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Introduction
Dr. G. Prayas , PharmD (PB)
‘All things are poisons and there is nothing that is
harmless …
the dose alone decides that something is a poison.’
(Paracelsus, 1500s)
 Medicinal substances or drugs are used to alter the
biological processes in the body.
 Uses of the medicinal substances carries on certain
risk of
unwanted or unintended effects.
 The use of the drugs in the patients depends on the
extend of it’s benefits balanced by the risk and

 The benefits and unwanted effects are recorded
during the clinical trials.
 This can give a signal or reasoned prediction of
medicines in patients.
 The observations and reporting of the unwanted
effects should be a routine activity that can
contribute to the better knowledge and better
medical treatment in the future.

 Adverse Drug Reaction (ADR): any noxious change
which is suspected to be due to a drug, occurs at dose
normally used in man, requires treatment or
decrease in dose or indicates caution in future use of
the same drug.

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

 The World Health Organization defines an
adverse drug reaction (ADR) as “a response to a
drug which is noxious and unintended, and
which occurs at doses normally used in man for
the prophylaxis, diagnosis, or therapy of disease,
or for the modification of physiological
function.”

Classification of ADRs
Depending on…..
 Onset of events: Acute (<60 mins), Subacute (1-24 hrs)
and
Latent (>2days)
 Types of reactions: Type A (Augmented), B
(Bizzare), C (Chemical), D (Delayed), E (Exit), F
(Familial), G (Genotoxicity), H (Hypersensitivity)
 Severity: Minor, Moderate, Severe, Lethal ADRs
 Others: side effects, secondary effects, toxic effects,
intolerance, idiosyncrasy, drug allergy,
photosensitivity, drug withdrawal reaction,
teratogenicity, carcinogenicity, drug induced
diseases (Iatrogenic)

 Mild ADRs: - minor type of ADR
- doesn’t require an antidote therapy or prolongation of
hospitalization for the treatment
- e.g. digestive disturbances, headache, fatigue
 Moderate ADRs: - requires change in but not necessarily
cessation of the
drug
- or may require prolong hospitalization
- or may require special treatment
- e.g. rashes, visual disturbances, muscle tremor,
mood
change
 Severe ADRs: - potentially life threatening, requiring
discontinuation of
drug or specific treatment of adverse
reaction
- e.g. liver failure, abnormal heart rhythm
 Lethal ADRs: - directly or indirectly contribute to death
- typically severe reactions that were not detected in

Classification of Adverse Drug Reaction
Rawlins and Thompson in the year 1977 classified the
ADR to Type A (Augmented) and Type B (Bizarre).
Type A (Augmented) reaction:
 This depends on the normal pharmacological actions
of the drugs.
 Caused by exaggeration of therapeutic effect due to
overdose or disease conditions like hepatic and renal
failure
 The type A reactions are predictable and thus
preventable and
are common
 Dose dependent
 Has low level of mortality but higher level of morbidity.
 E.g respiratory depression with
opioids bleeding with warfarin

Type A reactions (classes)
i) Toxicity of overdose (Drug
overdose)
An adverse drug reaction caused by
excessive dosing
e.g., hepatic failure with dose of
paracetamol Headache with
antihypertensives hypoglycemia with
sulfonylurea;

ii) Side Effects
Nearly unavoidable secondary drug
effect produced by therapeutic
doses
intensity is dose dependent
 Occur immediately after initially taking
drug or may not appear until weeks after
initiation of drug use
 E. g., Sedation with antihistamines
Bronchospasm with propranolol

iii) Drug Interactions
When two drugs taken together & they effect
each other’s response pharmacologically or
kinetically
 E.g., one drug slow metabolism of 2nd drug
blood conc.= toxicity
Theophylline toxicity in presence of
erythromycin

Type B (Bizzare) reaction:
 It is unrelated to the normal pharmacology of
the drug
 Dose independent
and
idiosyncratic
 Unpredictable and uncommon.
 Usually occurs due to
hypersensitivity
mechanism
 Low morbidity but mortality may be high.
 This accounts for many drugs withdrawn from market
 E.g  Hypersensitivity reactions, such as serious skin
rashes with lamotrigine
Anaphylaxis with Penicillin

Type B
Reactions
(classes
)
i) Drug Intolerance
Lower threshold to normal pharmacological
action of a drug
e.g., tinnitus (single average dose of aspirin)
ii) Hypersensitivity (immunological
reaction)
Immune mediated response to a drug
agent in sensitized patient
e.g., anaphylaxis with penicillin

iii) Idiosyncratic
Reactions
 A n uncommon & abnormal response to drug
Usually due to genetic abnormality
Affect drug metabolism & receptorsensitivity
Harmful even fatal, appear in low doses
E.g., Anemia (hemolysis) by
antioxidant drugs (G6PD deficiency) 
dapsone, isoniazid, rifampin (enzym
e
Paralysis due to
succinylcholine
Dr. Prayas Ghimire, Pharm

Type C
(Chronic):
- Occur with long term use;
- We l l known and can beanticipated
- Involves dose accumulation
- Adaptation occurs = discontinuation of drug = abstinence
syndrome
e.g Biphosphonates  osteonecrosis of the jaw
Benzodiazepines  Insomnia, anxiety following
withdrawl

Type D
(Delayed)
- Delayed in onset
- become apparent some time after the use of a medicine.
- Carcinogenic & teratogeniceffects
e.g Medication lead to cancer; take >20 y to develop
Drug- induced birth defects (birth defect that is evident
after birth
but the drug taken during 1st trimester of pregnancy)

19
Adverse Effects Vs Side Effects
 An adverse effect is an
undesirable and
unintended effect of a
drug. Adverse effects
are, then, always
harmful consequences
from the use of a drug.
 Side effect is an
imprecise term often
used to refer to a drug’s
unintended and
predictable effects that
occur within the
therapeutic range,
usually an undesirable
secondary effect.
 Unlike adverse effects,
side effects also have
potential to be
therapeutic too.

 Multiple Drug Therapy
- multiple drug therapy (prescription or over-the-counter
medicines)
 Increase the risk of ADR
 Age
- Infants and very young children  Inadequate capacity to
metabolize drugs  more risk to develop ADRs
- Older people  many health problems  under several
prescription and over-the counter drugs  elevate the risk of
ADRs
- Aging  reduce the hepatic metabolism and renal
elimination 
increasing the risk of kidney damage by a drug and other
ADRs
 Gender Dr. G. Prayas , PharmD (PB)
ADR Risk Factors

 Pregnancy and Breastfeeding
- pregnant women should not take any drugs, esp.
during 1st
and 3rd trimester.
-use of any prescription drugs, OTC drugs, and
dietary supplements during pregnancy requires
doctor’s supervision
 Co-morbid disease condition
-hepatic, renal failures, AIDS, etc  more prone to
develop ADRs
 Drug allergy
-individuals sensitive to particular drug 
immunological reactions  develop allergic
reactions like rashes, serum sickness, angioedema,
bronchospasm, anaphylaxis etc

 Others
 Inappropriate medication prescribing, use or
monitoring
 End-organ dysfunction
 Altered physiology
 Prior history of ADRs
 Extent and duration of exposure
 Genetic predisposition

Consequences of ADRs
 Adversely affects patients’ quality of life
 Complicate drug therapy
 Decrease compliance and delay cure
 Increase cost of patient care
 Cause patients to lose confidence in their
doctors
 May mimic disease, resulting in
unnecessary investigations and delay
in treatment

Who is most at risk from ADRs?
Patients who:
 are young, or old or female
 are taking multiple therapies
 50% of patients on 5 drugs or more
 have more than one medical problem
 have a history of allergy or a previous reaction to
drugs

What should raise suspicion of an ADR?
A symptom that….
 appears soon after a new drug is
started
 appears after a dosage increase
 disappears when the drug is
stopped
 reappears when a drug is restarted

Monitoring of ADRs
 Identifying Adverse Drug Reaction
 Assessing Causality (Relationship between
drug and suspected reaction)
 Documentation of ADR
 Reporting Serious ADRs to
Pharmacovigilance centers/ADR
regulating authorities

A) Identifying Adverse Drug
Reaction
Type of Post Marketing Surveillance Description
Anecdotal Reporting Clinicians encourage reporting any or all reactions
that believe may be associated with drug use
usually, attention is focused on new drugs and
serious ADRs
Population Statistics
Registers of Birth defects and cancer can be used if
the drug induced event is highly remarkable or
very frequent
Intensive Monitoring Studies
Special trained health care professionals devote
their full time efforts towards
recording all the drugs administered and all the
events, which might possibly be drug induced
Cohort studies
(Prospective studies)
Dr. Prayas Ghimire,
Pha
In these studies, patients taking a particular drug are
identified and events are then recorded
rm D.

Type of Post Marketing
Surveillance
Description
Case cohort studies
Patients who present with symptoms or an illness that could
be due to an adverse drug reaction are screened to see if they
have taken the drug. The results are then compared with the
incidence of the symptoms or illness in a prospective cohort of
patients who are taking the drug.
Record linkage
Brings together a variety of patient records like general
practice records of illness events and general records of
prescriptions. In this way it may be possible to match illness
events with the drugs prescribed

B) Causality Assessment Between Drug
and Suspected reaction
Assessment performed by usually 2 methods include:
 Clinical Judgment
An individual who is an expert in the area of ADRs
would evaluate the case
 Algorithms
Commonly used algorithm is the Naranjo algorithm

Naranjo’s
Algorithm
Question Yes No Don’t Know
1. Are there previous conclusive reports on this
reaction?
+1 0 0
2. Did the adverse event appear the suspected drug was
administered?
+2 -1 0
3. Did the adverse reaction improve when the drug was
discontinued or a specific antagonist was administered? +1 0 0
4. Did the adverse reaction reappear when the drug was
re-administered?
+2 -1 0
5. Are there alternative causes (other than the drug)
that could on their own have caused the reaction? -1 +2 0
6. Did the reaction reappear when a placebo was
given?
-1 +1 0
7. Was the drug detected in the blood (or other fluids)
in concentrations known to be toxic?
+1 0 0

Question Yes No Don’t Know
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 drugs in any previous exposure?
+1 0 0
10. Was the adverse event confirmed by any objective
evidence?
+1 0 0
Total Score
The total score calculated from this table defines the category an
adverse reaction belongs to the categories are defined as
follows:
• Definite(Certain)  (total score>8)
• Probable  (total score 5-8)
• Possible  (total score1-4)
• Doubtful(Unlikely)  (total score <1)

C) Documentation of
ADRs
Diagnostic
Documents used for Reporting ADRs:
 Source Documentation
eg. Patient's Medical Records, X-Ray or
Reports
 AE/SAE Forms
 Paper Case Report Form (CRF)/ Electronic CRF

D) Reporting Serious
ADRs
Information to be Captured for Reporting includes the
following:
 Patient details
Initials
Gender
Age and date of birth
Weight
Height

 Suspected drugs
Generic name of the drug
Indication(s) for which suspect drug was prescribed or
tested
Dosage form and strength
Daily dose and regimen (specify units - e.g., mg, ml,
mg/kg)
Route of administration
Starting date and time of day
Stopping date and time, or duration of treatment
 Other Treatment(s)
Concomitant drugs

 Details of Suspected Adverse Drug Reaction(s)
 Full description of reaction(s) including body site and
severity, as well as the criteria for regarding the report as
serious,whenever possible, describe a specific diagnosis for
the reaction
 Start date (and time) of onset of reaction
 Stop date (and time) or duration of reaction
 Outcome
 Information on recovery; results of specific tests and/or
treatment
 For a fatal outcome, cause of death and its possible
relationship to the suspected reaction; any post-mortem
findings
 Any Other information relevant to facilitate assessment of
the case, such as medical
 history of allergy, drug or alcohol abuse; family history;
findings from special investigations etc

 Details about the Investigator
Name
Address
Telephone number
Profession (speciality)
Date of reporting the event to Licensing
Authority
Date of reporting the event to Ethics
Committee overseeing the site
Signature of the Investigator

