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ADVERSE DRUGREACTIONS&

PHARMACOVIGILANCE
Curd yesterdayofmydisease
Idiedlastnightofmyphysician

MatthewPrior(16641721):remedyworsethanthedisease.
ADVERSE DRUGREACTIONS(ADRs)
Def.:anyharmfulorseriouslyunpleasant
effectsoccurringatdosesintendedfor
therapeutic(incl.prophylactic/diagnostic)
effectandwhichrequiresreductionofdoseor
withdrawalofdrug&/orforecastshazard
fromfutureadministration.
Defn

S/E
TOXICITY
SECONDARYEFFECTS
INTOLERANCE
IDIOSYNCRACY
ADVERSEEVENT
Adversedrugreactionscausedbyimmuneand
nonimmune mechanismsareamajorcauseof
morbidityandmortalityworldwide.Theyarethemost
commoniatrogenicillness,complicating5to15
percentoftherapeuticdrugcourses.
IntheUnitedStates,morethan100,000deathsare
attributedannuallytoseriousADRs.
Threeto6percentofallhospitaladmissionsare
becauseofADRs,and6to15percentofhospitalized
patients(2.2millionpersonsintheUnitedStatesin
1994)experienceaseriousadversedrugreaction.
ClassificationofADRs
TypeA:Augmentedeg S/E
TypeB:Bizzare eg drugallergy,idiosyncracy
TypeC:Continuous:d/tlongtermuse
TypeD:Delayed:durationorcriticaltimeexposure
eg teratogenesis
TypeE:Endofuseeg acuteadrenalinsuff d/tabrupt
steroidcessation
Causes
PATIENT:age,gender,geneticpredisposition,
allergicdiathesis,disease,personality,
DRUG:eg anticancerdrugsarecytotoxic,
digoxin hassteepDRCtypearxn ,AMAstype
Brxns
PRESCRIBER:ADRmayoccurifdrugusedfor
inappropriatelylongtime(TypeC),atacritical
phaseingestation(TypeD)orisabrubtly d/c
(TypeE)orgivenwithotherdrugs(Drugdrug
interactions)
PatientRiskFactorsforAdverseDrug
Reactions
Femalegender
Seriousillness
Renalinsufficiency
Liverdisease
Polypharmacy
HIVinfection
Herpesinfection
Alcoholism
Genetics(Pgenetics)
Allergyinresponsetodrugs:
Gell andCoombsClassificationofDrugHypersensitivityReactions
1.Immunereaction2.Mechanism
3.Clinicalmanifestations4.Timingofreaction
TypeI(IgEmediated)
DrugIgE complexbindingtomastcellswithreleaseof
histamine,inflammatorymediators
Urticaria,angioedema,bronchospasm,pruritus,vomiting,
diarrhea,anaphylaxis
Minutestohoursafterdrugexposure
TypeII(cytotoxic)
SpecificIgG orIgM antibodiesdirectedatdrughapten
coatedcells
Hemolytic anemia,neutropenia,thrombocytopenia
Variable
Allergyinresponsetodrugs.
TypeIII(immunecomplex)
Tissuedepositionofdrugantibodycomplexeswith
complementactivationandinflammation
Serumsickness,fever,rash,arthralgias,lymphadenopathy,
urticaria,glomerulonephritis,vasculitis
1to3weeksafterdrugexposure
TypeIV(delayed,cellmediated)
MHCpresentationofdrugmoleculestoTcellswith
cytokineandinflammatorymediatorrelease
Allergiccontactdermatitis,maculopapular drugrash*
2to7daysaftercutaneous drugexposure
MHC=majorhistocompatibility complex.
*SuspectedTypeIVreaction,mechanismnotfullyelucidated
Cutaneous symptomsofDrugHypersensitivity
Reactions(M.common)
Exanthematous ormorbilliform eruptionoriginatingon
trunk
Urticaria
Purpura
Maculopapular lesionswithdistributiononthefingers,
toes,orsoles
Blisteringlesionswithmucousmembraneinvolvement
Eczematousrashinsunexposedareas
Solitarycircumscribederythematous raisedlesion
Papulovesicular,scalylesion
DiagnosticTestingandTherapyforDrugHypersensitivity

Immunereaction Laboratorytests Therapeuticconsiderations


Skintesting Discontinuedrug.
TypeI(IgEmediated)
RAST Considerepinephrine,antihistamines,
systemiccorticosteroids,bronchodilators.
Serumtryptase Inpatientmonitoring,ifsevere

Discontinuedrug.
TypeII(cytotoxic) DirectorindirectCoombs'
test
Considersystemiccorticosteroids.

Transfusioninseverecases

ESR Discontinuedrug.
TypeIII(immunecomplex)
Creactiveprotein ConsiderNSAIDs,antihistamines,orsystemic
corticosteroidsorplasmapheresis ifsevere.
Immunecomplexes

Complementstudies

Antinuclearantibody,antihistoneantibody

Tissuebiopsyforimmunofluorescence
studies
Immunereaction Laboratorytests Therapeuticconsiderations

TypeIV(delayed,cell Patchtesting Discontinuedrug.


