D R J ER IN J AM ES
ADVERSE DRUG
REACTION

DEFINITION
 Any response to a drug, which is noxious ,
unintended and
 which occurs at doses normally used in man for the
prophylaxis , diagnosis or therapy of disease or for
the modification of physiological function ,
 requires treatment or decrease in dose or indicates
caution in future use of same drug

INCIDENCE OF ADR
 5% of hospital admission due to ADR
 10% to 20% experience during hospital stay
 0.1% drug related death in Medicine IP
 2% to 30% incidence of ADR in general practice
 Any drug can cause ADR

HISTORY OF ADR
 1870 and 1890 Chloroform – Cardiac toxicity
 1937 in USA 107 people died due to sulfanilamide
which contains diethylene glycol as a solvent
 1959-1961 Thalidomide incident – seal like limbs
 Phenacetin – Analgesic nephropathy
 Fenfluramine – Cardiac valvular defects
 Trpglitazone – Hepato toxicity
 Rofecoxib- Cardio toxicity

CLASSIFICATION
 Type A/Augmented/expected undesirable effects
 Type B/unexpected undesirable effects
 Type C/chronic effects
 Type D/delayed effects
 Type E/End of treatment effects
 Type F/Failure of drug to produce desired effect

TYPE – A ADRs
 Common , less serious , dose related
 Corrected by dose adjustment
 Includes : side effects
secondary effects
toxicity

SIDE EFFECTS
 Mild , manageable
 Undesirable effects observed with therapeutic doses
of drug
 eg: Cetrizine - sedation

SECONDARY EFFECTS
 These are indirect consequences of the main action
of the drug
 Eg: development of superinfection after supression
of bacterial flora by antibiotics
 Weakening of host defenses after use of
corticosteroids

TOXICITY
 These are exagerrated form of side effects which
occur due to overdose or after prolonged use of drug

TYPE B ADRs
 Unexpected undesirable effects/Bizarre effects
 These occur unexpectedly even when drug is used in
therapeutic doses , by a mechanism unrelated to
the main pharmacological effect of the drug
 Three types :
1. drug allergy
2. Genetically determined abnormal responses
3. Idiosyncratic drug responses

DRUG ALLERGY/HYPERSENSITIVITY
REACTIONS
 Immunologically mediated
 Independent of dose
 Prior sensitization required
 1-2 weeks after first dose.
 Drug act as an antigen or hapten
 Chemically related drug may show cross reactivity
 Same drug can cause different allergic reactions in
different individuals

TYPES OF HYPERSENSITIVITY
REACTIONS
 TYPE 1 HYPERSENSITIVITY REACTION
1. Ig E MEDIATED
2. On re exposure, antigen-antibody reaction take
place on mast cell surface, release of histamine ,PG,
5-HT ,LT
3. Urticaria, angio oedema, broncho constriction ,
anaphylactic shock

TYPES OF HYPERSENSITIVITY REACTIONS
 TYPE 2 HYPERSENSITIVITY REACTION ( CYTOLYTIC
RXNS)
1. Drug and component of host cell act as antigen
2. Ig G and Ig M mediated
3. Antigen-antibody reaction take place on the surface
of these cells , leads to complement activation and
hence cell lysis
4. Thrombocytopenia , hemolysis , SLE
5. Occurs within 72 hours of re exposure

TYPES OF HYPERSENSITIVITY REACTIONS
 TYPE 3 HYPERSENSITIVITY REACTIONS
1. Ag and Ab are circulating
2. IgG mediated
3. Antigen –antibody complexes are formed
4. Deposited on vascular endothelium , activation of
complement ,immune response
5. Eg: serum sickness, steven johnson syndrome

TYPES OF HYPERSENSITIVITY REACTIONS
 TYPE 4 HYPERSENSITIVITY REACTION (DELAYED
HYPERSENSITIVITY)
1. Sensitized T lymphocytes with receptors for antige
2. On exposure to antigen they produce mediators
3. Local /tissue allergic reactions
4. Eg: contact dermatitis

TREATMENT OF DRUG ALLERGY
 Offending drug must be stopped immediately
 Treatment for anaphylaxis
 Recliningposition, high flow oxygen
 Inj Adrenaline0.5mg (0.5ml of 1/1000 IM)
 H1 AntihistaminicsIMor slow IV
 Inj Hydrocortisone100 -200mg IV

GENETICALLY MEDIATED ABNORMAL RESPONSE
TO A DRUG
 Drug responses in some individual may be markedly
different from the effect usually observed
Eg1:
Presence of atypical Psuedocholine estrase – Prolongation of
action of succinylcholine
Succinylcholine apnoea → Respiratory failure
Eg2:
Acetylator Status
Slow acetylators – neurotoxicity with INH
Fast acetylators- Hepatotoxicity with INH

IDIOSYNCRATIC REACTIONS
 Harmful and sometimes fatal reactions that occur in a
small minority of individuals
Cause is not well understood
Eg: Malignant Hyperthermia with halothane
Aplastic anemia with single dose chloramphenicol

TYPE C ADRs (CHRONIC EFFECTS)
 These are associated with prolonged use of a drug
Eg: Cushing syndrome after chronic use of
prednisolone
Eg: Analgesic nephropathy with aspirin

TYPE D ADRs (DELAY DEFECTS)
 These occur remotely ie years after treatment, or
effects appearing in their children who didn’t receive
the treatment
Eg: Secondary cancers in patients treated for blood
cancer
Eg: Teratogenic effects

TYPE E ADRs (End –of – treatment Effects)
 These occur when a drug is suddenly discontinued
Eg: Rebound hypertension after abrupt withdrawal of
propranolol
Eg: adrenocortical insufficiency after sudden stopping of
prednisolone

