Anti-allergic drugs
Sue McKay and Antoon J.M. van Oosterhout
Introduction
ALLERGY is defined as a disease following a response
by the IMMUNE SYSTEM to an otherwise innocuous
ANTIGEN. Allergic diseases include allergic rhinitis,
atopic dermatitis,systemic anaphylaxis,food ALLERGY,
allergic asthma and acute urticaria and are mediat-
ed by unwanted type-I hypersensitivity reactions to
extrinsic allergen like pollen,house-dust,animal dan-
der,drugs and insect venom.These diseases are char-
acterised by the production of IgE antibodies to the
allergen that bind to the high-affinity IgE receptor,
FcεRI, on mast cells and BASOPHILS. Binding of aller-
gen to IgE cross-links these receptors and causes the
release of chemical mediators from mast cells lead-
ing to the development of a type-I hypersensitivity
reaction (Fig. 1). This acute response is often fol-
lowed by a late and more sustained inflammatory
response characterised by the recruitment of other
effector cells like EOSINOPHILS and T-helper type-2
(Th2) LYMPHOCYTES. This chapter will focus on anti-
allergic drugs that target the activation of the mast
cell or block the effects of its chemical mediators, in
particular histamine.
Disodium cromoglycate and
nedocromil sodium (chromones)
Dr. Altounyan first discovered that disodium cromo-
glycate possessed an anti-asthma action in the 1960s.
He induced an asthma attack by inhaling animal
dander ANTIGENS, and showed that cromoglycate
afforded protection against this bronchial provoca-
tion. Disodium cromoglycate was introduced as an
anti-allergic drug in 1967. Many companies tried to
C3
find improved versions of this compound, using the
chemical structure as a starting point, but most of
these attempts failed. Nedocromil was discovered
and introduced 20 years later by Eady.
The exact MECHANISM OF ACTION of disodium cro-
moglycate and the related drug nedocromil sodium
remains unclear, but their clinical activity probably
represents a combination of effects. It was originally
suggested that these non-steroidal anti-inflammatory
drugs act as mast cell stabilisers [1]. However,
although these drugs can prevent histamine release
from mast cells, it has been demonstrated that this
effect is not the basis of their action in allergic asth-
ma. Other compounds that more potently inhibit
mast cell histamine release have not proven to be
more effective in the treatment of allergic asthma.
Sodium cromoglycate and nedocromil sodium also
partly inhibit the IgE-mediated release of other medi-
ators from mast cells, such as prostacyclins and
LEUKOTRIENES [2]. In addition, they have been
described as exhibiting suppressive effects on
inflammatory cells such as MACROPHAGES, MONOCYTES,
NEUTROPHILS and EOSINOPHILS, but they do not have
any direct effects on smooth muscle and they do not
inhibit the actions of smooth muscle contractile ago-
nists [3, 4]. Sodium cromoglycate and nedocromil
sodium inhibit the influx of inflammatory cells and
the release of inflammatory mediators following
provocation with non-specific agents, such as cold
air and air pollutants [5–7]. Furthermore, they have
been reported to depress the exaggerated neuronal
reflexes that are triggered by the stimulation of “irri-
tant” receptors by decreasing neuropeptide release
from C fibres and via antagonism of tachykinin
receptors [8–10]. A comparison of the activities of
sodium cromoglycate and nedocromil sodium on a
variety of inflammatory cell types is shown in
Table 1. The chemical structures of sodium cromo-
266 Anti-allergic drugs

FIGURE 1. SCHEMATIC REPRESENTATION OF THE INDUCTION OF IGE SYNTHESIS BY B-LYMPHOCYTES

Once formed, IgE antibody circulates in the blood, eventually binding to high-affinity IgE receptors (FcεRI) on mast
cells and low-affinity IgE receptors (FcRII, or CD23) on eosinophils and macrophages. After subsequent encounters
with allergen, cross-linking of the high-affinity IgE receptors produces the release of preformed and newly generated
mediators. Once present in various tissues, mediators may produce various physiological effects, depending on the tar-
get organ [45].

glycate and nedocromil sodium are depicted in
Figure 2.
Mechanisms of action
Many studies have been performed to determine the
mechanisms by which chromones inhibit the activa-
tion of cells. Since these compounds affect a wide
variety of cells it has been assumed that a common
mechanism must exist. Experiments have been per-
formed to investigate whether this mechanism is reg-
ulated through a specific receptor or if it is due to the
modulation of a second messenger signal.
Initially Ca2+ ions were implicated as the target
for sodium cromoglycate [11], but this was discount-
ed after it was shown that sodium cromoglycate
could also inhibit mast cell activation in the pres-
 Disodium cromoglycate and nedocromil sodium (chromones) 267

