3.4.3. Hypolipidemic Drugs Flashcards
What are HMG-CoA reductase inhibitors also known as?
Statins
What are a few examples of statins?
Lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin
What is the mechanism of action of statins?
Inhibit rate-determining step in cholesterol synthesis . This and niacin best for decreasing LDL and TG
What are the effects of statins on LDL, HDL, and TGs?
(TG = triglyceride)
LDL
↓↓↓
HDL
↑
TGs
↓
What are some side effects of statins?
Increased LFTs (liver function tests), myositis, hepatotoxicity, rhabdo
What are some examples of bile acid resins?
Cholestyramine, colestipol, colesevelam
How do bile acid resins work?
Bind bile salts in the intestine thus preventing their reabsorption (along with cholesterol) in the intestine
What is the effect of bile acid resins on LDL, HDL, and TGs?
LDL
↓↓
HDL
-
TGs
Mild Increase
What are some side effects of bile acid resins?
Bad taste, bloating, constipation, impaired absorption of fat-soluble vitamins
What is an example of a cholesterol absorption inhibitor?
Ezetimibe
How do cholesterol absorption inhibitors work?
Block absorption of cholesterol in the small intestine
What are the effects of cholesterol absorption inhibitors on LDL, HDL, and TGs?
LDL
↓↓
HDL
-
TGs
-
What are the side effects of cholesterol absorption inhibitors?
Rarely increased LFTs, GI distress
What are some examples of fibrates/fibric acids?
Gemfibrozil, fenofibrate, clofibrate
What is the mechanism of action of fibrates?
Increase synthesis of lipoprotein lipase via activation of peroxisome proliferator-activated receptor-α (PPAR-α), contraindicated with hyperlipidemia
What are the effects of fibrates on LDL, HDL, and TGs?
LDL
↓
HDL
↑
TGs
↓↓↓
What are the side effects of fibrates?
Myositis, increased LFTs, gallstones
What is the mechanism of action of niacin?
Decreases formation and secretion of VLDL resulting in less formation of LDL
What is the effect of Niacin on LDL, HDL, and TGs?
LDL
↓↓
HDL
↑↑
TGs
↓
What is a side effect of niacin?
Flushed face (can be prevented by aspirin) hepatotoxicity
What are the risk factors for CHD?
- 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
What is the pathogenesis of CHD (Coronary Heart Disease)
- 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
What is a more detailed (than before) Mechanism of Action (MoA) for statins?
- 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)
What are some indications for using statins?
most hyperlipidemias
Familial Hypercholesterolemia
Combined Hyperlipidemia
What are some ways that statins protect the heart outside of their cholesterol effects?
- 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!
Lovastatin, simvastatin, atorvastatin are all metabolized by what?
Lovastatin, simvastatin, atorvastatin are all metabolized by CYP 3A4
ROSUVASTATIN IS NOT METABOLIZED BY THIS
Drugs that INDUCE CYP 3A4 → DECREASE statin activity
Phenytoin
Barbiturates
Rifampin, etc
Drugs that INHIBIT CYP 3A4 → INCREASE statin activity
Cyclosporine
Verapamil
Ritonavir
Ketoconazole, etc
Describe the major side effect associated with both statins and fibric-acid derivatives
side effects of Gemfibrozil and Fenofibrate:
- skin rash
- GI upset
- myopathy (especially with gemfibrozil) → increased risk of rhabdo if combined with a statin
- anemia
Name two compounds that can increase HDL
- 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..
How can we try to ensure the least facial flushing with niacin?
the least facial flushing occurs w/intermediate-release niacin
What do we see with slow release niacin?
some hepatotoxicity is seen w/slow release niacin
What are the indications for use of niacin?
- used alone for hypertriglyceridemia
- used w/statins for heterozygous familial hypercholesterolemia
- also useful in combination w/ atorvastatin or rosuvastatin for homozygous familial hypercholesterolemia
What are some side effects of niacin?
- flushing (due to increased PGD2, but can be reduced w/aspirin or laropiprant, a PD2 antagonist)
- pruritus, rashes
- hyperuricemia
- hepatotoxicity w/slow release preps
Which of the two fibric acid derivatives is the better choice in general?
Fenofibrate = better choice b/c it has fewer side effects
What are the actions of fibrates?
- 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% ! ***
What are the broad pharmacokinetics of fibrates?
- efficiently absorbed from the GI tract
- excreted as a glucuronide conjugate through the kidneys, so these are contraindicated in Pts w/renal failure
Why are postmenopausal women at an increased risk of CHD?
- 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
What are some common drug combinations used to treat common hyperlipidemias?
How does chylomicronemia present?
Increased chylomicrons and VLDL
How do we treat chylomicronemia?
Niacin and Fibrate
How does Familial hypertriglyceridemia present?
Increase in VLDL and chylomicrons
Treatment for Familial hypertriglyceridemia
Niacin and fibrate
Presentation of Familial Combined Hyperlipoproteinemia
Increased VLDL and REALLY increased LDL
Treatment fro Familial Combined Hyperlipoproteinemia
Niacin and Statin (or resin)
Presentation of Familial hypercholesterolemia
Heterozygous presents as LDL increase but homozygous, as you might expect, presents with a HUGE LDL increase
Treatment for familial hypercholesterolemia
Heterozygous form - Niacin and stain/resin
Homozygous form - Niacin and atorvastatin (or rosuvastatin) specifically
Presentation of Lp (a) hyperlipoproteinemia
Increase in Lp (a)
Treatment for Lp(a) Hyperlipoproteinemia
Niacin and Neomycin
