once a day b.d. bis in die twice a day b.i.d. bis in die twice a day t.i.d. ter in die three times a day t.d.s. ter die sumendum three times a day q.i.d. quarter in die four times a day h.s. hora somni at bed time stat statim at once s.o.s. si opus sit if necessary q.s. quantum sufficit A sufficient amount p.o./po per os by mouth ung unguentum ointment caps capsula capsules Tab Tabella Tablet a.c. ante cibum before food Dental Pharmacology 411