Usage
- Isosorbide dinitrate is prescribed for the prevention and treatment of angina pectoris (chest pain) due to coronary artery disease. It is also used as adjunctive therapy in heart failure, particularly in self-identified Black patients. It is important to note that it is not the drug of choice for aborting an acute anginal episode due to a slower onset of action than sublingual nitroglycerin.
- Pharmacological classification: Vasodilator, Antianginal agent, Nitrate
- Mechanism of Action: Isosorbide dinitrate is a nitrate that converts to nitric oxide in the body. Nitric oxide is a potent vasodilator, relaxing and widening blood vessels. This reduces venous return to the heart, decreasing preload and myocardial oxygen demand. It also dilates coronary arteries, improving blood flow to the heart muscle.
Alternate Names
- ISDN
- Brand names: Isordil, Dilatrate-SR, Isochron, Iso-Bid, Sorbitrate
How It Works
- Pharmacodynamics: Isosorbide dinitrate primarily affects the cardiovascular system, causing vasodilation and reducing cardiac preload. This leads to decreased myocardial oxygen demand and improved coronary blood flow.
- Pharmacokinetics:
- Absorption: Rapidly absorbed following sublingual or oral administration. The first-pass metabolism is extensive with oral administration, reducing bioavailability. Extended-release formulations bypass some of this first-pass effect.
- Metabolism: Extensively metabolized in the liver to isosorbide-2-mononitrate and isosorbide-5-mononitrate, both of which possess vasodilating activity.
- Elimination: Primarily eliminated via renal excretion as glucuronide conjugates.
- Mode of Action: Isosorbide dinitrate is denitrated intracellularly to release nitric oxide. Nitric oxide activates guanylate cyclase, increasing cyclic guanosine monophosphate (cGMP), which in turn activates protein kinase G, leading to smooth muscle relaxation and vasodilation.
- Elimination pathways: Renal excretion as glucuronide derivatives of the denitrated metabolites.
Dosage
Standard Dosage
Adults:
- Sublingual: 2.5 to 5 mg for angina prophylaxis 15 minutes before activity, repeated every 2-3 hours as needed.
- Oral (immediate release): Initial dose is 5 to 20 mg two or three times daily. Maintenance: 10 to 40 mg two to three times daily.
- Oral (extended-release): 40 to 160 mg once daily. A nitrate-free interval of at least 14 hours is necessary for immediate-release formulations and greater than 18 hours for extended-release to minimize tolerance.
- Intravenous: 2 to 12 mg/hour, titrated up to 20 mg/hour based on response.
Children:
Dosage must be determined by a doctor.
Special Cases:
- Elderly Patients: Start at the low end of the dosing range due to potential sensitivity to hypotensive effects.
- Patients with Renal Impairment: No specific dose adjustment is generally required.
- Patients with Hepatic Dysfunction: No specific dose adjustment is generally required.
- Patients with Comorbid Conditions: Use with caution in patients with congestive heart failure, hypertrophic cardiomyopathy, hypotension, or increased intracranial pressure.
Clinical Use Cases
- Intubation: No specific dosage recommendations for intubation itself, but ISDN infusion may be used to manage blood pressure and myocardial ischemia during this procedure.
- Surgical Procedures: Continue perioperative ISDN with heart rate and blood pressure monitoring.
- Mechanical Ventilation: No specific dosage recommendations. Continue regular ISDN with appropriate monitoring.
- Intensive Care Unit (ICU) Use: Continuous intravenous infusion may be used, titrated based on hemodynamic monitoring.
- Emergency Situations: Sublingual administration for acute angina; intravenous infusion for acute heart failure.
Dosage Adjustments
Dose adjustment may be needed based on clinical response and tolerability. A nitrate-free interval (usually overnight) is important for maintaining efficacy and preventing tolerance.
Side Effects
Common Side Effects
- Headache
- Dizziness
- Lightheadedness
- Flushing
- Nausea
Rare but Serious Side Effects
- Syncope
- Severe hypotension
- Reflex tachycardia
- Methemoglobinemia
Long-Term Effects
- Tolerance to nitrate effects can develop with continuous 24-hour dosing.
