Adverse drug reactions & Pharmacovigilance

1. Adverse Drug Effects
Dr. M. Ahsan (MBBS, MD)

2. Adverse Drug Effects
“Any undesirable or unintended consequence of drug
administration”

3. Adverse Drug Reaction
• ADR is defined as :
“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”

4. Classification
• A – Augmented
• B – Bizarre
• C – Continuous use
• D – Delayed
• E – End of dose

5. Classification
Type A :
Directly related to the pharmacological action of the
drug

6. Classification
Type B :
• Idiosyncratic and genetically determined

7. Classification
Type C :
• Associated with long term use of the drugs
• Eg: tardive dykinesia with neuroleptics

8. Classification
Type D :
• Teratogenicity or carcinogenicity
• Eg : fetal phenytoin syndrome

9. Classification
Type E :
• Due to abrupt stoppage of the drug
• Eg. Beta blockers, corticosteroids

10. Severity of ADR
• Minor
• Moderate
• Severe
• Lethal

11. Severity of ADR
• Minor : no treatment/antidote or hospitalisation
required

12. Severity of ADR
• Moderate : change in drug therapy required,
specific treatment, increase in hospitalisation by
atleast one day

13. Severity of ADR
• Severe : potentially life threatening, causes
permanent damage or requires intensive care

14. Severity of ADR
• Lethal : Directly or indirectly contributes to death
of the patient

15. Adverse Drug Effects
• Side effects
• Secondary effects
• Toxic effects
• Intolerance
• Idiosyncrasy
• Drug allergy
• Photosensitivity
• Drug dependence
• Drug withdrawal reactions
• Teratogenicity
• Mutagenicity &
Carcinogenicity
• Drug Induced diseases

16. Side effects
• Unwanted but unavoidable pharmacodynamic
effects
• Occur at normal doses
• Not serious and can be predicted
• Reduction in dose decreases the symptoms

17. Side effects
• Side effect based on the same action as therapeutic
effect :
• Atropine as preanesthetic drug also caused dryness
of mouth

18. Side effect
• Side effect based on different action than
therapeutic effect :
• Anti-histaminics used for allergies also cause
sedation

19. Side effect
• An effect may be side effect in one context and
therapeutic in the other
• Codeine used for cough produces constipation –
thus also used for traveller’s diarrhoea

20. Secondary effects
• Indirect consequences of a primary action
• Suppression of bacterial flora by broad spectrum
antibiotics causes superinfections

21. Toxic effects
• Excessive pharmacological action of the drug
• Caused by overdosage or prolonged use
• Overdosage can be absolute or relative
• Symptoms are predictable and dose related
• Symptoms are due to functional alteration or tissue
damage

22. Toxic effects
Result from extension of the pharmacological profile
:
Eg : barbiturates in over-dose produce coma

23. Toxic effects
• Action beside the therapeutic effect can be
responsible for toxic manifestations
• Eg : morphine used for analgesia produces
respiratory failure in overdose

24. Intolerance
• Appearance of toxic effects in an individual at
therapeutic doses
• Eg : Single dose of triflupromazine induces
muscular dystonias

25. Idiosyncrasy
• Genetically determined abnormal reactivity to a
chemical
• Related to the genotype of the individual
• Single dose of chloramphenicol caused bone
marrow suppression

26. Drug allergy
• Also called drug hypersensitivity
• Immunologically mediated reaction producing
typical symptoms which are unrelated to the
pharmacodynamic profile of the drug

27. Drug allergy
• Symptoms are not related to the pharmacodynamic
actions of the drug
• Severity of reaction poorly correlates with dose of drug
• Occurs in few recipients
• Prior sensitization is needed
• Chemically related drugs show cross sensitivity

28. Drug allergy
• Humoral
Type 1 / Anaphylactoid reactions
Type 2/ Cytolytic reactions
Type 3/ Arthus reactions
• Cell-mediated
Type 4/ Delayed hypersensitvity reactions

29. Drug allergy : Type 1
• Anaphylactic reaction
• On exposure to the drug AG:AB reactions take place
on the surface of mast cells releasing mediators (
histamine, 5-HT, LTs etc). IgE is involved.
• manifests as urticaria, itching, angioedema,
bronchospasm, rhinitis or anaphylactic shock
• Allergy develops within minutes and lasts for 1-2hrs

