Gliclada

Gliclada Mechanism of Action

gliclazide

Manufacturer:

KRKA

Distributor:

Uni Drug
Full Prescribing Info
Action
Pharmacotherapeutic Group: Sulfonamides, urea derivatives. ATC Code: A10BB09.
Pharmacology: Pharmacodynamics: Gliclazide is a hypoglycaemic sulphonylurea oral antidiabetic differing from other related compounds by an N-containing heterocyclic ring with an endocyclic bond.
Gliclazide reduces blood glucose levels by stimulating insulin secretion from the β-cells of the islets of Langerhans. Gliclazide shows high affinity, strong selectivity and reversible binding to the β-cell KATP channels with a low affinity for cardiac and vascular KATP channels. Increase in postprandial insulin and C-peptide secretion persists after two years of treatment.
In addition to these metabolic properties, gliclazide has extra-pancreatic effects and haemovascular properties.
Effects on insulin release: In type 2 diabetics, gliclazide restores the first peak of insulin secretion in response to glucose and increases the second phase of insulin secretion. A significant increase in insulin response is seen in response to stimulation induced by a meal or glucose.
Extra-pancreatic effects: Gliclazide has been shown to increase peripheral insulin sensitivity: In muscle, euglycaemic hyperinsulinaemic clamp studies with gliclazide have demonstrated significantly increased (35%) insulin mediated glucose uptake which may improve diabetes control.
Gliclazide potentiates insulin action on muscle glycogen synthase. These effects are consistent with a post-transcriptional action of gliclazide on GLUT4 glucose transporters.
Studies on glucose turnover have further shown that gliclazide decreases hepatic glucose production, leading to an improvement in fasting blood glucose levels.
Haemovascular properties: Gliclazide decreases microthrombosis by two mechanisms which may be involved in complications of diabetes: a partial inhibition of platelet aggregation and adhesion with a decrease in the markers of platelet activation (beta thromboglobulin, thromboxane B2); an action on the vascular endothelium fibrinolytic activity with an increase in tPA activity.
Other properties: Gliclazide has been shown in some studies to have actions independent of that on glucose levels.
Anti-oxidant properties, notably a reduction in plasma lipid peroxides and increased erythrocytesuperoxide dismutase activity.
Inhibition of the increased adhesiveness of type II diabetic patient's monocytes to endothelial cells in vitro.
The anti-oxidant, platelet inhibiting and fibrinolytic actions of gliclazide involve processes which have been implicated in the pathogenesis of vascular complications of type II diabetes. There is no clinical evidence that the haemovascular effects of gliclazide are of therapeutic benefit in type II diabetes patients.
Pharmacokinetics: Absorption: Plasma levels increase progressively during the first 6 hours, reaching a plateau which is maintained from the sixth to the twelfth hour after administration.
Intra-individual variability is low.
Gliclazide is completely absorbed. Food intake does not affect the rate or degree of absorption.
Distribution: Plasma protein binding is approximately 95%. The volume of distribution is around 30 litres. A single daily intake of gliclazide modified-release tablets maintains effective gliclazide plasma concentrations over 24 hours.
Biotransformation: Gliclazide is mainly metabolised in the liver and excreted in the urine; less than 1% of the unchanged form is found in the urine. No active metabolites have been detected in plasma.
Elimination: The elimination half-life of gliclazide is approximately 16 hours.
Linearity/non-linearity: The relationship between the dose administered ranging up to 90 mg/day and the area under the concentration-time curve is linear. At the highest evaluated dose (135mg/day), the AUC increases slightly more than proportionally to the dose.
Special populations: Elderly: No clinically relevant changes in the pharmacokinetic parameters have been observed in elderly patients.
Toxicology: Preclinical safety data: Preclinical data reveal no special hazards for humans based on conventional studies of repeated dose toxicity and genotoxicity. Long term carcinogenicity studies have not been done. No teratogenic changes have been shown in animal studies, but lower foetal body weight was observed in animals receiving doses 25 fold higher than the maximum recommended dose in humans.
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