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Kidney International, Vol. 18 (1980), pp. 677-685

Uricosuric diuretics

BRYAN T. EMMERSON

University of Queensland Department of Medicine at Princess Alexandra Hospital, Brisbane, Australia

Elevation of the serum urate is well recognized as It is now generally accepted that asymptomatic an invariable side effect of treatment with all diuret- hyperuricemia of moderate degree is not in itself a ics except those agents, such as triamterene and justification for drug treatment to lower the serum amiloride, that retain potassium. Practitioners can- urate. Such an acceptance, however, involves an not fail to appreciate the frequency of hyper- assessment of the risk of uric acid as a possible con- uricemia in many of their patients because, even in tributor to both renal disease and to degenerative asymptomatic patients, it is regularly brought to vascular disease [6]. Reports during the nineteenth their attention in the various profiles of biochemical century certainly included both renal and vascular tests. As diuretics are among the most commonly disease as part of the syndrome of gout, but the sug- used drugs, the development of a new drug of this gestion that uric acid might contribute to degenera- class that did not cause hyperuricemia, but which tive vascular disease has generally not been sub- retained many of the other beneficial effects of the stantiated until recently. The first support was pro- oral diuretics, would seem an advantage and would vided by the listing of hype ruricemia among the risk be of considerable interest. There is general agree- factors for coronary artery disease [7, 8], and al- ment that diuretic-induced hyperuricemia is due, at though such a listing does not imply a causative least in part, to increased tubular reabsorption of relationship, such a relationship was for a time as- urate as part of a generalized increase in reabsorp- sumed to exist. This problem of interpretation tion of sodium and other substances in the proximal arises from the fact that hyperuricemia is often an tubule. This results from the plasma volume con- associated feature of several other vascular risk fac- traction secondary to the electrolyte and fluid loss tors, particularly hypertension, obesity, and hyper- during the diuresis [1-4]. The additional possibility triglyceridemia. There have been many detailed as- remains that diuretics may also interfere with some sessments of this interrelationship [9], the most im- of the urate secretory or reabsorptive processes pressive being the Coronary Drug Project in USA within the kidney, either directly or as a result of [10], which concluded that the association of hyper- redistribution of blood flow. uricemia with vascular disease was secondary to other factors and that hyperuricemia was not in it- Uric acid as a risk factor in disease self a primary risk factor. Despite this, however, Enthusiasm for a diuretic that would not cause or there has been a more recent tendency, particularly aggravate hyperuricemia needs to be tempered by among hematologists, to regard hyperuricemia as a an appreciation of the risks of hyperuricemia, some factor that might modify platelet function so as to of which are well known and others of which are increase platelet adhesiveness [11, 12] and thereby less well defined. Thus, it is well established that promote atherosclerosis. The Anturan Study [13], the incidence of gouty arthritis rises roughly in pro- in which a lower incidence of recurrence was ob- portion to the degree of hyperuricemia and that this served in patients recovering from myocardial in- risk becomes considerable at serum urate concen- farction who were treated with large doses of sul- trations persistently over 0.6 mmoles/liter (10 mgI phinpyrazone or anturan, has been taken as indirect dl) [5]. Therefore, patients who have had an attack of gout present a particular problem when they need treatment with a diuretic, and a diuretic can some- Received for publication May 29, 1980 times not be used in patients in whom control of 0085—2538/80/0018-0677 $01.80 hyperuricemia is difficult. © 1980 by the International Society of Nephrology

