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Xanthine oxidase inhibitor

Allopurinol

Allopurinol is a xanthine oxidase inhibitor used primarily for chronic management of gout and prevention of tumor lysis syndrome. Unlike uricosuric agents, it reduces uric acid production rather than increasing renal excretion. The most high-yield fact: allopurinol can precipitate acute gout flares when initiated, so prophylactic colchicine or NSAIDs should be co-administered during the first months of therapy.

Practice questionsHigh-yield facts
Drug classXanthine oxidase inhibitor
MechanismInhibits xanthine oxidase, reducing uric acid synthesis
Main usesChronic gout prophylaxis, tumor lysis syndrome prevention
Key adverse effectAllopurinol hypersensitivity syndrome (DRESS), acute gout flares
5 min readFor medical studentsUpdated 2026-10-14

Mechanism of action

Allopurinol is a purine analog that inhibits xanthine oxidase, the enzyme responsible for converting hypoxanthine to xanthine and xanthine to uric acid. By blocking this final step in purine metabolism, allopurinol reduces serum and urinary uric acid levels.

Allopurinol itself is rapidly metabolized to oxypurinol (alloxanthine), which is also a xanthine oxidase inhibitor and has a much longer half-life than the parent drug. Oxypurinol is responsible for most of the sustained therapeutic effect.

The result is decreased production of uric acid, lower serum urate concentrations, and reduced deposition of urate crystals in joints and soft tissues. Unlike uricosuric agents such as probenecid, allopurinol does not increase urinary uric acid excretion, making it safer in patients with uric acid nephrolithiasis or chronic kidney disease.

High-yield for exams
  • Allopurinol inhibits xanthine oxidase, reducing uric acid production; its active metabolite is oxypurinol with a long half-life.
  • Always co-prescribe colchicine or NSAID prophylaxis for 3-6 months when starting allopurinol to prevent acute gout flares.
  • HLA-B*5801 allele strongly predicts allopurinol hypersensitivity syndrome (DRESS) in Han Chinese, Thai, and Korean patients.
  • Allopurinol increases toxicity of azathioprine and mercaptopurine by 3-4 fold; reduce immunosuppressant dose by 65-75% if co-administered.
  • Do not start allopurinol during an acute gout attack, but do not stop it if the patient is already on chronic therapy.
  • Allopurinol hypersensitivity syndrome presents with fever, rash (SJS/TEN), eosinophilia, hepatitis, and renal failure; mortality is 20-25%.
  • Dose adjustment required in renal impairment; oxypurinol accumulates and increases toxicity risk.
  • First-line urate-lowering therapy for chronic gout; target serum urate <6 mg/dL, or <5 mg/dL in severe tophaceous disease.

Indications

Allopurinol is indicated for:

  • Chronic tophaceous gout: First-line urate-lowering therapy for patients with recurrent gout attacks, tophi, or chronic gouty arthropathy
  • Asymptomatic hyperuricemia with high uric acid levels: Particularly when associated with frequent gout flares, urate nephropathy, or uric acid nephrolithiasis
  • Prevention of tumor lysis syndrome: In patients with hematologic malignancies (leukemia, lymphoma) undergoing chemotherapy; started before cytotoxic therapy
  • Recurrent calcium oxalate nephrolithiasis: In patients with hyperuricosuria
  • Secondary hyperuricemia: Due to chemotherapy, myeloproliferative disorders, or psoriasis

Allopurinol is not used for acute gout attacks and may worsen an acute flare if started during an attack. Acute gout is treated with NSAIDs, colchicine, or corticosteroids.

Pharmacokinetics

Absorption: Well absorbed orally, with peak plasma levels in 1.5 hours for allopurinol and 4-6 hours for its active metabolite oxypurinol.

Distribution: Allopurinol and oxypurinol are widely distributed. Neither binds significantly to plasma proteins.

Metabolism: Allopurinol is rapidly metabolized in the liver to oxypurinol by xanthine oxidase and aldehyde oxidase. Oxypurinol is the main active metabolite and has a half-life of 18-30 hours, allowing once-daily dosing.

Excretion: Primarily renal. Oxypurinol is excreted unchanged in urine. In patients with renal impairment, dose adjustment is required to prevent accumulation and toxicity.

