Cardiovascular Agents
Antihypertensive Agents

Description: Nitroprusside is an intravenous hypotensive agent effective in the acute management of hypertensive crisis and in the management of congestive heart failure. Nitroprusside is an extremely potent vasodilator with a rapid onset and a short duration of action. Nitroprusside is used primarily to manage hypertensive emergencies but can also be useful when immediate reduction of preload or afterload is needed. Other uses of the drug not currently included in the U.S. product labeling include the control of paroxysmal hypertension during surgery secondary to pheochromocytoma, treatment of peripheral vasospasm secondary to ergot alkaloid overdose, adjunctive treatment in valvular (mitral and aortic) regurgitation therapy, and reduction of afterload in patients with myocardial infarction associated with persistent chest pain. Prolonged infusions, however, have a high potential for toxicity, limiting general use of the drug. Because of its short duration, it must be administered via IV infusion. Although nitroprusside was discovered in 1850 and shown to exert hypotensive effects in humans as early as 1929, it was not approved by the FDA for clinical use until 1974.

Mechanism of Action: The peripheral vasodilatory effects of nitroprusside are due to a direct action of the drug on arterial and venous smooth muscle. Other smooth muscle tissue in the body is not affected, and myocardial contractility is unaffected. Nitroprusside's hypotensive effects are enhanced by other hypotensive agents and are not inhibited by adrenergic blocking agents. Pressor agents that exert a direct stimulatory effect on the myocardial tissue (i.e., epinephrine) are the only class of drugs that can cause an increase in blood pressure during nitroprusside therapy. Almost any desired blood pressure can be maintained with various infusion rates of the drug.

Nitroprusside-induced peripheral vasodilation results in a reduced left ventricular afterload, and this, along with a reduced venous return to the heart (due to venous pooling of the blood and decreased arteriolar resistance), results in a slight increase in heart rate and decrease in cardiac output in hypertensive patients. In patients with congestive heart failure, nitroprusside improves left ventricular heart performance, with increases in cardiac index, cardiac output, and stroke volume. Heart rate also slows in these patients, and arrhythmias can be reduced or abolished. Nitroprusside also can decrease myocardial oxygen demand, which is beneficial to patients with ischemia. Diuresis also occurs during nitroprusside therapy, producing increased urine volumes and increased sodium excretion.

Pharmacokinetics: Nitroprusside is administered intravenously, resulting in immediate blood pressure reduction. The distribution kinetics of the drug are unknown, but it is believed to penetrate cell membranes slowly and to be distributed predominantly into the extracellular space. It is not known whether the drug crosses the placenta or the blood-brain barrier, or if it is secreted into breast milk. Nitroprusside is rapidly metabolized to cyanide radicals, which are then converted to thiocyanate in the liver via the enzyme rhodanase (see below). These metabolites are excreted almost entirely in the urine. The drug is short-acting, with hypotensive effects lasting only 1—10 minutes following infusion. The circulatory half-life of nitroprusside is 2 minutes.

Nitroprusside is metabolized to cyanide and thiocyanate, which, although they do not contribute to the antihypertensive action, have the potential to cause severe toxic reactions. Nitroprusside molecules begin to break down immediately after contact with sulfhydryl groups located in the cell wall. An intraerythrocytic reaction occurs, in which a molecule of nitroprusside reacts with an equivalent amount of hemoglobin, forming methemoglobin and liberating five cyanide ions. One of these cyanide ions then reacts with the methemoglobin molecule to form cyanmethemoglobin, a biologically inert compound. A patient with a normal red cell count and normal methemoglobin concentration is able to buffer approximately 175 mcg of cyanide ion per kg body weight. In other words, an otherwise healthy patient can buffer a little less than 500 mcg/kg of infused nitroprusside.

Once the intraerythrocytic methemoglobin supply is saturated, the remaining cyanide radicals are converted to thiocyanate in the liver via the hepatic enzyme rhodanase. This reaction requires a sulfur donor, typically thiosulfate, cysteine, or cystine. Physiological concentrations of thiosulfate (11 mg/L) can convert cyanide ions to thiocyanate at about 1 mcg/kg/minute (roughly equivalent to a nitroprusside infusion of about 2 mcg/kg/minute). Cyanide accumulates at infusion rates that exceed this rate, and excess cyanide binds to mitochondrial cytochromes, inhibiting cellular respiration and possibly causing cell death. Thiocyanate toxicity occurs at plasma levels of 50—100 mcg/mL.