Pharmacology of Diabetes Flashcards
What is the primary mechanism of action of 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 of metformin?
5′-AMP-activated protein kinase (AMPK)
The primary site of metformin action is the hepatocyte mitochondria
What are the main side effects of 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 are 2 facts 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
How does a DPP-4 inhibitor work?
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 DPP-4 inhibitor’s site of action?
DPP-4. The primary site of DPP-4 inhibitor action is the vascular endothelium.
What are the main side effects of 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 are 2 facts about DPP-4 inhibitors and what is an example?
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.
Sitagliptin is an example of a DPP-4 inhibitor.
How do sulphonylureas work?
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. Gliclazide is an example.
What is sulphonylureas’ site of action?
ATP-sensitive potassium channel. The primary site of SUs inhibitor action is the pancreatic beta cell.
What are the main side effects of sulphonylureas?
Weight gain is a likely side effect. Hypoglycaemia (2nd most common).
What are 3 facts about sulphonylureas?
- 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.
How do SGLT-2 inhibitors work?
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 main site of action of SGLT-2 inhibitors?
SGLT2. The primary site of SGLT2 inhibitor action is the proximal convoluted tubule.
What are the main 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).
