Open Access Articles- Top Results for Allopurinol


Systematic (IUPAC) name
Clinical data
Trade names Zyloprim
AHFS/ monograph
MedlinePlus a682673
  • C(USA)
tablet (100, 300 mg)
Pharmacokinetic data
Bioavailability 78±20%
Protein binding Negligible
Metabolism hepatic (80% oxypurinol, 10% allopurinol ribosides)
Half-life 2 h (oxypurinol 18-30 h)
315-30-0 7pxY
PubChem CID 2094
DrugBank DB00437 7pxY
ChemSpider 2010 7pxY
KEGG D00224 7pxY
ChEBI CHEBI:40279 7pxY
Chemical data
Formula C5H4N4O
136.112 g/mol
 14pxY (what is this?)  (verify)

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.

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]

Medical uses

Allopurinol inhibits the breakdown (catabolism) of the thiopurine drug mercaptopurine, and was specifically invented by Gertrude Elion to enhance the action of mercaptopurine in the treatment of acute lymphoblastic leukemia. However, no improvement in leukemia response was noted with mercaptopurine-allopurinol cotherapy, and this use of the drug was abandoned.[3]

Gout and hyperuricemia

Subsequently, the uric acid-lowering capacity of allopurinol was noted and the drug went on to be developed for its more famous use: to treat hyperuricemia (excess uric acid in blood plasma) and its complications.[3] Allopurinol does not alleviate acute attacks of gout,[4] and currently controversy exists over the issue of whether it can actually make acute gout attacks worse initially, but is useful in chronic gout to prevent future attacks.

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treatments, as these regimens can rapidly produce severe acute hyperuricemia, although it has gradually been replaced by urate oxidase therapy.[5]

Thiopurine cotherapy

Allopurinol can cause severe pancytopenia if given with full-dose mercaptopurine or its prodrug azathioprine, due to the inhibition of xanthine oxidase that metabolizes mercaptopurine.[6] So, allopurinol has been strongly contraindicated during thiopurine therapy in the past. In recent years, though, the use of allopurinol in combination with azathioprine or mercaptopurine has been revived. First, an azathioprine/allopurinol combination was shown to significantly improve renal transplant graft survival.[7] More recently, this cotherapy was found to greatly improve the outcome for patients who do not respond to thiopurine monotherapy when treating inflammatory bowel disease, specifically Crohn's disease.[8] Cotherapy has also been shown to greatly improve hepatoxicity side effects in treatment of IBD.[9] 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.[10]

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).

Renal disease, heart failure, and angina

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."[11]

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.[12]

A recent study has suggested allopurinol may help reduce the effects of angina in ischaemic heart disease by reducing the workload on the heart.[13]


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.[14]

Blood pressure

Allopurinol can decrease blood pressure, thus reducing hypertension.[15]

Side effects

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

First, its dosing is complex.[16] Second, some patients are hypersensitive to the drug,[17] 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.[17] Allopurinol is one of the drugs commonly known to cause Stevens–Johnson syndrome and toxic epidermal necrolysis, two life-threatening dermatological conditions.[18] 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.[19]

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.[20]


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).[21][22] 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.[23] 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.[21][22] 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 2011 which reported a strong, reproducible and consistent association between the allele and allopurinol-induced SJS and TEN.[24] 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.[25] The Clinical Pharmacogenetics Implementation Consortium guidelines state that allopurinol is contraindicated in known carriers of the HLA-B*5801 allele.[26][27]

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.[28]


Allopurinol was first synthesized and reported in 1956 by Roland K. Robins (1926-1992), in a search for antineoplasitic agents.[29]


A common misconception is that allopurinol is metabolized by its target, xanthine oxidase, but this action is principally carried out by aldehyde oxidase.[30] 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 18–30 hours. For this reason, oxypurinol is believed responsible for the majority of allopurinol's effect.[31]

Brand names

File:Allopurinol substance photo.jpg
Pure allopurinol is a white powder.

