Gout Center

Uric Acid

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Allopurinol inhibits xanthine oxidase, the enzyme that catalyzes the conversion of hypoxanthine to xanthine and of xanthine to uric acid. Oxypurinol, a metabolite of allopurinol, also inhibits xanthine oxidase. By inhibiting xanthine oxidase, allopurinol and its metabolite block conversion of the oxypurines (hypoxanthine and xanthine) to uric acid, thus decreasing serum and urine concentrations of uric acid. The drug differs, therefore, from uricosuric agents which lower serum urate concentrations by promoting urinary excretion of uric acid. Xanthine oxidase concentrations are not altered by long-term administration of the drug.

Accompanying the decrease in uric acid produced by allopurinol is an increase in serum and urine concentrations of hypoxanthine and xanthine. Plasma concentrations of these oxypurines do not, however, rise commensurately with the fall in serum urate concentrations and are often 20—30% less than would be expected in view of urate concentrations prior to allopurinol therapy. This discrepancy occurs because renal clearance of the oxypurines is at least 10 times greater than that of uric acid. In addition, normal urinary purine output is almost exclusively uric acid, but after treatment with allopurinol, it is composed of uric acid, xanthine, and hypoxanthine, each having independent solubility. Thus, the risk of crystalluria is reduced. Alkalinization of the urine increases the solubility of the purines, further minimizing the risk of crystalluria. Decreased tubular transport of uric acid also results in increased renal reabsorption of calcium and decreased calcium excretion.

Allopurinol also interferes with de novo pyrimidine nucleotide synthesis by inhibiting orotidine 5-phosphate decarboxylase. Secondary orotic aciduria and orotidinuria result. Orotic acid is highly insoluble and could form a heavy sediment of urinary crystals; however, the increased excretion of orotic acid and orotidine rarely exceeds 10% of the total pyrimidines synthesized by the body. In addition, enhanced conversion of uridine to uridine 5-monophosphate usually occurs and, therefore, this partial inhibition of pyrimidine synthesis is considered innocuous.

In rats, allopurinol reportedly increases liver storage of iron by inhibiting the ferritin-xanthine oxidase system responsible for mobilization of iron from the liver; however, this effect has not been demonstrated clinically.

Allopurinol may also inhibit hepatic microsomal enzymes. Allopurinol is not cytotoxic and has no effect on transplantable tumors. The drug has no analgesic, anti-inflammatory, or uricosuric activity.

Drug Profile from Medscape Drug Info

Allopurinol is used to lower serum and urinary uric acid concentrations in the management of primary and secondary gout. The drug is indicated in patients with frequent disabling attacks of gout.  Because therapy with allopurinol is not without  risks, the drug is not recommended for the management of asymptomatic hyperuricemia.  Some clinicians have suggested that therapy should be initiated when serum urate concentrations exceed 9 mg/dL because these concentrations are often associated with increased joint changes and renal complications. 

Allopurinol is used for the management of gout when uricosurics cannot be used because of adverse effects, allergy, or inadequate response; when there are visible tophi or radiographic evidence of uric acid deposits and stones; or when serum urate concentrations are greater than 8.5—9 mg/dL and a family history of tophi and low urate excretion exists.  Allopurinol is also used for the management of primary or secondary gouty nephropathy with or without secondary oliguria. The goal of therapy is to lower serum urate concentration to about 6 mg/dL. Allopurinol will often promote resolution of tophi and uric acid crystals by decreasing serum urate concentrations. 

Dosage of allopurinol varies with the severity of the disease and should be adjusted according to the response and tolerance of the patient. To reduce the possibility of flare-up of acute gouty attacks, the manufacturers recommend that patients be started on allopurinol dosages of 100 mg daily and that the daily dose of the drug be increased by 100 mg at weekly intervals until the serum urate concentration falls to 6 mg/dL or less, or until the maximum recommended dosage of 800 mg daily is reached. 

In the management of mild gout, the usual adult dosage may range from 200—300 mg daily and, for moderately severe tophaceous gout, from 400—600 mg daily. Serum urate concentrations are often reduced more slowly with allopurinol than with uricosuric drugs and minimum concentrations may not be reached for 1—3 weeks. 

After serum urate concentrations are controlled, it may be possible to reduce dosage; the average adult maintenance dosage is 300 mg daily and the minimum effective dosage is 100—200 mg daily. Allopurinol therapy should be continued indefinitely; irregular dosage schedules may lead to increased serum urate concentrations.

When allopurinol is added to a therapeutic regimen of colchicine, uricosuric agents, and/or anti-inflammatory agents, a transition period of several months may be necessary before the latter drugs can be discontinued. During this period, the drugs should be administered concomitantly, and allopurinol dosage should be adjusted until serum urate concentrations are normal and freedom from acute gouty attacks is maintained for several months. When the uricosuric agent is being withdrawn, dosage of the uricosuric agent should be gradually reduced over several weeks.

The most common adverse effect of allopurinol is a pruritic maculopapular rash. Dermatitides of the exfoliative, urticarial, erythematous, hemorrhagic, and purpuric types have also occurred. Alopecia, fever, and malaise may also occur alone or in conjunction with dermatitis. In addition, severe furunculoses of the nose, ichthyosis, and Stevens-Johnson syndrome have been reported. The incidence of rash may be increased in patients with renal insufficiency. Skin reactions may be delayed and have been reported to occur as long as 2 years after initiating allopurinol therapy. Rarely, skin rash may be followed by severe hypersensitivity reactions which may sometimes be fatal.  Some patients who have developed severe dermatitis have also developed cataracts, but the exact relationship between allopurinol and cataracts has not been established. Pruritus, onycholysis, and lichen planus have also occurred rarely inpatients receiving allopurinol. Facial edema, sweating, and skin edema have also occurred rarely, but a causal relationship to the drug has not been established.

Hypersensitivity reactions to allopurinol have been reported rarely. These reactions are characterized by fever, chills, leukopenia or leukocytosis, eosinophilia, arthralgia, rash, pruritus, nausea, and vomiting.

Serious and fatal cases of toxic epidermal necrolysis, hypersensitivity angiitis, and allergic vasculitis involving erythematous maculopapular rash with desquamation, severe exfoliative dermatitis, arterial nephrosclerosis, oliguria, congestive heart failure, and acute onset of permanent deafness have also been reported during therapy with the drug. 

Allopurinol-induced hepatotoxicity may also be a hypersensitivity reaction to the drug. A generalized hypersensitivity vasculitis has rarely led to irreversible hepatotoxicity and death. The frequency of allopurinol-induced hypersensitivity reactions may be increased in patients with decreased renal function who receive allopurinol and a thiazide diuretic concomitantly. Allopurinol should usually not be administered to patients who have previously shown hypersensitivity to it or who have had a serious reaction to the drug.