Pharmacology: Pharmacodynamics: Gliclazide is a second generation sulfonylurea which acts by stimulating beta cells of the islet of Langerhans of pancreas to release insulin. Gliclazide also enhances peripheral insulin sensitivity. Metformin enhances peripheral glucose uptake by the tissues and its utilization. It also reduces hepatic glucose production. Metformin diminishes insulin resistance.
There are reports in which combination treatment of sulfonylurea with Metformin has shown to achieve satisfactory control of blood sugar level for several years, than either agent used alone. Such combination has been reported to be quite useful in comparative studies where secondary failure to sulfonylureas has occurred. The combination provides an additional glycemic control (shown to lower blood glucose by 20%) and thus obviates the need for insulin in some patients.
Gliclazide has less propensities to cause hypoglycemia and weight increase unlike other sulfonylureas. Gliclazide promptly induces the first phase of insulin release as is not commonly observed with Glibenclamide; the second phase of insulin release is as well maintained. Thus, the necessary insulin is released to meal intake. Further, Gliclazide has significantly shown to reduce the micro- and macro-vascular combinations. This can be attributed to its action in improving peripheral utilization of glucose, reducing insulin resistance and thus hyperinsulinemia which contributes to positive influence on the lipid metabolism. This ultimately results in reduction of oxidative stress on LDL, free fatty acids and deposition of cholesterol in the small or larger blood vessels.
Unlike other sulfonylureas, Gliclazide has beneficial effect in reducing platelet aggregation as well as mild increase in levels of tissue plasminogen activator (in patients with diabetes mellitus, levels of TPA are found to be suppressed). By improving TPA levels, Gliclazide improves microcirculation since the tendency of clot formation is hampered and there is clot lysis.
Metformin also reduces hepatic glucose production. Metformin in certain studies has also shown to reduce intestinal absorption of carbohydrates which at the moment appears to be insignificant in contributing to its antidiabetic action. It is less likely to cause lactic acidosis, unlike its counter part i.e. Phenformin. Metformin has favorable effect on the lipid metabolism. It has also shown to reduce blood fibrinogen levels, thus minimizing intravascular coagulation. It produces cholesterol uptake by the arteries and also reduces platelet adhesiveness, which contributes to the protection from intravascular coagulation. In obese diabetics it promotes weight loss. Thus besides being antidiabetic, it also exerts cardio-protective effects.
Pharmacokinetics: Single oral dose of Gliclazide, 40 to 120mg results in a Cmax of 2.2 to 8 mg/L within 2 to 8 hours. Steady state concentrations are achieved after 2 days of administration of 40-120 mg of Gliclazide. Administration of Gliclazide with food reduces Cmax and delays Tmax. The volume of distribution is low due to extensive protein binding (85-97%). The half life of Gliclazide varies from 8.1-20.5 hours after single dose administration. Gliclazide is extensively is metabolized to 7 metabolites predominantly excreted in the urine, the most abundant being the carboxylic acid derivative: 60-70% of the dose is excreted in the urine and 10-20% in the feces.
Metformin has absolute oral bioavailability of 50-60%. GIT absorption is complete within 6 hours of ingestion.