Allopurinol has been marketed in the United States since August 19, 1966, when it was first approved by FDA under the trade name Zyloprim.[32] 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, Zyloprim, Zyloric, Zyrik, and Aluron.[33]


File:Allopurinol synthesis.svg
Allopurinol synthesis.[34]


  1. ^ a b c Pacher, P.; Nivorozhkin, A; Szabó, C (2006). "Therapeutic Effects of Xanthine Oxidase Inhibitors: Renaissance Half a Century after the Discovery of Allopurinol". Pharmacological Reviews 58 (1): 87–114. PMC 2233605. PMID 16507884. doi:10.1124/pr.58.1.6. 
  2. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014. 
  3. ^ a b Elion GB. (1989). "The purine path to chemotherapy (Nobel lecture in physiology or medicine - 1988)". Science 244 (4900): 41–47. PMID 2649979. doi:10.1126/science.2649979. 
  4. ^ Taylor, MD, 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): 1126–1134. PMID 23098865. doi:10.1016/j.amjmed.2012.05.025. 
  5. ^ Jeha S. (2001). "Tumor lysis syndrome". Semin Hematol. 38 (4 Suppl 10): 4–8. PMID 11694945. doi:10.1016/S0037-1963(01)90037-X. 
  6. ^ Evans WE. (2004). "Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy". Ther Drug Monit. 26 (2): 186–91. PMID 15228163. doi:10.1097/00007691-200404000-00018. 
  7. ^ Chocair PR, Duley JA, Simmonds HA et al. (1993). "Low dose allopurinol, plus azathioprine/ cyclosporin/ prednisolone, a novel immunosuppressive regimen". Lancet 342 (8863): 83–84. PMID 8100914. doi:10.1016/0140-6736(93)91287-V. 
  8. ^ 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): 209–214. PMID 17296529. doi:10.1016/j.cgh.2006.11.020. 
  9. ^ 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): 640–647. PMID 20015102. doi:10.1111/j.1365-2036.2009.04221.x. 
  10. ^ 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): S28–33. 
  11. ^ Goicoechea, M.; De Vinuesa, S. G.; Verdalles, U.; Ruiz-Caro, C.; Ampuero, J.; Rincón, A.; Arroyo, D.; Luño, J. (2010). "Effect of Allopurinol in Chronic Kidney Disease Progression and Cardiovascular Risk". Clinical Journal of the American Society of Nephrology 5 (8): 1388–93. PMC 2924417. PMID 20538833. doi:10.2215/CJN.01580210. .
  12. ^ 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): 2508–16. PMID 17130343. doi:10.1161/CIRCULATIONAHA.106.651117. 
  13. ^ "Gout drug 'can prevent angina pain of heart disease'". BBC News. 8 June 2010. 
  14. ^ Drug-Resistant Epilepsy N Engl J Med 2011; 365:2238-2240December 8, 2011
  15. ^ 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): 924–32. doi:10.1001/jama.300.8.924. Lay summaryJournal Watch (September 3, 2008). 
  16. ^ 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): 391–5. PMID 17897242. doi:10.1111/j.1525-139X.2007.00270.x. 
  17. ^ a b Tsai TF, Yeh TY.; Yeh (2010). "Allopurinol in dermatology". Am J Clin Dermatol. 11 (4): 225–232. PMID 20509717. doi:10.2165/11533190-000000000-00000. 
  18. ^ 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): 1600–7. PMID 7477195. doi:10.1056/NEJM199512143332404. 
  19. ^ 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. 
  20. ^ 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): 2247–52. PMID 21815259. doi:10.1002/ajmg.a.34139. 
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  27. ^ 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): 153–8. PMC 3564416. PMID 23232549. doi:10.1038/clpt.2012.209. 
  28. ^ Cameron JS, Moro F, Simmonds HA.; Moro; Simmonds (1993). "Gout, uric acid and purine metabolism in paediatric nephrology". Pediatr Nephrol. 7 (1): 105–118. PMID 8439471. doi:10.1007/BF00861588. 
  29. ^ 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. 
  30. ^ Reiter S, Simmonds HA, Zöllner 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): 221–234. PMID 2323062. doi:10.1016/0009-8981(90)90107-4. 
  31. ^ Day RO, Graham GG, Hicks M et al. (2007). "Clinical pharmacokinetics and pharmacodynamics of allopurinol and oxypurinol". Clin Pharmacokinet. 46 (8): 623–644. PMID 17655371. doi:10.2165/00003088-200746080-00001. 
  32. ^
  33. ^
  34. ^

Further reading

  • The Third International Thiopurine Symposium 2010, published in RAMB, for information on Allopurinol co-therapy: [1]

External links