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Creative Consultants |
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CONCLUSIONS Atorvastatin is an inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. The reduction in intracellular cholesterol increases the number of low density lipoprotein (LDL) receptors, thus increasing the clearance of LDL-cholesterol from plasma. In dosages of 10 to 80 mg/day, atorvastatin reduces levels of total cholesterol, low-density lipoprotein (LDL)-cholesterol, triglyceride and very low-density lipoprotein (VLDL)-cholesterol and increases high-density lipoprotein (HDL)-cholesterol in patients with a wide variety of dyslipidaemias. The marked reduction in triglyceride levels with atorvastatin may result mainly from decreases in VLDL production caused in part by inhibition of cholesterol synthesis. In addition, the increase in number of LDL receptors combined with the decrease in LDL particles available to these receptors may enhance the binding of VLDL paticles thus reducing triglyceride levels. Atorvastatin reduces LDL-cholesterol levels in patients with homozygous familial hyperchloesterolaemia despite the absence of functional LDL receptors in these patients. This effect appears to result from marked inhibition of cholesterol synthesis which in turn decreases the rate of LDL production. In common with other statins, it
has non-lipid-lowering effects including improving endothelial function,
antiproliferative actions on smooth muscle and reducing platelet aggregation. It
also has anti-inflammatory effects and may reduce plasma glucose levels. About 30% of an oral dose of atorvastatin is absorbed and
undergoes extensive first-pass metabolism. The drug has a bioavailability of
about 14% and is >98% protein bound in the plasma. No significant changes in
area under the plasma concentration-time curve or elimination half-life were
observed with administration of atorvastatin 30 minutes after food intake,
although the rate of absorption was reduced.
After single doses of atorvastatin 10, 20, or 40 mg in healthy male
volunteers, the time to reach peak plasma concentration was 0.6 to 0.9 hours. Metabolism of atorvastatin by cytochrome P450 (CYP) 3A4 produces ortho- and para-hydroxylated derivatives and various b-oxidation products. 70% of the HMG-CoA reductase inhibitory activity associated with atorvastatin has been attributed to its active ortho- and para-metabolites. Clinically significant interactions of atorvastatin are likely to occur with its concomitant use with other drugs metabolized by CYP 3A4 including erythromycin, oral contraceptives, itraconazole etc. In large long-term trials in patients with primary hypercholesterolaemia. atorvastatin produced greater reductions in total cholesterol. LDL-cholesterol and triglyceride levels than other HMG-CoA reductase inhibitors. This pronounced effect of atorvastatin seems to be due to its long-lasting action, presumably a reflection of longer residence time of atorvastatin and its active metabolites in the liver. In patients with coronary heart disease (CHD), atorvastatin was more efficacious than lovastatin, pravastatin. fluvastatin and simvastatin in achieving target LDL-cholesterol levels and, in high doses, produced very low LDL-cholesterol levels. Aggressive reduction of serum LDL-cholesterol with atorvastatin 80 mg/day for 16 weeks in patients with acute coronary syndromes significantly reduced the incidence of the combined primary end-point events and the secondary end-point of recurrent ischaemic events requiring rehospitalisation in the large. well-designed MIRACL trial. Results of AVERT study, favoured the use of aggressive lipid lowering over percutaneous transluminal coronary angioplasty in patients with mild to moderate coronary disease. Treatment with atorvastatin significantly reduced low density lipoprotein cholesterol levels, and was associated with a 36% reduction in ischemic events and a significant delay in time to first ischemic event. In CHD patients with diabetes mellitus structured care of dyslipidemia with atorvastatin reduces all cause and coronary mortality, coronary morbidity, and stroke by more than one half within a 3-year period, in comparison to usual care (GREACE Study). Atorvastatin is well tolerated and adverse events are usually mild and transient. The tolerability profile of atorvastatin is similar to that of other available HMG-CoA reductase inhibitors and to placebo. Elevations of liver transaminases and creatine phosphokinase are infrequent. There have been rare case reports of rhabdomyolysis occurring with concomitant use of atorvastatin and other drugs.
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