1.2 - Pharmacology of diabetes (core drugs) Flashcards
What are the four classes of diabetes drugs?
- metformin
- dipeptidyl-peptidase 4 (DPP-4) inhibitor
- sulphonylurea
- sodium-glucose co-transporter (SGLT2) inhibitor
What is the primary mechanism of action of metformin?
- metformin activates AMPK in hepatocyte mitochondria
- this inhibits ATP production
- this blocks gluconeogenesis and subsequent glucose output
- it also blocks adenylate cyclase which promotes fat oxidation
- both help restore insulin sensitivity
What is the drug target of metformin?
5’-AMP-activated protein kinase (AMPK - enzyme) in hepatocyte mitochondria
What is the primary site of action of metformin?
Hepatocyte mitochondria
What is the overall action of metformin?
Decreased gluconeogenesis
What are the main side effects of metformin?
- GI side effects (20-30%) patients, evident when very high doses given (slow increase in dose may improve tolerability)
- abdominal pain
- decreased appetite
- diarrhoea
- vomiting
What is the polarity of metformin like and how does it access tissues?
- highly polar
- requires organic cation transporter-1 (OCT-1) to access tissues
- this explains why it can accumulate in the liver (therapeutic effects) and GI tract (side effects)
When is metformin most effective?
In the presence of endogenous insulin (so when there is some residual functioning of pancreatic islet cells)
What is an example of a DPP-4 inhibitor?
Sitagliptin
What is the primary mechanism of action of a DPP-4 inhibitor?
- inhibits action of DPP-4 which is present in vascular endothelium and can metabolise incretins in plasma
- incretins (e.g. GLP-1) are secreted by enteroendocrine cells and help stimulate insulin production after eating and reduce glucagon production by liver when not needed e.g. during digestion
- incretins also slow down digestion and decrease appetite
What is the drug target and primary site of action of DPP-4 inhibitors?
DPP-4 in vascular endothelium
What is the overall effect of a DPP-4 inhibitor?
Increased plasma incretin levels
What are the main side effects of DPP-4 inhibitors?
- upper respiratory tract infections (5%)
- flu-like symptoms e.g. headache, runny nose, sore throat
- less common but serious allergic reactions
Which patients should you avoid giving DPP-4 inhibitor to?
Avoid in patients with pancreatitis
What is an advantage of DPP-4 inhibitors compared to other diabetic drugs?
Do not cause weight gain
When are DPP-4 inhibitors effective?
Act mainly by augmenting insulin secretion so are only effective when some residual pancreatic beta cell activity is present
What is an example of a sulphonylurea?
Gliclazide
What is the primary mechanism of action of sulphonylureas?
- inhibit ATP-sensitive K+ channel (KATP) on pancreatic beta cell
- this channel controls beta cell membrane potential
- inhibition causes depolarisation which stimulates Ca2+ influx and subsequent insulin vesicle exocytosis
What is the drug target and primary site of action of sulphonylureas?
ATP-sensitive potassium channel on pancreatic beta cell
What is the overall effect of sulphonylureas?
Insulin secretion
What are the main side effects of sulphonylureas?
- weight gain is likely
- hypoglycaemia (2nd most common)
When are sulphonylureas effective?
Act by augmenting insulin secretion so only effective when there is residual pancreatic beta cell activity
How can weight gain by sulphonylureas be mitigated?
By also giving metformin
What do we need to inform patients about if they are on sulphonylureas?
Patients need to be informed about hypoglycaemia risk, especially if they are on other glucose-lowering drugs
