Advances in Nitrate Therapy PDF
Preview Advances in Nitrate Therapy
A. Schneeweiss M. Weiss Advances in Nitrate Therapy Second, Revised and Enlarged Edition Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Hong Kong Barcelona Adam Schnee weiss, M D 9, Kehilat Sofia Street Tel Aviv 69018, Israel Marija Weiss, DSc Arenzhofstrasse 28 5000 KOln 71, FRO ISBN-13: 978-3-642-75836-2 e-ISBN-13: 978-3-642-75834-8 DOl: 10.1007/978-3-642-75834-8 Library of Congress Cataloging-in-Publication Data Schneeweiss, Adam. Advances in nitrate therapy / A. Schneeweiss, M. Weiss. - 2nd rev. and en!. ed. Includes bibliographical references. ISBN 0-387-52798-2 1. Nitrates - Therapeutic use. 2. Angina pectoris - Chemotherapy. 1. Weiss, M. (Marija) II. Title. RC685.A6S36 1990 616.1 '22061 - dc20 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, re-use of illustrations, recitation, broadcasting, reproduction on microfilms or in other ways, and storage in data banks. Duplication of this publication or parts thereof is only permitted under the provisions of the German Copyright Law of September 9, 1965, in its current version, and a copyright fee must always be paid. Violations fall under the prosecution act of the German Copyright Law. © Springer-Verlag Berlin Heidelberg 1988 and 1990 Softcover reprint of the hardcover 1s t edition 1990 The use of registered names, trademarks, etc. in the publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product Liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. 2127/3140 - 543210 - Printed on acid-free paper Contents A. Introduction and Mechanism 1. Introduction ............... . 3 2. The Mechanism of Action of Nitrates at the Cellular Level 6 B. Indications 3. Stable Angina Pectoris . . . . . . . . . . . . . . . . 11 4. The Mechanism of Action of Nitrates in Angina Pectoris .. . . . . . . . . . . . . . . . . . . . . . . 14 5. Nitrates Compared and Combined with Other Antianginal Drugs . . . . . . . . . . . . . . . . . . 24 6. Unstable Angina Pectoris . . . . . . . . . . . . . 38 7. Long-Term Use of Nitrates in Angina Pectoris 43 8. Silent Ischemia . . . . . . . . . 53 9. Acute Myocardial Infarction ........... 55 10. Congestive Heart Failure ............. 64 11. Congestive Heart Failure and Valvular Diseases 70 12. Long-Term Nitrate Therapy in Congestive Heart Failure. . . . . . . . . . . . . . . . . . . . . . . . . 73 13. Nitrates Combined and Compared with Other Drugs in Congestive Heart Failure . . . . . . . . 77 14. Systemic Hypertension, Arrhythmias and Cardiac Surgery .......................... 84 15. Pulmonary, Abdominal, and Peripheral Vascular Effects. . . . . . . . . . . . . . . . . . . . . . . . 88 16. Non-Cardiovascular Indications for Nitrates 92 17. Nitrates in Children and the Elderly. . . . . . 94 VI Contents C. Nitrate Formulations and Routes of Administration 18. Sublingual Tablets and Oral Spray ..... 101 19. Intravenous Administration of Nitrates .. 109 20. Intracoronary Administration of Nitrates. 111 21. Oral Administration of Nitrates .... .. 115 22. Mononitrates ................ . 118 23. Transdermal Administration of Nitrates 130 24. Buccal Nitroglycerin ........... . 151 D. Pharmacology 25. Clinical Pharmacology ..... . . . 155 26. Side Effects and Drug Interactions 166 27. Dosage and Administration 173 E. Conclusions 179 References . . . 181 A. Introduction and Mechanism 1. Introduction Nitrates have been for many years the cornerstone of cardiovascular therapy for various indications. Not only have nitrates stood the test of time for treatment of chronic stable angina pectoris, but the indications for them have markedly ex panded. They now include all forms of angina pectoris and myocardial ischemia, congestive heart failure and hypertensive emergencies. The beneficial effects of nitrates in all these conditions result from their vasodilatory properties, but it is still unclear whether the central or peripheral effects predominate in the thera peutic mechanism. Recently nitrates have been shown to fulfill the most important requirement for each and every drug - to reduce mortality. A large scale study revealed that isosorbide dinitrate, combined with hydralazine, reduced long-term mortality by 28% in patients with congestive heart failure. This finding will certainly stimulate research on nitrates, and it might be expected that interest in these drugs will markedly increase. The primarily used nitrates in clinical practice are