ACTA FACULTATIS

MEDICAE NAISSENSIS

DOI: 10.1515/afmnai-2015-0001 UDC: 615.218

Review article

Histamine and Antihistamines

Nikola Stojković1, Snežana Cekić2, Milica Ristov3, Marko Ristić1,

Davor Đukić1, Maša Binić1, Dragan Virijević1

1University of Niš, Faculty of Medicine, PhD student, Serbia

Institute of Physiology, University of Niš, Faculty of Medicine , Serbia
2

3Doctor of Medicine

SUMMARY

In recent years, there has been a steady increase in the prevalence of allergic diseases. Allergic
immune response represents a complex network of cellular events involving numerous immune
cells and mediators. It represents the interaction of innate and acquired immune response. The key
role in the immune cascade is taken by histamine, a natural component of the body, which in the
allergic inflammatory response is releasesd by the mast cells and basophils. The aim of this study
was to highlight the role of histamine in allergic immunological events, their effect on Th1 and Th2
subpopulation of lymphocytes and the production of the corresponding cytokines, as well as the
role of histamine blockers in the treatment of these conditions.
Histamine achieves its effect by binding to the four types of its receptors, which are widely
distributed in the body. Histamine blockers block a numerous effects of histamine by binding to
these receptors. As a highly selective second-generation antihistamine, cetirizine not only achieves
its effects by binding to H1 receptors, but also attenuates numerous events during the inflammatory
process. Knowledge of the effects of histamine blockers, including cetirizine, may lead to the
selection of proper therapy for the treatment of allegic diseases.

Key words: histamine, immune response, histamine blockers, cetirizine

Corresponding author:
Nikola Stojković
phone: +381643455599
e-mail: [email protected]
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INTRODUCTION IL-3, IL-4, IL-5, IL-6, IL-8, IL-13) with strong inflows of
inflammatory granulocytes (eosinophils, basophils,
Over the last 30 years, the prevalence of allergic neutrophils and lymphocytes), except for eosinophils
diseases (asthma, allergic rhinitis, atopic dermatitis which have a particular role because they secrete
etc.) has been rapidly growing. The goal of treatment several substances that promote the chronic late-
of these conditions represents a blocking effect of phase inflammatory reaction. During the late phase of
histamine release from basophils and mast cells and is allergic inflammatory response, which is
considered to be the key cause of all the symptoms characterized by inflammation and tissue injury, there
associated with allergic inflammatory response. is a return of symptoms in the early stage.
Antihistamines are drugs that are widely used in Allergic diseases represent complex innate and
dealing with this type of disease. The aim of this adaptive immune responses to environmental
paper was to provide the insight into the mechanism antigens leading to inflammatory reactions with a T–
of allergic immune responses and highlight the helper-2 type cell and allergen-specific IgE
possibility of using histamine blockers, including predominance (3,4). Allergy is essentially an
cetirizine, a second generation antihistamine, in inflammatory disease. Our knowledge of the cells and
solving many problems in allergy caused by intracellular mediators that are involved in the allergic
communication and numerous mediators. inflammation has increased immensely during the
last decade. This knowledge provides the basis of a
more rational way for the development of therapeutic
ALLERGY principles and prevention of allergic symptoms. The
allergic inflammation involves a large number of cells.
An immune cascade of allergic conditions is However, three types of cells seem to be of particular
the interactions between numerous cell types and importance. These are the eosinophil granulocyte, the
inflammatory mediators (1). Allergic inflammatory mast cell and the T-lymphocyte of the Th2-type. The
response has three distinct phases: sensitization, cytokines and other molecules and the cells present in
early-phase responses and late-phase responses. The the microenvironment are the main factors which
sensitization phase begins with the production of determine differentiation of naive T cells into distinct
allergen-specific IgE-antibodies that bind to the subsets such as Th1, Th2, Th9, Th17 and Th22 type
surfaces of mast cells, basophils and antigen memory and effector cells (5). In conditions of allergic
presentation cells (APC), causing degranulation and diseases, effector Th2 cells produce not only
subsequent mediator release. Just before that occurs a traditional Th2 cytokines such as IL-4, IL-5, IL-9 and
differentiation and clonal expansion of allergen- IL-13 (6,7), but also novel cytokines such as IL-25, IL-
specific CD4+Th2 cells, with the capability of 31 and IL-33 which have proinflammatory functions
producing IL-4 and IL-13, which are the key events in (8-14). These cytokines induce eosinophilia, mucus
induction of IgE. Engagement of IgE on effector cells production, producing of allergen-specific IgE and the
leads to sensitization of patients to specific allergen recruitment of inflammatory cells to inflamed tissues.
(2). At the early stage of the reaction from the mast Th2 cells are the leader of the process. The main
cells and basophils are released many inflammatory effector cells are the eosinophils and mast cells.
mediators such as tryptase, eosinophil chemotactic Predominance of Th2 cells might be caused by an
factor in addition to histamine as well as newly increased tendency to activate induced cell death of
synthesized molecules (PGD2, LCT4, bradykinin). The high IFN-gama producing Th1 cells as it is commonly
process of secretion of these mediators is crucial observed in patients with atopic disorders (15). Th1
characteristic of the early stages of the response. cells induce apoptosis of keratinocytes in atopic
About half of all patients who exhibit an early-phase dermatitis and epithelial cells and/or smooth muscle
allergic response experience a late phase cells in asthma in the effector phase of these allergic
inflammatory reaction approximately 4-24 hours diseases (16-20). As the major consequences of the
following allergen exposure. Late phase response is activation of mast cells, the release of histamine and
manifested by activation of endothelial cells and other mediators occur, which leads to acute allergic
secretion of many inflammatory cytokines (TNF-α, reaction. Activation of eosinophils lead to the
granulocyte-macrophage colony-stimulating factor, extracellular release of a number of potent cytotoxic

