INTRODUCTION — Nitroglycerin was the first medication used in 1879 by William Murrell for the treatment of angina pectoris [1] and, in its extended release forms, still remains first-line drug therapy for many patients [2,3].
While they act as venodilators, coronary vasodilators, and modest arteriolar dilators, the primary antiischemic effect of nitrates is to decrease myocardial oxygen demand by producing systemic vasodilation more than coronary vasodilation. This systemic vasodilation reduces left ventricular systolic wall stress.
In patients with exertional stable angina, nitrates improve exercise tolerance, time to onset of angina, and ST-segment depression during exercise testing. In combination with beta blockers or calcium channel blockers, nitrates produce greater antianginal and antiischemic effects. (See "Angina pectoris: Chest pain caused by fixed epicardial coronary artery obstruction" and "Chronic coronary syndrome: Overview of care".)
Its use, however, is complicated by the development of tolerance with continuous therapy. (See 'Nitrate tolerance' below.)
MECHANISM OF ACTION — Nitrates dilate veins, arteries, and coronary arteries by relaxing vascular smooth muscle [4]. They produce these effects by entering vascular smooth muscle cells where they are metabolized to 1,2-glyceryl dinitrate and nitrite, via mitochondrial aldehyde dehydrogenase-2 (ALDH2 or mtALDH), and then nitric oxide and S-nitrosothiols (figure 1) [5]. Sulfhydryl groups on ALDH2 are required for activity, which can explain the known sulfhydryl requirement for vascular smooth muscle relaxation by nitrates [5].
Most of the antiischemic efficacy of nitrates pertains to their ability to decrease myocardial oxygen demand as a result of systemic vasodilatation rather than any activity as a coronary vasodilator. Nitrates do not have a direct effect on cardiac chronotropy or inotropy.
Effect on systemic hemodynamics — The nitrates are primarily venodilators due to increased bioavailability to venous smooth muscle cells. Venodilation lowers preload (left ventricular end-diastolic pressure) and therefore reduces wall stress, resulting in a decrease in myocardial oxygen demand. The fall in preload is more pronounced with sitting or standing.
At low doses, nitrates cause a lesser degree of arterial and arteriolar dilatation, leading to little or no change in systemic vascular resistance or blood pressure [4]. As the dose is increased, the blood pressure falls, often accompanied by reflex tachycardia. Wall stress is reduced at the lower blood pressure, resulting in a further decrease in myocardial oxygen demand.
Some patients, especially those with hypovolemia, are extremely sensitive to the arteriolar effect of nitrates and develop a profound drop in blood pressure which can aggravate myocardial ischemia. In addition, arteriolar dilatation of the face can cause flushing and meningeal arterial dilatation can cause headache, two common side effects of these drugs.
Problems can also occur with excessive venodilation. This can result in a marked decrease in venous return, which induces cardiac emptying that triggers mechanical receptors in the heart, possibly leading to hypotension and bradycardia consistent with the Bezold-Jarisch reflex (vasovagal response) [6]. (See "Reflex syncope in adults and adolescents: Clinical presentation and diagnostic evaluation".)
Effect on coronary hemodynamics — A nitrate-induced increase in coronary blood flow has been proposed as a potential mechanism for relieving ischemia. Animal and human studies have shown that nitrates dilate both normal and abnormal coronary arteries [7]; this response is preserved in saphenous vein grafts [8]. The clinical importance of this effect is uncertain because the coronary arterioles in patients with a flow-limiting coronary stenosis are already dilated to maintain resting blood flow, making further coronary dilation during ischemia difficult.
There are, however, settings in which a direct effect on coronary hemodynamics may be beneficial. Nitrates can reduce or reverse coronary vasospasm [9]. Thus, patients with primarily vasospastic angina or a large vasoconstrictor component to their angina can benefit from the direct coronary action of nitrate therapy. Nitrates also indirectly improve subendocardial blood flow as the reduction in left ventricular end-diastolic pressure induced by systemic venous dilatation decreases the resistance to coronary blood flow from epicardium to endocardium [10]. In addition, nitrates may lower the resistance to collateral vessel blood flow [11].