677 678 Einmerson support for such a thesis. This agent has both a po- suring that a high concentration of uric acid, either tent uricosuric effect as well as an action to reduce in the blood or in the urine, is of no consequence as platelet stickiness. It may well have other additional far as renal function is concerned. The incidence of actions, and there is still uncertainty about whether renal disease secondary to primary gout is quite sig- its apparent beneficial effect after myocardial in- nificant, and occasional patients who have never farction is mediated by its effect on uric acid or by suffered from gouty arthritis have been found to an alternative mechanism such as an antiarrhythmic have renal microtophi on biopsy or at autopsy. action. In summary, although there is some current Thus, although one does not regard uric acid as an evidence to suggest that hyperuricemia may pro- important factor in the induction of renal disease, mote degenerative vascular disease, this is far from one has to accept that there is, at least, some poten- conclusive. tial risk and that it would be better if its concentra- There is also relatively little hard data concerning tion in body fluids was no higher than avoidable. the risk of developing renal disease related to uric Uricosuric diuretics. There are only two un- acid. We know that there are at least two mecha- cosuric diuretics developed to a stage where they nisms whereby uric acid can induce renal damage have been administered to man. Both are phe- [14]. The first occurs when uric acid is deposited noxyacetic acid derivatives and, as such, are chem- within the renal tubules causing tubular obstruction ically most closely related to ethacrynic acid. Of the and subsequent nephron dysfunction. This is often two, ticrynafen or tienylic acid is the more potent reversible by an early, intense alkaline diuresis and uricosuric agent and is already marketed in the is presumably related to the concentration of uric USA.' The other agent, indacrinone, appears to acid in, and the pH of, the tubular fluid. The second have a different mode of action and shows some dis- mechanism by which uric acid can induce renal tinctive features. In man, it is less potently un- damage is by the deposition of monosodium urate cosunic than is ticrynafen, and its ultimate role crystals within the renal interstitium with a resulting seems more likely to be as an agent that does not foreign body reaction and the formation of an inter- affect the serum urate concentration either by in- stitial microtophus. There is evidence that in some creasing it or reducing it, rather than as one which cases this lesion may develop from a uric acid de- positively corrects hyperuricemia. posit that was originally intratubular [15, 16]. It may also develop in situ in the interstitium of the kidney Ticrynafen if local concentrations of urate are appropriate or if Ticrynafen or tienylic acid is the most potent un- there is a deficiency of inhibitors of urate crystalli- cosuric diuretic available. In doses of 250 mg, the zation. We also know that this interstitial micro- diuretic effect is comparable to that of 500 mg of tophus formation may occur in the kidney of pa- chlonothiazide, between 25 and 50 mg of hydro- tients who have never suffered from gouty arthritis chlorothiazide, 25 mg of chlorthalidone or 50 mg of and that it is a not uncommon finding at autopsy if it ethacrynic acid [17]. It has a relatively long duration is carefully sought. We have a local series of over 70 of action, being maximal within 4 hours of adminis- such cases, and a search of their records has in- tration with a slight residual effect persisting to 24 dicated that the major positive correlation of inter- hours. stitial microtophus formation was with preexisting Site and mode of action. During a water diuresis, renal disease. We also know that occasional pa- ticrynafen causes an increase in osmolar clearance tients with normal renal function may develop renal but a reduction in free water clearance, and urine insufficiency when given uricosuric drugs and that, volume does not change significantly. During hy- once again, this can often be reversed by an alkaline dropenia, however, free water reabsorption either diuresis. We presume that it is caused by uric acid crystal deposition in the tubules and that it should After this review was prepared, ticrynafen was withdrawn be preventable by a sufficiently good urine flow rate from the market in the USA because of an unexpectedly high or adequate alkalinization of the urine. When it incidence of hepatic toxicity. There is no evidence that this is does occur, it is likely to occur during the first few related to either the diuretic or uricosuric action of the drug. Be- days of uricosuric treatment when the outpouring of cause of the extensive basic and clinical pharmacology that has uric acid in the urine is greatest. been summarized in the present review, and because such stud- ies will undoubtedly be useful both in the evaluation of basic Thus, in our stage of incomplete knowledge con- mechanisms and in the development of other uricosuric diuret- cerning the factors that can induce renal damage ics, the review has been published in otherwise unmodified form. from uric acid, it is difficult to be too strongly reas- [Editorl Uricosuric diuretics 679

