Section5 - nes.scot.nhs.uk

1 29 Section 5 Factorsaffecti ng wa rfar inObjectivesOn co mplet ionofth is se ct ionyo u sh ould beableto: analys e thewid e ran geof factorsthatcanaff ect warfarintherapy summaris e th e mainfactors th at pharmacists an d pharmacytechniciansshoul d be particularly awareof(eg,druginteractions,di et, lifestyle) predi ct dr uganddiseasein te ra ct io nswi or s can af fe ct an indi vid ual s responseto warfarin , including: dr ug int eract io ns (i nc ludi ng he rbal remedies) diseasesta tes age preg nan cy diet alcoh ol con cord Dru g interactionsAlmostany dru g ca n inte rac t wi th warfar in. Interactionsinv olvi ng warfarin can bedivid ed int o two mai n groups: ph armacokinet ic ph rma cokineticeff ectsA ph armacokinet ic inte rac ti on is one that will alter the pla sma co ncent rationofwarfarinand res ult in a ch ang e in the IN R.

2 Thesetypes of interactionsare mainlydue to an ef fect on the me tab oli sm of warfarin , but somedrugsalso affectth eabso rp ti on of warf ari n, while ot her s can causedi splacement from proteinbin dingsites .Pha rma codynamic effe ct sA ph armacodynamic ef fe ct is one th at increasesth e ris k of bleedingwithoutalt eringth e plasmaco ncen trati on of warf ari n (eg , when paroxetine is taken with warfarin ).Th e mech anismof th is inte rac ti on is not fully unders tood. Any drug th at affectspla telet agg regat ion (e g, clop idogrel) wil l also increasethe risk of bleedingwithoutchan gi ng the INR .O C TO B E R 2 0 0 8 Read an y st an dar d cli nicalpharm ac y tex tb ook for moredetai ls ab out the mec han ismof drug inter ac ti ons wit hwarf ar signif ica nt drug int eract ionsTh e use of an inte ra cti ng drug wi th warfari n is very di fficultto av oid in pati entswith multi ple di se as e sta te s and conseq uent eractions maylea d to a lo ss of anti coa gu latio n (the reby in creasin g the ris k of thrombosis) or th eymay ca us e ove r-an tic oagu lati on (th ereby lead ing to a risk of haemorrhage).

3 Whe n a pati en t is stabi lis ed on warf ar in th e INR mu st be closelymoni tore d du rin gthe intro duc tio n, di sc ontin uati on or do sage ad ju stm en ts of any in te ra cti ngmedi ca tio n (eg , ami odaro ne ).Th e BC SH gu ide li nes on ora l ant icoagulantsstate that: if a drug chan ge lasts les s thanfive days eith er no change,minor dose reductionor om iton e co mpl ete do se of warfarin , if kn own potentiatingdruggiven if the dru g chan ge last s moreth an fi ve da ys chec k the IN R one weekaftercommen ci ngthe new dru g an d ad jus t th e warfarindo se on the basisof the actic e poi ntFind out wh at arrangementsare in place locallyfor add itionalINR blo odchec ks wh en intera cting drugs are co-prescribedfor a patientalread y onwa rf arin. How do you ensurethat these addi tionalINR checkshave beencar ri ed out?

4 It is impo rt ant to unde rst an d th e mechanism of any drug/ drug int eractio n wi thwarf ar in and to kno w what advi ce to giv e to the pat ient abouttheir wa rfar in wh enot her me dic ati on is alter ed in an y rfa rin is me taboli se d by se ve ral P450iso-enzymesin the liver . Any dru g thataf fe cts th e cyto chromeP4 50 P2C 9 enzymesys tem (wh ich is th e primar y sit e of themeta bo lis m of the S-i so me r of warfa rin , th e more potentform of warfarin ) ha s th epo ten tia l to hav e a marke d eff ec t on ant ico agu lation,eit her by increa sing ordec rea si ng the IN R. Bot h ami od aro ne and fluconazoleaffectthi s en zyme sys temand ca n po ten tia te the an tic oag ula nt effectof ere are othe r me di ci ne s wh ic h, if co-prescribed with warfarin , requireadd it io na lco uns elli ng advi ce suc h as : any me dic ine wit h the pot ent ial to causegast rointestinalul cerationan dsub se que nt ga st roi nte st in al ble ed in g (eg, alen dronicacid or NSAIDs) an y med ic ine th at inhi bit s plate le t functiontend s to in creaseth e ris k of bleed ing(e g, NSAID s, as pi ri n and clo pi dro grel).

