Clinical pharmacology of non-steroidal anti-inflammatory drugs

Pharmac. Ther. Vol. 33, pp. 383 to 433, 1987 Printed in Great Britain. All rights reserved

0163-7258/87 $0.00+0.50 Copyright © 1987 Pergamon Journals Ltd

Specialist Subject Editor: M. ORME

CLINICAL

PHARMACOLOGY OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

RICHARD O. DAY, GARRY G. GRAHAM, KENNETH M. WILLIAMS, G. DAVID CHAMPION and JULIEN DE JAGER Departments of Clinical Pharmacology and Rheumatology, St. Vincent's Hospital, Dadinghurst, N. S. W. 2010, Australia

1. INTRODUCTION Non-steroidal anti-inflammatory drugs (NSAIDs) are reversibly-acting drugs which are widely used for their analgesic, anti-inflammatory and antipyretic actions. NSAIDs are generally well tolerated, although they commonly cause adverse gastrointestinal effects. A large number of NSAIDs have been introduced in recent years. In general, the therapeutic effects of the new NSAIDs are not superior to the older drugs, such as aspirin, indomethacin and phenylbutazone, but the newer NSAIDs are better tolerated. This review contains a description of the general features of the pharmacological activities of NSAIDs relevant to their use in the rheumatic diseases. A feature of the NSAIDs is the marked intersubject variability in response and incidence of side effects. This aspect of the clinical pharmacology of NSAIDs is discussed in detail. 1.1. REVERSIBILITY OF ACTION

The pharmacological effects of NSAIDs are established rapidly once plasma concentrations have reached steady state. Maximal effects occur within a few days for NSAIDs with short half-lives (Aarons et al., 1983; Huskisson et al., 1974). By contrast, NSAIDs with long half-lives accumulate and maximal efficacy of these drugs may be delayed for several days (Section 2.3.5). Pain appears to respond faster than other signs of inflammation such as joint swelling and heat (Aarons et al., 1983; Bacon et al., 1976). Upon cessation of treatment with NSAIDs, drug effects dissipated as fast as they had appeared. The reversibility of action of NSAIDs is in keeping with their major mode of action, namely the reversible inhibition of cyclooxygenase, the enzyme complex involved in the synthesis of prostaglandins and other prostanoids (Section 2.2). Aspirin is the only NSAID which is an irreversible inhibitor of cyclooxygenase, the irreversible inhibition being due to acetylation of the cyclooxygenase enzyme complex. However, irreversible inhibition is not always demonstrated in the clinical effects of aspirin, although it can be detected by the presence of prolonged inhibition of platelet function. The marked toxicity of aspirin in the stomach may also be due to acetylation of cyclooxygenase or other constituents of the gastric mucosa (Rainsford and Brune, 1976). 1.2. DISTINCTIONBETWEENNSAIDs AND SAARDs NSAIDs are considered to provide symptomatic treatment only and not to slow the progression of rheumatoid arthritis (RA). This conclusion stems from the observations that NSAIDs have little effect on the erythrocyte sedimentation rate (ESR) or other acute phase reactants in patients with RA. They also have little effect on rheumatoid factor titres or the appearance of structural damage such as articular bone erosions and they do not induce remissions in RA. There is conflicting evidence about the influence of NSAIDs on the destruction of cartilage in osteoarthritis (OA) (Brooks et al., 1982; Doherty et al., 383

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1986). There is evidence that NSAIDs slow degenerative changes (Chrisman et al., 1972; Roach et al., 1975). On the other hand, NSAIDs inhibit cartilage synthesis in vitro although the unbound concentrations at which this effect is shown are greater than those observed during therapy (McKenzie et al., 1976; Palmoski et al., 1980). The therapeutic activity of NSAIDs contrasts with the actions of slow acting antirheumatic drugs (SAARDs) such as gold and penicillamine which do affect acute phase reactants and rheumatoid factor titres significantly and can induce complete or partial remissions in RA. However, the distinction between NSAIDs and SAARDs has become blurred, with some compounds possibly sharing properties of both NSAIDs and SAARDS. Thus, fenclofenac, in most respects a classical NSAID, has been observed to cause clinically significant declines in ESR and C-reactive protein as well as clinical responses in RA similar to those produced by D-penicillamine and gold complexes (Berry et al., 1980; Goldberg and Godfrey, 1983). Alclofenac, another phenylacetic acid, was thought to have SAARD-like properties, although this has been disputed (Bird et al., 1980). Both alclofenac and fenclofenac, however, have been withdrawn because of their adverse reactions. Dixon et al., (1982) proposed a technique of distinguishing NSAIDs from SAARDs in man based on comparisons of patterns of changes induced in multiple clinical and laboratory parameters of RA disease activity. Using this technique, a propionic acid derivative, clozic, was shown to have SAARD-Iike activity (Bird et al., 1983), although clozic has also been withdrawn, in this case, because of severe cutaneous toxicity in a few patients. 1.3. CHEMICALPROPERTIESAND CONSEQUENCES Most NSAIDs are weak acids with pKa values in the region of 3-6 and their un-ionized forms have high lipid solubilities. These chemical properties cause NSAIDs to be well absorbed from the gastrointestinal tract. The acidic nature of NSAIDs is also important because it controls the distribution and therefore the activity of these drugs. In physiological environments, NSAIDs are largely ionized as their pKa values are generally much lower than the pH of the environment. However, the proportion un-ionized can increase considerably in acidic environments such as the stomach, kidneys and inflamed joints. Thus, decreasing the environmental pH from 7.4 to 7.0 increases the un-ionized proportion by approximately 25%. The consequence is that, in an acidic environment, relatively more un-ionized drug will be available to diffuse into cells. Since intracellular pH changes to a lesser extent than extracellular pH, acidification of the extracellular fluid makes the intracellular environment relatively more alkaline. The relative alkalinity of the intracellular environment favours ionization and traps the NSAID intracellularly (Fig. 1). Enhanced cellular uptake of NSAIDs in increasingly acidic environments has been demonstrated for red blood cells and granulocytes (Brune and Graf, 1978). In experimental animals, inflamed joints also concentrate NSAID more than non-inflamed joints, in part because the pH of synovial fluid from such joints is usually lower than in nonExtroceLLuLor ReLo~(ivety oci¢l

IntroceLLuLor ReLativeLy oLkoLine

HA

II

H+ + ,6,-

FIG. 1. The effect of changes in p H on the cellular accumulation of NSAIDs.

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inflamed joints (Brune et al., 1976; Cummings and Nordby, 1966; Richman et al., 1981). In man, oxyphenbutazone is reported to be concentrated in synovial tissue from inflamed joints (Gaucher et al., 1983). It is of interest that paracetamol (acetominophen), although an inhibitor of prostaglandin synthesis in some tissues, has weak anti-inflammatory activity and causes very little gastrointestinal toxicity in man (Glenn et al., 1977; Johnson and Driscoll, 1981). The contrast in clinical effects of paracetamol and NSAIDs may be due in part to the failure of paracetamol, a neutral drug, to accumulate in cells in an acidic environment (Graf et al., 1975). However, it is more likely that paracetamol may inhibit prostaglandin synthesis only when it is oxidized and metabolically activated locally, a process which may. vary between tissues (Dalpe-Scott and Petersen, 1985). NSAIDs concentrate in the parietal cells in the stomach. This accumulation in parietal cells may be instrumental in the adverse gastric effects of these drugs (Brune et al., 1977; Rainsford and Brune, 1976). NSAIDs administered systematically or rectally may still cause gastric injury, although usually less than if given orally (Section 3.1). Gastric parietal cells are relatively alkaline as a consequence of their secretion of hydrogen ions (Kidder, 1980) and, consequently, NSAIDs may accumulate in them even when the drugs are not given orally. In addition to an acidic group, all NSAIDs contain at least one aromatic ring system, while some NSAIDs, such as phenylbutazone, indomethacin, diclofenac, flurbiprofen and flufenamic acid, contain two aromatic rings twisted relative to each other (Sallman, 1979). The characteristics of an NSAID receptor have been determined based on structure activity correlations (Gund and Shen, 1977; Magous et al., 1985; Shen, 1964, 1974). However, the anti-inflammatory actions of NSAIDs may involve several enzymes in addition to cyclooxygenase (Section 2.2). Thus, there may be multiple receptors for NSAIDS with differing structural requirements and it is difficult to accept the characteristics of a single NSAID receptor determined from structure-activity relationships in vivo, although such studies may be very important in the development of new NSAIDs.

2. VARIABILITY IN RESPONSE TO NSAID 2.1. CLINICAL EVIDENCE FOR VARIABILITYIN RESPONSE A large number of clinical trials have been conducted on the comparative activity of different NSAIDs in both RA and OA. However, many trials are not clinically relevant or have serious design flaws. In particular, many studies on NSAID are conducted over short periods of time with small numbers of patients, and because of inadequate patient numbers, even differences of 25% between responses to different NSAIDs may not be detectable (Vallance, 1982). Additionally, clinical measurement in rheumatic diseases remains imprecise, contributing to the difficulty in establishing significant contrasts between NSAIDs. However, there are a small number of studies which do demonstrate remarkable interpatient variability in the clinical response to a range of NSAIDs, despite the lack of substantial differences between the mean responses to these drugs as estimated by standard measures of efficacy (Huskisson et al., 1976, 1982). For example, from a comparative study of 10 NSAIDs in the treatment of RA, Scott et al., (1982) found that mean differences between drugs were much smaller than the variation in individual responses to these drugs. As a consequence, Scott et al. (1982) concluded that ranking of NSAIDs was not a particularly useful exercise and that short-term comparisons of NSAID may have little clinical relevance. Similar conclusions were made by Gall et al. (1982) from a comparison of ibuprofen, fenoprofen, naproxen, tolmetin and aspirin in patients with RA, and by Wasner et al. (1981) who examined 6 NSAIDs in RA and ankylosing spondylitis. Wasner et al. (1981), in their studies of NSAIDs in RA and ankylosing spondylitis, found that patient preferences for particular NSAIDs remained strong long after the study was complete (4-18 months). A high proportion (85%) continued to take their most LET, 33-2/3--L

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preferred NSAID. A similar sustained preference for an NSAID has been reported by Huskisson (1979). These data on patient preferences for particular NSAID are of considerable clinical interest but require confirmation in further clinical trials. Compliance to treatment in clinical trials on NSAIDs may be a useful measure of patient preference for a particular NSAID. Capell et al. (1979) considered that compliance to an NSAID may be a valid method of measuring the utility of the drug, particularly when study periods last 1 year or more. Interestingly, these workers showed that patient perceptions of the availability of alternative NSAIDs affected compliance (Capell et al., 1979). Little information is available concerning compliance to NSAID regimens, but the magnitude of the problem of poor compliance may be as substantial as with other classes of drugs (Belcon et al., 1984). The importance of regimen complexity is debated and other factors contributing to poor compliance with NSAID have not yet been fully identified (Capell et al., 1979; Deyo et al., 1981; Geertsen et al., 1973; Henry, 1985a). The involvement of clinical pharmacists in managing patients' medications may be useful in improving compliance in the rheumatic diseases (Kay, 1986). The interpatient variability in the response to NSAIDs may be related to a number of factors including variations in disease intensity, the perceptions of patients about the effects of treatment with NSAIDs (Deyo et al., 1981; Roberts et al., 1985) and patients' and doctors' knowledge of the availability of alternative NSAIDs (Capell et al., 1979). However, there may be more fundamental mechanisms for intersubject variability in response to NSAIDs. There is increasing evidence that individual rheumatic diseases, such as RA and OA, may result from a range of pathophysiological processes. Consequently, NSAIDs, with somewhat different modes of action (Section 2.2), may have variable efficacy in these diseases. Additionally, interpatient difference in pharmacokinetic parameters should contribute to the variable response to NSAIDs, particularly if dosage is not individualised. On the basis of available evidence, it appears that a range of NSAIDs should be available for prescription as each drug may suit the needs of at least a proportion of patients. The question of how many NSAIDs should be avaliable for use has not been resolved (Kragg, 1982). Availability of NSAIDs varies widely between countries (Dukes and Lunde, 1981) and this alone influences the practice of rheumatologists and the behaviour of patients in these countries. These and related issues have been discussed recently (Bellamy, 1985; Day, 1985; Kirwan, 1985; Roberts et al., 1985; Tugwell, 1985). 2.2. PHARMACODYNAMIC BASIS FOR VARIABILITY IN RESPONSE

It is widely held that inhibition of cyclooxygenase by NSAIDs and consequent inhibition of the synthesis of prostaglandins is responsible for the analgesic, anti-inflammatory and antipyretic actions of NSAIDs (Ferreira and Vane, 1979; Flower et al., 1980; Vane, 1971). There are differences between NSAIDs in their mechanism of inhibiting this enzyme (Lands, 1981). Most NSAIDs are reversible inhibitors of cyclooxygenase and plasma concentrations of NSAIDs correlate with inhibition of prostaglandin synthesis in vivo (Rane et al., 1978; Tomson et al., 1981). However, halogenated NSAIDs, such as indomethacin and flurbiprofen demonstrate progressively increasing inhibition of cyclooxygenase in vitro (Rome and Lands, 1975; Smith and Lands, 1971; Stanford et al., 1977), while aspirin irreversibly acetylates cyclooxygenase, leading to prolonged inhibition of this enzyme (Roth and Siok, 1978). At present, it is not known if these different mechanisms of inhibition lead to any qualitively different analgesic or anti-inflammatory effects in vivo. Recently, there has been considerable argument about the significance of inhibition of cyclooxygenase in the mode of action of NSAIDs. Much of the argument has been concerned with comparative pharmacological effects of aspirin and its metabolite salicylate. Aspirin is a potent inhibitor of cyclooxygenase, while salicylate is not (Smith et al., 1975; Smith, 1980). This difference is demostrated by the marked anti-platelet activity of aspirin, an activity not shown by salicylate. However, aspirin and salicylate are equipotent antiinflammatory agents, suggesting that effects, other than inhibition of cyclooxygenase, may be involved in the anti-inflammatory actions of these drugs (Atkinson and Collier, 1981).

