Glibenclamide

Not to be confused with gliclazide or glipizide.

Glibenclamide

File:Glibenclamide.svg
File:Glibenclamide 3D.png
Systematic (IUPAC) name
5-chloro-N-(4-[N-(cyclohexylcarbamoyl)sulfamoyl]phenethyl)-2-methoxybenzamide
Clinical data
[[Regulation of therapeutic goods |Template:Engvar data]]	US FDA: Glyburide
Pregnancy category	AU: C US: B (No risk in non-human studies)
Routes of administration	Oral
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Protein binding	Extensive
Metabolism	Hepatic hydroxylation (CYP2C9-mediated)
Biological half-life	10 hours
Excretion	Renal and biliary
Identifiers
CAS Number	10238-21-8
ATC code	A10BB01 (WHO)
PubChem	CID 3488
IUPHAR/BPS	2414
DrugBank	APRD00233
ChemSpider	3368
Chemical data
Formula	C23H28ClN3O5S
Molar mass	494.004 g/mol[[]]
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Glibenclamide (INN), also known as glyburide (USAN), is an anti-diabetic 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. As of 2007, it is one of only two oral anti-diabetics 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, which causes voltage-dependent calcium channels to open, which causes an increase in intracellular calcium in the beta cell, which stimulates insulin release.

Side effects and contraindications

This drug is a major cause of drug induced hypoglycemia. Cholestatic jaundice is noted.

Recently published data suggests that 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.

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.

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Hsi, R. S. P. (1973). "Synthesis of carbon-14 and tritium labeled glyburide". Journal of Labelled Compounds. 9: 91. doi:10.1002/jlcr.2590090112. 

References

de:Glibenclamid zh:格列苯脲