Table 1. Short-term effects of ticrynafen, pyrazinamide, probenecid, and combinations ofthese agents on fractional excretion of uratea Fractional excretion of urate Control Experimental

Ticrynafen 11.2 1.3 47.5 57c Pyrazinamide 10.6 1.3 5.1 0.7e Probenecid 10.7 1.3" 26.0 6•0b Ticrynafen +pyrazinamide 10.7 1.7 13.3 5.0 Ticrynafen +probenecid 11.6 1.4 66.4 2.6 Ticrynafen +probenecid+pyrazinamide 11.2 0•9b 19.6 4.0" a Datais from Ref. 21. Control is the mean SEM ofvalues during three control 20-mm collections. Experimental is the mean SEM of values during experimental 20-mm collections during the 4th hour after medication p <0.05. P <0.005. rises slightly or is unchanged. This indicates that Ticrynafen also induces an increase in net acid the major site of its natriuretic action is in the cor- excretion, and there is a regular fall in urinary pH tical diluting segment of the distal tubule [18, 19] [18]. There is also an overall reduction in urinary and suggests a mode of action similar to the thiazide calcium excretion and an increase in urinary magne- diuretics rather than to that of ethacrynic acid to sium and phosphate excretion [20]. As might be ex- which it is chemically related. Thus, ticrynafen ex- pected from the mode of action being similar to the hibits a natriuretic ceiling similar to the thiazide thiazide diuretics, there is a tendency for the serum group. As a uricosuric agent, it produces a consid- sodium and potassium to fall. Similarly, there is erable increase in urinary uric acid during the first controversy concerning whether the hypotensive few days of treatment, which steadily declines, so action of ticrynafen is fully explicable by the associ- that, with prolonged therapy, there is only a moder- ated loss of salt and water induced by the diuresis. ate increase in uric acid excretion over that in a con- Preliminary evidence in dogs in which the equiva- trol period. Accordingly, any risk of uric acid crys- lent of the urinary losses of salt and water were re- tal deposition within the renal tubules would be placed intravenously suggest a direct hypotensive maximal during the first few days of treatment. Be- effect unrelated to the diuresis [22]. cause the uricosuric response is more intense than The drug has been extensively studied in man. the diuretic response is, it is important to ensure Single doses induce an appreciable diuresis for be- that a good urine flow rate is maintained during this tween 4 and 8 hours. A particular dose will give a time. Studies with pyrazinamide (which, at the more prolonged diuresis if it is given in divided frac- doses used, chiefly blocks tubular secretion of tions at intervals, for example, 60 mg second hourly urate) strongly suggest that the uricosuric action of on four occasions will give a more prolonged diure- ticrynafen is due to inhibition of reabsorption, both sis than will 250 mg administered on one occasion of filtered urate as well as of urate that is secreted [23]. In short-term studies in man, the serum urate into the renal tubule [20]. It is believed that this in- falls within an hour, reaches a minimum at about 8 hibition of reabsorption occurs at presecretory as hours at a value of between 50 and 75% of the pre- well as at postsecretory sites (Table 1) [21]. The ex- treatment value, and returns close to normal values tent of the uricosuria is dose related, and the ef- within 24 hours. The fact that the uricosuric re- fective uricosuric dose is lower than the dose which sponse is the same to a single dose as it is to four will produce an effective antihypertensive or diuret- quarter doses suggests that the uricosuric effect is ic action. The uricosuria induced by 250mg of ticry- not dependent on the plasma concentration of the nafen is greater than that induced by 500 mg of drug. probenecid, and the uricosuria induced by a combi- Absorption, bioavailability, and protein binding. nation of these two drugs is greater than that in- There is a moderate variation in the bioavailability duced by either alone (Table 1). The uricosuric effect, of the drug with evidence of a 2.5-fold range [23]. both alone and with probenecid, is reduced by pyra- Absorption is rapid and plasma concentrations be- zinamide but still remains greater than it is in the tween 15 and 30 g/ml are achieved within an hour. control period. The uricosuria is also reversed by The drug is strongly protein-bound, with greater aspirin. There is no evidence that ticrynafen affects than 99% bound in vitro at therapeutic concentra- urate production or extrarenal elimination. Xan- tions. There appears to be one principal binding site thine oxidase is not inhibited. of high affinity to serum proteins [23]. Accordingly, 680 Einmerson filtration of the drug at the