5 Th is effecton plateletfunctionis no tref lec te d in the IN R and wi ll not be det ected by ents and pha rma ci sts sh ou ld be parti cu larly alert to the potential for in terac ti onbet we en warf ari n and ove r-th e-c ount er produ ct s (eg, cimeti dine, mi conazole an dora l or to pi cal NS AIDs ).In addi ti on, phar mac is ts sho uld also be awareof the potentialinteractions be twe enherb al medi ci nes an d warfa rin .30S E C T I O N 5O C TO B E R 2 0 0 8 Pharmacists sh ou ld also beawareof the po ten tialinteractions betw een herbalmedicinesan d war mostfr equ ent andsignificant in terac tionsinvolv e the hepat ic inhibitionor in ductionof war is list is not exh au to cu rren t pu blishedrefer en ces an d text for moredetai led inform at ion .FA C TO R S A F F E C T I N G WA R FA R I NTh e co-ad min istr ati on of warf ari n and NSAIDsis cited by the Nati on al PatientSafety Age ncy (NPSA)as th e dr ug interaction most commonlyass ociat ed wit hclinicallysigni ficantadv ers e re ac po ssib le, NSAIDssh ou ld be av oidedby pati en ts takin g wa rfar in, particularlybyth ose at great er ri sk from drug inte racti on s such as the elderlyor patientswithsevereliv er di sease.

6 If an NSAIDis requi red to tre at a pati ent wh o is takin g warfarin it sh ou ld preferablybe giv en at lo w dos ag es and introduced slowly,wit h close mo nitori ng of the INRand the pat ien t fo r sig ns of ble edin g complicat ions. Somecen tres also advisethe useof a pro to n pumpinhi bi descr ibe s somedr ug s whic h are knownto interact wit h warfarin , asdescr ibed in th eBr itishna tionalform ular LE 3 Sel ectedexample s of druginteractionswith warfarinDrugswh ich enhancetheDrugswhichreducetheant icoagulantef fectanticoagulanteffectAl lop uri no lCarbamazepineAm iod aron eOestrogensAs pi rinPhenytoin*Azo le anti fun ga ls (flu conazole, itraconazole,Primidoneke tcon azol e, mico nazole)Ci me tid in eProges to gen sCi pro fl oxaci nRifam ycin sEn ta capo neVitam in K pres en t in someenteralfeedsFi bra tesFl uv as tatinMe tron id azol eOme prazo leSi mv astati nTa moxi fenTe stosteroneTe tra cycl inesTh yr oxin eTra madolSSRI s* The metabol is m of coumarinsis acceleratedby phenytoin (thereis a possibility of a reducedantico agul an t effect,but enhancementhas also been reported).

7 Eryth rom yci n an d other macrolidesinteractwith warfarinunpredictablyand only ac tic e po intHav e a loo k at appendix 1 (Inter actio ns) in the cur rent editionof theBritishna ti onal fo rmularyand also loo k at the currentedi tion ofStockley ke a no te of th e cli nica lly sig nif icant drug interactionswi th warf ari n that you come acrossmost often in yo ur C TO B E R 2 0 0 8 Inf luenz a vacc inat ionThe co nc urre nt us e of warf arin an d influenzavaccineis normallysaf e, but therehav e be en so me re ports of ser io us ble eding in a few pati en ts. (The mec han ism ofinte rac ti on is no t un der sto od but it may inv olve an alterationin the synth es is ofbloo d clo tt ing fa ctors. )It is wo rth no ti ng th at in tra musc ular injectionsshouldbe giv en wi th care topati ent s suf fe ri ng fro m co agulat io n disorders or who are on anti coagulantthera py be ca use of the ri sk of lo cali se d me ce ntre s ad vi se gi vin g a dee p su bcutaneousinjectionand keepingthe targ etIN R at th e low end of the ran ge pri or to the inject ion.

