Glibenclamide

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Glibenclamide
Glibenclamide structural formula V.1.svg
Glibenclamide 3D.png
Systematic (IUPAC) name
5-chloro-N-(4-[N-(cyclohexylcarbamoyl)sulfamoyl]phenethyl)-2-methoxybenzamide
Clinical data
Trade names Diabeta, Glynase, Micronase Daonil, Semi-Daonil, Euglucon, Delmide
AHFS/Drugs.com International Drug Names
MedlinePlus a684058
Licence data US FDA:link
Pregnancy cat. C (AU) B (US)
Legal status POM (UK) -only (US)
Routes Oral
Pharmacokinetic data
Protein binding Extensive
Metabolism Hepatic hydroxylation (CYP2C9-mediated)
Half-life 10 hours
Excretion Renal and biliary
Identifiers
CAS number 10238-21-8 YesY
ATC code A10BB01
PubChem CID 3488
IUPHAR ligand 2414
DrugBank DB01016
ChemSpider 3368 YesY
UNII SX6K58TVWC YesY
KEGG D00336 YesY
ChEBI CHEBI:5441 YesY
ChEMBL CHEMBL472 YesY
Chemical data
Formula C23H28ClN3O5S 
Mol. mass 494.004 g/mol
 YesY (what is this?)  (verify)

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).[1]

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, Benimet and Glibomet.

Mechanism of action[edit]

The drug works by binding to and activating the sulfonylurea receptor 1 (SUR1), the regulatory subunit of the ATP-sensitive potassium channels (KATP)[2] in pancreatic beta cells. This inhibition causes cell membrane depolarization opening voltage-dependent calcium channel. This results in an increase in intracellular calcium in the beta cell and subsequent stimulation of insulin release.

After a cerebral ischemic insult the blood brain barrier is broken and glibenclamide can reach the central nervous system. Glibenclamide has been shown to bind more efficiently to the ischemic hemisphere.[3] Moreover, under ischemic conditions SUR1, the regulatory subunit of the KATP- and the NCCa-ATP-channels, is expressed in neurons, astrocytes, oligodendrocytes, endothelial cells[4] and by reactive microglia.[3]

Medical uses[edit]

It is used in the treatment of type 2 diabetes. As of 2011, it is one of only two oral antidiabetics in the World Health Organization Model List of Essential Medicines (the other being metformin).[5] As of 2003, in the United States, it was the most popular sulfonylurea.[6]

Side effects and contraindications[edit]

This drug is a major cause of drug induced hypoglycemia. The risk is increased against other sulfonylurea [7] Cholestatic jaundice is noted.

Glibenclamide may be contraindicated in for those with G6PD deficiency, as it may cause acute haemolysis.[8]

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.[9] Glibenclamide causes cholestasis as the major side effect.

Synthesis[edit]

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.[10]

Glibenclamide synth.png

Research[edit]

Recent research shows that glibenclamide improves outcome in animal stroke models by preventing brain swelling[11] and enhancing neuroprotection.[2] A retrospective study showed that in type 2 diabetic patients already taking glyburide, NIH stroke scale scores on were improved on discharge compared to diabetic patients not taking glyburide.[12]


References[edit]

  1. ^ Marble A (1971). "Glibenclamide, a new sulphonylurea: whither oral hypoglycaemic agents?". Drugs 1 (2): 109–15. doi:10.2165/00003495-197101020-00001. PMID 4999930. 
  2. ^ a b Serrano-Martín X, Payares G, Mendoza-León A (December 2006). "Glibenclamide, a blocker of K+(ATP) channels, shows antileishmanial activity in experimental murine cutaneous leishmaniasis". Antimicrob. Agents Chemother. 50 (12): 4214–6. doi:10.1128/AAC.00617-06. PMC 1693980. PMID 17015627. 
  3. ^ a b Ortega FJ, Gimeno-Bayon J, Espinosa-Parrilla JF, Carrasco JL, Batlle M, Pugliese M, Mahy N, Rodríguez MJ (May 2012). "ATP-dependent potassium channel blockade strengthens microglial neuroprotection after hypoxia-ischemia in rats". Exp. Neurol. 235 (1): 282–96. doi:10.1016/j.expneurol.2012.02.010. PMID 22387180. 
  4. ^ Simard JM, Woo SK, Schwartzbauer GT, Gerzanich V (September 2012). "Sulfonylurea receptor 1 in central nervous system injury: a focused review". J. Cereb. Blood Flow Metab. 32 (9): 1699–717. doi:10.1038/jcbfm.2012.91. PMC 3434627. PMID 22714048. 
  5. ^ WHO Expert Committee (March 2011). "The selection and use of essential medicines". World Health Organ Tech Rep Ser (965): i–xiv, 1–249. PMID 22891532. 
  6. ^ Riddle MC (February 2003). "Editorial: sulfonylureas differ in effects on ischemic preconditioning--is it time to retire glyburide?". J. Clin. Endocrinol. Metab. 88 (2): 528–30. doi:10.1210/jc.2002-021971. PMID 12574174. 
  7. ^ Gangji, A. S.; Cukierman, T.; Gerstein, H. C.; Goldsmith, C. H.; Clase, C. M. (1 February 2007). "A Systematic Review and Meta-Analysis of Hypoglycemia and Cardiovascular Events: A comparison of glyburide with other secretagogues and with insulin". Diabetes Care 30 (2): 389–394. doi:10.2337/dc06-1789. 
  8. ^ Meloni G, Meloni T (January 1996). "Glyburide-induced acute haemolysis in a G6PD-deficient patient with NIDDM". Br. J. Haematol. 92 (1): 159–60. doi:10.1046/j.1365-2141.1996.275810.x. PMID 8562390. 
  9. ^ Monami M, Luzzi C, Lamanna C, Chiasserini V, Addante F, Desideri CM, Masotti G, Marchionni N, Mannucci E (2006). "Three-year mortality in diabetic patients treated with different combinations of insulin secretagogues and metformin". Diabetes Metab Res Rev 22 (6): 477–82. doi:10.1002/dmrr.642. PMID 16634115. 
  10. ^ Hsi RSP (January 1973). "Synthesis of carbon-14 and tritium labeled glyburide". Journal of Labelled Compounds and Radiopharmaceuticals 9 (1): 91–105. doi:10.1002/jlcr.2590090112. 
  11. ^ Simard JM, Chen M, Tarasov KV, Bhatta S, Ivanova S, Melnitchenko L, Tsymbalyuk N, West GA, Gerzanich V (April 2006). "Newly expressed SUR1-regulated NC(Ca-ATP) channel mediates cerebral edema after ischemic stroke". Nat. Med. 12 (4): 433–40. doi:10.1038/nm1390. PMC 2740734. PMID 16550187. 
  12. ^ Kunte H, Schmidt S, Eliasziw M, del Zoppo GJ, Simard JM, Masuhr F, Weih M, Dirnagl U (September 2007). "Sulfonylureas improve outcome in patients with type 2 diabetes and acute ischemic stroke". Stroke 38 (9): 2526–30. doi:10.1161/STROKEAHA.107.482216. PMC 2742413. PMID 17673715.