Adverse drug reaction

Dr Shinde Viraj Ashok
Junior Resident 1
Department of Pharmacology
Guided by
Dr V. M. Motghare
Professor & Head
Department of Pharmacology

Definition of ADR
Statistics
Factors affecting
Classification
Pharmacovigilance

WHAT ARE ADVERSE DRUG REACTIONS
(ADRS)?
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 for in future use of the
same drug.

Adverse drug event –
Any untoward medical occurrence
that may present during treatment
with medicine , but which may not
have causal relationship with the
treatment.

STATISTICS
 ADR to drugs are most common cause of
iatrogenic disease.
 3-5% hospitalisations due to adverse
reactions results in 3,00,000
hospitalisations annually in US.
 Once hospitalised → 30% chance of ADR
→ Risk of each course is 5%
 3% chance of life threatning reactions →
Risk of each course is 0.4 %

COMMON CAUSES OF ADRS
 Failing to take the correct dosages at the
correct times.
 Overdosing.
 Allergies to chemical components of the
medicine.
 Combining the medicine with alcohol.
 Taking other drugs or preparations that
interact with the medicine.
 Taking a medicine that was prescribed
for someone else.

FACTORS AFFECTING ADVERSE DRUG
REACTIONS :
Patient-related factors
• Age
• Sex
• Genetic influences
• Concurrent diseases (renal ,liver , cardiac)
• Previous adverse drug reactions
• Compliance with dosing regimen
• Total number of medications
• Misc. (diet, smoking, environmental
exposure)

AGE
 Children are 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 if given
acetylsalicylic acid (aspirin) while infected
with chickenpox or influenza.

ELDERLY
1. ADRs, including drug interactions,
are a common cause of admission to
hospitals in the elderly
2. Reasons for ADRs in the elderly:
 Concomitant use of several
medications
 Decreased drug ADME activity
due to age
3. These conditions are exacerbated
by malnutrition and dehydration,
common in the elderly

PREGNANCY
1. Sulfonamides → Jaundice and brain
damage in the fetus
2. Warfarin → Birth defects, and
increased risk of bleeding problems
in newborns and mothers
3. Lithium → Defects of the heart
(Ebstein’s Anomaly), lethargy,
reduced muscle tone, and
underactivity of the thyroid gland

BREAST FEEDING
→ Many drugs can be passed from
mother to infant via breast milk
– Amantadine (antiviral)
– Cyclophosphamide (antineoplastic)
– Cocaine (Schedule 2 FDA drug)
– Carisoprodol (skeletal muscle relaxant)

Drug-related factors
 Dose
 Duration
 Inherent toxicity of the
agent
 Pharmacodynamic
properties
 Pharmacokinetic
properties
FACTORS AFFECTING ADVERSE DRUG
REACTIONS :

GENETIC BASIS
1. Atypical pseodocholinesterase
→ Faulty hydrolysis: AR,
normal action of
succinylcholine hydrolysis
takes 5 min ,here it takes 1-2
hours, results in prolonged
respiratory failure.
2. Hydroxylase polymorphism →
Faulty oxidation, AR ,
Phenytoin toxicity ↑ in slow
hydroxylators.

GENETIC BASIS
3. Acetylator status → AR
In fast acetylators → INH → Acetyl
hydrazine → Hepatotoxicity
In slow acetylators → INH →
peripheral neuritis
In slow acetylators → Dapsone →
hemolysis.
4. G6PD deficiency → X linked recessive →
Primaquine , sulfonamides, nitrofurantoin
causes hemolytic anemia.

5. Uroporphyrinogen Synthetase
Enzyme deficiency
→ AD ,required for haem
synthesis → Barbiturates ,
phenytoin , carbamazepine give
rise to acute intermittent
porphyria.
GENETIC BASIS

 Type A - (Augmented)
 Type B - (Bizarre)
 Type C - (Continuous)
 Type D - (Delayed)
 Type E - (Ending of Use)
 Type F - (Failure of Efficacy)
TYPES OF ADR

Type A (Augmented)
Predictable
Type B (Bizzare)
Unpredictable
Expected- Undesirable Unexpected- Undesirable
Based- Pharmacological
properties of drug
Based- Peculiarities of patient
More common Less common
Dose related Non dose related
Mostly preventable and reversible More serious, requires drug
withdrawl
Includes- Side effects ,
Secondary effects , Toxic
effects, Consequences of drug
withdrawal
Includes-Hypersensitivity/allergy
, Idiosyncrasy
ADR CLASSIFICATION

