ADVERSE

DRUG REACTIONS

By:-
Dr.Vijay Lambole
Objectives

• Definition of terms associated with Adverse Drug

Reactions (ADRs)

• Classification of ADRs

• Discussion on each type of ADR with examples

Definitions

• Adverse Event (AE): Any untoward medical occurrence

that may present during treatment with a pharmaceutical
product but which does not necessarily have a causal
relationship with this treatment.

• Adverse Drug Reaction (ADR): Any noxious change

which is suspected to be due to a drug, occurs at doses
normally used in man, requires treatment or decrease in
dose or indicates caution in future use of the same drug.

• Therefore, an adverse drug reaction is an adverse event

with a causal link to a drug.
 Drug administered

Pt. develops a new condition/symptom

ADE

Drug suspected?

Yes
Check literature

Documented ?
(for the product
Or
similar class of products)
Yes
Highly suggestive of ADR
 Not documented in literature

Drug continued Drug discontinued

Worsening of symptoms Symptoms improve

(+ve dechallenge)

Any other possible causes?

• Concomitant therapy Drug restarted
• Underlying conditions

Symptoms recur
(+ve rechallenge)
Simply….

• Adverse: Untoward, unintended, possibly causing harm

(noxious)

• AE: Adverse Event, Effect or Experience

• ADE (Adverse Drug Event): An AE which happens in a

patient taking a drug

• ADR (Adverse Drug Reaction): An ADE in which a

causal association is suspected between the drug and the
event
 ADEs Vs ADRs

Adverse drug events

No need to have
(ADEs)
a causal relationship

Adverse Drug
Reactions Causal relationship
(ADRs) is suspected/established
Classification of ADRs
• Depending on….
• Onset of event: Acute (<60 minutes), Sub-acute (1-24 hrs) and
Latent (>2 days)

• Type of reaction: Type A (Augmented), B (Bizarre), C

(Chemical),D (Delayed), E (Exit), F (Familial), G (Genotoxicity),
H (Hypersensitivity), U (Un classified)

• Severity: Minor, Moderate, Severe, Lethal ADRs

• Others: Side effects, Secondary effects, Toxic effects,

Intolerance, Idiosyncrasy, Drug allergy, Photosensitivity, Drug
Dependence, Drug Withdrawal Reactions, Teratogenicity,
Mutagenicity, Carcinogenicity, Drug induced disease (Iatrogenic)
Classification of ADRs....
Wills and brown

• Type A (Augmented)
• Type B (Bizarre)
• Type C (Chemical)
• Type D (Delayed)
• Type E (Exit/End of treatment)
• Type F (Familial)
• Type G (Genotoxicity)
• Type H (Hypersensitivity)
• Type U (Un classified)
Type A (Augmented) reactions

• Reactions which can be predicted from the known

pharmacology of the drug
• Dose dependent,
• Can be alleviated by a dose reduction

E.g.
• Anticoagulants  Bleeding,
• Beta blockers  Bradycardia,
• Nitrates  Headache,
• Prazosin  Postural hypotension.
Type B (Bizarre) reactions

• Cannot be predicted from the pharmacology of the drug

• Not dose dependent,
• Host dependent factors important in predisposition

E.g.
• Penicillin  Anaphylaxis,
• Anticonvulsant  Hypersensitivity
Type C (Chemical) reactions

• Biological characteristics can be predicted from the

chemical structure of the drug/metabolite

E.g.
• Paracetamol  Hepatotoxicity
Type D (Delayed) reactions

• Occur after many years of treatment.

• Can be due to accumulation.

E.g.
• Chemotherapy  Secondary tumours
• Phenytoin during pregnancy  Teratogenic effects
• Antipsychotics  Tardive dyskinesia
• Analgesics  Nephropathy
Type E (End of treatment) reactions

• Occur on withdrawal especially when drug is stopped

abruptly

E.g.
• Phenytoin withdrawal  Seizures,
• Steroid withdrawal  Adrenocortical insufficiency.
Classification of ADRs….
Depending on Severity
• Minor ADRs: No therapy, antidote or prolongation of
hospitalization is required.

• Moderate ADRs: Requires change in drug therapy, specific

treatment or prolongs hospital stay by atleast 1 day.

