ADVERSE DRUG REACTIONS

Prof . R . K. DIXIT
Dept. of Pharmacology & Therapeutics
King George’s Medical University, Lucknow
dixitkumarrakesh@gmail.com
 ADVERSE DRUG REACTION

Any noxious change which is

 Suspected to be due to a drug

 At doses normally used in man

 May requires treatment or decrease in dose or
 Caution in the future use of the same drug
 ADVERSE DRUG EVENT (ADE)

Any untoward occurrence that may present during medical treatment,

But
Does not necessarily have a causal relationship with the treatment
 Incidence of ADR more
 Polypharmacy
 Elderly
 Children
 Patient
with multiple diseases
 Pregnancy
 Malnourished
 Immunosuppression
 Drug Abusers and addicts

 Develop
 Immediately

or
• Prolonged medication
or
• After stopping.
 GRADING OF SEVERITY OF ADVERSE DRUG REACTIONS :

 Minor : No therapy, antidote or prolongation of

hospitalization is required.

 Moderate: Requires change in drug therapy, specific

treatment or prolongs hospital stay.

 Severe: Potentially life-threatening, causes permanent

damage or requires intensive medical treatment.

 Lethal : Directly or indirectly contributes to death of the

patient.
 CLASSIFICATIONS OF ADR

 A (Augmented)
 B (Bizarre)
 C (Continuous)
 D (Delayed)
 E (Ending Use)
 F (Failure of Efficacy)

Broadly
Type- A (Predictable)- Based on pharmacological properties
Type- B (Non-predictable) – Based on Immunological response
and genetic makeup of person
 TYPE A- AUGMENTED

 These are based on the pharmacological properties of the drug

so can be predicted.
 They are common and account for 75% of ADRs

 Dose related and preventable mostly reversible.

Examples:-
 Anticoagulants (e.g., warfarin, heparin) – bleeding
 Anti-hypertensives (e.g.. α1-antagonists) – hypotension
 Anti-diabetics (e.g. insulin) - hypoglycemia

Predictable
 TYPE B- BIZZARE OR UNPREDICTABLE

 Have no direct relationship to the dose of the drug or the

pharmacological mechanism of drug action.
 Develop on the basis of:
 Immunological reaction on a drug (Allergy)
 Genetic predisposition (Idiosyncratic reactions)
 More serious clinical outcomes with higher mortality and morbidity.
 Mostly require immediate withdrawal of the drug.

Un-predictable
 TYPE C – CHRONIC (CONTINOUS) USE

They are mostly associated with cumulative-long term

exposure
Example:-
Analgesic (NSAID)– interstitial nephritis, papillary
sclerosis, necrosis

Predictable
 TYPE D – DELAYED

 They manifest themselves with significant delay

 Teratogenesis -Thalidomide – Phocomelia (flipper-like fore limbs)

 Mutagenesis/Cancerogenesis

Others:
Tardive dyskinesis – during L-DOPA Parkinson disease
treatment

Predictable
 TYPE E – END OF USE

 Drug
withdrawal syndromes and rebound
phenomenons

 Example – sudden withdrawal of long term therapy with -

blockers can induce rebound tachycardia and
hypertension

Predictable
 PHARMACOVIGILANCE (DAUP)

The 'science and activities relating to the detection, assessment,

understanding and prevention of adverse effects or any other drug
related problems’

The information generated is useful in educating doctors and in the

official regulation of drug use.
It has an important role in rational use of medicines, as it provides
the basis for assessing safety of medicines.
Various activities involved in pharmacovigilance are:

 Postmarketing surveillance and other methods of ADR monitoring

such as voluntary reporting by doctors prescription event
monitoring.

 Dissemination of ADR data through 'drug alerts', 'medical letters,'

advisories sent to doctors by pharmaceuticals and regulatory
agencies.

 Changes in the labelling of medicines indicating

restrictions in use or statuary warnings, precautions,
or even withdrawal of the drug.
 The Uppsala Monitoring Centre (Sweden) is the international
collaborating centre.

 In India,
 National centre is located at Ghaziabad
 Peripheral Centres at Medical college levels and tertiary and above hospitals
 Reports generated by doctors, paramedical staff--to peripheral
centre...National centre...Uppsala Monitoring Centre...Compilation of
data..analysis of data..causal association is confirmed..guidelines issued
regarding the safe use of medicine or (restricted use or withdrawal from the
market)
PREVENTION OF ADVERSE EFFECTS TO DRUGS

 Avoid inappropriate use of drugs .

