What are nitrates?

Nitrates: Mechanism, Types, and Clinical Applications

Nitrates are organic products that undergo enzymatic denitrification in the vessel wall by mitochondrial aldehyde dehydrogenase, producing vasoactive nitric oxide which causes vasodilation. 1

Mechanism of Action

• Nitrates serve as exogenous sources of nitric oxide that help replenish or restore the actions of endothelium-derived relaxing factor, which is often impaired in patients with coronary artery atherosclerosis 1
• At low doses, nitrates primarily act as venodilators, reducing preload and venous return to the heart, leading to decreased ventricular volume and myocardial wall tension, which reduces myocardial oxygen demand 1
• At higher doses, nitrates also dilate coronary arteries, prevent coronary spasm, improve subendocardial blood flow to ischemic areas, decrease ventricular diastolic pressure, and lower blood pressure 1
• Nitrates improve collateral blood flow, which can be beneficial in patients with coronary artery disease 1
• The vasodilatory effects occur independently of endothelial integrity as they undergo bioconversion into nitric oxide both in endothelial cells and myocytes 1

Types of Nitrates and Formulations

• Nitroglycerin (NTG): Available as sublingual tablets (0.3-0.6 mg), spray (0.4 mg), intravenous infusion, and transdermal patches 2
• Isosorbide dinitrate (ISDN): Oral dosing 5-80 mg, 2-3 times daily with duration up to 8 hours 2
• Isosorbide mononitrate (ISMN): Oral dosing 20 mg twice daily with duration 12-24 hours 2
• Nitroglycerin is the only nitrate available for intravenous use in the United States 1

Clinical Applications

• Nitrates are effective for both immediate relief of acute angina attacks and prophylaxis of symptomatic and asymptomatic myocardial ischemia 2, 3
• They are particularly beneficial in patients with coronary vasospasm, providing clear symptom reduction 1
• Intravenous nitroglycerin is appropriate for managing unstable angina and early complications of acute myocardial infarction 4
• Nitrates are useful in patients with impaired left ventricular systolic function or congestive heart failure due to their favorable hemodynamic profile 1

Nitrate Tolerance

• Tolerance to nitrates can develop after 24 hours of continuous therapy, reducing their anti-ischemic effects 2, 3
• To prevent tolerance, a daily "nitrate-free interval" of 10-12 hours is recommended 2, 3
• Once-daily administration of high-dose sustained-release formulations can prevent tolerance development while maintaining efficacy 3

Side Effects and Precautions

• Headache is the most common side effect, reported by up to 82% of patients, often dose-related but typically diminishing with continued use 5
• Hypotension can occur and is sometimes asymptomatic but may occasionally be severe 5
• Nitrates should be carefully titrated in patients with right ventricular infarction as they can cause profound hypotension due to these patients' dependence on adequate RV preload 1, 6
• Nitrates are contraindicated with phosphodiesterase-5 inhibitors (used for erectile dysfunction) due to risk of profound hypotension 7, 5
• Nitrates may aggravate hypoxemia by increasing ventilation-perfusion mismatch 1

Important Clinical Considerations

• Small arterioles are nitrate-resistant, explaining why nitrates have limited action in the microcirculation 1
• Reflex tachycardia and increased myocardial contractility may partially offset the beneficial effects on preload and afterload 1
• Combining nitrates with beta-blockers can block reflex tachycardia, leading to a synergistic anti-ischemic effect 1
• Meta-analyses show no differences in symptom relief or exercise-testing parameters between nitrates and other antianginal agents 1
• No data support that nitrates improve outcomes (mortality) in patients with chronic stable angina 1