Allopurinol Systematic (IUPAC) name 1H-pyrazolo[3,4-d]pyrimidin-4(2H)-one Clinical data Trade names Lopurin, Zyloprim AHFS/Drugs.com MedlinePlus Pregnancy cat. C(USA) Legal status ℞-only (US) Routes tablet (100, 300 mg) Pharmacokinetic data Bioavailability 78±20% Protein binding Negligible Metabolism hepatic (80% oxypurinol, 10% allopurinol ribosides) Half-life 2 hours (oxypurinol 18-30 hours) Identifiers CAS number ATC code M04 PubChem DrugBank ChemSpider UNII KEGG ChEBI ChEMBL Chemical data Formula C5H4N4O Mol. mass 136.112 g/mol SMILES & (what is this?)
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, which are converted to closely related purine ribotides adenosine and guanosine monophosphates. Increased levels of these ribotides causes feedback inhibition of amidophosphoribosyl transferase, the first and rate-limiting enzyme of purine biosynthesis. Allopurinol, therefore, decreases both uric acid formation and purine synthesis.
The primary use of allopurinol is to treat hyperuricemia (excess uric acid in blood plasma) and its complications. Allopurinol does not alleviate acute attacks of gout, but is useful in chronic gout to prevent future attacks. Likewise, allopurinol commonly is used as prophylaxis with chemotherapeutic treatments (Ex: mercaptopurine and thioguanine), which can rapidly produce severe hyperuricemia. Other established indications for allopurinol therapy include ischemic reperfusion injury, kidney stones with a uric acid component (uric acid nephrolithiasis), and protozoal infections (Leishmaniasis).
Because allopurinol is not a uricosuric, it can be used in patients with poor kidney function. However, allopurinol has two important disadvantages: Its dosing is complex, and some patients will be hypersensitive to it. Therefore, use of this drug requires careful monitoring.
Allopurinol can be used in patients with poor kidney function, but it may also help them. 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."
Allopurinol is rapidly metabolized by its target, xanthine oxidase, to its active metabolite 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 to be responsible for the majority of allopurinol's effect.
Side-effects of allopurinol are rare, though significant when they occur. A small percentage of people develop a rash and must discontinue this drug. 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.
Study finds HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions which includes Steven Johnson Syndrome and toxic epidermal necrosis caused by allopurinol.
It is suspected to cause congenital malformations when used during pregnancy, and should be avoided whenever possible by women trying to conceive.
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.
- ^ 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. doi:10.1124/pr.58.1.6. PMC 2233605. PMID 16507884. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2233605.
- ^ 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. doi:10.1111/j.1525-139X.2007.00270.x. PMID 17897242.
- ^ Goicoechea, M.; De Vinuesa, S. G.; Verdalles, U.; Ruiz-Caro, C.; Ampuero, J.; Rincon, A.; Arroyo, D.; Luno, 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. doi:10.2215/CJN.01580210. PMC 2924417. PMID 20538833. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2924417.
- ^ Gout drug 'can prevent angina pain of heart disease', BBC News
- ^ Hung, SI; Chung, WH; Liou, LB; Chu, CC; Lin, M; Huang, HP; Lin, YL; Lan, JL et al. (2005). "HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol". Proceedings of the National Academy of Sciences of the United States of America 102 (11): 4134–9. doi:10.1073/pnas.0409500102. PMC 554812. PMID 15743917. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=554812.
- ^ 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 summary – Journal Watch (September 3, 2008).
- ^ 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.
- ^ http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
- ^ http://dailymed.nlm.nih.gov/dailymed/search.cfm?startswith=Allopurinol&x=0&y=0
- 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 et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=554812.
- Zyloprim (patient information)
Antigout preparations (M04) Uricosurics Xanthine oxidase inhibitors Mitotic inhibitors Other
anat(h/c, u, t, l)/phys
noco(arth/defr/back/soft)/cong, sysi/epon, injr
proc, drug(M01C, M4)
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