Fibric Acid Derivatives - Cardiovascular Poisons

FIBRIC ACID DERIVATIVES

Fibric acid derivatives, including clofibrate, fenofibrate, bezafi-brate, ciprofibrate, and simfibrate, are antilipidaemic agents which decrease serum lipids by reducing the very-low-density lipoprotein fraction (Sf 20 to 400) rich in triglycerides. These drugs reduce triglycerides (TG) and VLDL, while increasing HDL levels. They act by increasing the activity of lipoprotein lipase and other enzymes. Clofibrate also decreases serum cholesterol levels, primarily the low-density lipoprotein frac-tion (Sf 0 to 20).

Uses

·              Clofibrate is indicated as adjunctive therapy to diet for the treatment of type III hyperlipidaemia. It may also be helpful in some patients with severe hypertriglyceridaemia due to Type IIb, Type IV, and Type V hyperlipidaemias.

·              Fenofibrate is indicated as adjunctive therapy to diet for the treatment of Type IV and V hyperlipidaemia in patients who are at risk for pancreatitis.

·              Ciprofibrate is being investigated as a lipid regulating drug with actions on plasma lipids similar to those of bezafibrate.

Adverse and Toxic (Clinical) Features

·      Myalgia, GI upset, rash, alopecia (rare). Muscular syndrome may be dose-dependant; the most frequent effect is myalgia, with the most commonly affected muscles being those of the lower extremities. Arthralgia and flu-like symptoms have also been reported.

·      Nausea, vomiting, constipation, dyspepsia, diarrhoea, and flatulence occur transiently in approximately 10% of patients. Epigastric pain has been reported as a frequent side effect, and cholelithiasis is increased.

·      Impotence and decreased libido have been reported.

·      Clofibrate therapy has been associated with multiple cardiovascular side effects (peripheral vascular disease, pulmonary embolism, thrombophlebitis, angina pectoris, cardiac arrhythmias, cardiomegaly) of varying severity, fever, hepatotoxicity, myopathies, and gastrointestinal irritation. Fatigue, weakness, drowsiness, dizziness, and headache have also been reported. Renal effects of clofi-brate have included dysuria, haematuria, proteinuria and oliguria. Hepatomegaly, jaundice, hepatitis, and transient increases in serum transaminase levels have occurred.

·      Increases of serum transaminase levels greater than 3 times the upper limit of normal were reported following fenofi-brate therapy.

·              Concomitant administration of clofibrate with antico-agulants may cause hypoprothrombinaemia. When anti-coagulants are given concurrently with clofibrate, the dosage of the anticoagulant should usually be reduced by one-half (depending on the individual case) to maintain the prothrombin time at the desired level in order to prevent bleeding complications.

·      Co-administration of clofibrate with phenytoin may cause an increase in phenytoin serum levels due to displacement of phenytoin from its protein binding site.

·      An increased hypoglycaemic effect has been reported following concurrent administration of clofibrate and tolbutamide.

Treatment

·      Patients should be observed for potential CNS depres-sion, musculoskeletal, cardiovascular, and hepatic or renal damage, as these are the primary manifestations of toxicity due to therapeutic use.

·      Periodic examinations for muscle tenderness and dysfunc-tion are mandatory to detect the muscular syndrome, and determinations of CPK and AST should be performed during therapy.

·      Parameters that may increase—serum aldolase, BSP reten-tion, thymol turbidity, glutamic-oxaloacetic transaminase.

·      Parameters that may decrease—fibrinogen, gamma-glutamyl transpeptidase, serum alkaline phosphatase.

·      Therapeutic plasma levels of p-chlorophenoxyisobutyric acid (CPIB) have been reported to be 80 to 150 mcg/ml. The average maximum plasma level after a 500 mg oral dose was 44.0 mcg/ml.

·              Gastric decontamination is probably usually not necessary and should be considered only if several times the daily therapeutic dose was ingested.