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proteins. These proteins play a very important role in This treatment shows varying degrees of
the development of subacute and chronic symptoms success and there are many reasons for this
of allergy. Macrophages, epithelial cells, neutrophil variability. One of the very important reasons for this
granulocytes and endothelial cells also play an may be the fact that we are not seeing the mechanisms
important role in allergic diseases. Antigen-induced that underlie the individuality of the patient. It is clear
immunological cascade is presented in Figure 1. that there are large differences in terms of
Treatment of allergic diseases still has stereotyped inflammatory cells and mediators that are crucial for
character and consists of international and national allergic diseases.
recommendations.

Figure 1: The allergic cascade. Mast cell mediators, including cytokines, cause degranulation and contribute to
the bidirectional messaging with other inflamatory cells or their precursors, leading to lymphocyte activity,
and migration of immune cells to inflamatory sites (21) (source: Canonica GW, Blaiss M. Antihistaminic, anti-
inflammatory, and antiallergic properties of the nonsedating second-generation antihistamine desloratadine: a
review of the evidence. World Allergy Organ J 2011;4(2):47-53.)

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HISTAMINE permeability and a flare due to indirect

vasodilatation via the stimulation of axonal reflex.
Histamine (2-4 imodazol-ethylamine) was first Histamine has an essential role in the gastrointestinal
identified as a mediator of biological functions in the system for gastric acid secretion. Gastrin and vagal
early 20th century. It was identified in 1911, owing to stimulation induce enterochromaffine cells to release
vasoactive properties by Barger and Dale, and drugs histamine. Then histamine can act on the
that work on the principle of binding to histamine H+K+ATPases, which results finally in the secretion
receptor have been clinically used for more than 60 of H+, a key element for synthesis of HCl in the
years. It is one of the most extensively studied stomach.
molecules in medicine, of which synthesis, Level of histamine is increased in
metabolism, receptors, signal transduction, bronchoalveolar lavage fluid in patients with allergic
physiological and pathological effects there is a large asthma and this increase negatively correlates with
number of collected evidence. It has a wide range of airway function (24-29). An increase in histamine
both physiological and pathological effects, whereby levels has been noted in the skin and plasma of
the width of the spectrum has continuously been patients with atopic dermatitis (30,31) and in chronic
increasing by new research. Histamine is a low- urticaria (32, 33). Histamine levels are also increased
molecular-weight amine, a natural body constituent, in multiple sclerosis (34) and in psoriatic skin (35).
synthesized from L-histidine by histidine Both plasma and synovial fluid of patients with
decarboxylase, an enzyme that is expressed in many rheumatoid arthritis and plasma of patients with
tyipes of cells throughout the body, including the psoriatic arthritis have increased histamine levels
central nervous system neurons, gastric-mucosa (36, 37). It is know that the diverse biological effects
parietal cells, Mast cells, basophils, lymphocytes, and of histamine are mediated through different types of
enterophromaphiles cells. Histamine plays an histamine receptor in treatment. Histamine can have
important role in human health, exerting its diverse varying and sometimes counteracting effects on a
biological effects through four types of receptors. It particular cell depending on the concentration used,
plays a key role in the hematopoiesis, proliferation of and which histamine receptors are activated.
cells, differentiation of cells, regeneration and Receptor levels may change during different stages
wound healing, embryonic development. Histamine of cell development or under pathophysiological
is produced in neurons of the central nervous system conditions and could vary among species.
which have cell bodies located exclusively in the
tuberomamillary nucleus of the posterior
H I S T A M I NE R E CE P T O R S
hypothalamus. Their axons perform transmission of
histamine to the frontal and temporal cortexes of the
There are four major types of histamine
brain. In the phylogenetically old part of
receptors: H1, H2, H3 and H4 receptors which differ
neurotransmitter systems, histamine has a role in the
