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词条 Allopurinol
释义

  1. Medical uses

     Gout  Tumor lysis syndrome  Inflammatory bowel disease 

  2. Side effects

  3. Drug interactions

  4. Pharmacology

      Mechanism of action   Pharmacogenetics 

  5. History

  6. Society and culture

     Formulations  Brands 

  7. See also

  8. References

  9. External links

{{drugbox
| Watchedfields = changed
| verifiedrevid = 477318043
| IUPAC_name = 1H-Pyrazolo[3,4-d']pyrimidin-4(2H)-one
| image = Allopurinol V.1.svg
| width = 150
| image2 = Allopurinol_3d_structure.png
| tradename = Zyloprim, Caplenal, Zyloric, others
| Drugs.com = {{drugs.com|monograph|allopurinol}}
| MedlinePlus = a682673
| pregnancy_category = C(USA)
| legal_US = Rx-only
| legal_UK = POM
| routes_of_administration = by mouth (tablet), IV
| bioavailability = 78±20%
| protein_bound = Negligible
| metabolism = liver (80% oxipurinol, 10% allopurinol ribosides)
| elimination_half-life = 2 h (oxipurinol 18–30 h)
| IUPHAR_ligand = 6795
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 315-30-0
| ATC_prefix = M04
| ATC_suffix = AA01
| ATC_supplemental =
| PubChem = 2094
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00437
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 2010
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 63CZ7GJN5I
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00224
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 40279
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1467
| C=5 | H=4
| N=4 | O=1
| smiles = c1c2c([nH]n1)ncnc2O
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C5H4N4O/c10-5-3-1-8-9-4(3)6-2-7-5/h1-2H,(H2,6,7,8,9,10)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = OFCNXPDARWKPPY-UHFFFAOYSA-N
}}Allopurinol, sold under the brand name Zyloprim among others, is a medication used to decrease high blood uric acid levels.[1] It is specifically used to prevent gout, prevent specific types of kidney stones and for the high uric acid levels that can occur with chemotherapy.[2][3] It is taken by mouth or injected into a vein.[3]

Common side effects when used by mouth include itchiness and rash.[3] Common side effects when used by injection include vomiting and kidney problems.[3] While not recommended historically, starting allopurinol during an attack of gout appears to be safe.[4] In those already on the medication, it should be continued even during an acute gout attack.[4][2] While use during pregnancy does not appear to result in harm, this use has not been well studied.[5] Allopurinol is in the xanthine oxidase inhibitor family of medications.[3]

Allopurinol was approved for medical use in the United States in 1966.[3] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[6] Allopurinol is available as a generic medication.[3] The wholesale cost in the developing world is about US$0.81–3.42 per month.[7] In the United States a month of treatment costs less than $25.[8] In 2016 it was the 52nd most prescribed medication in the United States with more than 15 million prescriptions.[9]

Medical uses

Gout

Allopurinol is used to reduce urate formation in conditions where urate deposition has already occurred or is predictable. The specific diseases and conditions where it is used include gouty arthritis, skin tophi, kidney stones, idiopathic gout; uric acid lithiasis; acute uric acid nephropathy; neoplastic disease and myeloproliferative disease with high cell turnover rates, in which high urate levels occur either spontaneously, or after cytotoxic therapy; certain enzyme disorders which lead to overproduction of urate, for example: hypoxanthine-guanine phosphoribosyltransferase, including Lesch–Nyhan syndrome; glucose 6-phosphatase including glycogen storage disease; phosphoribosyl pyrophosphate synthetase, phosphoribosyl pyrophosphate amidotransferase; adenine phosphoribosyltransferase.

It is also used to treat kidney stones caused by deficient activity of adenine phosphoribosyltransferase.

