Nitrates and Nitrites General Statement (Monograph)

Drug class: Nitrates and Nitrites

Introduction

Organic nitrates and nitrites are vasodilating agents.

Uses for Nitrates and Nitrites General Statement

Chronic Stable Angina

Nitrates and nitrites are used for the acute symptomatic relief of angina pectoris secondary to coronary artery disease, for prophylactic management in situations likely to provoke angina attacks, and for long-term prophylactic management of chronic stable angina.^{600 806 807 809 810 811 813 817 823 1101}

Conventional measures in the management of angina pectoris are aimed at reducing the frequency, duration, and severity of attacks, and include coronary risk reduction (e.g., discontinuance of smoking, weight control, antilipemic strategies) rest, avoidance of precipitating circumstances (e.g., eating heavy meals, getting emotionally upset, performing strenuous exercise, exposure to cold air) and, if possible, treatment of the underlying cause.

Since nitrites and individual nitrates have similar pharmacologic and therapeutic properties, the choice of a preparation depends mainly on the onset and duration of action required. Short-acting nitroglycerin preparations (e.g., sublingual nitroglycerin tablets or nitroglycerin spray) generally are used for the immediate relief of acute angina attacks, but also may be used prophylactically prior to anticipated angina provoked by physical or emotional stress.^{802 806 807 809 817 823 1101} Sublingual nitroglycerin is considered the drug of choice for the acute relief of an attack of angina because it has a rapid onset of action, is inexpensive, and its efficacy is well established. Lingual nitroglycerin and other rapidly acting nitrates or nitrites (e.g., amyl nitrite inhalation) also may be useful. However, amyl nitrite is seldom, if ever, used for angina pectoris because it is expensive, inconvenient, has a high incidence of adverse effects (e.g., headache, orthostatic symptoms, tachycardia), and has an unpleasant odor.

β-Adrenergic blocking agents (β-blockers) generally are considered the initial antianginal drugs of choice for the long-term prophylactic management of chronic stable angina because of their proven benefits in reducing ischemic burden and threshold and in improving survival in patients with left ventricular dysfunction or prior myocardial infarction (MI).¹¹⁰¹ However, long-acting nitrates (i.e., oral preparations of isosorbide dinitrate or mononitrate and oral or topical nitroglycerin) also are effective antianginal agents and are recommended as second-line therapy in patients who do not tolerate or respond adequately to β-blocker therapy.¹¹⁰¹ Experts state that long-acting nitrate preparations may be considered for the prophylactic management of angina pectoris when β-blockers are contraindicated or associated with unacceptable adverse effects.¹¹⁰¹ Alternatively, long-acting nitrates may be added to β-blocker therapy if initial therapy with a β-blocker is not effective.¹¹⁰¹ Prolonged use of nitrates has been associated with the development of tolerance to the hemodynamic and antianginal effects of the drugs; therefore, a daily nitrate-free interval is recommended.¹¹⁰¹ (See Cautions: Tolerance and Dependence.) Physiologic changes (e.g., endothelial dysfunction from accumulation of oxygen free radicals) have occurred in patients receiving long-term nitrate therapy which may offset the short-term ischemic benefits of these drugs; however, further study is needed.¹¹⁰¹

Nitrates and nitrites have been used effectively with β-blockers; since these drugs act by different mechanisms of action, greater antianginal and anti-ischemic effects may be achieved when these drugs are used in combination than when either is used alone, and each agent may counteract some of the undesirable cardiac effects of the other. Calcium-channel blocking agents and nitrates act by different mechanisms, and clinical experience suggests a beneficial antianginal and anti-ischemic interaction in patients with angina. Although concomitant therapy with a nitrate, calcium-channel blocking agent, and β-blocker may be beneficial in some patients, the safety and/or efficacy of such therapy have not been fully determined.

Non-ST-Segment-Elevation Acute Coronary Syndromes

Nitrates are used in the management of non-ST-segment-elevation acute coronary syndromes (NSTE ACS).¹¹⁰⁰ Patients with NSTE ACS have either unstable angina or non-ST-segment-elevation MI (NSTEMI); because these conditions are part of a continuum of acute myocardial ischemia and have indistinguishable clinical features upon presentation, the same initial treatment strategies are recommended.^{805 1100} The American Heart Association/American College of Cardiology (AHA/ACC) guideline for the management of NSTE ACS recommends an early invasive strategy (angiographic evaluation with the intent to perform revascularization procedures such as percutaneous coronary intervention [PCI] with coronary artery stent implantation or coronary artery bypass grafting [CABG]) or an ischemia-guided strategy (initial medical management followed by catheterization and revascularization if indicated) in patients with definite or likely NSTE ACS; standard medical therapies for all patients should include a β-blocker, antiplatelet agents, anticoagulant agents, nitrates (e.g., nitroglycerin), and analgesic agents regardless of the initial management approach.¹¹⁰⁰

Sublingual nitroglycerin (0.3–0.4 mg every 5 minutes for up to 3 doses) is recommended in patients with NSTE ACS who have continuing ischemic pain; IV nitroglycerin may be used in patients with heart failure, hypertension, or persistent ischemia that is not relieved with sublingual nitroglycerin and administration of a β-blocker.¹¹⁰⁰ Since prolonged use of nitrates has been associated with the development of tolerance to the hemodynamic and antianginal effects of the drugs, an intermittent dosage schedule may be required to maintain efficacy.¹¹⁰⁰ (See Cautions: Tolerance and Dependence.) AHA and ACC state that topical or oral nitrates may be an acceptable alternative to IV therapy in patients who do not have refractory or recurrent ischemia.¹¹⁰⁰ The use of nitrates in patients with NSTE ACS is principally based on extensive clinical experience, experimental studies, and the pathophysiologic effects of the drugs rather than from randomized controlled studies.¹¹⁰⁰

Acute Myocardial Infarction

Nitroglycerin is used in the management of acute MI.^{217 218 240 241 242 527 812} The term MI is used when there is evidence of myocardial necrosis in the setting of acute myocardial ischemia.⁸⁰⁷ ST-segment-elevation MI (STEMI) is distinguished from NSTEMI based on the presence or absence of ST-segment elevation on ECG.^{527 807 808 1100} Patients with STEMI typically have complete arterial occlusion; therefore, immediate reperfusion therapy (with primary PCI or thrombolytic agents) is the current standard of care for such patients.^{527 803 805 808} Because the clinical presentation of NSTEMI is similar to that of unstable angina, these conditions are considered together in current expert guidelines.¹¹⁰⁰ (See Uses: Non-ST-Segment-Elevation Acute Coronary Syndromes.)

