E3: PCSK9/Fibrates/Niacin

Question 1

PCSK9 Inhibitors
General Use
MOA
ADR
Warnings/CI

Answer 1

General Use:
Heterozygous familial hypercholesterolemia
prevention/tx of clinical atherosclerotic CV disease
Statin intolerant

MOA:
-monoclonal antibody that inhibits PCSK9 enzyme
-Human IgG2 antibody binds to circulating PCSK9 enzyme
-Inhibits PCSK9 from binding to LDL receptors on the surface of hepatocytes
-LDL receptors now are allowed to return to the surface and accumulate leading to enhanced LDL clearance from the plasma

ADR:
-Injection site rxn (7-17%)
-symptoms of common cold, influenza (6%)

Warnings:
Hypersensitivity reactions (9%) reported

Question 2

Fibrate Agents (4)
Which one needs to be taken w/food
Which one has the best effects on lipid profile w/in class

Fibrates indication

Answer 2

Fenofibric acid-Fibricor
Fenofibrate-Lipofen: Take w/food
Choline fenofibrate: Trilipix: Best effects on lipid profile w/in class
Gemfibrozil

Indication: ↓ TG (hypertriglyceridemia)

Question 3

SAR of Fibrates
Active compound:
Prodrug:
Salt:

Which is more hydrophilic? Salt or prodrug

Answer 3

Active compound: Fenofibric acid
Prodrug: Fenofibrate
Salt: Choline fenofibrate (more hydrophilic)

Question 4

Functions of PPARα (4)

Answer 4

Functions:
1. Fatty acid oxidation
2. Ketogenesis
3. Lowers plasma triglycerides
4. Increases plasma HDL

Question 5

MOA of Fibrates

Answer 5

MOA: PPAR Agonists
1. Agonist at peroxisome proliferator activated receptors (PPAR-α)
2. Transported into cytoplasm
3. Bind to nuclear receptors
4. ↑synthesis and activity of lipoprotein lipase (LPL)
lipolysis (TG breakdown  fatty acids (FA) from adipose (↓ TG)
5. ↑ mitochondrial FA oxidation in hepatic and muscle cells–> ↓ TG
6. ↑ synthesis of apolipoproteins (apoA-I, apoA-II) results in ↑ HDL in hepatic cells

Question 6

Fibrates ADR
Which agent is most likely to ADR and which is least
DI:

Answer 6

ADR:
1. GI (1-10%): nausea, abdominal pain
- gemfibrozil (dyspepsia up to 20%, abdominal pain 10%)
2. Dermatologic (1-10%): eczema, skin rash
3. Hepatobiliary (<1%): gallstone formation
4. Myopathy (<1%)
—Trilipix least risk
—gemfibrozil more likely

DI:
*Statins with fibrates
each class alone can cause myopathies by different mechanisms
gemfibrozil&raquo_space; fenofibrate > choline fenofibrate-Trilipix®
-the possible benefit of combining gemfibrozil therapy with statins does not outweigh the risks
gemfibrozil ↓ metabolism (glucuronidation) of statins

NOTE: gemfibrozil Inhibits CYP1A2 (moderate), CYP2C19 (strong), CYP2C8 (strong), CYP2C9 (strong)
-fenofibrate can be used with moderate dose statin therapy with enhanced monitoring with only slight  risk of myopathy and rhabdomyolysis
risk of myopathy and rhabdomyolysis with TRILIPIX® and statins is very low

Question 7

Niacin is a ______ soluble vitamin ___3, nicotinic acid
Best class of drugs for ↑_____ & ↓_____

Answer 7

water soluble vitamin B3, nicotinic acid

Best class of drugs for ↑HDL; also decreases TG

Question 8

Niacin
MOA (3)
ADR (4)
CI (4)

Answer 8

MOA
1. Binds to niacin receptors (HCA2-nicotinic acid receptors)
–↓ hormone sensitive lipase (HSL) in adipose tissue
——-↓ fatty acids
2. Inhibits diacylgylerol transferase in liver
——↓ TG in liver  ↓ VLDL  ↓ LDL
3. ↓ catabolism of apolipoprotein A-1 (apoA-I) which  HDL activity

ADR
1. immediate release preps mostly;
Niaspan® extended release tabs only 6%
-↓ effect by: avoid alcohol, avoid hot beverages, spicy foods at same time as dose
-aspirin (325 mg) ,NSAID’s given 30 minutes prior to niacin
-titration of doses w/Niaspan® to prevent
2. GI: dyspepsia
3. hyperglycemia Niaspan® (5%)
4. hepatotoxicity variable on product
OTC sustained release preps > 2000 mg/day monitor LFT’s with all formulations (> 3x upper limit of normal)

CI
1. active liver disease/ monitor LFT’s
2. Peptic ulcer disease
3. Pregnancy (birth defects)
4. Rhabdomyolysis when administered in doses > 1 gm/day with statins