TABLE 1. COMPARISON OF EFFECTS OF SODIUM CROMOGLYCATE AND NEDOCROMIL SODIUM ON INFLAMMATORY CELLS

Effect Nedocromil sodium Sodium cromoglycate

Mast cells from BAL, lung, conjunctiva, nasal mucosa, gastric
mucosa and basophils
Mediator release following Ascaris Ag or α-IgE Ab-inhibited ↓
(histamine, PGD2, LTC4)
Release of cytokines (TNF-α) ↓ ↓
Release of histamine ↓ ↓
Numbers ↓ ↓
Macrophages/monocytes
Release of cytokines (IL-6) ↓
Release of lysosomal enzymes and oxygen radicals ↓
Numbers ↓
Eosinophils
Numbers in BAL ↓ ↓
Number of activated eos in submucosa ↓
Release of mediators (preformed and newly generated) ↓ ↓
Chemotactic response to PAF and LTB4 ↓
Chemotactic response to zymosan-activated serum ↓
Activation ↓
Survival time in presence of IL-5 ↓
Neutrophils
Activation ↓ ↓
Chemotactic response ↓ ↓
Release of mediators (TNF-α, IL-6) ↓ ↓
Numbers ↓
Platelets
Release of cytotoxic mediators ↓
IgE-mediated activation ↓
Generation of thromboxane B2 and IP3 ↓
Epithelial cells
Release of 15-HETE ↓
Release of cytokines (TNF-α, IL-8, GM-CSF) and ICAM-1 ↓
Expression of ICAM-1, VCAM-1, E-selectin ↓ ↓
B cells
IgE Ab formation ↓ ↓
T cells
Numbers ↓ ↓
Proliferation (allergen- or mitogen-induced) ± ±
Endothelial cells
Expression of ICAM-1, VCAM-1, E-selectin ↓ ↓
Sensory nerve (C fibres) activation
Release of neuropeptides ↓ ↓
↓ reduction; ± no change
268 Anti-allergic drugs
FIGURE 2. CHEMICAL STRUCTURES OF SODIUM CROMOGLY-
CATE AND NEDOCROMIL SODIUM
ence of Ca2+-chelating agents [12]. Sodium cromo-
glycate and nedocromil sodium have been shown to
reduce Ca2+ influx into cells, although it is believed
that they do not interfere directly with Ca2+ channels
[11]. These compounds have also been shown to
phosphorylate intracellular proteins preceding
mediator release from rat peritoneal mast cells; how-
ever, this does not hold true for mast cells isolated
from the macaque [1].Additionally, activation of pro-
tein kinase C (PKC) has been suggested as the
molecular target for sodium cromoglycate [11, 13,
14], although other researchers report an inhibition
of PKC activity [15].The ability of sodium cromogly-
cate and nedocromil sodium to affect intracellular
targets directly is unlikely if we consider the physical
properties of these compounds. Both compounds
are extremely polar and hydrophilic at pH 7.4, and
therefore unlikely to penetrate the cell membrane.
Consequently,it was assumed that they must function
via a cell membrane component,possibly a receptor.
Mazurek and colleagues have described a “sodium
cromoglycate-binding protein”, in rat basophil
leukaemia (RBL) cells, that may be involved in Ca2+
mobilisation [16–18].Eady and co-workers also iden-
tified proteins on rat peritoneal mast cells and
Chinese hamster ovary cells that may act as recep-
tors. Unfortunately, the identification of a specific
receptor has not yet been established.
There is an increasing amount of evidence sug-
gesting that modulation of chloride channel activity
is possibly the common mechanism to explain the
effects of sodium cromoglycate and nedocromil
sodium. An accumulation of intracellular Ca2+
(Ca2+i) often precedes cell activation and mediator
secretion in many cells. This accumulation of Ca2+i
can result from a Ca2+ influx due to a negative mem-
brane potential, which in turn is the result of an
inward flow of Cl– ions through chloride channels.
Degranulation is dependent on a sustained elevation
of intracellular Ca2+ – due to release of Ca2+ from
intracellular stores and influx of Ca2+ ions. A small-
conductance chloride channel (0.5-1 pS), identified
in rat peritoneal mast cells, can achieve this by pro-
viding the negative membrane potential necessary
for maintaining Ca2+ influx and its sustained eleva-
tion.The Ca2+ current activated by this mechanism is
described as ICRAC (Ca2+ release-activated Ca2+ cur-
rent). By replacing extracellular Cl– ions with non-
permeant isethionate or gluconate anions, Friis and
colleagues were able to inhibit ANTIGEN-stimulated
histamine secretion from rat peritoneal mast cells,
although some histamine secretion still occurred
[19]. Sodium cromoglycate can also block interme-
diate conductance chloride channels on RBL cell
membranes [11].
Studies on epithelial cells provide more evidence
that sodium cromoglycate and nedocromil sodium
affect chloride transport. Alton and colleagues [20]
showed that these compounds are able to block the
activity of a chloride channel present on the mucos-
al surface of airway epithelial cells. Moreover, epithe-
lial cells are sensitive to the concentration of solutes
in their environment, and chloride currents are
believed to be involved in the regulation of cell vol-
ume. Nedocromil and cromoglycate can inhibit the
chloride current induced in epithelial cells in
response to osmotic changes, thereby inhibiting cell
swelling [21]. Furthermore, Paulmichl and col-
leagues show that sodium cromoglycate and nedo-
cromil sodium inhibit hypotonic saline-induced acti-
vation of a chloride channel in mouse 3T3 fibrob-
lasts [22].

