Adverse Drug Reactions

-Rohit Shrivastava
Overview of this Presentation
• 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
 Introduction
• 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, diagnostic,
prognostic or therapeutic effects primarily required.
2. Drug reactions which are additional effects or non-relevant and not
primarily sought.

• The unintended and non-relevant effect of drugs are

termed as side effects of drugs or more specifically
“Adverse Drug Reactions”.
 History
• 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

 Definition
• “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”.
 Classification of Adverse Drug
Reaction
On the basis of onset of events
Acute
Sub-acute
•
Latent
–
–
–

On the basis of severity

Mild
Moderate
•
Severe
–
–
–
 Classification contd…
• 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)
 Common Causes of ADR

• Antibiotics
• Antineoplastics*
• Anticoagulants
• Cardiovascular drugs*
• Hypoglycemics
• Antihypertensives
• Analgesics
• CNS drugs*
 ADR Risk Factors

• Age
• Multiple medications
• Inappropriate medication prescribing or use
• Altered physiology
• Prior history of ADRs
• Extent (dose) and duration of exposure
• Genetic predisposition
 Dose related ADR’s

• 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.
• 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.
• 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.
 Non-dose related ADRs
• 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
• Pseudo allergic reactions
– non-immunological reactions
– e.g. radio contrast dye reaction

• Pharmacogenetic variations
– Include Idiosyncratic Reactions
– Heinz body hemolytic anemia – sulfones, primaquine,
phenylbutazone.
 Long term and Delayed effects of
ADRs
• 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.
• 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.
 Surveillance methods used to
detect ADRs
• 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

• 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
 References
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www.cc.nih.gov/training).
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• Ramanujam,T.R.ed (2009).Adverse Drug Reactions. E-pharma articles.
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• 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.
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• Davies,D.M. ed (1981).Textbook of Adverse Drug Reactions. Medical Oxford Publications.
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