Adverse Drug Reactions

Dr. Sahil Kumar Nautiyal

MBBS, MD Pharmacology (MAMC)
Assistant Professor and Head
Department of Pharmacology
 Specific Learning Objectives
At the end of this session the learner shall be able to
1. Understand the concept of adverse drug
reactions (ADRs) and pharmacovigilance (PV).
2. Enlist the types and examples of ADR subtypes.
3. Learn how to fill up a CDSCO form for a
suspected ADR.
4. Acquire the knowledge and promote culture of
reporting ADRs under the PvPI.
 “To undergo treatment you have to be very healthy, because
apart from your sickness you have to withstand the medicine.”

Molière

No medicinal product is entirely or absolutely safe for all people, in all places, at all times.

We must always live with some measure of uncertainty.

Definition:
Adverse Drug Reaction (ADR)-
A drug response which is noxious and unintended, and
which occurs at doses normally used for the
prophylaxis, diagnosis or therapy of disease, or for the
modification of physiological function.
(WHO Technical Report Series, 498, 1972)

Giving a drug is a risk –

• All drugs are capable of producing ADRs.
• Risk-Benefit analysis.
 An ADR can be:
 Unfavorable and unintended sign
 Symptom
 Disease
 Abnormal laboratory finding

 Symptoms - Headache, Nausea

 Physical findings- ↑ BP, Lump, Pallor, Edema

 Abnormal lab values- Deranged Liver Function tests,

Decreased hemoglobin
 ADRs: General Aspects
May develop promptly/ after prolonged medication/
even after stoppage of the drug.
Adverse effects are not rare - incidence of 10-25%.
They are more common with multiple drug therapy and
in the elderly.
 ADR : Types

• Type A : Augmented pharmacological effect

• Type B : Bizarre/idiosyncratic effect
• Type C : Chronic effects
• Type D : Delayed effects
• Type E : End of treatment effects
• Type F : Failure of therapy
 Type A :
• Accounts for 75% of all ADRs (more common)
• Extension/exaggeration of pharmacological effects
• Dose related, augmented, predictable
• Mostly preventable and reversible
• Eg. Atropine  dry mouth, Insulin  Hypoglycemia
 Type B :
• Less common
• Unusual (bizarre - अजीब/ अनोखा/ तकह न)
• Non-dose related, usually serious or fatal
• Unpredictable (rarely preventable)
• Eg. Penicillin  Anaphylaxis
Penicillin and other beta lactams
Local Anesthetics
Hydralazine
Sulfonamides
Salicylates
Methyldopa
ACE inhibitors
 Type C :
• Chronic/ prolonged treatment
• Eg. Analgesic nephropathy

Type D :
• Delayed
• Teratogenesis and Carcinogenesis
• Eg. Phenytoin – cleft lip/cleft palate

Type E :
• End of use
• Withdrawal effect
• Eg. Corticosteroid withdrawal - Adrenal crisis
 Severity of ADRs
Minor:
No therapy/ antidote/ prolongation of hospitalization

Moderate:
Requires change in drug therapy/ specific treatment/ prolongation of hospitalization

Severe:
Potentially life threatening/ permanent damage/ intensive medical treatment

Lethal:
Directly or indirectly contributes to death
 Preventing ADRs:
Rational Use of Medicines (RUM)

Previous history of drug reactions

History of allergic diseases and exercise caution

Rule out drug interactions

Correct drug administration technique (e.g. NSAIDs not to be given on empty

stomach)

Appropriate laboratory monitoring (e.g. prothrombin time with warfarin,

serum drug levels with lithium)
 Secondary effects

Side effects

Toxic effects

Intolerance

related to ADRs
Some aspects
Idiosyncracy

Drug Allergy

Photosensitivity

Drug Dependence

Drug withdrawal

Teratogenicity

Carcinogenecity

Drug induced
diseases
 Secondary effects
Indirect consequences of a primary drug action

• Tetracyclines  suppression of bacterial flora 

superinfections
• Corticosteroids  immunosuppression 
Activates (latent) TB
 Side effects
Unavoidable pharmacodynamic effects @ Normal doses
(Pharmacologically predictable)
• Based on the same action as the therapeutic effect e.g. anti-
inflammatory & gastric mucosal damaging effects of NSAIDs d/t PG syn. inh.
• Based on a different facet of action e.g. promethazine sedation
unrelated to antiallergic action
• May be therapeutic in one context but side effect in
another context e.g. codeine (cough)  constipation (S/E)  therapeutic
effect in traveller’s diarrhoea
 Toxic effects
Excessive drug action @ Overdosage/ prolonged use
(Pharmacologically predictable)
• Insulin overdose  Hypoglycaemia
• Heparin overdose  Bleeding
• Absolute (accidental, homicidal, suicidal) or relative (usual dose of
gentamicin in renal failure)
• Another action of the drug may be responsible for toxicity
• Morphine (analgesic) overdose  respiratory failure
• Gentamicin (antibacterial) overdose  vestibular (ear) damage
 Poisoning
Poison (definition):
‘Substance which endangers life by severely affecting one
or more vital functions’.