in their expression, signal transduction and function
regulation of basic body function through the H1-
(38-45). Exspression of H1 and H2 receptors are
receptor such as the cycle of sleeping and waking,
widely expressed in contrast to H2 and H4 receptors.
appetite, cognition and memory, energy and
H1, H2 and H4 receptors are expressed on the surface
endocrine homeostasis. Histamine also has
of many cells involved in inflammatory reactions,
anticonvulsant activity (22, 23).
with the H1-receptor playing a major role in
The roles of histamine in inflammation, gastric
potentiation of proinflammatory immune cell activity
acid secretion and as a neurotransmitter are the best
and effector responses fundamental to an allergic
described roles in the human body. Mast cells and
reaction. The H1 receptors have been associated with
basophils release histamine during inflammation.
many actions in relation to allergic inflammation,
Smooth muscle cells and endothelial cells are the
such as rhinorrhea, smooth muscle contraction and
target places of action of histamine. This leads to
many forms of itching (pruritus). This is mediated by
vasodilatation and increase in vascular permeability.
the transduction of extracellular signals through G
In the skin, histamine results in the triple response,
protein and intracellular second messengers (inositol
which is an immediate local reddening due to
triphosphate, diacylglycerol, phospholipase D and A2,
vasodilatation, a wheal due to increased vascular
and increases in intracellular calcium concentration).
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Making of H1 receptors is encoded by genes, receptor polymorphisms have been described,

localized on chromosome 3. The H2-receptor, in although it is not yet clear how they influence the
contrast, appears to suppress inflammatory and clinical response to H1-antihistamines (47). Target
effector functions, while data regarding the role of the disruption of the genes encoding the H1 receptor, is
H4-receptor in immune response is limited. Evidence applied in mice which results in CNS function
of the existence of a third histamine receptor groups disorders, such as memory, learning, locomotion and
(H3) was based on the activity of histamine, which aggressive behavior. H1 receptor deficiency also leads
could not be blocked by antagonists of H1 or H2- to numerous immunological abnormalities such as
receptor antagonist (46). The histamine H3 receptor weakening of antigenic-specific response of T and B
has been identified in the central and peripheral cells (48,49).
nervous systems as pre-synaptic receptors controlling The presence of histamine leads to
the release of histamine and other neurotransmitters. upregulation of H1 receptors. It was experimentally
The local concentratcion of histamine and proven that antagonists cause blockade of upregulation.
predominant type of histamine receptor undergoing The concept of constitutive activity has led to a
activation determines the type of effector response reclassification of drugs acting at the H1- receptor. For
that is elicited. example, the H1-receptor promotes NF-kB in both a
All four types of histamine receptor are constitutive and agonist-dependent manner and all
heptahelical transmembrane molecules that transduce clinically available H1-antihistamines inhibit
extracellular signals by way of G proteins to constitutive H1-receptor-mediated NF-kB production
intracellular second-messenger systems. The classic (50, 51).
model of receptor activation requires binding by a Histamine can also be linked to one type of
specific ligand, or agonist and binding of inverse intracellular histamine receptor (Hic), which was
agonist (antagonist in the older literature) leads to the described several years ago in the microsomes and
inactivation, blockade of these receptors. Aspartic acid nucleus. These types of receptors are comprised of the
located in the third transmembrane domain of the cytochrome P450 and cytochrome c (52). This type of
human receptor is crucial for the affinity of histamine receptor cannot yet be discussed with absolute
and histamine antagonists; this amino acid is a certainty, because it is not yet clear which type of
hallmark of G-protein-coupled receptors. All types of reactions are induced by histamine binding to this
receptor have constitutive activity, which is defined as receptor. Localization of histamine receptors as well
the ability to trigger events even in the absence of as the mechanism of their activation are presented in
ligand binding. It can be said that there is a balance Table 1.
between active and inactive states of the receptor. H1-

