Atherosclerosis

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Atherosclerosis

• Focal plaques within the intima containing
  cholesterol and cholesterol esters (CE)
• Affects large and medium sized arteries
• Causes coronary heart diseases (CHD)
• Hypercholesterolemia high serum cholesterol
  level
• Elevated LDL and triglycerides
• associated with increase risk
• Serum HDL levels inversely related to risk

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Pathogenesis

• Chronic inflammatory response of the vascular
  wall to endothelial injury or dysfunction
• Elevated plasma LDL levels causing the deposit of
  LDL in the subendothelium of blood vessels
• Oxidation of transmigrated LDL
• Activation of endothelial cells
• Recruitment of monocytes/macrophages which ingest
  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
LDL
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Formation of Atherosclerotic Plaques
lumen
neointima
Lipid Core
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Plaque Rupture and Thrombosis
Tissue Factor
Platelet Aggregation
Lipid Core
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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 TG for storage, CM remnants are
  transported to the liver.
• 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.

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Cholesterol and Triglyceride Metabolism
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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 TG. The remnant IDL
  is either taken up by the liver or circulates
  until the remaining TG is removed, forming LDL
  particles which are rich in cholesterol.
• LDL is cleared from plasma by LDL
  receptor-mediated endocytosis.
• Results 1) Transfer of TG from liver to target
  cells via VLDL 2) Transfer of CE from liver to
  target cells via LDL 3) Feedback regulation of
  cholesterol homeostasis by LDL receptor
  expression 4) Creation of a steady state LDL-CE
  reserve in plasma.

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Cholesterol and Triglyceride Metabolism
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Reverse Transport of Cholesterol

• Route for cholesterol recovery
• As cell dies and the cell membrane turnover, free
  cholesterol is released into the plasma. It is
  immediately absorbed onto HDL particles,
  esterified with a long chain fatty acid by
  lecithincholesterol acyltransferase (LCAT), and
  transferred to VLDL or IDL by a cholesteryl ester
  transfer protein (CETP) 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.

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Cholesterol and Triglyceride Metabolism
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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.

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Cholesterol Excretion by Enterohepatic Circulation

• Bile acids are synthesized from cholesterol in
  the liver, released into the intestine and
  reabsorbed in the jejunum and ileum.
• Results Conversion of liver cholesterol to bile
  acids for recycle.

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Genetic Defects of Lipid Metabolism

• Monogenic
• Familial hypercholesterolemia
• (homozygous or heterozygous)
• defect inactive LDL receptor
• Familial lipoprotein lipase deficiency
• defect inactive lipoprotein lipase
• Familial combined hyperlipidemia
• defect unknown
• Polygenic/multifactorial commonly encountered
• Hypercholesterolemia
• Hypertriglyceridemia

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Therapeutic Strategy

• Identify patients at risk
• 1. Routine screening of serum cholesterol
• 2. Assessment of contributing risk factors
• Non-pharmacologic therapy
• 1. Diet modification
• 2. Lifestyle modification
• C. Pharmacologic therapy

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Classification of Plasma Cholesterol
Concentrations
Total cholesterol (mg/dl) Classification
lt 200 Desirable
200 - 239 Borderline
gt 240 High
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Lovastatin aka statins(HMG-CoA reductase
inhibitors)

• Action 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 HDL
  levels 5) increased HDL/LDL ratio.
• Advantages specific effective well-tolerated.
• Disadvantages hepatotoxicity myopathy most
  expensive 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
  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 LDL receptors in
  hepatocytes 3) decreased serum LDL and
  cholesterol levels.
• Advantages clinically safe effective.
• Disadvantages unpleasant GI effects
  interference with GI drug absorption (e.g.,
  coumarin) may exacerbate hypertriglyceridemia
  (unknown mechanism).

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Ezetimibe

• Action inhibits dietary cholesterol uptake by
  jejunal enterocytes by binding to a key mediator
  of cholesterol absorption Neimann-Pick C1-Like1
  (NPC1L1).
• Results 1) reduction of cholesterol
  incorporation into chylomicrons 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 as
  monotherapy in statin-intolerant patients also
  used in combination 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
  decrease cAMP levels. Inhibits hormone-sensitive
  lipase involved in lipolysis 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 LDL and TG 3) reduced clearance of
  HDL or increased serum level of HDL 4) increased
  HDL/LDL ratio.
• Advantages long clinical experience effective
  least expensive.
• Disadvantages evokes flushing, itchiness,
  dyspepsia and GI discomfort, contraindicated for
  diabetic patients and pregnant women adverse
  effects in hepatic diseases and reactivation of
  gout.

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Fibrates (prototype clofibrateUS gemfibrozil
Europe fenofibrate)

• Action acts through peroxisome proliferator
  activated receptors (PPARs) to stimulate gene
  transcription of lipoprotein lipase increases
  the clearance of VLDL and reduce plasma TG
  levels decreases VLDL synthesis and lowers LDL
  levels moderately increases plasma HDL by
  increased synthesis and/or decreased clearance.
• Results decreased serum TG and cholesterol
  increased HDL/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
  displaces anticoagulant from albumin
  contraindicated in patients with renal failure.
  Clofibrate has toxic effect.

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CETP Inhibitors (Torcetrapib)

• Action Inhibits the transfer of cholesterol
  ester from HDL to VLDL.
• Results 1) increased serum level of HDL 2) by
  itself, no effect on LDL levels 3) use in
  combination of statins to lower LDL with further
  increase in HDL.

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Combined Drug Therapy

• Advantages Synergistic approaches utilizes
  complementary mechanisms of drug actions reduces
  effective 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 by macrophage foam cells. Decreases
  HDL production.
• Results 1) decreases atherosclerotic plaque
  formation 2) small reduction in serum
  LDL-cholesterol 3) greater reduction of serum
  HDL-cholesterol.
• Advantages may be used in combination therapy
  with other drugs that lower serum
  LDL-cholesterol.
• Disadvantages not effective in single drug
  therapy no long term clinical data.