Introduction
Allopurinol is a xanthine oxidase inhibitor widely used in clinical practice for the management of hyperuricemia and its complications. First approved by the FDA in 1966, it remains a cornerstone therapy for chronic gout and conditions associated with excessive uric acid production. As a structural analog of hypoxanthine, allopurinol effectively reduces serum urate levels by interfering with purine metabolism.
Mechanism of Action
Allopurinol and its primary active metabolite, oxypurinol, competitively inhibit xanthine oxidase, the enzyme responsible for converting hypoxanthine to xanthine and xanthine to uric acid. This inhibition reduces the production of uric acid, thereby decreasing serum and urinary uric acid concentrations. Unlike uricosuric agents, allopurinol reduces both synthesized and pre-formed uric acid, making it particularly effective in overproducers.
Indications
- Management of chronic gout (recurrent gouty arthritis, tophi, uric acid lithiasis)
- Treatment of secondary hyperuricemia associated with blood dyscrasias and their therapy
- Prophylaxis of tumor lysis syndrome in patients receiving cancer chemotherapy
- Management of recurrent calcium oxalate calculi in patients with hyperuricosuria
Dosage and Administration
Adults:- Initial: 100-300 mg daily, titrated upward based on serum uric acid levels
- Maintenance: 200-600 mg daily (maximum 800 mg/day)
- Severe cases: May require up to 800-900 mg daily in divided doses
- Renal impairment: Dose reduction required based on creatinine clearance
- CrCl 10-20 mL/min: 200 mg daily - CrCl 3-10 mL/min: 100 mg daily - CrCl <3 mL/min: 100 mg every other day
- Elderly: Consider reduced dosing due to decreased renal function
- Pediatrics: 10-20 mg/kg/day divided TID (maximum 600 mg/day)
- Oral administration with meals to minimize GI upset
- Adequate fluid intake (≥2 L daily) recommended
- Initiate with low doses to prevent acute gout flares
Pharmacokinetics
- Absorption: Approximately 90% orally absorbed, peak concentrations in 1-2 hours
- Distribution: Widely distributed throughout body tissues, Vd ~1.6 L/kg
- Metabolism: Rapidly metabolized to active metabolite oxypurinol via aldehyde oxidase
- Elimination: Oxypurinol eliminated renally with half-life of 18-30 hours
- Excretion: Primarily renal (76%), fecal (20%)
Contraindications
- Hypersensitivity to allopurinol or any component of the formulation
- Asymptomatic hyperuricemia
- History of severe cutaneous adverse reactions to allopurinol (DRESS, SJS, TEN)
Warnings and Precautions
- Hypersensitivity syndrome: Potentially fatal multi-organ reaction requiring immediate discontinuation
- Renal impairment: Increased risk of adverse effects; dose adjustment essential
- Hepatic impairment: Monitor liver function tests periodically
- Acute gout flares: May occur during initiation; concurrent prophylactic NSAIDs or colchicine recommended
- Xanthine deposition: Theoretical risk with extreme uric acid reduction
Drug Interactions
- Azathioprine/6-mercaptopurine: Allopurinol inhibits metabolism, requiring 75% dose reduction
- Warfarin: Enhanced anticoagulant effect; monitor INR closely
- Ampicillin/amoxicillin: Increased risk of skin rash
- Diuretics: May decrease allopurinol efficacy
- Theophylline: Increased serum concentrations possible
- ACE inhibitors: Potential increased risk of hypersensitivity reactions
Adverse Effects
Common (≥1%):- Skin rash (2%)
- Nausea, vomiting, diarrhea
- Elevated liver enzymes
- Acute gout flares (initial therapy)
- Severe cutaneous adverse reactions (DRESS, SJS, TEN)
- Hepatotoxicity
- Bone marrow suppression
- Eosinophilia
- Vasculitis
- Peripheral neuropathy
Monitoring Parameters
- Serum uric acid levels (target <6 mg/dL)
- Renal function (creatinine, BUN)
- Liver function tests (baseline and periodically)
- Complete blood count
- Signs of hypersensitivity reactions
- Uric acid crystals in urine (if symptomatic)
- Gout symptom frequency and severity
Patient Education
- Take medication exactly as prescribed, usually once daily after meals
- Maintain adequate fluid intake (8-10 glasses daily)
- Avoid high-purine foods (organ meats, anchovies, sardines)
- Limit alcohol consumption, especially beer
- Report any skin rash, fever, sore throat, or unusual bleeding immediately
- Be aware that gout attacks may initially increase when starting therapy
- Do not discontinue medication without consulting healthcare provider
- Regular follow-up appointments are essential for monitoring
References
1. Becker MA, Schumacher HR, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353(23):2450-2461. 2. Stamp LK, Taylor WJ, Jones PB, et al. Starting dose is a risk factor for allopurinol hypersensitivity syndrome: a proposed safe starting dose of allopurinol. Arthritis Rheum. 2012;64(8):2529-2536. 3. Day RO, Graham GG, Hicks M, et al. Clinical pharmacokinetics and pharmacodynamics of allopurinol and its metabolites. Clin Pharmacokinet. 2007;46(8):623-644. 4. US Food and Drug Administration. Allopurinol prescribing information. 2022. 5. Richette P, Doherty M, Pascual E, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017;76(1):29-42. 6. Ramasamy SN, Korb-Wells CS, Kannangara DR, et al. Allopurinol hypersensitivity: a systematic review of all published cases, 1950-2012. Drug Saf. 2013;36(10):953-980.