Anti-Atherosclerotic DrugsAntiatherosclerotic DrugsI. Introduction/SignificanceAtherosclerosisAffects large and medium sized arteries.Focal plagues within the intima containing cholesterol and cholesterol esters (CE).Causes Coronary Heart Disease.HypercholesterolemiaHigh serum cholesterol levelElevated LDL and triglycerides (TG) - associated with increased risk. Serum levels of HDL - inversely related to risk.II. Regulation of cholesterol and triglyceride metabolismA. Exogenous pathway: Route of uptake of dietary lipids.Chylomicrons (CM) - complexes of TG, CE and apoproteins. Chylomicron remnants - CM after removal of most TG.CM are degraded by lipoprotein lipase on endothelial cells of adipose tissue and muscle. After removal of TG for storage, the CM remnants are transported to the liver.Results: Dietary TG stored in adipose tissue and muscle. Cholesterol is stored in liver or excreted into the bile as cholesterol or bile acid.B. Endogenous pathway: Route for distribution of CE from liver to target cells.VLDL - secreted by the liver to plasma and transported to adipose tissue and muscle where lipoprotein lipase extracted most TG. The remnant IDL is either taken up by the liver and circulated until the remaining TG are removed forming LDL particles which are rich in cholesterol. LDL is cleared from plasma through LDL receptor-mediated endocytosis. Results: Transfer of TG from liver to target cells via VLDL; Transfer of CE from liver to target cells via LDL; Feedback regulation of cholesterol homeostasis by LDL receptor expression; Creation of a steady-state LDL-CE reserve in plasma. C. Reverse transport of cholesterol: Route for cholesterol recovery. As cell dies and the cell membrane turnover, free cholesterol is released into the Page 1Anti-Atherosclerotic Drugsplasma. It is immediately absorbed onto HDL particles, esterified with a long chain fatty acid by Lecithin:cholesterol acyltransferase (LCAT), and transferred to VLDL or IDL by a cholesteryl ester transfer protein in plasma. Eventually, it is taken up by the liver as IDL or LDL.Results: Recovery of cholesterol from cell membranes and reincorporation into LDL pool or return to liver.D. De novo cholesterol biosynthesis Liver synthesizes 2/3 of cholesterol made by the body. The rate limiting enzyme is 3-hydroxy 3-methyl glutaryl (HMG)-CoA reductase.Results: Provide feedback regulation by cholesterol concentrations in cells.E. Cholesterol excretion by enterohepatic circulationBile salts are synthesized from cholesterol in the liver, released into the intestine, and recycled. A small amount of bile acid is excreted.Results: Conversion of liver cholesterol to bile salts for excretion.III. Pathogenesis of atherosclerosisCurrent model of the formation of atherosclerotic plaque: chronic inflammatory response of the vascular wall to endothelial injury or dysfunction.Elevated LDL levels increases its probability to penetrate the endothelial lining of blood vessels. Oxidation of transmigrated LDL particles modifies apoproteins on LDL, and renders it recognizable to scavenger receptors of macrophages forming foam cells. Fatty streaks are made up largely of foam cells.Further responses: Proliferation of smooth muscle cells, platelet aggregation, deposition of extracellular matrix.IV. Genetic defects of lipid metabolismA. MonogenicFamilial hypercholesterolemia (homozygous or heterozygous) Defect: inactive LDL receptorFamilial lipoprotein lipase deficiency Defect: inactive lipoprotein lipaseFamilial combined hyperlipidemia Defect: unknownB. Polygenic/multifactorial - commonly encounteredHypercholesterolemiaHypertriglyceridemiaPage 2Anti-Atherosclerotic Drugs1.2.1.2.1.2.3.1.2.3.4.V. Therapeutic strategy of atherosclerosisA. Identify patients at riskRoutine screening of serum cholesterol Assessment of contributing risk factorsB. Non-pharmacologic therapyDiet modification Lifestyle modificationC. Pharmacologic therapy VI. Drug therapy of hyperlipidemia1. Single drug therapy A. Bile acid sequestrants (colestipol, cholestyramine) Taken orally. Actions: Anion exchange resins which bind negatively charged bile acids in the small intestine. Results: increased conversion of cholesterol to bile acid in hepatocytes; increased synthesis of cholesterol and LDL receptors in hepatocytes; decreased serum LDL and cholesterol levels. Advantages: clinically safe; effective; cost: $500/year. Disadvantages: unpleasant GI effects; interference with GI drug absorption; may exacerbate hypertriglyceridemia (unknown mechanism).B. Niacin (nicotinic acid) Actions: Decrease free fatty acid (FFA) available to the liver for synthesis of triglycerides. Inhibition of a hormone-sensitive lipase involved in lipolysis in adipose tissue. Results: decreased production and release of VLDL by liver; decreased serum levels of VLDL as well as LDL and TG; reduced the clearance of HDL or increased serum level of HDL; increased HDL/LDL ratio. Advantages: long clinical experience; effective; least expensive ($50/year) Page 3Anti-Atherosclerotic Drugs1.2.3.Disadvantage: evokes flushing, itchiness and GI discomfort; contraindicated for diabetic patients; adverse effects in hepatic disease and gout.C. Lovastatin (aka "statins", HMG-CoA reductase inhibitors) Actions: competitively inhibits HMG-CoA reductase, the key enzyme for de novo cholesterol biosynthesis. Results: 1) cells express more LDL receptors; 2) decreased serum LDL levels; 3) suppresses production of VLDL in liver; 4) increased serum HDL levels; 5) increased HDL/LDL ratio. Advantages: specific; effective; well-tolerated. Disadvantages: safety unknown for long term use; most expensive ($900/year)D. Fibrates (U.S.: gemfibrozil; Europe: fenofibrate; prototype: clofibrate) Actions: stimulate lipoprotein lipase; increase the clearance of VLDL and reduces plasma triglyceride levels; decrease VLDL synthesis which also lower serum LDL levels; increase plasma HDL by increase synthesis and/or decrease clearance. Results: decreased serum TG and cholesterol; increased HDL/LDL ratio. Advantage: recent clinical data support safety and efficacy; well-tolerated; cost: $375/year. Disadvantage: more effective in reducing TG than cholesterol; long-term effect not known. Clofibrate is not usable because of toxicity. E. Probucol (lipophilic antioxidant) Action: Taken up by LDL particle and endothelial cells. Inhibits oxidation of LDL and prevents ingestion by macrophage foam cells. Decreases HDL production. Results: decreases