Sublingual nitroglycerin has been administered for the initial relief of ischemic discomfort in patients with acute MI.^{527 808} However, the manufacturer states that the benefits of sublingual nitroglycerin in patients with acute MI have not been established; if the drug is used in this setting, careful hemodynamic and clinical monitoring are essential because of the possibility of hypotension and tachycardia.⁸⁰⁹ IV nitroglycerin may be used in patients with acute MI who have ongoing chest pain, hypertension, or heart failure.^{527 808 812} Because of its onset of action, ease of titration, and opportunity for prompt termination if adverse effects occur, IV administration of the drug is preferred during the early stage of acute MI.^{217 218 236 242} In the years prior to the introduction and acceptance of reperfusion therapy, IV nitroglycerin was one of the principal initial therapies for reducing mortality and major cardiovascular mortality in patients with acute MI.^{217 236 242} In addition to potentially alleviating ischemic myocardial pain, beneficial hemodynamic effects of nitroglycerin include vasodilation of the coronary arteries (especially at or near the site of recent plaque disruption), peripheral arteries, and venous capacitance vessels.^{217 218 236 240 241 242 527} However, nitroglycerin generally does not reduce myocardial injury associated with epicardial coronary artery occlusion unless there is substantial vasospasm.⁵²⁷ Although studies conducted prior to the routine use of reperfusion therapy suggested a mortality benefit with nitrates in patients with acute MI, this benefit was not confirmed in 2 large randomized controlled studies.^{243 244 801} In addition, systemic hypotension with resultant worsening of myocardial ischemia is a potential complication of nitroglycerin therapy.²³⁶ Therefore, patients with preexisting hypotension or at risk of hypotension should not receive nitrates.⁵²⁷ Nitrates also should be avoided in patients with marked bradycardia (e.g., less than 50 bpm) or tachycardia (e.g., exceeding 100 bpm),^{240 527} and those with suspected right ventricular infarction.^{241 527} (See Cautions: Precautions and Contraindications.)

The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline for the management of STEMI states that IV nitroglycerin may be beneficial in patients with STEMI and heart failure or hypertension.⁵²⁷ When the drug is used in this setting, patients must be carefully monitored for hypotension.⁸⁰⁹ The benefits of oral nitroglycerin have not been established in patients with acute MI,⁸¹⁰ and experts state there is no role for the routine use of oral nitroglycerin during the convalescent phase of STEMI.⁵²⁷

Heart Failure and Low-output Syndromes

Isosorbide Dinitrate and Hydralazine

Isosorbide dinitrate is used in fixed combination with hydralazine (BiDil) as an adjunct to standard therapy for the treatment of heart failure in self-identified black patients to improve survival, decrease rate of hospitalization for worsened heart failure, and improve patient-reported functional status.^{336 337 338} Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure.^{524 701 703 800} Additional agents (e.g., cardiac glycosides, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement and/or reduction in heart failure-related hospitalizations.^{524 800} The combination of isosorbide dinitrate and hydralazine is recommended by the American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) for self-identified black patients with New York Heart Association (NYHA) functional class III or IV heart failure and reduced ejection fraction who are receiving optimal therapy with ACE inhibitors and β-blockers (unless contraindicated).⁵²⁴ The ACCF and AHA also state that combined therapy with isosorbide dinitrate and hydralazine can be useful in patients with current or prior symptomatic heart failure with reduced ejection fraction who cannot receive an ACE inhibitor or angiotensin II receptor antagonist^{† [off-label]} because of drug intolerance, hypotension, or renal insufficiency.⁵²⁴

Efficacy of the isosorbide dinitrate/hydralazine fixed-combination preparation was evaluated in a multicenter, randomized, placebo-controlled, double-blind trial (the African-American Heart Failure Trial; A-HeFT trial) in 1050 self-identified black adults (mean age: 57 years) with stable moderate-to-severe heart failure (NYHA functional class III in over 95% of patients) secondary to left ventricular dysfunction (ejection fraction 35% or less).^{336 337 338} Patients were randomized to receive the fixed-combination preparation containing isosorbide dinitrate and hydralazine hydrochloride (initially, 20 mg of isosorbide dinitrate and 37.5 mg of hydralazine hydrochloride 3 times daily and titrated [as tolerated] to a target dosage of 40 mg of isosorbide dinitrate and 75 mg of hydralazine hydrochloride 3 times daily) or placebo for up to 18 months.^{336 337 338} Patients also received standard therapy (e.g., diuretics [mainly loop diuretics], β-blockers, ACE inhibitors, angiotensin II receptor antagonists, cardiac glycosides, and/or aldosterone antagonists).^{336 337 338}

The A-HeFT trial was terminated early (after a mean follow-up period of 10–12 months) principally because of a substantial reduction (43%) in all-cause mortality in patients receiving the fixed-combination preparation containing hydralazine and isosorbide dinitrate; mortality rate was about 10.2 or 6.2% in patients receiving placebo or the fixed-dose combination drug, respectively.^{336 337 338}

The primary end point of the study (a mean primary composite score consisting of all-cause mortality, first hospitalization for worsening of heart failure, and improvement of quality of life [as assessed by responses to the Minnesota Living with Heart Failure questionnaire]) also showed significant differences between drug therapy and placebo.^{336 337} Patients receiving the fixed combination containing isosorbide dinitrate and hydralazine experienced a significant reduction (33%) in the rate of first hospitalization for heart failure (16.4 or 24.4% for those receiving the drug or placebo, respectively) and a significant improvement in response to the Minnesota Living with Heart Failure questionnaire (a self-report of functional status).^{336 337 338} Factors of age, gender, baseline disease, or concomitant medications appear to have no effect on survival or rate of hospitalization.³³⁶ The fixed combination containing isosorbide dinitrate and hydralazine had a slight but significant blood pressure-lowering effect at 6 months; a mean decrease of 1.9 and 2.4 mm Hg from baseline in systolic and diastolic blood pressure, respectively, was observed in patients receiving the drug, while an increase of 1.2 and 0.8 mm Hg from baseline in systolic and diastolic blood pressure, respectively, was observed in patients receiving placebo.^{336 337} However, the role of reduced blood pressure in the improved outcome of patients receiving the study drugs has not been evaluated.³³⁶ The manufacturer states that there is no adequate clinical experience with hydralazine hydrochloride or isosorbide dinitrate as separate agents† or dosages of the drugs other than those used in the A-HeFT trial for the treatment of congestive heart failure.³³⁶

In another randomized, placebo-controlled, comparative, long-term (median 2.3 years; range: 6–68 months) study (Vasodilator Heart failure Trial [V-HeFT I]) in patients with chronic congestive heart failure associated with ischemic or nonischemic cardiomyopathy who were receiving conventional therapy (cardiac glycosides and diuretics, without an ACE inhibitor), addition of isosorbide dinitrate (up to 160 mg daily) given concomitantly with hydralazine hydrochloride (up to 300 mg daily) resulted in a 25–30% decrease in overall mortality rates after 2 years when compared with conventional therapy and placebo or prazosin (up to 20 mg daily).^{255 257} However, despite substantial increases in ejection fraction, the combination of the 2 vasodilators was not associated with decreased hospitalizations and many patients discontinued therapy during follow up,²⁵⁷ although retrospective analysis of such data indicate that there was a trend favoring the administration of the 2 vasodilators, which was attributed to an effect observed in black patients.³³⁶

In a subsequent randomized comparative, long-term (median 2.5 years; range: 6–68 months) study (V-HeFT II) in patients with ischemic or nonischemic cardiomyopathy and mild to moderate heart failure (NYHA functional class II and III) who were receiving conventional therapy (cardiac glycosides and diuretics), addition of enalapril maleate (up to 20 mg daily) resulted in a 28% decrease in overall mortality rates after 2 years when compared with conventional therapy and concomitant use of hydralazine hydrochloride (up to 300 mg daily) with isosorbide dinitrate (up to 160 mg daily).^{256 257} Retrospective analysis of the data indicates that such decreases in mortality rates in patients receiving enalapril in conjunction with conventional therapy were not observed in black patients.³³⁶ Concomitant administration of the 2 vasodilators had more favorable effects on ventricular ejection fraction and exercise tolerance than those associated with enalapril.²⁵⁷

Nitroglycerin

IV nitroglycerin has been used effectively in the treatment of acutely decompensated (e.g., congestive) heart failure^{† [off-label]} or other low cardiac output states^{† [off-label]}.⁵²⁴ Experts recommend that the precipitating cause of acute heart failure decompensation be carefully assessed to inform appropriate treatment, optimize outcomes, and prevent future acute events in patients with heart failure.⁵²⁴ IV vasodilators have not been shown to improve outcomes in patients hospitalized for heart failure; however, in the absence of symptomatic hypotension, IV nitroglycerin may be considered as an adjunct to diuretic therapy for relief of dyspnea in patients hospitalized for acutely decompensated heart failure.⁵²⁴ IV nitroglycerin causes venodilation, which lowers preload and may help rapidly reduce pulmonary congestion.⁵²⁴ Patients with heart failure and hypertension, coronary ischemia, or substantial mitral regurgitation are often considered ideal candidates for the use of IV nitroglycerin.⁵²⁴ However, tachyphylaxis to nitroglycerin may develop rapidly (e.g., within 24 hours), and up to 20% of those with heart failure may have inadequate response to even high doses of the drug.⁵²⁴

Hypertension

IV nitroglycerin is used to control blood pressure in perioperative hypertension, especially hypertension associated with cardiovascular procedures; to control blood pressure in patients with severe hypertension^{† [off-label]} or in hypertensive crises^{† [off-label]} for the immediate reduction of blood pressure in patients in whom such reduction is considered an emergency (hypertensive emergencies), especially those associated with coronary complications (e.g., coronary ischemia, acute coronary insufficiency, acute left ventricular failure, postoperative hypertension [especially following coronary bypass surgery]) and/or acute pulmonary edema; and to produce controlled hypotension during surgical procedures.^{500 502 812 1200} Elevated blood pressure alone, in the absence of manifestations or other evidence of target organ damage, rarely requires emergency therapy.¹²⁰⁰

Cocaine-induced Acute Coronary Syndrome

Nitroglycerin has been used adjunctively in the management of cocaine overdose^† to reverse coronary vasoconstriction.⁶⁹⁶ Experts state that administration of nitroglycerin also may be beneficial for cocaine-induced hypertension or chest discomfort.⁶⁹⁶

Diffuse Esophageal Spasm

In a limited number of patients with diffuse esophageal spasm without gastroesophageal reflux^†, long-term administration of oral isosorbide dinitrate or erythrityl tetranitrate (no longer commercially available in the US) has been effective in relieving pain, dysphagia, and spasm; sublingual nitroglycerin 0.4 mg also briefly relieved symptoms in these patients.

Nitrates and Nitrites General Statement Dosage and Administration

Administration

Nitrates, in appropriate dosage forms, may be administered orally, lingually, sublingually, intrabuccally, topically, or by IV infusion. With sublingual administration, tingling may occur at the point of tablet contact with the mucous membrane and, if objectionable, may be lessened by placing the tablet in the buccal pouch. Amyl nitrite is administered by nasal inhalation. Lingual, sublingual, or intrabuccal administration of a nitrate is preferred for the acute relief of angina pectoris.

Nitrates are administered lingually, sublingually, or intrabuccally for prophylactic management in situations likely to provoke angina attacks, such as climbing stairs, cold weather, walking uphill, or sexual activity. These patients should be instructed to take the nitrate shortly before an activity that is known to cause angina rather than waiting until an attack occurs. For long-term prophylactic management of angina pectoris, nitrates are given orally or applied topically. If acute attacks of angina occur in patients receiving long-term nitrate therapy, a short-acting preparation (e.g., sublingual nitroglycerin) should be administered for acute relief.

The possibility that lingual, sublingual, or intrabuccal nitrates may be inadequately absorbed, with resultant decreased efficacy, in patients with dry oral mucous membranes (e.g., xerostomia) should be considered.^{219 220} It has been suggested that wetting the mouth with water immediately before the administration of sublingual nitrate tablets may increase the rate of dissolution of these tablets.³⁰⁶ In one study in patients undergoing cardiac catheterization who had dry oral mucous membranes (due to fasting), wetting the mouth with water immediately before the administration of sublingual nitrate tablets consistently enhanced the hemodynamic effects (e.g., substantial decrease in aortic systolic blood pressure) of these tablets.³⁰⁶ Although improved relief of angina associated with nitrates as a result of wetting oral mucous membranes with water was not specifically studied, the time of hemodynamic changes reportedly coincided with the relief of angina.³⁰⁶

Dosage

Dosage of nitrates must be carefully adjusted according to the patient’s requirements and response and the smallest effective dosage should be used. For increased exercise tolerance in patients with angina, nitrates generally decrease systolic blood pressure (in sitting position) at least 10 mm Hg and/or increase heart rate at least 10 bpm.

Cautions for Nitrates and Nitrites General Statement

Adverse Effects

Serious adverse reactions to the organic nitrates and nitrites are uncommon and their adverse effects mainly involve the CNS and cardiovascular system. Adverse effects of IV nitroglycerin generally are dose-related.

Nervous System Effects

Headache, the most frequent adverse effect, may be severe (persistent or transient) and is perceived as a pulsating, throbbing sensation; headache is especially common after inhalation of amyl nitrite. Headache is most frequent early in therapy, usually diminishes rapidly, and may disappear within several days to weeks if treatment is continued. Headache may be relieved by a temporary reduction in dosage or administration of an analgesic such as aspirin or acetaminophen. However, patients should be advised to resist altering their nitrate dosage or schedule on their own in an effort to avoid headaches since a loss in antianginal efficacy could result.²³⁸

Cardiovascular Effects

Postural hypotension may occur in patients receiving nitrates or nitrites and may cause dizziness, weakness, and other signs of cerebral ischemia, especially if the patient is in a warm environment or standing immobile. Severe hypotension may occur even with small doses of nitroglycerin, especially in patients with constrictive pericarditis, aortic or mitral stenosis, volume depletion, or existing hypotension.^{806 807 823} Syncope may result and may be confused with acute myocardial infarction (MI) because the patient may be transiently pulseless, cold, clammy, and profusely sweating. Some patients may have a marked sensitivity to the hypotensive effects of nitrates and nitrites and nausea, vomiting, weakness, restlessness, pallor, cold sweat, involuntary passing of urine and feces, tachycardia, syncope, increased angina pectoris, rebound hypertension, shock, and cardiovascular collapse may occur with usual therapeutic doses; consumption of alcohol may enhance these effects. (See Drug Interactions: Alcohol.) In addition, the drugs may aggravate angina caused by hypertrophic cardiomyopathy. After administration of a rapidly acting nitrate or nitrite, reflex tachycardia may be marked if the patient is in an upright position. Patients should be sitting immediately after administration of rapidly acting nitrates and nitrites (e.g., amyl nitrite, lingual or sublingual nitroglycerin). If syncope occurs, the patient should be placed in the recumbent position. Measures that facilitate venous return (e.g., head-low [Trendelenburg’s] position, deep breathing, movements of the extremities) may increase recovery rate. The possibility that inadvertent systemic hypotension and associated reflex tachycardia may result in worsening of myocardial ischemia should be considered.²³⁶ Severe arterial hypotension with absolute or relative bradycardia has been reported in patients who received sublingual or IV nitroglycerin within the first 24 hours after MI; hypotension and bradycardia were reversed by discontinuing the drug and elevating the lower extremities.

Transient flushing may occur with nitrates, and inhalation of amyl nitrite commonly causes cutaneous flushing of the head, neck, and clavicular area. In patients with venous insufficiency or severe congestive heart failure receiving topical nitroglycerin, peripheral edema may occur or be exacerbated.

Dermatologic and Sensitivity Reactions

Allergic contact dermatitis and fixed drug eruptions have occurred rarely with topical nitroglycerin. Rash and/or exfoliative dermatitis may occur occasionally and are most common with pentaerythritol tetranitrate (no longer commercially available in the US). If rash occurs, the nitrate should be discontinued. There have been a few reports of anaphylactoid reactions in patients receiving nitroglycerin. Cross-sensitivity among the drugs may occur.

In clinical trials in patients receiving isosorbide dinitrate (20 mg) in fixed combination with hydralazine hydrochloride (37.5 mg) alopecia has been reported occasionally.³³⁶

Hematologic Effects

Nitrate ions released during metabolism of nitroglycerin can oxidize hemoglobin to methemoglobin. In patients without cytochrome-b₅ reductase activity, about 1 mg/kg of nitroglycerin is required before patients manifest clinically important (at least 10%) methemoglobinemia; patients with normal cytochrome_b reductase activity require even higher doses of nitroglycerin for methemoglobinemia to develop. Methemoglobinemia should be suspected in any patient who exhibits sign of impaired oxygen delivery (e.g., darkening of the blood) despite adequate cardiac output and adequate arterial pO₂. Methemoglobinemia also may occur in infants who receive large amounts of nitrite or nitrate; the infant’s relatively high GI pH causes bacterial reduction of unabsorbed nitrate to nitrite ion. Methemoglobinemia is extremely rare with therapeutic doses of nitrates and nitrites. However, large doses of amyl nitrite may cause formation of excessive methemoglobin which is characterized by blue skin and mucous membranes, vomiting, shock, and coma.

Local Effects

Nitrates may cause a burning or tingling sensation when administered sublingually.

GI Effects

GI upset has been reported during nitrate therapy and may be controlled by temporarily reducing the dosage. In addition, dry mouth was reported in some patients; the drug should be discontinued if this symptom occurs.

Adverse GI effects reported in self-identified black patients receiving isosorbide dinitrate in fixed-dose combination with hydralazine for adjunctive treatment of congestive heart failure (CHF) include nausea and vomiting; cholecystitis also has been reported occasionally.³³⁶

Other Adverse Effects

These drugs may cause blurred vision and should be discontinued if this symptom occurs.

In clinical trials in patients receiving isosorbide dinitrate (20 mg) in fixed combination with hydralazine hydrochloride (37.5 mg) bronchitis, sinusitis, sweating, hyperlipidemia, hyperglycemia, hypercholesterolemia, amblyopia, myalgia, and tendon disorders have been reported.³³⁶

Tolerance and Dependence

Tolerance to the vascular and antianginal effects of nitrates and nitrites has been shown in clinical studies, by experience from occupational exposure, and in isolated in vitro tissue experiments; such tolerance is a principal factor limiting the efficacy of long-term nitrate therapy. Rapid development of tolerance has occurred with oral, IV, and topical nitrate therapy (i.e., transdermal systems or nitroglycerin ointment); however, tolerance to the pharmacologic effects is generally minor with intermittent use of sublingual nitrates. In some controlled clinical studies in patients with angina, the improvement in exercise time on stress testing was substantially less and of shorter duration during sustained therapy with some nitrate preparations than during acute therapy; exercise capacity and/or angina frequency in some patients receiving transdermal nitrate therapy was similar to that in placebo-treated patients 24 hours or less (e.g., as little as 2–6 hours) after application of the transdermal system. Tolerance to the hemodynamic benefits of nitrates also has been reported in some patients with congestive heart failure. However, nitrate tolerance does not develop to the same degree in all patients, and some evidence suggests that up to 50% of patients may receive benefit from continuous nitrate therapy. Therefore, careful individualization of therapy is necessary in patients receiving nitrates.

Some evidence suggests that the development of tolerance can be prevented or minimized by use of the lowest effective dose of nitrates and an intermittent dosing schedule with a nitrate-free interval of 10–14 hours (e.g., removal of a transdermal nitroglycerin system in the early evening and application of a new system the next morning; omission of the last daily dose of oral nitrate preparations or use of an asymmetric daily dosing regimen for isosorbide mononitrate). An intermittent dosing regimen also has been recommended for topical (ointment) nitrate preparations.^{600 601 602} However, the minimum nitrate-free interval necessary for restoration of full first-dose effects of nitrate therapy has not been determined. Further studies are needed to determine the optimum regimen for minimizing or preventing tolerance to nitrate therapy.

Cross-tolerance to the effects of sublingual nitroglycerin reportedly may occur during long-term administration of nitrates. However, cross-tolerance to the effects of sublingual nitroglycerin apparently does not occur with long-term administration of extended-release preparations of isosorbide dinitrate or topical nitroglycerin. Available evidence is insufficient to warrant avoiding concomitant administration of sublingual nitroglycerin and long-acting nitrates.

Nitrate dependence has occurred in persons who manufacture organic nitrates and are in daily contact (either respiratory or skin exposure) with the drugs. Initially, headache, dizziness, or postural hypotension occurs and then tolerance to these effects develops. Following withdrawal from exposure, nonexertional ischemic cardiac pain and peripheral ischemic pain have occurred in some individuals without demonstrable organic vascular disease. Acute MI and even sudden death have also occurred in some industrial workers during temporary withdrawal of nitroglycerin exposure. These adverse effects generally have not been reported following sudden cessation of oral nitrate therapy in patients who have been receiving these drugs for long-term prophylactic management of angina, but there have been reports of anginal attacks being more easily provoked and of rebound in the hemodynamic effects soon after nitrate withdrawal in angina patients. The relative importance of these reports to the routine clinical use of nitrates is not known. Although many clinicians do not gradually reduce the dosage when discontinuance of oral nitrates is planned, it appears prudent that dosage be gradually reduced (e.g., over a period of about 1–2 weeks). Supplementary doses of sublingual nitroglycerin should be given if necessary during dosage reduction.

