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Risk Factors ForRisk Factors For

Cutaneous Adverse DrugCutaneous Adverse Drug

ReactionsReactions

Mukesh Kumar SharmaMukesh Kumar Sharma

(Intern)(Intern)

Doctor of pharmacyDoctor of pharmacy

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INTRODUCTIONINTRODUCTION

Complications of drug therapy are a majorComplications of drug therapy are a major

cause of patient morbidity and account for acause of patient morbidity and account for a

significant number of deathssignificant number of deaths

Drug eruptions are distinct disease entities andDrug eruptions are distinct disease entities and

must be approached as any othermust be approached as any other cutaneouscutaneous

diseasedisease

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All drugs are

dangerous

No Drugs are

Dangerous if

used properly

How dangerous a drug is depends

on the skill of the prescriber

The most dangerousdrugs have the

greatest potential for

benefit

Some drugs aredangerous in acute

poisoning but not

when used

therapeutically

Some drugs have

a low therapeutic

ratio

Some drugs have a

low incidence of

horrendous effects

Some adverseeffects can be

predicted if you

know the

pharmacology (Type

A); some are not

(Type B)

Some adverse

effects occur after

a delay or after

stopping

BADGOOD

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RISK BENEFIT

When prescribing drugs a doctor must assess risk to

benefit ratio in the individual patient by

Choosing an appropriate class of drug then an

appropriate individual agent

Is it effective ?

What are the chances of adverse effect ?

Are there features in this patient which affect

choice eg other drugs, organ failure, aged

Tailoring the dose

Considering duration of treatment

The Risk to Benefit Ratio

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Risk factorsRisk factors DrugDrug--related factorsrelated factors

Nature of the drugNature of the drug

Degree of exposure (dose, duration, frequency)Degree of exposure (dose, duration, frequency)

Route of administrationRoute of administration

CrossCross--sensitizationsensitization

Interactions between drugsInteractions between drugs

HostHost--related factorsrelated factors

AgeAge

SexSex

Genetic factors (HLA type,Genetic factors (HLA type, AcetylatorAcetylator status)status)

Concurrent medical illness (e.g.Concurrent medical illness (e.g. EbsteinEbstein--Barr Virus (EBV), human immunodeficiencyBarr Virus (EBV), human immunodeficiency

virus (HIV), asthma)virus (HIV), asthma)

Previous drug reactionPrevious drug reaction

Multiple allergy syndromeMultiple allergy syndrome

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DrugDrug--related risk factorsrelated risk factors

Nature of the drugNature of the drug

HaptenHapten concept (intrinsically reactive)concept (intrinsically reactive)

ProPro--haptenhapten concept (requires conversion to reactive intermediates)concept (requires conversion to reactive intermediates)

Danger concept (drug relatedDanger concept (drug related cytotoxicitycytotoxicity enhancing immune response)enhancing immune response)

Pharmacological interaction concept (direct nonPharmacological interaction concept (direct non--covalent binding tocovalent binding to

immune receptors, Timmune receptors, T--cell receptors, MHC)cell receptors, MHC)

Interactions between drugsInteractions between drugs

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Degree of exposureDegree of exposure

DoseDose

durationduration

frequencyfrequency

intermittent repeated administrationintermittent repeated administration

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RouteRoute

TopicalTopical

oraloral

parenteralparenteral

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CrossCross--sensitizationsensitization

Reactivity either to drugs with a close structural chemical relationshipReactivity either to drugs with a close structural chemical relationship

or to immunochemically similar metabolitesor to immunochemically similar metabolites

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HostHost--related risk factorsrelated risk factors

AgeAge

Most of the studies among children and adults not comparableMost of the studies among children and adults not comparable

PLEASE ELABORATE ON THIS.PLEASE ELABORATE ON THIS.

