Chapter: Modern Pharmacology with Clinical Applications: Drugs Used in Gout

Uricosuric Agents

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.


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 se-cretion. The quantitative importance of the secretory mechanism is relatively minor, however, and at high dosages these same drugs increase uric acid elimination by inhibiting its proximal tubular reabsorption. Thus, uricosuric drugs have a seemingly paradoxical effect on both serum and urinary uric acid levels: at low doses, they increase serum levels while decreasing the urinary levels; they have the opposite effect on these two levels at high dosages.

The two most clinically important uricosuric drugs, probenecid and sulfinpyrazone, are organic acids. The initial phase of therapy with uricosuric drugs is the most dangerous period. Until uricosuric drug levels build up sufficiently to fully inhibit uric acid reabsorption as well as secretion, there may be a temporary increase in uric acid blood levels that significantly increases the risk of an acute gouty attack. Therefore, it is wise to begin ther-apy with the administration of small amounts of colchicine before adding a uricosuric drug to the thera-peutic regimen. In addition, the initial rise in urinary uric acid concentrations during uricosuric drug therapy may result in renal stone formation.


When probenecid (ColBENEMID) is given in sufficient amounts, it will block the active reabsorption of uric acid in the proximal tubules following its glomerular filtra-tion, thereby increasing the amount of urate eliminated. In contrast, low dosages of probenecid appear to com-pete preferentially with plasma uric acid for the proxi-mal tubule anionic transport system and thereby block its access to this active secretory system. The uricosuric action of probenecid, however, is accounted for by the drug’s ability to inhibit the active reabsorption of fil-tered urate.

Probenecid is rapidly absorbed after oral administra-tion, with peak plasma levels usually reached in 2 to 4 hours. Its half-life is somewhat variable (6–12 hours) be-cause of both its extensive plasma protein binding and its active proximal tubular secretion. Since tubular back-diffusion is decreased at alkaline urinary pH ranges, probenecid excretion increases with increasing urinary pH. Probenecid is rapidly metabolized, with less than 5% of an administered dose being eliminated in 24 hours.The major metabolite is an acyl monoglucuronide.

Probenecid is an effective and relatively safe agent for controlling hyperuricemia and preventing tophi deposition in tissues. Chronic administration will de-crease the incidence of acute gouty attacks as well as di-minish the complications usually associated with hyper-uricemia, such as renal damage and tophi deposition. Probenecid is still used by some physicians to maintain high blood levels of penicillin, cephalosporin, acyclovir, and cyclosporine. It is not useful in treating acute at-tacks of gouty arthritis. If the total amount of uric acid excreted is greater than 800 mg/day, the urine should be alkalinized to prevent kidney stone formation and pro-mote uric acid.

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 con-comitantly with probenecid, their dosage should be mod-ified 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 distri-bution and hepatic metabolism of a number of drugs.

Adverse reactions associated with probenecid ther-apy include occasional rashes, allergic dermatitis, upper gastrointestinal tract irritation, and drowsiness. The drug is contraindicated in patients with a history of re-nal calculi.


Sulfinpyrazone (Anturane), another uricosuric agent, is chemically related to the antiinflammatory and urico- suric compound phenylbutazone. However, it lacks the antiinflammatory, analgesic, and sodium-retaining prop-erties of phenylbutazone and possesses a number of un-desirable side effects that limit its therapeutic useful-ness. The mechanism of sulfinpyrazone’s uricosuric activity is similar to that of probenecid.

Sulfinpyrazone is readily absorbed after oral admin-istration, with peak blood levels reached 1 to 2 hours af-ter ingestion. It is more highly bound to plasma protein (98–99%) than is probenecid (84–94%) and is a more potent uricosuric agent. Most of the drug (90%) is elim-inated through active proximal tubular secretion of the intact parent compound. Sulfinpyrazone also undergoes p-hydroxylation to form a uricosuric metabolite, the formation of which undoubtedly contributes to the drug’s prolonged activity (about 10 hours) and potency relative to probenecid. In contrast to probenecid, the rate of excretion of sulfinpyrazone is not enhanced by alkalinization of the urine, since the drug is largely ion-ized at all urinary pH ranges and therefore not a candi-date for passive back-diffusion.

Sulfinpyrazone, although less effective than allop-urinol in reducing serum uric acid levels, remains useful for the prevention or reduction of the joint changes and tophus deposition that would otherwise occur in chronic gout; it has no antiinflammatory properties. During the initial period of sulfinpyrazone use, acute at-tacks of gout may increase in frequency and severity. It is recommended, therefore, that either colchicine or a nonsteroidal antiinflammatory agent be coadministered during early sulfinpyrazone therapy.

