COfJt~fJts

S ummary

Om Pharmacok,,...,1. 19 (I~ 44-66.1990 OJI2-S96J/90{OOO7-0044/S II .SO/O e "dl~ Intcrnallonal Limned All "lhl5 <ncr,·W. ~~~

Pharmacokinetic Drug Interactions with Nonsteroidal Anti-Innammatory Drugs

Roger K. Verbeeck School of Pharmacy. Calholic University of Louvaln. Brussels. Belgium

Summary ..... . ........................... . I rharmacoklnclI~ of NSAIDs ..

1.1 Absorption 1.2 o.SlrIbUhon ........................ .

. ... .44

" " 47 1.3 Ellmmallon .................. .......................... . .................... _. 47

2. Drul-NSAID IntcrlIcllons ............................ .................. 48 2.1 Antac,ds .................. .......................... . . .-18 2.2 Sucralfale .............. ................. .............................. ...................... . .. .49 2.3 H,stamme H2-RcceplOr Blocker.; .. . ...... .49 2.4 I'robcnccld ........................................ 50 205 Choleli tyrammc ....................... .................. . ........ 51 2.6 Conlcoslerolds .......................................................................................... , I 2.7 Oral Con trllccpll vC Steroids ............ 52 2.8 En7.yme Inducers ........................................................ . . ................. _ ........................... 52 2.9 Alcohol ........................ . ................................................ _ .......... _ .. . . ..... 52

3. NSA ID-NSA ID InlerXlIOns 3.1 Asplnn-NSAID ........................................................................ . 3.2 NSA ID-NSAID

4. NSAID-Dru, Inlcrac1l0ns 4.1 Onl Anllcoolulanl5 4.2 Oral H }po&Iycacm l~

4.4 Anticonvulsant! ............... ........... .................. . 4.5 Llth,um ........................................................... . 4.6 Mctholll".\alc .................................................................. ... 4.7 Dlsease_ Modlf)lnl Anllrhrumallc DrulS ............ . ", 8 o.ull"lICS 4.9 Am1nOIJ)'Cosldcs ............... .

5. rharmacOO)'namlC InIC!<KIIOnS 6. ConclUSions ........... .

.51 .._ .............•..•..•.••.... 52

........ 53 .. 54

..... 54 ...... 55

...•.....•......•............ 56 . ........•......•............ 56

. ..... 57 . ...........•...•.... 57

. .58 . ....... 59

..... .59 . .... 60

.60

Nonsteroidal anti-IO Oammatory drugs (NSAIDs) are among the most wide ly used drugs. Drug in tcracllons wi lh this class of compounds arc freQuentl y reporlt'd and can be pharmacoklOcl ic and/or pharmacodynamic in nature. Thc pllarmacokmc llc Interac­tions can be dIvided InlO 3 classes: ( I ) drugs affccllnltllc pliarmacoklllCllCS of an NSAID.

Drug Into:ractions wi!h NSA IOs 45

(~) an NSA I D m!<'Tfc-n ng "lIh tho: pharmacokmellcs of another NSA I D and (3) NS"I Os aho:ring Iho: pharmacokmO:llcs of anotho:r drug.

Although tho: pharmacokino:ucs of some NSA I Os ma~ Ix slgnificanll~ affec ted by Iho: Concurfl'nt admmlstratlon of certam other drugs (mcludmg other NSA IDs). Ihts I) pi: of In lo:raCIiOn onl> ()('caSlonall~ leads to senous comphcahons. Concurrent adminlSlralion of antaCIds or sucralfalO: ma~ dela} tho: ralc of oral absorpllon of NSA IOs but gcnerall} has llitie effeci on the nlcn\. Use of ani aCids mCfl'ases urma~ pH. lead 109 10 mcreased rrnal l'~CrrtIOn of unchango:d sallc} Ilc aCid and drcrl'ased plasma concentralions of thiS antlrhl'umahc agl'nl. Thl' H2-rcco:plor block 109 agenl nmetldme mhlblls thr O.\ ldal!'O: n1l"taboh~m of man) concurrentl> admmls\('ro:d drugs. mcludtng co:rtam NSA IDs. Pro· bcnO:Cld mhlb!1S Iho: ro:nal seerO:llon of drug glucuromdo:s and this \ltlllo:ad to accumu· lallon 10 plasma of Ihose NSA1Ds dlmmaled pnmarll) b~ the formation of lab Ill' ac~1 glucuromdcs such as napro\o:n. ketoprofen. 1Odomethacln. carprofrn. Cholest) ramlne dl" creases Iho: oral absorpllon of man) concurrently administered drugs. 10rludlng NSAJ Ds. lima) also decrease plasma concentrations of those NSo\ !Ds undergomg enterohepallc elrcuJahon (r.g. plroxtcam. tenOXtCam) b) mto:rruptmg the enterohepatic cycle_ COrtiCO­sterOids stimulate the clearance of saltqlic acid. lead10g to 10\1 plasma salic)!ale con­central ions. Plasma concentrations of man~ NSA!Ds arl' slgn lflcantl~ uduced \I ho:n the NSAJ D IS coadmlnlsto:n'<I \I Ith aSplTln. T he chmcal rell'\anee of most of these Interac­lions IS n01 \lell established. HO\ll"cr. In those cases where the mteT;lction resuhs m elnatl'd plasma conccniralions of Ihe NSA ID. Spl:Clal caUllon should lx' e.\ercised to a, aid cACl'ssi, r accumulation of the NSA J D especiall} In elderl} and/or H'I") Sick patients "ho rna) be more sellSI1IW to the more senous gastroduodenal and renal side-effects of thl'S(' agents.

11) \Irtue of thl'lr pharmacoktnellc and pharmacod~namle propenl~s. NSA!Ds rna) Slgmficantl~ aOcct the diSpoSition kinetiCS of a number of OIher drugs_ The} can displace Other drugs from Iheir plasma protem bmdlng 5l1es. mhlbll the-ir metabolism or inte-rfe-re "lIh their renal e~trelion. If Ihe affected drug has a narro" the-rapeutlc lOde-A. the mter­a,'llon rna) be cll1l1call) slglllflcant. The P!razole NSA!Ds (phellylbutazone. o.\yphen­butaLOne. azapropafonl') mhlblt the meta holism of man) drugs such as the coumann anllcoagulants. oral anlldlabeucs and antlcon,'ulsants such as phen>toln. Sallc}laleS diS­place oral anticoagulants from their plasma protem binding sites. In addllion. aspirin mtreases the Tlsk of blcedmg b) mhlbltlon of plalelel function and h} productIOn of gastnc erosions. The h)pogl~caemlc errrcI of sulfon~lureas rna} be enhanced by large doses ofsalleylates through an mtnnslC hypoglyeaemle effcct. In all these cases. altern­all\e NSA10s \lhlch do not Interact \ll1h these agents should be used. Most. if nOt all. NSA!Ds mterfefl' \ll1h the renal e~crCllon ofhthlllm and methotrexate. "hich could lead to sc'ere to.\ic reactions due 10 elc'ated plasma concentrations of thl'se ~ drugs.

Fmall). chlllcall) Imponant mleraCtlons occur octween NSA!Ds and diuretics and antlh)pcnensi\e agents. These mtcractlons are larso:l) pharmacod)nanllc m na1Ure and In most cases sc.:m to be the fO:SUit of the prostaglandin mhlbltory o:ffects of the NSAIDs.

D rug Interactions fall into 2 major categories. T he first categOI) involves pharmacokinetic in ter­

actions. i.e. an in terference by one drug with the absorp tion. dis tri bution , metabolism and/or exere­\lOn of another drug causing a change in the con­ce ntra l ion of Ihe ac ti\e drug species al its phar­macological larget tissue. The second categol) in\olves pharmacod~namic InteractiOnS which re­sull fro m an alte red concenlTalion-Tesponsc rela-

tionsh lp a l the la rget lissue. Th iS review foc uses on those no nsteroidal anti-i nflam ma tol)' drug (NSA ID) interactions which arc mai n ly of a phar­macokincW: na ture. W he n an NSA ID is admini­stered In combi na \1on with ano ther d rug, the NSAI D ca n pertu rb the pharmacokinetics of the o lher drug or v ice versa. 8 0 lh these types of in­teractions are discussed in th is review.

Interactions bet ween NSA IDs and ot her d rugs

.,

occur relatively f~uen ll y. because of the wide usc of NSA IDs. Most of these interactions are mainly pharmacokinctic in nature. There are many poten­tial siles for pharmacokinclic drug inlcractions: gastroinlestinal absorption. displacement from plasma and tissue protem binding sites. metabol­ism, renal and biliary excretion. More oftcn than not. interactions occur simultaneously at different levels; e.g. displacement of a drug from albumin may increase tissue uptake and target organ reo S(XInsc. although metabolic elimination and renal excretion could also be increased. NSA IDs are po­len lially capable of interfering wit h the pharmaco­kinetic processes of o ther medications at vinually all these levels. Fortunately, man y o f the interac­tions are not of clinical importance since they in­volve drugs with large therapeutic indices. Those interactions that are potentially life-threatening in­volve drugs with a narrow therapeutic index used in serious disease sta tes, in particular oral anti­coagulants. card iac glycosides, antiarrhythmics. anticonvulsants and cytotoxics. It is imponant for the rheumatologist/ practitioner to know enough about the mechanisms of interactions and the pharmacokinetics of the drugs being use1 in com­bination to anticipate the poten tial for interaction and to minimise the consequences if an interaction occurs.

For the general aspects of phannacokinetic drug­d rug interactions the reader i s referred to a number of excellent reviews (Aarons 1981; MacKichan 1989: Mcinnes & Brod ie 1988; Offerhaus 1981).

I. Pharmacokinetics of NSA IDs

The currently available NSA IDs can be grouped in 7 major chemical classes (table I): ( I) salicylates, (2) propionic acid derivatives. (3) carbo- and het­erocyclic acetic acids. (4) fenamatcs. (5) oxicams, (6) phenylacetic acids and (7) pyrazoles. Members of these drug classes are all weak organic acids with pKa values typically less than 5. Despite their chemical diversity. the NSA IDs share many im­ponant pharmacokinetic characteristics (Brater 1988: Day et aL 1987a: Verbc«k 1988). wh ich are briefly reviewed here. The panicular pharmacoki-

elm l'hurmum/..1n1'1 19 (I) 1990

Table I. Ust 01 commonly used NSAIO$

c.fbo.. ItfI(I hetero<:yc:1Oe -eeoc -eid.

Etodol3c SuIonclac Indomethacon

Fena..,.,e.

FIuIenamoe; !lad

Medalenamoe; !lad

O.ic:arn. ISOIUCam"

Potoxocarn

Phenylec:allc: -eidl

Aidolanac:

Propionic: ac:1d derivatives

Carpi'ofen

Fenbufen

Fenopro!eo Flurtllpi'ofen

Ibupi'Ofeo

Py.uole. Azapropazone

Oxypheobuta,OfItt

SeJic:y\etes Asp" ... , (ASA)

o.flurv$al

a Withdrawn hom the markel

ToImIl,n

Oiclofenae

Ketoprofen

Napi'oxen

OX'pi'o~,n

P"pi'ofen Supro!en TJapi'ollnlC; .C>d

PhenylOutazone

netic characteristics of an NSA ID may indeed fonn the basis for its interaction wi th another therapeu­tiC agent.

