Allopurinol


Allopurinol (4 hydroxypyrazolol (3.4-d) pyramidine) is the drug most commonly prescribed for the treatment of hyperuricemia.
 
Incidence
2% of users develop a mild cutaneous rash.
 
Severe reaction: 1/260.
 
Allopurinol hypersensitivity syndrome: 100 cases described in the literature (1993)
 
Mortality: 27% (allopurinol hypersensitivity syndrome).
 
Risk factors
Impaired renal excretion.
 
Thiazide diuretics (co-administration).
 
Clinical manifestations
(developing days or weeks after initiation of treatment)
 
Criteria for diagnosis:
  1. Clear exposure to allopurinol.
     
  2. Clinical picture including:

    a) at least 2 of the major criteria

    - worsening renal function (84%)

    - acute hepatocellular injury (88%)

    - rash (93.1%): toxic epidermal necrolysis (25.7%) erythema multiforme (8.9%), diffuse maculopapular rash (53.5%), exfoliative dermatitis (20.8%)

    OR

    b) one of the major criteria + at least one of the minor criteria fever (95%)

    - eosinophilia (60%)

    - leukocytosis (40%)

    AND
     
  3. Lack of exposure to another drug which may have caused similar clinical manifestations.
Diagnostic methods
Skin-biopsy: granular deposits of IgM at the dermal-epidermal junction.
 
Liver-biopsy: T lymphocyte infiltration, granulomas, focal necrosis of hepatocytes.
 
Renal-biopsy: linear deposits of IgG and complement along the glomerule basement membrane; C3 deposits along tubular basal membrane, mesangium and arterioles.
 
Lymphocyte stimulation test: positive with oxypurinol but not allopurinol in 3 patients with allopurinol hypersensitivity syndrome.
 
Mechanisms
  1. Allopurinol accumulation.

    The risk of development of allopurinol hypersensitivity syndrome is related to the level of oxypurinol (metabolite of allopurinol).

    The accumulation of oxypurinol leads to tissue damage with development of antibodies against tissue components and formation of immune complexes.

  2. Type IV hypersensitivity reactions.

    T cell-mediated immune reaction could be involved in the pathogenesis of allopurinol hypersensitivity syndrome.

  3. Type III hypersensitivity reactions.

    Generalized vasculitis (formation of immune complexes that precipitate in the vascular endothelium and lead to complement activation and development of inflammatory reactions in and around arteriolar walls).

    Consumption of complement, circulating immune complexes and deposition of antibodies in different organs.
Management
Asymptomatic hyperuricemia is not an indication of allopurinol prescription.
 
Allopurinol dose must be adjusted to renal function.
 
Allopurinol should only be prescribed in good indications:
  • primary gout with tophi or uric acid stones (over production)
     
  • uric acid stones or calcium oxalate stones without gout combined with increased urinary excretion of urate
     
  • secondary renal gout with tophi
     
  • myeloproliferative diseases or other malignancies
     
  • high frequency of attacks despite colchicine prophylaxis
     
  • intolerance to uricosuric agents
     
  • Lesch-Nyhan syndrome
     
  • Von Gierke disease
Desensitization
  1. Fixed drug eruption (50 mg of allopurinol powder dissolved in 500 ml of distilled water with 14/1000 sodium bicarbonate)

    Day 1: 10 µg, 20 µg, 30 µg Day 2: 40 µg, 50 µg, 60 µg

    Day 3: 70 µg, 80 µg, 90 µg Day 4: 100 µg, 200 µg, 400 µg

    Day 5: 600 µg, 800 µg, 1mg Day 6: 2 mg, 4 mg, 8 mg

    Day 7: 16 mg, 25 mg, 35 mg Day 8: 50 mg

    Day 9: 75 mg Day 10: 100 mg

    Day 11: 125 mg Day 12: 150 mg

    Day 13: 175 mg Day 14: 200 mg

    Day 15: 250 mg Day 16: 300 mg
     
  2. Oral desensitization in minor rashes (renal insufficiency, chronic tophaceous gouty arthritis)

    Day 1 to 3: 50 µg Day 4 to 6: 100 µg

    Day 7 to 9: 200 µg Day 10 to 12: 500 µg

    Day 13 to 15: 1 mg Day 16 to 18: 5 mg

    Day 19 to 21: 10 mg Day 22 to 24: 25mg

    Day 25 to 27: 50 mg Day 28 and nexts: 100 mg
     
  3. Intravenous desensitization (when oral desensitization fails; in less than 12 hours)

    - 0.1 µg, 1 µg, 10 µg, 50 µg, 100 µg, 500 µg at 15 minute intervals

    - 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 50 mg, 100 mg at 30 minute intervals

    Desensitization can give life-threatening reactions.

References

  1. Pluim H.J, Van Deuren M, Wetzels J.F, "The allopurinol hypersensitivity syndrome", Neth. J. Med., 1998; 52 (3): 107-10
  2. Umpierrez A, Cuesta-Herranz J, de las Heras M, Lluch-Bernal M, Figueredo E, Sastre J, "Successful desensitization of a fixed drug eruption caused by allopurinol", J. Allergy. Clin. Immunol., 1998; 101 (2.1): 286-7
  3. Hamanaka H, Mizutani H, Nouchi N, Shimizu Y, Shimizu M, "Allopurinol hypersensitivity syndrome: hypersensitivity to oxypurinol but not allopurinol", Clin. Exp. Dermatol., 1998; 23 (1): 32-4
  4. Braden G.L, Warzynski M.J, Golightly M, Ballow M, "Cell-mediated immunity in allopurinol-induced hypersensitivity", Clin. Immunol. Immunopathol., 1994; 70 (2): 145-51
  5. Arellano F, Sacristan J.A, "Allopurinol hypersensitivity syndrome: a review", Ann. Pharmacother., 1993; 27 (3): 337-43 
  6. Kelsey S.M, Struthers G.R, Beswick T, Blake D.R, "Desensitisation to allopurinol", Ann. Rheum. Dis., 1987; 46 (1): 84

As in all diagnostic testing, the diagnosis is made by the physican based on both test results and the patient history.