Nitroglycerin and long-acting nitrates in clinical practice

Nitroglycerin and Long-Acting Nitrates in Clinical Practice

JONATHAN ABRAM,

M.D.

Albuquerque, New Mexico

From the Cardiology Division, Department of Medicine. he University of New Mexico School of Medicine. Albuquerque. New Mexico. Requests for reprints should be addressed to Dr. Jonathan Abrams, Cardiology Division, Department of Medicine,the ulllversity of New Mexico School of Medicine. Albuquerque, New Mexico 87 13 1.

Nitrates are potent relaxers of vascular smooth muscle and act by dilating veins, arteries, and arterioles (especially at hfgh doses). Their cllnkal effects have been co&dared to be dominantly related to peripheral actions: systemic venodilatation and a decrease In systemk vascular resktance, reducing the prekad and afterload of the heart. Considerable experimental work conflrms potent salutary effects on the coronary clrculatkn. These drugs are readily absorbed across mucoeal surfaces; they are avallable in muttlple formulations, including sufAkgual, buccal, oral, and topical delivery systems. Nltrate admintstratlon should begin wtth low doses and increased to doses that are often hlgher than previously recommended until a specific clinical end point or llmltlng side effects occur. Organic nitrate esters are effective in the treatment of stable angina pectorls, unstable angina, coronary vasospastk syndromes, and in vasodilator therapy in severe congestive heart failure. The pathophystokgy of these syndromes is reviewed with respect to the clinical actkns of nitrates on the central and peripheral circulations. The side effects of nitrates include headache, dizziness, and nausea. Nltrate tolerance, a controversial subject, does not appear to be an important clinical problem. Ustng the guidelines presented in this review, nitrate therapy provides effective, inexpensive, well-tolerated therapy for many patients wlth cardiovascular dlsease. The use of nitroglycerin and organic nitrate esters for the treatment of angina pectoris represents the oldest form of therapy in ischemic heart disease. Nitroglycerin, first synthesized by Sobrero in 1847 and used initially in explosives manufactured by the Swedish engineer Alfred Nobel, was successfully given to a patient with severe angina pectoris in 1879 by the distinguished English physician William Murrell [ 11. Murrell was well aware of the pioneering clinical experiments of Sir lauder Brunton [2], who first employed amyl nitrite in patients with angina and reported his results in 1857. Subsequently, various nitrates were used in the clinical treatment of angina and hypertension in Europe as well as the United States. Organic nitrate esters such as mannitol hexanitrate, erythrityl tetranitrate, and pentaerythrityl tetranitrate were widely employed as hypertensive therapy by the mid-third of the 20th century. During the 1970s and 1980s the use of nitrates was extended to a number of cardiovascular syndromes in addition to angina pectoris, including congestive heart failure and acute myocardial infarction. A

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remarkable variety of nitrate formulations are now available, including intravenous nitroglycerin and two new innovative “delivery systems,” transmucosal or buccal nitroglycerin and the transdermal nitroglycerin discs. In this discussion I will review the physiology and pharmacology of nitroglycerin and organic nitrates, and will focus on the clinical situations in which nitrate therapy is indicated. Appropriate guidelines and precautions regarding nitrate administration will be given and recommendations made for proper dosing with respect to the route of administration. PHYSIOLOGY

OF NITRATES

All nitrates act by inducing smooth muscle relaxation in vascular tissues, resulting in vasodilatatlon of arteries and veins. Nitroglycerin and nitrate esters are directacting vasodilators. The precise mechanism of vascular relaxation is not well understood. It has been proposed that nitroglycerin acts by combining with sulfhydryl groups on nitrate receptors in vascular smooth muscle [3]. A recent preliminary study demonstrated that in dogs, administration of an agent that increases sulfhydry1 availability resufted in markedly increased vascular sensitivity to infused nitroglycerin [4]. lgnarro et al [5] have suggested that nitrates act by inducing S-nitrosothiol production in blood vessels with a subsequent increase in cellular cyclic GMP as the mode of vasodilation. Finally, there is some evidence that nitroglycerin (and other vasodilators, such as nitroprusside) may act in part through the prostaglandin system, inducing a release of prostacyclin from vessel walls and suppressing platelet thromboxane A2 production [6-81. Nitrates are potent dilators of large (conductance) arteries, and even at low doses cause an increase in arterial compliance. At high concentrations nitroglycerin induces a relaxation of arterioles (resistance vessels) and a fall in systemic vascular resistance may result [ 91. Standard doses of sublingual nitroglycerin produce greater epicardial coronary artery dilatation than nifedipine [lo]. large doses may result in vasodilatation of the intramyocardial arterioles responsible for coronary vascular resistance. This may be clinically important in some patients with angina [ 111. The effects of nitroglycerin compounds on the veins are well known. Many investigators believe that systemic venodilatation and the subsequent reduction in venous return to the heart, resulting in decreased left ventricular size and pressure (preload), is the dominant mechanism of action by which nitroglycerin relieves angina1 pain [ 12,131. The venodilating effects of nitroglycerin are seen at low doses and do not usually increase further at higher plasma concentrations [9,141. Both the preload and afterload reducing properties of nitrates are critical to their efficacy as vasodilators

