Nitrostat - Drug Monograph

Introduction

Nitrostat (nitroglycerin) is an organic nitrate vasodilator medication primarily used for the treatment and prevention of angina pectoris. First synthesized in 1847 and introduced for medical use in 1878, nitroglycerin remains a cornerstone therapy in cardiovascular medicine. Nitrostat is specifically formulated as a sublingual tablet for rapid onset of action during acute angina episodes.

Mechanism of Action

Nitroglycerin functions as a prodrug that undergoes enzymatic conversion to nitric oxide (NO) within 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 concentrations
• Subsequent smooth muscle relaxation

The primary hemodynamic effects include:

• Venodilation (predominant effect) reducing preload
• Arterial dilation reducing afterload
• Coronary artery vasodilation improving myocardial oxygen supply
• Collateral vessel dilation enhancing blood flow to ischemic areas

Indications

• Treatment of acute angina attacks
• Prophylaxis of angina pectoris prior to physical or emotional stress

• Acute coronary syndrome management
• Controlled hypotension during surgical procedures
• Congestive heart failure (especially with pulmonary edema)
• Raynaud's phenomenon
• Esophageal spasm

Dosage and Administration

• One tablet (0.3 mg, 0.4 mg, or 0.6 mg) dissolved under the tongue or in the buccal pouch at the first sign of an angina attack
• May repeat every 5 minutes until relief obtained
• Maximum of 3 tablets within 15 minutes

• 5-10 minutes before anticipated physical or emotional stress

• Elderly: Start with lowest dose (0.3 mg)
• Hepatic impairment: Use caution; consider reduced dosing
• Renal impairment: No dosage adjustment typically needed

• Patient should sit down prior to administration
• Tablet placed under tongue or in buccal pouch
• Allow tablet to dissolve completely without swallowing
• Avoid eating, drinking, or smoking until tablet dissolved

Pharmacokinetics

• Rapid sublingual absorption
• Onset of action: 1-3 minutes
• Peak effect: 4-8 minutes
• Duration: 10-30 minutes
• Bioavailability: ~40% (extensive first-pass metabolism if swallowed)

• Volume of distribution: ~3 L/kg
• Protein binding: ~60%
• Rapidly distributes to vascular tissues

• Extensive hepatic metabolism via mitochondrial aldehyde dehydrogenase-2
• Metabolites: dinitroglycerin (active), mononitroglycerin (minimal activity)

• Half-life: 1-4 minutes
• Excretion: Primarily renal as metabolites
• Clearance: ~2 L/min

Contraindications

• Hypersensitivity to nitroglycerin, other nitrates, or nitrites
• Concurrent use with phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil)
• Severe anemia
• Increased intracranial pressure
• Severe hypotension (SBP <90 mmHg)
• Circulatory failure and shock
• Right ventricular infarction
• Constrictive pericarditis and cardiac tamponade

Warnings and Precautions

• Develops with continuous exposure to nitrates
• Prevent with 10-12 hour nitrate-free intervals
• More common with long-acting formulations

• May cause severe hypotension, especially with volume depletion
• Paradoxical bradycardia and increased angina may occur

• Common and often treatment-limiting
• Typically diminishes with continued therapy

• Pregnancy: Category C - use only if potential benefit justifies risk
• Lactation: Excreted in milk; use caution
• Hepatic impairment: Increased bioavailability; reduced dosing may be needed
• Geriatric: Increased sensitivity to hypotensive effects

Drug Interactions

• Phosphodiesterase-5 inhibitors: Profound hypotension (absolute contraindication)
• Other vasodilators: Additive hypotensive effects (calcium channel blockers, ACE inhibitors)
• Alcohol: Enhanced vasodilation and hypotension
• Aspirin: Increased nitroglycerin concentrations

• Beta-blockers: Additive hemodynamic effects
• Diuretics: Enhanced hypotensive effects
• Tricyclic antidepressants: Reduced antianginal effect
• Heparin: Possible reduced anticoagulant effect

Adverse Effects

• Headache (most frequent, ~80%)
• Dizziness (~15%)
• Hypotension (~10%)
• Tachycardia (~5%)
• Flushing (~5%)
• Nausea (~3%)

• Syncope
• Palpitations
• Weakness
• Restlessness
• Dry mouth
• Rash

• Severe hypotension
• Circulatory collapse
• Methemoglobinemia (rare)
• Anaphylactic reactions (rare)
• Increased intracranial pressure

Monitoring Parameters

• Blood pressure and heart rate (before and after dosing)
• Angina symptoms and ECG changes
• Signs of hypotension

• Blood pressure trends
• Heart rate
• Angina frequency and severity
• Development of tolerance
• Headache intensity and pattern
• Exercise tolerance

• Methemoglobin levels if cyanosis occurs (rare)
• Liver function tests with long-term use

Patient Education

• Demonstrate correct sublingual placement technique
• Remain seated during administration
• Do not chew or swallow tablet
• Allow complete dissolution without talking

• Store in original glass container
• Protect from light, moisture, and heat
• Do not transfer to other containers
• Discard after 6 months once opened

• Use at first sign of angina
• For prophylaxis, use 5-10 minutes before anticipated stress
• Do not exceed 3 tablets in 15 minutes

• No relief after 3 tablets
• Chest pain persists or worsens
• Severe dizziness or fainting
• Symptoms of overdose (severe headache, confusion, vision changes)

• Avoid alcohol during therapy
• Rise slowly from sitting/lying position
• Report frequent headaches or dizziness to provider
• Do not use with ED medications without consulting provider

References

1. FDA Prescribing Information: Nitrostat (nitroglycerin) sublingual tablets 2. Thadani U, Rodgers T. Side effects of using nitrates to treat angina. Expert Opin Drug Saf. 2006;5(5):667-674. 3. Münzel T, Daiber A, Gori T. Nitrate therapy: new aspects concerning molecular action and tolerance. Circulation. 2011;123(19):2132-2144. 4. Abrams J. Hemodynamic effects of nitroglycerin and long-acting nitrates. Am Heart J. 1985;110(1 Pt 2):216-224. 5. Parker JD, Parker JO. Nitrate therapy for stable angina pectoris. N Engl J Med. 1998;338(8):520-531. 6. Gori T, Parker JD. Nitrate tolerance: a unifying hypothesis. Circulation. 2002;106(19):2510-2513. 7. American Heart Association/American College of Cardiology Guidelines for the Management of Patients with Stable Ischemic Heart Disease. Circulation. 2012;126(25):e354-e471. 8. Pharmaceutical Manufacturers Association. Nitroglycerin Sublingual Tablets Bioequivalence Recommendations. 2019.