Nyperuricemia Induced by Drugs

Transcription

1 Nyperuricemia nduced by Drugs By FELX E. DEMARTN, M.D. Columbia University College of Physicians and Surgeons Alterations in the physiological mechanisms regulating the metabolism of purines obviously will result in changes in the concentration of uric acid in the serum. A great deal of attention in the past has been focused on drugs that lower the serum uric acid concentration and through the study of the action of these pharmacological agents knowledge has been accumulated concerning the nature of the regulatory mechanisms. Recently druginduced hyperuricemia has become a clinical problem and the study of this phenomenon also has produced some interesting information. The concentration of a substance in the serum can be altered by interfering with its production, distribution and/or excretion. n man the degradation of uric acid does not occur, as uricase is not present; the role of the peroxidases is quite insignificant in the overall metabolism of urate in the human. Therefore, we are left with the alterations by drugs of the excretion and production of uric acid. t can be adequately shown that hyperuricemia secondary to drugs results from their interference with excretion as well as their stimulation of production of uric acid. The main excretory pathway of uric acid in man is via the kidney, and in this discussion no mention will be made of the fraction that is excreted by the gastrointestinal tract. n Table 18 are listed several pharmacological agents that cause hyperuricemia. The mechanism operating is via an alteration in the normal renal excretory pathway for uric acid. The first three agents in the table have been shown to produce a paradoxical effect on urate excretion; under one set of circumstances there is urate retention, and under another experimental condition uricosuria is produced. n the case of salicylate, Gutman and YU1r2 have conclusively demonstrated this paradoxical effect in man. n Figure 97, taken from their article, during the infusion of sodium salicylate urate retention occurs at plasma salicylate levels below 1 mg. per cent and uricosuria at plasma levels above 1 mg. per cent. This paradoxical action has caused some confusion in the clinic when a differential diagnosis of joint pain is attempted while the patient is taking small amounts of salicylate. A paradoxical effect on the excretion of uric acid Table 18.Hyperuricemic DrugsRenal Salicylate Chloro thiazide Ethacrynic acid Pyrazinamide Angiotensin 1 Epinephrine Norepinephrine Mechanism 823 ARTHRTS AKD RHEUMATSM, VOL. 8, NO. &PART 1 (OCTOBER), 1965

2 824 GOUT AND PURNE METABOLSM CASE: J.S. U n a s o \.. *. /*. X W Fig. 97.CU1.te/Cnulir, (respectively, CUrate/CCreatlnlne) response to slowly rising plasma salicylate levels during slow infusion of sodium salicylate and declining plasma salicylate levels for 22 hours after the infusion was terminated. is also found with chlorothiazide administration.3 n Figure 98 the uricosuric response to the intravenous administration of 5 mg. of chlorothiazide is evident. However, when 1.5 Gm. of chlorothiazide in divided doses is given orally to a gouty man over a 24 hr. period for three weeks, urate retention and hyperuricemia occur (Table 19). The new potent diuretic drug, ethacrynic acid, has a urateretaining effect when given by mouth4 and a uricosuric effect when given intravenously,5 quite similar to chlorothiazide. These three agents produce their paradoxical effects on urate excretion by their action on renal tubular transport function. The explanation of this effect is that these drugs in high concentration block both tubular secretion and tubular reabsorption of uric acid, the former being of a more limited capacity than the latter, hence the overall effect is uricosuria. n lower serum concentrations only the limited tubular function of secretion is significantly altered and urate retention occurs. This explanation, which seems plausible, supports the concept of tubular secretion of urate by the kidney in man. The antituberculous drug, pyrazinamide, was first reported by Cullen et a1 in to produce hyperuricemia. This action of pyrazinamide was later shown to be due to retention of urate by the kidney,? resulting in an elevation in the serum urate. The last three pharmacological agents in Table 18 that alter the excretion of uric acid are drugs that produce efferent vasoconstriction in the kidney. Dr. Harvey Chase and have studied these agents and in Table 2 the effects on urate excretion in man of the administration of norepinephrine, epinephrine and angiotensin 1 are tabulated. From the changes produced in the PAH clearance it is apparent that efferent vasoconstriction occurred. The changes in the clearance of urate are striking. The ratio of the clearance of urate to that of the clearance of inulin (C,,/Cln) indicates that this effect was produced by interference with tubular transport of urate. nterpretation of the

