Jonathan Abrams, M.D., is an academic cardiologist at the University of New Mexico School of Medicine, where he was chief of the cardiofogv section for 15 years (1974- 19891. His clinical expertise includes ischemic heart disease, congestive heart failure, and valvular heart disease. He is an e&pert on the clinical pharmacology of a variety of cardiovascular drugs and has written extensively on nitroglycerin and the organic nitrates. He has coauthored a new book with Drs. Carl J. Pepine and Udho Thadani entitled Medical Therapy of Ischemic Heart Disease: Nitrates, Beta Blockers, and Calcium Antagonists, published by Little, Brown & Co. He has particular espertise in cardiac physical diagnosis and has written two books on the subject. He has written many chapters in textbooks of medicine and cardiology. He is currently a recipient of a National Institutes of Health Preventive Cardiology Academic Award at the University of New Mexico School of Medicine. Cur-r

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USE OF NITRATES IN ISCHEMIC HEART DISEASE

Nitroglycerin (NTG) has been the foremost anti-ischemic agent used in clinical medicine for over a century. This compound is extremely versatile and has been manufactured in a variety of formulations for oral, topical, transmucosal, sublingual, and intravenous administration. During the 20th century, chemists have qynthesized a variety of additional organic nitrate esters for medicinal use, including pentaerythritol tetranitrate and isosorbide dinitrate (ISDN). More recently, 5-isosorbide mononitrate (5ISMN), the major bioactive metabolite of ISDN, has been manufactured and is available in a number of countries around the world. The rationale for the introduction of other organic nitrates to our drug armamentarium relates to the very short half-life of NTG itself (several minutes), such that it has been difficult to provide a long duration of drug action with this compound. Other nitrate molecules, particularly ISDN and 5-ISMN, allow for greater dosing flexibility and represent compounds that provide for protracted nitrate drug delivery. A large body of research has evolved that probes the mechanisms of action of NTG and the organic nitrates in the normal heart as well as in ischemic heart disease. New discoveries and insights into the effects of the nitrates continue to appear, and our understanding of nitrate action has deepened considerably in the last decade, even though these drugs were first used in patients with angina in 1879.’ Fascinating new developments relating nitrate interactions with the endothelium (including the recognition that NTG is converted to nitric oxide) and antiplatelet activity of the organic nitrates provide important new hypotheses regarding the anti-ischemic efficacy of these agents. The nitrates are excellent agents for all the ischemic heart disease syndromes, including stable effort angina pectoris, mixed angina, unstable angina, and acute myocardial infarction (MI), and possibly for post-MI patients. In addition, nitrates are effective adjunctive drugs for acute and chronic heart failure; in intravenous formulation, NTG is useful for lowering or controlling systemic blood pressure. Although there have been a variety of pharmacologic advances Curr

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in the treatment of symptomatic patients with ischemic heart disease over the past 25 years (beta-adrenergic blockers, calcium antagonists), NTG and the nitrates are equally effective for the treatment of angina and may be the anti-ischemic agents of choice in patients with acute MI. While the beta blockers have been shown to be cardioprotective following acute MI, new evidence suggests that nitrate therapy may also have an important role in the post-MI period by preventing left ventricular cavity expansion and shape change (remodeling) after large transmural infarction. The side-effect profile of the organic nitrates is familiar to all physicians. These drugs are generally safe, have few important drug interactions, and can be administered to virtually all patients with ischemic heart disease. In fact, nitrates are particularly effective in patients with left ventricular (LV) dysfunction or overt congestive heart failure, conditions where administration of beta blockers and calcium antagonists may be contraindicated. In patients who do not develop limiting headaches, the nitrates are excellent drugs for acute or chronic administration. Nitrate tolerance, the loss of drug effect over time in spite of adequate bioavailability, is the single most important negative feature affecting the use of long-acting nitrates. Tolerance or attenuation of nitrate pharmacologic action has been well documented in all the ischemic syndromes and comes on with surprising rapidity when a protolerant nitrate drug dosing regimen is employed. There has been a tremendous amount of attention paid to this problem during the past decade by clinicians, investigators, the pharmaceutical industry, and the regulatory agencies. Today we are much more knowledgeable about the mechanisms that cause nitrate tolerance; it is well established that, in most patients, tolerance can be avoided with the use of carefully designed nitrate dosing regimens. Nevertheless, many physicians believe that attenuation of nitrate effectiveness during chronic dosing is so much of a problem that nitrates should not be used as first-line anti-ischemic therapy. I disagree with such a nihilistic approach; appropriate utilization of nitrate formulations and dosing regimens can provide the full benefits of nitrate action to patients. Long-acting nitrate therapy is effective; however, in order to maintain predictable drug efficacy, physicians who prescribe these drugs must be aware of the factors that increase and decrease the likelihood of nitrate tolerance. This monograph is organized to provide a systematic and comprehensive approach to the use of organic nitrates in ischemic heart disease. The initial section will review the mechanisms of action of these agents, including the cellular events leading to relaxation of vascular smooth muscle. Newer concepts of ischemia causation (endothelial dysfunction, stenosis constriction, collateral or distal coronary vessel constriction) will be discussed, as will the latest hypotheses relating to nitrate action. The interactions of the nitrates with 488

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endothelial function, the antiplatelet activity of nitrates, and the emerging role of nitrates in preventing post-MI remodeling will be discussed. The relevant clinical pharmacologv of the nitrates is reviewed. Adverse reactions to nitrates and the problem of nitrate tolerance, and its avoidance, are given considerable attention. Guidelines for using available nitrate formulations are provided. Finally, the clinical syndromes for which nitrates are employed are reviewed, and specific recommendations for providing optimal therapy for each condition are given. MECHANISMS

OF NITRATE

ACTION:

BASIC

The organic nitrates have one major physiologic effect: they relax vascular smooth muscle in veins, arteries, and arterioles throughout the body. Most, if not all, of the known clinical effects of NTG and the organic nitrates are related to vascular dilatation in one or more regional vascular territories. There are considerable new data indicating that the nitrates have important antiaggregatory and antiadhesive activity against circulating platelets.” 3 Thus nitrates may substantially interfere with platelet activation by reducing local and systemic factors related to platelet aggregation, and nitrate therapy could decrease the likelihood of thrombosis and vasoconstriction. The platelet effects of NTG and the organic nitrates are controversial; not all experts accept that there are important in vivo antiplatelet actions with clinically achievable nitrate plasma concentrations.’ If, however, a true antiplatelet role for these agents is ultimately established, the array of nitrate mechanisms of action will be broadened considerably. The clinical implications of nitrate therapy in the acute ischemic syndromes related to intracoronary thrombus (unstable angina, acute MI) would expand far beyond our current concepts of nitrate efficacy. INTRACELLULAR

