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 9/18/2018 MEDC 603 Steroids

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%. 9/18/2018 MEDC 603 Steroids

Lipoprotein Particles Structure 9/18/2018 MEDC 603 Steroids

Transport of Lipoprotein Particles 9/18/2018 MEDC 603 Steroids

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 9/18/2018 MEDC 603 Steroids

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 9/18/2018 MEDC 603 Steroids

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 9/18/2018 MEDC 603 Steroids

Anti-hyperlipidemic Drugs - Statins 9/18/2018 MEDC 603 Steroids

Anti-hyperlipidemic Drugs - Statins Atorvastatin Cerivastatin Fluvastatin Rosuvastatin Pitavastatin 9/18/2018 MEDC 603 Steroids

Anti-hyperlipidemic Drugs - Statins Rationale – competitive binding For example, Mevastatin Lovastatin Simvastatin Fluvastatin Atorvastatin Cerivastatin HMG CoA substrate 9/18/2018 MEDC 603 Steroids

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 10 - 80 ~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. 9/18/2018 MEDC 603 Steroids

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 Most used in Type III, IV and V hyperlipidemias 9/18/2018 MEDC 603 Steroids

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 9/18/2018 MEDC 603 Steroids

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 9/18/2018 MEDC 603 Steroids

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 9/18/2018 MEDC 603 Steroids