Atorvastatin 634622 224476278 2008-07-09T00:38:03Z 24.148.73.133 {{drugbox | |image=Lipitor.png |width=200 |image2=Atorvastatin-3D-balls.png |width=200 |IUPAC_name = [R-(R*, R*)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5- (1-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-1H- pyrrole-1-heptanoic acid |CAS_number = 134523-00-5 | ATC_prefix=C10 | ATC_suffix=AA05 | PubChem=60823 | DrugBank=APRD00055 | C=33 | H=35 | F=1 | N=2 | O=5 |molecular_weight = 558.64 | smiles = O[C@H](CCn1c(c2ccc(F)cc2)c(c2ccccc2)c(C(=O)Nc2ccccc2)c1C(C)C)C[C@@H](O)CC(= O)O |bioavailability = 12% |metabolism = [[Liver]] |elimination_half-life = 14 hours |excretion = [[Bile]] |pregnancy_AU = D |pregnancy_US = X |pregnancy_category = |legal_AU = S4 |legal_UK = POM |legal_US = Rx-only |legal_status = |routes_of_administration = oral }} '''Atorvastatin''' ([[International Nonproprietary Name|INN]]) ({{pronEng|əˌtɔrvəˈstætən}}), (marketed under the name '''Lipitor''', Lipidra, Aztor, Torvatin, Sortis, Torvast, Torvacard, Totalip, Tulip, Xarator, Atorpic, Liprimar, Atorlip and other names), is a member of the drug class known as [[statin]]s, used for lowering [[cholesterol]]. Atorvastatin inhibits the rate-determining [[enzyme]] located in [[liver|hepatic tissue]] that produces [[mevalonate]], a small molecule used in the synthesis of cholesterol and other mevalonate derivatives. This lowers the amount of cholesterol produced which in turn lowers the total amount of [[LDL cholesterol]]. With 2006 sales of US$12.9 billion under the brand name Lipitor, it is the largest selling drug in the world.<ref>{{cite news | last = Loftus | first = Peter | title = Pfizer's Lipitor Patent Reissue Rejected | publisher = The Wall Street Journal Online | date = [[2007-08-16]] | url = http://online.wsj.com/article/SB118730255664700229.html | accessdate = 2007-08-27 }}</ref> Lipitor is not the only statin; there are several other statins on the market.<ref name=saul>{{cite web |url=http://www.nytimes.com/2007/11/03/business/03generic.html?_r=1&oref=slogin&ref=todayspaper&pagewanted=all |title=Maker of Lipitor Digs In to Fight Generic Rival |first=Stephanie |last=Saul |coauthors=Alex Berenson |publisher=The New York Times |date=2007-11-03}}</ref><ref>{{cite web |url=http://www.timesonline.co.uk/tol/news/uk/health/article2634201.ece |title=Statins are the right prescription |first=Nigel |last=Hawkes |publisher=The Times (UK) |date=2007-10-11 |accessdate=2007-11-03}}</ref> ==Pharmacology== {{main|Statin}} As with other statins, atorvastatin is a competitive [[Enzyme inhibitor|inhibitor]] of [[HMG-CoA reductase]]. Unlike most others, however, it is a completely [[Chemical synthesis|synthetic]] compound. HMG-CoA reductase catalyzes the reduction of [[HMG-CoA reductase pathway|3-hydroxy-3-methylglutaryl-coenzyme A]] (HMG-CoA) to [[mevalonate]], which is the [[Rate-determining step|rate-limiting step]] in hepatic [[cholesterol]] biosynthesis. Inhibition of the enzyme decreases ''[[de novo synthesis|de novo]]'' cholesterol synthesis, increasing expression of low-density lipoprotein receptors ([[LDL receptor]]s) on [[hepatocyte]]s. This increases LDL uptake by the hepatocytes, decreasing the amount of LDL-cholesterol in the blood. Like other statins, atorvastatin also reduces blood levels of [[triglyceride]]s and slightly increases levels of [[High density lipoprotein|HDL-cholesterol]]. In clinical trials, adding [[ezetimibe]] (Zetia) to Lipitor lowered cholesterol more effectively than [[Vytorin]] (ezetimibe + simvastatin). {{Fact|date=August 2007}}. ==Clinical use== ===Indications=== Atorvastatin is indicated as an adjunct to diet for the treatment of [[dyslipidemia]], specifically [[hypercholesterolaemia]]. It has also been used in the treatment of [[combined hyperlipidemia]].