DIAZOXIDE

Absorption

Diazoxide is readily absorbed following oral administration; however, its absorption depends on the dissolution rate of the dosage form. Diazoxide has a bioavailability of 91%.

Toxicity

The oral LD50 of diazoxide in rats and mice are 980 mg/kg and 444 mg/kg, respectively. In the mouse, rat, rabbit, dog, pig, and monkey, the oral administration of diazoxide leads to a rapid and transient rise in blood glucose levels. In rats given 400 mg/kg of diazoxide orally during subacute toxicity studies, growth retardation, edema, increases in liver and kidney weights, and adrenal hypertrophy were observed. Rats given doses up to 1080 mg/kg for three months developed hyperglycemia, an increase in liver weight and an increase in mortality. Toxicity is increased when diazoxide was administered at high dosages concomitantly with either chlorothiazide to rats or trichlormethiazide to dogs. Reproduction and teratology studies in different animal species suggest that diazoxide may interfere with normal fetal development, possibly due to the alteration of glucose metabolism.

Description

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.

Chemical properties

White Solid

Originator

Eudemine,Allen and Hanburys,UK,1970

The Uses of DIAZOXIDE

Diazoxide has traditionally been used therapeutically for its antihypertensive and hyperglycemic properties. It acts as a potent arteriolar vasodilator in the short-term treatment of acute hypertension, malignant hypertension, and occasionally, in cases of pregnancy-induced hypertension. By relaxing peripheral arterioles of smooth muscle cells, peripheral vascular resistance is reduced. In rare cases, cardiac and pulmonary effects have occurred in neonates and in infants. In the treatment of hypertensive crisis with 300 mg of IV diazoxide, angina, myocardial and cerebral infarction, ischemia, and optic nerve damage could ensue. Diazoxide is used also in the management of hypoglycemia secondary to hyperinsulinism in adults with inoperable islet cell adenoma or carcinoma, or extrapancreatic malignancy; and in infants and children with leucine sensitivity, islet cell hyperplasia, nesidioblastosis, extrapancreatic malignancy, islet cell adenoma, or adenomatosis. In the treatment of hypoglycemia due to hyperinsulinism, diazoxide is an oral agent that decreases insulin release from the pancreas, enhancing glycogenolysis and inhibiting the uptake of glucose.

The Uses of DIAZOXIDE

Diazoxide reduces status epilepticus neuron damage in diabetes.

The Uses of DIAZOXIDE

wound healing agent

Background

Diazoxide is a non-diuretic benzothiadiazine derivative that activates ATP-sensitive potassium channels. It is chemically related to thiazide diuretics but does not inhibit carbonic anhydrase and does not have chloriuretic or natriuretic activity. Diazoxide is commonly used in the treatment of hyperinsulinaemic hypoglycemia due to its ability to inhibit insulin release. Diazoxide also exhibits hypotensive activity and reduces arteriolar smooth muscle and vascular resistance. When administered intravenously, diazoxide can be used to treat hypertensive emergencies; however, this specific form of diazoxide is no longer available in the US. Diazoxide is usually well tolerated, and some of its more common side effects include fluid retention and electrolyte disturbances. In September 2015, the FDA issued a safety alert regarding post-marketing reports of pulmonary hypertension occurring in infants and neonates.

Indications

Oral diazoxide is indicated to manage hypoglycemia due to hyperinsulinism associated with conditions such as inoperable islet cell adenoma or carcinoma, and extrapancreatic malignancy in adults, or leucine sensitivity, islet cell hyperplasia, nesidioblastosis, extrapancreatic malignancy, islet cell adenoma, and adenomatosis in infants and children. In infants and children oral diazoxide may be used preoperatively as a temporary measure, and postoperatively, if hypoglycemia persists. Diazoxide may also be used parentally or intravenously to treat hypertensive emergencies.

What are the applications of Application

Diazoxide is a selective ATP-dependent K+ (Kir6) channel activator

Definition

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.

brand name

Hyperstat (Schering); Proglycem (Baker Norton).

Therapeutic Function

Antihypertensive

Biological Functions

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.

General Description

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).

General Description

Diazoxide is used as the sodium salt of7-chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide(Hyperstat IV). Diazoxide lowers peripheral vascular resistance,increases cardiac output, and does not compromiserenal blood flow.
This is a des-sulfamoyl analog of the benzothiazine diureticsand has a close structural similarity to chlorothiazide. Itwas developed intentionally to increase the antihypertensiveaction of the thiazides and to minimize the diuretic effect.

Biological Activity

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.

Biochem/physiol Actions

Selective ATP-sensitive K+ channel activator in both vascular smooth muscle and pancreatic β-cells; antihypertensive.

