adverse drug reactins notes in detail summary

Adverse Drug Reaction
“Any response to drug, which is noxious &
unintended which occurs at doses normally
used for treatment, prophylaxis, diagnosis,
or modification of physiological function.”

Adverse Drug Event
“Any untoward medical occurrence that
may present during treatment with
medicine but does not necessary have
causal relationship with the treatment. “

Serious adverse event
Any untoward medical occurrence,
that at any dose;
Results in death
Requires hospitalization or prolongation of existing
hospitalization
Results in persistent significant disability or incapacity
Requires intervention to prevent permanent injury

 From the earliest times, pharmaceutical
formulations have been recognized as
being potentially dangerous.
 Everytime we give a drug we take a risk
 Public and professional concern about
these matters first arose in the late 19th
century.
 In 1922, there was an enquiry into the
JAUNDICE associated with the use of
SALVARSAN, an organic arsenical used

 In 1937 in USA,
107 people died from taking
an Elixir Of Sulfalinamide
that contained the Solvent
Di-ethylene Glycol
This led to establishment of FOOD AND DRUG
ADMINISTRATION (FDA), which was given the
task of enquiring into the safety of new drugs
before allowing them to be marketed

 In 1961, it was reported in West
Germany that there was an outbreak of
PHOCOMELIA (hypoplastic and
aplastic limb deformities) in the new
born babies.

 The Thalidomide Incident led to
development of a much more
sophisticated approach to preclinical
testing & clinical evaluation of drugs
before marketing, & greatly increased
awareness of adverse effect of
drugs and methods of detecting
them.

Importance of ADR’S in
Therapeutics

Incidence
Hospital in-patients:10-20%
Deaths in hospital in-patients: 0.3-3%
Hospital admissions: 0.3-5%
Worldwide – ADRs: 6th leading cause
of
death
US and Canada – ADRs: 4th leading
cause of death

Why incidence is more ?
1) Ever-increasing number of new drugs
in the market
2) Number of drugs prescribed are high
3) Medication errors
4) Lack of awareness of a system for
reporting ADR’S

Common causes
 Failing to take the correct dose 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

Factors affecting Adverse Drug
Reactions :
 Age
 Genetic influences
 Concurrent diseases (Renal, Liver,
Cardiac)
 Previous adverse drug reactions
 Compliance with dosing regimen
 Total number of medications
 Misc. (diet, smoking, environmental
exposure)

Rawlins and Thompson classification -1991
Type A Predictable
-More Common(80%)
-Augmented normal
response
-Dose dependent
-Hypo/Hyper response
Type B Unpredictable
-Less common (6-10%)
-Abnormal/bizarre
response
-Dose Independent
-Genetic/Immunological

Type A Predictable
-Low Mortality
-d/t Pharmacological
activity of drug
-Rx : Dose Adjustment
Eg., S/E, Toxic effect,
Withdrawal effect
Diarrhea due to antibiotics
Type B Unpredictable
-High Mortality
-d/t Patient peculiarities
-Rx : Withdrawal of drug
Eg., Allergy, Idiosyncrasy
Hypersensitivity to penicillin
Types of ADR’s – Contd…

Type C (Chronic)
- Reactions due to prolonged use of the
Drug.
e.g. HPA axis suppression by
corticosteroids

Type D (Delayed)
• Occuring years after the treatment
• Can be due to accumulation
E.g : Teratogenisis

Type E (End of use)
• Occur on withdrawal especially when
drug is stopped abruptly
E.g.
• Precipitation of MI by β blocker
withdrawl

Type F (Failure of drug)
 Underdosing of medications
 Drug interactions
Eg: OCP failure

Type Mnemonic Example
A Augmented Diarrohea due to antibiotics
B Bizzare Hypersensitivity due to penicillin
C Chronic Steroid decrease HPA axis
D Delayed Teratogenicity, carcinogenesis
E End of use Precipitation of MI by β blocker
withdrawl
F Failure OCP failure
Types of ADR’s in Brief:

