Gliclazide Explained

Gliclazide, sold under the brand name Diamicron among others, is a sulfonylurea type of anti-diabetic medication, used to treat type 2 diabetes. It is used when dietary changes, exercise, and weight loss are not enough.[1] It is taken by mouth.[2]

Side effect may include low blood sugar, vomiting, abdominal pain, rash, and liver problems.[1] [2] Use by those with significant kidney problems or liver problems or who are pregnant is not recommended.[2] [1] Gliclazide is in the sulfonylurea family of medications.[2] It works mostly by increasing the release of insulin.[2]

Gliclazide was patented in 1966 and approved for medical use in 1972.[3] It is on the World Health Organization's List of Essential Medicines.[4] It is not available for sale in the United States.[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 and when metformin has already been tried.[6]

National Kidney Foundation (2012 Update) claims that Gliclazide does not require dosage up titration even in end stage kidney disease.

Contraindications

Adverse effects

Common adverse effects over 10%:[8]

Uncommon adverse effect between 1 - 10%:

Rare adverse effects (under 1%):

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.[10]

Overdose

Gliclazide overdose may cause severe hypoglycemia, requiring urgent administration of glucose by IV and Monitoring.[11]

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.[12] This binding effectively closes these K+ ion channels. This decreases the efflux of potassium from the cell which leads to the depolarization of the cell. This causes voltage dependent Ca2+ ion channels to open increasing the Ca2+ influx. The calcium can then bind to and activate calmodulin which in turn leads to exocytosis of insulin vesicles leading to insulin release.[13]

The mouse model of Maturity-onset diabetes of the young (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.[14]

Its classification has been ambiguous, as literature uses it as both a first-generation[15] and second-generation[16] sulfonylurea.

Properties

According to the Biopharmaceutical Classification System (BCS), gliclazide falls under the BCS Class II drug, which is poorly soluble and highly permeable.

Water solubility = 0.027mg/L

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.[18] [19] But the pharmacokinetics of gliclazide MR are affected mainly by CYP2C19 genetic polymorphism instead of CYP2C9 genetic polymorphism.[20] [21]

