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  • Atorvastatin calcium: MECHANISM OF ACTION

All HMG-CoA reductase inhibitors work by competitively inhibiting the rate-limiting step in cholesterol synthesis, the conversion of HMG-CoA to mevalonate . As a result, cholesterol formation is inhibited, and intracellular cholesterol levels decrease, especially in the liver, which requires cholesterol as a substrate for bile acid synthesis. To overcome this shortfall, hepatocytes express a greater number of LDL receptors (apo B/E receptors), which allow for increased recognition and plasma clearance of particles containing apolipopro-teins B and E, in particular LDL particles, where the major apolipoprotein is apo B-100 (apo B).

Although the underlying mechanism of action of atorvastatin is probably the same as that for all HMG-CoA reductase inhibitors, its enhanced efficacy in lowering LDL-C may be related to increased LDL receptor (apo B/E receptor) effects and/or to the reduced availability of VLDL particles for conversion to LDL. buy diabetes drugs

Treatment with atorvastatin resulted in greater reductions in VLDL-C and LDL-C than did other HMG-CoA reductase inhibitors, including in patients with FH . As with HMG-CoA reductase inhibitors, atorvastatin is selectively taken up in the liver , where inhibition of cholesterol synthesis results in up-regulation of LDL receptors (apo B/E receptors) . However, the duration of action of atorvastatin is longer than that of other HMG-CoA reductase inhibitors, probably as a result of longer lasting metabolites . The mean plasma elimination half-life of atorvastatin is approximately 14 h, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 h (due to the contribution of longer-lived active metabolites). This sustained inhibition of HMG-CoA reductase most likely results in profoundly reduced intracellular cholesterol levels. This would lead to enhanced up-regulation of LDL receptors, resulting in a greater removal of VLDL and LDL. Thus, in addition to removal of LDL particles, there would be reduced amounts of VLDL substrate available for conversion to LDL, thereby further decreasing LDL levels. The greater effect of atorvastatin in lowering triglyceride levels compared with other HMG-CoA reductase inhibitors may also be due to the significant reductions in VLDL particles and/or decreased cholesterol synthesis.

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