The Full Wiki

Atorvastatin: Wikis

  
  

Note: Many of our articles have direct quotes from sources you can cite, within the Wikipedia article! This article doesn't yet, but we're working on it! See more info or our list of citable articles.

Encyclopedia

From Wikipedia, the free encyclopedia

Atorvastatin
Systematic (IUPAC) name
(3R,5R)-7-[2-(4-fluorophenyl)-

3-phenyl-4-(phenylcarbamoyl)-5-(propan-2-yl)- 1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid

Identifiers
CAS number 134523-00-5
ATC code C10AA05
PubChem 60823
DrugBank APRD00055
ChemSpider 54810
Chemical data
Formula C33H35FN2O5 
Mol. mass 558.64
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 12%
Metabolism Hepatic - CYP3A4
Half life 14 hours
Excretion Bile
Therapeutic considerations
Pregnancy cat. D(AU) X(US)
Legal status Prescription Only (S4) (AU) POM (UK) -only (US)
Routes oral
 Yes check.svgY(what is this?)  (verify)

Atorvastatin (INN) (pronounced /əˌtɔrvəˈstætən/) (Lipitor, Pfizer), is a member of the drug class known as statins, used for lowering blood cholesterol. It also stabilizes plaque and prevents strokes through anti-inflammatory and other mechanisms.

Atorvastatin inhibits HMG-CoA reductase, 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. Atorvastatin was first synthesized in 1985 by Bruce Roth while working at Parke-Davis Warner-Lambert Company (now Pfizer). With 2008 sales of US$12.4 billion, Lipitor was the top-selling branded pharmaceutical in the world.[1] US patent protection is scheduled to expire in June 2011.[2][3] However, Pfizer made an agreement with Ranbaxy Laboratories to delay the generic launch in the US until November 2011.[1]

Atorvastatin is one of many statins on the market.[4][5]

Contents

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.

In clinical trials, the combination of ezetimibe (Zetia) and atorvastatin lowered cholesterol more effectively than Vytorin (ezetimibe + simvastatin).[citation needed]

Pharmacokinetics

Atorvastatin has rapid oral absorption with an approximate time to maximum plasma concentration (Tmax) of 1–2 hours. The absolute bioavailability of atorvastatin is approximately 14%, however, the systemic availability for HMG-CoA reductase activity is approximately 30%. Atorvastatin undergoes high intestinal clearance and first-pass metabolism, which is the main cause for the low systemic availability. Food has been shown to reduce the rate and extent of atorvastatin absorption. Administration of atorvastatin with food produces a 25% reduction in Cmax (rate of absorption) and a 9% reduction in AUC (extent of absorption). However, food does not affect the plasma LDL-C lowering efficacy of atorvastatin. Evening atorvastatin dose administration is known to reduce the Cmax (rate of absorption) and AUC (extent of absorption) by 30% each. However, time of administration does not affect the plasma LDL-C lowering efficacy of atorvastatin.

Atorvastatin is highly protein bound (≥98%).

The primary proposed mechanism of atorvastatin metabolism is through cytochrome P450 3A4 hydroxylation to form active ortho- and parahydroxylated metabolites, as well as various beta-oxidation metabolites. The ortho- and parahydroxylated metabolites are responsible for 70% of systemic HMG-CoA reductase activity. The ortho-hydroxy metabolite undergoes further metabolism via glucuronidation. As a substrate for the CYP3A4 isozyme it has shown susceptibility to inhibitors and inducers of CYP 3A4 to produce increased or decreased plasma concentrations, respectively. This interaction was tested in vitro with concurrent administration of erythromycin, a known CYP 3A4 isozyme inhibitor, which resulted in increased plasma concentrations of atorvastatin. Atorvastatin is also an inhibitor of cytochrome 3A4.

It is primarily eliminated via hepatic biliary excretion with less than 2% of atorvastatin recovered in the urine. Bile elimination follows hepatic and/or extra-hepatic metabolism. There does not appear to be any entero-hepatic recirculation. Atorvastatin has an approximate elimination half-life of 14 hours. Noteworthy, the HMG-CoA reductase inhibitory activity appears to have a half-life of 20–30 hours, which is thought to be due to the active metabolites. Atorvastatin is also a substrate of the intestinal P-glycoprotein efflux transporter, which pumps the drug back into the intestinal lumen during drug absorption.[6]

In Hepatic insufficiency, Plasma drug concentrations are significantly affected by concurrent liver disease. Patients with A stage liver disease show a 4-fold increase in both Cmax and AUC. Patients with B stage liver disease show an 16-fold increase in Cmax and an 11-fold increase in AUC.