Precautions and Contraindications

Intermittent dosing of nitrates (e.g., use of a nitrate-free interval of 10–14 hours daily) has been recommended to minimize or prevent the development of tolerance to the hemodynamic and antianginal effects of the drugs.⁶⁰¹ (See Cautions: Tolerance and Dependence.) However, controlled clinical studies suggest that such intermittent use is associated with decreased exercise tolerance compared with placebo during the latter part of the nitrate-free interval. The clinical relevance of this observation currently is unknown, but the possibility of an increased frequency or severity of angina during the nitrate-free interval should be considered. Because substantial tolerance does not occur in all patients receiving nitrate therapy and because of the potential risks associated with withdrawal of nitrates in patients with angina, careful individualization of nitrate therapy is necessary. In patients with moderate to severe angina, unstable angina, or frequent episodes of chest pain at rest in whom nitrate therapy is to be interrupted on a daily basis, use of concomitant antianginal therapy with another class of drugs (e.g., calcium-channel blocking agents, β-blockers) has been suggested.

When isosorbide dinitrate is used in fixed combination with hydralazine, the cautions, precautions, and contraindications associated with hydralazine must be considered in addition to those associated with isosorbide dinitrate.³³⁶

Nitrates are contraindicated in patients with known hypersensitivity to the drugs or any ingredient in the formulations.^{809 814 815} Topical nitroglycerin (transdermal system) is contraindicated in patients who are allergic to the adhesives used in the system.⁸¹¹

Some manufacturers state that nitrates and nitrites should be used with caution²¹¹ or are contraindicated^{208 209 210} in patients with angle-closure or open-angle glaucoma;^{208 209 210 211} however, intraocular pressure is at most increased only briefly and drainage of aqueous humor from the eye is not impeded.^{102 104 212} In addition, in several studies in patients with open-angle or angle-closure glaucoma, nitrates did not affect or slightly decreased intraocular pressure.^{102 212 213 214 215}

Extended-release oral nitrate preparations should not be used in patients with functional or organic GI hypermotility or malabsorption syndrome.

Nitrates and nitrites should be used with caution, if at all, in patients with increased intracranial pressure (e.g., head trauma, cerebral hemorrhage) and are contraindicated in patients with severe anemia or with a previous idiosyncratic or hypersensitivity reaction to these drugs.

Although some manufacturers state that the benefits of oral, sublingual, or topical nitrates have not been established in patients with acute MI, IV nitroglycerin has been used in such patients.^{527 809 811 814} (See Uses: Acute Myocardial Infarction.) The use of any dosage form of nitroglycerin during the initial days following an acute MI requires particular attention to monitoring the hemodynamic and clinical status of the patient in order to avoid possible hypotension and tachycardia.^{235 238 809 811 814} In general, long-acting dosage forms should be avoided in the early management of acute MI since the effects are difficult to terminate rapidly should excessive hypotension or tachycardia occur. Nitrates in the setting of suspected acute MI should be avoided in patients with marked bradycardia (e.g., less than 50 bpm) or tachycardia (e.g., exceeding 100 bpm),^{240 527} and should not be used in patients with suspected right ventricular infarction.^{241 527} Patients with right ventricular infarction are particularly dependent on adequate right ventricular preload, which is reduced by nitrates, to maintain cardiac output and can experience profound hypotension during administration of the drugs.^{236 241}

Nitrates should be used with caution in patients with diuretic-induced fluid depletion. Patients receiving isosorbide dinitrate in fixed-dose combination with hydralazine should be advised that inadequate fluid intake or excessive fluid loss due to diarrhea, vomiting, or perspiration may result in excessive hypotension, possibly leading to lightheadedness or even syncope.³³⁶ If syncope occurs, isosorbide dinitrate and hydralazine should be discontinued, and the patient’s clinician should be notified as soon as possible.³³⁶ Isosorbide dinitrate is contraindicated in patients with shock or marked low blood pressure. In addition, IV nitroglycerin is contraindicated in patients with hypotension or uncorrected hypovolemia, since severe hypotension or shock could result, and in patients with constrictive pericarditis and pericardial tamponade. Nitrate-induced hypotension may produce paradoxical bradycardia and increased angina pectoris.^{238 803} The possibility that nitrates may aggravate angina associated with hypertrophic cardiomyopathy also should be considered.^{238 803}

IV administration of dilute solutions of nitroglycerin may cause fluid overload resulting in dilution of serum electrolytes, overhydration, congestive conditions, or pulmonary edema.²³⁷ The risk of dilutional conditions is inversely proportional to the electrolyte concentration administered, and the risk of solute overload and resultant congestive conditions with peripheral and/or pulmonary edema is directly proportional to the electrolyte concentration administered.²³⁷ Lower concentrations of IV nitroglycerin in 5% dextrose injection increases the potential precision of dosing, but such concentrations increase the total fluid volume, which is a consideration in patients with compromised cardiac, hepatic, and/or renal function.²³⁷

Patients receiving lingual or sublingual nitroglycerin for relief of acute attacks of angina pectoris should be instructed that if pain persists after 3 doses (administered approximately every 5 minutes) they should seek prompt medical attention, because inability of these drugs to relieve chest pain may indicate acute MI.

Phosphodiesterase (PDE) type 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil) are contraindicated in patients receiving organic nitrates or nitrites in any form (e.g., orally, sublingually, transmucosally, parenterally), given regularly or intermittently,^{262 809 823} or nitric oxide donors since severe, potentially fatal hypotensive episodes can occur.^{260 261 262 263 266 271 272 282 284 285 288 332 333} Experts state that coadministration of PDE type 5 inhibitors should be strictly avoided within 24 hours of nitrate administration.¹¹⁰¹ (See Drug Interactions: Selective Phosphodiesterase Inhibitors.) Clinicians unfamiliar with their patients’ drug history, especially those involved in emergency care (e.g., for presumed MI or ischemia), should take a careful history so that concomitant use of organic nitrates or nitrites with selective PDE inhibitors can be avoided.^{260 264 271} All patients receiving organic nitrates or nitrites should be warned about the potential interaction between the drugs and selective PDE inhibitors, even if they currently are not receiving the drugs, since there is substantial potential for patients to receive the drugs from another clinician, from a friend, with little or no clinical intervention (e.g., via the Internet),²⁸¹ or illicitly.^{260 281 282} Similarly, all patients taking either selective PDE inhibitors or organic nitrates or nitrites must be warned of the potential consequences of taking the drugs within close proximity (e.g., within 24 hours of sildenafil; possibly more prolonged periods of risk with longer-acting PDE inhibitors) of taking a nitrate- or nitrite-containing preparation.^{260 282 334} The use of nitrates (e.g., nitroglycerin) or nitrites (e.g., amyl nitrite) with a soluble guanylate cyclase (sGC) stimulator (e.g., riociguat) also is contraindicated because of the potential for additive hypotensive effects.^{804 807 823}

Pregnancy and Lactation

Pregnancy

Some experts state that use of nitroglycerin during pregnancy does not appear to present a risk to the fetus; however, experience with the drug in pregnant women is limited.^{809 823 825} Nitrates and nitrites generally should be used during pregnancy only when the potential benefits justify the possible risks to the fetus or only when clearly needed.^{809 813 814 815 816}

Lactation

It is not known whether nitrates or nitrites are distributed into human milk.^{809 813 814 815 816} The low molecular weight of nitroglycerin suggests that some distribution into milk may occur.⁸²⁵ Some manufacturers state that caution is advised if nitroglycerin is used in nursing women.⁸⁰⁹

Drug Interactions

Alcohol

Concomitant use of nitrates or nitrites and alcohol may cause hypotension. Although the clinical importance of this interaction has not been established, nitrates or nitrites should be used with caution in conjunction with alcohol.