NITRATE

METABOLISM

The organic nitrates are now recognized as prodrugs. These compounds penetrate the vascular smooth cell and undergo a series of denitration steps at or near the plasma membrane.’ The parent nitrate compound is immediately converted to nitric oxide (NO), a most important molecule that stimulates activation of guanylate cyclase, causing a cascade of events resulting in relaxation of vascular smcnth muscle (Figure 1). NO is also the end product of nitroprusside and molsidomine metabolism. These compounds are nitrovasodilators and are similar to NTG and the organic nitrates in their vasodilating capability. In addition, NO is the putative endothelialderived relaxant factor (EDRF; see below); in the particulate compoCurr

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489

ENDOTHELIUM organic

VASCULAR

SMOOTH

MUSCLE

n i trote

(RON02 ) Ni troprusside (NP) 1 NO S-nitrosothiol

(RSN~) Endothelium -dependent---EDRF vasodi Lotors

FIG 1. Cellular actions of nitroglycerin and other nitrovasodilators. Organic nitrates (RONO,) are denitrated to NO through enzymatic steps requiring reduced 3-i groups (R’SH). NO stimulates the enzyme guanylate cyclase (GC), which in turn results in increased formation of cGMP, followed by vascular smooth muscle relaxation in arteries and veins. Note that an alternative pathway of the metabolic cascade suggests that NO can be converted to Snitrosothiols (RSNO) that are capable of directly generating NO as well as stimulating guanylate cyclase to increase production of cGMP. Some believe that RSNO is an obligatory end-product of intracellular organic nitrate denitration, and that these compounds then result in NO production. Other nitrovasodilators, including nitroprusside (NP), exert their vasodilating actions through the production of NO and cGMP. Note that NP does not require SH groups for conversion to NO. EDRF is produced within the endothelium cellular monolayer. EDRF is probably NO, and when it diffuses into the vascular smooth muscle cell it results in smooth muscle relaxation. EDRF also is released into the lumen of the blood vessel, where in combination with prostacyclin it exerts potent antiplatelet adhesrve and aggregatory actrons. In the presence of abnormal EDRF production or release, endothelial-dependent vascular smooth muscle vasodilatation is impaired. Administration of exogenous nitrodilators, such as NTG or ISDN, stimulates the guanylate cyclase pathway and may overcome the relative or actual EDRF deficrt (see text). (With permission from Kowaluk E, Fung H-L: Pharmacology and pharmacokinetics of organic nitrates, in Abrams J. Peprne C, Thadani V (eds): Medical Therapy of lschemic Heart Disease. Boston, Little. Brown & Co.. 1992, pp 151 -176.)

nent of vascular smooth muscle cells, atrial natriuretic peptide (ANP) releases NO. Thus the metabolic conversion of organic nitrates to NO is an extremely fortuitous phenomenon, as it shares the final common pathway leading to vascular smooth muscle relaxation as well as antiplatelet activity with various other important physiologic and pharmacologic compounds (Table 1). There has been and remains considerable uncertainty about the precise steps leading to NO formation following administration of ni490

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TABLE 1. Nitmvasodilaton Exogenous Nitroglycerin Organic nitrates-ISDN, Nitmpmsside Molsidomine Endogenous EDRF

B-ISMN

trates. Of particular importance is the formation of short-lived, activated compounds known as nitrosothiols. These substances are also capable of activating guanylate cyclase, and it was initially hypothesized that nitrosothiols were critical end products of nitrate metabolism, leading to the formation of NO and subsequent vasodilatation.6 Recent evidence suggests that the nitrosothiols may not be obligatory components of the nitrate metabolic cascade and that t,hese compounds may be formed directly from NO itself, or when nitrates are administered concomitantly with thiol donors7’ ’ In the latter situation, it has been shown that the nitrosothiol may be formed outside the vascular smooth muscle cell and subsequently enter the cell, where it induces guanylate cyclase activation and cyclic guanosine monophosphate (cGMP) formation7 (Figure 1). An important aspect of the proximal nitrate metabolic cascade is the requirement for sulfhydryl groups derived from cysteine moieties within the cytoplasm (Figure 1). Nitrates cannot undergo denitration without the presence of reduced thiol, presumably derived from cysteine.5’ ‘, *O In the process of denitration, the available pool of reduced thiol or -SH groups becomes depleted, perhaps because production of sulthydryl moieties is insufficient to keep up with the continued presence of organic nitrate. Thus a state of relative sulfhydry1 depletion or inaccessibility ensues, slowing the nitrate metabolic process and diminishing the ability of vascular smooth muscle to relax. It has been believed that this is the core of the problem of nitrate tolerance: continued exposure of the vasculature to organic nitrates renders the blood vessels hyporesponsive over time, related to a deficiency of intracellular thiol groups to facilitate normal nitrate metabolism and the resultant formation of NO. While disagmement remains about the precise role and nature of the responsible thiol, it is generally accepted that nitrate tolerance is in part related to an alteration in the ability of vascular smooth muscle cells to take up and convert the exogenously administered nitrate prodrug to the active species NO. NTG and the other nitrates are members of a group of compounds known as nitrovasodilators (Table 1). These agents induce vascular Curr

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smooth muscle relaxation through a common series of events, beginning with NO-induced activation of guanylate cyclase, the enzyme responsible for the conversion of guanosine triphosphate to cGMP. As intracellular cGMP levels rise, phosphorylation of protein kinases occurs with a fall in cystosolic Ca++ and relaxation of the vascular smooth muscle in vein and arteries. While all of the nitrovasodilators share this final or distal limb of intracellular events, the steps leading up to guanylate cyclase activation are different for the various compounds. For instance, sodium nitroprusside and molsidomine do not require denitration in order to form NO but rather are converted to NO directly, without relying on a thiol interaction (Figure 1). It is generally believed that tolerance to nitrates is related directly to the proximal limb of denitration, prior to the formation of NO. Tolerance is not a major problem with nitroprusside or molsidomine, presumably because these compounds do not require a sulthydry1 group for their metabolic conversion to NO. Similarly, tolerance to EDRF itself would not be expected; attenuation to sustained exposure to or administration of NO has not been reported. Furthermore, the ability of vascular smooth muscle to generate NO may vary among vascular beds. Thus the distal coronary microvasculature appears to be missing the critical sulthydryl groups necessary for biotransformation of NTG to NO and therefore does not respond to the organic nitratesll Debate continues about the relative potency of nitrate action between arteries and veins. It appears that nitrate uptake by the vasculature tissue is more avid in venous tissue, thus explaining the greater effects of nitrates on the veins.” Such differences in vascular nitrate metabolism may also be important in understanding vascular tissue-specific differences in the development of nitrate tolerance.13