Further, evidence from in vitro studies suggests
that these compounds affect neuronal chloride
transport – chloride efflux from sensory nerves
leads to depolarisation and the generation of action
potentials.Nedocromil sodium prevents the contrac-
tion of guinea pig bronchus that is induced by elec-
tric field stimulation in the presence of atropine
[10]. Bronchoconstriction is probably mediated by
the release of neuropeptides from C fibre terminals.
This is supported by other studies that show
nedocromil inhibition of substance P-induced
potentiation of the cholinergic neural responses in
rabbit trachea [23] as well as inhibition of
tachykinin release [24].
Chloride channel activation is a mechanism that
occurs when cells are activated. By preventing chlo-
ride channel activation, sodium cromoglycate and
nedocromil sodium would be expected to maintain
cells in a normal resting physiological state, and this
is associated with the relative lack of toxicity of these
compounds.
Biochemical and pharmacological effects
The anti-inflammatory effects of sodium cromogly-
cate and nedocromil can result in a number of bio-
logical effects:
- Inhibition of mediator release from human mast
cells isolated from bronchoalveolar lavage (BAL)
fluid and from mast cells derived from lung, con-
junctiva and nasal mucosa. Human skin-derived
mast cells, however, do not respond to cromogly-
cate or nedocromil. Histamine secretion by ente-
rochromaffin-like cells from the gastric mucosa
can also be inhibited by sodium cromoglycate.
Mediator release from EOSINOPHILS, NEUTROPHILS and
platelets is also inhibited.
- The numbers of inflammatory cells such as
EOSINOPHILS, NEUTROPHILS, BASOPHILS (though not
unequivocally confirmed for nedocromil sodium),
mast cells, MACROPHAGES and T LYMPHOCYTES are
reduced, in both tissues and blood.
- Inflammatory cell infiltration depends on the acti-
vating effects of chemotactic factors that are often
released by infiltrating inflammatory cells. Cromo-
glycate and nedocromil can completely suppress
Disodium cromoglycate and nedocromil sodium (chromones) 269
the activating effects of chemo-attractant peptides
on human EOSINOPHILS, NEUTROPHILS and MONOCYTES.
- Inflammatory cell infiltration also depends on the
expression of ADHESION MOLECULES. These com-
pounds can inhibit the expression of various ADHE-
SION MOLECULES, such as ICAM-1, VCAM-1 and E-
SELECTIN, which are crucial for the passage of
inflammatory cells from the blood to peripheral
tissues.
- Cell activation and cytokine release from inflam-
matory cells such as T LYMPHOCYTES, MACROPHAGES
and mast cells is inhibited.
- Inhibition of IL-4-induced IgE ISOTYPE switching
and suppression of IgG4 production, without fur-
ther effects on B CELLS that have already undergone
switching.
- Sensory nerve (C-fibres) activation is inhibited
resulting in reduced release of neuropeptides such
as substance P and tachykinins.
- Survival of platelets can be increased and these
compounds inhibit IgE activation of platelets.
- MICROVASCULAR LEAKAGE is reduced, presumably
through functional antagonism of tachykinin
receptors.
Pharmacokinetics
Disodium cromoglycate and nedocromil are poorly
absorbed from the gastrointestinal tract, and are
therefore given locally per inhalation; as either an
aerosol, a nebulised solution or in powder form; or
they are given as eye drops. Nedocromil and disodi-
um cromoglygate are not metabolised and are
excreted unchanged.Their plasma half-life is approx-
imately 90 minutes.
Clinical indications
Therapeutic studies have revealed and confirmed
the clinical EFFICACY, protective effects and high safe-
ty/low side-effect profile of these drugs. The diverse
clinical effects, including the anti-inflammatory
character, of these drugs have been described in
detail.
270 Anti-allergic drugs
Allergic bronchial asthma
Sodium cromoglycate and nedocromil sodium have
been reported to demonstrate protective effects on
the immediate ASTHMATIC RESPONSE (IAR) as well as
the late ASTHMATIC RESPONSE (LAR) induced by
bronchial challenge with allergen.The delayed ASTH-
MATIC RESPONSE, however, was altered by nedocromil
but not by cromoglycate.These compounds not only
reduce the numbers of inflammatory cells in the BAL
fluid, but they also decrease the activation and/or
stimulation state of these cells.They also reduce the
number of circulating LEUKOCYTES (EOSINOPHILS, NEU-
TROPHILS and BASOPHILS) during the IAR and the LAR
following allergen challenge as well as decrease the
activation of circulating T LYMPHOCYTES. Cromogly-
cate and nedocromil can also inhibit the IAR that
occurs during exercise-induced asthma and reduce
bronchoconstriction due to non-specific hyperreac-
tivity mechanisms. However, not all asthma subjects
respond to these drugs and children respond more
often than adults do [1, 25, 26].
Allergic rhinitis
Similar to the treatment of allergic asthma, sodium
cromoglycate and nedocromil sodium have demon-
strated protective effects on the immediate nasal
response (INR) as well as the late nasal response
(LNR) induced by nasal challenge with allergen.
The delayed nasal response, however, was not
altered by cromoglycate and only partially prevent-
ed by nedocromil. Prophylactic treatment with
these compounds significantly reduces inflammato-
ry cell infiltration and epithelial cell numbers as
determined by cytological analysis of nasal secre-
tions following allergen challenge in patients with
allergic rhinitis [27]. Degranulation of mast cells,
BASOPHILS and EOSINOPHILS is inhibited and the
expression of ICAM-1 on epithelial cells is down-
regulated [28, 29].
Allergic conjunctivitis
The immediate and late responses to allergen chal-
lenge are prevented in the eye.Sodium cromoglycate
and nedocromil sodium inhibit the emergence of
conjunctival oedema and erythema and reduce
mast cell degranulation as well as vascular leakage
[30–32].
Food allergy
Adverse reactions to food, including ALLERGY, can
lead to unwanted organ responses. The various
organ responses to food ingestion challenge can be
inhibited by sodium cromoglycate treatment. This
compound significantly inhibits immediate and late
types of asthmatic, nasal, paranasal sinus, middle ear,
conjunctival, migraine, atopic eczema, urticarial and
Quincke’s oedema responses to food ingestion ALLER-
GY [1, 27, 33].
It can be concluded that sodium cromoglycate and
nedocromil sodium are effective drugs in the pro-
phylaxis of allergic bronchial asthma, allergic rhini-
tis, allergic conjunctivitis and related allergic disor-
ders. However, some authors suggest that it is not jus-
tified to recommend sodium cromoglycate as a first
line prophylactic agent in childhood asthma [34].
Unwanted effects
Unwanted effects are infrequent and consist pre-
dominantly of the effects of irritation in the upper air-
way. Hypersensitivity reactions have been reported
and include urticaria, bronchospasm, angio-oedema
and anaphylaxis, but these are uncommon.
Histamine receptor antagonists
Histamine was first identified in 1910 and the first
histamine receptor antagonists were synthesised
over 20 years later. Early anti-histamine studies were
qualitative, for example, the demonstration of their
effectiveness in protecting against histamine-
induced bronchospasm. Nevertheless, these studies
introduced compounds, such as mepyramine, that
remain major ligands to define histamine receptors.
It became apparent in the 1950s that there were mul-
tiple histamine receptors, and research still contin-
ues to identify novel histamine receptors.

