Allopurinol

• Gout
• Hyperuricemia
• Kidney Stones (uric acid or calcium oxalate)
• Tumor Lysis Syndrome Prevention

Allopurinol is a xanthine oxidase inhibitor used primarily for the management of gout and hyperuricemia. This medication works by reducing the body's production of uric acid, helping to prevent gout attacks and complications associated with elevated uric acid levels.

Mechanism of Action

Allopurinol and its active metabolite oxypurinol (also called alloxanthine) work by inhibiting xanthine oxidase, the enzyme responsible for the final two steps in uric acid synthesis: the conversion of hypoxanthine to xanthine and xanthine to uric acid. By blocking this enzyme, allopurinol reduces serum and urinary uric acid concentrations. Unlike uricosuric agents that increase uric acid excretion, allopurinol decreases uric acid production, making it effective regardless of renal function. The reduction in serum urate levels eventually leads to dissolution of existing urate crystal deposits, though this process takes months to years.

Available Formulations

Allopurinol is available as oral tablets in 100 mg and 300 mg strengths. Generic formulations are widely available and cost-effective. The tablets can be taken with food to minimize gastrointestinal upset. An intravenous formulation is available for patients unable to take oral medications, typically used in the prevention or treatment of tumor lysis syndrome.

Medical Uses

Allopurinol is indicated for the management of gout, including acute gouty arthritis prevention, tophi reduction, and prevention of urate nephropathy. It is also used for managing hyperuricemia secondary to cancer treatment (tumor lysis syndrome) and for recurrent calcium oxalate kidney stones with hyperuricosuria. Off-label uses include prevention of ischemia-reperfusion injury and treatment of certain metabolic disorders. Treatment goals in gout typically aim for serum urate levels below 6 mg/dL, or below 5 mg/dL in patients with tophi.

Dosing Guidelines

The initial recommended dose for gout is 100 mg daily, with gradual increases of 100 mg at weekly intervals until serum urate targets are achieved or the maximum dose of 800 mg daily is reached. Most patients achieve target levels with 300-600 mg daily. For patients with renal impairment, lower starting doses (50-100 mg) and slower titration are recommended. The daily dose may be taken once daily or divided into multiple doses. Doses greater than 300 mg should be divided. Adequate hydration is important to prevent xanthine stone formation during initial therapy.

Important Safety Information

Allopurinol can cause severe hypersensitivity reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be fatal. The HLA-B*5801 allele is strongly associated with severe cutaneous adverse reactions, particularly in patients of Han Chinese, Thai, and Korean ancestry. Screening for this allele is recommended before initiating therapy in high-risk populations. Allopurinol should be discontinued at the first sign of rash or hypersensitivity and should not be restarted. Acute gout attacks may increase during the initial weeks of therapy; prophylactic colchicine or NSAIDs should be considered.

Drug Interactions

Allopurinol significantly increases the toxicity of azathioprine and mercaptopurine by inhibiting their metabolism; doses of these medications must be reduced by 50-75% when used concurrently. The combination with ampicillin or amoxicillin increases the risk of rash. Allopurinol may enhance the anticoagulant effect of warfarin. ACE inhibitors may increase the risk of hypersensitivity reactions. Thiazide diuretics may increase the risk of allopurinol hypersensitivity and may also contribute to hyperuricemia.

Choosing Urate-Lowering Therapy and Treating to Target

Not every raised uric acid level needs allopurinol. Urate-lowering therapy is started when gout has declared itself as a recurring problem — repeated flares, a tophus, joint damage visible on imaging, or uric acid renal calculi (kidney stones) — rather than on the basis of a single high laboratory value in someone who has never had an attack. Once that threshold is crossed the choice is usually allopurinol, because it lowers urate whether the underlying problem is overproduction or underexcretion, it can be used across a wide range of kidney function, and it has the longest track record of the available agents.

What separates a successful course from an abandoned one is treating to a measured target rather than to a fixed tablet. The dose is raised in steps and the serum urate rechecked after each step until the target described above is reached and held; a patient left indefinitely on the starting dose is common, and it is the most frequent reason the drug appears not to work. Crystals that took years to deposit dissolve over months to years, so tophi shrink slowly and the value of continuing is not obvious from one week to the next. Treatment is intended to be long term, and urate rebounds within weeks of stopping.

What the First Months Feel Like

Flares often increase when allopurinol is started, because falling urate levels mobilize deposits that were already there. This is expected, it is not an allergy, and it is not a reason to stop — but it is disheartening if nobody warns the patient first, so anti-inflammatory prophylaxis with low-dose colchicine or an NSAID is usually prescribed alongside the early months of therapy and continued until urate has been stable and flares have settled. If a flare happens anyway, allopurinol is continued through it and the flare is treated separately.

Two other things derail the first months. One is a rash: any new rash after starting allopurinol is reported the same day, because the serious skin reactions described above begin this way and the drug is not restarted afterward. The other is diet. Patients often expect food restriction to do the work, when the larger gains usually come from reducing alcohol, losing weight, and revisiting a blood pressure medication or diuretic that is pushing urate up. Our musculoskeletal team reviews that medication list at the first visit. The MedlinePlus allopurinol monograph and the NIAMS overview of gout set out the same expectations in patient terms, and our article on gout as a misunderstood and rising form of arthritis covers why cases are increasing locally.

Special Populations

Allopurinol should be used during pregnancy only if clearly needed, as adequate human studies are lacking. The medication is excreted in breast milk; caution should be exercised when administering to nursing mothers. Safety and efficacy have not been established in pediatric patients except for those with hyperuricemia secondary to malignancy. Elderly patients may require lower doses due to age-related decreases in renal function. Dose reduction is required in patients with renal impairment; starting doses of 50-100 mg daily are recommended, with careful titration based on serum urate response and tolerability.