Diabetes Drugs- Sulphonylureas Flashcards
Sulphonylureas - Pharmacology (2)
1st Generation – Tolbutamide, Chlorpropamide very limited use now
2nd Generation – Gliclazide, Glipizide, Glimepiride,
Glibenclamide (Glyburide in US)
Sulphonylureas – molecular mechanism (glucose) (5)
Glucose stimulated insulin secretion
1.Glucose metabolism
2.Rise in intracellular ATP from glycolysis and mitochondrial metabolism
3.Closure of ATP sensitive K channel (KATP)
4.Rise in membrane potential triggers Voltage gated Calcium channel
5.Calcium influx leads to insulin exocytosis
Sulphonylureas – molecular mechanism ( sulphonylurea) (4)
- SU binds to SUR1
2.Closure of ATP sensitive K channel (KATP)
3.Rise in membrane potential triggers Voltage gated Calcium channel
4.Calcium influx leads to insulin exocytosis
Sulphonylureas - simply (3)
Act directly on pancreatic beta-cells to increase insulin secretion – as such are termed “Insulin secretagogues”
Are glucose independent i.e. insulin secretion even when not needed (when glucose is low or normal).
This results in HYPOGLYCAEMIA.
Sulphonylureas – clinical use (5)
Potent glucose lowering. HbA1c ~18 mmol/mol
Increase weight – by 1-2 kg on average
Risk of hypoglycaemia
Most common sulphonylurea in UK = Gliclazide.
Start at 40-80mg od; little benefit by increasing over 80mg bd although max dose 160mg bd.
Sulphonylurea side effects
Hypoglycaemia
-Do not over treat
-Caution in the elderly – especially with long acting SUs (like glibenclamide) that are renally cleared
-Caution where hypoglycaemia would be a risk – driving, working up ladders etc.
-However risk is much lower than insulin (5 times lower than insulin treated T2DM)
Weight gain
-Why? Insulin concentrations are increased. Insulin is anabolic – increased carbohydrate storage. Insulin increases appetite
Sulphonylureas and CV risk
A controversial area
-Some argues that SUs increase CV risk
-Theoretical basis – some SUs can bind to Cardiac KATP and may alter ‘ischaemic preconditioning’
-But Gliclazide is pancreatic specific
