pharmacology of diabetes Flashcards
what is the primary mechanism of action of metformin
activates AMPK in hepatocyte mitochondria. this inhibits atp production and blocks gluconeogenesis and subsequent glucose output.
- also blocks adenylate cyclase which promotes fat oxidation - both help restore insulin sensitivity.
what is the target of metformin
5’amp activated protein kinase (AMPK)
primary site = hepatocyte mitochondria
what are the main side effects of metformin
gi side effects (30-40%) - abdominal pain, decreased appetite, diarrhoea, vomiting
- particularly evident when very high doses given
extra info on metformin
*highly polar - requires organic cation transporter
can accumulate in live and gi tract
* most effective in presence of endogenous insulin
what is an example of a dipeptidyl peptidase 4 inhibitor
sitagliptin
what is the primary mechanism of action of dpp4 inhibitors
inhibit action of dpp4 - enzyme present in vascular endothelium and can metabolise incretins in plasma.
incretins e.g gpl1 are secreted by enteroendocrine cells and help stimulate production of insulin when needed and reduce production of glucagon by liver.
- incretins also slow down digestion and decrease appetite
what is the main drug target of dpp4 inhibitors
primary site of action is vascular endothelium
side effects of dpp4 inhibitors/ sitagliptin
upper resp tract infections - 5% of patients
flu like symptoms e.g headache, runny nose, sore throat
less common but serious allergic reactions-avoid in patients with pancreatitis
extra info on dpp4/sitaglipitn
compared to other antidiabetics (excpt metformin)these dont cause weight gain
effective only when some residual pancreatic beta cell activity is present
what is an example of a sulphonylurea
gliclazide
what is the primary action of sulphonylureas
inhibits atp sensitive potassium channel on pancreatic beta cell. this channel controls beta cell membrane potential. inhibition causes depolarisation which stimulates ca2+ influx and subsequent insulin vesicle exocytosis.
side effect of sulphonylureas e.g gliclazide
weight gain - likely side effect
hypoglycaemia - 2nd most common
target site of sulphonylureas
atp sensitive potassium channel
primary site = pancreatic beta cells
extra info on sulphonylureas
mainly act by augmenting insulin secretion therefore only effective when some residual pancreatic b cell activity is present.
weight gain mitigated by metformin
risk of hypoglycaemia should be discussed with patient
what is an example of sodium glucose co transporter sglt2 inhibitors
dapaglifozin
what is the primary action of sglt2 inhibitors
reversibly inhibits sodium glucose co transporter 2 in renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion
what is the target site of sglt2 inhibitors
sglt2 in proximal convoluted tubule
what are the side effects of sglt2 inhibitors
uro genital infections due to increased glucose load - 5% patients
slight decrease in bone formation
can worsen diabetic ketoacidosis - stop immediately
extra info on sglt2 inhibtors
cause weightloss and reduction in bp
less effective in patients with renal impairment
what can be given to adults if hbal1c rises to 48mmol/mol on lifestyle intervention
offer standard release metformin
support individual to aim for hba1c lower than 48
what should be given if patient with diabetes hba1c rises to 58mmol/mol
consider dual therapy of metformin with one of following:
e.g ddp4 inhibitor e.g sitagliptin (100mg/dayoral)
piogiltazone (15-45mg/day oral)
sulphonylureas e.g glicazide (40-80mg/day,oral)
sglt2 inhibitors e.g dapagliflozin (5mg/day,oral)
support to lower hba1c to 53mmol/mol
2nd intensification if hbal1c rises to 58mmol/mol after 1st intensification of meds
consider insulin based treatment / triple therapy with one of following combinations:
metformin, ddp4 and an su
metformin, pioglitazone and an su
metformin, pioglitazone/su and sglt2 inhibitor
support to lower hba1c to 53mmol/mol
metformin is a very polar structure, what is its pka
12.4
even in alkaline tissue is charged
why is metformin administered orally
small bowel oct1 allows it to be absorbed
hepatocyte oct1 allows it to be distributed to site of action
proximal tubule oct1 helps excretion