glomerulus is negligible. sufficiency, with or without a dull lumbar pain [27]. The drug is metabolized in the liver to two principal All features have reversed when the drug has been metabolites, the hydroxy metabolite and the diacid ceased or when a diuresis has been induced. The metabolite. Excretion of both drug and metabolites, significance of this finding is a most important one however, appears to be largely via the kidney, that needs further elucidation. Its most likely cause where elimination is complete within about 48 is either an acute tubular dysfunction [27], tubular hours. There is an elimination t'/2 of about 2.8 obstruction from uric acid crystals or an acute inter- hours. stitial nephritis, such as occurs with a wide variety Excretion. As it is so strongly protein-bound, ti- of drugs including allopurinol. When this side effect crynafen must reach the tubule from the antiluminal develops, it is difficult to assess the specific etiology side, and as such, it must be secreted into the tu- in an individual patient because of our limited un- bule. Increasing the pH of the urine increases the derstanding of many of the factors that can induce clearance of ticrynafen considerably. In the dog, a uric acid crystal formation within the renal tubules. fall in the U/P ratios of ticrynafen to creatinine Accordingly, it is now recommended that the drug along the nephron indicates that there is progressive should not be given to a dehydrated patient (or one reabsorption of the drug along the renal tubule. It is who has been on another diuretic during the preced- concluded that there is active secretion of ticryna- ing few days) or to one who cannot maintain a good fen in the proximal tubule with passive pH-depen- urine volume [27]. Only further experience will tell dent reabsorption along the rest of the nephron [24]. whether such preventive measures are sufficient to It seems that ticrynafen most likely enters the lu- eliminate this side effect. Assessment of whether an men through the common organic acid pathway. acute interstitial nephritis has occurred is just as dif- Para-aminohippurate (PA H) is found to depress its ficult because, even when renal biopsy evidence of transport in the proximal tubule and, conversely, ti- this is available, there is usually no comparative his- crynafen also interferes with PAH transport in the tology prior to use of the drug and the patient has proximal tubule. Ticrynafen also reduces the excre- often been on other therapeutic agents that could tion of penicillin, pyrazinamide, and phenolsulfo- themselves have caused such an interstitial nephri- nephthalein (PSP). It seems, therefore, that its tis. Those who use the drug, however, should be transport via the common organic acid pathway in- alert to these possibilities. It should be added, how- volves a carrier that has a higher affinity for ticryna- ever, that the risk of inducing uric acid crystal depo- fen than for PAH. sition within a tubule should be less with a un- Interactions. The major interaction of the drug is cosuric diuretic than it would be with a uricosuric most likely to be associated with the oral anti- drug that is not a diuretic. Studies have shown that coagulants because of its high protein-binding affini- the use of ticrynafen is not associated with an in- ty and the anticipation that protein-binding dis- crease in the degree of urinary supersaturation for placement might occur between ticrynafen and oth- uric acid or monosodium urate [28]. If this is cor- er anionic drugs. Although direct tests involving the rect, it makes it even more difficult to interpret addition of ticrynafen did not show an effect on the these occasional serious reactions involving the kid- serum protein binding of warfarin [25], it is general- ney. One must also bear in mind, however, the in- ly recommended that the drug not be used in con- creased acid excretion induced by the drug, and this junction with oral anticoagulants. may be one of the variables that contributes to any Complications. Side effects of the drug have been intratubular crystal deposition. It should be remem- relatively few. As high doses have been ototoxic in bered, however, that more ticrynafen will be reab- cats and guinea pigs, its use in very high dosage or sorbed from the tubular lumen as the pH of the in renal failure should be monitored by plasma lev- tubular fluid falls, and as the uricosuric response ap- els. No effect on hearing, however, has been dem- pears to be related to the concentration of ticryna- onstrated in man. The acute falls in the serum urate fen in the tubular fluid [29], so there should be a concentration that occur might be expected to pre- lessening of the uricosuria with increasing acidity of cipitate