Introduction to adverse drug reactions  Definitions and classification of ADRs  Detection and reporting  Methods in Causality assessment  Severity and seriousness assessment  Predictability and preventability assessment  Management of adverse drug reactions

1. PHARMACOVIGILANCE
MISS. GAYATRI K. BAHATKAR
ASSISTANT PROFESSOR
P. R. PATIL INSTITUTE OF PHARMACY , TALEGOAN
SP.

2. INTRODUCTION TO ADVERSE DRUG
REACTIONS
• Adverse drug reactions (ADRs) is an unwanted, undesirable effect of
a medicine that occurs during usual clinical application. It occurs
almost daily in health care institutions and can adversely affect a
patient’s quality of life; sometimes may lead to considerable
morbidity and mortality. Much attention has been given to identify
The patient populations most at risk, The drugs most commonly
responsible, and The potential causes of ADRs.
The factors responsible for the prevalence of ADRs worldwide are:
• Increase in the number of drugs in the market,
• An aging population, and
• An upward trend in polypharmacy.

3. • The difference between ADRS and ADES is that ADRs can occur even
after appropriate prescription and correct dosing. ADES are
generally associated with inappropriate use of the drug that usually
occurs during drug therapy. It may not be related to the
pharmacology o the drug itself. Adverse drug events (ADES) may
occur due to medication errors. The National Coordinating Council
for Medication Error Reporting and Prevention (NCC MERP) has
defined the medication errors as: “any preventable event that may
cause or lead inappropriate medication use or patient harm while
the medication is in the control of the Health care professional,
patient, or consumer.

4. Objectives of ADRs Monitoring
• (A) To help the drug regulatory authority, public health programmes, scientists
and consumers for taking appropriate action to reduce the risks of ADRs. It is
also necessary to find out the nature and frequency of ADRs with periodical
check of the benefit-risk ratio of medicinal products. The benefit-risk ratio of
medicinal products can be re for evaluated by:
• Providing updated drug safety information to health care professionals and other
stakeholders including WHO ADRs Monitoring Centers.
• Updating information in package and disseminating information which may result
recall or withdrawal of the product in the market or restrictions for marketing.
• Propagating information for designing proper education programme to
consumers and other users.
• Taking initiative to study the effect of a for further education. For example
benefit of the drug especially in long term for prevention of relapse or study of
new indication, overuse, possible mechanism underlying the adverse reaction
observed or misuse.

5. • (B) To identify the risk factors that may affect, induce or influence
the development, severity and incidence of adverse reactions in the
population; for example,
• 1 Patient factors such as genetics, racial differences, diets,
diseases, prescribing Practices, pattern of drug use and food habits
(high carbohydrate, fat diet etc.).
• 2. Drug interactions, drug distribution, storage and use including
indications, dose. Availability and other underlying conditions.
• Due to adverse drug reactions the patients may lose confidence in
the therapy or may show negative towards their physicians and may
look for self-treatment options. As a result additional ADRS may
not be observed. About 5% of the hospital admissions are the result
of an ADR, and at least one ADR would be found in about 10%-20%
of inpatients during their stay in hospitals. The actual frequency of
ADRS may be even greater than the above values. Because some

6. • Some ADRs present minor symptoms, others are serious and cause death
in as many as 0.1%-0.3% of hospitalized patients.
• Adverse drug reactions should be identified and managed as early as
possible to reduce their harmful effects on the patients. The cost of
managing ADRs can be high, whether they occur in the inpatients or the
outpatients. The clinical diagnosis of an ADR is not always observable.
Practitioners often advise Additional laboratory tests or procedures to
investigate the cause of a patient’s symptoms.
• Practitioners may also prescribe pharmacotherapy for conditions caused
by an unrecognized ADR. This increases the cost of treatment as well as
the risk of additional ADRs.
• If the ADR occurs when the patient is hospitalized, the duration of stay
can be increased and overall cost of treatment may also increase.
• Due to ADRs the anxiety or depression and loss of working days for the
Patient and/or Caregiver may take place, as a result additional indirect
cost may increase.

7. • The study of drug-related injuries and making warning or
withdrawal recommendations for pharmaceutical agents are the
major activities of pharmacovigilance; however, it includes
assessment, understanding, and prevention of ADRs.
• Pharmacists play a vital role in each step of the pharmacovigilance
activity; so that the Patients need not require unnecessary
procedures or take unnecessary drugs so that safety And quality of
life for the patient can be preserved.

8. DEFINITIONS AND CLASSIFICATION OF ADRS
• According to the World Health Organization (WHO) an ADR is
defined as "a response to a drug which is noxious and undesired
and which occurs at normal doses when used in man for
prophylaxis, diagnosis, or therapy of disease or for the
modification of physiologic function. Thus, an ADR is a type of ADE
whose cause can be directly related to a drug and its physiologic
properties.
• In many cases it may be observed that a particular patient develops
an adverse drug reaction, while another patient does not. There is
no specific reason for this. There are some relatively toxic drugs
which show adverse reactions in most cases. This can be
considered as the rule rather than the exception. Four special

9. • comprising inherent anomalies in patient response (allergic or
idiosyncratic),
• Acquired patient anomalies,
• Anomalies of drug presentation, and
• Anomalies in administration, and interactions.
Etiology
• Most of the adverse drug reaction and dose related . Others are
allergic or idiosyncratic dose- related ADRs are usually predictable
• Dose related ADRs are particularly of concern when drug have
narrow therapeutic index. For example, haemorrhage and oral
anticoagulant . ADRs may occurs due to decreased drug clearance
in patient with impaired renal or hepatic function due to drug drug

10. • Allergic ADRs are not dose-related and require prior exposure.
Allergies develop when a drug acts as an antigen or allergen. After
a patient is sensitized, subsequent exposure to the drug produces
one of several different types of allergic reaction. Clinical history
and appropriate skin tests can sometimes help to predict allergic
ADRs.
• Idiosyncratic ADRs are unexpected ADRs that are not dose-related
or allergic. They occur in small number of patients when a drug is
administered. Idiosyncrasy is not a precise term. It is defined as a
genetically determined abnormal response to a drug. However, all
idiosyncratic reactions do not have a pharmacogenetic cause. The
term may become obsolete when specific mechanisms of ADRS are
known.

11. CLASSIFICATION OF ADRS
• Drug induced ADRS are classified on the basis of:
1.Pharmacological mechanism, and
2.Their preventability.
Pharmacological mechanism
This is relatively simple method of classification. It was proposed by Rawlins in the
year 1981 and was widely accepted. According to this method, adverse drug
reactions (ADRs) are of two types – Type A and Type B. Characteristics of Type A
effect are dose related and predictable. Most of the predictable characteristics
would be either understood before registration or before marketing. While Type B
ADRS are not dose related, unpredictable and can be known after marketing.
Predictable ADRs can be classified on the basis of:
• Over doses,
• Adverse effects,

12. • Drug-drug interaction, and
• Drug-disease interaction.
Unpredictable ADRs may happen due to:
• Intolerance,
• Allergy,
• Pseudo-allergy, and
• Idiosyncrasy.
However, there are other methods of classification of ADRs. These
including Type A and Type B classification are tabulated below.
Classification according to Rawlins is shown below.

13. Type of reaction Mnemonic Features Example Mangement
Type A- Dose related Augmented • Predictable
• Related to
pharmacological
action
• Low mortality and
common
• Toxic effect-
Digoxin toxicity,
serotonin
syndrome
• Side effect-
anticholinergic
effect of tricyclic
antidepressant
• Reduced
dose
• With hold
• Consider
effects of
concomitant
therapy
Type B- non dose
related
Bizarre • Uncommon
• Not related to
phycological
action of drug
• Unpredictable
• High mortality
• Immunological
reaction –
penicillin
hypersensitivity
• Idiosyncratic
reaction-acute
porphyria ,
malignant
hyperthermia
• With hold
• Avoid in
future
Type C- dose related
and time related
Chronic • Uncommon
• Related to
cumulative dose
Hypothalamic
pituitary adrenal
axis Suppression
by corticosteroids
• Reduce dose
• Withhold
• Withdrawal
prolonged

14. Type D – time
related
Delayed • Uncommon
• Usually dose related
• Occurs or become
apparent sometime
after use of drug
Teratogenesis
carcinogenesis
Tardive dyskinesia
Often difficult to
manage
Type E-
withdrawal
End of
use
• Uncommon
• Occurs some after
• Withdrawal of drug
• Opiate
withdrawal
syndrome
• Myocardial
ischemia
Reintroduced or
Withdraw slowly
Type F-
unexacted
failure of
therapy
Failure • Common
• Dose related
• Often caused by drug
interaction
• Oral
contraceptive
when used with
enzyme inducer
• Increased
dose
• Consider
effect of
concomitant
therapy

15. Features Type A Type B
Pharmacology Augmented Strange
Predictable Yes No
Dose- dependent Yes No
Morbidity High Low
Mortility low High
Predictable ( dose- dependant)
Over dose Toxic reaction to specific organ system due to excessive
dose or impaired excretion
Adverse
effect
Undesirable pharmacologic effects by mechanisms related
to the desired effects.
Drug drug
interaction
Action of the drug on the effectiveness or toxicity of
another drug
Drug
disease
interaction
Some disease processes interfere with metabolism or
action of a drug

16. Unpredictable ( dose independent )
Intolerance Overstated, sometimes disabling effects even when the
drug is given in Usual doses
Idiosyncrasy Abnormal reactions to a drug related to metabolic or
enzyme deficiency Which can be genetically determined,
or altered activation/detoxification Pathways.
Allergy Reaction is Specific to a given Drug, Severe, Recurrent
And Immunologically mediated
Pseudo-allergy Clinically it is similar to allergic reactions, but involves an
unknown immune mechanism

17. PHARMACOLOGICAL CLASSIFICATION ACCORDING
TO GRUCHALLA
Type of ADRs Example
Type A reactions: predictable
Toxicity or overdose Hepatic failure with high-dose paracetamol.
Side effects Sedations with antihistamines.
Secondary effect Diarrhea with antibiotic such as Ampicillin due to alteration of
Gastrointestinal bacterial flora.
Drug interaction Toxicity of theophylline in presence of erythromycin therapy.
Type B reaction : unpredictable
Intolerance Tinnitus with use of aspirin.
Idiosyncratic reaction Occurrence of anemia with use of an antioxidant drug in Presence
of glucose-6-phosphate dehydrogenase deficiency.
Immunological
Hypersensitivity
reaction
Anaphylaxis with penicillin administration.
Pseudo-allergic
reaction (non
immunological)
Radio contrast dye reaction.

18. PHARMACOLOGICAL CLASSIFICATION ACCORDING
TO GHARAIBEH:
Feature Type 1 Type 2
Synonyms Augmented, predictable, Toxic,
quantitative, dose Related.
Strange, unpredictable,
idiosyncratic, allergic, drug-
intolerance, qualitative, Dose-
independent.
Mechanism Understood, predictable Generally poorly understood
Site (a)Same site of primary drug action
(b)another site for primary and
secondary actions
Usually the site of action is not
Related
Incidence High (70%) Low (30%)
Morbidity Severe Mortality
Mortality Low High
Causes
Pharmaceutica
l dosage form
Increased availability at the site of
absorption: quantity and release of
dosage form
Decomposition products,
additives excipients, etc.
Pharmacokine
tic
Amount of drug Increased at the
site of action due to
Abnormalities in ADME
Liberation of an abnormal
metabolite

19. Pharmacodynamic (a)Response of organ or
tissue increased due to
number sensitivity of
receptors
(b) Homeostatic imbalance
(C)Diseases state
(a) Genetic
(b) Immunologic
(c) Neoplastic
(d) Teratologic
Reproducibility Reproducible Not reproducible
Treatment Dose to be adjusted Treatment to be discontinued

20. PHARMACOLOGICAL CLASSIFICATION ACCORDING
TO ROYER & STEPHENS
Type Characteristics
Type A Reactions that result from exaggerated pharmacological action of a drug
given as normal therapeutic doses usually dose dependent. Sometimes
referred to as Type 1.
Type B Represents a new or novel response different from usual pharmacologic
action – sometimes referred to as Type 2.
Type C Adaptive changes, rebound phenomena, other long-term effects
Type D Carcinogenesis, effects concerned with reproduction (impaired fertility).
Teratogenesis (adverse effects on the fetus during early stages of
pregnancy), adverse effects on the fetus during later stages of pregnancy,
drug in breast milk.

21. PHARMACOLOGICAL CLASSIFICATION
ACCORDING TO WILLS & BROWN:
Type Characteristics
A Dose related, pharmacologically predictable, commonly improves after
Withdrawal of medicine.
B Involves interaction with a microorganism, pharmacologically predictable,
commonly improves after withdrawal of medicine.
C An Irritant reaction, related to concentration of a drug
D Depends on the route of administration or nature of formulation, improves if
the medicine is withdrawn or route of administration is Changed.
E Begins when medicine is Stopped Or The Dose Reduced, Pharmacologically
predictable
F Occurs only in those genetically predisposed, improves if the medicine is
Withdrawn.
G Causes irreversible genetic damage.
H Requires activation of immune system, improves if the medicine is withdrawn.
U Mechanism is not understood