What Isosorbide Dinitrate Is Used For
Isosorbide dinitrate is FDA-approved for the prevention of angina pectoris due to coronary artery disease, and is also recommended in combination with hydralazine for African American patients with heart failure who remain symptomatic despite optimal medical therapy. 1, 2
Primary FDA-Approved Indication
- Angina Prevention: Isosorbide dinitrate is indicated for the prevention of angina pectoris caused by coronary artery disease 1
- Important limitation: The onset of action is NOT sufficiently rapid to abort an acute anginal episode—it cannot be used to stop an attack in progress 1
- The drug works as a vasodilator affecting both arteries and veins, reducing cardiac preload through venodilation and afterload through arterial dilation 3, 1
Heart Failure with Reduced Ejection Fraction (HFrEF)
Specific Population Benefit
- African American patients with HFrEF: The combination of hydralazine and isosorbide dinitrate is specifically recommended for self-identified African American patients with symptomatic HFrEF (NYHA class II-IV) who remain symptomatic despite treatment with ACE inhibitors (or ARBs), beta-blockers, and mineralocorticoid receptor antagonists 2
- This recommendation is based on the A-HeFT trial, which demonstrated significant mortality reduction and decreased hospitalizations in this population 2
- The benefit is presumed related to enhanced nitric oxide bioavailability 2
Alternative Use in ACE Inhibitor Intolerance
- For patients intolerant of ACE inhibitors or ARBs: The combination of hydralazine and isosorbide dinitrate may be considered as a therapeutic option, particularly in patients with renal insufficiency or hypotension that precludes use of first-line agents 2
- Critical caveat: This combination should NOT be used in patients who have never tried an ACE inhibitor, and should NOT be substituted in patients tolerating ACE inhibitors without difficulty 2
Evidence for Non-African American Populations
- The benefit in non-African American patients with HFrEF remains unclear and unproven 2
- Historical data from V-HeFT I showed mortality reduction compared to placebo in patients treated with digoxin and diuretics (but not ACE inhibitors or beta-blockers), but ACE inhibitors proved superior in head-to-head comparison 2
Mechanism of Action
- Isosorbide dinitrate acts as a nitrate vasodilator, primarily through venodilation but also affecting arterial tone, by promoting nitric oxide release 3
- This reduces right and left ventricular preload, decreases afterload, lowers cardiac work, and reduces myocardial oxygen requirements 3
- The drug may serve as an exogenous source of nitric oxide, essentially substituting for endothelium-derived relaxing factor in patients with endothelial dysfunction 3, 4
Important Clinical Considerations
Tolerance Development
- Nitrate-free interval required: A nitrate-free interval of at least 10 hours is essential to minimize tolerance development 2, 5, 3
- Continuous dosing without a nitrate-free interval leads to complete loss of anti-ischemic effects 4
- Combining isosorbide with ACE inhibitors or hydralazine may improve tolerance 5
Common Adverse Effects
- Headache is the most frequent side effect and actually serves as a marker of drug activity 3, 1
- Patients should not alter their dosing schedule to avoid headaches, as loss of headache may indicate loss of efficacy 1
- Aspirin or acetaminophen can relieve nitrate-induced headaches without reducing anti-anginal efficacy 1
- Hypotension and dizziness are potentially serious side effects, especially when combined with alcohol or phosphodiesterase inhibitors 3, 1
Absolute Contraindications
- Concomitant use with phosphodiesterase inhibitors (sildenafil, tadalafil) is absolutely contraindicated due to risk of profound hypotension 3, 1
- Concomitant use with riociguat (a soluble guanylate cyclase stimulator) is contraindicated 1