Lipitor (Atorvastatin)
Classification:
Cardiovascular Agents
- Antilipemics
- HMG-CoA reductase inhibitors
Description: Atorvastatin is a selective, competitive HMG-CoA reductase inhibitor. Atorvastatin is primarily used to lower cholesterol and triglycerides in patients with hypercholesterolemia and mixed dyslipidemia. Atorvastatin may also be used in the treatment of homozygous familial hypercholesterolemia. At the maximum recommended dosage, atorvastatin has greater LDL-lowering efficacy relative to the maximum recommended dosage of other HMG-CoA reductase inhibitors. In a dose-dependent manner, atorvastatin lowers LDL cholesterol by as much as 60%; doses as low as 2.5 mg/day were as effective as lower doses of other HMG-CoA reductase inhibitors. Atorvastatin doses of 10-80 mg once daily result in mean LDL reductions ranging from 43-60%. Triglycerides are lowered in patients with hypertriglyceridemia by as much as 45% and HDL cholesterol increases by as much as 12% with atorvastatin monotherapy. The combination of atorvastatin and colestipol produced a 10% greater reduction in LDL-cholesterol than atorvastatin alone, however, adverse reactions were greater and compliance was lower for the combination. Atorvastatin’s unique structure, long half-life, and hepatic selectivity may explain its greater LDL-lowering potency compared to several HMG-CoA reductase inhibitors. Clinical outcome trials showing benefits of atorvastatin have been demonstrated in various patient populations including the patients treated for the first several months following acute coronary syndromes (MIRACLE), high-risk hypertensives (ASCOT-LLA), and type 2 diabetics (CARDS trial). Initial FDA approval for atorvastatin was granted on December 18, 1996.
Mechanism of Action: Atorvastatin is a selective, competitive inhibitor of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is the rate-limiting hepatic enzyme responsible for converting HMG-CoA to mevalonate, a precursor of sterols including cholesterol. Inhibition of HMG-CoA reductase lowers the amount of mevalonate and subsequently reduces cholesterol levels in hepatic cells. This, in turn, results in upregulation of LDL-receptors and increased hepatic uptake of LDL-cholesterol from the circulation. Atorvastatin ultimately reduces the levels of circulating total cholesterol, LDL-cholesterol, and serum triglycerides. Drug dosage rather than systemic drug concentration correlates better with LDL-cholesterol reduction. As with other HMG-CoA reductase inhibitors, atorvastatin exhibits no effects on antipyrine hepatic metabolism.
HMG-CoA reductase inhibitors have been reported to decrease endogenous CoQ10 serum concentrations; the clinical significance of these effects is unknown.
Pharmacokinetics: Atorvastatin is administered orally. Following oral administration, the drug is rapidly absorbed with peak plasma concentrations occurring within 1-2 hours. The extent of absorption increases in proportion to the dose of atorvastatin. The absolute bioavailability is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. Presystemic clearance and/or hepatic first-pass metabolism accounts for the low systemic bioavailability. Food decreases the rate and extent of atorvastatin absorption by approximately 25% and 9%, respectively, however, LDL-cholesterol reduction is similar whether the drug is given with or without food. Similarly, atorvastatin plasma concentrations are lower following evening doses compared with morning dosing and LDL-cholesterol reduction is the same regardless of the time of day the drug is administered. Atorvastatin is >= 98% bound to plasma proteins. A blood/plasma ratio of 0.25 indicates poor drug penetration into red blood cells. Animal data reveal that atorvastatin is likely to be secreted in human milk.
Atorvastatin undergoes extensive metabolism to active ortho- and parahydroxylated metabolites which account for approximately 70% of the circulating HMG-CoA reductase inhibitory activity. Based on in vitro studies, cytochrome P450 3A4 may also contribute to the metabolism of atorvastatin. In animals, the ortho-hydroxy metabolite is further metabolized by glucuronidation. Elimination of atorvastatin and its metabolites occurs primarily in bile following hepatic and/or extrahepatic metabolism. It does not appear that the drug undergoes enterohepatic recirculation. Less than 2% of a dose is recovered in the urine following oral administration. The mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, however, the half-life of HMG-CoA reductase inhibitory activity is 20-30 hours because of the active metabolites.
- Special Populations: Plasma concentrations of atorvastatin are higher (about 40% for Cmax and 30% for AUC) in healthy elderly subjects than in young adults. In addition, the LDL-cholesterol reduction in the elderly is also greater that seen in younger patient populations given equivalent doses atorvastatin. In patients with chronic alcoholic hepatic disease, atorvastatin plasma concentrations are increased. Cmax and AUC are both 4-fold greater in patients with Child-Pugh Class A hepatic disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Child-Pugh Class B hepatic disease. Renal disease has no influence on atorvastatin plasma concentrations or LDL cholesterol reductions; no dosage adjustments are needed. Plasma concentrations of atorvastatin are higher for women compared to men (approximately 20% higher for Cmax); however, clinically significant differences in LDL reduction are not observed.
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References
. Nawrocki JW, Weiss SR, Davidson MH et al. Reduction of LDL cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor. Arterioscler Thromb Vasc Biol 1995;15:678-82.
. Bakker-Arkema RG, Davidson MH, Goldstein RJ et al. Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia. JAMA 1996;257:128-33.
. Heinonen TM, Schrott H, McKenney JM et al. Atorvastatin, a new HMG-CoA reductase inhibitor as monotherapy and combined with colestipol. J Cardiovasc Pharmacol Ther 1996;1:117-22.
. Yang BB, Hounslow NJ, Sedman AJ et al. Effects of atorvastatin, an HMG-CoA reductase inhibitor, on hepatic oxidative metabolism of antipyrine. J Clin Pharmacol 1996;36:356-60.
. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001;285:1711-8.
. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361:1149-58.
. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364:685-96.
[ Revised 1/24/2006 4:16:00 PM ]
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