Gliclazide

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Not to be confused with glipizide or glyburide.
Gliclazide
Gliclazide.svg
Gliclazide ball-and-stick.png
Systematic (IUPAC) name
N-(hexahydrocyclopenta[c]pyrrol-2(1H)-ylcarbamoyl)-4-methylbenzenesulfonamide
Clinical data
AHFS/Drugs.com Micromedex Detailed Consumer Information
Pregnancy
category
  • AU: C
Legal status
  • AU: S4 (Prescription only)
Pharmacokinetic data
Biological half-life 10.4 hours
Identifiers
CAS Number 21187-98-4 YesY
ATC code A10BB09 (WHO)
PubChem CID: 3475
DrugBank DB01120 YesY
ChemSpider 3356 YesY
UNII G4PX8C4HKV YesY
KEGG D01599 YesY
ChEBI CHEBI:31654 YesY
ChEMBL CHEMBL427216 YesY
Chemical data
Formula C15H21N3O3S
Molecular mass 323.412 g/mol
  • O=S(=O)(c1ccc(cc1)C)NC(=O)NN3CC2CCCC2C3
  • InChI=1S/C15H21N3O3S/c1-11-5-7-14(8-6-11)22(20,21)17-15(19)16-18-9-12-3-2-4-13(12)10-18/h5-8,12-13H,2-4,9-10H2,1H3,(H2,16,17,19) YesY
  • Key:BOVGTQGAOIONJV-UHFFFAOYSA-N YesY
  (verify)

Gliclazide is an oral hypoglycemic (anti-diabetic drug) and is classified as a sulfonylurea. Its classification has been ambiguous, as literature uses it as both a first-generation [1] and second-generation[2] sulfonylurea. Gliclazide was shown to protect human pancreatic beta-cells from hyperglycemia-induced apoptosis.[3] It was also shown to have an antiatherogenic effect (preventing accumulation of fat in arteries) in type 2 diabetes.[4]

It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[5]

Medical uses

Gliclazide is used for control of hyperglycemia in gliclazide-responsive diabetes mellitus of stable, mild, non-ketosis prone, type 2 diabetes. It is used when diabetes cannot be controlled by proper dietary management and exercise or when insulin therapy is not appropriate.[citation needed] National Kidney Foundation (2012 Update) claims that Gliclazide does not require dosage uptitration even in end stage kidney disease.

Contraindications

Adverse effects

  • Hypoglycemia - while it was shown to have the same efficacy as glimepiride, one of the newer sulfonylureas, the European GUIDE study has shown that it has approximately 50% less hypoglycaemic confirmed episodes in comparison with glimepiride.[6]
  • Gastrointestinal disturbance (reported)[citation needed]
  • Skin reactions (rare)[citation needed]
  • Hematological disorders (rare)[citation needed]
  • Hepatic enzyme rises (exceptional)[citation needed]

Interactions

Hyperglycemic action may be caused by danazol, chlorpromazine, glucocorticoids, progestogens, or β-2 agonists. Its hypoglycemic action may be potentiated by phenylbutazone, alcohol, fluconazole, β-blockers, and possibly ACE inhibitors. It has been found that rifampin increases gliclazide metabolism in humans in vivo.[7]

Overdosage

Gliclazide overdose may cause severe hypoglycemia, requiring urgent administration of glucose by IV and monitoring.[citation needed]

Mechanism of action

Gliclazide selectively binds to sulfonylurea receptors (SUR-1) on the surface of the pancreatic beta-cells. It was shown to provide cardiovascular protection as it does not bind to sulfonylurea receptors (SUR-2A) in the heart.[8] This binding effectively closes the K+ ion channels. This decreases the efflux of potassium from the cell which leads to the depolarization of the cell. This causes voltage dependent Ca++ ion channels to open increasing the Ca++ influx. The calcium can then bind to and activate calmodulin which in turn leads to exocytosis of insulin vesicles leading to insulin release.[citation needed] The mouse model of MODY diabetes suggested that the reduced gliclazide clearance stands behind their therapeutic success in human MODY patients, but Urbanova et al. found that human MODY patients respond differently and that there was no consistent decrease in gliclazide clearance in randomly selected HNF1A-MODY and HNF4A-MODY patients.[9]

Properties

Water Solubility = 0.027 mg/L[10]

  • Hypoglycemic sulfonylurea, restoring first peak of insulin secretion, increasing insulin sensitivity.[citation needed]
  • Glycemia-independent hemovascular effects, antioxidant effect.[citation needed]
  • No active circulating metabolites.[citation needed]

Metabolism

Gliclazide undergoes extensive metabolism to several inactive metabolites in human beings, mainly methylhydroxygliclazide and carboxygliclazide. CYP2C9 is involved in the formation of hydroxygliclazide in human liver microsomes and in a panel of recombinant human P450s in vitro.[11][12] But the pharmacokinetics of gliclazide MR are affected mainly by CYP2C19 genetic polymorphism instead of CYP2C9 genetic polymorphism.[13][14]

References

  1. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Gopal Venkatesh Shavi et al. Enhanced dissolution and bioavailability of gliclazide using solid dispersion techniques; International Journal of Drug Delivery 2 (2010) 49-57
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.

External links

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