Adverse effects

Common adverse effects

  • Acute gout flares: Paradoxical worsening during initiation (up to 25% of patients) due to mobilization of urate deposits; prevented with prophylactic colchicine or NSAIDs for 3-6 months
  • Gastrointestinal symptoms: Nausea, diarrhea, dyspepsia
  • Rash: Maculopapular rash in 2-5% of patients; may be benign but requires careful monitoring for progression

Serious adverse effects

  • Allopurinol hypersensitivity syndrome (AHS): Also called DRESS (drug reaction with eosinophilia and systemic symptoms); presents with fever, rash (including Stevens-Johnson syndrome or toxic epidermal necrolysis), eosinophilia, hepatitis, and acute kidney injury. Mortality is 20-25%. Strongly associated with HLA-B*5801 allele, especially in patients of Han Chinese, Thai, or Korean descent. The syndrome typically occurs within the first 2 months of therapy.
  • Stevens-Johnson syndrome/Toxic epidermal necrolysis (SJS/TEN): Life-threatening mucocutaneous reactions
  • Hepatotoxicity: Elevated liver enzymes, hepatitis
  • Bone marrow suppression: Leukopenia, thrombocytopenia, aplastic anemia (rare)

Other adverse effects

  • Xanthine nephropathy (rare): Xanthine stones may form when uric acid is markedly reduced
  • Drowsiness, headache

Contraindications and warnings

Absolute contraindications

  • Hypersensitivity to allopurinol or any component
  • Use during an acute gout attack (relative; should not be started during flare but can be continued if already on therapy)

Warnings and precautions

  • HLA-B*5801 screening: Recommended before initiating allopurinol in patients of Han Chinese, Thai, Korean, or African American descent due to increased risk of severe cutaneous reactions
  • Renal impairment: Dose reduction required. Start at lower doses and titrate slowly. Risk of hypersensitivity reactions increases with impaired clearance.
  • Hepatic impairment: Use with caution; monitor liver function
  • Pregnancy: Category C. Use only if clearly needed; risk-benefit assessment required
  • Rash: Any rash should prompt immediate discontinuation and evaluation, as it may be the first sign of hypersensitivity syndrome
  • Acute gout prophylaxis: Co-prescribe colchicine or an NSAID for at least 6 months when starting allopurinol to prevent flares
  • Hydration: Maintain adequate fluid intake to reduce risk of xanthine stone formation

Drug interactions

Major interactions

  • Azathioprine and mercaptopurine: Allopurinol inhibits xanthine oxidase, which metabolizes these immunosuppressants. This leads to 3-4 fold increases in levels and severe bone marrow toxicity. If co-administration is necessary, reduce azathioprine/mercaptopurine dose by 65-75%.
  • Warfarin: Allopurinol may potentiate anticoagulant effects; monitor INR closely
  • Ampicillin/amoxicillin: Increased incidence of rash when combined with allopurinol (up to 20%)
  • Cyclophosphamide: Enhanced myelosuppressive effects

Moderate interactions

  • Thiazide diuretics: Increase risk of allopurinol hypersensitivity reactions, especially in renal impairment
  • ACE inhibitors: Possible increased risk of hypersensitivity reactions
  • Aluminum hydroxide antacids: Decrease allopurinol absorption; separate administration
  • Theophylline: Allopurinol inhibits metabolism, increasing theophylline levels; monitor and adjust dose

Other interactions

  • Uricosuric agents (probenecid): Increase renal excretion of oxypurinol, potentially reducing allopurinol efficacy, but combination may be used in refractory cases

Clinical pearls

  • Start low, go slow: Initiate at low doses and titrate every 2-4 weeks to reach target serum urate <6 mg/dL. This approach reduces acute flare risk.
  • Do not stop during a flare: If a patient on chronic allopurinol develops acute gout, continue the drug and treat the acute attack separately. Stopping allopurinol causes urate fluctuations that prolong the attack.
  • Always provide flare prophylaxis: Prophylactic colchicine or an NSAID should be given during the first 3-6 months of allopurinol therapy.
  • HLA-B*5801 testing: Cost-effective in high-risk populations (Asian descent). Positive result is a contraindication to allopurinol; consider febuxostat instead.
  • Tumor lysis syndrome: Start allopurinol 1-2 days before chemotherapy. Rasburicase is preferred for very high-risk patients because it works faster.
  • Allopurinol vs febuxostat: Allopurinol is first-line due to lower cost and longer safety record. Febuxostat is reserved for allopurinol-intolerant patients or those with renal impairment (febuxostat does not require dose adjustment in mild-moderate CKD).
  • Monitor serum urate: Target is <6 mg/dL (360 µmol/L); in severe tophaceous gout, target <5 mg/dL.
  • Discontinue immediately for rash: Any cutaneous reaction requires stopping allopurinol and assessing for hypersensitivity syndrome. Do not rechallenge.
  • Check renal function: Baseline and periodic monitoring; adjust dose for creatinine clearance <60 mL/min.
  • Xanthine stones: Rare complication when uric acid is drastically reduced and xanthine accumulates; ensure adequate hydration and consider urine alkalinization in high-risk patients.