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in congestive heart failure. In persons with relatively normal left ventricular function, nitrates may trigger considerable reflex tachycardia and an increase in cardiac contractile state as a result of sympathetic discharge caused by nitrate-induced hypotension. In the normal heart, nitroglycerin causes a decrease in stroke volume, but in congestive heart failure stroke volume is usually preserved or even increases modestly [ 151; it is unusual for hypotension or tachycardia to develop in such patients after nitroglycerin. Nitrates dilate pulmonary arteries and veins, and invariably reduce right atrial, pulmonary artery, and pulmonary capillary wedge pressures. Reflex sympathetic activity results in predominant vasoconstriction of the splanchnic circulation. Renal blood flow is related to arterial pressure and may decline if nitroglycerin causes a fall in systemic blood pressure. Nitrates dilate cerebral vessels and modestly dilate the cutaneous circulation. Mechanisms of Angina Relief. Although nitroglycerin’s peripheral effects on the veins and larger arteries have been emphasized over the past 10 to 15 years as the primary mechanism for relief of angina1 pain (via a decrease in myocardial oxygen requirements), there is suggestive evidence that nitrates have important direct effects on the coronary circulation and myocardial perfusion during myocardial ischemia. Nitroglycerin has been shown to dilate normal and diseased coronary arteries, as well as the actual vessel stenosis itself [ 16,171. Blood flow to coronary collateral vessels increases after nitroglycerin [ 181. During ischemia it has been shown that nitroglycerin increases flow to ischemic zones of myocardium [ 191, redistributing flow to the subendocardium and helping to restore the normal 1: 1 relationship of endocardial and epicardial blood flow. Although nitroglycerin results in an overall decrease in global coronary perfusion, regional myocardial flow may increase during myocardial ischemia. In addition, nitrates are very effective in reversing coronary artery spasm and decreasing coronary artery tone. Thus, these drugs are effective in angina resulting from an increase in myocardial oxygen requirements with a “fixed” or limited blood supply (secondary angina), and they may also be efficacious when an acute reduction in blood supply (for example, spasm) is the precipitating factor in the production of angina (primary angina). In summary, the actions of nitroglycerin in angina are complex and may vary from patient to patient, depending on the underlying pathophysiologic factors. McGregor has elegantly discussed this subject previously [ 111 and in this Symposium issue. He has stressed that nitroglycerin may relieve ischemia by decreasing myocardial oxygen demands; alleviating the compressive effect of elevated left ventricular diastolic pressure on intramyocardial flow to the subendocar-

NITFOGLYCERIN SYMF’OSIUM-ABRAMS

dium; reversing coronary vasospasm (large vessel); decreasing coronary arteriolar resistance; and improving regional blood flow. The direct vasodilating actions on normal, diseased, and collateral coronary arteries have been well demonstrated in the studies of Conti et al [ 161 and Brown et al [ 171. They are also reviewed elsewhere in this Symposium issue. PHARMACOLOGY OF NITRATES Nitroglycerin and organic nitrate esters are rapidly absorbed from the sublingual and intestinal mucosa and readily pass across the layers of the skin. Nitrate metabolism in the liver is extensive: nitroglycerin and its congeners are also taken up directly by vascular tissues, where nitrate phannacokinetics are slower than that in the blood 1201. The enzyme hepatic glutathione organic nitrate reductase has been the subject of much controversy as it relates to the systemic availability of active nitrate following oral administration [21]. Experiments in rats carried out by Needleman et al [22] demonstrated that organic nitrate esters administered directly into the portal vein are so completely metabolized by hepatic enzyme activity that the parent compound does not appear in the systemic circulation. Although this work suggested that oral nitrate administration in humans would be of no clinical value, subsequent investigations have clearly demonstrated adequate concentrations of the parent nitrate compound in the arterial and venous circulation after oral dosing; clinical studies have documented persistent efficacy of orally administered nitrates for many hours [21,23]. The demonstration of therapeutic nitrate plasma levels following oral dosing is consistent with these studies ]24]. There is an arteriovenous nitroglycerin gradient across the pulmonary and systemic circulations when nitroglycerin is assayed in arterial and venous plasma [25]. This suggests that nitroglycerin is taken up actively by smooth muscle in blood vessels, particularly the veins. Fung et al [26] have estimated that the plasma nitrate concentration represents only 1 percent of the total body nitrate pool. NITRATE DELIVERY SYSTEMS The rapidity of onset and the duration of activity of any nitrate is directly related to the method of administration (Figure 1 and Table I). Delayed-action oral formulations are available for nitroglycerin and isosorbide dinitrate. The new transdermal systems utilize nitroglycerin in some form of silicone matrix that allows a constant and predictable release of nitroglycerin across the skin for as long as 24 hours. Buccal nitroglycerin consists of active nitroglycerin enmeshed in a modified cellulose matrix.

