Warfarin toxicity

Anticoagulant Toxicity

1. Anticoagulant toxicity
managment

2. Warfarin Toxicity
•Overdoseoftheoralanticoagulant
warfarin
•ordruginteractionswithwarfarin,
canleadtotoxicity.
•Similarly,toxicitycanresultfrom
exposuretosuperwarfarins,which
arelong-actinganticoagulantsused
inrodenticides.

3. Etiology
•Coumarinsinhibithepaticsynthesisofthe
vitaminK̶dependentcoagulationfactorsII,
VII,IX,andXandtheanticoagulantproteinsC
andS.
•VitaminKisacofactorinthesynthesisof
theseclottingfactors.
•ThevitaminK̶dependentstepinvolves
carboxylationofglutamicacidresiduesand
requiresregenerationoftheusedvitaminK
backtoitsreducedform.

4. •Coumarinsandrelatedcompounds
inhibitvitaminK
1-2,3epoxide
reductase,preventingvitaminKfrom
beingreducedtoitsactiveform.The
degreeofeffectonthevitaminK̶
dependentproteinsdependsonthe
doseanddurationoftreatmentwith
warfarin.

6. •Theoralbioavailabilityofwarfarinandthe
superwarfarinsisnearly100%.
•Warfarinishighlybound(approximately
97%)toplasmaprotein,mainlyalbumin.
•Thehighdegreeofproteinbindingisone
ofseveralmechanismswherebyother
drugsinteractwithwarfarin.
•Itdoesnotappeartobedistributedto
breastmilkinsignificantamounts.
•Itcrossestheplacentaandisaknown
teratogen.

7. •Thedurationofanticoagulanteffect
afterasingledoseofwarfarinis
usually5-7days.
•However,superwarfarinproducts
maycontinuetoproducesignificant
anticoagulationforweekstomonths
afterasingleingestion.
•Inonereportedoverdosecasewith
measuredserumlevels,thehalf-life
ofbrodifacoumwas56days.

8. •Warfarinismetabolizedbyhepatic
cytochrome P-450 (CYP)
isoenzymes predominantlyto
inactivehydroxylatedmetabolites,
whichareexcretedinthebile

9. Drugsthatinhibitwarfarinmetabolisminclude
thefollowing:
•Allopurinol/Amiodarone
•Azoleantifungals/Cephalosporinantibiotics
•Chloramphenicol/Chlorpropamide
•Cimetidine/Cotrimoxazole
•Macrolideantibiotics/Omeprazole
•Penicillinantibiotics/Quinoloneantibiotics
•Statins(particularlylovastatinandpravastatin)
•Tolbutamide/Zafirlukast
•Zileuton
AntibioticscaninhibittheactivityofvitaminK,
possiblyduetodecreasedgastrointestinal(GI)
florasynthesisofvitaminK.

10. •Anadditiveanticoagulanteffectis
producedbythefollowingdrugs:
•Aspirin
•Clopidogrel
•Heparin
•Low̶molecularweightheparin
•Directthrombininhibitors(eg,
argatroban,lepirudin)

11. Drugs that interfere with protein
binding include the following:
•Clofibrate
•Diazoxide
•Miconazole(including intravaginal
use)
•Nalidixicacid (displaces protein
binding)
•Salicylates
•Sulfonamides
•Sulfonylureas

12. DrugsthatcanreducePTbydecreasingthe
warfarineffect
•Thefollowingdrugscauseinhibitionofwarfarin
absorption:
•Cholestyramine
•Sucralfate
•Colestipol
•Thefollowingdrugscauseenhancedwarfarin
metabolism:
•Barbiturates
•Carbamazepine
•Phenytoin
•Rifampin

13. Thefollowingfoodshaveaveryhigh
vitaminKcontent(>200mcg):
•Coriander
•Liver
•Parsley
•Red leaf lettuce
•Spinach
•Black/green teas
•Broocli
•Cucumber
•cabbage

14. Prognosis
1.Bleedingistheprimaryadverseeffectof
warfarintoxicityandisrelatedto:
•theintensityofanticoagulation,
•lengthoftherapy,
•thepatient'sunderlyingclinicalstate,and
•useofotherdrugsthatmayaffect
hemostasisorinterferewithwarfarin
metabolism.
•Fatalornonfatalhemorrhagemayoccur
fromanytissueororgan.

15. •MajorbleedingcomplicationsincludeGI
hemorrhage,intracranialbleeding,and
retroperitonealbleeding.Massivehemorrhage
usuallyinvolvestheGItractbutmayinvolve
thespinalcordorcerebral,pericardial,
pulmonary,adrenal,orhepaticsites.
•Generally,asingleingestionofwarfarin(10-20
mg)doesnotcauseseriousintoxication.
•Incontrast,chronicorrepeatedingestionof
evensmallamountsofwarfarin(2-5mg/day)
eventuallycanleadtosignificant
anticoagulation,especiallyinthepresenceof
interactingdrugs.

16. •Patientswithhepaticdysfunction,
malnutrition,orableedingdiathesisare
atthegreatestriskoftoxicityfrom
warfarinuse.
•Superwarfarins are extremely potent
and can produce prolonged effects
even after a small ingestion; as little as
1 mg in an adult can cause
coagulopathy.

