HYPERSENSITIVITY TO DRUGS AND THEIR MECHANISMS

Name : Mellya Rizki Pitriani

Student ID : B1B017031

CLASS ASSIGNMENT OF IMMUNOBIOLOGY

MINISTRY OF EDUCATION AND CULTURE

JENDERAL SOEDIRMAN UNIVERSITY
FACULTY OF BIOLOGY
PURWOKERTO
2020
I. INTRODUCTION
The human immune system is an essential part of defense against
infection, however the general defending immune system can occasionally
produce harmful responses to the host. The impression that persons who
have been formerly exposed to an antigen, marked noticeable responses to
that antigen later and are consequently supposed to be sensitized is called
hypersensitivity. Hypersensitivity responses can be produced through
endogenous self-antigens or exogenous antigens. Immune reactions to
endogenous or self-antigens effects in autoimmune diseases. On the other
hand, the immune response may take variety of forms against exogenous
antigens such as microbial and non-microbial such as drugs, foods, pollens,
chemicals and dust components. There are four type of hypersensitivity
based on mechanism and response such as type 1, type 2, type 3, and type
4 of hypersensitivity.
Type I hypersensitivity responses are immediate allergic reactions, for
example is anaphylaxis, where type II involves antibody mediated cytotoxic
responses to particular tissues. Type III hypersensitivity responses are
mediated by antibody-antigen complexes which cause several types of tissue
damage within the body. Type IV hypersensitivity or delayed type
hypersensitivity are cell mediated responses that incorporate with sensitized
T helper cells. Immune reactants that play a role in hypersensitivity are IgE,
antibodies, IgG, IgM, immune complexes, basophiles, complement of white
blood cells, T cells, and macrophages.
II. DISCUSSION
Drug hypersensitivity reactions should exclude patients from
treatment. Patients with true DHR need to be promptly identified
and managed as they may develop life-threatening complications
from the offending drug. Understanding the underlying
immunologic mechanisms of DHR can help clinicians distinguish
between true hypersensitivity vs inaccurate and potentially
harmful antibiotic allergy diagnoses. If DHR is suspected, further
work-up into classifying the immune-mediated process will be
necessary to appropriately manage the patient both acutely and
long-term.
The classification of reaction types is divided into 4, each of
which is based on reactions from low, moderate to high. The type
reaction include type I, type II, type III and type IV.
1. Type I Reaction
Anaphylaxis is a severe and potentially life-threatening
hypersensitivity reaction that typically involves multiple organ
systems. Antibiotics are the one of the leading causes of
anaphylaxis with beta-lactams being most commonly implicated.
The type reaction I consists of 3 such as immune-mediated IgE-
Dependent Anaphylaxis, immune-mediated IgE-Independent
Anaphylaxis, and Non-Immunologic Anaphylaxis.
a. Immune-mediated IgE-dependent Anaphylaxis
The IgE-mediated reactions occur when an allergen-specific
IgE binds to Fc-epsilon-RI IgE receptors on mast cells and
basophils, leading to mast cell degranulation and release of
multiple mediators, enzymes, and cytokines that trigger typical
signs and symptoms of anaphylaxis . The most relevant mediators
are further described below and their effects on the organ system
and associated symptoms are summarized in table

