Uricosuric Drugs

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Chapter: Essential pharmacology : Antirheumatoid and Antigout Drugs

Probenecid : It is a highly lipid soluble organic acid developed in 1951 to inhibit renal tubular secretion of penicillin so that its duration of action could be prolonged.


URICOSURIC DRUGS

 

1. Probenecid

 

It is a highly lipid soluble organic acid developed in 1951 to inhibit renal tubular secretion of penicillin so that its duration of action could be prolonged. It competitively blocks active transport of organic acids by OATP at all sites; that in renal tubules being the most prominent. This transport is bidirectional: net effect depends on whether secretion or reabsorption of the particular organic acid is quantitatively more important, e.g.:

 

·        Penicillin is predominantly secreted by the proximal tubules, its reabsorption is minimal. Net effect of probenecid is inhibition of excretion; more sustained blood levels are achieved.

 

·        Uric acid is largely reabsorbed by active transport, while less of it is secreted; only 1/10th of filtered load is excreted in urine. Probenecid, therefore, promotes its excretion and reduces its blood level.

 

Probenecid does not have any other significant pharmacological action; it is neither analgesic nor anti-inflammatory.

 

Interactions

 

i.          In addition to penicillins, probenecid inhibits the urinary excretion of cephalosporins, sulfonamides, Mtx and indomethacin.

 

ii.          It inhibits biliary excretion of rifampicin. Pyrazinamide and ethambutol may interfere with uricosuric action of probenecid.

 

iii.          Probenecid inhibits tubular secretion of nitrofurantoin which may not attain antibacterial concentration in urine.

 

iv.          Salicylates block uricosuric action of probenecid.

 

Pharmacokinetics

 

Probenecid is completely absorbed orally; 90% plasma protein bound: partly conjugated in liver and excreted by the kidney; plasma t½ is 8–10 hours.

 

Adverse Effects

 

Probenecid is generally well tolerated.

Dispepsia is the most common side effect (upto 25% incidence with high doses). It should be used cautiously in peptic ulcer patients. Rashes and other hypersensitivity phenomena are rare. Toxic doses cause convulsions and respiratory failure.

 

Uses

 

1. Chronic gout and hyperuricaemia: Probenecid is a second line/adjuvant drug to allopurinol. Started at 0.25 g BD and increased to 0.5 g BD, it gradually lowers blood urate level; arthritis, tophi and other lesions may take months to resolve. Colchicine/NSAID cover is advised during the initial 1–2 months to avoid precipitation of acute gout.

 

Probenecid and other uricosurics are ineffective in the presence of renal insufficiency (serum creatinine > 2 mg/dl). Plenty of fluids should be given with probenecid to avoid urate crystallization in urinary tract.

 

2. Probenecid is also used to prolong penicillin or ampicillin action by enhancing and sustaining their blood levels, e.g. in gonorrhoea, SABE.

 

BENEMID, BENCID 0.5 g tab.

 

2. Sulfinpyrazone

 

It is a pyrazolone derivative related to phenylbutazone having consistent uricosuric action, but is neither analgesic nor anti-inflammatory. At the usual therapeutic doses, it inhibits tubular reabsorption of uric acid, but smaller doses can decrease urate excretion as do small doses of probenecid. Its uricosuric action is additive with probenecid but antagonised by salicylates. It inhibits platelet aggregation.

 

Pharmacokinetics

 

Sulfinpyrazone is well absorbed orally; 98% plasma protein bound—displacement interactions can occur. Excretion is fairly rapid, mainly by active secretion in proximal tubule. Uricosuric action of a single dose lasts for 6–10 hours.

 

Sulfinpyrazone inhibits metabolism of sulfonylureas and warfarin.

 

Adverse effects

 

Gastric irritation is the most common side effect—contraindicated in patients with peptic ulcer.

 

Rashes and other hypersensitivity reactions are uncommon.

 

Unlike phenylbutazone, it does not produce fluid retention or blood dyscrasias.

 

Uses

 

In chronic gout, the results are comparable to probenecid; same precautions should be exercised. Start with 100–200 mg BD, gradually

increase according to response, maximal dose 800 mg/day.

 

ANTURANE, ARTIRAN 200 mg cap.

 

Benzbromarone is another uricosuric drug marketed in Europe, but not in India.

 

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