Hyperuricemia Associated with Gout
Probenecid is used to lower serum urate concentrations in the treatment of chronic gouty arthritis and tophaceous gout. The drug is indicated in patients with frequent disabling attacks of gout. The presence of elevated serum urate concentrations alone usually is not considered by most clinicians to be an indication for therapy. However, some clinicians believe that therapy should be initiated when serum urate concentrations exceed 9 mg/dL (by the colorimetric method) because these concentrations are often associated with increased joint changes and renal complications. Probenecid is also indicated when there are visible tophi or when serum urate concentrations are greater than 8.5-9 mg/dL in a patient with a family history of tophi or low uric acid excretion. The goal of probenecid therapy is to lower serum urate concentrations to about 6 mg/dL. By decreasing serum urate concentrations, probenecid prevents or reduces chronic joint changes and tophi formation, eventually reduces the frequency of acute gout attacks, and may improve renal function in gouty patients.
Since probenecid has no analgesic or anti-inflammatory activity, it is of no value in the treatment of acute gout attacks and will exacerbate and prolong inflammation during the acute phase. Probenecid should not be started until 2-3 weeks after an acute gout attack. The drug may increase the frequency of acute attacks during the first 6-12 months of therapy, even when normal or subnormal serum urate concentrations have been maintained. Therefore, prophylactic doses of colchicine should be administered concurrently during the first 3-6 months of probenecid therapy. (The usefulness of the commercially available fixed-dosage preparation of probenecid combined with colchicine is limited, however, because the colchicine present exceeds the amount required by most patients.) Acute attacks may occur in spite of prophylactic therapy, but usually become less severe and are of briefer duration after several months of probenecid therapy. During these acute attacks, probenecid should be continued without changing dosage and full therapeutic doses of colchicine or other anti-inflammatory agents should be administered.
In early uncomplicated gout, either a uricosuric agent or allopurinol may be used. Probenecid may be effective in gouty patients with mild renal impairment, but large doses may be required. The drug is not effective, however, when chronic renal insufficiency exists, particularly in patients with moderate to severe renal impairment (creatinine clearance of less than 50 mL/minute). Since uricosuric agents tend to increase urinary uric acid concentrations and the risk of stone formation, they should be avoided; allopurinol is preferred in patients with urinary uric acid excretion of greater than 900 mg/day or with gouty nephropathy, urinary tract stones or obstruction, or azotemia. Although sulfinpyrazone produces fewer rashes and hypersensitivity reactions than does probenecid, the latter drug is preferred because adverse GI and hematologic effects occur less frequently and are less severe than with sulfinpyrazone. Patients who are refractory to or cannot tolerate probenecid may respond to sulfinpyrazone or allopurinol. The activity of allopurinol and uricosurics is additive and when administered concomitantly, smaller doses of each drug can be used. Combined use of the 2 types of drugs is especially effective in the presence of tophaceous deposits. Some clinicians have suggested concurrent administration of sulfinpyrazone and probenecid if the uricosuric response to one of these drugs is insufficient at maximum therapeutic dosages.
Hyperuricemia Secondary to Other Causes
Probenecid has been used effectively and is commonly employed to promote uric acid excretion in hyperuricemia secondary to the administration of thiazide and related diuretics, furosemide, ethacrynic acid, pyrazinamide, or ethambutol. Uricosurics should not be used to treat hyperuricemia secondary to cancer chemotherapy, radiation, or myeloproliferative neoplastic diseases because they may increase the risk of uric acid nephropathy.
Probenecid is used as an adjuvant to therapy with penicillin G or V, ampicillin, oxacillin, cloxacillin, methicillin (no longer commercially available in the US), or nafcillin to elevate and prolong the plasma concentrations of these antibiotics when administered orally or parenterally. Probenecid is also used concomitantly with amoxicillin, cephalosporin antibiotics, or some other β-lactam antibiotics (e.g., cefoxitin). Combined antibiotic and probenecid therapy rarely is necessary and should be limited to those situations in which high plasma and tissue antibiotic concentrations are necessary. Combined therapy with penicillin antibiotics and probenecid may be indicated for infections caused by bacteria that are only moderately sensitive to the antibiotic. In addition, probenecid is used concurrently with amoxicillin as one of the US Centers for Disease Control's (CDC) recommended alternative treatments for uncomplicated gonococcal infections caused by susceptible nonpenicillinase-producing Neisseria gonorrhoeae; with cefuroxime axetil as part of one CDC-recommended alternative treatment for uncomplicated gonococcal infections caused by susceptible penicillinase-producing Neisseria gonorrhoeae; and with cefoxitin as part of the CDC-recommended treatment for acute pelvic inflammatory disease in ambulatory adults and adolescents. Probenecid is also used concurrently with penicillin G procaine as part of one CDC-recommended treatment for neurosyphilis in ambulatory patients in whom compliance with therapy can be ensured. Although not currently included in the CDC's recommended regimens for the treatment of gonococcal infections, probenecid also has been used concurrently with amoxicillin or penicillin G procaine for the management of infections caused by penicillin-susceptible N. gonorrhoeae.
Because of its effects on CSF concentrations of HVA and 5-HIAA, probenecid has been used in the diagnosis of parkinsonian syndrome and mental depression.