Tumor lysis syndrome

Allopurinol was also commonly used to treat tumor lysis syndrome in chemotherapeutic treatments, as these regimens can rapidly produce severe acute hyperuricemia,[18] although it has gradually been replaced by urate oxidase therapy.[10] Intravenous formulations are used in this indication when people cannot take medicine by mouth.[20]

Inflammatory bowel disease

Allopurinol cotherapy is used to improve outcomes for people with inflammatory bowel disease and Crohn's disease who do not respond to thiopurine monotherapy.[11][12] Cotherapy has also been shown to greatly improve hepatoxicity side effects in treatment of IBD.[13] Cotherapy invariably requires dose reduction of the thiopurine, usually to one-third of the standard dose depending upon the patient's genetic status for thiopurine methyltransferase.[14]

Side effects

Because allopurinol is not a uricosuric, it can be used in people with poor kidney function. However, allopurinol has two important disadvantages.

First, its dosing is complex.[15] Second, some patients are hypersensitive to the drug, therefore its use requires careful monitoring.[26][16]

Allopurinol has rare but potentially fatal adverse effects involving the skin. The most serious adverse effect is a hypersensitivity syndrome consisting of fever, skin rash, eosinophilia, hepatitis, and worsened renal function.[26] Allopurinol is one of the drugs commonly known to cause Stevens–Johnson syndrome and toxic epidermal necrolysis, two life-threatening dermatological conditions.[26] More common is a less-serious rash that leads to discontinuing this drug.[17]

More rarely, allopurinol can also result in the depression of bone marrow elements, leading to cytopenias, as well as aplastic anemia. Moreover, allopurinol can also cause peripheral neuritis in some patients, although this is a rare side effect. Another side effect of allopurinol is interstitial nephritis.[18]

Allopurinol should not be given to people who are allergic to it.[18]

Drug interactions

Drug interactions are extensive, and are as follows:[18]

  • Azathioprine and 6-mercaptopurine: Azathioprine is metabolised to 6-mercaptopurine which in turn is inactivated by the action of xanthine oxidase - the target of allopurinol. Giving allopurinol with either of these drugs at their normal dose will lead to overdose of either drug; only one-quarter of the usual dose of 6-mercaptopurine or azathioprine should be given;
  • Didanosine: plasma didanosine Cmax and AUC values were approximately doubled with concomitant allopurinol treatment; it should not be co-administered with allopuroinol and if it must be, the dose of should be reduced and the person should be closely monitored.

Allopurinol may also increase the activity or half-life of the following drugs, in order of seriousness and certainty of the interaction:[18]

  • Ciclosporin
  • Coumarin anticoagulants, such as warfarin (reported rarely, but is serious when it occurs)
  • Vidarabine
  • Chlorpropamide
  • Phenytoin
  • Theophylline
  • Cyclophosphamide, doxorubicin, bleomycin, procarbazine, mechlorethamine

Co-administration of the following drugs may make allopurinol less active or decrease its half-life:[18]

  • Salicylates and medicines that increase the secretion of uric acid
  • furosemide (see more on diuretics below)

Co-administration of the following drugs may cause hypersensitivity or skin rash:[18]

  • Ampicillin and amoxicillin
  • Diuretics, in particular thiazides, especially in renal impairment
  • Angiotensin-converting-enzyme inhibitors (ACE inhibitors)

Pharmacology

A common misconception is that allopurinol is metabolized by its target, xanthine oxidase, but this action is principally carried out by aldehyde oxidase.[19] The active metabolite of allopurinol is oxipurinol, which is also an inhibitor of xanthine oxidase. Allopurinol is almost completely metabolized to oxipurinol within two hours of oral administration, whereas oxipurinol is slowly excreted by the kidneys over 18–30 hours. For this reason, oxipurinol is believed responsible for the majority of allopurinol's effect.[20]