Table 1. Histamine receptors, the localization of their expression and mechanism of action (53) (source: Akdis
CA, Simons FER. Histamine receptors are hot in immunopharmacology. Eur J Pharmacol 2006; 533:69-76.)

Histamine Activated intracellular G

Expression
receptors signals proteins
Nerve cells, airway and vascular smooth muscles, hepatocytes,
Ca2+, cGMP, phospholipase
H1 receptors chondrocytes, endothelial cells, epithelial cells, neutrophils, Gq/11
D, phospholipase A2, NF-kB
eosinophils, monocytes, dendritic cells (DC), T and B cells
Nerve cells, airway and vascular smooth muscle, hepatocytes,
Adenylatecyclase, cAMP, c-
H2 receptors chondrocytes, endothelial cells, epithelial cells, neutrophils, Gαs
Fos, c-Jun, PKC, p70S6K
eosinophils, monocytes, dendritic cells, T and B cells
Histaminergic neurons, eosinophils, DC, monocytes, low MAP kinase, inhibition of
H3 receptors Gi/o
expression in peripheral tissues cAMP, Ca2+
High expression on bone marrow and peripheral hematopoetic
cells, eosinophils, neutrophils, DC, T cells, basophils, mast
H4 receptors Ca2+, inhibition of cAMP Gi/os
cells; low expression in nerve cells, hepatocytes and peripheral
tissues

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THE ROLE OF HISTAMINE IN Under the influence of histamine occurs

