Atorvastatin

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Atorvastatin, also known as Lipitor (1hwk)

Better Known as: Lipitor

  • Marketed By: Pfizer, Inc.
  • Major Indication: Hyperlipidemia & High Cholesterol (Hypercholesterolemia)
  • Drug Class: HMGR Inhibitor or Statin
  • Date of FDA Approval (Patent Expiration): 1996 (2011)
  • 2009 Sales: $12.7 Billion [1]
  • Importance: 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
  • See Pharmaceutical Drugs for more information about other drugs and disorders

Mechanism of Action

Atorvastatin is an inhibitor of HMG-CoA Reductase (HMGR), a 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 Pharmacokinetics at 10mg Dosage
Parameter Atorvastatin (Lipitor) Fluvastatin (Lescol) Lovastatin (Mevacor) Simvastatin (Zocor) Rosuvastatin (Crestor) Cerivastatin (Baycol)
Tmax (hr) 2.5 1 3 1.5 4 1.5
Cmax (ng/ml) 27-66 448 10-20 7.3 4.34 3.43
Bioavailability (%) 12 19-29 5 5 20 60
Protein Binding (%) 80-90 99 95 95 88 99
T1/2 (hr) 15-30 2 3 2.7 19 2.2
AUC (ng/ml/hr) 104 ~150 33 125 48 14.5
IC50 (nM) 154 198 800 66 320 50-90
Equivalent LDL Reduction Dosage (mg) 10 -- 80 20 5 --
Metabolism Hepatic
(CYP3A4)
Hepatic
(CYP2C9)
Hepatic
(CYP3A4)
Hepatic
(CYP3A4)
None Hepatic
(CYP2C8)

For References, See References

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 IC50 like due to its increased half-life and Cmax. [4]

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 statins, myopathy (muscle weakness) can also occur. [5] Along with Simvastatin and Rosuvastatin, taking atorvastatin was associated with modest increases in creatinine kinase levels, indicating possible smooth muscle and kidney damage, although rarely and at low rates. [6]

Interesting Facts

  • Lipitor is the best selling pharmaceutical drug in history, if one does not include illegal sales of Heroin, once marketed by Bayer.
  • Sales of Lipitor and other statins increased drastically in 2001 when the United States National Institute of Health announced new guidelines decreasing the level of cholesterol deemed to be healthy and calling for more aggressive use of cholesterol lowering statins. Sales of statins, particularly Lipitor increased nearly 3 fold. [7]
  • Consuming grapefruit juice can drastically alter the PKs of atorvastatin, increasing AUC by as much as 150% and Cmax by 200%. [8][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. 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
  5. http://www.rxlist.com/lipitor-drug.htm
  6. Ghirlanda G, Oradei A, Manto A, Lippa S, Uccioli L, Caputo S, Greco AV, Littarru GP. Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study. J Clin Pharmacol. 1993 Mar;33(3):226-9. PMID:8463436
  7. Josefson, D. Cholesterol guidelines will triple numbers taking drugs. BMJ. 2001 May 26; 322(7297): 1270. PMCID: PMC1173318
  8. Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin. Clin Pharmacol Ther. 1999 Aug;66(2):118-27. PMID:10460065 doi:10.1053/cp.1999.v66.100453001
  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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