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Allopurinol - Wikipedia, the free encyclopedia

Allopurinol
From Wikipedia, the free encyclopedia

Allopurinol, sold under the brand name Zyloprim and


generics, is a medication used primarily to treat excess uric
acid in the blood and its complications, including chronic
gout.[1] It is a xanthine oxidase inhibitor which is administered
orally.

Allopurinol

It is on the World Health Organization's List of Essential


Medicines, a list of the most important medication needed in
a basic health system.[2]

Contents
1 Medical uses
Systematic (IUPAC) name

1.1 Gout and hyperuricemia


1.2 Tumor lysis syndrome
1.3 Inflammatory bowel disease

1H-pyrazolo[3,4-d]pyrimidin-4(2H)-one

Clinical data
Trade names

Zyloprim

AHFS/Drugs.com monograph
MedlinePlus

1.4 Reperfusion injury


1.5 Epilepsy

a682673

Pregnancy
category
Legal status

C(USA)
POM (Prescription
only)
UK:

2 Side effects
3 Pharmacology
3.1 Mechanism of action
3.2 Pharmacogenetics

US:

Routes of
administration

tablet (100, 300 mg)

Pharmacokinetic data
Bioavailability

7820%

Protein binding

Negligible

Metabolism

hepatic (80% oxypurinol, 10%


allopurinol ribosides)

Biological halflife

2 h (oxypurinol 18-30 h)

4 History
5 Society and culture

Identifiers

6 Research

CAS Number

315-30-0

7 References

ATC code

M04AA01

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8 Further reading
9 External links

Medical uses
Gout and hyperuricemia
Allopurinol is used in chronic gout to prevent future attacks.
It does not alleviate acute attacks of gout and there is
currently controversy over the issue of whether it can actually
make acute gout attacks worse initially.[3]

PubChem

CID: 2094

IUPHAR/BPS

6795

DrugBank

DB00437

ChemSpider

2010

UNII

63CZ7GJN5I

KEGG

D00224

ChEBI

CHEBI:40279

ChEMBL

CHEMBL1467
Chemical data

Formula

C5H4N4O

Molecular mass 136.112 g/mol

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, although it

SMILES
InChI

(what is this?) (verify)

has gradually been replaced by urate oxidase therapy.[4]

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.[5][6] Cotherapy has also been shown to greatly improve
hepatoxicity side effects in treatment of IBD.[7] 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.[8]

Reperfusion injury
Other established indications for allopurinol therapy include ischemic reperfusion injury, kidney stones with a uric
acid component (uric acid nephrolithiasis), and protozoal infections (leishmaniasis).

Epilepsy
Allopurinol is used as an add-on drug for refractory epilepsy, because it is an adenosine agonist, which inhibits
glutamine release from excitatory neurons, but does not change the plasma concentration of other epilepsy drugs.[9]

Side effects
Because allopurinol is not a uricosuric, it can be used in patients with poor kidney function. However, allopurinol
has two important disadvantages.
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First, its dosing is complex.[10] Second, some patients are hypersensitive to the drug,[11] therefore its use requires
careful monitoring. 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, worsened renal
function, and, in some cases, allopurinol hypersensitivity syndrome.[11] Allopurinol is one of the drugs commonly
known to cause StevensJohnson syndrome and toxic epidermal necrolysis, two life-threatening dermatological
conditions.[12] More common is a less-serious rash that leads to discontinuing this drug.
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.[13]
It is suspected to cause congenital malformations in a newborn infant whose mother was on allopurinol treatment
through the pregnancy, and should be avoided whenever possible by women trying to conceive or during
pregnancy.[14]

Pharmacology
A common misconception is that allopurinol is metabolized by its target, xanthine oxidase, but this action is
principally carried out by aldehyde oxidase.[15] The active metabolite of allopurinol is oxypurinol, which is also an
inhibitor of xanthine oxidase. Allopurinol is almost completely metabolized to oxypurinol within two hours of oral
administration, whereas oxypurinol is slowly excreted by the kidneys over 1830 hours. For this reason, oxypurinol
is believed responsible for the majority of allopurinol's effect.[16]