Sublingual Nitroglycerin and lsosorbide Dinitrate. Sublingually administered nitroglycerin is the “gold standard” by which all antianginal therapies are assessed. The onset of action is within one to three minutes, with peak activity occurring at two to 10 minutes. Sublingual nitroglycerin may demonstrate persistent effects for up to 15 to 20 minutes; it is no longer active by 30 minutes. Sublingual isosorbide dinitrate has a somewhat longer onset of action with maximal effectiveness as early as 10 minutes. This formulation has a more sustained duration of activity than sublingual nitroglycerin, and in some studies activity has been shown for several hours. Buccal Nitroglycerin 127,281. The onset of hemodynamic activity following buccal nitroglycerin administration appears to be as rapid as sublingual nitroglycerin, that is, within two to three minutes. Peak effects are seen by 10 minutes. Duration of activity is related to the length of time the intact tablet remains in the buccal cavity. A gel-like seal forms around the tablet and the nitroglycerin is slowly absorbed across the mucosal membrane at a constant rate. The average patient can maintain the tablet in the mouth for three to five hours, occasionally longer. Patients quickly learn to control the rate of dissolution, and they are generally able to drink, eat, and talk without disturbing the buccal tablet. Oral Nitroglycerin and lsosorbide Dinitrate. These formulations generally have a slow onset of action, with peak effects seen at 60 to 90 minutes, and a duration of action from three to six hours. The larger the administered oral dose, the longer the nitrate effects persist. Despite the admonitions of Needleman and others, oral nitrates are clearly effective and bioavailable, providing sustained pharmacologic and physiologic effects when sufficient quantities are administered. High dose therapy with oral nitrates is mandatory for many patients. The Food and Drug Administration still considers oral nitrates as being only “possible effective,” and the recommended dosage of oral nitrates listed in package inserts and advertisements are inadequate for many persons [ 291. Topical Nitroglycerin. Nitroglycerin ointment has been available for many years, but only in the past seven or eight years has this formulation been subjected to rigorous clinical investigations in both heart failure and angina pectoris. The ointment represents a most effective way of administering nitroglycerin; the onset of action occurs within 60 minutes, and the duration of activity is prolonged for at least four hours and as long as eight hours in some studies [ 301. There is considerable variation in the way the ointment is applied, and absorption from different skin sites is variable [ 3 11. It is doubtful that these factors have any clinical significance.

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NITROGLYCERIN SYMPOSIUM-ASRAMS

SUBLINGUAL h

_AL

(_-Ted

I

I

2

3

4

I

1

5

6

HOURS

TABLE I

Dosage and Klnellcs of Nitroglycerin and Long-Acting Nltrates

OnselofActkm

(Mhutes)

Mkatlon SublingualNTG

0.3-0.8 2.5-10 l-3 lo-60 6.5-19.5 40-80 l&2 inches

Sublingual ISDN Buccal NTG Oral ISDN Oral NTG Oral PET NTG ointment (2%) NTG discs (transdermal)

5-10

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Peak Action

Durellos

OMmW

(MMes/hourr)

2-5 5-20 2-5 15-45 20-45 60 15-60

4-8 15-60 4-10 45-120 45-120 60-120 30-120

lo-30 Minutes 45- 120 Minutes 30-300 Minutest 2-6 tiourst 2-6 Houst 3-6 Hours 3-8 Hours

30-60

60-180

Up to 24 hours

NTG = nitroglycerin; ISDN = isosorbide dinitrate; PET = pentaerYttIrityl tetranitrate. ’ Up to three to four hours in some studies. t Effect persists so long as tablet is intact. t Some short-term dosing studies have demonstrated effects to eight hours.

