How are isosorbide dinitrate (ISDN) and isosorbide mononitrate (ISMN) dosed for acute relief and prophylaxis of angina (and chronic heart failure), and what are their contraindications, common adverse effects, nitrate‑tolerance considerations, and interaction with phosphodiesterase‑5 inhibitors?

Isosorbide Formulations: Dosing, Indications, and Safety

Acute Angina Relief

For acute angina attacks, use sublingual nitroglycerin (not isosorbide formulations), which provides symptom relief within 1-7 minutes and may be used for situational prophylaxis before activities that trigger angina. 1, 2

• Short-acting nitroglycerin spray or sublingual tablets rapidly terminate established angina attacks without causing tolerance when used infrequently 3
• An attack that does not respond to short-acting nitroglycerin should be regarded as a possible myocardial infarction 1
• Patients must be carefully instructed about proper use to avoid overdosing, which may cause postural hypotension and reflexogenic tachycardia leading to "paradoxical" angina 1

Angina Prophylaxis

Isosorbide Dinitrate (ISDN)

For chronic stable angina prophylaxis, isosorbide dinitrate should be dosed 20-40 mg three times daily (7 AM, 1 PM, 6 PM), which naturally provides the necessary nitrate-free interval to prevent tolerance. 1, 2, 4

• Standard oral ISDN has a duration of action of 4-8 hours with active metabolites extending effects up to 8 hours 2
• The three-times-daily regimen provides antianginal prophylaxis for approximately 6 hours after each dose while maintaining a nitrate-free overnight interval 3
• Doses of 15-30 mg produce near-maximal improvement in exercise tolerance; higher doses (60-120 mg) do not provide substantially greater benefit for angina 5

Isosorbide Mononitrate (ISMN)

For angina prophylaxis, isosorbide mononitrate should be dosed 20 mg twice daily with asymmetric timing (e.g., 8 AM and 3 PM) to provide a 10-14 hour nitrate-free interval overnight. 6, 3

• Standard oral ISMN has a duration of action of 12-24 hours 6
• Asymmetric twice-daily dosing (morning dose and second dose 7 hours later) decreases tolerance development compared to symmetric 12-hour intervals 3
• Extended-release ISMN 60-120 mg once daily in the morning provides effective daytime prophylaxis without tolerance when a nitrate-free overnight interval is maintained 7, 8
• The 20 mg twice-daily asymmetric regimen is more effective than 10 mg twice daily 3

Chronic Heart Failure

For heart failure with reduced ejection fraction, use isosorbide dinitrate (NOT mononitrate) 20-40 mg three times daily combined with hydralazine 75-100 mg three times daily. 1, 4

• This combination has proven mortality benefit, particularly in African American patients with NYHA class III-IV heart failure already on optimal therapy with ACE inhibitors/ARBs and beta-blockers 1, 4
• ISDN combined with hydralazine is also appropriate for patients intolerant to ACE inhibitors or ARBs due to hypotension or renal insufficiency 1
• Isosorbide mononitrate is explicitly NOT recommended for heart failure management 4
• The mortality benefit is presumed related to enhanced nitric oxide bioavailability 1

Nitrate Tolerance Prevention

A nitrate-free interval of at least 10-14 hours daily is mandatory to prevent tolerance; without this interval, anti-anginal efficacy is lost within 24 hours of continuous exposure. 1, 2

• ISDN three-times-daily dosing naturally provides the necessary overnight nitrate-free interval 2
• ISMN requires asymmetric twice-daily dosing or once-daily extended-release formulations to achieve adequate nitrate-free periods 8, 3
• Continuous transdermal nitroglycerin therapy is not effective; patches must be removed for part of the day or at night 1
• Combination with ACE inhibitors or hydralazine may help minimize tolerance development 1, 2
• During sustained therapy, partial tolerance develops rapidly even with appropriate dosing, reducing the magnitude and duration of effects compared to initial doses 5

Absolute Contraindications

Nitrates (both ISDN and ISMN) are absolutely contraindicated with concurrent use of phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil) due to risk of profound hypotension, myocardial infarction, and death. 4, 6

• This interaction results from synergistic vasodilation through the cyclic GMP pathway 1
• Patients must be explicitly counseled about this life-threatening drug interaction

Common Adverse Effects

Headache is the most common side effect of both isosorbide formulations, resulting from cerebral vasodilation; it is usually mild to moderate and improves with continued therapy. 1, 2, 6

• Hypotension is the second most common adverse effect and may be dose-dependent 1, 6
• Dizziness related to blood pressure changes occurs frequently 6
• Gastrointestinal complaints are common, particularly with the ISDN-hydralazine combination 1
• Headaches rarely lead to treatment discontinuation 7
• Hypotension can be managed by dose adjustment, leg elevation, fluid administration, or atropine if severe 6

Critical Clinical Caveats

Use nitrates with extreme caution in right ventricular infarction or inferior wall MI with RV involvement, as these patients depend on adequate RV preload to maintain cardiac output and may develop profound hypotension. 6

• Overdosing may cause postural hypotension and reflexogenic cardiac sympathetic activation with tachycardia, potentially worsening ischemia 1
• Abrupt discontinuation during long-term treatment may exacerbate anginal symptoms 7
• There is no evidence of rebound worsening of ischemia 24 hours after ISMN administration when properly dosed 7
• Compliance with ISDN-hydralazine combination is generally poor due to the large number of tablets required (up to 9 daily) and high incidence of adverse reactions 1
• Short-acting nitrate consumption serves as a simple and effective measure of treatment efficacy with other anti-anginal drugs 1

Mechanism of Action

Both isosorbide formulations work as exogenous sources of nitric oxide, replenishing endothelium-derived relaxing factor and causing dose-dependent vasodilation 2, 6:

• Primary effect: Venodilation increases venous pooling, decreases myocardial preload, and reduces left ventricular end-diastolic pressure 2
• Secondary effect: Arterial vasodilation reduces afterload, particularly when systemic vascular resistance is severely elevated 2
• Coronary effect: Coronary artery dilation improves oxygen supply to the myocardium 2
• The combined effects decrease cardiac work and lower myocardial oxygen requirements 2, 6