ALLERGIC INFLAMMATION AND secretion of proinflammatory cytokines such as IL-1α
IL-1β, IL-6 as well as chemokines such as regulated
IMMUNE MODULATION
activation (RANTES) or IL-8. This process takes place
in several types of cells and tissues and leads to the
Histamine plays a key role in allergic
progression of allergic-inflammatory responses.
inflammation, which is a complex network of cellular
Histamine H1 receptor and histamine H2
events that involve many cells and mediators.
receptor are found on the surface of endothelial cells.
Histamine is released from the mast cells and
Histamine through H1 receptor leads to increased
basophils together with tryptase and other preformed
expression of adhesion molecules such as vascular
mediators such as prostaglandins, leukotrienes, after
cellular adhesion molecule (VCAM-1), intracellular
the cross-linking of surface IgE by allergen or through
adhesion molecule (ICAM-1) and P-selectin.
mechanisms that are independent of IgE. After
Histamine regulates granulocyte accumulation
allergen challenge in sensitized persons, the local
in tissues in distinct ways. Allergen-induced
concentration of histamine is much higher compared
accumulation of eosinophils in the skin, nose and
to leukotrienes and other mediators. The
airways is inhibited by histamine H1 receptor
concentration of histamine can then be measured in
antagonists. The effect of histamine on eosinophil
micrograms, whereas the concentration of leukotrienes,
migration may differ according to the concentration.
and other mediators may be measured in picograms.
Whereas high concentrations inhibit eosinophil
Most of the changes in allergic disease occur as
chemotaxis via histamine H1 receptor, low
a consequence of binding histamine to H1 receptor
concentrations enhance eosinophil chemotaxis via
(38-40, 54). Hypotension, tachycardia, flushing and
histamine H1 receptor. One study has shown that
headache occur through both the H1 and H2 receptors
histamine H4 receptor is the histamine receptor
(55), whereas irritation of the skin in the form of
responsible for the selective recruitment of eosinophils.
itching and nasal congestion can be caused by the
Histamine possesses all the properties of a classical
activation of H1 and H3 receptors (56, 57). The role of
leukocyte chemoattractant, including: alteration in cell
histamine can be discussed also as a stimulatory
shape, mobilization of intracellular calcium and up-
signal for the production of cytokines and the
regulation of adhesion molecule expression.
expression of cell adhesion molecules in the late-
phase of allergic reaction (55, 56, 58, 59).
Histamine may have proinflammatory or A N T I H I ST A M I NE S
antiinflammatory effects, depending on the
predominance of the type of histamine receptor. More than 45 types of antihistamines are
Through the H1-receptor, histamine has widely used around the world, thus representing the
proinflammatory effect, which activation can be largest group of medicines used in the treatment of
greatly involved in several aspects of antigen-specific allergic conditions.
immune response, including maturation of dendritic Traditionally, this group of drugs is classified
cells and the modulation of the balance of Th1 cells in six chemical groups: ethanolamines, ethylenediamines,
and Th2 cells. Histamine may induce an increase in alkylamines, piperazines, piperidines and
the proliferation of Th1 cells and in the production of phenothiazines. If antihistamines are classified
interferon γ, which may result in blocking humoral according to function, then we distinguish two
immune responses by means of this mechanism. generations of antihistamines: first and second
Histamine has the capacity to influence the activity of generation antihistamines, which are distinguished
basophils, eosinophils and fibrobalsts. by the fact that first generation antihistamines
The binding of histamine to histamine H1 penetrate the blood-brain barrier and have a sedative
receptor leads to many effects that are associated with effect, while the second generation antihistamines do
symptoms of anaphylaxis and other allergic diseases not possess these qualities. They are very different in
(60), however, increasing evidence suggests that this terms of chemical structure, pharmacology and toxic
process also affects a number of immune potential. Representative of the first and second
/inflammatory and effector functions (38,59). generation of antihistamines are given in Figure 2.
Consequently, knowledge of their pharmacokinetic
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and pharmacodynamics characteristics is important for patients belonging to extreme age groups, pregnant
the correct usage of such drugs, particularly in women, or subjects with concomitant diseases.

Figure 2: Drugs of the first and second generation of antihistamines (61) (source: Simons FER, Simons KJ.
The pharmacology and use of H1-receptor antagonist drugs. N Engl J Med 1994; 330: 1663-1670)

After oral application, most antihistamines cytohrome system performs metabolization and
show a good degree of absorption. The effective detoxification of most antihistamines. Only acrivastine,
concentration of antihistamines is achieved three levocetirizine, desloratadine and fexofenadine (62)
hours after application, which confirms the above avoid this metabolic passage through the liver to an
thesis. These molecules have the characteristic of important degree, which makes them more predictable
liposolubility, which enables them to pass through in terms of their desirable and undesirable effects.
cell membranes with extreme ease. Concomitant Fexofenadine is eliminated in stool, while cetirizine and
administration with food can change the plasma levocetirizine are eliminated in urine. Fexofenadine is
concentrations of these drugs, which can be eliminated without metabolic changes while cetirizine
explained by the presence of P glycoprotein across and levocetirizine are eliminated in unaltered form.
cell membranes and the organic anion transporter Other antihistamines undergo the transformation in
polypeptides. These proteins function as active the liver, thereby resulting in metabolites which may
transport systems for other molecules, showing be active or inactive. Their concentrations in plasma
affinity for them. Antihistamine shows a good depend on the activity of the P450 enzyme system.
degree of binding to plasma proteins (78% to 99%). Metabolism of antihistamines and drug interaction are
The group of enzymes belonging to the P450 given in Table 2.

