4 Drug-induced gout J. T. S C O T T
Gouty arthritis occurs in people who have been, usually unknown to themselves, hyperuricaemic for a period of years, leading to deposition of crystals of sodium urate in the joints (and elsewhere) and thence to the acute inflammatory response characteristic of acute gout. Accumulation of deposits of urate later results in the formation of tophi and the condition of chronic tophaceous gouty arthritis. It has become commonplace to emphasize the multifactorial nature of hyperuricaemia and the many influences, genetic and environmental, which contribute to an individual's serum uric acid level. The familial occurrence of primary gout is polygenic, specific mendelian-inherited abnormalities of enzyme activity (such as deficiency of hypoxanthine guanine phosphoribosyltransferase) being very rare. To such genetic influences are often added important environmental factors, namely food (with regard to both calorie and purine content), alcohol and drugs, which can in various ways affect the formation and excretion of uric acid, the end-product of purine metabolism in man.
F O R M A T I O N A N D E X C R E T I O N OF URIC ACID
Purines are derived exogenously from the diet or endogenously either from the turnover of preformed nucleotide pools in cells and tissues (adenosine triphosphate [ATP], guanosine triphosphate [GTP] or the nucleic acids DNA and RNA, etc) or by de n o v o biosynthesis. It appears that dietary purines are not incorporated into intracellular purine nucleotide pools but instead are rapidly degraded to uric acid (L6ffler et al, 1982). A prime compound in purine biosynthesis is 5-phosphoribosyl-1pyrophosphate (PRPP), synthesis of which from ribose-5-phosphate and ATP is catalysed by the enzyme PRPP synthetase. The first specific step in purine biosynthesis, and one which appears to be rate-limiting for the whole subsequent sequence of reactions, consists of the conversion of PRPP to 5-phosphoribosylamine, the pyrophosphate group being replaced by the amide group of glutamine. The availability of PRPP appears to be the main regulator of de n o v o purine biosynthesis, which follows ten further stages to culminate in the formation of inosinic acid (inosine-5'-monophosphate; Bailli~re's Clinical Rheumatology-Vol. 5, No. 1, April 1991 ISBN 0-7020-1535-0
39 Copyright 9 1991, by Bailli6re Tindall All rights of reproduction in any form reserved
40
J.T. SCOTT
IMP), the first complete purine nucleotide. A complex process of interconversion reactions with other nucleotides takes place, with breakdown to nucleosides and purines (Wyngaarden and Kelley, 1976). Uric acid is formed from inosinic acid via oxidation to inosine, hypoxanthine and xanthine, the last two steps being mediated by the enzyme xanthine oxidase. Lacking the enzyme uricase (present in most mammals), man excretes uric acid as such. Less than one third of the uric acid to be excreted passes into the gastrointestinal tract, where it is oxidized to allantoin, allantoic acid, urea and carbon dioxide by uricase and other enzymes present in intestinal bacteria; approximately 1.2 mmol (200 mg) of uric acid is excreted daily in this way (Sorensen, 1960). Disposal of uric acid, however, is mainly through the kidney. The normal daily urinary excretion of uric acid on a purine-free diet averages 2.4 mmol (400 mg) and is usually less than 3.6 mmol (600 rag), although it can rise to as much as 6.0mmol or more on an unrestricted diet. Mean estimates of renal clearance of urate in normal subjects range from 5.8ml/min (Snaith and Scott, 1971) to 8.7 ml/min (Gutman and Y~i, 1957), less than one-tenth of the inulin clearance. Despite uncertainties concerning the significance of plasma urate binding, it is generally accepted that most uric acid in the plasma is freely filterable at the glomerulus, that a large part of the filtrate is reabsorbed in the proximal renal tubule, and that urinary urate is derived largely from further active tubular secretion (Milne, 1966; Steele, 1971). Evidence for active tubular secretion comes from various sources: (a) rare cases have been described of hypouricaemia associated with urate clearance which exceeded that of inulin, following the original report by Praetorius and Kirk in 1950; (b) it is possible, under certain experimental conditions, to raise urate clearance above that of inulin in normal individuals (Gutman et al, 1959); and (c) the paradoxical effect of salicylates and other uricosuric agents, which reduce urate excretion in low doses but enhance it when given in higher dosage, is most readily explained by postulating inhibition of secretion alone at low dose levels, and inhibition of both secretion and absorption at higher levels (Yii and Gutman, 1959). Although bidirectional tubular transport of urate is reasonably well established in different mammalian species (Roch-Ramel and Weiner, 1980), details of its components remain to be clarified. These include filtration followed by a bidirectional tubular transport system involving reabsorption, secretion and finally postsecretory reabsorption. The exact sites of these transport systems within the nephron are not known and they may coexist extensively throughout the proximal tubule (Weiner, 1979). The interrelationship of reabsorption and excretion is extremely complex: there is, for example, some evidence that further reabsorption takes place in segments distal to or coextensive with the site for active secretion and that a proportion of secreted urate is itself reabsorbed (Diamond and Paolino, 1973). In chronic renal disease, urate secretion is markedly decreased but with an increase in the fractional excretion of filtered urate. In severe renal disease 45% of filtered urate may escape reabsorption and be excreted. Thus, while tubular secretion is the principal mechanism for urate excretion in normal
DRUG-INDUCED GOUT
41
and moderately diseased kidneys, glomerular filtration takes on this role in advanced disease (Steele and Rieselbach, 1967). Drugs and chemical compounds can produce hyperuricaemia and gout by increasing the rates of formation of uric acid (e.g. 2-ethylamino-l,3,4thiadiazole) or by inhibiting excretion (e.g. diuretics, pyrazinamide). Sometimes both processes appear to be involved (e.g. alcohol, nicotinic acid). Diuretic-induced hyperuricaemia is a comparatively recent phenomenon but is now seen on a global scale and is a leading cause of secondary gout. The relation of alcohol (regarded here as a drug rather than simply as a beverage) to gout has been a clinical observation of much longer duration. The influence of these and other drugs upon uric acid levels and gout will now be considered in some detail. DIURETICS Diuretics and hyperuricaemia During the years when mercurial diuretics were in widespread use the complications of gout and hyperuricaemia were not noted. Nor were the effects of mersalyl upon uric acid excretion well documented, and in any case the drug was not administered on a continuous long-term basis (characteristically for the treatment of hypertension) in the same way as more recent diuretics. The introduction of benzothiadiazines and related compounds was soon followed by the realization that hyperuricaemia and gout could occur as a side-effect of their prolonged use (Laragh et al, 1958) and the same was subsequently found to apply to the 'loop' diuretics such as ethacrynic acid (Cannon et al, 1965) and frusemide (furosemide USP)(Stason et al, 1966), and, to a lesser extent, to the carbonic anhydrase inhibitor acetazolamide (Ayvazian and Ayvazian, 1961). Some elevation of serum uric acid is probably very common in patients taking these diuretics, although the level may not necessarily rise above the normal range. The incidence of definite hyperuricaemia is uncertain and indeed published sources differ in their findings. Case selection, different definitions of hyperuricaemia, choice and dosage of drug and many other factors no doubt contribute to such differences, while assessment of the effect is made more difficult by the fact that the diuretic is often being administered for a condition which may itself predispose to hyperuricaemia. This applies especially to hypertension. Breckenridge (1966) found that of 333 untreated patients with hypertension, 90 (27%) were hyperuricaemic, the prevalence rising to 274 out of 470 patients (58%) who were being treated. Cannon et al (1966) observed hyperuricaemia in 38% of all their untreated patients with hypertension, rising to 67% of patients receiving thiazides, whereas Beevers et al (1971) found a serum uric acid of greater than 420 txmol/1 in only 18% of their hypertensive patients treated with hydroftumethiazide, with only four of their 227 patients developing clinical gout.