TYPES BASED ON ONSET
Onset of event:
 Acute -
within 60 minutes
 Sub-acute -
1 to 24 hours
 Latent -
> 2 days

SEVERITY OF ADR
Minor Moderate Severe Lethal
No
treatment/
Antidote/
Prolongation
of
hospitalisati
on
Requires
treatment/
Change in
treatment/
Prolongation
by at least 1
day
Requires
intensive
treatment ,
Life
threatening,
Permanent
damage
Directly/
Indirectly
contributes
to the death
of the
patient

FDA defines Serious ADR as which
 Results in death
 Life-threatening
 Require hospitalization
 Prolong hospitalization
 Cause disability
 Cause congenital anomalies
 Require intervention to prevent permanent
injury

Pharmacological properties of a drug
Extension effects
 Predictable
 Dose - Related responses
 Prevention - Adjustment of dosage regimen
Examples
 Benzodiazepines - Sedation
 Furosemide - Water and electrolyte imbalance
 Heparin, warfarin - Spontaneous bleeding
 Insulin - Hypoglycemia
TYPE A REACTIONS OR AUGMENTED

ADVERSE EFFECTS
 Predictable, dose-dependent reactions unrelated to
the goal of therapy
 Often produced by the same drug-receptor
interaction responsible for the therapeutic effect,
differing only in the tissue/s or organ/s affected

EXAMPLES OF ADVERSE EFFECTS
 INH, Rifampicin, PZA – Hepatotoxicity
 Streptomycin -Ototoxicity, nephrotoxicity
 Captopril - Cough
 Simvastatin – Rhabdomyolysis
 Nitrates – Headache
 Propranolol – Bronchial asthma
 Tetracycline – Hypoplasia of the teeth

TYPE B REACTIONS OR BIZARRE
 Abnormal effects
 Unrelated from the
drug’s known
pharmacological
actions

EXAMPLES OF BIZARRE REACTIONS
 Hypersensitivity reactions
 Stevens-Johnson’s Syndrome
 Hemolytic anemia

Long term effects are usually related to the dose
and duration of treatment
 Examples
 Ethambutol - Retinopathy
 NSAIDs - Nephrotoxicity
TYPE C REACTIONS OR CONTINUOUS

 Carcinogenesis
 Teratogenesis
 Examples: Thalidomide
TYPE D REACTIONS OR DELAYED

Withdrawal Syndromes
Examples:
• Benzodiazepines – Rebound insomnia,
agitation
• Clonidine – Rebound hypertension
• Corticosteroids – Acute adrenal
insufficiency
TYPE E REACTIONS OR ENDING OF USE

TYPE F REACTIONS OR FAILURE OF
EFFICACY
 Counterfeit medicines
 Underdosing of medications
 Drug interactions

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

1. Side Effects - Undesirable effects at
therapeutic doses
e.g a)Atropine → Preanaesthetic
medication → (undesirable ) dry mouth
b) Codiene → Suppresses Cough (desirable)
→ Constipation (undesirable)
Making Use of side effects -
Minoxidil → Antihypertension → Hypertrichosis
→ Male pattern baldness
Codeine → used in travellers diarrhoea
ADVERSE DRUG EFFECTS MAY BE
CATEGORISED INTO

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

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

Type I - Anaphylactic reactions due to IgE
antibodies, min→2-3 hours
Examples - urticaria ,angioedema , anaphylactic
shock
Type II - Cytolytic reactions due to antigen
antibody complex , within 72 hours
Examples - hemolytic anemia , SLE.

Type III – Retarded or Arthus reaction -
Immune complex mediated reactions,
72 hours→1-2 weeks
Examples - serum sickness (fever, arthralgia,
lymphadenopathy),PAN , Steven Johnson
syndrome , procainamide induced systemic lupus
erythematous.
Type IV - Delayed hypersensitivity reaction
Examples - Contact dermatitis

5. Idiosyncrasy - Genetically determined
abnormal reactivity to a chemical.
Here drug interacts with some unique features
of individuals , not found in majority of subjects
, produces uncharacteristic reaction.
Examples -
a) Barbiturates → excitement and mental
confusion in some patients.
b) Chloramphenicol → Aplastic anemia in
some patients.
c) Quinine/ quinidine → cramps, diarrhoea ,
purpura , asthma & vascular collapse.

