Glibenclamide

Glibenclamide (INN), also known as glyburide (USAN), is an antidiabetic drug in a class of medications known as sulfonylureas, closely related to sulfa drugs. It was developed in 1966 in a cooperative study between Boehringer Mannheim (now part of Roche) and Hoechst (now part of Sanofi-Aventis).

It is sold in doses of 1.25 mg, 2.5 mg and 5 mg, under the trade names Diabeta, Glynase and Micronase in the United States and Daonil, Semi-Daonil and Euglucon in the United Kingdom and Delmide in India.

It is also sold in combination with metformin under the trade names Glucovance and Glibomet.

Uses
It is used in the treatment of type II diabetes. , it is one of only two oral antidiabetics in the World Health Organization Model List of Essential Medicines (the other being metformin). As of 2003, in the United States, it was the most popular sulfonylurea.

Additionally, recent research shows that glyburide improves outcome in animal stroke models by preventing brain swelling. A retrospective study showed that in type 2 diabetic patients already taking glyburide, there was improved NIH stroke scale scores on discharge compared to diabetic patients not taking glyburide.

Mechanism of action
The drug works by inhibiting ATP-sensitive potassium channels in pancreatic beta cells. This inhibition causes cell membrane depolarization opening voltage-dependent calcium channel. This results is an increase in intracellular calcium in the beta cell and subsequent stimulation of insulin release.

Side effects and contraindications
This drug is a major cause of drug induced hypoglycemia. Cholestatic jaundice is noted.

Recently published data suggest glibenclamide is associated with significantly higher annual mortality when combined with metformin than other insulin-secreting medications, after correcting for other potentially confounding patient characteristics. The safety of this combination has been questioned. Gilbenclamide causes cholestasis as the major side effect.

Glibenclamide has been demonstrated to block the protection offered by myocardial preconditioning in dogs.

Synthesis
The N-acetyl derivative of β-phenethylamine is reacted with chlorosulfonic acid to form the para sulfonyl chloride derivative. This is then subjected to ammonolysis, followed by base-catalyzed removal of the acetamide. This is then acylated with 2-methoxy-5-chlorobenzoic acid chloride to give the amide intermediate. This is then reacted with cyclohexyl isocyanate to yield the sulfonylurea glibenclamide.