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

Biosynthesis of Cholesterol

CH 3 -C-SCoA - OOC-CH 2 -C-CH 2 -C-SCoA O O OH CH 3 acetyl coenzyme A 3-hydroxy-3-methyl-glutaryl-CoA HMG CoA reductase cholesterol - OOC-CH 2 -C-CH 2 -CH 2 -OH OH CH 3 mevalonate Acetoacetyl coenzyme A HMG CoA Synthase

Common numbering system of Cholesterol

Metabolism of Cholesterol

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%.

Lipoprotein Particles Structure

Lipoprotein Particles Classification of lipoprotein particles CompositionDensitySize ChylomicronsTG >> C, CELowLarge VLDLTG > CE IDLCE > TG LDLCE >> TG HDLCE > TGHighSmall

Transport of Lipoprotein Particles

Hyperlipidemia Types of hyperlipidemias IIIaIIbIIIIVV Lipids CholesterolN- TriglyceridesNN- Lipoproteins ChylomicronsNNNN VLDLN- LDLN- HDLNNNN- N = normal, = increase; = decrease; = slight increase; = slight decrease

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

Anti-hyperlipidemic Drugs - Statins R R R R The oyster mushroom, a culinary mushroom, naturally contains lovastatin.

Anti-hyperlipidemic Drugs - Statins Atorvastatin Cerivastatin Fluvastatin Rosuvastatin Pitavastatin

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

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%Active Fluvastatin~24%10 – 8098%Active Lovastatin~5%10 – 80>95% Pravastatin~17%10 – 40~50% Simvastatin~5% ~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.

Anti-hyperlipidemic Drugs - Statins Metabolic properties of statins  Rapid first pass metabolism significantly reduces bioavailability  Metabolism is complex  Glucuronidated forms as well  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

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-  (peroxisome proliferator-activated receptor  Most used in Type III, IV and V hyperlipidemias Anti-hyperlipidemic Drugs - Fibrates

{No longer recommended because of an increase in overall mortality and adverse events} {rhabdomyolysis … highest PPAR-  affinity  clinical trials stopped in the US} Etofibrate

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

Anti-hyperlipidemic Drugs – Bile Acid Sequestrants

precursors for cloestipole

Anti-hyperlipidemic Drugs – Bile Acid Sequestrants precursors for colesevelam

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

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 Ezetimibe Orlistat

Ezetimibe Mechanism of action: - Impairs dietary and biliary cholesterol absorption at the brush border of the intestines without affecting fat-soluble vitamins. - Impairs dietary and biliary cholesterol absorption at the brush border of the intestines without affecting fat-soluble vitamins. - Reducing the pool of cholesterol absorbed from the diet results in a reduced pool of cholesterol available to the liver. - Reducing the pool of cholesterol absorbed from the diet results in a reduced pool of cholesterol available to the liver. -The liver in turn will upregulate the LDL receptor, trapping more LDL particles from the blood and result in a fall in measured LDL cholesterol. -The liver in turn will upregulate the LDL receptor, trapping more LDL particles from the blood and result in a fall in measured LDL cholesterol. Adapted from van Heek M et al Br J Pharmacol 2000;129:

Lomitapide Lomitapide inhibits the microsomal triglyceride transfer protein (MTP or MTTP) which is necessary for very low-density lipoprotein (VLDL) assembly and secretion in the liver AGI-1067

CETP inhibitor A CETP inhibitor is a member of a class of drugs that inhibit cholesterylester transfer protein (CETP). CETP inhibitors inhibit cholesterylester transfer protein (CETP), which normally transfers cholesterol from HDL cholesterol to very low density or low density lipoproteins (VLDL or LDL). Inhibition of this process results in higher HDL levels (the "good" cholesterol-containing particle) and reduces LDL levels (the "bad" cholesterol).

TorcetrapibDalcetrapib Evacetrapib