1. Drugs Used in HyperlipidemiaBy
Dr. Sasan Zaeri
PharmD, PhD

2. Introduction Cholesterol
Serves as a component of cell membranes and intracellular organelle membranes
Is involved in the synthesis of certain hormones including estrogen, progesterone, testosterone, adrenal corticosteroids
Needed for the synthesis of bile salts which are needed for digestion and absorption of fats

3. Origin of cholesterol Liver
Acetyl CoA is converted to mevalonic acid and ultimately to cholesterol by HydroxyMethyl Glutaryl Coenzyme A (HMG-CoA) reductase
Endogenous synthesis of cholesterol increases at night

4. Lipoproteins
Serve as carriers for transporting lipids (cholesterol and triglycerides) in the blood

5. Lipoproteins

6. Embedded in the lipoprotein shell Three functions
Apolipoproteins
Embedded in the lipoprotein shell
Three functions
Serve as recognition sites for cell-surface receptors; allowing cells to bind and ingest the lipoprotein
Activate enzymes that will metabolize the lipoprotein
↑ structural stability of the lipoprotein

7. Types of
lipoproteins

8. Types of
lipoproteins

9. VLDL (very low density lipoprotein)
Contain triglycerides (TGs) and some cholesterol
Account for nearly all TGs in the blood
Contain Apo B-100
Deliver triglycerides from the liver to adipose tissues and muscles

10. LDL (low density lipoprotein)
“Bad cholesterol”
Contains cholesterol
Accounts for 60-70% of cholesterol in the blood
Contains Apo B-100
Delivers cholesterol to peripheral tissues
Makes the greatest contribution to coronary atherosclerosis
Oxidized LDL contributes to atherosclerotic plaque

11. HDL (high-density lipoprotein)
“Good cholesterol”
Contain cholesterol
Account for 20-30% of cholesterol in the blood
Some contain Apo A-I and Apo A-II
Apo A-I is cardioprotective
Transports cholesterol from the peripheral tissues back to the liver – promotes cholesterol removal
Antiatherogenic

12. Metabolism of Lipoproteins of Hepatic Origin

13. Classification of Plasma Lipid Levels
Total cholesterol
<200 mg/dl
Desirable
HDL-C
<40 mg/dl
Low (consider <50 mg/dl as low for women)
LDL-C
<70 mg/dl
Optimal for very high risk (minimal goal for CHD equivalent patients)
<100 mg/dl
Optimal
Triglycerides
<150 mg/dl
Normal

14. Why to Treat Hyperlipidemia
To prevent or slow progression of atherosclerosis To reduce the risk of coronary artery disease To prolong life

15. Treatment of hyperlipidemia
Non-Pharmacological Therapy – first line treatment
Diet modification
Decrease intake of total fat and especially saturated fat
Increase fiber intake
Increase Omega-3-fatty acids (found in fish)
↑ fruits and vegetables (antioxidants)
↓ simple sugars (sucrose)
Exercise (↑ HDL levels)
Pharmacological Therapy

16. Sites of Drugs Action

17. Treatment of hyperlipidemia
Drug therapy
HMG-CoA Reductase Inhibitors (Statins)
Bile Acid-binding Resins (e.g. Cholestyramine, Cholestipol)
Inhibitors of cholesterol absorption (Ezetimibe)
Niacin (Nicotinic Acid)
Fibric Acid Derivatives (e.g. Gemfibrozil)

18. Statins (Atorvastatin, Lovastatin, Fluvastatin, Simvastatin etc.)
MOA
Inhibits hepatic HMG CoA reductase >>> Inhibition of cholesterol synthesis causes hepatocytes to synthesize more LDL receptors >>> Hepatocytes will remove more LDLs from the blood
Most Effective for ↓ LDL-C
Decrease production of apolipoprotein B-100, thereby ↓ production of VLDL
↓ Plaque cholesterol content and ↓ inflammation at the plaque site (Ani-atherosclorotic properties)

19. STATINS: effects on lipoproteins
LDL-C: 20-55%
TG: 7-45% (for TG>250 mg/dL, the percent is same as that of LDL; for TG<250 mg/dL maximum 25% reduction)
HDL-C: 5-15%

20. Statins-Indication: Used in hypercholesterolemia
Atorvastatin is most efficacious agent for use in severe hypercholesterolemia (>40-50% LDL-C lowering)
↓ LDL within 2 weeks; max reduction in 4-6 weeks
Used in Coronary Artery Disease (CAD)
Clinical trials have shown that they reduce mortality in patients with ischemic heart disease
Used in patients with triglycerides levels higher than 250 mg/dL and with reduced HDL-C levels

