Direct Vasodilators

Direct vasodilators relax vascular smooth muscle independently of receptors, lowering resistance and blood pressure. They provoke reflex tachycardia and sodium and water retention, so they are used with a beta blocker and a loop diuretic. Uses range from hypertensive emergencies to resistant hypertension and heart failure.

Members. Hydralazine, minoxidil, sodium nitroprusside, diazoxide and fenoldopam (where available). Organic nitrates act through the same nitric oxide mechanism and form a separate class.

Mechanism. Hydralazine relaxes arterioles through effects on calcium release and prolyl hydroxylase inhibition. Minoxidil sulphate opens ATP-sensitive potassium channels, hyperpolarising smooth muscle. Sodium nitroprusside releases nitric oxide, raising cyclic GMP, and dilates both arteries and veins. Diazoxide opens potassium channels in vessels and in pancreatic beta cells.

Selectivity. Hydralazine and minoxidil are arteriolar dilators and increase heart rate, contractility and renin. Nitroprusside dilates both arteries and veins, lowering preload as well as afterload.

Pharmacokinetics. Hydralazine undergoes acetylation, with fast and slow acetylators differing in exposure, and clinical effect lasts longer than plasma half-life. Minoxidil acts for 24 hours or more despite a half-life of about 4 hours. Nitroprusside acts within seconds, with effect ending 1 to 3 minutes after stopping, and releases cyanide that is converted to thiocyanate.

• Hydralazine: oral and intravenous; pregnancy hypertension, hypertensive emergencies, and heart failure with nitrate in selected patients.
• Minoxidil: oral, potent, for resistant hypertension under specialist care; topical for alopecia.
• Sodium nitroprusside: intravenous infusion for hypertensive emergencies, aortic dissection with beta blockade, and acute heart failure with raised afterload.
• Diazoxide: oral for hyperinsulinaemic hypoglycaemia; intravenous use for hypertension is obsolete.
• Fenoldopam: dopamine D1 agonist for hypertensive emergencies in some markets.

• Pregnancy, severe hypertension: hydralazine 5 to 10 mg intravenously slowly, repeated after 20 to 30 minutes, with labetalol or nifedipine as alternatives.
• Chronic hypertension (late line): hydralazine 25 mg twice daily, increased to a maximum of 200 mg daily, with a beta blocker and diuretic.
• Heart failure with reduced ejection fraction: fixed-dose hydralazine 37.5 mg with isosorbide dinitrate 20 mg 3 times daily, increased to 75 mg and 40 mg 3 times daily. Benefit is established in patients of African ancestry on optimal therapy, and as an alternative when an ACE inhibitor, angiotensin receptor blocker and sacubitril-valsartan cannot be used.
• Resistant hypertension: minoxidil 2.5 to 5 mg daily, increased every 3 days to 10 to 40 mg daily in 1 to 2 doses (maximum 100 mg), under specialist care with a beta blocker and loop diuretic.
• Hypertensive emergency: sodium nitroprusside 0.3 micrograms/kg/minute, increased every few minutes to the effect, usual maximum 2 micrograms/kg/minute for prolonged use and 10 micrograms/kg/minute for under 10 minutes. Invasive arterial monitoring is needed, and the infusion must be protected from light.
• Hyperinsulinaemic hypoglycaemia: diazoxide 5 to 15 mg/kg daily in divided doses under specialist care.
• Selection: nitroprusside only when safer alternatives (labetalol, nicardipine, glyceryl trinitrate) are unavailable or unsuitable.

Contraindications. Hydralazine: systemic lupus erythematosus, severe tachycardia, coronary artery disease without beta blockade, aortic dissection without beta blockade, mitral stenosis, and high-output heart failure. Minoxidil: phaeochromocytoma, pericardial effusion and pulmonary hypertension. Nitroprusside: compensatory hypertension, hepatic failure, vitamin B12 deficiency, Leber optic atrophy and raised intracranial pressure (relative).

Adverse effects. Reflex tachycardia, palpitations, headache, flushing, salt and water retention and oedema. Hydralazine: drug-induced lupus (mainly slow acetylators and doses over 200 mg daily; positive anti-histone antibodies), peripheral neuropathy and rash. Minoxidil: hypertrichosis, pericardial effusion, T-wave changes. Diazoxide: hyperglycaemia, hirsutism, fluid retention and, in infants, pulmonary hypertension.

Cyanide and thiocyanate toxicity. Risk rises above 2 micrograms/kg/minute for prolonged infusion and with renal or hepatic impairment. Features: metabolic acidosis with raised lactate, confusion, seizures and tachyphylaxis. Treat by stopping the infusion and giving hydroxocobalamin 5 g intravenously, or sodium thiosulphate if hydroxocobalamin is unavailable.

Interactions. Additive hypotension with other antihypertensives and anaesthetics. Phosphodiesterase 5 inhibitors with nitrates and nitroprusside can cause severe hypotension. NSAIDs reduce effect.

Monitoring. Continuous blood pressure and electrocardiogram for infusions, weight and oedema, antinuclear antibody and symptoms for hydralazine, echocardiography for pericardial effusion with minoxidil, and thiocyanate levels in prolonged nitroprusside therapy.

Special groups. Pregnancy: hydralazine is used, and neonates need observation for thrombocytopenia. Renal impairment: reduce hydralazine frequency, and avoid prolonged nitroprusside. Breastfeeding: hydralazine and minoxidil enter milk in small amounts. Older adults: lower starting doses.