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In pharmacology, the fibrates are a class of amphipathic carboxylic acids. They are used for a range of metabolic disorders, mainly hypercholesterolemia (high cholesterol), and are therefore hypolipidemic agents.

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Fibrates prescribed commonly are:

Indications

Fibrates are used in accessory therapy in many forms of hypercholesterolemia, usually in combination with statins.[1] Clinical trials do support their use as monotherapy agents. Fibrates reduce the number of non-fatal heart attacks, but do not improve all-cause mortality and are therefore only indicated in those not tolerant to statins.[2]

Although less effective in lowering LDL, fibrates improve HDL and triglyceride levels by increasing HDL levels and decreasing triglyceride levels, and seem to improve insulin resistance when the dyslipidemia is associated with other features of the metabolic syndrome (hypertension and diabetes mellitus type 2). They are therefore used in many hyperlipidemias.

Mechanism

Fibrates are agonists of the PPAR-α receptor[3] in muscle, liver, and other tissues. Activation of PPAR-α signaling results in:

  • Increased β-oxidation in the liver
  • Decreased hepatic triglyceride secretion
  • Increased lipoprotein lipase activity, and thus increased VLDL clearance
  • Increased HDL
  • Increased clearance of remnant particles

Side effects

Most fibrates can cause mild stomach upset and myopathy (muscle pain with CPK elevations). Since fibrates increase the cholesterol content of bile, they increase the risk for gallstones.

In combination with statin drugs, fibrates cause an increased risk of rhabdomyolysis, idiosyncratic destruction of muscle tissue, leading to renal failure. A powerful statin drug, cerivastatin (Lipobay), was withdrawn because of this complication. The less lipophilic statins are less prone to cause this reaction, and are probably safer when combined with fibrates.

They are also may increase the risk of cancer.

Pharmacology

Although used clinically since the 1930s,[4] if not earlier, the mechanism of action of fibrates remained unelucidated until, in the 1990s, it was discovered that fibrates activate PPAR (peroxisome proliferator-activated receptors), especially PPARα. The PPARs are a class of intracellular receptors that modulate carbohydrate and fat metabolism and adipose tissue differentiation.

Activating PPARs induces the transcription of a number of genes that facilitate lipid metabolism.

Fibrates are structurally and pharmacologically related to the thiazolidinediones, a novel class of anti-diabetic drugs that also act on PPARs (more specifically PPARγ)

Fibrates are a substrate of (metabolized by) CYP3A4.[5]

See also

References

  1. ^ Steiner G (December 2007). "Atherosclerosis in type 2 diabetes: a role for fibrate therapy?". Diab Vasc Dis Res 4 (4): 368–74. doi:10.3132/dvdr.2007.067. PMID 18158710. http://dx.doi.org/10.3132/dvdr.2007.067. 
  2. ^ Abourbih S, Filion KB, Joseph L, Schiffrin EL, Rinfret S, Poirier P, Pilote L, Genest J, Eisenberg MJ (2009). "Effect of fibrates on lipid profiles and cardiovascular outcomes: a systematic review". Am J Med 122: 962.e1-962.e8. doi:10.1016/j.amjmed.2009.03.030. PMID 19698935. 
  3. ^ Barter PJ, Rye KA (March 2006). "Cardioprotective properties of fibrates: which fibrate, which patients, what mechanism?". Circulation 113 (12): 1553–5. doi:10.1161/CIRCULATIONAHA.105.620450. PMID 16567579. http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=16567579. 
  4. ^ "Pharmaceutical composition and method for treatment of digestive disorders - Patent 4976970". http://www.freepatentsonline.com/4976970.html. Retrieved 2008-12-20. 
  5. ^ http://www.stacommunications.com/journals/cardiology/2004/June/Pdf/034.pdf
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