<ref name="AMH2006">Rossi S, editor. [[Australian Medicines Handbook]] 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3</ref> In 2005, the PROVE IT-TIMI 22 trial compared 40mg/day pravastatin with 80mg/day atorvastatin.<ref name="Rouleau2005">{{cite journal |author=Rouleau J |title=Improved outcome after acute coronary syndromes with an intensive versus standard lipid-lowering regimen: results from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial |journal=Am. J. Med. |volume=118 Suppl 12A |issue= |pages=28–35 |year=2005 |pmid=16356805 |doi=10.1016/j.amjmed.2005.09.014}}</ref> Taken directly from the results of the trial: "Standard treatment (statin) with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (pravastatin 40 mg/day) resulted in a 22% reduction in LDL cholesterol levels at 30 days compared with a 51% reduction with intensive therapy (atorvastatin 80 mg/day). At 2 years, a relative risk reduction of 16% (95% confidence interval, 5%-26%; P = 0.005) in the primary end point rate (death, myocardial infarction, documented unstable angina requiring hospitalization, coronary revascularization, or stroke) was seen in patients receiving intensive statin treatment compared with standard statin therapy. The benefit of intensive treatment was apparent as early as 30 days and was consistent over time. The PROVE IT-TIMI 22 data indicate that patients recently hospitalized for an ACS benefit from early and continued lowering of LDL cholesterol to levels substantially below current guideline recommendations." ===Available forms=== '''Atorvastatin calcium''' tablets are currently marketed by [[Pfizer]] under the trade name '''Lipitor''', in tablets (10, 20, 40 or 80 mg) for oral administration. Tablets are white, elliptical, and film coated. Pfizer also packages the drug in combination with other drugs, such as is the case with its [[Caduet]]. ===Adverse effects=== {{dablink|For additional information see: [[Statin#Safety|Statins]]}} Common [[adverse drug reaction]]s (≥1% of patients) associated with atorvastatin therapy include: [[myalgia]], mild transient gastrointestinal symptoms (diarrhea, constipation, passing gas), elevated hepatic [[transaminase]] concentrations, headache, insomnia, joint pain, and/or dizziness.<ref name="AMH2006" /> [[Myopathy]] and [[rhabdomyolysis]] occur in <0.1% of patients. Risk is increased in patients with [[renal failure|renal impairment]], serious concurrent illness; and/or concomitant use of drugs which inhibit [[CYP3A4]].<ref name="AMH2006" /> ==Patent challenge== The size of the market for atorvastatin has prompted the [[generic drug]] manufacturing company [[Ranbaxy]] to challenge the validity of some of Pfizer's [[patent]]s in patent courts across the world. As of March 2007, courts had mostly upheld the validity of Pfizer's original patent for atorvastatin, which is due to expire in European territories in 2011 (but 2007 in Canada). However a later patent for the specific [[enantiomer]] of the atorvastatin formula that is medically useful, which would have given Pfizer longer protection, has fared less well. Although upheld in the [[United States]]<ref>BBC News, [http://news.bbc.co.uk/1/hi/business/4542358.stm Patent ruling hits Ranbaxy shares], 19 December 2005</ref>, [[Spain]], and [[Ecuador]], the enantiomer patent has been declared invalid by courts in [[Austria]], [[Australia]], [[Canada]], the [[Netherlands]] and the [[United Kingdom]]<ref>Duncan Bucknell, [http://duncanbucknell.com/scorecards/51/ The global Lipitor patent scorecard], retrieved 2007-03-03</ref>. ==Pfizer fight against simvastatin alternative== After doctors and patients began switching to a cheaper alternative within the same class of drugs called [[simvastatin]] in the millions, Pfizer launched a campaign including advertisements, lobbying efforts, and a paid speaking tour by Dr. [[Louis W. Sullivan]], a former secretary of the federal [[Department of Health and Human Services]], to discourage the trend.