6. Drug Intolerance -
- Characteristic toxic effects at therapeutic
dose
- Converse of tolerance
- ↑ sensitivity to low doses
Examples -
Single dose triflupromazine → muscular
dystonia

7. Photosensitivity -
Cutaneous reactions → sensitized skin
→ UV radiation.
Two types:
a) Phototoxicity
b) Photoallergicity

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 like picture
Short wavelengths
(290-320nm) UV-B
Longer wavelengths
(320-400nm) UV-A
More common
e.g. Tetracyclines
Less common
e.g. Sulfonamides,Griseofulvin

8. Drug withdrawal reactions -
Sudden interruption of drug → worsens
clinical condition for which previously
drug was used.
Examples -
a) Corticosteroids in asthma →
precipitates acute attacks , myalgia,
depression
b) Beta Blockers → worsening of
angina , precipitates myocardial
infarction

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

DRUGS CAN AFFECT THE FOETUS AT 3
STAGES
1)Fertilization &
implantation
(blastocyst
formation)
Conception to 17
days - failure of
pregnancy -
Cytotoxic drugs ,
alcohol .
2) Organogenesis
- 18-55 days of
gestation - most
vulnerable
period -
deformities are
produced –
teratogens.
3) Growth and
development -
Developmental &
functional
abnormality
ACE inhibitors -
Hypoplasia of
organs
NSAIDS-
Premature closure
of ductus
arteriosus

RISK CATEGORY OF DRUGS DURING
PREGNANCY
Pregnancy
Category
Description
A
No risk :
Adequate and well-controlled human studies - Failed
to demonstrate a risk to the foetus
e.g. inj magnesium sulphate , thyroxine

Category Description
B
No evidence of risk in humans :
Animal reproduction studies - Failed to demonstrate a
risk to the foetus & no adequate and well-controlled studies in
pregnant women
OR
Animal studies have shown an adverse effect, but
adequate and well-controlled studies in pregnant women have
failed to demonstrate a risk to the foetus in any trimester.
E.g. Penicillin V, amoxicillin , cefaclor, erythromycin
paracetamol , lidocaine

C
Risk cannot be ruled out:
Animal reproduction studies have shown an adverse effect
on the foetus and there are no adequate and well-controlled
studies in pregnant women,
But potential benefits may warrant use of the drug in
pregnant women despite potential risks.
E.g morphine , codeine , atropine , corticosteroids
,adrenaline , thiopentone, bupivacaine

category Description
D
Benefit may outweigh potential risk:
Positive evidence of human foetal risk - on
adverse reaction data from investigational or
marketing experience or studies in humans,
But potential benefits may warrant use of
the drug in pregnant women despite potential risks .
E.g. aspirin , phenytoin , carbamazepine,
valproate, lorazepam , methotrexate

X
Contraindicated in Pregnancy:
Studies in animals or humans have
demonstrated foetal abnormalities
and/or
There is positive evidence of human foetal
risk based on adverse reaction data from
investigational or marketing experience, and the
risks involved in use of the drug in pregnant women
clearly outweigh potential benefits.
E.g oestrogens , isotretinoin ,
ergometrine, thalidomide.

10. Carcinogenecity and mutagenecity
Carcinogenecity -
Oxidation → reactive metabolites →
structural gene damage
e.g. Anticancer drugs , estrogens .

MUTAGENICITY
 Structural changes in DNA
 Oxidation of the drugs produces reactive
metabolites
 Covalent interaction with DNA
 Inheritable
 Takes 10-40 years to develop
 Anti cancer drugs, radioisotopes
 Usually marketed for life threatening conditions

11. Iatrogenic (Drug induced diseases) -
Examples -
a) NSAID'S → Peptic ulcers
b) Hydralazine → DLE
c) Phenothiazines → Parkinsonism
d) INH → Hepatitis

12. Drug Dependence - Use of drug produces a
state in which person believes that continuous use
is necessary for state of well being ( psychic
dependence) or to avoid withdrawal symptoms (
physical dependence.)
Psychological Physical
Here person believes
that state of wellbeing
achieved only with action
of drugs.
Here repeated administration
of drug required to maintain
physiological equilibrium
Discontinuation → withdrawl
e.g. Opiods ,
Benzodiazepins
e.g. Alcohol , Barbiturates ,
Benzodiazepins

PREVENTION OF ADR
1. Avoid all inappropriate use of drugs.
2. Use of appropriate dose , route & frequency of
drug administration.
3. Elicit & take into consideration previous history
of drug reactions.
4. Elicit h/o allergic diseases & exercise caution.
5. Rule out possibility of drug interaction.
6. Adopt correct drug administration technique.
7. Carry out appropriate laboratory investigation.
8. Be aware of interactions with certain
foods, alcohol and even with household
chemicals.