Aspirin

Concomitant use of nitroglycerin and high-dose aspirin (1 g) may increase exposure to nitroglycerin and enhance its vasodilatory and hemodynamic effects.^{806 823}

Disopyramide

Concomitant use of isosorbide dinitrate (as sublingual tablets) and disopyramide reportedly reduces the efficacy of isosorbide dinitrate.²⁹⁴ The antimuscarinic actions of disopyramide appear to decrease salivary secretions and thereby inhibit the dissolution of the sublingual tablets.²⁹⁴

Ergot Alkaloids

Dihydroergotamine may counteract the coronary vasodilatory effect of nitrates, including isosorbide dinitrate.^{303 316} Oral administration of nitroglycerin substantially decreases the first-pass metabolism of dihydroergotamine and subsequently increases its oral bioavailability.^{806 807 823} Since ergotamine is known to precipitate angina and has been used as a provocative test for angina, patients receiving nitroglycerin for antianginal therapy should not be receiving dihydroergotamine if possible.^{316 806 807 823} However, if nitrates are used concomitantly with ergotamine, patients should be monitored for enhanced ergotamine effects and dosages of the ergot alkaloid should be reduced as needed.^{316 806 807 823}

Heparin

Because some,^{203 204 237 245 247} but not all,²⁴⁶ evidence indicates that IV nitroglycerin may antagonize the anticoagulant effect of heparin when these drugs are administered concomitantly, caution should be exercised.^{203 204 237 245 247 812} Although initial data suggested that the solvent propylene glycol, used in parenteral dosage forms of nitroglycerin was responsible for this effect,²⁰³ additional study indicates that this interaction also occurs when nitroglycerin preparations not containing the solvent are used.^{204 245} Patients receiving heparin and IV nitroglycerin concomitantly should be monitored (e.g., measurement of activated partial thromboplastin time) closely to avoid inadequate anticoagulation.^{203 204 237 245 246 247} If IV nitroglycerin therapy is discontinued in patients receiving heparin, reduction in heparin dosage may be necessary.^{204 263 245 246 247}

Selective Phosphodiesterase Inhibitors

Sildenafil and other selective phosphodiesterase (PDE) type 5 inhibitors (e.g., avanafil, tadalafil, vardenafil) profoundly potentiate the vasodilatory effects (e.g., a greater than 25-mm Hg decrease in systolic blood pressure) of organic nitrates and nitrites (e.g., nitroglycerin, isosorbide dinitrate), and potentially life-threatening hypotension and/or hemodynamic compromise can result.^{259 260 261 262 263 264 266 271 272 274 275 282 284 285 334 823} Nitrates and nitrites promote the formation of cyclic guanosine monophosphate (cGMP) by stimulating guanylate cyclase, and sildenafil acts to decrease the degradation of cGMP via phosphodiesterase (PDE) type 5 by inhibiting this enzyme, resulting in increased accumulation of cGMP and more pronounced smooth muscle relaxation and vasodilation than with either sildenafil or nitrates/nitrites alone.^{259 261 262 263 264 289} This interaction probably occurs with any organic nitrate, nitrite, or nitric oxide donor (e.g., nitroprusside) regardless of their predominant hemodynamic site of action.^{259 260 261 273 283}

Selective PDE inhibitors also may potentiate the hypotensive effects of inhaled nitrites (e.g., amyl or butyl nitrite, sometimes referred to as “poppers”),^{260 265 267} which may be misused (“recreational use”) during sexual activity for purported effects in enhancing the sexual experience.^{259 260 263 264 265 267 271 272} Because these agents are used recreationally, patients may be unaware of their pharmacologic effects and potential risks and may not report their use to clinicians.^{259 260 263 265 271 272} Concurrent use of selective PDE inhibitors with poppers, which dilate blood vessels with a rapid onset of action, could result in sudden and marked blood pressure reduction and potentially serious or even fatal effects.^{260 265 267} Interactions with organic nitrates and nitrites may be even more pronounced in patients who also are taking certain HIV protease inhibitors concomitantly.^{260 264 265} Homosexual males may be at particular risk because of the greater likelihood of recreational inhaled nitrite use and antiretroviral therapy in this population.^{265 286}

Because of the serious risk of concomitant use of organic nitrates or nitrites and selective PDE inhibitors, such combined use is contraindicated.^{259 260 261 262 282 287 332 333} At least 19 deaths have been reported in patients who may have taken sildenafil and who took or were given nitroglycerin or another nitrate/nitrite or who were found with nitroglycerin in their possession.^{266 273 287} The manufacturers of selective PDE type 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil) state that the drugs are contraindicated in any patient receiving organic nitrates or nitrites, either regularly or intermittently and in any form (e.g., orally, sublingually, transmucosally, parenterally), or other nitric oxide donors.^{262 332 333} Although it is not known how much time must elapse between use of sildenafil and administration of a nitrate or nitrite, pharmacokinetic data suggest that these latter agents should not be given within 24 hours of sildenafil administration because an exaggerated hypotensive response is likely; plasma sildenafil concentrations 24 hours after a dose are substantially lower than peak concentrations.^{259 260 262 263} Pharmacodynamic data for tadalafil, a longer-acting PDE type 5 inhibitor, in healthy individuals (including geriatric individuals 70 years of age or older) indicate that the hypotensive effect of sublingual nitroglycerin (0.4 mg) was augmented by tadalafil when administered within 24 hours after administration of the last dose of tadalafil (20 mg once daily for 7 days) but not at 48, 72, or 96 hours after the dose.³³⁴ The potential interaction of nitrates or nitrites with vardenafil has not been well studied.^{335 1101}

The point at which nitrates or nitrites can be given safely is unclear,^{259 260 262 263 287} and therefore the drugs should be avoided unless, in the view of the treating clinician, the benefits outweigh the risks.^{260 273} Some experts state that coadministration of PDE type 5 inhibitors with long-acting nitrates should be strictly avoided within 24 hours of nitrate administration.¹¹⁰¹ Nitrates should not be taken for 24 hours after use of sildenafil or 48 hours after tadalafil.¹¹⁰¹ If consideration is given to administering a nitrate or nitrite beyond 24 or 48 hours after sildenafil or tadalafil use, respectively, the response to the initial doses must be monitored carefully and proper facilities for fluid and vasopressor (e.g., α-adrenergic agonists) support must be readily available to prevent acute ischemic episodes.^{260 289 334} If severe hypotension occurs, some manufacturers state that it is reasonable to treat the situation as a nitrate overdosage and provide appropriate supportive care (e.g., elevation of the extremities and central volume expansion).^{806 807 823} No specific antagonist to the vasodilator effects of nitroglycerin is known.^{806 807 823} In patients in whom clearance of sildenafil and/or its metabolites may be prolonged (e.g., those with hepatic [e.g., cirrhosis] or severe renal impairment [e.g., creatinine clearance less than 30 mL/minute], those receiving a potent inhibitor of cytochrome P-450 [CYP] isoenzyme 3A4, geriatric patients older than 65 years of age), elapse of a more extended period of time between use of sildenafil and administration of a nitrate or nitrite may be necessary.^{260 262 287} In either case, a short-acting nitrate formulation that can be titrated readily (e.g., IV nitroglycerin) would be preferred and such use should be accompanied by close hemodynamic monitoring.^{260 289}