DRUG REACTIONS IN EXTREMES OF AGEDRUG REACTIONS IN EXTREMES OF AGE WHETHERWHETHER

UNCOMMON ORMORE COMMONUNCOMMON ORMORE COMMON

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SexSex

No evidence, with the possible exception ofNo evidence, with the possible exception of cutaneouscutaneous reactions, thatreactions, that

allergic drug reactions are more common in females than in males.allergic drug reactions are more common in females than in males.

WHAT IS THE MEANING?WHAT IS THE MEANING?

DO YOU MEAN THAT ALLERGIC DRUG REACTION ISDO YOU MEAN THAT ALLERGIC DRUG REACTION IS

MORE COMMON IN FEMALES, ORTHAT OTHERMORE COMMON IN FEMALES, ORTHAT OTHERDRUG REACTIONS (OTHERTHAN ALLERGIC) AREDRUG REACTIONS (OTHERTHAN ALLERGIC) ARE

MORE COMMON IN FEMALESMORE COMMON IN FEMALES

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Genetic risk factorsGenetic risk factors

Immunogenetic disposition together with race:Immunogenetic disposition together with race:

HLAHLA--B*1502:B*1502: Carbamazepine:Carbamazepine: SJS/TEN, DRESS; HanSJS/TEN, DRESS; Han

Chinese but not CaucasiansChinese but not Caucasians

HLAHLA--B*5801:B*5801: Allopurinol:Allopurinol: DHSDHS//DRESS like, Han ChineseDRESS like, Han Chinese

HLAHLA--B*5701:B*5701: Abacavir:Abacavir: DRESS like, Caucasians, but notDRESS like, Caucasians, but not

Hispanics orAfricansHispanics orAfricans

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Viral infections & autoimmunityViral infections & autoimmunity::

Generalized immune stimulationGeneralized immune stimulation in the frame ofin the frame of

Acute EBV infections: maculopapular exanthem with aminopenicillinsAcute EBV infections: maculopapular exanthem with aminopenicillins

HIV infections:HIV infections:

Sulfonamides: MPE, SJS/TEN, DRESSSulfonamides: MPE, SJS/TEN, DRESS

SJS/TEN to various drugs is 500 fold more frequentSJS/TEN to various drugs is 500 fold more frequent

Nevirapine and abacavir: frequent side effectsNevirapine and abacavir: frequent side effects

Drug induced autoimmunity:Drug induced autoimmunity:

DrugDrug--induced Lupusinduced Lupus

DrugDrug--induced vasculitisinduced vasculitis

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Previous drug reactionPrevious drug reaction

Multiple allergy syndromeMultiple allergy syndrome

May have a predilection to more than one nonMay have a predilection to more than one non--crosscross--reactingreacting

medication, but the existence of this condition is controversialmedication, but the existence of this condition is controversial

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Causality Assessment of SuspectedCausality Assessment of Suspected

Adverse Drug ReactionAdverse Drug Reaction

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IntroductionIntroduction

CausalityCausality assessmentassessment partpart ofof thethe 11stst stepstep inin

casecase assessmentassessment andand isis basedbased onon aa generalgeneral

systemsystem thatthat isis intendedintended forfor allall reactionsreactions andand allall

drugdrug

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Case causality assessmentCase causality assessment

How close is the relationship between drugHow close is the relationship between drug

and event?and event?

Did the drug cause the event?Did the drug cause the event?

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How to assess causality?How to assess causality?

Assessing the strength of the relationship betweenAssessing the strength of the relationship betweenthe drug and the event.the drug and the event.

Can seldom say without any doubt that a specificCan seldom say without any doubt that a specificdrug caused a specific reactiondrug caused a specific reaction

Use the accumulation of case reports at nationalUse the accumulation of case reports at national

level is immensely valuable providing the meanslevel is immensely valuable providing the meansfor determining real cause and effect.for determining real cause and effect.