MANAGEMENT OF ADR
Discontinue the offending agent if -
 It can be safely stopped
 The event is life-threatening or intolerable
 There is a reasonable alternative
 Continuing the medication will further
exacerbate the patient’s condition
Continue the medication (modified as needed) if
-
 It is medically necessary
 There is no reasonable alternative
 The problem is mild and will resolve with
time

 Discontinue non-essential medications
 Administer appropriate treatment -
e.g., atropine,protamine sulfate ,digibind
antibodies, flumazenil.
 Provide supportive or palliative care -
e.g., hydration, glucocorticoids, warm / cold
compresses, analgesics or antipruritics
 Consider rechallenge or desensitization

PRINCIPLES OF DESCRIPTIVE TOXICITY
TESTING IN ANIMALS
1. Effects of chemicals produced in laboratory
animals when properly quantified apply to
human beings.
2. Exposure of experimental animals to toxic
agents in high doses – necessary & valid method
to discover possible hazards to human beings.

MANAGEMENT OF POISONING
A. Maintain vital & physiological functions from
impairment
B. Termination of exposure (decontamination)
C. Prevention of absorption of ingested
poison.(activated charcoal)
D. Hastening elimination
1. Urinary alkanlization
2. Multidose activated charcoal
3. Extracorporeal drug removal
E. Antidote therapy

PHARMACOVIGILANCE
Definition – Science and activities relating to
the detection ,assessment , understanding and
prevention of adverse effects or any other drug
related problems .
Activities involved in it
1. Postmarketing surveillance
2. Dissemination of ADR data
3. Changes in labelling of medicines

CAUSALITY ASSESSMENT
 Routine procedure in Pharmacovigilance
 Relationship of cause & effect
 Most outcomes : multiple interacting causes
 Aim : to define contribution due to drugs
 Problems:
 ADRs rarely specific
 Diagnostic tests usually absent
 Re challenge rarely ethically justified
Various methods: None is precise, reliable

Causality Assessment Methods
 Algorithmic: (algorithm - specify how to solve problem)
 Series of questions
 Answers are weighted
 Overall score determines causality category
 e.g. Naranjo’s scale
 Probalistic: (based on probability)
 Set of explicitly defined causality categories
 e.g. WHO UMC method
Uses of causality assessment
• Initial review of report
• Signal detection
• Scientific publications

THE NARANJO ADR PROBABILITY SCALE
Questions Yes No Don’t
Know
1) Are there previous conclusive reports on this
reaction?
+1 0 0
2) Did the ADR appear after the suspected drug
was administered?
+2 -1 0
3) Did the ADR improve when the drug was
discontinued?
+1 0 0
4) Did the ADR appear with re-challenge? +2 -1 0
5) Are there alternative causes for the ADR? -1 +2 0
6) Did the reaction appear when placebo was given? -1 +1 0
7) Was the drug detected in blood at toxic levels? +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 previous exposure?
+1 0 0
10) Was the ADR confirmed by any objective
evidence?
+1 0 0

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

CONCLUSION
 Every drug which has an effect has an adverse
effect every time a drug is given risk is involved.
 What is there that is not a poison ? all things are
poison & nothing is with out poison, solely dose
determines that a thing is not a poison.
 For rational use of drug not only its clinical
indications are important to be remembered
equally important is remembering adverse
effects.
 Early detection of adverse effects and its
proper management can be life saving in many
situations.

REFERENCES
 Goodman and Gilman's -12th The Pharmacological
basis of therapeutics
 Essentials of pharmacotherapeutics 5th edition –
F.S.K. Barar
 Essentials of Medical Pharmacology 7th
- K. D. Tripathi

WHY REPORT ADRS?
To prevent drug-induced human
suffering
 To avoid financial risks associated
with unexpected risks

June 22, 1963 as amended on May 22, 1987
Republic Act 3720 “Food, Drugs and Devices and
Cosmetics Act”
Creation of Food and Drug Administration now
Bureau of Food and Drugs
April 20, 1994
BFAD Memorandum Circular No. 5 s. 1994
Submission of ADR reports by pharmaceutical
establishments and parties concerned
June 30, 1994
Department Order No. 345 - I s. 1994
Creation of National Adverse Drug Reaction
Advisory Committee (NADRAC)
GOVERNMENT POLICY
ON ADR REPORTING

