Uricosuric Drugs

Uricosuric drugs lower serum urate by increasing renal urate excretion. They are second-line therapy in gout, used when xanthine oxidase inhibitors are not tolerated, or added when urate stays over target on the maximum tolerated dose. They suit patients who under-excrete urate, which accounts for most primary gout.

Mechanism. They inhibit the urate transporter URAT1 (and OAT4) in the proximal tubule, blocking urate reabsorption. Probenecid also inhibits organic anion transporters OAT1 and OAT3, which blocks the tubular secretion of many drugs.

Pharmacokinetics. Probenecid is well absorbed, highly protein bound, with a dose-dependent half-life of 3 to 12 hours. Benzbromarone is metabolised by CYP2C9 to active metabolites with a half-life of 17 to 30 hours. Effect depends on kidney function.

Differences. Probenecid is cheap but loses effect at eGFR under 50 mL/min and has many interactions. Benzbromarone works down to eGFR 20 to 30 mL/min but carries a risk of severe liver injury, and is withdrawn or restricted in several markets. Dotinurad is more selective for URAT1. Lesinurad was withdrawn. Losartan, fenofibrate and sodium-glucose cotransporter 2 inhibitors have mild incidental uricosuric effects.

• Choose when: urate-lowering with a xanthine oxidase inhibitor is not tolerated or does not reach target, and the patient has good renal function and no history of urate stones.
• Suitable patients: under-excretors, with 24-hour urinary uric acid under 4.8 mmol (800 mg) on a normal diet.
• Hydration: at least 2 litres of fluid daily, and alkalinise urine to pH 6 to 6.5 (potassium citrate or sodium bicarbonate) when urinary uric acid is high, to reduce stone risk.
• Starting: low dose, titrated monthly to a serum urate under 360 micromol/L (6 mg/dL), or under 300 micromol/L (5 mg/dL) with tophi.
• Flare prophylaxis: colchicine 0.5 mg once or twice daily for 3 to 6 months.
• Deliberate use of probenecid: 1 g with a single dose of some beta-lactams to prolong their levels, for example in specific infections where a single dose is needed.

Special groups. Pregnancy: avoid. Breastfeeding: avoid. Children: not used. Older adults: reduced effect with falling eGFR. Kidney impairment: avoid probenecid at eGFR under 50 mL/min and benzbromarone at eGFR under 20 mL/min. Liver impairment: avoid benzbromarone. Regional: pyrazinamide-induced hyperuricaemia from tuberculosis treatment does not respond to uricosurics, as pyrazinoic acid blocks urate secretion; probenecid availability is limited; benzbromarone is not widely available.

Adverse effects. Nausea and dyspepsia, rash, gout flares on starting, renal colic and urate stones, and haemolysis in G6PD deficiency. Benzbromarone: hepatitis and rare fulminant liver failure.

Contraindications. History of urate stones or urate nephropathy, tumour lysis syndrome, severe renal impairment, blood dyscrasias, and pregnancy. Benzbromarone in liver disease.

Interactions. Probenecid raises levels of penicillins, cephalosporins, methotrexate (toxicity), aciclovir, ganciclovir, zidovudine, dapsone, NSAIDs such as indomethacin and naproxen, and lorazepam. Salicylates in analgesic doses antagonise the uricosuric effect. Benzbromarone inhibits CYP2C9 and potentiates warfarin.

Monitoring. Serum urate monthly during titration, creatinine, urinary pH and 24-hour uric acid at baseline, full blood count, and liver enzymes monthly for the first 6 months with benzbromarone.

Referral and escalation. Renal colic, jaundice, haemolysis, urate not at target on combination therapy, or tophaceous disease.