Aspirin does however reduce the renal excretion of methotrexate and displaces
methotrexate from protein binding sites (Dixon, Henderson & Rall, 1965). At a renal
level aspirin inhibits the excretion ofsodium by spironolactone (Hotfman, Krufnick
& Garcia, 1972) and interferes with the uricosuric etfect of probenecid (Pascale ,
Dubin, Bronsky & Hoffman, 1955). Concurrent administration of absorbable
antacids which increase urinary pH, markedly reduce plasma salicylate levels by
increasing renal excretion (Levy & Leonards, 1971) and recently (Graham,
Champion, Day & PaulI, 1977) have demonstrated a reduction in plasma salicylate
level due to a more rapid rate of salicylate metabolism on concurrent administration
Indomethacin still holds a place as a potent NSAID with c1inical trials showing
etfectiveness in osteo-arthrosis, rheumatoid arthritis, ankylosing spondylitis and gout
(Rhymer & Gengos, 1979). The drug seems particularly useful when given at night for
reducing morning pain and stitfness. Arecent study by Baber, Halliday, Van den
Heuvel, Walker, Sibeon, Keenan, Littler & Orme (1979) has highlighted the problem
of responders and non-responders to NSAID. In this study no significant ditferences
that plasma indomethacin concentration inhibited malonyldialdehyde production by
the platelets. The biochemical ditferences demonstrated in this study between
responders and non -responders is worthy offurther investigation.
The major adverse reactions to indomethacin are dyspepsia and headache and
these are reduced if the drug is taken at night. Interactions occur with frusemide
(Brooks , Bell, Lee, Rooney & Dick, 1974) with reduction of plasma indomethacin
levels and in turn the naturetic and anti-hypertensive etfect of frusemide is reduced
(Tan & Mulrow, 1977). Probenecid increases indomethacin plasma levels (Baber,
1974). An interaction which deserves further investigation is the suppression of the
anti-hypertensive etfect of ß-adrenoceptor blocking drugs by indomethacin (Durao,
Phenylbutazone and Oxyphenbutazone
spondylitis and Reiters Syndrome). The long half-life (72 h) enables once daily
administration. Side etfects occur relatively frequently but are rarely serious. The
major side etfects are peptic ulceration, skin rashes and salt and water retention
giving rise to cardiac failure in the elderly. Occasionally bone marrow toxicity with
suppression of all marrow elements or individual cell series can occur and be fatal.
Although such fatal reactions occur rarely, phenylbutazone causes more than one
third of all drug induced blood dyscrasias in Great Britain excluding cancer chemo-
NON-STEROIDAL ANTI-INFLAMMATOR Y DRUGS 291
therapy (Inman, 1977). Because ofthese potential side efTects phenylbutazone should
be reserved for the severe inflammatory rheumatic diseases and given with great care
Phenylbutazone is highly protein bound and displaces the highly bound acidic
drugs warfarin, tolbutamide and chlorpropamide (Koch-Weser & Seilers , 1971;
Hansen & Christensen, 1977); it also acts as a potent inhibitor ofmetabolism ofthese
agents. Phenylbutazone also inhibits the hepatic metabolism of phenytoin and can
Ibuprofen is rapidly absorbed and has a short half-life of approximately 2 h.
Ibuprofen is extensively bound to albumin but at normal serum concentrations only
one fifth ofthe total binding capacity is taken up (Adams & Buckler, 1979). Ibuprofen
has been used extensively in clinical trials and has been shown to be efficacious in
rheumatoid arthritis, osteo-arthrosis, juvenile chronic polyarthritis and non-articular
to be weil tolerated (Brooks, Schagel , Sekhar & Sobota, 1973).
at therapeutic concentrations (Adams & Buckler, 1979). Flurbiprofen has been used
with efTect in rheumatoid arthritis, osteo-arthrosis and ankylosing spondylitis.
Comparative studies with othcr NSAID place it high in thc 'Ieague table ' (Lee ('[ al.,
1976). Ibuprofen and flurbiprofen can bc given safely to paticnts on anticoagulant
therapy (Goncalves, 1973; Adams & Buckler, 1979). Serum levels of ibuprofen and
flurbiprofen are lowered by concurrent aspirin administration (Grennan, Ferry,
Ashworth, Kenny & Mackinnon, 1979; Brooks & Khong, 1977), but the interactions
Naproxen is rapidly absorbed from the gut and strongly bound to plasma proteins. It
has a small volume of distribution and a metabolic half-life ranging from 11-20 h.