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Further actions of aspirin are also suggested since the doses of aspirin required to inhibit cyclooxygenase are grossly exceeded by the doses required to produce adequate anti-inflammatory effects (Boardman and Hart, 1967; Crook et al., 1976; Smith and Willis, 1971). Thus, the anti-inflammatory doses of aspirin are in the range 4--6 g daily, yet daily doses of only 20-100 mg inhibit thromboxane A 2 synthesis by platelets and prostacyclin synthesis by blood vessel walls (Editorial, 1986). The hypothesis that NSAIDs inhibit inflammation solely by inhibiting cyclooxygenase has come under further attack as a result of data which indicate that some of the stable prostaglandins have anti-inflammatory activity (Weissmann, 1983). Thus, effects additional to inhibition of cyclooxygenase may be required to explain the anti-inflammatory effects of aspirin and NSAIDs and, such additional actions that NSAIDs might variously possess, may contribute to the observed variability in response to these drugs. Considerable attention has recently been directed towards the lipoxygenase pathways of arachidonate metabolism and the effects of NSAIDs on these pathways. The 5-1ipoxygenase pathway occurs in neutrophils and one product, leukotriene B4 (LTB4) is a significant inflammatory mediator. LTB4 produces its effects, in part, by attracting and activating neutrophils. Interference with leukotriene production, clearance or actions will therefore influence inflammation, and considerable data have been presented implicating some NSAIDs in alterations of leukotriene synthesis by a variety of mechanisms (Bragt and Bonta, 1980; Franson et al., 1980; Higgs et al., 1980; Humes et al., 1983; Myers and Siegel, 1983; Siegel et al., 1980; Weissman, 1983). For example, there are recent data indicating that diclofenac, but not naproxen, piroxicam or ibuprofen, enhances the sequestration of arachidonic acid into lipid (largely triglyceride) pools in addition to its expected property of cyclooxygenase inhibition. This was most marked in monocytes and, as might be expected, was accompanied by reduced production of leukotrienes and 5lipoxygenase products (Ku et al., 1985). The neutrophil may be an important target cell for NSAIDs in inflammatory arthritis since large numbers of these are present in the synovial fluid in these diseases. Neutrophils release lysosomal hydrolases as well as LTB 4, and also generate reactive oxygen species in response to endocytosis of immune complexes (Weissman and Korchak, 1984). These various activities of activated neutrophils can be inhibited by specific NSAIDs (Higgs et al., 1980; Pekoe et al., 1982). Thus, ibuprofen inhibits neutrophil aggregation and lysosomal enzyme release but not the generation of reactive oxygen species induced by the chemotactic peptide, f-met-leu-phe (FMLP), whereas all these responses are blocked by piroxicam (Abramson et al., 1984). Different effects of NSAIDs were observed when other stimuli, such as concanavalin A or phorbol myristate acetate, were employed. Importantly, these effects were also observed in neutrophils collected e x vivo from individuals who had been treated with various NSAIDs. These specific cellular effects of individual NSAIDs, which are independent of inhibition of cyclooxygenase, could explain some of the variability in response between NSAIDs (Abramson et al., 1984). Of interest is the contrast between ibuprofen and aspirin in reducing experimental myocardial infarction size, the former drug being effective, the latter ineffective. Possibly this difference reflects the ability of ibuprofen to inhibit neutrophil aggregation and lysosomal enzyme release, an activity not shown by aspirin (Flynn et al., 1984). As prostaglandins are important mediators in immunoregulation, particularly during chronic inflammation, it is to be expected that NSAIDs should affect immune function (Goodwin and Cueppens, 1983; Goodwin et al., 1984). In fact, NSAIDs are potent inhibitots of IgM rheumatoid factor production in vitro as a consequence of the removal of the tonic inhibitory action of prostaglandin E 2 o n T-suppressor lymphocytes. This effect of NSAIDs was demonstrated in vivo for piroxicam, and may be particularly important in the synovium where large quantities of both prostaglandins and rheumatoid factors are elaborated (Goodwin et al., 1984). A large number of other biochemical effects have been reported with at least some NSAIDs, such as inhibition of membrane transport systems, lysosomal enzyme release, cellular migration, release of kinins, histamine and serotonin, and uncoupling of oxidative

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phosphorylation (Brune, 1974; Famaey et al., 1975; Hichens, 1974; Rooney et al., 1973; Smith and Dawkins, 1971; Whitehouse, 1965). The effects of NSAIDs, particularly the newer drugs, on these systems has not been fully explored. However, these effects are generally produced in the various in vitro systems at concentrations somewhat higher than the unbound concentrations found in plasma during treatment and the clinical relevance of these biochemical effects of NSAIDs is uncertain. 2.3. PHARMACOKINETICBASIS FOR VARIABILITYIN RESPONSE 2.3.1. Dose and Concentration Response Relationships Intersubject variability in response to drugs as a result of variations in drug pharmacokinetics is well established for a number of drugs such as theophylline and phenytoin. Ascribing variability in response to intersubject differences in pharmacokinetics presupposes a reasonably consistent concentration-response relationship, and that plasma concentrations of the drug correlate with those at the effector site. Under these conditions, there is a better correlation between NSAID plasma concentration and effect than between dose and effect. For reversibly acting drugs, such as NSAIDs, a relationship between drug concentration and effect would be expected, but this has been surprisingly hard to demonstrate for these drugs (Orme, 1985b; Grennan et al., 1985). Linear concentration-response relationships between plasma concentrations of both indomethacin and naproxen and indexes of inhibition of prostaglandin sythesis in vivo have been demonstrated in volunteers and patients (Rane et al., 1978; Tomson et al., 1981). However, no direct relationship between the degree of suppression of prostaglandin synthesis in vivo and anti-inflammatory effect has been demonstrated in rheumatic diseases. The difficulty in gathering clear evidence of relationships between response and either dose or plasma concentrations of NSAIDs may be related to various factors, such as difficulty in accurately quantitating disease activity, the limited dosage ranges studied and unsatisfactory study designs. It may be particularly difficult to demonstrate such relationships using NSAIDs with short half-lives (Section 2.3.5.1). For example, a recent wellconducted investigation of the relationship of ibuprofen concentrations to efficacy in RA failed to show a clear relationship (Grennan et al., 1983). Additionally, interpatient variability in the relative proportions of the active and inactive optical isomers of ibuprofen in plasma (Section 2.3.6) may have further lessened the chance of demonstrating clear concentration-response relationships. However, a weak relationship between pain relief and plasma concentration was apparent in this study (Grennan et al., 1983). Recent studies have revealed significant correlations between both the dose and plasma concentrations of naproxen and fenclofenac and the efficacy of these drugs (Fig. 2; Day et al., 1982; Dunagan et al., 1986; Luftstchein et al., 1981; McGill, 1985). The demonstrated relationships between plasma concentrations of naproxen and fenclofenac and efficacy explain only a proportion of the variance in these studies. However, these studies do indicate that adjustment of dosage in individual patients who respond to a particular NSAID may be helpful. A therapeutic range of plasma concentrations of any NSAID cannot be specified at this time. A therapeutic range of 1.1 to 2.2 mmol/l (150-300 #g/ml) is frequently quoted for salicylate, but the evidence supporting this is limited (Champion et al., 1975). A specific exception may be measurement of indomethacin plasma concentrations in neonates given the drug in order to close a patent ductus arteriosus (Brash et al., 1981). Further studies of the relationships between dosage, plasma concentrations (both total and unbound) and responses are needed, however, to determine the importance of adjustment of dosage of NSAIDs in the management of patients with rheumatic diseases (Furst, 1985a). 2.3.2. Responders and Non-Responders The signifance of variable pharmacokinetics of an NSAID between individuals may be ascertained by comparing responders and non-responders to the drug. In the very small

Non-steroidal anti-inflammatorydrugs

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80-70-

] Total [-----]

Unbound

60-®

-o

50 - -

o

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Total Unbound

10-24 0.08-0.21

25-41

42-54

55-92

0.22-0.35

0.36-0.44

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Serum naproxen concentration ( # g / m )

FIG. 2. The relationship between trough plasma naproxen concentrationsexpressed in quartiles and the percentage response (using a summedefficacyscore) in a population of patients with rheumatoid arthritis (Day et al., 1982; with permissionof the authors and publishers). number of studies which have been conducted, differences in plasma pharmacokinetics between responders and non-responders have never been demonstrated. A careful study by Baber et al. (1979) of a small number of responders and non-responders to indomethacin revealed no significant contrasts between either the total or unbound concentrations of indomethacin or any pharmacokinetic parameters in the two groups. Furthermore, concurrent treatment with probenecid, which increases the plasma concentrations of indomethacin, failed to improve the non-responders (Baber et al., 1978). A similar result was obtained in a comparison of flurbiprofen plasma concentration profiles in responders and non-responders (Capell et al., 1977). These results are consistent with the observation that a proportion of RA patients did not respond to daily doses of naproxen of up to 1500 mg while the majority of subjects showed increasing effect with increasing dose (Day et al., 1982). Further studies of this type are needed with particular attention to the rigorous definition of non-responders and with the addition, if possible, of measurement of synovial fluid NSAID concentrations (Section 2.3.4). However, one interpretation of the presently available data is that differences in disease mechanisms, or balance of pathophysiological processes, may preclude efficacy of a particular NSAID in a particular individual. According to this argument, increased dosage of a particular NSAID in a non-responder should not increase efficacy. Another NSAID with a slightly different balance of actions may be satisfactory. In support of this argument is the observation, discussed previously (Section 2.1), that patient preference for a particular NSAID in RA often remains long after the initial exposure to the drug. 2.3.3. Binding to P l a s m a Proteins NSAIDs are extensively bound to plasma proteins. It is widely believed that the efficacy of reversibly-acting drugs, such as NSAIDs, correlates more closely with the unbound concentration in plasma than to the total concentration, since only the unbound drug is free to diffuse across membranes to intracellular sites of action or to bind to receptors. While this is a general principle of pharmacology, there has been little work on the relationship between concentrations of unbound NSAID in plasma and efficacy despite the large number of in vitro studies on the binding of NSAIDs to plasma proteins. Intersubject variability in unbound NSAID concentrations, for given dosing rates, may be a significant source of variability in response. The clearance of NSAID is generally low and not altered by changes in perfusion of the liver, the major site of metabolism of these drugs. Consequently, the mean unbound

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concentration in plasma (Cuss), during long term dosage with an NSAID, is controlled by the dose rate and the unbound clearance of the drug (CLu), such that: Cuss = dose rate/CLu

Thus, it should be noted that the process of protein binding does not determine the unbound concentrations in plasma during long term treatment (Rowland and Tozer, 1980). The major plasma protein binding NSAIDs is albumin. NSAIDs bind to either of two major drug binding sites on albumin (Sudlow et al., 1976). NSAIDs, such as phenylbutazone, which bind to site I, are potent displacers of warfarin, although this displacement is probably not associated with any clinically significant drug interaction (Section 4). It is of interest that azapropazone, related chemically to phenylbutazone, appears to bind to a different area on site I, although it still displaces warfarin (Fehske et al., 1982). Most other NSAIDs, including the propionates, such as ibuprofen, bind to site II. For most NSAIDs, the proportion unbound in plasma, or free fraction (ratio of unbound to total plasma concentrations), is constant throughout the range of total plasma concentrations observed clinically since total plasma concentrations are not high enough to approach those required to saturate NSAID albumin binding sites. However, the plasma concentrations of naproxen (Runkel et al., 1976), phenylbutazone (Higham et al., 1981; Orme et al., 1976;), salicylate (Ekstrand et al., 1979; Furst et al., 1979) and possibly ibuprofen (Lockwood et al., 1983) attained by therapeutic dosage are sufficiently high so that albumin binding sites approach saturation with increasing total concentrations of NSAIDs in plasma. The result is that total concentrations increase less than expected with increasing doses because the decreased binding capacity leads to enhanced metabolic clearance of total drug (Fig. 3). It has been stated, therefore, that there is a ceiling dose for naproxen and phenylbutaxone. However, the unbound concentration of drug increases in proportion to the dosage rate, since the clearance of unbound drug is independent of the degree of protein binding. Thus, the concept of a ceiling dose for these drugs on the basis of saturable albumin binding appears to be invalid. The relationship between dosage and plasma concentrations of salicylate is complex because of the saturable metabolism of this drug (Levy et al., 1972). The unbound concentrations in plasma increase disproportionately with increasing dose in the anti-inflammatory dose range because of the saturable metabolism of salicylate, but the increases in total concentration are less marked with increasing dose because of saturation of binding to plasma albumin (Ekstrand et al., 1979; Furst et al., 1979). The metabolism of diflunisal 4000

J

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I

I

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FIG. 3. Non-linear relationship between naproxen dose and total plasma naproxen concentrations (Runkel et al., 1976; with permission of the authors and publishers).

