|Systematic (IUPAC) name|
|Legal status||℞-only (US)|
|Routes||tablet (100, 300 mg)|
|Metabolism||hepatic (80% oxypurinol, 10% allopurinol ribosides)|
|Half-life||2 h (oxypurinol 18-30 h)|
|Mol. mass||136.112 g/mol|
|(what is this?)|
Allopurinol (Zyloprim, and generics) is a drug used primarily to treat hyperuricemia (excess uric acid in blood plasma) and its complications, including chronic gout. 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.
- 1 Medical uses
- 2 Side-effects
- 3 Mechanism of action
- 4 History
- 5 Metabolism
- 6 Brand names
- 7 Synthesis
- 8 References
- 9 Further reading
- 10 External links
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. Allopurinol 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, 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chemotherapeutic treatments as these regimes can rapidly produce severe acute hyperuricemia, although it has gradually been replaced by urate oxidase therapy.
Allopurinol can cause severe pancytopenia if given with full-dose mercaptopurine or its pro-drug azathioprine, due to the inhibition of xanthine oxidase that metabolizes mercaptopurine. For this reason, allopurinol has been strongly contraindicated during thiopurine therapy in the past. However, in recent years the use of allopurinol in combination with azathioprine or mercaptopurine has been revived. First, it was shown that an azathioprine/allopurinol combination significantly improved renal transplant graft survival. More recently, it was discovered that this co-therapy greatly improves the outcome for patients that do not respond to thiopurine monotherapy when treating inflammatory bowel disease (IBD), specifically Crohn's disease. Co-therapy has also been shown to greatly improve hepatoxicity side effects in treatment of IBD. Co-therapy invariably requires dose reduction of the thiopurine, usually to 1/3 of the standard dose depending upon the patient's genetic status for thiopurine methyltransferase (TPMT).
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 that "Allopurinol decreases C-reactive protein and slows down the progression of renal disease in patients with chronic kidney disease. In addition, allopurinol reduces cardiovascular and hospitalization risk in these subjects."
A mechanistic study in patients with chronic heart failure has shown that 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 that a high dose (600 mg) is significantly better at improving endothelial function compared to standard doses.
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.
First, its dosing is complex. Second, some patients are hypersensitive to the drug, 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. Allopurinol is one of the drugs commonly known to cause Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TENS), two life-threatening dermatological conditions. 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.
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.
Studies have found the HLA-B*5801 allele to be a genetic marker for allopurinol-induced severe cutaneous adverse reactions, including Stevens-Johnson Syndrome and toxic epidermal necrolysis. 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% and 0.5%, respectively. The increase in risk for developing allopurinol-induced Stevens-Johnson Syndrome or toxic epidermal necrolysis 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. 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 Stevens-Johnson Syndrome and toxic epidermal necrolysis. 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. The Clinical Pharmacogenetics Implementation Consortium guidelines state that allopurinol is contraindicated in known carriers of the HLA-B*5801 allele.
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. 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. 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.
Allopurinol was first synthesized and reported in 1956 by Roland K. Robins (1926-1992), in a search for antineoplasitic agents.
Allopurinol inhibits the breakdown (catabolism) of the thiopurine drug mercaptopurine, and it was later employed 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 co-therapy, and this use of the drug was abandoned.
A common misconception is that allopurinol is metabolized by its target, xanthine oxidase, but this action is principally carried out by Aldehyde oxidase. 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.
Allopurinol has been marketed in the United States since August 19, 1966, when it was first approved by FDA under the trade name of Zyloprim. 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.
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- "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014.
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- "Gout drug 'can prevent angina pain of heart disease'". BBC News. 8 June 2010.
- Drug-Resistant Epilepsy N Engl J Med 2011; 365:2238-2240December 8, 2011
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- 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. doi:10.1002/ajmg.a.34139. PMID 21815259.
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- 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.
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- Day RO, Graham GG, Hicks M, et al. (2007). "Clinical pharmacokinetics and pharmacodynamics of allopurinol and oxypurinol". Clin Pharmacokinet. 46 (8): 623–644. doi:10.2165/00003088-200746080-00001. PMID 17655371.
- 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): 373–388. ISSN 1110-0303.
- Hung, Shuen-Iu; Chung, Wen-Hung; Liou, Lieh-Bang; Chu, Chen-Chung; Lin, Marie; Huang, Hsien-Ping; Lin, Yen-Ling; 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): 4134–9. doi:10.1073/pnas.0409500102. PMC 554812. PMID 15743917.
- The Third International Thiopurine Symposium 2010, published in RAMB, for information on Allopurinol co-therapy: 
- Zyloprim (patient information)
- Allopurinol pathway on PharmGKB
- Very Important Pharmacogene summary for HLA-B on PharmGKB