The Treatment of Gout

Transcription

1 DRUG LETTER The Treatment of Gout Stanley L. Wallace Gout is usually the most treatable of the arthritides. Acute attacks, if caught early enough, can 'be eradicated rapidly and completely. Recurrences can be prevented, and tophi dissolved. The drugs capable of producing these effects are well known. The purpose of this brief review of the therapy of gout is to consider both the basic principles of treatment and some of the newer aspects of the clinical pharmacology of these agents. Traditionally, the treatment of gout is divided into three parts: a) control of the acute episode, b) prevention of subsequent attacks, and c) dissolution of tophaceous deposits by reducing the serum urate level to normal. This subdivision of therapy is still conceptually valid. TREATMENT OF ACUTE GOUT Drugs that can be used in the therapy of acute gouty arthritis are listed in Table 1. Three of them will be considered in some detail. Colchicine Colchicine has both diagnostic and therapeutic value in acute gout. A dramatic, objective response to colchicine therapy suggests strongly that the patient has acute gout. The drug is usually given orally in multiple small doses, to minimize the ultimate severity of gastrointesti- From the Department of Medicine, Jewish Hospital of Brooklyn, 555 Prospect Place, Brooklyn, NY STANLEY L. WALLACE, MD: Associate Director of Medicine, Jewish Hospital of Brooklyn. Reprint requests should be addressed to: Dr. Stanley L. Wallace. nal toxic effects. For initial therapy,.5 or.6 mg of colchicine is given hourly (or twice as much, half as often) until one of three things occurs: a) therapeutic benefit, b) gastrointestinal side effects or c) the completion of an arbitrarily chosen maximum dose. This maximum total dose, taken orally, usually ranges from 8 to 16 tablets roughly according to body weight. After the toxic and/or effective dose is established for any individual, half that dose can generally be given at once in a subsequent attack and the remainder in divided doses hourly, with the same three alternative end-points. About 75% of unselected patients with acute gout respond rapidly (within 12 to 48 hours) and objectively to colchicine therapy. If treatment is initiated within a few hours after the onset of the attack, however, the response rate can be increased to more than 90%. Morbidity associated with full doses of orally administered colchicine is frequent. About 80% of patients so treated develop hyperperistalsis, cramping abdominal pain, diarrhea, nausea and/or vomiting; occasionally these side effects can be prostrating. Toxic manifestations usual- Table 1. Drugs Available in the Treatment of Acute Gout Drug Colchicine (orally or intravenously) Phenyl butazone Oxyphen butazone lndomethacin Adrenocorticotropic hormone Adrenocortical steroids (orally) Adrenocortical steroids (intraarticularly) Griseofulvin Vi n blasti ne Arthritis and Rheumatism, Vol. 15, No. 3 (May-June 1972) 317

2 WALLACE ly precede benefit by many hours. For these reasons, intravenously administered colchicine is preferable to orally administered colchicine. Since intravenous administration is rarely associated with gastrointestinal toxicity, there is no reason to parallel the oral experience by giving multiple fractional doses intravenously. A single dose of 3 mg is as effective as divided doses. Leukocyte concentrations of colchicine remain high and stable for more than 24 hours after a single intravenous administration of 3 mg (1). (The mechanism of colchicine action is presumably on the leukocyte-see below.) The major toxic effect of intravenously administered colchicine is venous irritation (and extravenous, if the solution is extravasated). One dose is less dangerous, therefore, than several smaller ones. Benefit from colchicine by this route is only a little faster than orally administered colchicine, and is not usually seen before 6 to 24 hours after injection. Colchicine is excreted, apparently unmetabolized, by the liver and kidney. Colchicine plasma levels are higher in patients with chronic disease of the liver than in controls after a single intravenous dose. In patients with chronic renal disease, the rate of colchicine disappearance from plasma is appreciably slowed. Colchicine doses in patients with gout and chronic kidney or liver disease should be reduced (2). Colchicine s effect in acute gout is most likely mediated