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also appears to be saturable, a three-fold increase in daily dosage leading to a six-fold increase in plasma concentrations (Ray and Day, 1984; Van Winzum and Verhaest, 1979), but the effect of dosage increases on unbound diflunisal concentrations is not known. Large interpatient variations in the proportion unbound (free fraction) in plasma may be expected for drugs such as NSAIDs that are highly protein bound. Genetic factors, sex, age, pregnancy, other drugs and disease states may contribute to the variation in the proportion unbound. However, the unbound concentrations are only affected in these states if there are changes in the unbound clearances of the drugs. An altered albumin composition and hypoalbuminaemia (Denko et al., 1970) have been reported in RA. It has been suggested that these changes are responsible for the increased binding of L-tryptophan (Aylward and Maddock, 1973; McArthur, 1974) as well as the decreased binding of tolmetin (Selley et al., 1978) and ibuprofen (Aarons et al., 1983) observed in this disease. In contrast to these results on the binding of tolmetin and ibuprofen, Wanwimolruk et al., (1982) found no significant contrast in the free fraction of indomethacin, salicylate, ibuprofen and flurbiprofen in patients with RA compared with matched controls suffering with osteoarthritis. These workers also found that the binding characteristics of site I and II were not substantially altered in patients with RA, indicating that albumin structure is not significantly perturbed in RA. The binding of NSAIDs to plasma proteins is generally reduced in patients with severe hypoalbuminaemia due to liver disease or malnutrition and, in patients with severe renal failure, due to the presence of endogenous binding inhibitors, possibly peptide molecules of molecular weight 1000-2000 (Kinniburgh and Boyd, 1981; Kober and Sjoholm, 1980; Krishnaswamy et al., 1981). An example is azapropazone, which is tightly albumin bound in normal volunteers (free fraction 0.0044), but in various degrees of renal failure the fraction unbound rises approximately six-fold to 0.0260 and, in chronic liver disease, to 0.0210 (Jahnchen et al., 1981). It is becoming apparent that the effect of age on the disposition of NSAIDs may be explained in part by changes in protein binding (Section 2.3.8). Thus diflunisal, salicylate and naproxen, show reduced binding in the elderly for a number of possible reasons including reduced concentrations of albumin and the presence of displacing substances resulting from mild renal impairment (Netter et al., 1985; Roberts et al., 1983; Upton et al., 1984; Verbeeck et al., 1979a). In the case of salicylate, decreased binding correlates with low plasma albumin (Netter et al., 1985; Roberts et al., 1983). Further careful studies of the relationship between efficacy and the unbound concentrations of NSAIDs in plasma are clearly needed. Interpatient variation in the response to a particular NSAID may be due, in part, to variation in the concentrations of unbound NSAIDs in plasma, but this possibility has not been adequately examined. 2.3.4. N S A I D

in Synovial Fluid

It is widely considered that the concentration of NSAIDs in synovial fluid is an important determinant of the clinical response to these drugs, since cells within the synovial fluid and the synovium are presumed to be the major sites of action of NSAIDs (Furst, 1985b). The time course of concentrations in synovial fluid is quite different from that in plasma, particularly for NSAID with short half-lives (Furst, 1985b). Peak synovial fluid concentrations are delayed and are lower than in plasma and the subsequent decline is, at least initially, slower than in plasma (Fig. 4). Thus, several hours after dosage, the concentrations in synovial fluid may exceed those in plasma (Ray et al., 1979). For example, the ratio of the concentrations of diclofenac in synovial fluid and plasma 7 hr after dosage were of the order of 4:1 (Fowler, 1983). By contrast, the synovial fluid concentrations of NSAIDs with long half-lives are lower than in plasma and decline in parallel with plasma concentrations (Bird et al., 1985). The kinetics of transfer of NSAIDs between plasma and synovial fluid has been analyzed in detail for ibuprofen, and it is evident that the access and exit of NSAID from the synovial space is slow (Knihinicki et al., 1985), the mean half-life of diffusion of ibuprofen enantiomers out of synovial fluid being approximately

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kps.V/Vs=0.24 +0.14 (n-8) ~

25

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ksp'0"33+0'23 (n'8)

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FIG. 4. Dosageinterval plasma (+) and synovial fluid (©) concentrationsof S ibuprofen during chronic dosing with ibuprofen 800 mg three times a day (Day et al., unpublished). Legend: Kps is the rate constant for movement of drug from plasma to synovial fluid; V is the volume of distribution and V~ the synovial fluid volume; K~p is the rate constant for movement of drug from synovial fluid to plasma and is expressed as hr- ~, S/R(~ough) is the ratio of synovial fluid S- to R-ibuprofen concentrations 8 hr post-dose in 8 subjects. Results are expressed as mean _+ standard deviation.

3 hr (Lee et al., 1985). The half-life of diffusion from synovial fluid to plasma is thus longer than the half-life of elimination of the drug from plasma (mean 2.1 hr). It is generally assumed that only unbound N S A I D is available for diffusion into and out of the synovial space, but confirmatory data are limited to experiments on salicylate. At steady state, the unbound concentrations of salicylate in plasma and synovial fluid are equal (Rosenthal et al., 1964). However, because of the lower binding of salicylate in synovial fluid than in plasma, the total concentrations in synovial fluid are lower than in plasma. A similar situation probably occurs with other NSAIDs with long half-lives. By contrast, the relative unbound concentrations of NSAIDs in synovial fluid and plasma varies with the time after dosage for those NSAIDs with short half-lives. Immediately after dosage, the unbound concentrations of these NSAID in synovial fluid may be lower than in plasma, but towards the end of the dosage interval, the concentration gradient is reversed. A number of studies have shown that NSAID binding is significantly lower in synovial fluid than in plasma because of the lower concentration of albumin in synovial fluid (Rosenthal et al., 1964; Soren, 1979; Wanwimolruk et al., 1983; Fig. 5). The concentration

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Non-steroidal anti-inflammatory drugs

393

of albumin in synovial fluid is, however, increased by inflammation and, consequently, the total concentration of NSAID should be higher in inflamed joints than in non-inflamed joints. As discussed previously (Section 1.3), the relatively acid pH of synovial fluid should promote uptake of NSAID into synovial lining cells and in cells, such as polymorphonuclear leucocytes, which are suspended in synovial fluid. Further studies on the kinetics of NSAID in synovial fluid are required. Correlations between concentrations of drug and levels of arachidonate products need to be sought (Bombardieri et al., 1981; Tokunaga et al., 1981). Interpatient variability in the transfer of NSAID between plasma and synovial fluid may be responsible, in part, for the poor correlations between the efficacy of NSAIDs and their concentrations in plasma, but this hypothesis has not been examined. Recently, a weak correlation between an index of joint inflammation, the thermographic index, and synovial fluid flurbiprofen concentrations has been demonstrated (Aarons et al., 1986), but is the only study of this type reported so far. 2.3.5. N S A I D Elimination Half-Life There are substantial differences in the half-lives (tl/z) of NSAIDs, both between the different members of this class of drugs and between different patients taking the one NSAID. Variability in the half-life of elimination of NSAID may reflect variability in the clearance (CL) or the volume of distribution (10 of a drug since half-life is related to V and CL: ill 2 = 0.693 V / C L

Because of their acidic nature, NSAIDs are generally highly protein bound and therefore have small volumes of distribution, approximately 0.1 1/kg (Champion and Graham, 1978). Differences in half-lives between both patients and drugs is related more to differences in CL than V. Clearance for most NSAID is largely accounted for by metabolism in the liver and this may be quite variable depending on the drug as well as genetic influences, age, sex, endogenous and environmental factors. The dosage schedules of many drugs are based upon their half-lives of elimination, the dosage intervals frequently being set approximately equal to or somewhat less than their mean half-lives of elimination. This limits fluctuations between peak and trough concentrations to two-fold or less. However, this approach to the design of dosage schedules may not always be applicable to NSAIDs. Half-lives of NSAIDs may be conveniently classified as short ( < 10 hr) or long (> 10 hr) (Table 1) (Graham et al., 1984). A number of the NSAIDs with short half-lives (e.g., ketoprofen) have slow terminal elimination phases but most of the drug is eliminated during the initial phase with little elimination during the slow terminal phase. Consequently, there is no significant accumulation during multiple dosing (Upton et al., 1981). 2.3.5.1. N S A I D s with short half-lives. NSAIDs with short half-lives are usually administered every 6 to 8 hr. However, recent clinical studies on NSAIDs with short halflives, such as ibuprofen (Brugueras et al., 1978), indoprofen (Huskisson et al., 1981) and flurbiprofen (Brown et al., 1986; Kowanko et al., 1981) indicate that dosage every 12 hr is as effective as 6 hourly dosage. Clearly, 12 hourly dosage of these short half-life NSAIDs yields wide fluctuations in plasma concentrations over a dosage interval, and relatively little drug is present in plasma prior to each dose. The effectiveness of dosing at intervals far in excess of the half-lives of these NSAIDs has a number of possible explanations. Firstly, synovial fluid concentrations fluctuate to a much lesser extent than plasma concentrations over a dosage interval (Section 2.3.4) and the range of synovial fluid concentrations produced by 12 hourly dosage may yield satisfactory suppression of inflammation. Secondly, it is also possible that discontinuous inhibition of prostaglandin synthesis may be all that is necessary to inhibit the process of inflammation. This may be the reason for the concentrations of PGE remaining suppressed 24 hr after cessation of treatment

394

R.O. DAYet al.

with tolemtin when both the plasma and synovial concentrations of the drug had fallen to very low levels (Dromgoole et al., 1982). Further, the inflammatory process may be more susceptible to inhibition at particular times of the day coinciding with maximum intensity of pain or inflammation (Harkness et al., 1982; Kowanko et al., 1981; Levi et al., 1985; Pownall and Pickvance, 1985). These same factors may be relevant to the difficulties in relating the efficacy of NSAIDs to the concentrations in plasma (Section 2.3). 2.3,5.2. N S A I D s with long half-lives. NSAID half-lives which are long, show a great deal of intersubject variability (Table 1), which may be clinically important. In contrast to NSAIDs with short half-lives, NSAIDs, with long half-lives accumulate to a significant degree and the time course for accumulation is a function of the half-life such that 90% of plateau values are achieved after three half-lives have elapsed. Thus, piroxicam accumulates for about 5 days and naproxen for about 2 days. Because of the interpatient differences in clearance, steady-state plasma concentrations vary considerably between patients. This may have important toxicological consequences. Phenylbutazone-induced aplastic anaemia may be more likely with sustained, high concentrations of drug (Cunningham et al., 1974) which may be found more often in the elderly. Similarly, it has been shown that elderly women eliminate piroxicam somewhat more slowly than younger women (Richardson et al., 1985). Sulindac and its active metabolite may also accumulate to a greater extent in the elderly (Sitar et al., 1985). The fatal hepatic and renal reactions with benoxaprofen, which led to the withdrawal of this drug, were more common in the elderly who eliminate the drug more slowly than younger patients. The half-life of benoxaprofen is markedly longer in elderly patients (mean 148 hr versus 33 hr in young subjects) (Hamdy et al., 1982). The increased serious toxicity in the elderly may be related to higher steady-state concentrations. In general, caution should be exercised in administering NSAIDs with long half-lives to elderly patients, particularly if the patients have renal or hepatic impairment (Section 2.3.8). NSAIDs with long half-lives can be administered twice daily, or daily, with little fluctuation in plasma concentrations. For example, naproxen (tl/:= 14 hr) and sulindac (the active metabolite of sulindac is the sulphide with a t~/2 of 18 hr) given twice daily, show a difference between peak and trough concentrations of approximately 2-fold. For sulindac sulphide, this difference increases little when sulindac is administered as a single daily dose of 400 mg (Swanson et al., 1982). The fluctuations in the plasma concentrations of piroxicam, phenylbutazone and oxyphenbutazone, are even smaller. For example, phenylbutazone with a mean half-life of 72 hr, shows a ratio of maximal to minimal concentrations during a dosage interval of approximately 1.15 : 1 when the drug is administered every 12 hr. This ratio increases to only 1.3:1 if phenylbutazone is administered once a day. Thus, it is possible to administer piroxicam, phenylbutazone, oxyphenbutazone and sulindac once a day and still have relatively small flunctuations in plasma concentrations. However, once-a-day dosage of phenylbutazone or oxyphenbutazone is not recommended because of the potential for gastrointestinal side effects, unless the total daily dose is small. By contrast, once daily dosage with piroxicam is well accepted because of the low degree of gastrointestinal side effects produced by this drug (Wiseman and Boyle, 1980). It would be expected that synovial fluid and tissue concentrations of NSAIDs with long half-lives would approach a closer equilibrium with plasma concentrations because of the smaller fluctuations in plasma concentrations. For this reason, plasma concentrations of NSAIDs with long half-lives are likely to correlate with efficacy, and measurement of plasma concentrations also may identify patients who are at risk of toxicity. 2.3.5.3. N S A I D half-life and absorption. The rate of absorption of NSAIDs may be slowed by administration with food or by formulation as enteric-coated or slow release (SR) tablets. In fact, several NSAIDs with short half-lives have recently been formulated as SR tablets (eg, ibuprofen, ketoprofen, indomethacin). Changing the rate of absorption