All patients receiving either an organic nitrate/nitrite or sildenafil should be warned about the contraindications and the potential consequences of taking sildenafil within 24 hours of nitrate or nitrite use, even sublingual nitroglycerin.^{260 262 282} Even more prolonged periods of risk are possible for longer-acting selective PDE inhibitors.³³⁴ Although sublingual nitroglycerin is relatively short-acting, any use during the previous 24 hours suggests that it may be needed again after sildenafil-enhanced sexual activity.²⁶⁰ In addition, the presence of even trace amounts of nitrates or nitrites may have unknown effects in combination with sildenafil.²⁶⁰

Because selective PDE inhibitors may be obtained without the knowledge of the physician and/or pharmacist, including via the Internet or illicitly, all patients prescribed nitrates or nitrites should be warned of the potential consequences of combined use with these drugs (e.g., sildenafil, tadalafil, vardenafil).^{260 268 269 270 281 282} The possibility or recreational use of inhaled nitrites (“poppers”) also should be considered whenever sildenafil is prescribed,^{260 265} particularly in homosexual males.²⁶⁵

Soluble Guanylate Cyclase Stimulators

Soluble guanylate cyclase (sGC) stimulators (e.g., riociguat) can potentiate the hypotensive effects of organic nitrates (e.g., nitroglycerin) and nitrites (e.g., amyl nitrite) when used concomitantly; such concomitant use is contraindicated.^{804 807 823} Because the time course and dose dependence of this interaction have not been established, use of these drugs within a few days of one another is not recommended.⁸²³ If severe hypotension occurs, some manufacturers state that it is reasonable to treat the situation as a nitrate overdosage and provide appropriate supportive care (e.g., elevation of the extremities and central volume expansion).⁸²³

Thrombolytic Agents

Concomitant administration of tissue-type plasminogen activator (t-PA) and IV nitroglycerin can reduce plasma levels of t-PA and its thrombolytic effect.^{806 823} Caution is advised if a patient is receiving such concomitant therapy.⁸⁰⁶

Other Drugs

Patients receiving antihypertensive drugs, calcium-channel blocking agents, β-blockers, or phenothiazines and nitrates or nitrites concomitantly should be observed for possible additive hypotensive effects. Dosage adjustment of either the nitrate/nitrite or the other agent with hypotensive activity may necessary to avoid orthostatic hypotension during concomitant use.

Laboratory Test Interferences

Nitrates and nitrites may interfere with the Zlatkis-Zak color reaction causing a false report of decreased serum cholesterol. Because of the propylene glycol content of IV nitroglycerin, serum triglyceride assays that rely on glycerol oxidase may yield falsely elevated serum triglyceride concentrations.²⁰⁸

Acute Toxicity

Manifestations

Adverse effects from nitrate and nitrite overdosage are extensions of the pharmacologic action of the drugs, namely the capacity to induce vasodilation, venous pooling, reduced cardiac output, and hypotension. Nitrate and nitrite overdosage may result in severe hypotension, tachycardia, bradycardia, heart-block, palpitation, death secondary to circulatory collapse, confusion, fever, syncope (especially in upright posture), persistent throbbing headache, visual disturbances, increased intracranial pressure, paralysis, and coma followed by seizures, flushing and diaphoresis, cold and clammy skin, nausea and vomiting, colic and diarrhea, dyspnea, and methemoglobinemia.^{208 235}

Treatment

Laboratory determinations of serum drug concentrations are not widely available and do not have an established role in the management of nitrate and nitrite overdosage. Data are not available to suggest physiologic maneuvers to increase the excretion of nitrates and nitrites, such as altering the pH of the urine. It is not known whether hemodialysis would remove any of the parent drugs or active metabolites.²⁰⁸ No specific antagonist to the vasodilator effects of nitrates and nitrites is known and no intervention has been subject to controlled study as a therapy for overdosage; use of epinephrine or other arterial vasoconstrictors is not recommended by the manufacturer²⁰⁸ Hypotension from nitroglycerin overdosage results from venodilation and arterial hypovolemia, and its prudent management should be directed toward increasing central fluid volume; passive elevation of the patient’s legs may be sufficient, although IV infusion of 0.9% sodium chloride injection or similar solution also may be necessary.^{208 235} If methemoglobinemia is present, IV administration of methylene blue (e.g., 1–2 mg/kg of body weight) may be required.^{208 235} Management of nitroglycerin overdosage in patients with renal disease or congestive heart failure may require invasive monitoring.^{208 235} Therapy that effects central volume expansion could be hazardous to such patients.^{208 235}

Pharmacology

All organic nitrates appear to have similar pharmacologic effects.³²³ The principal pharmacologic property of these drugs is relaxation of vascular smooth muscle, resulting in generalized vasodilation. Nitrates are metabolized to a free radical nitric oxide at or near the plasma membrane of vascular smooth muscle cells.^{236 248 249} Nitric oxide is an endothelium-derived relaxing factor (EDRF) that modulates vascular tone.^{248 249 802} Nitric oxide activates guanylate cyclase, resulting in an increase of guanosine-3′,5′monophosphate (cyclic GMP), which eventually leads to the dephosphorylation of the light chain of myosin, resulting in vasodilation.²³⁵ Nitrate administration provides an exogenous source of nitric oxide which replenishes or restores the actions of EDRF, which usually are impaired in patients with coronary artery disease.^{249 802}

Vascular Effects

Peripheral venous resistance is decreased via a selective action on venous capacitance vessels and results in venous pooling of blood and decreased venous return to the heart. The vasodilatory effect of the drugs on arteriolar resistance is not as great as the action on the venous side. As a result of this combined action, both venous filling pressure (preload) and, to a lesser extent, arterial impedance (afterload) are reduced. Left ventricular end-diastolic pressure (LVEDP) and volume (LVEDV) are decreased resulting in reduction of ventricular size and wall tension, particularly in patients with occlusive coronary artery disease and especially after exercise, atrial pacing, or added fluid load. Although nitrates and nitrites reflexly increase heart rate and myocardial contractility which increase myocardial oxygen consumption, the reduction in both right and left ventricular preload that results from peripheral vasodilation, particularly in the splanchnic and mesenteric circulations, combined with afterload reduction from arterial vasodilation, results in decreased cardiac work and a net decrease in myocardial oxygen consumption.^{236 250} By decreasing myocardial oxygen consumption, nitrates and nitrites alter the imbalance of myocardial oxygen supply and consumption which is thought to cause angina pectoris.^{236 250} Because of their hemodynamic profile, nitrates and nitrites are particularly beneficial in patients with left ventricular systolic dysfunction or heart failure.^{236 250}

