In addition to inhibiting prostaglandin synthase, NSAIDs inhibit urate crystal phagocytosis. Aspirin is not used because it causes renal retention of uric acid at low doses (≤2.6 g/d). It is uricosuric at doses greater than 3.6 g/d. Indomethacin is commonly used in the initial treatment of gout as a replacement for colchicine. For acute gout, 50 mg is given three times daily; when a response occurs, the dosage is reduced to 25 mg three times daily for 5–7 days.
All other NSAIDs except aspirin, salicylates, and tolmetin have been successfully used to treat acute gouty episodes. Oxaprozin, which lowers serum uric acid, is theoretically a good choice. These agents appear to be as effective and safe as the older drugs.
Probenecid and sulfinpyrazone are uricosuric drugs employed to decrease the body pool of urate in patients with tophaceous gout or in those with increasingly frequent gouty attacks. In a patient who excretes large amounts of uric acid, the uricosuric agents should not be used. Lesinurad (RDEA594) is a promising new uricosuric agent that is currently in phase 3 trials.
1. Chemistry and Pharmacokinetics: Uricosuric drugs are organic acids (Figure 36–6) and, as such, act at the anion transport sites of the renal tubule (see Chapter 15). Probenecid is completely reabsorbed by the renal tubules and is metabolized slowly with a terminal serum half-life of 5–8 hours. Sulfinpyrazone or its active hydroxylated derivative is excreted by the kidneys. Even so, the duration of its effect after oral administration is almost as long as that of probenecid, which is given once or twice daily.
2.
Pharmacodynamics: Uricosuric drugs—probenecid, sulfinpyrazone, as well as fenofibrate, and losartan—inhibit active transport sites for reabsorption and secretion in the proximal renal tubule so that net reabsorption of uric acid in the proximal tubule is decreased. Because aspirin in doses of less than 2.6 g daily causes net retention of uric acid by inhibiting the secretory transporter, it should not be used for analgesia in patients with gout. The secretion of other weak acids (eg, penicillin) is also reduced by uricosuric agents.
3.
As the urinary excretion of uric acid increases, the size of the urate pool decreases, although the plasma concentration may not be greatly reduced. In patients who respond favorably, tophaceous deposits of urate are reabsorbed, with relief of arthritis and remineralization of bone. With the ensuing increase in uric acid excretion, a predisposition to the formation of renal stones is augmented rather than decreased; therefore, the urine volume should be maintained at a high level, and at least early in treatment, the urine pH should be kept above 6.0 by the administration of alkali.
4.
Indications: Uricosuric therapy should be initiated in gouty patients with underexcretion of uric acid when allopurinol or febuxostat is contraindicated or when tophi are present. Therapy should not be started until 2–3 weeks after an acute attack.
5.
Adverse Effects: Both of these organic acids cause equivalent GI irritation, but sulfinpyrazone is more active in this regard. A rash may appear after the use of either compound. Nephrotic syndrome has occurred after the use of probenecid. Both sulfinpyrazone and probenecid may rarely cause aplastic anemia.
6.
Contraindications and Cautions: It is essential to maintain a large urine volume to minimize the possibility of stone formation.
7.