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has little influence on the plasma concentrations of NSAIDs with long half-lives. Thus, SR aspirin taken in high dose (e.g., 4g/day), does not produce a plasma salicylate concentration-time profile very different from regular aspirin tablets since the half-life of salicylate at these doses is approximately 15 hr. Conversely, slowing the rate of absorption of an NSAID with a short half-life will have a large effect on plasma concentrations, decreasing the peak concentrations and sustaining subsequent concentrations (Marchant, 1981). The efficacy and tolerance of most SR formulations are not substantially better than conventional rapid release formulations. Sustained release preparations of indomethacin have been studied in most detail because of the widespread use of this drug and also because adverse effects on the central nervous system are considered to be related to peaks in the plasma concentrations of this drug. Kaarela et al. (1972) showed a significant reduction in adverse effects, especially dizziness and diarrhoea, with a depot preparation of indomethacin (Indometin 50 mg., Orion Pharmaceutical Co.) which had good slow release characteristics. Indomethacin was also formulated in an osmotic pump capsule. Dosage of this product also yielded plasma concentration profiles that showed less fluctuation then during dosage with conventional capsules (Bayne et al., 1982). However, the preparation was withdrawn because of perforation of the small intestine associated with its use. Sustained release preparations of ibuprofen and ketoprofen have been investigated but, in limited trials, have shown little or no clinical advantage over conventional preparations (Fernandes et al., 1982; Russel and Labelle, 1983). Sustained release formulations of NSAIDs with short half-lives may lead to decreased fluctuations in plasma concentrations but should have little effect on the time course of concentration in the synovial fluid. Even after rapid absorption, synovial fluid concentrations fluctuate only to a small degree over a dosage interval. On this theoretical basis, significant advantage of sustained release formulations over conventional products is not anticipated in the treatment of the rheumatic diseases. 2.3.6. Metabolism o f N S A I D s The NSAIDs are primarily cleared by hepatic metabolism and their hepatic clearance is low, independent of hepatic blood flow but protein-binding dependent. An exception is diclofenac which has a clearance about 1/3 of liver blood flow and a bioavailability of about 54%, despite complete absorption (Willis et al., 1979). Also, aspirin has a high firstpass clearance with bioavailability of unchanged aspirin of about 60% (Rowland et al., 1972). A detailed review of the metabolic fate of most NSAIDs has recently been presented (Hucker et al., 1980). Two aspects of NSAID metabolism are of considerable clinical importance. These are the formation of active metabolites and the stereoselective disposition of some NSAIDs. 2.3.6.1. Metabolic activation o f N S A I D s . The principal anti-inflatory effect of several NSAIDs is due, at least in part, to the formation of an active metabolite. Both aspirin and its major metabolite, salicylate, are active NSAIDs. Phenylbutazone and its metabolite, oxyphenbutazone, are also both active. Other NSAIDs, such as fenbufen, nabumetone, benorylate and sulindac, are inactive but are converted to active drugs in vivo. Aspirin, the acetyl ester of salicylic acid, has pharmacological activity through irreversible acetylation of cyclooxygenase. However, it is rapidly hydrolysed to salicylic acid (Rowland et al., 1972), which is also an active NSAID. Further metabolism of salicylate to gentisate may also contribute to its pharmacological effects (Whitehouse and Cleland 1985). Other esters of salicylic acid, such as salicylsalicylic acid (the salicylate dimer) and benorylate (the paracetamol ester of aspirin), also depend on release of salicylate for their anti-inflammatory effect. These prodrugs of salicylate are well absorbed and are better tolerated with less gastrointestinal bleeding than aspirin. They are less soluble than aspirin and, consequently, there is little exposure of the gastric mucosa to these drugs.

Non-steroidal anti-inflammatory drugs

399

Sulindac, a sulphoxide, is activated by reversible metabolism to the sulphide and inactivated by the hepatic synthesis of the sulphone metabolite. An important site of reduction of sulindac to its suphide is the large bowel where microflora probably act upon sulindac excreted in the bile (Strong et al., 1985). Sulindac undergoes extensive enterohepatic recycling while its reduction product, sulindac sulphide, does not. The total amount of sulindac secreted in bile is approximately 140% of a dose but the total amount of sulindac sulphide secreted in bile is only 12%. Thus, there is a limited exposure of the small intestine to the active metabolite (Dobrinska et al., 1983; Duggan et al., 1977; Duggan and Kwan, 1979; Dujovne et al., 1983). However, sulindac does not show significantly less gastrointestinal toxicity than other NSAIDs, such as ibuprofen (Rhymer, 1983). Fenbufen, which is activated by metabolism to biphenylacetic acid (Mawdsley, 1982), was found in early studies to have a low incidence of gastrointestinal side effects (Greenberg, 1983). 2.3.6.2. Stereoselective disposition o f N S A I D s . Frequently, there is a large difference in the pharmacokinetic profiles of optical isomers (enantiomers) of drugs (Williams and Lee, 1985). However, many drugs are administered as their racemates, i.e., as an equal mixture of the R- and S-enantiomers. This is true of the important arylpropionic acid group of NSAIDs which includes drugs such as ibuprofen, fenoprofen, tiaprofenic acid, carprofen and ketoprofen. Naproxen is an exception being the only propionate marketed as the active S-enantiomer. A unique feature of the arylpropionates is the metabolic inversion of the inactive Renantiomer to the active S-enantiomer, which has been observed for several of these NSAIDs. In man there is marked inversion of fenoprofen (Rubin et al., 1985) and ibuprofen (Kaiser et al., 1976; Lee et al., 1985). The R-enantiomers are not inhibitors of the synthesis of prostaglandins in vitro, but their anti-inflammatory activities in vivo are often similar to those of the S-enantiomers (Hutt and Caldwell, 1984). However, although inversion has been commonly observed, it does not occur universally. Indoprofen, for example, does not undergo significant inversion (Tamassia et al., 1984). Interpatient variability in the extent of inversion should effectively lead to a variability in the dose of active drug administered to the patient and thus may contribute to the variability in response to treatment, but no data is available to indicate the extent of such variability. The R-enantiomers may also be viewed as prodrugs which are metabolically activated by inversion. Administration of the R-enantiomers alone would decrease exposure of the gastric mucosa to active drug and might be expected to lower the incidence of gastrointestinal toxicity. However, it may not be desirable to administer the R-enantiomer since arylpropionates can be incorporated into triglycerides (Fears et al., 1978) and these hybrid triglycerides may be associated with toxicity (Caldwell and Marsh, 1983). It has recently been demonstrated that this uptake into fat is stereoselective for the R-enantiomer of ibuprofen and that administered S-ibuprofen is stereospecifically excluded from this metabolic pathway (Williams and Day, 1985; Williams et al., 1986). Should toxicity be definitely associated with incorporation of the R-enantiomer into lipids, then it would be preferable to administer these drugs as the S-enantiomers, although this hypothesis requires investigation. Sulindac is also a racemic drug. The enantiomers are said to be equally active (Shen and Winter, 1977), although nothing is known of the differences in their metabolism. Similarly oxyphenbutazone is a racemate but there is no data on the relative activities or disposition of the enantiomers. It is certain that the stereochemistry of the disposition of NSAIDs is important. Attempts to correlate plasma concentrations with response are unlikely to be successful, unless the active enantiomer of the drug is monitored. 2.3.6.3. Effect o f liver disease. There have been few studies of the effect of liver disease upon the disposition and metabolism of NSAIDs. Breuing et al. (1981) found that the

400

R.O. DAy et al.

half-life of azaproprazone lengthened as hepatic function worsened. This was somewhat surprising as the drug is predominantly excreted unchanged in the urine. In a comparison of ibuprofen and sulindac, Juhl et al. (1983) found that there was little effect of liver disease on ibuprofen kinetics. By contrast, the concentrations of the pharmacologically active reduction product of sulindac, sulindac sulphide, were increased approximately four-fold by liver disease. Liver disease does not affect the pharmacokinetics of salicylate (Roberts et al., 1983). 2.3.7. R e n a l Execretion o f N S A I D s The NSAIDs are weak acids and their renal clearance is increased by alkalinization of urine. However, the renal excretion of unmetabolized NSAID is generally not a major pathway of elimination even when urine is alkaline. The only exception is salicylate. A large proportion is excreted unchanged in an alkaline urine (Fig. 6; Smith et al., 1946). Even small increases in urinary pH, for example as a result of antacid therapy, may markedly lower the plasma concentrations of salicylate (Hansten and Hayton, 1980; Levy and Leonards, 1971). It would be anticipated that renal failure, or probenecid, an inhibitor of the renal secretion of acids (anions at physiological pH), should also not affect the half-life of NSAIDs, if renal excretion is insignificant. However, this is not so. Renal failure or probenecid, decreases the urinary excretion of the acyl glucuronides of several acidic drugs including the NSAIDs, the result being retention of the acyl glucuronide and hydrolysis back to the parent NSAID (Meffin et al., 1983). NSAIDs which are significantly retained during renal failure, or during treatment with probenecid, include carprofen (Yu and Perel, 1980), diflunisai (Verbeeck et al., 1979a), indomethacin (Baber et al., 1978; Brooks et al., 1974), ketoprofen (Stafanger et al., 1981; Upton et al., 1982), benoxaprofen (Aronoff et al., 1982), zomepirac (Smith et al., 1985) and naproxen (Runkel et al., 1978). It is appropriate to reduce the dosage of these drugs in patients with renal failure or in patients who are taking probenecid. Racemic NSAIDs that are retained in patients with renal impairment may be particularly hazardous as the ratio of active S- to inactive R-enantiomers should be higher than in patients with normal renal function (Fig. 7, Merlin, 1985; Meffin et al., 1986). Renal impairment is of concern because not only is there retention of the NSAIDs but also it is a risk factor for renal toxicity (Section 3.2.6).

