Metformin is an orally administered drug used to lower blood glucose concentrations in patients with non-insulin dependent diabetes mellitus. It is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents.
Chemical Name : 1,1- dimethylbiguanide hydrochloride
Empirical Formula : C4H11N5.HCl
Molecular Weight : 165.62
Melting Point : 222 to 226 oC
Category : Hypoglycemic agent
Dose : 0.5 to 3 g daily, in divided doses
PKa : 12.4
Description : White, crystalline powder, hygroscopic
Solubility: Freely soluble in water, slightly soluble in ethanol (95%), practically insoluble in acetone, chloroform, dichloromethane and ether.
Absorption: It is a BCS class III (highly soluble- poorly permeable) drug. The absolute bioavailability of metformin hydrochloride under fasting conditions is approximately 50-60%. It is absorbed mainly from the upper part of small intestine. There is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin.The clinical relevance of these decreases is unknown.
Distribution: The apparent volume of distribution (V1) of metformin is 654 ± 358 liters. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules, steady state plasma concentrations of metformin reached within 24-48 hours and are generally less than 1 ?g/ml. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 ?g/ml, even at maximum doses.
Metabolism and elimination: Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 3 hours.In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
MECHANISM OF ACTION:
Proposed mechanism of action includes decreased intestinal absorption of glucose, increased glucose uptake from the blood into the tissues, decreased glucose production in liver and decreased insulin requirements for glucose disposal. Metformin is not a hypoglycemic agent but an antihyperglycemic agent. It lowers the blood glucose concentration in the presence of hyperglycemia, but does not decrease it below the normal range. Unlike sulfonylureas, metformin has no effect on pancreatic insulin secretion and is not effective in absence of insulin.
It has been noted that metformin does not lower blood glucose concentrations in non-obese and non-diabetic individuals.
Metformin hydrochloride is indicated as monotherapy, indicated as an adjunct to diet and exercise to improve glycemic control in patients with type II diabetes. Metformin immediate release dosage form is indicated in patients with 10 years of age and older, and metformin extended release dosage form is indicated in patients with 17 years of age and older. Metformin may be used concomitantly with a sulfonylurea or insulin to improve glycemic control in adults (17 years of age and older).
Dosage and Administration
The usual effective dosage of metformin hydrochloride is 1500- 2550 mg/day given in divided doses.
There is no fixed regimen for the management of hyperglycemia in patients with type II diabetes. Dosage must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily dose. The maximum recommended daily dose of extended release tablet in adult is 2500 mg.
Recommended starting dose of metformin is 500 mg twice daily given with the morning and evening meal. To further minimize gastrointestinal side effects, a starting dosage of 500 mg once daily may benefit some patients. The dosage may be increased gradually by 500 mg per week or 850 mg every other week. The usual maintenance dosage is 500 mg thrice daily or 850 mg twice daily given with morning and evening meals.
Although food decreases the extent of and slightly delays absorption of metformin, the manufacturer states that the clinical importance of these effects is not known and recommends that Metformin hydrochloride be taken with meals to decrease adverse G.I. effects.
Therapy with metformin hydrochloride is contraindicated in patients with:
1. Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels greater than 1.5 mg/dl [males], greater than 1.4 mg/dl [females] or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia.
2. Congestive heart failure requiring pharmacological treatment.
3. Known hypersensitivity to metformin hydrochloride.
4. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
Metformin should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.
Approximately 30% of patients may have gastrointestinal adverse effects, such as diarrhoea, nausea, epigastric discomfort, and anorexia.These effects are usually mild, resolve in days or weeks, and appear to occur more frequently in women. Gastrointestinal side effects are commonly dose related; gradually increasing the dosage. The most worrisome adverse effect of metformin is lactic acidosis.