Can isosorbide mononitrate and nitroglycerin be used together in patients with angina?

Can Isosorbide Mononitrate and Nitroglycerin Be Used Together?

Yes, isosorbide mononitrate and nitroglycerin can and should be used together in patients with angina—specifically, long-acting isosorbide mononitrate for chronic prevention and short-acting nitroglycerin for acute symptom relief. 1

Rationale for Combined Use

Different Clinical Roles

• Nitroglycerin sublingual is designed for acute angina episodes, with onset of action within 1-7 minutes and duration of effect lasting only 1-7 minutes, making it unsuitable for chronic prevention 1, 2
• Isosorbide mononitrate extended-release is indicated specifically for prevention of angina pectoris, not for aborting acute episodes due to insufficient rapidity of onset 3
• These complementary roles make combination therapy the standard approach 1

Evidence-Based Dosing Strategy

• Isosorbide mononitrate should be dosed as 20 mg twice daily with a 7-hour interval (e.g., 7 AM and 2 PM) to maintain antianginal efficacy while preventing tolerance development 4
• Nitroglycerin sublingual 0.3-0.6 mg should be used as needed for breakthrough angina, up to three doses taken 5 minutes apart 1, 2
• This asymmetric dosing regimen for isosorbide mononitrate provides 12-14 hours of daytime coverage when angina is most likely, while the overnight nitrate-free interval prevents tolerance 4

Clinical Implementation Algorithm

Step 1: Establish Background Nitrate Therapy

• Initiate isosorbide mononitrate 20 mg twice daily (7-hour separation between doses) 4
• Alternative: Extended-release isosorbide mononitrate 60-120 mg once daily in the morning 1, 3
• The nitrate-free interval (typically overnight) is critical and non-negotiable—continuous 24-hour nitrate exposure rapidly produces tolerance and loss of antianginal effect 3, 5

Step 2: Provide Rescue Nitroglycerin

• Prescribe nitroglycerin sublingual tablets 0.4 mg or spray for acute symptom relief 1, 2
• Instruct patients to use up to three doses, 5 minutes apart, before seeking emergency care 1
• Cross-tolerance to nitroglycerin does NOT develop when isosorbide mononitrate is dosed with appropriate nitrate-free intervals 6

Step 3: Consider Beta-Blocker Addition

• Combining nitrates with beta-blockers produces synergistic anti-ischemic effects by blocking reflex tachycardia that partially offsets nitrate-induced reductions in myocardial oxygen demand 1
• This combination is explicitly recommended in guidelines for enhanced symptom control 1

Critical Safety Considerations

Absolute Contraindications

• Never administer any nitrate within 24 hours of sildenafil or 48 hours of tadalafil use—this combination causes profound hypotension, myocardial infarction, and death 1, 2, 4
• Avoid nitrates when systolic blood pressure is <90 mm Hg or >30 mm Hg below baseline 1, 4
• Do not use in patients with marked bradycardia (<60 bpm) or tachycardia (>110 bpm) 1

Tolerance Prevention

• The most common pitfall is prescribing symmetric dosing (e.g., 8 AM and 8 PM), which produces rapid tolerance and treatment failure 7
• Continuous nitrate therapy—whether from overlapping long-acting and short-acting formulations used too frequently, or from symmetric dosing—leads to complete loss of antianginal efficacy within 24 hours 3, 5
• The 7-hour interval for twice-daily isosorbide mononitrate is specifically designed to provide a 10-hour nitrate-free period overnight 4

Monitoring Hemodynamic Effects

• Both agents reduce preload through venodilation and modestly reduce afterload 1
• When used together acutely (e.g., sublingual nitroglycerin during chronic isosorbide mononitrate therapy), monitor for additive hypotensive effects, though this is rarely clinically problematic when isosorbide mononitrate is dosed with nitrate-free intervals 6
• Mean arterial pressure reductions of 5-10 mm Hg are expected and generally well-tolerated 8

Practical Prescribing Example

For a patient with stable angina:

• Isosorbide mononitrate 20 mg at 7 AM and 2 PM daily 4
• Nitroglycerin 0.4 mg sublingual tablets, use as needed for chest pain (up to 3 doses, 5 minutes apart) 1, 2
• Add beta-blocker (e.g., metoprolol) for synergistic effect 1
• Ensure patient understands the nitrate-free overnight period is intentional and therapeutic 4, 5

Important Nuance on Vasodilator Combinations

• The 2018 expert consensus from Nature Reviews Cardiology notes that "long-term nitrates should be used with caution, together with other vasodilators" in chronic stable angina 1
• This refers to combining multiple long-acting vasodilators (e.g., isosorbide mononitrate + calcium channel blocker), not to the combination of long-acting isosorbide mononitrate with as-needed short-acting nitroglycerin
• The latter combination is standard practice and explicitly supported by ACC/AHA guidelines 1