Antihyperlipidemic agents

Question 1

What are the HMG CoA Reductase Inhibitors? (3)

Answer 1

1. Lovastatin
2. Simvastatin
3. Atorvastatin

Question 2

Statins MOA:

Answer 2

Act as reversible competitive inhibitors for the active site on HMG CoA reductase (the initial rate-limiting step in cholesterol biosynthesis).

Inhibition of an early AND RLS in cholesterol synthesis results in an increased need for exogenous cholesterol; this need is met via the increased uptake of LDL particles.
In response to low levels of endogenous cholesterol, SREBPs are cleaved and enhance the txn and synthesis of LDL receptors.

Question 3

Statins bioavailability and metabolism:

Answer 3

Lovastatin and simvastatin are both administered as an inactive lactone, which is then hydrolyzed to the beta-hydroxy acid.

Atorvastatin is administered in active form. Has the highest half-life of the 3.

All 3 metabolized by CYP3A4.

Question 4

Statins major side effect:

Answer 4

Myopathy and rhabdomyolysis.

Dose-related.

Risk for myopathy is greater when taking gemfibrozil.

Question 5

Statins contraindications:

Answer 5

Pregnancy

Question 6

Statins effect on lipid profile:

Answer 6

Lower TGs (more so if TG are originally high).
Slightly increase HDL.
Lower LDL.

1st line therapy in patients who are at high risk for MI.

Question 7

Cholestyramine MOA:

Answer 7

Anion-exchange resins that readily exchange chloride ions for bile salts in the small intestine and increase bile acid excretion in the feces.

Ultimately lowers the feedback inhibition by bile acids on 7-alpha hydroxylase and results in increased cholesterol catabolism. Liver will thus increase LDL receptor number.

Question 8

Cholestyramine adverse effects:

Answer 8

Nausea, constipation, abdominal cramps, bloating, flatulence.

Question 9

Cholestryamine effect on lipid profile:

Answer 9

*In patients with high TGs can significantly increase them even more.

Question 10

Ezetimibe MOA:

Answer 10

Inhibits cholesterol transfer from intestinal lumen into intestinal cell. Binds to NPCL1, results in decreased rate of cholesteryl ester incorporation into chylomicrons; reduced flux of cholesterol from intestine to liver; reduced flux of cholesterol to VLDL.

Lowers LDL by increased expression of LDL receptors.

Question 11

Ezetimibe clinical use:

Answer 11

Monotherapy for treatment of hypercholesterolemia in patients that are resistant to statin therapy.

Can be used in combination with simvastatin, but increased risk of myopathy.

Question 12

Niacin MOA:

Answer 12

In adipose tissue: inhibits breakdown of TG by hormone sensitive lipase (decreases TG synthesis in liver).

In liver: decreases synthesis of VLDL (and thus LDL).

Increases HDL and HDL biogenesis by inhibiting hepatocyte surface expression of B-chain ATP synthase and increasing hepatic expression of ABCA1.

Question 13

Niacin effect on lipid profile:

Answer 13

Lowers TG.

Lowers LDL

• Increases HDL
• Lowers Lp(a)

Question 14

What are the fibric acids? (2)

Answer 14

1. Gemfibrozil

2. Fenofibrate

Question 15

Fibric acids MOA:

Answer 15

Bind to PPAR, ultimately result in increased lipolysis and plasma clearance of TG-rich lipoproteins.

Also reduce the availability of FFA for TG synthesis; inhibition of de novo fatty acid synthesis; increases HDL cholesterol.

Question 16

Fibric acids kinetics:

Answer 16

Half life of fenofibrate is a lot more than gemfibrozil.

Question 17

Fibric acids adverse effects:

Answer 17

Generally well-tolerated, contraindicated in patients with renal failure.

Concurrent use of gemfibrozil and statins are associated with increases in CK, ultimately leading to renal failure.

Question 18

Fibric acids effect on lipid profile:

Answer 18

Main effect is on decreasing TG. Will decrease LDL, but highly variable.

Question 19

Fibric acids clinical use:

Answer 19

Approved primarily for treatment in individuals with very high serum TGs (greater than 750 mg/dl).

Question 20

Drugs of choice for hypercholesterolemia:

Answer 20

1. Statin
2. Cholestyramine
3. Ezetimibe
4. Niacin (useful for patients with both high TG and low HDL)

Question 21

Drugs of choice for hypertriglyceridemia:

Answer 21

1. Gemfibrozil/fenofibrate
2. Niacin
3. Omega-3 fatty acid

Question 22

Alirocumab MOA:

Answer 22

Targets PCSK9 for destruction, increasing number of available LDL receptors.

Question 23

Alirocumab clinical use:

Answer 23

Adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous FH or clinical atherosclerotic CV disease, who require additional lowering of LDL-C.

Question 24

Lomitapide MOA:

Answer 24

Directly binds and inhibits MTP, prevents the assembly of apo-B-containing lipoproteins; this inhibits the synthesis of chylomicrons and VLDL, and thus LDL-C.

Question 25

Lomitapide clinical use:

Answer 25

Treatment for homozygous FH.

Question 26

Mipomersen MOA:

Answer 26

Targets apoB-100 mRNA and disrupts its function.

*1st in class drug for treatment of homozygous FH.