Диазоксид химические свойства, назначение, производство
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.
Диазоксид препаратная продукция и сырье
сырьё
препарат