Drug Allergy

Drug allergy or hypersensitivity is a form of

Adverse Drug Reaction (ADR)

Ketut Suardamana
Ketut Suryana

Division of Allergy-Immunology
Department of Internal Medicine, Faculty Medicine of
Udayana University
Denpasar
DEFINITION
An ADR is
any undesirable effect of drug
that is administered in standard doses
by the proper route for the purpose of
prophylaxis, diagnosis, or treatment.
Classification of ADR ADR

Type A reaction Type B reaction

Dose dependent Dose independent
Predictable Unpredictable
More common Less common

Overdose Intolerance

Side effect Idiosyncrasy

(pharmacogenetics)
Drug interaction Drug allergy

Immunologic reaction
Pseudoallergic reaction
(Gell and Coombs classification

Type I reaction Type II reaction Type III reaction Type IV reaction

IgE mediated Antibody dependent Immune complex T-cell mediated
Anaphylactic cytotoxicity damage damage (CD8)
Urticaria IgG/IgM bind to antigens Antibody binding to Delayed Type
Angioedema on cells antigens in large Hypersensitivity
Bronchospasm Complement quantiles (CD4)
Hypotension Phagocyte
Drug allergy
an immunologically mediated reaction,
occur in a susceptible populations,
characterised by specificity,
transferability by antibodies or lymphocytes,
and recurrence on re-exposure
Epidemiology
ADR is estimated that up to 15% of drug
administrations
The risk is roughly doubled in the hospital
setting
Fatal drug reactions occur in approximately
0.1% of medical in patients
0.01% of surgical inpatients
Drug allergy account for only 5-10% of all ADRs
Classification of ADRs
Reactions that may occur in anyone
* Drug overdose ; toxic reactions linked to
excess dose or impaired excretion, or to
both
* Drug side effect ; undesirable
pharmacological effect at recommended
doses
* Drug interaction ; action of a drug
on the effectiveness or toxicity of another
drug.
 Reactions that occur only in susceptible
subjects
Drug intolerance ; a low threshold to the normal
pharmacological action of drug
Drug idiosyncrasy ; a genetically determined,
qualitatively abnormal reaction to a drug related to
a metabolic or enzyme deficiency
Drug allergy
Pseudoallergic reaction ; a reaction with the same
clinical manifestations as an allergic reaction, but
lacking immunological specificity.
Pathophysiology
Allergic drug reactions are usually defined as ;
reaction caused by suspected immunologic
mechanisms
result from the production of antibodies and / or
cytotoxic T cells directed against the drug,
its metabolite, a soluble / cell-bound carrier
protein
as a responses to prior or continuous exposure to
a drug
Complete Antigens
High-molecular weight (HMW) drugs
can induce the production of anti-drug
antibodies without the need to couple to
a carrier protein.

HMW drugs are more likely to provoke

an allergic reaction than Low molecular
weight (LMW).
Haptens
Most drugs are LMW agents
and cannot induce an immune response
Must covalently combine with carrier proteins
in the body to elicit an immune response
The actual allergen may be ;
- the hapten itself
- the hapten-protein complex
- a tissue protein that has been altered
by interaction with the drug
(recognized as foreign)
Immunologic mechanisms
(The Gell & Coombs classification)
Type I Immediate hypersensitivity, IgE mediated Anaphylaxis ;
the onset ; seconds to minutes for drugs urticaria/
parenterally, up to 1 hr for drugs taken orally Angioedema,
bronchospasm,
shock,
hypotension
Type II Antibody-dependent cytotoxic Hemolytic anemia,
hypersensitivity / vasculitis, rashes,
IgG & IgM-dependent complement mediated interstitial nephritis
cytolysis
Type III Immune complex-mediated hypersensitivity Serum sickness,
rashes, fever,
vasculitis
Type IV Delayed type hypersensitivity, T cell Contact dermatitis,
mediated Granulomatous
reaction

Mechanism unknown ; Stevens-Johnson syndrome (SJS), toxic epidermal

Necrolysis (TEN), Drug fever, acute interstitial nephritis, pulmonary infiltrates
with eosinophilia
Risk factors
Patient related
Age, sex, genetics, atopy, AIDS

Drug related
Macromolecular size ; bivalency, haptens,
route, dose, duration of treatment

Aggravating factors
Blockers, asthma, pregnancy
Diagnosis
Diagnosis of drug allergy based on ;
Clinical history
Clinical manifestations
Diagnostic test
Clinical history
A precise and detailed history, including ;
- clinical symptoms and their timing, duration in relation to drug
exposure.a
- the onset may be ;
- immediate (onset second to minutes / < 6 hrs) :
e.g : anaphylaxis,urticaria,angioedema,bronchospasm
- accelerated ( > 6 hrs to 72 hrs ) :
e.g : urticaria,bronchospasm, erythema multiforme,
maculopapular rash, Serum sickness
- delayed ( > 72 hrs ) :
e.g : maculopapular rash, fever, serum sickness, recurrent
urticaria
- The past history
- The family history
Clinical manifestations
Manifestation Clinical features Examples of drugs
Anaphylaxis Urticaria, angioedema, rhinitis, Penicillin, neuromuscular blocking drugs
asthma, abd. pain, CV collaps

Pulmonary Interstitial pneumonitis Amiodarone, nitrofurantoin, chemotherapiutic

agent
asthma Aspirin, NSAID, blockers
Hepatic Acute or chronic hepatitis Halothane, chlorpromazine,carbamazepine
Haematological Haemolytic anaemia Penicillin, -methyldopa, mephenamicacid
Thrombocytopenia Furosemide,thiazide, gold salts
Neutropenia Penicillin
Agranulocytosis Phenylbutazone, Chlorampenicol
Aplastic anaemia NSAID, sulphonamides
Renal Interstitial nephritis, NS Cimetidine
Cardiac Eosinophylic myocarditis -methyldopa

Other Serum Sickness, drug fever, Anticonvulsants,diuretics,antibiotics,hydralasine

vasculitis, lymphadenopathy procainamide, penicillamine
Diagnostic tests
SPT may be helpful for diagnosing IgE mediated
drug reactions (in vivo)
RAST may detect serum IgE antibodies to certain
drugs (e.g : penicillin and succinyl choline)
(in vitro)
Provocation tests
Oral provocation tests, may be as a gold
standard
They must be performed under strict medical
supervision with resuscitative equipment
available
Management
Avoidance

Premedication

Desensitisation
Avoidance
As a general rule,
a drug responsible for an allergic reaction
should not be reused
Unless there is an absolute need
and no alternative drug is available.
Premedication
Pretreatment with H1 antihistamines
should not be used
as they do not prevent anaphylactic shock
And may mask early signs.
However, in association with H1 antihistamines,
corticosteroids have been shown to be effective
in reducing reactions to radiocontrast media
Desensitisation
Desensitisation should be considered in patients
who have experienced IgE mediated allergic reactions to Penicillin
and who require penicillin for treatment of serious infections
(e.g ; bacterial endocarditis and meningitis)
Protocol using oral and parenteral routes have been proposed.
Should be performed under specialist supervision.
Oral administration is preferred because it is less likely to provoke
a life threatening reaction.
Desensitisation may occasionally be indicated for other antibiotics,
such as ;
sulphonamides, cephalosporins
Terima Kasih