Hyperlipidemia - Medchem

Bile Acid Sequestrants

• Structure: positively charged resins, quaternary ammonium groups, sec./tert. Amines, electrostatic interactions 

  • Can bind to any acidic drugs (ex. warfarin) → need to separate drugs (DDI)

• PK: oral, onset of action 1-2 days, excreted in feces

HMGRIs/Stains

• SAR

  • Pharmacophore: 3,5-dihydroxyhepatonic acid (carboxylic acid) and decalin 

  • 3R, 5R stereochemistry at 3 and 5 positions 

• Inactive lactone prodrugs (lovastatin, simvastatin) 

• Pravastatin is active by itself

• PK

  • Peak reduction of plasma cholesterol: 4-6 weeks of therapy (except atorvastatin - only 2 weeks)

  • Elimination half life for atorvastatin and rosuvastatin: ~19hr

Cholesterol Absorption Inhibitor: Ezetimibe

• Small molecule

• Very lipophilic: logP=3.5  → aqueous insolubility, long half life = 22hr 

Fibrates

• SAR

  • Pharmacophore: phenoxy and isobutyric acid 

  • Compounds containing ester are prodrugs → fenofibrate 

• PK: Excellent bioavailability (60-90%)

Nicotinic Acid (Niacin)

• SAR

  • Carboxylic acid has pKa of 4.76 → predominately ionized at physiologic pH 

  • Freely soluble in alkaline solutions 

• PK

  • Peak plasma concentration occur within 45 minutes

  • Half life ~1 hr → frequent dosing or extended release formulation 

  • Primarily excreted unchanged by kidney