definition, types of adverse drug reactions with examples

1. Adverse drug reactions
Dr. Padmavathi, Pharmacology

2. .

3. • Adverse reaction: WHO, (1972)
• A response to a drug which is noxious and unintended, and
which occurs at doses normally used in man for the
prophylaxis, diagnosis, or therapy of disease, or for the
modifications of physiological function'
Poisonous
effects

4. • Classification of ADRs: Depending on….
Onset of event
Severity
Type of reaction:
Cause or mechanism
 ONSET OF EVENT:
SUB-ACUTE
(1-24 HRS)
LATENT
(>2 DAYS)

5. Classification of ADRs
 Severity: Minor, Moderate, Severe, Lethal ADRs
 Minor ADRs: No therapy, antidote or prolongation of
hospitalization is required.
 Moderate ADRs: Requires change in drug therapy, specific
treatment or prolongs hospital stay by atleast 1 day.
 Severe ADRs: Potentially life threatening, causes
permanent damage or requires intensive medical
treatment.
 Lethal: Directly or indirectly contributes to death of the
patient.

6. • .

7. Classification of ADRs
Type of reaction…………………..wills and brown
AUGMENTED
DELAYED
END
OF
TREATMENT
FAMILIAL
GENOTOXICITY
HYPERSENSITIVITY
UNCLASSIFIED

8.  Type A (Augmented) reactions
Anticoagulants
↓ Intra Vascular
Coagulation
Antihypertensives
Vasodilators
Hypotension
Head ache
Antidiabetics
Antiarrhythmics
β blockers
Hypoglycemia
Normalize
Blood Glucose
Bleeding
therapeutic effect
Normalize
heart rate
Normalize
Blood pressure
Bradycardia
augmented
effect

9.  Type A (Augmented) reactions
– Reactions which can be predicted from the known
pharmacology of the drug
– Dose dependent
– Can be alleviated by a dose reduction

10.  Type B (Bizarre) reactions
Cannot be predicted from the pharmacology of the drug
Not dose dependent
Host dependent factors important in predisposition
Penicillin → Anaphylaxis
Anticonvulsant → Hypersensitivity
 Type C (Chemical) reactions
can be predicted from the chemical structure of the
drug/metabolite
Paracetamol → Hepatotoxicity

11.  Type D (Delayed) reactions
– Occur after many days of treatment
– Can be due to accumulation.
Chemotherapy → Secondary tumours
Phenytoin during pregnancy → Teratogenic effects
Antipsychotics → Tardive dyskinesia
Analgesics → Nephropathy

12.  Type E (End of treatment) reactions
– Occur on withdrawal especially when drug is stopped
abruptly
Phenytoin withdrawal → Seizures
Steroid withdrawal → Adrenocortical insufficiency

13. Predictable Unpredictable
Expected- Undesirable Unexpected- Undesirable
Based- Pharmacological
properties of drug
Based- Peculiarities of patient
More common Less common
Dose related Non dose related
Mostly preventable and
reversible
More serious, requires drug
withdrawl
Includes- Side effects , Secondary
effects , Toxic effects,
Consequences of drug
withdrawal
Includes-Hypersensitivity/allergy ,
Idiosyncrasy

15.  Side effects
 Unwanted but often unavoidable, pharmacodynamic
effects that occur at therapeutic doses
 Predicted from the pharmacological profile of a drug
 Known to occur in a given percentage of drug recipients
Range
of
Pharmacodynamic
Effects
Effect 1
Effect 2
Effect 3
Desirable
Undesirable

16. • Side effects

17. • Side effects

18.  Side effects
↓ Exocrine
Secretions
↓ Gi Smooth
Muscle
Mydriatic
Dry mouth
Constipation
PREANESTHETIC
MEDICATION
MYDRIATIC
DIARRHOEA
Blurred vision
Photophobia
Blurred vision
Photophobia
Dry mouth Constipation