1.1 Absorption

Most NSA IDs are rapidly absorbed following oral ingestion. the most common route of admin­istration for these agents. Peak plasma concentra­tions are generally reached within 2 to 3 hours fol­lowing oral administration (Verbeed et al. 1983). When NSAIDs are used in the long term trcatment of arthritic diseases, the rate of absorption is not very important si nce accumulation is thcn entirely controlled by extent of absorption [i.e. oral bio­availability (OJ a nd the rate of elimina tion of the compound [i .e. plasma clearance (el)):

f Do" CL ,

Drug Inl<."f"Jctlons .... lIh NSAID5

...... here Ca, represents the average slead)-slale pl:lsma conccntraUon and Dose/ r Ihe dosing rale. Ho ...... c\er ....... hen NS>\IOs arc used 10 treat acute condlllons such as he:ldaches (e.g. acule migraine allack) or d~sml"norrhoca (Chan 1983; Diamond & Frellag 191)9). a high :lbsorpllon rale IS deSirable since 11 ...... 111 red un' the l:lg lime bet ...... een drug in­take :lnd pain n;hd

In an attempl 10 maintain :lCII\C pl:lsma con­Cl"ntrations for a prolongl"d period of IImc for those NS.\IDs \\lIh short plasma half-h\es (t •. ). such as indomethaCin (t. '" 6h). con trolled release dosagl" forms havc been developed (Yeh 1985). In this case the rate of drug release from the dosage form con­trols the plasma concentrallon-time profile and thus the plasma half-life of the compound. Enteric coaled tablets arc also :l\allable for some NS-\IOs. Their absorpllon profilc IS usuall) charactcrised b) a \anable lag lime. rcflcctlng the residence time of the aCid-reSistant dosagc form In the SlOmach. This lag time IS usuall~ a fe ...... hours. but can be as long as 12 hours (Verbccck et al. 1988). >\s a result. fac­tors affecllng gastnc l"mpt~lng ma~ h,l\C a pro­found effcct on the IIml"-{"ourse of the cllntcal ef­ficac~ of thl" administered S.\I D.

The e\tent (completeness) of absorption IS more Imponantthan the rate ...... hcn the NS.\IDs arc ad­ministered to treat chroniC conditions. such as rhcumat01d arthritis. Informat ion concerning the absolute oral b103\3113blllty of most NSAIOs In

humans IS lacking. Solutions of NSAIOs suitable for Intra\("nous admlnlstrallon 10 pallents or \olunteers arc usually not commcrcially a\ailable. ESlimates of absolute oral a\ atlability of most of these agents an" thereforc based on mass balancc studies. often follo ...... lng administration of radlOla­belled drug. These studies sho ...... thai absorption from the gaslrolntestlnaltracl for this class of com­pounds IS \ Irlually complete. A few NSAIOs (e.g. tolfenamlC aCid. dlclOfcnac). however. undergo first­pass or prcs)stemic elimlnallon. a process which reduces s}stemlc avallabtlll) of the parent com­pound (Pond & Tozer 198-'. Verbceck 1988).

1.2 DlstnbullOn

All NSAIDs (with the excepllon of aspmnl are cxlensi\Cl) bound 10 human scrum albumin (Lin

el a1. 1987: Verbccrk 1988). For Ihe majority of Ihese agents less Ihan 1% of Ihe total plasma con­centration IS In the unbound form and Iherefore available to dlstnbull' to extravascular tlssues. Most NS.\!Ds ha\e a \olume of dlstnbullon (Vd) be­Necn 0.10 and 0.15 L/ kg. approxlmallng the ac­tual Vd ofalbumm (0.10 L/ kg). Impl)mg thai tis­sue blndmg IS not an Imponant detenmnant oflheir \olume of dlstTibUllon.

Bctause NSA IDs have such a small Yd. and be­cause they are used m relatl\ely high doscs. plasma concentrations achicved dUTlng long lerm therapy with some of Ihese agents approach or exceed 0.6 mmollL. the concentration of plasma albumin. Concentration-dependent plasma binding IS ex­p{"{:led for such drugs if albumm is their main binding protein In plasma and if only I high aOin­I\~ binding Site exists per albumin molecule (Tozer 1984). ConcenlratlOn-depcndent plasma bmding has been desenbed for a number of NSA IOs in­cluding sahqlate (Furst el al. 1979). naproxen (Runkel el al. 197-'). Ibuprofen (Aarons et al. 1983). diflumsal (Loc ...... en et al. 1988) and phenylbutazone (Higham el al. 1981). The dispoSition kmetics of Ihese agents ma) be slgmfican ll) affected b) Ihelr concentration-depcndent plasma protem bmdmg (Furst el al. 1979: Runkel el al. 1976). In addition. substantial drug displacement IS likel) to occur when the displacing agent shows salurable plasma binding charaeteTlstlcs or at least occupies a sub­stantial portion of the a\ailable bmdmg sites. As a result. most NSAIDs ha\e Ihc potenlial to displace other hlghl) protem-bound drugs from their al­bumin bmdmg Sites.

U Eliminallon

Hepatic blotransformallOn IS Ihe main elinun­atlOn pathwa) of Ihe majority of NSAIOs. Most are melabohsed In humans b) cytochrome N50-mediated oxidallon and/or glucuronide conJuga­lion (Verbceck ci al. 1983). The actlvil) of these hepatic microsomal enz)mes dcpends on a number of faclors (e.g. age. dlsea$(') and can be modified by enz)me Inducers and mhlbitors. Altemall\·cl). the biotransformation of o lher drugs ma) be 10-

48

hibited by the pyrazole NSAlDs phenylbutazone. oxyphcnbutazonc and azapropazonc.

The primary route of metabolism of several NSA IDs (e.g. naproxcn. kc\oprofcn. fenoprofcn. carprofcn. tiaprofenic acid. indoprofen. diflunisal) involves thc formation of acyl glucuronidcs (Vcr­bceck el at 1983). These eSler-type glucuronidcs arc unstable under physiological conditions (pH 7.4. 37"C) and can spontaneously hydrolyse with re­lease of Ihc paren t drug (Faed 1984). Whenever such a labile acyl glucuronide accumulates in thc plasma of a patien t due to reduced renal excretion (e.g. renal impairment. competilion with other compounds for renal excretion). systemic deeon­jugation may significantly slow down thc elimin­ation of the parent drug.

Renal excretion of unmetabolised drug is a mi­nor elimination pathway for most NSA IDs. usually accounting for less than 5% of the administered dose (Verbeeek 1988). Exceptions are salicylic acid (2 to 30% urinary recovery of unchanged drug). azapropazone (50 to 60%) and alclofenac (10 to 50%). Although metabolites of some NSAIDs arc excreted to a significant extent via the bile (e.g. in­domethacin. sulindac, oxaprozin. diclofenac. alclo­fenac. tolfenamic acid), urinary excretion is in gen­eral much more important. Since NSAIDs and their metabolites are organic acids, they arc able to in­hibit the renal secretion of other organic acids in the proximal tubule, which could possibly lead to a pharmacokinetic interaction.

All 2-arylpropionic acid NSAlDs (except na­proxen) are administered as a racemic mix ture of 2 optical isomers with different anti-inflammatory activity: the R-isomer (inactive or less active) and the active S-isomer. In 1';1'0 a unidirectional meta­bolic inversion of the R- to the S-isomer takes place (Hull & Caldwell 1983; Jamali 1988). Recently. stereoselective analytical techniques have been de­veloped enabling the characterisation of the phar­macokmetics of the active S-isomer of these 2-arylpropionic acids. To date. a number of stereo­selective pharmacokinetic studies of these chiral NSA IDs have been reported. mostly in healthy volunteers. There is a great need for addi tional in­formation regarding the stereoselective disposit ion

Clm. I'harmurokmel. 19 (I) 1990

of these agents in elderly patients and in those hav­ing a variety of disease states. In addition. very lill ie information is currently available on the question whether other drugs may interfere with this metabolic activation of the R-to the 5-isomer.

2. Drug-NSA ID Interactions

Although several drugs can affect the phar­macokinetics ofNSA IDs, these interactions do not generally lead to life-threatening conditions be­cause NSAIDs have a relatively large safety mar­gin. However, elderly and very sick patients may be more sensitive to some of the side-effects of NSA IDs. such as gastrointestinal bleeding and renal toxicity. Excessive accumulation of these antirheu­matic agents. due to interaction with other medi­calions, should be avoided in these patients.

2.1 Antacids

Antacids arc commonly administered to patients on long term NSAlD therapy to reduce the inci­dence of gastrointestinal irritation. a common side­effect of these agents. A large number of drugs have been reported to interact wi th antacids (D'Arcy & McElnay 1987; Hurwitz 1977). In general. concur­rent admin istration of antacids docs not signifi­cantly affect the pharmacokinetics of NSAIDs. but exceptions do exist.

A s ignificant effect of antacids on the ex/el1/ of absorption of an NSA ID has only been shown for naproxen. diflunisal and fendosal. The oral bio­availabili ty of naproxen was reduced by alumin­ium hydroxide alone. but not by a magnesium­alum in ium hydroxide mixture (Scgre et a1. 1974). The absorption of diflunisal was reduced by 40% when concurrently administered with aluminium hydroxide (Verbeeck et a!. 1979). and to a lesser extent by a magnesium-aluminium hydroxide mix­ture (Holmes et al. 1979). The effect of antacids on the absorption of diflunisal was modified by food: when diflunisal was administered with an antacid (alumin ium hydroxide or a magnesium-alumi n­ium hydroxide mixture) after a meal. its absorp­tion was not affected (Toben et a!. 198 1). A drastic

H'duCIIOIi IS{Ylt.) In the e.,tent of oral absorpllon of tcndo~11 lIas ob~nl'd \.Ihen this s:lllc~lale den\,­atlle 11:1\ :ldnlllllstercd follo\.llllg a 30ml dose ofa magneslUm-alurlIllllUm h~dro .\lde ml\IUre (Wills ('I al. 1985). Slight reductions In ('~Ienl of absorp­lion haq: aho Ix'en obserled \.Ihen IIIdofllethaCin \.las coadnllnlslcred II IIh alumllllUm- and magnes­lum-contallllllg anlaclds (Emon CI al. 1916 ~ Gal­~'alll 1971: Garnham et al. 1917). Ismail ('I a1. (19S1) found a Sllghl)~ reduced blOalallablllt~ for ~clOprofen Ilhcn coadmlnislercd \.11th aluminium h~drO\lde, based on a 21% decrease III uflna~ rc­COl cr} of the drug and Its mClaboll les. Thc coad­Illll1lSIralion ofalunllnlum phosphate. howcvcr. did not afTect the absorption of ke[oprofen (llra7ier et al. 1981 I.

