3.4.3. Hypolipidemic Drugs

Question 1

What are HMG-CoA reductase inhibitors also known as?

Answer 1

Statins

Question 2

What are a few examples of statins?

Answer 2

Lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin

Question 3

What is the mechanism of action of statins?

Answer 3

Inhibit rate-determining step in cholesterol synthesis . This and niacin best for decreasing LDL and TG

Question 4

What are the effects of statins on LDL, HDL, and TGs?

(TG = triglyceride)

Answer 4

LDL

↓↓↓

HDL

↑

TGs

↓

Question 5

What are some side effects of statins?

Answer 5

Increased LFTs (liver function tests), myositis, hepatotoxicity, rhabdo

Question 6

What are some examples of bile acid resins?

Answer 6

Cholestyramine, colestipol, colesevelam

Question 7

How do bile acid resins work?

Answer 7

Bind bile salts in the intestine thus preventing their reabsorption (along with cholesterol) in the intestine

Question 8

What is the effect of bile acid resins on LDL, HDL, and TGs?

Answer 8

LDL

↓↓

HDL

-

TGs

Mild Increase

Question 9

What are some side effects of bile acid resins?

Answer 9

Bad taste, bloating, constipation, impaired absorption of fat-soluble vitamins

Question 10

What is an example of a cholesterol absorption inhibitor?

Answer 10

Ezetimibe

Question 11

How do cholesterol absorption inhibitors work?

Answer 11

Block absorption of cholesterol in the small intestine

Question 12

What are the effects of cholesterol absorption inhibitors on LDL, HDL, and TGs?

Answer 12

LDL

↓↓

HDL

-

TGs

-

Question 13

What are the side effects of cholesterol absorption inhibitors?

Answer 13

Rarely increased LFTs, GI distress

Question 14

What are some examples of fibrates/fibric acids?

Answer 14

Gemfibrozil, fenofibrate, clofibrate

Question 15

What is the mechanism of action of fibrates?

Answer 15

Increase synthesis of lipoprotein lipase via activation of peroxisome proliferator-activated receptor-α (PPAR-α), contraindicated with hyperlipidemia

Question 16

What are the effects of fibrates on LDL, HDL, and TGs?

Answer 16

LDL

↓

HDL

↑

TGs

↓↓↓

Question 17

What are the side effects of fibrates?

Answer 17

Myositis, increased LFTs, gallstones

Question 18

What is the mechanism of action of niacin?

Answer 18

Decreases formation and secretion of VLDL resulting in less formation of LDL

Question 19

What is the effect of Niacin on LDL, HDL, and TGs?

Answer 19

LDL

↓↓

HDL

↑↑

TGs

↓

Question 20

What is a side effect of niacin?

Answer 20

Flushed face (can be prevented by aspirin) hepatotoxicity

Question 21

What are the risk factors for CHD?

Answer 21

• Age: men > 45, women > 55
• Low HDL cholesterol (<40 mg/dl)
• Total cholesterol > 200 mg/dl
• Blood pressure ≥ 140/90
• Cigarettes
• Obesity
• Diabetes (particularly type 2) - red flag
• A family history of premature death due to CHD - red flag

Question 22

What is the pathogenesis of CHD (Coronary Heart Disease)

Answer 22

• Endothelial cell dysfunction
• macrophage and LDL accumulation
• foam cell formation (macrophage + oxidized cholesterol/LDL)
• fatty streaks form
• smooth muscle cell migration (involves platelet-derived growth factor and fibroblast growth factor), proliferation, and extracellular matrix deposition
• fibrous plaque formation
• complex atheromas form

Question 23

What is a more detailed (than before) Mechanism of Action (MoA) for statins?

Answer 23

• competitively inhibit 3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG-CoA) reductase in the liver (primary action)
  
  • mevalonate, a precursor to cholesterol, is normally produced in a rate-limiting step. This step is catalyzed by HMG-CoA reductase.
• intra-hepatic cholesterol synthesis is reduced
• LDL receptors on hepatocytes are upregulated by ~180%
• increased clearance of lipoproteins containing Apo B and Apo E (such as VLDL, IDL, LDL)

Question 24

What are some indications for using statins?

Answer 24

most hyperlipidemias

Familial Hypercholesterolemia

Combined Hyperlipidemia

Question 25

What are some ways that statins protect the heart outside of their cholesterol effects?

Answer 25

* they improve the ability of endothelial cells to make NO, thus dilating arterioles * they appear to stabilize plaques by decreasing their lipid content and making them less likely to rupture * they may be anti-inflammatory because they decrease CRP * Rosuvastatin has been found to reduce thrombotic events by 43%! * if given immediately post-MI, statins decrease the risk of death by half!

