Isosorbide mononitrate - Drug Monograph

Introduction

Isosorbide mononitrate is an organic nitrate vasodilator used primarily in the management of angina pectoris. As the active metabolite of isosorbide dinitrate, it belongs to the nitrate class of antianginal medications and has been widely used since its approval by the FDA in 1991. This long-acting nitrate derivative provides predictable pharmacokinetics and has become a mainstay in the prophylactic treatment of chronic stable angina.

Mechanism of Action

Isosorbide mononitrate undergoes biotransformation to release nitric oxide (NO), which activates guanylate cyclase, increasing cyclic guanosine monophosphate (cGMP) levels in vascular smooth muscle. This leads to:

• Venodilation with reduced preload
• Arterial dilation with reduced afterload
• Coronary artery vasodilation improving myocardial oxygen supply
• Decreased myocardial oxygen demand through reduced ventricular wall stress

The drug primarily affects venous capacitance vessels at lower doses, with arterial effects becoming more prominent at higher concentrations.

Indications

• Prophylactic treatment of angina pectoris

• Chronic heart failure (as adjunct therapy)
• Pulmonary hypertension
• Esophageal spasm
• Raynaud's phenomenon

Dosage and Administration

• Initial dose: 20 mg twice daily (7-8 hours apart)
• Maintenance dose: 20-40 mg twice daily
• Maximum dose: 240 mg daily (in divided doses)

• Extended-release: 30-120 mg once daily

• Renal impairment: No dosage adjustment required
• Hepatic impairment: Use with caution; consider reduced dosing
• Elderly: Start with lower doses; monitor for hypotension
• Pediatric: Safety and efficacy not established

• Take on an empty stomach (1 hour before or 2 hours after meals)
• Do not crush or chew extended-release formulations
• Implement a nitrate-free interval (10-14 hours daily) to prevent tolerance

Pharmacokinetics

• Oral bioavailability: ~100%
• Not subject to first-pass metabolism
• Tmax: 30-60 minutes (immediate-release); 4-6 hours (extended-release)

• Volume of distribution: ~0.6 L/kg
• Protein binding: <5%
• Crosses placenta and enters breast milk

• Hepatic metabolism via denitration
• Forms inactive metabolites (isosorbide and isosorbide glucuronide)
• Not cytochrome P450 dependent

• Half-life: 4-6 hours
• Renal excretion: primarily as metabolites
• Dialysis: not effectively removed

Contraindications

• Hypersensitivity to nitrates or any component of the formulation
• Concomitant use with phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil)
• Severe anemia
• Increased intracranial pressure
• Severe hypotension (SBP <90 mmHg)
• Circulatory failure and shock
• Acute myocardial infarction with low filling pressure

Warnings and Precautions

• Develops with continuous therapy
• Prevent with daily nitrate-free intervals (10-14 hours)

• May cause severe hypotension, especially with volume depletion
• Caution in patients with autonomic dysfunction

• Common and may be severe
• Usually diminishes with continued therapy

• May occur during nitrate-free intervals
• Risk requires careful patient selection and monitoring

• Heart failure: May precipitate pulmonary edema in hypertrophic cardiomyopathy
• Aortic/mitral stenosis: Use with extreme caution
• G6PD deficiency: Risk of methemoglobinemia

Drug Interactions

• Phosphodiesterase-5 inhibitors: Profound hypotension (contraindicated)
• Other vasodilators: Additive hypotensive effects (calcium channel blockers, ACE inhibitors)
• Alcohol: Enhanced vasodilation and hypotension
• Sildenafil: Severe hypotension (avoid within 24 hours)
• Tadalafil: Severe hypotension (avoid within 48 hours)

• Antihypertensives: Enhanced hypotensive effect
• Aspirin: Increased nitrate bioavailability
• Heparin: Possible reduced anticoagulant effect

Adverse Effects

• Headache (20-30%)
• Dizziness (3-10%)
• Hypotension (2-5%)
• Nausea (2-5%)

• Flushing
• Tachycardia
• Syncope
• Weakness

• Methemoglobinemia
• Dermatitis
• Paroxysmal nocturnal dyspnea
• Exfoliative dermatitis

• Severe hypotension
• Circulatory collapse
• Myocardial infarction
• Cerebrovascular ischemia

Monitoring Parameters

• Blood pressure (standing and supine)
• Heart rate
• Angina frequency and characteristics
• Renal and hepatic function

• Blood pressure at initiation and dosage changes
• Heart rate regularly
• Angina diary (frequency, severity, nitrate use)
• Signs of hypotension (dizziness, syncope)
• Headache assessment and management
• Development of tolerance

• Methemoglobin levels if cyanosis occurs
• Hemodynamic monitoring in acute settings

Patient Education

• Take exactly as prescribed with attention to timing
• Do not stop abruptly; taper under medical supervision
• Implement daily nitrate-free interval as directed
• Rise slowly from sitting/lying positions to prevent dizziness
• Headaches are common but usually diminish with time

• Avoid alcohol due to additive hypotensive effects
• Report chest pain that differs from usual pattern
• Inform all healthcare providers about nitrate therapy

• Seek immediate medical attention for:

- Severe dizziness or fainting - Chest pain not relieved by rest or nitroglycerin - Bluish discoloration of lips or skin

• Store at room temperature
• Keep in original container
• Do not share medication

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. Nitrate tolerance and dependence. Am Heart J. 1980;100(1):113-123. 3. FDA Prescribing Information: Isosorbide Mononitrate. 2021. 4. Tarkin JM, Kaski JC. Vasodilator therapy: nitrates and nicorandil. Cardiovasc Drugs Ther. 2016;30(4):367-378. 5. Munzel T, Daiber A, Mulsch A. Explaining the phenomenon of nitrate tolerance. Circ Res. 2005;97(7):618-628. 6. Chrysant SG. Hemodynamic effects of isosorbide mononitrate. Am J Cardiol. 1987;60(15):35I-39I. 7. Parker JO. Nitrate therapy in stable angina pectoris. N Engl J Med. 1987;316(26):1635-1642. 8. Thadani U. Management of stable angina with nitrates. Curr Cardiol Rep. 2000;2(4):280-285.