Table Of ContentA. 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
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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.