nitroglycerin and the com plex organic nitrates, mainly isosorbide dinitrate. The organic mononitrates are now under clinical investigation, and isosorbide-5-mononitrate (IS-5-MN) appears to be especially promising. All investigators agree upon the short-term efficacy of nitrates in relief of angina pectoris and hemodynamic disturbances. Some investigators, however, claim that long-term administration of nitrates is associated with the develop ment of tolerance. This claim is not only controversial scientifically but has not stood the test of clinical practice. Every clinician can tell from his own experience that nitrates are effective over many years of treatment. Certain techniques may, however, improve the long-term efficacy of nitrates. These include the use oflow doses, eccentric dQsing and nitrate-free intervals. The expanding indications for nitrates and the increasing number of those receiving them have stimulated efforts to improve and simplify delivery of these agents. Among the most promising new delivery systems are the transdermal devices which supply a constant plasma level of nitrates throughout 24 h. It has been claimed that this constant level may be associated with early development of tolerance. One of the solutions suggested is treatment for about 16 h during daytime, with removal of the transdermal devices during the night. However, the possibility of tolerance developing to transdermally administered nitrates is still controversial, as it has been reported for only some of the available formulations. 4 Introduction Another new and important delivery system is the oral spray of isosorbide dini trate (ISDN) or nitroglycerin. The most rapid conventional route of adminis tration of nitrates to ambulatory patients is sublingual administration of tablets. Absorption of nitrates starts after dissolution of the tablet - a process which takes time and limits the rapidity of effect. The oral spray avoids this delay and also allows more rapid and convenient administration by medical personnel. Other exciting fields of investigation are the mechanism of action at the molecular level and new indications such as secondary prevention after acute myocardial infarc tion. An important new line of research is differential selectivity of the various nitrates. Generalized vasodilation is not always optimal, and in certain important indications selective vasodilation is preferred. For example, in patients with ischemic heart disease and angina pectoris or acute myocardial infarction venodi lation and coronary dilation are definitely beneficial. However, arteriolar dilation might be deleterious if it results in an excessive reduction of coronary perfusion pressure. Hence those nitrates which preferentially dilate the venous more than the arterial bed might be superior to other nitrates in these conditions. Prelimi nary data suggest that IS-5-MN might have such a therapeutic profile. The same rationale also applies to congestive heart failure, where venodilation is now considered to be the primary therapeutic effect. Thus about 100 years after the use of nitrates began, they are not only among the most important cardioactive agents, but also a group of agents undergoing dynamic and continuous investigation. It is the purpose of this book to describe the state of the art in the field, to report current fields of progress and to indicate some points which will require research in the future. Nitroglycerin, isosorbide dinitrate and isosorbide mononi trate are discussed in detail. Some new and investigational nitrates are briefly reviewed. 1.1. History Nitroglycerin was the first nitrate to be used in therapy. It was synthesized by Sobreto in 1846. Sublingual nitroglycerin has been available for about 140 years. Even in its early days it was noted that sublingual nitroglycerin can cause severe headache. Soon after its synthesis, attempts were made to use nitroglycerin for angina pectoris, with little success. Amyl nitrite was then considered to be more effective than nitroglycerin for this indication. However, the problems inherent in the use of amyl nitrite, including the unpredictable dose-response relationship and the very short duration of action, resulted in a search for other agents and increased interest in nitroglycerin. About 100 years ago sublingual nitroglycerin was established as a standard agent for relief of pain in patients with angina pectoris. In those early days it was also