Pharmacology of Glyceryl Trinitrate

1. Introduction/Overview

Glyceryl trinitrate, more commonly referred to as nitroglycerin, represents the prototypical agent within the organic nitrate class of vasodilators. Its discovery in 1847 by Ascanio Sobrero and subsequent introduction into clinical medicine by William Murrell in 1879 marked a pivotal advancement in cardiovascular therapeutics. The drug’s profound efficacy in relieving the pain of angina pectoris established its enduring clinical relevance. Glyceryl trinitrate functions primarily as a prodrug, requiring biotransformation to release nitric oxide, a critical endogenous signaling molecule. Its pharmacology is characterized by potent venodilation with concomitant arterial vasodilation at higher doses, leading to a reduction in cardiac preload and afterload. This hemodynamic profile underpins its principal therapeutic applications in ischemic heart disease and heart failure.

The clinical importance of glyceryl trinitrate remains substantial despite the development of numerous other antianginal and antihypertensive agents. It is considered first-line therapy for the acute relief of angina attacks and is a cornerstone in the management of chronic stable angina, unstable angina, and acute coronary syndromes. Furthermore, its utility extends to the treatment of acute decompensated heart failure, hypertensive emergencies, and certain esophageal spastic disorders. The availability of multiple formulations—sublingual tablets, translingual sprays, transdermal patches, ointments, and intravenous solutions—allows for tailored therapeutic strategies based on the clinical scenario, ranging from immediate abortive therapy to sustained prophylaxis.

Learning Objectives

• Explain the molecular mechanism of action of glyceryl trinitrate, detailing its biotransformation to nitric oxide and the subsequent activation of the soluble guanylyl cyclase-cyclic GMP pathway leading to vasodilation.
• Analyze the comprehensive pharmacokinetic profile of glyceryl trinitrate, including the significant first-pass metabolism, short half-life, and the implications of different administration routes on onset and duration of action.
• Evaluate the major therapeutic applications of glyceryl trinitrate, distinguishing between its use in acute abortive therapy for angina and sustained prophylaxis, as well as its role in managing acute heart failure and hypertensive crises.
• Identify the common and serious adverse effects associated with glyceryl trinitrate therapy, with particular emphasis on headache, hypotension, reflex tachycardia, and the phenomenon of nitrate tolerance.
• Assess critical drug interactions and contraindications, notably the absolute contraindication with phosphodiesterase-5 inhibitors, and formulate appropriate monitoring and dosing strategies for special populations including geriatric patients and those with hepatic impairment.

2. Classification

Glyceryl trinitrate is systematically classified within several overlapping pharmacological and chemical categories, which inform its clinical use and mechanistic understanding.

Pharmacotherapeutic Classification

The primary pharmacotherapeutic classification of glyceryl trinitrate is as a vasodilator. More specifically, it is categorized as an antianginal agent and an antihypertensive agent (particularly in acute settings). Within the broader group of drugs used for angina pectoris, it is a member of the nitrate class. Other members of this class include isosorbide dinitrate and isosorbide mononitrate. Nitrates are distinguished from other antianginal drugs such as beta-blockers (e.g., metoprolol) and calcium channel blockers (e.g., amlodipine) by their unique mechanism of action and hemodynamic effects.

Chemical Classification

Chemically, glyceryl trinitrate is an organic nitrate ester. Its systematic name is 1,2,3-trinitroxypropane. The molecular structure consists of a glycerol backbone where all three hydroxyl groups are esterified with nitric acid, forming O-NO₂ bonds. This structure is fundamental to its activity; it acts as a prodrug, as the intact molecule possesses minimal direct pharmacological activity. The presence of the nitrate ester groups is essential for its metabolism to nitric oxide (NO). It is a colorless, oily liquid in its pure form but is highly unstable and explosive when subjected to heat or shock. For pharmaceutical use, it is rendered stable by adsorption onto an inert carrier such as lactose in sublingual tablets or formulated in non-aqueous solutions for intravenous use.

Mechanistic Classification

From a mechanistic standpoint, glyceryl trinitrate is classified as a nitric oxide donor. It belongs to a group of agents that exogenously supply nitric oxide or its redox congeners to biological systems. This distinguishes it from direct-acting vasodilators like hydralazine (which may have some NO-mediated activity but a less defined mechanism) and from agents that work through other pathways such as adrenergic blockade or calcium influx inhibition. Its action is ultimately mediated through the same final common pathway as endogenous nitric oxide produced by endothelial nitric oxide synthase (eNOS).

