What are the uses of Sorbitrate (isosorbide dinitrate)?

Sorbitrate (Isosorbide Dinitrate) Uses

Sorbitrate is FDA-approved for the prevention of angina pectoris due to coronary artery disease, and when combined with hydralazine, it is strongly recommended for heart failure with reduced ejection fraction, particularly in African American patients. 1

Primary Indications

Angina Pectoris Prevention

• Isosorbide dinitrate is indicated for preventing angina attacks in patients with coronary artery disease 1
• The immediate-release oral formulation has insufficient rapid onset to abort acute anginal episodes 1
• Sublingual isosorbide dinitrate (2.5-5 mg) should be taken approximately 15 minutes before anticipated angina-provoking activity 2
• Sublingual formulation may abort acute anginal episodes in patients who fail to respond to sublingual nitroglycerin 2

Heart Failure with Reduced Ejection Fraction (HFrEF)

For African American Patients:

• The combination of hydralazine and isosorbide dinitrate is strongly recommended (Class I) to reduce morbidity and mortality in self-identified African American patients with NYHA class III-IV HFrEF who remain symptomatic despite optimal therapy with ACE inhibitors, beta blockers, and aldosterone antagonists 3
• This combination demonstrated a 43% relative risk reduction in mortality and 33% reduction in heart failure hospitalizations 3
• Target dosing: 37.5 mg hydralazine/20 mg isosorbide dinitrate three times daily, titrated to 75 mg hydralazine/40 mg isosorbide dinitrate three times daily (total daily: 225 mg hydralazine/120 mg isosorbide dinitrate) 3

For Non-African American Patients:

• The hydralazine-isosorbide dinitrate combination can be useful (Class IIa) in patients with current or prior symptomatic HFrEF who cannot tolerate ACE inhibitors or ARBs due to drug intolerance, hypotension, or renal insufficiency 3
• This represents an alternative when first-line neurohormonal antagonists are contraindicated 4

Acute Heart Failure

• Intravenous nitrates (including isosorbide dinitrate) are recommended early in acute heart failure patients without symptomatic hypotension, systolic blood pressure <90 mmHg, or serious obstructive valvular disease 3
• These agents decrease left and right heart filling pressures, systemic vascular resistance, and improve dyspnea 3
• Buccal isosorbide dinitrate (1 or 3 mg) can be used in the early phase of acute heart failure 3

Unstable Angina and Acute Myocardial Infarction

• Nitrates (including isosorbide dinitrate) are particularly useful in patients with impaired left ventricular systolic function or congestive heart failure complicating acute coronary syndromes 3
• They reduce myocardial oxygen demand through preload and afterload reduction while potentially improving coronary blood flow 3

Mechanism of Action

• Isosorbide dinitrate acts as a vasodilator with predominantly venodilator effects, increasing coronary artery blood supply and decreasing cardiac preload and afterload by enhancing nitric oxide levels 3, 5
• It dilates coronary collateral vessels, reverses vasoconstriction of small coronary arteries distal to obstructions, and reduces platelet aggregation 3
• The drug may inhibit abnormal myocardial and vascular growth, potentially attenuating ventricular remodeling 3

Pharmacokinetics

• Isosorbide dinitrate has a half-life of 40-90 minutes and is extensively metabolized in the liver to two active metabolites: isosorbide-2-mononitrate and isosorbide-5-mononitrate 3
• Duration of action is 4-8 hours with standard oral formulations, necessitating multiple daily doses 6
• This differs from nitroglycerin, which has a half-life of only several minutes 3

Critical Dosing Considerations

Tolerance Prevention:

• Every dosing regimen must provide a daily nitrate-free interval of at least 10-14 hours to minimize development of tolerance 6, 2
• Maintenance of continuous 24-hour plasma levels results in refractory tolerance 2
• Tolerance to antianginal and circulatory effects develops rapidly during sustained therapy 7

Dosing for Angina:

• During sustained therapy, 15-30 mg four times daily produces near-maximal improvement in exercise tolerance in most patients 7
• Higher doses (60-120 mg) do not provide significantly greater benefit than 15-30 mg during sustained therapy 7

Important Adverse Effects and Contraindications

Common Side Effects:

• Headache, dizziness, and gastrointestinal complaints are frequent, particularly with the hydralazine-isosorbide dinitrate combination 3, 4
• Headaches are more common with isosorbide dinitrate than with isosorbide mononitrate 6
• Hypotension and reflex tachycardia may occur 6

Critical Contraindications:

• Concurrent use with phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil) is an absolute contraindication due to risk of profound hypotension, myocardial infarction, and death 6
• Avoid in patients with systolic blood pressure <90 mmHg as it may reduce central organ perfusion 3
• Use with extreme caution in inferior wall myocardial infarction due to frequent association with right ventricular infarction, where patients are dependent on adequate RV preload 3

Monitoring Requirements:

• Blood pressure monitoring is required, especially during initiation 6
• Patients with aortic stenosis may demonstrate marked hypotension following initiation 3
• Slow titration and frequent blood pressure measurement is recommended to avoid large drops in systolic blood pressure 3

Clinical Pitfalls

• Adherence to the hydralazine-isosorbide dinitrate combination is generally poor due to the large number of tablets required (up to 6 tablets daily), frequency of administration (three times daily), and high incidence of adverse reactions 3
• Slower titration may enhance tolerance of therapy 3
• The combination should not be substituted for ACE inhibitor or ARB therapy in patients tolerating these agents without difficulty 3