Antiplatelet and antithrombotic properties — Nitrates have significant antiplatelet and antithrombotic properties; however the clinical importance of these potentially beneficial effects is unclear [12]. Stimulation of platelet guanylate cyclase by nitrates prevents fibrinogen binding to platelet IIb/IIIa receptors, which is essential for platelet aggregation [13]. Transdermal nitroglycerin has been shown to inhibit platelet aggregation and thrombus formation in patients with angina [14].
USE — Nitrates, usually in the form of a sublingual preparation, are the first-line therapy for the treatment of acute anginal symptoms. Patients should be instructed to use them at the onset of angina.
A sublingual nitroglycerin tablet may be recommended for the prophylaxis of anginal episodes and we often recommend them in patients with predictable and stable angina. For example, patients who have undergone incomplete revascularization who get angina at a predictable workload may be good candidates for prophylactic nitroglycerin. Some patients may benefit from a repeat dose if angina occurs during the activity.
Long-acting nitrates are added to beta blockers (with or without calcium channel blockers) to control stable angina. In patients with exertional stable angina, chronic nitrate therapy using oral or dermal preparations improves exercise tolerance, time to onset of angina, and ST-segment depression during exercise testing. In combination with beta blockers or calcium channel blockers, nitrates produce greater antianginal and antiischemic effects compared with those drugs without nitrates. However, the long-term utility of nitrates is limited by the induction of nitrate tolerance.
NITRATE TOLERANCE — Tolerance has been a major problem with the use of nitrates as chronic antianginal therapy. It was first observed in individuals exposed to nitroglycerin during the production of explosives. These workers developed severe headache and dizziness after the initial exposure. These side effects would then diminish after several days. If, however, exposure was avoided for several days, the symptoms would return after reexposure.
A similar sequence occurs in humans as chronic nitrate therapy for angina pectoris is associated with attenuation and at times abolition of the hemodynamic and antianginal effects.
Mechanisms of tolerance — How nitrate tolerance occurs is incompletely understood. It is due to attenuation of the vascular effect of nitrates, not to altered pharmacokinetics [2].
At least three, not mutually exclusive, mechanisms have been proposed to explain the development of nitrate tolerance [2]. These include:
●Impaired nitroglycerin bioconversion to 1,2-glyceryl dinitrate with decreased formation of nitric oxide. This effect is nitrate-specific and is not seen with non-nitrate sources of nitric oxide such as nitroprusside [15]. Consistent with this theory are the experimental observations that there is no tolerance to the effect of S-nitrosothiols and that the activity of mitochondrial aldehyde dehydrogenase-2 (mtALDH), the enzyme required for metabolism of nitrates to 1,2-glyceryl dinitrate in markedly reduced [5]. The same findings can be induced by inhibitors of mtALDH [5].
●Reduced bioactivity of nitric oxide [16]. Consistent with this theory is the finding in an animal study that vascular and hemodynamic tolerance to nitrates occurred despite high levels of nitric oxide and rates of nitric oxide formation that were similar in those animals that were not tolerant [17]. Also in support of this hypothesis is that transgenic animals that overexpress endothelial nitric oxide synthase have chronically elevated nitric oxide release, which is associated with reduced vascular reactivity to nitric oxide-mediated vasodilators [18].
●Activation of the vasoconstrictor renin-angiotensin-aldosterone and sympathetic nervous systems in response to nitrate-induced vasodilation [19,20]. There is also increased peripheral sensitivity to these vasoconstrictors, an effect that can be reversed by angiotensin converting enzyme inhibition [19]. Abnormal coronary vasoconstrictor responses have also been described with continuous nitrate exposure [21].
Prevention — Several strategies have been attempted to prevent nitrate tolerance, the most effective being intermittent therapy with an adequate nitrate-free interval (around 8 to 10 hours). It is thought that a nitrate-free interval permits the regeneration of reduced sulfhydryl groups, thereby restoring vascular responsiveness to nitrates. Chronic therapy with N-acetylcysteine, a sulfhydryl donor, does not appear to be effective in patients with stable angina [22], in contrast to its acute benefit with intravenous nitroglycerin in those with unstable angina. (See "Nitrates in the management of acute coronary syndrome".)
