Uricosuric drugs

Urea Transporter Uric Acid Uricostatic Drug Uricosuric Drug Urodilatin... 

Chronic hyperuricemia, because of under-excretion, is treated with a uricosuric drug (probenecid). 

Renal handling of uric acid. Uric acid may be actively reabsorbed from the ultrafiltrate following its glomerular filtration or it may be secreted from the blood across the basolateral membrane into the proximal tubular cell. Both passive and active transport mechanisms are involved in the handling of urate. Uricosuric drugs at appropriate doses interfere with these processes. 

The uricosuric drugs (or urate diuretics) are anions that are somewhat similar to urate in structure therefore, they can compete with uric acid for transport sites. Small doses of uricosuric agents will actually decrease the total excretion of urate by inhibiting its tubular secretion. The quantitative importance of the secretory... 

Allopurinol, in contrast to the uricosuric drugs, reduces serum urate levels through a competitive inhibition of uric acid synthesis rather than by impairing renal urate reabsorption. This action is accomplished by inhibiting xanthine oxidase, the enzyme involved in the metabolism of hypoxanthine and xanthine to uric acid. After enzyme inhibition, the urinary and blood concentrations of uric acid are greatly reduced and there is a simultaneous increase in the excretion of the more soluble uric acid precursors, xanthine and hypoxanthine. 

Allopurinol is largely absorbed after oral ingestion, reaching peak blood levels in about 1 hour. In contrast to the uricosuric drugs, allopurinol is not appreciably bound to plasma proteins and is only a minor substrate for renal secretory mechanisms. The formation of oxypurinol and the finding that this metabolite is in part actively reabsorbed in the proximal tubule account for the long half-life of the metabolite (18-20 hours) and permits once-a-day drug administration. 

Allopurinol is especially indicated in the treatment of chronic tophaceous gout, since patients receiving it show a pronounced decrease in their serum and urinary uric acid levels. Because it does not depend on renal mechanisms for its efficacy, allopurinol is particularly beneficial for patients who already have developed renal uric acid stones, patients with excessively high urate excretion (e.g., above 1,200 mg in 24 hours), patients with a variety of blood disorders (e.g., leukemia, polycythemia vera), patients with excessive tophus deposition, and patients who fail to respond well to the uricosuric 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. 

Uricosuric drugs are organic acids (Figure 36-6) and, as such, act at the anion transport sites of the renal tubule (see Chapter 15). Sulfinpyrazone is a metabolite of an analog of phenylbutazone. 

The uricosuric drugs(having uric acid in the urine) prevent reabsorption of... 

Gout is caused by the deposition of crystals of monosodium urate hydrate which are ingested by leucocyctes and trigger the inflammatory response. The biosynthesis of uric acid involves the oxidation of the more soluble compound xanthine (2,6-dihydroxypurine) by xanthine oxidase, and this enzyme is inhibited by allopurinol (187). The treatment of gout also relies on uricosuric drugs to accelerate urinary excretion of uric acid and antiinflammatory drugs to ease the pain and inflammation. 

Pyrazinamide interferes with the renal excretion of urate, resulting in hyperuricemia. Acute episodes of gout or arthralgia have occurred. Arthralgia responds better to NSAIDs than to uricosuric drugs (997). 

Chronic gout can be caused by (1) a genetic defect, for example, one resulting in an increase in the rate of purine synthesis, (2) renal deficiency, (3) Lesch-Nyhan Syndrome,4 or (4) excessive synthesis of uric acid associated with cancer chemotherapy. Treatment strategies for chronic gout include the use of uricosuric drugs that increase the excretion of uric acid, thereby reducing its concentration in plasma, and the use of allopurinol, which is a selective inhibitor of the terminal steps in the biosynthesis of uric acid. 

Renal excretion of uric acid consists of three components complete filterability of uric acid in the glomerulus, subsequent tubular reabsorption, and tubular secretion (Gutman and Yu 1961). Pronounced species differences have been described in uric acid metabolism including man. Mice were recommended for primary screening of uricosuric drugs. 

Onuma et al. (1988) used Cebus monkeys for evaluation of uricosuric effects of an aryloxyacetic derivative. Yonetani et al. (1987) performed clearance experiments with uricosuric drugs in anesthetized chimpanzees. Dan et al. (1989) tested the activity of AA-193, an uricosuric agent in rats, mice and Cebus monkeys. 

The options available are allopurinol, probenecid (named patient only) and sulfinpyrazone. Allopurinol is the drug usually chosen as a first line agent for the prevention of gout. Colchicine may be given at a dose of 500 micrograms twice or three times daily when allopurinol or uricosuric drugs are initially commenced in order to prevent an attack of gout. NSAIDs may also be used but this would not be an appropriate option for Mr KT. 

In principle it would seem reasonable that overproducers of urate be treated with allopurinol and xmderexcreters with a uricosuric drug. In practice most patients respond well to allopurinol, which is the drug of choice, especially if renal function is impaired a uricosuric may be given in addition. 

Cinchophen is a uricosuric drug that was formerly used in the treatment of gout (1). In 1991 the Spanish authorities withdrew cinchophen. It had been known for some time that it can cause severe hepatitis (SEDA-17,114). 

---