by inhibition of leukocyte motility, either chemotactically induced or random (3). The white cell has been shown to be necessary for urate crystal-induced inflammation ( 4 ). Peak leukocyte concentrations are achieved rapidly after single oral and single intravenous doses of colchicine (5); presumably colchicine, as a fat-soluble molecule, is transported rapidly across membranes. Phenylbutazone and Oxyphenbutazone Phenylbutazone and oxyphenbutazone are effective drugs in the treatment of acute gout, producing dramatic improvement in about 90% of patients. However, they have no diagnostic specificity. In patients with a valid diagnosis of gout, phenylbutazone or its analogue is preferred to orally administered colchicine, because of the latter s very frequent toxic manifestations. Optimal doses of phenylbutazone or oxyphenbutazone average 600 mg/day (generally 200 mg three times daily), and 3 to 5 days of such therapy are usually sufficient. Phenylbutazone and oxyphenbutazone are capable of causing rare but serious toxic manifestations. In treatment of such short duration, the chief danger is the deterioration of an already present peptic ulcer. Peptic ulceration for this reason is an absolute contraindication to phenylhutazone therapy. Phenylbutazone is 98% bound to albumin in the blood; only the free drug is available for therapeutic and toxic effects, and metabolism. Subjects receiving 1 6OO/mg/day attain plasma levels only 10% higher than those receiving 600 mg daily. The limiting plasma level is around 100 pg/ml. (6). Raising this level causes a disproportionate increase in free drug and an acceleration of liver microsomal hydrolase metabolism of phenylbutazone until the level returns to l00pg/ml. There is little clinical purpose of doses larger than 600 mg/day. A number of acidic drugs appear to compete for the same limited number of albumin binding sites with phenylbutazone and oxyphenbutazone. One acidic drug may be displaced by another increasing, at least temporarily, the concentration of free first drug at therapeutic and toxic locations. Such highly bound agents include phenylbutazone and oxyphenbutazone, warfarin, bishydroxycoumarin and ethylbiscoumacetate, salicylic acid, the sulfonamides and some oral antidiabetic agents such as tolbutamide. Phenylbutazone and oxyphenbutazone can potentiate for a time the anticoagulant effect of warfarin (7), the hypoglycemic effect of tolbutamide and the antibiotic and toxic effects 318 Arthritis and Rheumatism, Vol. 15, No. 3 (May-June 1972)

3 TREATMENT OF GOUT of the sulfonamides. (6). More than 200 drugs, insecticides, carcinogens and other chemicals are known to stimulate the activity of drug metabolizing enzymes in liver microsomes, although not all in man. Such drugs, in addition to phenylbutazone and oxyphenbutazone, include the barbiturates; glutethimide, methylprylone, chloral hydrate, meprobamate, chlordiazepoxide, chlorpromazine, triflupromazine and promazine; the anticonvulsants diphenylhydantoin, methylphenylhydantoin and paramethadione; and tolbutamide (8). Among all these drugs, only phenobarbital has been studied in man in regard to phenylbutazone metabolism; it does indeed induce metabolizing enzymes and shorten phenylbutazone half-life ( 9 ). T h e physician must be concerned with the possible influences of all these drugs on phenylbutazone metabolism in the human liver and conversely on the possible effect of phenylbutazone on the metabolism of any of these drugs a patient with acute gout might be taking at the same time. lndomethacin Indomethacin is about as effective in the treatment of acute gout as phenylbutazone. However, doses of indomethacin necessary to accomplish this result are large, ranging upward from 200 mg/day, for 5 or 6 days (lo), and in our experience produce very frequent central nervous system and gastrointestinal side effects. Boardman and Hart (11) noted that more than 60% of their patients on relatively high doses of indomethacin (mean of 2.9 mg/ kg/day) had side effects, and of these, more than two-thirds had toxic effects within 48 hours after instituting therapy. Our results are similar. Indomethacin is excreted chiefly by the kidney as the glucuronide. Probenecid interferes with renal excretion of indomethacin. After probenecid, peak blood levels were 50% higher, excretion was delayed and at 48 hours blood levels were six times control values (12). The evidence suggests