What are the types, dosing intervals, and side effects of nitrates, such as nitroglycerin (sublingual) and isosorbide mononitrate, in the management of angina?

Nitrates in Angina Management: Types, Dosing, and Side Effects

Nitrates are essential vasodilators for both acute symptom relief and prophylaxis of angina, with different formulations requiring specific dosing intervals to prevent tolerance and maintain efficacy. 1

Types of Nitrates and Their Characteristics

Short-Acting Nitrates

• Nitroglycerin (NTG) sublingual tablets: 0.3-0.6 mg (up to 1.5 mg), with effect duration of 1-7 minutes; should be dissolved under the tongue at first sign of angina attack 1
• NTG spray: 0.4 mg as needed, with similar duration to sublingual tablets 1
• These formulations provide rapid symptom relief for acute angina attacks and can be used prophylactically 5-10 minutes before activities that might trigger angina 2

Long-Acting Nitrates

• Isosorbide dinitrate (ISDN):

  • Oral: 5-80 mg, 2-3 times daily (duration up to 8 hours) 1
  • Oral slow-release: 40 mg 1-2 times daily (duration up to 8 hours) 1

• Isosorbide mononitrate (ISMN):

  • Oral: 20 mg twice daily (duration 12-24 hours) 1
  • Oral slow-release: 60-240 mg once daily 1, 3

• Other nitrates:

  • Transdermal NTG: 0.2-0.8 mg/hour every 12 hours (duration 8-12 hours during intermittent therapy) 1
  • Intravenous NTG: 5-200 mcg/min (tolerance develops in 7-8 hours) 1
  • Pentaerythritol tetranitrate: 10 mg sublingual as needed 1
  • Erythritol tetranitrate: 5-10 mg sublingual as needed or 10-30 mg oral three times daily 1

Mechanism of Action

• Nitrates act as endothelium-independent vasodilators with both peripheral and coronary vascular effects 1
• They primarily dilate capacitance vessels, decreasing cardiac preload and reducing ventricular wall tension 1
• Additional effects include:
  • Modest arterial circulation effects resulting in afterload reduction 1
  • Dilation of normal and atherosclerotic coronary arteries 1
  • Increased coronary collateral flow 1
  • Possible inhibition of platelet aggregation 1

Dosing Intervals and Administration Guidelines

Sublingual Nitroglycerin

• One tablet (0.3-0.6 mg) should be dissolved under the tongue at first sign of angina 2
• Dose may be repeated approximately every 5 minutes until relief is obtained 2
• If pain persists after 3 tablets in a 15-minute period, or if pain differs from typical angina, immediate medical attention is recommended 2

Intravenous Nitroglycerin

• Initiate at 10 mcg/min via continuous infusion through non-absorbing tubing 1
• Increase by 10 mcg/min every 3-5 minutes until symptom relief or blood pressure response is noted 1
• If no response at 20 mcg/min, use increments of 10 and later 20 mcg/min 1
• Maximum recommended dose is typically 200 mcg/min 1

Long-Acting Oral Nitrates

• Critical concept: To prevent tolerance, a daily nitrate-free interval of 10-12 hours is required 1
• For isosorbide mononitrate extended-release: Once-daily dosing (60-240 mg) in the morning is recommended 3, 4
• For isosorbide dinitrate: Appropriate timing of doses to ensure a nitrate-free interval 1

Transdermal Nitroglycerin

• Patches should be removed for part of the day or night to create a nitrate-free interval 1
• Continuous 24-hour therapy is not effective due to tolerance development 1

Side Effects and Precautions

Common Side Effects

• Headache (dose-dependent) 1
• Flushing 1
• Hypotension, especially postural 1, 2
• Reflex tachycardia 1

Serious Adverse Effects and Precautions

• Severe hypotension can occur, particularly with upright posture 2
• Paradoxical bradycardia and increased angina may accompany nitrate-induced hypotension 2
• Nitrates may aggravate angina caused by hypertrophic cardiomyopathy 2
• Contraindicated with phosphodiesterase inhibitors (sildenafil, vardenafil, tadalafil) due to risk of profound hypotension 2
• Should be avoided in patients with:
  • Initial systolic BP <90 mmHg or ≥30 mmHg below baseline 1
  • Marked bradycardia or tachycardia 1
  • Right ventricular infarction 1

Nitrate Tolerance

• Tolerance is dose and duration dependent, typically developing after 24 hours of continuous therapy 1
• Mechanisms to prevent tolerance:
  • Provide a daily "nitrate-free interval" of 10-12 hours 1, 4
  • Use appropriate timing of doses for intermediate-acting ISDN 1
  • Use formulations of ISMN that provide suitable plasma concentration profiles 1
  • For transdermal patches, remove during part of the day or night 1
• When tolerance develops during continuous IV therapy, responsiveness can often be restored by:
  • Increasing the dose 1
  • Adding a nitrate-free interval after symptoms have been controlled for several hours 1

Clinical Applications and Recommendations

• Short-acting nitrates are effective for immediate relief of acute angina attacks 1
• Long-acting nitrates reduce frequency and severity of anginal attacks and may increase exercise tolerance 1
• Intravenous nitroglycerin is beneficial in patients with heart failure, hypertension, or symptoms not relieved by sublingual nitroglycerin and beta-blockers 1
• For patients requiring continued IV nitroglycerin beyond 24 hours, convert to oral or topical nitrates within 24 hours when stabilized 1
• Patients should be instructed that angina not responding to short-acting nitroglycerin may represent myocardial infarction 1

Pitfalls to Avoid

• Continuous nitrate therapy without a nitrate-free interval leads to tolerance 1, 5
• Excessive dosing can cause severe headaches and significant hypotension 2
• Concomitant use with phosphodiesterase inhibitors can cause dangerous hypotension 2
• Patients should be seated when taking sublingual nitroglycerin to prevent falls from lightheadedness 2
• Nitroglycerin tablets must be kept in the original glass container and tightly capped after each use to prevent loss of potency 2