Adr

Adverse Drug Reactions

1. ADVERSE DRUG REACTIONS
SreenuThalla
Clinical Pharmacologist

2. WHAT ARE ADVERSE DRUG REACTIONS
(ADRS)?
•Anynoxiouschangewhichissuspectedto
beduetoadrug,occursatdosesnormally
usedinman,requirestreatmentor
decreaseindoseorindicatescautionfor
infutureuseofthesamedrug.

3. Adverse drug event
•Anyuntowardmedicaloccurrencethatmaypresent
duringtreatmentwithmedicine,butwhichmaynot
havecausalrelationshipwiththetreatment.

4. STATISTICS
ADRtodrugsaremostcommoncauseofiatrogenic
disease.
3-5%hospitalisationsduetoadversereactions
resultsin3,00,000hospitalisationsannuallyin
US.
Oncehospitalised→30%chanceofADR→Riskof
eachcourseis5%
3%chanceoflifethreatningreactions→Riskofeach
courseis0.4%

5. COMMON CAUSES OFADRS
Failingtotakethecorrectdosagesatthe
correcttimes.
Overdosing.
Allergiestochemicalcomponentsofthe
medicine.
Combiningthemedicinewithalcohol.
Takingotherdrugsorpreparationsthat
interactwiththemedicine.
Takingamedicinethatwasprescribedfor
someoneelse.

6. FACTORS AFFECTING ADVERSE DRUG
REACTIONS:
Patient-relatedfactors
•Age
•Sex
•Geneticinfluences
•Concurrent diseases (renal,liver,cardiac)
•Previous adverse drugreactions
•Compliance with dosingregimen
•Total number ofmedications
•Misc. (diet, smoking, environmental
exposure)

7. AGE
Childrenare often at risk
because their capacity to
metabolize drugs is usually not
fully developed
Children younger than 18 may be at risk
of developing Reye’s syndrome(Rare but
serious condition causes confusion,
swelling of brain, liver damage )ifgiven
acetylsalicylic acid (aspirin) whileinfected
with chickenpox orinfluenza.

8. ELDERLY
1.ADRs, including drug interactions,
are a common cause of admissionto
hospitals in theelderly
2.Reasons for ADRs in theelderly:
Concomitant use ofseveral
medications
Decreased drug ADMEactivity
due toage
3.These conditions are exacerbated
by malnutrition and dehydration,
common in theelderly

9. PREGNANCY
1.Sulfonamides → Jaundice and brain
damage in thefetus
2.Warfarin → Birth defects, and
increased risk of bleedingproblems
in newborns andmothers
3.Lithium → Defects of the heart
(Ebstein’s Anomaly), lethargy,
reduced muscle tone, and
underactivity of the thyroidgland

10. BREASTFEEDING
→ Many drugs can be passedfrom
mother to infant via breastmilk
–Amantadine(antiviral)
–Cyclophosphamide(antineoplastic)
–Cocaine (Schedule 2 FDAdrug)
–Carisoprodol (skeletal muscle relaxant)

11. Drug-relatedfactors
Dose
Duration
Inherent toxicity of the
agent
Pharmacodynamic
properties
Pharmacokinetic
properties
FACTORS AFFECTING ADVERSE DRUG
REACTIONS:

12. TYPES BASED ONONSET
Onset ofevent:
Acute-
within 60minutes
Sub-acute -
1 to 24hours
Latent-
>2 days

13. SEVERITY OFADR
Minor ModerateSevere Lethal
No Requires Requires Directly/
treatment/treatment/intensive Indirectly
Antidote/ Changein treatment,contributes
Prolongationtreatment/Life to thedeath
of Prolongationthreatening,ofthe
hospitalisati
on
by at least1
day
Permanent
damage
patient

14. FDAdefines Serious ADR aswhich
Results indeath
Life-threatening
Require hospitalization
Prolong hospitalization
Causedisability
Cause congenitalanomalies
Require intervention to prevent permanent
injury

15. Type A-(Augmented)
Type B-(Bizarre)
Type C-(Continuous)
Type D-(Delayed)
Type E-(Ending ofUse)
Type F-(Failure ofEfficacy)
TYPESOFADR

16. Type A(Augmented)
Predictable
Type B(Bizzare)
Unpredictable
Expected-Undesirable Unexpected-Undesirable
Based-Pharmacological
properties ofdrug
Based-Peculiarities ofpatient
More common Lesscommon
Doserelated Non dose related
Mostly preventable andreversibleMore serious, requires drug
withdrawl
Includes-Side effects ,
Secondary effects , Toxic
effects, Consequences ofdrug
withdrawal
Includes-Hypersensitivity/allergy
,Idiosyncrasy
ADRCLASSIFICATION

17. Pharmacological properties of adrug
Extensioneffects
Predictable
Dose -Relatedresponses
Prevention -Adjustment of dosageregimen
Examples
Benzodiazepines -Sedation
Furosemide-Water and electrolyteimbalance
Heparin, warfarin -Spontaneousbleeding
Insulin -Hypoglycemia
TYPE A REACTIONS ORAUGMENTED