Mild No need of Rx, antidote or Hospitalization
Moderate Requires drug change specific
Rx, hospitalization
Severe Potentially life threatening;
permanent damage, and prolonged hospitalization.
Lethal Directly or indirectly leads to
death
ADR Grading

“Unwanted but often unavoidable
pharmacodynamic effects of a drug at
therapeutic doses”
As Extension of therapeutic effect
Atropine - dry mouth
As distinctly different effect
Promethazine – Sedation.
Side effect exploited for therapeutic use
Codeine – Diarrhoea
1) SIDE EFFECTS

“Indirect consequence of Primary action of
a drug”
Eg:
- Tetracycline : Superinfection
- Corticosteroids : Activation of latent
Tuberculosis
2)SECONDARY EFFECTS

“Excessive pharmacological action of a
drug due to over dosage or prolonged
use”
Eg:
- Functional alteration : Atropine - delirium
- Drug induced tissue damage : PCM –
Hepatic necrosis
- Extension of therapeutic effect :
Barbiturates – Coma
- Another action : Morphine – Respiratory
failure
3) TOXIC EFFECTS

“Appearance of characteristic toxic
effects of a drug at therapeutic doses”
Eg.,
 Triflupromazine (single dose) - Muscular
dystonia
 Carbamazepine (few doses)– Ataxia
 Chloroquine (single dose) - Vomiting
4)INTOLERANCE

 Unusual response to a drug due to genetic
abnormality.
 Drug interacts with some unique feature of the
individual, not found in majority subjects, and
produces the uncharacteristic reaction.
E.g.
Isoniazid: N-Acetylation affects the metabolism of
isoniazid
Slow N-Acetylation: Isoniazid is more likely to cause
peripheral neuritis
Fast N-Acetylation: cause hepatotoxicity in this group
5) IDIOSYNCRASY

6) Photosensitivity
Phototoxic Photoallergic
 Photochemical / biological
Reaction
 UV - B
 Hyperpigmentation &
desquamation
 Eg. Acute – Tetracyclines
 Chronic – Nalidixic acid,
FQs, sulfonamides,
phenothiazines, thiazides,
Amiodarone
 Cell mediated immune
response
 UV - A
 Papular & eczematous,
flare & wheal
 Eg., Sulphonamides,
sulphonylureas,
griseofulvin, chloroquine,
CPZ

 US FDA graded documentation of risk for
causing birth defects into five categories
ABCDX
 Avoid all drugs unless benefits
outweighs the risks
Eg: Phenytoin – cleft palate
Valproate – Spina bifida
Aspirin – premature closure of ductus
arteriosus
7)TERATOGENECITY

8) Drug Allergy
◦ Acquired, altered reaction of the body to
drug.
◦ Immunologically mediated reaction.
◦ occur even with much smaller doses
◦ Also called Drug hypersensitivity
◦ Not genetic, not occur in all
◦ Occurs on re-exposure
◦ E.g. penicillin→1st time →stimulate
antibody →Ag-Ab reaction →allergy
◦ Chief organ: Skin, respiratory tract, GIT,
Blood & blood vessels

Type of
reaction
Time
before
clinical
sign
Characteristics Example
Anaphylactic
(Immediate
IgE-mediated
anaphylaxis)
< 30 min
IgE binds to must cell or
basophil,causes degranulation of
must cell & basophil& release of
reactive subs. histamine
Penicillin
anaphylaxis
Cytotoxic
(Antibody-
Dependent
Cellular
Cytotoxicity
5 –
12 hr
Antigen cause formation of IgG or
IgM antibodies to bind that .
Drug forms an antigenic complex
with the surface of the cell and
combination with antibody activate
complement system causing cell
destruction.
Hemolytic anemia:
Penicillin or
Methyldopa
Thrombocytopenia
: Quinidine
SLE:Hydralazine
or Procainamide.
Immune
complex
mediated
8-10 antigen antibody form complexes
that causes inflammation
Steven-Johnson
Syn
Serum Sickness
Cell mediated
allergy(delaye
d type)
24 to
48 hrs
Antigen specific receptors develop
on T-lymphocytes. Subsequent
administration leads to local or
tissue allergy.
Contact dermatitis
Rejection of
transplanted
tissue

9)Tachyphylaxis
 When responsiveness diminishes rapidly after
administration of a drug, the response is said
to be subject to tachyphylaxis.
 Tyramine can cause depletion of all NE
stores if we use it repeatedly at short
interval, resulting in tachyphylaxis.

