Adverse drug reactions

WHO defines an adverse drug reaction (ADR) as “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 a disease or, for the modification of physiological
functions.”
Often, the terms ‘adverse drug reaction’ and ‘adverse drug event’ are used
synonymously, although they are not.
Adverse Event (or Adverse Experience) is any untoward medical occurrence in a patient
or clinical investigation subject administered a pharmaceutical product and which does
not necessarily have a causal relationship with this treatment.
An adverse event (AE) can therefore be any unfavourable and unintended sign including
an abnormal laboratory finding, for example), symptom, or disease temporally
associated with the use of a medicinal product, whether or not considered to the
medicinal product.

CLASSIFICATIONS OF ADRs
Type-A (Augmented) reactions: These are exaggerated, but otherwise normal
pharmacological responses to the effects of the medicines given in therapeutic dose,
cause significant morbidity but are rarely severe. The reaction is treated by reducing the
dose or withholding the medicine and considering alternative therapy.
Eg: Bronchospasm from beta-blocker administration
Type-B (Bizarre) reactions: These reactions are often allergic in nature and
unpredictable with no relation to dose or pharmacological action of the medicine. They
are uncommon but are often severe and cause high mortality. The reaction is treated by
stopping the medicine and avoiding it in the future.
Eg: Anaphylactic reaction to penicillin administration
Type-C (Continuous) reactions: These reactions are chronic and related to cumulative
dose. The reaction is treated by reducing the dose or withholding the medicine, which
may have to be withheld for a long time.
Eg: Osteoporosis with oral steroids
Type-D (Delayed) reactions: These reactions are delayed (i.e., have a lag time) after
the use of a drug. They are uncommon but their treatment is often intractable.
Eg: Teratogenic effects with anticonvulsants or lisinopril
Type-E (End of use) reactions: These reactions occur soon after the end of use (i.e.,
withdrawal) and are uncommon. The reaction is treated by reintroducing the medicine
and then withdrawing it slowly.
 Eg: Withdrawal syndrome with benzodiazepines
Type-F (Failure of efficacy) reactions: These reactions occur when there is a failure of
efficacy. Such reactions are common, may be dose-related and are often caused by drug
interactions. The reaction is treated by increasing the dose and considering the effects of
concomitant therapy.
Eg: Resistance to antimicrobials

MECHANISM OF ADRs

Mechanisms of Type A ADRs:

A drug suspected to have caused an ADR in one patient may not necessarily cause a similar
adverse reaction in another patient. This is due to interindividual variability, which may
predispose an individual to an ADR.

Any type A reaction may be attributed to any one or more of the following mechanisms:

1. Pharmaceutical causes: include changes in the drug quantity present in a particular

product and changes in its drug release properties.
2. Pharmacokinetic causes: Alterations in the absorption, distribution, metabolism and
elimination of drugs may alter drug effects by changing the concentration of drug present
at the site of action. The change in drug effect due to alterations in pharmacokinetic
parameters may be experienced as therapeutic failure or as toxicity.
3. Pharmacodynamic causes: Increased sensitivity of target tissues or organs may
predispose a person to ADRs. Target tissue or organ sensitivity is influenced by the drug
receptors themselves, by homeostatic mechanisms and by disease.

Mechanisms of Type B ADRs:

Type B reactions are aberrant in terms of the normal pharmacology of the drug.

Any type A reaction may be attributed to any one or more of the following mechanisms:

1. Pharmaceutical causes: The main sources for the pharmaceutical causes of type B
reactions include decomposition of the active ingredient, effects of the nondrug
 excipients (additives, preservatives, colouring and solubilising agents) and synthetic by-
products of active constituents. In most cases, the use of decomposed drug products may
result in therapeutic failure.
2. Pharmacokinetic causes: Changes in pharmacokinetic parameters such as absorption,
distribution, metabolism and excretion may lead to type B reactions. The metabolism of a
drug to unusual reactive metabolites may give rise to type B reactions. Eg:
carbamazepine induced hypersensitivity reactions.
3. Pharmacodynamic causes: Many factors including age, sex, body weight, medical
condition and drug therapy influence the end response of a patient to an administered
drug. As a result, individual patients may vary in their response to drug therapy. The
qualitative differences in the target tissues or organ response to drugs may be due to
genetic, immunological, neoplastic or teratogenic causes.

