DR. SHABANA ALI

Adverse Drug Reactions (ADR)

Harm associated with the use of a given medications

ORUnwanted or harmful reaction experienced

after the administration of a drug or combination of drugs under normal

conditions of use

ADR= significant morbidity & mortalityRange from mild reactions

(drowsiness, nausea, itching& rash); disappear after discontinuation of drug

ORSevere reactions (respiratory

depression, neutorpenia, hepatocellualr injury, hemorrhage, anaphylaxis

ADR most common in

WomenElderly (>60 y old)Very young (1-4 y)Patients taking more than one drug

Classification of ADR

Rawlin & Thompson classification ABCDTraditional classification A & BAbout 80% of ADR----Type A reactions

1) Type A Reactionsa) Related to pharmacological action of drugExtensions of the principal pharmacological action

of the drugCont.

b) PredictableRelatively easily predicted by preclinical

and clinical pharmacological studies

c) CommonType A reactions not serious---common

d) Dose-dependentUsually dose dependent

Type A reactions (classes) i) Toxicity of overdose (Drug overdose)An adverse drug reaction caused by excessive

dosing

e.g., hepatic failure with dose of paracetamolHeadache with antihypertensiveshypoglycemia with sulfonylurea;

ii) Side EffectsNearly unavoidable secondary drug effect

produced by therapeutic doses

intensity is dose dependentOccur immediately after initially taking drug

or may not appear until weeks after initiation of drug use

E.g., sedation with antihistamines

iii) Secondary EffectsSecondary pharmacological effect

E.g., development of diarrhea with antibiotic therapy due to altered GIT bacterial flora

Orthostatic hypotension with a phenothiazine

iv) Drug InteractionsWhen two drugs taken together & they

effect each other’s response pharmacologically or kinetically

E.g., one drug slow metabolism of 2nd drug blood conc.= toxicity

Theophylline toxicity in presence of erythromycin

2) Type B ReactionsUnrelated to known pharmacological

actions of drugUnpredictableOften caused by immunological &

pharmacogenetic mechanismsUnrelated to dosage Comparatively rare & cause serious

illness or death cont.

Results (more likely) in withdrawal of marketing authorization

Often not discovered until after drug is marketed

Both environmental & genetic factors = important in this reaction

Type B Reactions (classes)

i) Drug IntoleranceLower threshold to normal pharmacological

action of a drug e.g., tinnitus (single average dose of aspirin)

ii) Hypersensitivity (immunological reaction)

Immune mediated response to a drug agent in sensitized patient

e.g., anaphylaxis with penicillin

iii) Pseudoallergic Reaction

Direct mast cell activation &

degranulation by drugs (opiates, vancomycin

& radiocontrast media)

Clinically indistinguishable form Type I

hypersensitivity but not involve IgE (non

immunologic reactions)

iv) Idiosyncratic Reactions

An uncommon & abnormal response to drugUsually due to genetic abnormalityAffect drug metabolism & receptor

sensitivityHarmful even fatal, appear in low doses

E.g., Anemia (hemolysis) by antioxidant drugs (G6PD deficiency)

Paralysis due to succinylcholine (enzyme deficiency)

3) Type C (chronic) Reactions

Associated with long-term drug therapy

Well known and can be anticipatedAdaptation occurs = discontinuation

of drug=abstinence syndrome

E.g. opoids, alcohol, barbiturates

4) Type D (delayed) ReactionsCarcinogenic & teratogenic effectsDelayed in onset Very rareCarcinogenic EffectMedication lead to cancer; take >20 y to

develop

Teratogenic EffectDrug- induced birth defects

Sign & Symptoms of ADRMild, moderate, severe or lethalSign & symptoms manifest soon after 1st

dose or only after chronic usee.g., Allergic reactions occur soon after drug

is taken usually 2nd time ( itching, rash, eruption, upper or lower airway edema with dyspnea & hypotension)

Idiosyncratic reactions=any unpredicted symptom

Mechanisms of ADR

Type A =non immunological, reversible with reduction of dose, non serious, extension of pharmacological effects

Type BBiochemical mechanism unrelated to

pharmacologicalImmunologic = Hypersensitivity (Type I, II, III,

IV)OR

Non immunologic (direct)= Pseudoallergic, idiosyncratic, intolerance

Mechanism of Type B Reactions

i) Often mediated by a chemically reactive metabolite

Non detoxification of metabolite

Direct cytotoxicity

Direct tissue damage + necrosis

ii) Bind to NA altered gene product

Bind to a larger macromolecule inducing immune response (produce Ab & bind to Ab)

Drug Hypersensitivity (allergic) Reaction

Common form of adverse response to drugs

Classification (Gell & Coombs) Type I reactions (IgE-mediated)

Type II reactions (cytotoxic)Type III reactions (immune complex)Type IV (delayed, cell mediated)