Usage
- Hydralazine is primarily prescribed for the treatment of moderate to severe essential hypertension, either alone or in combination with other antihypertensive agents (e.g., beta-blockers, diuretics). It is also indicated for the management of hypertensive emergencies and as adjunctive therapy for heart failure in self-identified Black patients (in combination with isosorbide dinitrate). In pregnancy, hydralazine is utilized to treat severe hypertension, particularly cases involving pre-eclampsia and toxaemia.
- Pharmacological Classification: Vasodilator (specifically, a direct-acting arteriolar vasodilator).
- Mechanism of Action: Hydralazine lowers blood pressure by directly relaxing the smooth muscle of arterioles. This leads to a decrease in peripheral vascular resistance. While the exact mechanism isn’t fully understood, it likely involves interference with intracellular calcium homeostasis, specifically by inhibiting inositol trisphosphate (IP3)-induced calcium release and myosin phosphorylation in arterial smooth muscle cells.
Alternate Names
- International and Regional Variations: While “hydralazine” is the widely accepted generic name, regional variations may exist.
- Brand Names: Apresoline, Alphapress (oral), and BiDil (in combination with isosorbide dinitrate).
How It Works
- Pharmacodynamics: Hydralazine primarily dilates arterioles, leading to decreased systemic vascular resistance and lowered blood pressure. It often triggers a reflex baroreceptor response, causing increased heart rate, cardiac output, and venous return. It has minimal effect on veins.
- Pharmacokinetics:
- Absorption: Hydralazine is well-absorbed orally, but undergoes extensive first-pass metabolism, affecting its bioavailability.
- Metabolism: Primarily hepatic metabolism, including acetylation (which is genetically determined – slow vs. fast acetylators), ring oxidation, and conjugation with endogenous compounds like pyruvic acid. Slow acetylators generally require lower doses.
- Elimination: Both unchanged hydralazine and its metabolites are excreted in urine and feces. Elimination half-life is typically 2-8 hours but can be prolonged in patients with renal impairment.
- Mode of Action: Hydralazine acts directly on vascular smooth muscle cells, inhibiting calcium release from the sarcoplasmic reticulum and reducing myosin phosphorylation. This leads to smooth muscle relaxation and vasodilation.
- Receptor Binding, Enzyme Inhibition, Neurotransmitter Modulation: Hydralazine does not bind to adrenergic receptors, but its vasodilating effects can indirectly influence neurotransmitter release, particularly norepinephrine, due to baroreceptor reflex activation. It does not directly inhibit enzymes or modulate neurotransmission.
- Elimination Pathways: Hydralazine and its metabolites are eliminated through both renal and hepatic routes.
Dosage
Standard Dosage
Adults:
- Hypertension: Initial dose is 10 mg orally four times a day for 2-4 days, then increased to 25 mg four times daily for the rest of the week. If needed, further increase to 50 mg four times daily in subsequent weeks. Maintenance dose is titrated to the lowest effective level. Maximum dose is usually 200 mg/day, especially for slow acetylators. Doses up to 300-400 mg/day may be necessary for some patients.
- Hypertensive Emergency: 20-40 mg IM or IV bolus. Repeat as needed. Alternatively, 10-20 mg IV, repeated every 4-6 hours as needed.
- Heart Failure (with isosorbide dinitrate): Initial dose is 37.5 mg hydralazine/20 mg isosorbide dinitrate three times daily. Titrate up as tolerated to a maximum of 75 mg hydralazine/40 mg isosorbide dinitrate three times daily.
Children:
- Hypertension: Initial dose is 0.75 mg/kg/day orally in four divided doses. May increase gradually over 3-4 weeks to a maximum of 7.5 mg/kg/day (or 200 mg/day).
- Hypertensive Emergency: 1.7-3.5 mg/kg/day IM or IV in 4-6 divided doses. Alternatively, for life-threatening symptoms, initial dose 0.1-0.2 mg/kg IM or IV, increasing up to 0.4 mg/kg every 4 hours if given IV bolus. For non-life-threatening symptoms, 0.25 mg/kg per dose (up to 25 mg per dose) every 6-8 hours.