Mechanism of action

Diazoxide reduces peripheral vascular resistance and blood pressure by a direct vasodilating effect on the VSM with a mechanism similar to that described for minoxidil by activating (opening) the ATP-modulated potassium channel. Thus, diazoxide prolongs the opening of the potassium channel, sustaining greater vasodilation on arterioles than on veins. The greatest hypotensive effect is observed in patients with malignant hypertension. Although oral or slow IV administration of diazoxide can produce a sustained fall in blood pressure, rapid IV administration is required for maximum hypotensive effects, especially in patients with malignant hypertension. Diazoxide-induced decreases in blood pressure and peripheral vascular resistance are accompanied by a reflex response, resulting in an increased heart rate, cardiac output, and left ventricular ejection rate. In contrast to the thiazide diuretics, diazoxide causes sodium and water retention and decreased urinary output, which can result in expansion of plasma and extracellular fluid volume, edema, and congestive heart failure, especially during prolonged administration.
Diazoxide increases blood glucose concentration (diazoxide-induced hyperglycemia) by several different mechanisms: by inhibiting pancreatic insulin secretion, by stimulating release of catecholamines, or by increasing hepatic release of glucose. The precise mechanism of inhibition of insulin release has not been elucidated but, possibly, may result from an effect of diazoxide on cell-membrane potassium channels and calcium flux.

Pharmacokinetics

Diazoxide is a potassium channel activator that enhances cell membrane permeability to potassium ions. By promoting a vasodilatory effect on the smooth muscle in peripheral arterioles, diazoxide lowers blood pressure and peripheral vascular resistance. Diazoxide-induced decreases in blood pressure lead to reflex increases in heart rate and cardiac output. The oral administration of diazoxide increases blood glucose in a dose-dependent manner. In patients with normal renal function, this effect is observed within an hour and lasts no more than eight hours. The hypotensive effects of diazoxide are usually not detected when administered orally.
Diazoxide administered intravenously may lead to sodium and water retention, severe hypotension, transient myocardial or cerebral ischaemia and gastrointestinal upsets such as nausea, vomiting and abdominal discomfort. Diazoxide administered orally may cause ketoacidosis and nonketotic hyperosmolar coma, especially in patients with other concurrent conditions. The use of intravenous or oral diazoxide may lead to the development of pulmonary hypertension in infants and neonates.

Pharmacology

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.

Pharmacokinetics

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.

Clinical Use

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.

Clinical Use

In contrast to the acute clinical uses of glucagon, diazoxidefinds use in chronic hypoglycemic conditions: inoperableislet cell adenoma or carcinomas, extrapancreatic malignanciesof insulin-secreting cells, or islet cell hyperplasias. Inchildren, additional indications include congenital hyperinsulinemia124and leucine sensitivity. Experimentally, diazoxideis among an array of ATP-sensitive potassium channel openersbeing studied for intermittently bringing aboutβ-cell rest.

Side Effects

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.

Synthesis

7-chloro-3-methyl-2-H-1,2,4-benzothiadiazin-1,1-dioxide (21.3.14), is synthesized by condensating 2-aminosulfonyl-4-chloroaniline with triethyl orthoacetate.

Veterinary Drugs and Treatments

Oral diazoxide is used in canine and ferret medicine for the treatment of hypoglycemia secondary to hyperinsulin secretion (e.g., insulinoma). Insulinomas are apparently very rare in the cat; there is little experience with this drug in that species.
In human medicine, intravenous diazoxide is sometimes used for treating severe hypertension.

Drug interactions

Potentially hazardous interactions with other drugs
Antihypertensives and vasodilators: enhanced hypotensive effect.
MAOIs: withdraw at least 14 days before starting diazoxide
Phenytoin: may reduce phenytoin levels.

Environmental Fate

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.

Metabolism

Diazoxide is metabolized in the liver through oxidation of the 3-methyl group, producing hydroxymethyl (MI) and carboxy (M2) derivatives. The MI derivatives undergo subsequent sulphate conjugation. It is estimated that, in subjects with normal renal function, 54-60% of diazoxide is metabolized. Diazoxide metabolites are inactive and do not contribute to its cardiovascular activity. Additionally, diazoxide metabolites do not displace diazoxide from protein binding sites.

Metabolism

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.

storage

Room temperature

References

1) Trube et al. (1986), Opposite effects of tolbutamide and diazoxide on the ATP-dependent K+ channel in mouse pancreatic beta-cells.l; Pflugers Arch., 407 493 2) Kim et al. (2006), Diazoxide acts more as a PKC-epsilon activator, and indirectly activates the mitochondrial K(ATP) channel conferring cardioprotection against hypoxic injury; Br. J. Pharmacol, 149 1059 3) Coetzee (2013), Multiplicity of effectors of the cardioprotective agent, diazoxide; Pharmacol. Ther., 140 167 4) Jasova et al. (2016), Stimulation of mitochondrial ATP synthase activity – a new diazoxide-mediated mechanism of cardioprotection; Physiol. Res., 65 Suppl 1 S119 5) Salgado-Puga et al. (2017), Subclinical Doses of ATP-sensitive Potassium channel Modulators Prevent Alterations in Memory and Synaptic Plasticity Induced by Amyloid-β; J. Alzheimers Dis., 57 205