. Both histamine and tryptase are preformed mediators stored

in the secretory granules of mast cells and released by mast cell
degranulation and basophils. Histamine can bind to four types of
histamine receptors (H1 through H4). The H1 and H2 receptors
mediate several systemic effects of anaphylaxis including
bronchoconstriction, tachycardia, hypotension, and flushing. Both
H1 and H2 antagonists are used as adjunctive therapies in the
treatment of anaphylaxis (further described in the Diagnosis and
Treatment section). H3 and H4 receptors have not been as
extensively studied but H4 receptors appear to be involved in
chemotaxis and pruritus development. Histamine plasma levels
correlate with the severity of anaphylaxis. Tryptase causes
activation of the coagulation pathways and kallikrein-kinin contact
systems, contributing to vasodilatation, hypotension, and
angioedema. Since tryptase is more stable than histamine, it has
been utilized as a biomarker of mast cell activation and may
support the diagnosis of anaphylaxis.
b. Immune-mediated IgE- Independent Anaphylaxis
Patients with low to undetectable IgE levels may experience
anaphylaxis, recent research has focused on identifying other
immune-mediated pathways that can contribute to the
development of anaphylaxis independent of IgE. It is not exactly
clear how some of these processes take place, but animal studies
point towards an IgG-dependent response which activates
macrophages and neutrophils and leads to the release of PAF
which, in turn, can also activate mast cells. Complement-mediated
anaphylaxis involving the production of anaphylatoxins C3a, C4a,
and C5a has also been described. The IgE-independent immune-
mediated reactions have been poorly studied with antibiotics so it
is unclear what role, if any, they play in antibiotic-related
hypersensitivity reactions.
c. Non-Immunologic Anaphylaxis
These reactions are not considered to be true DHR and are
sometimes referred to as anaphylactoid or pseudoallergies, as
they clinically resemble true anaphylaxis. Red man syndrome is
one such example which may develop when vancomycin is rapidly
infused (1 g or higher doses infused over less than 60 min) and
can lead to such symptoms as flushing, redness, and pruritus
affecting the upper part of the body such as face and neck.
Severe symptoms such as shortness of breath or hypotension are
rare but can occur as well. The underlying mechanism of this
reaction is direct stimulation of mast cell degranulation by
vancomycin and does not involve an immune mediated process.
Patients are typically managed by reducing the rate of
vancomycin infusion and premedication with antihistamines.
2. Type II Reaction
Type II reactions are delayed immune-mediated reactions
that typically involve antibody-mediated cell destruction of
circulating white blood cells (WBC), red blood cells (RBC), or
platelets. The pathogenesis has not been fully elucidated, and
different types of pathologic mechanisms have been associated
with different drug classes. In the case of antibiotics, the immune
mediated toxicity is thought to be most likely due to hapten-
dependent antibodies. Haptens are small molecules (less than
5000 Daltons) that do not elicit an immune response on their own
but can become immunogenic when they covalently bind to the
cell membrane of larger proteins. This leads to the production of
IgG (or, less commonly IgM) antibodies that target either the
bound drug or a cell membrane component altered by the drug.
The subsequent interaction between the antibody and antigen
destroys the cell, either via complement or phagocytosis. For
example, penicillin's beta-lactam ring can bind to the proteins on
RBCs and lead to production of antibodies. There is also evidence
that reactive metabolites of a drug can bind to the cell membrane
and lead to the production of antibodies. This bioactivation
typically occurs in the liver by the cytochrome P450 enzymes.
However, neutrophil enzyme myeloperoxidase can also produce
reactive drug metabolites via oxidation [33]. For example,
biotransformation of SMX / TMP by the liver leads to the
production of SMX-nitroso, which is highly chemically reactive and
can bind to cell membrane glycoproteins.
3. Type III Reaction
Type III reactions occur when IgG or IgM antibodies form
immune complexes with drugs. Normally, these complexes are
promptly removed; however, occasionally they can precipitate and
activate the complement pathway. The complement components
recruit and activate neutrophils and macrophages, which results in
tissue inflammation and injury. The site of the antigen-antibody
complex deposition and not the source of the antigen is what
determines the cluster of symptoms. As a result, the complexes
