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Glibenclamide Pharmacology, Uses,Dosage, Mechanism of action and side effects

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Glibenclamide is a second-generation sulphonylurea that is used either as monotherapy or in combination with biguanides in the management of diabetes Mellitus type 2.

Mechanism of action of Glibenclamide

Sulfonylureas appear to have several modes of action, apparently mediated by inhibition of ATP-sensitive potassium channels. Initially, secretion of insulin by functioning islet beta cells is increased.

Oral antidiabetics of the sulfonylurea type increase the sensitivity of B-cells towards glucose, enabling them to increase the release of insulin.

The hypoglycaemic effect of these drugs depends on the presence of functioning B cells. Sulphonylureas, like glucose, depolarize B cells and release insulin. They do this by binding to sulphonylurea receptors (SUR) and blocking ATP-dependent potassium channels (KATP); the resulting depolarization activates voltage-sensitive Calcium channels, in turn causing entry of calcium ions and insulin secretion.

Normally, these channels are closed when intracellular levels of glucose, hence of ATP, increase.

However, insulin secretion subsequently falls again but the hypoglycaemic effect persists and may be due to inhibition of hepatic glucose production and increased sensitivity to any available insulin.

Pharmacokinetics

Glibenclamide is readily absorbed from the gastrointestinal tract, peak plasma concentrations usually occurring within 2-4 hours, and is extensively bound to plasma proteins.

Absorption may be slower in hyperglycaemic patients and may differ according to the particle size of the preparation used.

Glibenclamide is almost completely metabolized by the liver to weakly active metabolites that are excreted in the bile and urine.

The activity of these metabolites is only clinically important in patients with renal failure, in whom they accumulate and can cause hypoglycaemia.

Tolbutamide is converted in the liver to inactive metabolites which are excreted in the urine.

The t1/2 shows considerable inter-individual variability but is usually four to eight hours.

About 50% of a dose is excreted in the urine and 50% via the bile into faeces.

Uses of Glibenclamide

Glibenclamide is used in the treatment of type 2 diabetes mellitus.

Doses and administration

Type 2 diabetes mellitus 2.5-5mg daily with breakfast, depending on patient response adjusted every 7 days by increments of 2.5mg daily up to 15mg daily.

The dose may be increased to 20mg.

Doses greater than 10mg daily may be given in two divided doses.

Contra-indications and warnings

Precautions

Sulfonylureas should not be used in type 1 diabetes mellitus. Use in type 2 diabetes mellitus is contraindicated in patients with ketoacidosis and those with severe infection, trauma, or other severe conditions where the sulfonylurea is likely to control the hyperglycaemia; insulin should be used in such situations.

Insulin is also preferred for therapy during pregnancy.

Sulfonylureas with a long half-life such as chlorpropamide or glibenclamide are associated with an increased risk of hypoglycaemia.

They should, therefore, be avoided in patients with impaired of renal or hepatic function, and a similar precaution would tend to apply in other groups with increased susceptibility to this effect, such as the elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency.

Adverse effects

Gastrointestinal disturbances such as nausea, vomiting, heartburn, anorexia, diarrhoea, and a metabolic taste may occur. Mild hypoglycaemia may occur, severe hypoglycaemia is usually an indication of overdosage and is relatively common.

Hypoglycaemia is more likely with long-acting sulfonylureas such as chlorpropamide and glibenclamide, which have been associated with severe, prolonged, and sometimes fatal hypoglycaemia.

Other adverse effects include hepatitis and cholestatic jaundice, leucopenia, thrombocytopenia, aplastic anaemia, agranulocytosis, haemolytic anaemia, erythema multiforme or the steven-johnson syndrome, exfoliative dermatitis and erythema nodosum.

Interactions

An increased hypoglycaemic effect has occurred or might be expected with ace inhibitors, alcohol, allopurinol, some analgesics{notably azapropazone, phenylbutazone, and the salicylates}, azole antifungals (fluconazole, ketoconazole, and miconazole), chloramphenicol, cimetidine, clofibrate and related compounds, coumarin anticoagulants, fluoroquinolones, heparin, MAOIs, octreotide[although this may also produce hyperglycemia], ranitidine, sulfinpyrazone, sulfonamides [including co-trimoxazole], tetracyclines, and tetracyclines, and tricyclic antidepressants.

Beta-blockers have been reported to increase hypoglycemia and to mask the typical sympathetic warning signs.

Pregnancy and breastfeeding

It is generally not recommended during pregnancy but can be used during breastfeeding.


Post References

  • Atlas of pharmacology, Davis drug guide, Medscape, Science direct

  • Revised on: 2021-07-06 12:18:36