88

FIgwe 7. Nitrate delivery systems. This schematic demonstrates the average time to onset and duration of action for the various nitrate formulations. Note that sublingual, buccal, and intravenous nitroglycerin have extremely rapid onsets of effectiveness (within minutes). The long-acting formulations, including oral and topical preparations, have a long duration of activity but do not reach peak effects until 60 minutes or later. Oral, ointment, and buccal formufations require multiple daily doses, whereas the new transdermal (disc) systems theoretically last for up to 24 bows after the application of a single dose. (See text for details.)

l

NITROGLYCERIN

The nitroglycerin discs (transdermal systems) represent an innovative attempt to produce truly sustained nitrate plasma levels. These preparations provide 24 hours of nitroglycerin delivered at a constant rate. The onset of action is slow, with peak effects occurring at one to two hours. Few clinical studies are available as of this writing documenting that these agents provide clinical benefit in angina or heart failure for a full 24 hours [32]. Several investigations are promising [33,34]. Some preliminary studies (unpublished) suggest that the duration of effect may be less than 24 hours and that the maximal clinical effect is relatively small when the smallest dose units are used. This probably relates to low plasma levels of nitroglycerin, as confirmed by the pharmaceutical companies that manufacture the discs. It is likely that larger amounts of nitroglycerin must be made available, requiring a greater surface area for nitroglycerin absorption across the skin, Higher dose preparations may be desirable in many patients. Intravenous Nitroglycerin. This formulation of nitroglycerin is now commercially available in the United States. Dosage administration has been a problem because of nitroglycerin absorption onto plastic, but special tubing systems are now commercially available to minimize this problem. Intravenous nitroglycerin is indicated in acutely ill hospitalized patients who require nitrate therapy; it is efficacious in various conditions such as complicated myocardial infarction, unstable angina, coronary vasospasm, pulmonary edema, and hypertension during neurosurgical or coronary bypass surgery. Although many believe that intravenous nitroglycerin has less arterial dilating action than nitroprusside, this may well be a dose-dependent phenomenon; at high concentrations intravenous nitroglycerin is a potent arterial vasodilator. Other Nltrates. Little clinical data are available on pentaerythrityl tetranitrate although this preparation is probably bioactive if enough is given. In West Germany a metabolite of isosorbide dinitrate, 5isosorbide mononitrate, is commercially available. Intravenous and ointment formulations of isosorbide dinitrate are used in Europe and may soon be available in the United States. CLINICAL INDICATIONS FOR LONG-ACTING NITRATES IN ANGINA PECTORIS The use of nitrates in the medical therapy of angina pectoris remains the most important indication for these drugs. Despite the wide variety of beta blocking drugs now available and the recent release of three calcium antagonists in the United States, nitrate therapy remains the first line of therapy of the uncomplicated patient with angina. Nitroglycerin is effective in the majority of patients with chronic stable angina, unstable angina1

SYMPOSIUM-ABRAM

syndromes, and variant or Prinzmetal’s angina. Although the calcium channel blockers are potent drugs in these conditions and have been singled out by some as firstline therapy for vasospastic and unstable angina, a number of recent investigations have documented the clear-cut effectiveness of nitrates in these syndromes [35-371. Mechanisms of Angina and Relationship to Nitrate Relief. A physiologic rationale exists for the employment of nitrates in the various types of angina. In classic effort angina, nitrates work primarily by decreasing myocardial oxygen consumption through the marked reduction in preload (left ventricular enddiastolic size and pressure) and the more modest decline in afterload (arterial blood pressure and systemic vascular resistance). In angina caused wholly or in part by coronary vasospasm (primary angina) or an increase in vasomotor tone superimposed on a fixed epicardial lesion (mixed angina), nitrates act by dilating the large coronary arteries, often reversing spasm, and may also dilate the actual stenosis site itself [ 16,171. It is unclear what role, if any, the latter action has in the relief of ischemia. Short-term Prophylaxis. The mainstay of angina1 relief is the administration of sublingual nitroglycerin. The dose range is highly variable, with as little as 0.15 mg being effective in some patients. The most common dosage forms in the United States are 0.3, 0.4, and 0.6 mg (l/ 1OOth, 1/150th, 11200th grain) tablets, although 0.8 mg may be required in some persons. Improvement from a single sublingual nitroglycerin tablet begins within one to three minutes; the effects are generally gone by 20 to 30 minutes, often sooner. Thus, sublingual nitroglycerin is not a practical drug for recurrent attacks of angina. Sublingual isosorbide dinitrate is effective in relieving angina, but its onset of action is relatively slow, and the total duration of action is 60 to 180 minutes. Therefore, this drug is not particularly useful for either short-term or long-term therapy, although it is a potent and bioactive nitrate. The newly developed transmucosal or buccal nitroglycerin formulation represents an interesting approach to acute prophylaxis of angina1 attacks [27,28]. This drug appears to act as promptly as sublingual nitroglycerin, producing hemodynamic alterations within two to five minutes after application. The tablet continues to release nitroglycerin into the circulation for hours, and as long as it remains intact in the buccal cavity there is a continuing nitrate effect and sustained prophylaxis against recurrent myocardial ischemia. The usual dose is 1 to 3 mg; the 1 mg dose should be used initially to assess the patient’s clinical response and the presence of side effects. Long-term Prophylaxis. Long-acting nitrate therapy

