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Difficult Gout

Robert Terkeltaub, MD  |  Issue: July 2007  |  July 1, 2007

Table 2: Pharmacology of Allopurinol in the Clinic

 

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  • Allopurinol is a pro-drug for oxypurinol;
  • Oxypurinol does not effectively inhibit the oxidized form of xanthine oxidase;
  • Renal elimination of oxypurinol complicates dosing with renal insufficiency;
  • Allopurinol nonselectively affects purine and pyrimidine metabolism;
  • Drug interactions may occur (e.g., with azathioprine or ampicillins);
  • Hepatotoxicity and minor gastrointestinal and central nervous system side effects may occur;
  • Rash occurs in about 2% of treated patients;
  • Major allopurinol hypersensitivity syndrome is rare but has a mortality rate of approximately 20%;
  • Oxypurinol cross-reactivity with allopurinol limits oxypurinol as an alternative to allopurinol in hypersensitive patients;
  • Many patients do not achieve serum urate level less than 6 mg/dL on standard doses, and optimal dosing is controversial, particularly with renal insufficiency;
  • Tophus reduction is typically slow; and
  • Patient compliance is only about 50%, indicating a need for improved patient education.

 

Limitations of Allopurinol

Allopurinol is primarily a pro-drug that must be intestinally absorbed and then converted in the liver to the active metabolite oxypurinol. The half-life of oxypurinol is largely determined by renal elimination and is normally 24 hours. Oxypurinol accumulates in association with diminished glomerular filtration rate. Notably, severe hypersensitivity to allopurinol appears partially dose-dependent. Major allopurinol hypersensitivity syndrome associated with multi-organ system damage has a mortality rate of approximately 20%. Fortunately this problem has been uncommon (i.e., no more than 100 reported cases). Nevertheless, a drug rash—typically preceded by pruritus—occurs in about 2% of allopurinol-treated patients. Only a half of these subjects (at most) successfully resumes maintenance allopurinol after oral desensitization.

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Pharmacogenomics of severe cutaneous adverse reactions to allopurinol in Han Chinese are such that the odds ratio is 580:1 in HLA-B*5801–positive subjects.2 However, it is not known if this finding holds for other populations. Stepwise upward adjustment of starting allopurinol doses based on creatinine clearance is common and acceptable medical practice to dampen the risk of severe allopurinol hypersensitivity. Yet there is no precise method to predict or prevent allopurinol hypersensitivity in the population at large. Moreover, optimal dosing of allopurinol remains controversial—particularly in patients with chronic renal insufficiency.

Concern about precipitating major allopurinol hypersensitivity syndrome often drives practitioners to use allopurinol maintenance doses that are too low for many patients (specifically, doses less than or equal to 300 mg/day in patients with preserved renal function and 100–200 mg/day in patients with creatinine clearance less than 60 mL/min), which probably enlarges the pool of refractory gout. The reported patient compliance with maintenance allopurinol is around 50%, indicating a systematic failure of gout patient education by practitioners.

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Filed under:ConditionsGout and Crystalline Arthritis Tagged with:Diagnostic CriteriaGoutPathogenesisTreatment

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