In Geriatric patients (>65 years old) show altered pharmacokinetics of atorvastatin compared to young adults. The mean AUC and Cmax values are higher (40% and 30%, respectively) for geriatric patients. Additionally, healthy elderly patients show a greater pharmacodynamic response to atorvastatin at any dose, therefore, this population may have lower effective doses.[7]

Clinical use

FDA approved indications

  • Concomitant therapy considerations
Atorvastatin may be used in combination with bile acid resins. It is not recommended to combine statin treatment with fibrates because of the increased risk of myopathy related adverse reactions[7].Drug dose must be adjusted according to age of patient, and must be lowered in Hepatic insufficiency

Contraindications

Precaution must be taken when treating with atorvastatin, because rarely it may lead to rhabdomyolysis,[22] it may be very serious leading to acute renal failure due to myoglobinuria. If rhabdomyolysis is suspected or diagnosed, atorvastatin therapy should be discontinued immediately.[6] Also Atorvastatin should be discontinued if a patient has markedly elevated CPK levels or if a myopathy is suspected or diagnosed. The likelihood of developing a myopathy is increased by the co-administration of cyclosporine, fibric acid derivatives, erythromycin, niacin, and azole antifungals.[7]

Atorvastatin is absolutely contraindicated in pregnancy, it is likely to cause harm to fetal development because of the importance of cholesterol and various products in the cholesterol biosynthesis pathway for fetal development, including steroid synthesis and cell membrane production. It is not recommended that nursing mothers take atorvastatin due to the possibility of adverse reactions in nursing infants, since experiments with rats indicate that atorvastatin is likely to be secreted into human milk.[7]

Drug and food interactions

Interactions with clofibrate, fenofibrate, gemfibrozil, which are fibrates used in accessory therapy in many forms of hypercholesterolemia, usually in combination with statins , increase the risk of myopathy and rhabdomyolysis.[23][24][25]

Co-administration of Atorvastatin with one of CYP3A4 inhibitors like itraconazole,[26] telithromycin, and voriconazole, may increase serum concentrations of atorvastatin, which may lead to adverse reactions. This is less likely to happen with other CYP3A4 inhibitors like diltiazem, erythromycin, fluconazole, ketoconazole, clarithromycin, cyclosporine, protease inhibitors, verapamil.[27] And only rarely with other CYP3A4 inhibitors like amiodarone, and aprepitant[6].often bosentan, fosphenytoin, and phenytoin which are CYP3A4 inducers can decrease the plasma concentrations of atorvastatin.But only rarely barbiturates, carbamazepine, efavirenz, nevirapine, oxcarbazepine, rifampin, and rifamycin[28], which are CYP3A4 inducers can decrease the plasma concentrations of atorvastatin. Oral contraceptives increased AUC values for norethindrone and ethinyl estradiol, these increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin.[29]

Antacids can rarely decrease the plasma concentrations of atorvastatin but do not affect the LDL-C lowering efficacy.

Niacin also is proved to increase the risk of myopathy or rhabdomyolysis[6]

Statins may also alter the concentrations of other drugs, such as warfarin or digoxin, leading to alterations in effect or a requirement for clinical monitoring.[6]

Vitamin D supplementation lowers atorvastatin and active metabolite concentrations yet has synergistic effects on cholesterol concentrations.[30] Grapefruit juice components are known inhibitors of intestinal CYP3A4. Co-administration of grapefruit juice with atorvastatin may cause an increase in Cmax and AUC, which can lead to adverse reactions or overdose toxicity[31]

Available forms

Pack and tablet of Atorvastatin (Lipitor) 40mg

Atorvastatin calcium tablets are 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. In some countries, atorvastatin calcium is made in tablet form by generic drug makers under various brand names including Atoris, Atorlip, Lipvas, Sortis, Torvast, Torvacard, Totalip, and Tulip.

Adverse effects

As stated earlier, myopathy with elevation of creatinine kinase (CK)[25] and rhabdomyolysis are the most serious, although rare <1%.[7][14]

  • Headache is the most common side effect, occurring in more than 10% of patients.

Side effects that occur in 1-10% of patients taking atorvastatin include:

Elevation of alanine transaminase (ALT) and aspartate transaminase (AST) has been described in a few cases[6][25]

Other very rare side effects occurring in less than 1% of patients are: alopecia, anaphylaxis, angina, angioneurotic edema, arrhythmia, bullous rashes, cholestatic jaundice, deafness, dyspnea, erythema multiforme, esophagitis, facial paralysis, glaucoma, gout, hepatitis, hyperkinesia, impotence, migraine, myasthenia, myositis, nephritis, pancreatitis, paresthesia, peripheral neuropathy, petechiae, photosensitivity, postural hypotension, pruritus, rectal hemorrhage, rhabdomyolysis, somnolence, Stevens-Johnson syndrome, syncope, tendinous contracture, thrombocytopenia, tinnitus, torticollis, toxic epidermal necrolysis, urticaria, vaginal hemorrhage, and vomiting.[7]