Reports
from
Participating
Hospitals
Reports
from
Private
Practitioners
Report
from
Drug Mfr.
Traders/
Outlets
Reports
on
Clinical
Investiga-
tions
Reports
from
Regulatory
Authorities
Reports
from
Int’l
ADR
Centers
BFAD ADR UNIT
NADRAC WHO Collaborating Center
Director - BFAD
Secretary of
Health - DOH
ADR Monitoring System

REPORTING SCHEME
NADRAC
(Trend Analysis)
CASE
Reporter Fills Out a Form
Hospital
Therapeutic Committees
ADRMP Office
(Central Database) WHO
WHO

THE PGH ADVERSE DRUG
REACTION REPORTING
SCHEME

HOW DO WE REPORT ADRS?
STEP 1 : Fill out the RED ALERT CARDS
PGH FORM # P – 60170
PGH ADVERSE DRUG SURVEILLANCE
ALERT CARD
(Clip this on chart front cover)
Name of patient:___________________________________
Ward & Bed No.:__________________________________
Name of suspect drug:______________________________
Manufacturer:_____________________________________
Lot/ Code No.:__________ (Retain empty vial or container)
Describe the reaction:_______________________________
_________________________________________________
_________________________________________________
Reporter: _________________________________________
(Please Print)
PLEASE NOTIFY: CENTRAL BLOCK PHARMACY
Loc. 3163 / 3170

STEP 2: Complete the ADR REPORT FORM
The Resident - in - charge of
the patient shall
complete the
necessary report of
ADR
circumstances.

 STEP 3: Submit the red alert card and the ADR
report form to the Central Block Pharmacy for
proper referral.
 STEP 4: The Pharmacy will then compile the reports
for review of the ADR Subcommittee and
submission to the Bureau of Food and Drugs
(BFAD).

The ADR Report Form should include the following:
 brand name of the suspect drug
 the manufacturer (if generic)
 the lot and batch number.
It should be done in duplicate.
ALL REPORTS ARE CONFIDENTIAL
IMPORTANT!!!!

COMMON REPORTS
RASH CAUSED BY OXACILLIN
RED FACE, FEVER SECONDARY TO VANCOMYCIN
UNCOMMON REPORTS
HAIR LOSS DUE TO ANTI THYROID AGENTS
NEUROLEPTIC MALIGNANT SYNDROME WITH
RISPERIDONE
Examples of Reported ADRs

TEN COMMANDMENTS TO REDUCE
ADVERSE DRUG REACTIONS
1. Critically review the total
condition of the patient. Be
particularly careful when you
prescribe to children, elderly,
seriously ill, pregnant patients
and those with renal, cardiac
or liver diseases.

TEN COMMANDMENTS to reduce
2. Use as few drugs as
possible. Balance the
seriousness of possible
reactions against the
beneficial effects of each
drug that is being
considered.

3. Know well the drugs that you use.
Compare the efficacy and
safety of each of the available
competitive medications that appear
to be worthy of consideration for the
patient.

4. Do not change too readily from one drug
you know to one you do not know. If you
decide to use a new drug, know that
drug.

5. Do not hesitate to use textbooks
and other references providing
information on drug reaction
and interaction.

6. Be especially careful when prescribing drugs
known to exhibit a large variety of reactions/
interactions.

7. Be aware of interactions with
certain foods, alcohol and
even with household
chemicals.

8. Regularly make an inventory of
the drugs your patient is receiving.

9. Review your patient regularly
for all the drugs used and
especially those bought without
prescriptions.

10. If your patient shows
signs and symptoms not
clearly explained by the
course of illness, think of
adverse drug reaction.

78,095
56,231
4,667
*
1
4
7
C
E
2
5
8
%
3
6
/
9
0
+
=
STATISTICS
 5% of adults are allergic to one or more
medications
 6 – 10% of ADRs result from a drug allergy
 3% of hospital admissions are due to ADRs
 28% of ADRs are preventable
 Drugs associated with ADRs: 29% analgesics,
10% sedatives, 9% antibiotics, and 7%
antipsychotics.
 PGH: Antibiotics (35%), anti-TB meds (34%),
anticonvulsants and ASA/NSAIDS (10%
each)

ADRS: 4TH LEADING CAUSE OF DEATH
Study: Drug reactions kill an estimated 100,000 a
year
 April 14, 1998

WHAT IS AN
ADVERSE DRUG EXPERIENCE?
 An undesirable drug effect, whether harmless,
resulting from medications administered in a
dosage normally given.
 It becomes an adverse drug reaction when it is
reported and subsequently evaluated to be
secondary to the drug usage.

Adverse drug reaction

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