Uricosuric agent

Probenecid inhibits renal tubular reabsorption of water and by this meehanism enhanees the urinary excretion of uric acid. This lowers the level of urate in the serum. It thus serves as a potent uricosuric agent in the treatment of gout. Probenecid also blocks the renal tubular seeretion of penicillins and cephalosporins. It is, therefore, used as an adjuvant therapy with penicillin V or G, ampicillin, cloxacillin, oxacillin, methicillin and naficillin to increase and prolong their plasma levels. Besides it also enhances the plasma levels of anti-inflammatory agents like naproxen and indomethacin, and a host of medicinal compounds such as sulphonamides, sulphonylureas, dapsone, etc. 

Dose Adult, oral, 500 mg to 2 g per day usual, 250 mg 2 times daily for one week, then 500 mg twice a day thereafter. 

IH-Pyrazolo [3, A-d purimidin-4-oI I, 5-Dihydro-4H-pyrazoIo [3, A-d pyrimidin-4-one BP USP Zyloprim (Burroughs Wellcome). 

Condensation of ethoxymethylenemalonitrile with hydrazine via deethylation, addition and cyclization gives rise to 3-amino-4-cyanopyrazole whieh upon hydrolysis in the presence of sulphuric acid yields 3-amino-4-amino pyrazole. This on heating with formamide inserts the last carbon atom to afford allopurinol which exhibits tautomerism. 

It is a struetural analogue of hypoxanthine and is classified as xanthine oxidase inhibitor. It is administered for an indefinite duration in the treatment of chronic gout. It helps to decrease the eoneentration of urie aeid in plasma by blocking the conversion of hypoxanthine and xanthine to uric acid and by reducing purine synthesis. Thus it causes gradual resolution of tophi and minimises the risk of the formation of uric acid calculi. 

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Replacement of the methyl ketone moiety in 78 by a phenyl sulfoxide, interestingly, leads to a relatively potent uricosuric agent with diminished antiinflammatory action. This effect in lowering serum levels or uric acid leads to the use of this drug in the treatment of gout. Alkylation of diethyl malonate with the chlorosulfide, 79, gives the intermediate, 80. The pyrazolodione (81) is prepared in the usual way by condensation with hydrazobenzene. Careful oxidation of the sulfide with one equiv-... 

Probenecid is a uricosuric agent that blocks the tubular reabsorption of uric acid, increasing its excretion. Because of its mechanism of action, probenecid is contraindicated in patients with a history of uric acid stones or nephropathy. Probenecid loses its effectiveness as renal function declines and should be avoided when the creatinine clearance is 50 mL/minute or less. Its uricosuric effect is counteracted by low aspirin doses, which many patients receive for prophylaxis of coronary heart disease. 

Management of an acute attack of gout involves the use of high doses of nonsteroidal anti-inflammatory agents (NSAIDs). Colchicine is useful in patients with heart failure where the use of NSAIDs is contraindicated because of water retention. Allopurinol and other uricosuric agents are not indicated for acute attacks as they may aggravate the condition. The use of an intra-articular corticosteroid injection in gout is unlicensed. 

Drugs that may be affected by aspirin include ACE inhibitors, acetazolamide, anticoagulants, anticonvulsants (hydantoins, valproic acid), beta blockers, diuretics, methotrexate, NSAIDs, oral hypoglycemics, and uricosuric agents (probenecid, sulfinpyrazone). 

Drugs that may affect allopurinol include ACE inhibitors aluminum salts thiazide diuretics uricosuric agents. 

Uricosuric agents, such as probenecid, enhance uric acid excretion via the kidneys. 

Most drugs act by reducing active transport rather than by enhancing it. Thus, drugs that promote uric acid loss (uricosuric agents, such as probenecid and sulfinpyrazone) probably inhibit active urate reabsorption, while pyrazinamide, which reduces urate excretion, may block the active tubular secretion of uric acid. A complicating observation is that a drug may primarily inhibit active reabsorption at one dose and active secretion at another, frequently lower, dose. For example, small amounts of salicylate will decrease total urate ex-... 

Urate excretion is subject to modification by a variety of organic anions, including uricosuric agents. 

Uric acid production is more easily controlled by drug therapy than by dietary restriction, because only a small portion of blood uric acid is derived from the dietary intake of purines. Excretion of uric acid may be increased by increasing the rate of urine flow or by using uricosuric agents. Since uric acid is filtered at the glomerulus and both actively secreted and reabsorbed by the proximal tubule cells, both approaches are effective. 

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... 

Probenecid can impair the renal active secretion of a variety of acidic compounds, including sulfinpyrazone, sulfonylureas, indomethacin, penicillin, sulfonamides, and 17-ketosteroids. If these agents are to be given concomitantly with probenecid, their dosage should be modified appropriately. Salicylates interfere with the clinical effects of both sulfinpyrazone and probenecid and should be avoided in patients treated with uricosuric agents. Uricosuric agents also can influence the volume of distribution and hepatic metabolism of a number of drugs. 

Sulfinpyrazone (Anturane), another uricosuric agent, is chemically related to the antiinflammatory and urico-... 

The addition of a phenylsulfoxide moiety to the end of the side chain markedly changes the activity of this class of compounds. This product, sulfinpyrazone (97-11), stimulates uric acid excretion, making it a valuable dmg for dealing with the elevated serum uric acid levels associated with gout. The compound is stiU one of the more important uricosuric agents available today. The starting ester (96-9) is available by alkylation of the dianion from ethyl malonate with 2-chloroethylphenyl thioether. Condensation with diphenylhydrazine (97-3) in the presence of a base then affords the pyrrazolodione (97-10). Oxidation of sulfur with a controlled amount of hydrogen peroxide leads to the sulfoxide and thus sulfinpyrazone (97-11) [107]. 

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. 

Adverse effects do not provide a basis for preferring one or the other of the uricosuric agents. Both of these organic acids cause gastrointestinal 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. 

It should be noted that allopurinol and/or uricosuric agents do not replace colchichine in acute attacks of gout because in most cases they don t work as effectively. Therefore they are used more in chronic cases and in combined therapy with cholchicine. 

Iopanoic acid is as potent a uricosuric agent as probenecid and this effect might explain some renal complications aspirin reduces the uricosuric effect but can also impair X-ray visualization because of competition at plasma protein-binding sites. Fluctuations of serum urate after oral cholecystography can interfere with diagnostic tests and even precipitate an attack of gout (578). 

If left untreated, the hyperuricemic state may precipitate an acute attack of gout, which first appears in metatarsal phalangeal joints. Ultimately, tophaceous deposits form in the joints and soft tissues such as the kidneys. The hyperuricemic state may be corrected either by inhibiting the synthesis of uric acid by allopurinol or by enhancing the elimination of uric acid by uricosuric agents. 

For patients with chronic gout, colchicine has established value as a prophylactic agent, especially when there is frequent recurrence of attacks. Prophylactic medication also is indicated upon initiation of long-term medication with allopurinol or the uricosuric agents, because acute attacks often increase in frequency during the early months of such therapy. 

In a pathological condition that causes pain, drugs may be used either to care for the acute attack of pain or as prophylaxis to prevent the occurrence of pain. For example, colchicine is used during an acute attack of gout, and after the pain has subsided initially, the patient is switched to uricosuric agents such as probenecid or an inhibitor of uric acid synthesis such as allopurinol. 

Drugs used in the treatment of gout Colchicine Allopurinol Uricosuric agents... 

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