ADVERSE DRUG REACTION TYPES AND VARIOUS SCENARIOS

DEFINATION:

• Adverse drug reaction (ADR)—The World Health Organization

defines an ADR as “any response to a drug which is noxious and
unintended, and which occurs at doses normally used in man for
prophylaxis, diagnosis, or therapy of disease, or for the
modification of physiological function.”
 CLASSIFICATION OF ADVERSE DRUG
REACTION:
• According to Rawlins–Thompson classification(Type of reaction):

• Type A(Augmented reaction/Predictable)

• Type B ( Bizzare reaction/Unpredictable)
• Type C ( Chronic reaction)
• Type D ( Delayed reaction)
• Type E (End of treatment)
Type A ( Augmented reaction):
•The reactions are related to pharmacological action of a drug
•They are common,dose related and mostly preventable and reversible

Examples:
•Anticoagulant (bleeding)
• Nitrates( Headache)
• Prazosin ( Postural hypotension)
• Beta blockers ( Bradycardia)
• Type B ( Bizzare or unpredictable):
• These are based on peculiarities of the patient.
• Reaction don’t depend upon drug known action.
. • They are less common,often nondose related.
•Generally more serious and require withdrawal of the drug.

Example:
•Penicillin ( Anaphylaxis)
•Anticonvulsant (Hypersensitivity)
•Type C ( Chronic reaction):
• Associated with long-term drug therapy
• Biology characteristics can be predicted from the chemical structure of the drug/
metabolite.
• Eg: Paracetamol( hepatoxicity)

• Type D (Delayed reaction):

• • Carcinogenic & teratogenic effects
• Delayed in onset
• Very rare
• Teratogenic drug causes foetal abnormalities.Eg Thalidomide( phocomelia) ,
alcohol ( low IQ baby)
• Type E( End of treatment): These reactions occurs due to sudden withdrawal of
drugs after long treatment.Eg:
Phenytoin withdrawal ( Seizures)
Steriod withdrawal ( Adrenal insufficiency)

Side effects:
•Unwanted and unavoidable effect of drug other than pharmacological action.
• Eg: Atropine( preanaesthetic medication )causes dryness of mouth,
Promethazine ( antiallergic) causes sedation
• Secondary effects: Indirect consequences of a primy action of the drug .
Eg: Tetracycline causes superinfection by suppression of GIT flora.

• Idiosyncrasy: Genetically determined abnormal reactivity towards chemical.

Eg: Barbiturates ( Excitement), Chloramphenicol ( Aplastic anaemia)

• Drug allergy; Immunological mediated reaction producing stereotypes

symptoms.
Eg : Penicillin ( Anaphylaxis) ,Procainamide( induced lupus)
DETECTION AND REPORTING:

Premarketing surveillance Post marketing surveillance

Studies like carcinogenecity, teratogenecity are done in
preclinical phases.
Clinical trials identifies adverse drug reactions greater
than 0.05 – 1.0%
Cohort studies (Prospective studies): It is used to find
out relative risk which is ratio of probability of disease
occurring in exposed group to unexposed group.
Case control studies ( Retrospective studies): It is used
to find out odd ratio. Case has disease whereas control
is group free from disease but have same chances of
suffering from disease

Record linkage : Patients records like records of

prescription are used.
• Cohort studies: Cohort are group of people with shared characteristics.It is used to find out the relative risk .
Requirements:
• Group should be free from disease which we are going to investigate.
• Both groups should have similar susceptibility towards disease.
Reporting is done as :

Who should What to report How and whom When to report Method
report to report

Health care All Adr as a result of Report should be on Adr should be Spontaneous
Professionals and prescription and case report reported as soon as reporting
providers nonprescription drugs form( patients and possible
reporter infor,
suspected drug and
reaction)

Manufacturer of A serious reaction , Completed form is Delay in reporting Active surveillance

Products whether expected or submitted to regional make repot unreliable
not or NCC
Health care center Adr occuring from Case series reporting
overdose, medication
error
Consumers patients Unusual lack of Stimulated reporting
efficacy or defects
observed
 CAUSALITY ASSESSMENT

 Definition :
Causality assessment is the assessment of relationship between a drug treatment and the
occurrence of an adverse event.
 Objective :
1. Provide relationship between the drug and events.
2. Provide better evaluation of the benefit/harm profiles of drugs.
3. Plays as an essential part of evaluating ADR reports in early warning systems and for
regulatory purposes.
 METHODS OF CAUSALITY
ASSESSMENT

 Methods Classified under three broad categories –

1. Expert Judgement
2. Algorithms
3. Probabilistic Methods
1. Expert Judgement / Global Introspection :

It is a process in which an expert expresses judgement about possible drug causation by considering all
available data relevant to a suspected ADR. Assessment of ADR is either done by single expert evaluator
or by a group of expert evaluators.
 METHODS OF CAUSALITY
ASSESSMENT

• Assessment is based on following four criteria-:

a) Time relationships between the drug use and the adverse event.

b) Absence of other competing causes (medications, disease process itself).

c) Response to drug withdrawal or dose reduction (de-challenge).

d) Response to drug re-administration (re-challenge).