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FIG. 8. The increasing use of NSAIDs by the elderly in the U.K.; date expressed as age-specific prescription rates for men and women receivingNSAIDs (Walt et al., 1986;with permission of the authors and publishers). 2.3.8. A g e The effect of age upon the pharmacokinetics of NSAIDs is an important issue. NSAIDs account for 5% of all N.H.S. prescriptions in the U.K. with a large increase in prescriptions over the past 20 years for elderly patients (Collier and Pain, 1985; Walt et al., 1986; Fig. 8). NSAIDs are responsible for 25% of all reports of adverse drug reactions to the Committee on Safety in Medicines in the United Kingdom. Twenty percent of the drugs taken by the elderly are NSAIDs and this group of patients are sustaining a large number of adverse reactions to these drugs (CSM Update 1986). There is now evidence that major gastrointestinal bleeding and perforation in the elderly are related to the intake of these drugs (Section 3.1). Renal function deteriorates with age and drugs that are excreted largely unmetabolized will have reduced renal clearance. However, it is unusual for NSAIDs not to be extensively metabolized, but an exception is azapropazone whose clearance is 0.55 l-hr -J in young adults falling to 0.29 1. h r - ~in the elderly. About 60-70% of this NSAID is excreted in the urine and the dose should be reduced in the elderly (Ritch et al., 1982). Some of the propionic acid derivatives, e.g. ketoprofen and benoxaprofen, have been found to have reduced clearance in the elderly (Advenier et al., 1983; Hamdy et al., 1982). These NSAIDs and others which are metabolized to acyl glucuronides will be retained in the elderly due to declining renal function (see Section 2.3.7.; Meffin et al., 1983a; Meffin, 1985). As noted above (Section 2.3.7), retention of many of the enantiomeric propionic acid NSAIDs in the elderly, or any patient with renal impairment, should lead to relatively higher concentrations of the active S-enantiomer than the inactive R-enantiomer and thus greater risk of adverse effects (Meffin, 1985). NSAIDs whose clearance is largely dependent on oxidative metabolism have also been examined. A number of studies have found no effect of age upon any of the pharmacokinetic parameters of piroxicam (Darragh et al., 1985; Woolf et al., 1983), although Richardson et al. (1985) found a significant, although small, reduction in the clearance of the drug in elderly females. The half-life o f racemic ibuprofen is longer in elderly than younger men, but there has been no examination of the effect o f age upon the disposition of the enantiomers of this drug (Greenblatt et al., 1985). The major finding in .LP.T. 33-2/3--M

402

R.O. DAYet al.

two studies of salicylate pharmacokinetics in the elderly was that higher unbound concentrations were observed in patients with lower plasma albumin concentrations (Netter et al., 1985; Roberts et al., 1983). It has been emphasized that examination of variables such as sex, smoking history and intake of other medications is important, particularly in studies of the effect of age upon drug disposition (Orme, 1985). It should be noted that marked individual variation in elimination of NSAIDs will lead to excessive accumulation of drug in occasional patients and that this is more likely to be a problem in the elderly because they are more prone to toxic reactions. 3. ADVERSE EFFECTS NSAIDs are associated with a high incidence of side-effects, but these reactions are generally not serious (Johnson et al., 1985; Rainsford, 1984). Published figures on the incidence of side-effects of NSAIDs must be regarded only as approximate. Data on the incidence of side-effects are largely obtained from controlled clinical trials, but there is often great variation in the incidence of side-effects reported in different trials. Furthermore, rare, but possibly serious, side-effects to treatment with NSAIDs may be noted only when a new member of this class of drugs is introduced into general clinical practice. A good example is benoxaprofen. The withdrawal of this drug in 1982 after 2 years marketing, highlighted a number of deficiencies in the performance of the pharmaceutical company, medical practitioners and regulatory agencies (Editorial, 1982), deficiencies which have been observed with the introduction of other anti-inflammatory drugs (Bakke et al., 1984; Dukes, 1984). Experience with benoxaprofen and also with alclofenac and zomepirac, which were withdrawn because of rare but serious toxicity, has led the FDA arthritis advisory committee to suggest that any new NSAID should be stipulated as being "not for initial therapy" (Paulus, 1983). The approach suggested by the FDA committee should lead to a more controlled introduction of a new NSAID, avoiding sudden use in a large number of patients, many of whom may be unsuitable for treatment with the drug because of factors such as advanced age or renal disease. It should be noted that the withdrawal of an effective NSAID may disadvantage some patients. In particular, drugs such as clozic, zomepirac and alcofenac which have been withdrawn may have had beneficial effects in addition to those of standard NSAIDs in some patients (Bird, 1983; Rainsford, 1984). The following sections contain a discussion of the more common side-effcts of NSAIDs. Reference should be made to the reviews of O'Brien and Bagbey (1985a,b,c,d) for useful descriptions of the more rare adverse reactions. 3.1. GASTROINTESTINAL 3.1.1. Clinical Manifestations o f Upper GI Damage 3.1.1.1. Dyspepsia. Dyspepsia is the commonest adverse effect of NSAIDs and occurs in up to 10-15% of subjects treated with the newer NSAIDs. Often this incidence is indistinguishable from that observed with placebo (Hamaty et al., 1974) but is considerably less than with high-dose regular aspirin (Blechman et al., 1975; Lee et al., 1974; Sigler et al., 1976), phenylbutazone (Fowler, 1983) and indomethacin (Rhymer and Gengos, 1983). While the newer NSAIDs all produce a similar incidence of dyspepsia, interpatient variation in the occurrence and severity of dyspepsia with different NSAIDs is well recognized and is probably a major factor in determining patient preferences for individual agents (Section 2.1). The mechanism for dyspepsia is in doubt as no clear relationship between dyspepsia and intestinal microbleeding (Baragar and Duthie, 1960; Scott et al., 1961) or gastroscopic lesions has been demonstrated (Caruso and Porrer, 1980; Collins et al., 1986: Lanza et al., 1979, 1982; Silvoso et al., 1979). However, it seems most likely that direct gastrointestinal irritation leads to dyspepsia. Generally, this symptom is mild and transient and can often be decreased by concurrent administration of NSAIDs with food and/or antacids.

Non-steroidal anti-inflammatory drugs

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3.1.1.2. Gastric microbleeding. Gastric microbleeding and gastroscopically proven damage have received more attention than dyspepsia. Gastric microbleeding, as measured by recovery of 5~chromium-labelled red blood cells in stools, ranges from a basal level of less than 0.3 ml/day up to 3-7 ml/day in subjects consuming high-dose, regular aspirin (Wood et al., 1962). Blood loss with newer NSAIDs is generally less than 2 ml/day and often not significantly different from placebo (Bianchine et al., 1982; Hooper et aL, 1982; Hunt et al., 1983). Gastric microbleeding due to NSAIDs rarely leads to anaemia and, in most instances, appears to be without clinical significance (Percy, 1982). It should be noted that the property of NSAIDs to inhibit platelet function enchances bleeding from any gastric lesion induced by NSAID intake.

3.1.1.3. Peptic ulcer. The relationship between NSAID intake and the development of peptic ulceration has been difficult to define. A number of epidemiological studies in the general population have demonstrated a very low association between heavy aspirin intake and gastric ulceration, but no association with duodenal ulceration (Cameron, 1975; Duggan, 1976; Levy, 1974; Silvoso et al., 1979). For example, the yearly risk for hospital admission for gastric ulcer was 10 per 100,000 heavy consumers of aspirin (Levy, 1974). Somewhat higher figures have been presented from studies in which aspirin was given to reduce the incidence of various vascular diseases. The acute myocardial infarction group study (AMIS) of the prophylactic use of aspirin 1 g/day in 4,324 patients showed a 1.3% incidence of peptic ulcer versus 0.2% in the controls (AMIS, 1980). An incidence of confirmed peptic ulcers of 3% was reported amongst 651 post-myocardial infarct patients given aspirin 1500 mg/day for an average of 29 months (E.P.S.I.M. Research Group, 1982). However, in the arthritic population taking NSAIDs, recent and largely uncontrolled gastroscopic studies have revealed a very high incidence (about 30%) of often unsuspected peptic ulceration (Caruso and Porro, 1980; Collins et al., 1986; Roth, 1982). Other studies had previously indicated that patients with RA may be more susceptible to peptic ulceration, although this is debatable (Rainsford, 1982). Interestingly, a large proportion of the arthritic subjects with previously unsuspected GI lesions could not recall any gastrointestinal symptoms, even after diagnosis of the GI lesions. Additionally, active ulcers heal while anti-rheumatics are continued and recur at no more than the exepected rate, even while aspirin is continued (Davies et al., 1986; Piper et al., 1975). Prescribing information accompanying the newer NSAID, such as ibuprofen, naproxen, sulindac, piroxicam and diflunisal, quote the incidence of peptic ulcers caused by these NSAIDs at around 1%. Examination of the relative risk for developing peptic ulcer in an individual has been a useful approach to risk definition in recent studies (Piper et al., 1981). A recent study has suggested that the relative risk for perforated peptic ulcer increases substantially in the elderly who are taking NSAIDs (Collier and Pain, 1985). The higher doses used in the treatment of RA may be associated with higher incidence of peptic ulcer. Well-controlled prospective endoscopic studies of patients commenced on NSAIDs and retrospective casecontrol studies of patients who develop gastrointestinal adverse effects to NSAIDs are required to define the true incidence of peptic ulceration due to NSAIDs and the relative risk for individuals who take NSAIDs (Henry, 1985a). 3.1.1.4. Major gastrointestinal adverse effects. Of most importance is the risk of major bleeding or performation of peptic ulcers induced by NSAIDs. Until recently, there has been little reasonable data allowing an assessment of relative risk for these adverse events. The risk for hospital admission for upper gastrointestinal bleeding, even in heavy aspirin users, is low, of the order of 15/100,000 heavy users per year (Levy, 1974). Weber (1984) has also presented the incidence of various serious adverse events and emphasized the importance of expressing adverse events possibly associated with NSAIDs in terms of the prescription volume. This perspective indicates that the incidence of this adverse effect is very low. Studies of hospitalized patients suggest that heavy aspirin consumption

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increases the risk of serious bleeding for an individual approximately two-fold when compared with non-aspirin taking controls (AMIS, 1980; Coggon et al., 1982; Editorial, 1983; Rees and Turnberg, 1980). Properly controlled studies recently published lead to considerable concern regarding NSAIDs and bleeding ulcers. Males and females over the age of 60 years admitted to hospital with bleeding duodenal or gastric ulcer were about 3 to 4 times as likely to be taking NSAIDs, other than aspirin, as matched controls, a contrast which was highly significant (Somerville et aL, 1986). Extrapolation of these findings to the population of the U.K. suggests that 2,000 cases of bleeding from peptic ulcer in patients over 60 years of age admitted to hospital each year could be induced by non-aspirin NSAIDs. A death rate of 10% is expected with this disease. Speculation is only possible regarding the number of patients similarly affected who are not admitted to hospital and consequently do not receive active treatment. It has also been observed that the rate of admissions for peptic ulcer perforation has been steadily increasing in elderly women in the U.K. This has been in parallel with increasing use of non-aspirin NSAIDs (Section 2.3.8), from 7.6 million prescriptions in 1967 to 22 million in 1985, with the steepest increase in prescriptions in those over 65 years of age (Fig. 8; Walt et al., 1986; Collier and Pain, 1985). Serious consideration is required before commencing patients, particularly the elderly, on NSAIDs, even for short periods of time, as it is clear that these drugs are associated with serious gastrointestinal reactions in a small number of patients. In particular, patients with past histories of such reactions or gastrointestinal disease are likely to be at even greater risk (CSM Update, 1986). 3.1.2. Pathogenesis of Upper GI Effects of N S A I D s Upper gastrointestinal damage induced by NSAIDs, is due to the breakdown of the gastric mucosal barrier (Coke, 1976; Ivey et al., 1972; Laule et al., 1982), allowing backdiffusion of hydrogen ions which causes mucosal and submucosal damage, inflammation and bleeding (Davenport, 1964). Although acid is essential for gastric mucosal injury, the ability of the mucosa and its blood supply to neutralize or clear back-diffused acid may also be an important factor controlling the development of gastric damage (Kivilaakso and Silen, 1979). 3.1.2.1. Gastric acid--clinical significance. The importance of gastric acidity in the gastrointestinal damage induced by aspirin is shown by the elimination of aspirin-induced blood loss after neutralization of gastric contents by large doses of antacids (Leonards and Levy, 1969; Thorsen et al., 1968). The required doses of antacid are, however, very large with the risk of systemic alkalosis and this is not a practicable way of improving the gastrointestinal intolerance induced by aspirin or other NSAIDs. Histamine2 antagonists, cimetidine and ranitidine, provide an alternative way of reducing gastric acidity and several groups have demonstrated the protective and healing effects of cimetidine either during or following treatment with aspirin or other NSAIDs (Croker et aL, 1980; Lanza et al., 1983; Mackercher et al., 1977; O'Laughlin et al., 1981; Welch et al., 1978). The results of two clinical studies must be set against the general conclusion that H2-antagonists prevent or arrest the gastrointestinal toxicity of NSAIDs. Firstly, perforation of peptic ulcers has been recorded when NSAID treatment was continued during treatment with cimetidine (Mitchell and Sturrock, 1982), and secondly, Davies et al. (1986) have reported that NSAID-associated ulcers healed as well during dosage with placebo as during treatment with cimetidine. At this stage Hz-antagonists are not recommended for routine use with NSAIDs. 3.1.2.2. Gastric mucosal barrier. Aspirin and the other NSAIDs may disrupt the gastric mucosal barrier by reducing the quality and quantity of gastric mucous secretion (Cooke, 1976; Menguy and Masters, 1965) due to interference with metabolic processes in the

