Диазоксид

Описание

Diazoxide is a nondiuretic derivative of thiazides that dramatically reduces blood pressure by direct relaxation of smooth muscles of the arterioles, possibly as a result of calcium channel activation of smooth musculature in arterioles. It has a weak effect on the venous system and on the heart. In addition to hypotensive action, diazoxide causes a sharp increase in the level of glucose in the blood as a result of the inhibition of insulin release from adrenal glands. Some of the undesirable effects are water and sodium ion retention in the body and increased concentrations of uric acid in the blood. It is used in urgent situations where blood pressure needs to be reduced in severe hypertension. Diazoxide is not used for essential hypertension. A synonym of this drug is hyperstat.

Химические свойства

White Solid

Использование

Diazoxide reduces status epilepticus neuron damage in diabetes.

Определение

ChEBI: A benzothiadiazine that is the S,S-dioxide of 2H-1,2,4-benzothiadiazine which is substituted at position 3 by a methyl group and at position 7 by chlorine. A peripheral vasodilator, it increases the oncentration of glucose in the plasma and inhibits the secretion of insulin by the beta- cells of the pancreas. It is used orally in the management of intractable hypoglycaemia and intravenously in the management of hypertensive emergencies.

Биологические функции

Diazoxide (Hyperstat) is chemically similar to the thiazide diuretics. It is devoid of diuretic activity and causes Na⁺ and water retention. Diazoxide is a very potent 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.

Общее описание

Diazoxide is 7-chloro-3-methyl-4H-benzo[e][1,2,4]thiadiazine-1,1-dioxide , and is currentlyavailable in the United States only as a 50-mg/mLoral suspension (Proglycem); discontinued formulations includedcapsules for oral administration, and injectable formsthat typically found use for indications other than hypoglycemicconditions. Diazoxide is a cyclic benzenesulfonamide,although the free acid in solution can exist in threetautomeric forms, and the 4H tautomer most likely predominatesto a very high proportion. Partly because of theadditional nitrogen in the quinazoline ring structure, themolecule is somewhat more acidic (pKa～8.4, 8.6)than benzenesulfonamide (pKa～10).

Биологическая активность

Antihypertensive, activates ATP-dependent K + channels. Induces activation of PKC ε , an intermediate in the opening of mitoK ATP channels, results in cardioprotection against hypoxia-induced death. Blocks desensitization of AMPA receptors.

Фармакокине?тика

Following rapid IV administration, diazoxide produces a prompt reduction in blood pressure, with maximum hypotensive effects occurring within 5 minutes. The duration of its hypotensive effect varies from 3 to 12 hours, but ranges from 30 minutes to 72 hours have been observed. The elimination half-life of diazoxide following a single oral or IV dose has been reported to range from 21 to 45 hours in adults with normal renal function. In patients with renal impairment, the half-life is prolonged. Approximately 90% of the diazoxide in the blood is bound to plasma proteins. Approximately 20 to 50% of diazoxide is eliminated unchanged in the urine, along with its major metabolites, resulting from the oxidation of the 3-methyl group to its 3-hydroxymethyl- and 3-carboxyl-metabolites.

Фармаколо?гия

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 cardiovascular reflexes, orthostasis is not a problem. Its administration is, however, associated with a reflex increase in cardiac output that partially counters its antihypertensive effects. Propranolol and other -blockers potentiate 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.

Клиническое использование

Diazoxide is used by intravenous injection as a rapidly acting antihypertensiveagent for emergency reduction of blood pressurein hospitalized patients with accelerated or malignanthypertension. More than 90% is bound to serum protein, andcaution is needed when it is used in conjunction with otherprotein-bound drugs that may be displaced by diazoxide.The injection is given rapidly by the intravenous route toensure maximal effect. The initial dose is usually 1 mg/kg ofbody weight, with a second dose given if the first injectiondoes not lower blood pressure satisfactorily within 30 minutes.Further doses may be given at 4- to 24-hour intervalsif needed. Oral antihypertensive therapy is begun as soon aspossible.

Побочные эффекты

Since diazoxide is not often used for long-term treatment, toxicities associated with chronic use are rare.The chief concern is the side effects associated with the increased workload on the heart, which may precipitate myocardial ischemia and Na⁺ and water retention. These undesirable effects can be controlled by concurrent 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.

Экологическая судьба

Diazoxide is a potassium channel activator, which causes local relaxation in smooth muscles by increasing membrane permeability to potassium ions. Consequently, voltage-gated calcium ion channels are ineffective, inhibiting the generation of an action potential. The primary mechanism by which diazoxide lowers blood pressure is by direct relaxation of medium sized blood vessels. The cardiac output and renin secretion increases, resulting in elevated angiotensin II levels and retention of salt and water. When used to treat low blood sugar, diazoxide decreases insulin release from the pancreas.

Метаболизм

Diazoxide lowers blood pressure within 3 to 5 minutes after rapid intravenous injection, and its duration of action 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.