In soml' ('ases antaCids ma~ alter the rale of ab­sorption of a particular i'!S ·\ID. e.g. aspirin (sce Hur\.llil 1917 ). lolfcnamie acid (Neul oncn & KII­ISIO 1988). Il'IlO\ICam (Da~ el al 1 9 8 'b~ FranCiS el al . 1985). plrprotcn (Cium &. Ludcrs 19!51). \\ hether or nOi an alteration occurs ma~ dep('nd o n the par­IIcular anland comtnnallon uSI:d . and the liller­action ll1a~ also be modified b~ food IIItake (sec Da~ eJ al. 19!54). hlagneslUm h~dro\ide, for e\­ample. acceleralcd III a dose-dep('ndcnl manner the absorption ofbolh IOlfenamlc and Illefenamle aCids (!\l' ulonen s.. I\.lIlStO 1988) . .l,lumllllum h}dro\­Ide alone or III comblllallOn \.Illh magneSium h~­dro\lde slgllIlicanll~ relarded Ihe absorpllon of to 1-fenamlc aCid. II hill' sodium bicarbonate had no slgnlficanl effect (Neulonen & 1\.111510 1988) . .l,s noted aboll'. the rate of absorption IS usuall~ nOI an Important faclor afTectlllg thc eflicac~ of a drug adnllllisiered on a long term basis. The effect of anlacids on the rale of absorpllon of NS.l,IDs, Iherefore. IS usuall~ nOI of dlllical Significance.

The usc of antaCids (e.g. magne~ium and alu­mlllium h~dro\ldes) III relatne)} high doscs \.1111 lead \0 a moderate IIlcrcasc in unna'1 pH (Glbaldl el al. 1975). Thc unna~ e>;cretlon of .... cak acids. such as the NSAIDs. is facililaled b} IIlcreaSlIlg ur­lIlaT) pH. Ho .... evcr. the unna'1 e\cretlon of un­metabolised drug is small for most NS ,\lDs, Sali­c}IIC aCid IS the onl} NS-\I[) for which alkallmsallon ofunnaf) pH has been shOlln 10 111-

crease Ihe renal excrellon of unchanged drug. thus leadlllg 10 a significant (25%) reduCllon 111 plasma salic} laiC concen!r3tlOns (HanSlen & Ha) Ion 1980).

No general conclUSIOns can be dra\ln conccrn­IIIg the antacid-NSAID II1leraClIon, because the ef­fect IS large!) sp('clfic for a panKular comblllallon . -\ rcducllOn III the e\len! ofabsorpl1on due to anl­aCid eoadnllllIstrallon . dlnlcall~ mOSt imponant slllce II could lead to subtherapeullc plasma con­centrations and thus lIIell'"cetlle anl1rheumauc Iherap~. occurs .... lIh onl~ a fe\l NS-\IDs and ma} elen be aVOided b~ choosmg Ihe 'right' antaCid.

2.2 Sucralf:llc

Sucralfate IS a complex substance formed from a sulfated dlsacchande (sucrose) and pol)aluml­mum h}dro\lde. It 15 effectl\e III the pre\enlion and Ireatment ofgastroduodenat lesions III patients ta~lng NS-\IDs (Shepherd el at. 1989: Tester & Lim 1981). Consequenll}. 115 potcntlal for IIlteraClmg \.IlIh gaslrOintesllllal absorption has bccn clalu­ated for certalll NSA IDs.

The e.\tent of absorpt ion of aspl rlll. Ibuprofen, IIldomethaclll. ketoprofcn and napro\en was nOI affected b~ COadnllll1stratlon \llIh sucralfate (An­aya el a!. 1986: Caliit' CI al. 1981a.b: Lau el at. 1986: Pugh el al. 1984: Tcsler & Lim 1981): hO\.leler. Ihe rale ofabsorpl1on of some of thesc agenls (I.C. Ibu­profen. IIIdomelhaclll. napro>;en) was slightt~ re­duced. The lack of effecl of sucralfatc on Ihe cxtent of absorpllon of thesc NSAlDs lo .... ers the proba­bill!} \hal other NS-\IDs \.Iould be affeclcd. al­though no e\penmental eVidence [0 provc thiS IS alallable.

2.3 HISlamllle H;:-ReceplOr Blockcrs

The H::-receptor blocking drugs cimelldllle and ramlldlne are e:\tcnslle!} used III the pf('lentlon and trealment of duodenal and gastnc ulcers (Fill­kelstelll & Issclbacher 1978). A number of sludles IIldicatc that cimellJine \.Iill heal NSA ID-lIIdueed p('ptlC uleers III palients despite COnllllUallon of NSAtD thcrap) (Crokcr el at. 1980: O'Laughlin el al. 1981), although olher studies do not agrce

(Mitchell & Sturrock 1980: Roth et al. 1987). Ci­metidine binds to cytochrome P450 and dimin­ishes the activity of the hepatic microsomal mixed­function oxidases. thus inhibiting the biotrans­forma tion of many drugs (Rendic et al. 1983). Ran­itidine binds less avidly to cytochrome P450 and therefore docs not inhibit cytochrome P450-mediated metabolism of other drugs to the same ex tent (Smi th & Kendall 1988). Glucuronide con­jugation. an important biotra nsformation pathway for several NSA IOs. docs not seem to be affected by Hz-receptor blocking agents.

Three studies were found in the literature de­scribing the effect of cimet idine/ rani tidine on the single dose pharmacokinetics of ibuprofen in healthy volunteers (Conrad et al. 1984; Ochs et al. 1985: Stephenson et al. 1988). The resu lts indicate that neither cimetid ine nor ranit idine seems to sig­nifica ntly alter the pharmacoki netics of ibuprofen. It has been suggested that the in l'i\'O conversion of the R- to S-cnantiomer of 2-arylpropionic acids such as ibuprofen may complicate the interpreta­tion of the data (Somogyi & Muirhead 1987), The results of a recent study by Evans et al. (1989) in healthy vol unteers. however. ind icate that the phannacoki netics of R(-)- and S(+ )-ibuprofen after oral ad minist ra tion ofa single dose of racemic ibu­profen 800mg were not affeeted by concurrent ci­metidine administration ( Ig daily for 3 days. start­ing I day before the ibuprofen ingest ion).

Howes et al. (1983) reponed a statistica lly sig­nificant fa ll (18%) in steady-state plasma concen­trations of indomethacin in rheumatoid arthritis patients following the start of long tenn cimetidi ne therapy. This slight reduction was not associated with any significant alteration in the clinical para­meters measured. and may have been due to an effect of cimetidine on the absorption of the NSA IO. The a rea under the plasma concentration­time profi le (AUe) of piroxicam (si ngle dose) was increased 16 to 31% by concurrent cimetidine admi nistration (Ma ilhot et al. 1986; Said & Foda 1989). but again the clinical significance of this interaction is not clear. Cimetidine, but not rani­tidine, significantly increased the AUC of concur­ren tly admin istered flurb iprofen (Su ll ivan et al.

Om. I'harmaroklnl'l. 19 (I) 1990

1986). The clinical relevance of this in teraction is also n01 known.

Holford et al. (198 1) showed that cimetidine docs not significantly interact with naproxen, Sim­ilarly, Scavone et al. (1985) found that cimetidine or rani tidine coadministration did not cause any cli nically significant changes in the pharmacokin­etics of a single dose of oxaprozin 1200mg.

The effect of cimetidine on the absorption and disposition of some enteric-coated NSA IDs has also been evaluated. Enteric-coated tablets consist of a core. containing the active ingred ient, enclosed within a coat of pH-sensit ive polymer designed to resist dissol ution at low pH (pH of 1.2 in simulated gastric juice). bUI which readily dissolves at a rel­atively alkaline pH of7.4. Transfer from the stom· ach to the duodenum is therefore a necessity fo r onsct of absorption. Cimetidine exerts little effeet on gastric emptying bu t significantly increases gas· tric pH to values between 3 and 5 and possibly higher (Pounder et al. [976). Whether such in­crease in gastric pH may be sullicient to stan to dissolve the pH-sensi tive coat may depend on the quali ty of the enteric-coated tablet used. Cimeti­dine has been shown t o increase serum concentra­tions of sal icylate followi ng ingestion of enteric­coated aspi rin (Paton et al. 1983: Willoughby et al. 1983). bu t the effect was sma ll and un likely to be of clinical relevance. Khoury et al. ( 1979) reported that cimetidine appeared to increase the absorp­tion rale of enteric-coated aspirin in those volu n­teers whose intragastric pH rose above 3.5. The single and multiple dose pharmacok inetics of en· te ric-coated ketoprofen in healthy volunteers were not affected by concurren t administration of ci· metidine (Verbceek et al. 1988).

2.4 Probcneeid

Probcneeid is a u ricosuric agen! used in the long term treatment of gou\. It is the classical compet­itive in hibitor of organic acid transport in the kid­ney and o ther organs including the liver (bi liary transport), Probcneeid is eliminated in huma ns by biotransformation involving oxidation and glucu­ronide conj ugation (Cunningham et al. 1981),

Drug Inll'mellOnS "Ilh NS.\IDs

Whereas renal e.\crCllOn of probenecid itself is mlnmla!. II IS thc major roUlC of elimination for lIS metabolllcs. Probenecid and liS OXldlsed me­tabolites arc c.\lensl\eI) bound 10 human scrum albumin. II can Ihcrcforc potcntlall) Interferc \\ilh thc pharmacol..lnCllCS of man~ agcnts at scvcral IC"\cls: (I) compellll\C inhlblliOn of Ihe renal tu­

bular sccretlon of organiC acids. (.:!) competilion for Ihe billar~ C\crl'1I0n of organic acids, (3) reduced glucuronidalion duc 10 competition for uridlnC di­phosphate glucuron) Ilransfcrase and (4) compcll­lion for binding silcs on human serum albumin.

Probenccid markcdly IIlcreascs thc plasma con­ccn\nHlons of scveral NSAIDs Ineluding indo­methacin (l3abt.'r ct al. 1978: Skcllh ct al. 1968). napro.\cn (Runkel 1.'1 al. 1978). kCloprofC"n (Upton C"t al. 1982). carproren (Spahn et al. 1989: Yu & Perel 1980). and LOmeplrae (Smilh et al. 1985) and beno\aprofen (Spahn l'l a1. 1987). bolh nov. "l1h­drawn from th(' market. For alllhl'sr NS-\IDs ac~1 glucuronide iormatlOn IS an Important ellmlnatlon path"a~ and probenecid probahl~ InhlhllS the rmal c\crellOI1 (and posslbi~ also the blllar~ c\crctlon) of these 1}OIar COnjugateS (Meffin et al. 1983). ThiS leads to accumulatIOn of thesc labile conJug.1tes In plasma With the potential of s}stC"mic deconJuga­tion (Faed 1984). DIH'Ct inhibition b) probene<:id of Ihe glucuronldallon of thl'se NS-\ IDs rna) also contnbute to the intC"raction (Spahn & Benet (987). ProbeneCId coadministration did nOI inhibit IhC" plasma c!carancC" of IbuprofC"n. an NSAID eliml­nall:d largC"I~ b) o\idatl\e mC"tabolism (sec Oa) el al. 1984).

ProbenC"cid rna) be used In combination wilh NS.l,.lDs In patients "ilh gouIY arthritis. Thcrc is no C\ Idcncc so far that thc Incrcascd plasma con­ccntralions of NSA IDs such as 1I1domClhacin and carprofcn ..... hC"n coadministered wilh probcnetid are associated with an increased risk of severc side­effects. IncTl'ased plasma concentrations of indo­mcthacin. when co-administered with probene<:id. enhanccd Ihe anti-inflammaloT) effect without any Increase in IOxicity (Baber CI al. (978). Howevcr. caution should be e\crClsed 111 those patiC"nts who ma) be morc suscepllblc 10 Ihe scrious gastrOin­testinal and rcnal sidc-cffects of NSAIDs.