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mucosa (Rainsford and Whitehouse, 1980). Bile reflux into the stomach (Cochrane et al., 1975) or concurrent alcohol (Goulston and Cooke, 1968; Puurunen et al., 1983) enhances NSAID-induced gastrointestinal mucosal damage. Inhibition of synthesis of prostaglandin E2 and prostacyclin in gastric mucosa may be an important mechanism of the gastrointestinal toxicity of NSAID (Miller, 1983b). Prostaglandins inhibit gastric acid secretion and also have other gastric cytoprotective actions which include stimulation of mucous and bicarbonate secretion and promotion of gastric mucosal blood flow which is important for clearance of back-diffused hydrogen ions (Kauffman and Grossman, 1978; Kivilaakso and Silen, 1979; Miller, 1983b; Robert, 1974). Inhibition of cyclooxygenase may divert the metabolism of arachidonic acid into the lipoxygenase pathway and it has been suggested that the products of this latter pathway promote the gastrointestinal toxicity of NSAIDs (Whittle, 1981). Prostaglandin administration prevents NSAID- and aspirin-induced gastric mucosal damage (Konturek et al., 1981a,b; Simmons et al., 1981), a further indication of the importance of inhibition of cyclooxygenase in the toxic effects of NSAIDs in the gastrointestinal tract. 3.1.2.3. Individual N S A I D s ; formulations, doses and routes o f administration. Aspirin causes greater gastrointestinal toxicity than other NSAIDs and this may be related to its distinctive biochemical properties, such as its irreversible inhibition of cyclooxygenase, prolonged binding of the acetyl group to constituents of the stomach mucosa or relatively high solubility in gastric contents (Hunt et al., 1983; Rainsford et al., 1981). Thus, less soluble salicylate preparations such as salicylsalicylic acid, aloxiprin and benorylate and relatively insoluble NSAIDs produce much less gastrointestinal damage and dyspepsia (Lanza et al., 1980; Leonards, 1966; Reizenstein and Doberl, 1973). Enteric-coated aspirin has similar gastrointestinal toxicity to the newer NSAIDs and these are much less damaging than regular aspirin (Chernish et al., 1979; Lanza et al., 1980; Loebl et al., 1977; Mielants et al., 1979; Portek et al., 1981; Silvoso et al., 1979). Diclofenac in an entericcoated formulation and the prodrugs sulindac (400 mg/day), benorylate and fenbufen may have marginally better profiles for endoscopic gastrointestinal damage and/or occult gastrointestinal blood loss than other newer NSAIDs (Danhof et al., 1972; Graham et al., 1985; Lanza et al., 1983; Osnes et al., 1979) but this is doubtful. It is assumed that the prodrugs and the newer NSAIDs are less likely to produce peptic ulcers, ulcer perforation or major bleeding, but definitive proof is lacking. Despite improvement in aspirin and NSAID formulations--such that the lumenal surface of the gastric mucosa is exposed to minimal amounts of drug in a form capable of direct injury to the gastric lining~yspepsia, occult bleeding and gastric lesions still occur, albeit less than with plain aspirin. It is possible that some of the symptoms and bleeding ascribed to the stomach may in fact arise in the duodenum (Lanza et al., 1980). Additionally, the rectal administration of indomethacin does not totally prevent dyspepsia or gastric irritation visible on endoscopy (Baber et al., 1980; Lanza et al., 1982) and parenteral indomethacin decreases gastric transmucosal potential difference similarly to oral indomethacin (Pendleton and Stavorski, 1983). These data indicate that systemic NSAIDs can induce gastric damage, although less than observed with oral drugs. There is conflicting data on parenteral aspirin. Intravenous aspirin has been shown to increase occult blood loss (Grossman 1961; Mielants et al., 1979), although other studies found that intravenous aspirin did not increase bleeding (Cooke and Goulston, 1969; Ivey et al., 1980; Leonards and Levy, 1970). 3.1.2.4. Patient factors. Patients with previous peptic ulcers, or who are concurrently taking other drugs that have a propensity for causing peptic ulcer, are probably overrepresented in patients reported as having NSAID-induced peptic ulcer or haematemisis or melaena. Thus, more care in selection of patients to be given NSAIDs could avoid some of these serious adverse effects (Laake et al., 1984). Other factors associated with a relative predisposition to NSAID-induced upper GI damage have been summarized by

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Rainsford (1984) and include older age groups, females and patients with blood group O (CSM Update, 1986). 3.1.3. Effects on the Lower Gastrointestinal Tract Diarrhoea has been observed with NSAID use, particularly with the fenamate class (flufenamic, mefenamic, meclofenamic acids) and this has limited the usefulness of this group of NSAIDs in rheumatic diseases (Ward et al., 1978). Studies have shown that NSAIDs of the fenamate group may produce diarrhoea by increasing mucosal permeability by inducing membrane damage similar to the effects of laxatives such as dioctyl sodium sulphosuccinate (Gullikson et al., 1982). On the other hand, a small proportion of patients report constipation as a consequence of NSAID intake, perhaps an expected effect as prostaglandins induce fluid secretion into the bowel (Beubler and Juan, 1978). Recent studies indicate that NSAIDs increase gastrointestinal permeability in both the proximal and distal intestine and that this is systemically mediated. It was speculated that this effect may contribute to the persistence of rheumatoid disease by facilitating antigen absorption from the intestine (Bjarnason et al., 1984). Additionally, colonic and small bowel perforation or haemorrhage is more than twice as likely in patients taking NSAIDs, although the risk of such events during treatment with NSAIDs is very low (Langman et al., 1985; Schwartz, 1981). 3.2. RENAL TOXICITY

NSAIDs can produce a variety of toxic effects on the kidney, although it should be noted that the incidence of renal toxicity is low. The incidence of renal toxicity may be decreased further as various risk factors for the development of some of these reactions have been identified in recent years. However, some toxic reactions, particularly interstitial nephritis, may involve hypersensitivity reactions and are not predictable at present. Excellent reviews have been published on this topic (Blackshear et al., 1985; Clive and Stoff, 1984; Dunn, 1984; Garella and Matarese, 1984; Lifshitz, 1983). Most experimental studies on the renal toxicology of NSAIDs have involved either aspirin, indomethacin or ibuprofen, although it is assumed that the same range of toxic effects are produced by most other NSAIDs since much NSAID-induced renal toxicity is related to inhibition of the synthesis of prostaglandins. Sulindac may be an exception to this generalization as this drug may have less effect on renal funcion than other NSAIDs although recently published data has led to doubts about the renal sparing effects of this drug (Section 3.2.6). A recent report has emphasized that the pattern of renal disease attributable to NSAIDs may be more extensive than previously suspected, extending to chronic renal failure. Thus, NSAIDs should be considered as a potential cause of unexplained renal failure (Adams et al., 1986). 3.2.1. Acute Renal Failure, Changes in Glomerular Filtration Rate and Renal Blood Flow A reduction in glomerular filtration rate (GFR) may occur during treatment with NSAIDs. There is conflicting data on the effect of NSAIDs on the GFR of subjects with normal renal function. Temporary reductions in creatinine clearance have been found during treatment with aspirin (Beeley and Kendall, 1971; Brooks and Cossum, 1978; Burry and Dieppe, 1976; Robert et al., 1972), although this result has not been confirmed in more recent studies (Akyol et al., 1982; Muther and Bennett, 1980). Moreover, there may be problems in the use of creatinine clearance as a measure of GFR during treatment with aspirin. For example, Burry and Dieppe (1976) found that creatinine clearance was inhibited by aspirin, but the clearance of chromium edetate complex, another marker of GFR, was not depressed. While there is doubt about the effect of NSAIDs on GFR in normal subjects, there clearly is a reduction in GFR in salt-depleted humans and dogs during treatment with

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both aspirin and indomethacin (Blasingham and Nasjletti, 1980; Muther et al., 1981; Oliver et al., 1980). Creatinine clearance is also significantly decreased by NSAIDs in subjects with lupus erythematosus (Kimberly et al., 1978; Kimberly and Plotz, 1977), mild chronic glomerulonephritis (Ciabottoni et al., 1984), cirrhosis with ascites (Zipser et al., 1979) and heart failure (Walshe and Venuto, 1979). In a study with etodolac in moderate renal impairment, this effect appeared to be more marked following acute dosing than during chronic dosing (Brater et al., 1985), an important result that may extend to other NSAIDs. Sulindac may not inhibit creatinine clearance in patients with chronic glomerulonephritis to the same extent as other NSAIDs (Ciabottoni et al., 1984; Bunning and Barth 1982). However, sulindac does depress urinary prostaglandin E2 and urinary sodium in normals (Brater et al., 1985; Roberts et al., 1985), patients with essential hypertension (Koopmans 1986), patients with chronic renal failure (Berg and Talseth, 1985) and RA patients with heart failure (Svendsen et al., 1984). NSAIDs generally decrease renal blood flow to a similar degree to the depression in G F R (Ciabottoni et al., 1984). 3.2.2. Salt and W a t e r Retention The retention of salt and water is a significant side-effect of NSAIDs. Recent data indicate that NSAIDs inhibit the initiation of diuresis and decrease urine volume and free water clearance because these functions are dependent on prostaglandin synthesis (Schwertschlag et al., 1986). Some peripheral oedema occurs in approximately 10% of patients taking ibuprofen (Clive and Stoff, 1984) but the incidence of oedema with other NSAIDs has not been well documented. Very considerable oedema may be seen in occasional patients. The retention of salt and water is shown particularly by the antagonism of the natriuresis produced by frusemide and other loop diuretics (Section 4.2; Bartoli et al., 1980; Chennavasin et al., 1980; Pedrinelli et al., 1980). This interaction has been seen with several NSAIDs including indomethacin, ibuprofen, diflunisal, sulindac, piroxicam, flurbiprofen and aspirin (Wilkins et al., 1986), although there is dispute concerning flurbiprofen and sulindac (Allen et al., 1981; Koopmans et al., 1986; Symmons et al., 1983). Aspirin has also been reported to block the natriuresis produced by spironolactone (Tweeddale and Ogilvie, 1973). Interactions with the loop diuretics and spironolactone should be considered if any NSAID is added to the dosage regimen of patients taking these diuretics. There is conflicting data on the effects of NSAID on the natriuresis produced by thiazides. Antagonism has been found in some studies (Brater, 1977; Dusing et al., 1983), while no antagonism was shown in two other studies (Fanelli et al., 1980; Williams et al., 1982). However, antagonism of the hypotensive activity of thiazides by indomethacin and other NSAIDs is well recognized (Koopmans et al., 1986; Lopez-Overjero et al., 1978; Steiness and Waldorff, 1982; Watkins et al., 1980). Since the hypotensive activity of the thiazides is widely attributed to their natriuretic activity, it would seem that the antagonism of the hypotensive activty of the thiazides by NSAIDs is due to inhibition of the natriuretic activity of these diuretics. The general lack of effect of sulindac on the hypotensive response to thiazides is consistent with this hypothesis (Steiness and Waldorff, 1982), although occasional patients taking thiazides may still show a hypertensive reaction when treated with sulindac (Blackshear et al., 1983; Easton and Koval, 1980) and sulindac does antagonize the natriuresis produce by frusemide (Roberts et al., 1985). 3.2.3. H y p e r k a l a e m i a Hyperkalaemia, together with renal insufficiency, has been reported during treatment with many NSAIDs. Most patients have had some degree of renal insufficiency before the

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development of hyperkalaemia (Clive and Stoff, 1984). The retention of potassium is attributed to decreased secretion of renin leading, in turn, to a reduction in angiotensin II and aldosterone levels. 3.2.4. Papillary Necrosis Papillary necrosis is the primary and characteristic lesion of analgesic nephropathy. There is secondary cortical atrophy, the renal lesions eventually leading to end-stage renal failure (Kincaid-Smith, 1967; Prescott, 1982a). Papillary necrosis is clearly associated with the abuse of analgesic combinations and there is biochemical evidence that combinations of either phenacetin or paracetamol with aspirin may be synergistic in producing papillary necrosis (Duggin, 1980). However, there has been considerable debate about the development of papillary necrosis in patients taking NSAIDs only for the treatment of arthritic disease. Present evidence indicates that this toxic effect can occur during treatment with a single NSAID, although papillary necrosis progressing to end-stage renal failure, is probably a very rare event. Approximately 90 cases, described as analgesic nephropathy or papillary necrosis have been reported in patients taking only aspirin (Prescott, 1982a). In addition, a small number of cases of papillary necrosis have been found during treatment with a variety of NSAIDs, including phenylbutazone, indomethacin, fenoprofen, mefenamic acid, zomepirac, tolmetin, fenclofenac, naproxen, ketoprofen and ibuprofen (Husserl et al., 1979; Mitchell et al., 1982; Morales and Steyn 1971; Munn et al., 1982; Prescott, 1982a, 1984; Robertson et al., 1980; Shah et al., 1981). Papillary necrosis is thus a potential problem with all NSAIDs and should be considered if patients treated with NSAIDs develop haematuria and azotemia. Clearly, treatment with NSAIDs should be stopped in any patient in whom papillary necrosis is found. The prognosis of patients is generally good, provided that both NSAIDs and paracetamol are not administered again (Prescott, 1982a). 3.2.5. Interstitial Nephritis Several NSAIDs have been associated with the development of an interstitial nephritis, characterized by acute renal failure with variable amounts of proteinuria and infiltration of T-lymphocytes (Finkelstein et al., 1982; Stachura et al., 1983). The most common NSAID involved is fenoprofen, particularly when the interstitial nephritis occurs with diffuse fusion of glomerular foot processes (minimal change glomerulopathy). This syndrome has also been reported with indomethacin, tolmetin, naproxen, piroxicam and phenylbutazone (Clive and Stoff, 1984). In many cases, the proteinuria results in the nephrotic syndrome which is reversible, although dialysis and corticosteroids may be required during its resolution. Proteinuria, a urinary sediment containing cells and casts and previously normal kidneys, differentiates this syndrome from other NSAID-induced acute renal failure. 3.2.6. Risk Factors For Renal Side Effects It is notable that various treatments and conditions sensitize patients to the renal sideeffects of NSAIDs. Risk factors for such renal toxicity of NSAIDs include salt restriction, diuretic treatment, heart failure, cirrhosis with ascites, glomeruionephritis, atherosclerotic cardiovascular disease, lupus erythematosus and, possibly advanced age (Blackshear et al., 1983). In these conditions, it is probable that renal prostaglandins are important in maintaining renal perfusion and function and are elaborated in response to activation of the adrenergic and renin angiotensin systems (Clive and Stoff, 1984). Any inhibition of prostaglandin synthesis then becomes more important than in healthy subjects. The NSAIDinduced reduction in renal function generally is reversible and cessation of treatment with NSAIDs rapidly leads to recovery. Some guidelines can be put foward for the use of NSAIDs with regard to their renal toxicity.