Histamine
Histamine (2-(4-imidazolyl)ethylamine or 5-amino-
ethylimidazole) plays a significant role in the regula-
tion of physiological processes and it is an important
mediator during allergic reactions. It is synthesised
from L-histidine by histidine decarboxylation and
stored in various cells including mast cells, BASOPHILS,
neurones and enterochromaffin-like cells. Other
cells,predominantly from the hematopoietic lineage,
can also synthesise and secrete histamine, although
these cells lack specific storage granules. Histamine
can closely mimic the anaphylactic response that
usually results from an ANTIGEN-ANTIBODY reaction in
sensitised tissue. Once released, histamine can be
metabolised by diamine oxidase (DAO) and hista-
mine N-methyltransferase (HMT).The effect of hista-
mine is produced by its action on specific receptors,
which are subdivided into several groups – H1,H2,H3,
and H4-receptors. All subtypes are members of the
seven membrane-spanning G protein-coupled recep-
tor (GPCR) family.
Characterisation of H-receptors
The receptor subtype determines the biological
effects of histamine. H1-receptors are expressed on
most smooth muscle cells, endothelial cells, adrenal
medulla, heart and central nervous system (CNS).
They have also been reported to be expressed on
bronchial epithelial cells, fibroblasts, T CELLS, MONO-
CYTES, MACROPHAGES, DENDRITIC CELLS and B CELLS.Their
stimulation leads to smooth muscle contraction,
stimulation of NO formation, endothelial cell con-
traction, stimulation of hormone release, negative
ionotropism, depolarisation and increased neuronal
firing as well as increased vascular permeability.
Stimulation of H1-receptors can also lead to pro-
inflammatory reactions such as induction of the
expression of ADHESION MOLECULES on endothelial
cells and the production of CYTOKINES by these cells
as well as the induction of co-stimulatory molecules
on DENDRITIC CELLS. H1-receptor expression can be
modified during inflammatory reactions. H2-recep-
tors are expressed on parietal cells in the gut, vascu-
lar smooth muscle cells, heart, suppressor T CELLS,
Histamine receptor antagonists 271
NEUTROPHILS,CNS and BASOPHILS.Their stimulation trig-
gers gastric acid secretion, vascular smooth muscle
relaxation, positive chronotropic and ionotropic
effects on cardiac muscle, inhibition of lymphocyte
function, basophil chemotaxis and other immune
responses. H3-receptors are found mainly on cells in
the CNS and peripheral nervous system as pre-synap-
tic receptors. They have also been identified on
endothelium and enterochromaffin cells. These
receptors control release of histamine and other
neurotransmitters, such as acetylcholine and
dopamine, from neurones. H4-receptors have only
recently been described and appear to be expressed
on cells of the haematopoietic lineage and on
immunocompetent cells such as mast cells,
BASOPHILS, T CELLS, DENDRITIC CELLS, NEUTROPHILS and
EOSINOPHILS. Stimulation of H4-receptors mediates
chemotaxis of mast cells, NEUTROPHILS and regulates
CYTOKINE release from CD8+ T CELLS [35–40].
H1-receptor antagonists are clinically effective
when used to treat inflammatory and allergic reac-
tions.The main clinical effect of H2-receptor antago-
nists is on gastric secretion and the clinical rele-
vance of H3-receptor antagonists is still being
explored, although they appear to be effective in the
treatment of CNS disorders. Neither H2-receptor
antagonists nor H3-receptor antagonists are consid-
ered to be clinically effective in anti-allergic thera-
pies. H4-receptor antagonists are being developed
and it is thought that may be useful in the treatment
of allergic diseases such as allergic rhinitis and asth-
ma in the future [37].
Mechanisms of action of H1-receptor
antagonists
The term ANTI-HISTAMINE conventionally refers to H1-
receptor antagonists and these drugs are discussed
in this section. The EFFICACY of these drugs is attrib-
uted principally to down-regulation of H1-receptor
activity. In Table 2 a number of first, second and third
generation H1-receptor antagonists are shown.
Signal transduction by H1-receptors (and proba-
bly also for H4-receptors) occurs through the hydrol-
ysis of phosphatidylinositols. Histamine binds to the
receptor, which in turn activates the Gαq protein (Gi/o
272 Anti-allergic drugs

