Antihistamine Mechanism on Allergic Disease Treatments:

Receptor blockage – Receptor inactivation

Saut Sahat Pohan

Department of Dermato-Venereology Faculty of Medicine, Airlangga University/

Dr. Soetomo Hospital, Surabaya, Indonesia

Abstract: H1 antihistamines are competitive inhibitors to histamine H1 receptor. They bind to

the receptor without activating it but prevent the subsequent binding of histamine. However,
recent studies have shown that H1 antihistamines are not antagonists but inverse agonists. They
have capacity to turn off an active receptor. H1 antihistamines, acting as inverse agonists, have
the ability to turn off these receptors and reduce allergic inflammation. Classical models of G-
proteincoupled receptors (GPCRs) require the occupation of receptors by an agonist to initiate
the activation of signal transduction pathways. Recently, the expression of GPCRs in
recombinant systems revealed a constitutive spontaneous receptor activity, which is independent
to receptors occupancy by an agonist. An agonist would lead the increase of the basic activity
leading to continuous activation signals. Gbg and Gaq/11 sub unit have an important role in
sending constitutive signal and agonist-mediated signal. Thus, H1 constitutive receptor has an
important role in activating the constitutive NF-kB. The H1 receptor-mediated NF-kB activation
is inhibited by several H1 antagonists, such as cetirizine, ebastine, levocetirizine. Histamine
molecules exist and their reactions take place in three-dimensional space. Therefore, they are
stereospecific binding between the H1 receptors and the histamine/antihistamine. Several
antihistamines such as cetirizine, loratadine, levocetirizine, dextrocetirizine bind perfectly with
the H1-receptors in a stereo specific binding, but the binding affinity among the antihistamines is
different.
Further investigations in knowing how antihistamines work, such as the anti-inflammation
mechanisms, the H1 receptor structure and the binding affinity of H1 antihistamines to receptors
are needed in finding effective antihistamines to treat allergic diseases.
Key words: H1 receptor, agonist, inverse agonist, NF-kB
Preliminary

The increased prevalence of allergic diseases stimulated the researchers looking for effective
drugs to tackle the disease.

Histamine is one of the factors that cause acute and chronic disorders, so it needs
investigated the mechanism of antihistamines in the treatment of allergic diseases.
Antihistamines is competitive inhibitors to histamine. Antihistamines and histamine occupied the
same receptors. Receptor blockade by H1 antagonist of the receptor that inhibits histamine
effects due to eg smooth muscle contraction, increased vascular permeability and vasodilatation.
Lately proved that not only as an antihistamine H1 antagonists, but also as an inverse agonist that
has the capacity to inhibit the activity of the H1 receptor antagonist H1 whereas no effect on the
activity of the H1 receptor. Receptors on the cell surface (including the H1 receptor) can bind to
G proteins present in the cell membrane in the area adjacent to the cytoplasm (cytosolic domain
of the cell membrane) .1 The change / increase in H1 receptor activity are influenced molecule
from outside the cell resulting in a change / improvement Changes in the activity of G protein /
increased activation of G proteins induce signal transduction (signal transduction) to multiple
targets (effectors), resulting in activation of NF-kB is a transcription factor that plays a role in
the inflammatory reaction.

Some researchers interested in examining the H1 receptor activation that caused

inflammation and seek effective antihistamines which has no side effects, to overcome the
inflammation.

In this paper discussed the mechanism of antihistamines in the treatment of allergic diseases
such as antihistamines mechanism of anti-inflammatory, H1 receptor structure and receptor
binding affinity to H1 antihistamines.

