isosorbide dinitrate (Rx)

Frequency Not Defined

Cardiovascular: Rebound hypertension (uncommon), syncope, unstable angina flushing, hypotension/orthostatic hypotension, lightheadedness, palpitations, tachyarrhythmia

Central nervous system (CNS): Dizziness, headache, restlessness, weakness

Gastrointestinal (GI): Nausea

Hematologic: Methemoglobinemia (infrequent)

Contraindications

Hypersensitivity

Recent use (within several days) of PDE-5 inhibitors (eg, avanafil, sildenafil, tadalafil, or vardenafil) may cause dangerously low hypotension; the time course of the interaction appears to be related to the PDE-5 inhibitor half-life

Severe anemia, shock, markedly low blood pressure (BP)

Concomitant administration with guanylate stimulator riociguat

Cautions

Allergies to nitrates, head trauma/cerebral hemorrhage (potential contraindication), hypertrophic cardiomyopathy, increased intraocular pressure, postural hypotension, acute myocardial infarction (MI), congestive heart failure, hyperthyroidism

Inability to relieve chest pain after 3 doses may signal acute MI necessitating emergency management

Tolerance to extended-release formulation may develop, rendering formulation ineffective after a few weeks

Do not change brands unintentionally; formulations are not all bioequivalent

Severe hypotension, particularly with upright posture, may occur with even small doses; use with caution in patients who may be volume depleted or who are already hypotensive; hypotension induced by isosorbide dinitrate may be accompanied by paradoxical bradycardia and increased angina pectoris

Nitrate therapy may aggravate angina caused by hypertrophic cardiomyopathy

Treat drug-induced headache with aspirin or acetaminophen

Provide nitrate-free interval (10-12 hours or overnight) to prevent development of tolerance

Use supportive treatment in overdose

Avoid use of extended release formulation in acute MI or acute heart failure; adverse events are not easily reversible if they develop

Avoid use in patients with hypertrophic cardiomyopathy with outflow tract obstruction; nitrates may reduce preload, which may cause exacerbation of obstruction and cause hypotension or syncope and/or worsening of heart failure

Pregnancy category: C

Lactation: Unknown whether drug is distributed into breast milk

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Vasodilating agent (nitric oxide donor); relaxes smooth muscle via dose-dependent dilation of arterial and venous beds to reduce both preload and afterload, as well as myocardial oxygen demand; also improves coronary collateral circulation, lowering blood pressure, increasing heart rate, and causing occasional paradoxical bradycardia

Absorption

~100% absorbed from GI tract or oral mucosa

Bioavailability: Immediate release, 40-50%

Duration: 1-2 hr

Distribution

Vd: 2-4 L/kg

Metabolism

Extensively metabolized in liver to conjugated metabolites

Elimination

Half-life: 1 hr

Excretion: Urine (80-100%), feces