TYPE F ADRs (Failure of a Drug to Produce desired
effect)
 Failure of drug to produce the desired therapeutic
effect in some people due to genetic variability

ORGAN TOXICITIES
 HEPATOTOXICITY
 Direct (predictable)
hepatocellular damage
eg: Paracetamol Metabolites tetracyclines
 Cholestatic jaundice (unpredictable)
eg: Chlorpromazine erythromycin
 Unpredictable hepatitis like reaction
eg: INH, rifampicin, halothane

MAJOR ORGAN TOXICITIES
Phenacetin Analgesicnephropathy
Aminoglycosideantibiotics,
iodinated x-ray contrast media
Tubularnecrosis
Gold salts, penicillamine Nephrotic syndrome
Lithium Carbonate, demeclocycline Nephrogenicdiabetes insipdus
Acetazolamide,calcium salts Nephrolithiasis
Methicillin, hydralazin Interstitial nephritis, SLE
NEPHROTOXICITY

ORGAN TOXICITES
Primaquine nitrofurantoin Nalidixic Acid Hemolytic anemia in G-6PD deficiency
Sulphonamides sulphones, methotrexate Megaloblastic Anemia
Nitrate and nitrate sulphones Methemoglobinemia
Sodium valporate co-trimoxazole Thrombocytopenia
Chloramphenicol,Phenylbutazone,
Carbemazepine
Pancytopeniaand aplastic anemia
Chloramphenicol,thiouracil,derivatives
used as antithyroid drugs, sulphones
Agranulocytosis
HEMATOLOGICAL TOXOCITY

ENDOCRINE AND METABOLIC DISORDERS
Lithium Carbonate prolongeduse of
iodine-containing expectorants
Disorders of thyroid funciton
Spironolactonedigitalis Gynecomastia
Antipsychotic phenothiazines,
methyldopa
Galactorrhea-amenorrheasysndrome
Lithium, phenothiazines, methyldopa,
clonidine
Impotence in males
Probenecid, frusemide ethambutol Hyperuricemia
Oral cotraceptivesthiazide and loop
diuretics
Hyperglycemia

ELECTROLYTE IMBALANCE
Hypernatremia Mineralocorticoids,
glucocorticoids
Hyperkalemia Spironolactone, ACE
INHIBITORS
Hypokalemia Loop diuretics

DERMATOLOGICAL TOXICITY
Dimethylchlortetacycline, nalidixic acid,
sulfonamides
Photodermatits
Long-acting sulfonamides, sulfones,
ethosuximide
Stevens- johnson syndrome
Heparincyclophosphamideand other
cytotoxicdrugs
Alopecia
Oral contraceptives androgens
sulfonamides, sulfones, penicillins
Acne Urticaria
Busulfan, chloroquineoral contraceptives Hyperpigmentation
Chloroquine, chloropromazine Lichenoidskin eruptions
Sulfonamides, salicylates Fixed drug Eruptions
Ampicillin, Allopurinol Nonspecific skinrashes

NEUROLOGICAL DISORDERS
Haloperidol, metoclopramide Parkinsonismand other
extrapyramidaldisorders
Nalidixic acid, lignocaine, theophyline Convulsions
Nitroglycerine hydralazine Headache
Corticosteroids, tetracyclines, oral
contraceptives
Pseudotumor cerebri
(intracranialhypertension)
Ether Exacebationof preexisting
myesthenia
INH vincristine, clioquinol PeripheralNeuropathy

PSYCHIATRIC DISORDERS
Reserpine, methyldopa Depression
L-dopa, amphetamine Hypomaniaor Mania (Excited
reaction)
Amphetaminecorticosteroids Schizophrenia-likestate(or
paranoid reaction)
Bromocriptine, Propranolol Hallucinatory States
Atropine, digitalis glycosides, amantadine Delirious state
Amphetamine, L-dopa, bromocriptine Insomnia

DISORDERS OF THE GASTROINTESTINAL TRACT
Aspirin, corticosteroids Peptic ulcerationor
gastrichaemorrhage
Valporate Clindamycin, broad spectrum
antibiotics
Pancreatitis
Pseudomembranous colitis
Opioids ferrous sulphate, tricyclic
antidepressants
Constipation

CARDIOVASCULAR DISORDERS
Daunorubicin,doxorubicin Cardiomyopathy
Carbenoxolone, steroids, propranolol Exacerbationof congestive
cardiac failure
Thyroidhormones, cardiac glycosides Carida arrhythmias
Clonidinewithdrawal, oralcontraceptives,
corticosteroids
Hypertension
Propranolol withdrawal, ∝ adrenoceptor
blockers
Exacerbationof angina
Ergot Alkaloids Raynaud’s phenomenon
vasospasm, gangrene

MUSCULOSKELETAL DISORDERS
Corticosteroidsclofibrate Myopathy
Phenytoin,
Phenobarbitone
Osteomalacia
Heparin, glucocorticoids
Buserelin
Osteoporosis

OCULAR DISORDERS
Hyperbaric oxygencorticosteroids Cataract
Antipsychotic phenothiazines,
chloroquine
Retinopathy
Digoxin, ethambutol Aletrations in colour vision
Chloroquine, indomethacin Corneal opacities
Ethambutolpenicillamine Optic neuritis

Pharmacovigilance
 The Detection, Understanding, Assessment and
Prevention of ADRs
 For patient safety
 Pharmacovigilance Programme of India launched in
2010
 All ADRs should be notified to the respective ADR
monitoring Centre, from where it is sent to PvPI and
then to the International Drug Monitoring Centre,
WHO.

Important Questions
 Define ADR
 Describe the typres of ADRs with examples
 Management of ADRs/Drug Allergy
 Pharmacovigilance

THANK YOU