Anti-Atheroscrerotic Drugs
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1 Anti-Atheroscrerotic Drugs Masuko Ushio-Fukai, PhD, FAHA Dept. of Pharmacology University of Illinois at Chicago Anti-Atherogenic Drugs: Treatment of Hyperlipidemias Knowledge 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 metabolism. 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), Fibrates, and Ezetimibe. 1
2 I. Introduction/Significance Atherosclerosis Focal plaques within the intima containing cholesterol and cholesterol esters (CE). Affects large and medium sized arteries. Causes coronary heart diseases 2
3 Mechanism of Atherosclerosis A) Atherosclerosis begins with endothelial injury or dysfunction that is characterized by enhanced endothelial permeability and low-density lipoprotein () deposition in the sub-endothelial space. This is followed by leukocyte adhesion and transmigration across the endothelium. B) In intermediate stages, atherosclerosis is characterized by foam cell formation and an inflammatory response including T-cell activation, platelet adhesion and aggregation, and further entry of leukocytes into the arterial wall along with migration of smooth muscle cells into the intima. C) Finally, advanced atherosclerosis is characterized by continued macrophage accumulation, fibrous cap formation, and formation of necrotic core. New England J. of Medicine, 1999, vol. 340 Hypercholesterolemia High serum cholesterol level Elevated and triglycerides (TG)- associated with increased risk. Serum levels of HDL-inversely related to risk. (Definitions) : 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. 3
4 Largest!of!the! lipoproteins!and! formed!in!the! intestine. Carry!fat!from!the! gut!to!the!blood! stream Secreted!by!the! liver;!the!initial! transporter!of! cholesterol!from! the!liver!to!the! peripheral!tissue Remnants!of!!particles! depleted!of! triglycerides!!by! lipoprotein! lipase Remnants!of! IDL!depleted!of! triglycerides Lp(a)! Lipoprotein 4
5 II. Regulation of cholesterol and triglyceride metabolism Cholesterol and Triglyceride Metabolism Exogenous pathway Route of uptake of dietary lipids Endogenous pathway Route of distribution of cholesterol esters (CE) from liver to target cells Intestine Endogenous!cholesterol Liver Extrahepatic tissues Macro" phages Chylomicrons Chylomicron remnants V IDL HDL Form cells Lipoprotein!lipase Lipoprotein!lipase Free!fatty!acid Free!fatty!acid LCAT:!lecithin!cholesterol! acyltransferase Adipose!tissue,!muscle Adipose!tissue,!muscle 5
6 Exogenous pathway A. Exogenous Pathway: Route for uptake of dietary lipids. Intestine Chylomicrons cholesterol Liver Chylomicron remnants 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, CM remnants are transported to the liver. Lipoprotein!lipase Free!fatty!acid Adipose!tissue,!muscle Results: Dietary TG is 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. V-secreted by the liver to plasma and transported to adipose tissue and muscle where lipoprotein lipase extracted TG. The remnant IDL is either taken up by the liver or circulates until the remaining TG is removed. is cleared from plasma by receptor-mediated endocytosis. Results 1) Transfer of TG from liver to target cells via V 2) Transfer of CE from liver to target cells via 3) Feedback regulation of cholesterol homeostasis by receptor expression 4) Creation of a steady state -CE reserve in plasma 6
7 C. Reverse Transport of Cholesterol: Route for cholesterol recovery. As cell dies and the cell membrane turn over, free cholesterol is released into the plasma. It is immediately absorbed onto HDL particles, esterified with a long chain fatty acid by lecitin:cholesterol acyltransferase (LCAT), and transferred to V or IDL by a cholesterol ester transfer protein in plasma. Eventually, it is taken up by the liver as IDL or. Results Recovery of cholesterol from cell membranes and reincorporation into 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-hydroxyl 3-methyl glutaryl (HMG)CoA reductase. Results: Provide feedback regulation by cholesterol concentrations in cells. GUT Hepatocytes Ac-CoA HMG-CoA R Cholesterol Bile acids R Blood IDL V V Endothelial Cells Lipoprotein lipase Resins Lipid oxidation apoproteins 7