Special Cases:
- Elderly Patients: Start with lower doses and titrate cautiously. Monitor closely for hypotension and other adverse effects.
- Patients with Renal Impairment: Dosage adjustment is necessary in patients with creatinine clearance less than 30 mL/min or serum creatinine concentration greater than 2.5 mg/100 mL. Reduce the dose or prolong the dosing interval according to the clinical response. For creatinine clearance 10-50 mL/min, administer every 8 hours. For creatinine clearance <10 mL/min, administer every 8-16 hours or even 12-24 hours based on patient response.
- Patients with Hepatic Dysfunction: Dosage or dosing interval adjustments are needed. Careful monitoring is essential.
- Patients with Comorbid Conditions: Caution should be used in patients with coronary artery disease, heart failure, mitral valvular rheumatic heart disease, and other cardiovascular conditions. For diabetic patients with concomitant cardiovascular disease, combine with a beta blocker. For patients post stroke, a thiazide diuretic is recommended.
Clinical Use Cases
- Intubation: Hydralazine can be used to prevent or treat hypertension during intubation, usually given as an IV bolus or infusion. 0.4 mg/kg as a bolus prior to induction has been used.
- Surgical Procedures: May be used to manage hypertension during surgery. However, if hypotension occurs, avoid using epinephrine for correction as it can exacerbate hydralazine’s cardiac-accelerating effects.
- Mechanical Ventilation: Hydralazine can be administered as a continuous IV infusion for blood pressure control in mechanically ventilated patients. The initial rate is usually 0.2-0.3 mg/minute.
- Intensive Care Unit (ICU) Use: Frequently employed for managing hypertension in the ICU, with dosage titrated according to the patient’s blood pressure and clinical condition.
- Emergency Situations: Essential for the rapid reduction of blood pressure in hypertensive emergencies such as hypertensive encephalopathy, acute heart failure, or severe pre-eclampsia. The standard dosage is 10-20mg IV with repeated doses as needed.
Dosage Adjustments:
- Adjust dosage in renal/hepatic impairment, monitoring the clinical response.
- Consider genetic polymorphisms affecting acetylation status (slow acetylators need lower doses).
Side Effects
Common Side Effects
- Headache, dizziness, nausea, vomiting, diarrhea, palpitations, tachycardia, flushing, and hypotension.
Rare but Serious Side Effects
- Drug-induced lupus erythematosus, myocardial ischemia, myocardial infarction, peripheral neuritis, blood dyscrasias (e.g., leukopenia, agranulocytosis, thrombocytopenia).
Long-Term Effects
- Drug-induced lupus can develop with prolonged use.
Adverse Drug Reactions (ADR)
- Severe hypotension, myocardial ischemia/infarction, drug-induced lupus, blood dyscrasias.
Contraindications
- Hypersensitivity to hydralazine.
- Coronary artery disease, mitral valvular rheumatic heart disease, and other cardiovascular conditions should be evaluated before initiating treatment.
- Dissecting aortic aneurysm.
- Idiopathic systemic lupus erythematosus (SLE) and related connective tissue disorders.
Drug Interactions
- Other Antihypertensives: Additive hypotensive effects with other blood pressure-lowering medications.
- Beta-Blockers: May be used concomitantly to mitigate reflex tachycardia.
- Diuretics: Concurrent use can enhance hydralazine’s antihypertensive effects.
- Nitrates: Synergistic effect in heart failure treatment, particularly in Black patients.
- CYP450 Interactions: Hydralazine can interact with drugs metabolized by CYP3A4, potentially altering their levels. Atogepant and axitinib are two examples of such drugs. Consult drug information resources for a complete list.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: C.
- Fetal Risks: Potential for fetal harm due to maternal hypotension. Close monitoring is essential. Hydralazine is used for treatment of severe hypertension in pregnancy, after considering risks and benefits.
- Breastfeeding: Hydralazine is excreted in breast milk. Use caution. Consider alternative safer options if necessary.
Drug Profile Summary
- Mechanism of Action: Direct-acting arteriolar vasodilator, reducing peripheral vascular resistance.
