Direct-Acting Vasodilators

     Hydralazine, minoxidil, sodium nitroprusside, and fenoldopam are examples of directacting vasodilators. Hydralazine and minoxidil are used primarily as long-term oral vasodilators, whereas nitroprusside and fenoldopam are administered intravenously in more acute settings.
     Hydralazine is a potent and direct arteriolar dilator that acts at the level of the precapillary arterioles and has no effect on systemic veins. The cellular mechanism of its effect is unknown. The fall in blood pressure following arteriolar dilation results in a baroreceptormediated increase in sympathetic outfl ow and cardiac stimulation (e.g., reflex tachycardia), which could precipitate myocardial ischemia in patients with underlying CAD. Therefore, hydralazine is often combined with   a -blocker to blunt this undesired response.
     As newer drugs have emerged, hydralazine is now used only occasionally as an antihypertensive, often in combination with other drugs. It is sometimes prescribed concurrently with the venodilator isosorbide dinitrate to treat heart failure in patients with systolic dysfunction. This combination improves symptoms in patients with mild-to-moderate heart failure and has been shown to reduce morbidity and mortality rates.
     Hydralazine possesses low bioavailability because of extensive fi rst-pass hepatic metabolism. However, such metabolism depends on whether the patient displays fast or slow hepatic acetylation; on average, 50% of Americans are fast and 50% are slow acetylators. Slow acetylators show less hepatic degradation, higher bioavailability, and increased antihypertensive effects, whereas fast acetylators demonstrate the opposite responses. Hydralazine has a short half-life (2 to 4 hours) in the circulation, but its effect persists as long as 12 hours because the drug binds avidly to vascular tissues.
     The most common side effects of hydralazine include headache (increased cerebral vasodilation), palpitations (refl ex tachycardia), flushing (increased systemic vasodilation), nausea, and anorexia. In addition, a syndrome similar to systemic lupus (characterized by arthralgias, myalgia, skin rashes, and fever) may develop, especially in patients who are slow acetylators.
     Minoxidil also results in arteriolar vasodilation without signifi cant venodilation. Its mechanism of action involves an increase in potassium channel permeability, which results in smooth muscle cell hyperpolarization and relaxation. Like other agents that selectively cause arteriolar dilation, reflex adrenergic stimulation leads to increased heart rate and contractility, an undesired effect that can be blunted by coadministration of a -blocker. In addition, decreased renal perfusion often results in fl uid retention, so that a diuretic usually must be administered concurrently.
     Minoxidil’s primary clinical indication is in the treatment of severe or intractable hypertension. It is especially useful in patients with renal failure who are often refractory to other antihypertensive regimens. It is well absorbed from the gastrointestinal tract and is metabolized primarily by hepatic glucuronidation, but approximately one fi fth is excreted unchanged by the kidney. Although it has a short half-life, its pharmacologic effects persist even after serum drug concentration falls, probably because, like hydralazine, the drug binds avidly to vascular tissues.
     Side effects of minoxidil, in addition to reflex sympathetic stimulation and fluid retention, include hypertrichosis (excessive hair growth) and occasional pericardial effusion (unknown mechanism).   
     Sodium nitroprusside, a potent dilator of both arterioles and veins, is administered intravenously to treat hypertensive emergencies and, in intensive care settings, for blood pressure control. It is also prescribed for preload and afterload modulation in severe CHF. Sodium nitroprusside is a complex of iron, cyanide groups, and a nitroso moiety, and its metabolism by red blood cells results in the liberation of nitric oxide. Nitric oxide causes  asodilation through activation of guanylate cyclase
in vascular smooth muscle.
     Sodium nitroprusside’s hemodynamic effects result from its ability to decrease arterial resistance and to increase venous capacitance. In patients with normal left ventricular function, it can actually decrease cardiac output because of the reduction in venous return. However, in a patient with impaired left ventricular contractile function, the decreased systemic resistance induced by sodium nitroprusside (i.e., decreased afterload) augments forward cardiac output, while venous dilation reduces return of blood to the heart. The latter decreases pulmonary capillary hydrostatic
pressure and improves symptoms of pulmonary congestion.
     Sodium nitroprusside is often the treatment of choice for hypertensive emergencies because of its great potency and rapid action. A-blocker is often administered concurrently to counteract the refl ex increase in sympathetic outflow that may occur with this drug.
     Sodium nitroprusside is administered by continuous intravenous infusion. Its onset of action begins within 30 seconds, and its peak effect is achieved in 2 minutes. Its effectiveness dissipates within minutes of its discontinuation. After sodium nitroprusside is metabolized into nitric oxide and cyanide, the liver, in the presence of a sulfhydryl donor, transforms cyanide into thiocyanate; the thiocyanate, in turn, is excreted by the kidney. Thiocyanate accumulation and toxicity, manifested by blurred vision,
tinnitus, disorientation, and/or nausea, may occur with continued use, especially in the setting of renal impairment. Thus, it is important  to monitor serum levels of thiocyanate if sodium nitroprusside is administered for more than 24 hours. In addition, excessive infusion rates of sodium nitroprusside, or a defi ciency in hepatic thiosulfate stores, can result in lethal cyanide toxicity, the early signs of which
include metabolic acidosis, headache, and nausea, followed by loss of consciousness.
     Fenoldopam is a rapidly acting potent arteriolar vasodilator administered intravenously to treat severe hypertension. It is a selective agonist of peripheral dopamine 1 (D1) receptors, the activation of which results in arteriolar vasodilation through a cAMP-dependent mechanism. Unlike other intravenous antihypertensive agents, it benefi cially maintains or enhances renal perfusion, and its activation of renal tubular D1 receptors facilitates natriuresis. Unlike dopamine, fenoldopam does not stimulate - or -adrenergic receptors.
     Fenoldopam is administered by continuous intravenous infusion. Its onset of action is rapid, achieving 50% of maximal effect within 15 minutes and steady state in 30 to 60 minutes. It is metabolized by the liver to inactive substances that are excreted through the kidney. It has a rapid offset of action after discontinuation (an elimination half-life of 10 minutes), which is a desirable effect that minimizes the risk of excessive blood pressure reduction during the treatment of hypertensive emergencies. These pharmacologic properties also make fenoldopam useful for controlling hypertension in the postoperative setting. However, nitroprusside works even faster and remains more popular for 1this purpose. Unlike nitroprusside, fenoldopam does not cause thiocyanate toxicity. The most common side effects are headache, dizziness, and tachycardia. Fenoldopam also increases intraocular pressure (probably by slowing aqueous humor drainage) and should therefore be avoided in patients with glaucoma.