Introduction
Nitroglycerin is an organic nitrate vasodilator that has been used clinically for over 140 years. It remains a cornerstone therapy for angina pectoris and is classified as an essential medicine by the World Health Organization. Originally discovered as an explosive compound, its medicinal properties were identified when factory workers exposed to nitroglycerin experienced relief from chest pain and headaches.
Mechanism of Action
Nitroglycerin functions as a prodrug that is metabolized to release nitric oxide (NO) in vascular smooth muscle cells. Nitric oxide activates guanylate cyclase, increasing cyclic guanosine monophosphate (cGMP) levels. This leads to:
- Dephosphorylation of myosin light chains
- Reduction of intracellular calcium
- Vasodilation primarily of venous capacitance vessels
- Reduced preload and afterload
- Decreased myocardial oxygen demand
- Coronary artery vasodilation improving blood flow to ischemic areas
Indications
FDA-approved indications:- Treatment and prophylaxis of angina pectoris
- Acute hypertension during surgical procedures
- Congestive heart failure associated with acute myocardial infarction
- Raynaud's phenomenon
- Esophageal spasm
- Anal fissures (topical formulation)
- Tocolytic therapy in preterm labor
Dosage and Administration
Sublingual tablet:- 0.3-0.6 mg every 5 minutes as needed for angina attacks
- Maximum 3 doses within 15 minutes
- 0.5-2 inches every 8 hours
- Apply to clean, hairless area without rubbing
- 0.1-0.8 mg/hour applied daily
- Remove for 10-12 hours daily to prevent tolerance
- Initial: 5 mcg/minute, titrate by 5-10 mcg/minute every 3-5 minutes
- Maximum: 200 mcg/minute
- Hepatic impairment: Use caution, no specific dose adjustment
- Renal impairment: No dose adjustment required
- Elderly: Start with lower doses due to increased sensitivity
Pharmacokinetics
Absorption: Variable depending on formulation; sublingual bioavailability ~40% Distribution: Volume of distribution ~3 L/kg; extensively distributed Metabolism: Primarily hepatic via glutathione-organic nitrate reductase Elimination: Half-life 1-4 minutes; metabolites excreted renally Onset/Duration:- Sublingual: onset 1-3 minutes, duration 30-60 minutes
- Transdermal: onset 30-60 minutes, duration 8-12 hours
- IV: immediate onset, duration while infused
Contraindications
- Hypersensitivity to nitrates or any component of formulation
- Concomitant use with phosphodiesterase inhibitors (sildenafil, tadalafil, vardenafil)
- Severe anemia
- Increased intracranial pressure
- Severe hypotension (SBP <90 mmHg)
- Right ventricular infarction
- Constrictive pericarditis
Warnings and Precautions
Tolerance: Develops with continuous exposure; implement 10-12 hour nitrate-free interval Withdrawal: Abrupt discontinuation may cause rebound angina Hypotension: May cause severe hypotension, especially with volume depletion Headache: Common side effect that typically diminishes with continued use Methemoglobinemia: Risk with high doses or prolonged use CAD patients: Use caution in patients with inferior wall MI with right ventricular involvementDrug Interactions
Major interactions:- Phosphodiesterase-5 inhibitors: Profound hypotension (contraindicated)
- Alcohol: Enhanced hypotensive effects
- Antihypertensives: Additive hypotensive effects
- Heparin: Reduced anticoagulant effect (monitor aPTT)
- Aspirin: Increased nitrate bioavailability
- Beta-blockers: Additive hemodynamic effects
- Calcium channel blockers: Enhanced hypotensive effects
- Diuretics: Potentiated hypotension
Adverse Effects
Common (≥10%):- Headache (≥50%)
- Dizziness (3-6%)
- Hypotension (2-8%)
- Flushing (2-6%)
- Nausea
- Tachycardia
- Syncope
- Weakness
- Methemoglobinemia
- Allergic reactions
- Dermatitis (with transdermal forms)
- Paradoxical angina
Monitoring Parameters
Acute monitoring:- Blood pressure and heart rate (before and after dose)
- Angina symptoms and frequency
- ECG changes during episodes
- Blood pressure trends
- Development of tolerance
- Liver function tests (with long-term use)
- Methemoglobin levels with high-dose therapy
- Skin reactions with transdermal forms
Patient Education
Proper administration:- Sit down before taking sublingual dose
- Place tablet under tongue without swallowing
- Expect burning or tingling sensation
- Carry medication at all times
- Replace sublingual tablets every 3 months
- Keep in original glass container
- Protect from light, heat, and moisture
- Do not transfer to other containers
- Chest pain not relieved by 3 doses in 15 minutes
- Severe or persistent headache
- Dizziness or fainting
- Signs of allergic reaction
- Avoid alcohol
- Rise slowly from sitting/lying position
- Report all medications to healthcare providers
- Never take ED medications while on nitroglycerin
References
1. FDA Prescribing Information: Nitroglycerin (2023) 2. Abrams J. Nitroglycerin and long-acting nitrates. N Engl J Med. 2005;353(8):827-838. 3. Thadani U. Nitrate therapy in stable angina pectoris. N Engl J Med. 2010;362(10):943-945. 4. Munzel T, et al. Nitrate tolerance: a unifying hypothesis. Cardiovasc Res. 2011;89(3):527-535. 5. ACC/AHA Guidelines for the Management of Patients With Stable Ischemic Heart Disease (2021) 6. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 14th Edition 7. Lexicomp Online: Nitroglycerin Monograph (2023)
