Chemistry:Allopurinol

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Short description: Medication
Allopurinol
Allopurinol V.1.svg
Allopurinol 3d structure.png
Clinical data
Trade namesZyloprim, Caplenal, Zyloric, others
AHFS/Drugs.comMonograph
MedlinePlusa682673
License data
Pregnancy
category
Routes of
administration		Oral, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability78±20%
Protein bindingNegligible
Metabolismliver (80% oxipurinol, 10% allopurinol ribosides)
Elimination half-life2 h (oxipurinol 18–30 h)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC5H4N4O
Molar mass136.114 g·mol−1
3D model (JSmol)
  (verify)

Allopurinol is a medication used to decrease high blood uric acid levels.[4] 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.[5][6] It is taken orally (by mouth) or intravenously (injected into a vein).[6]

Common side effects when used orally include itchiness and rash.[6] Common side effects when used by injection include vomiting and kidney problems.[6] While not recommended historically, starting allopurinol during an attack of gout appears to be safe.[7][8] In those already on the medication, it should be continued even during an acute gout attack.[7][5] While use during pregnancy does not appear to result in harm, this use has not been well studied.[1] Allopurinol is in the xanthine oxidase inhibitor family of medications.[6]

Allopurinol was approved for medical use in the United States in 1966.[6] It is on the World Health Organization's List of Essential Medicines.[9][10] Allopurinol is available as a generic medication.[6] In 2021, it was the 40th most commonly prescribed medication in the United States, with more than 15 million prescriptions.[11][12]

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;[13] however, it has gradually been replaced by urate oxidase therapy.[14] Intravenous formulations are used in this indication when people are unable to swallow medication.[3]

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.[15][16] Cotherapy has also been shown to greatly improve hepatoxicity side effects in treatment of IBD.[17] 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.[18]

Psychiatric disorders

Allopurinol has been tested as an augmentation strategy for the treatment of mania in bipolar disorder. Meta-analytic evidence showed that adjunctive allopurinol was superior to placebo for acute mania (both with and without mixed features).[19] Its efficacy was not influenced by dosage, follow-up duration, or concurrent standard treatment.[19]

Cardiovascular disease

There is a correlation between uric acid levels and cardiovascular disease and mortality, and so allopurinol has been explored as a potential treatment to reduce risk of cardiac disease.[20] However, the data is inconsistent and conflicting, and the use of allopurinol for use in cardiovascular disease is controversial. Independently of its effects on uric acid, it may also have effects on oxidative stress and inflammation.[21]

Side effects

Because allopurinol is not a uricosuric, it can be used in people with poor kidney function. However, for people with impaired kidney function, allopurinol has two disadvantages. First, its dosing is complex.[22] Second, some people are hypersensitive to the drug; therefore, its use requires careful monitoring.[23][24]

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, collectively referred to as DRESS syndrome.[23] Allopurinol is one of the drugs commonly known to cause Stevens–Johnson syndrome and toxic epidermal necrolysis, two life-threatening dermatological conditions.[23] More common is a less-serious rash that leads to discontinuing this drug.[23]

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.[25]

Drug interactions

Drug interactions are extensive, and are as follows:[13]

  • 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 allopurinol 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:[13]

Co-administration of the following drugs may make allopurinol less active or decrease its half-life:[13]

  • 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:[13]

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

Pharmacology

A common misconception is that allopurinol is metabolized by its target, xanthine oxidase, but this action is principally carried out by aldehyde oxidase.[26] 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.[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.[4] Xanthine oxidase is responsible for the successive oxidation of hypoxanthine to xanthine and subsequently uric acid, the product of human purine metabolism.[4] 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 ribonucleotides, hypoxanthine can be salvaged to the purine ribonucleotides adenosine and guanosine monophosphates. Increased levels of these ribonucleotides 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]

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).[29][30] 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.[31] 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.[29][30] 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.[32] 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.[33] The Clinical Pharmacogenetics Implementation Consortium (CPIC)[34] guidelines state that allopurinol is contraindicated in known carriers of the HLA-B*5801 allele.[35][36]

History

Allopurinol was first synthesized and reported in 1956 by Roland K. Robins (1926-1992), in a search for antineoplastic agents.[4][37] 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.[4][38] 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 therapeutic for gout.[39] Allopurinol was first marketed as a treatment for gout in 1966.[38]

Society and culture

Pure allopurinol is a white powder.