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Table 2:Antihistamines, their metabolism and interaction with other drugs (63) (modified from del Cuvillo A,
Mullol J, Bartra J, Davila I et al. Comparative pharmacology of the H1 antihistamines.
J Investig Allergol Clin Immunol 2006; 16(1):3-12.)

Generation of
Drug Liver metabolization Drug interactions
antihistamines
Chlorpheniramine
Yes Possible
Diphenhydramine
Yes Possible
First Doxepin
Yes Possible
Hydroxyzine
Yes Possible

Acrivastine <50%
Cetirizine <40% -
Loratadine Yes -
Ebastine Yes -
Second Fexofenadine <8% Possible
Mizolastine Yes Yes (P glycoprotein)
Levocetirizine <15% Possible
Desloratadine Yes -
Rupatadine Yes

Antagonists of H1 receptors are used in CETIRIZINE

treatment of allergic rhinoconjuctivitis and relieve
sneezing nasal and ocular itching, rhinorrhea, Cetirizine is a highly selective, long-acting,
conjujctival erythema and early phase of peripheral H1 antagonist of the second generation,
inflammatory response, but they are less effective in carboxylated metabolite of hydroxyzine, which
the treatment of late phase of inflammatory response represents a combination of the two enantiomers
(64). levocetirizine (R enantiomer) and dextrocetirizine
Pretreatment with H1 antagonists may (S enantiomer). It has very low affinity for the
provide some protection against bronchospasm number of types of receptors such as α1-adrenergic,
induced by histamine, exercise, hyperventilation of dopaminergic (D2 receptors), muscarinic and
cold and dry air, hypertonic or hypotonic saline, serotonergic receptors. Cetirizine also shows a low
distilled water, adenosine 5 monophosphate, or degree of affinity for calcium channels. Owing to
allergen. The amount of protection varies with the some of its properties in the allergic response to
dose of H1 antagonists and stimulus used (65-68). antigenic stimulus, cetirizine shows antiallergic, anti-
In patients with chronic urticaria, H1 inflammatory and antihistamine effect. It exists as a
antagonists relieve pruritus and reduce the number, zwitterion (has a separate positive and negative
size and duration of urticarial lesions (69-75). charged groups). The absorption of cetirizine is good
In patients with anaphylactic or anaphylactoid after the oral administration of this drug. After oral
reactions, the initial drug of choice is epinephrine; application of cetirizine in a dosage of 10 to 20 mg,
however, H1 antagonists are useful in the ancillary the maximum plasma concentration (Cmax) is
treatment of priuritus, urticarial and angioedema. attained for 1h and it is 257μg/L to 580μg/L. There is
For anaphylaxis, H2 antagonists are used concurrently no difference in action of this medication if it is
with H1 antagonists to reduce the effects of administered in the form of tablet or in the form of
histamine on the peripheral vasculature and the syrup. Ninety percent of the drug binds to plasma
myocardium (76,77). albumin. Cetirizine is widely distributed throughout