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(1) Patients at risk of NSAID-induced renal syndromes, such as decreased GFR or renal blood flow or retention of sodium, potassium or water, should have their renal function monitored regularly, particularly by measuring the plasma concentration of creatinine, blood pressure and body weight, and examining the urine and its sediment. (2) Patients should be asked to report any symptoms consistent with interstitial nephritis or papillary necrosis, such as back pain, polyuria, oedema or haematuria. It is widely claimed that sulindac has less renal effects than other NSAIDs but sulindac should still be used with caution in patients with risk factors for renal side-effects induced by NSAIDs. 3.3. HEPATOTOXICITY 3.3.1. Elevation o f Hepatic Enzymes The commonest hepatotoxic adverse effect of NSAIDs is the transient, asymptomatic elevation of plasma transaminases (Crossley, 1983). The elevation generally resolves itself despite continued intake of the particular NSAID. In particular, high-dose salicylate therapy is associated with elevated hepatic transaminase enzymes in juvenile rheumatoid arthritis and in systemic lupus erythematosus in adults (Athreya et al., 1975; Bernstein et al., 1977; Doughty et al., 1979; Manso et al., 1956; Miller and Weissman, 1976; Rich and Johnson, 1983; Russel et al., 1971; Seaman et al., 1974; Wolfe et al., 1974). Patients identified with NSAID-induced elevations of hepatic enzymes should be observed more closely. Dosage of NSAIDs may be temporarily reduced or ceased, depending on the degree of elevation of marker enzymes. Treatment with the NSAID should be ceased if there is any indication of more severe hepatotoxicity, such as prolongation of the prothrombin time (Benson, 1983). In the U.S.A., a paragraph describing the potential hepatotoxicity of NSAIDs has been added to the labelling of all NSAIDs and the FDA has suggested discontinuation of any NSAID if liver function tests exceed three times normal (Paulus, 1983). 3.3.2. Jaundice and Symptomatic Hepatitis Jaundice and severe NSAID-induced liver toxicity are quite rare. Benoxaprofen was withdrawn from the market in August 1982, because it had been associated with the deaths of 61 patients in the U.K. and 11 in the U.S.A. as a result of liver and kidney damage, cholestatic jaundice being the major reason for withdrawal (Goudie et al., 1982; Taggart and Alderdice, 1982). Of note was that many of the fatalities occurred in elderly patients, some of whom had renal impairment (Shedden, 1982). Virtually all NSAIDs have been associated with a few such cases which might be described as idiosyncratic despite some suggestion of association with excessive retention of drug (Mills and Sturrock, 1982). Sulindac may have a higher risk of hepatotoxicity than other NSAIDs, but again the risk is low (Wood et al., 1985). Reye's syndrome, a rare and often fatal disease of children, which is characterized by fatty degeneration of the liver and kidneys and encephalopathy, may be linked with aspirin intake in association with a viral illness (Halpin et al., 1982; Partin et al., 1982; Starko and Mullick, 1983; Young et al., 1984). Children with juvenile rheumatoid arthritis probably have a greater risk for this adverse effect. Paracetamol has been recommended as a safer antipyretic in children. 3.3.3. Mechanisms o f Hepatotoxicity The milder forms of hepatotoxicity, leading to elevated plasma transaminases, are seen more commonly in JRA and systemic lupus erythematosus than in RA. Biopsy samples show mild hepatocellular damage with scattered necrosis and mononuclear cell infiltrates

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of portal tracts and sometimes some centrilobular biliary stasis. These reactions are not usually accompanied by fever, rash or eosinophilia, indicating that they are not typical hypersensitivity reactions. The biochemical mechanisms that may be relevant to NSAID-induced hepatotoxicity have been discussed (Drew and Knights, 1985; Timbrell et al., 1983). The concept of the formation of reactive metabolites, or free-radical intermediates, of these drugs, particularly in situations where there is limited availability of detoxifying adducts, such as glutathione, receives support from the mechanisms of the hepatotoxicity associated with paracetamol. Recently, it has been proposed that the NSAID, alclofenac (now withdrawn), caused hepatotoxicity by way of a reactive epoxide intermediate metabolite (Rainsford, 1984). A review of data concerning hepatotoxicity of individual NSAIDs has been published (Lewis, 1984).

3.4. BLEEDING DISORDERS 3.4.1. Platelets Aspirin and the NSAID are being increasingly used in the prevention and treatment of cardiovascular and thrombotic diseases. The beneficial effects of these drugs in these conditions relate to their effects on platelet and vascular prostanoid production (Castaldi, 1981). Much discussion concerns the appropriate dosage of aspirin in these conditions (Editorial, 1986). It is well known that aspirin inhibits platelet aggregation induced by collagen, adrenaline and ADP and that this effect lasts the 5-7 day lifetime of the platelet (O'Brien, 1986). Aspirin exerts this effect by irreversibly inhibiting platelet cyclooxygenase, thus limiting thromboxane A2 formation which is an extremely potent platelet aggregating factor (Smith and Willis, 1971). Salicylate, which is a very weak, reversible cyclooxygenase inhibitor, does not inhibit platelet function (Weiss et al., 1968). Other NSAIDs are reversible inhibitors of cyclooxygenase and platelet function, this effect being dose-related and paralleling plasma concentrations of NSAIDs (Mclntyre, 1978; Rane et al., 1978).

3.4.2. Bleeding Time Despite the marked effects of aspirin and NSAID on platelet function in vitro, there is only a small prolongation of the bleeding time (approximately 2 min). This limited effect of aspirin and NSAIDs may relate in part to the lack of potency of aspirin (and probably other NSAIDs) in inhibiting thrombin-induced platelet aggregation, thrombin being an important aggregating substance in vivo (Majerus, 1976). The effect on bleeding time induced by aspirin shows considerable intersubject variability and subsides within 24 hr after stopping aspirin (Quick, 1966; Mielke, 1969). Of great importance is the prolongation of bleeding time in patients concurrently taking anticoagulants (Section 4.2), subjects who have coagulation disorders (Rothschild, 1979) or individuals who have taken alcohol within the preceding 36 hr (Deykin et al., 1982). However, studies in haemophiliacs show ibuprofen to be relatively safe (Hasiba, 1980: Mclntyre, 1978). Ibuprofen and choline magnesium trisalicylate have been used successfuly in treating the symptoms of haemophiliac arthropathy (Steven et al., 1985; Thomas et al., 1982).

3.4.3. Hypoprothrombinaemia Aspirin and salicylates lengthen the prothrombin time only if the plasma salicylate concentration is maintained above 300/~g/ml. This is widely considered to be the upper limit of the therapeutic range of plasma concentrations for salicylates. This effect has not been reported with other NSAIDs except in rare cases of hepatotoxicity.

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3.4.4. Clinical Bleeding There is little good evidence that significant haemorrhagic complications are more likely in surgical patients who are taking aspirin (Amrein et al., 1981; Schondorf and Hey, 1976) although aspirin intake within 5 days of delivery renders mother and baby significantly more liable to bleeding complications (Stuart et al., 1982). However, many surgeons believe that aspirin intake is associated with excessive perioperative bleeding in at least some patients and recommend avoidance of aspirin and other NSAIDs before surgery. If there is considered to be a risk of bleeding during surgery, treatment should be changed to paracetamol or a short-acting reversible NSAID, such as ibuprofen or ketoprofen, which can be terminated just prior to surgery.

3.5. ANAPHYLACTOID AND SKIN REACTIONS Dermatological and gastrointestinal adverse reactions are the commonest adverse reactions reported in the two years following initiation of marketing of NSAIDs in the U.K. (Weber, 1984). Although most skin reactions to NSAID are not serious, some severe reactions have been described (Bailin and Matkaluk, 1982) and the anaphylactoid responses are often life-threatening. 3.5.1. Anaphylactoid Responses to Aspirin and N S A I D s Patients with classic aspirin intolerance often suffer from rhinitis associated with nasal polyposis as well as asthma. Minutes to hours after ingestion of aspirin, acute asthma and/or angio-oedema or urticaria occurs, which may even result in shock and death. Attacks are often accompanied by rhinorrhoea, erythema and conjunctival inflammation. This serious effect of aspirin is not a classic type I allergic response, but appears to be related to prostaglandin synthesis inhibition since other NSAIDs are equally dangerous, whereas sodium salicylate, a weak prostaglandin synthesis inhibitor is often well tolerated (Editorial, 1981; Samter, 1973; Seale, 1983; Szcseklik and Gryglewski, 1983). Zomepirac, a classic NSAID, was marketed by emphasizing its analgesic activity and downplaying the fact that it was a NSAID. Consequently, there was a high rate of serious anaphylactoid reactions to the drug in patients who were aspirin/NSAID intolerant, these reactions leading to the withdrawal of the drug. Potency in this adverse effect parallels the relative potency of NSAIDs as cyclooxygenase inhibitors, but whether this syndrome is due to decreased levels of prostaglandins or to increased synthesis of leukotrienes or some combination of these effects remains to be elucidated (Szczeklik et al., 1975,1977). A proportion of subjects who have anaphylactoid responses to NSAIDs react similarly to the yellow food dye, tartrazine, which is commonly found in coloured drugs and food products. The mechanism for this similar response to NSAID is not known (Buswell and Lefkowitz, 1976; Miller, 1983a; Szczeklik and Gryglewski, 1983; Vargaftig et al., 1980). Interestingly, tolerance to aspirin can be induced in some subjects by repeated administration of the drug and some of these subjects develop bronchodilator responses (Asad et al., 1984; Szczeklik and Gryglewski, 1983) but his procedure is not recommended as a general approach to the problem of aspirin/NSAID intolerance. The prevalence of aspirin intolerance as described in asthmatic populations, ranges from 5-25% (Chaffee and Settipane, 1974; McDonald et al., 1972; Seale, 1983; Settipane, 1984). However, some of these cases simply refer to asthmatics whose disease is worsened by aspirin and not to the full anaphylactoid response. The range of responses to aspirin in sensitive patients is considerable (Seale, 1983). In summary, patients with true aspirin anaphylactoid reactions will react similarly to all NSAIDs which are also prostaglandin synthesis inhibitors. Paracetamol, narcotic analgesics, sodium salicylate or choline magnesium trisalicylate and salsalate may be used with great caution since, although these drugs have been used safely in aspirin-sensitive