17. •Donotexpecttoseephysicalevidence
ofbleedingafteranacuteingestionforat
least24hours.
•Morecommonfindingsofexcessive
anticoagulationaresubconjunctival
hemorrhage,epistaxis,vaginalbleeding,
bleedinggums,orhematuria.
•Inallpatients,ifprolongationofthePTis
observedafteranacuteingestion,itmay
appearinasearlyas8-12hours;
however,peakeffectscommonlyare
delayeduntilatleast1-2days
postingestion.

18. Workup
•Bloodlevelsofwarfarinareneither
readilyavailablenorhelpful.
•Specificlevelsofsuperwarfarin
rodenticides(eg,brodifacoum)may
beusefulincasesinwhichthe
ingestionisdeniedorforpurposesof
estimatingthenecessarydurationof
vitaminK
1therapy.
•However,mostreferencelaboratories
donotperformthisanalysis.

19. •Theanticoagulanteffectisbest
quantifiedbybaselineanddaily
repeatedmeasurementofthe
prothrombintime(PT)andthe
InternationalNormalizedRatio
(INR).
•Ifintracranialbleedingissuspected,
obtainanoncontrastcomputed
tomography(CT)scanofthehead

20. •Thereisacloserelationbetweenthe
INRandriskofbleeding.Theriskof
bleedingincreaseswhentheINR
exceeds4,andtheriskrisessharply
withvalues>5.
•Threeapproachescanbetakento
loweranelevatedINR.

21. •Thefirststep:istostopwarfarin;
•thesecondistoadministervitaminK1;
Significantsuperwarfarinpoisoningmay
requiremanyweeksofvitaminK
1
therapy.
•andthethirdandmostrapidlyeffective
measureistoinfusefreshplasmaor
prothrombinconcentrate.
•Thechoiceofapproachisbasedlargely
onclinicaljudgementbecauseno
randomizedtrialshavecomparedthese
strategieswithclinicalendpoints.

22. •Administeractivatedcharcoalfor
recent(withinthelast1-2hours)
clinicallysignificantingestions(onlyin
acuteingestion).

23. •Afterwarfarinisinterrupted,theINR
fallsoverseveraldays(anINR
between2.0and3.0fallstothe
normalrange4to5daysafter
warfarinisstopped).
•Incontrast,theINRdeclines
substantiallywithin24hoursafter
treatmentwithvitaminK1

24. •10mgofvitaminK1givenbyslow
intravenousinfusion;Thiscanbe
repeated,accordingtotheINR,.
•Ifwarfarinistoberesumedafter
administrationofhighdosesof
vitaminK,thenheparincanbegiven
untiltheeffectsofvitaminKhave
beenreversedandthepatientagain
becomesresponsivetowarfarin.

25. •Phytonadione(VitaminK1)canovercome
competitiveblockproducedbywarfarinand
other,relatedanticoagulants.(Notethat
vitaminK3[menadione]isnoteffectiveforthis
purpose.)Theclinicaleffectisdelayedfor
severalhourswhileliversynthesisofclotting
factorsisinitiatedandplasmalevelsofclotting
factorsII,VII,IX,andXaregraduallyrestored.
•VitaminK1isnottobeadministered
prophylactically;useonlyifevidenceof
anticoagulationexists.Therequireddose
varieswiththeclinicalsituation,includingthe
amountofanticoagulantingestedandwhether
itisashort-actingorlong-actinganticoagulant.

26. •EarlyPCCproducts,includingthose
currentlyavailableintheUnited
States,containfactorsII,IXandX.
NewerproductsincludefactorVII.
SomecontainproteinCandprotein
Z,antithrombinII,and/orheparin.
Across4-factorproductshowever,
thereappearstoberapidreversalof
coagulopathywithin10-30minutes

27. •RecombinantfactorVIIahasbeenshown
tocorrectINRwithinhours.
•thepotentialbenefitsofrFVIIaorPCCover
FFPincluderapidAdministration(because
rFVIIaandPCCdonothavetobe
thawed),smallerinfusionvolumes,and
decreasedriskoftransfusion-associated
adversereactions.
•Studieshaveshownimprovementonlyof
secondaryendpoints,suchasintracranial
hematomasize,totalvolumeofblood
products,andtimetooperativeintervention

28. Heparin toxicity
•when clinicalcircumstances
(bleeding)requirereversalof
heparinization,protaminesulfate
(1%solution)byslowinfusionwill
neutralizeheparinsodium.
•Nomorethan50mgshouldbe
administered,veryslowlyinany10
minuteperiod.

29. •Administrationofprotaminesulfate
cancauseseverehypotensiveand
anaphylactoidreactions.
•Becausefatalreactionsoften
resemblinganaphylaxishavebeen
reported,thedrugshouldbegiven
onlywhenresuscitationtechniques
and treatment of
anaphylactoidshockarereadily
available.

30. Streptokinase toxicity
•1-aminocaproic acid; tissue
plasminogen activator inhibitor.
•2-fibrinogen infusion
•Fresh whole blood