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PHARMACODYNAMICS

Atorvastatin calcium is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. HMG-CoA reductase, catalyzes the conversion of HMG-CoA to mevalonate and constitutes the rate-limiting step in the biosynthesis of cholesterol. Atorvastatin inhibits the action of HMG-CoA reductase and thereby decreases endogenous cholesterol synthesis, leading to a decrease in circulating low-density lipoprotein cholesterol. In addition to its effect on lipoprotein profile, atorvastatin reduces triglycerides to a greater extent than other HMG-CoA reductase inhibitors. These actions occur in a dose-dependent fashion.^(1,2)  

Studies in guinea pigs have shown that the plasma LDL lowering induced by atorvastatin is due to a decreased secretion of apoB in combination with an increase of hepatic apoB/E receptors.⁽³⁾

In a rabbit atherosclerosis model, atorvastatin diminishes the neointimal inflammation, and this could contribute to the stabilization of the atherosclerotic plaque.⁽⁴⁾

Studies in cholesterol-fed swines suggest that atorvastatin may prevent platelet attachment to eroded vessels and hence, contribute to reducing the thrombotic risk associated with the erosions of the luminal surface and the platelet-dependent progression of atherosclerotic plaques.⁽⁵⁾ A study in rat showed that atorvastatin delays thrombus formation in arterial channels exposed to oxidant stress. This effect of atorvastatin is independent of its effects on plasma cholesterol levels.⁽⁶⁾

Atorvastatin treatment decreased the susceptibility of LDL particles to oxidation by 95% and resulted in 80% decrease in the transfer of cholesteryl ester between high-density lipoprotein (HDL) and the apo-B-containing lipoproteins. Atorvastatin-treated guinea pigs exhibited 175% faster LDL fractional catabolic rates compared with control animals.⁽⁷⁾

Atorvastatin treatment reduced lesion area and consequently increased aortic lumen in dyslipidemic rabbits but did not modify media thickening. It also prevented the majority of the ultrastructural changes observed in endothelial cells.⁽⁸⁾ Short-term (3 days) atorvastatin (10-75 mg/kg/d) in rats significantly reduced myocardial infarct size. This protective effect is thought to be mediated via the nitric oxide synthase pathway.⁽⁹⁾  

Smooth muscle cell proliferation and inflammation in stented vessels has been shown to be reduced by atorvastatin both in hypercholesterolemic rabbits and in animals with normal lipid levels.⁽¹⁰⁾

The triglyceride reduction with atorvastatin seems to stem from the following two indirect mechanisms, limiting VLDL secretion from the liver and increase in clearance of triglyceride-rich lipoprotein via induced LDL receptors from plasma.⁽¹¹⁾

Atorvastatin gas been shown to prevent the enhanced uptake of Ca⁺⁺ by sarcoplasmic reticulum and non- sarcoplasmic reticulum Ca⁺⁺ stores in diabetic dyslipidemic pigs.^(12,13)

Atorvastatin exerts cellular antioxidant effects in cultured rat vascular smooth muscle cells and in the vasculature of spontaneously hypertensive rats. These effects of atorvastatin may contribute to its vasoprotective effects.⁽¹⁴⁾

Studies in normolipemic rabbits show that atorvastatin given in low doses may improve erythrocyte rigidity without altering blood lipids in short term.⁽¹⁵⁾

Atorvastatin was more efficacious than lovastatin in normal, chow-fed rats, and more potent in rats with endogenous hypertriglyceridemia (sucrose-fed). In hypertriglyceridemic rats plasma apoB concentrations decreased only with atorvastatin (30 mg/kg) and VLDL-triglyceride secretion was also decreased more by atorvastatin. In normal, chow-fed guinea pigs atorvastatin was a more potent cholesterol-lowering drug and unlike lovastatin, lowered plasma triglycerides and VLDL-cholesterol. In casein-fed rabbits with endogenous hypercholesterolemia and in chow-fed rabbits atorvastatin lowered LDL-cholesterol more potently than lovastatin.⁽¹⁶⁾ 

Atorvastatin and simvastatin exhibited similar IC50's for inhibition of either rat or human reductase, and single oral dosing in rats showed the compounds to be nearly equipotent at inhibiting hepatic cholesterol synthesis. Treatment of rats with simvastatin or atorvastatin in the feed for four days yielded comparable inductions of hepatic reductase activity and reductase protein. It was also shown that these two drugs induce similar adaptive responses in cells and that their actions are qualitatively and mechanistically identical.⁽¹⁷⁾