What is the recommended dosing for hydralazine (direct vasodilator) in adults?

Hydralazine Dosing in Adults

For heart failure with reduced ejection fraction (HFrEF), start hydralazine at 25-50 mg orally three to four times daily combined with isosorbide dinitrate, titrating to a target of 75 mg three times daily (maximum 300 mg/day in divided doses); for hypertensive emergencies, give 10-20 mg IV as a slow bolus, repeated every 4-6 hours as needed, though hydralazine is not a first-line agent due to unpredictable response. 1

Oral Dosing for Heart Failure

Standard Regimen

• Initial dose: 25-50 mg orally three to four times daily, always combined with isosorbide dinitrate 20-30 mg three to four times daily 1
• Target dose: 75 mg hydralazine three times daily (225 mg total daily) 1
• Maximum dose: 300 mg daily in divided doses 1

Fixed-Dose Combination

• Initial dose: 37.5 mg hydralazine/20 mg isosorbide dinitrate three times daily 1
• Target dose: 75 mg hydralazine/40 mg isosorbide dinitrate three times daily 1
• Mean dose achieved in trials: ~175 mg hydralazine/90 mg isosorbide dinitrate total daily 1

The combination provides substantial mortality benefit with a 43% relative risk reduction and an NNT of 7 for preventing all-cause mortality over 36 months. 1, 2 This makes hydralazine-isosorbide dinitrate particularly valuable in patients who cannot tolerate ACE inhibitors or ARBs, especially in Black patients with HFrEF. 1

Oral Dosing for Resistant Hypertension

Step 5 Therapy

• Initial dose: 25 mg three times daily 1
• Titration: Increase upward to maximum dose as tolerated 1
• Maximum dose: 200 mg daily (implied from guideline context) 1
• Important: Must be used with a beta-blocker and diuretic to prevent reflex tachycardia and fluid retention 1, 3

Hydralazine is reserved for Step 5 in resistant hypertension algorithms, after optimizing thiazide-like diuretics, mineralocorticoid receptor antagonists, and beta-blockers. 1 In patients with HFrEF and resistant hypertension, hydralazine should be combined with isosorbide mononitrate 30 mg daily (maximum 90 mg daily). 1

Intravenous Dosing for Hypertensive Emergencies

Acute Administration

• Initial dose: 10 mg via slow IV infusion (maximum initial dose 20 mg) 1, 2
• Repeat dosing: Every 4-6 hours as needed 1, 2
• Onset: Blood pressure begins to decrease within 10-30 minutes 1, 2
• Duration: Hypotensive effect lasts 2-4 hours 1, 2

Critical caveat: The unpredictability of response and prolonged duration of action make hydralazine undesirable as a first-line agent for acute hypertension treatment in most patients. 1, 2 Preferred agents include nicardipine, clevidipine, or labetalol for more predictable and titratable blood pressure control. 1

Recent observational data from hospitalized patients showed that IV hydralazine (mean dose 11.4 mg) produced highly variable blood pressure reductions (24/9 ± 29/15 mmHg) with hypotension occurring in 12% of patients, and was inappropriately used in 98% of cases where no urgent hypertensive condition existed. 4

Dosing Frequency Considerations

Three to Four Times Daily vs. Twice Daily

• Three to four times daily: Standard for heart failure management to maintain consistent vasodilation 1
• Twice daily: Adequate for blood pressure control when combined with beta-blockers and diuretics 5, 6
• Once daily: Unsatisfactory, as hypotensive effect wanes at 24 hours, particularly in rapid acetylators 5

Research demonstrates that twice-daily conventional hydralazine and once-daily slow-release hydralazine provide satisfactory 24-hour control in both rapid and slow acetylators when combined with atenolol and a diuretic, though the hypotensive effect is larger in slow acetylators. 5

Acetylator Status and Dose Response

Pharmacokinetic Considerations

• Slow acetylators: D50 (dose producing 50% of maximum response) = 0.87 mg/kg daily 7
• Fast acetylators: D50 = 1.68 mg/kg daily 7
• Maximum antihypertensive response (Emax): 9.4 mmHg reduction in diastolic blood pressure 7

Slow acetylators achieve greater blood pressure reduction at lower doses and are at higher risk for drug-induced lupus-like syndrome, particularly at doses above 200 mg daily. 1, 3 Fast acetylators require higher doses to achieve equivalent blood pressure control. 7, 5

Critical Safety Considerations

Common Side Effects

• Reflex tachycardia: Prevented by concurrent beta-blocker use 1, 3, 6
• Fluid retention: Requires concurrent diuretic therapy 1, 3
• Headache: Common, often dose-related 3
• Drug-induced lupus-like syndrome: Risk increases with doses >200 mg daily, especially in slow acetylators 1, 3

Contraindications and Precautions

• Avoid abrupt discontinuation after prolonged use 3
• Monitor for lupus-like syndrome with higher doses and prolonged therapy 1, 3
• Use with caution in patients with coronary artery disease due to reflex tachycardia 3
• Always combine with beta-blocker and diuretic for hypertension to prevent compensatory mechanisms 1, 3

When propranolol 80 mg was combined with hydralazine 50 mg twice daily, cardiovascular events (severe tachycardia, palpitations) occurred in 10% of patients on hydralazine alone but in none taking the combination, with mean heart rate increases of 12.4 beats/min for hydralazine alone versus 1.8 beats/min for the combination. 6