42
~. T. scott
Treatment of hypertension with bendrofluazide was found to raise the serum uric acid by a mean of 68 txmol/1 in men and 72 ~mol/1 in women (Medical Research Council Working Party on Hypertension, 1981), with a significant incidence of gout in men. A fixed dose of 10 mg was used. Carlsen et al (1990) found that doses of bendrofluazide varying from 1.25 to 10mg daily all reduced the diastolic blood pressure to the same degree, but that serum uric acid levels were increased in a graded manner, from a mean rise of 19 txmol/1 with 1.5 mg daily to 68 txmol/1 with 10 mg daily. Treating 23 elderly patients for systolic hypertension with hydrochlorothiazide 50 mg daily, Vardan et al (1983) found a mean increase in serum uric acid from 336 ixmol/l to 390 Ixmol/1 (P
Gouty arthritis occurs in people who have been, usually unknown to themselves, hyperuricaemic for a period of years, leading to deposition of crystals of sodium urate in the joints (and elsewhere) and thence to the acute inflammatory response characteristic of acute gout. Accumulation of deposits of urate later results in the formation of tophi and the condition of chronic tophaceous gouty arthritis. It has become commonplace to emphasize the multifactorial nature of hyperuricaemia and the many influences, genetic and environmental, which contribute to an individual's serum uric acid level. The familial occurrence of primary gout is polygenic, specific mendelian-inherited abnormalities of enzyme activity (such as deficiency of hypoxanthine guanine phosphoribosyltransferase) being very rare. To such genetic influences are often added important environmental factors, namely food (with regard to both calorie and purine content), alcohol and drugs, which can in various ways affect the formation and excretion of uric acid, the end-product of purine metabolism in man.
F O R M A T I O N A N D E X C R E T I O N OF URIC ACID
Purines are derived exogenously from the diet or endogenously either from the turnover of preformed nucleotide pools in cells and tissues (adenosine triphosphate [ATP], guanosine triphosphate [GTP] or the nucleic acids DNA and RNA, etc) or by de n o v o biosynthesis. It appears that dietary purines are not incorporated into intracellular purine nucleotide pools but instead are rapidly degraded to uric acid (L6ffler et al, 1982). A prime compound in purine biosynthesis is 5-phosphoribosyl-1pyrophosphate (PRPP), synthesis of which from ribose-5-phosphate and ATP is catalysed by the enzyme PRPP synthetase. The first specific step in purine biosynthesis, and one which appears to be rate-limiting for the whole subsequent sequence of reactions, consists of the conversion of PRPP to 5-phosphoribosylamine, the pyrophosphate group being replaced by the amide group of glutamine. The availability of PRPP appears to be the main regulator of de n o v o purine biosynthesis, which follows ten further stages to culminate in the formation of inosinic acid (inosine-5'-monophosphate; Bailli~re's Clinical Rheumatology-Vol. 5, No. 1, April 1991 ISBN 0-7020-1535-0
39 Copyright 9 1991, by Bailli6re Tindall All rights of reproduction in any form reserved
40
J.T. SCOTT
IMP), the first complete purine nucleotide. A complex process of interconversion reactions with other nucleotides takes place, with breakdown to nucleosides and purines (Wyngaarden and Kelley, 1976). Uric acid is formed from inosinic acid via oxidation to inosine, hypoxanthine and xanthine, the last two steps being mediated by the enzyme xanthine oxidase. Lacking the enzyme uricase (present in most mammals), man excretes uric acid as such. Less than one third of the uric acid to be excreted passes into the gastrointestinal tract, where it is oxidized to allantoin, allantoic acid, urea and carbon dioxide by uricase and other enzymes present in intestinal bacteria; approximately 1.2 mmol (200 mg) of uric acid is excreted daily in this way (Sorensen, 1960). Disposal of uric acid, however, is mainly through the kidney. The normal daily urinary excretion of uric acid on a purine-free diet averages 2.4 mmol (400 mg) and is usually less than 3.6 mmol (600 rag), although it can rise to as much as 6.0mmol or more on an unrestricted diet. Mean estimates of renal clearance of urate in normal subjects range from 5.8ml/min (Snaith and Scott, 1971) to 8.7 ml/min (Gutman and Y~i, 1957), less than one-tenth of the inulin clearance. Despite uncertainties concerning the significance of plasma urate binding, it is generally accepted that most uric acid in the plasma is freely filterable at the glomerulus, that a large part of the filtrate is reabsorbed in the proximal renal tubule, and that urinary urate is derived largely from further active tubular secretion (Milne, 1966; Steele, 1971). Evidence for active tubular secretion comes from various sources: (a) rare cases have been described of hypouricaemia associated with urate clearance which exceeded that of inulin, following the original report by Praetorius and Kirk in 1950; (b) it is possible, under certain experimental conditions, to raise urate clearance above that of inulin in normal individuals (Gutman et al, 