Pharmacology of Diabetes Flashcards
What are the 4 most common main drug classes prescribed for diabetes?
And what is an example of each of these?
- Metformin
- Dipeptidyl-peptidase 4 (DPP-4) inhibitors - Sitagliptin
- Sulphonylurea - Gliclazide
- Sodium-glucose co-transporter (SGLT-2) inhibitors - Dapaglifozin
What is the primary mechanism of action for Metformin?
Primary effect – 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 to restore insulin sensitivity.
What is the drug target site for Metformin?
5′-AMP-activated protein kinase (AMPK)
The primary site of metformin action is the hepatocyte mitochondria
What are the main side effects for Metformin?
GI side effects (20-30% of patients)
e.g. Abdominal pain, decreased appetite, diarrhoea, vomiting)
Particularly evident when very high doses are given. A slow increase in dose may improve tolerability
What is some extra information about Metformin?
Metformin is highly polar and requires organic cation transporter-1 (OCT-1) to access tissues. This explains why it can accumulate in the liver (therapeutic effect) and gastrointestinal tract (side effects)
Metformin is most effective in the presence of endogenous insulin so is most effective with some residual functioning pancreatic islet cells
In 2020 – Metformin was the 4th most commonly prescribed drug in West London area
What is the primary mechanism of action for DPP-4 inhibitors?
Primary effect - Work by inhibiting the action of DPP-4. This enzyme is present in vascular endothelium and can metabolise 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 (e.g. after eating) and reduce the production of glucagon by the liver when it is not needed (e.g. during digestion). Incretins also slow down digestion and decrease appetite.
What is the drug target site for DPP-4 inhibitors?
DPP-4
The primary site of DPP-4 inhibitor action is the vascular endothelium
What are the main side effects for DPP-4 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
What is some extra information about DPP-4 inhibitors?
Compared to other anti-diabetic drugs (although not metformin) these drugs do not appear to cause weight gain.
DPP-4 I’s act mainly by augmenting insulin secretion and consequently are effective only when some residual pancreatic beta-cell activity is present.
What is the primary mechanism of action for Sulphonylurea?
Primary effect – 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 drug target site for Sulphonylurea?
ATP-sensitive potassium channel
The primary site of SUs inhibitor action is the pancreatic beta cell
What are the main side effects for Sulphonylurea?
Weight gain is a likely side effect
Hypoglycaemia (2nd most common)
What is some extra information about Sulphonylurea?
The sulfonylureas act mainly by augmenting insulin secretion and consequently are effective only when some residual pancreatic beta-cell activity is present.
Weight gain is mitigated by the concurrent administration with metformin.
The risk of hypoglycaemia associated with sulfonylureas should be discussed with the patient, especially when concomitant glucose-lowering drugs are prescribed.
What is the primary mechanism of action for 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 is the drug target site for SGLT-2 inhibitors?
SGLT2
The primary site of SGLT2 inhibitor action is the proximal convoluted tubule