that probenecid interferes with tubular secretion of indomethacin. In the face of probenecid therapy, indomethacin doses must be reduced. Recent studies have suggested a possible mechanism of action for indomethacin (1 3). The drug has been shown to inhibit synthesis in guinea pig lung homogenates of prostaglandins E, and F2, The concentrations of indomethacin necessary to induce such activity were well within the ranges in plasma after therapeutic doses. Evidence is accumulating that the prostaglandins may be involved in the mechanisms of inflammation. PREVENTION OF RECURRENT EPISODES There are two roads to the prevention of recurrent attacks of gout. Colchicine given in small daily doses (.6 or 1.2 mg/day average) will reduce the frequency of subsequent attacks in nearly all patients, and in many will completely abolish recrudescences (14). Maintaining the miscible pool of urate at a normal level in the patient with gout will ultimately lead to cessation of attacks. The clinical equivalent to this is to keep the serum urate normal for a period of months after the last recognizable tophus has disappeared or, in the patient without tophi, to keep the serum urate level normal for about 1 year. The uricosuric and xanthine oxidase inhibitor drugs capable of accomplishing this result are considered in detail below. However, when these agents have succeeded in reducing the serum urate level to normal but deposited urate still persists, the likelihood of recurrent attacks is high. Small doses of colchicine must be given in conjunction with the drug reducing the serum urate level, in order to minimize these attacks, at least for the period until the miscible pool of urate is normal. TREATMENT OF TOPHACEOUS GOUT The dissolution of tophi depends on reduc- Arthritis and Rheumatism, Vol. 15, No. 3 (May-June 1972) 319

4 WALLACE tion of serum urate to normal. The upper limit of normal is generally defined as the mean of serum urates in a population, plus two standard deviations. It must be emphasized that no single serum urate level is the proper end point; upper limits of normal vary from 6.0 (some colorimetric methods) to 8.4 mg% (some autoanalyzer methods). Each laboratory using each method must establish its own normal urate range. A proper end point might then be the reduction of the serum urate level to about 1.5 or 2.0 mg below the upper limit of normal for that laboratory and method. Table 2 lists drugs that are capable of reducing the serum urate level. Three of these will be considered in some detail here, two uricosuric drugs and a xanthine oxidase inhibitor. Probenecid Probenecid has been in use for many years. It acts on the renal tubule to inhibit tubular reabsorption of urate, thus increasing urinary excretion and secondarily, lowering the serum level. Effective doses vary very much from patient to patient. The selection of doses must be carefully titrated according to the desired serum urate level. Forty percent of patients require 1.5 g/day of probenecid or more, and 15% need 2.5 g/day or more to lower the serum urate level appropriately (1 5). Gouty patients with seriously impaired renal function are often not Table 2. Drugs That Can Effect a Reduction in Serum Urate Levels Uricosuric agents Probenecid Sulfinpyrazone Acetylsalicylic acid (in doses greater than 3 g/day) X-ray contrast agents, including iopanoic acid, sodium ipodate, iodipamide and sodium diatrizoate Chlorprothixene Xanthine oxidase inhibitors Allopurinol Oxipurinol amenable to uricosuric drug action. There is little need to use the preparation combining probenecid and colchicine in the same tablet. The obligatory relationship of doses makes it likely that either too much colchicine or too little probenecid will be given, if effective doses of either are desired. Uricosuric drugs, by increasing urinary excretion of urate, increase the risk of both urate stone and microliths in and around the distal sections of the nephron. It is imperative for the patient to maintain a very large urine volume, (at least 2500 to 3000 ml/day), and if the urine is persistently quite acid, to take alkalinizing agents. The urine should not be made alkaline; a ph of 6.0 is adequate to minimize stone formation. Probenecid produces infrequent significant toxicity, other than the precipitation of new gouty attacks and the risk of stone. However, the presence or history of urate stone is an absolute contraindication to