medpharm atherosclerosis

8/4/2019 MedPharm Atherosclerosis

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Atherosclerosis

Focal plaques within the intima containing cholesteroland cholesterol esters (CE)

Affects large and medium sized arteries

Causes coronary heart diseases (CHD)

Hypercholesterolemia high serum cholesterol level

Elevated LDL and triglyceridesassociated with increase risk

Serum HDL levels inversely related to risk


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Pathogenesis

Chronic inflammatory response of the vascularwall to endothelial injury or dysfunction

Elevated plasma LDL levels causing the depositof LDL in the subendothelium of blood vessels

Oxidation of transmigrated LDL Activation of endothelial cells

Recruitment of monocytes/macrophages whichingest oxLDL through scavenger receptors

Formation of foam cells fatty streaks Proliferation of smooth muscle cells

Deposition of extracellular matrix proteins


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Monocyte Recruitment

intima

lumen LDL


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Lipid Core

lumen

neointima

Formation of Atherosclerotic Plaques


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Plaque Rupture and Thrombosis

Lipid Core

Tissue Factor Platelet Aggregation


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Cholesterol and Triglyceride Metabolism


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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 TGfor storage, CM remnants are transported to the liver.

Results: Dietary TG is stored in adipose tissue andmuscle. Cholesterol is stored in liver or excreted into thebile as cholesterol or bile acid.


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Endogenous Pathway

Route for distribution of CE from liver to target cells

VLDL secreted by the liver to plasma and transportedto adipose tissue and muscle where lipoprotein lipaseextracted TG. The remnant IDL is either taken up by theliver or circulates until the remaining TG is removed,forming LDL particles which are rich in cholesterol.

LDL is cleared from plasma by LDL receptor-mediatedendocytosis.

Results: 1) Transfer of TG from liver to target cells via

VLDL; 2) Transfer of CE from liver to target cells viaLDL; 3) Feedback regulation of cholesterol homeostasisby LDL receptor expression; 4) Creation of a steadystate LDL-CE reserve in plasma.


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Reverse Transport of Cholesterol

Route for cholesterol recovery

As cell dies and the cell membrane turnover, freecholesterol is released into the plasma. It is immediatelyabsorbed onto HDL particles, esterified with a long chainfatty acid by lecithin:cholesterol acyltransferase (LCAT),

and transferred to VLDL or IDL by a cholesteryl estertransfer protein (CETP) in plasma. Eventually, it is takenup by the liver as IDL or LDL.

Results: Recovery of cholesterol from cell membranesand reincorporation into LDL pool or return to liver.


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De NovoCholesterol 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.


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Cholesterol Excretion byEnterohepatic Circulation

Bile acids are synthesized from cholesterol in the liver,released into the intestine and reabsorbed in the jejunumand ileum.

Results: Conversion of liver cholesterol to bile acids forrecycle.


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Genetic Defects of Lipid Metabolism

Monogenic

Familial hypercholesterolemia

(homozygous or heterozygous)

defect: inactive LDL receptor

Familial lipoprotein lipase deficiencydefect: inactive lipoprotein lipase

Familial combined hyperlipidemia

defect: unknown

Polygenic/multifactorial commonly encountered

Hypercholesterolemia

Hypertriglyceridemia


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Therapeutic Strategy

A. Identify patients at risk1. Routine screening of serum cholesterol

2. Assessment of contributing risk factors

B. Non-pharmacologic therapy

1. Diet modification

2. Lifestyle modification

C. Pharmacologic therapy


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Classification ofPlasma Cholesterol Concentrations

Total cholesterol

(mg/dl)

Classification

< 200 Desirable

200 - 239 Borderline

> 240 High


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Lovastatin aka statins(HMG-CoA reductase inhibitors)

Action: competitively inhibits HMG-CoA reductase, thekey enzyme for de novocholesterol biosynthesis.

Results: 1) cells express more LDL receptors; 2)

decreased serum LDL levels; 3) suppresses productionof VLDL in liver; 4) increased HDL levels; 5) increasedHDL/LDL ratio.

Advantages: specific; effective; well-tolerated.

Disadvantages: hepatotoxicity; myopathy; mostexpensive; contradicted in pregnant and nursing women.


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Bile acid sequestrants(colestipol, cholestyramine, colesevelam)

Taken orally, not absorbed from the intestine.