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.[17]

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).[18][19] The frequency of the HLAB*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.[20] 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.[18][19] Currently, the FDA-approved drug label for allopurinol
does not contain any information regarding the HLA-B*5801 allele, though FDA scientists did publish a study in
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2011 which reported a strong, reproducible and consistent association between the allele and allopurinol-induced
SJS and TEN.[21] 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.[22] The Clinical
Pharmacogenetics Implementation Consortium (http://www.pharmgkb.org/page/cpic) guidelines state that
allopurinol is contraindicated in known carriers of the HLA-B*5801 allele.[23][24]

History
Allopurinol was first synthesized and reported in 1956 by Roland K. Robins (1926-1992), in a search for
antineoplasitic agents.[25] 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.[26] 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.[27] Allopurinol was first marketed as a treatment for gout in 1966.[26]

Society and culture


Allopurinol has been marketed in the United States since August 19,
1966, when it was first approved by FDA under the trade name
Zyloprim.[28] Allopurinol was marketed at the time by BurroughsWellcome. Allopurinol is now a generic drug sold under a variety of
brand names, including Allohexal, Allosig, Milurit, Alloril, Progout,
rikoliz, Zyloprim, Zyloric, Zyrik, and Aluron.[29]

Research

Pure allopurinol is a white powder.

Allopurinol can be used in patients with poor kidney function. A study of


allopurinol use in patients with chronic kidney disease suggested, "Allopurinol decreases C-reactive protein and
slows the progression of renal disease in patients with chronic kidney disease. In addition, it reduces cardiovascular
and hospitalization risk in these subjects."[30]
A mechanistic study in patients with chronic heart failure has shown the actions of allopurinol may be due to its
inhibition of xanthine oxidase rather than a urate-lowering effect. This study also showed, for the first time, a high
dose (600 mg) is significantly better at improving endothelial function compared to standard doses.[31]
A recent study has suggested allopurinol may help reduce the effects of angina in ischaemic heart disease by
reducing the workload on the heart.[32]
Allopurinol can decrease blood pressure, thus reducing hypertension.[33]

