Urate Lowering Drugs

Urate lowering drugs reduce serum urate to dissolve crystals and prevent gout flares, tophi and joint damage. The classes are xanthine oxidase inhibitors, uricosurics and uricases. Treatment is long term and is not given for asymptomatic hyperuricaemia.

Mechanism. Xanthine oxidase inhibitors block urate production. Uricosurics (probenecid, benzbromarone, dotinurad) inhibit URAT1 reabsorption in the proximal tubule. Uricases (pegloticase, rasburicase) convert urate to soluble allantoin.

Pharmacokinetics. Allopurinol is converted to oxipurinol and cleared by the kidney. Uricosurics are less effective at low eGFR. Uricases are given intravenously.

Xanthine oxidase inhibitors. Allopurinol and febuxostat; first-line.

Uricosurics. Probenecid 250 mg twice daily rising to 500 mg to 1 g twice daily; benzbromarone 50 to 100 mg daily. Used as add-on or alternative. Need fluid intake of 2 litres daily and urine alkalinisation to prevent stones.

Uricases. Pegloticase 8 mg intravenously every 2 weeks for refractory tophaceous gout, with methotrexate to reduce anti-drug antibodies; test for G6PD first. Rasburicase 0.2 mg/kg intravenously daily for up to 5 days for tumour lysis syndrome.

Others. Losartan, fenofibrate and sodium-glucose cotransporter 2 inhibitors modestly lower urate.

• Indications: 2 or more flares each year, tophi, erosive gout, urate stones, chronic kidney disease stage 3 or worse with gout, or a first flare with serum urate over 540 micromol/L (9 mg/dL).
• Target: serum urate under 360 micromol/L (6 mg/dL), or under 300 micromol/L (5 mg/dL) with tophi or severe disease.
• Starting: once the acute flare has settled (or during it, with cover), at a low dose, with titration monthly.
• Flare prophylaxis: colchicine 0.5 mg once or twice daily (or low-dose NSAID, or prednisolone 5 to 10 mg) for 3 to 6 months while starting.
• Review contributors: thiazide and loop diuretics, low-dose aspirin, ciclosporin, pyrazinamide and ethambutol, alcohol (especially beer), sugary drinks, obesity.
• Lesch-Nyhan syndrome and tumour lysis: allopurinol or rasburicase.

Special groups.

• Pregnancy: avoid unless essential.
• Breastfeeding: avoid probenecid and benzbromarone.
• Children: tumour lysis and enzyme disorders only.
• Older adults: renal dosing.
• Kidney impairment: allopurinol with low starting dose; uricosurics lose effect under eGFR 30 mL/min.
• Liver impairment: caution.
• Regional: gout is common with tuberculosis treatment (pyrazinamide) and alcohol use; HLA-B*58:01 testing is rarely available, and the allele is more frequent in people of Asian and some African ancestry, so start allopurinol at 50 to 100 mg daily and counsel about rash.

Adverse effects. Gout flares on starting, rash, hepatitis, cytopenias, renal stones with uricosurics, and infusion reactions or anaphylaxis with pegloticase. Haemolysis with rasburicase and pegloticase in G6PD deficiency.

Contraindications. Rasburicase and pegloticase in G6PD deficiency; uricosurics in urate stones with low urine volume or severe renal impairment.

Interactions. Allopurinol with azathioprine or mercaptopurine causes severe bone marrow suppression. Probenecid raises levels of penicillins, methotrexate and aciclovir. Aspirin blunts uricosuric effect.

Monitoring. Serum urate monthly during titration then every 6 to 12 months; creatinine, liver enzymes and blood count; skin review in the first 3 months.

Referral and escalation. Urate not at target on maximum dose, tophaceous disease, recurrent stones, allopurinol hypersensitivity, or need for uricase.