51

2.5 Cholcstyraminc

Cholcstyraminc (an anion cxchangc rCSIn used In Ihc ueatmcnt ofhypercholcsterolacmia) not only 1I11erferes "i\h Ihe oral absorption of acidic drugs. but has also been sho"n to enhancc thc elimina­lion of some acidic xenoblotlcs (e.g. digitoxin. war­farin. phenprocoumon) Ihrough Inlerruplion of Ihelr enterohepallc cycling (Klaassen & Watkins 1984).

The oral absorplion of naproxen 250mg was dc­layed by concu rrenl administration of choleslyr­amine 4g (Calvo & Domlngucz-Gil 1984). To min­imise the effect of cholcstyramlnf on the oral absorpllon of NSAI Ds, the admln istralion Ilmcs of the NSA ID and cholcstyramll1e should Ix sepa­raled as far as possible.

Cholcst~ ramine administrat ion significantly en­hances Ihe ellm1l1atlon of piroxicam and lenoxi­cam 111 healthy voluntC"ers. probably by interrupt­Ing thC"lr enterohcpallc Circulation (Guentert el al. (988). In:ldequatc efficacy of Ihe l\'SAID ,herapy could be the result.

2.6 CorllCOSlerOlds

COr1lCosteroids and sallc) lates arc frequently admll1lstcrcd togC"ther and thC"ir conromitanl use is not contra indicated (Wilkens 1989). Concurrent thcrapy of aspinn and a glucocorticoid (by oral admll1lstration or 1I1lra-anicular inJc("lion) willicad to Increascd S<11icylatC" dearance and a s ignifican t rcduction In plasma sal icylate concentrations (Baer et ai. 1987: Edelman et ai. 1986: Graham et al. 1977: Koren el al. 1987). As a result. plasma salicylate conccn tralions ha\"e been reponcd 10 increase as Ihe daily dosage of corticoslcroids was rcduced in palienls rcceiving a combinalion or these 2 anll­rheumatic agcnts (Klincnberg & Miller 1965: Muir, den & Barraclough (976). Clinicians. IherC"fore, should be aware thai discontinuation of cortico­steroids dUring high dose salic)lal!' therapy may rcsult in salicylatc toxiClt). Intravenous injcction of hydrocortlsonc has been shown to increase the oxidation of phcnylbutazonc (Aarbakke CI ai. (977). In addition to the potential effect of COrticosteroids

52

on Ihc metabolism of NSAIDs, thc possibility that NSA ID-corticQslcroid com bination therapy may increase the incidence or scverity of gastrointes­tinal ulceration should be kepI in mind (Emman­uel & Montgomery 1971).

2.7 Oral Con traceptive Steroids

Oral con traceptive steroids arc only weak in­hibitors of thc microsomal drug hydroxylaling en­zymes in humans, and no significant clinica l in­teractions have been reponed thai might be due \0

an inhibition of drug metaboli sm by these agents (Drme c\ at. 1983). The elimination of a number of drugs metabolised by uridine diphosphate glu­curonyltrans(crasc. however. has been shown to be enhanced by cont racepti ve steroids. The plasma concentrations of phenylbutazone, a compound eliminated in humans by gJucuronidation and hy­droxylation. were not affected by oral contracep­tive steroid use (Gupta et .11. 1982: O'Malley et al. 1972). Plasma clea rance of sa licylic acid was in· creased (41%) and plasma concentrations de­creased in women taking oral contraceptive ster­oids (Gupta et .11. 1982: Miners et al. 1986). Glucuronidation of s.1 licylic acid was markedly in­duced in contraceptive steroid users (Miners et .11.

1986). Similarly. the plasma clearance of diflunisal. a salicylate deri vative mostly elimi nated in hu­mans by glucuronide conjugation. was significantly increased (50%) in women using oral contracepti ve steroids (Macdonald et al. 1990).

It seems. therefore. that the plasma cleara nce of those NSA IDs which are eliminated in humans mainl y by glucuron idation may be enhanced in women taking o ral contracepti ve steroids. The clinical significance of this interactio n i s not clear.

2.8 Enzyme Inducers

Several drugs. e.g. phenobarbital. phenytoin and rifampicin. are poten t enzyme inducers and can potentially increase the oxidative and conjugative metabolism of other drugs. Little infomlation seems to be available on the effect of these enzyme in· ducers on the pharmacoki netics of NSA 1Ds. Hel·

Om. I'harmam kmel. 19 (I) /990

leberg et al. (1974) showed that phenobarbital pre­treatment resul ted in reduced plasma fenoprofen concentrations. Although no elpcrimental evi­dence is available to date. it is to be expecled that elimination of certai n other NSA IDs will also be increased when they are coadministered with p<)­

lent enzyme inducers. Subthcrapeutic plasma NSA ID concen trations may be the result.

2.9 Alcohol

It is well established that alcohol consumpti on can affect drug metabolism (Lane et .11. 1985). Short term consumption of alcohol (i.e. acute effect) is most frequently associated with a temporary in· hibition of the metabolism of certai n drugs. whereas long term consumption (i.e. ch ronic effect) has been shown t o induce the metabolism of several thera­peutic agents. LillIe is known about the effecl of alcohol on the pharmacokinetics of NSA IDs. How­ever. alcohol has been shown 10 enhance NSA ID­induced gastric mucosal damage. and excessive use should be avoided by patien ts requiring NSA ID therapy (Needham et al. 1971).

3. NSA ID-NSAID Interactions

Although it appears that concurrent administra­tion of NSA 1Ds may lead to a grea ter risk of tox­icity with lillie or no increase in efficacy. combin­ations of NSA IDs arc frequently being used in cli nical practice (Brooks et al. 1977: Huskisson 1979). and the combined use of these agents may lead to pharmacokinelic interactions.

3.1 Aspirin-NSAID

The concurrent use of aspirin and other NSA [Ds results in most cases in reduced plasma concen tra­tions of many NSA lDs. e.g. naproxen (5cgre et al. 1974), ibuprofen (Albert & Gcrnaat 1984: Grennan et a!. 1979). flurbiprofen (Brooks & Khong 1977: Kaiser et a1. 1986). fenbufen (Sloboda ct a1. 1980). fenoprofen (Rubin et .11. 1973). kelOprofen (Wil· Iiams et al. 1981). pirprofen (Luders et a1. 1982). indomethacin (Champion et al. 1972: Kwan et a!.

Dru&lnll.'ractlOns "'lIh NS~[Ds

[978), 10lnH'Iin (Cressman el .11. 1976). dlflunisal (Tempero el al. (977). diclofenac (Muller l'l al. 1977: WilliS I.'t al. (980). meclofcna1llate (Bar3gar & Snllth 1978). isoxicam (Esqu1\c! l' t ,II. 1984). tl.'nOXICa1ll (Da~ et .11. 1988) The mechanism of this pharmacoklnetlc Inlt'r3Ctlon IS prob..lbl~ com­pelHlOn oct\\",,'n aspirin (or sahc~latl'l and Ihc i\S~ ID tor albumin blndmg Slles. NS·\ IDs arc rc­SlnC1!1 l'I~ ckared drugs and mcrl'ased unbound plasma con{'l.'ntra1l0ns. due to mleraCllon \\ Ith as­pirin. \\llIlherefore Increase bod~ dl'arancc and rc­duce Ihc total eoncentralion of NSAI D III plasma (Mac Klchan 1984). The unbound plasma canCl'n­[ralions of Ihe NSA ID \\111 return 10 predisplace­mcnl values. and Ihl' unbound plasma fracllon (unbound concenlratlon/ lolal conccnlratlon) \\I(] Ihrrcforr br elclatcd.

Coadmllllstr.lIlOn of asptnn "1Ih plro\lC'am or lIaprofrnlc aCid did nOI S("cm 10 (('suit In dcrrt'aS("d plasma ~S ·\lD conccntratlOn~. Although Hobbs and T\\omc~ (1979) concludl.'d Ihal '10 InlcmC'llon lOOt.. plan' bcl\\el'n asplnn and plrOllcam. Ihl'~

found a det'rease In plasma plrOXlcam l'onn'ntra· lions of 2010 3o<"b m hcalth~ loluntcers Ilhl'n as· pi rill 972mg 4 lImes dall~ \\as coadmintslrrrd on Ihc laSI 2 da)s of a S-da) admlnlstrallOn penod \\lIh plrOIIC'am 20mg dall), The slud~ .... as also poorl) dl'signed; blood samples .... ere onll co(]ecled for 24 hours fo(]o .... lng the la'll plrO.\lcam dose ( .... l1h or "Ilhoul asptnn). For a drug such as plro\icam \\lIh a plasma half·lIfe of appro\lmalcl) 1 da)s. such a short collectIOn period is nOI sufficienl 10 clalual(' 115 ellmmallon. In .... e(] deslgncd sludies. aspmn has ocrn sholln to signtiicaml) decrease Ih(' pilisma canCi:ntralions of 2 olh('r O.llcam NS-\I Ds. I.C. isoxica1ll (Esquivel el al. 1984) and lenoxicam (D'ArC~ 1989: Da) el a!. 1988). In Ihe aspmn· Ilaprofentc aCid Inleraclion stud) no changc \\as obsen'cd III the single doS(" pharmacokmellc para­meters (illdudlllg AUe) of liaprofenic acid 200mg \\hen Ihls NSA ID was coadmlmSlercd \\llh a single dose ofaspmn 500mg (tl. larccek el .11. 1981).

Smcc drug responS(" and IO.\ICII) arc usua(]~

closely relaled 10 Ihc un bound concenlrallon of a drug In plasma. no changl.' III Ihe eflkac~ or $(". lertl~ ofadlersc cffecls of Ihe NS-\ID IS 10 be rl'

"

peeled. Results of cllntC31 sludlCS lookmg InlO Ihe emcac~ and to.\ICII~ of aspm n-NSA ID combma· lions are grneraily tonSISlen! \\lIh IhlS predlcllon (Oa) CI 31. 1984).

Sallc~ laIc plasma CQncl'nlrallor.s arc generall} nOI 3ffl'cled b~ concurrrnl NS·\ID admmlSlrallon as sho .... n for mcclofrn3matl.'. flurblprofl'n, na­pro\cn. mdOnH'lhaclll 3nd krloprofl.'n (Barag.ar & SnHth 1978; Brooks & Khong 1977; Furst CI al. 1987: Kllan CI a!. 1978; \\llliamsrl .11. 1981).

3.2 NSAID-NS-\ID

Although $("Ieral rcports hal(' indicaled Ih31 NS~IDs arc frequentl~ prescribed togelher. Iherr is lillie l'\ idencc 10 mdic31e Ih3l Ihis provides ther­apeullc 3d\anlagl' 3nd II is Iherefore generally diS­couraged (Brooks el .11. 1977: Husklsson 1979: r-.lll1rr 1981). VeT) lillie mformalion. hO .... cler. 15 alailable on IhlS I~PC of IIlteracllon. HO"l.'ll'r, III \ le\\ of Ihl' man~ slmllanlies thaI CXISI III Ihe dIS­tnbutlon and rlimlllallOn characlensllcs of NSAIDs. pharmacoklllcllC 1I11l'r3ctlons arc 10 be expecled "hen 2 or morl' oflh('se agenls arc coad­m1l1lstered.

