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Anti-Hypercholesterolemic Agents

Anti-Hypercholesterolemic Agents. Biosynthesis and Metabolism of Cholesterol What is arteriosclerosis? - Link between arteriosclerosis and cholesterol Lipoproteins particles - Structure and classification of lipoprotein particles Hyperlipidemias

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Anti-Hypercholesterolemic Agents

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  1. Anti-Hypercholesterolemic Agents • Biosynthesis and Metabolism of Cholesterol • What is arteriosclerosis? - Link between arteriosclerosis and cholesterol • Lipoproteins particles - Structure and classification of lipoprotein particles • Hyperlipidemias - Types and overall strategy to control hyperlipidemias • Anti-hyperlipidemic Agents - Classes • Statins • Fibrates • Bile Acid Sequestrants • Nicotinic Acid • Ezetimibe

  2. O CH3 O CH3-C-SCoA -OOC-CH2-C-CH2-C-SCoA OH acetyl coenzyme A 3-hydroxy-3-methyl-glutaryl-CoA CH3 -OOC-CH2-C-CH2-CH2-OH OH mevalonate cholesterol Biosynthesis of Cholesterol HMG CoA reductase

  3. Metabolism of Cholesterol

  4. Arteriosclerosis Arteriosclerosis is excessive formation and deposition of endogeneous products from blood. In 1984 a 1% drop in serum cholesterol was found to reduce the risk to coronary heart disease (CHD) by nearly 2%.

  5. Lipoprotein Particles Structure

  6. Lipoprotein Particles Classification of lipoprotein particles

  7. Transport of Lipoprotein Particles

  8. Hyperlipidemia Types of hyperlipidemias N = normal, = increase; = decrease; = slight increase; = slight decrease

  9. Biosynthesis Diet LDL-R Cellular Cholesterol Serum Cholesterol Conversion to hormones within cells or storage as granules Bile Acids Re-absorption Intestine Lipoprotein catabolism Feces Strategy for Controlling Hyperlipidemia STATINS HMG CoA reductase Ezetimibe BILE ACID SEQUESTRANTS FIBRATES

  10. R R R R Anti-hyperlipidemic Drugs - Statins

  11. Anti-hyperlipidemic Drugs - Statins Atorvastatin Cerivastatin Fluvastatin Rosuvastatin Pitavastatin

  12. HMG CoA substrate For example, Mevastatin Lovastatin Simvastatin For example, Fluvastatin Atorvastatin Cerivastatin Anti-hyperlipidemic Drugs - Statins Rationale – competitive binding

  13. Anti-hyperlipidemic Drugs - Statins Pharmacokinetic properties of statins – case of cerivastatin Typically all statins possess side effects. The most dominant side effect, cited in the withdrawal of cerivastatin, is rhabdomyolysis (lysis of rhabdomyose) or weakening of skeletal muscles.

  14. Anti-hyperlipidemic Drugs - Statins Metabolic properties of statins • Rapid first pass metabolism significantly reduces bioavailability • Metabolism is complex • Extensive conversion between the lactone and open-chain forms • Glucuronidated forms as well • Other than these three, many other lesser metabolites • Inhibitors of cytochrome P450 increase bioavailability of statins ….. Greater incidences of myopathy ….. E.g., cyclosporin, gemfibrozil, erythromycin, itraconazole, etc. • Rhabdomyolysis …. A rare complication of statin treatment …. Characterized by breakdown of muscles ….. Release of myoglobin into blood, which travels to kidneys and stops working of its tubules …. Also muscle breakdown increase K+, which induces cardiac arrythmias and death

  15. Anti-hyperlipidemic Drugs - Fibrates • Older generation drugs; introduced in 1981 • Second most useful anti-hyperlipidemic drugs • Primarily decrease serum triglycerides • Increase lipoprotein catabolism; increase TG usage by the body • activate PPAR-a (peroxisome proliferator-activated receptor a) • Most used in Type III, IV and V hyperlipidemias

  16. Anti-hyperlipidemic Drugs - Fibrates {No longer recommended because of an increase in overall mortality and adverse events} {rhabdomyolysis … highest PPAR-a affinity  clinical trials stopped in the US}

  17. Anti-hyperlipidemic Drugs – Bile Acid Sequestrants • Anion exchange resins • Water insoluble and inert to digestive enzymes • Not absorbed through the GI tract • Positively charged nitrogens sequester bile acid re-absorption • Lower serum LDL levels • Most useful in type IIa and IIb hyperlipidemias

  18. Anti-hyperlipidemic Drugs – Bile Acid Sequestrants

  19. Anti-hyperlipidemic Drugs – Nicotinic Acid • Administered in large doses (0.5 to 6 grams daily) • Reduces triglycerides and total cholesterol • Increases biliary secretion of cholesterol, but not bile acids • Useful in Type IIa, IIb, III, IV and V hyperlipidemias

  20. Anti-hyperlipidemic Drugs – Ezetimibe • Approved in October 2002 • Reduces serum LDL, TC, and TG and increases HDL • Prevents the absorption of cholesterol from diet • Useful in Type IIa, IIb, III, IV and V hyperlipidemias

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