ENDOTHELIAL

FUNCTION

During the last few years there has been a remarkable interest in the endothelium in health and in a variety of disease states. The observation just over a decade ago that the endothelium is important in the modulation of normal physiologic responses to a variety of dilator compounds14 has led to an enormous body of research into functional and dysfunctional endothelium. This subject is too large and complex to discuss in detail in this monograph. Excellent IX+ views are available to the interested reader.15-17 Suffice it say, it is now recognized that the endothelium monolayer that lines veins and arteries is a literal factory for the synthesis of many bioactive substances. Furthermore, the endothelium responds to a variety of stimuli with the production of dilator and constrictor substances. 492

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Some important molecules produced by the endothelium (prostacyclin, EDRF) also have important antiplatelet activity. In the presence of disordered endothelial function or overtly damaged endothelium (eg, severe focal coronary atherosclerosis), the normal physiologic balance between vasodilatation and vasoconstriction in the blood vessel may be altered, favoring a state of increased vascular tone and a propensity to vascular constriction and even overt spasm. In addition, stimuli that normally result in antiplatelet activity modulated through release of EDRF and prostacyclin (such as circulating platelet aggregates that become activated) may induce a proaggregatory and prothrombotic state in the setting of disordered endothelial function.‘7’ Is This could lead to deleterious alterations in local vascular function, with the precipitation of vasoconstriction and thrombosis. Figure 2 depicts in a schematic format the interactions between the endothelium, vascular smooth muscle, and platelet in the normal state and in the presence of endothelial dysfunction. The consequences of disordered endothelial-mediated responses are the subject of intensive basic and clinical research. It is believed that individuals with coronary atherosclerosis, even without overt ischemic symptoms, may have deranged coronary arterial responses to a variety of stimuli and in fact appear to have disordered coronary vasodilatory activity in response to endothelial-dependent vasodilator compounds. Thus the diseased coronary bed has the propensity for vasoconstriction rather than vasodilation, and possibly for focal spasm as well (Figure 3). Furthermore, recent work suggests that the vascular abnormalities need not be particularly severe; deranged dilatory responses to acetylcholine, serotonin, and other probes of endothelial function may result in paradoxic vasoconstriction, even at sites of minimal atherosclerosis.‘Y2 ‘O In animals and possibly humans, hypercholesterolemia without definite histologic abnormalities can induce endothelial dysfunction.‘l’ 22 Administration of HMgCoA reductase inhibitors can normalize this disordered vascular state.‘l Hypertension, diabetes, and hyperlipoproteinemia have all been associated with impaired endothelial-dependent vasodilation. Investigations into endothelial function have resulted in the concept that various coronary vasodilator substances can be classified into endothelial-dependent and endothelial-independent agents.15-17 The former require an intact and functional endothelial layer to produce vascular smooth muscle relaxation, presumably through the release of EDRF, which induces vasodilatation via the cGMP cascade (see Figure 1). It is currently believed that EDRF is NO, or a closely related molecular species. Decreased or disordered EDRF release is thus a condition of inadequate NO availability to the arterial media. This state may be considered NO-penia and is assoCurr

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493

FIG 2. Interactions between the endothelium and circulating platelets. These diagrams illustrate the interrelationships between EDRF production and platelet aggregation in the presence of a normal or intact endothelium (Figure 2A) and in endothelial dysfunction (Figure 26). EDRF is released by the endothelial cell and diffuses into the vascular smooth muscle and the vessel lumen. In the normal situation (Figure 2A), EDRF IS a potent vasodilator, and in conjunction with prostacyclin (PGI,) exerts an antiplatelet effect. Furthermore, platelet aggregation itself, through the release of ADP and 5HT (serotonin), may exert vasodilatory actions by stimulating EDRF release. Serotonin and thromboxane (TEA,). released from platelets, also exert direct constricting influences on the vascular smooth muscle wall, In the.presence of endothelial dysfunction (Figure 28) whrch has been documented in 494

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FIG 3. Effects of acetylcholine on coronary vessel caliber in patients with coronary atherosclerosis. In this catheterization laboratory experiment, graded doses of acetylcholine (ACH) were infused into coronary arteries. A, In segments with mild but definite atherosclerosis and in those where severe atherosclerotic narrowings were present, ACH induced a reduction in luminal caliber. Of considerable importance is the observation that even mildly diseased segments of the coronary arterial tiee prestenotic exhibrted paradoxic vasoconstrictor responses to ACH and endothelial-dependent vasodilation. Note that nitroglycerin (TNG) completely reversed the vasoconstriction. B, Normal coronary artery segments dilated modestly in response to ACH. (With permission from Ludmer PL, Selwyn AP, Shook TL, et al: Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic arteries. N Engl J Med 1986; 315: 1046- 1051.)

ciated with disordered coronary vasodilator responses, a propensity to coronary vasoconstriction and spasm, and possibly enhanced platelet activation/aggregation. It is now widely accepted that coronary atherosclerosis, an inherently diffuse process with focal exacerbations within the artery, is accompanied by disordered endothelial function and paradoxic responses to endothelial-dependent stimuli.15-17,

19-20

FIG 2 (cont.). mild and severe coronary atherosclerosis, hypercholesterolemia, etc, factors favoring relaxation (EDRF and PGI,) are decreased in favor of a generalized vasoconstrictor tone. Aggregating platelets initiate vasoconstriction, as the vasodilatory influences of platelet release products are attenuated. The decrease in EDRF release or action further accentuates vasoconstriction and platelet aggregation, creating a substrate for adverse vascular advents such as thrombosis and vasospasm. (With permission from Vanhoutte PM, Shimokawa H: Endothelium-derived relaxing factor and coronary vasospasm. Circulation 1989; 80:1-9.) Cur-r

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495

FIG 4. Effects of bradykinin, an endothelium-dependent dilator, and NTG in normal and diseased coronary artery segments. In this experiment, bradykinin was infused directly into the coronary artery in patients undergoing coronary catheterization. Quantitative coronary angiography was carried out, followed by administration of intracoronary NTG. When all vessel segments were analyzed, bradykinin had a minimal effect on coronary arterial diameter, whereas nitroglycerin (TNG) dilated most segments (Figure 4A). However, when segments were analyzed as to whether there was an initial vasodilator response to bradykinin, important differences in the response to nitroglycerin were noted. Vessel segments that dilated following bradykinin infusion were relatively insensitive to subsequent TNG (Figure 496