Naproxen clearance is accelerated as the administered dose increases (Runkel,
Chaplin, Sevelius, Ortega & Segre, 1976). This is due to the limited capacity of the
primary plasma protein binding sites and hence higher levels of free drug which are
more rapidly cleared by the kidneys . Naproxen has been used with good efTect in
rheumatoid arthritis, osteo-arthrosis, ankylosing spondylitis and gout. All these
studies show the drug to be equivalent to or slightly better than other NSAID and it
has a low incidence of gastric side efTects. The normal adult dose is 500-750 mg/day
Concurrent administration of salicylate with naproxen alters naproxen kinetics
and decreases plasma naproxen levels but these etTects do not appear to be clinically
significant (Runkel, Mroszczak, Chaplin, Sevelius & Segre, 1978). Though an in vitro
increase in the serum free fraction of warfarin by naproxen can be demonstrated no
change in anticoagulant activity of warfarin under steady state conditions is seen .
Because of the high degree of protein binding similar potential interactions exist
between naproxen and sulphony lurea s. Naproxen blood levels a re signifi cantly
increased by the administrat ion of probenecid , apparently med iat ed by competition
for glucuro ny l transferase (Segre, 1979 ; Runkel er al., 1978).
Fenoprofen is anot her relat ively short hal f-life (160 min) proprionic acid der ivative
which ha s been shown to be usefu l in rheumatoid arthritis and osteo-arthrosis with a
lo w inci dence of gastric side effects. Plasma fenopro fen levels are reduced by
conc ur rent asp irin th erap y (R ubin, Wa rrick , Wolen , C hern ish, Ridolfo & Gruber ,
1973 ) and being highl y protein bound it has the potential for displacing less strongly
Ketoprofen has a relatively short half-life (1-2 h) with rapid elimi nation by the
osteo-arthrosis and acute attacks of gout. In do ses of 100-300 mg/day ketoprofen
compares favourabl y with other NSAID and ha s a low incidence of gastric side
Patients react individua lly to th e pro prionic ac id derivatives as Hu sk isson et al.
(1976) have shown. In this st udy compari ng fou r non -stero ida l a nti-intla mmatory
drugs, fenoprofen and naproxen were preferred to ketoprofen or ibuprofen, and the
incide nce of gastroint estinal side elTects were slightly greater with ketoprofen and
fenoprofen than with naproxen or ibupro fen. In th is study naproxen proved to
combine greatest efficac y with the least side elTects.
The ph armacology of diclofenac has been reviewed by Fo wler (1 97 9). The drug is
rapidly absorbed from the duodenum and has a relatively short half-life in man with
a protein bind ing of 99 %. A nurn ber of do uble-b lind crossover studies su ppo rt the
reported long term multi-centre trial s showing continuing efficacy and a low
inc idence of side elTects. Concurrent aspirin therapy reduces diclofenac levels
(Muller, Hundt & Muller, 1977) and although the drug is strongly bound to plasma
Alclofenac is a phenylacetic ac id deri vati ve wh ich is c1aimed to ha ve a long term
advantage in reducing th e activ ity ofrheumatoid arthritis in addition to analgesic and
anti-inflammatory properties (Ay lward, Parker, Holly, Maddock & Davies, 1975).
The drug has high protein bind ing , a low volume of distribution and a short plasrna
half-life of about 2.5 h. The major drawback with this drug is the occurrence ofskin
rashe s and vasculitis (Billings, Burry, Em slie & Kerr, 1974).
NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
Sulindac is absorbed and converted into its metabolites, the sulphide and sulphone. It
is the sulphide which is the active anti-inflammatory constituent and undergoes
enterohepatic circulation having a plasma half-life of approximately 16 h. Sulindac
seems to be weil tolerated and has been shown to be efficacious in rheumatoid
arthritis, ankylosing spondylitis, acute gout and osteo-arthrosis (Rhymer, 1979). Side
efTects occur infrequently, gastric intolerance being the most common. No clinically
significant interactions have been reported between oral anticoagulants and oral
Tolmetin has a half-life of approximately 5 hand is extensively bound to plasma
arthritis (Ehrlich, 1979; Brogden, Heel , Speight & Avery, 1978). Interactions with the
anticoagulants or sulphonylureas have not been shown to occur.
Azapropazone is a relatively new NSAID which also has uricosuric efTects.
Chemically it is closely related to the pyrazole compounds. Plasma half-life is
approximately 12 h in man and it is extensively bound to plasma proteins and
eliminated primarily by the kidneys (Sondervorst, 1979). Double-blind studies have
interaction between anticoagulants and azapropazone has been reported
(Sondervorst, 1979) and care should be taken when this drug is prescribed with oral
Diflunisal is a new salicylate derivative which lacks the O-acetyl group and thus
cannot participate in protein acetylation reactions. Diflunisal is tightly bound to
plasma proteins and has a plasma half-life of about 8 h (Van Winzum & Verhaest,
1979). Plasma levels of diflunisal increase more rapidly in proportion to the dose ,
suggesting that its elimination is dose dependent. To date, diflunisal has been used as
an analgesie in short term studies and in doses ofup to 750 mg/dose for the treatment
ofosteo-arthrosis (Brogden, Heel, Pawes, Speight & Avery, 1980).
