- Enhance peripheral action of insulin
- ↑ rate of anaerobic glycolysis and ↓ rate of gluconeogenesis
- Inhibit intestinal absorption and ↓ peripheral utilization of glucose

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

CVS:
- ↓ intestinal absorption of glucose, folate, vit B12
- no effect on gastric motility
- ↑ utilization of glucose and cause weight loss
Metabolic/Other:
- ↑ sensitivity to peripheral actions of insulin by ↑ no of low affinity binding sites (RBC, Adipocytes, hepatocytes, sk. Muscle)
- inhibits metabolism of lactate and ↓ plasma TG, cholesterol, pre-beta lipoprotein

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)

Slowly absorbed from small intestine
PO BA: 50-60%

Well absorbed
PO BA: 100%

Not protein bound

95-99% Albumin bound

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

No metabolites

extensive hepatic metabolism via
CYP2C9 to inactive metabolites

Unchanged in urine

30-50% excreted in urine
Remainder in feces

> GFR (Active tubular secretion)

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

Elimination half life 1.7-4.5 hrs

Elimination impaired in severe renal impairment

- Does not cause hypoglycaemia when used on its own
- GI disturbances
- Lactic acidosis (rare)

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

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

Biguanides

Sulfonylurea

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

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

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

Level 3

Level 3

Hypoglycaemia

Hypoglycaemia

As 500/850 mg tablets of metformin hydrochloride
MR also available.

tablet form
MR also available.

PO
1-3gm daily in divided doses

PO

Not recommended in renal impairment

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

Long acting sulfonylureas should be stopped prior to major surgery