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NITROGLYCERIN AND THE ORGANIC NITRATES: INDEPENDENT VASODILATORS

ENDOTHELIUM-

As already discussed, it is believed that the nitrates are prodrugs that must be converted to NO in order to exert their vasodilatoxy effects in vascular smooth muscle. Furthermore, nitrate tolerance is clearly in part a state of decreased NO availability, ie, NO-penia. Because NTG supplies its own NO, it is not reliant on an intact endothelial cell layer to produce EDRF. As such, the nitrates (and many other drugs, such as calcium antagonists, hydralazine, and angiotensin converting enzyme inhibitors) are known as endotheliumindependent vasodilators: these compounds do not require a functional endothelial monolayer for their vasorelaxant activity. As the nitrates are NO donors, they are distinguished from other vasodilator drugs except other nitrovasodilators (see Table 1). This characteristic provides an important role for the nitrates in clinical medicine. Fundamentally, NTG and related compounds are capable of inducing coronary artery dilation in the presence of atherosclerosis and/or endothelial dysfunction by providing NO to the smooth muscle cell, literally replacing EDRF. Some have called NTG the “exogenous endothelial-relaxing factor”! There is a constant, basal production and release of EDRF from coronary arteries. As EDRF appears to be NO, it is reasonable to assume that the endogenous production of this vasodilating substance would compete with drugs that act as NO donors, eg, the nitrovasodilators. In fact, it has been shown that NTG is less potent in the presence of normal endothelial function (Figure 4); presumably, the continuing presence of NO in the lumen of an artery or vein (via EDRF release), as well as in the vascular smooth muscle cell, exerts an ongoing relaxant effect on vascular tone. Thus one can conceptualize NTG and the other nitrates as providing enhanced benefits to subjects with coronary atherosclerosis partly as a result of their specific endothelial action, inducing local or generalized coronary arterial dilation in the presence of endothelial dysfunction and preventing or attenuating the vasoconstrictor-platelet aggregatory propensity present in such patients. It appears that NO stimulation of the

48, bottom). Conversely, those segments that showed Me initial response to bradykrnin (endothelial dysfunction) had a marked vasodilator response to nrtroglycenn (Figure 45, top). These observations suggest that the organic nitrates may be panrcularly effectrve in patients with coronary atherosclerosis and impaired endothelial function, and that the effects of NTG in such a setting may actually be greater than rn the normal coronary artery with intact endothelial function. (With permissron from Rafflenbeul W, Bassenge E, Lichtlen P: Konkurrenz zwischen. Endothelabhangiger und nitroglycerin-induzlerter koronarer vasodilatation. Z Kardiol 1989; 78[suppl 2]:45-47.) Cum

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437

guanylate cyclase cascade represents the most physiologic vasodilatory mechanism currently available through the use of pharmacologic agents. The organic nitrates provide such a mechanism of vasodilatation. It is in the most diseased vessels that nitrates are likely to be effective, as has been demonstrated in countless clinical experiments employing sublingual, intravenous, or intracoronary NTG as the gold-standard anti-ischemic drug. ANTIPLATELET

ACTIVITY

For years investigators have been debating whether or not NTG or other nitrate formulations have significant antiplatelet activity. It has been long recognized that these drugs can inhibit various aspects of in vitro platelet function. Many experts believed that this only occurred in the presence of pharmacologic or industrial doses of nitrate, denying any clinically relevant antiplatelet activity for the organic nitrates. Recently, however, a variety of studies, many preliminary in nature, have been presented or published that appear to provide a solid scientific basis for a major antiplatelet action of these compounds.” 3,23--25 Nitroglycerin has been shown to inhibit platelet deposition and resultant arterial constriction in response to deep arterial injuti3 and has also been demonstrated to suppress phasic platelet aggregates in the dog model with a constricted left anterior coronary artery.24 Platelets tested ex vivo immediately after being harvested from humans receiving intravenous NTG have been shown to be deactivated.25 Some or much of this controversy may be related to the difficulties in testing platelet function ex vivo in animals or humans.’ The nature of the platelet-rich preparation and the time between phlebotomy and formal platelet function testing are critical factors that can seriously distort an accurate assessment of platelet function. Loscalzo, De Caterina, and Lam are vigorous supporters of an important role of the nitrates in interfering with platelet adhesion and aggregation. ‘, 3823, X, 27 Others are less easily convinced.4, ” It is readily demonstrated that the addition of thiol donors will accentuate the antiplatelet actions of NTG.” Such experiments do not necessarily prove the overall hypothesis of nitrate efficacy with respect to platelet actions. If it becomes generally accepted that platelet function is a target of nitrate action, an important new role for nitrates in ischemic heart disease will have been established. For instance, the recognition that many patients with unstable angina pectoris have an unstable plaque with ulceration, fissuring, and platelet aggregation leading to in situ thrombosis could provide a new rationale for the use of intravenous NTG in this syndrome. A number of studies have documented a favorable role for nitrate administration in unstable 498

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angina.3”-32 One of the mechanisms that could be important when intravenous NTG is given to unstable angina patients relates to the proposed antithrombotic and antiaggregatory actions of the nitrate; stabilization of intracoronary thrombus could be beneficial in the acute ischemic syndromes.30-32 Nitrates are very effective in patients with this syndrome. Furthermore, nitrate use in acute MI is a subject of current investigation that holds great promise (see below). Data from a relatively small number of subjects suggest that the use of intravenous NTG in the first 24 to 48 hours after infarction imparts major clinical benefits, including a substantial reduction in mortality compared to placebo controls (Figure 5).33, 34 In addition to the hemodynamic actions of these drugs, it is likely that nitrate antithrombotic activity could act to stabilize the intracoronary thrombus mass, increase ischemic zone perfusion, and decrease infarct size. Finally, speculative aspects of an antiplatelet role for the nitrates in patients include a suppression of the circadian variation in platelet activation in stable angina,35 perhaps leading to a decrease in morning isch-

Odds Roho (k 95% Cl ) Nltropruss&

Risk Red&on (SD)

trlols

Hock,nqs DWW

-

Cohn SUBTOTAL 011I v mtroprussldc

242

(14)

N~troqlyccrm trmls Chlche BUSs~0~

-t--f

floherly Nelson (no deaths) J0fle

H

LIS Juqdult +

SUBTOTAL 011( I ndroqlycerm

101M (all ( Y nIlrate trlols)

y

49x

(14)

35%

(10)

00

20 N~lroli 5beUet

‘,’

Odds Rotlo (treated

Ndro:e5*orse control)

