Gliclazide

Products

Gliclazide has been commercially available in sustained-release tablet form and approved in many countries since 1978. The sustained-release dosage forms entered the market in 2001. In addition to the original Diamicron MR, sustained-release generics have been available since 2008. Sales of the non-retarded Diamicron 80 mg were discontinued in 2012.

Structure and properties

Gliclazide (C15H21N3O3S, Mr = 323.4 g/mol) is an active ingredient of the 2nd generation sulfonylurea group. It is a white to almost white powder that is practically insoluble in water. Compared to the structurally similar tolbutamide, it also carries a bicyclic N-heterocycle.

Effects

Gliclazide (ATC A10BB09) has antihyperglycemic and antidiabetic properties. It stimulates insulin secretion by pancreatic beta cells. Endogenous insulin production is a prerequisite for efficacy, so it is not indicated in type 1 diabetes. Gliclazide has pleiotropic and hemovascular effects, is antioxidant, and lowers HbA1c. Insulin secretagogue effects usually diminish with years of treatment.

Mechanism of action

The molecular target of sulfonylureas is ATP-dependent potassium channels (KATP). Gliclazide binds with high affinity and selectivity to the sulfonylurea receptor (SUR), closing potassium channels and inhibiting potassium efflux. This leads to depolarization of the cell membrane, opening of voltage-gated calcium channels, influx of calcium ions, and eventual release of endogenous insulin by exocytosis. Another group of antidiabetic drugs, the glinides, have the same mechanism of action but different binding sites. Because potassium channels also occur in the heart and blood vessels, there is a theoretical risk of cardiac ischemic or proarrhythmic adverse effects with all sulfonylureas. Gliclazide is reported to be specific and not to bind to cardiac potassium channels. This is in contrast to glibenclamide, which is therefore used more cautiously today. Sulfonylureas with a long half-life such as glibenclamide are also more likely to induce hypoglycemia. Gliclazide has a mean half-life of approximately 11 hours.

Indications

Gliclazide is used to treat type 2 diabetes mellitus.

Dosage

According to the drug label. The sustained-release medication is taken once daily together, unchewed, with water at breakfast. The maximum daily dose is 120 mg (2 tablets of 60 mg or 4 tablets of 30 mg). To prevent the development of hypoglycemia, it is important not to skip meals.

Contraindications

  • Hypersensitivity to gliclazide, other sulfonylureas, sulfonamides, or excipients.
  • Diabetes mellitus type 1
  • Ketoacidosis, diabetic precoma
  • Severe hepatic or renal insufficiency.
  • Severe dysfunction of the adrenal glands or thyroid gland.
  • Treatment with miconazole
  • Pregnancy and lactation
  • Children and adolescents (no data)

Full precautions can be found in the SmPC.

Interactions

Numerous drugs and substances can affect blood glucose and enhance or attenuate the blood glucose-lowering effect of gliclazide. Agents that may potentiate the effect and increase the risk of hypoglycemia include: ACE inhibitors, alcohol, anabolic steroids and androgens, antifungal agents, e.g., miconazole (also as oral gel), fluconazole, beta blockers, fluoxetine, H2 antihistamines, MAO inhibitors, NSAIDs, e.g., phenylbutazone, pentoxifylline, probenecid, sulfonamides, tetracyclines, quinolones, vitamin K antagonists, and cytostatic agents. Both pharmacokinetic and pharmacodynamic interactions are possible. Gliclazide is biotransformed in the liver by CYP2C9 and CYP2C19, among others, to inactive metabolites and excreted via the kidney. For example, azole antifungals such as fluconazole inhibit CYP2C9 and the degradation of gliclazide and promote its effects. Phenylbutazone displaces gliclazide from protein binding. In addition, numerous agents may also lead to attenuation of the antidiabetic effect.

Adverse effects

The most common and important adverse effect is hypoglycemia. Risk factors for the development of hypoglycemia include:

  • High dose
  • Lack of information to patients
  • No regular blood glucose control
  • Drug interactions
  • Irregular intake of the drug or meals.
  • Heavy physical exertion
  • Poor general condition, diseases, liver and kidney insufficiency.

Occasionally, nausea, vomiting, dyspepsia, diarrhea and constipation may occur. Taking with food may reduce these adverse effects. Skin rash, itching, and hives also occur occasionally. Elevation of liver enzymes, hepatitis, cholestatic hepatitis, blood count abnormalities, and anemia are rare. Sulfonylureas may cause weight gain, but this has not been documented for gliclazide.