Adverse Drug Reactions

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 Introduction
 History
 Definition of Adverse drug reaction
 Classification of Drug interactions
 Dose related ADR’s
◦ Pharmaceutical, Pharmacokinetic,Pharmacodynamic
 Non-dose related ADR’s
◦ Immunological, Pharmacogenetic
 Long term and delayed effects causing ADR’s
◦ Adaptive, Carcinogenesis, Hormonal, Gene toxicity
 Surveillance methods used to detect ADR’s
◦ Anecdotal, CSM, Yellow card, Post marketing
PHARMASRI PHARMASRI
 Medicines are classified according to their therapeutic
action, but no drug induces only one specific effect.
 They induces two kinds of effects-

1. Desired drug actions which result in the preventive, diagnost
prognostic or therapeutic effects primarily required.
2. Drug reactions which are additional effects or non-relevant an
not primarily sought.
 The unintended and non-relevant effect of drugs are

termed as side effects of drugs or more specifically
“Adverse Drug Reactions”.
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 Adverse Drug Reactions have been occurring since the use of
medicine has begun.
 Some evidences from History.

◦ Babylonians
◦ Homer, Hippocrates, Galen & Rhazes
◦ Hohustufen Emperor
◦ Royal College of Physicians
 1st reported Adverse Drug Reaction
PHARMASRI PHARMASRI
 “An adverse reaction is any response to a drug
that is noxious and unintended and that occurs
at doses used in man for prophylaxis, diagnosis
or therapy of disease or for the modification of
physiologic function excludes therapeutic
failures, overdose, drug abuse, noncompliance,
and medication errors” – W.H.O definition.
 F.D.A definition –“ any experience associated with
the use of a drug whether or not considered
drug-related and includes any side effect, injury,
toxicity or sensitivity reaction or significant
failure of expected pharmacological action”.
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 On the basis of onset of events
◦ Acute
◦ Sub-acute
◦ Latent
 On the basis of severity

◦ Mild
◦ Moderate
◦ Severe
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 Type A(augmented)
◦ Related to pharmacologic effect of drug
◦ often predictable and dose dependent
◦ E.g. toxicity due to overdose
 Type B(bizarre)
◦ Not related to pharmacological effect of drug
◦ idiosyncratic or immunologic reactions.
◦ E.g. Hypersensitivity
 Type C
◦ involves dose accumulation
◦ E.g. antimalarials and ocular damage
 Type D
◦ delayed effects (dose independent)
◦ E.g Teratogenicity ( thalidomides and neonatal defects)
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 Antibiotics
 Antineoplastics*
 Anticoagulants
 Cardiovascular drugs*
 Hypoglycemics
 Antihypertensives
 Analgesics
 CNS drugs*
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 Age
 Multiple medications
 Inappropriate medication prescribing or use
 Altered physiology
 Prior history of ADRs
 Extent (dose) and duration of exposure
 Genetic predisposition
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 Occurs in all patients which may vary from patient to
patient and are specific for the drug.
 Dose related ADR may occur because of the variations in

the pharmaceutical, pharmacokinetic, pharmacogenetic
or pharmacodynamic properties of the drug.
PHARMASRI PHARMASRI
 Pharmaceutical variation
◦ E.g. Phenytoin toxicity was enhanced in Australia in 1960
when the expedient of phenytoin was changed from
calcium sulphate to lactose which resulted the undue
increase in the bioavailability of the active drug.
 Pharmacokinetic variation
◦ E.g. Renal dysfunction enhanced toxicity of digitalis,
aminoglycoside, allopurinol, cephalosporins, Li and
amphoterecin B.
 Pharmacodynamics variation
◦ Hepatic disease may influence pharmacodynamic response
to drugs. Drugs like oral anticoagulants by inhibiting
clotting may cause bleeding.
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 Pharmacogenetic variation
◦ Variation in drug response and drug metabolism
due to genetic polymorphism.
◦ E.g. Acylation process –hydralazine metabolism is

influenced by genetic type of the drug enzyme that
is rapid or slow acylators. The drug toxicity is
enhanced in slow acylators.
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 It is independent of dose.
 Occurs in small number of patients as compared to dose related
ADRs.
 Immunological reactions
◦ Commonly known as Allergy or Hypersensitivity.
◦ No relation to pharmacological effect
◦ Always delay between first and subsequent exposure to drug
◦ E.g. Ampicillin causes rashes in patients with Infectious mononucleosis.
◦ Types of immunological reactions-

◦ I- Antibody IGE mediated e.g.Urticaria
◦ II-Cytotoxic e.g. Haemolytic anemia
◦ III- Drug antibody complexes are deposited in tissues e.g. serum sickness
◦ IV- delayed hypersensitivity e.g. topical antimicrobials
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 Pseudo allergic reactions
◦ non-immunological reactions
◦ e.g. radio contrast dye reaction
 Pharmacogenetic variations
◦ Include Idiosyncratic Reactions
◦ Heinz body hemolytic anemia – sulfones,
primaquine, phenylbutazone.
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 Long term effects causing ADR:
 1. Due to Adaptive changes :
◦ physical dependence by narcotic analgesics.Tardive dyskinesia
associated with long term neuroleptic therapy for schizophrenia.
 2. Due to Rebound phenomenon:

◦ Narcotic analgesics, alcohol, benzodiazepines producing
withdrawal syndrome.
◦ Withdrawal of beta blockers in hypertension leading to rebound
cardiac ischemia and rebound hypercoagulability is noted in
patients receiving protamine to counter act heparin overdose.
 3. Other Long terms effects:

◦ Chloroquine induced corneal deposits and pigmentary
retinopathy.
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 Delayed Effects causing ADR
◦ Carcinogenesis:
 Uterine endometrial carcinoma with post menopausal
estrogen replacement therapy.
 vaginal adenocarcinoma of the female off spring whose
mother received estrogen for threatened abortion.
 Benign liver tumors with oral contraceptives
◦ Hormonal :
 Hormone treatment did not confer cardiac protection to the
women on Hormonal therapy. Instead it had increased the
risk for all strokes attributed to oestrogen plus progestin.
 Women Health Initiative as well as the Million Women
Study reported an increased risk for breast cancer in long-
term users of HT.
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 Anecdotal reporting by individual doctors
◦ A patient or doctor's report of a personal experience with illness or
treatment. An anecdotal report is different from a report that presents data
from a clinical trial that uses a large number of patients, gathered and
analyzed in a scientifically controlled process. Many anecdotal reports are
appealing, often inspiring.
 CSM
◦ Adverse drug reactions (ADRs) may account for up to 5% of all hospital
admissions. However, few suspected reactions are reported to regulatory
authorities. Yellow card spontaneous reports were sent to the Committee
on Safety of Medicines for only 6.3% of ‘reportable’ reactions.
 Yellow Card
◦ The Committee on Safety of Medicine yellow card scheme is regarded as
one of the world’s best spontaneous reporting schemes for suspected
ADRs, acting as an early warning system for the identification of previously
unrecognised reactions. It has helped to identify many safety issues
including: e.g.renal failure due to aristolochia in Chinese herbs
◦ (www.show.scot.nhs.uk/CSMScotland/) Yellow cards can be submitted

electronically
PHARMASRI PHARMASRI
 Post marketing surveillance:
 Post marketing studies generally provide the
best source of quantitative information on

ADRs, given the limitations of clinical trials
and case reports. They fall into two broad
categories:
 Cohort studies
 Case control studies
PHARMASRI PHARMASRI
PHARMASRI PHARMASRI
 Calis, K.A.(2009).FDA medical products reporting program. National
Institute of health (www.cc.nih.gov/training).
 Cox,A.R.(2001) . Adverse drug reactions in patients admitted to
hospitals identified by discharge ICD-10 codes by spontaneous
reports.Br. J. Clin. Pharmacol.52(3).337-339
 Ramanujam,T.R.ed (2009).Adverse Drug Reactions. E-pharma articles.
 Pirmohamed et al (1998).Adverse drug Reactions. NHS clinical
knowledge summary
 Hoffman,M et al.(2005).Changes in women's attitudes towards and use
of hormone therapy after HERS and WHI. The European Menopause
Journal.52.11-17
 Stephens,M.D.B.(1985).The detection of New Adverse drug reactions. M
Stockton Press.p 6-20.
 Griffin,J.P, D’Arcy,P.F. (1984).A Manual of Adverse Drug Interactions.John
wright & Sons. P64-223
 Davies,D.M. ed (1981).Textbook of Adverse Drug Reactions. Medical
Oxford Publications. P 1-8, 11-29
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Adverse Drug Reactions

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PHARMASRI PHARMASRI

 They induces two kinds of effects-

 The unintended and non-relevant effect of drugs are

 Some evidences from History.

 1st reported Adverse Drug Reaction

 On the basis of severity

 Dose related ADR may occur because of the variations in

◦ E.g. Acylation process –hydralazine metabolism is

◦ Types of immunological reactions-

 2. Due to Rebound phenomenon:

 3. Other Long terms effects:

◦ (www.show.scot.nhs.uk/CSMScotland/) Yellow cards can be submitted

best source of quantitative information on

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