oral hypoglycaemics Flashcards
sulfonylurea example and MOA
gliclazide - blocks ATP sensitive potassium channels causing depolarisation and downstream actions causing insulin release
sulfonylurea discovery
accidental - from sulphonamide antibiotics lead to hypoglycaemia
sulfonylureas in clinic
weigh gain, hypoglycaemia - shorter acting
meglitinides example and MOA
nateglinide - blocks ATP sensitive potassium channels causing depolarisation and downstream actions causing insulin release
discovery of meglitinides
looking for sulfonylurea acternative
GLP-1 agonist discovery
exendin 4 was discovered in 1992 from gila monster saliva
GLP-1 agonist use in clinic
dual therapy - insulin production and inhibition of glucagon production, low hypo risk, injectable only!
example and MOA of dpp-4 inhibitors
alogliptin - inhibits DPP4 which normally breaks down GLP-1 in the blood - increases glucose dependent insulin secretion
discovery of dpp-4 inhibitors
cyan pyrrolidines found to be proline mimetics that covalently bind to dpp4 - reversible found through high throughput screening
biguanides example and MOA
metformin, binds to OTC1 and inhibits complex 1 to decrease ATP:AMP ratio, cAMP is decreased and gene transcription is reduced - gluconeogenesis inhibition and increased insulin sensitivity
biguanide discovery
from French lilac galega officinialis, diguanides toxic
biguanides in practice
requires endogeneous insulin, GIT side effects, no weight gain - popular self medication
example and MOA of PPAR gamma agonists
pioglitazone - targets nuclear receptor peroxisome proliferator gamma receptor which regulates transcription
discovery of PPAR gamma agonists
1953 - substituted acetic acids have hypocholesteraemia effects, 1982 first ppar ligand identified
PPAR gamma uses in clinic
can be used in combination with metformin, sulfonylureas and insulin, no hypos - but weight gain and fluid retention
SGLT2 inhibitor examples and MOA
dapagliflozin - targets sodium glucose co transporter 2 in the kidney to increase glucose being excreted
discovery of SGLT2
phlorizin from tree bark - non selective! final drugs are c-glycosides that are not susceptible to hydrolysis
use of SGLT2 in clinic
no weight gain, independent of insulin but can cause glucosuria and UTIS
MOA and example of alpha glucosidase inhibitors
acarbose - targets alpha glucosidase in the gut, breaks down short chain oligosaccharides for digestion - inhibition reduces glucose absorption from food
Alpha glucosidase inhibitors in clinic
GI side effects and independent of insulin secretion
