Title: Atherosclerosis
1Atherosclerosis
- 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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4Pathogenesis
- 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
5Monocyte Recruitment
LDL
6Formation of Atherosclerotic Plaques
lumen
neointima
Lipid Core
7Plaque Rupture and Thrombosis
Tissue Factor
Platelet Aggregation
Lipid Core
8Cholesterol and Triglyceride Metabolism
9Exogenous 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.
10Cholesterol and Triglyceride Metabolism
11Endogenous 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.
12Cholesterol and Triglyceride Metabolism
13Reverse 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.
14Cholesterol and Triglyceride Metabolism
15De 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.
16Cholesterol 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.
17Genetic 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
18Therapeutic 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
19Classification of Plasma Cholesterol
Concentrations
Total cholesterol (mg/dl) Classification
lt 200 Desirable
200 - 239 Borderline
gt 240 High
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21Lovastatin 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.
22Bile 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).
23Ezetimibe
- 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.
24Niacin (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.
25Fibrates (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.
26CETP 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.
27Combined 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) -
28- Hypercholesterol with hypertriglycerides
- Nicotinic acid plus lovastatin
- Lovastatin plus gemfibrozil
- Nicotinic acid plus lovastatin plus bile acid
sequestrant
29Probucol(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.