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is available in many formulations. All have been shown to be effective in clinical investigations, with a protracted duration of activity for many hours [21,23,27-291. Oral Nitrates. Both orally administered isosorbide dinitrate and nitroglycerin are valuable agents in the ambulatory therapy of angina. These drugs must be given in sufficient dosage to saturate the liver’s biodegradation capacity and to ensure that enough parent nitrate reaches the systemic circulation in therapeutic quantities. More rather than less of the oral nitrate is needed in many patients. lsosorbide din&ate has been far more extensively studied than oral nitroglycerin. The minimum starting dose of isosorbide dinitrate is 10 mg; it is often necessary to use 30 to 60 mg per dose to obtain maximal effect. Oral nitroglycerin should not be initiated in a dose of less than 6.5 mg; 9 mg, 13 mg, or even 19.5 mg per dose are needed in many patients. The oral nitrate esters have clinical effects that last for three to six hours; a recent study suggests that isosorbide dinitrate may act for up to eight hours in shortterm dosing trials, but only two to four hours after daily administration [36]. These drugs should be employed three to four times daily in patients with frequent angina. Buccal Nitroglycerin. The transmucosal formulation of nitroglycerin represents another approach to angina prophylaxis. The average duration of tablet longevity is three to five hours; some patients dissolve buccal nitroglycerin pills too rapidly (that is, within two hours) for effective long-acting therapy. Most patients readily learn to keep the tablet intact during eating, drinking, and talking. Buccal nitroglycerin clearly requires more physician time for patient education than the more familiar preparations. Buccal nitroglycerin is also useful for patients with relatively infrequent angina1 attacks; the medication can be used on an as needed basis to abort an acute episode as well as to provide prolonged nitrate efficacy for many hours. Topical Nitroglycerin. Ointment formulation of nitroglycerin is familiar, effective, and inexpensive. However, for active ambulatory patients it poses definite limitations. The problems relating to this preparation are essentially cosmetic: many patients do not like to smear on an ointment several times daily because of the messiness, staining of clothing, and the like. The optimal skin surface area for administration is not certain: some investigators suggest rubbing the ointment over a 6 by 6 inch square area, but in clinical practice this is infrequently done, and the ointment is often applied over a far smaller area. The site of application may influence the amount of nitroglycerin absorbed [31] ; the thorax and proximal arms are the most practical areas. Finally, precision regarding the amount of nitroglycerin ointment administered per dose is lacking, and it appears that the

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actual delivered dose is variable when applied by different persons [39]. Nitroglycerin ointment has a peak onset of action at 30 to 60 minutes and a duration of activity of four to eight hours. The initial dose is I/* to 1 inch (7.5 to 15 mg) every four to six hours: up to 2 to 3 inches per application can be given in increasing doses, as tolerated. This formulation is especially useful for hospitalized patients or in those with nocturnal angina. In the latter setting, the ointment can be applied at bedtime with great effectiveness. Nitroglycerin Discs. These agents are quite appealing in concept, representing a simple, once-daily administration that physicians and patients prefer to multiple dosing. The discs have not been adequately tested as yet to provide meaningful comparisons of efficacy with the other formulations. Blood levels are very low after application of the lowest-strength discs. In the absence of the desired clinical response to a single unit, multiple discs may be applied at one time. Preliminary data in small numbers of patients are encouraging [33,34], but dose-response relationships and the duration and magnitude of clinical effects remain to be evaluated in future clinical investigations. The lowest-dose discs deliver 2.5 to 5 mg of nitroglycerin over 24 hours at a constant rate (Table I). Higher strength units may be necessary for many patients. This innovative delivery system is relatively expensive, with the average daily dose for a single unit being approximately a dollar a day or more.

