isosorbide dinitrate
nitrate vasodilator· Brands: Isordil, Sorbitrate, Isoket, CedocardPOSL
Mechanism of action
Isosorbide dinitrate is a nitrate prodrug that undergoes biotransformation in the body to release nitric oxide (NO). NO activates soluble guanylate cyclase in vascular smooth muscle, increasing cyclic guanosine monophosphate (cGMP) levels. Elevated cGMP causes smooth muscle relaxation, leading to vasodilation. It predominantly dilates veins, reducing preload and myocardial wall tension, thus decreasing myocardial oxygen demand. It also dilates coronary arteries to a lesser extent, improving coronary blood flow. Its antianginal effect results from this balanced action on preload, afterload, and coronary perfusion.
Pharmacokinetics
Isosorbide dinitrate has low and variable oral bioavailability (about 20-30%) because of extensive first-pass hepatic metabolism. Sublingual administration bypasses hepatic metabolism, giving rapid onset. It is metabolized to isosorbide-2-mononitrate and isosorbide-5-mononitrate, both of which are active and have longer half-lives. The half-life of isosorbide dinitrate is approximately 1 to 4 hours, while the active mononitrate metabolites have half-lives of 4 to 6 hours. Onset of action is 2 to 5 minutes after sublingual use and 30 to 60 minutes after oral administration. Duration of action is 30 to 60 minutes for sublingual and 4 to 6 hours for oral formulations. Tolerance develops with continuous exposure; a nitrate-free interval is required to maintain effectiveness.
Indications & dosing
Prophylaxis of angina pectoris
Use with a nitrate-free interval to avoid tolerance.
- adult · PO: 10–40 mg 2-3 times daily · Use with a nitrate-free interval to avoid tolerance.
Treatment of acute angina pectoris
May be repeated after 5-10 minutes if needed.
- adult · SL: 2.5–5 mg As needed · May be repeated after 5-10 minutes if needed.
Adjunctive treatment of congestive heart failure
Usually given with hydralazine in refractory heart failure.
- adult · PO: 20–40 mg 3 times daily · Usually given with hydralazine in refractory heart failure.
Contraindications & precautions
- Concurrent use of PDE5 inhibitors (e.g., sildenafil, tadalafil) · Increased risk of severe hypotension and cardiovascular collapse
- Marked hypotension (systolic blood pressure < 90 mmHg) · Nitrates cause vasodilation, worsening hypotension
- Hypersensitivity to isosorbide dinitrate or other nitrates · Risk of anaphylaxis
- Severe anemia · Nitrates reduce oxygen delivery to tissues
- Increased intracranial pressure · Nitrates may exacerbate intracranial hypertension
- Constrictive pericarditis or cardiac tamponade · Vasodilation may reduce cardiac filling
- Avoid concurrent use of PDE5 inhibitors; if necessary, wait at least 24 hours after last dose of sildenafil.
- Monitor blood pressure during dose titration, especially in patients on antihypertensive therapy.
- Use with caution in patients with hypovolemia or dehydration to avoid severe hypotension.
- Do not discontinue abruptly; taper dosage to avoid rebound angina.
- Caution in hypertrophic obstructive cardiomyopathy, as nitrates may worsen obstruction.
Adverse effects
- Headache
- Flushing
- Dizziness and lightheadedness
- Hypotensionserious
- Reflex tachycardia
- Syncopeserious
- Methemoglobinemiaserious
- Tolerance (with continuous use)
Renal & hepatic adjustment
- Hepatic impairment (severe): Use with caution; consider dose reduction as hepatic metabolism may be impaired, leading to increased plasma concentrations.
Monitoring, pregnancy & toxicity
- Blood pressure · At baseline and during dose titration
- Heart rate · At baseline and during dose titration
- Headache · At each review
- Signs of hypotension, such as dizziness or syncope · At each review
- Pregnancy: Isosorbide dinitrate is not recommended for use during pregnancy unless there is no safer alternative. It may be used under specialist supervision when the benefits outweigh the potential risks.
- Toxicity: Severe hypotension · Supportive care, place patient in supine position with legs elevated. Administer intravenous fluids. Use vasopressors such as norepinephrine if required.
- Toxicity: Reflex tachycardia · Monitored, usually resolves with blood pressure support. Beta-blockers may be considered if persistent and not contraindicated.
- Toxicity: Methemoglobinemia (rare) · Administer oxygen and methylene blue (1-2 mg/kg intravenously) as an antidote. Monitor methemoglobin levels and provide supportive care.
Clinical notes
Isosorbide dinitrate is used for the prophylaxis and acute relief of angina pectoris. Sublingual administration is used for acute anginal attacks, while oral formulations are used for long-term prophylaxis. It is also used as an adjunct in the management of heart failure. To avoid tolerance, a daily nitrate-free interval of 8 to 12 hours is recommended, often achieved by scheduling the last daily dose in the evening. Common adverse effects include headache, dizziness, flushing, and hypotension. It is contraindicated in patients taking phosphodiesterase-5 inhibitors (e.g., sildenafil) because of the risk of severe hypotension. Caution is needed in hypotension, right ventricular infarction, and hypertrophic cardiomyopathy. Education on proper sublingual use and headache management is important.
Log in to read the full isosorbide dinitrate monograph
A free account unlocks the complete drug reference, the interaction checker, prescription practice and every other learning tool.
BNF; local formulary