mediated

Lymphocyteproliferation Considertopical
assay* corticosteroids,antihistamines,
orsystemiccorticosteroidsif
severe.
Distinctivefeaturesofallergicrxns
Diagnosisandtreatmentofallergicdrug
reactions
Adrenaline0.30.5mlof1:1000IM,rpted 35
minifreqdlifesaving,
OthersAntihisaminicsCPM,Corticosteroids,
Pseudoallergic rxns
Mimicallergicrxns BUThaveno
immunologicalbasis,arelargelygenetically
determined.Ared/treleaseofendogenous
mediatorslikehistamine,LTs.PARmimicking
Type1rxn anaphylactoid rxn eg aspirin,
nsaids
PARmimickingtype2rxn eg hemolysis d/t
antimalarials,sulphones inG6PDdefpt.
ADRsonprolongeduse TypeC,D
EYE cataractd/t:chloro,corticosteroids,
Cornealopacities:phenothiazines
Retinalinjury:thioridazine,chloro,indo
CNS:Tardive dyskinesia neuroleptics,
Polyneuritis metronidazole
Opticneuritis ETM
LUNG:pulm fibrosis amiodarone,busulphan,
KIDNEYS:nephropathygoldsalts,NSAIDs
LIVER: fibrosis,failureMTX,alcohol,PZA
Carcinogenesis
Takesmonthstoyears35yrs
Mech:1.AlterationofDNA(mutagenicity)
chemicals/metab
2.Immunosuppression:
3.Hormonal longtermuseofERT
endometrialCa,DESexpinutero vaginal
adenoCa infemales
Adverseeffectonreproduction
Drugsmayactonembryo&fetusdirectlyeg
teratogens ;indirectlyeg onuterus
vasoconstrictors;onmothershormonalbalance.
Earlypregnancy:m.vulnerable pd 28weeks(10
56days)ofIUlifeorganogenesis
Teratogenesis (teratosmonster)
Teratogens:thalidomide,cytotoxics,warfarin,
alcohol,lithium,valproate,phenytoin,
methotrexate,isotretinoin,ACEinhb....
Phocomelia duetoThalidomide
Teratogenic drugs
Definitivelistnotpractical dependsondose
taken,andatwhatstageofpregnancy.VV
cautioususeofdrugsduringpregnancy
Latepregnancy:eg Iandantithyroid drugs
fetal goitre,tetracyclines ,Aceinhib.,
NSAIDs,
Duringlabour opioid anagesics,diazepam
AdverseeffectsonMalereproductive
system
Impotence :ANSdrugseg betablockers,
thiazides
Decreasedspermatogenesis:sulfasalazine,
cytotoxic anticancerdrugs,nitrofurantioin

Iatrogenicdiseases
GeneralCriteriaforDrugHypersensitivity
Reactions
Thepatient'ssymptomatology isconsistentwithan
immunologicdrugreaction.
Thepatientwasadministeredadrugknowntocause
suchsymptoms.
Thetemporalsequenceofdrugadministrationand
appearanceofsymptomsisconsistentwithadrug
reaction.
Othercausesofthesymptomatology areeffectively
excluded.
Laboratorydataaresupportiveofanimmunologic
mechanismtoexplainthedrugreaction(notpresentor
availableinallcases).
EvaluationandManagementofDrugReaction
Pharmacovigilance
Referstotheprocessofcontinous monitoring
forunwantedeffectsandothersafetyrelated
aspectsofmarketeddrugs.Itisthescience
andapplicationofdetection,assessment
,understandingandpreventionofadverse
drugreactions.
Postmarketingsurveillance/phase4trials
PSURs
SevereADRs:
Naranjo ADRprobibility scale
Score>9=definite,58=probable,14=possible,0=doubtful
WHOUppsala
Causalityterm
Assessmentcriteria(allpointsshouldbereasonablycomplied)

Eventorlaboratorytestabnormality,withplausibletimerelationshiptodrugintake
Cannotbeexplainedbydiseaseorotherdrugs
Responsetowithdrawalplausible(pharmacologically,pathologically)
Certain
Eventdefinitivepharmacologicallyorphenomenologically (ie,anobjectiveandspecific
medicaldisorderorarecognizedpharmacologicphenomenon)
Rechallenge satisfactory,ifnecessary

Eventorlaboratorytestabnormality,withreasonabletimerelationshiptodrugintake
Unlikelytobeattributedtodiseaseorotherdrugs
Probable/likely
Responsetowithdrawalclinicallyreasonable
Rechallenge notrequired

Eventorlaboratorytestabnormality,withreasonabletimerelationshiptodrugintake
Possible Couldalsobeexplainedbydiseaseorotherdrugs
Informationondrugwithdrawalmaybelackingorunclear

Eventorlaboratorytestabnormality,withatimetodrugintakethatmakesarelationship
Unlikely improbable(butnotimpossible)
Diseaseorotherdrugsprovideplausibleexplanation
Eventorlaboratorytestabnormality
Conditional/unclassified Moredataforproperassessmentneeded,or
Additionaldataunderexamination
Reportsuggestinganadversereaction
Unassessable/unclassifiable Cannotbejudgedbecauseinformationisinsufficientorcontradictory
Datacannotbesupplementedorverified
ADR_form_PvPI.pdf1.pdf
Pharmacovigilance Programmeof
India(PvPI)
Objectives
TomonitorAdverseDrugReactions(ADRs)inIndian
population
Tocreateawarenessamongsthealthcareprofessionals
abouttheimportanceofADRreportinginIndia
Tomonitorbenefitriskprofileofmedicines
Generateindependent,evidencebased
recommendationsonthesafetyofmedicines
SupporttheCDSCOforformulatingsafetyrelated
regulatorydecisionsformedicines
Communicatefindingswithallkeystakeholders
Createanationalcentreofexcellenceatparwith
globaldrugsafetymonitoringstandards