FIG 5. Apparent effects of intravenous nitroprusside and NTG on mortality in the randomized trials of the treatment of acute MI. (With permission from Yusuf S, Collins R, MacMahon S, et al: Effect of intravenous nitrates on mortality in acute myocardial infarction: An overview of the randomized trials. Lancet 1988; 2:10881092.) Curr

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emia. Platelet activation may occur during angina1 angina, and NTG antiplatelet activity could reduce tion during attacks.36 There is also a possibility that let activity could play a role in diminishing in situ progression of coronary atherosclerotic lesions.

attacks in stable platelet aggreganitrate antiplatethrombosis and

D. MCCALL: The author has provided the readers with an excellent overview of the various mechanisms of action of nitrates. Of particular interest is the increasing awareness that these drugs may have effects beyond those of simple vasodilatation. In this regard, as the author points out, there is increasing interest in the effects of nitrates on endothelial function and on the ability of platelets to aggregate. Because it has been clearly demonstrated in many studies in the past that antiplatelet drugs have a’beneficial effect in unstable angina, it is possible that the beneficial effects of nitrates in this clinical syndrome may be reflective not only of their vascular actions but also of their actions on attenuating platelet aggregation. b

MECHANISMS PEFUPHEHAL

OF NITHATE ACTION: VASODILATATION

The classic view of nitrate efficacy relates to the well-known actions of these drugs on the peripheral venous and arterial circulations (Table 2). It was initially believed that the direct coronary arterial dilating actions of NTG were responsible for the drug’s antiischemic and antianginal effects. An important observation in patients paced to ischemia suggested that the peripheral circulatory vasodilatory actions of sublingual NTG were predominantly responsible for ischemia relief, as direct administration of NTG into the coronary circulation did not prevent pacing ischemia.37 This study, as well as others, stimulated investigators to pursue the concept that nitrates were effective in preventing or reversing myocardial ischTABLE

2.

Beneficial

Effects

Perinheral

or Svstemic

of Nitrates

Venous dilatation (systemic pulmonary veins)

Arterial

Arteriolar

500

in Angina

Actions

(high

Potential

Mechanisms

of Action,

I.

Result and

dilatation

dilatation

Pectorls:

doses.1

Smaller right and left heart volumes (preload and afterloadi Lower right and left heart filling pressures tpreload) Altered LV pressure-volume relationship Reduced arterial reflectance wave Decreased systolic blood pressure Decreased aortic impedance Increased efficiency of LV ejection Decreased LV afterload Decreased systemic vascular resistance Decreased afterload

Cvrr

Probl

Cardiol,

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1992

emia because they decrease cardiac work rather than augment coronary blood supply. NTG has been shown to lower both systolic and diastolic wall tension (Figure 61, and it induces a significant fall in myocardial oxygen consumption.38 How do the nitrates decrease cardiac work? The peripheral vasodilating activity is the major contributor to this component of nitrate action (Figure 7). At low doses and plasma concentrations, the nitrates induce venorelaxation, with a subsequent redistribution of the circulating blood volume toward the splanchnic and mesenteric circulations. In individuals with normal cardiac function, this sequestration of blood away from the heart and lungs due to peripheral venodilatation induces a fall in forward cardiac output and stroke volume. However, in subjects with impaired LV function, the arterial unloading or dilating actions of the nitrates preserve forward cardiac performance; stroke volume usually does not fall or may even rise .3g

RATE 30

ESTIMATES OF LV WALL TENSION CONTRACTILE STATE

20 IO (t) PERCENT CHANCE t-1 IO

FIG 6. Alterations in determinants of myocardial oxygen consumption followrng NTG. In thus study, LV angiography was performed before and after 0.6 mg of sublingual NTG. Note the substantial decreases in parameters contributing to LV wall tension, including reductions in ventricular size and pressure. There was a decrease in peak developed tensron and a fall of 57% in calculated end-diastolic wall tension. Heart rate, electron fraction, and VCF were augmented because of reflex sympathetic discharge followrng the fall in systolic blood pressure. LVSP = left ventricular systolrc pressure; EDV = end-diastolrc volume; PST = peak systolic tension; PDT = peak developed tension. (With permissron from Greenberg H, Dwyer EM, Jameson AG, et al: Effects of nitroglycerin on the major determrnants of myocardial oxygen consumption. An angiographic and hemodynamic assessment. Am J Card/o/ 1975; 36:426-432.) Cum

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501

NITRATE

INDUCED

VEINS

AND

VASODILATION

OF

ARTERIES

VEINS kopocitance)

ARTERIES (conductance)

ARTERIOLES (resistonce)

0

I

NITRATE

DOSE

FIG 7. Vasodilatory actions of organic nitrates in the major vascular beds. Note that the venous or capacitance system dilates maximally with low doses of organic nitrates. Increasing the amount of drug does not cause appreciable additional venodilatation. Arterial dilatation and enhanced arterial conductance begin or low doses of nitrate. With further vasodilation, appearing with increasing dosage at high plasma concentrations, the arteriolar or resistance vessels dilate, resulting in a decrease in systemic and regional vascular resistance. (With permission from Abrams J: Hemodynamic effects of nitroglycerin and long acting nitrates. Am Heart d 1985; 110:216-224.)

Arterial relaxation and alterations in vascular compliance and conduction occur with relatively low doses of nitrate. As nitrate plasma levels increase, arterial vasodilatation increases in a dose-dependent manner (see Figure 7). Even very small NTG doses induce some arterial effects. At high concentrations or infusion rates of intravenous NTG, the systemic arteries become markedly dilated and the muscular resistance vessels or arterioles relax, decreasing peripheral vascular resistance. Decreases in arterial and arteriolar tone cause a fall in systolic blood pressure that is most marked in the upright position. Venodilatation and the subsequent decrease in LV preload contribute to the fall in systemic blood pressure. A recent observation from O’Rourke’s group in Australia indicates that routine brachial artery cuff blood pressure determinations may underestimate the peripheral arterial dilating effects of NTG.40 These investigators, experienced in assessing blood flow and pulse wave mechanics, noted that central aortic systolic blood pressure is often 502

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1992

discordant with the simultaneous pressure measured directly in the brachial artery following the administration of sublingual NTG. Central aortic pressure decreases predictably after the NTG, whereas in some patients brachial artery systolic pressure did not decline (Figure 8). These investigators attribute the failure of brachial arterial pressure measurements to reflect true central aortic pressure following NTG to a lack of effect of the drug on the reflected waves returning from the peripheral vasculature. Thus a distal vessel, such as the brachial artery, may fail to demonstrate the actual decline in systolic blood pressure. This mechanism could be responsible for an underestimation of the effects of nitrates on afterload or arterial tone. Regional circulatory adjustments after nitrate administration are predictable and relate to the systemic vasodilatation produced by these drugs. Reflex vasoconstriction often follows the acute dilative effects of nitrates in specific vascular beds.41