Plasma 1I1domelhacill concenlratlons arc sig­nificanll) 1I1crrascd (::!-IO 3·fold) "hen IhlS NSAID is concurrcntl~ 3dmlllisiered \\1\h dlflumsal in heallh) volunlccrs (Enksson el .11. 1989; Van Hecken CI a!. 1989). Urina'1 e\Crelion of mdo-­methacm glucurolllde was significantl) reduced, suggesllng Ihal dlflunisal. whIch I; ma1l11) chml­n31ed b} glucuronide conJugal1on. mOl} h3'1C m, hlbilcd Ihe glucuronld3lion of IIltiomClhacin. In \ ie\\ of Ihc magnItude of the elTect. coadmlnlstra­lion of 1IldOmelhacill and dlflumsal should be alOlded. The pharmacokinelics of napro\en 500m& dall~. on Ihr olher h3nd. arc not slgmfic3nll) af­fcclrd b) thr simultaneous admlmSlra\lon of dl' flumsal 750mg d311~ (Dressc el al. 1978).

Flurblprofen ..... hlch IS melaboh$("d b~ Ihe C) to­chromc NSO S~Slrm. docs nOI affeci the ph3r­macoklllCtlcS of IIldomrlhaclIl and \ ICC versa (Rudge el 31. 198::!). The stud} \\as c3rried OUI m 10 palll.'nlS \\ Ilh rheumatoid arthntlS folio" Ing dall} oral admlllls[rlillon of fiurblprofrn ISOmg and Ill-

54

domethacin 75mg individually or in combination for periods of 2 weeks.

4. NSA ID-Drug Interactionr

Most oflhe clinica lly significant interactions in­volving NSAIDs belong 10 this category. NSA IDs are among the mOSt widely used medications and in most cases arc administered on a long term ba­sis. Consequently, p.1licnts on maintenance NSA ID therapy arc likely 10 be treated fo r other serious ailments, frequen tly with drugs having a narrow therapeutic index. In such cases. il is vcry import­ant for the clinician 10 be aware of the potential of NSAIDs \0 aller the plasma concentrations and therefore efficacy of cenain concurrently admini­stered drugs.

4.1 Oral Anticoagulants

The safelY of oral anticoagulation therapy is often threatened by inter.tctions with concurrent medications, including NSAI Ds. There are several mechanisms by which NSAIDs can increase the likelihood of bleeding in patien ts receiving oral an­ticoagula nts: (I) pharmacokineticall y, (2) pharma­codynamically, i.e. through their efTex: t on primary haemostasis, and (3) because of their possible det­rimental effects on the gastric mucosa (O'Cal­laghan et a1. 1984),

Aspi rin is not only a potent inh ibi tor of platelet function but, like the oth(,r NSA IDs, inhibits pros­taglandin synthesis, causi ng gastric erosions (M ielke 1983). At high doses (i.e. > 3 g/day) aspirin may also enhance the hypoprothrombinaemic response to oral a nticoagu lants. It is therefore generally rex:­om mended that aspirin should not be used in com­bination with warfarin and other oral anticoagu­lants.

Phenylbutazone. oxyphenbutazone and azapro­pazone dramatically enhance the hypoprothrom­binaemic response to warfarin (Aggeler et a1. 1967; Powell-Jackson 1977). T hese 3 NSA IDs arc pyra­zoic derivatives and inhibit the metabolism ofsev­eral other drugs, including warfarin. Phenylbutaz­one has even been shown to stereoselectively

Ow. f'harmocokml'l. /9 (I) 199Q

dex:rease the plasma clearance of the more potent enantiomer, S-warfarin. while the plasma clearance of the R-cnantiomer is increased (Banfield et al. 1983; O'Reilly et ai. 1980). In addition. they com­pete for the specific binding si te of warfarin on al­bumin. causing a much greater /n I"I/ro displace­men t than most other NSA IDs. Phenylbutazone, oxyphenbutazone and azapropazone should there­fore not be used in combi nation with warfarin or other oral anticoagulants.

III l'llro stud ies have shown that most NSAIDs displace coumarin anticoagulants from their bi nd­ing si tes on plasma albumin (Diana et al. 1989; Lin el a1. 1987). An increase in Ihe unbound concen­tration of anticoagulan t in plasma is also likely 10

occur ill \'il"O immediately following the in troduc­tion of the displacing NSA ID. Since cou marin a n­ticoagulants are restrictively cleared from plasma by the liver. the increase in unbound plasma con­centrations will lead to increased plasma clearance of the a nticoagulant, a nd its unbound plasma con­centrations will return to pre-<iisplacement values (MacKichan 1984). Consequently. clinicians should be aware of the factlha t addition of an NSA ID 10 oral anticoagulant therapy may result in a transient rise in unbound plasma concentrations of antico­agulant, which could be cl inically significa nt. How­ever. the increase in unbound plasma concentra­tions of anticoagulant IS temporary and will dissipate wi th time (Aarons 19B I: Mac Kichan 1989). Consisten t wi th this theory. Serlin et al. (1980) have shown in heal thy volunteers that di­fl un isal 500mg twice dai ly for 2 weeks was asso­ciated with an increase in the unbound frac tion of warfarin in plasma from 1.02 to U4%, and a de­crease in sleady-state total plasma warfarin con­centration from 141 to 533 m&lL. Unbound plasma concentrations of warfarin and the magnitude of anticoagulan t response. however. were not alTex: ted by concu rren t diflunisal ad ministration. No trans­ien t effccl of di fl un isal on the unbound plasma concentrations of warfarin was observed following the start of difl unisal administration, and this was auributed to the slow mput of the displacer. in­terestingly, however. the authors did show a de­creased anticoagu lant activity which persisted for

Drug InlrracllOns wnh NSo\lOs

at least:! "ee).,s after treatmen! "I[h d lnumsal "as stopped. Slmllar1~. on dlsconunuauon ofsullnd3C. "hich did not 311er the 3nllco3gul3nt effect of phenprocoumon. 3 reductIOn of 3nllco3gu l3nt ef­fect h3S bel'n obsencd (Pullar & Capell 1983). -\1-though Loftm & \'escll (1979) sho\\ cd th3t sulln­dac (400 mgda~ for 10 da~s) did not am'cI the responS\: 10 "arfann m 1 0 health~ \olunlcers. sc\­eral casn haH' 1x:en rcportcd descnbmg enhanced h~poprOlhomblnaemla 3nd bleeding \\hen sulln­d3c "as added 10 "arfann therap} tCarter 1979: Ross & Bee Ie} (979). The effect of seleral other NSA IDs on the pharmacokmetlcs and/or hypo­thromblllaemic response of warfann or other cou­mann anllcoagulams has 1x'cn StudK'd. and m man~ cases (e.g. mdomelhacin. napro\en. tiaprofcnlc acid. fenbufen. dlclofenac. Ibuprofen. oxaprozm) no sig­mficant changes ha\l' ix'en found {Bockhout-!\.Ius­sert & LCk'llger 1974, Oa\ls el al. 1984. Durr l"1 al. 1981: "-ahn ~t Hubsher 1983; Penncr 8, -\bbrC'(hl 1975; S;l\IISI..~ el ai, 1980: Sl-oulal..lS e[ al. 1988. SlallCr} et a1. 1979; \'esl'lll·t a1. 19751. !\' I an~ case reports. hO"l'ler. descntx' marh'd prolongatIons of prothrombIn [I me and sonll"lll1les serIOus bleed­m&. especIal!} 111 the fraI l eldl"r1~ rhcumatlC patient. "hen an NS"- ID lsconcurrentl~ admlmstcrcd \\l1h "arfann or another coumann antll"oagulanl.

The potential for a serious NS-\ ID-oral anti­coagulant II1teraction is further Increased because of the detnnll'ntal effC'(ts of NS·\ I Os on the gastric mucosa and on platelet functIon. Ibuprofen. for in­stance. inhibIts platelet aggregatIOn and slightl~

prolongs bleedmg I1mc (Schulman 8, Il cnnksson 1989). ProthrombIn I1nH'S during oral anticoagu­latIon therap~ should thcn'fore he closd~ monl· tored. eSPl'clall} dunng the firSI lIed or t"O after an NS.\ ID IS addl'd to or "I!hdra"n from a pallent's drug therap~. because IranSltOI) changes 111 unbound plasma concentral10ns and eOieac~ of the oral anucoagulanl ma~ then occur.

4.2 Oral H}pogl}caemics

Sul fon)lureas (e.g. tOlbutamIde. chlorpropam, Ide. ghbendamide (gl~ buride)) are a class of oral med lcallons useful fo r Ireallng h}pcrgl}caemla

"

In non-Illsu lln-depcndent diabetICS. ~he~ late admlnlstrauon Increases the hypoglycaenllC re­sponse 10 sulfonylureas (GlUgliano 1981: Hansen & Chnstensen 1977). Thc exact mcchanism of the Inll"raCtlon IS nOt kno"n. The oral h} poglycacmics arc hlghl~ bound 10 plasma prolclnS and //I I'/Iro

siudies hale sho"n that sa.lic)late d Isplaces 101-butamldc and chlorpropamide from plasma pro­tein bmdlllg SIiCS. thus temporaTlI} mcrcasmg un­bound concentratIons of these antldlabellc agents In plasma. More Importan tl). howc\er. large doses of sahC)late seem to hale an In tnnsic hypogl}­caemlC aCll1lt} and can poten lia te the h)P<lgl}­caemic effect of sulronylureas and insu lin (Rich­ardson CI al. 1986).

The py ra7.0lc dcnlall\es phl"n)lbutal.One_ OA)­phenbutazone and azapropazone are kno .... n to In­hlbl! the melabollsm of S<"leral other drugs. In' dudlng sulfon) lurea h) pogl~caemlcs (Pond Ct al. 1977). Concurrenl adminIstration of onc or Ihese p~fazok NS-\IDs .... nh an oral h~pogl)caem l c sul­fonylurea has been sho"n to signlficantl} reduce Iht' clearanee of Ihc :mtldl3betlC agent. thus 111-creasing liS h~ poglyc3elllIC action (Andreasen Ct al. 1981: Chnstenscn t't al. 1963: Harris 1971: Shah et al. 1984).

In addIt Ion. phenylbutazone has been shown to inhibit the renal excretIOn ofhydroxyhc.\amidc. the actl\c metabolltc of acctohc.\amide. thus poten­tiating the hypogl)cacmlc effect (Field et al . 1967). Consequenll~. coadm IniStratIOn of p) razo le NS-\lDs and sulron~lurea h~pogl~caemics shou ld be alolded.

Pharmacoklllctle studIes. usually III healthy I'oluntcers. hal e r:lIled to show a slgllllicant IIlter­aCIIon bel"een sulfon) lureas and a number of othl"r NSAIOs such as Ibuprofen (Shah el al. 1984). na­pro\en (WhitIng Ct al . 1981). kelOprofen (RaIner et a1. 1977). plrprofen (MOTTlson el al. 1982). dIdo­fenac (Chlud 1976: Fo"ler 1979). IOlmClln (Chlud & Kalk 1977). sullndac (R~an el a1. 1977). tenox­lcam (Stocckel et al. 1985) and d lnulllsal (Tempero el al. 1978). It IS Ihercfore recommended that one of these NS "-I Ds be used In patients on or31 an­tldlabetlCS Instead of aspirin or o nc of the p}razole NSA IDs.

