ADR study

1. ADVERSE DRUG
REACTIONS
DR HARIKRISHNAN A R

2. Outline
Introduction
Pharmacovigilance
Classification
Categories
Prevention

3. Introduction
 Adverse effect  any undesirable consequence of
drug administration
 Adverse drug reaction  any noxious change 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 drug

4. Incidence and severity
 Patient characteristics  age, sex, ethnicity, coexisting
disorders, genetic or geographic factors
 Drug factors  type of drug, administration route,
treatment duration, dosage, bioavailability

6. Pharmacovigilance
 Science and activities relating to the direction,
assessment, understanding and prevention of
adverse effects or any other drug related problems

7. Classification of ADRs
 Type of reaction: Type A (Augmented), B (Bizarre),
C(Chemical),D (Delayed), E (Exit), F (Familial), G (Genotoxicity),
H (Hypersensitivity), U (Un classified)
 Severity: Minor, Moderate, Severe, Lethal ADRs
 Others: Side effects, Secondary effects, Toxic effects,
Intolerance, Idiosyncrasy, Drug allergy, Photosensitivity, Drug
Dependence, Drug Withdrawal Reactions, Teratogenicity,
Mutagenicity, Carcinogenicity, Drug induced disease
(Iatrogenic)

8. Severity
 Minor  no therapy, antidote or prolonged
hospitalisation required
 Moderate  requires change in drug therapy,
specific treatment and prolongs hospital stay
 Severe  potentially life threatening, causes
permanent damage or requires intensive medical
treatment
 Lethal  directly or indirectly contributes to death of
patient

9. Classification of ADRs....
Wills and Brown
 Type A (Augmented)
 Type B (Bizarre)
 Type C (Chemical)
 Type D (Delayed)
 Type E (Exit/End of treatment)
 Type F (Familial)
 Type G (Genotoxicity)
 Type H (Hypersensitivity)
 Type U (Un classified)

10. 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
 Anticoagulants  Bleeding
 Beta blockers  Bradycardia
 Nitrates  Headache
 Prazosin  Postural hypotension

11. 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

12. Type C (Chemical) reactions
 Biological characteristics can be predicted from the
chemical structure of the drug/metabolite
 Paracetamol  Hepatotoxicity

13. Type D (Delayed) reactions
 Occur after many years of treatment.
 Can be due to accumulation.
 Chemotherapy  Secondary tumours
 Phenytoin during pregnancy  Teratogenic effects
 Antipsychotics  Tardive dyskinesia
 Analgesics  Nephropathy

14. Type E (End of treatment)
reactions
 Occur on withdrawal especially when drug is stopped
abruptly
 Phenytoin withdrawal  Seizures,
 Steroid withdrawal  Adrenocortical insufficiency.

15. Type F (Familial)
 Occurs only in genetically predisposed
 G6PD deficiency  primaquine  haemolytic
anaemia

16. Type G (Genotoxicity)
 Irreversible genetic damage
 Thalidomide  phocomelia

17. Categories
1) Side effects
2) Secondary effects
3) Toxic effects
4) Poisoning
5) Intolerance
6) Idiosyncrasy
7) Drug allergy
8) Photosensitivity
9) Drug dependence
10) Withdrawal reactions
11) Teratogenicity
12) Mutagenicity and carcinogenicity
13) Drug induced diseases

18. Side effects
 Unwanted unavoidable pharmacodynamic effects at therapeutic
doses
 Based on same action  atropine causes dryness of mouth
 Based on different action  promethazine causes sedation
 Therapeutic in one context side effect in other  codeine causes
constipation which is used therapeutically in traveller’s diarrhoea
 Drugs developed by observation of side effects  sulphonamides
causes hypoglycaemia now used as OHA

19. Secondary effects
 Indirect consequence of a primary action of the
drug
 Suppression of bacterial flora by tetracyclines 
superinfections

20. Toxic effects
 Excessive pharmacological action of the drug 
overdosage/prolonged use
 Absolute  accidental/suicidal/homicidal
 Relative  usual dose of gentamycin in renal failure patients
 Extended therapeutic effect  barbiturates causing coma
 Another action  morphine causing respiratory failure

21. Poisoning
 Large doses of the drugs
 Endangers life by severely affecting one or more
vital functions
 Specific antidotes are available for some drugs

22. Intolerance
 Toxic effects at therapeutic doses
 Low threshold of the individual to the action of the
drug
 Carbamazepine  ataxia
 Chloroquine  vomiting, abdominal pain

23. Idiosyncrasy
 Genetically determined abnormal reactivity to a chemical
 Interacts with some unique feature off the individual 
uncharacteristic action
 Barbiturates  excitement and mental confusion
 Quinine/quinidine  cramps, diarrhoea
 Chloramphenicol  aplastic aneamia