General supportive measures:

Hastening
Resuscitation, Termination elimination -
maintenance of exposure inducing
of vitals - (decontamination) Prevention of “forced”
airway, ventilation, - fresh air, absorption - diuresis, altering
oxygen support, washing, emesis
(not in
activated charcoal urinary pH,
BP & HR, body
temperature, comatosed), haemodialysis
blood sugar. lavage and
haemoperfusion
 Intolerance
Appearance of characteristic toxic effects @ Normal doses
Indicates a low threshold of the individual to drug action

 Only few doses of carbamazepine  ataxia in some people.

 One tablet of aspirin  gastric bleeding
 Idiosyncrasy
Unknown genetically determined abnormal reactivity

• Barbiturates  excitement, mental confusion in some

• Chloramphenicol  serious aplastic anaemia in some
• Known = Pharmacogenomics/ Pharmacogenetics
 Drug allergy/ hypersensitivity
an immunologically mediated reaction
producing stereotype symptoms
• Occur in very small proportion of population
• Prior sensitization, latent period of at least 1–2 wks reqd.
• Drug (antigen/ hapten)  induces Ab production
• “Cross sensitivity” with other drugs of the same class
• Individual previously sensitive to a drug may subsequently
tolerate it without a reaction (vice versa)
 Drug Hypersensitivity Reactions: Types

• Type I: IgE - mast cell, “immediate”, dentist must treat

Anaphylaxis, urticaria, angioedema
• Type II: IgG or IgM mediated, “cytolytic”
Lupus erythematosus, hemolytic anemia
• Type III : IgG mediated, “immune complexes”
Serum Sickness, Glomerulonephritis, SJS
• Type IV: T-cell mediated responses, “delayed”
Contact dermatitis

Dentists may develop contact dermatitis by repeated handling of local anaesthetics;

surgical gloves must be used.
 Treatment of Drug Allergy
This is a Medical Emergency
STOP the offending drug immediately!
• Mild reactions (like skin rashes) subside by themselves.
 H1-Antihistaminics
• Anaphylactic shock/ angioedema of larynx:
 Reclining position
 Administer oxygen at high flow rate and
 Perform cardiopulmonary resuscitation if required
Inj. ADRENALINE 0.5 mg (0.5 ml of 1:1000 solution) i.m.;
repeat every 5–10 min in case the patient does not improve or improvement is
transient.

Adrenaline should not be injected i.v. (can itself be fatal)

unless shock is immediately life threatening.
 Treatment of Drug Allergy
• If adrenaline is to be injected i.v., it should be diluted to
1:10,000 or 1:100,000; infused slowly with constant
monitoring.
• H1 antihistaminic (CHLORPHENIRAMINE 10–20 mg) i.m./
slow i.v. (adjuvant)
• Glucocorticoid i.v. (HYDROCORTISONE sod. succinate 200
mg) should be added in severe/ recurrent cases.
• Glucocorticoids are the only effective drugs in type II, III, IV

Skin tests (intradermal injection, patch application) may forewarn in case of

Type I hypersensitivity. Eg. Penicillin, Cephalosporins
 Photosensitivity
Drug induced sensitization of the skin to UV radiation.

Phototoxic Reaction (UV-B) Photoallergic Reaction (UV-A)

Drug accumulates in the skin, absorbs light Drug induces a cell-mediated immune
 photochemical, photobiological reaction response  produces a papular or
 local tissue damage (sunburn etc). eczematous contact dermatitis like picture.
Eg. Tetracyclines (especially demeclocycline) Eg. Chloroquine
 Drug dependence
Drugs altering mood and feelings - liable to repetitive use -
euphoria, recreation, withdrawal, social adjustment, etc.

Definition:
Drug use for personal satisfaction is accorded a higher priority
than other basic needs

Psychological dependence
Physical dependence
Drug Abuse
Drug Addiction
Drug Habituation
 Drug dependence
Psychological dependence
• Individual believes that optimal state of wellbeing is
achieved only through the actions of the drug. (desire to
craving)
• Reward & Reinforcement- Strong - opioids, cocaine
• Faster drug more reinforcing: Inhaled, injected i.v. are highly
reinforcing.
 Drug dependence
Physical dependence
• Necessitates the continued presence of the drug to
maintain physiological equilibrium.
• Intensity: Discontinuation - characteristic withdrawal
(abstinence) syndrome.
• Neuroadaptation- adaptation of the nervous system to
function normally in the presence of the drug
• Opioids, barbiturates, alcohol
 Drug dependence
Drug Abuse
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 Habituation
Less intensive involvement, withdrawal produces only mild
discomfort. tea, coffee, tobacco, social (alcohol) drinking

Drug Addiction (Drug seeking behaviour/ craving)

Compulsive pattern of drug use characterized by
overwhelming involvement with the use of a drug.
• Cannabis/ Marijuana – Highly addictive but no phy. dep.
 Movie recommendation

Requiem for a dream (2000)*

*Not for the faint hearted!
 Drug withdrawal reactions
Sudden interruption of therapy results in adverse
consequences: worsening of the clinical condition for
which the drug was being used.