3. Mechanism of Action

The mechanism of action of glyceryl trinitrate is a canonical example of prodrug activation leading to the potentiation of a fundamental physiological signaling pathway. Its effects are predominantly vascular, with a preferential action on venous capacitance vessels.

Biotransformation to Nitric Oxide

Glyceryl trinitrate itself is pharmacologically inert at vascular smooth muscle receptors. Its activity is entirely dependent on enzymatic biotransformation within vascular smooth muscle cells and, to a lesser extent, within the vascular endothelium and red blood cells. The conversion requires a reductive process, facilitated by mitochondrial aldehyde dehydrogenase (ALDH-2) and other enzymatic systems including cytochrome P450 enzymes and glutathione-S-transferase. ALDH-2 is considered the primary enzyme responsible for the denitration of glyceryl trinitrate, particularly at low, clinically relevant concentrations. This enzymatic step cleaves the organic nitrate, releasing inorganic nitrite (NO₂^–) and ultimately leading to the formation of nitric oxide (NO) or a related nitroso-thiol species (S-nitrosothiols) that can function as an NO donor. This biotransformation is the rate-limiting step in its action and is a saturable process, which has implications for the development of tolerance.

Activation of Soluble Guanylyl Cyclase

The released nitric oxide diffuses into vascular smooth muscle cells and binds to the heme moiety of the enzyme soluble guanylyl cyclase (sGC). This binding activates sGC, markedly increasing its catalytic activity. Activated sGC catalyzes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). Intracellular cGMP levels may increase up to 50-fold following nitrate administration.

cGMP-Mediated Vasodilation

The elevated cGMP acts as a critical second messenger. Its primary vascular effect is mediated through activation of cGMP-dependent protein kinase (PKG). PKG activation leads to a cascade of phosphorylation events that result in smooth muscle relaxation through two principal mechanisms:

1. Reduction of Intracellular Calcium: PKG promotes the sequestration of calcium (Ca²⁺) into the sarcoplasmic reticulum and inhibits calcium influx from extracellular spaces through voltage-gated and receptor-operated channels. It also stimulates the extrusion of calcium from the cell via plasma membrane Ca²⁺-ATPase.
2. Calcium Desensitization: Independently of lowering cytosolic calcium, PKG decreases the sensitivity of the contractile apparatus to calcium. It does this by phosphorylating proteins such as the myosin light chain phosphatase, enhancing its activity, which leads to dephosphorylation of myosin light chains and relaxation.

Additionally, cGMP may promote the opening of potassium channels, leading to hyperpolarization of the smooth muscle cell membrane, which further inhibits calcium entry.

Hemodynamic Consequences

The vasodilatory effect is not uniform across the vascular tree. At low therapeutic doses, glyceryl trinitrate produces predominant venodilation. Dilation of systemic veins and venules increases venous capacitance, leading to pooling of blood in the periphery. This reduces venous return to the heart, decreasing preload (end-diastolic volume and pressure). The reduction in preload diminishes ventricular wall tension (according to the Laplace law, wall tension = pressure × radius ÷ (2 × wall thickness)), which in turn lowers myocardial oxygen demand (MVO₂).

At higher doses, glyceryl trinitrate also causes dilation of arterioles, reducing systemic vascular resistance and afterload. While this further decreases MVO₂, the arterial dilation can also lead to a reflex activation of the sympathetic nervous system. The net hemodynamic profile in angina is thus characterized by decreased cardiac work and oxygen demand, which helps restore the balance between myocardial oxygen supply and demand. In coronary arteries, nitrates preferentially dilate large epicardial conductance vessels and collateral channels, potentially improving blood flow to ischemic regions, though they may cause a “coronary steal” in some circumstances by dilating normal vessels more than stenotic ones.

Anti-Ischemic and Anti-Anginal Effects

The relief of angina pain is achieved through multiple complementary mechanisms. The primary mechanism is the reduction in myocardial oxygen demand secondary to decreased preload and afterload. Additionally, coronary vasodilation may improve oxygen supply. Nitrates also demonstrate antiplatelet effects mediated by the NO-cGMP pathway, which may be clinically relevant in acute coronary syndromes. The venodilation reduces left ventricular end-diastolic pressure, which can improve subendocardial perfusion by lowering the extravascular compressive forces on coronary vessels during diastole.