24. Drug allergy/hypersensitivity
 Immunologically mediated reaction  symptoms
unrelated to the pharmacodynamic profile of the
drug
 Occurs even at smaller doses
 Different time course of onset and duration
 Prior sensitisation is needed
 Latent period 1-2 weeks
 Drug or its metabolite acts as an antigen or hapten
and induce production of antibodies

25. Types of allergic reactions
 Humoral
 Cell mediated

26. Humoral
 Type-1(anaphylactic) reactions  reaginic antibodies(IgE)
when exposed to the antigen  inflammatory mediators
urticaria, itching, angioedema, rhinitis or anaphylactic shock
 Type-2(cytosolic) reactions  drug + cell component 
antibodies(IgM, IgG) bind to target cells  re-exposure 
AG:AB reaction  complement activation  cytolysis.
Thrombocytopenia, agranulocytosis, aplastic anaemia,
haemolysis, etc.
 Type-3(retarded) reactions  circulating antibodies(IgG).
AG:AB complex  complement  precipitate on vascular
endothelium  destructive inflammatory response. Serum
sickness, PAN, SJS

27. Cell mediated
 Type-4(delayed hypersensitivity) reactions 
sensitized T-lymphocytes  contact with AG 
lymphokines  granulocytes  inflammatory
response. Contact dermatitis, rashes, fever

28. Photosensitivity
 Cutaneous reaction  drug induced sensitization of skin
to UV radiation
 Phototoxic - drug/metabolite accumulates 
photochemical reaction  photobiological reaction 
tissue damage, i.e. erythema, oedema, blistering,
hyperpigmentation and desquamation. Tetracyclines, tar
products
 Photoallergic – drug/metabolite  cell mediated
immune response  exposure to UV  popular or
eczematous contact dermatitis. Sulphonamides,
griseofulvin, chloroquine

29. Drug dependence
 Alters mood and feelings
 Repetitive use  euphoria, withdrawal from reality,
social adjustment
 Use of drugs for personal satisfaction given higher
priority

30. Psychological dependence
 Optimal state of well being  action of the drug
 Intensity varies from desire to craving
 Reinforcement  ability of the drug to produce
effects that make the user wish to take it again or to
induce drug seeking behaviour
 Strong reinforcers  opioids, cocaine
 Weak reinforcers  benzodiazeoines

31. Physical dependence
 Altered physiological state  repeated
administration of a drug which necessitates
continued presence of the drug to maintain
physiological equilibrium
 Discontinuation  withdrawal syndrome
 Opioids, barbiturates, alcohol, benzodiazepines

32. Drug abuse
 Use of a drug by self medication
 Deviates from the approved medical and social
patterns
 Social disapproval of the manner and purpose of
drug use

33. Drug addiction
 Compulsive drug use
 Overwhelming involvement with the use of a drug
 Relapse is common
 Amphetamines, cocaine, cannabis, LSD
 Most have little or no physical dependance

34. Drug habituation
 Less intensive involvement with the drug
 Withdrawal produces only mild discomfort
 Tea, coffee, tobacco, social drinking
 Physical dependence absent

35. Drug withdrawal reactions
 Sudden interruption of therapy with certain drugs 
adverse consequences
 Worsening of clinical condition mostly
 Abrupt cessation of corticosteroid therapy  acute
adrenal insufficiency
 Clonidine  severe hypertension, restlessness and
sympathetic overactivity
 β blockers  worsening of angina, precipitation of MI
 Minimised by gradual withdrawal

36. Teratogenicity
 Capacity of a drug to cause foetal abnormalities
when administered to a pregnant mother
 Fertilisation and implantation  conception – 17
days  failure of pregnancy
 Organogenesis  18 – 55 days  deformities (most
vulnerable period)
 Growth and development  56 days onwards 
developmental abnormalities

39. Mutagenicity and carcinogenicity
 Capacity of a drug to produce genetic defects and
cancer
 Covalent interaction with DNA  mutations
 When the modified DNA sequences code factors
like protooncogenes  cancer or tumour
 Chemical carcinogenesis  without interacting with
DNA, takes 10-40 years to develop
 Anti cancer drugs, radioisotopes, oestrogen,
tobacco

40. Drug induced
diseases(Iatrogenic)
 Functional disturbances caused by drugs
 Persists even after the offending drug has been
withdrawn
 Salicylates and corticosteroids  peptic ulcer
 Antipsychotics  parkinsonism
 Isoniazid  hepatitis
 Hydralazine  DLE

41. Prevention
 Avoid inappropriate use
 Appropriate dose, route and frequency
 h/o drug reactions
 h/o allergic disease
 Drug interactions
 Administration technique
 Lab monitoring

42. Summary
 Definition
 Classification
 Categories
 Prevention

43. Thank you