ADVERSE DRUG

REACTIONS (ADR)
Adverse Drug reactions MODERATOR
Dr. SIDDALINGAPPA
ASSO.PROFFESSOR.
PHARMACOLOGY & THERAPEAUTICS

SUNANDA.BPV.
M.SC
DEF:
 Any noxious change which is suspected to be due to a
drug, occurs at doses normally used in man, requires
treatment or decrease in dose or indicates caution in the
future use of the same drug.

 The magnitude of risk has to be consider along with the

magnitude of expected therapeutic benefits.

Ex: Bone marrow depression – treatment of cancer.

Drowsiness – in treatment of common cold.

SEVERITY OF ADVERSE DRUG REACTION

Mainly they are four types :

 Minor : no changes in drug therapy, antidote

 Moderate : requires changes in drug therapy, specific

treatment (or) prolong hospitalization at least one day.

 Severe : Potentially life-threatening, cause permanent damage

(or) requires intensive medical treatment.

 Lethal : Directly (or) indirectly contributes to death of the

patient.
 CLASSIFICATION

Predictable (Type A or Augmented) reactions :

 Side effects, toxic effects, secondary effects :
common, preventable, reversible.
Pharmacological Mechanism
* Excess of desired pharmacology (β – blockers,
antidiabetics, diuretics)
* Unwanted but documented Pharmacology
(antihistamine, NSAIDS).
 Unpredictable (Type B or Bizarre) reactions
 Less common, non-dose related, more serious
 Susceptible individuals only
 Anaphylaxis, Cytotoxic, Immune complex,
Cell mediated, unknown.
 Allergy and Idiosyncrasy.
 Type – C or Chronic reactions
Due to repeated insult by the drug
 Time relationship variable
 Mechanism uncertain.
Type D (Delayed reactions)
 Take time to develop
 Carcinogenesis, teratogenesis
Type E or End of treatment effects
 After termination of therapy
 Symptoms of abstinence
 rebound Phenomena
Type F or Failure reactions
 Therapeutic failure
 Inefficiency (Vaccines, OCPs)
SS
 Side effects

Secondary
Toxic effects
effects
1. Side effects:
 Unwanted but often unavoidable Pharmacodynamic
effects that occur at therapeutic dose.
 Reduce the dose generally ameliorates the symptoms.
Ex: Insulin – hypo glycemia.
Atropine – dry mouth.
Acetazolamide – acidosis.
 Side effects may also based on different facet of action
Ex: Estrogens- nausea.
Promethazine- sedation.
An effect may be therapeutic in one context but side effect

in another context.

Ex: Codeine : constipation – therapeutically is used

diarrhea
2. Secondary Effects:
Indirect consequences of primary action of the
drug.

Ex: Tetracycline - Suppression of bacterial flora in gut.

Corticosteroids - decreases defense mechanism- TB.
 3. Toxic effects :
Excessive Pharmological action of the drug due to
the
over dose (or) prolonged use.

 Over dose may be absolute/relative , it may be

accidental, homicidal, suicidal.
 Ex: Normal dose of paracetomal is 500mg 4/6 hrly ,
>10gr is toxicity
 Toxicity results in functional alteration:
High dose of Atropine causing Delirium.

 It results in drug induced tissue damage:

Hepatic necrosis from paracetamol over dose.
In prolonged therapeutic effects ;

Coma – Barbiturates.

Complete AV block in Digoxin.

Bleeding due to heparin.

Vestibular damage-streptomycin.
 Over dose of the drugs also leads to the toxicity;
Ex: Morphine – Respiratory failure.
Imipramine – Cardiac arrhythmias.

 Poisoning: May result in large doses of drugs.

 Poison is substance which endanger life by severely affecting one

(or) more vital functions.
 Not only drugs but other house hold, industrial and
insecticides are frequently involved in Poisoning.

 Specific Antidotes which are receptors antagonists,

chelating(or) specific antibodies.

Example for chelating :

Desferrioxamine & penicillamine – metal poising.
Treatment of
Drug
Poisoning
Measures are....

 General principles of Management.

 Clinical Features.

 Specific Therapies.
General principles of Management

 Resuscitation.

 Termination of exposure.

 Prevention of absorption.

 Hastening elimination.
Resuscitation
 A - Airway.
 B- Breathing.
 C- Circulation.
 D- Disability.
 E- Exposure.
 Don’t Ever Forget Glucose.
 Termination of exposure

 By moving the patient to fresh air.

 Washing the skin, eyes & GIT.
 GIT - 3 methods
 Removing toxins from stomach via the mouth.

Induced Vomiting- Ipecac syrup.

Gastric lavage- Not in unconscious patient.

 Recommended for up to 2 hrs after ingesting poison.

 Contraindicated in kerosene, CNS stimulant poisoning
 Prevention of absorption

Activated charcoal
 Adsorbs toxic substances or irritants, thus inhibiting GI
absorption.
 Addition of sorbitol →laxative effect.

