ADVERSE DRUG REACTIONS

Dr. Dilip Singh

AP
Pharmacology MIMS
 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
 Patientwith 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
 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