8 E. Cholesterol excretion by enterohepatic circulation Bile acids are synthesized from cholesterol in the liver, released into the intestin and recycled. A small amount of bile acid is excreted. Results: Conversion of liver cholesterol to bile acids for excretion. GUT Hepatocytes Ac-CoA HMG-CoA R Cholesterol Bile acids R Blood IDL V V Endothelial Cells Lipoprotein lipase Resins Lipid oxidation apoproteins 8
9 III. Genetic Defects in Lipid Metabolism Monogenic Familial hypercholesterolemia (homozygous or heterozygous) defect: inactive receptor Familial lipoprotein lipase deficiency defect: inactive lipoprotein lipase Familial combined hyperlipidemia defect: unknown Polygenic/multifactorial- commonly encountered Hypercholesterolemia Hypertriglyceridemia IV. Therapeutic Strategy for Atherosclerosis A. Identify patients at risk 1. Routine screening of serum cholesterol 2. Assessment of contributing risk factors B. Non-pharmacologic therapy 1. Diet modification 2. Lifestyle modification C. Pharmacologic therapy 9
10 V. Drug therapy of hyperlipidemia 1. Single drug therapy Lipid-lowering agents Exogenous pathway Route of uptake of dietary lipids Resins HMG" CoA! reductase! inhibitors Endogenous pathway Route of distribution of cholesterol esters (CE) from liver to target cells Ezetimibe Intestine Chylomicrons cholesterol Liver Chylomicron remnants " Niacin Extrahepatic tissues V IDL HDL Macro" phages Form cells + Free!fatty!acid Free!fatty!acid Fibrates LCAT:!lecithin!cholesterol! acyltransferase Adipose!tissue,!muscle Adipose!tissue,!muscle 10
11 1) Bile acid sequestrants Resins (colestipol, cholestyramine) Taken orally. Actions: Anion exchange resins which bind negatively charged bile acids in the small intestine. Results: 1. increased conversion of cholesterol to bile acid in hepatocytes; 2. increased synthesis of cholesterol and receptors in hepatocytes; 3. decreased serum and cholesterol levels. Advantages: clinically safe; effective; cot: $500/year. Disadvantages: unpleasant GI effects, interference with GI drug absorption; may exacerbate hypertriglyceridemia (unknown mechanism). Bile acid sequestrants Resins 11
12 2) Niacin (nicotinic acid) Action: decreases free fatty acid (FFA) available to the liver for synthesis of triglycerides. Inhibition of a hormonesensitive lipase involved in lipolysis in adipose tissue. Results: 1. inhibits production and release of V by liver; 2. decreased serum levels of V as well as and TG; 3. reduced clearance of HDL or increased serum level of HDL; 4. increased HDL/ ratio. Advantages: long clinical experience; effective; least expensive ($50/year). Disadvantages: evokes flushing, itchiness and GI discomfort, contraindicated for diabetic patients; adverse effects in hepatic disease and gout. 3) HMG-CoA reductase inhibitors (Lovastatin, Statin) Action: competitively inhibits HMG-CoA reductase, the key enzyme for de novo cholesterol biosynthesis. Results: 1. reduce cholesterol synthesis 2. upregulates receptors on hepatocyte; 3. decreased serum and TG levels; 4. suppresses production of V in liver; 5. Increased HDL and HDL/ ratio. Advantages: specific; effective; welltolerated. Oral. Disadvantages: safety unknown for long term use; more expensive ($900/year). 12
13 Competitive Inhibitors of HMG-CoA Reductase("Statins") Lovastatin,!atorvastatin,!fluvastatin,!pravastatin,!simvastatin, and!rosuvastatin belong!to!this! class.!they!are!most!effective!in!reducing!, oxidative!stress!and!vascular!inflammation!with! increased!stability!of!atherosclerotic!lesions.!there!is!standard!practice!to!initiate!reductase! inhibitor!therapy!immediately!after!acute!coronary!syndromes,!regardless!of!lipid!levels. Top:!The!HMG"CoA!intermediate!that!is!the!precursor!of!Mevalonate,!a!critical! compound!in!the!synthesis!of!cholesterol Bottom:!The!structure!of!lovastatin and!its!active!form,!showing!the!similarity!to! the!normal!hmg"coa!intermediate!(shaded!areas). Inhibitors of HMG-CoA Reductase 13