its use. Probenecid is about 90% bound to plasma proteins, chiefly albumin (15). The effects of probenecid on the transport of other albuminbound drugs is not known. As noted above, probenecid interferes with tubular secretion of indomethacin. Sulfinpyrazone Sulfinpyrazone is an analogue of phenylbutazone with uricosuric but no antiinflammatory effect. It is roughly equivalent to probenecid in effectiveness as a uricosuric and much, of the caution expressed above in regard to the kidney must be reemphasized with sulfinpyrazone. Doses range from 200 to 800 mg/day, should be carefully chosen, as with probenecid, according to the required serum urate level. Some patients with renal malfunction will not respond at all to sulfinpyrazone. Sulfinpyrazone, like phenylbutazone, is bound 98 to 99% to albumin. Salicylate, which is also bound to albumin in the serum, partially displaces sulfinpyrazone from its binding sites, 320 Arthritis and Rheumatism, Vol. 15, No. 3 (May-June 1972)

5 TREATMENT OF GOUT leading to a prompt fall in sulfinpyrazone levels. In addition, salicylate competes with both probenecid and sulfinpyrazone at the renal tubule, interfering with their uricosuric effects. Interestingly, sulfinpyrazone does not block the uricosuric effect of probenecid (1 6). Allopurinol Allopurinol is an analogue of hypoxanthine, and a potent inhibitor of xanthine oxidase, which catalyzes the conversion of hypoxanthine to xanthine and xanthine to uric acid. Allopurinol thereby lowers both serum and urinary urate levels, increasing xanthine and hypoxanthine levels at the same time. Allopurinol is rapidly cleared from the plasma, partly because of oxidative conversion to oxipurinol, which also inhibits xanthine oxidase. Oxipurinol is cleared slowly, so that the resulting xanthine oxidase inhibition is due to the combined effect of both compounds (17). In addition to xanthine oxidase inhibition, allopurinol and oxipurinol have been shown to inhibit early steps in de novo purine synthesis, resulting in a greater reduction in urate levels (18). Allopurinol doses must be selected to accomplish the urate level reduction needed. Dose range varies from 200 to 800 mg/day with patients with only moderate hyperuricemia requiring 400 mg/day or less, while those with severe hyperuricemia and/or extensive tophaceous deposition need more than 400 mg/ day. In contrast to the uricosuric drugs, however, allopurinol will exert its uric acid lowering effect in all patients (if an adequate dose is given), even those with renal disease. Allopurinol may trigger acute attacks of gout in spite of a normal urate level, as the uricosuric drugs do, and therefore, until the urate miscible pool is persistantly normal (see above), colchicine in small doses should be given along with this agent. Since allopurinol is effective in reducing serum urate levels in all patients and does not contribute to the risk of stone, one might con- sider that it is the drug of choice in the treatment of tophaceous gout. This question is not yet resolved. The major theoretic worry in regard to allopurinol toxicity in gout (ie, the production of xanthine stone) is not a significant problem. Only 2 patients have been reported to develop xanthine stones during allopurinol therapy, l with Lesch-Nyhan syndrome (19) and 1 with lyrnphosarcoma treated with large doses of chemotherapeutic agents (20). However, other toxic phenomena do occur. Four patients with gout have been reported with profound disseminated vasculitis during allopurinol therapy, with renal insufficiency, exfoliative dermatitis, other visceral involvement, fever and eosinophilia (21). Lesser rashes (presumably also on a vasculitic basis), hepatocellular chemical changes and gastrointestinal symptoms can also occur. Allopurinol, in addition to its effects on urate, also interferes with pyrimidine nucleotide synthesis (22). No clinical evidence of toxicity can yet be blamed on the pyrimidine effects of allopurinol therapy in gout. Finally, allopurinol has been shown to alter enzyme function in liver microsomes. Allopurinol in man markedly prolongs the plasma half-life of antipyrine and bishydroxycoumarin, presumably by slowing the hepatic biotransformation of these drugs (23). Its effect on hepatic metabolism of other drugs has not been studied. Because the ultimate risk from allopurinol therapy cannot yet be completely evaluated, some caution in its use is necessary. At present, allopurinol is particularly indicated in tophaceous gout in patients with stone, in those with known gross over-production of urate, (such patients are in greatest danger of stone or extensive tophaceous deposition), in those with renal malfunction sufficient to make them resistant to uricosuric drugs and in those unable to tolerate uricosuric drugs. Allopurinol is also most useful in the prevention of acute uric acid Arthritis and Rheumatism, Vol. 15, No. 3 (May-June 1972) 321