30. Drug allergy : Type 2
• Cytolytic reaction
• AG= drug +component of tissue
• AB= IgG/IgM
• AG:AB reaction occurs on the surface of cells,
activating complement and resulting in cytolysis
• Manifests as : thrombocytopenia, agranulocytosis,
aplastic anemia etc
• Eg. Penicillin or methyldopa-induced hemolytic
anemia

31. Drug allergy : Type 3
• Arthus reaction
• AG and AB form large complexes which acivate
complement.
• Small blood vessels are damaged or blocked.
• Leucocytes attracted to the site of reaction start an
inflammatory process
• Manifests as serum sickness,glomerulonephritis,
vasculitis, Steven-Johnson syndrome

32. Drug allergy : Type 4
• Delayed hypersenstivity reaction
• Sensitized T-lymphocytes bind to the AG and
generate lymphokines which attract granulocytes
to generate an inflammatory response
• Manifests as contact dermatitis, photosensitization
etc

33. Photosensitivity
• Cutaneous reactions resulting from drug induced
sensitization of the skin to UV radiation
Phototoxic
Photoallergic

34. Photosensitivity
Phototoxic reaction :
• UV-B (290-320nm)
• Drug accumulates in skin and undegoes a
photochemical reaction followed by a
photobiological reaction causing local tissue
damage
• Manifests as erythema, edema, blistering
• Eg : Tetracyclines, tar products, sulfonamides,
flouroquinolones

35. Photosensitivity
Photoallergic reaction :
• UV-A (320-400nm)
• Drug induces cell mediated immunity which on
exposure to light produces a contact dermatitis like
picture
• Persists long after exposure and lesions may extend
beyond the exposed area.
• Eg. Sulfonamides. Griseofulvin, Chloroquine etc

36. Adverse Drug Effects
• Side effects
• Secondary effects
• Toxic effects
• Intolerance
• Idiosyncrasy
• Drug allergy
• Photosensitivity
• Drug dependence
• Drug withdrawal reactions
• Teratogenicity
• Mutagenicity &
Carcinogenicity
• Drug Induced diseases

37. Drug dependence
• It is a state in which use of drugs for personal
satisfaction is given a higher priority than other
basic needs, often in face of known risks to health.
Types :
• Psychological dependence
• Physical (Physiological) dependence

38. Dependence
• Psychological dependence :
• It is said to have developed when the individual
believes that optimal state of well being is achieved
only through the actions of drug

39. Dependence
• Physical dependence :
• Physical dependence implies that repeated
exposure to a drug induces adaptive changes in the
body so that tolerance occurs and discontinuation
results in a withdrawl reaction

40. Other terms
Drug abuse:
• persistent or sporadic excessive drug use
inconsistent with or unrelated to acceptable
medical practice. Intentional use of excessive drugs
for purposes other than the indication for which
the drug was prescribed.

41. Other terms
Drug addiction:
• compulsive drug use charachterized by
overwhelming involvement with the use of drug.
Procuring the drug and using it take precedence
over other activities
Drug habituation:
• Less intensive involvement with the drug, so that
withdrawl produces only mild discomfort.

42. Withdrawal reactions
• Sudden cessation of therapy with certain drugs
results in worsening of the clinical condition of the
patient.
Corticostroids : Acute adrenal insufficiency
Clonidine : Severe hypertension and sympathetic
overactivity
Beta blockers : Worsening of angina, precipitaion of
MI

43. Teratogenicity
• It is the capacity of the drug to cause fetal
abnormalities when given during pregnancy.
• The type of malformation depends on the drug and
the stage at which exposure occurred.

44. Teratogenicity
Drug affect fetus at 3 stages:
• Fertilization and implantation – conception to 17 days-
failure of pregnancy
• Organogenesis – 18-55 days of gestation-most susceptible
period for adverse effects- deformities are produced
• Growth & Development – 56days onwards- developmental
and functional abnormalities can occur

45. Teratogenicity
• According to their effect on fetus, drugs have been
classified into 5 categories by the US-FDA
A- No risk
B- No evidence of risk in humans
C- Risk cannot be ruled out
D- Benefit may outweigh potential risk
X- Contraindicated

46. Teratogenicity
• All drugs should be avoided during the first
trimester
• Well known single component drugs should be
preferred to combination therapy
• Drugs which have been used extensively in
pregnancy are safer compared to new drugs
• Neural tube defects are reduced by folate therapy
during pregnancy