4.3 Digoxin

Digoxin . a widely prescribed inotropic agent. is eliminated in humans mostl y by renal mechanisms involving tubular secretion (Koren 1987). Studies in dogs ha ve shown that aspirin. indomethacin and ibuprofen decreased the renal clearance of digoxin (Wilkerson et al. 1980). Since NSAIDs arc known to depress kidney function in patien ts with under­lying renal di sease (Kimberly et a1. 1978), the po­lential exists that concurrent NSAID-digoxin administration will result in increased plasma dig­oxin concentralion s due to a decrease in its renal excretion.

Digoxin plasma concentrations were not af­fected by concurrent administration of ketoprofen 50mg 4 times dail y in 12 patients (aged 34 to 69 years) who were previously on long established doses of digoxin (Lewis el al. 1985). or tiaprofenic acid 200mg J times dally (Doering & Ishary 1983). The latter study was carried out over a lO-day pe­riod in 12 healthy volunteers. using a daily dose of digoxin 0.5ms. For aspirin and indomethacin, con­flicting results have been reponed. Some StUrliC5 in healthy volunteers have failed to demonstrate a sign ificant interaction (Fenster et al. 1982: Finch el al. 1984: Sziegoleit et al. 1986). while others showed a significant increase in plasma digoxin concen trations following the addition of aspirin (30%) or indomethacin (25 to 55%) [lsOO ry et al. 1982: Koren 1985\. Olher NSAlDs that have been shown to increase serum digoxin concentrations arc fenbufen (Brogden et al. 1981), ibuprofen (Quat­trocchi el al. 1983) and dic10fenac (Isbary el al. 1982).

Although some reports suggest thaI cenain NSAIDs may not affect the serum digoxin concen­lralions. il has to be noted Ihat some of these inter­action studies were carried out in healthy volun­leers. The potential for an NSAlD-digoxin interaction may be much greater in patients ac­tually requiring digoxin therapy, especiall y when Ihey are elderly and/or have reduced kidney func­lion (Marcus 1985). Therefore. seru m digoxi n con­centrations shou ld be carefull y monitored when-

Clm PharmQco4"wt. 19 (I) 199Q

ever NSAID therapy IS initiated or discontinued In

digitaliscd patients.

4.4 Anllconvulsants

The most commonl y used antlcom'ulsanl agents such as phenytoin. phenobarbital. valprOlc acid and carbamazepine are eliminated in humans mostly by biotransformation. The pyrazole NSAIDs phenylbutazone and a1.3propralOne inhibilthe me­tabolism of phenytoin . resulti ng in increased plasma concenlrations of the anticonvulsan t and increased risk of intoxication (Andreasen et al. 1973: Ge::lOey el a1. 1983: Neuvonen e\ a1. 1979). It has been shown. for exa mple. that administration of a1.3-propazone 600mg twice daily to healthy volun teers receiving phenytoin 100 to 300mg dail y resulted in at least a 2-fold increase in steady-state plasma phen ytoin concentrations (Geaney et al. 1983). Animal studies suggest that a si milar interaction may occur with oxyphenbutazone (Soda & Levy 1975). Pyrazole NSA IDs should therefore be avoided in patients receivlOg phenytoin therapy.

Phenytoi n and val proic acid are highly bound \0 plasma protei ns (> 90%) [Perucca 1984J. Sali­cylic acid can displace phenytoin from plasma pro­tein binding si tes (Fraser el at 1980: Leonard et at 1981). As a result. ad miOlstration of large doses of asp Inn \0 patients on phenytolO therapy w;lIlcad to a fall in total plasma phenyloin concentrations. but unbound plasma phenytoin concen trations do not seem to be affected due to an increased plasma clearance of phenyloin. This should be considered when interpreling plasma phenytoin concentra­tions in Ihe prese nce of salicylate thera py. In ad­dition. long term phenytoin therapy has been im­plicated in folate deficiency (Norris & Pratt 1974). Inoue and Walsh (1983) showed elevaled serum phenytoin concen trations and serum folate defic­iency in a patien t chronicall y treated with pheny­toin and salicylic acid. They claimed that serum folate. which is essential to malOtalO the metabolic clearance of phenytOin. may ha\c been depleted due to the increased ehm lnallon of phenytoin when coadministered With aspirin. thus lead 109 to a re­duced metabolic clearance of the anticonvulsant.

Drtlg hlh."r.a(1I0ns "'lIh NS>\IDs

The aspmn-\alprolc acid inlcraclion is more comple\. since sahc~hc aCid bolh displaces 1..11-prolC aCid from liS plasma proleln binding SIIl"S and InhlbllS ,j--o>;idation of Ihl" anliepllepllc agenl (-\b­

bon el ..11. 1986: Orr 1."1 ..11. 1982). Gouldl"n el ..11. I I 987) r("port("d Ihal aSplfln-\ alprolc acid coad-1ll1l1l~tr..1l10n resull("d 111 seflou~ \alprolC aCid \0\­

I C II~ In J pa("dl3tr1c 1><111eniS (4 10 16 ~ears) on long Il"rm anllCOn\ ulsanl Iherap~ . Conscquenll~ . high dose aspmn admlnlSlraliOn should be a\Olded In pallen IS rcceiling lalprOic acid thcrap} .

Trealmenl \\Ith Ibuprofcn 1.6g dall} for 7 da)s did nOI significanl]) affeci Ihe pharmacokincllcs of ..1 single oral dose of phcn) loin ]OOmg in heallhy 10lunteers. despile sligh I changes In Ihc 1)lasma protein binding of thl" anlicon\ ulsanl (Bachmann clal. 1986).

Gflmaldl Cl ..11. 11984) C\ alualed the Single dose phannacoklnellcs of \ alprOic aCid 800mg In hl"alth} loluntccrs \\lIh and \llIhout coadnlllll~tra\loll of naprO\l'n 500mg 11\1('(' dall) for 5 da~\ "iaprO\l'n dl~pla Cl'J \a]prOlc and from liS pla~ma hlndlng ~ltCS. Th(' resullant mtn.:aSl: In Ih(" m("laOOllc (lear­ance of\alprolc aCid kd to lo\\cr total plasma con­Cl"ntral1ons but unbound plasma conCl"ntratlons of Ihe anticon\ ulsanl \\cre malnlalned \\lIhln Ihe normal IlmiIS. The cllilical siglllficance of th iS ml("raClion IS nOI kllOI\ n.

4.5 LuhlUm

Ehmillalion of lithIUm. an anllps~chotlc agent \\uh a \er~ narro\\ therapcullc Inde>.:. IS almosll"\­clusl\eI~ through Ihe kldne}s and plasma concen­Iratlons muSI be carefull~ controlkd \0 prCIl"nl se­flOUS to\ICII~ (Schou 1988). Scleral NS",IDs (e.g. dlclofcnac. Ibuprofen. IndomelhaCln. plro\icam) ha\e tx-en rl"poned 10 dl"crease plasma clearance of lithIUm and thus to Increase plasma IlIhlUm concenlrations (Frohlich el ..11. 1978: Kerf) ct at. 1983: Knstoff el ..11. 1986: Kagheb el OIL 1980; Rei­mann & Frolich 1980). The reducllon oflhe plasma clearance of lithium b~ concurrent adm Inlstrallon of Ihese NS-\IDs IS probabl~ due to a dcrrease III the renal excretIOn of thiS ion produCt"d b~ the In­hlbl\lon of the s~nthesls of renal prostaglandins

"

(Leftwich el a1. 1978: Norman el al. 1984). Con­Sl'quentl}. most If nOI all NS-\IDs \\ill cause the same InleraCtlOn \\I\h IIlhlUm .

Whcre the combined use of tnhlUm and an NS-\ID IS necessaT). a reduction In IIlhlUm dose halo betn recommended and plasma Il\hlUm con­centralions should be' frcquenll~ monitored.

~ .6 Ml"lhotre\ate

Melhotrcl:at(' IS a folic aCid antagonlsl Iradl­tlonall} used In cancer chemolherap). bul \\hlch IS becoming IIlcreasingly popular In Ihe trealment ofrefraCIOT) rheumatoid anhrillS (Furst et al. 1989). Since NSA IDs arc common I) preSCribed to rheu­matoid anhrllls pallents. the polenllal for an Inler­aCtion bel\\een these 2 1)jX'S of anllTheUmallc agcnts IS obI 10US. InteractIOns bct\\ccn methOlrel:­ate and seleral NS-\.lDs (e.g. aspirin. phenylbula­wnc. IIldomClhaclll. dlclofenac. ~eloprofen. na­pro>.:cn. a/apropawlle). somelimes \\llh falal OUlconll'. hale been reporled (-\dams & Huntcr 1976: Dal~ el at. 1985: Eilisson It Ser\! 1985: Ga­brielli 1'1 al, 1987: Singh 1'1 ..11. 1986: Th}SS et al. 1986: ZUlk &. Mandel 1975).

The 10\lClt~ of melhOlrcl:ale (m high or con­\cnllonal doses) precludes prOSpi.'cIII'C inleraction sludles 1\llh NS>\ IDs III I'oluntecrs to establish Ihe mechallIsm of Ihe IIlteraclion. Howe\er. renal ex­crellon of unchanged drug is Ihe major elimination rouie for methotrexate III humans. 'JSAIDs inhibit renal proslaglandln s~nlhesls. rcsultlllg III a de­crease In renal perfusion rale. Conscquentl). Ihe renal ('\CTellOn of melhOlrexate IS mOSI probably r("duced \\ hen NS-\IDs are coadmlnlstered. leading to a fiSC III serum concenlralions and IIlcr("aSC<i 10\ICI1~

-\llhough se\ere 10\ICII~ IS mOSI likely dunng Intermedlale or high dose melhOlrel:ale therap~ .