• Severe ADRs: Potentially life threatening, causes

permanent damage or requires intensive medical treatment.

• Lethal: Directly or indirectly contributes to death of the

patient.
Side effects
• Unwanted but often unavoidable, pharmacodynamic effects
that occur at therapeutic doses
• Predicted from the pharmacological profile of a drug
• Known to occur in a given percentage of drug recipients

• E.g.
• Side effect based on therapeutic effect:
Atropine (preanaesthetic) dryness of mouth
Acetazolamide (diuretic-bicarbonate excretion) Acidosis
• Side effect based on a different action:
Promethazine (anti-allergic) sedation
Estrogen (Anti ovulatory)  Nausea
• Depending on the context:
Codeine (anti-tussive)  constipation Used in Traveller’s
diarrhea
Side effects….
• Drug discovery
• Occasionally, “adverse” effects may be exploited to develop an
entirely new indication for a drug.

• E.g:
• Unwanted hair growth during Minoxidil treatment of severely
hypertensive patients  development of the drug for hair
growth.
• Sildenafil was initially developed as an antianginal, but its
effects to alleviate erectile dysfunction  a new drug indication
in erectile tissue.
• Sulfonamides used as antibacterials were found to produce
hypoglycemia and acidosis as side effects  development of
Hypoglycemic Sulfonylureas and Carbonic anhydrase inhibitor
Acetazolamide.
Secondary effects

• Indirect consequences of a primary action of the drug

• E.g.
• Tetracyclines Suppression of bacterial flora
Superinfections
• Corticosteroids Weaken host defence Activation of
latent tuberculosis
Toxic effects

• Result of excessive pharmacological action of the drug

due to over dosage or prolonged use.
• Over dosage may be
1. Absolute (Accidental, homicidal, suicidal)
2. Relative (Gentamycin in Renal failure)
• Result from
1. Extension of therapeutic effect:
E.g. Barbiturates  Coma,
Digoxin  Complete A-V block,
Heparin  Bleeding
2. Functional alteration:
E.g. Atropine  Delirium
3. Drug induced tissue damage:
E.g. Paracetamol  Hepatic necrosis
Intolerance

• Appearance of characteristic toxic effects of a drug in an

individual at therapeutic doses
• Converse of tolerance,
• Indicates a low threshold of the individual

• E.g.
• Triflupromazine (single dose)  Muscular dystonias in
some individuals
• Carbamazepine (few doses) Ataxia in some individuals
• Chloroquine (single tablet)  Vomiting and abdominal
pain in some individuals
Idiosyncrasy

• Genetically determined abnormal reactivity to a chemical

• Certain Bizarre drug effects due to peculiarities of an
individual for which no definite genotype has been
described, are also included.
• Drug interacts with some unique feature of the individual,
not found in majority subjects, and produces the
uncharacteristic reaction.
• E.g.
• Barbiturates Excitement and mental confusion in some individuals
• Quinine  Cramps, diarrhea, asthma, vascular collapse in some
individuals
• Chloramphenicol  Aplastic anemia in rare individuals
Drug allergy

• Immunologically mediated reaction producing stereotype

symptoms, unrelated to the pharmacodynamic profile of the drug
• Generally occur even with much smaller doses
• Also called Drug hypersensitivity
• Types:
• Type I: Immediate, anaphylactic (IgE)
• E.g: Penicillins  Anaphylaxis
• Type II: Cytotoxic antibody (IgG, IgM)
Humoral
• E.g: Methyldopa  hemolytic anemia immunity
• Type III: Serum sickness (IgG, IgM)
• Antigen-antibody complex
• E.g: Procainamide-induced lupus
• Type IV: Delayed hypersensitivity (T cell) Cell mediated
• E.g: Contact dermatitis immunity
Photosensitivity
• Cutaneous reaction resulting from drug induced sensitization of the
skin to UV radiation. The reactions are of two types

• Phototoxic: Drug or its metabolite accumulates in the skin, absorbs

light and undergoes a photochemical reaction resulting in local tissue
damage (sunburn-like, i.e., erythema, edema, blistering, hyper
pigmentation)
E.g. Tetracyclines (esp. Demeclocycline), and Tar products,
Nalidixic acid, Fluoroquinolones, Sulfones etc

• Photo allergic: Drug or its metabolite induces a cell mediated

immune response which on exposure to light (longer wave length)
produces a papular or eczematous contact dermatitis like picture.
E.g. Sulfonamides, Sulfonylureas, Griseofulvin, Chloroquine,
Chlorpromazine
Drug dependence

• Drugs capable of altering mood and feelings are liable to repetitive use
to derive euphoria, withdrawal from reality, social adjustment, etc.

