What are the latest updates, guidelines, indications, effects, side effects, mechanism of action, contraindications, and important miscellaneous information for Nitroglycerin (NTG) injection?

Nitroglycerin (NTG) Injection: Comprehensive Clinical Guide

Intravenous nitroglycerin is a potent endothelium-independent vasodilator indicated primarily for unstable angina/NSTEMI unresponsive to sublingual nitrates, acute heart failure with elevated filling pressures, perioperative hypertension, and controlled hypotension during surgery, with proven mortality benefit when used appropriately in acute coronary syndromes. 1

FDA-Approved Indications

• Perioperative hypertension 1
• Congestive heart failure in the setting of acute myocardial infarction 1
• Angina pectoris unresponsive to sublingual nitroglycerin and β-blockers 1
• Induction of intraoperative hypotension 1

Mechanism of Action

Nitroglycerin functions as an endothelium-independent vasodilator with dual peripheral and coronary vascular effects that reduce myocardial oxygen demand while enhancing oxygen delivery. 2

Primary Hemodynamic Effects:

• Venodilation (capacitance vessels): Increases venous pooling, decreases preload, and reduces ventricular wall tension—the primary determinant of myocardial oxygen consumption 2
• Arterial dilation: Modest reduction in afterload and systolic wall stress 2
• Coronary vasodilation: Dilates both normal and atherosclerotic epicardial coronary arteries, promotes collateral flow, and redistributes blood to ischemic regions 2
• Antiplatelet effects: Inhibits platelet aggregation, though clinical significance remains unclear 2

Important caveat: Reflex tachycardia and increased contractility can partially offset the reduction in myocardial oxygen demand unless a beta-blocker is administered concurrently 2

Dosing Protocols

Acute Coronary Syndromes (Unstable Angina/NSTEMI)

For patients with ongoing ischemia unrelieved by three 0.4-mg sublingual NTG doses, initiate IV NTG at 10 mcg/min via continuous infusion through non-absorbing tubing. 2

Titration algorithm:

• Increase by 10 mcg/min every 3-5 minutes until symptomatic relief or blood pressure response 2
• If no response at 20 mcg/min, continue with 10 mcg/min increments 3
• For more aggressive titration, increase to 20 mcg/min increments 3
• Although no official maximum exists, a ceiling of 200 mcg/min is commonly used 2
• Recent evidence supports safety up to 300-400 mcg/min for 2-4 weeks without methemoglobin elevation 2

Acute Heart Failure/Pulmonary Edema (SCAPE)

Start at 10 mcg/min and rapidly titrate upward by 10 mcg/min every 3-5 minutes, with doses potentially reaching 200-400 mcg/min for optimal afterload reduction in sympathetic crashing acute pulmonary edema. 3

Blood pressure targets:

• Do not reduce systolic BP below 110 mmHg in previously normotensive patients 3
• In hypertensive patients, do not reduce mean arterial pressure by more than 25% below baseline 3

Perioperative Use

The prophylactic use of intraoperative nitroglycerin for preventing myocardial ischemia in high-risk noncardiac surgery patients is of unclear benefit (Class IIb recommendation). 2

• One study showed benefit at 1 mcg/kg/min in carotid endarterectomy patients with stable angina 2
• Most studies show no reduction in MI or death 2
• Critical consideration: Venodilation combined with anesthetic agents can cause significant hypotension and paradoxical myocardial ischemia 2
• Use only when hemodynamic effects of other agents and intravascular volume status are considered 2

Absolute Contraindications

Nitroglycerin is absolutely contraindicated in the following scenarios: 1, 2

• Phosphodiesterase-5 inhibitor use:
  • Sildenafil within 24 hours 2
  • Tadalafil within 48 hours 2
  • Vardenafil (suitable delay undetermined) 2
  • Risk: Profound hypotension, MI, and death 3
• Hypotension: Systolic BP <90 mmHg or >30 mmHg below baseline 2, 3
• Pericardial tamponade (cardiac output dependent on venous return) 1
• Restrictive cardiomyopathy 1
• Constrictive pericarditis 1
• Known allergy to organic nitrates (extremely rare) 1

Relative Contraindications:

• Marked bradycardia or tachycardia 3
• Right ventricular infarction (preload-dependent state)

Side Effects

Common:

• Headache: Dose-dependent, most common side effect 4
• Hypotension: Especially postural 4
• Reflex tachycardia 2
• Dizziness/lightheadedness

Serious:

• Severe hypotension: Particularly when combined with other vasodilators or in volume-depleted states 2
• Paradoxical bradycardia
• Methemoglobinemia: Rare, even with prolonged high-dose infusions (300-400 mcg/min for 2-4 weeks) 2

Nitrate Tolerance

Tolerance to hemodynamic effects is dose and duration dependent, typically developing after 24 hours of continuous therapy. 2, 4

Prevention strategies:

• Provide a daily "nitrate-free interval" of 10-12 hours 4
• Use lower doses and intermittent dosing when possible 2
• For patients requiring IV NTG beyond 24 hours, periodic dose increases may be needed to maintain efficacy 2, 3

Transition protocol:

• When symptom-free for 12-24 hours, attempt to reduce IV NTG dose 3
• Transition to oral or topical nitrates with appropriate nitrate-free intervals 2, 4

Administration Requirements

CRITICAL: Nitroglycerin injection must be diluted in Dextrose 5% or Sodium Chloride 0.9% prior to infusion—NOT for direct IV injection. 1

• Use non-absorbing tubing for infusion 2, 3
• The administration set significantly affects the amount delivered to the patient 1
• Topical nitroglycerin has uneven absorption intraoperatively; use IV route when clinically indicated 2

Clinical Pearls and Pitfalls

When to Use:

• High-risk UA/NSTEMI patients with ongoing ischemia despite sublingual NTG and beta-blockers 2
• Acute MI with elevated left ventricular filling pressure (>20 mmHg): Increases cardiac output while decreasing filling pressure 5, 6
• Acute pulmonary edema: Sublingual NTG 0.8 mg can be given 3-4 times at 5-10 minute intervals depending on severity and blood pressure 5

When to Avoid:

• Patients without left ventricular failure: Cardiac output may decrease slightly 5
• Volume-depleted states: Risk of severe hypotension 2
• Concurrent use with multiple vasodilators or anesthetic agents: Additive hypotensive effects 2

Monitoring Requirements:

• Continuous ECG monitoring 2
• Frequent blood pressure checks (every 3-5 minutes during titration) 2
• Auscultation for rales (pulmonary edema) 2
• Assess for symptomatic relief 2

Combination Therapy:

• Beta-blockers should be administered concurrently to prevent reflex tachycardia and maximize reduction in myocardial oxygen demand 2
• Morphine sulfate (1-5 mg IV) can be added for refractory symptoms, with careful blood pressure monitoring 2

Alternative Formulations

For patients without ongoing refractory symptoms, topical or oral nitrates are acceptable alternatives: 2, 4

• Sublingual NTG: 0.3-0.6 mg (up to 1.5 mg), duration 1-7 minutes 2, 4
• NTG spray: 0.4 mg as needed 2, 4
• Transdermal NTG: 0.2-0.8 mg/h every 12 hours 2
• Isosorbide dinitrate: 5-80 mg, 2-3 times daily (duration up to 8 hours) 2, 4
• Isosorbide mononitrate: 20 mg twice daily (duration 12-24 hours) 2, 4

All long-acting formulations require a 10-12 hour nitrate-free interval to prevent tolerance. 4