Chapter: Modern Pharmacology with Clinical Applications: Antihypertensive Drugs

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Vasodilators: Diazoxide

Diazoxide (Hyperstat) is chemically similar to the thi-azide diuretics.

Diazoxide

Diazoxide (Hyperstat) is chemically similar to the thi-azide diuretics. It is devoid of diuretic activity and causes NA+ and water retention. Diazoxide is a very po-tent vasodilator and is available only for intravenous use in the treatment of hypertensive emergencies. The mechanism by which diazoxide relaxes vascular smooth muscle is related to its ability to activate potassium channels and produce a hyperpolarization of the cell membrane.

Absorption, Metabolism, and Excretion

Diazoxide lowers blood pressure within 3 to 5 minutes after rapid intravenous injection, and its duration of ac-tion may be 4 to 12 hours. Interestingly, if diazoxide is either injected slowly or infused its hypotensive action is quite modest. This is believed to be due to a rapid and extensive binding of the drug to plasma proteins. Both the liver and kidney contribute to its metabolism and excretion. The plasma half-life is therefore prolonged in patients with chronic renal failure.

Pharmacological Actions

The hemodynamic effects of diazoxide are similar to those of hydralazine and minoxidil. It produces direct relaxation of arteriolar smooth muscle with little effect on capacitance beds. Since it does not impair cardiovas-cular reflexes, orthostasis is not a problem. Its adminis-tration is, however, associated with a reflex increase in cardiac output that partially counters its antihyperten-sive effects. Propranolol and other β-blockers potenti-ate the vasodilating properties of the drug. Diazoxide has no direct action on the heart. Although renal blood flow and glomerular filtration may fall transiently, they generally return to predrug levels within an hour.

Clinical Uses

Diazoxide is administered intravenously for the treat-ment of hypertensive emergencies, particularly malig-nant hypertension, hypertensive encephalopathy, and eclampsia. It is effective in 75 to 85% of the patients to whom it is administered and rarely reduces blood pres-sure below the normotensive range.

In patients with coronary insufficiency, a β-blocker can be given in conjunction with diazoxide to decrease the cardiac work associated with reflex increases in sym-pathetic stimulation of the heart. However, β-blockers potentiate the hypotensive effect of diazoxide, and therefore, the dose of the vasodilator should be low-ered. The dose of diazoxide should also be lowered if the patient has recently been treated with guanethidine or another drug that depresses the action of the sympa-thetic nervous system. Such drugs permit a greater hy-potensive effect because they reduce the increase in cardiac output that normally partially counteracts the fall in pressure.

Diazoxide appears to have a direct antinatriuretic action. This direct action, coupled with the neuroen-docrine reflexes that are activated by a decrease in pe- ripheral vascular resistance, leads to severe retention of NA+ and water. Since tolerance to diazoxide can de-velop rapidly, it is frequently administered in conjunc-tion with a diuretic.

Adverse Effects

Since diazoxide is not often used for long-term treat-ment, toxicities associated with chronic use are rare.The chief concern is the side effects associated with the in-creased workload on the heart, which may precipitate myocardial ischemia and NA+ and water retention. These undesirable effects can be controlled by concur-rent therapy with a β-blocker and a diuretic.

Diazoxide may cause hyperglycemia, especially in diabetics, so if the drug is used for several days, blood glucose levels should be measured.

When used in the treatment of toxemia, diazoxide may stop labor, because it relaxes uterine smooth muscle.

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