Adverse drug reaction

1. ADVERSE DRUG REACTIONS

2. OBJECTIVES
 Define adverse drug reactions
 Discuss epidemiology and classification of ADRs
 Describe basic methods to detect, evaluate, and
document ADRs
 ADR monitoring in India

3. DEFINITION
 The WHO defines adverse drug reaction as a:
 response to a drug that is noxious and unintended
and that occurs at doses used in humans for
prophylaxis, diagnosis, or therapy of disease, or for
the modification of physiologic function.
 excludes therapeutic failures, overdose, drug
abuse, noncompliance, and medication errors.
 UK commission on human medicines defines an
ADR as an unwanted or harmful reaction
experienced after administration of a drug or
combination of drugs under normal conditions of
use and suspected to be related to the drug.

4. EPIDEMIOLOGY OF ADRS
 substantial morbidity and mortality
 estimates of incidence vary with study
methods, population, and ADR definition
 4th to 6th leading cause of death among
hospitalized patients
 6.7% incidence of serious ADRs
 0.3% to 7% of all hospital admissions.
 annual dollar costs in the billions.
 30% to 60% are preventable.

5. WHY IS ADR MONITORING NEEDED?
 To make drugs safer
 To identify the risk factors associated with the development of
ADRs and mechanism of their causation.
 Systematic analysis of the obtained data and dissemination to
the health agencies, regulatory authorities, pharmaceutical
companies, physicians, and other members of the health care
system so that the safety of drugs and modification of the
prescribing patterns can be ensured.
 To detect unexpected and severe ADRs to established drugs
and even minor ones to new drugs.
 Estimation of pharmacoeconomic data related to ADRs.

6. CLASSIFICATION OF ADVERSE DRUG REACTIONS
Type A(Augmented) reactions:
o mechanism based adverse reactions.
o based on pharmacologic properties of drug.
o often predictable and dose dependent,
preventable and reversible.
o responsible for at least two-thirds of ADRs
o Includes side effects, toxic effects and
consequences of drug withdrawal.
o Examples: hypoglycemia with Sulfonylureas,
anticholinergics and dry mouth, respiratory
depression with Opioids.

7. CLASSIFICATION
Type B (Bizarre) reactions:
• Not predictable on the basis of a drug’s
pharmacology.
• Based on the peculiarities of the patient.
• Generally unrelated to dosage, comparatively rare
and are more likely to cause serious illness and
death.
• Require withdrawal of drug.
• Include idiosyncratic or immunologic, intolerance
reactions.
• Examples :Malignant hyperthermia of inhalation
anesthesia, chloramphenicol induced aplastic
anemia

8. CLASSIFICATION
Type C (chronic) reactions:
associated with long-term use
involves dose accumulation
Reactions with chronic effects related to long term
drug use.
Cumulative toxic effects of a drug used over time
in which adverse effects increase gradually.
Examples: analgesic nephropathy or anti -
malarials and ocular toxicity, osteonecrosis of
the jaw with biphosphonates.

9. CLASSIFICATION
Type D(Delayed) reactions:
delayed effects (dose dependent), become
apparent some time after the use of the drug
Timing of these reactions make them more difficult
to detect.
Craniofacial malformations in infants whose
mothers have taken isotretinoin.
Development of secondary cancers in patients
treated with alkylating agents .
Teratogenicity (e.g. fetal hydantoin syndrome)

10. CLASSIFICATION
 Type E reactions:
 ‘End-of-use’ reactions, are associated with the
withdrawal of a medicine.
 An example is insomnia, anxiety and perceptual
disturbances following the withdrawal of
benzodiazepines
 Withdrawal seizures when anti- convulsants such
as phenytoin are stopped.
 Management: reintroduce and withdraw slowly

11. CLASSIFICATION
 Type F reactions:
 Unexpected failure of therapy
 Common, dose related and often caused by drug
interaction.
 Example: inadequate dosage of oral contraceptive
particularly when used with enzyme inducers.
 Management: increase dosage and consider
concomitant therapy.