 Appropriate drug administration (Rational Therapeutics)
 Dose
 Dosage form
 Duration
 Route
 Frequency
 Technique

 Ask for previous history of drug reactions and allergies

 Always suspect ADR when new symptom arises after initiation of
treatment. ( No new drug for new symptom).
 Ask for laboratory findings like serum creatinine etc.
Categorized into:
 Side effects-

 Secondary effects

 Toxic effects

 Intolerance

 Idiosyncrasy

 Drug allergy

 Photosensitivity

 Drug dependence

 Drug withdrawal reactions

 Teratogenicity

 Mutagenicity and Carcinogenicity

 Drug induced diseases (Iatrogenic disorders or Iatrogenicity)

Beware of – Iatrogenic, Idiosyncrasy, Idiopathic, Intolerance

 SIDE EFFECTS

 Unwanted often unavoidable Pharmaco-dynamic effects.

 Occur at therapeutic doses.

 Predictable

Examples.
Benzodiazepines- Motor in coordination
H1 Anti-histaminics- Sedation

An effect may be therapeutic in one context but side effect in another context

 Depression of A-V conduction is the desired effect of digoxin in atrial

fibrillation, but the same may be undesirable when it is used for CHF.
Constipation by codeine is side effect but can be used as therapeutic effect in
patient with loose motions
 SECONDARY EFFECTS

 Indirect consequences of a primary action of the drug.

 E.g. corticosteroids weaken host defence

mechanisms so that latent tuberculosis gets activated.
 TOXIC EFFECTS (Poisonous effect)
It is the dose and duration which makes a poison.... Paracelsus

 Over dose or prolonged use.

 The effects are predictable and dose related.

 The CNS, CVS, kidney, liver, lung, skin and bone marrow are most
commonly involved in drug toxicity.
 Toxicity may result from extension of the therapeutic effect
itself, e.g. complete A-V block by digoxin, bleeding due to
heparin.

 Poisoning: Poison is a substance which endangers life by

severely affecting one or more vital functions.
 Specific antidotes such as receptor antagonists, chelating
agents or specific antibodies are available for few poisons.
 For others as well as for those poisons which have a selective
antagonist general supportive and symptomatic treatment
should be done.
 These measures are:

1. Resuscitation and maintenance of vital functions:

maintenance of ABC , body temperature and blood glucose.
2.Termination of exposure (decontamination)
3. Prevention of absorption of ingested poisons.
4. Hastening elimination of the poison by inducing
diuresis or altering urinary pH
 INTOLERANCE

 It is the appearance of characteristic toxic effects of a

drug in an individual at therapeutic doses

 It indicates a low threshold of the individual to the action

of a drug

 Example:- Only few doses of carbamazepine may cause

ataxia in some people

Un-Predictable
 IDIOSYNCRASY
 It is genetically determined abnormal reactivity to a chemical.

 The drug interacts with some unique feature of the individual, not
found in majority of subjects, and produces the uncharacteristic
reaction.
Example :-

 Chloramphenicol produces nondose-related

serious aplastic anaemia in rare individuals.

 Barbiturates cause excitement and mental confusion in some

individuals

Un-Predictable
 DRUG ALLERGY
 It is also called drug hypersensitivity.

 It is an immunologically mediated reaction producing

stereotype symptoms which are unrelated to the
pharmacodynamic profile of the drug.

 It generally occur even with much smaller doses and have a

different time course of onset and duration.

Un-Predictable
 Allergic reactions occur only in a small proportion of
the population exposed to the drug .
 History of prior sensitization may or may not be evident.

 The drug or its metabolite acts as antigen (AG) or more

commonly hapten (incomplete antigen) and induce
production of antibody (AB)/sensitized lymphocytes.
 TYPES OF ALLERGIC REACTIONS

A) HUMORAL
1. Type I/ anaphylactic reactions.
2. Type-II / cytolytic reactions.
3. Type-Ill / retarded or Arthus reactions.

