Diazoxide

DIAZOXIDE

Diazoxide is an effective and relatively long-acting parenterally administered arteriolar dilator that is occasionally used to treat hypertensive emergencies. Diminishing usage suggests that it may be withdrawn. Injection of diazoxide results in a rapid fall in sys-temic vascular resistance and mean arterial blood pressure. Studies of its mechanism suggest that it prevents vascular smooth muscle contraction by opening potassium channels and stabilizing the membrane potential at the resting level.

Pharmacokinetics & Dosage

Diazoxide is similar chemically to the thiazide diuretics but has no diuretic activity. It is bound extensively to serum albumin and to vascular tissue. Diazoxide is partially metabolized; its metabolic pathways are not well characterized. The remainder is excreted unchanged. Its half-life is approximately 24 hours, but the relation-ship between blood concentration and hypotensive action is not well established. The blood pressure-lowering effect after a rapid injection is established within 5 minutes and lasts for 4–12 hours.

When diazoxide was first marketed, a dose of 300 mg by rapid injection was recommended. It appears, however, that excessive hypotension can be avoided by beginning with smaller doses (50–150 mg). If necessary, doses of 150 mg may be repeated every 5 to 15 minutes until blood pressure is lowered satisfactorily. Nearly all patients respond to a maximum of three or four doses. Alternatively, diazoxide may be administered by intravenous infu-sion at rates of 15–30 mg/min. Because of reduced protein bind-ing, hypotension occurs after smaller doses in persons with chronic renal failure, and smaller doses should be administered to these patients. The hypotensive effects of diazoxide are also greater when patients are pretreated with β blockers to prevent the reflex tachycardia and associated increase in cardiac output.

Toxicity

The most significant toxicity from diazoxide has been excessive hypotension, resulting from the recommendation to use a fixed dose of 300 mg in all patients. Such hypotension has resulted in stroke and myocardial infarction. The reflex sympathetic response can provoke angina, electrocardiographic evidence of ischemia, and cardiac failure in patients with ischemic heart disease, and diazoxide should be avoided in this situation.

Diazoxide inhibits insulin release from the pancreas (probably by opening potassium channels in the beta cell membrane) and is used to treat hypoglycemia secondary to insulinoma. Occasionally, hyperglycemia complicates diazoxide use, particularly in persons with renal insufficiency.

In contrast to the structurally related thiazide diuretics, diazox-ide causes renal salt and water retention. However, because the drug is used for short periods only, this is rarely a problem.