Gout Phenylbutazone

Clinical use Phenylbutazone (Brogden, 1986) is a nonsteroidal anti-inflammatory drug used for the acute treatment of ankylosing spondylitis, chronic polyarthritis and gout. Phenylbutazone on its own shows only weak inhibition of COX-1 and COX-2 with IC50s >30 pM (Brideau et al., 1996) and active metabolites are mainly responsible for its actions. 

In addition to the agents in this section, sulindac and indomethacin (see Nonsteroidal Anti-inflammatory Agents monograph) and phenylbutazone and oxyphenbutazone (see individual monographs) are indicated for the treatment of gout. 

Phenylbutazone (Butazolidin) is metabolized to oxy-phenbutazone (Phlogistol), and both compounds have all of the activities associated with the NSAIDs. Their use is accompanied by serious adverse reactions, such as anemia, nephritis, renal failure or necrosis, and liver damage. Because of their toxicity, they are prescribed only for the treatment of pain associated with gout or phlebitis or as a last resort for other painful inflammatory diseases resistant to newer and less toxic treatments. Interactions with a large number of other drugs... 

Colchicine (an alkaloid obtained from meadow saffron or autumn crocus) may be used both diagnostically to ascertain the presence of gout and prophylactically to prevent its further occurrence. Usually, 0.5-mg oral doses of colchicine are given hourly until either the therapeutic effects appear or the side effects develop. In addition to colchicine, phenylbutazone, indomethacin, adrenocorticotropic hormone (ACTH), and steroidal anti-inflammatory agents may be used to treat the acute attack of gout. 

Therapeutic uses Phenylbutazone is prescribed chiefly in shortterm therapy of acute gout and in acute rheumatoid arthritis when other NSAID agents have failed. The usefulness of phenylbutazone is limited by its toxicity. Aspirin and newer NSAIDs are superior to phenylbutazone in most applications. 

Since 1983 phenylbutazone and oxyphenbutazone have been removed from the market in many countries or have been hmited to specific indications. In 1985, Ciba-Geigy decided to stop sales of systemic dosage forms of oxyphenbutazone worldwide and to reduce the indications for phenylbutazone (SEDA-9, 85) (SEDA-10, 78). Nevertheless, phenylbutazone is still to be found in many places. Phenylbutazone and its congeners are now used only for ankylosing spondyhtis and sometimes for acute gout, psoriatic arthritis, and active rheumatoid arthritis in patients who have not responded to other therapy, including other NSAIDs. For other indications, less toxic alternatives suffice (1,2). 

It is a uricosuric agent structurally related to phenylbutazone. It is normally employed for the long term treatment of chronic gout where it effects slow depletion of urate tophi in the tissues. 

Sulfinpyrazone is a structural derivative of the anti-inflammatory drug phenylbutazone. Unlike phenylbutazone, however, sulfinpyrazone does not have significant anti-inflammatory activity. It does have potent uricosuric effects and frequently is used in the treatment of gout. At least four metabolites of sulfinpyrazone have been identified, including the sulfide, sulfone, p-hydroxysulfide, and p-hydroxysulfinpyrazone derivatives (Fig. 31.16) (24). Only the parent sulfinpyrazone and its reduced sulfide metabolite, however, are active as COX inhibitors (98). Because these compounds are reversible inhibitors, the antithrombotic activity lasts only as long as blood levels of the drug and metabolite persist (half-life, 4-6 hours for parent sulfinpyrazone, 11-14 hours for the sulfide metabolite). Sulfinpyrazone is not yet approved in the United States for use in acute myocardial infarction or for transient ischemic attack prophylaxis. 

Horwitz D, Thorgeirsson SS, Mitchell JR. The influence of allopurinol and size of dose on the metabolism of phenylbutazone in patients with gout. EurJ Clin Pharmacol ( 97T) 12,133-6. 

The therapeutic approach differs depending upon whether the patient is in the acute or chronic phase. In acute gout, the drug of choice has for a long time been colchicine. The exact mode of action of colchicine is not known, but it is believed to inhibit leukocyte phagocytosis and thereby interfere with the inflammatory cycle. Phenylbutazone and indomethacin are also used in the treatment of the acute phase of gout. The administration of anti-inflammatory corticosteroids enhances the effect of colchicine. 

The 10 patients with gout (Table 1) had episodes of hyperuricemia in association with a typical history of recurrent acute arthritis and/or demonstration of monosodium urate monohydrate crystals on synovianalysis or examination of tophaceous deposits. Patients J.P., A,H. and J.R. were on allopurinol at the time their leucocytes were taken for investigation. Patient J.M. was on phenylbutazone for 4 days before his studies were done. All the other patients in this group were off medication for 3 days prior to investigation. 

Bone marrow depression and agranulocytosis have been observed after therapeutic doses of colchicine (202, 203 ). Fatal bone marrow depression occurred in a 70-year-old man with gout shortly after operation for perforation of a gastric ulcer associated with administration of phenylbutazone. He had been given 12 mg of colchicine intravenously over a period of 5 days (202 ). Acute myelomonocytic leukaemia and multiple myeloma occurred in 3 of 25 patients with gout given sulphinpyrazone and colchicine. Colchicine was taken intermittently and for shorter periods than the sulphinpyrazone (204 ). 

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