acute attacks of gout but this has not been a the urine. Such increasing acidity would be associ- frequent development. The chief problem has been ated with an increased tendency to intraluminal uric the development in a few patients of an episode of acid precipitation. acute reversible renal insufficiency, the incidence Clinical use. Ticrynafen has had extensive clini- being assessed as about 1 in 50,000 cases [26]. cal use prior to its release in the USA. A dose of 250 When it occurs, this has tended to be seen after the mg a day is effective in causing a fall in blood pres- first or the second dose and has shown up either as a sure, a fall in the serum urate concentration, and reduction in urine volume or with transient renal in- effects on sodium, potassium and chloride very sim- Uricosuric diuretics 681 ilar to those of the thiazide diuretics. As shown in a velopment than ticrynafen, and there have been recent large Veterans Administration study of the fewer studies of its action in man. Regarding its site treatment of hypertension [30], there is a tendency of action, studies in the rat demonstrated depres- for a greater elevation of the serum creatinine sion of both net solute-free water excretion and wa- concentration with ticrynafen than with hydro- ter reabsorption and were therefore interpreted as chiorothiazide, but both of these effects reverse on indicating that its major diuretic action occurred in withdrawal of the drug. It is of particular interest the loop of Henle and the collecting ducts [34]. Mi- that simultaneous frusemide has an additive diuretic cropuncture studies [35] showed that sodium and effect, whereas hydrochlorothiazide does not have water reabsorption was unchanged in the proximal any such additive effect [17], thereby providing fur- tubules, and there was no effect on transport in the ther support for a different site for the diuretic ac- distal tubule, whereas reabsorption was markedly tion of the two drugs. As a uricosuric, the response inhibited between the late proximal and early distal at lower doses is dose-related. Uricosuria is appar- micropuncture sites, namely the loop of Henle. If ent with a dose of as little as 50 mg, which has no similar conclusions are reached from studies in appreciable diuretic effect [17]. In acute studies, the man, it will indicate quite a different site of action uricosuric effect increases as the doses rise to 250 or for this compound from ticrynafen and will suggest 500 mg per day. In the large Veterans Administra- that its mode of action will be more like frusemide tion study of patients with hypertension [30], there than chlorothiazide. was, however, no greater fall in serum urate with a The uricosuric effect has been attributed to inhi- dose of 500 mg than with a dose of 250 mg, so that bition of reabsorption and secretion of urate in the the potential for considerable uricosuria by progres- proximal tubule [34, 36], the net effect being an in- sive increase in dose appears to be limited. The si- crease in urate excretion. Its uricosuric action has multaneous administration of hydrochlorothiazide been extensively studied in the chimpanzee [37], or frusemide does not overcome the uricosuria. In which, despite some significant differences, is prob- one study [31], a fall of the serum potassium was ably as close an animal model as one can get to man noticed with 6 weeks of treatment with ticrynafen, a in regard to renal handling of urate. These studies rise in serum potassium with comparable treatment showed a fivefold to sevenfold increase in the urate with propranolol, and no net effect on serum potas- clearance in relation to the GFR. Indacrinone over- sium when the combination of ticrynafen and pro- comes the urate retention induced by pyrazinamide, pranolol was administered. As a hypotensive agent, and pyrazinamide only slightly reduces the un- it is comparable with hydrochlorothiazide [32], and cosuria due to indacrinone. This is in contrast to the the hypotensive effect is additive to that of beta effect of probenecid, the uricosuria of which is con- blockers. Its special therapeutic value is most likely siderably reduced by pyrazinamide. Pyrazinamide to be as an adjuvant hypotensive agent in persons has no effect on the diuretic action, again empha- who are already hyperuricemic or who have suf- sizing the disparity between the diuretic and the un- fered from gout. cosuric effects of the drug. No effect has been dem- There is relatively little information concerning onstrated on phosphate excretion, and this absence its use in significant renal insufficiency, that is, at a of any effect on the excretion of another substance serum creatinine concentration greater than 0.2 that is transported in the proximal