4. Pharmacokinetics

The pharmacokinetics of glyceryl trinitrate are complex, characterized by extensive and variable presystemic metabolism, a very short half-life, and a strong dependence on the route of administration, which directly dictates its clinical application.

Absorption

Absorption is highly formulation-dependent. Glyceryl trinitrate is well absorbed across mucous membranes and the skin, but oral bioavailability is extremely low due to near-complete first-pass metabolism in the liver.

• Sublingual: Absorption through the buccal mucosa is rapid and complete, bypassing the portal circulation. Plasma concentrations become detectable within 30 seconds, with a peak (C_max) achieved within 4-6 minutes. This route is ideal for rapid abortive therapy.
• Translingual Spray: Similar to sublingual tablets, with a very rapid onset of action (1-3 minutes).
• Oral (Sustained-Release): Bioavailability is typically less than 1% due to extensive hepatic first-pass metabolism. Sustained-release formulations are therefore not used for reliable systemic effects but may have a role in hepatic portal vasodilation for specific conditions like variceal bleeding.
• Transdermal (Ointment/Patch): Absorption through the skin is continuous but variable, influenced by skin thickness, blood flow, and surface area. Onset of action with ointment is within 30-60 minutes; patches are designed for prolonged, controlled delivery over 12-24 hours. A key consideration is the need for a daily nitrate-free interval to prevent tolerance.
• Intravenous: Provides immediate and titratable delivery with 100% bioavailability. Effects begin within 1-2 minutes, and steady-state is achieved rapidly due to the short half-life.

Distribution

Glyceryl trinitrate is a small, lipophilic molecule with a large volume of distribution (approximately 3 L/kg), indicating extensive distribution into tissues. It readily crosses cell membranes. Protein binding is not considered clinically significant. Its distribution is not a major limiting factor in its pharmacokinetics due to the overwhelming influence of its rapid metabolism.

Metabolism

Metabolism is extensive and represents the dominant process governing its duration of action. The initial step is denitration, primarily catalyzed by mitochondrial aldehyde dehydrogenase-2 (ALDH-2) in vascular smooth muscle, which is the therapeutically relevant site of activation. Hepatic metabolism by glutathione S-transferases and cytochrome P450 enzymes also occurs, particularly following oral administration. The metabolism proceeds sequentially: glyceryl trinitrate (GTN) → glyceryl dinitrate (GDN) → glyceryl mononitrate (GMN) → glycerol and inorganic nitrite/nitrate. The dinitrate and mononitrate metabolites possess weak vasodilatory activity (approximately 1/10th and 1/1000th the potency of GTN, respectively) and have much longer half-lives (40 minutes and 4-5 hours, respectively). They are eventually excreted renally. The high clearance of glyceryl trinitrate, exceeding hepatic blood flow, suggests extrahepatic metabolism, consistent with its activation in vascular tissues.

Excretion

The inactive end products of metabolism, primarily inorganic nitrate (NO₃^–), are excreted almost entirely by the kidneys. Less than 1% of an administered dose is excreted unchanged in urine. The elimination half-life (t_1/2) of the parent compound glyceryl trinitrate is remarkably short, approximately 1-4 minutes. The effective duration of pharmacological action, however, is longer than the plasma half-life would suggest, likely due to the persistence of active intermediates or the sustained effects of the cGMP pathway within cells. For example, the hemodynamic effects of a sublingual dose may last 20-30 minutes, while a transdermal patch provides effects for 8-12 hours or more.

Dosing Considerations

The extremely short half-life necessitates specific dosing strategies. For acute angina, sublingual dosing (0.3-0.6 mg) can be repeated every 5 minutes for up to three doses if pain persists. For prophylactic therapy, dosing must be spaced to allow for a daily nitrate-free period (e.g., patch-on for 12-14 hours, patch-off for 10-12 hours; or isosorbide mononitrate given once daily) to mitigate tolerance. Intravenous infusions are typically initiated at 5-10 µg/min and titrated upward by 5-10 µg/min every 5-10 minutes until the desired hemodynamic or clinical response is achieved, with careful monitoring for hypotension.

