Page 649 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 35 Agents Used in Dyslipidemia 635

Its plasma half-life is 20 hours. Sixty percent is excreted in the in reduction in the exchange of triglycerides into HDL in place
urine as the glucuronide, and about 25% in feces. of cholesteryl esters.
CH 3
CH 3 Therapeutic Uses & Dosage
O CH 2 CH 2 CH 2 C COOH Fibrates are useful drugs in hypertriglyceridemias in which
VLDL predominate and in dysbetalipoproteinemia. They also
CH 3
CH 3 may be of benefit in treating the hypertriglyceridemia that
Gemfibrozil results from treatment with antiviral protease inhibitors. The
usual dose of gemfibrozil is 600 mg orally once or twice daily.
The dosage of fenofibrate as Tricor is one to three 48-mg tablets
CH 3 (or a single 145-mg tablet) daily. Dosages of other preparations
Cl C O C C O CH(CH ) vary. Absorption of gemfibrozil is improved when the drug is
3 2
taken with food.
O CH O
3
Fenofibrate
Toxicity
Mechanism of Action Rare adverse effects of fibrates include rashes, gastrointestinal
symptoms, myopathy, arrhythmias, hypokalemia, and high blood
Fibrates function primarily as ligands for the nuclear transcription levels of aminotransferases or alkaline phosphatase. A few patients
receptor PPAR-α. They transcriptionally upregulate LPL, apo A-I, show decreases in white blood count or hematocrit. Both agents
and apo A-II, and they downregulate apo C-III, an inhibitor of may potentiate the action of anticoagulants, and doses of these
lipolysis. A major effect is an increase in oxidation of fatty acids in agents should be adjusted. Rhabdomyolysis has occurred rarely.
liver and striated muscle (Figure 35–4). They increase lipolysis of Risk of myopathy increases when fibrates are given with reductase
lipoprotein triglyceride via LPL. Intracellular lipolysis in adipose inhibitors. Fenofibrate is the fibrate of choice for use in combi-
tissue is decreased. Levels of VLDL decrease, in part as a result of nation with a statin. Fibrates should be avoided in patients with
decreased secretion by the liver. Only modest reductions of LDL hepatic or renal dysfunction. There appears to be a modest increase
occur in most patients. In others, especially those with combined in the risk of cholesterol gallstones, reflecting an increase in the
hyperlipidemia, LDL often increases as triglycerides are reduced. cholesterol content of bile. Therefore, fibrates should be used with
HDL cholesterol increases moderately. Part of this apparent caution in patients with biliary tract disease or in those at higher
increase is a consequence of lower triglyceride in plasma, resulting risk such as women, obese patients, and Native Americans.

Skeletal muscle Fatty acid oxidation

Fatty acids
Endothelium
Blood Lipoprotein lipase Transcription of LPL
vessels
Hydrolysis of VLDL
and chylomicron
VLDL, triglycerides
Chylomicron

Liver Triglycerides
Secretion
Apo Clll synthesis
Synthesis
Apo Al and Apo AII synthesis Fatty acids
Oxidation
Oxidation products

FIGURE 35–4 Hepatic and peripheral effects of fibrates. These effects are mediated by activation of peroxisome proliferator-activated receptor-α,
which decreases the secretion of VLDL and increases its peripheral metabolism. LPL, lipoprotein lipase; VLDL, very-low-density lipoproteins.