• The level of causal association is grouped into four categories which are based on a
number of the above criteria being met. (i) Certain (ii) Probable (iii)Possible (iv)
Unlikely
 METHODS OF CAUSALITY
ASSESSMENT

(i) CERTAIN -: When all the four criteria(a,b,c,d) are met.

(II) PROBABLE -: When criteria a, b and c are met.
(III) POSSIBLE-: When only criteria a is met.
(IV) UNLIKELY -:When criteria a and b are not met.
 Beside these four categories, ADR can also be categorized into:-
1. UNCLASSIFIED/CONDITIONAL -: Applied when more data is needed and such
data is being sought or is already under examination.
2. UNASSESSABLE/ UNCLASSIFIABLE-: Finally when the information in a report
is incomplete or contradictory and cannot be verified, then it is Unclassifiable.
 METHODS OF CAUSALITY
ASSESSMENT

2. Algorithms – It consists of a problem-specific flow chart with step-by-step

instruction on how to arrive at an answeADR. Actually, its form contain some
questionnaire, whose answers provide the causality of particular ADR. It give structured
and standardized methods of assessment in a systematic approach.
-Types Of Algorithms Method – There are many algorithmic methods of causality
assessment but no single algorithm is accepted as the “gold standard‟, because of many
shortcomings. Important Algorithmic Methods are- (i) Dangaumou’s french method (ii)
Kramer et al. method (iii) Naranjo et al. method (Naranjo scale) (iv) Balanced
assessment method (Lagier et al.) (v) Summary time plot (Castle et al.)
 Naranjo et al. method (Naranjo scale) - Widely accepted method.
 METHODS OF CAUSALITY
ASSESSMENT

 It consists of ten questions that are answered as “yes‟, “no‟, “unknown” (don‟t know). These answers are
assigned via a score termed Definite, Probable, Possible Or Doubtful. Definite- when a total score of ≥ 9.
Probable- when a total score of 5–8. Possible- when a total score of 1–4. Doubtful- when a total score of ≤ 0.
1. Are there previous conclusive reports on this reaction?
2. Did the adverse event occur after the suspected drug was administered?
3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?
4. Did the adverse reaction reappear when the drug was readministered?
5. Are there alternative causes (other than the drug) that could have on their own caused the reaction?
6. Did the reaction reappear when a placebo was given?
7. Was the blood detected in the blood (or other fluids) in concentrations known to be toxic?
8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased?
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?
10. Was the adverse event confirmed by any objective evidence?
 METHODS OF CAUSALITY
ASSESSMENT

3.Probabilistic Or Bayesian Approaches-: Causality assessment based on study of prior

probability and posterior probability. The prior probability is calculated from epidemiological
information. The posterior probability combines this epidiological background information
with the evidence in the individual case. This method allows the simultaneous assessment of
multiple causes.
-Bayesian Adverse Reactions Diagnostic Instrument (BARDI) – BARDI is used to calculate
the odds in favour of a particular drug causing an adverse event compared with an alternative
cause(posterior odds).
Preventability, Predictability
Assessment & Management of
ADRs
 Preventability Assessment

• According to WHO factsheet, at least 60 percent of ADRs are preventable.