Practice questions

1. A 58-year-old man with chronic tophaceous gout and stage 3 chronic kidney disease is started on allopurinol 100 mg daily along with colchicine prophylaxis. He is also taking azathioprine for inflammatory bowel disease. Two weeks later, he develops fever, sore throat, and petechiae. Laboratory studies show hemoglobin 8.2 g/dL, WBC 1,800/µL, and platelets 45,000/µL. Which of the following best explains this presentation?

Answer: C. Allopurinol inhibits xanthine oxidase, which normally metabolizes azathioprine. This causes a 3-4 fold increase in azathioprine levels, leading to severe myelosuppression. The azathioprine dose must be reduced by 65-75% when co-administered with allopurinol. Allopurinol hypersensitivity syndrome typically presents with rash, eosinophilia, and organ involvement. Colchicine toxicity usually causes diarrhea before bone marrow suppression.

2. A 62-year-old woman of Han Chinese descent with recurrent gout is being considered for allopurinol therapy. She has a history of two gout attacks in the past year and a serum urate level of 9.2 mg/dL. She has no known drug allergies. Which of the following is the most appropriate next step before starting allopurinol?

Answer: B. HLA-B*5801 testing is recommended before starting allopurinol in patients of Han Chinese, Thai, Korean, and Southeast Asian descent due to significantly increased risk of allopurinol hypersensitivity syndrome (DRESS) in carriers. A positive test is a contraindication to allopurinol, and febuxostat should be used instead. Starting allopurinol without testing in this population carries unacceptable risk of life-threatening cutaneous reactions.

3. A 55-year-old man with newly diagnosed acute myeloid leukemia is scheduled to begin induction chemotherapy in 48 hours. His laboratory studies show WBC 85,000/µL, uric acid 11.5 mg/dL, creatinine 1.1 mg/dL, potassium 4.2 mEq/L, and phosphate 4.5 mg/dL. Which of the following is the most appropriate management to prevent tumor lysis syndrome?

Answer: C. This patient has severe pre-existing hyperuricemia (11.5 mg/dL) with high tumor burden (WBC 85,000/µL), indicating laboratory tumor lysis syndrome and very high risk. Rasburicase is the drug of choice because it rapidly degrades existing uric acid via urate oxidase, whereas allopurinol only blocks new synthesis and would not clear the 11.5 mg/dL fast enough. Allopurinol is appropriate for prevention in patients without severe baseline hyperuricemia, but rasburicase is preferred for high-risk patients with established hyperuricemia.

Frequently asked questions

How does allopurinol work?

Allopurinol inhibits xanthine oxidase, the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid. By blocking this final step in purine metabolism, allopurinol reduces uric acid production and lowers serum urate levels. Its active metabolite, oxypurinol, provides prolonged xanthine oxidase inhibition with a half-life of 18-30 hours, allowing once-daily dosing.

What are the side effects of allopurinol?

Common side effects include acute gout flares during initiation, nausea, and rash. The most serious adverse effect is allopurinol hypersensitivity syndrome (DRESS), which presents with fever, severe rash (Stevens-Johnson syndrome or toxic epidermal necrolysis), eosinophilia, hepatitis, and kidney injury, with 20-25% mortality. This risk is highest in patients with the HLA-B*5801 allele. Other serious effects include bone marrow suppression and hepatotoxicity.

Can I take allopurinol during a gout attack?

You should not start allopurinol during an acute gout attack, as initiating urate-lowering therapy can worsen or prolong the flare. However, if you are already on chronic allopurinol therapy when an acute attack occurs, you should continue taking it and treat the acute attack separately with NSAIDs, colchicine, or corticosteroids. Stopping allopurinol causes urate level fluctuations that can prolong the attack.

Allopurinol vs febuxostat — what is the difference?

Both are xanthine oxidase inhibitors used for chronic gout, but allopurinol is first-line due to lower cost and a longer safety record. Febuxostat is reserved for patients who are intolerant to allopurinol or have moderate renal impairment, as febuxostat does not require dose adjustment in CKD (while allopurinol does). Febuxostat may have a slightly higher cardiovascular risk based on some studies, though this remains debated.

Why do I need to take colchicine with allopurinol?

When allopurinol is first started, it lowers serum uric acid levels, which can mobilize urate crystals from tissue deposits and trigger acute gout flares in up to 25% of patients. Prophylactic colchicine or an NSAID for the first 3-6 months of therapy prevents these flares. Once urate levels stabilize and crystal deposits dissolve, prophylaxis can be discontinued.

Conditions it is used for

GoutHyperuricemiaTumor lysis syndromeTophaceous goutUric acid nephrolithiasisCalcium oxalate nephrolithiasis with hyperuricosuria
febuxostatprobenecidcolchicineindomethacinpegloticaserasburicaselesinuradbenzbromarone

Sources and further reading

DailyMed (FDA labels)StatPearls (NCBI Bookshelf)MedlinePlusWHO ATC/DDD index: M04AA01

Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.