19.  Secondary effects
 Indirect consequences of a primary action of the drug
Broad Spectrum
Antibiotics
Activation of latent TB
Weakens host defense
Immunosupressant
Corticosteroids
Super infections
↓Microbial flora
Antibacterial 1⁰ action

20.  Toxic effects
Result of excessive pharmacological action of the drug due
to over dosage or prolonged use
Over dosage may be
1. Absolute (Accidental, homicidal, suicidal)
2. Relative (Gentamycin in Renal failure)
Result from
 Extension of therapeutic effect: augmented effects
 Functional alteration:
Atropine → Delirium
 Drug induced tissue damage:
Paracetamol → Hepatic necrosis

21.  Intolerance
 Appearance of characteristic toxic effects of a drug in an
individual at therapeutic doses
 Converse of tolerance
 Indicates a low threshold of the individual
 Triflupromazine (single dose) → Muscular
dystonias in some individuals
 Carbamazepine (few doses) → Ataxia in some
individuals
 Chloroquine (single tablet) → Vomiting and
abdominal pain in some individuals

22.  Intolerance
ATAXIA Muscle Dystonias

23.  Idiosyncrasy
 Drug interacts with some unique feature of the
individual, not found in majority subjects, and produces
the uncharacteristic reaction.
 Genetically determined abnormal reactivity to a
chemical
 Barbiturates → Excitement and mental confusion in
some individuals
 Quinine → Cramps, diarrhea, asthma, vascular
collapse in some individuals
 Chloramphenicol → Aplastic anemia
in rare individuals

24.  Photosensitivity
 Cutaneous reaction resulting from drug induced
sensitization of the skin to UV radiation.
 The reactions are of two types
 Phototoxic: Drug or its metabolite accumulates in the skin,
absorbs light and undergoes a photochemical reaction
resulting in local tissue damage (sunburn-like, i.e.,
erythema, edema, blistering, hyper pigmentation)
E.g. Tetracyclines, Nalidixic acid, Fluoroquinolones etc

25.  Photosensitivity
 Photo allergic: Drug or its metabolite induces a cell
mediated immune response which on exposure to light
(longer wave length) produces a papular or eczematous
contact dermatitis like picture.
E.g. Sulfonamides, Sulfonylureas, Griseofulvin, Chloroquine

26.  Drug dependence
 Drugs capable of altering mood and feelings are liable to repetitive
use to derive euphoria, withdrawal from reality, social adjustment,
etc.
 Psychological dependence: Individual believes that optimal state of
well being is achieved only through the actions of the drug
 Physical dependence: 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.

27.  Drug dependence
 Drug abuse: 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 abuse refers to any
use of an illicit drug.
 Drug addiction: Compulsive drug use characterized by overwhelming
involvement with the use of a drug
 Drug habituation: Less intensive involvement with the drug,
withdrawal produces only mild discomfort
 Habituation and addiction imply different degrees of psychological
dependence.

28.  Drug dependence
Salicylates, Caffeine,
Nicotine, Cocaine,
Amphetamine
Alcohol,
Barbiturates,
Morphine, Heroin

29. Drug withdrawal reactions (end of treatment)
Rebound effects

30. Drug withdrawal reactions (end of treatment)
Sudden interruption of therapy with certain drugs result
in adverse consequences, mostly in the form of
worsening of the clinical condition for which the drug
was being used.
– Corticosteroid → Adrenal insufficiency
– β-blockers → worsening of angina, precipitation of MI

31. Drug withdrawal reactions (end of treatment)
Switch Off The
Hypothalamo Adrenal
Axis
Adrenal
insufficiency

32.  Teratogenicity
Capacity of a drug to cause foetal abnormalities when
administered to the pregnant mother.
• Thalidomide → Phocomelia, multiple defects
• Anticancer drugs → Cleft palate, hydrocephalus,
multiple defects
• ACE inhibitors → Hypoplasia of organs (lungs, kidney)

