Diazoxide

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals

1.3

1.08

Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Vasodilator Agents; Blood Glucose; Glycemic Control

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

Medicines for hypoglycaemia

330ºC

330.5 °C

142.65 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

143.7 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Danger

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P260, P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P318, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 89 reports by companies from 9 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Diazoxide

Ambiguous-DILI-concern

3

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

V - Various

C - Cardiovascular system

QV - Various

QC - Cardiovascular system

V03AH01

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.

Diazoxide is a nondiuretic benzothiadiazine derivative used for the management of symptomatic hypoglycemia. By binding to the sulfonylurea receptor (SUR) subunit of the ATP-sensitive potassium channel (K_ATP) on the membrane of pancreatic beta‐cells, diazoxide promotes a potassium efflux from beta-cells. This hyperpolarizes the cell membrane and prevents the influx of calcium to the pancreatic beta‐cells. Without a sufficient amount of calcium in the cell, insulin release is inhibited. Therefore, the use of diazoxide produces an increase in glucose levels. Diazoxide is chemically related to thiazide diuretics but does not inhibit carbonic anhydrase and does not have chloriuretic or natriuretic activity. It also exhibits hypotensive activity by reducing arteriolar smooth muscle and vascular resistance. The mechanism of action of its hypotensive effect has not been fully elucidated; however, it is possible that it involves the antagonism of calcium.

Diazoxide is mainly metabolized by CYP1A2 and to a minor extent by CYP3A4, 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. In patients with Prader-Willi syndrome, only metabolite M1 (3-hydroxymethyl-7-chloro-1,2,4- benzothiadiazine-1,1-dioxide) is detectable in circulation.

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS.

Drugs used to cause dilation of the blood vessels.

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%.

Diazoxide and its metabolites are mainly eliminated through urine. Since diazoxide is extensively protein-bond, it has a slow excretion and a prolonged half-life. In subjects with normal renal function, the urinary excretion rates of diazoxide peak on the first day after oral administration.

The apparent volume of distribution of diazoxide in adults with normal renal function is 13 L (21% of body weight), while in children with normal renal function, it is 2 L (33% of body weight). Other sources show that the volume of distribution of diazoxide is 0.21 L/kg.

In subjects with normal renal function given 300 mg of diazoxide intravenously, renal clearance was 4 ml/min. Other sources show that the clearance of diazoxide is 0.06 ml/min/kg.