Antihistamines as Anti-Inflammatory Mechanisms

Although the recent studies about antihistamines developed rapidly, in order to increase the
value of the treatment of allergic diseases, until today to found the effective and no side effects
of antihistamin, it known as a neutral antagonist. It expected to have blockade receptor of H1
with several properties, but do not have unexpected side effects, so it is an antihistamine that has
a specific character. Until now, the neutral antagonists have not been identified, so it is often
defined by a neutral antagonist H1 antagonist that is effective in the treatment of diseases alergi.2

Based on the observations, it supposed most of receptor on the cell surface including H1
receptors are in an active state to a certain extent known as constitutive activity (constitutive
activity), without the presence of agonist. The result was a reclassification in terms of ligand
binding to the receptor H1 into three subdivisions, namely agonists, inverse agonists, and
antagonists netral.3 previous classification consists of agonists and competitive antagonists.
Interaction receptors on the cell surface with agonists increase receptor constitutive activity,
although agonists do not have to occupy /bound receptor H1.2 bound to the agonists are
molecules that have ability to stimulate / increase constitutive activity of the receptor. Interaction
of receptor and inverse agonists decrease the constitutive activity of the receptor, while the
interaction with the receptor neutral antagonist did not affect constitutive activity of the receptor.
Neutral antagonist which binds to receptors can only inhibit agonist activity. H1 antihistamines
are also suspected as the inverse agonist.4 There were pharmacologic differences between
inverse agonists and neutral antagonists, but this assumption needs furtherinvestigated.2

The cell membrane is the boundary between cell and outside of the cell. The cell membrane
is permeable to the fat-soluble molecules, such as steroids. Steroids do diffusion into the cell
through the cell membrane. The cell membrane is impermeable to water-soluble materials such
ions, small molecules and polypeptides inorganic. The response to the hydrophilic material
depends on the interaction between the material / extracellular molecules with protein
components in the plasma membrane. The extracellular molecules called ligands, where as the
plasma membrane proteins that bind ligands call receptors. Extracellular material that can not be
directly entered into the cell through the plasma membrane such macromolecules going through
lipids bilayer.5 In addition ligands that can not pass through the cell membrane, can send a signal
by changing the properties of the protein from the cell membrane extracellular portion
(extracellular domain of cell membrane), and finally the signal is sent to the adjacent cell
membrane to the cytoplasm / cytosolic domain of the cell membrane (Figure 1). Cytosolic signal
amplitude that is much larger than the first signal received by the cell membrane will interact
with some protein in the cytoplasm.
 Cytosolic signaling proteins sequentially inducing activity or increase the amount of small
molecules in the cell.

Receptor also has protein kinase activity; kinases are activated when ligand bound to the cell
membrane, which would lead to the cytoplasmic domain otofosforilase receptor, thus inducing a
target protein in the cytoplasm which eventually form a new substrate in the cell. In general,
receptor tyrosine kinase is a kinase, but it got too receptor serine kinase / threonine kinase.
Several researchers have demonstrated the activation of NF-kB, through tyrosine akivasi kinase.4

Receptor outside (extracellular domain receptor) also interact with G protein receptor that is
found on the border with the cytoplasm (cytoplasmic domain receptor). Inactive G protein is
obtained in the form of a trimer that binds to guanine diphosphate (GDP). In the state of being
active receptor, confirming changes that will lead to changes in the confirmation of a G protein
subunits. The changes are causing the release of GDP previously bound to the G protein subunits
a and substituted guanine triphosphate (GTP). Binding of GTP causes the G protein subunit a
break away from the receptor and G protein subunit b g. Long the G protein activation is
controlled by the G protein subunit a. G protein subunits A is a form of GTPases, which will
hydrolyze GTP to GDP, and finally a G protein subunits would be tied again with the G protein
subunit bg, so the cycle as they are going to take place again. Increased activation of multiple
receptors on the cell surface including H1 receptor results in increased activation of the G protein
resulting in signal transduction to multiple target / effector (Figure 2).

Since it was established that histamine activates NF-kB through H1 receptor activation;
activation of NF-kB mechanism in a wider sense is investigated further. H1 receptor activity can
be either constitutive activity; receptor has been in a state of "ready" to some degree.