FIG 8. Discordance between central (ascending aorta) and distal (brachial artery) arterial pressure following NTG. In this study, some patients did not transmit the hypotensive effect of NTG to the peripheral circulation, as evidenced by failure of the brachial artery pressure to decline after 0.3 mg of sublingual NTG. Note the expected fall in ascending aortic pressure with NTG, but not at the brachial artery. The authors attribute this phenomenon to the inability of NTG to affect the reflectance waves returning from distal vessels in the arm; thus there is no decrease in the late returning reflecting waves in the brachial artery that is clearly demonstrable in the central aorta. The failure of brachial artery or cuff blood pressure measurements to detect a nitrateinduced decrease in systolic arterial pressure may result in an important misrepresentation of the actions of NTG on arterial conductance, systemic pressure, and LV afterload. (With permission from Kelly RP, Gibbs HH, Morgan JJ, et al: Nitroglycerin has more favorable effects on left ventricular afterload than apparent from measurements of pressure in a peripheral artery. Eur Heart J 1990; 11 :138- 144.) Curr

Pmbl

Cardiol,

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1992

603

TABLE 3. Hemodynamic Effects of Nitrates in the Normal Circulation and in Congestive Heart Failure with Contractile Dysfunction Normal Blood pressure Heart rate LV filling pressure Stroke volume

SYMPATHETIC

NERVOUS

LV

CHF

Decrease

No change

Increase Decrease

No change Decrease

Decrease

No change modest

or increase

SYSTEM

If blood pressure falls following nitrate administration, reflex sympathetic discharge may act to counteract systemic hypotension. Thus tachycardia and vasoconstriction often follow nitrate administration; these changes can obviate some of the beneficial effects of the administered drug. Sympathetic discharge is more marked in regional circulations with a rich autonomic nerve supply and may be different in magnitude among different vascular beds. An increase in heart rate is common after NTG and may produce symptoms of palpitations. Marked reflex tachycardia can increase myocardial work and negate some of the benefits of nitrate-induced peripheral dilation. Patients with impaired LV function, particularly those with congestive heart failure, demonstrate far less sympathetic discharge than do those with a normal circulation. In fact, nitrates are particularly well tolerated in such patients. Table 3 lists some of the differences in hemodynamic responses to nitrates between normal patients and those with LV dysfunction. MYOCARDIAL

OXYGEN

CONSUMPTION

The net effect of the varied peripheral actions of the nitrates in the venous, arterial, and even arteriolar vasculature is a reduction in the preload and afterload of both the left and right ventricles. Venodilatation results in a sequestration of blood away from the heart and lungs and causes a decrease in cardiac chamber size (Figure 9). Many studies have confirmed a reduction in LV end-diastolic and end-systolic cavity dimensions after nitrate administration.42 In addition, there is a substantial fall in ventricular filling pressure. A lower pulmonary capillary pressure contributes to decreased pul504

Curr

Probl

Cardiol,

August

1992

END - DIASTOLIC VOLUME SuBLlNGueLNTG

5J

wo

w

MINUTES

FIG 9. Reduction in LV end-diastolic volume following administration of sublingual NTG or 2% NTG ointment. The data represent calculations derived from measurements of LV diameter obtained by M-mode echocardiography in nine normal subjects. Similar reductions in LV end-systolic diameter and volume were observed. (With permission from Abrams J: Pharmacology of nitroglycerin and long-acting nitrates and their usefulness in the treatment of congestive heart failure, in Gould L, Reddy CVR (eds): Vasodilator Therapy for Cardiac Disorders. Mt. Kisco, New York, Futura Publishing, 1979, pp 1299167.)

monary artery pressure at rest and exercise. Nitrates directly dilate the pulmonary arterial bed and have been used with varying degrees of success to treat pulmonary hypertension in a variety of conditions. The increase in arterial conductance and decrease in vascular tone, and at high nitrate concentrations the fall in peripheral resistance, result in substantial unloading of the left ventricle. Systolic blood pressure falls and LV ejection is more efficient and complete. These peripheral manifestations of nitrates contribute to reduced cardiac work and lowered myocardial oxygen requirements (Figure 6). In patients with ischemic heart disease, the decline in myocardial energy demands following nitrate administration improves the oxygen demand/supply ratio and alleviates or even prevents myocardial ischemia in patients with coronary artery obstructions. Nitrates improve both systolic and diastolic indices of oxygen consumption.3n These drugs are also effective in lowering MVO, during exercise because of the reduction in intracardiac volumes and pressures during physical activity.43 This effecta lowering of MVO,- has long been believed to be the primary mode of action for NTG and the organic nitrates. Curr

Probl

Cardiol,

August

1992

505

MECHANISMS OF NITRATE ACTION: CORONARY VASODILATATION

CENTRAL

OR

It is well known that NTG is a potent dilator of the coronary arterial bed. In fact, the nitrates are more potent than the calcium antagonists in increasing coronary arterial diameter in the resting state.& Global coronary blood flow increases transiently after sublingual NTG but declines below baseline after several minutes as the heart becomes smaller, intracardiac systolic and diastolic pressure declines, and MVO, decreases. In spite of this late decrease of total coronary flow after the peak nitrate effect, it has been shown repeatedly that regional zones of myocardial ischemia are improved following NTG, with a restoration toward normal of the disordered subendocardial/epicardial blood flow ratio.4”’ 46 It is now widely accepted that nitrates have beneficial effects on the coronary circulation in most patients with ischemic heart disease. Table 4 lists the various central actions of nitrates. Whereas it has previously been believed that epicardial coronary arterial dilation was of little clinical significance,“’ it now seems clear that the coronary dilating actions of these drugs are important in some or many patients. Disordered coronary vasomotor tone or episodic coronary artery vasoconstriction is common in patients with angina or silent myocardial ischemia. Phasic reductions in coronary caliber and blood flow probably occur throughout the day in many to most patients with coronary atherosclerosis. Some of these alterations may reflect disordered endothelial function; some may be a result of increased sensitivity of coronary arteries to catecholamines and other potential constrictor stimuli. Thus in mixed angina, a clinical diagnosis made in patients who have a variable angina threshold from day to day and/or frequent episodes of pain at rest, it is specuTABLE Beneficial Central

4. Effects or Coronary

of Nitrates

in Angina

Pectoris:

Actions

Coronary artery (epicardial) vasodilatation Prevention/reversal of coronary artery vasoconstriction and spasm Coronary stenosis dilatation (eccentric lesions) Enhanced collateral caliber and flow Prevention of distal coronary vessel and/or collateral constriction Preserved coronary vasodilator response in presence of endothelial dysfunction Dilation of small (resistance) vessels with large doses 506

Potential

Mechanisms

of Action.

