Isosorbide Dinitrate

• Angina Pectoris
• Coronary Artery Disease
• Heart Failure
• Chest Pain Prevention

Isosorbide dinitrate is an organic nitrate vasodilator used for the prevention and treatment of angina pectoris and as part of combination therapy for heart failure. This medication works by releasing nitric oxide, causing vasodilation and reducing cardiac workload.

Mechanism of Action

Isosorbide dinitrate is an organic nitrate that undergoes biotransformation to release nitric oxide (NO), which activates guanylate cyclase in vascular smooth muscle cells. This increases cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation and vasodilation. The predominant effect is venodilation, which reduces preload by pooling blood in the venous capacitance vessels, decreasing venous return and left ventricular end-diastolic pressure. At higher doses, arterial dilation reduces afterload. These effects decrease myocardial oxygen demand and relieve angina. In heart failure, vasodilation improves cardiac output and symptoms.

Available Formulations

Isosorbide dinitrate is available as immediate-release tablets (5 mg, 10 mg, 20 mg, 30 mg, 40 mg), sublingual tablets (2.5 mg, 5 mg), and extended-release tablets and capsules. It is also available in fixed-dose combination with hydralazine (BiDil) for heart failure in African Americans. The sublingual tablets are used for acute angina relief; other forms are for prevention.

Medical Uses

Isosorbide dinitrate is FDA-approved for the prevention and treatment of angina pectoris due to coronary artery disease. The onset of action and duration vary by formulation: sublingual (2-5 minutes onset, 1-2 hours duration) for acute relief; oral immediate-release (15-30 minutes onset, 4-6 hours duration) for prevention. In combination with hydralazine, it is approved for heart failure in African American patients to improve survival, prolong time to hospitalization, and improve patient-reported functional status.

Dosing Guidelines

For angina prevention with immediate-release tablets, typical starting dose is 5-20 mg two to three times daily. The dosing schedule should include a daily nitrate-free interval (8-12 hours, usually overnight) to prevent tolerance. For sublingual tablets, 2.5-5 mg sublingually at the onset of an attack. For extended-release preparations, once or twice daily dosing with an eccentric schedule is used. In heart failure (combination with hydralazine), 20-40 mg three times daily with the last dose by 7 PM.

Important Safety Information

Nitrate tolerance develops with continuous exposure; nitrate-free intervals are necessary to maintain efficacy. Severe hypotension, especially with concurrent PDE-5 inhibitors, can occur. Isosorbide dinitrate is contraindicated with PDE-5 inhibitors (sildenafil, tadalafil, vardenafil) or riociguat. Headache is common, especially initially. In acute MI, use with caution due to hypotension risk. Methemoglobinemia has been reported rarely. Do not discontinue abruptly in patients with angina; gradual dose reduction is recommended.

Drug Interactions

PDE-5 inhibitors (sildenafil, tadalafil, vardenafil) are contraindicated; severe hypotension may occur. Riociguat is contraindicated; hypotension risk. Other antihypertensives, alcohol, and vasodilators may enhance hypotensive effects. Aspirin may enhance nitrate's vasodilatory effects. Ergot alkaloids may antagonize vasodilation. Tissue-type plasminogen activator (t-PA) may increase clearance of isosorbide dinitrate.

Special Populations

There are no adequate studies in pregnant women. Use during pregnancy only if clearly needed. It is unknown whether isosorbide dinitrate is excreted in human breast milk. Safety and efficacy have not been established in pediatric patients. Elderly patients may be more sensitive to hypotensive effects; start with lower doses. No specific dose adjustment is established for renal impairment; use with caution. No specific dose adjustment is established for hepatic impairment; metabolism may be reduced.