5. Therapeutic Uses/Clinical Applications

Glyceryl trinitrate has established roles across a spectrum of cardiovascular conditions, primarily centered on its ability to reduce myocardial oxygen demand and relieve ischemia.

Approved Indications

• Acute Relief of Angina Pectoris: This is the classic and most immediate use. Sublingual tablets or translingual spray are first-line for aborting an acute anginal attack. Patients are instructed to use it at the first sign of chest discomfort.
• Prophylaxis of Angina Pectoris: Used to prevent anticipated angina, such as before physical exertion or emotionally stressful events (sublingual). For chronic prophylaxis, long-acting formulations like transdermal patches or isosorbide mononitrate are employed to reduce the frequency and severity of attacks.
• Unstable Angina and Non-ST-Elevation Myocardial Infarction (NSTEMI): Intravenous glyceryl trinitrate is used to manage ongoing ischemic pain, control hypertension, and treat associated pulmonary congestion. It is a standard component of medical management in these acute coronary syndromes.
• Acute Decompensated Heart Failure: Particularly in settings with hypertension and pulmonary edema, intravenous nitrates provide rapid preload and afterload reduction, alleviating dyspnea and improving hemodynamics. They are often used in combination with diuretics.
• Hypertensive Emergencies: Intravenous glyceryl trinitrate is effective, especially in emergencies associated with acute coronary ischemia or heart failure. Its titratability and short duration of action are advantageous.
• Perioperative Hypertension: Used to control blood pressure during and after cardiac surgery or other procedures.
• Anal Sphincter Relaxation: Topical nitroglycerin ointment is used to treat chronic anal fissures by relaxing the internal anal sphincter and improving blood flow to promote healing.

Off-Label Uses

• Esophageal Spastic Disorders: Sublingual administration may provide temporary relief of pain from diffuse esophageal spasm or “nutcracker esophagus.”
• Raynaud’s Phenomenon: Topical nitrate formulations have been used with variable success to promote vasodilation in affected digits.
• Biliary Colic: May provide temporary pain relief due to smooth muscle relaxation.
• Assisted Reproduction: Very low-dose transdermal patches have been investigated to improve uterine blood flow and endometrial receptivity.

6. Adverse Effects

The adverse effect profile of glyceryl trinitrate is directly related to its primary pharmacological action of vasodilation and the body’s compensatory responses.

Common Side Effects

• Headache: This is the most frequently reported side effect, occurring in over 50% of patients initiating therapy. It is typically throbbing, frontal, and dose-related, caused by dilation of cerebral arteries. Headaches often diminish in frequency and severity with continued use over several days.
• Hypotension: Postural hypotension, dizziness, lightheadedness, and syncope (particularly with initial doses or dose escalation) can occur due to excessive venodilation and reduced venous return.
• Reflex Tachycardia: A compensatory increase in heart rate mediated by baroreceptor activation in response to decreased blood pressure. This can paradoxically increase myocardial oxygen demand and may precipitate angina in some patients.
• Flushing: Cutaneous vasodilation leads to a sensation of warmth and visible redness of the face and upper body.
• Development of Tolerance: With continuous, uninterrupted exposure (e.g., 24-hour transdermal patches, frequent dosing), a diminished hemodynamic and anti-ischemic response develops, typically within 24-48 hours. The mechanism involves depletion of sulfhydryl groups necessary for biotransformation, neurohormonal activation, and increased vascular superoxide production. Tolerance is preventable by instituting a daily nitrate-free interval of 10-12 hours.

Serious/Rare Adverse Reactions

• Severe Hypotension and Cardiovascular Collapse: Can occur with overdose or in particularly sensitive patients (e.g., hypovolemic, elderly). This may be accompanied by bradycardia (a vagally-mediated Bezold-Jarisch reflex) rather than tachycardia.
• Methemoglobinemia: A rare but serious condition where the ferrous iron (Fe²⁺) in hemoglobin is oxidized to ferric iron (Fe³⁺), forming methemoglobin, which cannot bind oxygen. This risk is higher with high doses of intravenous nitrates, especially in patients with predisposing conditions (e.g., G6PD deficiency). Symptoms include cyanosis, dyspnea, and fatigue unresponsive to oxygen. Treatment is with intravenous methylene blue.
• Withdrawal/Recurrent Ischemia: Abrupt discontinuation of chronic nitrate therapy, particularly without a beta-blocker, can precipitate rebound angina or even myocardial infarction due to heightened vascular sensitivity. A gradual dose reduction is recommended when discontinuing long-term therapy.
• Increased Intraocular Pressure: Theoretical concern in patients with narrow-angle glaucoma, though absolute contraindication is debated; caution is advised.