18. ADVERSEEFFECTS
Predictable,dose-dependentreactionsunrelatedto
thegoaloftherapy
Oftenproducedbythesamedrug-receptor
interactionresponsibleforthetherapeuticeffect,
differingonlyinthetissue/sororgan/saffected

19. EXAMPLES OF ADVERSEEFFECTS
INH, Rifampicin, PZA –Hepatotoxicity
Streptomycin -Ototoxicity,nephrotoxicity
Captopril -Cough
Simvastatin –Rhabdomyolysis
Nitrates –Headache
Propranolol –Bronchialasthma
Tetracycline –Hypoplasia of theteeth

20. TYPE B REACTIONS ORBIZARRE
Abnormaleffects
Unrelated from the
drug’s known
pharmacological
actions

21. EXAMPLES OF BIZARREREACTIONS
Hypersensitivityreactions
Stevens-Johnson’sSyndrome
Hemolyticanemia

22. Long term effects are usually related to thedose
and duration oftreatment
Examples
Ethambutol -Retinopathy
NSAIDs -Nephrotoxicity
TYPE C REACTIONS ORCONTINUOUS

23. Carcinogenesis
Teratogenesis
Examples:Thalidomide
TYPE D REACTIONS ORDELAYED

24. WithdrawalSyndromes
Examples:
•Benzodiazepines –Rebound insomnia,
agitation
•Clonidine –Reboundhypertension
•Corticosteroids –Acute adrenal
insufficiency
TYPE E REACTIONS OR ENDING OFUSE

25. TYPE F REACTIONS OR FAILUREOF
EFFICACY
Counterfeitmedicines
Underdosing ofmedications
Druginteractions

26. DRUGINTERACTION
Warfarin which is highly protein
bound is displaced by valproic acid
leading tobleeding
Aspirin inhibit platelet aggregation
together with heparin an
anticoagulant leads increased risk of
bleeding.

27. 1. Side Effects-Undesirable effects at
therapeuticdoses
e.ga)Atropine → Preanaesthetic
medication → (undesirable ) drymouth
b) Codiene → Suppresses Cough(desirable)
→ Constipation(undesirable)
Making Use of side effects-
Minoxidil →Antihypertension→Hypertrichosis
→ Male patternbaldness
Codeine → used in travellersdiarrhoea
ADVERSE DRUG EFFECTS MAY BE CATEGORISED
INTO

28. 2.Secondary Effects-Indirect consequence of
primary action of drug
Examples-
a)Corticosteroids → ↓Immunity → LatentT.B.
activated
b)Tetracyclines → ↓Bacterial flora →Super-infection.
3.Toxic Effects-Exaggerated form of side effectsdue
to overdosage/prolongeduse
Examples-
a)High dose heparin →Bleeding
b)Prolonged use of streptomycin →Ototoxicity,
nephrotoxicity

29. 4. Allergy/Hypersensitivity-Immunologically
mediated allergic responses occurs when sensitised
individuals are re-exposed to same drugagain
Humoral-Type I,II,III
Cell mediated-Type IV

30. Type I -Anaphylactic reactions due toIgE
antibodies, min→2-3hours
Examples -urticaria,angioedema, anaphylactic
shock
TypeII-Cytolytic reactions due toantigen
antibody complex, within 72hours
Examples -hemolytic anemia,SLE.

31. TypeIII–Retardedor Arthusreaction-
Immune complex mediatedreactions,
72 hours→1-2weeks
Examples -serum sickness (fever, arthralgia,
lymphadenopathy),PAN , Steven Johnson
syndrome , procainamide induced systemic lupus
erythematous.
Type IV -Delayed hypersensitivityreaction
Examples -Contactdermatitis

32. 5.Idiosyncrasy-Genetically determined
abnormal reactivity to achemical.
Here drug interacts with some unique features
of individuals , not found in majority ofsubjects
, produces uncharacteristicreaction.
Examples-
a)Barbiturates → excitement and mental
confusion in somepatients.
b)Chloramphenicol → Aplastic anemia in
somepatients.
c)Quinine/ quinidine → cramps, diarrhoea ,
purpura,asthma& vascularcollapse.