There are, however, two concerns regarding intermittent therapy:
●A time-zero effect, which refers to a deterioration in exercise performance relative to placebo prior to the morning dose of nitrates.
●Rebound angina, which refers to an increase in angina during the nitrate-free interval. There may result from a supersensitivity of the vessel wall to vasoconstrictors [23] or an increased vasomotor response to acetylcholine, suggesting the development of endothelial dysfunction [24].
Whether these effects occur to a clinically significant degree remains unclear [25-28]. Their importance with the different nitrate preparations will be discussed below.
Several other methods have been proposed to reduce nitrate tolerance, although none is as yet used clinically:
●Folic acid can reverse endothelial dysfunction, possibly by restoring the bioavailability of tetrahydrobiopterin, a cofactor for nitric oxide synthase and/or arginine, its substrate. This suggests a possible role for folic acid in preventing nitrate tolerance. This was examined in a study of 18 subjects who were randomly assigned to folic acid (10 mg/day) or placebo for one week; all patients received continuous transdermal nitroglycerin (0.6 mg/hour) [29]. Compared to placebo, folic acid prevented the development of both endothelial dysfunction and nitrate tolerance.
●Treatment for five to 10 days with L-arginine, the substrate for nitric oxide synthesis, can modify or prevent the development of nitrate tolerance during continuous transdermal nitroglycerin use [30].
●Hydralazine may attenuate nitrate tolerance, perhaps by preventing superoxide generation [31]. This relationship could contribute to the efficacy of combined nitrate-hydralazine therapy in patients with heart failure. (See "Overview of the management of heart failure with reduced ejection fraction in adults".) In patients with angina pectoris, hydralazine should be given in combination with a beta blocker because of the reflex sympathetic activation.
●Other antioxidants may be helpful, at least from a theoretical perspective, such as vitamin E [32] and vitamin C [33,34]. In addition, carvedilol, a beta and alpha blocker that also has antioxidant activity, may prevent nitrate tolerance [35]. The importance of antioxidant activity was suggested by a second report which compared carvedilol with another beta and alpha blocker (arotinolol) that was devoid of antioxidant properties; only carvedilol prevented nitrate tolerance [36].
Other drugs have had variable or no effect. These include angiotensin converting enzyme inhibitors [19,37-39], and diuretics, which may have some antianginal activity by reducing the plasma volume [39,40].
COMMONLY USED NITRATE PREPARATIONS — Numerous nitrate preparations are commercially available, including sublingual, buccal, oral, spray, ointment, and transdermal preparations.
Sublingual nitroglycerin — Sublingual nitroglycerin remains the therapy of choice for acute anginal episodes and prophylactically for activities known to elicit angina such as mowing the lawn, playing tennis, or walking in cold weather. Our impression is that the prophylactic use of nitroglycerin is not sufficiently emphasized to patients.
The onset of action is within two to five minutes and the duration of action is 15 to 30 minutes. Tolerance is not a problem with sublingual nitroglycerin because of its intermittent administration, even in patients on chronic nitrate therapy [41].
The recommended nitroglycerin dose is 0.3 mg (1/200 grains) to 0.4 mg (1/150 grains).
The traditional recommendation is for patients to take one nitroglycerin dose sublingually every five minutes for up to three doses before calling for emergency medical services (EMS) evaluation. However, studies suggest that this approach may result in significant delays in obtaining EMS assistance [42,43]. For patients known to their providers to have frequent angina, physicians may consider a selected, more tailored message that takes into account the frequency and character of the patient's angina and their typical time course of response to nitroglycerin.
If the sublingual nitroglycerin is potent, a slight tingling sensation should be felt under the tongue. Tablets that crumble easily should not be used. The sublingual mucosa should be moist for adequate dissolution and absorption of the tablet. A drink of water in patients with dry sublingual mucosa prior to ingestion of the tablet may be necessary [44].