33. Drug Effect
Thalidomide phocomelia and multiple defects
Anticancer drugs
cleft palate, hydrocephalus, multiple
defects and foetal death
Androgens
virilization; limb, esophageal, cardiac
defects
Progestins virilization of female foetus
Stilboestrol
vaginal carcinoma in teenage female
offspring
Tetracyclines &
Glycylcyclines
discolored and deformed teeth,
retarded bone growth
Warfarin
depressed nose; eye and hand
defects, growth retardation

34. Drug Effect
Phenytoin
hypoplastic phalanges, cleft lip/palate,
microcephaly
Phenobarbitone various malformations
Carbamazepine neural tube defects, other abnormalities
Valproate spina bifida and other neural tube defects
Alcohol
low IQ baby, growth retardation, fetal
alcohol syndrome
ACE inhibitors
hypoplasia of organs, growth retardation,
fetal loss
Lithium fetal goiter, cardiac and other abnormalities
Indomethacin/a
spirin
premature closure of ductus arteriosus
Isotretinoin craniofacial, heart and CNS defects

35.  Mutagenecity and Carcinogenicity
Capacity of a drug to cause genetic defects and cancer
respectively
Chemical carcinogenesis generally takes several (10-40)
years to develop.
 Anticancer drugs
 Radio-isotypes
 Estrogens
 Tobacco

36.  Drug induced diseases
Also called Iatrogenic(Physician induced) diseases
Functional disturbances caused by drugs which persist
even after the offending drug has been withdrawn and
largely eliminated
• Salicylates, Corticosteroids→ Peptic ulcer
• Phenothiazines, other antipsychotics → Parkinsonism
 Isoniazid → Hepatitis

37.  Drug allergy (bizarre reactions)
 Immunologically mediated reaction producing
stereotype symptoms, unrelated to the
pharmacodynamic profile of the drug
 Generally occur even with much smaller doses
(dose independent)
 Also called Drug hypersensitivity

38.  Drug allergy

39.  Drug allergy

40.  Drug allergy
Hypersensitivity Reactions
Type I Type IV
Type III
Type II
Antibody Mediated Immunity
Cell Mediated
Immunity
Fast Response
Minutes
Intermediate Response Late Response
Arthralgia
Glo nephritis
Cell Mediated
Cytotoxicity
Body Cells
Directly Attacked
By Antibodies
Allergic
Reactions
Urticaria
Anaphylxia
Hemolytic
anemia
granulocytopenia
Complex
accumulation
and destruction
Contact
dermatitis

41.  Drug allergy (typeS)

42.  Drug allergy (typeS)
 Immune reaction: Type I (IgE-mediated)
 Mechanism: Drug-IgE complex binding to mast cells with
release of histamine, inflammatory mediators
 Clinical manifestations: Anaphylaxis, urticaria,
angioedema, bronchospasm
 Time of reaction: Minutes to hours after drug exposure

43.  Drug allergy (typeS)
 Immune reaction: Type II (Cytotoxic)
 Mechanism: Specific IgG or IgM antibodies directed at
drug-hapten coated cells
 Clinical manifestations: Hemolytic Anemia, leukopenia,
Thrombocytopenia
 Time of reaction: Variable

44.  Drug allergy (typeS)
 Immune reaction: Type III (immune complex)
 Mechanism: Tissue deposition of drug-antibody complexes
with complement activation and inflammation
 Clinical manifestations: Serum sickness, vasculitis,
fever, rash, arthralgia
 Time of reaction: 1 to 3 weeks after drug exposure

45.  Drug allergy (typeS)
 Immune reaction: Type IV (delayed, cell mediated)
 Mechanism: MHC presentation of drug molecules to T cells
with cytokine and inflammatory mediator release; may
also be associated with activation and recruitment of
eosinophils, monocytes, and neutrophils
 Clinical manifestations: Contact sensitivity, Skin rashes,
organ-tissue damage
 Time of reaction: 2 to 7 days after drug exposure

46.  Drug allergy
Skin reactions
 Urticaria (hives) and angioedema (swelling)
Anticonvulsants, neuromuscular blocking agents,
Antibiotics, ACE inhibitors, NSAIDs, narcotics
 Fixed drug eruption: Hyper-pigmented plaques that occur
at the same site upon re-exposure to the culprit drug
Sedatives, Anticonvulsants, Chemotherapeutic Agents,
Sulfonamide And Tetracycline Antibiotics NSAIDs,