considered effective for angina prophy laxis. The other organic nitrates such as ISDN, erythrityl tetranitrate, pentaerythritol tetranitrate and manito! hexanitrate were developed and introduced into clinical practice when it was realized that the effect of sublingual nitroglycerin is short- Introduction 5 lasting and that the effect of oral nitroglycerin is limited and unpredictable. Later, when the pharmacokinetic profile of the various nitrates was better understood and the therapeutic requirements in different cardiovascular diseases were better defined, new agents, such as the mononitrates, were developed and studied. All these agents are nitrate esters or nitrite esters, characterized by a sequence of carbon-oxygen-nitrogen, which is essential for vasodilator properties. There fore nitroglycerin is actually not a nitro compound and the name glyceryl trini trate may be preferred. The organic nitrites, such as amyl nitrite, are esters of nitrous acid (NO), and the organic nitrates are esters of nitric acid (N02)' The use of organic nitrates in prophylactic clinical practice has largely been delayed by a conclusion made by a group of investigators and reported first in 1972 and repeated thereafter. Needleman and coworkers [1] reported that orally administered organic nitrates were ineffective because of complete first-pass hepatic metabolism. Based on this thesis the use of long-acting organic nitrates declined markedly. It took almost a decade until the pharmacokinetic and phar macodynamic profiles of ISDN and its metabolites were fully understood. Only then was it possible for Needleman's thesis to be rejected on a strong scientific basis. 2. The Mechanism of Action of Nitrates at the Cellular Level Nitrates are considered "direct-acting" vasodilators. Their effect is not mediated by a neurohumoral mechanism involving the adrenergic system, the renin-angio tensin system or other vasodilatory mechanisms. Although it has been suggested that some of the dilatory effect of nitrates is exerted by the release of vasodilating prostaglandins, most investigators believe that this is not the main mechanism of action. Thus it is generally accepted that nitrates act directly, at the cellular level, in vascular smooth muscle. The fundamental biochemical mechanisms of action of nitrates have been extensively studied in the past two decades. Almost all studies have been per formed with nitroglycerin. One of the most important achievements in the field was the study by Needleman et al [2], who observed that incubation of aortic strips with ethacrynic acid, which is a sulfhydryl alkylating agent, resulted in a decrease in sensitivity to nitroglycerin. These investigators also suggested that tolerance to nitroglycerin could be induced by oxidation of sulfhydryl groups with the formation of bisulfide [3]. These findings support the view that the direct vasodilator action of nitroglycerin is mediated by sulfhydryl groups on the membrane of vascular smooth muscle. According to this theory the sulfhydryl group is the essential component of receptors to nitrates in cell membrane. Interaction between nitrates and sulfhy dryl groups results in reversible oxidation of these groups, with formation of a disulfide group. This group has a low affinity for nitrates. Interaction of nitroglyc erin with the sulfhydryl groups forms 5-nitrosothiol groups, which activate the enzyme guanylate cyclase [4]. Activation of this enzyme results in an increase in intracellular concentrations of guanosine 3-monophosphate (cyclic GMP). This has recently been shown in aortic preparations, in vivo and in vitro with nitro glycerin, ISDN and even IS-5-MN. Recently Horowitz et al [5] reported a study evaluating whether the availability of sulfhydryl groups modulates responsiveness to nitroglycerin. As S-nitrosocys teine is the S-nitrosothiol most effective in stimulating guanylate cyclase activa tion, the investigators evaluated whether the availability of this compound affects the hemodynamic response to nitroglycerin in patients undergoing cardiac cathe terization. The hemodynamic response was measured before and after infusion of N-acety\cysteine, which is a source of cysteine. The N-acety\cysteine potentiated the vasodilator effect of nitroglycerin. This finding supports the theory that the availability of sulfhydryl groups determines the responsiveness to nitroglycerin.
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