TABLE 2. FIRST, SECOND AND THIRD GENERATION H1-RECEPTOR ANTAGONISTS

Antagonist Disorder

First generation
Clemastine Anaphylactic reactions to insect bites or food allergy
Dexchlorofeniramine Allergic conditions
Dimethindene Allergic conditions
Diphenhydramine Rhinitis/urticaria
Emedastine Conjunctivitis/rhinitis
Hydroxyzine Pruritis/chronic urticaria
Mebhydroline Allergic conditions
Oxatomide Allergic conditions
Promethazine Allergic conditions/anaphylactic shock

Second generation
Acrivastine Allergic rhinitis/hayfever
Astemizole Urticaria
Cetirizine Allergic rhinitis/conjunctivitis/ urticaria
Fexofenadine Allergic rhinitis/chronic urticaria
Ketotifen Allergic rhinitis/allergic skin conditions/prophylactic for asthma
Levocabastine Allergic rhinitis/conjunctivitis
Levocetirizine Allergic rhinitis/chronic urticaria
Terfenadine Allergic rhinitis/conjunctivitis/allergic skin disorders

Third generation
Azelastine Allergic rhinitis/conjunctivitis
Desloratidine Allergic rhinitis
Ebastine Allergic rhinitis/conjunctivitis
Loratadine Allergic rhinitis/conjunctivitis/ chronic urticaria/pruritis
Mizolastine Allergic rhinitis/conjunctivitis/urticaria

protein of H4-receptors). Activation of these G pro- Pharmacological effects of H1-receptor

teins precedes activation of phospholipase C (PLC)
which cleaves phosphatidylinositol bisphosphate
(PIP2) to form inositol tri-phosphate (IP3) and diacyl-
glycerol (DAG). IP3 activates IP3 receptors on the
endoplasmic reticulum, causing the release of intra-
cellular Ca2+,as depicted in Figure 3.The various bio-
logical effects follow the rise in Ca2+.
antagonists
H1-receptors modulate inflammatory and allergic
responses by controlling NO formation and smooth
muscle and endothelial cell contraction, which sub-
sequently result in increased vascular permeability.
Histamine can also stimulate sensory nerve endings,
 Histamine receptor antagonists 273

FIGURE 3. SIGNALLING PATHWAY OF H1 RECEPTOR (AND POSSIBLY H4 RECEPTOR)

Histamine binds to the receptor, which in turn activates the Gαq protein (Gi/o protein of H4-receptors). Activation of
these G proteins precedes activation of PLC which hydrolyses IP3. IP3 activates IP3 receptors on the endoplasmic retic-
ulum, causing the release of intracellular Ca2+. The rise in Ca2+ is followed by the biological effect. Abbreviations:
HR, histamine receptor; Gp, G protein; PLC, phospholipase C; PIP2 phosphatidylinositol bisphosphate; DAG, diacyg-
lycerol; PKC, protein kinase C; GTP, guanosine triphosphate; GDP, guanosine diphosphate; IP3, inositol triphosphate;
Ca2+, calcium.

