Usage
- Hydralazine + Isosorbide Dinitrate is prescribed as an adjunctive treatment for heart failure, specifically in self-identified Black patients. It is used alongside standard heart failure therapies like diuretics, beta-blockers, ACE inhibitors, and others to improve survival, reduce hospitalizations due to heart failure, and enhance the patient’s functional status. Its use is primarily indicated for patients with NYHA Class III or IV heart failure, though experience with Class IV patients is limited.
- Pharmacological Classification: Vasodilator, Antihypertensive combination
- Mechanism of Action: This combination drug employs two distinct mechanisms to improve heart function. Hydralazine acts as a direct-acting arteriolar vasodilator, reducing systemic vascular resistance (afterload). Isosorbide Dinitrate, a nitrate, is a venodilator that primarily reduces preload by decreasing left ventricular end-diastolic pressure. It also has a modest afterload reducing effect. The combined effect of reduced preload and afterload decreases cardiac workload and improves cardiac output.
Alternate Names
- BiDil (brand name)
- Hydralazine hydrochloride and isosorbide dinitrate
- H-ISDN (abbreviation used in research literature)
How It Works
- Pharmacodynamics: Hydralazine primarily dilates arterioles, decreasing systemic vascular resistance (afterload). Isosorbide dinitrate, by stimulating intracellular cyclic GMP, relaxes vascular smooth muscle, predominantly in veins, reducing preload. It also modestly decreases afterload and improves coronary artery blood flow, benefiting ischemic areas of the heart.
- Pharmacokinetics:
- Absorption: Both drugs are well-absorbed orally.
- Metabolism: Hydralazine is metabolized by acetylation (influenced by the NAT2 gene, with “fast acetylators” having lower exposure and “slow acetylators” increased exposure). Isosorbide dinitrate is metabolized to isosorbide-2-mononitrate and isosorbide-5-mononitrate, which also have vasodilatory effects.
- Elimination: Both drugs and their metabolites are eliminated renally and hepatically. Hydralazine’s half-life is approximately 4 hours, and isosorbide dinitrate’s is about 2 hours.
- Mode of Action: Hydralazine’s exact mechanism is unclear but involves direct relaxation of arteriolar smooth muscle. Isosorbide dinitrate acts by releasing nitric oxide, which activates guanylate cyclase, increasing cyclic GMP, leading to smooth muscle relaxation and vasodilation. This lowers cardiac workload and enhances myocardial perfusion.
Dosage
Standard Dosage
Adults:
- Initial: 37.5 mg hydralazine/20 mg isosorbide dinitrate (one tablet) three times daily.
- Titration: Increase as tolerated to a maximum of 75 mg hydralazine/40 mg isosorbide dinitrate (two tablets) three times a day. Titration may occur over 3-5 days, although it may take longer in some patients. If side effects are intolerable, reduce to one-half tablet three times daily and retitrate upward as tolerated.
Children:
- Not established. Use and dose must be determined by a doctor based on clinical status and response.
Special Cases:
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Elderly Patients: Initiate at the lower end of the dosing range. Monitor closely for hypotension due to greater frequency of age-related hepatic and renal dysfunction.
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Patients with Renal Impairment: No dose adjustment is typically required.
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Patients with Hepatic Dysfunction: Use with caution. Isosorbide dinitrate levels may be elevated in patients with cirrhosis, necessitating careful monitoring. Dose adjustments may be necessary.
Clinical Use Cases
This medication is not specifically indicated for intubation, surgical procedures, mechanical ventilation, ICU use, or acute emergency situations. Its primary role is in the chronic management of heart failure in self-identified Black patients.
Dosage Adjustments
- Dosage should be adjusted based on patient response and tolerability. Side effects, particularly hypotension, may necessitate dosage reduction.
Side Effects
Common Side Effects
- Headache
- Dizziness
- Lightheadedness
- Nausea
- Vomiting
- Tachycardia
- Flushing
- Peripheral edema
Rare but Serious Side Effects
- Symptomatic hypotension
- Drug-induced lupus erythematosus
- Myocardial ischemia
- Peripheral neuritis (may be treated with pyridoxine)
Adverse Drug Reactions (ADR)
- Severe hypotension
- Syncope
- Myocardial ischemia
- Lupus-like symptoms
- Blood dyscrasias (rare)
Contraindications
- Hypersensitivity to nitrates or hydralazine.
