Pharmacology Of Diabetes Flashcards
Metformin primary mechanisms of 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.
Drug target for metformin and therapeutic effects
5′-AMP-activated protein kinase (AMPK)
The primary site of metformin action is the hepatocyte mitochondria
It increases insulin sensitivity,reduce glucose production and causes weight loss
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.
Extra info 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 as expression of OCT1 is highest here(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
Dipeptidyl peptidase 4 inhibitors
Sitagliptin
Mechanism of action of DPP-4
Primary effect - Work by inhibiting the action of DPP-4. This enzyme is present in vascular endothelium and can metabolise incretins in the plasma.(breaks them down thus less are broken down as this enzyme is blocked so more incretin in plasma thus more insulin release)
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.
Drug target of DPP-4
vascular endothelium
Side effects of DPP-4
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
Extra info of DPP4
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.
Cause increased insulin production,decease glucagon,slower digestion and reduced appetite
In 2020 – Sitagliptin was the 49th most commonly prescribed drug in West London area
Sulphonylurea
Gliclazide
Mechanism of action of 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.
Drug target for Sulphonylurea
ATP-sensitive potassium channel
The primary site of SUs inhibitor action is the pancreatic beta cell
Side effect of Sulphonylurea
Weight gain is a likely side effect
Hypoglycaemia (2nd most common)
Not good for overweight pt and those with erratic meal time as induce hypoglycemia
Extra info on 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.
In 2020 – Gliclazide was the 15th most commonly prescribed drug in West London area
SGLT-2 inhibitors
Dapaglifozin
Mechanism of action of SGLT-2
Reversibly inhibits sodium-glucose co-transporter 2 (SGLT2) in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion.
Site of action of SGLT-2
SGLT2
The primary site of SGLT2 inhibitor action is the proximal convoluted tubule
Side effects of SGLT-2
Uro-genital infections due to increased glucose load (5% of patients)
Slight decrease in bone formation
Can worsen diabetic ketoacidosis (stop immediately)
Extra info of SGLT-2
SGLT2 inhibitors cause weight loss and a reduction in BP
SGLT2i action depends on normal renal fucntion so they are less effective in patients with renal impairment
Therapeutic affects include low blood glucose and low CVD mortality in T2DM
In 2020 – Dapaglifozin was the 127th most commonly prescribed drug in West London area
Therapeutic objectives
Weight loss to reduce insulin resistance and cardiovascular disease
Reduce blood pressure to reduce cardiovascular disease
Improve lipid profile to reduce cardiovascular disease
Reduce blood glucose to reduce microvascular and macro vascular disease
Metformin pharmacokinetics
Pka is 12.4 so will be changed in even the most alkaline tissue
Diabetic keto acidosis
Patient who take SGLTS-early warning signs may be slower ,pt checks glucose and its normal-get acidosis
Problems strategy solutions
Excess hepatic glucose production,we need to reduce this,can e done via metformin
Resistance to action of circulating insulin,improve insulin sensitivity metformin
Inadequate insulin production,boost insulin secretion via sulphonyurea,DPP4 inhibitors,GLP1 agonist
Excess glucose in circulation,inhibit carbohydrate gut absorption and renal glucose resorption done via SGLTW,ALPHA GLUCOSIDASE INHBITOR
Weight loss helps w everything