tubule suggests mmoles/liter. Like the thiazides, the response be- strongly that the uricosuric action is not part of a comes less with increasing renal insufficiency. The generalized effect on proximal tubular transport, need for a uricosuric diuretic, however, is particu- but rather a specific one on urate transport alone. larly great in patients with renal insufficiency, and This is further supported by the finding that the drug we are currently studying the kinetics of the drug in has no effect on proximal tubular transport of so- this situation and the pharmacodynamic response. dium. There is, however, an increased excretion of As with hydrochiorothiazide, there is a transient both calcium and magnesium, which has been at- but appreciable increase in the serum creatinine and tributed to inhibition of their reabsorption at a distal urea concentrations [32, 33], but to-date we do not site. have sufficient information to make a direct com- Absorption, protein binding, and metabolism. In- parison between these two drugs. dacrinone is well absorbed from the alimentary tract, and peak plasma levels are achieved within an Indacrinone hour in both animals and man. Like ticrynafen, The second uricosuric diuretic, indacrinone, a more than 99% is strongly bound to protein. Its me- phenylindanyloxyacetic acid, was originally re- tabolism differs in different species, but its major ferred to as MK-196. It has been a more recent de- metabolite appears to be derived from para-hy- 682 Einmerson droxylation of the phenyl moiety, with subsequent control excretion. The increases in urinary urate methylation. There appears to be minimal, if any, that occurred were not significant, and there was no glucuronide formation in man. The peak plasma significant change in the serum urate concentration. concentration of metabolite occurs at between 4 It has an effective antihypertensive action. As well and 6 hours after administration. as being uricosuric, it promotes the renal excretion Excretion. Although its excretion appears to be of potassium, calcium, and magnesium but does not chiefly by the fecal route in the rat and dog [38, alter phosphate excretion. Potassium supplements 39], the major route of excretion in both man and may be needed. the chimpanzee appears to be by the kidney. The Dose-response study. Initial studies in human pattern of elimination is similar to that of other volunteers indicated that, although a 10-mg dose weak organic acids and ticrynafen in that it is se- was both diuretic and uricosuric, it had relatively creted by the proximal tubule (a process strongly little sustained effect on the serum urate concentra- inhibited by probenecid and a high PAH load) and tion. We therefore looked at the question of the passively diffuses back across the tubular epithe- dose-response relationship of indacnnone in healthy hum by a pH-dependent process. Alkalinization of subjects to determine whether larger doses of the the urine increases its excretion by up to ten times. drug would have a greater uricosuric effect without In man, 50%ofa dose of the labeled drug is ex- there necessarily being an equivalent increase in the creted in the urine, mostly in the first 24 hours, and diuretic action [40]. Thus, in volunteers under stan- another 40%isexcreted in the feces. Of that ex- dardized conditions, the response to different doses creted in the urine, 25%appearsas indacrynone and of the drug was compared with excretion rates dur- 70% as metabolites, the excretion of the metabolites ing a control period and compared with the response being somewhat slower than that of the parent com- to frusemide. The changes that occurred after its pound. administration in the rate of excretion of sodium Clinical use. Indacrinone appears to be inter- and urate in comparison with the preceding control mediate between a short-acting diuretic such as day, at intervals of 0 to 6 hours, 6 to 12 hours and 12 frusemide and a longer acting diuretic such as hy- to 24 hours, are shown in Figs. 1 and 2. There was drochiorothiazide in relation to time of onset of a progressive dose-dependent increase in urine flow maximum activity and the duration of diuretic activ- rate and in the urinary excretion of sodium, potas- ity. Most of its activity occurs within 8 hours, and a sium, and urate with doses of indacrinone between 10-mg dose is comparable with 40 mg of frusemide 20 mg and 80 mg. The natriuretic response to the or 50 mg of hydrochiorothiazide. Repeated daily ad- 20-mg dose was comparable with that to 40 mg of ministration for up to 2 weeks has shown sustained frusemide but was of significantly greater duration but barely significant increases in saluresis over the at each of the dose levels tested. Urate excretion

