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Drugs Used in H yperlipidemia

Drugs Used in H yperlipidemia. By Dr. Sasan Zaeri PharmD , PhD. 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

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Drugs Used in H yperlipidemia

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  1. Drugs Used in Hyperlipidemia By Dr. SasanZaeri 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 HydroxyMethylGlutaryl 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. 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

  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 (Anti-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/dLand 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 15-20%) • Normally used as adjuncts to the statins to ↓ LDL-C (by 50%) • Can be used to relieve pruritisin 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, thyroxineetc. • 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. 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 HDLcatabolic rate

  30. NICOTINIC ACID: effects on lipoproteins LDL-C: 5-25 %; TG: 20-50 % HDL-C: 15-35 %

  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 • 325mg aspirin 30 minutes before morning dose prevents prostaglandin synthesis • Nausea and abdominal discomfort • Hyperuricemia, hepatotoxicity • Niacin is NOT well-tolerated

  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

  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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