1959); and (c) the paradoxical effect of salicylates and other uricosuric agents, which reduce urate excretion in low doses but enhance it when given in higher dosage, is most readily explained by postulating inhibition of secretion alone at low dose levels, and inhibition of both secretion and absorption at higher levels (Yii and Gutman, 1959). Although bidirectional tubular transport of urate is reasonably well established in different mammalian species (Roch-Ramel and Weiner, 1980), details of its components remain to be clarified. These include filtration followed by a bidirectional tubular transport system involving reabsorption, secretion and finally postsecretory reabsorption. The exact sites of these transport systems within the nephron are not known and they may coexist extensively throughout the proximal tubule (Weiner, 1979). The interrelationship of reabsorption and excretion is extremely complex: there is, for example, some evidence that further reabsorption takes place in segments distal to or coextensive with the site for active secretion and that a proportion of secreted urate is itself reabsorbed (Diamond and Paolino, 1973). In chronic renal disease, urate secretion is markedly decreased but with an increase in the fractional excretion of filtered urate. In severe renal disease 45% of filtered urate may escape reabsorption and be excreted. Thus, while tubular secretion is the principal mechanism for urate excretion in normal
DRUG-INDUCED GOUT
41
and moderately diseased kidneys, glomerular filtration takes on this role in advanced disease (Steele and Rieselbach, 1967). Drugs and chemical compounds can produce hyperuricaemia and gout by increasing the rates of formation of uric acid (e.g. 2-ethylamino-l,3,4thiadiazole) or by inhibiting excretion (e.g. diuretics, pyrazinamide). Sometimes both processes appear to be involved (e.g. alcohol, nicotinic acid). Diuretic-induced hyperuricaemia is a comparatively recent phenomenon but is now seen on a global scale and is a leading cause of secondary gout. The relation of alcohol (regarded here as a drug rather than simply as a beverage) to gout has been a clinical observation of much longer duration. The influence of these and other drugs upon uric acid levels and gout will now be considered in some detail. DIURETICS Diuretics and hyperuricaemia During the years when mercurial diuretics were in widespread use the complications of gout and hyperuricaemia were not noted. Nor were the effects of mersalyl upon uric acid excretion well documented, and in any case the drug was not administered on a continuous long-term basis (characteristically for the treatment of hypertension) in the same way as more recent diuretics. The introduction of benzothiadiazines and related compounds was soon followed by the realization that hyperuricaemia and gout could occur as a side-effect of their prolonged use (Laragh et al, 1958) and the same was subsequently found to apply to the 'loop' diuretics such as ethacrynic acid (Cannon et al, 1965) and frusemide (furosemide USP)(Stason et al, 1966), and, to a lesser extent, to the carbonic anhydrase inhibitor acetazolamide (Ayvazian and Ayvazian, 1961). Some elevation of serum uric acid is probably very common in patients taking these diuretics, although the level may not necessarily rise above the normal range. The incidence of definite hyperuricaemia is uncertain and indeed published sources differ in their findings. Case selection, different definitions of hyperuricaemia, choice and dosage of drug and many other factors no doubt contribute to such differences, while assessment of the effect is made more difficult by the fact that the diuretic is often being administered for a condition which may itself predispose to hyperuricaemia. This applies especially to hypertension. Breckenridge (1966) found that of 333 untreated patients with hypertension, 90 (27%) were hyperuricaemic, the prevalence rising to 274 out of 470 patients (58%) who were being treated. Cannon et al (1966) observed hyperuricaemia in 38% of all their untreated patients with hypertension, rising to 67% of patients receiving thiazides, whereas Beevers et al (1971) found a serum uric acid of greater than 420 txmol/1 in only 18% of their hypertensive patients treated with hydroftumethiazide, with only four of their 227 patients developing clinical gout.
42
~. T. scott
Treatment of hypertension with bendrofluazide was found to raise the serum uric acid by a mean of 68 txmol/1 in men and 72 ~mol/1 in women (Medical Research Council Working Party on Hypertension, 1981), with a significant incidence of gout in men. A fixed dose of 10 mg was used. Carlsen et al (1990) found that doses of bendrofluazide varying from 1.25 to 10mg daily all reduced the diastolic blood pressure to the same degree, but that serum uric acid levels were increased in a graded manner, from a mean rise of 19 txmol/1 with 1.5 mg daily to 68 txmol/1 with 10 mg daily. Treating 23 elderly patients for systolic hypertension with hydrochlorothiazide 50 mg daily, Vardan et al (1983) found a mean increase in serum uric acid from 336 ixmol/l to 390 Ixmol/1 (P