Role of Pharmacist in ADR
monitoring
 Identification and Documentation
 Monitoring and Reporting
 Prevention
Pharmacists should facilitate:
- analysis of each reported ADRs
- identification of drugs and patient at risk
-development of policies and procedures for
ADR monitoring
- interaction between physicians, nurses and
pharmacists
- educational purposes

Impact on Health Care Cost
 Accounts for 5-10% of all hospital admissions
 Occurs in 10-20% of hospital inpatients
 Causes deaths in 0.1% of medical and 0.01% of
surgical inpatients
 Adversely affect patients’ quality of life
 Causes patients to lose confidence in their
doctors
 Increase cost of patient care
 May mimic disease, resulting in
unnecessary investigation and delay in
treatment

Prevention of ADRs
1. Avoid inappropriate drugs in context of
clinical conditions
2. Use right dose, route, frequency based on
patient variables
3. Elicit medication history
4. Elicit history of allergy
5. Rule out drug interactions
6. Carry out appropriate monitoring ( e.g. PT
with warfarin)

Management of ADRs
1. Discontinue the offending agent
2. Discontinue non-essential medication
3. Administer appropriate treatment
4. Provide supportive or palliative care
 Generally,
- For dose-related ADRs  Modify the dose or
reduce
precipitating factors
-For ADRs unrelated to dose  The drug usually
should be withdrawn and reexposure should be
avoided.

44
Preventability Assessment Scale
• According to WHO factsheet, it is estimated that at least 60% of ADRs are
preventable. In some countries ADR-related costs, such as hospitalization,
surgery and lost productivity, exceed the cost of the medications.
• Historically, studies have shown that between 20% and 80% of ADEs and
ADRs are preventable with the majority of latter studies showing around 60-
70% preventability.
• Preventability of ADRs is assessed by using Schumock andThornton scale

45

PHARMOCOVIGILANCE
 “ science and activities relating to the detection,
assessment, understanding and prevention of ADRs or
other drug related problems.” (WHO)
 Pharmakon (Gree k)  drug
vigilare (latin)  keep watch
 Medication errors (overdose, and misuse and abuse of a
drug)
 ADR
 Pharmacovigilance is an essential acivity since:
- clinical trials use very less samples of patients
- these patients are not treated for a sufficiently long
peroid of
time to detect all the adverse effects of the medications
-other adverse reactions may be rare or delayed or result
from interactions with other drugs, or may only affect a

Necessity of Pharmacovigilance
 Use of alternative medicine is very common in
Nepal
 There are different races of
population in Nepal having different
genetic makeup
 Self medication is one of the common cause of
ADRs in Nepal
 There is no mandatory requirements for clinical
trial data to be submitted to the drug regulatory
authority prior to
exact risk
of
drug registrationin Nepal. Thus
the occurrence of ADRs is unknown
 There is very less safety data on the
drugs

National Pharmacovigilance Program
in Nepal
 Concept of ADR monitoring and
pharmacovigilance is new to Nepal
 DDA has taken steps to establish an ADR
monitoring program
 In 2006, Nepal was given full member status by
the Uppsala Monitoring Center (Sweden), the
WHO collaborating center for International Drug
Monitoring
 The Ministry of Health and Population has
designated DDA as the national center for ADR
monitoring
 DDA has established regional centers that

 At present, regional pharmacovigilance program in Nepal:
1. Tribhuvan University Teaching Hospital (TUTH),
Maharajgunj
2. Nepal Medical College Teaching Hospital (NMCTH), Jorpati
3. KIST Medical College, Lalitpur
4. Manipal Teaching Hospital, Pokhara
5. Civil Service Hospital, Minbhawan
6. Patan Hospital, Lalitpur
7. BPKIHS, Dharan
8. Dhulikhel Hospital, Banepa
9. Shree Birendra Hospital, Chauni
10. Norvic International, Thapathali
11. Nepal Cancer Hospital and Research Center, Harisiddhi
The regional centers report the ADRs to the national center
via a web
based system for ADR management called “Vigi-flow”

Uppsala Monitoring Center
(WHO), at Sweden
National Pharmacovigilance
Center, DDA
Regional Pharmacovigilance
Centers
Hospitals
Pyramid of ADR reporting system in Nepal

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