 Oral: 20-40 g as a single dose(1g/kg).

 Not effective for cyanide, mineral acids, organic solvents, iron,

ethanol, methanol poisoning, lithium.

Hastening elimination.
 Forced alkaline diuresis-Diuretics – Furosemide.
 Hemodialysis or haemoperfusion
 Universal Antidote

Charcoal (Activated powdered) 2 Parts by weight

Magnesium oxide 1 Part by weight

Tannic acid 1 Part by weight

 .
 Unexpected undesirable effects (Type B - ADR)

 Hypersensitivity / Allergy.

 Genetically determined adverse effects.

 Idiosyncratic responses (of unknown

etiology)
 Hypersensitivity / Allergy;

 Type I (immediate type).

 Type II (auto/accelerated allergy).

 Type III (delayed allergy).

 Type IV (cell mediated allergy).

 A. Humoral:
Type – I ( Anaphylactic) reactions:

Most prominent antibodies are Ig E.

AG: AB reactions on mast cells  mediators like Histamine,

5-HT, Leukotrienes (LT – C4 & D4) Prostaglandins, PAF 

Urticaria, itching, angioedema, bronchospasm, rhinitis or

Anaphylactic Shock.

Anti histaminic are used

Type –II ( Cytolytic) reactions

Most prominent antibodies are IgG & IgM

Drug + Component of a cell acts as AG. AG: AB

reaction on surface of this cell  Cytolysis

Ex: Thrombocytopenia, agranulocytosis, A plastic

anemia, haemolysis, organ damage, SLE.
 Type– III ( retarded, Arthrus) reactions:

 AG: AB complexes + Compliment  precipitate on a vascular

endothelium  destructive inflammatory response.

 Rashes, serum sickness (fever, arthralgia, lymphadenopathy)

polyartatitis nodosa, Steven Johnson Syndrome (arthritis
erythemia mulforme, nephritis, myocarditis, mental symptoms).
Subsides in 1-2 weeks
 B. Cell Mediated
Type IV (delayed Hypersensitivity) reactions:

Mediated through production of sensitized T-Lymphocytes

carrying receptors for the AG  Lymphokines  attract
granulocytes  inflammatory response.

Ex: contact dermatitis, fever, photo sensitization

 Treatment of Anaphylaxis

Inj. Adrenaline : 0.5 ml(1 in 1000 dilution)

im/sc.

Inj. Chlorphenaramine : 50 mg im / slow iv.

Maleate

Inj. Hydrocortisone : 100 mg iv/im.

Acetate

Adrenaline may be administered : Diluted to 1 in 10,000

or 1 in 1000,000 infused slowly with constant monitoring.
 Genetically determined adverse effects
Three types

 Pharmacogenetic variations in phase I.

 Pharmacogenetic variations in phase II.

 Pharmacogenetic variations in Drug response due to

Enzyme Deficiency.
 Pharmacogenetic variations in phase I.

Ex :

 Presence of Atypical pseudo cholinesterase.

 Hydroxylase polymorphism(faulty oxidation).

 Pharmacogenetic variations in phase II.

Ex : Acetylator status.

Pharmacogenetic variations in Drug response due

to Enzyme Deficiency.

Ex : - G6PD Deficiency.
 Idiosyncratic responses
An idiosyncratic reaction is a qualitatively abnormal drug
effects that occurs in small population of individuals.

Idiosyncratic Reaction Offending Drugs

Hemolytic anemia Oxidizing agent, e.g. 8-

aminoquinolines, sulphonamides.

Acute porphyria A large number of CNS-active

drugs and some antimicrobial
agents.

Malignant hyperthermia Halothane, Suxamethonium.

 Photosensitivity
A cutaneous reaction due to drug induced sensitization of the
skin to UV radiation.

a). Phototoxic: Exposure to light of shorter wave lengths

(290 – 300 nm, UVB)

Acute : Demeclocycline .
Chronic: Nalidixic acid, Fluroquinolone , Thiazides .
 b) Photoallergic

Drugs – induces – cell mediated immune reaction – on

exposure to light of longer wave lengths (320 – 400 nm,

UVA)

– produces papular or eczematous contact dermatitis .

Ex: Sulfonamides, Sulfonylurea's, Griseofulvin,

Chloroquine.
Intolerance :
Appearance of characteristic toxic effects of a drug in an
individual at therapeutic doses.

Ex : Single dose of triflupromazine  Muscular

dystonias

Single Tab. of chloroquine  vomiting &

abdominal pain.
 Drug dependence
A state in which use of drugs for personal satisfaction is
accorded a higher priority than other basic needs, often in the
face of known risks to health.

Psychological dependence:

Individual believes that optimal state of wellbeing is achieved

only through the actions of drug.

Intensity may vary from desire to carving.

