Hypoglycemic Drugs

This set of vocabulary flashcards covers the classification, mechanisms of action, pharmacokinetics, and SAR of various hypoglycemic drugs used in the treatment of Diabetes Mellitus.

Sulphonylureas Mechanism of Action

They bind to SUR in $\beta$-cell membranes, closing ATP-dependent $K$-channels, which leads to membrane depolarization, calcium influx, and insulin release.

Sulphonylureas pKa

They are acidic with a $pKa$ of approximately $5$, meaning over $95\%$ exists as a negatively charged conjugate base at blood pH.

Chlorpropamide

A first-generation sulfonylurea with a chloro group that blocks benzylic oxidation, resulting in the longest duration of action.

Acetohexamide

A 1st generation sulfonylurea whose metabolite (reduced acetyl group to secondary alcohol) has 2.5-fold more activity than the parent drug.

Glimepiride

A 2nd generation sulfonylurea metabolized by $CYP2C9$ to an active metabolite (M-1) and then to an inactive metabolite (M-2).

Meglitinides

Drugs with the same mechanism as sulfonylureas but with a more rapid onset and shorter duration ($< 1\,hr$), resulting in lower hypoglycemia risk.

Repaglinide

A meglitinide that is not tissue specific and binds to SUR1, SUR2A, and SUR2B found on cardiac and smooth muscle cells.

Nateglinide

A phenylalanine analog of meglitinide that binds selectively to SUR1 on $\beta$-cells and closes ATP-sensitive $K$-channels 3-fold more rapidly than repaglinide.

Thiazolidinediones (Glitazones)

Selective agonists to $PPAR\text{-}\gamma$ that improve insulin sensitivity in muscles and adipose tissues and decrease hepatic gluconeogenesis.

Troglitazone

The first marketed glitazone, containing a trimethyl chromanol moiety similar to $\alpha$-tocopherol (Vitamin E), but withdrawn due to hepatotoxicity/CV effects.

Biguanides (Mechanism)

Insulin sensitizers that increase glucose uptake, decrease gluconeogenesis, and increase glycolysis via activation of AMP-dependent protein kinase.

Metformin

An anti-hyperglycemic drug that does not induce weight gain and is useful for insulin-resistant obese patients; it is excreted unmetabolized in urine.

$\alpha$-Glucosidase Inhibitors

Drugs that catalyze the inhibition of membrane-bound enzymes in the small intestine to decrease the absorption of dietary carbohydrates.

Acarbose

A natural oligosaccharide and competitive inhibitor of sucrase used to prevent postprandial hyperglycemia in Type II diabetes.

DPP-4 Inhibitors (Gliptins)

Drugs that inhibit the dipeptidyl peptidase-4 enzyme to prevent the deactivation of incretin hormones GLP-1 and GIP.

Vildagliptin and Saxagliptin Chemical Feature

They contain a cyano (CN) group at the 2-position of the pyrrolidine ring, which forms a covalent imidate adduct with $Ser630$ for irreversible inactivation.

Saxagliptin Potency

A DPP-4 inhibitor that is $10$ times more potent than either vildagliptin or sitagliptin.

Linagliptin

A xanthine-derived DPP-4 inhibitor that is $85\%$ excreted unchanged via the feces and binds extensively to plasma proteins.