Classification:
-
First-generation compounds: chlorpropamide, tolbutamide, acetohexamide.
-
Second-generation compounds: glibenclamide, glyclazide and glipizide; up to 200 times more potent than first-generation.
-
Third-generation compounds: glimepiride; may interact with different cellular proteins.
Pharmacokinetics
- Absorbed from GIT. Given 30 minutes before breakfast.
- Food can reduce the absorption.
- Plasma protein binding is high 90 – 99 %.
- Metabolized by liver and their metabolites are excreted in urine with about 20 % excreted unchanged.
MOA
Pancreatic actions:
- ↑ Insulin release from B-cells by closing ATP-sensitive K+ channels → opening of voltage sensitive Ca2+ channels → ↑ insulin release.
- ↓ Glucagon release from a-cells (direct effect or by insulin release).
Extra-pancreatic actions:
- ↑ Sensitivity of insulin receptors.
- ↑ Aerobic oxidation of glucose and ↓ lipolysis.
- ↓ Hepatic output of glucose (i.e. ↓ gluconeogenesis).
- ↓ Insulin degradation by the liver.
Therapeutic uses:
- NIDDM after failure of diet regime.
- With insulin in special cases.
- Chloropropamide is used in ttt of nephrogenic diabetes insipidus (it ↑ sensitivity of renal tubules to the effect of ADH).
Side effects:
- Hypoglycemia: especially with long acting drugs or in elderly patients with hepatic or renal dysfunction.
- Cholestatic jaundice.
- Allergy: due to presence of sulfur (sulphonylureas). There is no cross reactions between different drugs.
- Teratogenicity.
- Tachyphylaxis and secondary failure to sulfonylureas: it is failure to maintain good response to sulfonylurea therapy over long term.
Contraindications:
- Presence of complications: e.g. ketoacidosis and infections.
- Pregnancy.
- Hepatic or renal dysfunctions.