Isosorbide dinitrate - Drug Monograph

Introduction

Isosorbide dinitrate is an organic nitrate vasodilator that has been used clinically for over six decades in the management of angina pectoris and heart failure. As a prodrug that requires enzymatic conversion to its active metabolites, it represents an important therapeutic option in cardiovascular medicine with both rapid-acting and extended-release formulations available.

Mechanism of Action

Isosorbide dinitrate undergoes denitration in the liver and vascular smooth muscle to form active metabolites, primarily isosorbide-5-mononitrate and isosorbide-2-mononitrate. These metabolites activate guanylate cyclase, increasing cyclic guanosine monophosphate (cGMP) levels. Elevated cGMP leads to dephosphorylation of myosin light chains, resulting in vascular smooth muscle relaxation. This causes venodilation (reducing preload) and arterial dilation (reducing afterload), ultimately decreasing myocardial oxygen demand. Additionally, coronary artery dilation improves oxygen supply to ischemic myocardial regions.

Indications

• Angina Pectoris Prophylaxis: Prevention of angina attacks in patients with coronary artery disease
• Acute Angina Relief: Sublingual formulation for acute angina episodes
• Heart Failure Adjunct Therapy: Used in combination with other agents for chronic heart failure management (off-label)
• Esophageal Spasm: Occasionally used for symptomatic relief (off-label)

Dosage and Administration

• Sublingual tablets: 2.5-5 mg every 5 minutes for up to 3 doses for acute angina
• Oral immediate-release: 5-20 mg 2-3 times daily with 10-12 hour nitrate-free interval
• Oral extended-release: 20-80 mg once or twice daily

• Hepatic impairment: Reduce dose due to decreased metabolism
• Renal impairment: No significant adjustment needed
• Elderly: Start with lowest effective dose
• Pediatric: Safety and efficacy not established

Pharmacokinetics

• Absorption: Well absorbed orally (bioavailability 20-25% due to first-pass metabolism)
• Distribution: Volume of distribution ~4 L/kg; protein binding <5%
• Metabolism: Extensive hepatic metabolism via glutathione-organic nitrate reductase to active metabolites (isosorbide-5-mononitrate and isosorbide-2-mononitrate)
• Elimination: Renal excretion (primarily as metabolites); elimination half-life of parent drug ~1 hour, metabolites 4-6 hours

Contraindications

• Hypersensitivity to nitrates or any component of formulation
• Concomitant use with phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil)
• Severe anemia
• Increased intracranial pressure
• Circulatory failure or shock
• Hypotension (SBP <90 mmHg)

Warnings and Precautions

• Tolerance: Develops with continuous exposure; requires daily nitrate-free interval
• Hypotension: May cause severe hypotension, especially with volume depletion
• Headache: Common and may be severe; typically diminishes with continued therapy
• Rebound ischemia: Possible during nitrate-free intervals
• Hypertrophic cardiomyopathy: Use with caution due to potential for exacerbating outflow obstruction
• Acute myocardial infarction: Use with caution in right ventricular infarction

Drug Interactions

• Phosphodiesterase-5 inhibitors: Contraindicated combination causing severe hypotension
• Antihypertensive agents: Additive hypotensive effects
• Alcohol: Enhanced vasodilation and hypotension
• Aspirin: May increase nitrate concentrations
• Heparin: Possible reduced anticoagulant effect
• Sympathomimetics: May counteract antianginal effects

Adverse Effects

• Headache (dose-related)
• Dizziness, lightheadedness
• Flushing
• Hypotension
• Reflex tachycardia

• Nausea, vomiting
• Weakness
• Syncope
• Cutaneous vasodilation

• Methemoglobinemia (especially with overdose)
• Dermatitis
• Paroxysmal nocturnal dyspnea
• Allergic reactions

Monitoring Parameters

• Blood pressure (standing and supine) at initiation and periodically
• Heart rate and rhythm
• Angina frequency and severity
• Signs of hypotension (dizziness, syncope)
• Headache severity and pattern
• Liver function tests in patients with hepatic impairment
• Methemoglobin levels if cyanosis occurs

Patient Education

• Take exactly as prescribed; do not stop abruptly
• Sit or lie down when taking dose to prevent falls from dizziness
• Sublingual tablets should produce tingling sensation; replace if no tingling
• Maintain nitrate-free interval as directed by healthcare provider
• Report severe or persistent headaches
• Avoid alcohol consumption
• Never take with erectile dysfunction medications (Viagra, Cialis, Levitra)
• Store medication in original container away from heat and moisture
• Carry medication at all times if used for angina prevention
• Seek immediate medical attention if chest pain persists after 3 sublingual doses

References

1. Thadani U, Rodgers T. Side effects of using nitrates to treat angina. Expert Opin Drug Saf. 2006;5(5):667-674. 2. Abrams J. Nitrates in the treatment of angina pectoris. Am J Cardiol. 1992;70(8):43B-51B. 3. FDA Prescribing Information: Isosorbide dinitrate tablets. 4. Münzel T, Steven S, Daiber A. Organic nitrates: update on mechanisms underlying vasodilation, tolerance and endothelial dysfunction. Vasc Pharmacol. 2014;63(3):105-113. 5. Gibson GR, Hunter JB, Raabe DS Jr, et al. Methemoglobinemia produced by high-dose intravenous nitroglycerin. Ann Intern Med. 1982;96(5):615-616. 6. Parker JD, Parker JO. Nitrate therapy for stable angina pectoris. N Engl J Med. 1998;338(8):520-531. 7. Gori T, Parker JD. Nitrate tolerance: a unifying hypothesis. Circulation. 2002;106(19):2510-2513.