uricosuric agents

Introduction

Uricosuric agents act directly on renal tubule → increased uric acid renal excretion;
They can also alter plasma binding, distribution & renal excretion of other organic acids;
Uric acid in man generally demonstrates net reabsorption in most instances with about 10% of filtered uric acid being excreted, although net secretion is possible;
This net reabsorption is via an inhibitable specific transporter which allows luminal uric acid to be exchanged with cellular anions (incl. PAH); The uric acid then exits cell via a different transporter on basolateral membrane not involving PAH;
Uricosuric agents when present in lumen, compete with urate for the brush border transporter, thus decreased urate reabsorption;
Probenecid also inhibits a specific PAH transporter on basolateral memb. → decreased i/cell. PAH & thus causing decreased PAH secretion;
Biphasic effects on urate excretion are usually present depending on the concentration of the uricosuric agent.
- Low doses usually cause decreased excretion presumably due to extreme sensitivity of urate secretion transporter to these drugs at the lower dose → decreased secretion & no effect on reabsorption;
- Higher doses usually increased excretion as inhibition of reabsorption » inhibition of secretion;

one drug may decrease tub. secret. of another drug → decreased luminal [] → decreased inhibition of urate reabsorption.
inhibition of urate secretion by one drug may counter the inhibition of reabsorption by another;

Probenecid
Sulfinpyrazone:
- Strong organic acid congener of phenylbutazone with more potent uricosuric effect similar to probenecid, but lacks BTZ's anti-inflamm. effect although inhib. platelet function & may induce hypoglycaemia by decr. metabolism of sulfonyureas & also it inhibits metabolism of warfarin;
high doses of vitamin C supplementation