References

  1. ^ a b "Pfizer 2008 Annual Report". Pfizer. 2009-04-23. http://media.pfizer.com/files/annualreport/2008/annual/review2008.pdf. Retrieved 2009-08-07. 
  2. ^ Details for patent 5,273,995
  3. ^ . Associated Press. 2009-01-06. http://www.nj.com/business/index.ssf/2009/01/pfizer_wins_patent_extension_o.html. Retrieved 2009-08-07. 
  4. ^ Saul, Stephanie; Alex Berenson (2007-11-03). "Maker of Lipitor Digs in to Fight Generic Rival". The New York Times. http://www.nytimes.com/2007/11/03/business/03generic.html?pagewanted=all. 
  5. ^ Hawkes, Nigel (2007-10-11). "Statins are the right prescription". The Times. London. http://www.timesonline.co.uk/tol/news/uk/health/article2634201.ece. Retrieved 2007-11-03. 
  6. ^ a b c d e f Williams D, Feely J (2002). "Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors". Clin Pharmacokinet 41 (5): 343–70. doi:10.2165/00003088-200241050-00003. PMID 12036392. 
  7. ^ a b c d e f g h i j k l m n o http://www.pfizer.com/files/products/uspi_lipitor.pdf Lipitor (Atorvastatin Calcium) Tablets - LAB-0021-23.0 February 2009
  8. ^ a b c McCrindle BW, Ose L, Marais AD (July 2003). "Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled trial". J. Pediatr. 143 (1): 74–80. doi:10.1016/S0022-3476(03)00186-0. PMID 12915827. http://linkinghub.elsevier.com/retrieve/pii/S0022347603001860. 
  9. ^ Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, Davignon J, Erbel R, Fruchart JC, Tardif JC, Schoenhagen P, Crowe T, Cain V, Wolski K, Goormastic M, Tuzcu EM (2006). "Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial". Journal of the American Medical Association 295 (13): 1556–65. doi:10.1001/jama.295.13.jpc60002. PMID 16533939. http://jama.ama-assn.org/cgi/content/full/295/13/1556. 
  10. ^ Nawrocki JW, Weiss SR, Davidson MH, et al. (May 1995). "Reduction of LDL cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor". Arteriosclerosis, Thrombosis, and Vascular Biology 15 (5): 678–82. PMID 7749881. http://atvb.ahajournals.org/cgi/pmidlookup?view=long&pmid=7749881. 
  11. ^ Bakker-Arkema RG, Davidson MH, Goldstein RJ, et al. (January 1996). "Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia". Journal of the American Medical Association 275 (2): 128–33. doi:10.1001/jama.275.2.128. PMID 8531308. 
  12. ^ Ozaki K, Kubo T, Imaki R, et al. (August 2006). "The anti-atherosclerotic effects of lipid lowering with atorvastatin in patients with hypercholesterolemia". Journal of Atherosclerosis and Thrombosis 13 (4): 216–9. PMID 16908955. http://www.jstage.jst.go.jp/article/jat/13/4/216/_pdf. Retrieved 2010-02-06. 
  13. ^ Marais AD, Firth JC, Bateman ME, Byrnes P, Martens C, Mountney J (August 1997). "Atorvastatin: an effective lipid-modifying agent in familial hypercholesterolemia". Arteriosclerosis, Thrombosis, and Vascular Biology 17 (8): 1527–31. PMID 9301631. http://atvb.ahajournals.org/cgi/pmidlookup?view=long&pmid=9301631. Retrieved 2010-02-06. 
  14. ^ a b Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
  15. ^ Sever PS, Dahlöf B, Poulter NR, et al. (April 2003). "Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial". Lancet 361 (9364): 1149–58. doi:10.1016/S0140-6736(03)12948-0. PMID 12686036. http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(03)12948-0. 
  16. ^ Law MR, Wald NJ, Rudnicka AR (June 2003). "Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis". BMJ 326 (7404): 1423. doi:10.1136/bmj.326.7404.1423. PMID 12829554.& PMC 162260. http://www.bmj.com/cgi/content/full/326/7404/1423. 
  17. ^ Wilson P, D'Agostino R, Levy D, Belanger A, Silbershatz H, Kannel W (19 May 1998). "Prediction of coronary heart disease using risk factor categories". Circulation 97 (18): 1837–47. PMID 9603539. http://circ.ahajournals.org/cgi/content/full/97/18/1837. 
