Adverse drug reactions

ADVERSE DRUG REACTION
Dr. Ramesh Bhandari
Asst. Professor
Department of Pharmacy Practice,
KLE College of Pharmacy, Belagavi

ADVERSE DRUG REACTION (ADR)
Any response to a drug which is noxious and unintended, and
which occurs at doses normally used in man for prophylaxis,
diagnosis or therapy of disease or for the modification of
physiological function.

ADVERSE DRUG REACTION (ADR)
Adverse drug reaction Vs Adverse drug event Vs Side effect
Adverse drug event is broader term and defined as ‘any
untoward medical occurrence presenting during the
administration of a drug’.
All ADRs are ADE but not all ADEs are ADRs.
Any effect caused by drug other than the intended therapeutic
effect whether beneficial, neutral or harmful is called side effect.

SERIOUS ADVERSE DRUG REACTION (ADR)
An ADR that at any dose:
Results in death
Is life threatening
Requires inpatient hospitalization or prolonged
hospitalization
Results in persistent or significant disability
Results in congenital anomaly/birth defect

UNEXPECTED ADVERSE DRUG REACTION
(ADR)
An adverse reaction, the nature or severity of which is not
consistent with the applicable product information.

CLASSIFICATION OF ADR
1) Type A (Augmented)
2) Type B (Bizzare)
3) Type C (Continuous)
4) Type D (Delayed)
5) Type E (End of treatment)
6) Type F (Failure of treatment)
}Traditional
Classification
Recent
Classification

1) Type A (Augmented):
 Usually exacerbation of the pharmacological effects of a drug
 Dose dependent
 Predictable due to known of pharmacology of a drug
 Preventable
Incidence of type A is high however, less severe so associated with less
morbidity and mortality
 Eg: Insulin induced hypoglycaemia, hypotension caused by
antihypertensives, dehydration caused by diuretics.

2) Type B (Bizzare):
 Usually hypersensitivity reactions
 Not dose dependent
 Often not predictable and not preventable (unless present with a
known past history)
 Incidence of type A is low however, more severe so associated
with high morbidity and high mortality
 Eg: Penicillin's induced hypersensitivity reactions

3) Type C (Chronic/Continuous):
Occurs after prolonged exposure to a drug
Higher frequency among exposed patients than unexposed
 Exact mechanism is unknown.
Eg: Higher frequency of cardiovascular events among patients
exposed to the COX-2 inhibitor rofecoxib, osteoporosis caused
by corticosteroids

4) Type D (Delayed):
 Delayed until long after drug exposure, making diagnosis
difficult.
Eg: Malignancies that occurs after immunosuppressive
treatment post transplantation, vaginal cancer occurring many
years after exposure to diethylstilbestrol.

5) Type E (End of treatment):
 Occuring after abrupt drug withdrawal
 Eg: Alcohol withdrawal – Anxiety, Panic, delusions, visual
and auditory hallucinations

6) Type F (Failure of treatment):
 Common to all
 Often caused by drug interactions

DoTS Classification of ADRs:
A. Dose
B. Timing
C. Susceptibility

A. Dose:
 Below Therapeutic dose – Eg: Anaphylaxis with penicillin
In therapeutic dose range – Eg: Nausea with morphine
At high dose – Eg: Hepatotoxicity with paracetamol

B. Timing:
 With the first dose – Anaphylaxis with penicillin
 Early stages of treatment – Hyponatremia with diuretics
 On stopping treatment – Benzodiazepine withdrawal syndrome
 Significantly delayed – clear cell carcinoma with DES

C. Susceptibility:
 Elderly age
Gender
Polypharmacy
 Genetic Predispostion
 Disease altering pharmacokinetics
 Adherence problems

PREDISPOSING FACTORS FOR ADR
1. Polypharmacy
2. Multiple and inter-current diseases
3. Age
4. Drug characteristics
5. Gender
6. Race and genetic factors

1. Polypharmacy:
 Multiple drug therapy – more prone to develop ADR
 Either due to interaction mechanism or by synergistic effect