47.  Drug allergy----Skin reactions
 Urticaria (hives) and angioedema (swelling)
 Fixed drug eruption:

48.  Drug allergy
Skin reactions
• Severe forms of cutaneous drug reactions are
 Stevens-Johnsonsyndrome (SJS): SJS begins with a
maculopapular rash that often progresses to bullae,
mucous membrane ulcerations, conjunctivitis, fever, sore
throat and fatigue.
 Toxic epidermal necrolysis (TEN): Same symptoms of SJS +
exfoliative dermatitis (detachment of skin’s outer most
layer + scalded skin appearance.
Anticonvulsants, Phenytoin, Carbamazepine, Lamotrigine,
Barbiturates, Psychotropic Agents, Sulfonamides,
Corticosteroids, NSAIDs (oxicams)

49.  Drug allergy---Skin reactions
 Stevens-Johnsonsyndrome (SJS), Toxic epidermal necrolysis (TEN)

50.  Drug allergy
Other organ systems
 Renal, Hepatic And Hemolytic Systems
 Hematologic : Hemolytic anemia, leukopenia,
thrombocytopenia
Anticonvulsants, Penicillin, Sulfonamides, Cephalosporins
 Renal: Interstitial nephritis, glomerulonephritis
Penicillin, Sulfonamides, ACE inhibitors, NSAIDs
 Hepatic: Hepatitis, cholestatic jaundice
Phenothiazines, Carbamazepine, Sulfonamides,
Erythromycin, Anti-tuberculosis Agents

51.  Drug allergy--Other organ systems-Renal, Hepatic
 Renal:
 Hepatic:

52.  Drug allergy
 Multi-organ reactions
 Serum sickness: an immune-complex reaction that presents
with fever, lymphadenopathy (swollen/enlarged lymph
nodes), arthralgia, and cutaneous lesions.
Heterologous antibodies, infliximab, allopurinol,
thiazides, antibiotics (e.g., cefaclor)
 Drug-induced lupus erythematosus (DILE): The typical
symptoms of DILE include sudden onset of fever and
malaise; myalgia, arthralgia, and arthritis may also occur
several weeks after drug initiation.
Hydralazine, procainamide, isoniazid, quinidine,
minocycline, antibiotics, and anti–TNF-alpha agent

53.  Drug allergy----Multi-organ reactions
 Serum sickness:
 Drug-induced lupus erythematosus (DILE):

54.  Drug allergy
 Multi-organ reactions
 Vasculitis : a heterogeneous group of disorders that are
characterized by inflammatory destruction of blood
vessels).
Sulfonamide antibiotics and diuretics, hydralazine,
penicillamine, propylthiouracil
 Anaphylaxis : a serious systemic allergic reaction that is
rapid in onset and may cause death
Antibiotics, neuromuscular blocking agents, anesthetics,
recombinant proteins (e.g., omalizumab)

55.  Drug allergy---Multi-organ reactions
 vasculitis
 anaphylaxis

56. • .

57. Name of the drug Year of withdrawl country reason
aceclofenac 1979 UK Vasculitis
Cyclobarbital 1980 Norway Risk of overdose
Dexfenfluramine 1997
European Union, UK,
US
Cardiotoxic
Gatifloxacin 2006 US
Increased risk of
dysglycemia
Ketorolac 1993
France, Germany,
others
Hemorrhage, Kidney
Failure
Lysergic acid
diethylamide (LSD)
1950s–1960s
Marketed as a
psychiatric drug;
withdrawn after it
became widely used
recreationally. Now
illegal in most of the
world.
Phenformin and Bufor
min
1977 France, Germany US Severe lactic acidosis
Rofecoxib (Vioxx) 2004 Worldwide
Withdrawn by Merck
& Co. Risk
of myocardial
infarction and stroke[2]