pharmacology of diabetes Flashcards
Primary mechanism of action 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.
Primary mechanism of action of action of 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.
Primary mechanism of action of action of sulphonylureas
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.
Primary mechanism of action 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
Ex of SGLT-2 inhibitors
dapagliflozin
Ex of sulphonyurea
gliclazide
example of DPP-4 inhibitor
sitagliptin
Drug target of metformin
AMPK
hepatocyte mitochondria
DDP-4 inhibitor drug target
DDP-4 in vascular endothelium
sulphonylurea drug target
ATP sensitive potassium channels in pancreatic beta cells
SGLT-2 inhibitor target
SGLT-2 in PCT
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 does metformin need to access tissues and why and what are the consequences of that
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)
When is metformin most effective
Metformin is most effective in the presence of endogenous insulin so is most effective with some residual functioning pancreatic islet cells
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
weight effect of DPP-4 inhibitors
appears not to have weight gain
When are DPP-4 inhibitors affective only
DPP-4 I’s act mainly by augmenting insulin secretion and consequently are effective only when some residual pancreatic beta-cell activity is present.
Side effect of sulphonylureas
weight gain likely
What should be discussed with patients on sulphonylureas
The risk of hypoglycaemia associated with sulfonylureas should be discussed with the patient, especially when concomitant glucose-lowering drugs are prescribed.
Sulphonylureas are only effective when
The sulfonylureas act mainly by augmenting insulin secretion and consequently are effective only when some residual pancreatic beta-cell activity is present.
How can weight gain on sulphonyureas be mitigated
Weight gain is mitigated by the concurrent administration with metformin.
Side effect 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)
SGLT 2 inhibitors effect on weight and BP
decrease both
SGLT2i only work when
SGLT2i action depends on normal renal fucntion so they are less effective in patients with renal impairment
1st line for first presentation of T2DM treatment
lifestyle intervention
If HbA1c rises to 48 mmol/mol on lifestyle intervention what do you do
give metformin
to support them to get target of 48
If HbA1c rises to 58 mmol/mol after metformin and lifestyle advice
1st intensification - give dual therapy with metformin one of the following: DDP-4 inhibitors (eg sitagliptin) sulphonylureas (eg gliclazide) SGLT-2i (dapagliflozin) pioglitazone
If HbA1c rises to 58 mmol/mol after metformin and lifestyle advice, what level should they be supported to achieve
53
if HbA1c rises to 58 mmol/mol after double based therapy@
insulin or triple therapy:
1) metformin, DPP4i and SU
2) metformin, pioglitazone, SU
3) metformin, pioglitazone or an SU and a SGLT-2i
The expression of the organic cation transporter 1 (OCT-1) is highest in the following tissues: Liver hepatocytes (highest expression), the small intestinal enterocytes and the renal proximal tubules. Why do you think this is relevant to the pharmacokinetics of orally administered metformin?
Means that metformin would be absorbed in small intestine by transporters in enterocytes
Would then encounter hepatocytes, and the site of action for metformin is the mitochondria of hepatocytes and so it’s good for absorption that OCT1 is present more in the liver
Proximal tubule OCT 1 helps excretion
This all means it is orally available
10 years later and Mrs Wallace has a stabilized Hb1Ac of 62mmol/mol. Her drug treatment for her diabetes remains unchanged – metformin and sitagliptin. However, during this time, Mrs Wallace has developed chronic kidney disease. NOTE - It is CLINICALLY very important that you monitor kidney function in any patient on metformin with signs of renal impairment. Mrs Wallace’s most recent serum creatinine estimated her GFR at 37. The table below describes how metformin administration should be changed based on underlying kidney function (eGFR). How should you change the treatment strategy for Mrs Wallace and why do you think renal impairment could cause problems for diabetic patients on metformin?
Consider halving dose as reduced renal function means less metformin is excreted so more is retained in the blood so there is a risk of hypoglycaemia