2. Multiple and inter-current diseases:
 Multiple diseases are at increased risk of developing an ADR
 Patient with renal and hepatic diseases are also at high risk
 Eg: Patient with decreased renal function treated with normal
dose of aminoglycosides is at risk of developing
nephrotoxicity until dose adjustment

3. Age:
 Elderly and paediatric patients are more vulnerable to ADRs
 Elderly patient are more susceptible due to physiological
changes
 Eg: Nitrates and ACEI induced postural hypotension in an
elderly patient, grey baby syndrome with chloramphenicol in
childrens

4. Drug characteristics:
 Some drugs are toxic in nature and patients treated with those
agents are at increased risk of ADRs.
 Eg: Nausea and vomiting with cytotoxic anticancer drugs
 Patients treated with narrow therapeutic index drugs are more
at risks

5. Gender:
 Women are reported to be more susceptible to ADRs than men
 Eg: Chloramphenicol induced aplastic anemia and
phenylbutazone induced agranulocytosis are twice and thrice
as common in women as in men respectively.

6. Race and genetic factors:
 More prone to ADRs in genetically predisposed individuals
 Eg: Patients G6PD deficiency are at higher risk of developing
haemolysis due to primaquine.

MECHANISM OF TYPE A ADR
Any Type A reaction which occurs in an individual may be due to
one of the following reasons:
Pharmaceutical causes
Pharmacokinetic causes
Pharmacodynamic causes

Pharmaceutical causes:
• Changes in the drug quantity present in a particular product
• Changes in drug releasing properties
• Eg: Griseofulvin having different particle size in final dosage
form. Switching its larger particle size product with smaller
one leads to toxicity by increasing peak concentration

Pharmacokinetic causes:
• Alteration in the ADME of drugs – changing concentration of drug
at site of action
• Absorption: changes in rate and extent of drug absorption
• Distribution: changes in blood flow and protein or tissue binding
• Metabolism: Reduced metabolism lead to higher rate of type A
ADRs whereas therapeutic failure occurs as metabolism increases
• Excretion: changes in drug excretion rate

Pharmacodynamic causes:
• Increased sensitivity of target tissues or organs
• Drug receptors: inter-individual variation in drug receptor
• Homeostatic mechanism: changes in physiological factors
determine the extent of a drug’s effect
• Disease: Eg: asthmatic patient developing bronchoconstriction
after taking non-selective beta blockers (Propranolol)

MECHANISM OF TYPE B ADR
Any Type B reaction which occurs in an individual may be due to
one of the following reasons:
Pharmaceutical causes
Pharmacokinetic causes
Pharmacodynamic causes

Pharmaceutical causes:
• Decomposition of the active ingredients
• Effects of drug excipients (Eg: propylene glycol and
carboxymethylcellulose causes hypersensitivity)
• Synthetic by product of active constituents
• Death have been reported due to decomposition of paraldehyde to
acetaldehyde and its subsequent oxidation to acetic acid.

Pharmacokinetic causes:
• Although pharmacokinetic changes lead to type B ADRs but
there are no documented type B ADRs due to absorption and
distribution.
• Metabolism: unusual reactive drug metabolite leads to type B
ADRs. Eg: Carbamazepine induced hypersensitivity reactions

Pharmacodynamic causes:
• Age, sex, body weight, medical condition and drug therapy
influence the end response of a patient to an administered drug.
• Genetic causes for abnormal responses: Eg G6PD deficiency
results in hemolysis
• Immunological reasons for abnormal response
• Teratological and neoplastic reasons for abnormal response

REFERENCES
1) Brian R Walker, Nicki R Colledge, Stuart H. Ralston, Ian D.
Penman. Davidson’s Principles and practice of medicine. 22nd
Edition, Churchill living stone. 2014.
2) G. Parthasarathi, Karin Nyfort Hansen, Milap C Nahata. A
textbook of clinical pharmacy practice Essential concepts and
skills. 2nd edition, Universities Press.

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