Mechanism of action

Allopurinol is a purine analog; it is a structural isomer of hypoxanthine (a naturally occurring purine in the body) and is an inhibitor of the enzyme xanthine oxidase.[1] Xanthine oxidase is responsible for the successive oxidation of hypoxanthine and xanthine, resulting in the production of uric acid, the product of human purine metabolism.[1] In addition to blocking uric acid production, inhibition of xanthine oxidase causes an increase in hypoxanthine and xanthine. While xanthine cannot be converted to purine ribotides, hypoxanthine can be salvaged to the purine ribotides adenosine and guanosine monophosphates. Increased levels of these ribotides may cause feedback inhibition of amidophosphoribosyl transferase, the first and rate-limiting enzyme of purine biosynthesis. Allopurinol, therefore, decreases uric acid formation and may also inhibit purine synthesis.[21]

Pharmacogenetics

The HLA-B*5801 allele is a genetic marker for allopurinol-induced severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).[22][23] The frequency of the HLA-B*5801 allele varies between ethnicities: Han Chinese and Thai populations have HLA-B*5801 allele frequencies of around 8%, as compared to European and Japanese populations, who have allele frequencies of around 1.0% and 0.5%, respectively.[24] The increase in risk for developing allopurinol-induced SJS or TEN in individuals with the HLA-B*5801 allele (as compared to those who do not have this allele) is very high, ranging from a 40-fold to a 580-fold increase in risk, depending on ethnicity.[22][23] As of 2011 the FDA-approved drug label for allopurinol did not contain any information regarding the HLA-B*5801 allele, though FDA scientists did publish a study in 2011 which reported a strong, reproducible and consistent association between the allele and allopurinol-induced SJS and TEN.[25] However, the American College of Rheumatology recommends screening for HLA-B*5801 in high-risk populations (e.g. Koreans with stage 3 or worse chronic kidney disease and those of Han Chinese and Thai descent), and prescribing patients who are positive for the allele an alternative drug.[26] The Clinical Pharmacogenetics Implementation Consortium guidelines state that allopurinol is contraindicated in known carriers of the HLA-B*5801 allele.[27][28]

History

Allopurinol was first synthesized and reported in 1956 by Roland K. Robins (1926-1992), in a search for antineoplastic agents.[1][29] Because allopurinol inhibits the breakdown (catabolism) of the thiopurine drug mercaptopurine, and it was later tested by Wayne Rundles, in collaboration with Gertrude Elion's lab at Wellcome Research Laboratories to see if it could improve treatment of acute lymphoblastic leukemia by enhancing the action of mercaptopurine.[1][30] However, no improvement in leukemia response was noted with mercaptopurine-allopurinol co-therapy, so that work turned to other compounds and the team then started testing allopurinol as a potential for gout.[31] Allopurinol was first marketed as a treatment for gout in 1966.[30]

Society and culture

Formulations

Allopurinol is sold as an injection for intravenous use[32] and as a tablet.[33]

Brands

Allopurinol has been marketed in the United States since August 19, 1966, when it was first approved by FDA under the trade name Zyloprim.[34] Allopurinol was marketed at the time by Burroughs-Wellcome. Allopurinol is now a generic drug sold under a variety of brand names, including Allohexal, Allosig, Milurit, Alloril, Progout, Ürikoliz, Zyloprim, Zyloric, Zyrik, and Aluron.[35]