10\\ dose therap~ cannOI be regardcd as Without hazard \\hen NSAIDs arc coadnllnlslered (Weln­blalt et at. 1988: Welllstein 1'1 at. 1985). Therefore. all NS-\ID usc should be alOided III patients re­CCII Ing Intermediate or high doses of mcthOlTe.\­ale. and pallenls rcct'11 IIlg 10\\ doses of IhlS drug and NSA IDs concurrentl~ must be car("full~ mon-

"

htMe II. Pharmacokone6e c:lr'u9-NSAlD and NSAI[).N$AID

interactions

Combonation Elled Suggested action

Antacid·NSAIO Reduced absorption NOI relevlnt rate 01 some NSAI~ Reduced extent 01 UN .ltematr.<e

absorptlOr'l 01 antacid !'Iapro~en. ditlunosaJ,

fendosal WIth 0811'111

."""', Antacid·asp.ron Decreased plasma U ... tt ... NlI,ve

plicylal8 NSAIO Of ... M

coooent'IIIQnS due to mod,nut doses 01 Increased urine pH antlcod

Suer.lllle· Reduced absorptlOll Not releYlnt

NSAIO rite of some NSAIOs Cwnalidin&- Increased plasma Clinical IJI9IllliCance

NSAID concenllations of unknown tJurbiprolen. Plfo~icam

Pl'QbIn8CiG. Increased ReduCe NSAID oose NSAIO concentnlllOllS 01 0( select alternatIVe

NSAIDs fOfTTllog acyl N5Al0 glucuronodes (10

napr-ollen, ketopfolen , c"prolen, Indomethacin)

Choiestyremine· Reduced eJltent 01 separ,'e doSing NSAIO absorpbOo 01 itCIdic \Jmes 01 thtl 2

compounds such as medlc~lIlO1ls as much NSAIDs as possible Reduced plasma Phe!'Iotn&rIon not well

COOI:*ltI1Itions 01 studied and clinocaJ

C8f1ain NSAJDs due sognifietnce I.IOknown

to inle<'upbOn 01

enterohepatic cycling

CorIicostflroids- Reduced plasma AvOId eombonation Of

aspirin salicy181e adjust asprrin dON

concentratIOns and monitor salICylate coneentrltlOlls

OCS·NSAID Increased pla!;ffi& Clinical sign,tieance

clearance 01 unknown

salicylate and

dotlunlsal

Asptnn-NSAID Decreased plasma CIifjcaI ~ficance

concentrations or .... -NSAJD

NSAID·NSAID Oollun,salincreases AVOid thiS

plasma indomelha(;111 c:omblllation

c::onc::entr ations

AbbffWiations OCS· oral OOI1lra<:epllV8 st8fOiClS

Om. Phurlnocol..ml't 19 (I) 199()

itored for toxic signs and symptoms, including reg­ular haematological assessmcnt.

4.7 Disease-Modifying Antirheumatic Drugs

The combinauon of NSA IDs and disease-mod­ifying antirheumatic drugs (DM.o\RDs) is com­monly used (Wilkens 1989). Ho ..... ever. IIttlc IS known about the poten tial for pharmacokinetic drug interactions between agents of both classes. with the exception of the NSAID-methotrexate interaction discussed in section 4.4.

A single dose of indomethaci n 50mg whcn coadministcn..'d with penicillamine 250mg daily has been shown to increase the AUC of thc lallcr by 26% in 6 patients with rheumatoid arthritis (Seide­man & Lindstrom 1989). The clinical significance of this interaction is not known but the authors suggest that the efficacy of penicillamine ca nnot be reliably cvaluated unless the intake of other anti­rheumat ic agents, including NSAIDs. is carefully con trolled.

Similarly, corticosteroids arc being used in com­bination with ccrtain NSA IDs (Luftschein et at \979). Rae et at (1982) observed a highly signifi­cant increase in unbound (i.e. active) prednisolone concentrations in plasma of II patients wnh chronic rheumatoid disease receiving long term prednisolone therapy (2.5 to IOmgdaily) after con­current administration of either indomethacin 75mg twice dai ly or naproxen 250mg twice daily for 2 weeks. Total plasma pred nisolone concentrations were unaltered. These results suppon cli nical re­ports that naproxen and indomethaci n. and pos­sibly other NSA IDs. are steroid-sparing. allowing a reduction In the daily corticosteroid dose while maintaining the same therapeutic effect (Aores & Rojas 1975: Morkel 1966). Both NSA IDs and cor­ticostcroids have been implicated in producing damage to the gast rointestinal mucosa. Combina­tion therapy wi th these agents may increase the risk of the patient's experiencing severe gastrointestinal side effects such as ulceration (Emmanuel & Mont­gomery 1971).

Drug Inl('I";I('lIon5 "'lIh NSAIDs

hble III. Pha.maCOlunetoc NSAIO..(j.ug ,nte.actlOns (.he. Oay

el al 1984)

O.ug or CIUs EUecl 01 NSAIO Suggested IC"O.,

Oral ASp'"n ennaflCeS AvOId UPI"n anllCOlI\lulanlS hypothrombonaemlC

response Py.azole NSAIOS A",,, IIIno\)ll rnelabobsm 01 phenylbutazone oral anllCOagulants olyphenbutazone

azapropuone AN NSAIOs causa Other NSAIOs can De

lIlCfeaseC! "sk 01 uSed bul bI&eCImg due 10 anllCOlI\lulanl mh,btllOfl 01 platelet response ShOIJlCI De /uncllOll and gaslnc closely mom/oreC! mIJCosal aamage

Oral ASPllln (hogh Closes) AvOOCl asPl"". hypogl~aemlCS potent,ates pf1&1'1ytbulazone.

hypogtycaemlC eUeet o~yphe"butazone. PyrazOle NSAtOs azapropazOtll. sallet onh,bol metabohsm 01 "I'lna\,ve NSAtO sulfonylu.eas

AntlConvulsants Pyrazole NSAIOs use IItarnal,ve 'nhlbol metabol'sm 01 NSAIO phenytOIn ASp'ron a,splaces U'le allernatove pherlylo,n from NSAID plasma prOI"n b'"<l!rIg Slies Asp"," d,splaces Use allernat,ve valprooc acod trom NSAID plasma prolelll bond'ng Mes and ,"hll)IIS ,'s melabollsm

""", .. NSAJOs may lI'IC.easa Plasml plasma dogolOn concerl\ratoons 01

concenllallOnS. e g dogoxon should be on the elderly and on more ,ruenslvely .edUCed kodney 1T\Of1,lored fUrlClIOrl

Methotre~ate NSAIOs (posSIbly all) Reduce MTX (lose (MTX) reduce Ihe renal aOCl moMO' plasma

clearance 01 MTX. MTX concent'ltlOllS leading 10 elevaled more Intensively MTX concentrabOns and toxocoty

lJthlum NSAIOS (posSfbly all) Reduce hltwum do$e reduce the renal and ITIOnIIOf WlOUm elaebOn 01 blfllUm. concentrabOnS more leadng to elevated II'IlenSlvely kthoum COI'Icent.atlOO'lS and toxlC'ty

Ca.DOt\IC ASPIron aecteases AvOId &SPI"n. select anhy(lrase plasma prOI"n alternat,ve NSAIO ,nh,botors bond'ng and .enal

e_cretlOll 01

IcetazolamKle

"

4.8 DlUrellcs

The clinicall y important inleraCilon between certain NSA IDs and loop diurellcs and thiazldes SCC'ms to be based on pharmacodynamic rather than pharmacokinetlc mechanisms (Chcnna\ asin et al. 1980: Koopmans el al. 1985: Wilhams CI al. 1981). Ho,,",e\cr. Sweenc) et al. (1989) reccntl) showed that aspirin slgnlficantl) decreases the plasma pro. tetn btndtng and renal tubular sccrctLon of aceta­zolamIde. a carbontc anhydrase inhibitor tn hcalth~ volunteers. This pharmacokinetic interacllon may have serious toxic consequences (Sweeney ct al. 1986). In the same study (Swecney el al. 1989) nur­biprofen was shown not 10 interact with acetazol­amide. and it may therefore be a safer NSAID 10 coadmlOtster .... Ith acetazolam ide.

~.9 Amtnogl~cosides

The extensIve use of indomethactn to Induce pharmacological closure of patent ductus arterIO­sus in preterm mfants IS associated wllh acutc re­duction tn renal function. Decreases in glomcrular filtration rate. unne flow ratc. frcc watcr clearance and electrol) te excretIOn haye been reported (Ci­fuentes ct al. 1979). Inasmuch as thc elimination of aminoglycostdes tS dependent on glomcrular fil­tration rate. theIr administration wllh tndometh­acin creates a potential hazard of amtnogl)coside accumulation and. consequently. nephrotoxicity.

Zarfin ct a1. (1985) assessed the effect of indo­methacin 0.1 mg/kg at 8-hour intervals on seru m concentrations of gentamicin (3.4 to 7.5 mg/kg/day) or amikacin (12 to 20 mg/kg/day) in 20 prctcrm tnfants. Significan t increases (17 to 48%) in bolh trough and peak serum concentrallons of the amtnoglycosldes .... ere seen in association With tn­domethactn therapy. The authors advise conSid­eration of a reducllon of aminoglycoslde dosage prior to commencemen t of indomethacin thcrapy in pretcrm infants. Further adjustmcnt of the ammoglycosidc dose should be based on careful monitoring of Its serum concentrations, tn con­junction with assessment of the altcration m renal function caused b) mdomethacin.

60

5. Pharmacodynamic Interactions

Inhibition of prostaglandin synthesis by NSA1Ds forms the basis ora number of clinically important pharmacodynamic interactions between NSA IDs and diuretics. and between NSAIDs and .a-block­ing agents (Webster \985). Thus NSA IDs, by in­hibiting renal prostaglandin synthesis. interfere wilh the effects of loop diuretics. such as furosemide and bumc\anide, whose action is prostaglandin-mc­diated. The diuretic response to thiazide d iuretics, however, does nOI seem 10 be affected by NSA IDs (Koopmans CI a1. 1984). which strongly indicates that their response is not mediated by prostaglan­dins.

NSA IDs have also been shown to decrease the hypotensive response to Ihiazides, tI-blockcrs a nd caplopril (Moore et a!. 1981; Watkins et al. 1980). Indomethacin. for instance, blunts the hypotensive effects of various ,8-blockers, incl uding propranolol and atenolol (Watkins et al. 1980; Salvetti et al. 1984). Naproxen and sulindac. however. do not appear to interfere with the hypotensive effect of propra nolol (Schuna et al. 1989), suggesting that the a ntihypotensive effect of indomethacin in the presence of propranolol is not due to its inhibition of prostaglandi n synthesis.

Aspi rin and i ndomethacin have been shown to inhibi t the diuretic effect of spironolactone (Favre et al. 1983; Tweeddale & Ogilvie 1973), a nd coad­

mi nistration of indomethacin and triamterene may lead to acute renal fai lure (Favre et al. 1983; Wein­

berg el al. 1985). The mechan isms of these phar­macodynamic interact ions involving NSAIDs re­main unexplained.

In conclusion. NSA IDs arc capable of interfer­ing with the activity of various d iuret ics and hypo­tensive agents. Many of these pharmacodynamic interactions are clin ically significan t. For a more detailed accou nt of pharmacodynamic interactions with NSAI Ds readers are referred to a number of recent reviews (Brater 1986; Brooks 1988; Day et al. 1984; Furst 1988).

Cilll. PharmaCQkm('f. 19 (I) /990

6, Conclusions

NSA IOs are among Ihe most frequently pre­scribed drugs, and some of them can even be pur­chased over the coun ter in many countries. It was estimated in 1985 that. if aspirin is included, more than 30 million people worldwide take one of these agents o n an average day (O' Brien & Bagby 1985). In addition. many patien ts requiring NSAID therapy are elderly, and therefore are likely to re­ceive a number of other drugs concurrently. Con­sequently, pharmacokinetic interact ions involving NSA lDs arc qui te common. but in the majority of cases they are not serious. If the practising physi­cian is aware that an interaction may take place when a particular combination of d rug and NSA1D is being used. he can choose to prescribe a different NSAID which is known not to interact. or by ad­justing the usual dose of the drug he may try to avoid a toxic or subtherapeutic response.

