population (see Chapter 4). As a consequence, rapid acetylators have greater first-pass metabolism, lower blood levels, and less antihypertensive benefit from a given dose than do slow acetylators. The half-life of hydralazine ranges from 1.5 to 3 hours, but vascular effects persist longer than do blood concentrations, possibly due to avid binding to vascular tissue.
Usual dosage ranges from 40 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 vasodilation 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, nausea, anorexia, palpitations, sweating, and flushing. In patients with ischemic heart disease, reflex tachycardia and sympathetic stimulation 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 arthralgia, myalgia, skin rashes, and fever that resembles lupus erythematosus. 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.
tial antihypertensive effect, minoxidil should replace hydralazine when maximal doses of the latter are not effective or in patients with renal failure and severe hypertension, who do not respond well to hydralazine.
Minoxidil is a very efficacious orally active vasodilator. The effect results from the opening of potassium channels in smooth muscle Fe2+ membranes by minoxidil sulfate, the active metabolite. Increased potassium permeability stabilizes the membrane at its resting potential and makes contraction less likely. Like hydralazine, min-CN– oxidil dilates arterioles but not veins. Because of its greater poten-
Pharmacokinetic parameters of minoxidil are listed in Table 11–2. Even more than with hydralazine, the use of minoxidil is associated with reflex sympathetic stimulation and sodium and fluid retention. Minoxidil must be used in combination with a β blocker and a loop diuretic.
Tachycardia, palpitations, angina, and edema are observed when doses of co-administered β blockers and diuretics are inadequate. Headache, sweating, and hypertrichosis (the latter particularly bothersome in women) are relatively common. Minoxidil illustrates how one person’s toxicity may become another person’s therapy. Topical minoxidil (as Rogaine) is used as a stimulant to hair growth for correction of baldness.
Sodium nitroprusside is a powerful parenterally administered vasodilator that is used in treating hypertensive emergencies as well as severe heart failure. Nitroprusside dilates both arterial and venous vessels, resulting in reduced peripheral vascular resistance and venous return. The action occurs as a result of activation of guanylyl cyclase, either via release of nitric oxide or by direct stimulation of the enzyme. The result is increased intracellular cGMP, which relaxes vascular smooth muscle (see Figure 12–2).
In the absence of heart failure, blood pressure decreases, owing to decreased vascular resistance, whereas cardiac output does not change or decreases slightly. In patients with heart failure and low cardiac output, output often increases owing to afterload reduction.