II.

Results All actions: increased regional coronary during ischemia

Curr

Probl

global and/or blood flow, especially

Cardiol,

August

1992

lated that transient increases in focal or generalized coronary vasomotor tone occur, often precipitating painful or painless ischemia. Nitrates should be excellent drugs in reducing such ischemia because they provide a vasodilator milieu and prevent coronary vasoconstriction. Rare patients with true vasospastic or Prinzmetal’s angina have long been known to respond to nitrates; some studies suggest that calcium antagonists offer no greater benefit than nitrates in this syndrome .47,48 An important observation more than a decade ago has provided an additional insight into nitrate efficacy. Brown et al demonstrated that many coronary atherosclerotic stenoses are capable of an alteration in luminal area4’ (Figure 101. Thus, a stable coronary lesion may undergo enlargement or dilatation, or a reduction in crosssectional area (stenosis constriction). NTG and other nitrates are capable of enlarging such stenoses, and the concept of coronary steno-

cl

CONTROL

rNORMALq 0 -25

25-45

45-65

86es

CONTROL DIAMETER STENOSIS tX STENOSISI

FIG 10. NTG-induced increases in luminal cross-sectional area of coronary arteries and coronary atherosclerotic stenoses. Each bar represents the average increase in cross-sectional area for the group before and after sublingual NTG. The calculated percent increase in the cross-sectional area was greater in smaller coronary arteries and in the more severe coronary narrowings. (With permission from Brown BG, Bolson EL, Peterson RB, et al: The mechanisms of nitroglycerin action. Stenosis vasodilation as a major component of drug response. Circulation 1981; 65: 10891097.) Curt- Probl

Cardiol,

August

1992

607

sis dilatation has emerged. Other laboratories, particularly in Switzerland and West Germany, have confirmed these observations,“o’51 which are somewhat controversial. It is postulated that stenosis caliber change can occur in atherosclerotic lesions when a sufficient rim or arc of normal media remains in the arterial wall; this portion of vascular smooth muscle retains the ability to constrict or relax. NTG induces relaxation, with a resultant increase in the stenosis diameter and a fall in the resistance across the obstruction. Furthermore, recent data from Gage et al have indicated that coronary stenoses may change their diameter during physical exertion, usually with a deleterious narrowing or worsening of the obstruction5’ (Figure II). These investigators believe that exercise-induced constriction of stenoses may be common in patients with chronic stable angina, and that this mechanism is of considerable importance in the precipitation of ischemia and angina during physical activity or emotional stress. NTG is able to prevent and reverse this phenomenon (Figure 11). Stenosis dilatation represents another mechanism of nitrate efficacy in patients with ischemic heart disease. Coronary collateral vessel dilatation, with increased collateral flow, is an additional beneficial action of nitrates. Furthermore, a recent observation by Pupita et al suggests that collateral vessel or distal coronary arterial vasoconstriction may induce myocardial ischemia in patients with a totally obstructed coronary artery where the downstream vessel distal to the obstruction is supplied by collateral or small distal coronary arteries.5’ This is reversed by NTG. Disordered endothelial function, as previously discussed, is an important new concept in our understanding of nitrate effectiveness in ischemic heart patients. NTG and ISDN are endothelial-independent dilators of vascular smooth muscle and are actually more effective in the presence of abnormal EDRF release (see Figure 4).5”, ” Furthermore, platelet aggregation and activation, with subsequent release of serotonin and other vasoactive substances, are potent factors in producing coronary vasoconstriction in the setting of coronary atherosclerosis and disordered endothelial function. Two recent studies have utilized serotonin as a probe to induce coronary artery constriction and myocardial ischemia.55,56 These adverse responses to serotonin, a ubiquitous compound in circulating platelets, suggest that platelet activation is a potentially deleterious phenomenon in susceptible patients with disordered endothelial responsiveness. NTG is predictably effective in reversing serotonin-induced vasoconstriction (Figure 12). If the organic nitrates truly have an antiaggregating effect on circulating platelets, as discussed above, these drugs could be particularly effective in preventing or decreasing coronary thrombosis, particularly early in the evolution of an intracoronary thrombus. Thus nitrates should be effective in the acute ischemic syndromes of un508

Cm-r

Probl

Cardiol,

August

1992

1 150 tu

NORMALVESSEL

6ROUP I

STENOSIS T

150

1,100

FIG 11. Coronary artery and atherosclerotrc stenosrs caliber changes with exercise in patients wrth angina. In this study, patients with severe angina pectoris were exercised on a bicycle in the catheterization laboratory to the onset of chest pain. Coronary arteriography was carried out using careful methodology to isolate a normal coronary vessel as well as the maxrmal atherosclerotic narrowing in a diseased artery. Patients in group 1 were exercrsed to the point of angina pectoris and were then given sublrngual NTG. Repeat arteriograms were obtained at peak exercise and after NTG. Individuals in group 2 were pretreated with intracoronary NTG immediately prior to exercise. Note that in group 1 patients there was a modest but definite enlargement of the normal coronary artery caliber during exercise, which further increased with the administration of sublingual NTG. On the contrary, there was a significant reduction in the diameter of the coronary stenosrs during exercise and at peak exercise. This was reversed with the administration of sublingual NTG. In the NTGpretreated patients (group 2) intracoronary NTG produced coronary vasodilation that increased slightly during exercise. Pretreatment with rntracoronary NTG completely prevented the decrease in atherosclerotic stenosis diameter; the stenosis area Increased during exercise. Thus study is consistent with exercise-induced stenosis constriction in angina pectoris, which is preventable or reversible by NTG. (With permission from Gage JE, Hess OM, Murakami T, et al: Vasoconstriction of stenotic coronary arteries during dynamic exercise in patients wrth classic angrna pectoris. Reversibility by nitroglycerin. Circulation 1986; 73865-876.)

stable angina pectoris and acute MI. Considerable data are concordant with nitrate efficacy in these important clinical conditions.3”-34 In summary, the organic nitrates have a wide variety of potential mechanisms to provide relief or prevention of ischemia in subjects with coronary atherosclerosis (see Tables 2, 4). Their classic peripheral vascular actions in reducing cardiac size and myocardial oxygen consumption are amplified by a number of direct coronary circulatory effects that have been shown to be beneficial in various investigations. The emerging understanding of endothelial dysfunction (NO-penis), coupled with the recognition that the nitrates are prodrugs that release NO within the vascular smooth muscle cell, proCurr