Formulations

Allopurinol is sold as an injection for intravenous use[3] and as a tablet.[13]

Brands

Allopurinol has been marketed in the United States since 19 August 1966, when it was first approved by FDA under the trade name Zyloprim.[40] Allopurinol was marketed at the time by Burroughs Wellcome. Allopurinol is a generic drug sold under a variety of brand names, including Allohexal, Allosig, Milurit, Alloril, Progout, Ürikoliz, Zyloprim, Zyloric, Zyrik, and Aluron.[41]

See also

  • Lesinurad/allopurinol, a fixed-dose combination drug

References

  1. ↑ 1.0 1.1 "Allopurinol Use During Pregnancy". https://www.drugs.com/pregnancy/allopurinol.html. 
  2. ↑ "Allopurinol tablet". 13 December 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=30ad5ba2-1cef-4933-b104-0597f6a2aaa2. 
  3. ↑ 3.0 3.1 3.2 "Label for injectable Allopurinol". DailyMed. June 2014. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=10cc918f-aa44-415b-932d-2404695ac449. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 "Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol". Pharmacological Reviews 58 (1): 87–114. March 2006. doi:10.1124/pr.58.1.6. PMID 16507884. 
  5. ↑ 5.0 5.1 WHO Model Formulary 2008. World Health Organization. 2009. p. 39. ISBN 9789241547659. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 "Allopurinol". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/allopurinol.html. 
  7. ↑ 7.0 7.1 "The management of gout: Much has changed". Australian Family Physician 45 (5): 299–302. May 2016. PMID 27166465. 
  8. ↑ "Early versus Late Allopurinol Initiation in Acute Gout Flare (ELAG): a randomized controlled trial". Clinical Rheumatology 41 (1): 213–221. January 2022. doi:10.1007/s10067-021-05872-8. PMID 34406530. 
  9. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  10. ↑ World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. 2021. WHO/MHP/HPS/EML/2021.02. 
  11. ↑ "The Top 300 of 2021". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  12. ↑ "Allopurinol - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Allopurinol. 
  13. ↑ 13.0 13.1 13.2 13.3 13.4 13.5 "300 mg Allopurinol tables". UK Electronic Medicines Compendium. 7 April 2016. https://www.medicines.org.uk/emc/medicine/25728. 
  14. ↑ "Tumor lysis syndrome". Seminars in Hematology 38 (4 Suppl 10): 4–8. October 2001. doi:10.1016/S0037-1963(01)90037-X. PMID 11694945. 
  15. ↑ "Optimizing 6-mercaptopurine and azathioprine therapy in the management of inflammatory bowel disease". World Journal of Gastroenterology 17 (37): 4166–73. October 2011. doi:10.3748/wjg.v17.i37.4166. PMID 22072847. 
  16. ↑ "Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine". Clinical Gastroenterology and Hepatology 5 (2): 209–14. February 2007. doi:10.1016/j.cgh.2006.11.020. PMID 17296529. 
  17. ↑ "Low-dose azathioprine or mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease". Alimentary Pharmacology & Therapeutics 31 (6): 640–7. March 2010. doi:10.1111/j.1365-2036.2009.04221.x. PMID 20015102. 
  18. ↑ "Azathioprine co-therapy with allopurinol for inflammatory bowel disease: trials and tribulations". Rev Assoc Med Bras 58 (Suppl.1): S28–33. March 2012. http://espace.library.uq.edu.au/view/UQ:272955/UQ272955_OA.pdf. 
  19. ↑ 19.0 19.1 "Repurposed drugs as adjunctive treatments for mania and bipolar depression: A meta-review and critical appraisal of meta-analyses of randomized placebo-controlled trials". Journal of Psychiatric Research 143: 230–238. September 2021. doi:10.1016/j.jpsychires.2021.09.018. PMID 34509090. 
  20. ↑ "Allopurinol as a cardiovascular drug". Cardiology in Review 19 (6): 265–271. November 2011. doi:10.1097/CRD.0b013e318229a908. PMID 21983313. 