• Psychological dependence: Individual believes that optimal state of

well being is achieved only through the actions of the drug.
• E.g. Opioids, Cocaine.

• Physical dependence: Altered physiological state produced by

repeated administration of a drug which necessitates the continued
presence of the drug to maintain physiological equilibrium.
Discontinuation of the drug results in a characteristic withdrawal
(abstinence) syndrome.
• E.g. Opioids, Barbiturates, Alcohol, Benzodiazepines
Drug dependence….

• Drug abuse: Use of a drug by self medication in a manner and

amount, that deviates from the approved medical and social
patterns in a given culture at a given time.
Drug abuse refers to any use of an illicit drug.

• Drug addiction: Compulsive drug use characterized by

overwhelming involvement with the use of a drug.

• Drug habituation: Less intensive involvement with the drug,

withdrawal produces only mild discomfort.

• Habituation and addiction imply different degrees of

psychological dependence.
Drug withdrawal reactions

• Sudden interruption of therapy with certain drugs result in

adverse consequences, mostly in the form of worsening
of the clinical condition for which the drug was being
used.

• E.g:
• Corticosteroid Adrenal insufficiency
• β-blockers  worsening of angina, precipitation of MI
• Clonidine  severe HTN, restlessness, sympathetic over
activity
Teratogenicity

• Capacity of a drug to cause foetal abnormalities when

administered to the pregnant mother.
• Drugs can affect the foetus at 3 stages:
1. Fertilization and implantation (Conception to 17
days): failure of pregnancy which often goes
unnoticed.
2. Organogenesis(18 days to 55 days): most vulnerable
period, deformities are produced.
3. Growth and development (> 56 days): developmental and
functional abnormalities can occur.

• E.g:
• Thalidomide Phocomelia, multiple defects
• Anticancer drugs  Cleft palate, hydrocephalus, multiple defects
• ACE inhibitors  Hypoplasia of organs (lungs, kidney)
Mutagenecity and
Carcinogenicity
• Capacity of a drug to cause genetic defects and
cancer respectively.
• Chemical carcinogenesis generally takes several
(10-40) years to develop.

• E.g.
• Anticancer drugs,
• Radio-isotypes,
• Estrogens,
• Tobacco.
Drug induced disease

• Also called Iatrogenic(Physician induced) diseases.

• Functional disturbances caused by drugs which persist
even after the offending drug has been withdrawn and
largely eliminated

• E.g.
• Salicylates, Corticosteroids  Peptic ulcer
• Phenothiazines, other antipsychotics  Parkinsonism
• Isoniazid  Hepatitis
• Hydralazine  DLE (discoid lupus erythematosus)
Summary

• Adverse Drug Reactions (ADRs) are adverse events with a

causal link to a drug.

• Types of Classification of ADRs:

• Onset of event: Acute (<60 minutes), Sub-acute (1-24 hrs) and
Latent (>2 days)
• Type of reaction: Type A (Augmented), B (Bizarre), C
(Chemical),D (Delayed), E (Exit), F (Familial), G (Genotoxicity),
H (Hypersensitivity), U (Un classified)
• Severity: Minor, Moderate, Severe, Lethal ADRs
• Others: Side effects, Secondary effects, Toxic effects,
Intolerance, Idiosyncrasy, Drug allergy, Photosensitivity, Drug
Dependence, Drug Withdrawal Reactions, Teratogenicity,
Mutagenicity, Carcinogenicity, Drug induced disease
(Iatrogenic)
Detecting adverse drug reaction(ADR).