See also

  • Lesinurad/allopurinol, a fixed-dose combination drug

References

1. ^1 2 3 4 {{cite journal |pages=87–114 |pmc=2233605 |doi=10.1124/pr.58.1.6 |title=Therapeutic Effects of Xanthine Oxidase Inhibitors: Renaissance Half a Century after the Discovery of Allopurinol |year=2006 |last1=Pacher |first1=P. |journal=Pharmacological Reviews |volume=58 |pmid=16507884 |last2=Nivorozhkin |first2=A |last3=Szabó |first3=C |issue=1}}
2. ^1 {{cite book|title=WHO Model Formulary 2008|date=2009|publisher=World Health Organization|isbn=9789241547659|page=39|url=http://apps.who.int/medicinedocs/documents/s16879e/s16879e.pdf|accessdate=8 December 2016|deadurl=no|archiveurl=https://web.archive.org/web/20161213060118/http://apps.who.int/medicinedocs/documents/s16879e/s16879e.pdf|archivedate=13 December 2016|df=}}
3. ^1 2 3 4 5 6 {{cite web|title=Allopurinol|url=https://www.drugs.com/monograph/allopurinol.html|publisher=The American Society of Health-System Pharmacists|accessdate=8 December 2016|deadurl=no|archiveurl=https://web.archive.org/web/20160429134301/http://www.drugs.com/monograph/allopurinol.html|archivedate=29 April 2016|df=}}
4. ^1 {{cite journal|last1=Robinson|first1=PC|last2=Stamp|first2=LK|title=The management of gout: Much has changed.|journal=Australian Family Physician|date=May 2016|volume=45|issue=5|pages=299–302|pmid=27166465}}
5. ^{{cite web|title=Allopurinol Use During Pregnancy {{!}} Drugs.com|url=https://www.drugs.com/pregnancy/allopurinol.html|website=www.drugs.com|accessdate=20 December 2016|deadurl=no|archiveurl=https://web.archive.org/web/20160820031050/https://www.drugs.com/pregnancy/allopurinol.html|archivedate=20 August 2016|df=}}
6. ^{{cite web|title=WHO Model List of Essential Medicines (19th List)|url=http://www.who.int/medicines/publications/essentialmedicines/EML_2015_FINAL_amended_NOV2015.pdf?ua=1|work=World Health Organization|accessdate=8 December 2016|date=April 2015|deadurl=no|archiveurl=https://web.archive.org/web/20161213052708/http://www.who.int/medicines/publications/essentialmedicines/EML_2015_FINAL_amended_NOV2015.pdf?ua=1|archivedate=13 December 2016|df=}}
7. ^{{cite web|title=Allopurinol|url=http://mshpriceguide.org/en/single-drug-information/?DMFId=19&searchYear=2014|website=International Drug Price Indicator Guide|accessdate=8 December 2016|deadurl=no|archiveurl=https://web.archive.org/web/20180122072027/http://mshpriceguide.org/en/single-drug-information/?DMFId=19&searchYear=2014|archivedate=22 January 2018|df=}}
8. ^{{cite book|last1=Hamilton|first1=Richart|title=Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition|date=2015|publisher=Jones & Bartlett Learning|isbn=9781284057560|page=465}}
9. ^{{cite web |title=The Top 300 of 2019 |url=https://clincalc.com/DrugStats/Top300Drugs.aspx |website=clincalc.com |accessdate=22 December 2018}}
10. ^{{cite journal |author= Jeha S. |title= Tumor lysis syndrome |journal= Semin Hematol.|volume= 38 |issue=4 Suppl 10 |pages=4–8 |year=2001 |pmid=11694945 |doi= 10.1016/S0037-1963(01)90037-X }}
11. ^Bradford K, Shih DQ. Optimizing 6-mercaptopurine and azathioprine therapy in the management of inflammatory bowel disease. World J Gastroenterol. 2011 Oct 7;17(37):4166-73. Review. {{PMID|22072847}} [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3208360/ PMC 3208360/] {{webarchive|url=https://web.archive.org/web/20171105200041/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3208360/ |date=2017-11-05 }}