8 They als o ask pat ients tohav e th ei r INR che cke d one we ek af te r the vaccinationand advis e them about theris k of blee di actic e poi ntWhatadv ice is giv en in your own local area/trustfor administeringinfluenzava ccine to pa tients on warfa rin and checkingthe INR afterw ards?Herb al and othe r alt erna tive medicinesOve r th e las t 10 yea rs th e use of alter nativ e medicines has increasedsubs tantiallyand the ref ore it is impo rta nt to edu cate pat ients on the safetyof these med ic in eswhile taki ng warf ar in. A surve y of 515 users of herbalmedi cines in the UK fou ndthat 26 pe rce nt wouldcon su lt the ir GP for a ser ious ad ver se drug re acti onas so ci ate d wi th a conv en ti on al ove r-t he-c oun ter med icine,but not for a simi la rrea cti on to a he rbal me dic in me alt erna tiv e medicines,in cl ud ing foodsupp lements, may intera ct wi thwarf ar in.

9 Ma ny alte rn ati ve he alt h pro du ct s hav e no regulationson the strengt h andquan tit ie s of ac tiv e ingre dien ts an d thereforemonitoring th e add ition of analte rn ati ve me di ci ne to a pat ie nt sta bili sed on warfarin can be me wi dely us ed alter nat ive med ic ines that can affectINR are: ch ondro itin gi ng er garli c gi ns eng gi nkg o bi lo ba gluc os ami ne St Jo hn s wort .32S E C T I O N 5O C TO B E R 2 0 0 8FA C TO R S A F F E C T I N G WA R FA R I NPr actic e po intFind out what adviceyo ur lo cal an ticoagulantcl inic gives aboutuse ofherbaland co mplementary medi ci nes with warfarin . What does the NPSA advi se? Ar e there an y di fferencesin approach? Di seasestatesManydi sease st ate s may alte r th e ef fect s of warf ar in, in clu ding: hyp ot hy ro idis m hyp ert hyroi dism and fe ve r liv er di sease con gest iv e he art fai lure.

10 HypothyroidismTh is med ical con di ti on re sult s in a re ducedmetabolicrat e, wh ich mea ns vitaminK-dep enden t clot tin g fa ctors re mai n in th e ,a patientwith anund eractive thyroi d wi ll re qui re a high er dos e of warfarin . However,whenthepa tien t takes levo th yroxi ne and the th yroid fun ction starts to normalise,the warfarinrequ irementwill thyroidismand fe ve rBo th hyper th yroi dis m and fev er re sult in a hyp ermetabolicstate,whichmayacceleratethe clearance of vi tami n K-dependen t clot ting factor s. Thus th e amountof warfarin re qui re d to produce an ant ic oagulanteffect wou ld decre ase. Thi s mea nswhen a pat ien t starts to take ca rb ima zo le or propylthiouracilto cor rect their thyroidfun ct ion , theirwarfarinreq uirem ent wi ll incre as e as thei r th yro id func tionno dis ea seTh e use of warfarin in pa tie nts with sev ere liv er diseaseis co ntraindicateddu e toth e un pred ictableeff ects of li ve r dis ease on coagulation, such as: vitamin K de ficie nc y du e to intra - or extra-hepatic ch olest as is red uced synth es is of coag ulat ion fa ctors due to severehep atocellulardamage fu nct io nal ab nor mali ti es of plate le ts and fib rin og en foundin manypatientswithliv er estivehe ar t failureHeartfailurecan ca us e hep ati c conge st ion of bloodflow and in hibit the metabolismof warfarin leadi ng to ex ce ssi ve anti co agulationwith a risk of bleed ing.