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References
1. Pacher, P.; Nivorozhkin, A; Szab, C (2006). "Therapeutic Effects of Xanthine Oxidase Inhibitors: Renaissance
Half a Century after the Discovery of Allopurinol". Pharmacological Reviews 58 (1): 87114.
doi:10.1124/pr.58.1.6. PMC 2233605. PMID 16507884.
2. "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April
2014.
3. Taylor, TH; Mecchella, JN; Larson, RJ; Kerin, KD; Mackenzie, TA (November 2012). "Initiation of allopurinol at
first medical contact for acute attacks of gout: a randomized clinical trial". JAMA 125 (11): 11261134.
doi:10.1016/j.amjmed.2012.05.025. PMID 23098865.
4. Jeha S. (2001). "Tumor lysis syndrome". Semin Hematol. 38 (4 Suppl 10): 48. doi:10.1016/S00371963(01)90037-X. PMID 11694945.
5. 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 PMC 3208360/
(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3208360/)
6. Sparrow MP, Hande SA, Friedman S; et al. (2007). "Effect of allopurinol on clinical outcomes in inflammatory
bowel disease nonresponders to azathioprine or 6-mercaptopurine". Clin Gastroenterol Hepatol. 5 (2): 209214.
doi:10.1016/j.cgh.2006.11.020. PMID 17296529.
7. Ansari AR, Patel N, Sanderson J; et al. (2010). "Low dose azathioprine or 6-mercaptopurine in combination with
allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease". Aliment
Pharmacol Ther 31 (6): 640647. doi:10.1111/j.1365-2036.2009.04221.x. PMID 20015102.
8. Ansari AR, Duley JA. (March 2012). "Azathioprine co-therapy with allopurinol for inflammatory bowel disease:
trials and tribulations". Rev Assoc Med Bras 58 (Suppl.1): S2833.
9. Drug-Resistant Epilepsy (http://www.nejm.org/doi/full/10.1056/NEJMc1111683) N Engl J Med 2011; 365:22382240December 8, 2011
10. Dalbeth, Nicola; Stamp, Lisa (2007). "Allopurinol Dosing in Renal Impairment: Walking the Tightrope Between
Adequate Urate Lowering and Adverse Events". Seminars in Dialysis 20 (5): 3915. doi:10.1111/j.1525139X.2007.00270.x. PMID 17897242.
11. Tsai TF, Yeh TY.; Yeh (2010). "Allopurinol in dermatology". Am J Clin Dermatol. 11 (4): 225232.
doi:10.2165/11533190-000000000-00000. PMID 20509717.
12. Roujeau JC, Kelly JP, Naldi L, Rzany B, Stern RS, Anderson T, et al. (1995). "Medication use and the risk of
Stevens-Johnson syndrome or toxic epidermal necrolysis". N Engl J Med 333 (24): 16007.
doi:10.1056/NEJM199512143332404. PMID 7477195.
13. Marc E. De Broe, William M. Bennett, George A. Porter (2003). Clinical Nephrotoxins: Renal Injury from Drugs
and Chemicals. Springer Science+Business Media. ISBN 9781402012778. "Acute interstitial nephritis has also been
reported associated with by the administration of allopurinol."
14. Kozenko, Mariya; Grynspan, David; Oluyomi-Obi, Titi; Sitar, Daniel; Elliott, Alison M.; Chodirker, Bernard N.
(2011). "Potential teratogenic effects of allopurinol: A case report". American Journal of Medical Genetics Part A
155 (9): 224752. doi:10.1002/ajmg.a.34139. PMID 21815259.
15. Reiter S, Simmonds HA, Zllner N; et al. (1990). "Demonstration of a combined deficiency of xanthine oxidase and
aldehyde oxidase in xanthinuric patients not forming oxipurinol". Clin Chim Acta 187 (3): 221234.
doi:10.1016/0009-8981(90)90107-4. PMID 2323062.
16. Day RO, Graham GG, Hicks M; et al. (2007). "Clinical pharmacokinetics and pharmacodynamics of allopurinol and
oxypurinol". Clin Pharmacokinet. 46 (8): 623644. doi:10.2165/00003088-200746080-00001. PMID 17655371.
17. Cameron JS, Moro F, Simmonds HA.; Moro; Simmonds (1993). "Gout, uric acid and purine metabolism in
paediatric nephrology". Pediatr Nephrol. 7 (1): 105118. doi:10.1007/BF00861588. PMID 8439471.
18. http://www.pharmgkb.org/haplotype/PA165956630#tabview=tab3&subtab=
19. http://www.pharmgkb.org/pathway/PA165980774
20. http://www.allelefrequencies.net
21. Zineh I, Mummaneni P, Lyndly J; et al. (December 2011). "Allopurinol pharmacogenetics: assessment of potential
clinical usefulness". Pharmacogenomics 12 (12): 17419. doi:10.2217/pgs.11.131. PMID 22118056.
22. Khanna D, Fitzgerald JD, Khanna PP; et al. (October 2012). "2012 American College of Rheumatology guidelines
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23.
24.

25.
26.
27.
28.
29.
30.

31.

32.
33.