There are no FDA-mandated black box warnings for glyceryl trinitrate itself, but its formulations carry strong warnings regarding the concomitant use with phosphodiesterase-5 inhibitors.

7. Drug Interactions

Glyceryl trinitrate interacts with several drug classes, primarily through additive pharmacodynamic effects on vasodilation and blood pressure.

Major Drug-Drug Interactions

• Phosphodiesterase-5 (PDE5) Inhibitors (Sildenafil, Tadalafil, Vardenafil, Avanafil): This is an absolute contraindication. PDE5 inhibitors impair the breakdown of cGMP, the second messenger through which nitrates exert their effects. Concomitant use leads to profound, potentially life-threatening hypotension, myocardial infarction, or stroke. A minimum separation of 24 hours (48 hours for tadalafil due to its long half-life) is required between the last dose of a PDE5 inhibitor and nitrate administration.
• Other Vasodilators: Additive hypotensive effects occur with other nitrates, calcium channel blockers (especially dihydropyridines like amlodipine), alpha-adrenergic blockers (e.g., prazosin), angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and direct vasodilators like hydralazine. Concurrent use requires careful blood pressure monitoring.
• Antihypertensives: All classes of antihypertensive drugs can potentiate the hypotensive effect of nitrates.
• Alcohol (Ethanol): Produces additive vasodilation and orthostatic hypotension, increasing the risk of syncope.
• Heparin: Intravenous glyceryl trinitrate may reduce the anticoagulant effect of heparin by an unknown mechanism, potentially requiring an increase in heparin dose. Activated partial thromboplastin time (aPTT) should be monitored closely.
• Ergot Alkaloids (e.g., Ergotamine): These drugs cause vasoconstriction and may antagonize the antianginal effects of nitrates. Their concomitant use is generally avoided.

Contraindications

• Absolute Contraindications:
  • Concurrent use with PDE5 inhibitors.
  • Known hypersensitivity to nitrates or any component of the formulation.
  • Severe anemia (as vasodilation could compromise tissue oxygen delivery further).
  • Increased intracranial pressure (due to risk of cerebral vasodilation).
  • Cardiac tamponade or constrictive pericarditis (these conditions require adequate preload, which nitrates would dangerously reduce).
• Relative Contraindications (Require Extreme Caution):
  • Hypotension or hypovolemia.
  • Hypertrophic obstructive cardiomyopathy (nitrates may exacerbate left ventricular outflow tract obstruction by reducing preload and afterload).
  • Acute inferior wall myocardial infarction with right ventricular involvement (these patients are preload-dependent, and nitrates can cause catastrophic hypotension).
  • Closed-angle glaucoma (theoretical risk).
  • Severe hepatic impairment (may affect metabolism, though clinical significance is uncertain due to extrahepatic activation).

8. Special Considerations

Pregnancy and Lactation

Pregnancy (Category C): Animal reproduction studies have not been conducted, and there are no adequate and well-controlled studies in pregnant women. Glyceryl trinitrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Its use may be considered in specific obstetric emergencies, such as severe pregnancy-induced hypertension or tocolysis in preterm labor, under specialist supervision. Fetal hemodynamics should be monitored.

Lactation: It is not known whether glyceryl trinitrate is excreted in human milk. Given its rapid metabolism and short half-life, significant exposure to the nursing infant is considered unlikely. However, caution is advised when administering to a nursing woman, and monitoring the infant for signs of hypotension or tachycardia may be prudent.

Pediatric Considerations

The use of glyceryl trinitrate in pediatric populations is limited and generally off-label. It may be used in specialized settings such as:

• Controlling hypertension following surgical repair of coarctation of the aorta.
• As a vasodilator in the management of low cardiac output states in intensive care.
• To assess coronary artery vasoreactivity during cardiac catheterization.