UNSTABLE ANGINA Nitrates have been commonly used by clinicians as part of the pharmacologic approach to unstable angina1 syndromes [35,40]. In general, such patients often require more than one type of therapy, and the addition of a beta blocker or calcium channel antagonist is frequently necessary. There are no data that support the exclusive use of one group of drugs over another. Intravenous nitroglycerin is very effective in the initial treatment of unstable angina [35]; the infusion rate is determined by the clinical response. The beginning dose is 15 to 30 pg per minute, with a doubling of the dose every 15 to 30 minutes as tolerated until chest pain is alleviated. It is not necessary to routinely use an indwelling arterial line or pulmonary artery catheter to initiate intravenous nitroglycerin therapy so long as the systolic blood pressure is over 100 mm Hg. A significant increase in heart rate (reflex tachycardia) cr fall in blood pressure below 90 to 100 mm Hg mandates cessation of the therapy or cutting back to a lower infusion rate. In patients with a history of hypertension, the lowest desirable level of systolic blood pressure may be somewhat higher than 100 to 110 mm Hg; this is par-

NITROGLYCERIN

titularly true in elderly patients so as to avoid an unwanted decrease in cerebral perfusion. Any decrease in central aortic pressure carries the risk of lowering coronary artery perfusion to a level that could be harmful; therefore, the administration of intravenous nitroglycerin must be very carefully monitored with frequent blood pressure and heart rate determinations. Patients require constant observation and evaluation to assess the desired clinical response (decrease or abolition of chest pain, and electrocardiographic manifestations of ischemia) and to detect adverse effects. Concomitant administration of topical nitrates after pain control has been achieved is useful for the tapering of intravenous therapy and conversion to ointment, disc, or oral nitrate administration. Buccal nitroglycerin has not been studied in unstable angina, but this formulation should be very effective. It provides immediate achievement of therapeutic nitrate plasma levels, and continues to maintain a nitroglycerin “infusion” so long as the tablet is in place in the mouth. This route of nitroglycerin administration may obviate the need for intravenous nitroglycerin. Potential complications of hypotension, reflex tachycardia, or nitroglycerin-induced bradyarrhythmias may occur with nitrate administration in the acute setting, and must be judiciously sought and monitored. CORONARY VASOSPASM Nitrates have long been a mainstay in the medical therapy of variant or Prinzmetal’s angina. Nitroglycerin is a potent large coronary arterial vasodilator, and nitrates have been shown to be effective for the short- and long-term prophylaxis of vasospasm [36,37,41]. Sublingual or intravenous nitroglycerin is routinely used during coronary angioplasty and streptokinase infusion for acute myocardial infarction to prevent or abort coronary spasm. Buccal nitroglycerin should be equally effective in these situations. Although calcium blockers have been shown to be extremely effective in the therapy of coronary vasospasm, it is still reasonable to use a nitrate first when variant angina has been confirmed. Sublingual nitroglycerin remains the mainstay for the immediate treatment of vasospastic angina, and it stands to reason that adequate amounts of long-acting nitrate should be employed in responsive patients. Many physicians advocate the use of both a nitrate and a calcium antagonist in the long-term therapy of patients with variant angina of moderate to severe nature. Such combination therapy has not been rigorously evaluated in randomized. double-blind studies. In two clinical trials of nitrates versus calcium blockers in pure vasospastic angina, no major differences in therapeutic efficacy could be

