Adverse Drug Reactions

PHARMASRI www.pharmasri.com


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



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”.



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



“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”.



On the basis of onset of events◦ Acute◦ Sub-acute◦ Latent

On the basis of severity◦ Mild ◦ Moderate◦ Severe



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)



Antibiotics Antineoplastics* Anticoagulants Cardiovascular drugs* Hypoglycemics Antihypertensives Analgesics CNS drugs*



Age Multiple medications Inappropriate medication prescribing or use Altered physiology Prior history of ADRs Extent (dose) and duration of exposure Genetic predisposition



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.



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 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.



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



http://www.show.scot.nhs.uk/CSMScotland/

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





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



http://www.cc.nih.gov/training

Adverse Drug Reactions

Documents

drug toxicity

drug response

drug metabolism

drug abuse

drug enzyme

active drug

adverse drug reactions

pharmacologic effect