  18. ^ Jones P, Kafonek S, Laurora I, Hunninghake D (1998). "Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study)". Am J Cardiol 81 (5): 582–7. doi:10.1016/S0002-9149(97)00965-X. PMID 9514454. 
  19. ^ Colhoun HM, Betteridge DJ, Durrington PN, et al. (2004). "Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial". Lancet 364 (9435): 685–96. doi:10.1016/S0140-6736(04)16895-5. PMID 15325833. http://linkinghub.elsevier.com/retrieve/pii/S0140673604168955. 
  20. ^ Neil HA, DeMicco DA, Luo D, et al. (November 2006). "Analysis of efficacy and safety in patients aged 65–75 years at randomization: Collaborative Atorvastatin Diabetes Study (CARDS)". Diabetes Care 29 (11): 2378–84. doi:10.2337/dc06-0872. PMID 17065671. http://care.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=17065671. 
  21. ^ Gentile S, Turco S, Guarino G, et al. (December 2000). "Comparative efficacy study of atorvastatin vs simvastatin, pravastatin, lovastatin and placebo in type 2 diabetic patients with hypercholesterolaemia". Diabetes Obes Metab 2 (6): 355–62. doi:10.1046/j.1463-1326.2000.00106.x. PMID 11225965. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=1462-8902&date=2000&volume=2&issue=6&spage=355. 
  22. ^ Monica Hermann; Martin P. Bogsrud, Espen Molden, Anders Ã…sberg, Beata U. Mohebi, Leiv Ose, Kjetil Retterstøl, Monica Hermann, PhD (19 February 2006). "Clinical Pharmacology & Therapeutics - Abstract of article: Exposure of atorvastatin is unchanged but lactone and acid metabolites are increased several-fold in patients with atorvastatin-induced myopathy". doi:10.1016/j.clpt.2006.02.014. http://www.ncbi.nlm.nih.gov/pubmed/16765141. 
  23. ^ Steiner G (December 2007). "Atherosclerosis in type 2 diabetes: a role for fibrate therapy?". Diab Vasc Dis Res 4 (4): 368–74. doi:10.3132/dvdr.2007.067. PMID 18158710. 
  24. ^ Graham DJ, Staffa JA, Shatin D, et al. (2004). "Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs". JAMA 292 (21): 2585–90. doi:10.1001/jama.292.21.2585. PMID 15572716. http://jama.ama-assn.org/cgi/content/full/292/21/2585. 
  25. ^ a b c Ghirlanda G, Oradei A, Manto A, Lippa S, Uccioli L, Caputo S, Greco A, Littarru G (1993). "Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study". J Clin Pharmacol 33 (3): 226–9. PMID 8463436. 
  26. ^ Arthur L. Mazzu; Kenneth C. Lasseter, E. Cooper Shamblen, Vipin Agarwal, John Lettieri, Pavur Sundaresen, Arthur L. Mazzu, PhD (2000/10). "Clinical Pharmacology & Therapeutics - Abstract of article: Itraconazole alters the pharmacokinetics of atorvastatin to a greater extent than either cerivastatin or pravastatin". doi:10.1067/mcp.2000.110537. http://www.nature.com/clpt/journal/v68/n4/abs/clpt2000118a.html. 
  27. ^ "Clinical Pharmacology & Therapeutics - Abstract of article: Drug interactions with lipid-lowering drugs: Mechanisms and clinical relevance". http://www.nature.com/clpt/journal/v80/n6/abs/clpt2006451a.html. 
  28. ^ Janne T. Backman, Harri Luurila, Mikko Neuvonen, Pertti J. Neuvonen, Janne T. Backman, MD. "Clinical Pharmacology & Therapeutics - Abstract of article: Rifampin markedly decreases and gemfibrozil increases the plasma concentrations of atorvastatin and its metabolites [ast"]. doi:10.1016/j.clpt.2005.04.007. http://www.nature.com/clpt/journal/v78/n2/abs/clpt2005479a.html. 
  29. ^ "FDA SPL Approved Application Filing for NDC Code 0071-0155 (Atorvastatin by Pfizer Inc.)". C6E131FE-E7DF-4876-83F7-9156FC4E8228.xml. 
  30. ^ Schwartz JB (February 2009). "Effects of vitamin D supplementation in atorvastatin-treated patients: a new drug interaction with an unexpected consequence". Clinical Pharmacology and Therapeutics 85 (2): 198–203. doi:10.1038/clpt.2008.165. PMID 18754003. 
  31. ^ Kane GC, Lipsky JJ (2000). "Drug-grapefruit juice interactions". Mayo Clin. Proc. 75 (9): 933–42. doi:10.4065/75.9.933. PMID 10994829. 

External links

Further reading








Got something to say? Make a comment.
Your name
Your email address
Message