Hydralazine, a hydrazine derivative, dilates arterioles but not veins. It has been available for many years, although it was initially thought not to be particularly effective because tachyphylaxis to its antihypertensive effects developed rapidly. The benefits of combi-nation therapy are now recognized, and hydralazine may be used more effectively, particularly in severe hypertension. The combi-nation of hydralazine with nitrates is effective in heart failure and should be considered in patients with both hypertension and heart failure, especially in African-American patients.
Hydralazine is well absorbed and rapidly metabolized by the liver during the first pass, so that bioavailability is low (averaging 25%) and variable among individuals. It is metabolized in part by acety-lation at a rate that appears to be bimodally distributed in the population . As a consequence, rapid acetylators have greater first-pass metabolism, lower blood levels, and less antihypertensive benefit from a given dose than do slow acetyla-tors. The half-life of hydralazine ranges from 1.5 to 3 hours, but vascular effects persist longer than do blood concentrations, pos-sibly due to avid binding to vascular tissue.
Usual dosage ranges from 40 mg/d to 200 mg/d. The higher dosage was selected as the dose at which there is a small possibility of developing the lupus erythematosus-like syndrome described in the next section. However, higher dosages result in greater vasodi-lation and may be used if necessary. Dosing two or three times daily provides smooth control of blood pressure.
The most common adverse effects of hydralazine are headache, nau-sea, anorexia, palpitations, sweating, and flushing. In patients with ischemic heart disease, reflex tachycardia and sympathetic stimula-tion may provoke angina or ischemic arrhythmias. With dosages of 400 mg/d or more, there is a 10–20% incidence—chiefly in persons who slowly acetylate the drug—of a syndrome characterized by arth-ralgia, myalgia, skin rashes, and fever that resembles lupus erythema-tosus. The syndrome is not associated with renal damage and is reversed by discontinuance of hydralazine. Peripheral neuropathy and drug fever are other serious but uncommon adverse effects.