14 4) Fibrates (US: gemfibrozil; Europe: fenofibrate; prototype: clofibrate) Action: Activate PPAR!; increase lipoprotein lipase; increase the clearance of V and reduce plasma TG levels; decrease V synthesis which also lower serum levels; increase plasma HDL by increased synthesis and/or decreased clearance. Results: 1. Decreased serum TG and cholesterol; 2. Increased HDL/ ratio. Advantages: recent clinical data support safety and efficacy; well-tolerated cost Lipoprotein!lipase $375/year. Disadvantages: more effective in reducing TG than cholesterol; long-term effect not known. Clofibrate is not usable because of toxicity. Fibrates analogs 14
15 5) Ezetimibe (Inhibitors of Intestinal Cholesterol absorption) Action: Inhibits luminal cholesterol uptake by enterocytes by inhibiting the transport protein NPC1L1. Results: 1. Decreases levels 2. Reduces delivery of cholesterol to the liver by chylomicron remnants. 3. Inhibits diet-induced atherosclerosis. Advantages: can be used in combination therapy with statins. Disadvantages: Other than rare allergic reactions, specific adverse effects have not been observed in patients taking ezetimibe. The safety has been established. Lipid-lowering agents Exogenous pathway Route of uptake of dietary lipids Resins HMG" CoA! reductase! inhibitors Endogenous pathway Route of distribution of cholesterol esters (CE) from liver to target cells Ezetimibe Intestine Chylomicrons cholesterol Liver Chylomicron remnants " Niacin Extrahepatic tissues V IDL HDL Macro" phages Form cells + Free!fatty!acid Free!fatty!acid Fibrates LCAT:!lecithin!cholesterol! acyltransferase Adipose!tissue,!muscle Adipose!tissue,!muscle 15
16 V. Drug therapy of hyperlipidemia 2. Combined 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 (Resins) plus Niacin Bile acid sequestrant plus lovastatin Bile acid sequestrant plus lovastatin plus probucol Bile acid sequestrant plus Fibrates (less common) Hypercholesterol with hypertriglycerides: Nicotinic acid plus lovastatin Lovastatin plus Fibrates Niconitnic acid plus lovastatin plus Bile acid sequestrant Summary: Anti-hyperlipidemic drugs Bile acid resins (cholestyramine, colestipol) HMG-CoA reductase inhibitors (lovastatin, atrovastatin, pravastatin, simvastatin) V secretion inhibitor (Niacin) Lipoprotein lipase stimulants (Fibrates: clofibrate, gemfibrozil, fenofibrate) Ezetimibe Subclass HDL TG Clinical Applications Elevated, digitalis toxicity, pruritus Atherosclerotic vascular disease Acute coronary syndrome Low HDL Elevated V,, Lp(a) Hypertriglyceridemia Low HDL Elevated, effective in combined therapy with statins GUT " Dietary! cholesterol " Ezetimibe Resins Hepatocytes Ac-CoA HMG"CoA! reductase! inhibitors HMG-CoA " R Cholesterol Bile acids " Niacin Blood IDL V V Endothelial Cells Lipid oxidation Lipoprotein lipase Fibrates + apoproteins 16
17 The Primary Hyperlipoproteinemias and Their Drug Treatment Disorder Manifestations Single Drug Drug combination Primary chylomicronemia Chylomicrons, V Dietary management Niacin plus fibrate increased (niacin, fibrate) Familial hypertriglyceridemiasevere Moderate Familial combined hyperlipoproteinemia Familial dysbetalipoproteinemia Familial hypercholesterolemia V, chylomicrons increased V and chylomicrons are increased V predominantly increased V, increased V remnants, chylomicron remnants increased Niacin, fibrate Niacin, fibrate Niacin, fibrate, reductase inhibitor Niacin, reductase inhibitor Fibrate, niacin Heterozygous increased Reductase inhibitor, resin, niacin, ezetimibe Homozygous increased Niacin, reductase inhibitors, ezetimibe Familial ligand-defective apo B increased Niacin, reductase inhibitor, ezeimibe Niacin plus fibrate Two or three of the individual drugs Niacin or fibrate plus reductase inhibitor Fibrate plus niacin, or either, plus reductase inhibitor Two or three of the individual drugs Niacin plus reductase inhibitor plus ezetimibe Niacin plus reductase inhibitor or ezetimibe Lp(a) hyperlipoproteinemia Lp(a) increased Niacin Basic & Clinical Pharmacology: Chapter 35. Recommended readings Goodman & Gilman s The Pharmacological Basis of Therapeutics, Chapter 31 Katzung, Basic & Clinical Pharmacology, Chapter 35 17
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