Hyperlipoproteinemia

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Hyperlipoproteinemia

Post  counselor on Mon Oct 15, 2012 11:42 am

Hyperlipoproteinemia




E 'characterized by excessive levels of cholesterol and triglycerides transported in plasma in the form of lipoproteins, globular macromolecules containing:
a) Core with non-polar lipids (cholesteryl esters and triglycerides).
b) Outer polar phospholipids, free cholesterol and apoproteins.

We distinguish six major classes of lipoproteins:
1) Chylomicrons are formed in the intestinal mucosa from cholesterol and triglyceride of the diet. Pass into the lymphatic system and then into the bloodstream. Have a size of 80-500 nm.
2) Fragments of chylomicrons These stem from the early work of lipoprotein lipase to endothelial cells of capillaries. They have more cholesterol than triglycerides.
3) VLDL (Very Low Density Lipoproteins). Have a size of 30-80 nm. Triglycerides that contain more cholesterol. Are secreted by the liver after high caloric intake.
4) IDL (intermediate density). These stem from VLDL by the action of lipoprotein lipase and contain mainly cholesterol.
5) LDL (Low Density). Are devoid of triglycerides, they just cholesterol. (60-70% of plasma cholesterol!). Have a size of 18-28 nm.
6) HDL (High Density). Absorb free cholesterol in plasma, which after esterification is transferred to the liver and tissues.

Lipoproteins are eliminated not only by the liver.
When their concentration is high it is also sensitive magrofagi deposit in the arterial wall and in macrophages of the tendons and skin.

You can have:
Atheroma: literally "mush". Containing formation inside amorphous material and unctuous consisting of lipids, whose composition is similar to that of the plasma. The transition of lipids from the plasma to the arterial wall is an active process. Atheroma accumulate if there is functional impairment of the endothelium.
Xanthomas: small tumors yellowish in color, high in cholesterol.
Acute pancreatitis: it may be a result of increases in VLDL and chylomicrons. It 'frequent in patients with high triglyceride concentrations.
For HDL was highlighted negative correlation between their concentration in plasma and the risk of coronary heart disease.
In women in pre-menopausal you have higher HDL levels and higher HDL / LDL.


THERAPEUTIC STRATEGIES
Numerous epidemiological and clinical studies documenting the benefits for the prevention and treatment of cardiovascular diseases resulting from:
• reduction in total cholesterol
• reduction of cholesterol associated with LDL
• increase in HDL
• A contribution in this respect may be given by the low-calorie diet and low in cholesterol. Should be encouraged in order intake of fatty acids polyunsaturated vegetable because they reduce LDL-cholesterol.


PHARMACOLOGICAL APPROACHES

1. Inhibit the absorption of cholesterol

The cholesterol is absorbed in the proximal part of the intestine. Nell'enterocita cholesterol is esterified cholesterol acyltransferase-dall'acilCOA. The ester becomes part of chylomicrons.

Can reduce the absorption of cholesterol:

Phytosterols
Includes 5-5-sterols and sterols reduced (stanols). Are plant sterols structurally similar to cholesterol.
A dose of 2 g per day reduces LDL by 10%.


Ion-exchange resins
Include colestipol and cholestyramine

Pharmacodynamics
Are not absorbed from the intestine.
Bind bile acids and therefore hinder the absorption of cholesterol.
The reduced availability of cholesterol raises LDL receptors sull'epatocita.
It also increases the production of microsomal hydrolase enzyme which converts cholesterol to bile acids.


TOXICITY '
Can induce
• Nausea
• Constipation
• Abdominal pain
• Reduced absorption of fat-soluble vitamins

Can reduce the absorption of many drugs administered orally (administer 1 hour before or 4 hours after the resin)


Ezetimibe

Pharmacodynamics
Selectively inhibits the absorption of cholesterol by inhibiting the transport of this (the protein Niemann-Pick C1 like 1)
Reduces LDL by about 18-20% when combined with statins has further additional reduction of 20%.

PHARMACOKINETICS
Is converted in the liver to active metabolite glucuronide, which is then eliminated in the intestines where it exerts its action.

