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Drugs Used in Hyperlipidemia

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Presentation on theme: "Drugs Used in Hyperlipidemia"— Presentation transcript:

1 Drugs Used in Hyperlipidemia
By 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


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