In addition, both direct vasodilatory effects of nitrates and nitrites on the coronary bed and drug-induced prevention of episodic coronary artery vasoconstriction increase total coronary blood flow.²³⁶ However, in patients with ischemic hearts in whom the coronary vessels may be occluded or maximally dilated secondary to regional hypoxia, these drugs may not increase total coronary blood flow, but instead may cause a beneficial redistribution of coronary blood flow resulting in decreased myocardial ischemia. Nitroglycerin has been shown to preferentially increase subendocardial blood flow without changing total coronary blood flow.^{236 251 252} Redistribution of coronary blood flow may occur because nitrates and nitrites preferentially dilate the large conductance vessels (e.g., epicardial coronary arteries) rather than the arteriolar resistance vessels with resultant shunting of blood to the ischemic myocardium or because collateral vessels which may develop secondary to myocardial ischemia may be dilated by these drugs. As a result of increased global and regional myocardial blood flow, nitrates and nitrites improve the subendocardial-to-epicardial blood flow ratio.^{236 251 252} Vasodilation in intact vascular smooth muscle contained in obstructive atherosclerotic lesions can increase the caliber of some stenoses, improving coronary flow.^{236 253} The drugs also have been shown to dilate coronary collateral vessels and reverse vasoconstriction of small coronary arteries distal to coronary obstruction.^{236 254} Although systemic and coronary vascular effects may vary slightly among these drugs (e.g., in animals, the coronary vasodilator activity of isosorbide-5-mononitrate and isosorbide-2-mononitrate are 1/100–1/30 and ¼–(1/3) that of isosorbide dinitrate, respectively), both of these effects are probably responsible for the beneficial effect of nitrates and nitrites in the treatment of angina pectoris.

After therapeutic doses of nitrates and nitrites, cardiac output may increase transiently and then decrease. Systemic arterial pressure is usually decreased (systolic blood pressure more than diastolic) as a result of vasodilation, and the decrease may be marked in individuals kept in a static upright position. Some patients may be especially sensitive to these hypotensive effects, particularly when there is little compensatory tachycardia, and syncope may result. In doses that do not appreciably decrease blood pressure, inhalation of amyl nitrite causes intense cutaneous flush of the head, neck, and clavicular area; this effect is less marked with nitrates. The meningeal vessels are dilated and a pulsating headache may occur. Net splanchnic vasoconstriction and decreased renal blood flow may occur. Pulmonary vascular resistance and pulmonary arterial pressure are decreased in healthy individuals and in those with angina pectoris.

Antiplatelet and Antithrombotic Effects

Results of in vitro and in vivo studies suggest that nitrates also may have antiplatelet and antithrombotic effects.^{319 320} Administration of IV nitroglycerin may inhibit platelet aggregation and adhesion.^{319 320} The free radical nitric oxide resultant of nitrate metabolism activates guanylate cyclase, resulting in an increase of cyclic GMP which leads to decreased fibrinogen binding to the glycoprotein IIb/IIIa receptors.⁸⁰² The platelet inhibition by nitrates may suggest an additional mechanism to improve perfusion to ischemic myocardium.⁸⁰²

Other Effects

In addition to vascular smooth muscle, nitrates and nitrites relax bronchial, biliary (including the gallbladder, biliary ducts, and sphincter of Oddi), GI (including the esophagus), ureteral, and uterine smooth muscle. These drugs relax all smooth muscle irrespective of autonomic innervation and are functional antagonists of norepinephrine, acetylcholine, and histamine.

Nitroglycerin may cause a marked increase in urinary vanillylmandelic acid (VMA) and catecholamine excretion, possibly secondary to adrenergic response to the hypotensive effect of the drug.

Nitrates and Nitrites General Statement Pharmacokinetics

Absorption

Amyl nitrite is readily absorbed via the respiratory tract and probably is rapidly hydrolyzed to isoamyl alcohol and nitrite ion. In general, the organic nitrates are well absorbed from the oral mucosa following administration lingually, sublingually, intrabuccally, or as chewable tablets. The organic nitrates are also well absorbed from the GI tract but undergo first-pass metabolism in the liver. Nitroglycerin is well absorbed through intact skin when applied topically as an ointment or transdermal system.

Following nasal inhalation, amyl nitrite has a more rapid onset and a shorter duration of action than do sublingually administered organic nitrates. Sublingually administered nitroglycerin has the most rapid onset of antianginal and hemodynamic effects compared to the other organic nitrates. When administered lingually, sublingually, intrabuccally, or as chewable tablets, the organic nitrates have a more rapid onset of action than when they are given orally or topically. Amyl nitrite inhalation, sublingual or buccal nitroglycerin, or sublingual or chewable isosorbide dinitrate is rapidly acting. Generally, orally administered nitrates and topical nitroglycerin are relatively long acting, but rapid tolerance to the hemodynamic and antianginal effects of these dosage forms may occur with continuous therapy. (See Cautions: Tolerance and Dependence.)

Distribution

Following IV administration, highly lipophilic nitrates (e.g., nitroglycerin, isosorbide dinitrate) are widely distributed into vascular and other peripheral tissues while less lipophilic nitrates (e.g., isosorbide mononitrate) are not as widely distributed in the body.³²²

At plasma concentrations of 50–500 ng/mL, approximately 60, 60, or 30% of nitroglycerin, 1,2-dinitroglycerin, or 1,3-dinitroglycerin are bound to plasma proteins, respectively.³²¹ In addition, isosorbide dinitrate and isosorbide mononitrate are approximately 28 and 4–5% bound to plasma proteins, respectively.^{290 291 292 303}

Elimination

Animal studies indicate that the organic nitrates are rapidly denitrated in the liver by the glutathione-organic nitrate reductase system which is dependent on endogenous glutathione. In addition, nitrates are metabolized in the serum independent of glutathione. Hepatic biotransformation is initiated by a redox reaction and the therapeutically active lipid soluble parent ester is converted to less active soluble metabolites. Isosorbide mononitrate (isosorbide-5-mononitrate), the principal active metabolite of isosorbide dinitrate, also is prepared synthetically for formulation of commercially available preparations that share the uses of other nitrates and nitrites.

Studies using IV nitrates indicate that the active nitrate esters have a shorter plasma half-life than do the less active metabolites. The metabolites and, to a lesser extent, the active nitrate esters are excreted by the kidneys.

Chemistry and Stability

Chemistry

The organic nitrates and nitrites are esters of nitrous or nitric acid and are used mainly for the acute relief and prophylactic management of angina pectoris. Amyl nitrite is the only commercially available organic nitrite and is a mixture of isomeric amyl nitrites, principally isoamyl nitrite. Structural variations in the organic nitrates result in differences in onset and duration of action and potency. Although the orientation of nitrate ester groups may affect potency, there is no relationship between the number of nitrate groups and the amount of activity. Isosorbide dinitrate is metabolized in the liver to 2 active metabolites, isosorbide-2-mononitrate and isosorbide-5-mononitrate; isosorbide-5-mononitrate, the principal active metabolite, also is commercially available and is referred to simply as isosorbide mononitrate.^{227 228 230 232 233}

Stability

Amyl nitrite is very volatile and flammable. The organic nitrates (erythrityl tetranitrate [no longer commercially available in the US], isosorbide dinitrate, isosorbide mononitrate, nitroglycerin, and pentaerythritol tetranitrate [no longer commercially available in the US]) are rendered nonexplosive by the addition of an inert excipient such as lactose.

Related Monographs

For specific dosages and additional information on nitrates and nitrites, see the individual monographs in 24:12.08.

Medical Disclaimer