No clinically significant interaction has been reported with aspirin or naproxen,
Tjandramaga, Mullie, Verbesseit & de Schepper, 1979).
Potential drug interactions occur commonly in rheumatology as polypharmacy is the
rule rather than the exception, Pharmacokinetic interactions occurring between non-
steroidal anti-inflamrnatory drugs are summarized in Table 2. Mielens, Drobeck,
Rozitis & San Sone (1968) and Van Arman, Nuss & Risley (l973)showed that
combinations ofNSAID were not advantageous in reducing inflammation in animal
models. Significant cIinical etTects of NSAID combinations have not been shown in
man and there is so me evidence that combinations ofNSAID produce an increase in
adverse reactions (Brooks et al., 1974; Caruso & Porro, 1980).
Table 2 Interaction between non-steroidal anti-inflamrnatory drugs
Drug interactions between non-steroidal anti-inflarnmatory drugs and drugs
commonly taken by patients with arthritis are summarized in Table 3. They will
occur at sites of absorption, protein binding sites, sites of drug metabolism and sites
of excretion. As with all drug interactions importance must be placed on cIinical
Table 3 Examples ofinteractions ofnon-steroidal anti-inflammatory drugs
Aluminium hydroxide Reduces diflunisal bioavailability
Magnesium oxide Reduces naproxen levels
Sodium bicarbonate Increases absorption ofindomethacin
Have the potential to displace
anticoagulants and sulphonylurea
hypoglycaemic agents but few c1inically
relevant interactions are reported
Metabolism induced by phenobarbitone
Metabolism induced by phenobarbitone
Metabolism induced by corticosteroids
Metabolism induced by pyrazoles
Metabolism inhibited by phenylbutazone
Increases naproxen, ketoprofen and
indomethacin levels by inhibition
Reduces methotrexate excretion
Increases excretion ofsalicylate
Reduces excretion ofsalicylate
NON-STEROIDAL ANTl-INFLAMMATORY DR UGS 295
The major non-steroidal anti-inflamrnatory drugs have been summarized as
regards their cIinical efTects and interactions. While these drugs tend to act similarly
on the inflammatory process individual response by both patient and disease is cIear.
While it is difficult in cIinical trials to show significant difTerences between the
NSAID these difTerences may be very real when individual patients are considered.
Because of this ind ivid ua l variation in response to these agents, it is essential that a
selection is av a ilable and the most appropriate is chosen, as rapidl y as possible, in an
efTort to stern the tide ofinflammation.
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Anderson, J. (1977). Disorders of metabolism. In Text book 0/ Adverse Drug Reactions, ed.
Davies, P. M. pp . 217-227 . London: Oxford University Press.
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indomethaci n and alclofenac in treatment ofrheumatoid arthritis. Brit. med. J.. 2, 7-9.
Baber, N., Halliday, L., Sibeon, R., Littler, T. & Orme, M. L.' E. (1978). The interaction
between indomethacin and probenecid. A clinical and pharmacokinetic study. Clin.
Baber, N., Hall iday, L. D. c., Van den Heuv el, W. J. A. , Walker, R. W., Sibeon, R., Keenan ,
J. P., Littler, T. & Orme, M. L.' E. (1979). Indomethacin in rheumatoid arthritis: Clinical
effects, pharmacokinet ics and platelet studies in responders and non-responders. Annals
Baum, J. J. (1970). BloOO salicylate levels and clinical trial s with a new form of enteric coated
aspirin: Stud ies in rhematoid arthritis and degenerative joint disease. Clin. Pharmac. Ther..
Beeley, L. & Kendall, M. J. (1971). Effect ofaspirin on renal clearance ofl, 125-<1iatrizoate. Brit.
Bensen, W. G ., Laskin, C. A., Paton, T. W., Little , H. A. & Farn, A. G. (1979). Twice dail y
dosing of enteric coated aspirin in patients with rheumatic diseases. J. Rheumat. , 6,
Billings, R. A., Burry , H. c., Emslie, F. S. & Kerr , G. D. (1974). Vaseul itis with alclofenac
therapy. Brit. med. J.. 4,263-265.
Brogden , R. N., Heel, T. M., Speight, T. M. & Avery, G . S. (1978). To lmetin: A review of its
pharmacological properties and therapeutic effrcacy in rheumatic diseases. Drugs, 15,
Brogden, R. N., Heel, R. c., Pawes, G. E., Speight, T. M. & Avery, G. S. (1980). Dillunisal: A
review of its pharmacological properties and therapeutic use in pain and musculoske1etal
strains and sprains and pain in osteo-arthrosis, Drugs, 19, 84-10 6.
Brooks , C. D., Schagel , C. A., Sekhar, N. C. & Sobota, J. T. (1 973). Tolerance and
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