Dosing must be carefully individualized based on weight and hemodynamic response, typically starting with very low doses. Safety and efficacy for chronic use in children have not been established.

Geriatric Considerations

Elderly patients (≥65 years) are more sensitive to the hypotensive effects of glyceryl trinitrate due to age-related reductions in baroreceptor reflex sensitivity, decreased vascular compliance, and a higher prevalence of volume depletion. The risk of postural hypotension, syncope, and falls is significantly increased. Therapy should be initiated at the low end of the dosing range, with careful titration and patient education about rising slowly from sitting or lying positions. Renal and hepatic function, which may be impaired, should be assessed, though the impact on nitrate pharmacokinetics is usually minimal.

Renal Impairment

Renal impairment has no clinically significant effect on the pharmacokinetics of glyceryl trinitrate itself, as the parent drug is not renally excreted. However, the inactive metabolites (nitrate ions) accumulate in renal failure. These metabolites are not thought to contribute to efficacy or toxicity. Dose adjustment is generally not required for renal impairment, but patients with end-stage renal disease may have concomitant volume overload or electrolyte disturbances, making them more susceptible to hypotension. Careful hemodynamic monitoring is essential.

Hepatic Impairment

Severe hepatic impairment could theoretically affect the hepatic component of glyceryl trinitrate metabolism. However, because the clinically relevant activation occurs extrahepatically via vascular ALDH-2, hepatic dysfunction is unlikely to markedly alter its hemodynamic effects. Bioavailability after oral administration might increase due to reduced first-pass metabolism, but oral formulations are not used for systemic effects. No specific dose adjustments are recommended for hepatic impairment, but caution is advised due to the potential for increased sensitivity and the possibility of impaired clearance of metabolites.

9. Summary/Key Points

• Glyceryl trinitrate (nitroglycerin) is an organic nitrate prodrug that requires enzymatic conversion, primarily by mitochondrial aldehyde dehydrogenase (ALDH-2), to release nitric oxide (NO).
• The released NO activates soluble guanylyl cyclase, increasing intracellular cGMP, which leads to vascular smooth muscle relaxation via reduced calcium availability and calcium desensitization.
• Its hemodynamic effects are dose-dependent: low doses cause predominant venodilation (reducing preload), while higher doses also cause arteriodilation (reducing afterload), collectively decreasing myocardial oxygen demand.
• Pharmacokinetics are defined by rapid absorption via non-oral routes, extensive first-pass metabolism (making oral bioavailability negligible), extrahepatic activation, and an extremely short plasma half-life of 1-4 minutes.
• Primary clinical uses include acute abortive therapy for angina (sublingual), chronic angina prophylaxis (transdermal/long-acting nitrates with a nitrate-free interval), and management of acute heart failure or hypertensive emergencies (intravenous).
• The most common adverse effects are headache, hypotension, reflex tachycardia, and flushing. Tolerance develops with continuous exposure and is managed by ensuring a daily nitrate-free period.
• A critical, absolute contraindication exists with phosphodiesterase-5 inhibitors (e.g., sildenafil) due to the risk of severe, refractory hypotension.
• Special caution is required in geriatric patients due to increased sensitivity to hypotension and in clinical conditions where patients are preload-dependent (e.g., right ventricular infarction, cardiac tamponade).

Clinical Pearls

• Instruct patients using sublingual tablets for angina to sit down before administration to prevent injury from syncope, to expect a tingling or burning sensation if the tablet is potent, and to seek emergency help if pain is not relieved after three doses taken 5 minutes apart.
• For transdermal patches, apply to a hairless area of skin on the upper body or arm, rotate application sites daily to prevent skin irritation, and remove the patch to provide a 10-12 hour nitrate-free interval (often overnight) to prevent tolerance.
• Intravenous infusions should be administered using non-PVC (polyvinyl chloride) tubing and bags, as glyceryl trinitrate adsorbs significantly to PVC, reducing the delivered dose. Special polyethylene or glass infusion sets are required.
• When treating acute pulmonary edema with hypertension, the combination of sublingual nitroglycerin (every 5 minutes) and intravenous furosemide is a rapid and effective initial strategy while preparing for intravenous nitrate infusion.
• Always explicitly question patients presenting with angina or heart failure about recent use of medications for erectile dysfunction before administering any nitrate preparation.

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