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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
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Biosynthesis of Cholesterol
CH3-C-SCoA OOC-CH2-C-CH2-C-SCoA O OH CH3 acetyl coenzyme A hydroxy-3-methyl-glutaryl-CoA HMG CoA reductase cholesterol -OOC-CH2-C-CH2-CH2-OH OH CH3 mevalonate
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Metabolism of Cholesterol
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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%.
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Lipoprotein Particles
Structure
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Lipoprotein Particles
Classification of lipoprotein particles Composition Density Size Chylomicrons TG >> C, CE Low Large VLDL TG > CE IDL CE > TG LDL CE >> TG HDL High Small
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Transport of Lipoprotein Particles
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Hyperlipidemia Types of hyperlipidemias I IIa IIb III IV V Lipids
Cholesterol N- Triglycerides N Lipoproteins Chylomicrons VLDL LDL HDL N = normal, = increase; = decrease; = slight increase; = slight decrease
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Strategy for Controlling Hyperlipidemia
STATINS Diet Biosynthesis HMG CoA reductase Ezetimibe Cellular Cholesterol LDL-R Serum Cholesterol Bile Acids Intestine Re-absorption Lipoprotein catabolism Conversion to hormones within cells or storage as granules Feces BILE ACID SEQUESTRANTS FIBRATES
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Anti-hyperlipidemic Drugs - Statins
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Anti-hyperlipidemic Drugs - Statins
Atorvastatin Cerivastatin Fluvastatin Rosuvastatin Pitavastatin
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Anti-hyperlipidemic Drugs - Statins
Rationale – competitive binding For example, Mevastatin Lovastatin Simvastatin Fluvastatin Atorvastatin Cerivastatin HMG CoA substrate
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Anti-hyperlipidemic Drugs - Statins
Pharmacokinetic properties of statins – case of cerivastatin Bioavail. Dosage (mg) Protein Binding Metabolites Atorvastatin ~14% 10 – 80 >98% Active Cerivastatin ~60% 0.2 – 0.3 >99% Fluvastatin ~24% 98% Lovastatin ~5% >95% Pravastatin ~17% 10 – 40 ~50% Simvastatin ~95% 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.
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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
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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
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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}
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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
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Anti-hyperlipidemic Drugs – Bile Acid Sequestrants
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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
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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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