12. ^{{cite journal |vauthors=Sparrow MP, Hande SA, Friedman S |title= Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine |journal= Clin Gastroenterol Hepatol |volume= 5 |issue=2 |pages=209–214 |year=2007 |pmid=17296529 |doi=10.1016/j.cgh.2006.11.020 |displayauthors= etal }}
13. ^{{cite journal |vauthors=Ansari AR, Patel N, Sanderson J |title= Low dose azathioprine or 6-mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease |journal= Aliment Pharmacol Ther |volume= 31 |issue=6 |pages=640–647 |year=2010 |pmid=20015102 |doi=10.1111/j.1365-2036.2009.04221.x |displayauthors= etal }}
14. ^{{cite journal |vauthors=Ansari AR, Duley JA |title= Azathioprine co-therapy with allopurinol for inflammatory bowel disease: trials and tribulations |journal= Rev Assoc Med Bras |volume=58 |issue=Suppl.1 |pages=S28–33 |date=March 2012 }}
15. ^{{cite journal |pages=391–5 |doi=10.1111/j.1525-139X.2007.00270.x |title=Allopurinol Dosing in Renal Impairment: Walking the Tightrope Between Adequate Urate Lowering and Adverse Events |year=2007 |last1=Dalbeth |first1=Nicola |last2=Stamp |first2=Lisa |journal=Seminars in Dialysis |volume=20 |issue=5 |pmid=17897242}}
16. ^{{cite journal |vauthors= Tsai TF, Yeh TY |title= Allopurinol in dermatology |journal= Am J Clin Dermatol |volume= 11 |issue=4 |pages=225–232 |year=2010 |pmid=20509717 |doi=10.2165/11533190-000000000-00000}}
17. ^1 2 3 {{cite journal|last1=Chung|first1=WH|last2=Wang|first2=CW|last3=Dao|first3=RL|title=Severe cutaneous adverse drug reactions.|journal=The Journal of dermatology|date=July 2016|volume=43|issue=7|pages=758–66|pmid=27154258|doi=10.1111/1346-8138.13430}}
18. ^{{cite book|author1=Marc E. De Broe |author2=William M. Bennett |author3=George A. Porter |title=Clinical Nephrotoxins: Renal Injury from Drugs and Chemicals |url=https://books.google.com/?id=sLM8F-IBgNcC&pg=PA317&dq=interstitial+nephritis+allopurinol#v=onepage&q=interstitial%20nephritis%20allopurinol&f=false|year=2003|publisher=Springer Science+Business Media|quote=Acute interstitial nephritis has also been reported associated with by the administration of allopurinol.|isbn=9781402012778}}
19. ^{{cite journal |vauthors=Reiter S, Simmonds HA, Zöllner N |title= Demonstration of a combined deficiency of xanthine oxidase and aldehyde oxidase in xanthinuric patients not forming oxipurinol |journal= Clin Chim Acta |volume= 187 |issue=3 |pages=221–234 |year=1990 |pmid=2323062 |doi= 10.1016/0009-8981(90)90107-4 |displayauthors= etal }}
20. ^{{cite journal |vauthors=Day RO, Graham GG, Hicks M |title= Clinical pharmacokinetics and pharmacodynamics of allopurinol and oxypurinol |journal= Clin. Pharmacokinet. |volume= 46 |issue=8 |pages=623–644 |year=2007 |pmid=17655371 |doi= 10.2165/00003088-200746080-00001 |displayauthors= etal }}
21. ^{{cite journal |vauthors= Cameron JS, Moro F, Simmonds HA |title= Gout, uric acid and purine metabolism in paediatric nephrology |journal= Pediatr. Nephrol.|volume= 7 |issue=1 |pages=105–118 |year=1993 |pmid=8439471 |doi= 10.1007/BF00861588 }}
22. ^1 http://www.pharmgkb.org/haplotype/PA165956630#tabview=tab3&subtab= {{webarchive|url=https://web.archive.org/web/20140808045855/http://www.pharmgkb.org/haplotype/PA165956630 |date=2014-08-08 }}
23. ^1 {{cite web |url=http://www.pharmgkb.org/pathway/PA165980774 |title=Archived copy |accessdate=2014-08-01 |deadurl=no |archiveurl=https://web.archive.org/web/20140808045844/http://www.pharmgkb.org/pathway/PA165980774 |archivedate=2014-08-08 |df= }}
24. ^http://www.allelefrequencies.net {{webarchive|url=https://web.archive.org/web/20090828074156/http://www.allelefrequencies.net/ |date=2009-08-28 }}
