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.

Contents 1 Members 2 Indications 3 Mechanism 4 Side effects 5 Pharmacology 6 See also 7 References

[edit] Members

Fibrates prescribed commonly are:

• Bezafibrate (e.g. Bezalip)
• Ciprofibrate (e.g. Modalim)
• Clofibrate (largely obsolete due to side-effect profile, e.g. gallstones)
• Gemfibrozil (e.g. Lopid)
• Fenofibrate (e.g. TriCor)

[edit] 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.

[edit] 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

[edit] 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 A powerful statin drug, cerivastatin (Lipobay), was withdrawn because of this complication.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.

[edit] 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]

[edit] See also

• Statin

[edit] References

v • d • e Pharmacology: Major drug groups Gastrointestinal tract/metabolism (A) stomach acid (Antacids, H2 antagonists, Proton pump inhibitors) • Antiemetics • Laxatives • Antidiarrhoeals/Antipropulsives • Anti-obesity drugs • Anti-diabetics • Vitamins • Dietary minerals Blood and blood forming organs (B) Antithrombotics (Antiplatelets, Anticoagulants, Thrombolytics/fibrinolytics) • Antihemorrhagics (Platelets, Coagulants, Antifibrinolytics) Cardiovascular system (C) cardiac therapy/antianginals (Cardiac glycosides, Antiarrhythmics, Cardiac stimulants) Antihypertensives • Diuretics • Vasodilators • Beta blockers • Calcium channel blockers • renin-angiotensin system (ACE inhibitors, Angiotensin II receptor antagonists, Renin inhibitors) Antihyperlipidemics (Statins, Fibrates, Bile acid sequestrants) Skin (D) Emollients • Cicatrizants • Antipruritics • Antipsoriatics • Medicated dressings Reproductive system (G) Hormonal contraception • Fertility agents • SERMs • Sex hormones Endocrine system (H) Hypothalamic-pituitary hormones • Corticosteroids (Glucocorticoids, Mineralocorticoids) • Sex hormones • Thyroid hormones/Antithyroid agents Infections and infestations (J, P, QI) Antibiotics (Antimycobacterials) • Antifungals • Antivirals • Antiparasitics (Antiprotozoals, Anthelmintics) • Ectoparasiticides • Intravenous immunoglobulin • Vaccines Malignant disease (L01-L02) Anticancer agents (Antimetabolites, Alkylating, Spindle poisons, Antineoplastic, Topoisomerase inhibitors) Immune disease (L03-L04) Immunomodulators (Immunostimulants, Immunosuppressants) Muscles, bones, and joints (M) Anabolic steroids • Anti-inflammatories (NSAIDs) • Antirheumatics • Corticosteroids • Muscle relaxants • Bisphosphonates Brain and nervous system (N) Anesthetics (General, Local) • Analgesics • Antimigraines • Anticonvulsants/Mood stabilizers (Lithium pharmacology) • Antiparkinson drugs Psycholeptics (Anxiolytics, Antipsychotics, Hypnotics/Sedatives) • Psychoanaleptics (Antidepressants, Stimulants) Respiratory system (R) Decongestants • Bronchodilators • Cough medicines • H1 antagonists Sensory organs (S) Ophthalmologicals • Otologicals Other ATC (V) Antidotes • Contrast media • Radiopharmaceuticals • Dressings

v • d • e Lipid modifying agents (C10) GI tract Cholesterol absorption inhibitor, NPC1L1 Ezetimibe • SCH-48461 Bile acid sequestrants/resins (LDL) Cholestyramine • Colestipol • Colestilan • Colextran • Colesevelam Liver Statins (HMG-CoA reductase, LDL) Simvastatin# • Atorvastatin • Fluvastatin • Lovastatin • Mevastatin • Pitavastatin • Pravastatin • Rosuvastatin • Cerivastatin‡ Niacin and derivatives (HDL and LDL) Niceritrol • Niacin • Nicofuranose • Aluminium nicotinate • Nicotinyl alcohol • Acipimox Blood vessels Fibrates (PPAR) Clofibrate‡ • Bezafibrate • Aluminium clofibrate • Gemfibrozil • Fenofibrate • Simfibrate • Ronifibrate • Ciprofibrate • Etofibrate • Clofibride • Clinofibrate CETP inhibitors (HDL) Anacetrapib† • Torcetrapib§ • JTT-705 Combinations Niacin/lovastatin • Niacin/simvastatin • Ezetimibe/simvastatin • Niacin/laropiprant Other Dextrothyroxine • Probucol • Tiadenol • Benfluorex • Meglutol • Omega-3-triglycerides • Magnesium pyridoxal 5-phosphate glutamate • Policosanol • Lapaquistat§ • Alipogene tiparvovec #WHO-EM. ‡Withdrawn from market. CLINICAL TRIALS: †Phase III. §Never to phase III