DRUG ALLERGY

INTRODUCTION
Allergic reaction to drugs get into the classification of intersection of drug (adverse drug
reaction), which includes toxicity, side effects, idiosyncrasy, intolerance and medications
allergy. Drug allergy is an abnormal response to the medicine or metabolites through
immunological reactions are known as hypersensitivity reaction that occurs during or after
use of the drug.
 INTERACTION OF DRUGS WITH
THE IMMUNE SYSTEM
Drugs can elicit drug-specific immune responses in two ways:
1. The drug may act as an antigen and elicit one of several classic immune responses.
2. The drug may directly interact with immune receptors and under certain circumstances, lead
to activation of specific immune cells .
Some drugs can bind directly to effector cells of the immune system (eg, mast cells) and
cause mast cell degranulation with the clinical symptoms of urticaria or anaphylaxis . Such
symptoms are very similar to some drug-allergic reactions (immunoglobulin E [IgE]) and
are called pseudoallergic or nonallergic hypersensitivity reactions. They do not involve
drug-specific antibodies or T cells and are thus not truly immune-mediated reactions.
 MECHANISMS
DHRs can be classified as allergic and non-allergic reactions based on the
mechanism involved:

1. Allergic reactions are mediated by a specific immune response to a drug acting as hapeten
that can lead to all types of Coombs and Gell-mediated immune reactions: types I (IgE-
mediated, produced by B cells), type II (IgG/IgM-mediated cytotoxicity), type III
(immunocomplex) and IV (T cell-mediated
2. Non-allergic reactions

They are clinically indistinguishable from allergic reactions and they are produced after drug
interaction with inflammatory cells as mast cells, basophils, and neutrophils through
mechanisms based on
(i) over-inhibition of specific enzymes such as the COX-1 inhibition (pharmacological effect)
in non-steroidal anti-inflammatory drugs reactions or
(ii) the off-target occupation of receptors by drugs (direct stimulation) such as the Mas-related
G-protein receptor (MRGPRX2) on mast cells by neuromuscular blocking agent (NMBAs)
and fluoroquinolones.
 SIGNS/ SYMPTOMS
Rash is the most common symptom. The
symptoms and severity of drug allergy
reactions can vary from person to person and
also depend on the specific medication(s) you
are taking.
Rash including raised or flat skin color changes
Hives, or itchy, raised bumps
Swelling of the skin or mouth
Tightness in the throat or hoarse voice
Trouble breathing or wheezing
 There are three main processes by which T cells are stimulated by drugs
1. Hapten concept: Haptens are chemically reactive small compounds (<1000 d) that bind to
proteins/peptides and modify them covalently. These subsequently may

stimulate the innate immune system by covalently binding to cellular proteins, thereby transmitting a
danger signal, which in turn results in stimulation; or
stimulate the specific immune system by forming hapten-carrier complexes, which in turn can form
neoantigens. The hapten-protein complexes are processed and then presented as hapten-modified
peptides to T cells, which can react with these peptides.
2. Pro-hapten concept: Pro-haptens are not chemically reactive and cannot form a covalent bond
with a peptide. To become chemically reactive, they must first be converted into a hapten by being
metabolized into a compound that is chemically reactive.
3. Pi (pharmacologic interaction with immune receptors) concept: A chemically inert drug,
unable to covalently bind to proteins, is still able to "fit" to some of the many immune receptors
(as it does to other proteins/receptors).
 RISK FACTORS AND HOST FACTOR
OF DHR
Drug Factors
Nature of the drug
Degree of exposure (dose, duration, frequency)
Route of administration
Cross-sensitization
Host Factors
Age and Sex
Genetic factors (HLA type, Acetylator status)
Concurrent medical illness (e.g. Ebstein-Barr Virus (EBV), human immunodeficiency virus (HIV),
asthma)
Previous drug reaction
Multiple allergy syndrome
 COOMBS AND GELL'S
CLASSIFICATION
Coombs and Gell's classification divides allergies into four pathophysiological types,

The four types of hypersensitivity are:

