Diabetes Flashcards
Drugs
Metformin
Dipeptidyl-peptidase 4 (DPP-4) inhibitors (Sitagliptin)
Sulphonylurea (Gliclazide)
Sodium-glucose co-transporter (SGLT2) inhibitors (Dapaglifozin)
Metformin action
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.
Metformin drug target
5′-AMP-activated protein kinase (AMPK)
The primary site of metformin action is the hepatocyte mitochondria
Metformin main side effects
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.
Metformin other
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
DPP-4 inhibitors action
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.
DPP-4 inhibitor target
DPP-4
The primary site of DPP-4 inhibitor action is the vascular endothelium
DPP-4 side effects
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
DPP-4 inhibitor other
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.
In 2020 – Sitagliptin was the 49th most commonly prescribed drug in West London area
Sulphonylurea action
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.
Sulphonylurea target
ATP-sensitive potassium channel
The primary site of SUs inhibitor action is the pancreatic beta cell
Sulphonylurea side effects
Weight gain is a likely side effect
Hypoglycaemia (2nd most common)
Sulphonylurea other
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.
In 2020 – Gliclazide was the 15th most commonly prescribed drug in West London area
SGLT2 inhibitors action
Reversibly inhibits sodium-glucose co-transporter 2 (SGLT2) in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion.
SGLT2 inhibitors target
SGLT2
The primary site of SGLT2 inhibitor action is the proximal convoluted tubule
