Diazoxide

Abstract

Diazoxide was initially developed as a non-diuretic hypotensive agent, an action for which it is still used clinically, before it was also noted to have a significant hypoglycaemic effect. Diazoxide is primarily indicated for the treatment of severe hypertension (particularly when associated with renal disease) and chronic intractable hypoglycaemia occurring, for instance, in the context of an insulinoma. Research in the last few years has suggested other potential uses for diazoxide including hypo-glycaemia unawareness in type 1 diabetes (T1DM), hyperlipidaemia and obesity and, perhaps more surprisingly, type 2 diabetes (T2DM). See Figure 1. Diazoxide is a benzo-thiadiazine derivative (7-chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1 dioxide), that is extensively protein bound (>90%) and is excreted by the kidneys. The plasma half-life following IV administration is 28±8.3 hours. The primary mode of action of diazoxide is through ATP-sensitive potassium (KATP) channels, which are a type of potassium channel gated by ATP and hence play a critical role as sensors of the metabolic status. KATP channels are composed of Kir6.x-type subunits and sulphonylurea receptor (SUR) subunits, along with some additional components. The Kir6.x- (either Kir6.1 or Kir6.2) subunits form the inward-rectifier potassium channel, while the SUR subunits (SUR1, SUR2A or SUR2B) are transmembrane proteins that allow nucleotide modulation of the potassium channel. The mechanism of action of diazoxide Dia…