6 WALLACE nephropathy following the cytotoxic treatment of neoplasm. ASYMPTOMATIC HY PERURICEM I A The need to treat individuals without symptoms but with elevated serum urate levels depends on the risk from the hyperuricemia. Only a relatively small fraction of hyperuricemic individuals ever develop gout. In those that do, the duration of serum urate elevation prior to the first attack of gout averages 20 years. The prevention of acute gout, therefore, is no reason to treat the elevated serum urate level. The risk of stone formation is a separate problem. Hyperuricemia, of itself, does not contribute to urate stone; only hyperuricosuria does. All patients with hyperuricemia should be studied as to urinary urate excretion after a rigid purine restricted diet. Overexcretors are more likely to develop stone than normoexcretors of urate. Even in these individuals the risk can be minimized by increasing the urine volume. Serious clinical consequences from hyperuricemia, other than gout or stone, have not been established. In general, therefore, only rarely is there a reason to treat the hyperuricemic patient prophylactically with drugs, chiefly in those who are marked overexcretors of urate. REFERENCES 1. Ertel NH, Wallace SL: Measurement of colchicine in urine and peripheral leukocytes. Clin Res 19:416, 1971, (abstr) 2. Wallace SL, Omokoku B, Ertel NH: Colchicine plasma levels: Implications as to pharmacology and mechanism of action. Am J Med 48: , Wallace SL, Ertel NH: Colchicine: current problems. Bull Rheum Dis 20: , Phelps P, McCarty DJ, Jr: Crystal-induced inflammation in canine joints. I1 Importance of polymorphonuclear leukocytes, J Exp Med 124: , Omokoku B, Ertel NH, Wallace SL: Unpublished data 6. Brodie BB: Displacement of one drug by another from carrier or receptor sites. Proc R SOC Med 58: , Aggeler PM, O Reilly RA, Leong L, et al: Potentiation of anticoagulant effect of warfarin by phenylbutazone. N Engl J Med 276: , Conney AH: Pharmacologic implications of microsomal enzyme induction. Pharmacol Rev 19 : , Levi AJ, Sherlock S, Walker D: Phenylbutazone and isoniazid metabolism in patients with liver disease in relation to previous drug therapy. Lancet I: , Smythe CJ: Indomethacin-its rightful place in treatment, Ann Intern Med 72: , Boardman PL, Hart FD: Side effects of indomethacin. Ann Rheum Dis 26: , Skeith MD, Simkin PA, Healey LA: The renal excretion of indomethacin and its inhibition by probenecid. Clin Pharmacol Therap 9:89-93, Aspirin-like drugs and prostaglandins. Lancet 2:363-4, Yu TF, Gutman AB: Efficacy of colchicine prophylaxis in gout. Ann Intern Med 55: , Gutman AB: Uricosuric drugs, with special reference to probenecid and sulfinpyrazone, Advances in Pharmacology. Vol 4. Edited by S Garattini, PA Shore. New York, Academic Press, 1966, pp Yu TF, Dayton PG, Gutman AB: Mutual suppression of the uricosuric effects of sulfinpyrazone and salicylate. J Clin Invest 42: , Elion GB, Yu TF, Gutman AB, et al: Renal clearance of oxipurinol, the chief metabolite of allopurinol. Am J Med 45:69-77, Kelley WN, Wyngaarden JB: Effects of allopurinol and oxipurinol on purine synthesis in cultured human cells. J Clin Invest 49: , Greene ML, Fujimoto WY, Seegmiller J: Urinary xanthine stones, a rare complication of allopurinol therapy. N Engl J Med 280: , Band PR, Silverberg DS, Henderson JF, et al: Xanthine nephropathy in a patient with lym- 322 Arthritis and Rheumatism, Vol. 15, No. 3 (MayJune 1972)

7 TREATMENT OF GOUT phosarcoma treated with allopurinol. N Engl J teration in pyrimidine metabolism in man. Med 283: ,1970 Science 169: , Mills RM, Jr: Severe hypersensitivity reactions 23. Vesell ES, Passanante GT, Greene FE: Imassociated with allopurinol. JAMA 216:799- pairment of drug metabolism in man by al- 802,1971 lopurinol and nortriptyline. N Engl J Med 22. Kelley WN, Beardmore TD: Allopurinol: al- 283: ,1970 Arthritis and Rheumatism, Voi. 15, No. 3 (May-June 1972) 323