Core pharmacology

Class Group

Sulfonylurea

Legacy Cicm Level

Level 3

Introduction

1. first-generation: tolbutamide
2. second-generation: gliclazide, glibenclamide
3. third-generation: glimepiride.

Indications Uses

treatment of non-insulin-dependent
(type II) diabetes mellitus

Chemical Pharmaceutics

An s-phenylsulfonylurea structure with substitutions on the
phenyl ring and urea terminus

Presentation

tablet form
MR also available.

Main Action

Hypoglycaemia

Mechanism of action

- Liberates insulin from pancreatic beta-cells
(prolong depolarization in membrane → ↓ permeability to K+ → open Ca++ channel → Ca++ influx → Insulin release)

Physiological effects

Metabolic/Other:
- ↓ plasma TG, cholesterol, FFA

Gliclazide ↓ microthrombosis:
- partially inhibit platelet aggregation and adhesion
- fibrinolytic - ↑ tPA activity

Glimepiride extra-pancreatic:
- ↑ active glucose transport molecules
- lipogenesis and glycogenesis in fat and muscle
- inhibits hepatic gluconeogenesis (by ↑ Fructose-2,6-bisphosphate)

Adverse Effects Toxicity

- Hypoglycaemia
- GI disturbances
- Cholestatic jaundice
- LFT derangement
- Leucopenia, thrombocytopenia
- some Potentially teratogenic

Absorption

Well absorbed
PO BA: 100%

Protein binding

95-99% Albumin bound

Volume of distribution

gliclazide 0.42 l/kg
glibenclamide 0.15 l/kg
glimepiride 0.12 l/kg

Metabolism

extensive hepatic metabolism via
CYP2C9 to inactive metabolites

Excretion

30-50% excreted in urine
Remainder in feces

Clearance

Gliclazide 12-20 hrs
Gliblencamide 1-2hrs
Glimepiride 5-8hrs

Half-life

Elimination impaired in severe renal impairment

Special Points

Hypoglycaemia with NsAIDs, salicylates, sulfonamides, oral anticoagulants, MAoIs, and beta-adrenergic antagonists

Long acting sulfonylureas should be stopped prior to major surgery

Route And Dose

PO