Hydralazine

Hydralazine is a direct arteriolar vasodilator used in severe hypertension in pregnancy, resistant hypertension and, with isosorbide dinitrate, heart failure with reduced ejection fraction in patients of African ancestry. It causes reflex tachycardia and fluid retention and should be combined with a beta blocker and a diuretic. Drug induced lupus is the best known long term risk.

Classification. Direct acting arteriolar vasodilator; hydrazinophthalazine.

Mechanism. Relaxes arteriolar smooth muscle, probably through inhibition of inositol trisphosphate mediated calcium release and by raising nitric oxide bioavailability. It has little effect on veins.

Pharmacodynamics. Oral onset 20 to 30 minutes, peak 1 to 2 hours, duration 2 to 6 hours. IV onset 10 to 20 minutes, peak 20 to 30 minutes, duration 2 to 6 hours. Diastolic pressure falls more than systolic.

Pharmacokinetics. Extensive first pass metabolism and acetylation in the liver; oral bioavailability 10% in rapid acetylators and 30 to 35% in slow acetylators. Half life 2 to 8 hours; effect lasts longer than the half life because of tissue binding. Mostly excreted in urine as metabolites.

Severe hypertension in pregnancy and pre-eclampsia, adult (IV).

• 5 mg IV over 5 to 10 minutes.

• Repeat 5 to 10 mg every 20 to 30 minutes if the target is not reached.

• Cumulative maximum 20 mg in the first hour in some practice.

• Or infusion: 200 to 300 micrograms/minute initially, then 50 to 150 micrograms/minute as maintenance.

• Labetalol or nifedipine are preferred first line; hydralazine causes more maternal hypotension and foetal distress in some reports.

Hypertension, adult (oral).

• Start 25 mg twice daily.

• Increase to 50 mg twice daily after 1 to 2 weeks; usual maintenance 50 to 100 mg twice daily.

• Maximum 200 mg daily (doses over 100 mg a day raise the risk of drug induced lupus, particularly in slow acetylators).

• Some labels use 10 mg four times daily, increased to a maximum of 50 mg four times daily.

• Always combine with a beta blocker or other rate control drug and a diuretic.

Heart failure with reduced ejection fraction in patients of African ancestry (with isosorbide dinitrate), adult. Hydralazine 37.5 mg with isosorbide dinitrate 20 mg three times daily; increase to hydralazine 75 mg with isosorbide dinitrate 40 mg three times daily, as tolerated (target daily dose 225 mg and 120 mg). Add to a renin angiotensin agent, beta blocker and mineralocorticoid antagonist.

Children, hypertension. Oral 0.75 mg/kg daily in 2 to 4 divided doses, increased over 3 to 4 weeks to a maximum of 7.5 mg/kg or 200 mg daily. IV: 0.1 to 0.2 mg/kg every 4 to 6 hours as needed. Specialist.

Contraindications. Systemic lupus erythematosus; severe tachycardia; high output heart failure; cor pulmonale; mitral valve obstruction; dissecting aortic aneurysm; porphyria; hypersensitivity.

Warnings. Reflex tachycardia, worsening angina and myocardial ischaemia, which can be severe without a beta blocker. Fluid retention and oedema. Drug induced lupus (arthralgia, fever, rash, serositis) is dose and acetylator related, usually reversible on stopping; check antinuclear antibodies if symptoms appear. Peripheral neuropathy (pyridoxine antagonism); give pyridoxine in long term use. Hypotension and foetal distress after IV use in pregnancy.

Adverse effects. Headache, flushing, palpitations, tachycardia, oedema, nausea, vomiting, diarrhoea, lupus like syndrome, neuropathy, rarely blood dyscrasias.

Interactions. Beta blockers: raise hydralazine bioavailability; combined use is intended. Other antihypertensives and anaesthetics: additive hypotension. Monoamine oxidase inhibitors: hypotension. Diazoxide: severe hypotension. Sympathomimetics: reduced effect.

Special groups.

• Pregnancy: used in severe hypertension when other agents fail; monitor mother and foetus.

• Breastfeeding: small amounts in milk; compatible.

• Patients of African ancestry: used with isosorbide dinitrate for heart failure with reduced ejection fraction.

• Older adults: start 10 to 25 mg twice daily.

• Kidney impairment: creatinine clearance under 30 mL/min: lengthen the dose interval to every 8 to 16 hours; titrate to effect.

• Liver impairment: reduce the dose because first pass metabolism falls.

Formulations. Tablets 10, 25, 50, 100 mg; injection 20 mg/mL (to be diluted).

Administration. Oral with food (raises bioavailability). IV: dilute and inject slowly or infuse in 0.9% sodium chloride; do not mix with glucose solutions (precipitation).

Baseline. Blood pressure, heart rate, ECG, antinuclear antibodies if history of autoimmune disease, acetylator status if available.

Monitoring. Blood pressure and heart rate every 5 to 10 minutes during IV dosing; foetal heart rate in pregnancy; weight and oedema; symptoms of lupus; full blood count and antinuclear antibodies in long term high dose treatment.

Stopping. Taper where possible; stop for lupus like syndrome, severe tachycardia or ischaemia.

Common prescribing errors. Giving without a beta blocker or diuretic; using IV hydralazine as first line in pregnancy when labetalol is available; exceeding 200 mg daily without checking for lupus; mixing with glucose.