Abdominal pain, nausea, and possible reactivation of peptic ulcer have been reported. The drug should be used with caution in patients with compromised renal function, and adequate fluid intake should always ac-company sulfinpyrazone administration to minimize the possibility of renal calculus formation.


Allopurinol (Zyloprim) is the drug of choice in the treat-ment of chronic tophaceous gout and is especially useful in patients whose treatment is complicated by renal in-sufficiency.

Mechanism of Action

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 metabo-lism of hypoxanthine and xanthine to uric acid. After enzyme inhibition, the urinary and blood concentra-tions of uric acid are greatly reduced and there is a si-multaneous increase in the excretion of the more solu-ble uric acid precursors, xanthine and hypoxanthine.

Allopurinol itself is metabolized by xanthine oxi-dase to form the active metabolite oxypurinol, which tends to accumulate after chronic administration of the parent drug. This phenomenon contributes to the thera-peutic effectiveness of allopurinol in long-term use. Oxypurinol is probably responsible for the antigout ef-fects of allopurinol. Oxypurinol itself is not adminis-tered because it is not well absorbed orally.

Absorption, Metabolism, and Excretion

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 oxy-purinol and the finding that this metabolite is in part ac-tively reabsorbed in the proximal tubule account for the long half-life of the metabolite (18–20 hours) and per-mits once-a-day drug administration.

Clinical Uses

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 mecha-nisms 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.

Allopurinol also inhibits reperfusion injury. This in-jury occurs when organs that either have been trans-planted or have had their usual blood perfusion blocked are reperfused with blood or an appropriate buffer so-lution. The cause of this injury is local formation of free radicals, such as the superoxide anion, the hydroxyl free radical, or peroxynitrite. These substances are strong oxidants and are quite damaging to tissues.

Adverse Effects

Common toxicities associated with allopurinol adminis-tration include a variety of skin rashes, gastrointestinal upset, hepatotoxicity, and fever. These reactions are of-ten sufficiently severe to dictate termination of drug therapy. It is advised that therapy not be initiated dur-ing an acute attack of gouty arthritis. As with the urico-suric drugs, therapy with allopurinol should be accom-panied both by a sufficient increase in fluid intake to ensure water diuresis and by alkalinization of the urine. Prophylactic use of colchicine also helps to prevent acute attacks of gout that may be brought on during the initial period of allopurinol ingestion.

Drug Interactions

Since allopurinol is metabolized by the hepatic micro-somal drug-metabolizing enzymes, coadministration of drugs also metabolized by this system should be done with caution. Because allopurinol inhibits the oxidation of mercaptopurine and azathioprine, their individual administered doses must be decreased by as much as 75% when they are given together with allopurinol. Allopurinol may also increase the toxicity of other cy-totoxic drugs (e.g., vidarabine). The actions of allopuri-nol are not antagonized by the coadministration of sal-icylates.


A number of drugs other than those discussed have been used to control the symptoms of acute gouty arthritis. Since the principal aspects of their pharmacology have been described elsewhere, they are mentioned only briefly here.

Indomethacin (Indocin)  exerts an-tiinflammatory, antipyretic, and analgesic properties. These qualities make it useful for the short-term man-agement of the symptoms of acute gouty arthritis, al-though it has little effect on serum uric acid levels. Its antiinflammatory activity and ability to inhibit leuko-cytic phagocytosis make it particularly valuable in treat-ing the early stages of gout, because a decrease in the leukocytic phagocytosis of urate crystals results in a de-crease in the amount of peptides, prostaglandins, and other substances released from leukocyte lysosome or-ganelles.

Phenylbutazone (Butazolidin,Tandearil) (see displays antipyretic, analgesic, and antiinflam-matory activity. In addition, it possesses some uricosuric potency and therefore is widely used for the treatment of acute attacks of gouty arthritis, in which it is about equal to colchicine in effectiveness. Although the drug does promote the renal excretion of uric acid, its use-fulness is generally attributed to its antiinflammatory actions.

Oxyphenbutazone (Oxalid, Tandearil) is the princi-pal uricosuric metabolite of phenylbutazone. It has the same indications and toxicities as phenylbutazone.



The use of corticosteroids is often suggested for elderly patients with chronic tophaceous gout, since gout in the older individual often displays symptoms similar to those of rheumatoid arthritis. Patients can be given short-term administration of corticosteroids, especially for acute flare-ups. The concomitant use of alcohol, non-steroidal antiinflammatory drugs, and most diuretics should be avoided.


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