<ref name=saul/> The main clinical advantage of Lipitor over Simvastatin is that it is not metabolised by certain liver enzymes, and thus its blood concentration is not increased when combined with grapefruit juice which inhibits these enzymes. Simvastatin patients should avoid drinking large amounts of grapefruit juice for this reason. <!-- Pfizer has begun promoting a study, conducted by Pfizer’s own researchers, concluding switching increased the rate of heart attacks among British patients.<ref name=saul/><ref>{{cite web |url=http://money.cnn.com/2007/09/05/news/companies/pfizer/index.htm |title=Lipitor beats Zocor, says Pfizer: Zocor switchers run risks, says Pfizer |first=Aaron |last=Smith |publisher=CNN Money |date=2007-09-05 |accessdate=2007-11-03}}</ref> What study is this? Did Pfizer back away from this? See: O'Riordan M. Pfizer Backtracks on the Benefit of Atorvastatin Over Simvastatin: "Programming Error" in Flawed Study Cited. Medscape.com. URL: [http://www.medscape.com/viewarticle/558491 http://www.medscape.com/viewarticle/558491]. Accessed on: December 9, 2007. --> An independent analysis showed that, at commonly prescribed doses, atorvastatin and simvastatin have no [[statistical significance|statistically significant]] differences in reducing cardiovascular morbidity and mortality.<ref>{{cite journal |author=Zhou Z, Rahme E, Pilote L |title=Are statins created equal? Evidence from randomized trials of pravastatin, simvastatin, and atorvastatin for cardiovascular disease prevention |journal=Am. Heart J. |volume=151 |issue=2 |pages=273–81 |year=2006 |pmid=16442888 |doi=10.1016/j.ahj.2005.04.003}}</ref> ==Withdrawal of advertisements featuring Dr. Robert Jarvik== On [[February 25]], [[2008]], Pfizer announced that it will voluntarily withdraw all advertisements for Lipitor featuring Dr. [[Robert Jarvik]], and committing to ensuring greater clarity in the roles and responsibilities of its spokespeople in its consumer advertising and promotion. <ref>{{cite web |url=http://www.drugs.com/news/pfizer-voluntarily-withdraws-lipitor-advertising-featuring-dr-robert-jarvik-7815.html |title=Drugs.com, Pfizer Voluntarily Withdraws Lipitor Advertising Featuring Dr. Robert Jarvik |accessdate=2008-03-08 |format= |work= }}</ref> ==References== {{reflist}} ==External links== *[http://www.lipitor.com Lipitor.com] – manufacturer's site *[http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a600045.html MedlinePlus Drug information: Atorvastatin (Systemic)] – information from USP DI Advice for the Patient ==Further reading== *{{cite journal |author=Maggon K |title=Best-selling human medicines 2002-2004 |journal=Drug Discov. Today |volume=10 |issue=11 |pages=739–42 |year=2005 |pmid=15922927 |doi=10.1016/S1359-6446(05)03468-9}} *[http://www.lipitor.com/content/lipitor-pi.jsp Lipitor: Prescribing Information.] (2004) Pfizer Ireland Pharmaceuticals. {{Statins}} [[Category:Statins]] [[Category:Pyrroles]] [[de:Atorvastatin]] [[es:Atorvastatina]] [[fr:Atorvastatine]] [[it:Atorvastatina]] [[hu:Atorvasztatin]] [[nl:Atorvastatine]] [[no:Atorvastatin]] [[pl:Atorwastatyna]] [[fi:Atorvastatiini]] [[th:อะโทวาสแตติน]] [[zh:阿托伐他汀]]