Action: Anion exchange resins which bind negativelycharged bile acids in the small intestine.

Results: 1) increased conversion of cholesterol to bileacid in hepatocytes; 2) increased synthesis ofcholesterol and LDL receptors in hepatocytes; 3)decreased serum LDL and cholesterol levels.

Advantages: clinically safe; effective.

Disadvantages: unpleasant GI effects; interference withGI drug absorption (e.g., coumarin); may exacerbatehypertriglyceridemia (unknown mechanism).


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Ezetimibe

Action: inhibits dietary cholesterol uptake by jejunalenterocytes by binding to a key mediator of cholesterolabsorption Neimann-Pick C1-Like1 (NPC1L1).

Results: 1) reduction of cholesterol incorporation intochylomicrons and delivery to hepatocytes; 2) increased

synthesis of cholesterol and LDL receptors in hepatocytes;3) decreased serum LDL and cholesterol levels.

Advantages: clinically safe; effective; used asmonotherapy in statin-intolerant patients; also used incombination with statins in statin-tolerant patients for

further reduction of serum LDL and cholesterol. Disadvantages: no effect on TG absorption; a new class of

anti-atherosclerotic drug long term effect not known.


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Niacin (nicotinic acid)

Action: Acts through a Gi-coupled GPCR to decreasecAMP levels. Inhibits hormone-sensitive lipase involved inlipolysis in adipose tissue and decreases free fatty acid(FFA) transfer to the liver for synthesis of triglycerides.

Results: 1) decreased production and release of VLDL by

liver; 2) decreased serum levels of VLDL as well as LDLand TG; 3) reduced clearance of HDL or increased serumlevel of HDL; 4) increased HDL/LDL ratio.

Advantages: long clinical experience; effective; leastexpensive.

Disadvantages: evokes flushing, itchiness, dyspepsia andGI discomfort, contraindicated for diabetic patients andpregnant women; adverse effects in hepatic diseases andreactivation of gout.


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Fibrates (prototype: clofibrateUS: gemfibrozil; Europe: fenofibrate)

Action: acts through peroxisome proliferator activatedreceptors (PPARs) to stimulate gene transcription oflipoprotein lipase; increases the clearance of VLDL andreduce plasma TG levels; decreases VLDL synthesis andlowers LDL levels moderately; increases plasma HDL byincreased synthesis and/or decreased clearance.

Results: decreased serum TG and cholesterol; increasedHDL/LDL ratio.

Advantages: recent clinical data support safety and

efficacy; well-tolerated, potential anti-thrombotic effect. Disadvantages: more effective in reducing TG than LDL;

increased LDL levels in some patients; displacesanticoagulant from albumin; contraindicated in patientswith renal failure. Clofibrate has toxic effect.


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CETP Inhibitors (Torcetrapib)

Action: Inhibits the transfer of cholesterol ester from HDLto VLDL.

Results: 1) increased serum level of HDL; 2) by itself, noeffect on LDL levels; 3) use in combination of statins tolower LDL with further increase in HDL.


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Combined Drug Therapy

Advantages: Synergistic approaches utilizes

complementary mechanisms of drug actions; reduceseffective doses of single drug to prevent side effects.

Hypercholesterol without hypertriglycerides:

Bile acid sequestrant plus lovastatin

Ezetimibe plus lovastatin

Bile acid sequestrant plus lovastatin plus ezetimibe

Bile acid sequestrant plus nicotinic acid

Bile acid sequestrant plus gemfibrozil (less common)


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Hypercholesterol with hypertriglycerides:

Nicotinic acid plus lovastatin

Lovastatin plus gemfibrozil

Nicotinic acid plus lovastatin plus bile acid sequestrant


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Probucol(lipophilic antioxidant)

Action: Taken up by LDL particles and endothelial cells.Inhibits oxidation of LDL and prevents ingestion bymacrophage foam cells. Decreases HDL production.

Results: 1) decreases atherosclerotic plaque formation;

2) small reduction in serum LDL-cholesterol; 3) greaterreduction of serum HDL-cholesterol.

Advantages: may be used in combination therapy withother drugs that lower serum LDL-cholesterol.

Disadvantages: not effective in single drug therapy; nolong term clinical data.

medpharm atherosclerosis

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