thereby causing itching of the mucosa and skin
through stimulation of C fibres.Regulation of the tran-
scription factor NF-κB and subsequent generation of
ADHESION MOLECULES (ICAM-1 and P-selectin) and
CYTOKINES (IL-6, IL-8, GM-CSF, RANTES) are also H1-
receptor dependent. The pharmacological actions of
H1-receptor antagonists are therefore useful for the
inhibition of contraction of the smooth muscle and
the inhibition of histamine-induced vascular perme-
ability. Additionally, H1-receptor antagonists inhibit
the constitutive activation of NF-κB which results in
an inhibition of CYTOKINE production. H1-receptor
antagonists inhibit histamine-induced bronchospasm
in the guinea pig,but they are not effective in decreas-
ing allergen-induced bronchospasm in human air-
ways. Furthermore, first generation H1-receptor antag-
onists can exhibit anti-serotoninergic, anti-emetic
and/or anti-cholinergic characteristics, depending on
the particular H1-receptor antagonist used. Second
generation H1-receptor antagonists, however, are
more selective, have minimal sedative effects and
have little affinity for muscarinic cholinergic, α-adren-
274 Anti-allergic drugs
ergic or serotoninergic receptors, although they still
have dose-related adverse effects at high doses.Third
generation H1-receptor antagonists are either active
metabolites or enantiomers of second generation
compounds and show reduced adverse effects.
Pharmacokinetics
Most H1-receptor antagonists are given orally, some
are given as nose sprays or eye drops, they are well
absorbed and reach their peak effect in 1–2 hours.
The duration of activity depends largely on whether
first, second or third generation drugs are adminis-
tered, and can vary between 2 hours and a few days.
Most of these drugs are widely distributed through-
out the body, but the third generation drugs do not
pass the blood-brain barrier. They are largely
metabolised in the liver and excreted in the urine.
Clinical indications
H1-receptor antagonists can effectively control aller-
gic disorders with mild symptoms, especially of the
upper airways and skin.Allergic disorders with more
severe symptoms and a complicated clinical picture,
such as severe asthma, require other therapies but
H1-receptor antagonists may be supplemental.
Allergic rhinitis
H1-receptor antagonists,administered either orally or
topically to mucosal surfaces, are the most frequent-
ly used first-line medication for intermittent (season-
al) and persistent (perennial) allergic rhinitis. Non-
sedating second-generation H1-receptor antagonists
such as cetirizine, fexofenadine and loratadine have
been proven effective in short and long-term studies.
Also desloratadine, levocetirizine and tecastemizole
have been found to be effective in allergic rhinitis.
H1-receptor antagonists reduce sneezing and rhinor-
rhea as well as itchy, watery, red eyes. They reduce
itchy nose, palate, or throat and sometimes reduce
nasal congestion. There are very few clinical differ-
ences between the H1-receptor antagonists. Some
investigators have reported that H1-receptor antago-
nists reduce the influx of inflammatory cells into
nasal secretion whereas other investigators report a
lack of inhibitory effects.
Mild atopic asthma
Cetirizine, desloratidine and loratidine have been
reported to improve mild “seasonal” asthma symp-
toms and to reduce the amount of β2-agonist usage,
as well as improve pulmonary function. These com-
pounds prevent and relieve allergic INFLAMMATION in
both the upper and lower airways. H1-receptor antag-
onists have not been reported to be clinically effec-
tive in the treatment of bronchial asthma and are
therefore not a first choice for the treatment of this
disorder. They do not affect histamine- or metha-
choline-induced bronchospasm but they may be
useful as additional or supplemental therapy.
Allergic conjunctivitis
This disorder usually occurs as part of an allergic
syndrome, i.e., together with allergic rhinitis. If acute
symptoms arise, the eyes can be treated locally with
azelastine, emadine, ketotifen, levocabastine or
olopatadine. The main symptoms are red, itchy,
watery eyes.
Acute and chronic urticaria
This disorder can be treated with oral, H1-receptor
antagonists.These compounds reduce itching as well
as the number,size and duration of urticarial lesions.
Erythema may not be completely inhibited because
the vascular effects of histamine are also mediated
via H2-receptors as well as by other vasoactive sub-
stances such as proteases,eicosanoids (LEUKOTRIENES,
prostaglandin E1) and neuropeptides (substance P).
First and second generation H1-receptor antagonists
have been shown to be equally effective. Urticarial
vasculitis cannot be satisfactorily treated with H1-
receptor antagonists.
Treatment of anaphylactic shock
The initial treatment of choice is epinephrine, but
treatment of anaphylactic shock can be accom-