3 HYPERURCEMA NDUCED BY DRUGS 525 Curate ml/min 65 r n, Fig. 98.The ance. 1 i 5t 1 ' ' TME N MNUTES effect of the acute administration of chlorothiazide on urate clear mechanism involved is difficult, but the observation indicates to us that an alteration in renal blood flow should be considered as a possible mechanism in regulating the excretion of urate. These findings may have some bearing on the high incidence of hyperuricema found in patients with hypertension.8 t has been known for many years that drugs can increase the production of uric acid in man, and thereby cause hyperuricemia. n Table 21 are listed three agents which when employed in special clinical situations cause hyperuricemia. Liver extract was shown by Riddleg in 1929 to produce hyperuricemia and uricosuria when it was given to a patient with pernicious anemia in relapse. The hyperuricemia corresponded in time with the onset of marked reticulocytosis. t is well known that large doses of adrenocortical steroids can produce severe hyperuricemia when given to patients with acute myeloid leukemia. These two agents produce their effect by the degradation of nucleic acid and soluble nucleotides, with subsequent oxidation of their purines to uric acid. n the first example it is associated with maturation of the megaloblastic marrow by liver extract, and in the second example hyperuricemia is associated with the destruction of the myeloblasts. The last group of drugs is the thiadiazole compounds that have been studied extensively by Krakoff and Ba1is.lo These agents produce hyperiiricemia by increasing de novo purine synthesis.

4 ~~ Angiotensin 826 GOUT AND PURNE METABOLSM Table 19.The Effect of Prolonged Chlorothiazide Administration on Urate Excretion in a Sixfytwo Year Old Man with Tophaceous Gout rate Time V inillin tirate UVura+e Furate itrate inillin (rnin.) (mljrnin.1 (ml./min.) (mg. %) (rng./min.) (mg./min.) (rnl./rnin.) (%) Control Chorothiazide 1.5 Gm. Orally for Three Weeks Mean Values Control During chlorothiazide Table 2. Uric Acid Clearance Effect of Epinephrine, Norepinephrine and Angiotensin 1 in Noneoutw Man Urine FLOW PAH inulin ml./rnin. ml./rnin. ml./rnin. ml./min. JCin Control Epinephrine.M Control Norepinephrine.V Control Above values are averages of 3 ten minute control clearance periods and 3 or more ten minute clearance periods during the administration of the above pressor substances. Table %Hypsruricernic Drugs Due to ncreased Production 1Liver extract and vitamin B,, in the treatment of megaloblastic anemia. 2Adrenocortical steroids in the treatment of leukemia. 3Thiadiazoles. n summary, it is possible to show that various pharmacologic agents can produce hyperuricemia, not only by interfering with the renal excretion of uric acid but also by increasing the production of uric acid, by accelerated tissue breakdown and by stimulating de novo purine synthesis. REFERENCES 1. Yu, T. F., and Gutman, A. B.: Paradox SOC. Exp. Biol. and Med. 9:542, ical Retention of Uric acid by Uri cosuric Drugs in Low Dosage. Proc. 2., and : The Study of the Paradox

5 HYPERURCEMA NDUCED BY DRUGS 827 ical Effects of Salicylate in Low, ntermediate and High Dosage on the Renal Mechanism for Excretion of Urate in Man. J. Clin. nvmt. 38: 1298, Demartini, F. E., Wheaton, E. A., Healey, L. A., and Laragh, J. H.: The Effect of Chlorothiazide in the Renal Excretion of Uric Acid. hner. J. Med. 32:572, Cannon, P. J., Ames, R. P., Laragh, J. H.: Methylenebutyryl Phenoxyacetic Acid. Navel and patent naturetic and diuretic agent. J. A. M. A. 185:834, Wilkinson, W. H.: Personal Communication. 6. Cullen, J. H., Early, L. J. A., and Fiore, J. M.: The Occurrence of Hyperuricemia during Pyrazinamide soniazide Therapy. Amer. Rev. Tuberc. and Pulm. Dis. 74:289, Yu, T. F., Berger, L., Stone, D. J., Wolf, J., and Gutman, A. B.: Effect of Pyrazinamide and Pyrazinoic Acid on Urate Clearance and Other Discrete Renal Functions. Proc. SOC. Exp. Biol. Med. 96:264, Kinsey, D., Walther, R., Sise, H. S., Whitelaw, G., and Smithwick, R.: ncidence of Hyperuricemia in 4 Hypertensive Patients. Circulation 24:97$ Riddle, M. C.: The Endogenous Uric Acid Metabolism in Pernicious Anemia. J. Clin. nvest. 8:69, Krakoff,. H., and Balis, hil. C.: Stndies of the Uricogenic Effect of 2 substituted Thiadiazoles in Man. J. Clin. nvest. 38:97, Discussion DR. AYVASAN: A few years ago speculated in print that the paradoxical increase in uric acid excretion seen with chlorothiazide might be just a prerenal effect, possibly similar to that of EATDA, as shown by Dr. Krakoff. Since then have had occasion to give chlorothiazide over a wide dosage range to a patient with xanthinuria and could not find any change in his purine excretion. am forced to conclude that the effect of chlorothiazide is specific to uric acid renal regulatory mechanisms. DR. GUTMAN: You measured xanthine and hypoxanthine in the urine? DR. AYVASAN: That's right and there was no change. DR. C. SMYTH: Our group has been interested in the influence of salicylates on serum levels especially in regard to the paradoxical effect of small doses of salicylates versus high doses. Patients in the hospital without any known metabolic disease were given a loading dose of varying amounts of salicylates. An illustration of experiments conducted within a six week period in one individual is shown in the first series of graphs (Fig. 99). n this study the immediate effects over a four hour period of oral salicylate administration upon the serum urate and salicylate levels are shown in one individual. The single loading dose for the first week was 32 mg.; for the second week, 64 mg. and so on at higher doses each week until 2,65 mg. was given on the sixth week. Blood samples were taken at the first, second, and third and fourth hour and analyzed for urate and salicylate conceatrations. The plan of study was similar to a glucose tolerance test. As can be seen, the serum urate values (upper solid line) in all instances remained within the normal range. The concentration of salicylates increased progressively as the loading dose was raised and reached a peak at the fourth hour. The results in this case are illustrative of all the other 15 patients that have now been studied in this same manner. n this investigation the question of the influence of the daily ingestion of

