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 action is needed
What does metformin use to access it’s target?
- highly polar
- requires organic cation transporter-1 (OCT-1)
- therefore accumulates in liver (therapeutic effect), and the GI tract (side effects)
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
- NO weight gain associated
When are DPP-4 inhibitors effective?
augmenting insulin secretion and therefore only effective when residual pancreatic beta-cell activity is present
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?
They augment insulin secretion and therefore are only effective when residual pancreatic beta-cell activity is present.
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 concomitant 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)
When are SGLT2 inhibitors most effective?
When renal function is normal, is less effective when renal function is impaired
What are occasionally side effects of SGLT2 inhibitors?
- weight loss
- reduction in BP
What is the risks associated with Pioglitazone?
- greater risk of CVD (heart failure)
What should always be considered before prescribed drugs in type 2 diabetes?
Lifestyle
review should be undertaken
What are the main things when deciding on which treatment to prescribe?
- identify the problem
- specify the treatment objective
- select drug based on: comparative efficacy, safety, cost and suitability