• Several instruments/scales suggested for assisting the preventability of an ADR.
MODIFIED SCHUMOCK & THORNTON SCALE(1992) is most acceptable method for classifying preventability of adverse
drug events.
Preventability assessment was divided into Three categories definitely preventable, probably preventable, and not preventable.
Schumock and Thornton criteria: • It has three sections namely definitely preventable, probably preventable and not-
preventable.
• Section A comprises of five questions while section B has four questions.
• All the answers are categorized as "yes" or "no".
• ADRs are "definitely preventable" if answer was "yes" to one or more questions in section A.
• If answers are all negative ("no"), then proceed to section B•
ADRs are "probably preventable" if answer was "yes" to one or more questions in section B.
• If answers were all negative then proceed to section C. In section C, the ADRS are not-preventable
Schumock & Thornton Scale
 Predictability Assessment

The expectedness of the reaction is assessed in accordance with the approved product information, the reaction is
defined as expected if it is included in package insert or the Summary of product characteristics (SPC).
Type A (predictable)
1. Augmented reactions
2. Extension of pharmacologic effect
3. Often predictable and dose dependent
4. Responsible for at least 30% of ADRS
5. Example: Dry mouth induced by anti-cholinergics.
Predictability Assessment

Type B (unpredictable)
1. Idiosyncratic or immunologic reactions
2. Bizzare Reactions
3. Rare and unpredictable
4. Example: Penicillin induced anaphylactic shock.

Following approach is helpful in assessing possible drug-related ADRs:

5. Ensure that the medicine ordered is the medicine received and actually taken by the patient at the dose
advised.
6. Take a proper history and do a proper examination of the patient.
Predictability Assessment

3. Effect of Dechallenge and Rechallenge should be determined.

Dechallenge (withdrawal of the suspected medicine): Positive dechallenge is the Improvement.
Rechallenge (re-introducing the suspected medicine after a dechallenge) Rechallenge requires serious
ethical considerations.
4. Carry out a thorough physical examination with appropriate laboratory investigations if necessary:
5. Ask The patient if this adverse reaction can be explained by any other cause e.g. patient’s
Underlying disease, other medicines including over-the-counter medicines or traditional medicines,
toxins or foods
Management of ADRs

Adverse drug reaction is one of causes of morbidity and mortality on animal as well as human being. So Rapid
action towards the management of adverse drug reaction is important because of the serious nature of suspected
adverse drug reaction. Ex- Anaphylactic Shock.
Following points are considered to manage ADR:-
1. First and foremost step is withdrawal of suspected drug(s), if the reactionis likely to be dose related, dose
reduction should be considered,
2. For allergic and idiosyncratic ADRs, the drug usually should be withdrawn and not tried again.
3. The most important and effective therapeutic measure in managing drug hypersensitivity reactions is the
discontinuation of the offending medication, if possible. Alternative medications with unrelated chemical
structures should be substituted when available.
4. Avoid all inappropriate use of drug in context of patient’s clinical condition.
5. Use of appropriate dose, route and frequency of administration on base of patients, specific variable.
 Management of ADRs

6. In the case of Gastrointestinal adverse effects, common adverse effect like nausea, Vomiting, diarrhoea, hepatitis
etc. Can be cure by withholding drug until such problem Resolves.
7. If the patient is not doing well after withdrawal of the first drug, the next most likely Culprit should be
considered and the withdrawal process repeated.
8. On the other hand, the patient may be suffering through being deprived of the medicine Dosage With held. In the
case, either another suitable drug should be substituted, or the same drug should be tried at a lower dosage.
9. If the patient unable to manage without a medicine that has caused an adverse reaction, Provide symptomatic
relief while continuing the essential treatment.
10. While managing an ADR, always have a clear therapeutic objective in mind, do not treat for longer than
necessary, review the patient regularly and simplify management.
Role of Pharmacist in Management Of ADRs

The fundamental role of health care providers (HCPs) is,

1. To identify potential and actual drug related problems
2. Resolve problems, and prevent potential drug-related problems.
3. A pharmacist plays a pivotal role in the identification, detection, prevention, and management of
drug-drug interactions, drug-food interactions and adrs.
4. HCPs are encouraged to take responsibility in development of Adverse Drug Reaction Monitoring
and Reporting Programs to increase awareness of ADR(s), increase reporting of ADR(s), and
increase opportunities to review drug selection and prescribing practices directly affecting patient
outcome.
5. To investigate every suspected ADR for its nature, probability, and severity, Develop risk reduction
strategies as part of an ongoing program.
Role of Pharmacist in Management Of ADRs

6. Provide information to other healthcare professionals to better identify ADR(s).

7. The intervention of pharmacists by organising lectures and group discussions thus providing
information about the importance, seriousness, preventability and necessity of reporting
8. All health professionals play their respective roles in balancing between benefits and risks of
medication when it is introduced in the market.
9. In a community pharmacy, a pharmacist may not have direct and definite patient list but the patients
coming to the same pharmacy to refill their prescription gives the pharmacist an opportunity to detect a
possible adr that the patient might be experiencing and can help in the management and the reporting
of that adr.