6 828 GOUT AND PURNE METABOLSM r MMEDATE EFFECT [hrr) OF ORAL ASPRN ON SERUM URATE EXAMPLES OF NDVDUAL CASES WTH 1 REASNG DOSES OADNG DOSE 96 mg S.U. v s s. OADNG DOSE.D.2\56 mq P bs.s. s.u. RELATONSHtP OF ASPRN TO SERUM URATE 3 NORMAL SUBJECTS 5. BLOOD SALCYLATE O mg % l.o 9. SERUM 8. URATE mg % yo.* TME 1st WEEK 2nd WEEK 3rd WEEK 4th WEEK Fig. 1. 2, 4 or more aspirin tablets (32 mg.) was also considered. n the clinical situation the interpretation of a single serum urate value obtained from a patient with rheumatic complaints who has taken one OT several aspirin tablets is a common occurrence. A group of 3 medical students agreed to cooperate in this aspect of the study. Each student took one aspirin tablet (32 mg.) daily for the first week, two tablets (64 mg.) daily for the second week, three tablets (96 mg.) daily for the third week and four tablets (1,28 mg.) daily for the fourth week (Fig. 1). At the beginning of the study and at the end of each week the serum concentration of urate and salicylate were determined. The results of the mean values before and at weekly

7 HYPERURCEMA NDUCED BY DRUGS 829 intervals showed no significant changes in either the urate or salicylate concentration. From these preliminary studies it would appear that, in the usual amounts in which salicylate is taken, it need not be considered in the interpretation of serum urate values. For example, in population studies don t think it is necessary to ask each individual whether or not he has taken any salicylates. DR. BLAND: The occurrence of hyperuricemia in hyperparathyroidism; hypophosphatemia in certain cases of gout; hypercalciuria, phosphaturia and uricosuria in Wilson s disease; and the occasional simultaneous existence of both gout and hyperparathyroidism in the same patient suggested that uric acid, calcium and phosphorus might have metabolic relationships in common. t was believed that if a common mechanism did exist, then it might be elucidated by experimentally altering metabolic handling of calcium and/or phosphorus and observing a resulting change in uric acid metabolism. Dr. Christobal G. Duarte and attempted to investigate this hypothesis by studying the renal clearance of uric acid, calcium, and phosphorus under the influence of intravenous chlorothiazide, prolonged oral administration of chlorothiazide, calcium, and phosphorus depletion diets and calcium infusions. ntravenous chlorothiazide resulted in a significant increase of the clearance of both phosphorus and uric acid while the decrease of diffusible calcium was equivocal. n contrast, when the drug was given by mouth for 15 days both calcium and uric excretion decreased while changes in phosphorus were equivocal. On the depletion diet there was a fall in clearance of both calcium and uric acid but no significant change in phosphorus clearance. When such diets were followed by calcium infusions the clearance of calcium increased, that of phosphorus decreased while uric acid clearance did not change. Similar results were obtained in hyperuricemic gouty subjects as well as in normals. These results, then, provide little support for an interrelationship in the metabolism and renal handling of calcium, phosphorus, and uric acid in normal and gouty patients.