The collection of symptoms that comprise the metabolic syndrome accompanies an increased risk of cardiovascular disease and type 2 diabetes. The risk factors for the syndrome include elevated blood pressure, increased plasma glucose levels, and dyslipidemia. Although initial treatment has its primary focus on lifestyle modification, with emphasis on weight reduction, increased physical activity, and a restructured diet, drug therapy often is introduced to counteract these specific risk factors.
Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, commonly known as statins, are among the most commonly prescribed drugs for the control of lipid disorders. A recent addition to those statins available generically is pravastatin.
Statins, such as pravastatin, competitively inhibit the enzyme HMG-CoA reductase, a catalyst to the conversion of HMG-CoA to mevalonic acid, an early precursor to cholesterol.
Administration and Dosing
For adult treatment of hyperlipidemia or for the prevention of coronary events, pravastatin is dosed at 40 mg daily, increasing at 4-week intervals to a maximum daily dose of 80 mg. Children 8 to 13 years old tolerate 20 mg daily; those up to 18 years old may take 40 mg daily. Dosing of pravastatin should be timed either 1 hour before or 4 hours following the use of either colestipol or cholestyramine.
Adverse Effects and Drug Interactions
Whereas up to 5% of patients using a statin drug may experience muscle disorders, fatalities from myopathy are factored at less than 1 per million of the combined prescriptions for all currently marketed statin preparations.
The risk factors surrounding the development of statin-based myopathies include advanced age, alcohol abuse or hepatic disease, diabetes, chronic renal insufficiency, and hypothyroidism. Ironically, some of these risk factors contribute to dyslipidemia and the need for statin therapy. Prior to treatment with a statin, baseline creatine kinase (CK) and thyroid-stimulating hormone levels should be obtained, both to monitor for statin-induced CK elevations later on and to determine whether a thyroid malfunction is contributing to the dyslipidemia.
Patients should be warned of the potential for myopathy and be told to report any muscle pain or weakness to their physicians immediately. Patients should be interviewed regarding their muscle condition 6 to 12 weeks after starting therapy and with each physician visit. Sources also recommend stopping statin therapy before major surgery or prior to planned strenuous activity such as running a marathon.
The risk of myopathy increases if pravastatin is given concurrently with gemfibrozil. Patients using any statin will benefit from the addition of coenzyme Q10 (CoQ10, or ubiquinone) as a means to counteract the potential for myopathy at daily doses of 60 to 120 mg. CoQ10 generally is well-tolerated and has no significant adverse effects.
In addition, a recent Danish study found that patients using a statin are 14 times more likely to develop peripheral neuropathy than those in the general population. Pravastatin is not extensively metabolized by the isozyme cytochrome P450 3A4 (CYP3A4), with a lesser potential for drug interactions.
As a class of drugs, statins will become increasingly prescribed as cholesterol goals are lowered and the drugs' indications are expanded. Recent studies imply that statin use may lower the lifetime risk of Alzheimer's disease, lower cardiovascular risk among the elderly, and provide benefits to postmenopausal women. Pravastatin has the advantage of fewer CYP3A4-based interactions and is now in a more economical generic form. Pravastatin currently is available from Teva Pharmaceutical Industries Ltd in 10-, 20-, and 40-mg tablets.
At least 100 million Americans have total cholesterol levels exceeding 100 mg/dL; 40 million have levels over 240 mg/dL. Current treatment guidelines for hypercholesterolemia encourage a significant reduction in low-density lipoprotein (LDL). To date, the statins represent the most effective drug treatment for the reduction of LDL cholesterol. Statins, such as simvastatin, reduce circulating lipoproteins through interference with mevalonate, an intermediary in the biosynthesis of cholesterol.
Simvastatin is an antilipidemic agent that is useful with dietary and lifestyle changes for preventing cardiovascular events and dyslipidemia and for reducing triglyceride levels. In addition, it has been shown to reduce the progression of atherosclerosis in coronary arteries and to lower the risk for postsurgical thrombotic complications following artery bypass grafting.
Simvastatin should be dosed on an individual basis according to patient response. Serum lipoproteins should be checked 4 weeks after initiation of treatment and periodically thereafter.
The initial adult daily dose for simvastatin is 20 to 40 mg taken in the evening. Monthly adjustments can follow, with a maximum suggested daily dose of 80 mg. Although simvastatin has been administered to children as young as 10 years of age, daily doses above 40 mg have not been evaluated.
In patients being treated for the condition known as homozygous familial hypercholesterolemia, the recommended adjunctive dose of simvastatin is 40 mg in the evening or a multiple-dosing regimen of two 20-mg doses during the day, with a 40-mg dose in the evening.
Because of an increased risk of myopathy, patients taking simvastatin concurrently with cyclosporine should begin with only a 5-mg dose and not exceed a daily regimen of 10 mg.
The risk for myopathy is the greatest concern with statin therapy. In addition to the restrictions surrounding concurrent treatment with cyclosporine, simvastatin may interact with other drugs to increase this risk. Muscle condition should be examined 6 to 12 weeks after initial dosing and with each physician visit. Sources also recommend stopping statin therapy before major surgery or prior to planned prolonged strenuous activity.
Patients using any statin at daily doses of 60 to 120 mg will benefit from the addition of coenzyme Q10 (CoQ10; ubiquinone) to counteract the potential for myopathy. CoQ10 has no significant adverse effects and is generally well-tolerated.
The combination of simvastatin and gemfibrozil should be avoided, and concurrent use of niacin should be approached cautiously. If employed, the maximum daily simvastatin dose is 10 mg. In addition, patients taking amiodarone or verapamil should restrict simvastatin to a daily intake of 20 mg.
Patients should be advised that simvastatin shares the toxic potential of other statins, especially the risk for rhabdomyolysis. Commercial combinations of simvastatin with other agents, such as ezetimibe, do little to minimize that risk.
The enthusiasm for statin therapy continues to grow. One of the obstacles to having patients share that enthusiasm has traditionally been the cost. With the appearance of simvastatin in generic forms, economical options are emerging to treat what is regarded as an epidemic of high cholesterol. Additionally, studies suggest that statins such as simvastatin may lower the lifetime risk of Alzheimer's disease, reduce cardiovascular risk among the elderly, and provide benefits to postmenopausal women.
FDA approval for generic simvastatin in 5-, 10-, 20-, 40-, and 80-mg tablets has been granted to Teva Pharmaceutical Industries Ltd and Ranbaxy Laboratories. Dr. Reddy's Laboratories has exclusive rights from Merck for an authorized generic.
Mr. Middleton is an instructor of pharmacology at Kellogg Community College in Battle Creek, Mich.
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