In pharmacology, the fibrates are a class of amphipathic carboxylic acids.
They are used for a range of metabolic disorders, mainly hypercholesterolemia,
and are therefore hypolipidemic agents. Members
Fibrates prescribed commonly are: Bezafibrate
Ciprofibrate Clofibrate
Gemfibrozil Fenofibrate
Clinofibrate Indications
Fibrates are used in accessory therapy in many forms of hypercholesterolemia,
usually in combination with statins. 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 indicated only in those
not tolerant to statins. Although less effective in lowering LDL
and triglyceride levels, the ability of fibrates to increase HDL and lower
triglyceride levels seems to reduce insulin resistance when the dyslipidemia
is associated with other features of the metabolic syndrome. They are therefore
used in many hyperlipidemias. Fibrates are not suitable for patients with low
HDL levels. As per US FDA label change of trichor, it is recommended that the
HDL-C levels be checked within the first few months after initiation of fibrate
therapy. If a severely depressed HDL-C level is detected, fibrate therapy
should be withdrawn, and the HDL-C level monitored until it has returned to
baseline. Fibrate therapy should not be re-initiated Medwatch
Mechanisms of action Evidence from studies in rodents and in
humans is available to indicate five major mechanisms underlying the
above-mentioned modulation of lipoprotein phenotypes by fibrates:
Induction of lipoprotein lipolysis: Increased triglyceride-rich lipoprotein
lipolysis could be a reflection of changes in intrinsic lipoprotein lipase
activity or increased accessibility of TRLs for lipolysis by LPL owing to a
reduction of TRL apoC-III content. Induction of hepatic fatty acid uptake
and reduction of hepatic triglyceride production: In rodents, fibrates
increase FA uptake and conversion to acyl-CoA by the liver owing to the
induction of FA transporter protein and acyl-CoA synthetase activity. Induction
of the ß-oxidation pathway with a concomitant decrease in FA synthesis by
fibrates results in a lower availability of FAs for triglyceride synthesis, a
process that is amplified by the inhibition of hormone-sensitive lipase
in adipose tissue by fibrates. Increased removal of LDL particles:
Fibrate treatment results in the formation of LDL with a higher affinity
for the LDL receptor, which are thus catabolized more rapidly.
Reduction in neutral lipid exchange between VLDL and HDL may result from
decreased plasma levels of TRL. Increase in HDL production and
stimulation of reverse cholesterol transport: Fibrates increase the
production of apoA-I and apoA-II in liver, which may contribute to the
increase of plasma HDL concentrations and a more efficient reverse cholesterol
transport. Side effects
Most fibrates can cause mild stomach upset and myopathy. 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, 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. Drug toxicity includes acute kidney
injury. Pharmacology
Although used clinically since the 1930s, if not earlier, the mechanism of
action of fibrates remained unelucidated until, in the 1990s, it was discovered
that fibrates activate PPAR, 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 Fibrates are a substrate of CYP3A4.
Fibrates have been shown to extend lifespan in the roundworm C. elegans.
See also Statin
Hypertriglyceridemia References