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Fibric acid Derivatives

Clofibrate

Clofibrate is the 1st drug discovered, but rarely used because of toxic effects. Better drugs with less toxicity and more effects are available.

It acts by:

  • Stimulating activity of lipoprotein lipase enzyme involved in breakdown of TGs. In this way, TGs are decreased.
  • Acting as an agonist at PPAR alpha receptor (peroxisome proliferated activated receptor alpha), involved in fatty acid metabolism.
  • Fibric acid derivatives also cause up and down regulation of genes involved in fatty acid metabolism

Upregulation of apolipoprotein alpha 1 gene.

Down regulation of apolipoprotein C2 gene.

So produce hypolipidemic effects. Also increase:

  • LDL receptor expression in liver under effect of PPAR alpha. More extraction of LDL from plasma occurs.
  • Also decrease TGs synthesis by liver.
  • Decrease TGs by 40-60%
  • Decrease LDL, but to a lesser extent 10-15%
  • Increase HDL by 10-25%
 Uses

Different kinds of hyperlipidemias (type III)

Regression of xanthomas

Dysbetalipoproteinemia

Hypertriglyceridemias

MI

Mobilize cholesterol from storage sites

Decrease incidence of coronary heart diseases by 50% when used for prolonged time.

Pharmacokinetics

Absorbed after oral administration. Bioavailability is increased with food.

  • PPC

Plasma peak concentration is achieved in 3-4 hours

  • PPB

Extensively bound to plasma proteins

Metabolized in liver and predominantly eliminated in urine.

Half life of Bezafibrate and Gemfibrozil is 2 hours.

Half life of Fenofibrate is 20 hours.

Adverse effects

May produce:

a. GIT disturbances

b. Allergic reactions

c. Myopathies esp. when combined with HMG CoA reductase inhibitors (muscle weakness, tenderness and cramps), less frequently with Fenofibrates. (Rosuvastin amongst statins has lesser incidence of myopathies.

d. Can produce hypokalemias

e. Clofibrate produces blood dyscrasias and cardiac arrhythmias

f. In experimental animals, are found to be teratogenic

g. Liver injuries

h. Can displace oral anticoagulants from protein binding sites

i. Can enhance toxicity of warfarin

j. Increase the incidence of gall stones as increase the secretion of cholesterol in bile.

k. Decrease the conversion of cholesterol into bile acids, so chances of gall stones are more.

l. Cholelithiasis

m. Anemias, decrease WBC count

n. Hair loss

Contraindications

1. Pregnancy

2. Liver disease

3. Gall stones

4. Renal failure

5. Alcohol

6. Children

Dose

300 mg, which may be increased up to 600 mg, twice or thrice daily, depending upon the severity of disease. Usually taken with meals.

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