PREDISPOSING FACTORS

Patients who have one or more of the following predisposing factors are at high risk of
developing an ADR:

1. Polypharmacy: Patients on multiple drug therapy are more prone to develop an

ADR.
2. Multiple and intercurrent diseases: Patients with multiple diseases are at increased
risk of developing an ADR due to multiple drug use for their diseases. Similarly,
patients with impaired hepatic or renal status are also at high risk of developing an
ADR. Eg: A patient with decreased renal function who is treated with
aminoglycosides is at increased risk of developing nephrotoxicity.
3. Age: Elderly and paediatric patients are more vulnerable to ADRs. Eg: Nitrate or an
ACE inhibitor induced postural hypotension in an elderly patient & grey baby
syndrome with chloramphenicol in a paediatric patient.
4. Drug characteristics: Some drugs are highly toxic in nature and patients treated
with these agents are at an increased risk of ADRs. Eg: Nausea and vomiting is a
common ADR seen in patients treated with cytotoxic anti-cancer drugs. Patients
 treated with narrow therapeutic index drugs such as digoxin and theophylline are
more susceptible to ADRs.
5. Gender: Women are reported to be more susceptible to ADRs than men for a
number of reasons such as physiological, pharmacokinetic, pharmacodynamic and
hormonal. Eg: Chloramphenicol induced aplastic anaemia is twice as common in
women as in men.
6. Race and genetic factors: ADRs are more common in genetically predisposed
individuals. Eg: Patients who are deficient in glucose-6-phosphate dehydrogenase
(G6PD) are at higher risk of developing haemolysis due to primaquine than those
who are not.

CAUSALITY ASSESSMENT
Causality assessment means finding a causal association or relationship between a drug
and a drug reaction. It is an evaluation of the likelihood that a particular treatment is the
cause of an observed adverse event.
Methods for causality assessment of ADRs are classified into three groups:
a. Opinion of experts, clinical judgment or global introspection methods
b. Algorithms (with or without scoring) or standardised assessment methods
c. Probabilistic or Bayesian approaches
WHO Causality Assessment Scale:
Naranjo’s Causality Assessment Scale:

Definite ≥ 9; Probable 5–8; Possible 1–4; Unlikely ≤ 0

The common factors considered in causality assessment include:
 The temporal (time) relationship between the administration of the suspected drug
and the reaction
 Dose and duration of drug treatment
 Possible alternative causes, other than the drug, for the occurrence of an ADR
 Outcome of the reaction upon cessation of drug (Dechallenge)
 Outcome of the reaction upon reintroduction of drug (Rechallenge)

The assessment and establishment of causality relationship between suspected drugs and
reactions has following applications:
 Patient treatment
 Signal generation
 Drug regulation
 Scientific publication
 Data exchange

Every suspected ADR should be assessed for its causality and documented in the
patient’s medical record which will serve as a useful reference to alert clinicians to the
possibility of a particular drug causing a suspected reaction.
Severity of ADRs:
After the causality assessment has been done, the severity of the ADR is analyzed using
adapted Hartwig’s severity assessment scale.

The scale is classified as:

1. Mild: A reaction that does not required treatment or prolongation of hospital stay.
2. Moderate: A reaction that requires treatment and or prolongs hospitalization by at
least one day.
3. Severe: A reaction that is potentially life threatening or results in death or requires
inpatient hospitalisation or prolongation of existing hospitalisation or results in
persistent or significant disability/incapacity or a congenital anomaly/birth defect at any
dose.

Predictability of an ADR:
Criteria for determining Predictability of an ADR

Incidence rate Incidence description Predictability

≥1/10 Very common Predictable
≥1/100 and <1/10 Common Predictable
≥1/1000 and <1/100 Uncommon Not predictable
≥1/10,000 and <1/1000 Rare Not predictable
<1/10,000 Very rare Not predictable