Lipid-lowering drugs

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Atherosclerosis and lipoprotein metabolism
Atheromatous disease is ubiquitous and underlies the commonest causes
 of death (e.g. myocardial infarction) and disability (e.g. stroke) in  industrial
countries
Hypertension and dyslipidemia are ones of the most important risk factors, amenable to drug therapy
ATHEROMA is a focal disease of the intima of large and medium-sized arteries
Atherogenesis  involves several stages:
 endothelial dysfunction with altered PGI2 and NO synthesis
 monocyte attachment
 endothelial cells bind LDL
 oxidatively modified LDL is taken up by macrophages
 having taken up oxidised LDL, these macrophages (now foam cells) migrate subendothelially
 atheromatous plaque formation
 rupture of the plaque

LIPIDS, including CHOLESTEROL (CHO) and TRIGLYCERIDES (TG), are transported in the plasma as lipoproteins, of which there are four classes:
     - chylomicrons transport TG and CHO from the GIT to the tissues, where
     they are split by lipase, releasing free fatty acids.There are taken up in muscle and adipose  tissue. Chylomicron remnants are taken up in the liver
     - very low density lipoproteins (VLDL), which transport CHO and newly synthetised TG to the tissues, where TGs are removed as before, leaving:
    - low density lipoproteins (LDL) with a large component of CHO, some of which is taken up by the tissues and some by the liver, by endocytosis via specific
     LDL receptors
    - high density lipoproteins (HDL).which absorb CHO derived from  cell breakdown in tissues and transfer it to VLDL and LDL

There are two different pathways for exogenous and endogenous lipids:
THE  EXOGENOUS  PATHWAY: CHO + TG absorbed from the GIT are transported in the lymph and than  in the plasma as CHYLOMICRONS to capillaries in muscle and adipose tissues. Here the core TRIGL are hydrolysed by lipoprotein lipase, and the tissues take up the resulting FREE FATTY ACIDS
      CHO is liberated within the liver cells and may be stored, oxidised to bile aids or secreted in the bile unaltered
    Alternatively it may enter the endogenous pathway of lipid transpor in VLDL

THE  ENDOGENOUS  PATHWAY
CHO and newly synthetised TG are transported from the liver as VLDL to muscle and adipose tissue, there TG are hydrolysed and the resulting
      FATTY ACIDS enter the tissues
    The lipoprotein particles become smaller and ultimetaly become LDL ,
    which provides the source of CHO for incorporation into cell membranes, for synthesis of steroids, and bile acids
    Cells take up LDL by endocytosis via LDL receptors that recognise LDL apolipoproteins
    CHO can return to plasma from the tissues in HDL particles and the resulting cholesteryl esters are subsequently transferred to VLDL or LDL
        One species of LDL – lipoprotein - is associated with atherosclerosis (localised in atherosclerotic lesions). LDL can also activate platelets, constituting a further thrombogenic effect

Dyslipidemia
The normal range of plasma total CHO concentration < 6.5 mmol/L.
          There are smooth gradations of increased risk with
elevated LDL CHO conc, and with reduced HDL CHO conc.

Dyslipidemia can be primary or secondary.
 The primary forms are genetically determined
 Secondary forms are a consequence of other conditions such as diabetes mellitus, alcoholism, nephrotic sy,chronic renal  failure,  administration of drug

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