Atorvastatin

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Atorvastatin, also known as Lipitor

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Atorvastatin

Better Known as: Lipitor

Marketed By: Pfizer, Inc.
Major Indication: Hyperlipidemia & High Cholesterol (Hypercholesterolemia)
Date of FDA Approval: 1996
2009 Sales: $12.7 Billion [1]
Why You Should Care: It is the best selling drug in the world. Statins are so ubiquitous, doctors have even suggested handing them out with fast food. See: the article

Mechanism of Action

Atorvastatin is an inhibitor of HMG-CoA Reductase, a highly regulated enzyme responsible for the committed step in cholesterol synthesis. Atorvastatin via a number of polar interactions with the "cis loop" of HMGR, particularly residues Ser 684, Asp 690, Lys 691, Lys 692, and hydrogen bond interactions between Glu 559 and Asp 767 with the O5-hydroxyl of the statins. Van der Waals interactions between Leu 562, Val 683, Leu 853, Ala 856, and Leu 857 of HMGR and hydrophobic ring structures of Atorvastatin contribute to binding as well.[2] These interactions help Atorvastatin outcompete outcompete HMG-CoA, the substrate of HMGR in binding to HMGR.[3]

Pharmacokinetics

Statin PK Comparison at 10mg doses[4][5][6]
Parameter Atorvastatin (Lipitor) Fluvastatin (Lescol) Lovastatin (Mevacor) Simvastatin (Zocor) Rosuvastatin (Crestor)
Tmax (hr) 2.5 1 3 1.5 4
Cmax (ng/ml) 27-66 448 10-20 7.3 4.34
Bioavailability (%) 12 19-29 5 5 20
Protein Binding (%) 80-90 99 95 95 88
T1/2 (hr) 15-30 2 3 2.7 19
AUC (ng/ml/hr) 104 125 48
IC-50 (nM) 154 198 800-4200 66 320
Metabolism Hepatic (CYP3A4) Hepatic (CYP2C9) Hepatic (CYP3A4) Hepatic (CYP3A4) Not Metabolized

Effectiveness and Side Effects

Effectiveness

Compared to the other statins, Atorvaststin is the most effective with typical reductions in LDL of 30-40% at the 10mg level. At 10mg, Atorvastatin reduces LDL about 2% more than 20mg Simvastatin despite having a lower IC-50 like due to its increased half-life and Cmax. [7]

Side Effects

The most common side effects were nasopharyngitis (cold like symptoms) and Arthralgia (arthritis), occurring in about 7% of patients although not significantly higher than was seen with the placebo. As with all statyins, myopathy (muscle weakness) can also occur. [8] Interstingly, grapfruit juice can drastically increase the effect of statins, increasing AUC by as much as 1500%[9]

The Jist

The statins work! They are generally viewed as very safe and have been proven effective over the past 15 years. Since the cost between statins doesn't differ much, and they are covered by most insurance programs, proceeding with the most effective statin is the way to go. Efficacy will largely be determined by the user as each statin works differently for each person. That being said, Atorvastatin (Lipitor) is the best selling statin because it is effective for the most people. With Lipitor going off patent in November of 2011, the statin market will continue to decline as generics eat away at pharmaceutical sales and the statins will become even more ubiquitous. Of note, the drug Rosuvastatin (Crestor) has made recent headlines as being nearly equivalent in efficacy to Lipitor, but also cuts the rate of heart attacks and strokes significantly. [10]

References

  1. ↑ http://www.forbes.com/2008/06/18/pfizer-ranbaxy-lipitor-biz-healthcare-cx_mh_0618bizpfizer.html
  2. ↑ Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science. 2001 May 11;292(5519):1160-4. PMID:11349148 doi:10.1126/science.1059344
  3. ↑ Corsini A, Maggi FM, Catapano AL. Pharmacology of competitive inhibitors of HMG-CoA reductase. Pharmacol Res. 1995 Jan;31(1):9-27. PMID:7784310
  4. ↑ Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on clinical pharmacokinetics and drug interactions. Circulation. 2004 Jun 15;109(23 Suppl 1):III50-7. PMID:15198967 doi:10.1161/01.CIR.0000131519.15067.1f
  5. ↑ Lins RL, Matthys KE, Verpooten GA, Peeters PC, Dratwa M, Stolear JC, Lameire NH. Pharmacokinetics of atorvastatin and its metabolites after single and multiple dosing in hypercholesterolaemic haemodialysis patients. Nephrol Dial Transplant. 2003 May;18(5):967-76. PMID:12686673
  6. ↑ Kiser JJ, Gerber JG, Predhomme JA, Wolfe P, Flynn DM, Hoody DW. Drug/Drug interaction between lopinavir/ritonavir and rosuvastatin in healthy volunteers. J Acquir Immune Defic Syndr. 2008 Apr 15;47(5):570-8. PMID:18176327 doi:10.1097/QAI.0b013e318160a542
  7. ↑ Weng TC, Yang YH, Lin SJ, Tai SH. A systematic review and meta-analysis on the therapeutic equivalence of statins. J Clin Pharm Ther. 2010 Apr;35(2):139-51. PMID:20456733 doi:10.1111/j.1365-2710.2009.01085.x
  8. ↑ http://www.rxlist.com/lipitor-drug.htm
  9. ↑ Kantola T, Kivisto KT, Neuvonen PJ. Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther. 1998 Apr;63(4):397-402. PMID:9585793 doi:10.1016/S0009-9236(98)90034-0
  10. ↑ Everett BM, Glynn RJ, MacFadyen JG, Ridker PM. Rosuvastatin in the prevention of stroke among men and women with elevated levels of C-reactive protein: justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER). Circulation. 2010 Jan 5;121(1):143-50. Epub 2009 Dec 21. PMID:20026779 doi:10.1161/CIRCULATIONAHA.109.874834


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