Type I: reaction mediated by IgE antibodies.
Type II: cytotoxic reaction mediated by IgG or IgM antibodies.
Type III: reaction mediated by immune complexes.
Type IV: delayed reaction mediated by cellular response.
TYPE 1(REACTION MEDIATED BY IGE
ANTIBODIES)
MECHANISMS
 TYPE II: CYTOTOXIC REACTION
MEDIATED BY IGG OR IGM ANTIBODIES
 TYPE III: REACTION MEDIATED BY
IMMUNE COMPLEXES
Type III hypersensitivity is antibody excess (primarily IgG), coupled with a relatively low
concentration of antigen, resulting in the formation of small immune complexes that deposit
on the surface of the epithelial cells lining the inner lumen of small blood vessels or on the
surfaces of tissues . This immune complex accumulation leads to a cascade of inflammatory
events that include the following:
IgG binding to antibody receptors on localized mast cells, resulting in mast-cell
degranulation
Complement activation with production of pro-inflammatory C3a and C5a.
Increased blood-vessel permeability with chemotactic recruitment of neutrophils and
macrophages
Autoimmune diseases such as systemic
lupus erythematosus (SLE) and rheumatoid
arthritis can also involve damaging type III
hypersensitivity reactions when auto-
antibodies form immune complexes with
self antigens. These conditions are
discussed in Autoimmune Disorders.
 TYPE IV: DELAYED REACTION
MEDIATED BY CELLULAR RESPONSE
Type IV hypersensitivities are not mediated by antibodies like the other three types of
hypersensitivities. Rather, type IV hypersensitivities are regulated by T cells and involve
the action of effector cells. These types of hypersensitivities can be organized into three
subcategories based on T-cell subtype, type of antigen, and the resulting effector
mechanism.
TYPE:IV SUBTYPES
 DIAGNOSIS OF DRUG
HYPERSENSITIVITY

Patient’s report of a reaction soon after taking a drug

1. Skin testing
2. Sometimes drug provocation testing
3. Sometimes direct and indirect antiglobulin assays
The following can help differentiate drug hypersensitivity from toxic and adverse drug effects and
from problems due to drug interaction.
1. Time of onset
2. Known effects of a drug
3. Results of a repeat drug challenge
For example, a dose-related reaction is often drug toxicity, not drug hypersensitivity.
 IN VITRO TESTS

Measurement of mediators (histamine, tryptase, leukotrienes)

total tryptase levels: with serial specimens taken at 1 and 6 hours after an acute
anaphylactic reaction. Although elevated levels support a diagnosis of anaphylaxis, this
criterion is not completely reliable; normal levels have been found even in cases of fatal
anaphylaxis.
Allergen-specific IgE levels are measured by either radioallergosorbent tests (RASTs) or
radioimmunoassay (RIA).

Drug discontinuation
Supportive treatment (eg, antihistamines,
corticosteroids, epinephrine)
Sometimes desensitization
Symptomatic and supportive treatment for acute
reactions may include
a. Antihistamines for pruritus
b. Nonsteroidal anti-inflammatory drugs (NSAIDs) for
arthralgias
c. Corticosteroids for severe reactions (eg, exfoliative
dermatitis, bronchospasm)
d. Epinephrine for anaphylaxis
TREATMENT OF DRUG
HYPERSENSITIVITY
Desensitization
Desensitization is based on incremental dosing of the
antigen every 15 to 20 minutes, beginning with a
minute dose to induce subclinical anaphylaxis before
exposure to therapeutic doses. This procedure depends
on constant presence of drug in the serum and so must
not be interrupted; desensitization is immediately
followed by full therapeutic doses. Hypersensitivity
typically returns 24 to 48 hours after treatment is
stopped. Minor reactions (eg, itching, rash) are
common during desensitization.
For allergies to trimethoprim-sulfamethoxazole
and vancomycin, regimens similar to those for
penicillin can be used.
 PROGNOSIS FOR DRUG
HYPERSENSITIVITY
Hypersensitivity decreases with time.
IgE antibodies are present in 90% of patients 1 year after an allergic reaction but in only
about 20 to 30% after 10 years.
Patients who have anaphylactic reactions are more likely to retain antibodies to the
causative drug longer
 SUMMARY
Hypersensitivity reactions to drugs are often type I (immediate, IgE-mediated), but they can be type II, III, or IV.
Drug hypersensitivity can often be diagnosed based on history (mainly the patient's report of a reaction after
starting to take the drug), but known adverse and toxic effects of the drug and drug-drug interactions must be
excluded.
If the diagnosis is unclear, usually skin tests but occasionally drug provocation testing or other specific tests can
identify some drugs as the cause, particularly if type I hypersensitivity reactions are primarily involved.
A negative skin test result rules out the possibility of anaphylaxis but does not predict incidence of subsequent
serum sickness.
Hypersensitivity tends to decrease over time.
Treat acute type I hypersensitivity reactions supportively with antihistamines for pruritus, NSAIDs for
arthralgias, corticosteroids for severe reactions (eg, exfoliative dermatitis, bronchospasm), and epinephrine for
anaphylaxis.
If the causative drug must be used, try rapid desensitization, in collaboration with an allergist if possible, to
temporarily reduce the risk of type I hypersensitivity reactions to the drug.
 REFERENCE
https://www.msdmanuals.com/professional/immunology-allergic-disorders/allergic,-autoimmune,-and-othe
r-hypersensitivity-disorders/drug-hypersensitivity
https://www.worldallergy.org/education-and-programs/education/allergic-disease-resource-center/profe
ssionals/drug-allergies
https://www.uclahealth.org/allergy/drug-allergies
THANK YOU!