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.
Class: Second-generation sulfonylurea
Indication: Type 2 Diabetes Mellitus (T2DM) – monotherapy or in combination with metformin (a biguanide)
Mechanism of Action
Glibenclamide acts primarily by stimulating insulin secretion from pancreatic β-cells . Its effects are mediated through the inhibition of ATP-sensitive potassium channels on β-cell membranes:
- Binding to Sulfonylurea Receptors (SUR1):
Glibenclamide binds to SUR1 subunits on ATP-sensitive potassium channels, causing them to close. - Membrane Depolarization:
Closure of ATP-sensitive potassium channels leads to cell membrane depolarization. - Calcium Influx:
Depolarization opens voltage-gated calcium channels , allowing calcium influx. - Insulin Secretion:
Increased intracellular calcium stimulates exocytosis of insulin-containing granules.
Important Note:
The drug requires functioning β-cells . It increases their glucose sensitivity and enhances insulin secretion in response to glucose. Over time, insulin levels may normalize, but improved peripheral insulin sensitivity and reduced hepatic glucose output maintain the hypoglycemic effect.
Pharmacokinetics
- Absorption: Rapid from the gastrointestinal tract; peak plasma concentration in 2–4 hours.
- Protein Binding: ~99% bound to plasma proteins.
- Metabolism: Hepatic – converted to weakly active metabolites.
- Excretion: Metabolites excreted via bile and urine (~50% each).
- Half-life (t<sub>1/2</sub>): ~4–8 hours (inter-individual variability).
- Renal Impairment: Accumulation of metabolites increases hypoglycemia risk.
Note: Absorption may be slower in hyperglycemic states and varies with formulation particle size.
Therapeutic Use
Indication:
- Management of Type 2 Diabetes Mellitus in patients unresponsive to dietary and lifestyle modifications.
Dosage and Administration
- Initial dose: 2.5–5 mg orally once daily (with breakfast)
- Adjustment: Titrate by 2.5 mg increments weekly based on blood glucose
- Maintenance dose: Up to 15 mg daily
- Maximum dose: 20 mg daily (in divided doses if >10 mg/day)
Contraindications
- Type 1 Diabetes Mellitus
- Diabetic ketoacidosis
- Severe infection, trauma, or surgery requiring insulin
- Pregnancy (insulin preferred)
- Hepatic or renal impairment due to increased risk of hypoglycemia
Precautions
Use cautiously in:
- Elderly
- Malnourished or debilitated patients
- Those with adrenal or pituitary insufficiency
- Patients on multiple hypoglycemia-enhancing drugs
Adverse Effects
Common:
- GI disturbances (nausea, vomiting, diarrhea, anorexia, metallic taste)
- Hypoglycemia (mild to severe/prolonged; dose-dependent)
Serious:
- Hepatic: Hepatitis, cholestatic jaundice
- Hematologic: Agranulocytosis, aplastic anemia, leukopenia, thrombocytopenia, hemolytic anemia
- Dermatologic: Stevens-Johnson Syndrome, exfoliative dermatitis, erythema multiforme/nodosum
Drug Interactions
Increased Hypoglycemic Risk with:
- ACE inhibitors , alcohol , salicylates , NSAIDs (e.g., azapropazone, phenylbutazone)
- Antifungals (ketoconazole, fluconazole, miconazole)
- Chloramphenicol , cimetidine , fluoroquinolones
- Sulfonamides (including co-trimoxazole)
- MAOIs , tetracyclines , tricyclic antidepressants
- Beta-blockers (may also mask symptoms of hypoglycemia)
- Octreotide (can cause either hypo- or hyperglycemia)
Use in Pregnancy and Lactation
- Pregnancy: Generally not recommended ; insulin is preferred due to better glycemic control and safety.
- Breastfeeding: May be used with caution; low transfer into breast milk reported.
Clinical Pearls
- Glibenclamide has a longer half-life than some other sulfonylureas, increasing the risk of prolonged hypoglycemia .
- Not suitable for elderly or renally impaired patients.
- Always start low and go slow to minimize hypoglycemia risk.
- Monitor renal and hepatic function before and during treatment.