Documentation of ADR

Reporting serious ADRs to

pharmacovigilance centers

Assessing causality between drug and

suspected reaction
 Detection of ADRs

Pre- Marketing Studies Post– Marketing Surveillance

Phase 1

Spontaneous Epidemiological
adverse methods
Phase 2 reaction
reporting

Case Control Cohort

Phase 3 Studies Studies
 PRE- MARKETING STUDIES

•During the development of new medicines, their safety is tested in

animal models.
•A great deal of risk information may be obtained from such tests, such
as the level of acute toxicity and which organs will be affected in case
of toxicity.
•If animal test do not reveal worrying results, safety tests proceed onto
testing in human.
•Clinical trials are carried out in three different phases prior to
submission of a marketing authorisation application
•Consequence of above is that at the time of general marketing of a new
medicine only the most common (Type A) adverse reactions will be
known.
•Passive and Active pharmacovigilance methodologies are used for
detection of risk and for the collection of risk information.

Spontaneous adverse reaction reporting

•Powerful and cost effective system for the identification of unknown

drug-related risk.

•Health care practitioner should see it as their duty to report any

suspicion of drug causing risk situation in patient under his care.

•Spontaneous reporting creates signals of previously unknown problems

•These methods are used to verify the hypothesis of a causal
link between drug exposure and an adverse outcome.

•Two epidemiological methods most commonly used are:

Case Control
Cohort Studies studies

Exposure Outcome

Exposed Outcome ? Exposed ? Outcome

Not Exposed Outcome ? Exposed ? Control
 COHORT STUDIES CASE CONTROL STUDIES

Patients exposed to a  Individuals affected by the

particular drug are adverse event being studied are
followed up actively and identified.
systematically and ADR Each case is matched with
frequencies are compared several disease – free control
to an unedxposed control patients, randomly recruited
population. from the study base.
Drug histories of both the
Advantage: Reveals groups are traced backwards for
unsuspected ADRs the comparison.
 The suspicion is strengthened
if high association is found.
Advantage: Can be analysed
quickly as number of patients
analysed is small.
 Collection of Data For Detection of ADR

Patient Related Details of suspected ADR

•Patient’s demographic •Time of onset and duration of
information. reaction and severity of reaction
•Presenting Complaints •Details of dose , frequency, and
•Past medication history time of administration of drug
•Drug therapy details including •Duration of treatment and
over the counter plasma concentration of Drug
•Current medications • Data on other risk factors and
•Lab data such as haematological, predisposing factors.
liver and renal function tests.
 Role of Healthcare Professionals in Detecting ADRs

Possibility of an ADR should always be considered during

differential diagnosis.

ADR may be detected during ward round with the medical team.

Patient counselling , medication history interview and

communicating with other healthcare professional may provide
additional clues.

Patients who are at higher risk should be monitored closely

• Patients with renal or hepatic impairment.
• Patients who had histrory of allergic reactions.
• Patients taking multiple drugs.
• Pregnant and breastfeeding women.
 Reporting an ADR
What may happen
when you don’t
report?

A) Who can Report?

All healthcare professionals (clinicians, dentists, pharmacists,
nurses etc) and
Non-healthcare professionals including consumers can report
suspected adverse drug reaction.
B) Where to report ?
Duly filled Suspected Adverse Drug Reaction Reporting Form
can be send to the nearest Adverse Drug Reaction Monitoring
Centre (AMC) or directly to the National Coordination Centre
(NCC).

 Call on Helpline (Toll Free) 1800 180 3024 to report ADRs.

Or can directly mail this filled form to [email protected] or
[email protected]
A list of nationwide AMCs is available at:
http://www.ipc.gov.in, http://www.ipc.gov.in/PvPI/pv_home.html
 C) What to report ?
Report serious adverse drug reactions. A reaction is serious when
the patient outcome is:

• Life-threatening
• Hospitalization (initial or prolonged)
• Disability (significant, persistent or permanent)
• Congenital anomaly
•Required intervention to prevent permanent impairment or
damage
Report non-serious, known or unknown, frequent or rare adverse
drug reactions due to Medicines, Vaccines and Herbal products.
D) Mandatory field
for suspected ADR
reporting form.

 Patient initials,
Age at onset of reaction,
Reaction term(s),
Date of onset of reaction,
 Suspected medication(s)
 reporter information.
D) What happens to the submitted
information?
ADR reported by Causality Forwaded to
HCP, Patient or assessment at NCC-PvPI
Others AMCs throughADR
database

Reports are Data is

periodically Analysed &
reviewed by the forwarded
NCC-PvPI

Global
Information is Pharmacovigilance
Suggests required submitted to the Database
interventions Steering committee (Managed by WHO-
of PvPI UMC)
 Assessing Causality
Causality assessment is the method by which the extent of
the relationship between a drug and a suspected reaction is
estimated .

