Pharmacology of Diabetes Flashcards
What is the primary mechanism of action of metformin?
- activates AMPK in hepatocyte mitochondria, inhibiting ATP production
- blocks glucneogenesis and therefore glucose output
- blocks adenylate cyclase, promoting fat oxidation
(helps restore insulin sensitivity)
What is the drug target of metformin?
5’-AMP-activated protein kinase (AMPK) in the hepatocyte mitochondria
What are the main side effects of metformin?
GI (20-30% of patients) - abdominal pain - decreased appetite - diarrhoea - vomiting (common in very high doses, gradual increase in dose over time may increase tolerability)
When is metformin the most effective?
- in the presence of endogenous insulin
residual beta-cell function is needed
What does metformin use to access it’s target?
- highly polar - charged even in the most alkaline tissue
- requires organic cation transporter-1 (OCT-1)
Where is OCT-1 expressed in the body?
- enterocytes in small bowel which allow metformin to be absorbed
- hepatocytes in the liver which allow it to be distributed to sites of action
- proximal tubules in the kidney which allow it to be excreted
What is an example of Dipeptidyl-peptidase 4 (DPP-4) inhibitors?
sitagliptin
What is the primary mechanism of action of DPP-4 inhibitors?
- inhibit DPP-4, enzyme in vascular endothelium that metabolises incretins in the plasma
What are Incretins?
(eg: GLP-1)
- secreted by enteroendocrine cells
- stimulate the production of insulin when necessary
- reduce the production of glucagon by the liver when not needed
- slow down digestion, decrease appetite
What is the drug target of DPP-4 inhibitors?
DPP-4 (in vascular endothelium)
What are the main side-effects of DPP-4 inhibitors?
- Upper respiratory infections (5% of patients)
- Flu like symptoms (headache, runny nose, sore throat)
- Serious allergic reactions
- AVOID in patients with PANCREATITIS
- doesn’t cause weight gain
When are DPP-4 inhibitors effective?
- when some residual beta cell function is present
- work by augumenting insulin
What is the primary mechanism of action of Sulphonylurea?
- inhibit the ATP-sensitive potassium channel (KATP) on the pancreatic beta cell
- KATP controls beta cell membrane potential
- Inhibition of KATP causes depolaristaion, stimulating Ca2+ influx and subsequent insulin vesicle exocytosis
What is the drug target of Sulphonylurea?
ATP-sensitive potassium channel in the pancreatic beta cell
What are the main side effects of taking Sulphonylureas?
- weight gain
- hypogylcaemia
When are Sulphonylureas effective?
- when some residual beta cell function is present
- work by augumenting insulin
What is the result of concurrent administration of Sulphonylureas and Metformin?
mitigation of weight gain
What is a risk that should be highlighted when Sulphonylureas are administered?
hypoglycaemia, especially when other glucose-lowering drugs are prescribed
What is an example of Sulphonylureas?
Gliclazide
What is an example of Sodium-Glucose co-transporter (SGLT2) inhibitors?
Dapaglifozin
What is the mechanism of action of SGLT2 inhibitors?
- reversibly inhibits sodium-glucose co-transporter 2 in the renal proximal convoluted tubule
- reduces glucose reabsorption and increases urinary glucose excretion
What is the drug target of SGLT2 inhibitors?
SGLT2 in the proximal convoluted tubule
What are the common side effects of taking SGLT2 inhibitors?
- Uro-genital infections (5% of patients) due to increased glucose load
- slight decrease in bone formation
- can worsen diabetic ketoacidosis (immediately cease treatment)
- weight loss
- decreased blood pressure
When are SGLT2 inhibitors most effective?
When renal function is normal, is less effective when renal function is impaired
