chemistry of oral antidiabetics

Question 1

biguanides physiochemistry

Answer 1

metformin: logP: -1.2 pKa: 12.4
buformin: logP: -1.0 pKa: 12.4
phenformin: logP: -0.8 pKa: 12.0
high pKa due to resonance forms of biguanide stabilising the conjugate acid positive charge so equilibrium lies to left of the dissociation equilibrium (permanently charged)

Question 2

sulfonylureas

Answer 2

glibenclamide: logP 3.5; pKa 5.4
glimepiride: logP 2.8; pKa 5.4
glicazide: logP 2.6; pKa 5.8
glipizide: logP 1.9; pKa 5.9

Question 3

sulfonylureas mechanism of action

Answer 3

stimulate insulin secretion by binding to sulfonylurea receptor 1 sub unit of ATP sensitive K channels in the beta cell plasma membrane

Question 4

meglitinides physiochemistry

Answer 4

nateglinide: logP 3.8; pKa 3.6
repaglinide: logP 5.2; pKa 4..1/6.0

Question 5

glitazones (thiazolidinediones) physiochemistry

Answer 5

rosiglitazone: logP 3.2; pKa 6.1
pioglitazone: logP 3.6; pKa 6.6/5.2
posses the thiazolidinedione (TDZ) moiety

Question 6

glitazones mechanism of action

Answer 6

activate the gamma isoform of the peroxisome proliferator activated receptor (PPAR gamma)
this helps improve insulin sensitivity