Notes and References

  1. Web site: Gliclazide Accord-UK 30mg Prolonged-release Tablets - Summary of Product Characteristics (SmPC) . (emc) . 12 February 2021 . 30 December 2021 . 22 September 2022 . https://web.archive.org/web/20220922022052/https://www.medicines.org.uk/emc/medicine/31089 . dead .
  2. Book: British National Formulary : BNF 69. 2015. British Medical Association. 9780857111562. 474. 69.
  3. Book: Fischer J, Ganellin CR . Analogue-based Drug Discovery. 2006. John Wiley & Sons. 9783527607495. 449. en. live. https://web.archive.org/web/20161227201818/https://books.google.ca/books?id=FjKfqkaKkAAC&pg=PA449. 27 December 2016.
  4. Book: ((World Health Organization)) . World Health Organization model list of essential medicines: 21st list 2019 . 2019 . 10665/325771 . World Health Organization . World Health Organization . Geneva . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO . free .
  5. Web site: Gliclazide Advanced Patient Information - Drugs.com. www.drugs.com. 27 December 2016. live. https://web.archive.org/web/20161227202213/https://www.drugs.com/cons/gliclazide.html. 27 December 2016.
  6. Web site: My Site - Special Article: Remission of Type 2 Diabetes . 2023-06-01 . guidelines.diabetes.ca . 2 June 2023 . https://web.archive.org/web/20230602185226/https://guidelines.diabetes.ca/cpg/special-article-remission-of-type-2-diabetes . live .
  7. Web site: GLICLAZIDE 60 MG MR TABLETS DRUG LEAFLET . Drugs.com . 23 March 2020 . en . 21 April 2019 . https://web.archive.org/web/20190421171118/https://www.drugs.com/uk/gliclazide-60-mg-mr-tablets-leaflet.html . live .
  8. Web site: Wolters Kluwer N.V. . Gliclazide . Lexicomp . 1 June 2023 . 2 June 2023 . https://web.archive.org/web/20230602191128/https://www.wolterskluwer.com/en/solutions/lexicomp . live .
  9. Schernthaner G, Grimaldi A, Di Mario U, Drzewoski J, Kempler P, Kvapil M, Novials A, Rottiers R, Rutten GE, Shaw KM . 6 . GUIDE study: double-blind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients . European Journal of Clinical Investigation . 34 . 8 . 535–542 . August 2004 . 15305887 . 10.1111/j.1365-2362.2004.01381.x . free . 13636359 . 1874/10657 .
  10. Park JY, Kim KA, Park PW, Park CW, Shin JG . Effect of rifampin on the pharmacokinetics and pharmacodynamics of gliclazide . Clinical Pharmacology and Therapeutics . 74 . 4 . 334–340 . October 2003 . 14534520 . 10.1016/S0009-9236(03)00221-2 . 21519151 . free .
  11. Mégarbane B, Chevillard L, Khoudour N, Declèves X . Gliclazide disposition in overdose - a case report with pharmacokinetic modeling . Clinical Toxicology . 60 . 4 . 541–542 . April 2022 . 34698608 . 10.1080/15563650.2021.1993245 . 239887850 .
  12. Lawrence CL, Proks P, Rodrigo GC, Jones P, Hayabuchi Y, Standen NB, Ashcroft FM . Gliclazide produces high-affinity block of KATP channels in mouse isolated pancreatic beta cells but not rat heart or arterial smooth muscle cells . Diabetologia . 44 . 8 . 1019–1025 . August 2001 . 11484080 . 10.1007/s001250100595 . free .
  13. Mégarbane B, Chevillard L, Khoudour N, Declèves X . Gliclazide disposition in overdose - a case report with pharmacokinetic modeling . Clinical Toxicology . 60 . 4 . 541–542 . April 2022 . 34698608 . 10.1080/15563650.2021.1993245 . 239887850 .
  14. Urbanova J, Andel M, Potockova J, Klima J, Macek J, Ptacek P, Mat'oska V, Kumstyrova T, Heneberg P . 6 . Half-Life of Sulfonylureas in HNF1A and HNF4A Human MODY Patients is not Prolonged as Suggested by the Mouse Hnf1a(-/-) Model . Current Pharmaceutical Design . 21 . 39 . 5736–5748 . 2015 . 26446475 . 10.2174/1381612821666151008124036 .
  15. Ballagi-Pordány G, Köszeghy A, Koltai MZ, Aranyi Z, Pogátsa G . Divergent cardiac effects of the first and second generation hypoglycemic sulfonylurea compounds . Diabetes Research and Clinical Practice . 8 . 2 . 109–114 . January 1990 . 2106423 . 10.1016/0168-8227(90)90020-T .
  16. Shimoyama T, Yamaguchi S, Takahashi K, Katsuta H, Ito E, Seki H, Ushikawa K, Katahira H, Yoshimoto K, Ohno H, Nagamatsu S, Ishida H . 6 . Gliclazide protects 3T3L1 adipocytes against insulin resistance induced by hydrogen peroxide with restoration of GLUT4 translocation . Metabolism . 55 . 6 . 722–730 . June 2006 . 16713429 . 10.1016/j.metabol.2006.01.019 .
  17. Mégarbane B, Chevillard L, Khoudour N, Declèves X . Gliclazide disposition in overdose - a case report with pharmacokinetic modeling . Clinical Toxicology . 60 . 4 . 541–542 . April 2022 . 34698608 . 10.1080/15563650.2021.1993245 . 239887850 .
  18. Rieutord A, Stupans I, Shenfield GM, Gross AS . Gliclazide hydroxylation by rat liver microsomes . Xenobiotica; the Fate of Foreign Compounds in Biological Systems . 25 . 12 . 1345–1354 . December 1995 . 8719909 . 10.3109/00498259509061922 .
  19. Elliot DJ, Lewis BC, Gillam EM, Birkett DJ, Gross AS, Miners JO . Identification of the human cytochromes P450 catalysing the rate-limiting pathways of gliclazide elimination . British Journal of Clinical Pharmacology . 64 . 4 . 450–457 . October 2007 . 17517049 . 2048545 . 10.1111/j.1365-2125.2007.02943.x .
  20. Zhang Y, Si D, Chen X, Lin N, Guo Y, Zhou H, Zhong D . Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics of gliclazide MR in Chinese subjects . British Journal of Clinical Pharmacology . 64 . 1 . 67–74 . July 2007 . 17298483 . 2000619 . 10.1111/j.1365-2125.2007.02846.x .
  21. Xu H, Williams KM, Liauw WS, Murray M, Day RO, McLachlan AJ . Effects of St John's wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide . British Journal of Pharmacology . 153 . 7 . 1579–1586 . April 2008 . 18204476 . 2437900 . 10.1038/sj.bjp.0707685 .

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