Abrupt cessation of corticosteroid therapy 

Acute adrenal insufficiency
 Teratogenicity
Capacity of a drug to cause foetal abnormalities when
administered to the pregnant mother.
Placenta - not a strict barrier; any drug can cross to a
greater/ lesser extent

1) Fertilization and implantation— conception to 17 days—failure

of pregnancy which often goes unnoticed.
2) Organogenesis—18 to 55 days of gestation—most vulnerable period,
deformities are produced.
3) Growth and development—56 days onwards—developmental and
functional abnormalities can occur, e.g. ACE inhibitors can cause hypoplasia of
organs, especially of lungs and kidneys.
 Phocomelia Tragedy –
The Thalidomide Disaster
(1958–61)
Thalidomide first marketed (1957) in West Germany.
To alleviate morning sickness in pregnant women.
Throughout the world ~10,000 cases; only 50% survived.
Australian obstetrician William McBride &
German pediatrician Widukind Lenz suspected a link b/w
birth defects and the drug in 1961.
In the US, pharmacologist Frances Kelsey withstood
pressure & refused FDA approval.
DO NOT Prescribe In Pregnancy!
 US-FDA Categories
(now obsolete)
Only emergency dental treatment should be undertaken during the most vulnerable
period of organogenesis.
 Carcinogenicity & Mutagenicity
Capacity of a drug to cause cancer and genetic defects
• Drug Oxidation  Reactive metabolites  Chromosome
damage
• Takes 10–40 years to develop
• Eg. anticancer drugs, radioisotopes, estrogens, tobacco.

Drug-induced diseases
• Iatrogenic (physician induced) diseases
 Peptic ulcer by NSAIDs and corticosteroids
 Parkinsonism by Antipsychotics
 Hepatitis by Isoniazid
 DLE by hydralazine
 Pharmacovigilance

Pharmacovigilance
 Pharmaco = medicine
 Vigilare = to watch

“ The science and activities

relating to the detection,
assessment, understanding
and prevention of adverse
effects or any other possible
drug related problem”
 Includes…

Drugs
Herbals
Traditional & Complementary medicine
Blood products
Biologicals
Medical devices
Vaccines
 ADR Reporting : Misconceptions

• All serious ADRs are known before drug is marketed

• Causality assessment difficult
• Reporting only when absolutely certain
• A stray report is of no particular significance
 Pharmacovigilance Programme of India

Goal

To ensure that the benefits of use of medicine

outweighs the risks and thus safeguard the health
of the Indian population.
 Pharmacovigilance Programme of India
(PvPI)
• The Central Drugs Standard Control Organization
(CDSCO), Directorate General of Health Services under
the aegis of Ministry of Health & Family Welfare,
Government of India in collaboration with Indian
Pharmacopoeia commission, Ghaziabad initiated a
nation-wide Pharmacovigilance programme for
protecting the health of the patients by assuring drug
safety.

• Indian Pharmacopoeia commission, Ghaziabad is a

National Coordinating Centre (NCC).
CDSCO Zonal and subzonal centers
• North – Ghaziabad and Chandigarh
• South – Chennai, Hyderabad , Bengaluru
• East – Kolkata
• West – Mumbai, Ahmedabad
PV Reports from all over the world go to the UMC, Sweden
 ADRs leading to withdrawal of some drugs…
Name Drug Class Marketing Observation Withdrawal
year
Troglitazone Anti-diabetic 1997 Hepatotoxicity 1997

Cisapride Prokinetic 1993 QT prolongation 2000

Rofecoxib NSAID 1999 Cardiovascular 2004

events
(Vioxx)
Gatifloxacin Quinolones 1999 Dysglycemia 2005

Sibutramine Anti- Obesity 1995 Cardiovascular 2010

events
 Who can report?

• Nurses & Paramedics

• Academia
• Pharmacists
• Practicing Clinician
• Pharmaceutical Industry
• Consumers/ Patients
 What to report?
ANY SUSPICION-REPORT !
•Advised to report all suspected AEs (builds the reporting
culture).

•Developing a profile of ADRs of locally used medications

could be beneficial.

• Unexpected (serious and non serious) adverse events.

Case report

• Name- Sunita, Age- 1 year, Sex-F, Wt.-5 Kg

• Date- 04/02/2023

• Presenting Complaint- Vomiting, decreased food

intake for the last 2 days.

• On Physical examination: She had signs of jaundice

(yellowish discoloration of sclera, body till the level of
soles, and dark colored urine).
• History of present Illness-

Four days back, she developed high grade fever and

cough for which she was given Syrup Crocin
(Paracetamol) 15mg/kg every 6 hrly and Syrup Amox
(amoxycillin) 15mg/kg 8hrly

• Management and follow up

Syrup Crocin discontinued, supportive care given and
patient improved in 5 days
Questions:

• What is the probable ADR?

• What is the mechanism of the above ADR
• Was this patient at a greater risk of toxicity?
Why?
• Fill up the CDSCO form based on the
information provided