SYMPOSIUM-ABRAMS

identified [36,37]; some persons clearly respond more favorably to one class than the other, and many patients respond equally well to nitroglycerin or a calcium blocker. CONGESTWE HEART FAILURE The use of long-acting nitrates for vasodilator therapy of heart failure has been widely employed and is clearly efficacious in many patients [ 15,42-441. The venodilating properties of nitroglycerin are particularly important in reducing left ventricular preload, resulting in a decrease in left ventricular filling pressure and a concomitant decrease in pulmonary artery and right atrial pressures. Left ventricular size does not always decrease significantly following nitroglycerin administration in patients with heart failure in contradistinction to the consistent reduction in dimensions of the normal left ventricle. The arterial dilating properties of nitrates also play a role in the beneficial response to nitrates in heart failure. As systemic vascular resistance decreases (not necessarily with a decrease in blood pressure), the left ventricle is able to empty more efficiently. Thus, stroke volume and cardiac output are well maintained and may even increase slightly as afterload is reduced: this is different from the decline in stroke volume that usually follows nitrate administration in patients with relatively normal left ventricular function 1451. Nitrates dilate the peripheral veins at relatively low concentrations, and the decline in ventricular preload, as assessed by pulmonary capillary wedge or pulmonary artery diastolic pressure, is seen with modest doses of nitrate [ 9,141. Arterial dilating actions are seen at higher doses and the arteriolar resistance vessels are affected only at high concentrations of nitrate [ 9,11,14]. Therefore, it is often necessary to employ large amounts of organic nitrate esters in the treatment of heart failure in order to obtain the optimal therapeutic effect [ 461. Dosage. The recommended starting doses of nitrates are greater than those used in the treatment of patients with angina pectoris and normal left ventricular function; patients with congestive heart failure tolerate nitrates very well, and rarely does reflex tachycardia or hypotension develop. Buccal nitroglycerin in single doses of 5 to 10 mg has been successfully utilized in England [ 47 1. Oral isosorbide dinitrate dosage should be at least 20 mg; 40 to 80 mg may be necessary for an optimal response. As always, begin with smaller amounts and titrate upwards, closely following clinical response and side effects. Topical nitroglycerin is a particularly useful formulation in heart failure, especially in hospitalized patients or severely ill patients. The use of nitroglycerin ointment

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at bedtime is valuable as adjunct therapy in those who have orthopnea or paroxysmal nocturnal dyspnea. Problems with Nitrate Therapy of Heart Falfure. Several studies in congestive failure have identified patients who appear to be nonresponders to nitroglycerin [48,49]. This may in part be related to marked peripheral edema and hepatic congestion [49]; elegant work from Ontario, Canada, clearly demonstrates that inadequate nitrate plasma levels are not the reason for this apparent nitrate resistance [ 481. High doses of nitrate can result in methemoglobinemia [50]; this has not been extensively evaluated in heart failure, but it could be a problem in such patients. Nitrate tolerance, addressed elsewhere in this Symposium issue has been studied in patients given longterm isosorbide dinitrate therapy and has not been found after two to three months of therapy [51]. However, some data from West Germany suggest that this controversial problem needs further investigation [52]. Ideal Candidates for Nitrate Therapy In Congestive Heart Failure. Nitrates, and other vascxlilators for that matter, should only be used in patients who are significantly limited by symptoms of dyspnea and orthopnea, despite digitalis and diuretic therapy. The ideal candidate is a patient with a high left ventricular filling pressure, low cardiac output, and increased peripheral resistance. Patients in whom the left ventricular diastolic pressure is only modestly increased may actually manifest a decrease in stroke volume with nitroglycerin administration; this can be dangerous in the setting of acute myocardial infarction [45]. It is not necessary to hemodynamically monitor patients for the initiation of nitrate therapy, as these drugs have been demonstrated to be quite safe in the setting of heart failure. However, it is difficult to know what dose of nitrate to use (or any other vasodilator); although empiricism is usually satisfactory, occasionally the placement of a pulmonary artery catheter will facilitate dosage decisions. This is particularly true in very ill patients. The combination of a nitrate plus hydralazine has been successfully used to achieve maximal stroke volume and pulmonary wedge pressure response to vasodilator therapy; nitrates have a minimal effect on cardiac output, and the afterload reduction produced by hydralazine usually results in a major increase in stroke volume [53]. The combination of hydralazine and nitroglycerin produces hemodynamic responses that are identical to single dose drug therapy with prazosin or captopril [54]. It is best to utilize hemcdynamic measurements to determine the appropriate dosage of both hydralazine and the nitrate when combination therapy is employed. Acute Pulmonary Edema. In severe congestive heart failure of recent onset or overt pulmonary edema, nt-

