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PHARMACODYNAMIC PROPERTIES

Atorvastatin is a liver-selective, competitive 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. Sterol synthesis is inhibited 1 to 8 hours after a single oral dose of atorvastatin. The resultant decrease in endogenous hepatic cholesterol synthesis leads to compensatory upregulation of hepatic LDL cholesterol receptors which promote LDL catabolism and apo B degradation. LDL production is also decreased because of impaired synthesis and/or secretion of its precursor, VLDL.⁽¹⁾

The major metabolites of atorvastatin are the para- and ortho-hydroxy metabolite. The para- and ortho-hydroxy metabolites are active, displaying inhibitory activity towards HMG-CoA reductase in vitro human liver microsomes. Approximately 70% of the HMG-CoA reductase inhibition associated with atorvastatin has been attributed to its active metabolites.⁽¹⁾

The inhibition of cholesterol forrmation by HMG-CoA reductase inhibitors reduces intracellular stores of cholesterol, predominantly in the liver, which is exposed to a much higher concentration than systemic tissues. This results in upregulation of LDL receptors, which increases the clearance of LDL cholesterol from plasma. Plasma cholesterol levels may also be lowered by inhibition of hepatic synthesis of VLDL cholesterol, a precursor of LDL cholesterol, causing reduced production of LDL cholesterol. In patients with hypertriglyceridemia, atorvastatin significantly lowers triglycerides. It is generally accepted that HMG-CoA reductase does not play a direct role in the regulation of triglycerides. Two indirect mechanisms have been suggested to explain the effect of atorvastatin on triglyceride levels. Substantial reduction of cholesterol synthesis may impair VLDL particle assembly and secretion, resulting in lower triglyceride levels because VLDL transports triglycerides.⁽²⁾ Marked reductions in hepatic cholesterol levels may lead to increased LDL receptor expression, which in turn causes reductions in triglyceride levels through increased binding of VLDL remnant particles and LDL.⁽³⁾

Plasma mevalonic acid levels give a good indication  of the in vivo rate of cholesterol biosynthcsis.⁽⁴⁾ Atorvastatin 80 mg per day reduced fasting plasma mevalonic acid levels by 59% in separate studies of 6 weeks' duration involving patients with heterozygous familial hypercholesterolemia.⁽⁵⁾

Atorvastatin 40 mg per day for 15 days, taken in the evening by 16 normolipidemic volunteers, reduced total cholesterol by 34%, LDL cholesterol by 48%, VLDL cholesterol by 37%, triglycerides by 25%. apolipoprotein A_l by 6%, and apo B by 34%. HDL cholesterol levels were increased by only 2%.⁽⁶⁾ A dose-response relationship exists between multiple dosing with atorvastatin  and lipid parameters for doses up to 80 mg per day. The greater cholesterol-lowering effect of atorvastatin 80 mg per day than the maximal recommended doses of pravastatin and simvastatin, 40 mg per day, probably reflects greater inhibition of HMG-CoA reductase at the higher atorvastatin dose.⁽⁷⁾  The proportional reduction of plasma lipids appears to be greatest for those parameters showing the largest elevation.⁽⁸⁾  Levels  of the soluble adhesion molecules are significantly increased in both hypercholesterolemic and hypertriglyceridemic patients.⁽⁹⁾   Both low (10 mg/day) and high (80 mg/day) doses of atorvastatin, significantly reduced soluble intercellular adhesion molecule-1 at 2 weeks, further reduced at 3 months and maintained at 9 months.⁽¹⁰⁾ 

Atorvastatin produces greater plasma LDL-cholesterol reductions than other statins. 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.⁽¹¹⁾

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.⁽⁵⁸⁾

HMG-CoA reductase inhibitors have been shown to significantly reduce the risk of cardiovascular events. These benefits have been ascribed to the plasma LDL-cholesterol reducing ability of statin therapy. In addition, non-lipid mechanisms of statins may also be involved; these include plaque stabilization, improved endothelial functions and decreased tendency towards thrombus formation.^(12,13,14)

Activation of factor VII by tissue factor may represent a critical event during plaque rupture in acute coronary syndromes. Patients with combined hyperlipemia are at high risk for developing coronary heart disease and their tendency to thrombosis may be accelerated during postprandial hyperlipemia.⁽¹⁵⁾.  The effects of atorvastatin on plasma levels of factor VII were examined in 30 hyperlipidemic patients. After 12 weeks of atorvastatin treatment, factor VII activity and factor VII antigen levels had decreased significantly by 13%  and 12% , respectively. No significant changes were seen in activated factor VII  levels. Plasma concentrations of fibrinogen were slightly, but not significantly, increased at 12 weeks. No significant changes were seen in plasminogen activator inhibitor-1 levels. The effects of atorvastatin on factor VII may contribute to a decreased thrombotic potential, resulting in fewer thromboembolic events, including a reduction in coronary heart disease.⁽¹⁶⁾

Vascular endothelial growth factor (VEGF) is suggested to be involved in the growth of atherosclerotic plaque by inducing its neovascularization. Atorvastatin therapy reduced VEGF plasma levels in CAD patients by about 40%. The VEGF plasma concentration tended to be higher in CAD patients before treatment compared to control patients. This represents represent a novel beneficial effect of atorvastatin.⁽¹⁷⁾

Atherosclerosis is characterized by macrophage foam cells formation, which originate from differentiating blood monocytes that have taken up oxidised LDL at enhanced rate. Atorvastatin therapy in hypercholesterolemic patients reduces the enhanced cellular uptake of oxidized LDL during ex-vivo differentiation of monocytes into macrophages, and decreases cellular scavenger receptors gene expression. These effects may account for the attenuation of atherogenesis in hypercholesterolemic patients following atorvastatin treatment.⁽¹⁸⁾

Atorvastatin has also been shown to significantly decrease CRP concentrations after 4 weeks of therapy. The decrease in CRP lowering was thus fully established by 1 month and this response was independent of lipid and lipoprotein changes as well as atorvastatin doses.⁽¹⁹⁾

Inflammation promotes acute coronary syndromes and ensuing clinical complications. High-dose atorvastatin potentiated the decline in inflammation in patients with acute coronary syndromes,  supporting the value of early statin therapy in these patients.⁽²⁰⁾