21. Some Points about Statins
Statins have high first pass extraction by liver
Prodrugs – lovastatin and simvastatin
Statins have greatest efficacy when taken at night
Atorvastatin has the longest half-life
Tolerated best among other hypolipemic drugs

22. Statins – Adverse Effects
Rash
GI disturbances (dyspepsia, cramps, flatulence, constipation, abdominal pain)
Hepatotoxicity
Myopathy (myositis and rhabdomyolysis)
Risk highest especially in combination with fibrates
Cyp450 3A4 drug interactions
Statins are pregnancy category X

23. Bile Acid-Binding Resins (Cholestyramine and Colestipol)
MOA
Binding to bile acids (the metabolites of cholesterol) in the intestinal lumen and inhibition from their reabsorption >>> ↑ LDL receptors by liver cells to capture more cholesterol and synthesize bile acids

24. Bile-acid binding resins- Indications
Used in hypercholesterolemia (↓ LDL-C %)
Normally used as adjuncts to the statins to ↓ LDL-C (by 50%)
Can be used to relieve pruritis in patients with cholestasis
Can be used for severe digitalis toxicity
Available in powder form (must be mixed with fluid)
Must be taken with meals

25. Bile Acid-Binding Resins- Adverse Effects and Drug Interactions
GI discomfort: (bloating, dyspepsia, nausea, constipation)
Large doses may impair absorption of fats or fat soluble vitamins (A, D, E, and K)
Resins bind many drugs e.g. digoxin, warfarin, tetracycline, thyroxine etc.
These agents should be given either 1 hour before or 4 hours after the resins

26. Inhibitors of cholesterol absorption (Ezetimibe)
MOA:
Prevention of absorption of
dietary cholesterol and
cholesterol that is excreted
in bile >>> ↑ LDL receptors
in liver and ↑removal of
LDL-C from
the blood

27. Ezetimibe- Indication
Used in hypercholesterolemia
As monotherapy, ezetimibe reduces LDL-C by about 18%
When combined with a statin, it is even more effective
Ezetimibe is well tolerated

28. Niacin (Nicotinic acid)

29. Decreases HDL catabolic rate
MOA of Niacin (Nicotinic acid)
Inhibits VLDL secretion into the blood thereby preventing production of LDL
Increases clearance of VLDL via lipoprotein lipase pathway
Inhibits FFA release from adipose tissues by inhibiting the intracellular lipase system
Decreases HDL catabolic rate

30. NICOTINIC ACID: effects on lipoproteins
LDL-C: 5-25 %;
TG: %
HDL-C: %

31. Niacin- Indications Hypertriglyceridemia
Mixed elevation of LDL-C and TG (in combination with statins)
Elevation of TG (VLDL) and low levels of HDL
Start with low dose and gradually increase

32. Niacin - Adverse effects
Flushing
Prostaglandin-mediated
Occurs after drug is started or ↑ dose
Lasts for the first several weeks
Can give 325mg aspirin 30 minutes before morning dose (prevents prostaglandin synthesis)
Nausea and abdominal discomfort
Hyperuricemia, hepatotoxicity
Niacin is NOT well-tolerate

33. Fibrates (Gemfibrozil, Fenofibrate, Clofibrate)
Little or no effect on LDL, ↓VLDL (TG), moderate ↑ of HDL
MOA: Activation of Peroxisome Proliferator-Activated Receptor-α (PPAR- α)
↑ Activity of endothelial lipoprotein lipase
↑ FFA oxidation in hepatocytes
↓ Secretion of VLDL by liver
↑ HDL levels moderately by ↑ Apo AI and Apo AII

34. Hepatic & Peripheral Effects of Fibrates
Hepatic and peripheral effects of fibrates. These effects are mediated by activation of peroxisome proliferator-activated receptor-, which modulates the expression of several proteins. LPL, lipoprotein lipase; VLDL, very-low-density lipoproteins

35. Fibrates - Indications
Hypertriglyceridemia
Mixed elevation of LDL-C and TG (in combination with statins)

36. Fibrates - Adverse Effects
Nausea (most prevalent)
Rashes (prevalent)
Cholesterol gallstones (Gemfibrozil)
Use with caution in patients with biliary tract dx, women, obese people
Myopathy (muscle injury)
Will increase risk of statin-induced myopathy when used together