Avamax Mechanism of Action

Pharmacology: Pharmacodynamics: Atorvastatin, a synthetic lipid-lowering agent, is a selective, competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase catalyzes the reduction of HMG-CoA to mevalonate, which is the rate-limiting step in hepatic cholesterol synthesis.
Atorvastatin decreases plasma cholesterol and lipoprotein levels by inhibiting hepatic cholesterol synthesis resulting in a compensatory increase in the production of low-density lipoprotein (LDL) receptors by cells in the liver; these receptors bind circulating LDL and remove them from serum. In addition to the increased production of LDL receptors, in vitro and animal studies indicate that a simultaneous compensatory increase in the amount of HMG-CoA reductase in the liver occurs as a result of increased synthesis and/or decreased degradation of this enzyme. LDL production may also be decreased as a result of decreased hepatic production of very low-density lipoprotein (VLDL) or increased binding and catabolism of VLDL remnants (i.e., intermediate-density lipoprotein, IDL) by the LDL receptor, since VLDL and VLDL remnants normally are converted to LDL. Thus, LDL receptors are involved both in enhancing clearance and inhibiting production of LDL.
Atorvastatin decreases total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (Apo B) in patients with homozygous and heterozygous familial hypercholesterolemia, nonfamilial forms of hypercholesterolemia and mixed dyslipidemia. It also decreases very low-density lipoprotein cholesterol (VLDL-C) and triglycerides (TG) and produces variable increases in high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-1. Atorvastatin decreases total-C, LDL-C, VLDL-C, Apo B, TG, and non-HDL-C, and increases HDL-C in patients with isolated hypertriglyceridemia. Atorvastatin decreases intermediate-density lipoprotein cholesterol (IDL-C) in patients with dysbetalipoproteinemia.
Atorvastatin limits the development of lipid-enriched atherosclerotic lesions and promotes regression of pre-established atheroma in animal studies.
Pharmacokinetics: Atorvastatin is rapidly absorbed from the gastrointestinal tract after oral administration. Peak plasma concentration is achieved within 1 to 2 hours. The amount of absorption increases in proportion to atorvastatin dose. Atorvastatin's absolute bioavailability is about 14%; the systemic availability of HMG-CoA reductase inhibitory activity is about 30%. The amount of drug reaching the systemic circulation is low because of presystemic clearance in the GI mucosa and/or extensive hepatic first-pass metabolism. Food decreases the rate and extent of atorvastatin absorption by approximately 25% and 9%, respectively: LDL-C reduction is the same whether atorvastatin is given with or without food. Drug administration in the evening decreases plasma concentrations (about 30% for Cmax and AUC) of atorvastatin compared with morning administration. However, LDL-C reduction is the same regardless of the time of day the drug is administered.
Atorvastatin's mean volume of distribution is about 381 L. At least 98% of atorvastatin is bound to plasma proteins.
Atorvastatin is extensively metabolized by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and beta-oxidation products. HMG-CoA reductase inhibition by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin in vitro. About 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.
Biliary excretion is the major route of elimination. Mean plasma atorvastatin elimination half-life is about 14 hours. The half-life of HMG-CoA reductase inhibitory activity is 20 to 30 hours due to the contribution of active metabolites. After oral administration, less than 2% of an atorvastatin dose is recovered in urine.