10) Drug dependence
 Drugs capable of altering mood and feelings
are liable for 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.
 E.g. Opioids, Barbiturates, Alcohol,

11) Mutagenicity and Carcinogenicity
 Capacity of a drug to cause genetic defects and
cancer respectively.
 Chemical carcinogenesis generally takes several
(10-40) years to develop.
 Unpredictable
e.g.
 Estrogen- Endometrial carcinoma.
 OCP- Ca cervix, breast Ca
 Iron S/C or I/M – blackening of area – increase
incidence of sarcoma (cause is unknown).
 Anticancer drug.

Organ Specific ADR’S
Hemopoietic system & bone marrow
Liver damage/ Hepatic injury
Renal damage

Sr.
No.
Drugs ADR’S
1 Quinine, Rifampicin, Sulfonamide,
Thiazide
Thrombocytopenia.
2 Carbamazepine, Sulfonamide,
carbimazole, clozapine
fatal neutropenia ,
drug allergy (type II
reaction),
Granulocytopenia
3 Chloramphenicol Aplastic anemia
4 Anti cancer, cytotoxic drugs direct bone marrow
depression
5 primaquine, quinine, chloroquine,
dapsone, sulfonamide(due to
idiosyncracy) Methyldopa used in
pregnancy
Hemolytic anemia
Hemopoietic system & bone
marrow

 Chloroform, Halothane,
Enflurane
 Chlorpromazine,
Flucloxacillin, OCP
 INH, Rifampicin,
Methyldopa
 Methotrexate, Alcohol
 Paracetamol overdose
(8–10 gm of paracetamol
in 10–24 hours if taken)
 Minocycline (newer
tetracycline)
Liver damage/ Hepatic injury –
When given in repeated dose –
hepatotoxicity – jaundice
Cholestatic jaundice
Hepatocellular necrosis – jaundice
Cirrhosis of liver.
Toxic metabolite (Epoxide):
Hepatocellular necrosis.
Chronic Active Hepatitis.

 Phenylbutazone, Sulfonamide, Hydralazine :
Glomerulonephritis.
 Aminoglycoside (Gentamicin), Amphotericin,
High dose paracetamol, Cefalothin : Acute
tubular necrosis.
 NSAID, Lithium, Penicillamine – long term use in
rheumatoid arthritis – Acute interstitial nephritis.
 ACEI – Renal vascular damage.
Renal damage –

Who can get an ADR?
Anyone who takes medicine
Differential diagnosis should
include the possibility of an
ADR if the patient is taking any
form of medication

If symptoms,
Appears soon after a new drug is
started
Appears after an increase in dose
Disappears when the drug is
stopped
Reappears when a drug is restarted
When To Report :

Pharmacovigilance
The science and activities relating to
detection, assessment, understanding
& prevention of adverse effects or any
other drug related problem
- WHO 1972
Why Pharmacovigilance ?
Humanitarian concerns “First do no harm”
Reduce disease related economic loss
Check if drugs available in market fulfill
their intended role in society.