Therefore, it is important for practising physi­cians to know which NSAID-drug combinations may cause problems. The drug interactions dis­cussed in the text are summarised in tables II and III , a nd possible ways 10 avoid or to control the effects of the interaction are suggested. Cl inicia ns should bear in mind that close monitori ng of patients on suspect NSA ID-drug combinations wi ll always be necessary, especially in elderly patients and those requiring m ulti ple medica tions bcx:ause of serious illness.

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\na,a \1 \b,,·.\Ohn \I . Conr.:ad Jo,.,\ I),mmlll IX Influ~nU'"

"I wnalfJI" un ,bop.or,·n ab-.o,pllon ,n h~allh, adoh malc, B,,,ph3rma<"<,01"', and D'ug 1)"I'O,,"on~' J,n·~51 l'IlI~

\ndn.-awn \'B \,.,Iand \ '>'0""",, I \ndc .... :n '>0\ Ilao,,· \1 l),pho.·n)lh)d.lnlllon h'lf· hl~ ,n man and '1\ ,nh,b",on b, ph,·n,lbuIJf"n,· Ih,' fill.' of ,,'11\'1,,- fa<I'''' ·kU M'""Ka 'i<-an' d,na'",'J I~' '1>1.'fo~ 1~1.'

\ndn.-a .... ·n I'B '>'m"n .... 'n I... B"",., I... n,mn B ts.'ul·hdouo;h,· I' Il<po..,:l"a,·m,' III.Jun-.J h) J/ap"'p;i"ln~.tulhulam".k 'nl~';}< I,"n It"',,h journal 01 ('I"''''al l'hJrn'a, ul"l' L ~ ~I) I . SII \ 11j~ I

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I\.l,-hmann 10..-\ ..... ·h"anJ 11. f ome) RB Jau'qu, I '>ull"an TJ Inab,IoI' 01 'huprof~n 10 aile. "n,le do ... : ph"n) ""n 0.1'11'0'" ""n Bro".h Journal of Cion, GIl Pha.mJ('olos, : I 165·169. 1986

I\.lN P,\ ~ho'" \ ,"~man RL Tran ~'rnl faIL ,n ",.um "'''0 laic I~,d, follo",ng ,mr.:a·aruruI3r "'J«lIon of""ro,d ,n p.ll;~n" ""h .h,·umalU,d arlhnl". o\'lhroliS and Rhl'umal,~m .10. 1~5· 1~ 7. 19~1

I\.lnfidd ( O·R,·,II, R (han r Ro"land \1 l'htnllbuI3lon~· "arla"n ,nl<'fa'I;"n ,n man funh"r "en·(l.;hcm,,~i ~nd meta· !>oh, ( .. n"d.-r~I, .. n' Brol"h Journal uf( hn'GlI I'h,rm~colOCI 16 MI<I·f>'~ l<1~l

Bar.:ag;lr FI) ~m"h H I)rug "",·r.:a<'l,on ~luJ" ... ""h ,,>d,um Ilk'· clofcnamal" t \I"'klll"'n', I. ( u ... ·nl ·fh,·rapo.·utl' I('· .... ·~n h ~.1

4"uprll "'i1-~'<I. 1<1"' Roclhool·\lu' .... ·,1 'U I OI:IoIl'" r \ Inll"'·n ... · "I' ,huprukn un

or.:al anl",">JguTaliun ""h ph"npml;uumun J()u.n~1 ", Inl,·'· nal,,)nal \k.J"~II(,·,,,~,,·h~· ~"~.~~~ I~~-'

IlraiC. IX [)'u~·<I'UI Jnd d.u~.,J'''''·J''''· ,nl.-ra<,,,.,n, ""h non· "tll"dal anll·",tlammai"f\ Jru~, -\n ... ".,n Juu",;,\.,1 \1,',1. ","nc ~(H'>uPI'1 I \) 6~·7<;. I~~I>

1Ir.:aIN IX (,hn"al pha.man>h>g)'" ''>,\\1>-. J .. urn~I .. 1 (I"'",'JI I'ha'mJ<olog' :g 'IH·5~.1. 11I8~

lIr.:aller JL T~nu~'~r JV -\mocn D. Bann,er .\ B'o'Ha,lahl"" of ~tlOprokn In man "'Ih and ""houl l"nWm"Jm aUm,n· '~IQIIon of alum,n,um ~ale. Euro",·"n Jou'n.JI ofClmlGll '·harm3l. .... '" 10 \(1<;·_lO~ 1981

Bm&den R' 11 .... 1 1('. '>P.""" T\l o\Ie" C," "'nbukn a",· I",,, 0' '"' pha.m""olo8 .... 1 prop<'no~ ar>d Iherap<'ulK UK ,n .heumal,,· d, ...... , .... and 3.ul<· P-1,n f)ruS~ ~1 I.~~_ 1<11)1

B.ool, 1'\1 '>'de ... ·fl~l~ of non·5It.oodal anIHntlammal<>f\ dru,. \led",! J .. u",al \11 \U\1raloa 1~1I ~ ~ H·!51 I<lM

B",o~\ 1'\1 11<'11 \1·\ \b",n DI 1Iu.·hanan \\ \\ Inlcr.:a"",n\,,1 anll.h,·umall, druJ' \I,'nl< and -\,I'On\ 1 !'>uppl II: ~5·<I~_ 11111

B",o~, 1'\1 I... hong TI... Rurh lprof,·n·a,plfm ,n"'raUl,,n a duuhl," hl'nd <'"",,",'r \Iud' ('u.",nl \I ,""Kal Rc,,'a,,'h and Opln",n ~ S\·~" III~~

('a,11(, (j, du '>ou,.-h I' (icrla" I' Bo.'\n~' J(, '>,nlk oJ"" pha.· mx~",elrn \If leloprokn. n>dom~IIu<'n. and ""pro,,'n lalcn alone Or ""h , ..... ·"'Ifalc B,opha,macrull" and I)rul O'~po'>. "on 8 I"l-I~l, 199'a

("a,11<: G. <Iu SouKh P (j.e,,"a,~ P ~r J(i \c/lna \1 EIT ..... ,I~ of roll('urn"nl ~oKTalfa1e adm,n"'r;lIIOn on pIlumacQl,ocl"'" of ""pro\en "men .... n Journal of \ted", ..... &J 67. ,~. 1911'b

('allo M\ f)omonl<K'/-GII -\ Inlo.·r.:a.-t,on of napro.en ... nh C~'r;lm, ..... B'oph'lnnacrlll>n and Drul 1),~"lOn j 11-~ 2, 198~

('ancr So\ rOI~nllal ~1T<.'C, of ~uhodac on .-.:\pon ..... uf prOLhrom· b,n'lIn'e It) oral anlltQagulan" \..;onc~! ~ /\'18·6<111. I'-IN

('h3mp,on [X i, 1'3 ~lu~ HE. Morgan E. O~uo 1( . I"'ar",m ( \1 cl al Th,' c1T«1 of a~por'n On ":'um ,ndumdhacon (, lIn"al PhMma..-ulos, 3nu Th~r3p<'Ul"" I' ~'~.~~J I<I'~

('han "' Pffl\lailandlll~ and nun\1e,,,,dal anl1.,nflammaLU,,"

61

d'UI~ ,n d)~mcnorrh~a -\nnuall(c"e" ofPharm3<'010l' and TO\1roIOS)!J ,",1 -''1.1'1113

('henna'a"n I' "-:,,,,'11 R. Hr.:aI .... IX- Ph3rm3co~,ntIK..<J)nJm" an31)"~ of Ihr ,ndomClhaCln.furo~m,d<· ,nlnawon In man Journal uf I'harmarolog~ and E\p"romcnlal Ther.:aP<'uI,n ~15 71-81 1'11\0

Chlud I... In"''',&:'' ,on, ,n lO ~~'b1e ,nlcra<,lI0n\ OCI ........ ·n <lIdo· fena, and Ihb.·nd3m,d,· "·"",hnfl fur Rhcumafor1(hunS H _l'~·.'K~_ 1'1'6

(,hlud I... I...a ,~ 8 (IIn,ul "ud1<'$ Oil"', Inlrra.uon OCI ... ('C'n 101· melln and &hbo.·",,·laml<ll· Inlcrnallon31 Journ.J1 0'- Chn"31 Ph3.ma<.010&) l~ .lIN....I1U I'P:

('hmlen .... 'n ll... Ibn .... ·n J '>I Io.. ""~n~n \1 "ulphap/!cna/ok'·,n. du ...... -.J h'P"II\IJcm,,· 3l1a.-h on lolbulam,dc.lre'alni oJ,aociln \..;on'''~. 1~'-IIi·1 ill I 1<16'

(,fucm« PI Oil,') 1'\1 !blf~ J" Radde I(' "old,n '>J Indo­mClha,· ,n and r;.'Oal funn'on III l'.em3lure ,nfanl) ""h P<'" S'SI,'nl l)'lICn! dll("'u~ am·w"u~. Journal of P«I,am", '15. 5~J· 51i7.19N

Conr.:ad 1....\ M3l~rwhn M. Bloss M c.ll1eud,"~ do,,, not all,·. 'bup.ofen ~ lnchC5 after a "nilc d~. Bnll~h Journal OfelOO'(31 i'harmacolOCl 18 6~ ~·6~6. 19SJ

{''''~~man " .\ . " onham (ii' Plo"n"'h J -\b..orpllon and n· ere'uon of,otme'ln 10 man Chm .... 1 PharmacolOl' anoJ r htr· ap"uloc, 19 !~ J·H.l 1\1':>6

( ..... l~r JR ('ollon PH Bolk -\ ( I... ,nlo<'l13 P (,meud,ne tor Pl'1'­Ut uk"rr ,n p.lllrnl~ "lIh anhnhl'. \ nnal~ or IOC I(htumall< ['>Ilo<'a ... ." ill ~".~.,~. I'-IM)

(unn,n&ham I(r I\r;I,1o III 1>3"on PG. ChnlCal pha.ma.ol,. n,,'''''' 01 p'll"'·.......,'d ( hn"·all"hafm;K"Ol ' ..... Iocs 6. 115·151. I<I~ I

[);j" 11\1 ..... ·.m (,I 1I"~lc J_ I(oocn~ ('J \klhulrnalC 10\1C'" p"","pllalcd h<. a/Jprup,lIoo<' Bm"h Journal of [krm31olog) IIJ ~H.7.1S, 1'I~5

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I)' '\"') 1'1 Md:tna, J( D,ug·antaCid IIII~'~"lllln' 3''>'!'~mcnl of d",,,'al ,mporI3nn' Drug [mell'8"nce 3nu (hn,.al I·ha.· rna\") ~I 61)'·trl', IWP

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Da} RO_ (;r;lham (;(;_ ",1l'3m~ 10.. \1 . Champ,on DO. IN Jat<'r J ('hnlGlI pharma.olos, of non'~I~ro,dal anll·,nflammaIOI) drUJ' I'ha.ma,·olos<. and Ther.:ap<'ullc, H ~8_'"",.H 1 987~

In) I( D. \..;om .. Paull 1'1), \\ adt 0' Fff<Xl of food and la"ou) 31113.-,d, on Ih~ ab\oOrpllon of IcnO\lcam. a n~" non.sINo,dal anlHnilammato" a,~nl IJrn,~h Journal ofO onlCal Pharma· ml<>g) ~~ \:l.l~g I'IS7b

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