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individuals, there have been rare reports of serious reactions (Merrit and Selle, 1978; Seale, 1983). 3.5.2. Skin Reactions to N S A I D s The commonest skin reactions to NSAIDs are pruritis and simple erythematous, macular rashes which resolve quickly on cessation of drugs (Bigby and Stern, 1985). Acute and chronic urticaria may be due to aspirin in 5-10% of cases and a proportion of chronic urticaria patients sensitive to aspirin will also react with other NSAIDs, tartrazine and preservatives, notably sodium benzoate. As noted previously, urticaria may be part of the anaphylactoid resonse to aspirin and other NSAIDs. Skin rash, lymphadenopathy and fever have been described with a number of NSAIDs sometimes in association with aseptic meningitis and pulmonary infiltrates and eosinophillia (Buscaglia et al., 1984; Nader and Schillaci, 1983; Sprung, 1982). Benoxaprofen was notable for causing not only cholestatic jaundice and death, but also severe phototoxicity and onycholysis (Mikulaschek, 1982). This related to the amount of exposure to ultraviolet light, the dose of benoxaprofen and the level of pigmentation of the patients (Editorial, 1982; Diffey and Brown 1982). Phototoxicity has occurred with other NSAIDs but is a rare side effect (Sachs, 1983; Stern, 1983). Idiosyncratic severe skin reactions, such as Stevens Johnson Syndrome, toxic exidermal necrolysis, erythema multiforme and pemphigus vulgaris, occur very rarely with all NSAIDs (Bailin and Matkaluk, 1982; Medical Letter, 1983). 3.6. CENTRAL NERVOUS SYSTEM AND SPECIAL SENSES TOXICITY

NSAIDs have been increasingly implicated in a variety of central nervous system adverse effects and up to 10 percent of subjects suffer a variety of these symptoms, such as headache, depression, depersonalization, tinnitus, etc., even with the newer NSAIDs (Blechman et al., 1975; Cuthbert, 1974; Goulton and Baker, 1980). Measurable cognitive dysfunction has been ascribed to new NSAIDs, particularly in the aged (Goodwin and Regan, 1982). However, only a very small proportion of subjects need to cease treatment with most NSAIDs for these adverse effects. Exceptions are indomethacin and salicylate. 3.6.1. Indomethacin Headache occurs in over 10% of patients taking this drug, while depression, fatigue, dizziness and vertigo are found in 3-9% of patients (Rhymer and Gengos, 1983). No other NSAID causes such a high incidence of these adverse reactions. It is possible that these adverse affects of indomethacin are due to direct effects of the drug on cranial blood vessels, including both vasoconstriction, as plasma concentrations increase, and rebound vasodilatation, once the drug has been eliminated. Significant vasoconstriction of coronary arteries in humans with coronary artery disease has been demonstrated with indomethacin (Friedman et al., 1981). These central nervous system effects are more likely in migraine sufferers and may be decreased somewhat by lessening the fluctuations in plasma indomethacin concentrations by the use of slow or controlled-release formulations (Section 2.3.5.3). 3.6.2. Tinnitus and Deafness Although tinnitus is reported rarely with most NSAIDs, this adverse effect is commonly seen in subjects prescribed high-doses of salicylate who also experience a reversible sensorineural hearing deficit of up to 30~0 decibels across all frequencies (Mongan et al., 1973; Myers et al., 1965). Recently, it has been demonstrated that the intensity of salicylate induced ototoxicity is linearly related to unbound plasma concentrations of salicylate (Day et al., 1984b).

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3.6.3. Aseptic Meningitis A number of cases of this complication have been reported in patients with systemic lupus erythematosus, particularly with ibuprofen, but also with other NSAIDs such as sulindac. Concurrent fever, rash, lymph-node enlargement, gastrointestinal upset and elevation of hepatic enzymes, suggest a hypersensitivity reaction (Section 3.5.2.; Ballas and Donta, 1982; Giansiracusa, 1980; Park et al., 1982; Schonfeld, 1980; Sonnenblick and Abraham, 1978; Von Reyn, 1983; Widener and Littman, 1978) perhaps further supported by a recent case of eosinophillic meningitis induced by ibuprofen (Quinn et al., 1984). Encephalopathy has been associated with sulindac therapy (Neufeld and Korczyn, 1986). 3.6.4. Ophthalmic Effects Ophthalmic effects of NSAIDs are exceedingly rare. Toxic amblylopia has been associated with ibuprofen in three cases (Adams and Warwick-Buckler, 1983; Collum and Bowen, 1971). Rare cases of corneal deposits and retinal abnormalities have been noted with indomethacin (Burns, 1978; Carr and Siegel, 1973; Henkes et al., 1973).

3.7. SALICYLATEAND N S A I D OVERDOSE

Salicylate poisoning is common, particularly in children (Dreisback, 1980) and death is probably due to toxic brain concentrations of salicylate (Hill, 1973). Acidosis promotes trapping of salicylate in the relatively alkaline brain cells and is associated with a poor prognosis. Thus, the major objective in management of these patients is to keep salicylate out of the brain. Systemic alkalinization not only enhances elimination of salicylate due to urinary alkalinization, but also reduces partitioning of the drugs into the brain (Hill, 1973). Other NSAIDs are much less commonly taken in overdose, but their increasing availability, sometimes as propietary preparations, make overdose attempts with them increasingly likely (Prescott, 1982b). In general, morbidity and mortality is uncommon unless overdosage is massive (Vale and Meredith, 1986). Mefenamic acid, relatively freely available as a treatment for menstrual pain, is quite commonly used for self-poisoning and is associated with grand mal convulsions in 20 percent of cases (Prescott, 1982b). Ibuprofen was implicated in 75 self-poisoning episodes in a two year survey at the Guys Hospital Poison Unit, London. Most of these cases were asymptomatic (Court et al., 1983). 3.8. HAEMATOLOGICAL

Thrombocytopenia, agranulocytosis and aplastic anaemia are rare adverse effects of NSAIDs. However, phenylbutazone and its active metabolite, oxyphenbutazone, have been linked with a relatively high incidence of serious haematological adverse effects. Phenylbutazone was the leading cause of drug-caused deaths in the U.K. between 1964 and 1980 (Venning, 1983). Phenylbutazone-associated agranulocytosis is a hypersensitivity response occurring in younger patients within the first months of therapy while aplastic anaemia is more likely to occur after prolonged therapy in patients over the age of 60, particularly women (Fowler, 1967; Fowler and Faragher, 1977; Inman, 1977; Paulus, 1985). Phenylbutazone-induced aplastic anaemia may be a consequence in part of the longer half-life of elimination of phenylbutazone in the elderly (Section 2.3.5.2). Given these serious effects of phenylbutazone, which occur at a rate much greater than with other NSAIDs, this drug should only be used in conditions such as seronegative spondyloarthropathies, acute gout and rheumatoid arthritis which have not responded to treatment with other NSAIDs (Australian Adverse Drug Reactions Bulletin, 1983). If phenylbutazone or oxyphenbutazone are used, careful haematological monitoring, especially in aged patients, is mandatory, but even this will not avoid all cases of aplastic anaemia.

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Weber (1984) has compiled a number of serious haematological adverse effects associated with the first two years marketing in the U.K. of some NSAIDs and expressed the incidence as the number of reported reactions per 1000 prescriptions. Thrombocytopenia is the commonest of the severe dyscrasias seen with NSAIDs.

4. DRUG INTERACTIONS Interactions between NSAIDs and other drugs are of considerable clinical significance because of the wide use of NSAIDs. There are now several well-documented interactions between NSAIDs and other groups of drugs and these have been reviewed recently (Day et al., 1984a). Most of these interactions involve the effects of NSAIDs on the metabolism or function of other drugs, with very few significant effects of other drugs on the activity of NSAIDs. Most interactions involving NSAIDs are pharmacokinetic interactions, changes being produced in the rate or extent of absorption, characteristics of distribution or the rate of elimination of at least one of the interacting drugs. A pharmacokinetic interaction leads to changes in the concentration of one of the interacting drugs at its site of action without any change in the concentration-response relationship. Pharmacodynamic interactions also occur with NSAIDs. Such interactions result from a change in the relationship between the intensity of the response to the drug and the concentration of the drug at its site of action. Few interactions of this type occur with the anti-rheumatic drugs, but they may be of considerable clinical importance.

4.1. EFFECTSOF OTHER DRUGS ON NSAIDs 4.1.1. Antacids Antacids are frequently administered with NSAID in order to reduce gastrointestinal side-effects. In general, antacids do not significantly affect the total absorption of NSAID, although there may be minor effects on their rates of absorption. The only reports of a significant effect on the total absorption of NSAID concern naproxen and diflunisal. The absorption of naproxen is decreased by aluminium hydroxide alone (Segre, 1973), but not by a magnesium-aluminium hydroxide mixture (Segre et al., 1974). The absorption of diflunisal is reduced considerably by aluminium hydroxide (Verbeeck et al., 1979b) and, to a lesser extent, by a mixture of magnesium and aluminium hydroxides (Holmes et al., 1979). However, these effects are only seen in the fasting state and with very large doses of antacids. There is no effect of antacids on the total absorption of diflunisal when antacid and drug are given after meals (Tobert et al., 1981). The administration of soluble or buffered tablets containing small amounts of antacids decreases the epigastric discomfort produced by aspirin, but does not greatly reduce the gastrointestinal damage associated with high doses of this drug (Lanza et al., 1980; Leonards and Levy, 1969; Wood et al., 1962). Sucralfate, a newer ulcer-healing agent, does not affect the pharmacokinetics of aspirin (Lau et al., 1986). 4.1.2. Probenecid

Probenecid markedly increases the plasma concentrations of several NSAIDs during long-term treament due to inhibition of the excretion of labile acyl glucuronides (Section 2.3.7). The clinical significance of these interactions is not known. In the case of indomethacin, the plasma levels of the drug are increased by probenecid, enhancing antiinflammatory effects without any increase in toxicity (Baber et al., 1978; Brooks et al., 1974), although further work is required to confirm this interesting finding. Probenecid does not inhibit the clearance of NSAIDs such as ibuprofen, which are eliminated largely by oxidative metabolism (Warwick, 1979).

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Probenecid inhibits the renal excretion of salicylate (Gutman et al., 1955), but this interaction is of little clinical significance since very little salicylate is excreted unchanged unless the urine is alkaline. Salicylate does, however, inhibit the uricosuric activity of probenecid, inhibition of probenecid-induced uricosuria being observed at salicylate concentrations above 50 #g/ml (Pascale et al., 1955). Occasional small doses of aspirin or other salicylates may be given to patients who are taking probenecid, but it is preferable to use analgesics or NSAIDs such as paracetamol or ibuprofen which do not interact with probenecid (Brooks and Ulrich, 1980). 4.1.3. Inducing Agents Several drugs, particularly phenobaritone, phenytoin and rifampicin, increase the rate of elimination of several other drugs by inducing oxidative and glucuronidation metabolic pathways in the liver. However, there has been only one report of this type of interaction involving NSAIDs in man, a decrease in the plasma concentration of fenoprofen due to enhancement of its metabolism by phenobarbitone (Helleberg et al., 1974).

4.2. EFFECTSOF NSAIDs ON OTHER DRUGS NSAIDs modify the activity of several other drugs (Table 2). In several cases, interactions have been reported with a limited number of NSAIDs, but a common mode of action of NSAIDs (inhibition of prostanoid synthesis) indicates that several interactions will occur with practically all NSAIDs. Interactions which are probably common to most NSAIDs include the decreased renal clearance of lithium and reduction in the natriuretic or hypotensive activities of several diuretics and anti-hypertensive agents (Section 3.2.2; Davis et al., 1986). An alternative agent is paracetamol which has not been shown to produce any of these interactions. This analgesic should be considered in the treatment of disease states such as as osteoarthritis, where it is often a reasonable substitute for NSAIDs. Another interaction which is probably common to all NSAIDs, but not paracetamol, is the potential for increased bleeding in patients taking anticoagulants, such as warfarin or heparin. Some interactions are specific to particular NSAIDs. An example is the effect of the pyrazoles (phenylbutazone, oxyphenbutazone and azapropazone) on the metabolism of other drugs. The metabolism of several other drugs, including phenytoin, tolbutamide and warfarin, is inhibited by this group of NSAIDs. While the dosage of phenytoin, tolbutamide and warfarin could be modified when treatment with one of the pyrazoles is commenced, it is more convenient to avoid treatment with the pyrazoles and to use an alternative NSAID (Table 2). A potentially dangerous interaction occurs between methotrexate and several NSAIDs (Adams and Hunter, 1976; Leigler et aL, 1969) and the resulting accumulation of methotrexate has been associated with fatal pancytopenia (Mandel, 1976). In general, high-dose methotrexate should not be used in patients taking NSAIDs. If NSAIDs are considered to be essential in patients who are also taking high-dose methotrexate, a reduced dose of methotrexate, together with intensive monitoring of methotrexate dosage, is required.

5. CONCLUSIONS Many questions concerning NSAIDs remain to be answered, but of major importance is the origin of the marked variability in response to these drugs. This reveiw has presented the clinical evidence for variability in effectiveness of NSAIDs and suggested that the reasons for this might include individual variation in pharmacokinetic parameters, variations in the balance of pathophysiological mechanisms for individual rheumatic diseases, and variable biochemical effects of NSAIDs. Adverse drug reactions and drug interactions with NSAIDs provide further examples of intersubject variablility in response

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