Dosage: Probenecid is usually started at a dosage of 0.5 g orally daily in divided doses, progressing to 1 g daily after 1 week. Sulfinpyrazone is started at a dosage of 200 mg orally daily, progressing to 400–800 mg daily. It should be given in divided doses with food to reduce adverse GI effects.
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.
1. Chemistry and Pharmacokinetics: The structure of allopurinol, an isomer of hypoxanthine, is shown in Figure 36–7. Allopurinol is approximately 80% absorbed after oral administration and has a terminal serum half-life of 1–2 hours.
FIGURE 36–7 Inhibition of uric acid synthesis by allopurinol occurs because allopurinol and alloxanthine inhibit xanthine oxidase. (Reproduced, with permission, from Meyers FH, Jawetz E, Goldfien A: Review of Medical Pharmacology, 7th ed. McGraw-Hill, 1980. Copyright © The McGraw-Hill Companies, Inc.)
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.
2.
Pharmacodynamics: 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.
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Indications: Allopurinol is often the first-line agent for the treatment of chronic gout in the period between attacks and it tends 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 6 months or longer. Thereafter, colchicine or the NSAID can be cautiously stopped while continuing allopurinol therapy.
4.
Adverse Effects: In addition to precipitating gout (the reason to use concomitant colchicine or NSAID), GI intolerance (including nausea, vomiting, and diarrhea), peripheral neuritis and necrotizing vasculitis, bone marrow suppression, and aplastic anemia may rarely 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.
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Interactions and Cautions: When chemotherapeutic purines (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.
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