H1 is a histamine H1 agonist that increases affinity H1 receptor constitutive activity.

Due to constitutive receptor signal transduction, there was a constitutive activation of NF-
kB. Likewise, in the same way an increase in the activation of NF-kB activation due to increased
receptor agonist induced. Bakker et al4 prove that the activation of NF-kB mediated by
activation of histamine H1 receptor G protein subunits played by bg and aq / 11. 4 Increased
activity of NF-kB is mainly found in patients with asthma, so the alleged NF-kB plays an
important role in the pathogenesis of asthma. Inhibition of NF-kB activation induced constitutive
constitutive activation of the H1 receptor antagonists can be done only H1, H2 and H3
antagonists while not play a role, so it is suspected H1 antagonists also act as inverse agonists.
Allegedly some H1 antagonist cetirizine example, ebastin, loratadine, Fexofenadine can inhibit
the activation of NF- B constitutive constitutive activation mediated by H1 receptors.
 Treatment of allergic diseases by inhibiting inflammatory allegedly caused an increase in the
activity of NF-kB being contemplated by several researcher.4 Some H1 antagonist that has been
known to relieve the itching can be used as an anti-inflammatory disease caused alergik
reaction.2 6,7

Ciprandi et al6 examined the efficacy of cetirizine in patients with conjunctivitis caused by
specific allergens that Parietaria judaica. From the research, it was concluded that the group
given cetirizine found decreased expression of ICAM-1 and the number of inflammatory cells, as
compared with the placebo group.

Boguniewicz8 suspect that cetirizine also has anti-inflammatory properties by inhibiting the
migration of eosinophils. Holgate et al,2 express anti-inflammatory mechanism that held some
antihistamines do not always depend on the inverse agonist, so that still needs to be further
investigated as an anti-inflammatory mechanism of antihistamines.

Until now still attempted to get antihistamines efficacious as "H1 antagonist plus an extra
factor" especially extra factors that are anti-inflammatory.

H1 receptor structure

Bond with the histamine H1 receptor is obtained in the form of three-dimensional,9 thus
concluded that the histamine H1 receptor binding / antihistamine is bond stereo-specific. Some
antihistamines such as cetirizine, loratadine and levocetirizin can bind to H1 receptors in specific
binding stereo.9
 The results showed that the binding affinity and duration of antihistamines with receptors
play a role in the effectiveness of antihistamines. Methods for measuring the effectiveness of
antihistamines can by way of the skin prick test (skin prick test), which is followed by
assessment of inhibition of antihistamines to red (flares) and swollen (wheal) caused
histamin.10,11

Antihistamines that have a great affinity for the H1 receptor, the duration of the bond
between the receptor antihistamines longer and have anti-inflammatory properties will have
better effectiveness than other antihistamines. In addition, pharmacokinetic and
pharmacodynamic antihistamines still need to be investigated to obtain an antihistamine which
does not cause significant side effects.

Closing

At first the mechanism of antihistamines in the treatment of allergic disease known as blockade
of the histamine H1 receptor. Lately demonstrated that antihistamines

have anti-inflammatory properties. Antihistamines mechanism for inhibiting inflammation

through suppression of adhesion molecule expression, inhibiting migration of inflammatory cells
has been demonstrated. Have also investigated the relationship antihistamine H1 receptor
constitutive activity, increased activity caused H1 receptor agonist eg histamine. Increased
activity of the H1 receptor results in increased activity of NF-kB which is a transcription factor
that plays a role in the inflammatory reaction, whereas the H1 antagonist can not affect the
activity of the H1 receptor. Lately allegedly H1 antagonists have some efficacy as an inverse
agonist that inhibits the activation of H1 receptors, resulting in inhibition of the activation of NF-
kB. Concluded inflammation can also inhibited antihistamines. In the treatment of allergic
disease, antihistamines which are expected to have anti-inflammatory properties may reduce the
use of corticosteroids often cause unwanted side effects.
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