- Side Effects: Headache, dizziness, tachycardia, palpitations, flushing, hypotension, nausea, and vomiting. Rarely: drug-induced lupus, myocardial ischemia.
- Contraindications: Hypersensitivity, coronary artery disease, dissecting aortic aneurysm, SLE.
- Drug Interactions: Other antihypertensives (additive hypotension).
- Pregnancy & Breastfeeding: Use with caution. Category C. Excreted in breast milk.
- Dosage: Highly variable, depending on indication and patient factors. See detailed dosage section above.
- Monitoring Parameters: Blood pressure, heart rate, renal function (creatinine clearance, serum creatinine), signs and symptoms of drug-induced lupus (especially during prolonged therapy). Complete blood counts, especially during long-term therapy.
Popular Combinations
- Hydralazine + Isosorbide Dinitrate: Specifically indicated for heart failure in self-identified Black patients. Offers synergistic hemodynamic benefits.
- Hydralazine + Beta-Blockers: Used to control blood pressure while minimizing reflex tachycardia.
- Hydralazine + Diuretics: Combines vasodilation with volume reduction for enhanced blood pressure control.
Precautions
- General Precautions: Monitor blood pressure and heart rate closely, especially during initial dose titration. Monitor for symptoms of lupus erythematosus during prolonged treatment. Screen for relevant contraindications and comorbidities before prescribing. Monitor blood pressure and heart rate to ensure blood pressure control and watch for tachycardia. Monitor blood counts and ANA titre.
- Specific Populations:
- Pregnant Women: Use only if potential benefits outweigh fetal risks. Close monitoring is mandatory.
- Breastfeeding Mothers: Exercise caution due to drug excretion in breast milk. Consider infant risk and drug concentrations. If drug is necessary during lactation, monitor infant for adverse effects.
- Children & Elderly: Careful dose adjustment and monitoring.
- Menstruating Individuals: No specific precautions typically required.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Hydralazine?
A: The dosage varies considerably depending on indication, patient age, and comorbidities. See the detailed dosage section above.
Q2: What is the mechanism of action of Hydralazine?
A: Hydralazine is a direct-acting arteriolar vasodilator, primarily lowering blood pressure by decreasing peripheral vascular resistance.
Q3: What are the most common side effects of Hydralazine?
A: Common side effects include headache, dizziness, reflex tachycardia, palpitations, flushing, nausea, vomiting, and diarrhea.
Q4: What are the serious side effects of Hydralazine?
A: Rare but serious side effects include drug-induced lupus-like syndrome, myocardial ischemia or infarction, and blood dyscrasias.
Q5: When is Hydralazine contraindicated?
A: Hydralazine is contraindicated in patients with hypersensitivity to the drug, coronary artery disease, dissecting aortic aneurysm, and idiopathic SLE.
Q6: How should Hydralazine be administered in patients with renal impairment?
A: Reduce the dose or increase the dosing interval based on the patient’s creatinine clearance and clinical response.
Q7: Can Hydralazine be used during pregnancy?
A: Hydralazine is a Pregnancy Category C drug and should only be used if the potential benefits outweigh the risks to the fetus. It is often used for severe hypertension or pre-eclampsia in pregnant women. Close monitoring is essential.
Q8: What is the role of acetylator status in Hydralazine dosing?
A: Hydralazine undergoes acetylation in the liver. Slow acetylators have reduced drug clearance and are at greater risk of side effects; therefore, they generally require lower doses.
Q9: How does Hydralazine interact with other antihypertensive medications?
A: Hydralazine can have additive hypotensive effects with other antihypertensives. Concomitant use with beta-blockers can help mitigate reflex tachycardia.
Q10: What monitoring parameters are important for patients on Hydralazine?
A: Regularly monitor blood pressure, heart rate, renal function tests (especially during long-term treatment), and be vigilant for signs and symptoms of drug-induced lupus, particularly during prolonged therapy. Blood tests such as complete blood counts, especially during long-term treatment are recommended. ANA titers should also be followed. If hepatic disease is present, liver function tests may be necessary.