33. 6.Drug Intolerance-
-Characteristic toxic effects at therapeutic
dose
-Converse oftolerance
-↑ sensitivity to lowdoses
Examples-
Single dose triflupromazine → muscular
dystonia

34. 7.Photosensitivity-
Cutaneous reactions → sensitizedskin
→ UVradiation.
Twotypes:
a)Phototoxicity
b)Photoallergicity

35. Phototoxicity Photoallergy
Drug/ metabolite accumulates
in skin → absorbs light →
photochemical and
photobiological reaction →
local tissue damage
i.e.erythema,edema,blistering,
hyperpigmentation
Drug/metabolite → cell
mediated immune response →
UV light → papular or
eczematous contact
dermatitis likepicture
Shortwavelengths
(290-320nm)UV-B
Longerwavelengths
(320-400nm)UV-A
Morecommon
e.g.Tetracyclines
Less common
e.g.Sulfonamides,Griseofulvin

36. 8.Drugwithdrawalreactions-
Sudden interruption of drug → worsens
clinicalconditionfor which previously
drug wasused.
Examples-
a)Corticosteroids in asthma →
precipitates acute attacks ,myalgia,
depression
b)Beta Blockers → worsening of
angina , precipitatesmyocardial
infarction

37. 9. Teratogenicity–
Drug → pregnant mother → foetal
abnormalities
Examples-
1.Thalidomide →Phocomelia.
2.Diethylstilbesterol → Vaginaladenocarcinoma.
3.Valproic acid → Neural tubedefects.
4.Antithyroid drugs → Foetal goiter,
hypothyroidism.
5.Phenytoin → Cleft lip ,microcephaly.

38. PREVENTION OFADR
1.Avoid all inappropriate use ofdrugs.
2.Use of appropriate dose , route & frequency of
drugadministration.
3.Elicit & take into consideration previous history
of drugreactions.
4.Elicit h/o allergic diseases & exercisecaution.
5.Rule out possibility of druginteraction.
6.Adopt correct drug administrationtechnique.
7.Carry out appropriate laboratoryinvestigation.
8.Beawareofinteractionswithcertain
foods,alcoholandevenwithhousehold
chemicals.

39. MANAGEMENT OFADR
Discontinue the offending agent if-
It can be safelystopped
The event is life-threatening orintolerable
There isa reasonablealternative
Continuing the medication willfurther
exacerbate the patient’scondition
Continue the medication (modified as needed)if
-
It is medically necessary
There is no reasonablealternative
The problem is mild and will resolvewith
time

40. Discontinue non-essentialmedications
Administer appropriate treatment-
e.g., atropine,protamine sulfate ,digibind
antibodies,flumazenil.
Provide supportive or palliative care-
e.g., hydration, glucocorticoids, warm / cold
compresses, analgesics orantipruritics
Consider rechallenge ordesensitization

41. PHARMACOVIGILANCE
Definition –Science and activities relating to
the detection ,assessment , understanding and
prevention of adverse effects or any other drug
related problems.
Activities involved init
1.Postmarketingsurveillance
2.Dissemination of ADRdata
3.Changes in labelling ofmedicines

42. ADR REPORTING FORM

43. CAUSALITYASSESSMENT
Routine procedure inPharmacovigilance
Relationship of cause &effect
Most outcomes : multiple interactingcauses
Aim : to define contribution due todrugs
Problems:
ADRs rarelyspecific
Diagnostic tests usuallyabsent
Re challenge rarely ethicallyjustified
Various methods: None is precise,reliable

44. Causality AssessmentMethods
Algorithmic: (algorithm -specify how to solveproblem)
Series ofquestions
Answers areweighted
Overall score determines causalitycategory
e.g.Naranjo’sscale
Probalistic: (based onprobability)
Set of explicitly defined causalitycategories
e.g.WHO UMC method
Uses of causalityassessment
•Initial review of report
•Signaldetection
•Scientificpublications

45. THE NARANJO ADR PROBABILITYSCALE
Questions Yes No Don’t
Know
1) Are there previous conclusive reports onthis
reaction?
+1 0 0
2) Did the ADR appear after the suspected drug
wasadministered?
+2 -1 0
3) Did the ADR improve when the drugwas
discontinued?
+1 0 0
4) Did the ADR appear withre-challenge? +2 -1 0
5) Are there alternative causes for theADR? -1 +2 0
6) Did the reaction appear when placebo wasgiven? -1 +1 0
7) Was the drug detected in blood at toxiclevels? +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 previousexposure?
+1 0 0
10) Was the ADR confirmed by any objective
evidence?
+1 0 0

46. THE NARANJO PROBABILITYSCALE
The score:-
≥ 9 = Definite
5-8 =Probable
1-4 =Possible
0 =Doubtful
Naranjo CA et al. Clin PharmacolTher
1981;30:239-45.

48. Hartwig’sSeverity Assessment Scale
48

49. Schumockand Thornton Scale for
Preventability

50. CONCLUSION
Everydrugwhichhasaneffecthasanadverse
effecteverytimeadrugisgivenriskisinvolved.
Whatistherethatisnotapoison?allthingsare
poison&nothingiswithoutpoison,solelydose
determinesthatathingisnotapoison.
Forrationaluseofdrugnotonlyitsclinical
indicationsareimportanttoberemembered
equallyimportantisrememberingadverse
effects.
Earlydetectionofadverseeffectsandits
propermanagementcanbelifesavinginmany
situations.

51. KEY POINTS TOREMEMBER
ADRs

52. ADRREPORTING