Nitroglycerin tablets are both heat and light sensitive. They should therefore be stored in a tightly capped dark bottle in the refrigerator with only a small supply being carried by the patient. Nitroglycerin tablets in an opened bottle should be discarded after 12 months.
Patient education is extremely important for the proper use of sublingual nitroglycerin. A survey of 50 patients revealed a surprising lack of knowledge concerning the administration, storage, and side effects of this preparation [45]. Only 12 percent knew the maximum dose in a 15 minute period, 28 percent knew the proper storage conditions for sublingual tablets, and 52 percent knew the most common side effects. It is important for health care providers, when reviewing the medication list of coronary artery disease patients, to ensure that patients have an active prescription for nitroglycerin.
Nitroglycerin spray — A less popular but equally effective means of administering sublingual nitroglycerin is by metered dose spray. The spray dispenses of 0.4 mg of nitroglycerin. One to two sprays can be used at the start of an attack and up to three sprays can be used in a 15 minute period. It has a shelf life of two to three years [46].
Isosorbide dinitrate — Isosorbide dinitrate (ISDN) is uncommonly used in practice. It has an onset of action within 15 to 30 minutes and the duration of action is three to six hours. Low bioavailability from hepatic metabolism has necessitated relatively large doses of 10 to 40 mg three times daily.
The beneficial effects of a single dose of ISDN (15, 30, 60, 120 mg) were demonstrated in 12 patients with chronic stable angina [41]. There was a dose-related reduction in systolic blood pressure that persisted for eight hours. Exercise duration improved up to eight hours after the 15 and 30 mg dose; there was no added benefit with the 60 and 120 mg doses (figure 2).
Unfortunately, tolerance has limited the usefulness of ISDN as a chronic antianginal agent. In the study above, ISDN was given four times daily for two weeks [47]: both the blood pressure and exercise responses were attenuated (figure 2). In particular, exercise duration was only increased for two hours after a dose and doses above 15 mg four times daily produced no added benefit. The development of tolerance occurred despite higher plasma concentrations of ISDN during maintenance therapy.
Several studies have altered the drug regimen in an attempt to prevent the development of tolerance. One study, for example, examined the effect of 30 mg of ISDN given two (7 AM and 12 PM), three (7 AM, 12 PM, and 5 PM), and four (7 AM, 12 PM, 5 PM, and 11 PM) times daily for one week [48]. Exercise duration until the onset of angina was assessed before and one, three, and five hours after the morning dose. After a single initial dose, exercise duration significantly increased versus placebo over the five hour observation period. After one week of therapy, two and three (but not four) times daily dosing was associated with improved exercise tolerance compared placebo; however, the benefit was less pronounced late in the day, indicating partial tolerance. One limitation to the clinical utility of these results is that the response was measured only to the morning dose of ISDN.
Another report questioned the antianginal efficacy of three times daily ISDN [49]. Eight patients with chronic stable angina were given ISDN at 8 AM, 1 PM, and 6 PM. Exercise time increased for at most three hours after the morning and afternoon dose but not substantially after the evening dose (figure 3). It was concluded that ISDN given three times daily offered antianginal protection for at most six hours.
Isosorbide mononitrate — Extended-release isosorbide mononitrate is the most commonly used oral nitrate. The dose and side effects of the mononitrates are similar to those of isosorbide dinitrate, and intolerance can occur [50].
Transdermal nitroglycerin — Transdermal nitroglycerin patches obtained United States Food and Drug Administration approval in 1981 and gained wide acceptance for its convenience. They are rarely used by our contributors.
Pentaerithrityl tetranitrate — Pentaerithrityl tetranitrate is a long-acting nitrate vasodilator that has been used in patients with angina, in part because some studies have shown that it did not induce nitrate tolerance [51]. In the CLEOPATRA study, 655 patients with chronic stable angina were randomly assigned to pentaerithrityl tetranitrate (80 mg twice) daily or placebo [52]. After 12 weeks, there was no difference in the primary end point of total exercise duration.
