Zocor (Simvastatin)
Simvastatin
Zocor®
Classification:
Cardiovascular Agents
- Antilipemics
- HMG-CoA reductase inhibitors
Description: Simvastatin is an oral antilipemic agent which inhibits HMG-CoA reductase. Simvastatin is the methylated form of lovastatin. Both simvastatin and lovastatin are prodrugs that require hydrolysis for activation. Simvastatin is used in the treatment of primary hypercholesterolemia and is effective in reducing total and LDL-cholesterol as well as plasma triglycerides and apolipoprotein B. Simvastatin has a high affinity for HMG-CoA reductase. At therapeutic doses of 5 to 80 mg once daily, simvastatin reduces mean LDL concentrations by approximately 26- 47%. Simvastatin was approved by the FDA in December 1991. As a result of the Scandinavian Simvastatin Survival Study, on July 5, 1995, the FDA approved simvastatin for use, in combination with diet, to prevent myocardial infarction in patients with hypercholesterolemia and preexisting coronary artery disease. In April 2003, the FDA approved simvastatin 40 mg as a starting dose for a broad population of patients at high risk for coronary events, including patients with existing coronary heart disease, diabetes, peripheral vessel disease, or patients with a history of stroke or other cerebrovascular disease. This approval was based on the favorable findings of the 5 year Heart Protection Study, which demonstrated reduced all-cause mortality, coronary deaths, and rates of stroke, myocardial infarction, and revascularization in high-risk patients treated with simvastatin 40 mg/day, regardless of initial cholesterol concentrations. The Heart Protection Study Collaborative Group subsequently reported that diabetic patients randomized to simvastatin 40 mg/day experienced a lower rate of first vascular events (major coronary event, stroke, or revascularization) relative to placebo. The initial patent for Zocor® is expected to expire in December 2005.
Mechanism of Action: Like lovastatin, simvastatin is a prodrug with little or no inherent activity. The 6-membered lactone ring is hydrolyzed in vivo to generate mevinolinic acid. Mevinolinic acid, one of simvastatin’s several active metabolites, is structurally similar to HMG-CoA (hydroxymethylglutaryl CoA). Once hydrolyzed, simvastatin competes with HMG-CoA for HMG-CoA reductase, a hepatic microsomal enzyme. Interference with the activity of this enzyme reduces the quantity of mevalonic acid, a precursor of cholesterol. This process occurs within the hepatocyte and is one of two mechanisms that generate cholesterol. Cholesterol can also be taken up from LDL by endocytosis. Since de novo synthesis of cholesterol is impaired by simvastatin, cholesterol uptake is augmented. Thus, simvastatin also enhances clearance of LDL.
Simvastatin decreases total cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B, while increasing HDL. In one head-to-head study of simvastatin vs. pravastatin involving 291 patients, simvastatin produced slightly greater improvements in total, LDL, and HDL cholesterol and triglycerides after 6 weeks. Both drugs were given in a dose of 10 mg PO once daily. It should be noted that higher doses can produce more dramatic results. These agents should be administered at bedtime since there is evidence for diurnal variation in the hepatic synthesis of cholesterol.
HMG-CoA reductase inhibitors have been reported to decrease endogenous CoQ10 serum concentrations; the clinical significance of these effects is unknown.
Pharmacokinetics: Simvastatin is an inactive prodrug. It is the methylated derivative of lovastatin and, like lovastatin, must be activated in the liver. Absorption is about 85%, but bioavailability is less than 5%. Absorption is not significantly reduced if taken before a low-fat meal; the drug can be administered with or without food. To optimize the action of simvastatin, it should be administered in the evening hours or at bedtime. Peak plasma concentrations are reached in 1.3- 2.4 hours. Both simvastatin and the active metabolite are strongly bound to plasma proteins (95%). Simvastatin and lovastatin are lipophilic, while pravastatin is hydrophilic. Being lipophilic, simvastatin is taken up by cells other than hepatocytes and, unlike pravastatin, simvastatin penetrates the CNS. Sixty percent of an oral dose is excreted in the feces and 13% in the urine. Half-life of simvastatin is 1.9 hours.
Special Populations: A pharmacokinetic study with simvastatin showed the mean plasma level of HMG-CoA reductase inhibitory activity to be approximately 45% higher in patients aged 70- 78 compared with patients aged 18- 30 years. Although pharmacokinetic data are lacking for simvastatin in patients with renal failure, data for a related HMG-CoA reductase inhibitor (lovastatin) suggest the need for cautious dosage escalation in such patients (see Dosage). In patients with severe renal impairment (CrCl 10- 30 ml/min), the plasma concentrations of total inhibitors after a single dose of lovastatin are approximately two-fold higher than those in healthy volunteers.
Zocor Tablets(Tab 40 mg) [1 of 5 - Click here to see more photos]
[ Last Revised: 9/6/2005 6:05:00 PM ]
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