Use epidemiological studies to confirm causalityUse epidemiological studies to confirm causality

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Methods of Causality AssessmentMethods of Causality Assessment

There were several method that can be use to make a causality assessment of ADRsThere were several method that can be use to make a causality assessment of ADRs

reports:reports:--

The literature (9 points of considerationThe literature (9 points of consideration MorgesMorges, Switzerland , 1981), Switzerland , 1981)

Probability calculation (Probability calculation (BayesBayes Theorem) Theorem)

EtiologicalEtiological Diagnostic Systems (Diagnostic Systems (BnchiousBnchious group method)group method)

French imputation systemsFrench imputation systems

The European ABO SystemsThe European ABO Systems

The US Reasonable Possibility SystemsThe US Reasonable Possibility Systems

TheThe NaranjoNaranjo ADRProbability ScaleADRProbability Scale

WHOCausality CategoriesWHOCausality Categories

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TheThe NaranjoNaranjo ADR Probability ScaleADR Probability ScaleQuestions Yes No Dont

Know1) Are there previous conclusive reports on this reaction? +1 0 0

2) Did the ADR appear after the suspected drug was administered? +2 -1 0

3) Did the ADR improve when the drug was discontinued? +1 0 0

4) Did the ADR appear with re-challenge? +2 -1 0

5) Are there alternative causes for the ADR? -1 +2 0

6) Did the reaction appear when placebo was given? -1 +1 0

7) Was the drug detected in blood at toxic levels? +1 0 0

8) Was the reaction more severe when the dose was increased, or

less severe when the dose was decreased?

+1 0 0

9) Did the patient have a similar reaction to the same or similar

drug in any previous exposure?

+1 0 0

10) Was the ADR confirmed by any objective evidence? +1 0 0

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TheThe NaranjoNaranjo Probability ScaleProbability Scale

The score :The score :--

> 8 = Highly probable> 8 = Highly probable55--8 = probable8 = probable

11--4 = possible4 = possible

0 = doubtful0 = doubtful

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How to do the causality assessmentHow to do the causality assessment

Case 1Case 1

A 42A 42--yearyear--old female experienced vomitingold female experienced vomitingduring treatment with 200mcgduring treatment with 200mcg PulmicortPulmicort atat

night by inhalation for her asthma. The onsetnight by inhalation for her asthma. The onsetof the reaction was on 3of the reaction was on 3rdrd August 2006 until 5August 2006 until 5thth

August 2006. She been prescribed this drugAugust 2006. She been prescribed this drugsince end of July. The drug was stopped on thesince end of July. The drug was stopped on the

55thth of August and patient recovered. Noof August and patient recovered. Norechallengerechallenge performed and her doctor changeperformed and her doctor changethe drug.the drug.

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Case 2Case 2

A 68A 68--yearyear--old male patient was started withold male patient was started withCrestorCrestor on the 29on the 29thth Jan. 2007 for hisJan. 2007 for hishyperlipidaemiahyperlipidaemia. On the 2. On the 2ndnd of Feb. 07, patientof Feb. 07, patient

felt very ill. Upon admission, the diagnosis wasfelt very ill. Upon admission, the diagnosis wasmyositismyositis and abnormal hepatic function (ALT:and abnormal hepatic function (ALT:100 units/ml). Patient also took100 units/ml). Patient also took SandimmunSandimmunNeoralNeoral for his bonefor his bone marrow transplantmarrow transplant

rejection since October 2006.rejection since October 2006. CrestorCrestor waswasdiscontinued and patient recovered a few daysdiscontinued and patient recovered a few dayslater. Nolater. No rechallengerechallenge been performed.been performed.

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IF POSSIBLE, PLEASE MENTIONIN BRIEF ABOUT ALL THE VARIOUS

METHODS OF CASUALTYASSESSMENTAS GIVENIN SLIDE 21. (2-3

SENTENCES FOR EACH, WILL SUFFICE)

EXPLAINABOUT WHO CAUSALTY SCORE IN DETAIL IF POSSIBLE

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