What is the recommended dosage and treatment protocol for Hydralazine (hydralazine) in managing hypertension?

Hydralazine Dosing and Treatment Protocol for Hypertension

For chronic oral hypertension management, initiate hydralazine at 10 mg four times daily for 2-4 days, then increase to 25 mg four times daily for the remainder of the first week, followed by 50 mg four times daily for maintenance, with a maximum dose of 300 mg daily in divided doses. 1

Oral Dosing for Chronic Hypertension

Initial Titration Schedule

• Days 1-4: Start at 10 mg four times daily 1
• Days 5-7: Increase to 25 mg four times daily 1
• Week 2 and beyond: Increase to 50 mg four times daily for maintenance 1
• Maximum dose: Up to 300 mg daily may be required in resistant patients, though this increases risk of lupus-like syndrome 1

Dosing Frequency Considerations

• Twice-daily dosing is adequate for most patients when combined with beta-blockers and diuretics, as the hypotensive effect is maintained for 24 hours 2
• Once-daily conventional hydralazine is unsatisfactory because its hypotensive effect wanes at 24 hours, particularly in rapid acetylators 2
• Extended-release formulations can be given once or twice daily with equivalent efficacy to conventional formulations given 2-4 times daily 3, 4

Dose-Response Relationships

• The maximum antihypertensive response (Emax) is approximately 9.4 mmHg reduction in diastolic blood pressure 4
• The D50 (dose achieving 50% of maximum response) is 0.87 mg/kg daily for slow acetylators and 1.68 mg/kg daily for fast acetylators 4
• Concomitant beta-blocker therapy provides an additional 6.6 mmHg reduction beyond hydralazine effects 4

Combination Therapy Requirements

Hydralazine should virtually always be combined with a beta-blocker and diuretic to counteract reflex tachycardia and fluid retention 5, 1, 6. When combining therapy:

• Add a thiazide diuretic and/or beta-blocker to lower effective hydralazine doses 1
• Individual titration of each component is essential 1
• The propranolol-hydralazine combination produces significantly better blood pressure control than either agent alone (mean additional reduction of 13-16 mmHg systolic and 7-15 mmHg diastolic) 6

Heart Failure with Reduced Ejection Fraction (HFrEF)

For HFrEF, hydralazine is used in combination with isosorbide dinitrate:

Fixed-Dose Combination

• Initial: 37.5 mg hydralazine/20 mg isosorbide dinitrate three times daily 7
• Target: 75 mg hydralazine/40 mg isosorbide dinitrate three times daily 7
• Mean dose achieved in trials: ~175 mg hydralazine/90 mg isosorbide dinitrate total daily 7

Separate Components

• Initial: 25-50 mg hydralazine 3-4 times daily with 20-30 mg isosorbide dinitrate 3-4 times daily 7
• Maximum: 300 mg hydralazine daily in divided doses and 120 mg isosorbide dinitrate daily in divided doses 7

Clinical Impact in HFrEF

• Provides 43% relative risk reduction in mortality (NNT = 43 over 10 months, or NNT = 7 when standardized to 36 months) 7
• Reduces hospitalizations by 33% 7

Hypertensive Emergencies (IV Administration)

Hydralazine is NOT a desirable first-line agent for acute hypertensive emergencies due to unpredictability of response and prolonged duration of action 7. When used:

• Initial dose: 10 mg via slow IV infusion (maximum initial dose 20 mg) 7
• Repeat dosing: Every 4-6 hours as needed 7
• Onset: Blood pressure begins to decrease within 10-30 minutes 7
• Duration: Effect lasts 2-4 hours 7

Resistant Hypertension Protocol

In the stepwise approach to resistant hypertension, hydralazine appears at Step 5 (after optimizing RAS blocker, calcium channel blocker, thiazide-like diuretic, mineralocorticoid receptor antagonist, and beta-blocker) 7:

• Initial: 25 mg three times daily 7
• Titration: Increase upward to maximum dose 7
• Maximum: 200 mg daily 7
• Special consideration: In patients with HFrEF, administer hydralazine with isosorbide mononitrate 30 mg daily (maximum 90 mg daily) 7

Critical Safety Monitoring

Drug-Induced Lupus-Like Syndrome

• High risk with large doses, particularly in slow acetylators 5, 1
• Monitor for symptoms especially at doses approaching 300 mg daily 1
• Discontinue if blood dyscrasias develop (reduction in hemoglobin, leukopenia, agranulocytosis, purpura) 1

Common Adverse Effects

• Reflex tachycardia: Mean increase of 12.4 beats/min when used without beta-blocker 6
• Fluid retention: Requires concurrent diuretic therapy 5
• Headache: Common, particularly during initial titration 5
• Avoid abrupt discontinuation after prolonged use 5

Drug Interactions

• MAO inhibitors: Use with caution 1
• Diazoxide: Profound hypotensive episodes may occur; continuous observation required for several hours 1
• Food: Administration with food results in higher plasma levels 1

Pediatric Dosing

Although not established in controlled trials, the usual recommended approach is 1:

• Initial: 0.75 mg/kg daily in four divided doses 1
• Titration: Increase gradually over 3-4 weeks 1
• Maximum: 7.5 mg/kg or 200 mg daily, whichever is less 1

Common Pitfalls to Avoid

• Do not use hydralazine monotherapy without beta-blocker and diuretic coverage, as reflex tachycardia and fluid retention will limit efficacy and tolerability 5, 6
• Do not use once-daily conventional hydralazine as the hypotensive effect wanes at 24 hours, particularly in rapid acetylators 2
• Do not select hydralazine as first-line for hypertensive emergencies due to unpredictable response and prolonged duration of action 7
• Do not exceed 300 mg daily without careful monitoring for lupus-like syndrome 1
• Do not combine with diazoxide without continuous blood pressure monitoring 1