Pharmacology: Mechanism of Action: HMG-CoA reductase is the rate-limiting enzyme responsible for the conversion of 3-hydroxy-3 methyl-glutaryl-coenzyme A (HMG-CoA) to mevalonate, a precursor of sterols including cholesterol. Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase. Besides lowering plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver; atorvastatin also increases transcription of LDL receptors leading to enhanced removal of LDL from plasma and increased catabolism of LDL. There is also decreased production of VLDL. Atorvastatin reduces total cholesterol (total-C); LDL cholesterol (LDL-C) and apolipoprotein-B (apoB) in patients with homozygous and heterozygous familial forms of hypercholesterolemia, non-familial forms of hypercholesterolemia, and mixed dyslipidemias. It also reduces VLDL cholesterol (VLDL-C) and triglycerides and producing variable increases in LDL-C and apo A.
Pharmacodynamics: Atorvastatin calcium, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response.
Pharmacokinetics: Absorption: After oral administration, atorvastatin is rapidly absorbed. Max. plasma concentrations are reached with 1-2 hours after administration. Absolute bioavailability of the parent drug is approximately 14% and systemic bioavailability of HMG-CoA reductase inhibiting activity is approximately 30%.
Drug dosage rather than systemic drug concentration correlates better with LDL-C reduction and although food decreases the rate and extent of drug absorption, LDL-C reduction is similar whether atorvastatin is given with or without food LDL-C reduction is same regardless of the time of day of administration even though plasma concentrations are lower following evening drug administration compared with morning.
Distribution: More than 98% of the drug is bound to plasma proteins. The mean volume of distribution is approximately 565 litres. A blood plasma ratio of approximately 0.25 indicates poor drug penetration into RBC's.
Metabolism: Cytochrome P450 3A4 metabolites atorvastatin to ortho and para hydroxylated derivatives and various beta oxidation products. The ortho and para hydroxylated derivatives of atorvastatin are active metabolites, approximately 70% of circulatory inhibitory activity of HMG-CoA reductase is attributed to active metabolites.
Excretion: The primary route of elimination of atorvastatin and its metabolites is bile following hepatic and/or enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours; but the half-life of inhibitory activity for HMG-CoA reductase is 20-30 hours due to contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration.
Geriatric: Although plasma concentrations are higher in healthy elderly subjects than in young adults, the LDL-C reduction is comparable to that seen in younger patient population given equal doses of atorvastatin.
Paediatric: No pharmacokinetic data is available.
Gender: There is no clinically significant difference in LDL-C reduction with atorvastatin between men and women.
Renal insufficiency: Renal disease has no influence on the plasma concentrations or lipid effects of atorvastatin.
Hepatic insufficiency: In-patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased.