ADVERSE DRUG
REACTIONS
Definition:
Any response that is
noxious and
unintended, that occurs
at the doses used for
diagnosis, prevention
and treatment of
diseases.
The World Health
Organization defines it
as:
An adverse drug reaction (ADR)
is ‘a response to a medicine
which is noxious, undesirable
and unintended, and which
occurs at doses normally used
in human for diagnosis,
prophylaxis and treatment ’.
EPIDEMIOLOGY :
30% of medical inpatients
develop an ADR
3% of all hospital admissions are
due to ADRs
Risk of an allergic reaction is
approximately 1-3%
Types:
1. Side effects
2. Untoward effects
3. Toxic effects
(1) SIDE EFFECTS:
These are pharmacological effects of
drugs produced at therapeutic doses,
that depending upon condition may be
desirable and undesirable
Eg: Atropine produces dryness of
mouth, it is side effect when
drug is given for sinus bradycardia,
but it is desired when the drug is
given as pre- anesthetic medication
(2) UNTOWARD EFFECTS:
These are the undesired effects
produced at the therapeutic doses
They necessitate the cessation of
therapy
Eg: Hypokalemia produced by loop
diuretics
(3) TOXIC EFFECTS:
These are produced
when drug is rapidly
administered or when
drug is given in large
doses
Eg: Respiratory
depression produced by
morphine
Impact of ADRs :
Increased risk of death
Prolongation of hospital stay
FREQUENCY.
The World Health Organization
recommends
very common (>1/10 patients)
common (>1/100)
uncommon (>1/1000)
rare (>1/10,000)
very rare (<1/100,000)
CLASSIFICATION ;
Rawlin and Thompson
(1991)
Type A:
Dose-related; pharmacologically
predictable, high morbidity, low mortality.
This type was the most common with the
most common offending drugs being
warfarin, insulin, and digoxin.
Toxicity of overdose (e.g. hepatic failure with
high dose Paracetamol),
Side effects (e.g. sedation with antihistamines) ,
Secondary effects (e.g. development of diarrhea
with antibiotic therapy due to altered
gastrointestinal bacterial flora),
Drug interaction (e.g. Theophylline toxicity in
the presence of erythromycin therapy)
Type B:
Non-dose related; bizarre
and unpredictable, low
morbidity, high mortality.
Intolerance (e.g. tinnitus
with use of Aspirin).
Immune related such as
hypersensitivity reactions
(e.g. Anaphylaxis with
penicillin administration ).
Pseudoallergic /non-immunologic-
radio contrast dye
Non-immune reactions such as
porphyria, neuroleptic malignant
syndrome, or malignant
hyperthermia.
Idiosyncratic reaction(e.g.
development of anemia with the
use of anti-oxidant drugs in The
presence of glucose-6 phosphate
dehydrogenase deficiency).
Type C:
Dose-related and time-related.
This is related to duration and
dosage of exposure. These
reactions are associated with
long-term drug therapy.
An example is hypothalamic-
pituitary-adrenal suppression
from glucocorticoid therapy.
Benzodiazepine dependence &
Analgesic nephropathy.
They are well known and can be
anticipated.
Type D:
These reactions refer to
carcinogenic and
teratogenic effects.
These reactions are
delayed in onset and are
very rare since extensive
mutagenicity and
carcinogenicity studies are
done before drug is
licensed. ..
Type E:
Withdrawal; end of dose
reaction. An example is narcotic
or beta-blocker withdrawal.
Type F:
Unexpected failure of therapy.
This may be caused by drug
interactions. An example is
failure of oral contraceptives
due to induction of enzymes by
a second drug.
Severity of ADR:
Minor: no need of therapy,
antidote, or hospitalization
Moderate: requires drug change ,
specific treatment, hospitalization
Severe: Potentially life
threatening; permanent damage,
and prolonged hospitalization.
Lethal: Directly or indirectly leads
to death
Strategies to Avoid ADR :
Avoid poly pharmacy
Rational prescribing
Prescribe the drugs of known ADR only when
there is no choice left
Obtain history of the patient
Educate the patient about the early symptoms of
ADR
A person susceptible to certain reaction should be
provided with cards Strategies to Avoid ADR
ADR detection methods :
Premarketing clinical trials
Post approval spontaneous case reports
Aggregate population-based data
sources
Computerized data collections
Post marketing studies
Case reports ADR detection methods
IMPORTANT SYSTEMIC
SIDE EFFECTS:
1. Drug intolerance
2. GIT disturbances
3. Hemopoietic toxicity
4. Hepatotoxicity
5. Nephrotoxicity
6. Behavioral toxicity
7. Electrolyte imbalance
8. Endocrine disturbances
9. Skin toxicity
10. Carcinogenesis
11. Teratogenecity
12. Drug dependence
13. Unmasking of diseases
14. Iatrogenic effect
1) DRUG INTOLERENCE:
It is the inability to tolerate drugs.
1. Quantitative: "Hyper-reactors“. Eg:
GIT bleeding and vomiting with single
dose of salicylates
2. Qualitative
*Idiosyncrasy
*Hypersensitivity
(B) Qualitative Intolerance:
Idiosyncrasy (Allergy):
An exaggerated sensitivity to certain
foreign substances which are
harmless to majority of population
It has an immunological basis
approximately 10% of all the adverse
reactions are allergic reactions
Drugs commonly producing allergic
reactions are penicillins,
sulfonamides, quinidine, insulin and
dextran
Types of
Hypersensitivity:
Type I:
Immediate form of allergy,
minutes or hours after taking of
drug
The underlying immune
reaction is initiated by the
attachment of antigen to Ig E
antibodies to the surface of
mast cells and basophils.
Erythema, urticaria, itching,
bronchoconstriction, edema.
abdominal cramps and diarrhea histami
Anaphylaxis is the severe form ne
of Type I reaction causes
cardiopulmonary collapse
Type II:
IgG
Responses are usually
delayed, and may take
several hours to several days
for appearance after drug
exposure
Haemolysis, leucopenia and
thrombocytopenia
Type III:
Immune complexes are formed between antigen and
antibody, and these complexes are deposited in small
vessels or within interstitial spaces resulting in
activation of complement cascade that attract
neutrophils
The lysosomal enzymes liberated by neutrophils
cause local damage and promote thrombosis of
affected blood vessels
Type IV:
Sensitized T-lymphocytes
Reaction is usually delayed
(2) GIT DISTURBANCES:
Many drugs produce GIT
disturbances like nausea and
vomiting eg: digitalis, reserpine and
anticancer drugs
Constipation is produced by opiates,
verapamil and anticancer drugs
Certain drugs produce diarrhea like
colchicine and progesterone
(3) HEMOPOIETIC TOXICITY:
Anemia: chloramphenicol, primaquine,
methyldopa, sulfonamides
Leukopenia: phenylbutazone,
thiouracil, chlorpromazine, imipramine
chloramphenicol
Thrombocytopenia: quinidine,
tolbutamide, digitalis, rifampin
Bleeding: aspirin, corticosteroids,
heparin and warfarin
(4) HEPATOTOXICITY:
Patients with liver damage may remain
asymptomatic or hepatotoxicity is
manifested as hepatomegaly, abdominal
pain or jaundice.
Direct hepatotoxicity may be caused by
isoniazid, tetracyclines and halothane.
Certain drugs cause immunological
disturbances like isoniazid, rifampin,
pyrazinamide, methyldopa, indomethacin
and chlorpromazine.
(5) NEPHROTOXICITY:
Many drugs cause nephrotoxicity
like aminoglycosides, amphotericin
B, vancomycin, bacitracin,
polymixins, sulfonamides,
hydralazine, penicillinamine,
phenacetin and acetaminophen
(6) BEHAVARIOURAL TOXICITY:
Reserpine causes suicidal
tendencies, amphetamine causes
disorientation and confusion and
glucocorticoids cause euphoria
(7) ELECTROLYTE
DISTURBANCES:
Diuretics produce hypokalemia, and
carbenexolone and corticosteroids
produce hypernatremia
(8) ENDOCRINE DISTURBANCES:
Chlorpromazine cause menstrual irregularities
Oral contraceptives cause suppression of
lactation
Corticosteroids cause hyperglycemia
Cimetidine and ketoconazole cause
gyanaecomastia
Lithium carbonate cause goiter
(9) SKIN TOXICITY:
Skin rashes (urticaria) can be produced by
penicillin, cephalosporins, amiodarone,
clofazemine, sulfonamides and tetracyclines
(10) CARCINOGENESIS:
Certain drugs lead to carcinogenesis
Eg: Estrogens produce breast and
endometrial cancer
Reserpine produce breast cancer
Metronidazole produces certain
tumors
(11) TERATOGENECITY:
Some drugs produce developmental
abnormalities in fetus, when given in
pregnancy
Eg: Phocomelia by thalidomide and cleft
(12) DRUG DEPENDENCE:
Certain drugs when used repeatedly,
may make individual psychologically
and physically dependent on the drug i-
e discontinuation of drug may produce
withdrawal syndrome eg: morphine,
alcohol, cocaine
(13) UNMASKING OF THE DISEASE:
Thiazide and corticosteroids unmask
the diabetes mellitus
Isoniazid unmask the epilepsy
(14) IATROGENIC EFFECT:
Antipsychotic drugs produce
Parkinson’s disease
NSAIDs produce peptic ulcer
