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 to everyone. 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

{{| class="wikitable" border="1" width="70%" style="text-align:center" |- ! colspan="6" align="center"| Statin PK Comparison |- ! Class ! Function and Oligomeric State[4] |- ! IgG | Dimeric - The most abundant Ig in the extravascular fluids. Neutralizes toxins and combats microorganisms by activating the compliment system and facilitating the binding of phagocytic cells. |- ! IgA | Dimeric - Is the major Ig in seromucous secretions, where it serves to defend the external body surfaces. |- ! IgM | Pentameric – It is an intravascular antibody and is produced very early in the immune response. Due to it high oligomeric state, it is extremely effective as a bacterial agglutinator and mediator of complement-dependent cytolysis, making it a powerful first-line defense against bacterial pathogens. |- ! IgD | Dimeric - It is present on the lymphocyte and functions together with IgM as the antigen receptor on naïve B-cells. |- ! IgE | It binds to mast cells and upon contact with antigen, leads to local recruitment of antimicrobial agents via degranulation of the mast cell and release of inflammatory mediators. IgE is important for certain kinds of parasitic infections and is responsible for the symptoms of atopic allergies like eczema and asthma. |}

Atorvastatin (Single 40mg Dose): vs Simvastatin (Zocor) (single 20mg Dose) [5] Bioavailability (Systemic Availability): 14% (30%) vs Cmax = 28.6 ng/ml AUC = 205 ng*h/ml Tmax 1hr vs 1.3hr T1/2 = 11.5 hr vs

IC-50: 154nM vs 66nM


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. [6]

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. [7] Interstingly, grapfruit juice can drastically increase the effect of statins, increasing AUC by as much as 1500%[8]

The Jist

THis is a wildly successful drug large in part becaues Pfizer is incredible at marketing its products...

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. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Roit
  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. ↑ 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
  7. ↑ http://www.rxlist.com/lipitor-drug.htm
  8. ↑ 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


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David Canner, Alexander Berchansky

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