deposited in blood vessels, kidneys, and joints, will present as
vasculitis, nephritis, and arthritis, respectively. The reaction time
can take anywhere from days to weeks to develop. Examples of
Type III reactions include serum sickness and small vessel
vasculitis.
4. Type IV Reaction
Type IVa is described as a type 1 helper (Th-1) lymphocyte
mediated response leading to macrophage activation by interferon
(IFN) -γ secretion. Allergic contact dermatitis is induced by topical
antibiotics is an example of such a reaction, and consists of a
sensitization and elicitation phase. The sensitization phase is
initiated by hapten binding to skin carrier proteins. This hapten-
protein complex is engulfed and processed by the antigen
presenting cells (such as the dermal dendritic cells) which migrate
to the regional lymph nodes and prime the T cells. The
sensitization period typically lasts between 10 to 15 days. If the
individual is exposed to the same hapten again, the elicitation
phase occurs within 24 to 72 h. In this phase, the activated CD8 +
T cells, the main effector cells associated with allergic contact
dermatitis, are recruited to the skin where they induce
keratinocyte apoptosis and release inflammatory cytokines such
as IFN-γ and TNF-α, among others [53]. The clinical
manifestations include erythema, pruritus, and formation of scaly
plaques or vesicles. The most commonly implicated antibiotics are
topical agents such as bacitracin, polymyxin B, and neomycin.
The other hipersensitivity are in injured or CRPS (Complex
Regional Pain Syndrome. Complex regional pain syndrome
(CRPS) is a severe and debilitating pain condition which can be
induced by surgery, fractures, limb trauma, ischemia or nerve
lesion. CRPS can develop into chronic conditions which severely
affect the daily activity and quality of the patient's life. CRPS can
be further divided into two subtypes: type-I without identifiable
nerve injury and type-II with identifiable nerve injury. CRPS-I is
usually initiated after an initial noxious event and is accompanied
by edema, changes in skin blood flow as well as thermal and
mechanical hyperalgesia / allodynia in the affected area.
Physiotherapy, sympathetic blockade, corticosteroids, and non-
steroidal anti-inflammatory drugs are available treatment options
for CRPS-I. However, all of these options showed inadequate
therapeutic effects on CRPS-I, rendering it a clinically difficult to
treat pain condition. The underlying CRPS-I mechanisms still
remain largely unknown. Chronic post-ischemia pain (CPIP) rat
model is a well-recognized animal model of CRPS-I, which
reproduces peripheral pathology of CRPS-I via ischemia /
reperfusion of the hind paws of rats. The CPIP model induces
early hyperemia and edema, which are followed by chronic
neuropathic-like pain symptoms, including spontaneous pain,
long-term mechanical and thermal hypersensitivity. These
symptoms recapitulate the typical features of CRPS-I in human
patients. By means of this model, several mechanisms, including
central glial activation, central pain sensitization, reactive oxygen
species increase and activation of peripherals TRPA1, etc. have
been proposed to contribute to CRPS-I.
TRPV1 is a non-selective cation channel exclusively
expressed in nociceptive primary sensory neurons. It is a
polymodal channel which responds to varies physical and
chemical stimuli, including heat, acid pH and mechanical stimulus.
It is also the principal detector of noxious heat in the peripheral
nervous system and plays an important role in mediating thermal
hyperalgesia. Genetic ablation or pharmacological blockage of
TRPV1 significantly alleviates pain responses in animal models of
chronic pain conditions.
III. CONCLUSION
Drug hypersensitivity reactions related to antibiotics are
broadly classified into four groups, based on the underlying
immunological processes. Each type has manifestations, onset,
and severity of disease. The risk of hypersensitivity reactions
varies greatly between different antibiotics and some classes of
drugs such as beta-lactam, can cause immediate and delayed
reactions. Treatment usually consists of stopping the offending
drug but, depending on the severity of the reaction, additional
supportive measures may be needed.

REFERENCE
Basu, S. & Banik, B. M., 2018. Hypersensitivity: An Overview.
Immunology: Current Research, 2(1), pp. 1-3.

Hu, Q., Wang, Q., Wang, C., Tai, Y., Liu, B., Shao, X., Fang, J.,
Liu, B., 2019. TRPV1 Channel Contributes to the Behavioral
Hypersensitivity in a Rat Model of Complex Regional Pain
Syndrome Type 1. Frontiers in Pharmacology, 10(453), pp.
1-16.

Maker, J. H., Stroup, C. M., Huang, V., James, S. F., 2019.

Antibiotic Hypersensitivity Mechanisms. Pharmacy, 7(122),
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