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.
7. Classification of ADRs
Type of reaction…………………..wills and brownAUGMENTED
DELAYED
ENDOFTREATMENT
FAMILIAL
GENOTOXICITY
HYPERSENSITIVITY
UNCLASSIFIED
8. Type A (Augmented) reactions
Anticoagulants
↓ Intra Vascular
Coagulation
Antihypertensives
Vasodilators
Hypotension
Head ache
Antidiabetics
Antiarrhythmics
β blockers
HypoglycemiaNormalize
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
14.
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
Rangeof
Pharmacodynamic
Effects
Effect 1
Effect 2
Effect 3
Desirable
Undesirable
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
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.
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
40. Drug allergy
Hypersensitivity Reactions
Type I Type IVType IIIType 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
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)
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
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)