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the body, although it does not pass the blood-brain particular, it highlights the role of fibroblasts in the
barrier easily. 70% of the cetirizine is eliminated via respiratory system, where they play an important
urine, and about 10% through the digestive tract in role in allergic and inflammatory diseases of the
the feces. This H1 antagonist has a low degree of respiratory system, not only in the formation of
interaction with other drugs, since it avoids the fibrosis, because they have the ability to respond to
metabolic pathway through the liver. Th2 cytokines. Cetirizine may have a very significant
The consensus of the British Society for antifibrotic effect for its ability to reduce the level of
Allergology and Clinical Immunology confirmed the profibrotic cytokine, transforming growth factor beta
anti-allergic and anti-inflammatory properties of (TGF-β), tumor necrosis factor (TNF-α) and IL-6 (99).
cetirizine in vitro and in vivo. Antihistamine agents It has been shown that the fibroblasts of the airways
such as cetirizine do not act only through H1 have functional receptors for IL-4 and IL-13.
receptors, but may attenuate many events during the Numerous studies have shown that cetirizine results
inflammatory process. Cetirizine shows some in a reduction of the expression of CD54 induced by
modulation effects on the inflammatory response. It IFN-γ.
leads to reduction of the migration of eosinophils
that is induced by inflammatory mediators in atopic
and nonatopic individuals (78-87). In addition to the CONCLUSION
classic role in antagonizing the H1 receptor,
cetirizine induces reduction of the expression of Knowledge of the mechanisms underlying the
adhesion molecules associated with the migration of allergic reaction, records a constant growth and tells
eosinophils and eosinophil cells in in vitro studies us about the complex network of cells and
(88-90) and in atopic patients (91-94), so that the mediators, which are at the core of allergic
recipients and the effect of cetirizine consists of the inflammatory response. Through its receptors,
inhibition of eosinophil infiltration into tissues. It has histamine as an important chemical messenger plays
a lipophilic and ionizing properties enabling it to act an important role in the physiological response,
directly on the cell membrane leading to its including neurotransmission, allergic inflammation
stabilization. Cetirizine inhibits binding of NF-kB, and immunomodulation. Drugs that have the
inhibits the expression of adhesion molecules histamine receptors as target for their activity can be
(ICAM-1) on immune cells and endothelial cells. It considered as a very good choice for the treatment of
also inhibits migration of inhibitory factor (MIF) (95) allergic conditions. Pharmacodynamic and
as well as the production of IL-8, and leukotriene B4 pharmacokinetic differences between the first and
production of two very potent chemoattractans. second generation of antihistaminics should be well
Cetirizine leads to the release of PGE2, suppressors known, because it can help when choosing the right
of expression of antigen and presentation of MHC drug. Cetirizine is a potent second-generation
class II on monocytes and reducing macrophages antihistamine which shows remarkable
(96), reducing the chemotaxis of monocytes and T immunoregulatory properties. It influences the
lymphocytes (97). Cetirizine reduces the number of interaction of mediator cells with all systems. It
tryptase-positive mast cells at sites of inflammation affects the interaction of eosinophils, mast cells and
(98). An increasing number of data points to the fibroblasts and thus may participate in the
importance of fibroblasts in many organs. In regulation of the internal environment

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Histamin i antihistamini

Nikola Stojković1, Snežana Cekić2, Milica Ristov3, Marko Ristić1, Davor Đukić1, Maša Binić1,
DraganVirijević1

1Univerzitet u Nišu, Medicinski fakultet, Student postdiplomskih studija, Srbija

2Institut za patofiziologiju, Univerzitet u Nišu, Medicinski fakultet, Srbija
3Doktor medicine

SAŽETAK

Poslednjih godina beleži se kontinuirani rast prevalencije alergijskih oboljenja. Alergijski imunski
odgovor predstavlja jednu kompleksnu mrežu ćelijskih događaja u kojoj učestvuju mnogobrojne imunske
ćelije i medijatori. On predstavlja interakciju urođenog i stečenog imunskog odgovora. Ključnu ulogu u
imunološkoj kaskadi zauzima histamin, prirodni sastojak tela, koga u alergijskom inflamatornom odgovoru
oslobađaju mastociti i bazofili. Cilj ovog rada bio je naglasiti ulogu histamina u alergijskim imunološkim
događajima, njegov efekat na Th1 i Th2 subpopulaciju limfocita i produkciju odgovarajućih citokina, kao i
ulogu blokatora histamina u tretmanu ovih stanja. Histamin ostvaruje svoj efekat vezivanjem za četiri tipa
svojih receptora koji su široko distribuirani u organizmu. Blokatori histamina blokiraju mnogobrojne efekte
histamina vezivanjem za ove receptore. Cetirizin, visoko selektivni antihistaminik druge generacije, ne
ostvaruje svoje efekte samo vezivanjem za H1 receptore već dovodi do atenuisanja mnogobrojnih zbivanja
tokom inflamacijskog procesa. Dobro poznavanje efekata histaminskih blokatora, među njima i cetirizina,
može dovesti do pravog odabira terapije u tretmanu alergijskih oboljenja.

Ključne reči: histamin, imunski odgovor, blokatori histamina, cetirizin

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