plished with intramuscular or subcutaneous injec-
tions of epinephrine. The H1-receptor antagonist
clemastine may be given intravenously (2 mg) as an
ADJUVANT. H1-receptor antagonists may also be useful
in the ancillary treatment of pruritis, urticaria and
angio-oedema.
Atopic dermatitis (= eczema)
is often treated with oral H1-receptor antagonists,that
also exhibit a sedative action, in conjunction with
TOPICAL glucocorticoids to relieve itching. Second
generation H1-receptor antagonists are generally less
effective than first generation drugs.
Unwanted effects
Most H1-receptor antagonists have few unwanted
effects when used at the recommended doses,
although adverse CNS effects have been observed.
The first generation H1-receptor antagonists have
marked sedative effects due to the fact that they can
cross the blood-brain barrier.The second generation
H1-receptor antagonists are more specific for the H1-
receptor than first generation drugs, and therefore
have little affinity for muscarinic cholinergic, α-
adrenergic or serotoninergic receptors, these com-
pounds have less sedative effects. Third generation
H1-receptor antagonists have been recently devel-
oped to further reduce adverse effects. Dry mouth,
urinary dysfunction, constipation, tachycardia and
other unwanted effects are consequently not often
observed.Allergic dermatitis following TOPICAL appli-
cation has been reported.
Suppression of mediator release from mast cells
and BASOPHILS are thought to occur independently of
the H1-receptor. Neither mast cells nor BASOPHILS
express H1-receptors on their surface.However,it was
recently shown that mast cells, BASOPHILS and
EOSINOPHILS express the H4-receptor on their surface.
H4-receptor antagonists
Increased numbers of mast cells are found in the air-
ways of allergic asthma and allergic rhinitis patients.
Anti-IgE 275
Hofstra and colleagues suggest that migration of
these mast cells towards inflamed tissues may be
mediated through histamine.To support their hypoth-
esis they have recently shown that stimulation of H4-
receptors with histamine mediates cell signalling
and mast cell chemotaxis in a dose-dependent man-
ner [37]. Redistribution of mast cells during allergic
episodes may be mediated by this mechanism, indi-
cating that specific H4-receptor antagonists may
prove to be useful in the treatment of allergic dis-
eases in the future. Since EOSINOPHILS have also been
demonstrated to express H4-receptors,we can specu-
late that specific H4-receptor antagonists may also
inhibit their migration and infiltration of tissues dur-
ing allergic reactions. Furthermore, H4-receptors may
play a role in the control of CYTOKINE release from
CD8+ T CELLS,and possibly other cells that express the
H4-receptor, during inflammatory disorders such as
asthma [35].
Some of the currently available H3-receptor ago-
nists and antagonists are also recognised by the H4-
receptor, although they are much less potent for the
H4-receptors. Using cells transfected with the H4-
receptor, it has been shown that specific H1 and H2
receptor agonists and antagonists do not bind to the
H4-receptor. Specific antagonists for the H4-receptor
need to be developed and tested.
Anti-IgE
Ever since the discovery of the function of IgE, more
than 3 decades ago [41], research focussed on the
selective inhibition of either the activity or the pro-
duction of IgE. Omalizumab, marketed as Xolair, is a
monoclonal ANTIBODY that targets IgE. Xolair is a
recombinant DNA-derived humanised IgG1κ mono-
clonal ANTIBODY that selectively binds to human IgE.
It is a humanised mouse ANTIBODY that contains only
5% amino acid sequence derived from the mouse.
The ANTIBODY has a molecular weight of approxi-
mately 149 kilo Daltons and is produced by Chinese
hamster ovary cells.Xolair has been approved by the
FDA for the treatment of adults and adolescents (12
years of age and older) with moderate to severe per-
sistent asthma who have a positive skin test or in vitro
reactivity to a perennial aeroallergen and whose
276 Anti-allergic drugs
FIGURE 4. STRUCTURE OF IGE AND POSITION OF BINDING
SITE FOR FCεRI [43]
symptoms are inadequately controlled with inhaled
corticosteroids. Xolair is given by subcutaneous
injection at a dose of 150 mg to 375 mg every 2 to 4
weeks based upon pre-treatment serum IgE levels
and total body weight.
Biochemical and pharmacological effects
Xolair binds to free IgE at the FcεRI binding site on
the Cε3 domain of the IgE ANTIBODY, thereby inhibit-
ing the binding to FcεRI on the surface of mast cells,
BASOPHILS and other FcεRI+ cells (Fig. 4). The reduc-
tion of surface-bound IgE on FcεRI-bearing cells pre-
vents or limits the release of chemical mediators of
the allergic response. Levels of serum-free IgE
decrease by >90% from pre-treatment values within
24 hours of subcutaneous administration of Xolair.In
addition, the expression of FcεRI appears to be
down-regulated as demonstrated on BASOPHILS after
continued (3 months) Xolair treatment [42].
Clinical trials
Several clinical studies using recombinant human-
ised monoclonal ANTIBODY to human IgE (E25, Xolair,
Omalizumab) have been conducted and published
(reviewed in [43]).
The approval of Xolair was based upon EFFICACY
data from several multicenter placebo-controlled
phase-III clinical trials with symptomatic patients
with moderate to severe persistent asthma who had
a positive skin test reaction to a perennial aeroaller-
gen [44–46].All patients were also being treated with
inhaled corticosteroids and short-acting β-agonists.
EFFICACY in these trials was based upon the number
of asthma exacerbations per patient, defined as a
worsening of asthma that required treatment with
systemic corticosteroids or a doubling of the base-
line dose of inhaled corticosteroid. Study results
showed that the number of exacerbations per pa-
tient was reduced in patients receiving Xolair com-
pared with placebo. Reduction of asthma exacerba-
tions was not observed in Xolair-treated patients who
had baseline FEV1 > 80% or in patients who required
oral steroids as maintenance therapy. Comparative
clinical studies between Xolair and other agents
used to treat asthma are currently not available.
Xolair has not been shown to alleviate asthma exac-
erbations acutely and it is not indicated for the treat-
ment of bronchospasm or status asthmaticus.
The following effects of Xolair have been ob-
served in clinical trials with allergic asthma patients:
- >90% drop in serum IgE levels within hours after
injection [47, 48].
- Partial reduction of drop in FEV1 during early- and
LATE-PHASE ASTHMATIC RESPONSE after allergen chal-
lenge [49, 50].
- Reduction of asthma symptom scores and
increase of quality-of-life scores; decreased use of
β-agonists after high dose of Xolair; reduction of
oral or inhaled steroid use [45, 47].
- Reduction of asthma exacerbations during stable-
and steroid-reduction phase; steroid sparing effect
[45, 46].