B) CELL MEDIATED
Type-IV (delayed hypersensitivity) reactions.
 PHOTOSENSITIVITY
 It is a cutaneous reaction resulting from drug induced sensitization of
the skin to UV radiation.
 The reactions are of two types:

a) Photo-toxic :- (T-S)
a) Drug or its metabolite Accumulates in the skin,
b) absorbs light and undergoes a Photochemical reaction followed by
c) Photobiological reaction resulting in
d) Tissue damage (sunburn-like),
a) i.e. erythema, edema, blistering , hyper pigmentation, desquamation.

The shorter wave lengths (290-320 nm, UVB) are responsible

(b) Photo-allergic: (A-L)

Drug or its metabolites induce a cell mediated immune response which

on exposure to
Light of longer wave lengths (320-400 nm, UV -A)
Produces a papular or eczematous contact dermatitis like picture.

Drugs involved are sulfonamides, sulfonylureas, griseofulvin,

chloroquine, chlorpromazine
 DRUG DEPENDENCE
 Use of drugs for personal satisfaction

 Higher priority than other basic needs, often in the face of known risks
to health.

Physical dependence It is an altered physiological state produced by

repeated administration of a drug which necessitates the continued
presence of the drug to maintain physiological equilibrium.

 Discontinuation of the drug results in a characteristic withdrawal

(abstinence) syndrome.
 Drugs producing physical dependence are opioids, barbiturates and
other depressants including alcohol and benzodiazepines
 Drug abuse :

Refers to use of a drug by self medication in a manner and

amount that deviates from the approved medical and social
patterns in a given culture at a given time.

 Drug addiction

It is a pattern of compulsive drug use characterized by

overwhelming involvement with the use of a drug. Procuring the
drug and using it takes precedence over other activities
 Drug habituation (Psychological dependence)

It denotes less intensive involvement with the drug, so that its

withdrawal produces only mild discomfort.
 Consumption of tea, coffee, tobacco, social drinking are regarded
habituating, physical dependence is absent
 DRUG WITHDRAWAL REACTIONS

 Sudden interruption of therapy with certain other drugs results in

adverse consequences, mostly in the form of worsening of the clinical
condition for which the drug was being used

 Example: Acute adrenal insufficiency may be precipitated by abrupt

cessation of corticosteroid therapy.
 TERATOGENICITY (Teratos- Monster)
 Drug to cause foetal abnormalities when administered to the pregnant
mother.
 Drugs can affect the foetus at 3 stages-

(i) Fertilization and implantation-conception to

17 days-failure of pregnancy which often goes unnoticed.

(ii) Organogenesis- 18 to 55 days of gestation most

vulnerable period, deformities are produced.
(iii) Growth and development-56 days onwards
developmental and functional abnormalities
can occur,
e.g. ACE inhibitors , Thalidomide, Warfarin,
Barbiturates,...............................
 MUTAGENICITY AND CARCINOGENICITY

 Cause genetic defects and cancer respectively.

 Reactive intermediates which affect genes and may cause

structural changes in the chromosomes

 Even without interacting directly with DNA, certain

chemicals can promote malignant change in genetically
damaged cells, resulting in carcinogenesis.

 Examples- anticancer drugs, radioisotopes, estrogens,

tobacco...................................................
 DRUG INDUCED DISEASES

 These are also called iatrogenic (physician induced) diseases,

and are functional disturbances (disease) caused by drugs .

 Hepatitis by isoniazid and Rifampicin

 Peptic ulcer by salicylates and corticosteroids

 Retinal damage by chloroquine

MCQ ON ADR
 Which of the following drugs is teratogenic in nature
 Warfarin
 Ampicillin
 Paracetamol
 Adrenaline

Warfarin
MCQ ON ADR
 ADRs which are due to typical genetic make of person
are known as
 Side Effects
 Secondary Effects
 Iatrogenic disorders
 Idiosyncratic disorders

Iatrogenic disorders
 MCQ ON ADR
 Withdrawal symptoms are common in which of the following drugs
 Caffenine
 Paracetamol
 Opioids
 Cocaine

Opioids
 MCQ ON ADR
 The most dangerous period regarding teratogenic effect is
 Firsttrimester
 Second trimester
 Third trimester
 Early neonatal life

First Trimester
 MCQ ON ADR
 International collaborating centre of Pharmacovigilance is situated at
 United States of America
 Australia
 Sweden
 United Kingdom

Sweden
THANKS