Adverse Drug Reactions (ADR)
- Severe hypotension requiring intervention
Contraindications
- Hypersensitivity to nitrates
- Severe anemia
- Shock
- Markedly low blood pressure
- Hypertrophic obstructive cardiomyopathy
- Constrictive pericarditis
- Cardiac tamponade
- Increased intracranial pressure
- Concomitant use of PDE5 inhibitors (e.g., sildenafil, tadalafil) or riociguat
Drug Interactions
- PDE5 inhibitors: Can cause severe hypotension.
- Antihypertensives: Additive hypotensive effects.
- Alcohol: May potentiate hypotension.
- Hydralazine: Commonly used in combination with ISDN for heart failure in Black patients.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: C. Use only if potential benefit outweighs risk.
- Limited data available on use during breastfeeding. Use with caution.
Drug Profile Summary
- Mechanism of Action: Vasodilator, increases nitric oxide, leading to smooth muscle relaxation and reduced cardiac preload.
- Side Effects: Headache, dizziness, hypotension, flushing, nausea. Rarely, syncope and methemoglobinemia.
- Contraindications: Hypersensitivity to nitrates, severe hypotension, increased intracranial pressure, concomitant use of PDE5 inhibitors or riociguat.
- Drug Interactions: PDE5 inhibitors, antihypertensives, alcohol.
- Pregnancy & Breastfeeding: Use with caution. Category C.
- Dosage: Varies based on formulation and indication. See above for details.
- Monitoring Parameters: Blood pressure, heart rate, angina symptoms.
Popular Combinations
- Hydralazine/ISDN (BiDil) for heart failure in Black patients.
Precautions
- Monitor blood pressure and heart rate, especially during initiation of therapy.
- A nitrate-free interval is crucial for preventing tolerance.
- Use cautiously in patients with pre-existing cardiovascular disease.
- Alcohol may potentiate hypotension.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Isosorbide Dinitrate?
A: The dosage varies depending on the formulation (sublingual, immediate-release oral, extended-release oral, or intravenous) and indication. Please refer to the detailed dosage section above.
Q2: How should ISDN be administered?
A: Sublingual tablets should be dissolved under the tongue. Oral tablets should be swallowed whole, not crushed or chewed. Extended-release formulations should be taken consistently with a nitrate-free interval. Intravenous infusions should be administered via an infusion pump with appropriate dilution and monitoring.
Q3: What are the most common side effects of ISDN?
A: Headache, dizziness, lightheadedness, and flushing are the most common side effects.
Q4: What are the serious side effects of ISDN?
A: Severe hypotension, syncope, reflex tachycardia, and methemoglobinemia are rare but serious side effects.
Q5: What are the contraindications to using ISDN?
A: Contraindications include hypersensitivity to nitrates, severe hypotension, increased intracranial pressure, concomitant use of PDE5 inhibitors or riociguat, and certain cardiac conditions.
Q6: Does ISDN interact with other medications?
A: Yes, ISDN interacts with PDE5 inhibitors (e.g. sildenafil, tadalafil), antihypertensives, and alcohol. These interactions can potentiate hypotension.
Q7: Can ISDN be used during pregnancy or breastfeeding?
A: ISDN is Pregnancy Category C. It should be used during pregnancy only if the potential benefit outweighs the risk. Limited information is available regarding use during breastfeeding, so caution is advised.
Q8: How can tolerance to ISDN be prevented?
A: Maintaining a nitrate-free interval (usually overnight) is essential for preventing tolerance to ISDN.
Q9: Why isn’t ISDN the drug of choice for acute angina attacks?
A: The onset of action of ISDN is slower compared to sublingual nitroglycerin, making it less suitable for aborting an acute anginal episode.
Q10: Is there a specific dosage adjustment for elderly patients?
A: Elderly patients should generally start at the low end of the dosing range due to increased sensitivity to hypotensive effects. Careful titration and monitoring are essential.
