oral hypoglycaemics

Question 1

sulfonylurea example and MOA

Answer 1

gliclazide - blocks ATP sensitive potassium channels causing depolarisation and downstream actions causing insulin release

Question 2

sulfonylurea discovery

Answer 2

accidental - from sulphonamide antibiotics lead to hypoglycaemia

Question 3

sulfonylureas in clinic

Answer 3

weigh gain, hypoglycaemia - shorter acting

Question 4

meglitinides example and MOA

Answer 4

nateglinide - blocks ATP sensitive potassium channels causing depolarisation and downstream actions causing insulin release

Question 5

discovery of meglitinides

Answer 5

looking for sulfonylurea acternative

Question 6

GLP-1 agonist discovery

Answer 6

exendin 4 was discovered in 1992 from gila monster saliva

Question 7

GLP-1 agonist use in clinic

Answer 7

dual therapy - insulin production and inhibition of glucagon production, low hypo risk, injectable only!

Question 8

example and MOA of dpp-4 inhibitors

Answer 8

alogliptin - inhibits DPP4 which normally breaks down GLP-1 in the blood - increases glucose dependent insulin secretion

Question 9

discovery of dpp-4 inhibitors

Answer 9

cyan pyrrolidines found to be proline mimetics that covalently bind to dpp4 - reversible found through high throughput screening

Question 10

biguanides example and MOA

Answer 10

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

Question 11

biguanide discovery

Answer 11

from French lilac galega officinialis, diguanides toxic

Question 12

biguanides in practice

Answer 12

requires endogeneous insulin, GIT side effects, no weight gain - popular self medication

Question 13

example and MOA of PPAR gamma agonists

Answer 13

pioglitazone - targets nuclear receptor peroxisome proliferator gamma receptor which regulates transcription

Question 14

discovery of PPAR gamma agonists

Answer 14

1953 - substituted acetic acids have hypocholesteraemia effects, 1982 first ppar ligand identified

Question 15

PPAR gamma uses in clinic

Answer 15

can be used in combination with metformin, sulfonylureas and insulin, no hypos - but weight gain and fluid retention

Question 16

SGLT2 inhibitor examples and MOA

Answer 16

dapagliflozin - targets sodium glucose co transporter 2 in the kidney to increase glucose being excreted

Question 17

discovery of SGLT2

Answer 17

phlorizin from tree bark - non selective! final drugs are c-glycosides that are not susceptible to hydrolysis

Question 18

use of SGLT2 in clinic

Answer 18

no weight gain, independent of insulin but can cause glucosuria and UTIS

Question 19

MOA and example of alpha glucosidase inhibitors

Answer 19

acarbose - targets alpha glucosidase in the gut, breaks down short chain oligosaccharides for digestion - inhibition reduces glucose absorption from food

Question 20

Alpha glucosidase inhibitors in clinic

Answer 20

GI side effects and independent of insulin secretion