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Pharmacology: Pharmacodynamics: Atorvastatin is a synthetic antilipemic agent. The drug is a selective, competitive inhibitor of HMG-CoA reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonate which is an early and ratelimiting step in cholesterol biosynthesis.
Atorvastatin lowers plasma cholesterol, lipoprotein levels, inhibits cholesterol synthesis in liver and increases the number of hepatic low-density lipoprotein (LDL) receptors on the cell surface for enhanced uptake and catabolism of LDL-cholesterol (LDL-C) from blood.
Atorvastatin is effective in reducing LDL in patients with homozygous familial hypercholesterolemia, a population who has not normally responded to lipid-lowering medication.
The primary site of action of Atorvastatin is the liver, which principal site of cholesterol synthesis and LDL clearance. LDL-C reduction correlates better with drug dose than it does with systemic drug concentration. Atorvastatin reduces serum total cholesterol, LDL-C, apolipoprotein B (apo B), triglyceride, very low-density lipoprotein (VLDL)-cholesterol, intermediate-density lipoprotein (IDL)-cholesterol and non-high-density lipoprotein (HDL) cholesterol concentrations, and increases serum HDL-cholesterol and apolipoprotein A-1 concentrations in patients with primary hypercholesterolemia, mixed dyslipidemia, hypertriglyceridemia and primary dysbetalipoproteinemia.
Pharmacokinetics: Atorvastatin is rapidly absorbed from gastrointestinal tract. Maximum plasma concentrations occur within 1-2 hours. The absolute bioavailability of Atorvastatin is approximately 14%. It has low absolute bioavailability due to presystemic clearance in the gastrointestinal mucosa and/or first-pass metabolism in the liver. Although food decreases the rate and extent of drug absorption, LDL-C reduction is similar whether Atorvastatin is given with or without food.
Atorvastatin is distributed mainly to the liver. It is 98% bound to plasma proteins.
Atorvastatin is metabolized by the cytochrome P450 isoenzyme CYP 3A4 to several active metabolites and in vitro studies also indicate that Atorvastatin is a weak inhibitor of CYP 3A4.
Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extrahepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. The 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 the contribution of active metabolites. Less than 2% of an orally administered dose of Atorvastatin is recovered in urine.