47. Teratogenicity
• ACE inhibitors : hypoplasia of organs
• Alcohol : low IQ baby, growth retardation, fetal alcohol syndrome
• Indomethacin : Premature closure of ductus arteriosus
• Phenytoin : hypoplastic phalanges, cleft lip. microcephaly
• Tetracyclines : discolored and deformed teeth, retarded bone
growth

48. Mutagenicity & Carcinogenicity
• It is the capacity of the drug to cause genetic
defects and cancers respectively.
• Drug exposure needs to be prolonged (3-5yrs)
Mechanisms involved :
• Alteration of DNA
• Immunosuppression
• Hormonal

49. Mutagenicity & Carcinogenicity
• Alteration of DNA :
Drugs or their metabolites act by causing mutations
and activating oncogenes.
Eg. Griseofulvin
Alkylating agents
Manifests as leukemias or lymphomas

50. Mutagenicity & Carcinogenicity
• Immunosuppression :
Malignancies develop in immunosuppressed
patients.
Eg. After organ transplantation and cancer
chemotherapy
Lymphoid neoplasms are common

51. Mutagenicity & Carcinogenicity
• Hormonal :
Long term use of estrogen induces endometrial
cancer
Diethylstilbesterol causes vaginal adenosis in
female offsprings of mothers who took it during
pregnancy

52. Drug Induced Diseases
• Eye :
Toxic cataracts : chloroquine , steroids,
Corneal opacities : phenothiazines, chloroquine
Retinal injury : indomethacin
Visual field defects : Vigabatrin
• CNS :
Tardive dykinesia : neuroleptics

53. Drug Induced Diseases
 Lungs
Amiodarone causes pulmonary fibrosis
 Kidney :
Gold salts cause nephropathy
 Liver :
Methotrexate causes hepatic fibrosis
Amiodarone induces steatohepatitis

54. Management of poisoning
• Resuscitation and maintenance of vital functions
A – patent airway
B – adequate breathing ( ventilation), 100% oxygen
C – (circulation) maintain BP and heart beat with
i.v fluids, pressor agents etc
Maintain body temp
Maintain blood sugar level with dextrose infusion

55. Management of poisoning
• Termination of exposure
Inhaled poison : remove patient to fresh air
Cutaneous: wash the skin and eyes
Ingested : induce emesis with syrup ipecac
perform gastric lavage
Emesis is contraindicated in :
Kerosene poisoning
Corrosive poisons
CNS stimulant poisons

56. Management of poisoning
• Prevention of absorption of ingested poisons
1gm/kg of activated charcoal
• Hastening elimination
Inducing diuresis
Altering urinary pH
Hemodialyis & hemoperfusion

57. Management of Drug allergy
• Stop the offending drug
• Mild type I reactions (rashes, urticaria, rhinitis)
subside spontaneously
respond to antihistaminics

58. Anaphylactic shock
Put the patient in reclining position
Oxygen inhalation
Start CPR if required
Inject 0.5ml of 1:1000 Adr i.m – repeat every 5-10
mins till the patient improves
Don’t give i.v
i.v of 1:10000 or 1:100000 given only when shock is life
threatening
H1 antihistaminic – chlorpheniramine 10-20 mg
i.m/slow i.v
Hydrocortisone 200mg i.v

59. Management of Drug allergy
• Type II reaction :
Glucocorticoids
• Type III reaction :
Glucocorticoids
• Type IV reaction :
Glucocoticoids

60. Pharmacovigilance
Defined as :
“ science and activities relating to the detection,
assessment, understanding and prevention of
adverse effects or any other drug related problems”

61. Pharmacovigilance
A systematic collection of information on adverse
drug reactions is important to provide information
regarding :
• Patient at risk
• Drug interactions
• Adverse reactions to new drugs not identified
before marketing

62. Pharmacovigilance
Activities involved are :
• Collection of data
• Dissemination of ADR data through drug alerts,
medical letters etc
• Changes in labelling of medicines eg. Black box
warning

63. Pharmacovigilance
Data collection methods are :
A. Premarketing Clinical trials
B. Postmarketing methods
• Case reports
• Cohort studies
• Prescription event monitoring
• Case-control studies
• Spontaneous reporting- yellow card system
• Phase IV clinical trial (Post marketing surveillance)

64. Thank you