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trate therapy is extremely helpful. In this setting intravenous or buccal nitroglycerin is the ideal first-line drug. Topical nitrates are effective and easy to use, but the slow onset of action and more modest peak effect make these agents less desirable for acute congestive heart failure. ACUTE MYDCARDIAL INFARCTtON A review of nitrates in acute myocardial infarction is covered elsewhere in this Symposium issue. At the present time routine nitrate therapy for acute infarction should be considered experimental. There is suggestive evidence that early administration of nitroglycerin may reduce infarct size, ventricular arrhythmias, and morphine requirements, but experimental results in animals and humans are conflicting as to true reductions in myocardial damage. Nitrates can be very useful in treating the patient with complicated infarction. For those with concomitant hypertension, heart failure, or recurrent/refractory chest pain, intravenous or buccal nitroglycerin should be employed promptly. Conversion to oral or topical nitrates can easily be accomplished if indicated. There have been reports of hypotension and bradyarrhythmias in patients with acute infarction given sublingual nitroglycerin, and these uncommon complications should be treated immediately (leg elevation, atropine) if they occur. Nitrate-induced hypotension and reflex tachycardia are potentially hazardous in this setting. PROBLEMS WKH NITROGLYCERIN THERAPY Slde Effects. Side effects associated with nitroglycerin have been recognized for over 100 years and most prominently include headaches that follow nitrate administration. These can range from a very mild sensation of fullness in the head to an intense and severe generalized headache. The headaches may be so severe as to dissuade the patient from ever utilizing nitroglycerin again. Physicians should be careful to caution those who have never used sublingual nitroglycerin or other long-acting nitrates that a headache of some type is to be anticipated. Use of mild analgesics is encouraged for the first few days if these side effects are very bothersome. In most persons the headaches will abate over a period of time, usually within one to two weeks, and disappear completely or become mild enough so that the patient can tolerate the nitrate therapy. Some patients get dizzy after receiving nitrates; rarely, overt syncope can occur if cerebral perfusion is substantially reduced. These symptoms are caused by a reduction in stroke volume and a decrease in blood pressure. To familiarize themselves with possible nitrate side effects, patients should be encouraged to try

NITROGLYCERIN

sublingual nitroglycerin on a “test basis” when they are free from acute symptoms. Nausea is a problem in some patients. This is usually shortlived and not severe. Flushing of the skin, warmth, throbbing of the head and neck, palpitations and a sensation of cardiac action can all occur with nitrate therapy, but these symptoms are usually not very bothersome. Bradycardia and hypotension are rarely noted following sublingual nitroglycerin administration during acute ischemia. This is presumably due to a vasovagal reaction and should be promptly treated with leg elevation, atropine, and, rarely, rapid infusion of saline solution. NITRATE TOLERANCE Armstrong has reviewed this subject elsewhere in this Symposium issue. Nitrate tolerance has been demonstrated in animals for more than 50 years. Studies in patients with angina pectoris and congestive heart failure have resulted in generally negative conclusions [55,56]. However, some convincing data from Canada [38], West Germany [52], and elsewhere raise the spectre that nitrate tolerance may be more of a problem than many clinicians believe. Certainly, tolerance should be considered in any patient who requires increasingly large doses of nitrates. Partial tolerance to some actions of nitroglycerin action can develop while other physiologic effects remain undiminished. Cross-tolerance to sublingual nitroglycerin or other nitrates can appear but has been uncommonly demonstrated. Because of the potential problem of nitrate dependence, clearly documented in munitions workers, it is important not to abruptly discontinue long-acting nitrates, particularly if they have been used in large

SYMPOSIUM-ABRAMS

quantities. There are only anecdotal data that rebound coronary vasoconstriction may occur in patients with ischemic heart disease when nitrates are suddenly discontinued [ 151, and caution is advisable in this setting. There is no evidence that one nitrate formulation is more likely to produce tolerance than another. It has been suggested that the 24-hour transdermal nitroglycerin systems may produce tolerance more readily than other preparations, as experimental evidence indicates that intermittent use of nitrates may slow or prevent the development of tolerance and that a nitrate-free interval will restore vascular responsiveness. The problem of tolerance to nitrates continues to be intensively investigated in a number of countries. CONCLUSION Physicians have a remarkable diversity of long-acting nitrate formulations available to them. These drugs are of proved effectiveness in a variety of cardiovascular conditions. Their use over many years has demonstrated a remarkable record of safety and clinical efficacy. They are relatively inexpensive, and physicians are quite familiar with the side effects of these drugs. Although there are some unresolved questions, particularly with respect to nitrate tolerance and whether nitrates should be used as first-line treatment for coronary vasospastic disorders, these drugs remain exceedingly useful and effective in patients with different types of angina as well as in acute and chronic congestive heart failure. Intelligent utilization of nitrates, including the willingness to utilize higher doses than used in the past, will provide important clinical benefits to many patients with cardiovascular disease.

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