Question 26

Lovastatin, simvastatin, atorvastatin are all metabolized by what?

Answer 26

Lovastatin, simvastatin, atorvastatin are all metabolized by CYP 3A4 ROSUVASTATIN IS NOT METABOLIZED BY THIS

Question 27

Drugs that INDUCE CYP 3A4 → DECREASE statin activity

Answer 27

Phenytoin Barbiturates Rifampin, etc

Question 28

Drugs that INHIBIT CYP 3A4 → INCREASE statin activity

Answer 28

Cyclosporine Verapamil Ritonavir Ketoconazole, etc

Question 29

Describe the major side effect associated with both statins and fibric-acid derivatives

Answer 29

side effects of Gemfibrozil and Fenofibrate: * skin rash * GI upset * myopathy (especially with gemfibrozil) → increased risk of rhabdo if combined with a statin * anemia

Question 30

Name two compounds that can increase HDL

Answer 30

* Statins - these two here are the ballers of the statin game * Atorvastatin raises HDL by 2-6% * Rosuvastatin raises HDL by ~8-10%​​ * ​Niacin (nicotinic acid) (Vitamin B3) - it’s unclear whether or not raising HDL w/niacin benefits Pts, but it does raise HDL..

Question 31

How can we try to ensure the least facial flushing with niacin?

Answer 31

the least facial flushing occurs w/intermediate-release niacin

Question 32

What do we see with slow release niacin?

Answer 32

some hepatotoxicity is seen w/slow release niacin

Question 33

What are the indications for use of niacin?

Answer 33

* used alone for hypertriglyceridemia * used w/statins for heterozygous familial hypercholesterolemia * also useful in combination w/ atorvastatin or rosuvastatin for homozygous familial hypercholesterolemia

Question 34

What are some side effects of niacin?

Answer 34

* flushing (due to increased PGD2, but can be reduced w/aspirin or laropiprant, a PD2 antagonist) * pruritus, rashes * hyperuricemia * hepatotoxicity w/slow release preps

Question 35

Which of the two fibric acid derivatives is the better choice in general?

Answer 35

Fenofibrate = better choice b/c it has fewer side effects

Question 36

What are the actions of fibrates?

Answer 36

* acts as a ligand at PPAR-alpha receptors (involved in transcription regulation) * increases LPLase activity → increased VLDL catabolism seen → serum triglyceride levels are lowered * decreased VLDL synthesis and excretion by the liver * increased HDL by ~10-15% (b/c PPAR-alpha is activated, more ApoA-1 is made) * \*\*\* these decrease the incidence of MI and CHD by 22% ! \*\*\*

Question 37

What are the broad pharmacokinetics of fibrates?

Answer 37

* efficiently absorbed from the GI tract * excreted as a glucuronide conjugate through the kidneys, so these are contraindicated in Pts w/renal failure

Question 38

Why are postmenopausal women at an increased risk of CHD?

Answer 38

* E increases the HDL cholesterol up to 15% and decreases LDL cholesterol approximately 15%. * However, in postmenopausal women, E causes an increased risk of heart disease & breast cancer

Question 39

What are some common drug combinations used to treat common hyperlipidemias?

Answer 39


Question 40

How does chylomicronemia present?

Answer 40

Increased chylomicrons and VLDL

Question 41

How do we treat chylomicronemia?

Answer 41

Niacin and Fibrate

Question 42

How does Familial hypertriglyceridemia present?

Answer 42

Increase in VLDL and chylomicrons

Question 43

Treatment for Familial hypertriglyceridemia

Answer 43

Niacin and fibrate

Question 44

Presentation of Familial Combined Hyperlipoproteinemia

Answer 44

Increased VLDL and REALLY increased LDL

Question 45

Treatment fro Familial Combined Hyperlipoproteinemia

Answer 45

Niacin and Statin (or resin)

Question 46

Presentation of Familial hypercholesterolemia

Answer 46

Heterozygous presents as LDL increase but homozygous, as you might expect, presents with a HUGE LDL increase

Question 47

Treatment for familial hypercholesterolemia

Answer 47

Heterozygous form - Niacin and stain/resin Homozygous form - Niacin and atorvastatin (or rosuvastatin) specifically

Question 48

Presentation of Lp (a) hyperlipoproteinemia

Answer 48

Increase in Lp (a)

Question 49

Treatment for Lp(a) Hyperlipoproteinemia

Answer 49

Niacin and Neomycin