Allopurinol - Wikipedia, the free encyclopedia

for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to
hyperuricemia". Arthritis Care Res (Hoboken) 64 (10): 143146. doi:10.1002/acr.21772. PMC 3683400.
PMID 23024028.
http://www.pharmgkb.org/guideline/PA166105003
Hershfield MS, Callaghan JT, Tassaneeyakul W; et al. (February 2013). "Clinical Pharmacogenetics Implementation
Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing". Clin Pharmacol Ther 93
(2): 1538. doi:10.1038/clpt.2012.209. PMC 3564416. PMID 23232549.
R. K. Robins (1956). "Potential Purine Antagonists. I. Synthesis of Some 4,6-Substituted Pyrazolo \3,4-d]
pyrimidines1". J. Amer. Chem. Soc. 78 (4): 784. doi:10.1021/ja01585a023.
Walter Sneader. Drug Discovery: A History. John Wiley & Sons, 2005 ISBN 9780471899792. page 254
(https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA254)
Elion GB. (1989). "The purine path to chemotherapy (Nobel lecture in physiology or medicine - 1988)". Science
244 (4900): 4147. doi:10.1126/science.2649979. PMID 2649979.
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
http://dailymed.nlm.nih.gov/dailymed/search.cfm?startswith=Allopurinol&x=0&y=0
Goicoechea, M.; De Vinuesa, S. G.; Verdalles, U.; Ruiz-Caro, C.; Ampuero, J.; Rincn, A.; Arroyo, D.; Luo, J.
(2010). "Effect of Allopurinol in Chronic Kidney Disease Progression and Cardiovascular Risk". Clinical Journal of
the American Society of Nephrology 5 (8): 138893. doi:10.2215/CJN.01580210. PMC 2924417.
PMID 20538833..
George, J; Carr, E; Davies, J; Belch, JJ; Struthers, A (2006). "High-dose allopurinol improves endothelial function
by profoundly reducing vascular oxidative stress and not by lowering uric acid". Circulation 114 (23): 250816.
doi:10.1161/CIRCULATIONAHA.106.651117. PMID 17130343.
"Gout drug 'can prevent angina pain of heart disease' ". BBC News. 8 June 2010.
Feig, D. I.; Soletsky, B.; Johnson, R. J. (2008). "Effect of Allopurinol on Blood Pressure of Adolescents with
Newly Diagnosed Essential Hypertension: A Randomized Trial". JAMA: the Journal of the American Medical
Association 300 (8): 92432. doi:10.1001/jama.300.8.924. Lay summary Journal Watch (September 3, 2008).

Further reading
Zahran AM, Azab KS, Abbady MI (2006). "Modulatory role of allopurinol on xanthine oxidoreductase system and
antioxidant status in irradiated rats". Egyptian Journal of Radiation Sciences and Applications 19 (2): 373388.
ISSN 1110-0303.
Hung, Shuen-Iu; Chung, Wen-Hung; Liou, Lieh-Bang; Chu, Chen-Chung; Lin, Marie; Huang, Hsien-Ping; Lin, YenLing; Lan, Joung-Liang; Yang, Li-Cheng; Hong, H.-S.; Chen, M.-J.; Lai, P.-C.; Wu, M.-S.; Chu, C.-Y.; Wang, K.H.; Chen, C.-H.; Fann, C. S. J.; Wu, J.-Y.; Chen, Y.-T. (2005). "HLA-B*5801 allele as a genetic marker for severe
cutaneous adverse reactions caused by allopurinol". Proceedings of the National Academy of Sciences 102 (11):
41349. doi:10.1073/pnas.0409500102. PMC 554812. PMID 15743917.

The Third International Thiopurine Symposium 2010, published in RAMB, for information on Allopurinol cotherapy: [1] (http://www.ramb.org.br/edicao_atual/suplemento1.pdf)

External links
Zyloprim (http://www.drugs.com/cdi/zyloprim.html) (patient information)
Allopurinol pathway on PharmGKB (http://www.pharmgkb.org/pathway/PA165980774)
Very Important Pharmacogene summary for HLA-B on PharmGKB
(http://www.pharmgkb.org/gene/PA35056#tabview=tab3&subtab=31)

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Categories: Antigout agents Xanthine oxidase inhibitors World Health Organization essential medicines
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