Lipid Lowering

Question 1

Niacin

Answer 1

Class: Nicotinic Acid Preparations
Use: Rx hyperlipidemias, ↑HDL
MOA: Massive dose (>1gm/day) blocks FFA release from adipose tissue (GPCR-mediated) and hepatic VLDL synthesis (less FFAs available)
Effect: ↓TGs/LDL, ↑HDL by blocking ApoA1 hepatic uptake
AE: Liver damage, cutaneous flush (Pg-mediated, take ASA), GI

Question 2

Gemfibrozil

Answer 2

Class: Fibric Acids
Use: Reduce TG, ↑HDL
MOA: Activate PPAR-α, ↓TG by ↑LPL activity/FA oxidation, ↓LDL secretion from liver, ↑LDL recepors, ↑HDL by Apo-A1/2 expression
Effect: ↓TG (↑LPL), ↓LDL (↑LDL recepors), ↑HDL (Apo-A1/2 genes)
Metabolism: Hepatic glucuronidation
AE: Can increase LDL, dyspepsia, gallstones, increased SkM side effects with statins

Question 3

Cholestyramine

Answer 3

Class: Bile Acid Binding Resins
Use: Lowers LDL
MOA: Bind bile in intestines (Cl- for bile acid), ↑cholesterol→bile conversion, ↑LDL receptors
Effect: ↑LDL clearance→ ↓LDL, ↑Serum TG
Metabolism: Limited bioavailability
AE: ↑TG during therapy (more CE production/VLDL release), GI side effects (Constipation, impaired fat absorption), can’t take with anionic drugs

Question 4

Atorvastatin

Answer 4

Class: Statins
Use:↓LDL, plaque regression/stabilization, ↓inflammation/thrombogenicity/endothelial dysfunction
MOA: HMG-CoA reductase competitive inhibition, ↑LDL receptor (protease→Sterol regulatory element binding protein in ER binds LDL-receptor promoter) ↑hepatic clearance of LDL and VLDL, ↓ intrahepatic cholesterol → ↓VLDL production
Effect: ↓LDL-cholesterol 25-60%, slight ↑HDL/↓TG, weeks to reach full effect, reduce risk of MI/stroke
Metabolism: Varies by drug: hepatic by OATP, CYP2D6/3A4/2C9, sulfation, longer t½ with newer agents
AE/Comment: Teratogenic, ↑Serum hepatic enzymes, Myopathy (SkM inflammation/pain, ↑CK) genotype variation in uptake. Pravastatin doesn’t use 3A4, best option for co-therapy with CYP450 inhibitors (erythromycin, ketoconazole, HIV protease inhibitors, grapefruit juice)

Question 5

Ezetimibe

Answer 5

Class: Cholesterol absorption inhibitor
Use: Additive decrease with statin use
MOA: Blocks intestinal CE absorption by NPC1L1 transporter (intestinal mucosa)
Effect: Reduce LDL 20%
AE/Comment: Doesn’t reduce plaque size, may increase cancer risk, less effective than niacin+statin