Adverse Drug

Reaction and
Management
By

Dr. Sheba Salome T

 • WHO defines ADR as any response to a drug which is
noxious and unintended that occurs at appropriate doses
ADVERSE used for prophylaxis, diagnosis or therapy of disease.
DRUG • Causal relationship is established/suspected.

REACTIONS
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 • ADE is a broader term that includes any untoward

ADVERSE medical occurrence presenting during the

administration of a drug. It includes overdose, drug
DRUG EVENT abuse, treatment failure and administration errors.
• No need of Causal relationship.
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 • Any unintended medical occurrence presenting
SIDE EFFECTS during the administration of a drug regardless of
dose. It is usually foreseen and resolve on its own.

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Predisposing Factors
• Polypharmacy
• Multiple diseases
• Age
• Drug characteristics
• Gender
• Race and Genetic factors

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 TYPES OF REACTIONS
• Type A – Augmented
• Type B – Bizzare
• Type C – Chemical
• Type D – Delayed
• Type E – End of treatment
• Type F – Familial
• Type G – Genotoxicity
• Type H – Hypersensitivity
• Unclassified type

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Type A - AUGMENTED
• Exacerbation of pharmacological effects of a drug.
• Predictable and preventable
• Less morbidity and mortality.

Mechanisms:

Pharmaceutical Causes:
• Changes in drug quantity
• Altered drug release properties.

Example:
• Griseofulvin brands having different particle size
• Anticoagulants increased bleeding
• Prazosin increases postural hypotension
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 Pharmacokinetic Causes:
• Alteration in absorption, distribution, metabolism and elimination of drugs

Example:
• Inhibition of CYP3A4 ( erythromycin, nifedipine, cyclosporine) by grapefruit
juice.

Pharmacodynamic Causes:
• Drug receptors – Inter variability of different individuals.
• Disease

Example:
Non-selective Beta blockers cause bronchoconstriction in asthmatic patient.

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Type B - BIZZARE
• Unpredictable
• Non-dose dependent
• High morbidity and mortality
• Rare

Examples:
• Death by decomposition of paraldehyde to acetaldehyde and acetic acid.
(Additives)
• Eosinophilia-myalgia syndrome by L-Tryptophan (Genetic factor)
• Phenacetin (analgesic) induced methemoglobinemia

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 Type C - CONTINOUS
• High frequency of occurrence

Example:
• High cardiovascular events in rofecoxib (COX-2 Inhibitor)

Type D - DELAYED
• Delayed occurrence
• Accumulation

Example:
• Chemotherapy causing secondary tumors.
• Phenytoin in pregnancy causing teratogenic effects.

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 Type E – END OF TREATMENT
• Withdrawal symptoms caused when drug stopped suddenly.

Example:
• Phenytoin causes seizures

Type F - FAMILIAL
• Occurs only in susceptible individuals
• Inherited metabolic disorders.

Example:
• Hemolysis in G6PD deficiency by primaquine, chloramphenicol, quinine and
quinidine. (Genetic factor).

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Type G – GENOTOXICITY
• Produce genetic damages in future

Example:
• Phenytoin in pregnancy causing teratogenic effects.

Type H - HYPERSENSITIVITY
• Activation of immune response
• Not dose dependent
• Most common

Example:
• Steven Johnson syndrome
• Photo allergy
• Anaphylaxis Sample Footer Text
 CLASSIFICATION BASED ON SEVERITY

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 DETECTION AND MONITORING OF ADR

Epidemiological Methods

• Cohort Studies
Exposed patients are followed up actively and systematically and ADR
frequencies are compared to unexposed control group.

• Case Control Studies

Affected individuals are identified and matched with disease free
control group to investigate the possible causative agents prior to
occurrence of the event.

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 DETECTION AND MONITORING OF ADR

Susceptible Patients
• Patient with renal or hepatic impairment
• Patient using drug with narrow therapeutic index
• Patients who have allergic history
• Patients with polypharmacy
• Pregnant and Breastfeeding women

Details of Suspected ADR to be collected:

• Onset and duration of reaction
• Nature and severity of reaction
• Drug dose, frequency, time of administration, duration of treatment, plasma
concentration
• Previous ADR history
• Risk factors or predisposing factors
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 CAUSALITY ASSESSMENT
• Estimating the extent of the relationship between a drug and a suspected reaction.
• A temporal or possible association is sufficient for an ADR report.
• Highly subjective

Methods:
• Clinical judgment
• Algorithms
• Probabilistic or Bayesian approaches

Clinical Judgment:
• Established based on the clinical judgment of the expert or panel of experts with
existing data.
• Eg: WHO-UMC Scale

WHO-UMC Scale – Combined assessment of clinical-pharmacological aspects of case

history and quality of the documentation of the observation.
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 WHO-UMC SCALE

Certain
• Event of laboratory test abnormality, with plausible time relationship to drug intake
• Cannot be explained by disease or other drugs
• Response to withdrawal plausible (pharmacologically, pathologically)
• Event definitive pharmacologically or phenomenologically (an objective and specific medical disorder or a
recognized
• pharmacological phenomenon)
• Rechallenge (if necessary)

Probable
• Event or lab test abnormality, with reasonable time relationship during intake
• Unlikely to be attributed to disease or other drugs
• Response to withdrawal clinically reasonable
• Rechallenge not necessary

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 WHO-UMC SCALE

Possible
• Event or laboratory test abnormality, with reasonable time relationship to drug intake
• Could also be explained by disease or other drugs
• Information on drug withdrawal lacking or unclear

Unassessable/ Unclassifiable
• A report suggesting an adverse reaction
• Cannot be judged because of insufficient or contradictory information
• Report cannot be supplemented or verified

Unlikely
• Event or laboratory test abnormality with a time to drug value that
• makes a relationship improbable (but not impossible)
• Diseases or other drugs provide plausible explanations

Conditional/ Unclassified
• Event or laboratory test abnormality
• More data for proper assessment needed
• Additional data under examination
Algorithms:
• Questionnaire form
• Eg: Naranjo’s scale, Karch and Lasagna’s scale, Kramer’s scale

Probablitic/Bayesian Method:
• Transformation of prior probability into a posterior probability of drug causation.
• Eg: BARDI (Bayesian Adverse Reaction Diagnostic Instrument) & MacBARDI

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Naranjo’s Scale

Definite ≥ 9; Probable 5–8; Possible 1–4; Unlikely ≤ 0 20

Applications:
• Patient treatment
• Signal generation
• Drug regulation
• Scientific publication
• Data exchange

REPORTING
Factors affecting:
• New drugs
• Serious ADRs only
• Drug sponsor
• Unwanted publicity of ADR

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Reasons for not reporting:
• Lack of time
• Lack of knowledge
• Uncertain
• The reaction is already well known
• Belief that all registered medicines are safe
• Non-availability of reporting forms

Communicating ADRs:
• Basic training
• Continuous education programmes
• Drug information centres
• Package inserts
• Patient counselling
• Mass media campaigns

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De-challenge:
• Stopping of the drug after an adverse event.
• It can be complete or partial.

Re-challenge:
• Re-introduction of the suspected medication at the same dose, in the same route,
frequency and dosage form.
• Reaction to the rechallenge is a strong indicator of causality.

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THANK YOU