- Concomitant use of PDE-5 inhibitors (e.g., sildenafil, tadalafil, vardenafil) or soluble guanylate cyclase stimulators (e.g., riociguat) due to the risk of severe hypotension.
- Mitral valve rheumatic heart disease
Drug Interactions
- PDE-5 Inhibitors: Contraindicated due to severe hypotension risk.
- Nitroglycerin: Additive hypotensive effects.
- Antihypertensives: Increased hypotensive effects.
- Alcohol: Increased risk of dizziness and hypotension.
- Migraine Medications (Ergotamine): Potential interactions.
Pregnancy and Breastfeeding
- Pregnancy: Insufficient data to assess risk. Hydralazine has shown teratogenicity in animal studies. Use only if benefit clearly outweighs risk.
- Breastfeeding: Insufficient data to assess risk. Hydralazine is excreted in breast milk. Consider the risks and benefits.
Drug Profile Summary
- Mechanism of Action: Hydralazine decreases afterload, isosorbide dinitrate reduces preload and improves coronary perfusion.
- Side Effects: Headache, dizziness, hypotension, reflex tachycardia.
- Contraindications: Nitrate hypersensitivity, PDE-5 inhibitor use, mitral valve rheumatic heart disease.
- Drug Interactions: PDE-5 inhibitors, nitrates, antihypertensives.
- Pregnancy & Breastfeeding: Insufficient data, use with caution if benefits outweigh risks.
- Dosage: Start with 37.5mg/20mg TID, titrate up to 75mg/40mg TID.
- Monitoring Parameters: Blood pressure (standing and sitting/supine), heart rate, complete blood count, and ANA titers (if lupus symptoms appear).
Popular Combinations
- Used in conjunction with standard heart failure therapies (diuretics, beta-blockers, ACE inhibitors, ARBs, ARNIs). Careful blood pressure monitoring is necessary, especially when combined with ARNIs, as this combination has not been extensively studied.
Precautions
- Monitor for hypotension, especially in the elderly and those with volume depletion.
- Monitor for lupus-like symptoms.
- Caution in patients with coronary artery disease due to potential reflex tachycardia.
- Advise patients about potential for dizziness and to avoid activities requiring alertness until effects are known.
- Encourage lifestyle changes (diet, exercise).
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Hydralazine + Isosorbide Dinitrate?
A: Initial dose is one tablet (37.5mg hydralazine/20mg isosorbide dinitrate) three times daily, titrated up to two tablets three times daily as tolerated.
Q2: Is Hydralazine + Isosorbide Dinitrate safe for children?
A: Safety and efficacy in children haven’t been established.
Q3: What are the common side effects?
A: Headache, dizziness, lightheadedness, nausea, and tachycardia are common.
Q4: What should I do if a patient develops hypotension?
A: Advise the patient to lie down and elevate their legs. Consider reducing the dosage or temporarily discontinuing the medication. Monitor vital signs closely. Ensure adequate hydration.
Q5: Are there any specific contraindications I should be aware of?
A: Yes. Contraindications include hypersensitivity to nitrates, concomitant use of PDE-5 inhibitors or riociguat, and mitral valve rheumatic heart disease.
Q6: Can Hydralazine + Isosorbide Dinitrate be used during pregnancy or breastfeeding?
A: Data are insufficient to assess risk. Use with extreme caution only if the potential benefit justifies the potential risk to the fetus or infant. Discuss risks and benefits with the patient.
Q7: What monitoring parameters are essential while a patient is on this medication?
A: Monitor blood pressure (sitting and standing), heart rate, and for signs and symptoms of lupus. Periodic complete blood counts and ANA titers may be necessary.
Q8: What are the main drug interactions to watch out for?
A: Avoid concomitant use of PDE-5 inhibitors, other nitrates, and other antihypertensives. Exercise caution with migraine medications. Counsel patients about alcohol consumption, which may increase hypotension risk.
Q9: Why is this medication specifically indicated for self-identified Black patients?
A: Clinical trials demonstrated a significant benefit in this population. The underlying reasons are still being investigated, but potential factors include differences in nitric oxide bioavailability and response to vasodilators.
A: The NAT2 gene influences acetylation rate, affecting hydralazine’s pharmacokinetics. “Fast acetylators” may have lower drug exposure, while “slow acetylators” may have increased exposure. While genotyping isn’t routine, it highlights the potential for interindividual variability in drug response.