ADVERSE EFFECTS — Headache and flushing are common symptoms in patients taking nitrate therapy, and hypotension can occur.
Contraindications — Nitrates are contraindicated in the following settings:
●In patients who have taken sildenafil or vardenafil within 24 hours or tadalafil within 48 hours (because of the risk of severe hypotension). (See "Sexual activity in patients with cardiovascular disease".)
●In patients with hypertrophic cardiomyopathy in whom nitrates can induce or increase outflow tract obstruction, even in those not known to have a resting gradient. (See "Hypertrophic cardiomyopathy: Medical management for non-heart failure symptoms".)
●In patients with suspected right ventricular infarction, nitrates should be avoided, if possible, because of the increased risk of inducing hypotension. (See "Right ventricular myocardial infarction".)
In addition, nitrates should be used cautiously in patients with severe aortic stenosis or volume depletion.
Our recommendations for the use of nitrates are generally consistent with those of guideline organizations.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic coronary syndrome".)
SUMMARY AND RECOMMENDATIONS
●Nitrates – Sublingual nitroglycerin remains the treatment of choice for an acute anginal attack or for prophylaxis prior to activities known to exacerbate angina. Chronic nitrate therapy is used to prevent recurrent anginal episodes but must be dosed correctly in order to prevent tolerance. Allowing for a sufficient nitrate-free interval, nitrates may be given during the day or at night depending upon the patient's symptom complex:
•In patients with primarily exertional angina, nitrates are given during the day when the patient is more active.
•In patients with nocturnal angina or heart failure, therapy at night may be more beneficial.
Nitrates are especially useful in patients with heart failure, particularly at night in those with significant orthopnea or paroxysmal nocturnal dyspnea. In addition, patients with exertional dyspnea may benefit if nitrates are taken prior to exertion.
There is no difference in efficacy among isosorbide dinitrate and transdermal nitroglycerin. Because of the problems with tolerance and rebound angina in the nitrate-free interval, we usually reserve chronic nitrate therapy for second line antianginal therapy. What follows are our recommendations for administering the most commonly used nitrate preparations. The use of nitrates in specific clinical settings is discussed separately.
•Sublingual nitroglycerin – Sublingual nitroglycerin remains the therapy of choice for acute anginal episodes and prophylactically for activities known to elicit angina such as mowing the lawn, playing tennis, or walking in cold weather. Our impression is that the prophylactic use of nitroglycerin is not sufficiently emphasized to patients.
We give all patients with stable angina a prescription for sublingual nitroglycerin (tablets or spray, depending upon patient preference). Patient education concerning proper dosing, storage, and side effects of sublingual nitroglycerin is extremely important. (See 'Sublingual nitroglycerin' above.)
•Isosorbide dinitrate – Proper dosing with isosorbide dinitrate is essential to prevent tolerance. We recommend a dosing schedule of 8 AM, 1 PM, and 6 PM, which results in a 14 hour nitrate dose-free interval. We begin with a dose of 10 mg three times daily, and advance to 40 mg three times daily as needed. Alternatively, isosorbide dinitrate can be taken twice daily at 8 AM and 4 PM. For this reason, we rarely use this preparation; we prefer the sustained-release once-a-day preparation (see below) since it can be given once daily.
•Isosorbide mononitrate – Some of our experts prefer isosorbide mononitrate to dinitrate. When chosen, we prefer the sustained release preparation given its ease of use. (See 'Isosorbide mononitrate' above.)
•Transdermal nitroglycerin – Nitroglycerin can be given transdermally in the form of a patch. The patient must remember to remove the patch for 12 to 14 hours. If the patient has angina with activity, we suggest that the patch be applied at 8 AM and removed at 8 PM. If the patient has significant nocturnal angina, the patch can be worn from 8 PM to 8 AM. We begin with a dose of 0.2 mg/hour; the dose can be increased to 0.8 mg/hour as needed. Since it can be difficult to remember to remove the patch after 12 hours, we do not use this option often, preferring the once-daily sustained-release isosorbide mononitrate.
