Allopurinol
The preferred and standard-of-care therapy for gout in the intercritical period (the period between acute episodes) is allopurinol, which reduces total uric acid body burden by inhibiting xanthine oxidase.
The structure of allopurinol, an isomer of hypoxanthine
Allopurinol is approximately 80% absorbed after oral administration and has a terminal serum half-life of 1–2 hours. Like uric acid, allopurinol is itself metabolized by xanthine oxidase, but the resulting compound, alloxanthine, retains the capacity to inhibit xanthine oxidase and has a long enough duration of action so that allopurinol is given only once a day.
Dietary purines are not an important source of uric acid. Quantitatively important amounts of purine are formed from amino acids, formate, and carbon dioxide in the body. Those purine ribonucleotides not incorporated into nucleic acids and derived from nucleic acid degradation are converted to xanthine or hypoxanthine and oxidized to uric acid . Allopurinol inhibits this last step, resulting in a fall in the plasma urate level and a decrease in the size of the urate pool. The more soluble xanthine and hypoxanthine are increased.
Treatment of patients in the intercritical period of gout with allopurinol, as with uricosuric agents, is begun with the expectation that it will be continued for years if not for life. Allopurinol is often the first urate-lowering drug used. When starting allopurinol, colchicine or an NSAID should also be used until steady-state serum uric acid is normalized or decreased to less than 6 mg/dL. Thereafter colchicine or the NSAID can be stopped, while allopurinol is continued. Aside from gout, allopurinol is used as an antiprotozoal agent (see Chapter 52) and is indicated to prevent the massive uricosuria following therapy of blood dyscrasias that could otherwise lead to renal calculi.
See above for protection against an acute attack during the initial use of allopurinol.Gastrointestinal intolerance, including nausea, vomiting, and diarrhea, may occur. Peripheral neuritis and necrotizing vasculitis, depression of bone marrow elements, and, rarely, aplastic anemia may also occur. Hepatic toxicity and interstitial nephritis have been reported. An allergic skin reaction characterized by pruritic maculopapular lesions occurs in 3% of patients. Isolated cases of exfoliative dermatitis have been reported. In very rare cases, allopurinol has become bound to the lens, resulting in cataracts.
When chemotherapeutic mercaptopurines (eg, azathioprine) are given concomitantly with allopurinol, their dosage must be reduced by about 75%. Allopurinol may also increase the effect of cyclophosphamide. Allopurinol inhibits the metabolism of probenecid and oral anticoagulants and may increase hepatic iron concentration. Safety in children and during pregnancy has not been established.
The initial dosage of allopurinol is 100 mg/d. It may be titrated upward until serum uric acid is below 6 mg/dL; this level is commonly achieved at 300 mg/d but is not restricted to this dose.
As noted above, colchicine or an NSAID should be given during the first weeks of allopurinol therapy to prevent the gouty arthritis episodes that sometimes occur
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