25. ^{{cite journal|vauthors=Zineh I, Mummaneni P, Lyndly J |title=Allopurinol pharmacogenetics: assessment of potential clinical usefulness|journal=Pharmacogenomics|volume=12 |issue=12|pages=1741–9|date=December 2011|pmid= 22118056|pmc=|doi=10.2217/pgs.11.131|url=|displayauthors=etal }}
26. ^{{cite journal|vauthors=Khanna D, Fitzgerald JD, Khanna PP |title=2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia|journal= Arthritis Care Res (Hoboken)|volume=64|issue=10|pages=1431–46|date=October 2012|pmid= 23024028 |pmc=3683400|doi=10.1002/acr.21772|url=|displayauthors=etal }}
27. ^{{cite web |url=http://www.pharmgkb.org/guideline/PA166105003 |title=Archived copy |accessdate=2014-08-01 |deadurl=no |archiveurl=https://web.archive.org/web/20140808045834/http://www.pharmgkb.org/guideline/PA166105003 |archivedate=2014-08-08 |df= }}
28. ^{{cite journal|vauthors=Hershfield MS, Callaghan JT, Tassaneeyakul W |title=Clinical Pharmacogenetics Implementation Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing|journal=Clin Pharmacol Ther|volume=93|issue=2|pages=153–8|date=February 2013|pmid=23232549|pmc=3564416|doi=10.1038/clpt.2012.209|url=|displayauthors=etal }}
29. ^{{cite journal | author = R. K. Robins | journal = J. Am. Chem. Soc. | volume = 78 | pages = 784–790 | year = 1956 | doi = 10.1021/ja01585a023 | title = Potential Purine Antagonists. I. Synthesis of Some 4,6-Substituted Pyrazolo \\3,4-d] pyrimidines1 | issue = 4}}
30. ^1 Walter Sneader. Drug Discovery: A History. John Wiley & Sons, 2005 {{ISBN|9780471899792}}. [https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA254 page 254] {{webarchive|url=https://web.archive.org/web/20160610200540/https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA254 |date=2016-06-10 }}
31. ^{{cite journal |author= Elion GB. |title= The purine path to chemotherapy (Nobel lecture in physiology or medicine - 1988) |journal= Science |volume= 244 |issue=4900 |pages=41–47 |year=1989 |pmid=2649979 |doi=10.1126/science.2649979|bibcode= 1989Sci...244...41E }}
32. ^1 FDA [https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=10cc918f-aa44-415b-932d-2404695ac449 Label for injectable Allopurinol] {{webarchive|url=https://web.archive.org/web/20160913084333/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=10cc918f-aa44-415b-932d-2404695ac449 |date=2016-09-13 }} Last updated June 2014
33. ^1 2 3 4 5 6 UK Electronic Medicines Compendium [https://www.medicines.org.uk/emc/medicine/25728 300 mg Allopurinol tables] {{webarchive|url=https://web.archive.org/web/20160911024141/https://www.medicines.org.uk/emc/medicine/25728 |date=2016-09-11 }} Last updated April 7, 2016
34. ^{{cite web |url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm |title=Archived copy |accessdate=2013-11-08 |deadurl=no |archiveurl=https://web.archive.org/web/20120814072104/http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/index.cfm |archivedate=2012-08-14 |df= }}
35. ^{{cite web |url=http://dailymed.nlm.nih.gov/dailymed/search.cfm?startswith=Allopurinol&x=0&y=0 |title=Archived copy |accessdate=2011-07-27 |deadurl=no |archiveurl=https://web.archive.org/web/20120325001706/http://dailymed.nlm.nih.gov/dailymed/search.cfm?startswith=Allopurinol&x=0&y=0 |archivedate=2012-03-25 |df= }}

External links

  • [https://www.drugs.com/cdi/zyloprim.html Zyloprim] (patient information)
  • Allopurinol pathway on PharmGKB
{{Antigout preparations}}{{Purinergics}}{{portal bar|Pharmacy and pharmacology|Medicine}}

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