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The preferred and standard-of-care therapy for gout during 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, is shown in Figure 36–7.
Allopurinol is approximately 80% absorbed after oral administra-tion and has a terminal serum half-life of 1–2 hours. Like uric acid, allopurinol is 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 (Figure 36–7). Allopurinol inhibits this last step, resulting in a fall in the plasma urate level and a decrease in the overall urate burden. The more soluble xanthine and hypoxanthine are increased.
Allopurinol is often the first-line agent for the treatment of chronic gout in the period between attacks and it aims to prolong the intercritical period.
As with uricosuric agents, the therapy is begun with the expectation that it will be continued for years if not for life. When initiating allopurinol, colchicine or NSAID should be used until steady-state serum uric acid is normalized or decreased to less than 6 mg/dL and they should be continued for 3-6 months or even longer if required. Thereafter, colchicine or the NSAID can be cautiously stopped while continuing allopurinol therapy. In addition to gout, allopurinol is also used as an antipro-tozoal agent and is indicated to prevent the mas-sive uricosuria following therapy of blood dyscrasias that could otherwise lead to renal calculi.
See above for prophylaxis against an acute attack during the initia-tion of allopurinol, which can occur as a result of acute changes in the serum uric acid level. Among the side effects, GI intolerance including nausea, vomiting, and diarrhea, peripheral neuritis and necrotizing vasculitis, bone marrow suppression, and rarely aplastic anemia may also occur. Hepatic toxicity and interstitial nephritis have been reported. An allergic skin reaction characterized by pru-ritic 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 purines (eg, azathioprine) are given con-comitantly 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 antico-agulants 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 should be titrated upward until serum uric acid is below 6 mg/dL; this level is com-monly achieved at 300 mg/d but is not restricted to this dose; doses as high as 800 mg/d may be needed.
As noted above, colchicine or an NSAID should be given dur-ing the first several weeks of allopurinol therapy to prevent the gouty arthritis episodes that sometimes occur.
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