Probl

Cardiol,

August

1992

509

1401

Group1

Group2

Base

S

lo-'

10-G

W5

lo-'

ISDN

Line

Serotonin

(mol/liter)

FIG 12. Abnormal responses of the coronary atherosclerotic artery to intracoronary serotonin. In this protocol, graded doses of serotonin were directly infused into the coronary arteries in normal patients (group 1) and in patients with coronary artery disease and angina pectoris (group 2). Quantitative angiography was used to assess epicardial coronary artery caliber in the proximal, middle, and distal segments of each coronary artery. The normal or control group revealed a mild vasodilatory response at the first three doses infused, with coronary artery vasoconstriction seen at the 10m4 M/L dose. In contrast, patients with coronary artery disease showed detectable coronary artery constriction beginning with the 1O-6 M/L dose, becoming progressively greater with increasing serotonin concentrations, In these patients with stable angina, the maximal coronary artery decreases in diameter were 23.9%, 33.1%, and 41.7%, respectively, from baseline in the proximal, middle, and distal segments at the highest concentration of infused serotonin. Furthermore, angina and EKG changes of ischemia were noted in most of the patients with stable angina. These findings suggest that patients with angina and coronary atherosclerosis have an abnormal vasoconstrictor response to serotonin instead of the physjologic biphasic response with vasodilatation at lower doses. Furthermore, these data suggest that activation of platelets within the coronary circulation could produce myocardial ischemia in such subjects with disordered endothelial function. (With permission from McFadden EP, Clarke JG, Davies GJ, et al: Effect of intracoronary serotonin on coronary vessels in patients with stable angina pecoris and with variant angina. N Engl J Med 1991; 324:648-653.)

510

Curr

Probl

Cardiol,

August

1992

vides a fascinating coincidence that links clinical efficacy of these old drugs with our most contemporary understanding of vascular pathology. LEFT VENTRICULAR

DYSFUNCTION

AND NITRATE

ACTION

Many of the actions of nitrates, particularly systemic venodilatation and arterial dilatation, are beneficial in the compromised heart with systolic or contractile impairment. Reduction of cardiac preload, concomitant with a decrease in afterload, is an important factor contributing to the usefulness of these drugs in patients with congestive heart failure and possibly asymptomatic LV dysfunction. In heart failure patients, as in normal patients, NTG compounds cause a sequestration of the central blood volume away from the heart and lungs, with a decrease in right heart and left heart filling pressures (see Tables 2, 3). The reduction in afterload preserves LV stroke volume, typical of vasodilator effects of arterial dilators in congestive heart failure?s Although many physicians do not believe that the degree of arterial relaxation is important with nitrate administration, this is a misconception; without such an effect in peripheral arteries, nitrates would decrease stroke volume in patients with heart failure (see Table 3). PHARMACOLOGY

AND P HARMACOKINETICS

OF NITRATES

A variety of organic nitrates have been marketed over the past few decades. Several molecules were synthesized in the mid-20th century, but most have gone by the wayside ieg, erythrityl tetranitrate, pentaerythritol tetranitrate, mannitol hexanitrate). Only three organic nitrates are in use today: NTG, ISDN, and 5-ISMN. All are clinically effective. Nitrates are metabolized in the vascular wall of veins and arteries, in red blood cells, and in the liver CXSMN does not undergo hepatic degradation). NITROGLYCERIN NTG is one of the oldest effective drugs available. It has a short half-life of several minutes. NTG is rapidly metabolized to two congeners, l,2- and 1,3-glyceryl dinitrate; these molecules are bioactive, but most experts do not believe that they play a practical role in NTG therapy. NTG undergoes rapid elimination from the plasma and is distributed widely throughout the body. Plasma NTG concentrations, difficult to assay, are quite low; the therapeutic threshold has been estimated to be 1 to 1.5 mc#m1.57’ 58 There is wide intraand inter-subject variability in plasma concentrations of NTG after Cur-r Probl

Car&d,

August

1992

511

any form of administration. Fung has estimated that plasma NTG levels reflect only 1% of the total body stores.5Y Plasma clearance of NTG is quite high (10 to 50 L/min) and is in part dependent on cardiac output. There is a large arterial-venous gradient of NTG in the plasma, which is augmented in heart failure. Nitroglycerin is a very malleable molecule and can be utilized in a variety of drug delivery systems. It is available in the following formulations: sublingual, transmucosal or buccal, intravenous, oral spray, ointment, patch (NTG in a matrix or gel) formulation, and oral sustained-release capsules and tablets.

ISOSORBIDE

DINITRATE

ISDN is a useful nitrate compound. It was first synthesized in 1938. It is the most widely prescribed nitrate effective for oral therapy, although 5-ISMN appears to be equally beneficial. Plasma levels of ISDN and its metabolites are quite high when compared with NTG, and ISDN compounds are easily assayed (Figure 13). Hepatic degradation is an important factor relating to pharmacokinetics of ISDN; after oral dosing, only 20% to 25% of the molecule is bioavailable. Its two metabolites, 2 and 5-ISMN, are easily measured in the plasma and have longer half-lives than the parent compound (see Figure 13). The half-life of ISDN is 40 to 90 minutes, whereas the halflife of 5-ISMN is 4 to 5 hours. Differences in biologic activities of the various organic nitrates have been seen in isolated smooth muscle and platelet aggregation experiments, and it is possible that important aspects of nitrate action may differ among the various compounds. Nevertheless, among the three major nitrate compounds, there are no clinical data suggesting substantive differences in hemodynamic action or in effectiveness in relieving symptoms. Plasma concentrations of ISDN and its metabolites are more predictable and fluctuate less than do those of NTG. The systemic clearance of ISDN is much lower than that of NTG and is approximately equivalent to the cardiac output. There is a very small arterialvenous gradient of this compound.

5-ISOSORBIDE

MONONITRATE

This molecule was synthesized de novo and has been commercially available in Europe and Scandinavia. The U.S. Food and Drug Administration (FDA) approved 5-ISMN for use in angina pectoris in December 1991. The major advantages of this compound are lack of hepatic biodegradation, with 100% bioavailability after oral administration; high and sustained plasma concentrations; and the absence Thus 5-ISMN provides predictable of any bioactive metabolites. 512

Curr

Probl

Cardiol,

August

199.2

blood levels after oral dosing, with a long duration of action (see Figure 13). Both ISDN and 5-ISMN are available in sustained-release formulation.

ISDN VS 5-ISMN Although pharmaceutical manufacturers and some experts believe that 5-ISMN is a superior drug because of its different pharmacokinetic profile, it is not clear that there are any notable differences between these two