TOXICITY '
The drug is well tolerated, however, in combination with statins ago transaminase increase markedly.


2. Inhibit the synthesis of cholesterol

Statins (or HMG CoA)
The 3-hydroxy-3-methyl-glutaryl-CoA-reductase catalyzes the conversion of HMGCoA to mevalonate, limiting step in the formation of cholesterol.
The first inhibitors of natural origin (mevastatina and lovastatin) were isolated from microbial cultures, while the others are of synthetic origin.
Are currently on the market in Italy simvastatin, pravastatin, fluvastatin, atorvastatin, and rosuvastatin.

FARMACIDINAMIA
The hydroxy acid that appears in the molecule of these inhibitors has strong structural similarities with the HMGCoA (enzyme substrate).
Therefore fail to evoke competitive and reversible inhibition of the enzyme.

However, this mechanism is relevant especially at the beginning of treatment, because the administration of inhibitor triggers increased cellular synthesis of redattasi.
The marked effect of these inhibitors in chronic treatment is due to increased synthesis of LDL receptors.

• They cause marked reduction of LDL (20-60%).
• Reduction in VLDL.
• Increase in HDL (10-13%).

More recently, were also demonstrated interesting 'non-lipid "of statins:
• improvement of endothelial function
• stabilizing effect of the atheromatous plaque through
-Reduction of the deposit of lipids,
-Reduction of the infiltration of macrophages,
-Increase of collagen
• antithrombotic effect

PHARMACOKINETICS
Lower the excretory elimination in the urine.
For the most statins are metabolized primarily by CYP3A4 and CYP2C9.

TOXICITY '
• Gastrointestinal disorders,
• increased liver transaminases,
• myopathies (rarely rhabdomyolysis)
• possible cataracts.

THERAPEUTIC USE
• There are drugs of choice in sogetti with heterozygous familial hypercholesterolemia.
• They are used for primary and secondary hypercholesterolemia.
• are recommended in post-myocardial infarction.


Fibrates
Include clofibrate fenofibrate, the bezafibrate, gemfibrozil.

Pharmacodynamics
Recent acquisitions have demonstrated that fibrates act by activating the PPAR  (Peroxisome Proliferator Activated Receptor ).
It is nuclear receptors activated by fatty acids and their derivatives, which control gene transcription.

Have been identified 3 subtypes of receptors
THE PPAR  controls the lipid and lipoprotein metabolism
PPAR  controls adipogenesis and is influenced by insulin

Decreased VLDL (30-50%)
LDL decreased slightly (10%).
Increase HDL (10%)
Fall markedly triglyceride levels (40%)



The effect on triglycerides is linked to
• Increased expression of lipoprotein lipase
• reduction in the expression of apolipoprotein C-III inhibits lipoprotein lipase
• Increased expression of scavenger receptor class B1 that mediates uptake of cholesterol esters in the liver
• promotes efflux of triglycerides and cholesterol from the cells to increase in mRNA for the protein ATP-binding cassette transporter A1.


PHARMACOKINETICS
Rapid and complete gastrointestinal absorption.
Renal excretion as glucuronides.

TOXICITY '
1) Abdominal pain
2) myalgia
3) Possible increased incidence of bile alcohols

THERAPEUTIC USE
The main use is in the treatment of hypertriglyceridemia



Probucol
It 'a lipophilic antioxidant structurally related to' ossitoluene.

PHARMACOLOGICAL EFFECTS
Has negligible effects on VLDL and triglycerides.
Lowers LDL (10%) but lowers even more HDL.
Causes significant reduction in skin and tendon xanthomas.
For the very modest reduction of LDL mechanism is unknown.
For the reduction of HDL the effect seems to be due to reduced synthesis of apoprotein A1 and A2.
The reduction of xanthomas seems to be due to its antioxidant effect. In fact, the vascular endothelium of magrofagi recognize and incorporate the oxidized LDL.

PHARMACOKINETICS
Only 10% is absorbed orally.
Especially biliary elimination.

SIDE EFFECTS
Diarrhea and abdominal pain.
Possible development of arrhythmias if the diet is rich in cholesterol.
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