Download Pharmacology 13a – Atherosclerosis and Lipid Metabolism

Pharmacology 13a – Atherosclerosis and Lipid Metabolism
Anil Chopra
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To give an outline of the process of atherosclerosis
To summarise the metabolism of lipoproteins
To describe the mechanisms of action of the major lipid-lowering drugs
To outline the clinical evidence for their effect on cardiovascular disease
Role of Lipids
 Lipids such as triglycerides and cholesterylesters are insoluble in water, They are
transported in plasma in the core of particles (lioproteins) that have a hydrophilic
shell of phospholipids and free cholesterol
 2/3 of plasma lipoproteins are synthesised in the liver
 Triglycerides are secreted into the blood as VLDL
 In muscle and adipose tissue lipoprotein lipase hydrolyses them to fatty acids so
they can enter the cells for energy and storage
 The residual particles contain a core of rick cholesterylester (CE) = LDL particles
 The liver and other cells posses LDL receptors which remove LDL from the
plasma via endocytosis
 VLDL are too big to penetrate endothelial walls
 HDL accepts excess (unesterified) cholesterol from cells and lipoproteins that
have lost triglyceride and so remove cholesterylesters from vessel walls – antiatherogenic activity
LDLs are the prime component of
atherosclerosis whereas HDL’s have
a protective component.
Neither are water soluble.
77% of cholesterol is made by the
liver, which only gives a small
amount that can be accounted for in
the diet.
LDL Cholesterol
- LDL (low density lipoprotein) cholesterol levels in the blood are strongly
associated with atherosclerosis risk.
- A 10% increase in LDL results in a 20% increase in atherosclerosis risk.
- It is modified by other risk factors such as smoking, hypertension and diabetes.
HDL Cholesterol
- HDL cholesterol has a protective effect for risk of atherosclerosis and CHD.
- The lower the HDL cholesterol level, the higher the risk for atherosclerosis and
CHD.
- HDL cholesterol tends to be low when triglycerides are high.
- HDL cholesterol is lowered by smoking, obesity and physical inactivity.
Triglycerides
- Triglycerides are also associated with an increased risk of atherosclerosis.
- Normal triglyceride levels <200mg/dl
(2.3mmol/l) – or less.
- Very high triglycerides >1000mg/dl,
(11.3mmol/l) increase pancreatitis risk
Cholesterol levels are a very important factor in the development of atherosclerosis
and coronary heart disease:
• 10% reduction in total cholesterol results in:
– 15% reduction in CHD mortality (p<0.001)
– 11% reduction in total mortality (p<0.001)3
Pathogenesis of Atherosclerotic plaques:
7 stages to the formation of atheromas:
 Endothelial damage
o Increased endothelial permeability
 Protective results in production of cellular adhesion molecules
o Up regulation of adhesion molecules
 Monocytes and T lymphocytes attaché to “sticky” surface of endothelial cells
 Cells migrate through arterial wall to sub-endothelial space
o Migration of leukocytes and smooth muscle cells
 Macrophages take up oxidised LDL-cholesterol
 Lipid-rich foam cells are formed by macrophage death
 Fatty streaks and plaques are formed
o Fibrous cap with necrotic core forms a complicated atherosclerotic plaque
o Thinning of the fibrous cap causes plaque to become unstable
o Can get haemorrhage from micro-vessels of plaque
Matrix degrading enzymes breakdown the fibrous cap. The plaque is now unstable
and rupture can occur.
Types of plaques:
Clinical Manifestations of Atherosclerosis:
Coronary Heart Disease:
 Angina pectoris
 MI
 Sudden cardiac death
Cerebrovascular Disease:
 Transient Ischaemic Attacks
 Stroke
Peripheral Vascular Disease:
 Intermittent claudication
 Gangrene
Atherosclerosis is an
inflammatory
fibroploriferative disorder:
i.e. it is an active process
which can be inhibited but
can progress quickly.
Remnant Lipids:
damaging to the
endothelium and lead to
dysfunction.
Statins
Statins are generally accepted as the best treatment for raised cholesterol.
Names
Lovastatin, Pravastatin, Simvastatin
Usage
Lowers LDL cholesterol levels and raises HDL levels.
Mode of Action
It inhibits HMG Co-A reductase, which stops the conversion of HMG Co-A to
mevalonic acid and thus inhibits synthesis of cholesterol. It also increases the number
of LDL receptors on hepatocytes which causing a reduction of LDL in the blood.
 The statins are the most important lipid lowering drugs
 They are HMG CoA Reductase Inhibitors
 Inhibition of the enzyme leads to decreased hepatic cholesterol synthesis
 Inhibition of enzyme leads to expression of more enzyme tending to resotre
cholesterol synthesis to normal, however the compensatory response in
incomplete
 Fall in production of cholesterol also induces a compensatory increased in
hepatic LDL receptors which increase clearance of cholesterol from the plasma
 These together cause a fall in plasma cholesterol
 Do not work in patients with familial hyperchloesterolamia (who have no LDL
receptors)
acetyl CoA
Non-cholesterol effects of statins
include:
 Increased NO synthesis
 Inhibition of free radical
relase
 Reduced number and
activity of inflammatory cells
 Inhibition of platelet
adhesion and aggregation
together with reduced blood
viscosity
HMG-CoA synthase
HMG-CoA reductase
HMG-CoA
X Statins
mevalonic acid
mevalonate pyrophosphate
isopentenyl pyrophosphate
Modification
of proteins
(rho, ras)
geranyl pyrophosphate
farnesyl pyrophosphate
squalene
cholesterol
Fibrates
Names
Benzafibrate, ciprofibrate, gemfibrozil, fenofibrate.
Usage
Effective in atherosclerosis.
Mode of action
They activate of PPAR (peroxisome proliferator activated receptors) alpha receptors.
This results in:
- decrease of cell recruitment
- decrease in foam cell formation
- increased cholesterol efflux
- decreased inflammatory response
- decreased vasoconstriction
- decreased thrombosis risk
- increase in plaque stability
Others
Name - Nicotinic Acid
Mode of Action
 Reduces release of VLDL and so lowers plasma triglycerides by 30-50%
 Lowers cholesterol by 10-20% and increases HDL
Inhibitors of Intestinal Cholesterol Absorption
Name – Ezetimibe
Mode of Action
 Reduces absorption
 Decreases cholesterol by 18% with little change in HDL
 May synergise with statins and so a good choice for combination therapy