- Steroid sparing effect in asthmatic children; no
change in asthma symptom scores [51].
The following effects of Xolair have been observed
in clinical trials with seasonal allergic rhinitis
patients:
- No significant difference in daily symptom scores;
no significant difference in the use of rescue med-
ication [48].
- Reduction of rescue ANTI-HISTAMINES; decreased
daily nasal symptom severity scores [52].
- Dose-dependent reduction of nasal and ocular
symptom severity and duration scores; reduction
of rescue ANTI-HISTAMINES [53].
Unwanted effects
Single- and multiple-dose trials in adults with and
without allergic diseases have demonstrated that
Xolair is well tolerated. Immune-complex formation
of Xolair with IgE leads to relatively small complexes
(<1000 kDa) that are not complement-fixing and do
not accumulate within any organ system [54]. The
immune complexes have a serum half-life of approx-
imately 20 days and are cleared via Fcγ receptors of
the reticuloendothelial system [54]. The most com-
monly reported adverse effect is an urticarial rash,
with an incidence of 0.5 to 0.7%. The rash develops
within one hour of receipt of the first dose and
responds to ANTI-HISTAMINE therapy. Other adverse
effects associated with Xolair are headache, fatigue
and vertigo.There are no reports of systemic anaphy-
lactic reactions, and no antibodies to the anti-IgE
ANTIBODY have been detected.
Conclusions
The IgE-mast-cell pathway plays a central role in the
pathogenesis of allergic diseases. It is therefore not
surprising that many of the anti-allergic drugs are tar-
getted at this pathway.These drug are either prevent-
ing or reversing allergen-induced mast-cell activa-
tion by blocking IgE (Xolair) or stabilizing mast-cells
(chromones) or block the biological effects of hista-
mine released upon allergen-induced mast-cell acti-
Summary 277
vation (ANTI-HISTAMINES). ANTI-HISTAMINES have proven
to be safe and successful, although they may not
block all effects of mast cells. Chromones can be
used as prophylactic drugs for allergic diseases but
their clinical EFFICACY is not undisputed.Xolair is very
effective in reducing serum IgE levels and the pre-
vention of mast-cell activation. However, this protein
drug needs to be administered parenterally and the
costs of treatment is estimated to be very high com-
pared to other anti-allergic treatments. Thus, Xolair
will probably not become the first line of prophylac-
tic treatment for allergic diseases.
Summary
Allergy is defined as a disease following a response
by the IMMUNE SYSTEM to an otherwise innocuous
agent. This chapter describes the actions of anti-
allergic drugs and therapeutics on diseases such as
allergic rhinitis, atopic dermatitis, allergic conjunc-
tivitis, systemic anaphylaxis, food ALLERGY, allergic
asthma and acute urticaria.The putative MECHANISMS
OF ACTION of disodium cromoglycate and
nedocromil sodium (chromones) are discussed in
detail as well as the biochemical and pharmacolog-
ical effects, clinical applications and unwanted
effects of these drugs.The characterisation of hista-
mine receptors is detailed and the MECHANISMS OF
ACTION as well as the observed biological effects of
H1 and the relatively new H4 receptors are
explained. Further, the biochemical and pharmaco-
logical effects of anti-IgE therapy are described and
recent clinical trials with these drugs are briefly
reviewed.
Selected readings
Hill SJ, Ganellin CR, Timmerman H, Schwartz JC, Shankley
NP,Young JM,Schunack W,Levi R,Haas HL (1997) Inter-
national Union of Pharmacology. XIII. Classification of
Histamine Receptors. Pharm Rev 49: 253–278 (see
also: http://pharmrev.aspetjournals.org/cgi/reprint/
49/3/253, accessed December 2004)
278 Anti-allergic drugs
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