I ndacrinone Fru semide 0.8 20 mg 40 mg 60mg 80 mg 40 mg

0.6 I I

LU 0.4

1 I 0.2 0to 6hr E 6tol2hr •l2to24hr I 0.4 0to21hfJ

Fig.1. Mean changes (+sD) in urinary sodium excretion rate of healthy volunteers at various time intervals on the day of treatment with indacrinone or frusemide, in comparison with the control day. (Reproduced from Emmerson et al [40] with permission of Plenum Publishing Corporation) Uricosuric diuretics 683 excretion of urate or to a response to the plasma volume contraction resulting from the diuresis, which results in an increase in proximal tubular 0. I ndacrinone Frusemide reabsorption of urate leading to a reversal of the 20mg 40mg 40mg primary uricosuric effect. Weight loss occurred with the diuretic effect, resulting in an average loss 0 of 0.9 kg at a 20-mg dose, 1.4 kg at the 40-mg dose, and 2.2 kg at the 60- and 80-mg dose. There was no >. significant fall in the standing blood pressure, al- C S though postural hypotension was seen occasionally. 0 The pulse rate, however, did rise and consistently C reached a peak between 12 and 24 hours after ad- nS 0.1 0 ministration of the drug (Fig. 3), and this may well be a reflection of a reduced circulating plasma vol- Oto 6hrj fl 6tol2hr ume. Certainly, a rise in the serum urate tends to U12 to 24 hr parallel and follow the rise in the pulse rate, and it to 24 hr may be that, at this time, the uricosuric effect is not Fig.2. Mean changes (+ SD)inurinary urate excretion rate of sufficiently great to overcome the urate retention in- healthyvolunteers at various time intervals on the day of treat- duced by the plasma volume contraction resulting ment with indacrinone orfrusemide, in comparison with the con- trol day. (Reproducedfrom Emmerson et a! [40] with permission from the diuresis. Further studies with replacement of Plenum Publishing Corporation) of the losses of salt and water have not been under- taken, so that the precise mechanism of this rever- sal of the unicosuric effect has not been determined. (Fig. 2), however, was of particular interest be- Combination with amiloride. Our subsequent cause, whereas frusemide caused an invariable studies, again in healthy volunteers, have been di- reduction in urinary urate excretion at all time in- rected towards a different question, namely the as- tervals, indacrinone induced an appreciable un- sociated increase in the excretion of potassium and cosuria during the first 6-hour period but a reduc- the fall in urine pH. On this occasion, a dose of 10 tion in urate excretion in the remainder of the mg of indacrinone was used, which gave a response 24-hour period of observation. The overall effect comparable with that of 40 mg of frusemide or 50 resulted in no net change in urinary urate excretion. mg of hydrochlorothiazide. Its effect was studied in Such a biphasic response is of considerable interest 12 healthy subjects by comparing, in random order, and could be due either to the paradoxical effect the response to a placebo, to a 10-mg dose of in- of different concentrations of the drug on net renal dacrinone, and to the addition to this dose of in-

Frusemide 0.8 20mg 40mg 60mg 80mg 40mg 40

0.6 30

0.4 20 0 0.2 E g0= / = LI , 0.2 = H6 L :1 4: of o 0.4 Hours after medication A0 E=24 0.6 B=4 F=32 C=8 G=48 0 = 12