Reinforcement:
Ex: Strong reinforces: Opioids, Cocaine
Weak reinforces : BZDs
 Physical dependence:

An altered physiological state produced by repeated

administration of drug which necessitates the continued

presence of the drug to maintain physiological equilibrium.

Discontinuation  Withdrawal (abstinence) syndrome

Neuroadaptation
Ex: Opioids, barbiturates, alcohol, BZDs
Cocaine, Amphetamine  Little or no
physical dependence.
 Drug abuse:
Use of drugs by self medication in a manner & 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.

Ex: Amphetamine, Cocaine, Cannabis.

 Drug habituation:
It denotes less intensive involvement with the drug, so that its
withdrawal produces only mild discomfort.

Ex: Tea, Coffee, Tobacco, Social drinking's

 Drug withdrawal reactions:

Sudden interruption of therapy with certain drugs  worsening

of the clinical condition for which the drug was being used.

Ex:
i) Severe hypertension, restlessness & sympathetic over
activity – clonidine.
ii)Worsening of Angina, Precipitation of MI- β - blockers.
iii) Frequencies of seizures – Antiepileptic.
 Teratogenicity

Capacity of a drug to cause fetal abnormalities

when administered to the pregnant mother.
Thalidomide disaster (1958 –1961) -
Phocomelia.

Drugs can affect the fetus at 3 stages

i) Fertilization & implantation - up to 17 days
ii) Organogenesis - 18-55 days of gestation.
iii) Growth & Development - 56 days onwards
Mutagenicity & Carcinogenicity

Capacity of a drug to cause genetic defects and cancer

respectively.

Drug  Reactive intermediates  Affect Gene 

Structural changes in the chromosomes.

Chemical carcinogenesis  several years ( 10 – 40),

Anticancer drugs, Radioisotopes, Estrogen, Tobacco.
 Drug induced disease / Iatrogenic diseases

They are functional disturbances caused by drugs which persist

even after the offending drug has been withdrawn & largely
eliminated.

Peptic Ulcer - Salicyaltes, Corticosteroids

Parkinsonism - Phenothiazines

Hepatitis - INH
 Common Causes of ADRs
 Antibiotics

 Antineoplastics

 Anticoagulants

 Cardiovascular drugs

 Hypoglycemic

 Antihypertensive

 NSAID/Analgesics

 Diagnostic agents

 CNS drugs
 ADR Risk Factors

 Age (children and elderly)

 Multiple medications
 Multiple co-morbid conditions
 Inappropriate medication prescribing, use, or monitoring
 End-organ dysfunction
 Altered physiology
 Prior history of ADRs
 Extent (dose) and duration of exposure
 Genetic predisposition
 ADR Detection

Subjective report
 patient complaint

Objective report:
 direct observation of event
 abnormal findings
 physical exam

 laboratory test

 diagnostic procedure
 Preliminary Assessment

 Preliminary description of event:

Who, what, when, where, how?
Who is involved?

What is the most likely causative agent?

When did the event take place?

Where did the event occur?

How has the event been managed thus far?

MEDWATCH
3500A
REPORTING
FORM
HTTPS://WWW.ACCESSDATA.
FDA.GOV/SCRIPTS/MEDWATCH
 PREVENTION OF ADR TO DRUGS

1. Avoid inappropriate use

2. Appropriate dose, route, frequency
3. past history of drug reactions
4. History of allergic diseases
5. Drug interactions.
6. Correct technique of drug administration
7. Laboratory monitoring
 PHARMACOVIGILANCE
 Greek: Pharmakon = adrug , vigilare = to be observant.
 The history of pharmacovigillance is 4 decades.
 In 1956, the World Health Assembly brought the problem of
ADR.
 In 1970, the International Drug Monitoring programme came
in to begin.
 WHO prepared a document on Safety Monitoring of Medical
and suggested guidelines for setting up and running a
pharmacovigillance centre in every country .
 ADR data should be shared with global health care
community through WHO Uppsala monitoring centre located
at Sweden.
ring center in AMIIS at New

ties relating to the detection,

evention of adverse effects or
 WHO Def n : Science & activities relating to the detection,
assessment, understanding and prevention of adverse effects or
any other drug related problems.
Activities involved are
1. Post marketing surveillance
& other methods of ADR
monitoring.
2. Dissemination of ADR data
 Drug alerts, Medical letters
3. Changes in labeling :
Restrictions, stationary
warnings, precautions.
4. Withdrawal of drug.
 REFERENCES:-
 Pharmacological basis of Therapeutics – Goodman &
Gilman11th Edition .

 Principles of pharmacology – HL Sharma & KK sharma .

 Pharmacology – Rang & Dale 5th Edition.

 Text book of pharmacology – K. D. Tripathi.6th Edition.

 Basics & clinical pharmacology – Katzung.

 Text book of pharmacology –S.D.Seth.

 Pharmacology & pharmacotherapeutics - sathoskar

Thank U