Pharmacology of diabetes Flashcards
(27 cards)
Which drugs are used to treat diabetes?
- Metformin
- Dipeptidyl-peptidase 4 inhibitors
- Sulphonylurea
- Sodium-glucose co-transporter inhibitors
What are examples of Dipeptidyl-peptidase 4 (DPP-4) inhibitors?
Sitagliptin
What are examples of sulphonylurea?
Gliclazide
What is an example of sodium-glucose co-transporter (SGLT2) inhibitors?
Dapaglifozin
What is the drug target for metformin?
5′-AMP-activated protein kinase (AMPK) - hepatocyte mitochondria
What is the drug target for sitagliptin?
The primary site of DPP-4 inhibitor action is the vascular endothelium
What is the drug target of sulphonylurea?
ATP-sensitive potassium channel
Pancreatic beta cell
What is the drug target for sodium-glucose co-transporter (SGLT2) inhibitors?
The primary site of SGLT2 inhibitor action is the proximal convoluted tubule
What is the mechanism of action of metformin?
Activates AMPK in hepatocyte mitochondria -> inhibits ATP production.
–> Blocks gluconeogenesis and subsequent glucose output
Blocks adenylate cyclase which promotes fat oxidation
Both help to restore insulin sensitivity.
What is the primary mechanism of action of Dipeptidyl-peptidase 4 (DPP-4) inhibitors?
Inhibit DDP-4 -> Metabolism of incretins in the plasma.
Incretins (e.g. GLP-1) are secreted by enteroendocrine cells and help stimulate the production of insulin when it is needed and reduce the production of glucagon by the liver when it is not needed
Incretins also slow down digestion and decrease appetite.
What are the side effects of Metformin?
GI side effects (20-30% of patients)
e.g. Abdominal pain, decreased appetite, diarrhoea, vomiting)
Why does metformin cause GI side effects?
Metformin is highly polar and requires organic cation transporter-1 (OCT-1) to access tissues. Accumulates in the liver (therapeutic effect) and gastrointestinal tract (side effects)
When is metformin most effective?
In the presence of endogenous insulin so is most effective with some residual functioning pancreatic islet cells
What is the side effect of DDP4 inhibitors?
Upper respiratory tract infections (5% of patients) Flu-like symptoms e.g. headache, runny nose, sore throat
Less common but serious:
Serious allergic reactions/ avoid in patients with pancreatitis
When are DDP-4 I’s effective?
When some residual pancreatic beta-cell activity is present.
What is the primary mechanism of action of sulphonylurea?
Inhibit the ATP-sensitive potassium (KATP) channel on the 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 side effect of sulphonylurea?
Weight gain
What mitigates weight gain with sulphonylurea?
Administration with metformin
What is the mechanism of action of SGLT-2 inhibitors?
Reversibly inhibits sodium-glucose co-transporter 2 (SGLT2) in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion.
What are the side effects of SGLT-2 inhibitors?
Uro-genital infections due to increased glucose load (5% of patients)
Slight decrease in bone formation
Can worsen diabetic ketoacidosis (stop immediately)
What other positive effects can SGLT-2 have?
weight loss and a reduction in BP
What does SGLT-2 action depend on?
normal renal fucntion so they are less effective in patients with renal impairment
What is the property of metformin that leads to accumulation in the liver in GI tract?
Metformin is highly polar and requires organic cation transporter-1 (OCT-1) to access tissues
When are metformin & DDP4is & sulphonylurea most effective?
Presence of some residual beta cell activity