Fig. 3.Changesin serumurate concentrations on treatment day in comparison with control day at different times after the administra- tion ofindacrinone orfrusemide(blocks).The changes in the pulse rate have been superimposed and joined by a line. (Reproduced from Emmerson et al [40] with permission of Plenum Publishing Corporation) 684 Emmerson dacrinone of either 2.5 or 5 mg of the potassium- as causing natriuresis and chloruresis, both pro- retaining agent amiloride. This dose of indacrinone mote excretion of potassium, hydrogen, and magne- produced a significant diuresis and natriuresis, sium ions. Both are strongly protein-bound, and which were not affected significantly by the addition both appear to enter the renal tubule by active se- of either dose of amiloride. Again, uricosuria was cretion via the common organic acid pathway, demonstrated during the first 4-hour period and which can be blocked by PAH. Within the tubule, slight urate retention during the 12- to 24-hour peri- they are reabsorbed by a passive pH-dependent od; there was minimal net effect on the serum urate process, which is reduced by alkalinization of the concentration. The addition of 2.5 mg of amiloride urine. The extent of the uricosuria appears to be re- reduced potassium excretion to levels not signifi- lated to the concentration of the drug in the urine. cantly different from those in the control period. In- There also appear to be some distinctive features. dacrinone alone caused a considerable fall in urine In man, ticrynafen appears to exert its diuretic ef- pH, which was greatly reduced (although not quite fect by an action on the cortical diluting segment of to that of the control period) by the addition of 2.5 the distal tubule. This is similar to that of the thia- mg of amiloride. It seems, therefore, that the addi- zides, and frusemide has an additive diuretic effect, tion of 2.5 mg of amiloride to a 10-mg dose of in- thereby suggesting a different site of action in the dacrinone results, in normal subjects, in the correc- nephron. The diuretic action of indacrinone, by tion of the associated kaluresis and the fall in urine contrast, appears to lie in the ascending limb of the pH. Correction of this latter feature may be of par- loop of Henle in the rat, but has not been precisely ticular significance in view of the associated un- defined in man. In this, it seems more like frusemide cosuria, in which the increased urinary uric acid ex- itself. Ticrynafen has a potent uricosuric effect in cretion would otherwise occur into an increasingly man, and its use has rarely been associated with acid urine. transient renal insufficiency, which has reversed on More recent studies of indacrinone have shown stopping the drug. This has been attributed to uric that apparently minor variations in its structure can acid crystal deposition within the renal tubules, but produce important alterations in its pharma- alternative explanations are possible. Its use should codynamic responses. It is therefore possible to be avoided in dehydrated patients or those with a produce a number of compounds with a wide range persistently acid urine. Indacrinone by comparison of uricosuric/diuretic ratios. For a given diuretic ef- appears to resemble the high-ceiling diuretics in fect, some of these compounds exhibit a lesser un- man, and increasing doses show an increasing diu- cosuric effect, whereas others may have a greater retic and uricosuric effect. In healthy subjects, the uricosuric response. Alternatively, if the uricosuria initial uricosuria of indacrinone lasts only about 6 is the desired response, a variety of diuretic re- hours and is followed by urate retention, so that sponses can be developed. In particular, it has been there is minimal resultant change in the plasma realized that the parent compound, indacrinone, is a urate concentration. The concomitant administra- racemic mixture of two enantiomorphs, each with tion of amiloride with indacrinone abolishes the in- apparently different uricosuric/diuretic activities, creased excretion of hydrogen and potassium ions. and each individually different from the racemate Both agents promise to provide a useful extension (Jeremy, personal communication). The positive of our current diuretic and antihypertensive thera- enantiomorph is potently uricosuric and only mod- py. erately natriuretic, whereas the negative enanti- omorph has a greater natriuretic action but a much Reprint requests to Prof. B. T. Emmerson, Department of Medicine, Princess Alexandra Hospital, lpswich Road, Brisbane smaller uricosuric action. 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