Methods Of Causality Assessment

Group-1 Group-2
Opinion of Experts, Algorithms (with or
Clinical Judgment or without scoring) or
Global introspection standardised
methods assesment methods
 Group-1 Opinion of Experts, Clinical Judgment or
Global Introspection methods
Causation is established based on the clinical judgment of the expert or panel of
the experts. Such Judgements are mostly based on the
WHO-UMC causality assesment scale given below.
Causality term Assessment criteria*
Certain •Event or 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
(i.e. an objective and specific medical disorder or a recognised
pharmacological phenomenon)
• Rechallenge satisfactory, if necessary
Probable/ Likely •Event or laboratory test abnormality, with reasonable time
relationship to drug intake
• Unlikely to be attributed to disease or other drugs
• Response to withdrawal clinically reasonable
• Rechallenge not required
Causality term Assessment criteria*

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 may be lacking or unclear

Unlikely •Event or laboratory test abnormality, with a time to drug intake

that makes a relationship improbable (but not impossible)
• Disease or other drugs provide plausible explanations

Conditional/ • Event or laboratory test abnormality

Unclassified • More data for proper assessment needed, or
• Additional data under examination

Unassessable/ • Report suggesting an adverse reaction

Unclassifiable •Cannot be judged because information is insufficient or
contradictory
• Data cannot be supplemented or verified
 Group-2 Algorithms (Naranjo’sAlgorithms)

S.No Questions Yes No Don’t

Know
1 Are there previous conclusive reports on this reaction? -1 0 0
2 Did the adverse event appear after the suspected drug was +2 -1 0
given?
3 Did the adverse reaction improve when the drug was +1 0 0
discontinued or a specific antagonist was given?
4 Did the adverse reaction appear when the drug was +2 -1 0
readministered?
5 Are there alternative causes that could have caused the -1 2 0
reaction?
6 Did the reaction reappear when a placebo was given? -1 +1 0
7 Was the drug detected in any body fluid in toxic +1 0 0
concentrations?
8 Was the reaction more severe when the dose was increased, or +1 0 0
less severe when the dose was decreased?
9 Did the patient have a similar reaction to the same or similar +1 0 0
drugs in any previous exposure?
 Definite ≥ 9
Probable 5-8
Scoring Possible 1-4
Unlikely ≤ 0

But Still There Is No Universally Accepted Method For The

Causality Assessment Of Adrs
 70% ADRs are
potentially avoidable

Patient
More rational counselling
Prescribing

Consider risk
factors for
ADRs
Better
• Better communication
• monitoring of
treatment
Adverse Drug Reaction: A Response to a medicine which is
noxious and which occurs at doses normally used in man.
Adverse Drug Event: Any untoward medical occurance that
may present during the treatment with a medicine but which does
not necessarily have a causal relationship with this treatment.
Side Effects: an unpleasant effect of a drug that happens in
addition to the main effect.
Benefit and risk analysis: Examination of favorable (benefit)
& Unfavorable result of undertaking a special cause of action.
Adverse Case Report: A case report in ADR is a notification
relating to a patient with an adverse effect or laboratory test
abnormality suspected to be induced by medicinal product
1. Adverse Drug Reactions By Stephanie N. Schatz, Pharm.D., BCPS; and Robert J.
Weber, Pharm.D., BCPS Reviewed by Kyle E. Hultgren, Pharm.D.; Erin M. Timpe
Behnen, Pharm.D., BCPS; and Michael C. Barros, Pharm.D., BCPS, BCACP.
2. https://www.who-umc.org/media/2768/standardised-case-causality-assessment.pdf.
3. Naranjo et.al. Clin Pharmacol Ther. 1981 Aug;30(2):239-45
4. http://www.ephor.nl/media/1223/naranjo-causality-scale.pdf
5. http://www.who.int/medicines/regulation/medicines-safety/npvc-
meeting/Bloolet_poci2016.pdf
6. A Textbook of clinical Pharmacy by Parthasarathi, Nyfort –Hansen, Nahata, Second
Edition.
If you suspect an ADR do not
assume someone else
will report it……