12. CLASSIFICATION
 Joining the DOTS: a new approach to classify
adverse drug reactions.
 Dose
 Timing
 Susceptibility

13. GRADING ADVERSE DRUG REACTIONS
o Severity of adverse drug reactions has been
graded as:
o Minor: no therapy, antidote or prolonged
hospitalization required.
o Moderate: require change in drug therapy, specific
treatment or prolonged stay in hospital.
o Severe :potentially life threatening, causing
permanent damage or requires intensive medical
treatment
o Lethal: directly or indirectly contributes to death of
patient

14. DRUG INTOLERANCE
 It is the appearance of characteristic toxic effects of
a drug in an individual at therapeutic doses.
 Converse of tolerance and indicates a low
threshold of the individual to the action of a drug.
 Tinnitus after normal dose of aspirin or a single
dose of triflupromazine induces muscular
dystonias in some individuals.

15. IDIOSYNCRASY
 It is genetically determined abnormal reactivity to a
chemical .
 Reaction is restricted to individuals with a particular
genotype.
 Drug interacts with some unique feature of the individual
not found in majority of subjects and produces
characteristic reaction.
 Most commonly, this is caused by an enzymopathy,
congenital or acquired, so that the triggering
substance cannot be processed properly in the
organism and causes symptoms by accumulating or
blocking other substances to be processed.
 An idiosyncrasy causing symptoms like an allergy is
also called pseudoanaphylaxis.
 Barbiturates cause excitement and mental
confusion in some individuals.

16. DRUG ALLERGY
 Immunologically mediated reaction producing
stereotype symptoms which are unrelated to
pharmacodynamic profile of drug.
 Occur even at smaller doses and have a different
course of onset and duration.
 Prior sensitization needed and latent period of 1-2
weeks required.
 Reaction disappears on withdrawal.
 Allergic reactions vary from rash, serum sickness
and angioedema to life threatening bronchospasm
and hypotension.
 variations of the HLA-B gene are associated with
adverse reactions to certain drugs.

17. DRUG ALLERGY
 Individuals who have HLA-B*1502 are more likely
to experience a severe skin disorder
called Stevens–Johnson syndrome in response to
Carbamazepine .
 Type 1 reactions: immediate hypersensitivity
reactions. drug/antigen-specific IgE crosslinks with
receptors on mast cells and basophills.
 Type-2 reactions: based on IgG or IgM
mechanisms. Complement system involved .
 Type-3 reactions: intravascular immune
complexes involving IgG or IgM.
 Type 4 reactions: T-cells mediated delayed
hypersensitivity.

18. ADR FREQUENCY BY DRUG USE
0
10
20
30
40
50
60
0-5 6-10 11-1516-20
Number of Medications
Frequency
(%)

19. PREDISPOSING FACTORS
 Age
 Gender
 Multiple drug therapy
 Intercurrent disease
 Race and genetic polymorphism

20. MECHANISMS OF DOSE RELATED ADRS
 Pharmaceutical causes: alterations in either the
quantity of drug present or its release
characteristics.
 Pharmacokinetic causes: alterations in ADME
lead to alterations of concentration of drug at site of
action.
 Example: slow acetylators are at increased risk
of developing type A reactions(isoniazid
induced perpheral neuropathy)
 Pharmacodynamic causes: altered sensitivity of
target organs or tissues

21. MECHANISM OF NON DOSE RELATED ADRS
 Pharmaceutical causes: presence of degradation
products of the active constituents, non-drug
components of the formulation.
 Example: diethylene glycol used as a solvent in
the sulphanilamide elixir(caused105 deaths)
 Pharmacokinetic causes: differences in oral
bioavailability due to genetic polymorphism in drug
transporters.
 Pharmacodynamic causes: genetic causes for
abnormal response examples: (G6PD deficiency
and haemolytic anemia)
 Oxidant drugs and methaemoglobinaemia,
glucocorticoids causing glaucoma.

22. DETECTION AND MONITORING OF ADRS
 Premarketing clinical trials
 Animal studies, human studies—Phases I, II, III
 Detects only most common ADRs
• Cannot identify ADRs with incidence < 1%
• Common methods employed in Postmarketing
surveillance are:
Case reports or case series of ADRs
 Cohort studies
 Case control studies
 Meta analysis
 Spontaneous reporting schemes

23. SPONTANEOUS REPORTING
 Best method for detecting new ADRs
 Necessary because many ADRs not detected in
pre- or post marketing studies
 Initiated by physicians, pharmacists, nurses,
patients. Capable of detecting rare and common
reactions.
 Problems include underreporting, inaccurate
reporting that may not show causality.

24. DETERMINING CAUSALITY OF ADRS
 Factors in determining causality:
 Strength of the association
 Consistency of the observed evidence
 Temporality of the relationship
 Any ADR that occurs in association with a
medicine does not mean the medicine is
responsible
 Delayed reactions do not rule out the medicine
as causing the ADR
 Possible involvement of other causes.
 Outcome of the reaction upon de-challenge
and re-challenge.
 Concomitant drug or disease

25. CAUSALITY ASSESSMENT
 Are there alternative causes that could on their own
have caused the reaction?
 Did the ADR reappear when a placebo was given?
 Was the drug detected in the blood (or other fluids)
in concentrations known to be toxic?
 Was the ADR more severe when the dose was
increased or less severe when the dose was
decreased?
 Did the patient have a similar ADR to the same or
similar drugs in any previous exposure?

26. CLASSIFYING CAUSALITY OF AN ADR:WHO
 Certain causality
 Probable or likely causality
 Possible causality
 Unlikely causality

27. CLASSIFYING CAUSALITY OF AN
ADR:NARANJO ALOGRITHIM
Question Yes No Do Not
Know
Are there previous conclusive reports on this reaction? +1 0 0
Did the adverse event appear after the suspected medicine was
administered?
+2 -1 0
Did the adverse reaction improve when the medicine was
discontinued or a specific antagonist was administered?
+1 0 0
Did the adverse reaction reappear when the medicine was re-
administered?
+2 -1 0
Are there alternate causes (other than the medicine) that could
solely have caused the reaction?
-1 +2 0
Was the medicine detected in the blood (or other fluids) in a
concentration known to be toxic?
+1 0 0
Was the reaction more severe when the dose was increased or less
severe when the dose was decreased?
+1 0 0
Did the patient have a similar reaction to the same or similar
medicines in any previous exposure?
+1 0 0
Was the adverse event confirmed by objective evidence? +1 0 0

28. PHARMACOVIGILANCE CENTERS IN INDIA

29. ADR MONITORING IN INDIA
 The Central Drugs Standard Control
Organization (CDSCO), Directorate General of
Health Services in collaboration with Department of
Pharmacology, All India Institute of Medical
Sciences (AIIMS), New Delhi has launched the
nation-wide Pharmacovigilance programme for
protecting the health of the patients by assuring
drug safety.
 Department of pharmacology at AIIMS : as national
coordinating center.
 Nineteen ADR monitoring centers.

31. FUNCTIONS OF THE WHO PROGRAM

32. MANAGEMENT OF ADRS
Step 1. Evaluate the nature of the event.
 Obtain a detailed history of the patient.
 Identify and document the clinical
reaction. Look up suspected medicines and
known ADRs in the literature and match
them with the reactions described by the
patient
 Classify the severity of the reaction.

33. MANAGEMENT OF ADRS
Step 2. Establish the cause.
 Use the Naranjo algorithm (or other
system) to assess the patient’s reaction.
 Evaluate the quality of the medicine.
 Check for a medication error.

34. MANAGEMENT OF ADRS
Step 3. Take corrective and follow-up action.
Corrective action will depend on cause and
severity
 Severe ADRs
 Educate and monitor prescribers.
 Change the formulary or standard treatment guideline if
necessary to substitute a medicine that is safer or that is
easier to use by staff.
 Modify patient monitoring procedures.
 Notify drug regulatory authorities and manufacturers.
 All ADRs
 Educate and warn patients

35. REFERENCES
 Walker, “ Clinical Pharmacy and Therapeutics”, 4th
edition, Page 51.
 Koda Kimble& Young’s Applied therapeutics, 10th
edition, Page 42.