Atorvastatin
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Atorvastatin
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| Systematic (IUPAC) name | |
| [R-(R*, R*)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5- (1-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-1H- pyrrole-1-heptanoic acid | |
| Identifiers | |
| CAS number | |
| ATC code | C10 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C33H34FN2O5 |
| Mol. mass | 558.64 |
| Pharmacokinetic data | |
| Bioavailability | 12% |
| Metabolism | Liver |
| Half life | 14 hours |
| Excretion | Bile |
| Therapeutic considerations | |
| Pregnancy cat. | |
| Legal status | |
| Routes | oral |
Atorvastatin (INN) (IPA: [əˈtɔvəˌstætn]), marketed under the trade name Lipitor and several others, is a member of the drug class known as statins, used for lowering cholesterol. Atorvastatin inhibits the rate-determining enzyme located in 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 2005 sales of US$12.2 billion under the brand name Lipitor, it is the largest selling drug in the world.
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[edit] Pharmacology
As with other statins, atorvastatin is a competitive inhibitor of HMG-CoA reductase. Unlike most others, however, it is a completely synthetic compound. HMG-CoA reductase catalyzes the reduction of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, which is the rate-limiting step in hepatic cholesterol biosynthesis. Inhibition of the enzyme decreases de novo cholesterol synthesis, increasing expression of low-density lipoprotein receptors (LDL receptors) on hepatocytes. 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 triglycerides and slightly increases levels of HDL-cholesterol.
[edit] Clinical use
[edit] Indications
Atorvastatin is indicated as an adjunct to diet for the treatment of dyslipidaemia, specifically hypercholesterolaemia. It has also been used in the treatment of combined hyperlipidemia.[1]
In 2005, the PROVE IT-TIMI 22 trial compared 40mg/day pravastatin with 80mg/day atorvastatin.[2] 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."
[edit] 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. In some countries it may also be known as: Sortis, Torvast, Totalip, Tulip, Xarator, Atorpic, or Liprimar. It is also packaged in combination with other drugs, such as is the case with Pfizer's Caduet.
[edit] Adverse effects
Common adverse drug reactions (≥1% of patients) associated with atorvastatin therapy include: myalgia, mild transient gastrointestinal symptoms, elevated hepatic transaminase concentrations, headache, insomnia, and/or dizziness.[1]
Myopathy and rhabdomyolysis occur in <0.1% of patients. Risk is increased in patients with renal impairment, serious concurrent illness; and/or concomitant use of drugs which inhibit CYP3A4.[1]
[edit] 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 patents 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[3], Spain, and Ecuador, the enantiomer patent has been declared invalid by courts in Austria, Australia, Canada, the Netherlands and the United Kingdom[4].
[edit] References
- ^ a b c Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
- ^ Rouleau J., 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. Am J Med. 2005 Dec;118 Suppl 12A:28-35. PMID 16356805.
- ^ BBC News, Patent ruling hits Ranbaxy shares, 19 December 2005
- ^ Duncan Bucknell, The global Lipitor patent scorecard, retrieved 2007-03-03
[edit] External links
- Lipitor.com – manufacturer's site
- MedlinePlus Drug information: Atorvastatin (Systemic) – information from USP DI Advice for the Patient
- Links to external chemical sources
[edit] Further reading
- Maggon, Krishan. "Best-selling human medicines 2002-2004 (editorial)". 2005. Drug Discovery Today, 10(11):739-742. DOI:10.1016/S1359-6446(05)03468-9
- Lipitor: Prescribing Information. (2004) Pfizer Ireland Pharmaceuticals.
Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin
