3/29/20111Anti-Atherogenic Drugs:Treatment of HyperlipidemiasKnowledge Objectives:1) Know the mechanism of atherosclerosis as an inflammatory disease mediated through lipid oxidation.2) Know the definition of lipoproteins involved in atherosclerosis.3) Know the exogenous and endogenous pathways involved in cholesterol and triglyceride mechanism.4) Know the dietary management of hyperlipoproteinemia.5) Know the mechanism of action and side effects of bile acid-binding resins, HMG-CoA reductase (cholesterol synthesis) inhibitors, Niacin (niconitic acid), gemfibrozil, and probucol.3/29/20112Atherosclerosis begins with endothelial injury or dysfunction (A) that is characterized by enhanced endothelial permeability and low-density lipoprotein (LDL) deposition in the sub-endothelial space. This is followed by leukocyte adhesion and transmigration across the endothelium. In intermediate stages (B), atherosclerosis is characterized by foam cell formation and an inflammatory response including T-cell activation, the adherence and aggregation of platelets, and further entry of leukocytes into the arterial wall along with migration of smooth muscle cells into the intima. Finally, advanced atherosclerosis (C) is characterized by continued macrophage accumulation, fibrous cap formation, and necrosis in the core of the lesion.New England J. of Medicine, 1999, vol. 340 Mechanism of Atherosclerosis LDL becomes entrapped in the subendothelial space where it is subject to oxidative modification by resident vascular cells such as smooth muscle cells, endothelial cells, and macrophages. Oxidized LDL stimulates monocyte chemotaxis (A), prevents monocyte egress (B), and supports foam cell formation (C). Once formed, oxidized LDL also results in endothelial dysfunction and injury (D), and foam cells become necrotic due to the accumulation of oxidized LDL (E). (From N Engl J Med 337: 408–416, 1997)proliferationAtherosclerosis- an inflammatory disease3/29/20113LipoproteinsHypercholesterolemia• High serum cholesterol level• Consists of elevated LDL and triglyceride (TG) levels: associated with premature coronary artery disease (CAD)• Serum levels of HDL: inversely related to risk• LDL: Low-density lipoproteins; major form in which lipid is recaptured by the liver. “bad cholesterol, most closely associated with cardiac disease.• HDL: High-density lipoproteins; formed in the tissues. “good” cholesterol, involved in removing cholesterol from tissues and protecting against CAD.• TG: Triglycerides; Ester of three fatty acids with glycerol. A major form of fat storage contributes to heart disease.(Definitions)3/29/20114Largest of the lipoproteins;Carry fat from the gut to the other tissuesSecreted by the liver; the initial transporter of cholesterol from the liver to the peripheryRemnants of LDL particles that have been depleted of FFA by lipoprotein lipase3/29/20115Cholesterol and Triglyceride MetabolismExogenous pathwayEndogenous pathwayRoute of uptake of dietary lipidsRoute of distribution of cholesterol esters (CE) from liver to target cellsFree fatty acidFree fatty acidLCAT: lecithin cholesterol acyltransferaseAdipose tissue, muscleAdipose tissue, muscleEndogenous cholesterolChylomicronsChylomicronremnantsVLDLIDLHDLLDLIntestineExtrahepat ictissuesMacro‐phagesFormcellsLiver3/29/20116Cholesterol and Triglyceride MetabolismExogenous pathwayEndogenous pathwayRoute of uptake of dietary lipidsRoute of distribution of cholesterol esters (CE) from liver to target cellsFree fatty acidFree fatty acidLCAT : lecithin cholesterol acyltransferaseAdipose tissue, muscleAdipose tissue, muscleEndogenous cholesterolChylomicronsChylomicronremnantsVLDLIDLHDLLDLIntestineExtrahepat ictissuesMacro‐phagesFormcellsLiver3/29/20117Cholesterol and Triglyceride MetabolismExogenous pathwayEndogenous pathwayRoute of uptake of dietary lipidsRoute of distribution of cholesterol esters (CE) from liver to target cellsFree fatty acidFree fatty acidLCAT : lecithin cholesterol acyltransferaseAdipose tissue, muscleAdipose tissue, muscleEndogenous cholesterolChylomicronsChylomicronremnantsVLDLIDLHDLLDLIntestineExtrahepat ictissuesMacro‐phagesFormcellsLiver3/29/20118Cholesterol and Triglyceride MetabolismExogenous pathwayEndogenous pathwayRoute of uptake of dietary lipidsRoute of distribution of cholesterol esters (CE) from liver to target cellsFree fatty acidFree fatty acidLCAT: lecithin cholesterol acyltransferaseAdipose tissue, muscleAdipose tissue, muscleEndogenous cholesterolChylomicronsChylomicronremnantsVLDLIDLHDLLDLIntestineExtrahepat ictissuesMacro‐phagesFormcellsLiver3/29/20119RAc-CoAHMG-CoACholesterolBile acidsGUTResinsLDLLDLIDLVLDLVLDLLDLLipoproteinlipaseBloodLDLHepatocytesLipidoxidationEndothelialCellsRapoproteins3/29/2011103/29/201111Drug therapy of hyperlipidemiaSingle drug therapyLipid-lowering agentsBile acid resins (cholestyramine, colestipol)HMG-CoA reductase inhibitors (lovastatin, atrovastatin, pravastatin, simvastatin)VLDL secretion inhibitor (Niacin)Lipoprotein lipase stimulants(Fibrates: clofibrate, gemfibrozil, fenofibrate)ProbucolSubclass LDL HDL TGSide effects/problemsTastes bad and causes GI discomfortSafety unknown for long term use;Most expensiveEvokes flushing; itchiness and GI discomfortMore effective in reducing TG than cholesterol; long-term effect not knownHDL decrease, not effective in single drugtherapy; no long term clinical data.Ac-CoAHMG-CoACholesterolBile acidsGUT‐Resins‐LDLHMG‐CoA reductase inhibitorsLDLIDLVLDLVLDLLDLLipoproteinlipaseBloodLDLHepatocytesGemfibrozil+LipidoxidationProbucol‐EndothelialCellsNiacin‐Rapoproteins3/29/201112Cholesterol and Triglyceride MetabolismExogenous pathwayEndogenous pathwayRoute of uptake of dietary lipidsRoute of distribution of cholesterol esters (CE) from liver to target cellsFree fatty acidFree fatty acidLCAT : lecithin cholesterol acyltransferaseAdipose tissue, muscleAdipose tissue, musclecholesterolChylomicronsChylomicronremnantsVLDLIDLHDLLDLIntestineExtrahepat ictissuesMacro‐phagesFormcellsLiverResinsNiacinGemfibrozil+ProbucolHMG‐ CoA reductase inhibitors‐3/29/2011133/29/2011143/29/201115Combined Drug Therapy• Advantages: Synergistic approaches utilize complementary mechanisms of drug actions; reduces effective doses of single drug to prevent side effects.• Hypercholesterol without hypertriglycerides:Bile acid sequestrant plus niconitnic acidBile acid sequestrant plus lovastatinBile acid sequestrant plus lovastatin