ADR Monitoring in India
 1980- Concept of Pharmacovigilance in India
 1982- 5 Centers established by DCGI for
nationwide monitoring of ADR
 1987- ICMR establishes many centers for
nationwide monitoring of ADR
 Nov. 2004- National Pharmacovigilance
programme was started consisting of national
centers, 2 zonal centers, 5 regional centers and 28
peripheral centers

GMC,NAGPUR
 Recognized in dec.2012
 Started reporting from 2013
 No. of cases reported:
2013-77
2014-388
2015-347
2016-162

Why is ADR Monitoring Needed?
 Unreliability of pre-clinical studies
 Limitations of pre-marketing phases of clinical
trial
 Aggressive marketing strategies of
pharmaceutical companies
 Changing physician and patient preference
 Easy accessibility of drugs

Limitations of pre-marketing phases
of clinical trial
 Conducted in strictly controlled
conditions, in highly selected and
limited number of patients
 Fails to detect rare and delayed ADRs
 Do not provide data –
- In children, elderly patients,
pregnant/lactating women
- In patient suffering from other
disease
- In patient receiving other drugs
- On interpopulation difference

Various reporting systems are-
 WHO international system(Uppsala
monitoring centre, Sweden)
 US FDA "Med watch"
 UK "Yellow card system"
 PvPI under CDSCO, India

• Doctors
• Dentists
• Nurses
• Pharmacists
Health care
professiona
ls
• Patients
• Consumers
• Relatives
Others
Who can report
??

Problems in ADR reporting
Patient Related
(i) Cannot
recognize ADR
(ii) Recognize but
do not report
(iii) Illiteracy
Health proffesional
Related
(i) Cannot recognize ADR
(ii) Recognize but do not
report due to
- Lack of time
- Hesitancy
- Ignorance
- Fear of litigation
- Guilt


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

Causality Assessment Methods
Algorithmic:
Series of questions
Answers are weighted
Overall score determines causality
category
e.g. Naranjo’s scale
Probalistic:
Set of explicitly defined causality
categories

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

Drugs restricted due to adverse
reactions

Drug Year Adverse Reaction Outcome
Sulfanilamide 1937 Liver damage due
to diethylene
glycol
Solvent changed;
FDA established
Thalidomide 1961 Congenital
Malformations
Withdrawn
Chloramphenicol 1966 Blood Dyscrasias Uses restricted
Benoxaprofan 1982 Liver damage Withdrawn
Aspirin 1986 Reye’s syndrome Uses restricted
Flecainide 1989 Cardiac
Arrhythmias
Uses restricted
Noscapine 1991 Gene toxicity Withdrawn
Triazolam 1991 Psychiatric
disorders
Withdrawn

Drug Year Adverse
reaction
Outcome
Temafloxacin 1992 Various serious
adverse effects
Withdrawn
Co-trimoxazole 1995 Serious allergic
reactions
Uses
restricted
Terfenadine 1997 Interactions
(e.g. with
grapefruit juice)
Withdrawn
from OTC sale
Sotalol 1997 Cardiac
arrhythmias
Uses
restricted
Astemizole 1998 Interactions Withdrawn
Cisapride 2000 Cardiac
arrhythmias
Withdrawn
Cerivastatin 2001 Rhabdomylosis Withdrawn

Drug Event Outcome
Fenfluramine,
Dexfenfluramine
Heart valve disease, Pulmonary
hypertension, Cardiac fibrosis
Banned
Sibutramine Heart attack , Stroke Banned
Astemizole
,Terfinadine
Arrhythmias Banned
Rofecoxib ,Valdecoxib Myocardial infarction Banned
Rosiglitazone MI, stroke,CHF,death Banned
Cisapride QT interval prolongation-
ventricular arrhythmias
Banned
Gatifloxacin Arrhythmias, Phototoxicity,
Unpredictable hypoglycemia
Banned
Nimesulide
(Paediatric)
Fulminant hepatic failure Paediatric use -banned
Phenylpropanolamine Hemorrhagic stroke Banned( Banned order

Summary
 Every drug which has an effect has an adverse
effect every time a drug is given risk is involved
 For rational use of drug not only its clinical
indications are important but the knowledge of
adverse effects as well
 Early detection of adverse effects and its
proper management can be life saving in many
situations
 ADR Reporting (Pharmacovigilance) plays a
important role in the evolution and life history of
a drug

adverse drug reactins notes in detail summary

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