Pharmacology Flashcards
metformin mechanism
inhibits complex 1 of mitochondrial respiratory chain - reducing efficiency of mitochondrial respiration -> lower ATP
Causing:
- rise in AMP:ATP
- rise in AMP kinase
- reduction in gluconeogenesis
So lowers glucose production and increases glucose utilisation (similar to insulin but independent)
physiological effects of metformin
Lowers hepatic glucose production by decreasing lipogenesis and gluconeogenesis
Increases gut glucose utilisation and metabolism
benefits of metformin
potent glucose lowering (by around 18mmol/mol for HbA1c)
weight loss
CV benefit
low hypoglycaemic risk
negatives of metformin
GI intolerence (1/5 get) MALA = metformin associated lactic acidosis - as it increases lactate production, only issue if kidney disease as cannot clear lactic acid so builds up
example of sulphonylurea
gliclazide
mechanism of sulphonylurea
binds to SUR1 receptor subunit causing Katp channel closure
This causes opening of Ca2+ channels due to rise in membrane potential.
Ca2+ influx = insulin release
So…releases insulin independently of glucose
benefits of sulphonylureas
potent glucose lowering
cheap
negatives of sulphonylureas
weight gain
hypoglycaemia risk as acts independently of glucose - so even if glucose is low will still be stimulating insulin secretion (caution if prescribing to driver)
mechanism of TZDs
Bind and activate PPAR gamma (transcription facotr) causing increased transcription activation of gene targets
physiological effects of TZDs
PPAR gamma present in lots of tissues:
adipocytes: increase differentiation from immature -> mature
Increases fat mass (sc - healthy place to store), removes fat from unhealthy places (liver and muscle)
Increases adiponectin which acts on liver to increase insulin sensitivity
Net result = increased insulin sensitivity
example TZD
pioglitazone
TZD benefits
good efficacy - esp in obese women reduces BP cheap low hypo risk probably CV benefit
TZD negatives
weight gain
fluid retention
# risk
what is the incretin effect?
if take OGTT orally then BG rises and insulin is secreted
if give OGTT IV BG rises to same amount but not as much insulin is released.
so incretins must be released from the gut when glucose is taken orally.
example of incretins
GIP
GLP-1
DPP4i example
gliptins: sitagliptin
DPP4i mechanism
inhibit breakdown of incretins (GLP-1 and GIP) by inhibiting DPP4 - this would usually inactive the incretins
so more circulating GLP-1 and GIP therefore increasing incretin effect and causing an increased insulin release in response to high glucose
NOTE: will only work if triggering pathway is active (ie: when high glucose, insulin is released) - so AMPLIFY this process
benefits of DPP4i
weak glucose lowering
weight neutral
no hypo risk - as will only amplify triggering pathway
negatives of DPP4i
no cv benefit
minimal side effects
possible risk of pancreatitis
mechanism of GLP-1 receptor agonists
modifies GLP-1 making it resistant to breakdown by DPP4i
so increased circulating GLP-1 -> increasing incretin effect -> increasing insulin secretion -> decreasing glucose
GLP-1 also have other beneficial effects: lowers glucagon etc
benefits of GLP-1 RA
potent
weight loss
lowers BP
low risk of hypo
negatives of GLP-1 RA
N+V
increased risk of gallstones, pancreatitis
example of SGLT2i
empaglifozin
mechanism of SGLT2i
inhibit renal sodium glucose transporters (SGLT2) to decrease kidney glucose reabsorption by 25%
so pee out 25% of glucose