  21. ↑ "Allopurinol for pain relief: more than just crystal clearance?". British Journal of Pharmacology 156 (1): 4–6. January 2009. doi:10.1111/j.1476-5381.2008.00065.x. PMID 19133987. 
  22. ↑ "Allopurinol dosing in renal impairment: walking the tightrope between adequate urate lowering and adverse events". Seminars in Dialysis 20 (5): 391–5. 2007. doi:10.1111/j.1525-139X.2007.00270.x. PMID 17897242. 
  23. ↑ 23.0 23.1 23.2 23.3 "Severe cutaneous adverse drug reactions". The Journal of Dermatology 43 (7): 758–66. July 2016. doi:10.1111/1346-8138.13430. PMID 27154258. 
  24. ↑ "Allopurinol in dermatology". American Journal of Clinical Dermatology 11 (4): 225–32. 2010. doi:10.2165/11533190-000000000-00000. PMID 20509717. 
  25. ↑ Clinical Nephrotoxins: Renal Injury from Drugs and Chemicals. Springer Science+Business Media. 2003. ISBN 9781402012778. https://books.google.com/books?id=sLM8F-IBgNcC&q=interstitial+nephritis+allopurinol&pg=PA317. "Acute interstitial nephritis has also been reported associated with by the administration of allopurinol." 
  26. ↑ "Demonstration of a combined deficiency of xanthine oxidase and aldehyde oxidase in xanthinuric patients not forming oxipurinol". Clinica Chimica Acta; International Journal of Clinical Chemistry 187 (3): 221–34. March 1990. doi:10.1016/0009-8981(90)90107-4. PMID 2323062. 
  27. ↑ "Clinical pharmacokinetics and pharmacodynamics of allopurinol and oxypurinol". Clinical Pharmacokinetics 46 (8): 623–44. 2007. doi:10.2165/00003088-200746080-00001. PMID 17655371. 
  28. ↑ "Gout, uric acid and purine metabolism in paediatric nephrology". Pediatric Nephrology 7 (1): 105–18. February 1993. doi:10.1007/BF00861588. PMID 8439471. 
  29. ↑ 29.0 29.1 "Uric Acid-Lowering Drugs Pathway, Pharmacodynamics". PharmGKB. http://www.pharmgkb.org/haplotype/PA165956630#tabview=tab3&subtab=. 
  30. ↑ 30.0 30.1 "PharmGKB". http://www.pharmgkb.org/pathway/PA165980774. 
  31. ↑ "Allele Frequency Net Database". http://www.allelefrequencies.net. 
  32. ↑ "Allopurinol pharmacogenetics: assessment of potential clinical usefulness". Pharmacogenomics 12 (12): 1741–9. December 2011. doi:10.2217/pgs.11.131. PMID 22118056. https://zenodo.org/record/1236437. 
  33. ↑ "2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia". Arthritis Care & Research 64 (10): 1431–46. October 2012. doi:10.1002/acr.21772. PMID 23024028. 
  34. ↑ "CPIC". 27 November 2023. https://cpicpgx.org/. 
  35. ↑ "Annotation of CPIC Guideline for allopurinol and HLA-B". PharmGKB. http://www.pharmgkb.org/guideline/PA166105003. 
  36. ↑ "Clinical Pharmacogenetics Implementation Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing". Clinical Pharmacology and Therapeutics 93 (2): 153–8. February 2013. doi:10.1038/clpt.2012.209. PMID 23232549. 
  37. ↑ "Potential Purine Antagonists. I. Synthesis of Some 4,6-Substituted Pyrazolo [3,4-d] pyrimidines". Journal of the American Chemical Society 78 (4): 784–790. February 1956. doi:10.1021/ja01585a023. 
  38. ↑ 38.0 38.1 Drug Discovery: A History.. John Wiley & Sons. 2005. p. 254. ISBN 9780471899792. https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA254. 
  39. ↑ "The purine path to chemotherapy". Science 244 (4900): 41–7. April 1989. doi:10.1126/science.2649979. PMID 2649979. Bibcode: 1989Sci...244...41E. 
  40. ↑ "FDA Approved Drug Products". Drugs@FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. 
  41. ↑ "Search Results for Allopurinol". DailyMed. http://dailymed.nlm.nih.gov/dailymed/search.cfm?startswith=Allopurinol&x=0&y=0. 

Further reading

External links



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